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Smoking, gender, and survival association with allele loss for the LOH11B lung cancer region on chromosome 11. We have reported frequent allele loss for the marker HRAS on chromosome 11p in human lung cancer and defined the smallest common region of deletion (designated LOH11B) to approximately 500 kb. Here, we investigated the association of allele loss for LOH11B with epidemiological, pathological, and clinical parameters. Analysis of allele loss was performed using Southern blotting on a cohort of 200 patients with lung cancer, and data were interpreted with the use of a phosphorimager. Results were statistically compared with retrospectively collected variables. LOH11B allele loss was significantly associated with cigarette consumption (P = 0.009), gender (P = 0.02), and survival (P = 0.04). None of the nonsmokers had allele loss as compared with 28% of the patients with low and 43% with high cigarette consumption. Allele loss was more frequent in men (43%) than in women (11%). The median survival of patients without allele loss was 42 months compared with 25 months for patients with allele loss. These results suggest that the LOH11B region contains a gene responsible for a more malignant phenotype independent of the metastatic potential of lung cancer. They also suggest that alterations in this gene are associated with cigarette consumption and are more frequent in men than in women.
Cigarette smoking and chromosome 9 alterations in bladder cancer. Epidemiological studies suggest that bladder cancer may be caused by carcinogens in tobacco and certain occupational exposures. Molecular studies have shown that chromosome 9 alterations and TP53 mutations are the most frequent events in bladder cancer. To date, the relationships between epidemiological risk factors and genetic alterations have not been fully explored in bladder cancer. The purpose of this study was to explore the association between smoking and chromosome 9 aberrations in bladder cancer cases. Seventy-three patients with bladder cancer at Memorial Sloan-Kettering Cancer Center were evaluated for smoking history, occupational history, and chromosome 9 alterations. The epidemiological data were abstracted from medical charts. Patients' tumor tissues were analyzed using RFLP and microsatellite polymorphism assays for detection of chromosome 9 alterations. Elevated odds ratios (ORs) were found for chromosome 9 alterations in smokers compared to those in nonsmokers (OR = 4.2; 95% confidence interval, 1.02-17.0) after controlling for age, sex, race, occupational history, and stage of disease. The ORs were 3.6 for those smoking < or = 20 cigarettes per day and 5.8 for those smoking > 20 cigarettes per day. No association was found between occupational history and chromosome 9 alterations. This study supplies evidence suggestive of the link between smoking and chromosome 9 alterations in the etiology of bladder cancer and indicates that potential tumor suppressor genes on chromosome 9 may be involved in smoking-related bladder carcinogenesis.
Temporal variation in chlorinated hydrocarbons in healthy women. Chlorinated hydrocarbons may increase breast cancer risk. Most epidemiological studies addressing this possibility have used one biological sample to measure a subject's cumulative exposure to these compounds. Little is known about short-term temporal variation in organochlorines, particularly in individuals with low levels. Thus, the reliability of using one sample to assess blood levels of chlorinated hydrocarbons in an epidemiological study is unknown. To better understand the temporal changes in blood measures among women with nonoccupational exposures to these compounds, we collected two 5-ml blood samples, an average of 2 months apart, from each of 31 nonfasting healthy women, ages 45-81 years. Samples were assayed for 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), polychlorinated biphenyls (PCBs), and trans-nonachlor in blinded, matched pairs. Results were adjusted for estimated total plasma lipids. The correlations between the two blood samples were high for DDE and PCBs (lipid-adjusted, r = 0.96 and r = 0.89, respectively). For trans-nonachlor, the correlation was relatively poor (lipid-adjusted r = 0.57); however, with the removal of one outlier, the correlation improved substantially (lipid-adjusted, r = 0.90). The mean difference between the two blood samples in unadjusted [-0.36 ng/ml, 95% confidence interval (CI), -0.97, 0.24 ng/ml, P = 0.23] and lipid-adjusted (-0.035 microgram/g lipid; 95% CI, -0.124, 0.055; P = 0.44) DDE levels was small. Similarly, there was little change in the mean difference for unadjusted (-0.14 ng/ml; 95% CI, -0.53, 0.25 ng/ml; P = 0.47) and lipid-adjusted (0.006 microgram/g lipid; 95% CI, -0.050, 0.062; P = 0.82) PCB levels. The mean differences in trans-nonachlor levels between the two blood draws were also small: unadjusted (-0.03 ng/ml; 95% CI, -0.07, 0.02 ng/ml; P = 0.20) and lipid-adjusted (-0.003 microgram/g lipid; 95% CI, -0.010, 0.004; P = 0.33). These data suggest that temporal changes in organochlorine levels within a 1 to 3-month period are minimal for noncancer patients and that a single measure for estimating exposure is highly reliable for DDE and PCB. For trans-nonachlor, however, where the correlation between blood draws was lower, three samples would be needed for estimating exposure; if an outlier is removed from our data, however, then we can conclude that only a single measure is sufficient. These data, therefore, offer no clear conclusion for the use of a single measurement for trans-nonachlor.
Reduced aliquot size for a plasma organochlorine assay for use in epidemiological studies. Because archived blood specimens are an important but limited resource for conducting epidemiological studies using biomarkers, it is important to develop analytical techniques that minimize the amount of sample needed. We modified an established 1.0-ml blood plasma organochlorine assay to use smaller volumes. We assessed its utility by comparing the accuracy and precision of measurements obtained with different-sized aliquots of spiked plasma from three pools of known concentration of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and polychlorinated biphenyls (PCBs; low, medium, and high). There was a modest sacrifice in accuracy using 0.5 as opposed to 1.0 ml. However, the within-batch coefficients of variation, a measure of laboratory error, were consistently low when 0.5-ml aliquots were used. For both DDE and PCB concentrations, this error was less than 5% for the medium and high pools [5-20 parts per billion (ng/ml)] and less than 9% for the low pool (< 1 part per billion). After determining that aliquots of 0.5 ml were sufficient, we performed a blinded quality control analysis of stored plasma. In this study, the within-subject variation was low for DDE and PCBs and substantially lower than the between-subject variation, suggesting that the assay would rank subjects with reasonable precision. Our results suggest that use of 0.5-ml as opposed to 1.0-ml aliquots should not compromise the power of a nested case-control study to detect differences between subjects and would thus save plasma for future research. For populations with very low levels of organochlorines, however, the larger volumes should still be used.
Urinary phytoestrogen levels in young women from a multiethnic population. Phytoestrogens include several classes of chemical compounds (i.e., isoflavones, coumestans, and lignans) which are structurally similar to endogenous estrogens. In biological systems, they have both estrogenic and antiestrogenic effects and may reduce the risk of developing certain types of hormonally related diseases. However, little information is available on population differences in exposure to phytoestrogens. To examine racial/ethnic differences in urinary phytoestrogen levels, 50 young women (ages 20-40 years) were randomly selected from participants in a previous epidemiological study in which 24-h urine specimens and a dietary assessment were obtained. Subjects were members of the Kaiser Permanente Medical Care Program of northern California. Selection was stratified on race/ethnicity. Urinary levels of seven phytoestrogens were measured using high-performance liquid chromatography-mass spectrometry. Substantial variation in phytoestrogen levels was observed and racial/ethnic differences are described. The highest levels of coumestrol and the lignans were observed in white women and the lowest levels in Latina and African American women. Genistein levels, however, were highest in Latina women; other isoflavone levels did not differ significantly by race/ethnicity.
Use of a food frequency questionnaire to screen for dietary eligibility in a randomized cancer prevention phase III trial. Cancer prevention clinical trials use food frequency questionnaires (FFQs) to assist in eligibility screening. FFQ reliability and validity studies are available, but these studies do not evaluate FFQs as screening tools. The Wheat Bran Fiber Trial of the University of Arizona used a FFQ as an eligibility screen with the goal of screening out subjects whose true daily calcium intake was less than 500 mg per day (for safety) and whose true dietary fiber intake was greater than 30 g per day (for safety and trial efficiency). Subjects ineligible by FFQ were interviewed for final dietary eligibility determinations. A study was undertaken within the Wheat Bran Fiber Trial to evaluate the sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of the FFQ used in this context. Four-day food records were collected on 183 potential participants before entry into the study. Using the 4-day averages as the "true" value, sensitivity, specificity, positive predictive value, and NPV were calculated for men and women separately under two screening conditions: using the target calcium and dietary fiber values and using "revised" values identified in interim analysis within the study. NPV was acceptable in all analyses. Sensitivity for low calcium intake was inadequate under the original criteria (0.33 for men and 0.09 for women) but acceptable under the revised criteria (0.80 for men and 0.81 for women). With the revised criteria, specificity declined, resulting in heavy screening burdens deemed worthwhile for the safety considerations. Dietary fiber eligibility screening worked well at target values. These differences were not predicted by reliability/validity studies.
Application of a behavioral approach to measuring dietary change: the fat- and fiber-related diet behavior questionnaire. This study reports the validity, reliability, and responsiveness of a 33-item fat- and fiber-related behavior questionnaire (FFB) and describes how this instrument provides insight into the process of adopting healthy diets. Data are from the Eating Patterns Study, a randomized clinical trial of a physician-delivered, self-help intervention to reduce fat and increase fiber intake. Intervention (n = 850) and control participants (n = 945) completed both a food frequency questionnaire and the FFB at baseline and at 3 and 12 months postintervention. Validity, as assessed by correlation of the FFB with the food frequency questionnaire at baseline, was 0.53 for fat (fat scale with percentage energy from fat) and 0.50 for fiber (fiber scale with fiber g/1000 kcal; both P < 0.001). Reliability, as assessed by the intraclass correlation in controls across all three time points, was 0.77 for the fat scale and 0.74 for the fiber scale (both P < 0.001). The largest changes in fat-related behavior were in avoiding fat as a flavoring and in using specially manufactured low-fat foods, and the largest changes in fiber-related behavior were in substituting high-fiber versions of common foods. Overall, the FFB was a reasonably valid and reliable measure of dietary intake, which provided insight into the behavioral effects of the dietary intervention.
Serum responses to the combination of Epstein-Barr virus antigens from both latent and acute phases in nasopharyngeal carcinoma: complementary test of EBNA-1 with EA-D. Elevated serum IgA to antigens of EBV is associated with nasopharyngeal carcinoma (NPC). We have tested 620 NPC sera by ELISA for the presence of antibodies to EBV-encoded DNA binding protein, EBV-specific DNA polymerase, early antigen-diffused (EA-D), EBV nuclear antigen 1 (EBNA-1), EBV-specific thymidine kinase, and BamHI Z fragment EBV replication antigen. Sensitivity of these proteins was in the range of 51.5-79.5% for IgA and 69.4-82.8% for IgG. The complementary use of EBNA-1 with EA-D, however, could increase the sensitivity significantly to 98.1%. Western blot analysis further showed that the combination of EBNA-1 and EA-D is most useful for the detection of NPC. This is the first report of using double biomarkers including EBV gene products from both latent and active infections. The results of this study suggest that EBV in NPC may not be latent alone and that the method may be valuable for the early detection, early treatment, and better survival rate of patients with NPC. Because the application of recombinant EBV protein in ELISA is cost-effective and feasible for mass screening, the method may be of worth for further clinical investigation.
Etiology of Barrett's metaplasia and esophageal adenocarcinoma. The incidence of esophageal adenocarcinoma in the United States is rising at an epidemic rate. Although the cause for this rapid rise is unclear, it is well established that nearly all cases of esophageal adenocarcinoma arise from a premalignant lesion of the esophagus, known as Barrett's esophagus. Although Barrett's esophagus is recognized as a precursor lesion, the etiology, prevalence, and malignant risk of this lesion remain unclear. The relatively short, two-decade time frame for the rise in esophageal adenocarcinoma incidence and the increase across populations is a strong argument for environmental factors as etiological agents, perhaps interacting with genetically determined characteristics that define personal susceptibility. Because of the strong link between Barrett's esophagus and esophageal adenocarcinoma and the link between Barrett's esophagus and gastroesophageal reflux disease, risk factors for gastroesophageal reflux disease have been the prime suspects offered as possible explanations for the rise in esophageal adenocarcinoma. A plethora of hypotheses have been advanced, implicating tobacco and alcohol consumption, changes in obesity and diet, and the changing pattern in use of medications that affect the upper gastrointestinal tract. The following text will review what is currently known about the epidemiology of Barrett's metaplasia, its risk for malignant transformation, and the proposed theories of etiogenesis.
Distinct roles of the receptor tyrosine kinases c-ErbB and c-Kit in regulating the balance between erythroid cell proliferation and differentiation. In the bone marrow, multipotent and committed hematopoietic progenitors have to closely regulate their balance between sustained proliferation without differentiation (self renewal) and entering a terminal differentiation pathway. A useful model to analyze this regulation at the molecular level is committed avian erythroid progenitors. These are induced to undergo long-term self renewal by the ligand-activated receptor tyrosine kinase (RTK) c-ErbB, in cooperation with steroid hormone receptors. This self-renewal induction by c-ErbB even occurs in the presence of differentiation factors (erythropoietin and insulin). Under the same conditions, the RTK c-Kit is unable to sustain erythroid progenitor self renewal, stimulating cell proliferation without arresting terminal differentiation. Two mechanisms are involved in these differential activities of c-Kit and c-ErbB. The first one, differential regulation of receptor expression, proved to be of minor importance, because c-Kit was unable to induce self renewal, even if exogenously expressed from a retrovirus at high levels. Rather our results support the second mechanism, i.e., that receptor-specific signal transduction is responsible for the differential biological activity of c-Kit and c-ErbB: (a) specific tyrosine kinase inhibitors (tryphostins) were found which selectively inhibited the biological function of either c-Kit or c-ErbB in erythroblasts but did not affect ligand-induced autophosphorylation of either RTK; and (b) c-ErbB selectively induced SHC phosphorylation and STAT5 activation. The Ras pathway was similarly activated by c-Kit and c-ErbB. The c-ErbB-specific tyrphostin AG30 specifically blocked STAT5 activation, implicating this signal transducer in c-ErbB-induced self renewal.
C-Jun and JunD suppress maturation of chondrocytes. To analyze the function of AP-1 in cartilage formation, two types of primary chondrocytes, LS and US cells, were prepared from caudal (lower) and cephalic (upper) regions of chicken sterna, respectively. All the known components of chicken AP-1 (c-Fos, Fra-2, c-Jun, and JunD) were detected in both cell types, but the expression level of c-Jun was much higher in LS cells, which are rich in less mature chondrocytes than US cells. In the sterna, the expression level of c-Jun was also lower in the maturating or hypertropic chondrocytes than in proliferating chondrocytes. When US cells were treated with parathyroid hormone (PTH), which prevented maturation as judged from the maturation-associated markers such as alkaline phosphatase and type X collagen, the expression levels of c-Jun and JunD were constitutively elevated. To analyze the possible relationship between differentiation status and expression levels of Jun family proteins, they were exogenously introduced into the entire population of US cells within 2 days by using high titer, replication-competent retroviral vectors. Maturation-associated markers in US cells were specifically lowered by exogenous expression of c-Jun or JunD to similar levels to those of LS cells or US cells treated with PTH. When US cells were infected with the virus encoding a dominant negative mutant of AP-1 (supJunD-1), maturation markers were moderately increased 10 days after infection. The potent induction of alkaline phosphatase activity in US cells by all-trans retinoic acid was annulled by exogenous expression of either c-Jun or JunD. These results suggest that Jun family proteins negatively regulate the maturation process of chondrocytes.
Differential expression of MEK1 and MEK2 during mouse development. Map/Erk kinase 1 (MEK1) and MEK2 activate the Erk/ MAP kinases and have been implicated in cell growth and differentiation. To investigate the role of MEKs during mouse development, we have examined their expression and activity in various murine tissues during embryonic development and in the adult mouse. MEK2 RNA message is expressed at high levels in all embryonic tissues examined, including all neural tissues, and liver. This can be observed by in situ hybridization of tissue sections of 14.5-day-old mouse embryos, as well as by Northern blot analyses. MEK1, on the other hand, is expressed at very low levels in most embryonic murine tissue but can be detected in developing skeletal muscle. It is expressed at higher levels in adult tissue, particularly in brain, where it is expressed at high levels. Western blot analyses of MEK1 and MEK2 in 14.5-day-old embryonic and adult mouse tissue confirm the RNA analysis. Levels of MEK1 kinase activity are particularly high in adult brain tissues as well. These findings suggest that MEK2 may be the primary Erk/MAP kinase activator during development and that MEK1 may play a role in the proliferative or mitogenic response in adult mouse tissues. This study also raises the possibility that MEK1 and MEK2 might not have redundant functions in cells but may possess unique specificity in their interactions with upstream activators or downstream targets.
Short-chain fatty acid-initiated cell cycle arrest and apoptosis of colonic epithelial cells is linked to mitochondrial function. Butyrate, a short-chain fatty acid produced during microbial fermentation of fiber, induces growth arrest, differentiation, and apoptosis of colonic epithelial cells in vitro, and our prior work has shown that this induction is tightly linked to mitochondrial activity. Here we demonstrate that 12 h following induction, SW620 human colonic carcinoma cells accumulate simultaneously in G0-G1 and G2-M of the cell cycle. Four h later, during this G0-G1 to G2-M arrest, cells begin to undergo apoptosis. Using a series of unrelated agents that modulate mitochondrial functions, we demonstrate that mitochondrial electron transport and membrane potential are critical in initiation of this butyrate-mediated growth arrest and apoptosis. Colonic tumorigenesis is characterized by abnormalities in proliferation, apoptosis, and mitochondrial activities. Thus, butyrate may reduce risk for colon cancer by inducing a pathway that enhances mitochondrial function, ultimately resulting in initiation of growth arrest and apoptosis of colonic epithelial cells.
Transfection of rhabdomyosarcoma cells with connexin43 induces myogenic differentiation. Normal cell physiological processes rely heavily on cues from the extracellular environment to coordinate the proper functioning of cellular activities. The intercellular communication that takes place through gap junctions in neighboring cells has been implicated in growth control and embryonic differentiation. Indeed, many tumorigenic cells induced to overexpress gap junction proteins exhibit increased differentiation and decreased cell proliferation. Although absent in mature skeletal muscle, studies have demonstrated that gap junctions are present during the early stages of myogenesis, indicating their possible role in muscle development. In our present study, we have attempted to induce a more differentiated phenotype in communication-deficient rhabdomyosarcoma cells. These tumorigenic human cells were transfected with cDNA encoding the gap junction protein connexin43 (Cx43) such that clones of varying expression were isolated. Intercellular communication as measured with dye passage assays was directly proportional to the level of Cx43 expressed, and in those cells expressing Cx43 at high levels, a marked increase in cell membrane fusion and myosin expression was observed. Furthermore, clones expressing Cx43 at high levels exhibited a significant reduction in growth rate when grown under nonadhesive conditions, an indication that their tumorigenicity had been reduced. This apparent increase in myogenic differentiation lends further evidence to the possible role of gap junctional coupling during developmental processes.
Immortalization of primary epithelial cells by E1A 12S requires late, second exon-encoded functions in addition to complex formation with pRB and p300. Immortalization of primary cells is an early and important event in multistep tumorigenesis and is itself a multistep process. Adenovirus E1A 12S encodes an oncoprotein that can rescue cells from senescence and overcome apoptosis, leading to their immortalization. Five regions of 12S, located in both exons, are required for immortalization. Two regions in the first exon are necessary to activate the cell cycle, increase the number of population doublings, and overcome the M1 stage of mortality. However, extension of life span requires overcoming crisis or M2, which can be accomplished by the expression of the second exon. Several cellular proteins associate with the peptide encoded by the first exon of 12S including pRB, p107, p130, and p300. The importance of pRB-E1A and p300-E1A complexes in transformation is well established; however, their roles in 12S-mediated immortalization remain undefined. Results obtained from the present study using a panel of second exon immortalization-defective mutants demonstrate that formation of pRB-E1A and p300-E1A complexes is insufficient for immortalization of primary cells. We further demonstrate that the expression levels of another tumor suppressor protein, p53, also do not correlate with the inability of the mutants to immortalize. Thus, mutations in the second exon of 12S do not affect the early steps in the immortalization pathway. The second exon mutants are defective in performing a late function in immortalization, involving the reactivation of the cell cycle, indicating that it is a crucial event in immortalization.
Expression patterns of the E2F family of transcription factors during murine epithelial development. The E2F family of transcription factors includes five E2F and three DP forms. E2F is involved in the regulation of cell proliferation, but little is known about E2F function during vertebrate development. We have explored the regulation of E2F expression during mouse organogenesis by in situ hybridization. We find selective up-regulation of E2F-2, E2F-4, and E2F-5 transcripts in epidermis and intestinal epithelium at important developmental stages. E2F-4 transcript levels are high in early, undifferentiated single-cell-layer ectoderm, and later in 13.5-14.5-day-postcoitus (dpc) embryo epithelium, which contains several layers of proliferating cells. E2F-2 is up-regulated following the onset of E2F-4 expression and is first apparent in undifferentiated epithelium at 13.5-14.5 days of gestation. In contrast, E2F-5 transcripts are detected later in gestation, once the epidermis shows evidence of stratification. Stratification of the epidermis into basal, proliferating cells and suprabasal, terminally differentiating cells at 15.5-19.5 days of gestation coincides with expression of E2F-2 and E2F-4 in basal cells and of E2F-5 in suprabasal cells. Similarly, in intestinal epithelium, E2F-4 up-regulation in pseudostratified epithelium at 13.5 days of gestation precedes appearance of E2F-2 transcripts, in 14.5-dpc embryos, in the proliferating, intervillus epithelium. In 16.5-19.5-dpc embryos, no E2F-2 transcripts were detected at the tip of the developing villi, which contain terminally differentiating cells. In contrast, E2F-5 transcripts were limited to the upper half of the villi and were absent in the intervillus epithelium. This suggests that E2F-2 and E2F-4 may participate in maintaining epithelial cells in a proliferative, undifferentiated phenotype, whereas E2F-5 may be important to maintain the differentiated state. Thus, selective regulation of E2F forms occurs during murine epithelial development, irrespective of the ectodermal or endodermal origin of such epithelia.
Time correlation of commitment to calcium-induced apoptosis and terminal differentiation in human ectocervical keratinocytes in suspension cultures. The terminal differentiation of epithelial keratinocytes has been proposed to be a specialized form of programmed cell death (apoptosis). We examined the time correlation of apoptosis and terminal differentiation by human ectocervical keratinocytes in a suspension culture that induces either of these events in epithelial cells. We found that a loss of cell anchorage did not result in the immediate onset of apoptotic DNA degradation but sensitized the cells to that triggered by calcium. This susceptibility appeared in parallel with the irreversible loss of growth potential and the accumulation of involucrin, suggesting that the ectocervical keratinocytes in suspension become competent to calcium-inducible apoptosis as they committed to terminal differentiation. Cycloheximide, which inhibited the calcium induction of DNA fragmentation, was also inhibitory to terminal differentiation. These correlations support the notion that terminal differentiation of keratinocytes couples with apoptosis. Apoptosis seemed to be independent of p53 because it was down-regulated in suspension cultures of ectocervical keratinocytes.
Phosphatidylinositol 3-kinase inhibitor wortmannin blocks mitogenic activation of the transferrin receptor gene promoter in late G1. Expression of the transferrin receptor is necessary for cells to progress through S-phase. The transferrin receptor gene promoter is activated as a delayed event following growth factor stimulation of quiescent fibroblasts. Serum stimulation in the presence of vanadate leads to superactivation of the transferrin receptor promoter, suggesting a role for tyrosine phosphorylation. Wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, a tyrosine kinase-regulated enzyme, blocks mitogen-dependent activation of the transferrin receptor promoter. Furthermore, wortmannin was able to block activation of this promoter when added several hours after serum stimulation of quiescent cells. This suggests that phosphatidylinositol 3-kinase may be required in mid to late G1 and that it is directly involved in a pathway leading to activation of the transferrin receptor promoter. This is further supported by the finding that the transferrin receptor promoter is much less responsive to mitogenic stimulation in cells that have been stably transfected with a dominant negative form of the phosphatidylinositol 3-kinase regulatory subunit. Activation of S6 kinase, an event known to be downstream of phosphatidylinositol 3-kinase activation, appears not to be involved in activation of the transferrin receptor promoter since no effect was observed by treatment of cells with rapamycin.
Triggering of HLA-DR antigens differentially modulates tumor necrosis factor alpha release by B cells at distinct stage of maturation. Triggering of HLA class II antigens by the anti-HLA-DR monoclonal antibody (mAb) L243 significantly (P < 0.05) and differentially enhanced the release of tumor necrosis factor alpha (TNF-alpha) by the non-Hodgkin's lymphoma cells Ri-I, Ci-I, and Sc-I, which are at a distinct stage of B-cell differentiation, and by the more mature Burkitt lymphoma cell Raji; in contrast, it did not induce TNF-alpha release by the pre-B leukemia cells Nalm-6 and BV173. TNF-alpha release peaked at 24 h and decreased thereafter, and it was dose dependent and preceded by an increase of TNF-alpha mRNA detectable after 3 h of stimulation with mAb L243. Secreted TNF-alpha mediated the enhancement of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding activity; in fact, the triggering of HLA-DR antigens in the presence of antihuman TNF-alpha-neutralizing antibodies did not upregulate NF-kappa B and AP-1. In contrast, released TNF-alpha was not responsible for the homotypic aggregation of Ri-I, Ci-I, Sc-I, and Raji cells induced by mAb L243, and it did not affect the proliferation of B cells investigated. Altogether, our data demonstrate that: (a) the ability of B cells to release TNF-alpha after triggering of HLA-DR antigens depends on their stage of differentiation; (b) levels of released TNF-alpha seem to correlate with the stage of B-cell maturation but do not correlate with the amounts of cell surface HLA-DR antigens; (c) secreted TNF-alpha regulates the levels of expression of NF-kappa B and AP-1 by an autocrine loop; and (d) intracellular signals mediating TNF-alpha release by B cells are distinct from those regulating homotypic aggregation and proliferation.
Response of a primary human fibroblast cell line to H2O2: senescence-like growth arrest or apoptosis? Hydrogen peroxide has been shown to induce either apoptosis or features of senescence in different cultured cell lines. We now show that both processes can be induced in the same culture of primary human diploid fibroblasts and that the outcome of apoptosis or the senescence-like phenotype is determined by the H2O2 concentrations. At 50 and 100 microM, H2O2 predominantly induced the senescence-like state, characterized by a reduced rate of proliferation, an increased number of cells in G0-G1, typically enlarged and flattened morphology, and increased CIP1 and fibronectin expression. At 300 and 400 microM, H2O2 mainly triggered apoptosis. At the intermediate 200 microM H2O2, features of both senescence and apoptosis were observed in the same culture. Thus, the higher the H2O2 concentration, the higher the proportion of cells undergoing apoptosis, suggesting a key role of the level of damage in the choice of a cell population to enter apoptosis and/or the senescence-like state. Before the induction of one or the other process, cells entered a transient "shock state" characterized by a typical morphological change, cell cycle arrest in G0-G1, and the induction of CIP1 and BCL-2.
Differential expression of nucleoskeleton- and cytoskeleton-associated proteins in Burkitt lymphoma-derived and Epstein-Barr virus-immortalized lymphoblastoid cell lines. Mouse monoclonal antibodies raised against nuclear bodies isolated from an EBV-immortalized lymphoblastoid cell line (LCL) known to contain several viral and cellular proteins (Jiang et al., Exp. Cell Res., 197: 314-318, 1991; Szekely et al., J. Gen. Virol., 76: 2423-2432, 1995; Szekely et al., J. Virol., 70: 2562-2568, 1996). Seventy six clones gave detectable immunofluorescence staining on LCLs. Five independent monoclonal antibodies detected a group of apparently novel, high M(r) (> 200,000) proteins that shared common features of subcellular distribution. In LCLs, these proteins were preferentially associated with vimentin filaments in the cytoplasm and with distinct nuclear foci. The appearance of the latter differed from the premyelocytic leukemia-associated protein, EBV nuclear antigen #5, and retinoblastoma-protein-positive bodies that were used for immunization. They seemed to be connected to the cytoplasmic filaments through thin fibrillar nuclear structures. In mitotic cells, these complex structures rearranged into a perichromosomal basket that was associated with vimentin filaments. The target proteins, operationally designated as proteins associated with nuclear dots and cytoplasmic filaments (pNDCFs), were not present in resting human B cells or were expressed at a low level. The level increased considerably after EBV infection or mitogenic stimulation by interleukin 4 and anti-CD40 antibodies. In Burkitt lymphoma (BL) type I lines phenotypically representative of the in vivo tumors, the pNDCFs were either absent or exclusively localized to the nucleus, usually to well-defined nuclear foci. EBV-positive type I BLs often shift to a more LCL-like (type III) phenotype during prolonged in vitro propagation. Type I cells express only EBV nuclear antigen 1 and the surface markers CD10 and CD77, whereas type III express all nine growth-associated EBV-encoded proteins and a gamut of B-cell activation markers. Most of the type III BL cell lines contained increased amounts of pNDCFs bound to cytoplasmic filaments, as seen in the LCLs. We propose that the expression of vimentin-associated pNDCFs should be included in the definition of type III BL phenotype.
Ontogeny and localization of an oncostatin M-like protein in the rat testis: its possible role at the start of spermatogenesis. Oncostatin M (OSM), a member of the interleukin 6 family of cytokines, was found to be highly expressed in the late fetal and early neonatal rat testis, as well as in the maturing and adult testis. Two different forms of OSM were observed, one of M(r) 22,000 and the other of M(r) 36,000. In the prepubertal rat testis [19 days post coitum, 8 days post partum (dpp), and 15 dpp], the form with the higher molecular weight prevailed, whereas in the maturing testis (30 dpp, 45 dpp, and 12 weeks post partum), a shift toward the lower molecular weight form was observed, as well as a decrease in its relative amount. By immunohistochemistry on testicular sections, OSM-specific immunostaining was observed in the interstitial tissue at every age studied. In contrast, OSM immunoreaction was localized in the Sertoli cells exclusively around the start of spermatogenesis, being strongest at 3 dpp. In vitro studies revealed that neonatal Sertoli cells produce OSM. The possible role of OSM at the start of spermatogenesis was investigated by using a coculture of Sertoli cells and gonocytes isolated from newborn rats. OSM significantly increased the survival of both Sertoli cells and gonocytes in a dose-dependent manner. The proliferative activity of the Sertoli cells was not affected by OSM, whereas that of gonocytes was increased by almost 60% after 6 days of culture. Comparison of the effect of OSM on these cocultures with other members of the interleukin 6 family of cytokines demonstrated that this factor is more potent than leukemia inhibitory factor or ciliary neurotrophic factor. On the basis of these findings, it can be concluded that OSM is present in the rat testis, and it is likely to play an important role at the start of spermatogenesis.
The Q-Prep system: effects on the apparent expression of leucocyte cell surface antigens. To facilitate the analysis of immunolabelled peripheral blood or bone marrow leucocytes by flow cytometry, a number of reagents are available commercially that lyse erythrocytes and fix leucocytes. This study has investigated the effect on antibody-labelled whole blood of the Q-Prep procedure, in which erythrocytes are lysed with formic acid, and leucocytes are fixed with formaldehyde. Whole blood samples were labelled with the nuclear dye LDS-751 and with antibodies to HLA-DR or belonging to CD2, CD3, CD4, CD7, CD8, CD10, CD13, CD14, CD19, CD20, CD29, CD33, CD45, CD45RA, CD56, and CD62L (TQ-1) that were directly conjugated to either phycoerythrin (PE) and/or fluorescein isothiocyanate (FITC). Leucocytes were analysed by flow cytometry either in unfixed, unlysed whole blood (15) or after preparation using the Q-Prep system. The binding of eight antibodies, CD19-FITC, CD2-PE, CD3-PE, CD4-PE, CD19-PE, CD29-PE, CD45RA-PE, and CD56-PE, to the surface of lymphocytes was reduced, resulting in significant changes (P < 0.05) in the percentages of cells that stained positively and/or their mean molecules of equivalent fluorochrome (MEF). Further analysis revealed that this was due to the formic acid used during the erythrocyte lysis stage.
Toward a new reference method for the leukocyte five-part differential. A flow cytometric method performing a five-part leukocyte differential based on three-color staining with anti-CD45-fluorescein isothiocyanate (FITC), anti-CD-14-phycoerythrin (PE)/Cy5, and a cocktail of PE-labeled anti-CD2, anti-CD16, and anti-HLA-DR antibodies was evaluated. Results obtained by using three different sample preparation procedures and two different flow cytometers were compared with those of a 1,000-cell manual differential for evaluation of accuracy. We observed excellent correlations with the manual differential for all leukocyte subclasses and even higher correlations between the different flow cytometric methods. Flow cytometric basophil results were identical to the manual counts, regardless of which sample preparation technique or flow cytometer was used. Therefore, we propose our flow cytometric method as the first acceptable automated reference method for basophil counting. The flow cytometric results for the other leukocyte subclasses were apparently influenced by the sample preparation, which could not be explained by cell loss during washing steps. Moreover, a small influence of the flow cytometer was also observed. Assessing the influence of sample storage, we found only minimal changes within 24 h. In establishing reference values, high precision of flow cytometric results facilitated detection of a significantly higher monocyte count for males (relative count: 7.08 +/- 1.73% vs. 6.44 +/- 1.33%, P < 0.05; absolute count: 0.536 +/- 0.181 x 10(9)/liter vs. 0.456 +/- 139 x 10(9)/liter, P < 0.01). Our data indicate that monoclonal antibody-based flow cytometry is a highly suitable reference method for the five-part differential: It also shows, however, that studies will have to put more emphasis on methodological issues to define a method that shows a high interlaboratory reproducibility.
Quality control study of the Italian Group of Cytometry on flow cytometry DNA content measurements: II. Factors affecting inter- and intralaboratory variability. A multicentric national quality control study has been organized under the auspices of the Italian Group of Cytometry to find a possible influence of some procedural steps in DNA flow cytometry measurements on DNA index (DI) values and to identify the main parameters affecting the interlaboratory variability. To 40 participating laboratories we provided suspensions containing unknown mixture of different cell types: an homogeneous thymocyte population used to check instrument linearity; one mixture composed of two cell types characterized by DI = 1.00 and 1.10; and another composed of three different cell types with relative DIs of 1.00, 1.26, and 1.62, respectively. Possible effects due to staining protocols were studied, allowing the participants to stain cellular DNA according to the procedure routinely adopted in each laboratory, in addition to a standardized procedure with a fixed PI solution. As far as the influence of instrument linearity on DI values is concerned, we did not find any correlation with the DI variability observed, even if the use of a standardized staining protocol could lead to a sensible gain in interlaboratory DI reproducibility. Twenty-five of 40 (65%) laboratories were able to discriminate the near-diploid subpopulation, and a coefficient of variation of less than 4% was the minimum condition necessary to recognize the DI = 1.1 population. In samples containing two aneuploid subpopulations, 25 of 35 (71.4%) laboratories showed a high reproducibility with the standard staining protocol and 22 of 38 (57.9%) with the free staining protocol. However, a sensible improvement in interlaboratory reproducibility emerged with respect to the previous trial.
Sequential immunophenotypic analysis of mast cells in a case of systemic mast cell disease evolving to a mast cell leukemia. The immunophenotypic characteristics of both bone marrow (BM) and peripheral blood (PB) mast cells (MC), from a patient suffering from an aggressive systemic mast cell disease (SMCD), were sequentially analyzed by flow cytometry using direct immunofluorescence. Analysis was carried out at diagnosis, during clinical response induced by interferon alfa-2h/prednisone therapy, and later at relapse. Our results show that together with the CD117 and IgE characteristic markers, at diagnosis BM MC showed strong expression of CD11c, CD13, CD29, CD33, CD44, CD45, CD63, and CD71, and they were also positive for CD2, CD22, CD25, and CD54 although at a lower level. PB MC displayed similar immunophenotypic characteristics although they had a lower expression of CD11c, CD25, CD33, CD63, CD69, and CD71 with a higher reactivity for CD117. Unlike BM MC, PB MC were weakly positive for CD41a and CD61. Sequential studies showed decreased numbers of both BM and PB MC during clinical response associated with a higher expression of the CD29 and CD54 adhesion molecules. In turn, clinical relapse was related to increased numbers of PB and BM MC together with lower CD2, CD11c, CD45, and and CD54 expression and a higher reactivity for the CD117 and CD25 antigens. CD2 had become negative at the last follow-up study. In addition, an increased proportion of S-phase MC was observed at relapse. These findings suggest that the assessment of the quantitative expression of cell-adhesion molecules and growth-factor receptors together with cell cycle studies of mast cells could be of value for monitoring therapy and predicting clinical outcome in aggressive SMCD.
Visual attention in infant monkeys: effects of dietary fatty acids and age. Effects of dietary essential fatty acids on visual attention were explored longitudinally in infant rhesus monkeys with a visual paired-comparison paradigm. Sets of primate faces and of patterns were presented at Weeks 2, 5, 9, and 13 to 9 infants deficient in omega-3 fatty acids and 8 fed a standard nursery diet. Familiarization to 1 member of each pair preceded simultaneous presentation of both stimuli. Infants fed the deficient diet showed longer individual looks in both immediate and 24-hr tests. Duration of looks decreased with age to familiar but not to novel stimuli. The proportion of time looking at the novel stimulus (% novel) increased with age but was not affected by diet. Look duration and % novel were differentially affected and may reflect different underlying processes.
By land or by sea: the role of perceptual similarity in infants' categorization of animals. In 3 experiments, the authors used an object-examining task to investigate the role of perceptual similarity in infants' categorization. In Experiment 1, infants were familiarized with a set of either perceptually similar or perceptually variable exemplars from 1 category and tested with novel exemplars from both categories. Ten-month-olds did not respond to the category in either condition, and 13-month-olds responded categorically in both conditions but somewhat differently in the 2 conditions. Experiment 2 showed that when 10-month-olds were familiarized with similar exemplars but not with variable exemplars, they responded to the categorical distinction when given tests with typical exemplars. Experiment 3 established that 10-month-olds could differentiate among the exemplars. These results suggest that the perceptual similarity of the exemplars influences infants' recognition of categorical distinctions.
Interpreting infant looking: the event set x event set design. Theory, data, and mathematical models presented suggest that perceptual processing may be crucial in young infant cognition. Prior results indicating early or innate physical knowledge are reinterpreted. Assumptions that young infants use higher level cognitive processes to infer, reason, believe, and so on are challenged in favor of perceptual processes and the effects of novelty and familiarity. The 2-test habituation design that compares looking at the "possible" with looking at the "impossible" and the problems of that design are considered. The authors' approach, based on regression analysis of Event Set X Event Set factorial designs, eliminates those problems, refines gauging the contribution of various variables, quantifies these contributions with standard parameter estimation, unconfounds the crucial variables, and tests which variables are responsible for looking time differences. Data are presented that support the perceptual processing perspective. Application of the new design to 2 seminal studies of infant cognition are suggested.
Numerical abstraction in infants: another look. This article examines an important finding from the literature on infant numerical competence. The finding, reported by P. Starkey, E. S. Spelke, and R. Gelman (1990), was that infants looked longer toward a visual display that was equal in number to an auditory set. In Experiment 1, when the procedures described by P. Starkey et al. were followed and duration was held constant across auditory sequences that varied in number, infants looked longer toward the display that was not numerically equivalent to the auditory set. In Experiment 2, when the rate and duration of the auditory sequences were varied randomly within infants, no significant preference for either the equivalent or nonequivalent visual display was shown. These results raise questions about P. Starkey et al.'s claims that infants can represent the numerosity of sets in different modalities and then perform one-one correspondence computations over them.
Effects of bilingualism and biliteracy on children's emerging concepts of print. Three groups of 4- and 5-year-old children were examined for their concepts of how print refers to language. All of the children could identify printed letters and their sounds but not read alone. The groups studied were monolingual speakers of English, bilingual speakers of French and English, and bilingual speakers of Chinese (Mandarin) and English. Bilingual children were equally proficient in both languages and were familiar with print and storybooks in both languages. The tasks assessed children's understanding of the general correspondence between print and language in which the printed form represents a word and the specific correspondence between a constituent of print and one of language that determines representation in a given writing system. The general correspondence relation applies to all writing systems, but the specific correspondence relation changes for different kinds of writing systems. Bilingual children understood better than monolingual children the general symbolic representation of print. The older Chinese-English bilingual children also showed advanced understanding of the specific correspondence relations in English print.
The effect of talker variability on word recognition in preschool children. In a series of experiments, the authors investigated the effects of talker variability on children's word recognition. In Experiment 1, when stimuli were presented in the clear, 3- and 5-year-olds were less accurate at identifying words spoken by multiple talkers than those spoken by a single talker when the multiple-talker list was presented first. In Experiment 2, when words were presented in noise, 3-, 4-, and 5-year-olds again performed worse in the multiple-talker condition than in the single-talker condition, this time regardless of order; processing multiple talkers became easier with age. Experiment 3 showed that both children and adults were slower to repeat words from multiple-talker than those from single-talker lists. More important, children (but not adults) matched acoustic properties of the stimuli (specifically, duration). These results provide important new information about the development of talker normalization in speech perception and spoken word recognition.
What's communication got to do with it? Gesture in children blind from birth. It is widely accepted that gesture can serve a communicative function. The purpose of this study was to explore gesture use in congenitally blind individuals who have never seen gesture and have no experience with its communicative function. Four children blind from birth were tested in 3 discourse situations (narrative, reasoning, and spatial directions) and compared with groups of sighted and blindfolded sighted children. Blind children produced gestures, although not in all of the contexts in which sighted children gestured, and the gestures they produced resembled those of sighted children in both form and content. Results suggest that gesture may serve a function for the speaker that is independent of its impact on the listener.
Changing relations between phonological processing abilities and word-level reading as children develop from beginning to skilled readers: a 5-year longitudinal study. Relations between phonological processing abilities and word-level reading skills were examined in a longitudinal correlational study of 216 children. Phonological processing abilities, word-level reading skills, and vocabulary were assessed annually from kindergarten through 4th grade, as the children developed from beginning to skilled readers. Individual differences in phonological awareness were related to subsequent individual differences in word-level reading for every time period examined. Individual differences in serial naming and vocabulary were related to subsequent individual differences in word-level reading initially, but these relations faded with development. Individual differences in letter-name knowledge were related to subsequent individual differences in phonological awareness and serial naming, but there were no relations between individual differences in word-level reading and any subsequent phonological processing ability.
Mother-child problem solving: continuity through the early childhood years. Maternal ratings of child temperament and observed maternal behaviors in the home were collected when children were 18 months old. Both variables were examined as predictors of mothers' problem-solving behaviors with their toddlers at 30 months and the children's independent problem solving at 5 years. Maternal instructional behavior in the home at 18 months and maternal ratings of temperament at 18 months predicted maternal behaviors when the children were 30 months old and child performance in a cognitive problem-solving task. Maternal cognitive assistance during the 18- and 30-month tasks also predicted child cognitive task performance in the laboratory at 5 years of age. These same maternal behaviors were related to the child's performance on the Wechsler Preschool and Primary Scale of Intelligence (D. Wechsler, 1967) at age 5, and lack of maternal assistance was related to teacher ratings of learning problems at age 5.
Attachment, parenting, and peer interactions of toddler children. The relation of parenting variables and attachment classification to peer relations was studied for 156 families with toddler children. Children were observed at 18 months of age in the home with their parents and from 18 to 24 months of age in peer playgroups. Playgroup teachers rated the children's ability to get along with their peers. Also when children were 18 months, they were assessed with their mothers in the Strange Situation, and an attachment classification was made. There were significant differences in peer reactions to children of different attachment classifications. Insecure-resistant children received fewer positive reactions to their positive behaviors, and both resistant and avoidant children received more negative reactions to their positive behaviors. Hierarchical regressions were computed to examine the contribution of observed parent-child interactions and the attachment classification to peer interactions.
Mothers' and fathers' singing to infants. Mothers and fathers sang a song of their choice, once to their infant and once as if to their infant (simulated). The pitch of songs was higher and the tempo slower for infant-directed than for simulated versions. Listeners varying in child-care experience, musical background, and cultural origin reliably identified which of the two versions was infant-directed (Experiment 1). Identification accuracy was enhanced by musical training, knowledge of the singers' language and culture, and by greater pitch and tempo differences between versions. Other adult listeners who rated the singer's emotional engagement assigned significantly higher ratings to infant-directed than to simulated versions (Experiment 2). Differences in pitch and tempo between both versions predicted emotional engagement ratings. Finally, rating differences between infant-directed and simulated versions were highly correlated with identification accuracy.
"You can try or you can just give up": the impact of perceived control and coping style on childhood homesickness. Research on children's coping with homesickness during relatively uncontrollable separations has suggested that secondary control coping (i.e., adjusting oneself to fit objective conditions) is often preferred over primary control coping (i.e., modifying objective conditions to fit oneself). Related research suggests that negative affect is associated with (a) relinquishing control or using primary control to cope with uncontrollable stressors and (b) perceiving low control over stressors. The convergence of these factors was examined for the stressor of homesickness. Among 1,032 boys and girls spending 2 weeks at residential summer camps, the most frequent and effective way of coping with homesickness was to exert secondary control by engaging in a distracting physical activity. Contrary to speculation, the use of secondary control coping rose in adolescence. Congruent with empirical predictions, the most homesick children perceived low control over homesickness and separation, and coped by relinquishing control.
Relation between academic achievement and social adjustment: evidence from Chinese children. A sample of children in Shanghai, P.R. China, initially aged 10 and 12 years, participated in this 2-year longitudinal project. Information on academic achievement and indexes of social adjustment, including social competence, aggression, social inhibition, leadership, and peer acceptance, was collected from multiple sources. It was found that academic achievement predicted children's social competence and peer acceptance. In turn, children's social functioning and adjustment, including social competence, aggression-disruption, leadership, and peer acceptance, uniquely contributed to academic achievement. These results generally supported the "reciprocal effects" model concerning the relations between academic achievement and social adjustment (S. P. Hinshaw, 1992).
Developmental differences in the understanding of and reaction to others' inhibition of emotional expression. In Study 1,160 individuals from kindergarten (kd), 3rd, 6th, 9th, and college grades were presented story protagonists who facially expressed or did not express sadness/fear when encountering events that likely caused (relevant-inhibitory cause) or did not cause (irrelevant cause) the inhibition of the expression of emotion. In Study 2, 108 kd, 3rd-, and 6th-grade children viewed peers engaging in real interactions similar to the stories. In both studies, kindergartners judged that relevant-inhibitory causes decreased a peer's emotions. Older individuals displayed an understanding of the inhibition of emotional expression by ascribing greater emotion to the peer under relevant-inhibitory than irrelevant causal conditions. In Study 2, age differences in children's search for social information and prosocial behavior paralleled judgments of emotion.
Age and sex differences in dyadic and group interaction. This study examined age and sex differences in dyadic and group interaction in a standardized setting. Seven classes of 4-year-old children and 6 classes of 6-year-old children participated. From these classes, 13 male playgroups and 13 female playgroups were formed. The playgroups were videotaped, and frequencies of dyadic and group interaction were tabulated. Results showed that boys and girls at both ages engaged in similar frequencies but different patterns of dyadic interaction. Only 6-year-old boys, however, interacted in groups. The discussion considers the etiology of these age and sex differences.
Exploring the genetic etiology of low general cognitive ability from 14 to 36 months. The genetic and environmental etiology of low general cognitive ability (g) during infancy and early childhood has not previously been investigated. The current study examined the genetic etiology of low cognitive ability at 14, 20, 24, and 36 months with twins from the MacArthur Longitudinal Twin Study. Low g groups were formed from the lowest 10th percentile at each age. Univariate probandwise concordance rates and DeFries-Fulker (J. C. DeFries & D. W. Fulker, 1985, 1988) multiple regression techniques suggest genetic etiology in low general cognitive ability groups. The stability of low general cognitive ability over time also appears to be primarily due to genetic factors. Although replication is necessary, these results suggest that the genetic etiology of low g during infancy and early childhood is at least as great as the heritability of g in the unselected population.
Developmental changes in speed of information processing in young children. This study investigated developmental increases in processing speed in young children, relative to adults, with only nonverbal stimuli. R. Kail's (1991) model of the rate of change in processing speed from childhood to adulthood was evaluated. Processing speed was measured in 34 children at 4 years, 37 at 5 years, and 38 at 6 years and in 43 adults, with a battery of 8 computer-administered tests. Results showed clear age-related increases in processing speed that cannot be attributed to increased accuracy and error rate monitoring. Kail's model adequately accounted for the observed rate of developmental change in processing speed; however, the parameter estimates of R. Kail and Y. Park (1992) provided more accurate predictions than did the meta-analytically derived estimates of Kail (1991). Findings support the global developmental trend hypothesis and suggest that this trend extends beyond the range of verbal skills evaluated in previous research.
Challenging the notion of a thematic preference in young children. Many researchers have argued that early cognitive development is characterized by a conceptual preference for thematic over taxonomic relations. However, more recent research indicates that infants and toddlers may not favor thematic relations. To resolve this discrepancy, the conceptual preferences of children ranging from 2 to 4 years of age were examined, using a forced-choice task including a target (e.g., a carrot), a thematic alternative (e.g., a rabbit), and a taxonomic alternative (e.g., a tomato). The effects of age, experimenter's instructions, hierarchical level (basic vs. superordinate), and stimulus medium (pictures vs. objects) were examined systematically. Children revealed no pervasive preference for either thematic or taxonomic relations. This challenges the notion of a developmental shift in conceptual preferences and suggests a more continuous trajectory in early conceptual development.
An STS-based radiation hybrid map of the human genome. We have constructed a physical map of the human genome by using a panel of 83 whole genome radiation hybrids (the Stanford G3 panel) in conjunction with 10,478 sequence-tagged sites (STSs) derived from random genomic DNA sequences, previously mapped genetic markers, and expressed sequences. Of these STSs, 5049 are framework markers that fall into 1766 high-confidence bins. An additional 945 STSs are indistinguishable in their map location from one or more of the framework markers. These 5994 mapped STSs have an average spacing of 500 kb. An additional 4484 STSs are positioned with respect to the framework markers. Comparison of the orders of markers on this map with orders derived from independent meiotic and YAC STS-content maps indicates that the error rate in defining high-confidence bins is < 5%. Analysis of 322 random cDNAs indicates that the map covers the vast majority of the human genome. This STS-based radiation hybrid map of the human genome brings us one step closer to the goal of a physical map containing 30,000 unique ordered landmarks with an average marker spacing of 100 kb.
A linkage map of the rat genome derived from three F2 crosses. We report the construction of a dense linkage map of the rat genome integrating 767 simple sequence length polymorphism markers, combined over three crosses with high rates of polymorphism. F2 populations from WKY x S (n = 159), BN x S (n = 91), and BN x GK (n = 139) were selected and genotyped for combinations of microsatellite markers. The loci define 21 linkage groups corresponding to the 20 rat autosomal chromosomes and the X chromosome. The map spans a genetic length of 1998 cM. This combined linkage map should facilitate the advancement of genetic studies for a wide variety of rat models characterized for complex phenotypes.
Clone-contig and STS maps of the hereditary hemochromatosis region on human chromosome 6p21.3-p22. YAC-based and bacterial-clone based STS-content maps were constructed that served as the framework physical maps for the positional cloning of a candidate gene for hereditary hemochromatosis. The YAC-based map comprises 43 YACs and 86 STS and spans approximately 8 Mb of DNA between the class I region of the major histocompatibility complex on human chromosome 6p21.3 and D6S276 in 6p22. Comparison with published maps revealed a hole in the MIT/Whitehead and CEPH YAC maps that includes the immediate region around the hemochromatosis gene itself. Approximately 3 Mb of DNA was covered by a bacterial clone contig that consists of 38 BACs, 45 PACs, 26 PI clones and one lambda phage. The bacterial clone-based STS map comprises 153 STSs. A contiguous block of 8 STSs could be amplified from both human chromosome 6 and 5. Further characterization of selected STSs and bacterial clones by radiation hybrid mapping and fluorescence in situ hybridization, respectively, revealed the presence of a multicopy DNA segment, more than one bacterial clone length in size, which is duplicated near the chromosome-6 centromere and part of which is present in multiple copies on chromosome 5. Possible implications of the incomplete public YAC-contig map and of the multicopy segment for physical mapping and linkage disequilibrium studies of the hemochromatosis candidate region are discussed.
Low frequency of microsatellites in the avian genome. A better insight into the occurrence of microsatellites in a range of taxa may help to understand the evolution of simple repeats. Previous studies have found the relative abundance of several repeat motifs to differ among mammals, invertebrates, and plants. Absolute numbers of microsatellites also tend to correlate positively with genome size. We analyzed the occurrence, frequency, and distribution of microsatellites in birds, a taxon with one of the smallest known genome sizes among vertebrates. Dot-blot hybridization revealed that about half of 22 different di-, tri-, and tetranucleotide repeat motifs were clearly more common in human than in three species of birds: chicken, woodpecker, and swallow. For the remaining motifs no clear difference was found. From searching avian database sequences we estimated there to be 30,000-70,000 microsatellites longer than 20 bp in the avian genome. The number of (CA) > or = 10 would be around 7000-9000 and the number of (CA) > or = 14 about 3000. The calculated density of avian microsatellites (total, one every 20-39 kb; (CA) > or = 10, one every 136-150 kb) is much lower than that estimated for the human genome (one every 6 and 30 kb, respectively). This may be explained by the fact that the avian genome contains relatively less noncoding DNA than most mammals and that avian SINE/LINE elements do not terminate in poly(A) tails, which are known to provide a resource for the evolution of simple repeats in mammals. We found no association between microsatellites and SINEs in birds. Primed in situ labeling suggested fairly even distribution of (CA)n repeats over chicken macrochromosomes and intermediate chromosomes, whereas the microchromosomes, a large part of the Z and W chromosomes, and most telomeres and centromeres had very low concentrations of (CA)n microsatellites. The scarcity of microsatellites on the microchromosomes is compatible to these regions likely being unusually rich in coding sequences. The low microsatellite density in the genome in general and on the microchromosomes in particular imposes an obstacle for the development of marker-rich genetic maps of chicken and other birds, and for the localization of quantitative trait genes.
Fine localization of the torsion dystonia gene (DYT1) on human chromosome 9q34: YAC map and linkage disequilibrium. The DYT1 gene, which maps to chromosome 9q34, appears to be responsible for most cases of early-onset torsion dystonia in both Ashkenazic Jewish (AJ) and non-Jewish families. This disease is inherited in an autosomal dominant mode with reduced penetrance (30%-40%). The abnormal involuntary movements associated with this disease are believed to be caused by unbalanced neural transmission in the basal ganglia. Previous linkage disequilibrium studies in the AJ population placed the DYT1 gene in a 2-cM region between the loci D9S62a and ASS. A YAC contig has now been created spanning 600 kb of this region including D9S62a. The location of the DYT1 gene has been refined within this contig using several new polymorphic loci to expand the linkage disequilibrium analysis of the AJ founder mutation. The most likely location of the DYT1 gene is within a 150 kb region between the loci D9S2161 and D9S63.
Computational and biological analysis of 680 kb of DNA sequence from the human 5q31 cytokine gene cluster region. With the human genome project advancing into what will be a 7- to 10-year DNA sequencing phase, we are presented with the challenge of developing strategies to convert genomic sequence data, as they become available, into biologically meaningful information. We have analyzed 680 kb of noncontiguous DNA sequence from a 1-Mb region of human chromosome 5q31, coupling computational analysis with gene expression studies of tissues isolated from humans as well as from mice containing human YAC transgenes. This genomic interval has been noted previously for containing the cytokine gene cluster and a quantitative trait locus associated with inflammatory diseases. Our analysis identified and verified expression of 16 new genes, as well as 7 previously known genes. Of the total of 23 genes in this region, 78% had similarity matches to sequences in protein databases and 83% had exact expressed sequence tag (EST) database matches. Comparative mapping studies of eight of the new human genes discovered in the 5q31 region revealed that all are located in the syntenic region of mouse chromosome 11q. Our analysis demonstrates an approach for examining human sequence as it is made available from large sequencing programs and has resulted in the discovery of several biomedically important genes, including a cyclin, a transcription factor that is homologous to an oncogene, a protein involved in DNA repair, and several new members of a family of transporter proteins.
A differential hybridization scheme to identify photoreceptor-specific genes. Identification of genes expressed preferentially or exclusively in photoreceptors will facilitate the understanding of photoreceptor biology as well as provide candidate genes for inherited retinal degenerations. To achieve this goal we performed a differential hybridization screen of 3717 well-isolated phage clones from a human retinal cDNA library. Clones were selected for further study if they hybridized exclusively or strongly preferentially to a probe derived from RNA isolated from the cone-predominant retina of 13-line ground squirrels as compared to a probe derived from human fibroblast RNA. Twenty percent of clones (9/45) identified by this screen were derived from photoreceptor-specific genes and an additional 24.4% (11/45) were from neural-specific genes, demonstrating the utility of this strategy in identifying genes important for retinal biology.
The organization of the gamma-glutamyl transferase genes and other low copy repeats in human chromosome 22q11. A clone map consisting of YACs, cosmids, and fosmids has been constructed covering low copy repeat regions of human chromosome 22q11. A combination of clone restriction digest analysis, single-copy landmark content analysis, HindIII-Sau3AI fingerprinting, and sequencing of PCR products derived from clones was required to resolve the map in this region. Seven repeat-containing contigs were placed in 22q11, five containing gamma-glutamyl transferase (GGT) sequences described previously. In one case, a single interval at the resolution of the YAC map was shown to contain at least three GGT sequences after higher resolution mapping. The sequence information was used to design a rapid PCR/restriction digest technique that distinguishes the GGT loci placed in the YAC map. This approach has allowed us to resolve the previous cDNA and mapping information relating to GGT and link it to the physical map of 22q11.
The human homolog of a mouse-imprinted gene, Peg3, maps to a zinc finger gene-rich region of human chromosome 19q13.4. Peg3 (paternally expressed gene 3) is the first imprinted gene detected in the proximal region of mouse chromosome 7. Because imprinting is a trait that is generally conserved among mammals, and imprinted domains generally encompass several adjacent genes, expression patterns and chromosomal environment of the human counterpart of Peg3 are of special interest. In this study we have localized human PEG3 approximately 2 Mb proximal of the telomere of chromosome 19q, within a region known to carry large numbers of tandemly clustered Krüppel-type zinc finger-containing (ZNF) genes. Peg3 also encodes a Krüppel-type ZNF protein but one that is distinguished from other ZNF gene products by the fact that it carries two novel proline-rich motifs. Comparison between mouse Peg3 and partial human PEG3 gene sequences revealed a high level of conservation between the two species, despite the fact that one of the two proline-rich repeats is absent from the human gene. Our data demonstrate that the human gene is expressed at highest levels in ovary and placenta; mouse Peg3, by contrast, is transcribed at highest levels in the adult brain. These comparative mapping, sequencing, and expression data provide the first clues to the potential activities of PEG3, and generate new tools to aid in the analysis of structure and function of a potentially new imprinted domain located in human chromosome 19q13.4 and mouse chromosome 7.
Sequence mapping by electronic PCR The highly specific and sensitive PCR provides the basis for sequence-tagged sites (STSs), unique landmarks that have been used widely in the construction of genetic and physical maps of the human genome. Electronic PCR (e-PCR) refers to the process of recovering these unique sites in DNA sequences by searching for subsequences that closely match the PCR primers and have the correct order, orientation, and spacing that they could plausibly prime the amplification of a PCR product of the correct molecular weight. A software tool was developed to provide an efficient implementation of this search strategy and allow the sort of en masse searching that is required for modern genome analysis. Some sample searches were performed to demonstrate a number of factors that can affect the likelihood of obtaining a match. Analysis of one large sequence database record revealed the presence of several microsatellite and gene-based markers and allowed the exact base-pair distances among them to be calculated. This example provides a demonstration of how e-PCR can be used to integrate the growing body of genomic sequence data with existing maps, reveal relationships among markers that existed previously on different maps, and correlate genetic distances with physical distances.
A transposon-based strategy for sequencing repetitive DNA in eukaryotic genomes. Repetitive DNA is a significant component of eukaryotic genomes. We have developed a strategy to efficiently and accurately sequence repetitive DNA in the nematode Caenorhabditis elegans using integrated artificial transposons and automated fluorescent sequencing. Mapping and assembly tools represent important components of this strategy and facilitate sequence assembly in complex regions. We have applied the strategy to several cosmid assembly gaps resulting from repetitive DNA and have accurately recovered the sequences of these regions. Analysis of these regions revealed six novel transposon-like repetitive elements, IR-1, IR-2, IR-3, IR-4, IR-5, and TR-1. Each of these elements represents a middle-repetitive DNA family in C. elegans containing at least 3-140 copies per genome. Copies of IR-1, IR-2, IR-4, and IR-5 are located on all (or most) of the six nematode chromosomes, whereas IR-3 is predominantly located on chromosome X. These elements are almost exclusively interspersed between predicted genes or within the predicted introns of these genes, with the exception of a single IR-5 element, which is located within a predicted exon. IR-1, IR-2, and IR-3 are flanked by short sequence duplications resembling the target site duplications of transposons. We have established a website database (http:(/)/www.welch.jhu.edu/approximately devine/RepDNAdb.html) to track and cross-reference these transposon-like repetitive elements that contains detailed information on individual element copies and provides links to appropriate GenBank records. This set of tools may be used to sequence, track, and study repetitive DNA in model organisms and humans.
Training in firearm safety counseling in family practice residency programs. The purpose of this study was to establish a national baseline regarding the prevalence of training of family practice residents regarding firearm safety counseling. A national survey of the residency directors at the 420 accredited family practice residency programs in the coterminous United States was used to assess the prevalence of training in firearm safety counseling, perceived effectiveness of such training, and perceived barriers to such counseling in residency programs. Program directors were sent a two-page questionnaire on firearm safety counseling activity in their programs and 71% responded. Few residencies (16%) had formal training in firearm safety counseling. The most common perceived barriers were no trained personnel (31%), too many other important issues (31%), not enough time (30%), and lack of educational resources (28%). Patient education materials (57%), video training programs (49%), and a curriculum guide (46%) were identified as resources that would be most helpful in implementing a firearm safety counseling program. The results showed that formal training in firearm safety counseling is virtually absent from family practice residency training programs. This finding is not surprising given that less than 14% of the directors perceived firearm safety counseling would be effective in reducing firearm-related injuries or deaths and that research on effectiveness of such counseling is very limited.
The extent of barriers and linkages to health care for head start children. Data were gathered as part of a larger survey of 218 Head Start Programs in Region II (New York City, New York State (excluding New York City), New Jersey, Puerto Rico and U.S. Virgin Islands) in 1993-94. The general purpose of the survey was to obtain information on child health, screening practices, training needs, family health and community problems, barriers to diagnosis and treatment and the extent of linkages between Head Start programs and health and nutrition providers at the local level. In this study barriers to the care of Head Start children and their families were examined as perceived by the Health Coordinators or other health related staff of the Health Services Component of these programs. The extent of linkages with health and nutrition service providers were also examined. The most frequently reported barriers were lack of parent participation (72%), private transportation not available (67%), parents' perception of quality of care (64%), distance to provider (63%), cost of transportation (63%), lack of funding (56%), limited/inconvenient hours (56%), and health services not available in the community (55%). On average, programs reported linkages to 14.5 providers (including an average of 4 nutrition programs). More than 90% of them reported linkages with public health services, child protective services, WIC and private physicians/dentists. Finally, the extent of barriers and linkages were compared across different geographic areas. Significant barriers were identified in this study, yet the survey confirmed and validated the extensive nature of formal linkages with health and nutrition service providers at the local levels. These findings may indicate that the current levels of service availability may not be sufficient to meet the severity and diversity of health needs of this population.
Developing and evaluating a Spanish TEL-MED message on breast cancer. A Spanish TEL-MED message on breast cancer was designed for Delaware. The message, created from a focus group of Latino professionals and volunteers from the American Cancer Society, Delaware Division, provides information for Latinas on breast cancer. In one minute, forty-five seconds the message answers in Spanish the following questions: (1) What are the symptoms of breast cancer? (2) What can women do to protect themselves against breast cancer? (3) What is a mammogram? (4) When should I have a mammogram done? (5) How much does a mammogram cost? The message also provides information on where to obtain low cost or free mammograms. A pamphlet in Spanish, featuring a picture of an elderly Latina listening to the phone message, describes how to access the tape. The message targets older Latinas who prefer to speak Spanish. The American Cancer Society, Delaware Division, distributed a press release featuring the Spanish TEL-MED and circulated the pamphlets to Latino organizations and churches. Evaluation of the TEL-MED message in Spanish suggests it to be an innovative way to reach older Latino women. The Spanish message on breast cancer was requested 58% as often as the breast cancer message in English, and 193% more often than the epilepsy tape in Spanish. The peak period for the calls to the Spanish TEL-MED message occurred after the initial promotional activities. These findings suggest that education of older Latinas on breast cancer can be augmented by the use of TEL-MED message in Spanish. They further suggest that the combination of TEL-MED and mass media campaign had a positive effect on Spanish speaking users of the TEL-MED.
Prevalence and predictors of tobacco use among Lumbee Indian women in Robeson County, North Carolina. Tobacco use among some Native American tribes is high compared to the overall US population. Little is known, however, about tobacco use among Native Americans in North Carolina, a state with strong economic ties to tobacco. To assess the epidemiology of tobacco use in this population, data from the North Carolina Native American Cervical Cancer Project was reviewed. Nine hundred eighty-two Lumbee Indian women in Robeson County provided general demographic information as well as information on cancer risk knowledge, attitudes and behaviors during the 5-year study. Women were selected from the community using a random sample of 5200 persons from the tribal roll of approximately 40,000 persons. 20.6% of women were current smokeless tobacco users, while 23.7% were current smokers. Demographic and social support predictors were unique for the different types of tobacco use. Cigarette smoking was associated with younger age, higher education, excellent or good self-reported health, having a recent physical exam, separated or divorced marital status, low church participation, and alcohol consumption. Conversely, use of smokeless tobacco was associated with older age, lower education level, fair or poor self-reported health, widowed marital status, and having a high number of friends. These data show a high prevalence of smokeless tobacco use among women in this population, and a contrast in the predictors of tobacco use by source. Intervention programs for tobacco use cessation should be sensitive to these differences.
Preventing teen pregnancy through persuasive communications: realities, myths, and the hard-fact truths. Effective campaigns are desperately needed to combat the serious social problem of teen pregnancy. However, public health campaigns are most often noted for failures, rather than successes. One reason for a campaign failing to have the intended effect is lack of theoretical guidance at the formative evaluation stage. The study reported here is a theoretically-based formative evaluation with inner city teens. Six focus groups were conducted to determine knowledge, attitudes, beliefs, and recommendations for effective campaigns to deter teen pregnancy. The results indicate that campaign messages need to combat positive attitudes toward pregnancy, negative attitudes toward birth control, the perception of personal invulnerability, and emphasize the negative consequences of sexual intercourse. This study's findings also suggest that campaigns with these messages need to start at an early age in order to effectively prevent teen pregnancy.
Characterization of phosphate sites in native ovine, caprine, and bovine casein micelles and their caseinomacropeptides: a solid-state phosphorus-31 nuclear magnetic resonance and sequence and mass spectrometric study. The phosphate sites in native ovine, caprine, and bovine casein micelles have been analyzed using sequence analysis, mass spectrometric analysis, and solid-state 31P nuclear magnetic resonance spectroscopy. Using a combination of S-ethylcysteine derivatization, sequence analysis, and mass spectrometric analysis, the phosphorylation sites of ovine (SerP151 and SerP168), caprine (SerP151 and SerP168), and bovine (SerP149) caseinomacropeptides have been localized. Various solid-state 31P methods using magic angle spinning have been applied to ascertain the local structure and dynamics of the phosphorylated serine residues and the inorganic calcium phosphates within the micelles. Contributions from the phosphorylated serine residues of kappa-CN, located in the C-terminal portion of the molecule, to the mobile constituents of the micelles were assigned by comparison with 31P nuclear magnetic resonance spectra of purified caseinomacropeptides from the various species in the dissolved state. Comparison of the 31P magic angle spinning nuclear magnetic resonance spectra of ovine, caprine, and bovine casein micelles indicates that the micelles from these species are very similar but not identical.
Structural studies on casein micelles of human milk: dissociation of beta-casein of different phosphorylation levels induced by cooling and ethylenediaminetetraacetate. Information on the structure of human casein micelles has been obtained from dissociation of beta-casein (CN). Two approaches were used: cooling at 4 degrees C and addition of EDTA. An initial loss of about 80% of the protein optical density occurred upon cooling to 4 degrees C. Dissociation was time dependent, and at > or = 24 h about 10% remained. However, mean size and voluminosity of micelles increased, as indicated by laser light scattering and viscosity measurements. This process was reversible, and 95% of the protein reentered the micelles upon incubation for 3 h at 37 degrees C. Upon cooling, amounts of nonphosphorylated beta-CN increased, and singly phosphorylated beta-CN levels were almost constant relative to the total beta-CN in micelles. Upon addition of EDTA (0 to 5 mM), the forms with three to five phosphates were the major dissociating constituents; EDTA that was added by dialysis produced similar results but at lower concentrations. These data suggest that, in the absence of significant amounts of alpha s1-CN, nonphosphorylated and singly phosphorylated human beta-CN may form a framework, as proposed for alpha s1-CN for bovine milk, along with the colloidal calcium phosphate for the development of the final micelle structure by addition of the more highly phosphorylated forms. The results also indicate that human casein micelles have a less rigid structure than those of other species.
Comparative effects of recombinant ovine placental lactogen and bovine growth hormone on galactopoiesis in ewes. The effects of recombinant ovine placental lactogen and bovine growth hormone on milk yield, milk composition, and concentrations of blood hormones and metabolites were compared in ewes during an established lactation. Beginning on d 17 of lactation, ewes were treated for 5 d with twice daily subcutaneous injections of ovine placental lactogen (n = 9), bovine growth hormone (n = 10) at a dose of 0.10 mg/d per kg of body weight, or saline (n = 10). Circulating concentrations of ovine placental lactogen were 24.6 +/- 1.6 ng/ml on d 5 for ewes treated with ovine placental lactogen, but concentrations of ovine placental lactogen were undetectable in ewes treated with either saline or bovine growth hormone. Treatment with bovine growth hormone increased circulating concentrations of growth hormone, insulin-like growth factor-I, and nonesterified fatty acids and decreased urea concentrations relative to those in ewes treated with ovine placental lactogen or saline. Compared with saline treatment, no parameters were affected by treatment with ovine placental lactogen. Treatment with bovine growth hormone or ovine placental lactogen treatment had no significant effects on plasma concentrations of insulin, glucose, or creatinine. Treatment with bovine growth hormone, but not ovine placental lactogen, increased yields of milk, fat, and lactose. Weight of the mammary gland was increased by bovine growth hormone, but not by ovine placental lactogen. Despite the fact that ovine placental lactogen is a potent somatogen, it does not appear to exhibit the same galactopoietic activity as bovine growth hormone in lactating ewes.
Effects of fatty acids and hormones on fatty acid metabolism and gluconeogenesis in bovine hepatocytes. Primary cultures of hepatocytes were used to study the effects of extracellular oleate concentration and hormones on fatty acid metabolism and gluconeogenesis. Rates of oleate uptake and oxidation to acid-soluble products varied linearly as oleate concentrations increased (0.1 to 2 mM), but rates of triglyceride accumulation varied quadratically. Insulin increased the proportion of oleate that was esterified by 22% without affecting the formation of acid-soluble products. Cells incubated with 2 mM [1-(14)C]oleate for 24 h eliminated 9.6% of the labeled intracellular lipid as acid-soluble products in the following 24 h when no oleate was present during depletion and eliminated 7.7% when 2 mM oleate was present. Insulin reduced labeled triglyceride depletion by 49%. Gluconeogenesis from [2-(14)C] propionate was depressed by 24%, and formation of acid-soluble products was increased by 46% in cells infiltrated with lipid because of previous exposure to 2 mM oleate for 45 h. Rates of gluconeogenesis from propionate were reduced 23% when 2 mM oleate was present during the 3-h period that gluconeogenesis was measured, and the effect was not modified by lipid infiltration. Lipid infiltration influenced hepatic function, and insulin regulated hepatic triglyceride concentration.
Hepatic gene expression of apolipoprotein B100 during early lactation in underfed, high producing dairy cows. The hepatic gene expression of apolipoprotein B, the major protein of very low density lipoproteins in plasma, was studied using 8 Holstein x Friesian cows during the first 12 wk of lactation. Cows were fattened during gestation and were underfed just after parturition to increase fat mobilization and subsequent hepatic steatosis. Intracellular concentrations of apolipoprotein B and apolipoprotein B mRNA and control parameters (albumin, total lipids, RNA, and proteins) were determined in liver samples obtained by biopsy from each cow on four occasions at 1, 2, 4, and 12 wk after calving. Results were compared with those obtained from 5 dry cows in late pregnancy and 4 dry nonpregnant cows. The hepatic concentration of apolipoprotein B was lower (approximately 25%) during wk 1, 2, and 4 after calving, a period of intense liver steatosis (44.2 to 95.7 mg of triglycerides/g of fresh tissue), than for nonsteatotic dry cows (pregnant or nonpregnant); hepatic concentrations were also lower than those during wk 12. In contrast, hepatic concentrations of mRNA coding for apolipoprotein B, total proteins, RNA, and albumin did not vary significantly during early lactation. These results suggested that synthesis of apolipoprotein B during early lactation is specifically regulated at a posttranscriptional level by a decrease in the rate of translation, or by a higher rate of intracellular degradation of apolipoprotein B, or both.
Antibacterial peptides of bovine lactoferrin: purification and characterization. Three peptides with antibacterial activity toward enterotoxigenic Escherichia coli have been purified from a pepsin digest of bovine lactoferrin. All peptides were cationic and originated from the N-terminus of the molecule in a region where a bactericidal peptide, lactoferricin B, had been previously identified. The most potent peptide, peptide I, was almost identical to lactoferricin B; the sequence corresponded to residues 17 to 42, and the molecular mass was 3195 as determined by mass spectrometry. A second, less active peptide, peptide II, consisted of two sequences, residues 1 to 16 and 43 to 48 (molecular mass of 2673), linked by a single disulfide bond. The third peptide, peptide III, also a disulfide-linked heterodimer, corresponded to residues 1 to 48 (molecular mass of 5851), cleaved between residues 42 and 43. Peptides I and II displayed antibacterial activity toward a number of pathogenic and food spoilage microorganisms, and peptide I inhibited the growth of Listeria monocytogenes at concentrations as low as 2 microM. Bacterial growth curves showed that bactericidal effects of peptides I and II were observable within 30 min of exposure. The results confirmed and extended those of earlier studies suggesting that the bactericidal domain of lactoferrin was localized in the N-terminus and did not involve iron-binding sites.
Replacement of alfalfa neutral detergent fiber with a combination of nonforage fiber sources. Sixteen Holstein cows in midlactation were used in a 4 x 4 Latin square design to determine the effect of replacing alfalfa neutral detergent fiber (NDF), with NDF from a combination of whole linted cottonseed, dried distillers grains, and wheat middlings. The four diets were a basal control diet that was low in forage and fiber [(5.9 g of corn silage NDF and 6.1 g of alfalfa NDF/100 g of dry matter (DM)], a normal forage diet (low forage plus 10 g of additional alfalfa NDF/100 g of DM), and two low forage diets with either 5 or 10 g of NDF from the nonforage fiber sources added per 100 g of DM. Milk yield, milk protein yield, and milk protein percentage were higher, and milk fat percentage and fat yield were lower, for cows fed the low forage diets than for those fed the alfalfa control diet that was higher in fiber. Among the low forage diets, dry matter intake, milk fat percentage, and fat yield all increased linearly as NDF content increased. The ratio of acetate to propionate in the rumen and rumination times were greater for the normal forage control diet than for the high nonforage fiber diet. Added NDF from these nonforage fiber sources increased milk fat percentage and yield, but this increase was less than the NDF from alfalfa and less than predicted. In agreement with results of similar previous trials, milk protein yield and percentage were increased when alfalfa NDF was replaced with fiber from nonforage fiber sources.
Influence of level of concentrate allocation and fermentability of forage fiber on chewing behavior and production of dairy cows. Nine midlactation dairy cows were offered one of three mixed silage rations with neutral detergent fiber (NDF) that was similar in concentration but different in fermentability. Differences in fermentability were achieved by substituting a high quality alfalfa silage for a low quality alfalfa silage and substituting a combination of ryegrass and timothy silages for a barley silage. In addition, concentrate was allocated at 0.30, 0.82, or 1.37 kg of dry matter/kg of dry matter intake (DMI) from the mixed silage ration. As expected, the NDF content of the mixed silage ration did not differ, although fermentability of NDF increased numerically as forage quality increased. Intake of NDF increased linearly, and DMI tended to increase linearly, as fiber fermentability of the mixed silage ration increased. In addition, cows produced more milk, milk fat, and milk protein and generated more total and milk energy. The calculated concentration of net energy for lactation of the total diet also increased. Results support the concept that NDF quality influences and can be used to predict voluntary feed intake, at least in relatively high producing dairy cows. The DMI increased, and intake of NDF and crude protein declined, as the allocation of concentrate increased. In addition, as concentrate allocation increased, cows spent less time eating and ruminating and more time resting and produced more milk, milk protein, and milk lactose. Cows also generated more total energy and milk energy, although, despite a sharp decrease in the forage proportion of the diet, the calculated energy density of the diet did not differ among concentrate levels. The lack of significant interactions between concentrate level and fiber fermentability for any parameter measured supports the contention that high quality forage is critical to a successful dairy ration, regardless of the proportion of forage in the diet.
Protein degradation in response to spontaneous heating in alfalfa hay by in situ and ficin methods. Alfalfa forage, field-wilted to 29.9 or 19.7% moisture and packaged in five baling treatments (prestorage control; conventional bales; and laboratory bales made at 1.0, 1.5, and 2.0 times the density of conventional bales), was evaluated for protein degradation characteristics by in situ and ficin assays. Relationships between degradation rates and accumulated heating degree days suggested that these degradation rates are controlled by two conditions. Degradation rates increased concurrently with conservation and minimal heating, primarily because of a large redistribution of highly degradable N that was soluble in prestorage controls, but not in conserved hays. For both methods, this effect appeared to be maximized between 100 and 125 heating degree days. With respect to the in situ method, these effects appeared to be less pronounced, and degradabilities were not affected. After bales accumulated about 125 heating degree days, degradation rates decreased predictably in response to heating by both methods, as did N degradabilities calculated from in situ data. Increases in degradation rates concurrent with conservation and minimal heating appear to be especially important considerations when results of the ficin assay are being interpreted.
Effect of processed grain sorghum and expeller soybean meal on performance of lactating cows. Forty-four Holstein cows were used to measure milk production responses to dry-rolled versus pelleted grain sorghum and expeller versus solvent soybean meal in a 2 x 2 factorial arrangement of treatments. Pelleted grain sorghum was processed by grinding, increasing moisture to 31%, extruding, and drying to an exist temperature of 93 degrees C. Grain sorghum was included in the diets at 27% of dry matter, and soybean meal was the primary source of supplemental protein. Few interactions were observed between the methods of processing grain sorghum and sources of soybean meal. Pelleting of grain sorghum decreased dry matter intake 5%, but increased milk production 3%, protein yield 4%, and efficiency 7%; fat yield was unaffected. Replacement of solvent soybean meal with expeller soybean meal had little effect on intake, but increased milk production 3%, fat yield 5%, and efficiency 4%; protein yield was unaffected. Plasma concentrations of amino acids (AA) were increased by pelleted grain sorghum and by expeller soybean meal at 5 and 10 wk after initiation of treatment, indicating that both of these treatments increased the supply of AA to the intestine. Pelleting improved the nutritive value of grain sorghum for lactating cows. Although total milk production and fat yield increased in response to expeller soybean meal, the lack of response in protein yield to this increased supply of RUP indicated that the effect was not solely due to an increased supply of AA to the intestine.
Lactational performance of cows fed low or high ruminally undegradable protein prepartum and supplemental methionine and lysine postpartum. Multiparous Holstein cows (n = 24) were fed diets containing 34 or 41% ruminally undegradable protein (RUP) for 30 d before parturition; then each group was fed a basal diet supplemented with or without ruminally stable Met (10.6 g/d) and Lys (15.2 g/d) for 75 d in the subsequent lactation. Supplementation of Met and Lys increased the milk yield of cows previously fed the low RUP diet, but milk yields before and after amino acid (AA) supplementation were similar for cows previously fed the high RUP diet. Milk protein content (percentage) increased from 2.83 to 2.96 for cows previously fed the high RUP diet. Milk protein yield increased from 1.13 to 1.21 kg/d when Met and Lys were fed. Data on AA concentration in plasma and AA extraction by the mammary gland suggest that the supplementation of Met and Lys corrected a Met limitation. According to the Cornell Net Carbohydrate and Protein System, the lactation diet was limiting for Met for maximum milk yield and was corrected by AA supplementation. Based on limiting AA, allowable milk yield was 42.5 kg/d, and the observed yield was 40.9 kg/d averaged across treatments. The group with the greatest allowable milk yield (45.2 kg/d) had the greatest actual milk yield (43.0 kg/d). The regression equation of observed milk yield on allowable milk yield was Y = 3.4 + 0.8805X.
Effects of energy and protein allowances in the diets of prepubertal heifers on growth and milk production. Sixty-one Italian Friesian heifers between 100 and 300 kg of body weight (BW) were fed one of four diets. Heifers that were fed the diet with low energy and low protein received 90% of the amounts of total digestible nutrients (TDN) and crude protein (CP) recommended by the National Research Council for large breed dairy heifers growing at a rate of 0.7 kg/d. Ninety and 110% of recommended amounts of TDN and CP, respectively, were supplied to heifers fed the diet containing low energy and high protein. The diet with high energy and low protein provided 110 and 90% of recommended amounts of TDN and CP, respectively, and heifers fed high energy and high protein received 110% of the recommended amounts of both TDN and CP. When heifers reached 300 kg of BW, all were fed an identical diet. Heifers were bred at approximately 370 kg of BW. The increase of either TDN or CP improved average daily gain (608.1 g/d for heifers fed the low energy and low protein diet; 658.9 g/d for heifers fed the low energy and high protein diet; 794.4 g/d for heifers fed the high energy and low protein diet; and 847.6 g/d for heifers fed the high energy and high protein diet). Milk production through 36 wk of the first lactation was not influenced by the increased TDN or CP in the diet (22.7 kg/d for heifers fed low energy and low protein, 22.2 kg/d for heifers fed low energy and high protein diet, 20.2 kg/d for heifers fed the high energy and low protein diet, and 21.8 kg/d for heifers fed high energy and high protein diet). Results showed that Italian Friesian heifers can tolerate an average daily gain of approximately 800 g from 100 to 300 kg of BW without any detrimental effect on future milk production.
Effect of volatile fatty acid infusion on development of the rumen epithelium in neonatal sheep. The purpose of this study was to determine whether the continuous intraruminal infusion of calculated physiological concentrations of volatile fatty acids (VFA) stimulated the metabolic development of the neonatal rumen. Eight 1-wk-old lambs were assigned to one of three treatments: saline infusion (three lambs), VFA infusion (three lambs), or no infusion (two lambs). Rumen catheters were surgically implanted into lambs in the infusion groups. The amount of VFA infused, beginning at 2 wk of age, increased weekly in equal increments of 12.5% of the estimated net energy requirement until, at 6 wk of age, lambs received 50% of their estimated net energy requirement from the infused VFA. All lambs consumed milk replacer for ad libitum intake and had free access to water. The lambs that were infused with VFA tended to have longer rumen papillae. There were no differences in width or number of papillae per square centimeter across treatments. Rumen epithelial cells isolated from lambs that were infused with VFA tended to oxidize less glucose and produce more acetoacetate than did cells from lambs that were infused with saline or from uninfused lambs. beta-Hydroxybutyrate production by isolated rumen epithelial cells and concentrations of blood glucose, acetoacetate, and beta-hydroxybutyrate were not different among the three treatments. Thus, infusion of physiological concentrations of VFA appears to stimulate some aspects of rumen metabolic development.
Effects of quality, quantity, and timing of colostrum feeding and addition of a dried colostrum supplement on immunoglobulin G1 absorption in Holstein bull calves. Three experiments were conducted to examine the effects of quality, quantity, and timing of colostrum feeding and the administration of a dried colostrum supplement on serum Ig in Holstein bull calves. In Experiment 1, calves were fed colostrum that had low concentrations of immunoglobulin (Ig; 23.9 mg of IgG1/ml) as follows: group 1-1 (n = 6), 2 L at birth and 2 L at 12 h; group 1-2 (n = 6), 4 L at birth and 2 L at 12 h; and group 1-3 (n = 6), 2 L at birth, 2 L at 6 h, and 2 L at 12 h. Doubling the volume of colostrum administered at birth did not result in higher serum Ig at 48 h, but additional colostrum at 6 h did increase serum Ig. In Experiment 2, calves received 2 L of colostrum that had low concentrations of Ig (25.7 mg of IgG1/ml) at birth and 2 L at 12 h. Calves in group 2-1 (n = 6) received colostrum only. Calves in groups 2-2 (n = 5) and 2-3 (n = 5) were fed additional dried colostrum supplement (136 and 272 g, respectively) at each meal. Addition of the supplement reduced efficiency of IgG1 absorption and did not result in higher serum Ig at 48 h. In Experiment 3, calves were fed as follows: group 3-1 (n = 6), 2 L of colostrum containing 32.9 mg of IgG1/ml (low Ig) at birth and 2 L at 12 h; group 3-2 (n = 6), 2 L of colostrum containing 60.1 mg of IgG1/ml (high Ig) at birth and 2 L at 12 h, and group 3-3 (n = 5), 4 L of colostrum containing 60.1 mg of IgG1/ml at birth and 2 L at 12 h. Colostrum high in Ig resulted in higher serum Ig concentrations at 48 h; the concentrations were highest when 4 L of colostrum high in Ig were fed to calves at birth.
Effect of dystocia on yield, fertility, and cow losses and an economic evaluation of dystocia scores for Holsteins. Lactation records of US Holstein cows were analyzed with mixed models to determine the effect of dystocia on 305-d milk, fat, and protein yields, days open, number of services, and cow losses and to estimate the economic loss associated with dystocia. The data were 122,715 records of 71,618 cows from 1980 to 1991. The single-trait animal model included herd-year-season, sex of calf, age of dam, and dystocia score as fixed effects and animal and permanent environment as random effects. The effect of dystocia was significant (P < 0.01) on all traits within and across parities. Over multiple parities, the differences between score 5 (extreme difficulty) versus score 1 (no problem) for milk yield, fat yield, protein yield, days open, number of services, and cow deaths were 703.6 kg, 24.1 kg, 20.8 kg, 33 d, 0.2 services, and 4.1%, respectively. The losses associated with traits were priced and summed to determine the total economic loss associated with dystocia. In addition, calf mortality was considered to be a cost. Across parities, estimates of costs were $0.00, $50.45, $96.48, $159.82, and $379.61 for scores 1 to 5, respectively. Cost of dystocia was relatively higher on a per incidence basis than would be expected from the mean of the population. The total cost associated with dystocia (i. e., within-parity sum of costs associated with dystocia scores weighted by the probability of occurrence) was $28.53 for an average heifer and about $10.00 for an average cow for other parities.
Estimates of genetic parameters for a test day model with random regressions for yield traits of first lactation Holsteins. A model that contains both fixed and random linear regressions is described for analyzing test day records of dairy cows. Estimation of the variances and covariances for this model was achieved by Bayesian methods utilizing the Gibbs sampler to generate samples from the marginal posterior distributions. A single-trait model was applied to yields of milk, fat, and protein of first lactation Holsteins. Heritabilities of 305-d lactation yields were 0.32, 0.28, and 0.28 for milk, fat, and protein, respectively. Heritabilities of daily yields were greater than for 305-d yields and varied from 0.40 to 0.59 for milk yield, 0.34 to 0.68 for fat yield, and 0.33 to 0.69 for protein yield. The highest heritabilities were within the first 10 d of lactation for all traits. Genetic correlations between daily yields were higher as the interval between tests decreased, and correlations of daily yields with 305-d yields were greatest during midlactation.
Relationship of yield during early lactation and days open during current lactation with 305-day yield. To measure and to partition the effect of pregnancy on yield, the relationships among milk, fat, and protein yields during early lactation, current days open, and 305-d yields were investigated using sample day records of 247,310 Holstein cows. The model included fixed effects of calving herd-year-season, calving age, and days open; the continuous variable of early cumulative yield to 80, 100, 120, or 140 d; and a random residual effect. As days open during first lactation increased from 30 to 100 d, 305-d milk yield increased by 876 kg; as days open increased from 100 to 200 d, milk yield increased by only 172 kg. The impact of current days open was greater on second lactation than on first; the difference in 305-d milk yield between cows open 40 and 290 d was 1199 kg for first lactation and 1613 kg for second lactation. If early yield to 120 d was included in the model, the corresponding difference was reduced to 860 kg for first lactation and 1001 kg for second lactation. Inclusion of early yield in the model reduced regression coefficients for days open during first lactation by 22% for 80-d yield, 24% for 100-d yield, 27% for 120-d yield, and 30% for 140-d yield and by 31, 35, 38, and 41%, respectively, for second lactation. Statistical models to derive adjustment factors should account for early lactation yield so that those factors can remove effects of pregnancy but not correlations between yield and fertility caused by early yield.
Implementing a quality assurance program using a risk assessment tool on dairy operations. Concerns and perceptions about antibiotic residues in milk prompted the dairy industry to develop a voluntary program to support rational antibiotic use on dairy farms. One deficiency of this program is the inability of producers to identify easily the weaknesses in antibiotic management in order to develop control plans. To overcome this deficiency, an educational approach was designed. The program centered on an on-farm risk assessment tool used by the producer and an industry educator to determine the current risk for residue violation. The risk assessment tool was tested by 25 field personnel working with northeastern milk receivers and 250 producers in seven states. The participants in the study identified a lack of adequate treatment records as being the highest risk factor for antibiotic residues, followed by deficiencies in understanding how to use antibiotics and poor relationships between veterinarians and their clients. When field representatives utilized the risk assessment tool, for most producers, risk of antibiotic residue decreased by approximately 19%. In particular, more farms kept written records or more complete records. Finally, producers with reported histories of antibiotic residues were less likely to implement management changes to reduce the risk of antibiotic residue.
A non-invasive method for studying in vivo carpal kinematics. Seven uninjured and three injured patients were studied using midsagittal computed tomographic (CT) images at 10 degrees increments from full extension to full flexion. Each injured patient had a confirmed scapholunate ligament tear and normal radiographs. CT bony contours were digitized, and incremental motion determined using a specifically designed automated contour-matching algorithm. We expressed wrist motion as a ratio of lunocapitate (midcarpal) motion, and radiolunate (radiocarpal) motion. In normal wrists, motion occurred equally at the midcarpal and radiocarpal joints. In wrists with scapholunate ligament disruption, lunocapitate motion increased significantly throughout the arc of motion.
Activity of selected antimicrobial agents against strains of Staphylococcus aureus isolated from bovine intramammary infections that produce beta-lactamase. The activity of selected antimicrobial agents was determined against strains of Staphylococcus aureus that were isolated from bovine intramammary infections and that were positive or negative for beta-lactamase. A total of 107 S. aureus strains (70 that were positive for beta-lactamase and 37 that were negative for beta-lactamase) were used in the study. Production of beta-lactamase was determined using a chromogenic cephalosporin disk method. Minimum inhibitory concentrations (MIC) for each test strain were determined using a commercially available microdilution panel. The following compounds were tested: penicillin, ampicillin, oxacillin, cephapirin, ceftiofur, penicillin plus novobiocin, erythromycin, and pirlimycin. Of the five beta-lactam compounds tested, penicillin and ampicillin were most affected by beta-lactamase activity, but oxacillin, cephapirin, and ceftiofur were not affected. Penicillin plus novobiocin also demonstrated excellent activity against strains of S. aureus that were both positive and negative for beta-lactamase. Erythromycin and pirlimycin demonstrated good activity against the S. aureus strains that were negative for beta-lactamase; 90% of the isolates had an MIC of < or = 0.5 microgram/ml (MIC90). The MIC90 for erythromycin and pirlimycin for strains that were positive for beta-lactamase was > 64.0 micrograms/ml. However, 8 strains, in addition to producing beta-lactamase, were also resistant to macrolides and lincosaminides. Recalculation of the MIC90 without these 8 strains yielded equivalent values for both erythromycin and pirlimycin with strains that were positive or negative for beta-lactamase (MIC90 < or = 0.5 microgram/ml).
Experience with scaphoid grafting. Over a period of 24 years, the author has used five different methods of bone-grafting for ununited scaphoid fractures. The clinical and radiological results have been reviewed, with a minimum follow-up of 1 year. Radiologically the best results (78% definite union) were obtained with a "wedge" graft and Herbert screw, while the worst results followed the original Russe operation. The clinical result often did not coincide with the radiological outcome. All methods led to a decrease in pain in most cases, but little or no pain was achieved most often by the modified Russe graft. With proximal pole fractures, bony union was only achieved in 54% but the symptoms were always lessened.
Registration bone scan in the evaluation of wrist pain. We assessed the value of bone scintigraphy combined with X-ray registration for the diagnosis and management of wrist pain in 65 patients. Studies were reported independently by two observers before and after registration. Registration improved localization of scan abnormalities in 53% (observer 1) and 61% (observer 2). In these patients, the bone scan contributed to the diagnosis independently of the X-ray in 37% and the management was altered in 31%. The value of the bone scan in the early diagnosis and management of wrist pain is increased when it is registered with X-rays.
Congenital fusion of the scaphoid, trapezium, trapezoid and capitate. We describe an unusual case of carpal coalition in an otherwise asymptomatic 28-year-old man. The combination of scaphoid, trapezium, trapezoid and capitate fusion detailed in this article has not, to the best of our knowledge, been previously recorded.
Bilateral transscapholunate dislocations. Bilateral transscapholunate dislocations were treated with immediate open reduction and internal fixation. Eighteen months after injury the patient was asymptomatic.
Scapholunate dissociation in the skeletally immature carpus. Scapholunate dissociation is well documented as a condition occurring in adult patients. We report it in a 14-year-old female patient. Persistent wrist pain 9 months after a well healed fracture of the distal radius triggered further investigation. Dynamic clinical and radiological studies demonstrated the instability.
Nonunion of a distal radial fracture in a healthy child. Nonunion of distal radial fractures in children are rare. We report a case of a closed distal radial fracture in a healthy child, which developed a nonunion following closed reduction and plaster immobilization.
Algodystrophy is an early complication of Colles' fracture. What are the implications? One hundred patients who had sustained a Colles' fracture were observed for features of algodystrophy at 1, 5, 9 and 12 weeks following injury. The diagnosis of algodystrophy was possible as soon as 1 week after fracture. Early diagnosis has important clinical implications: the aetiological factors may become apparent and different treatment modalities be identified; furthermore, early treatment can be started, limiting the morbidity of the condition. It is proposed that patients with features of algodystrophy require physiotherapy after a Colles' fracture. Those without features may not.
Anatomical and biomechanical studies of the pathogenesis of trapeziometacarpal degenerative arthritis. An anatomical and biomechanical study of the stabilizing ligaments of the thumb trapeziometacarpal joint was conducted on 32 hand specimens. Five main ligamentous structures could be identified. The mechanical properties (in particular, strength) of the five ligaments using a strain-rate failure test were determined and evaluated quantitatively. The maximum tensile strength of each ligament was correlated with the condition of the trapeziometacarpal articular cartilage. In studying the anterior oblique ligament, maximum strength decreased from Grade 0 to Grade 1 by 51%. With the first intermetacarpal ligament, the drop from Grade 1 to Grade 2 was 53%. With the posterior oblique ligament, the decrease was closely related to the grade of the deterioration of the trapeziometacarpal articular surface. These three ligaments also significantly decreased in strength with age. Our results may suggest that the anterior oblique ligament, intermetacarpal ligament and posterior oblique ligament play a large role in stabilizing the trapeziometacarpal joint and that the decrease in their strength is related to the pathogenesis of trapeziometacarpal osteoarthritis.
Day care surgery for advanced Dupuytren's contracture. Seventy-six consecutive patients suffering from advanced Dupuytren's contracture were analysed in order to evaluate the safety of day care surgery. The complication rates for haematoma, necrosis, infection and reflex sympathetic dystrophy were acceptable, but we found an unacceptably high percentage of nerve lesions. Day care treatment was achieved in all but seven cases. We concluded that advanced Dupuytren's contracture can be treated by day care surgery but the operations should be performed by surgeons who are skilled in hand surgery, and individual selection of patients with recurrence seems advisable.
Skin replacement in Dupuytren's disease. We have reviewed 90 rays in 67 patients who had undergone radical digital dermofasciectomy. Follow-up was from 24 to 100 months. Problems with skin grafts, moving two-point discrimination and active range of joint movement were noted. The recurrence rate in this series was 8%, a very much better figure for disease control than has been reported for standard approaches for Dupuytren's disease. Radical digital dermofasciectomy is strongly recommended for all cases of recurrent Dupuytren's disease requiring reoperation and as a primary procedure when there is significant skin involvement.
A historical record of traumatic rupture of Dupuytren's contracture. Traumatic rupture of Dupuytren's contracture is rare. It has been reported only twice in recent times and only on four previous occasions over the last millenium. These cases are reported and the forces involved in rupturing Dupuytren's contracture are discussed.
The consequences of punching glass. We carried out a retrospective and prospective study of 67 patients who had sustained hand injuries from punching glass over a period of 33 months. All had consumed alcohol and had argued with a partner. The mean age was 25 years, 90% were male and 56% were unemployed. Seventy per cent of injuries occurred between 23.00 and 04.00 hours. Total damage included division of 149 tendons, 33 nerves and nine arteries. Fifty-two per cent of patients required admission for more than 1 day. The mean number of follow-up visits was 3.6 and the majority needed hand therapy and occupational therapy services. Cost per injury was estimated as 1,120 pounds. Such injuries cause major disability in an already disadvantaged section of society. The challenge is to educate the susceptible patient group.
The distally based ulnar artery island flap in hand reconstruction. The distally based ulnar artery island flap is a highly versatile flap for hand reconstruction. It fulfils all the necessary criteria required for a flap to the hand providing thin pliable hairless skin. It can be used as a composite flap including tendon and bone and provides an ideal tunnel for tendons to glide in. It can be used as a fasciocutaneous flap or as a fascial flap and can easily be rotated to the dorsum of the hand by opening Guyon's canal. The palm or dorsum of the hand and even the fingertips can be reached easily. A superficial venous anastomosis should be made if marked venous congestion is noted intraoperatively. Six cases utilizing a distally based ulnar island flap in hand reconstruction are presented.
Improving the results of ganglion aspiration by the use of hyaluronidase. We present the results of a prospective randomized trial comparing the treatment of ganglia by aspiration under local anaesthetic and either instillation of steroid alone or with the prior use of hyaluronidase. Thirty-five patients were treated in each group and followed up for 2 years. The cure rate with the combined use of hyaluronidase and methylprednisolone was 89%, compared to 57% when treated by aspiration and instillation of methylprednisolone alone.
Complications following mucous cyst excision. Eighty-six mucous cysts in 79 patients were surgically excised. Follow-up was carried out at an average of 2.6 years. Fifteen digits (17%) had a residual loss of extension of 5 to 20 degrees at the IP or DIP joints. One patient developed a superficial infection and two developed a DIP pyarthrosis, which eventually required DIP arthrodesis. Nail deformities were present in 25 of 86 digits preoperatively (29%), 15 of which resolved after surgery (60%). Four of 61 digits developed a nail deformity which was not present preoperatively (7%). Three of 86 digits (3%) developed recurrence. Other complications included persistent swelling, pain, numbness, stiffness, and radial or ulnar deviation at the DIP joint. We recommend that patients be informed preoperatively of the potential risks of decreased range of motion, persistent swelling and pain, infection, recurrence, and persistent or postoperatively acquired nail deformity.
The distribution of fibrous flexor sheath ganglions. The distribution of fibrous flexor sheath ganglions was studied in 57 patients. They were found to be more common in the third decade and in the middle finger. Both hands were equally affected. There was no clear relationship to occupation or repeated trauma. The striking finding in our study was the male predominance.
Subungual glomus tumours: a different approach to diagnosis and treatment. Nine cases of subungual glomus tumour in which a transillumination test was used for diagnosis and a different operative technique was used to prevent postoperative nail deformity are described. The transillumination test is a new method for identifying a glomus tumour. With our surgical technique it is simple to approach a glomus tumour under the proximal nail bed and it produces a minimal defect.
The treatment of enchondromas in the hand by endoscopic curettage without bone grafting. Nine patients with enchondromas in the hand were treated by endoscopic curettage of the tumour without bone grafting. The procedure was performed on an out-patient basis using axillary block anaesthesia. New bone formation and remodelling of the lesions were observed in all patients. There were no postoperative fractures, infections, recurrences or other complications. Functional recovery was rapid. We conclude that endoscopic curettage without bone grafting is an effective treatment of enchondroma in the hand.
Enchondroma of the scaphoid. Enchondroma is a common benign cartilaginous tumour which arises from the medullary cavity, most commonly in the phalanges of the hands and feet. Enchondroma involving the carpal bones, however, is rare; only three cases of scaphoid enchondromata and one patient with multiple carpal enchondromata have been reported in the English literature. We report the diagnosis and treatment of a case of scaphoid enchondroma presenting as chronic wrist pain after relatively trivial injury.
Transient bradycardia in a mouse model for the oromandibulofacial limb hypogenesis syndrome following chorionic villus sampling. Amniotic sac puncture carried out on day 13 mouse embryos induces a high incidence of craniofacial and limb abnormalities that resemble the anomalies seen in the oromandibulofacial limb hypogenesis syndrome occasionally encountered following chorionic villus sampling carried out during early human pregnancy. It has been hypothesized that this syndrome probably has a vascular basis, possibly due to hypotension and hypoperfusion of tissues secondary to placental trauma, though no detailed aetiology has so far been described. We have determined embryonic heart rates in control embryos, in embryos at intervals following anaesthesia, and following amniotic sac puncture. An increased duration of bradycardia is seen following this procedure which is not observed in anaesthetic-only controls and in embryos in the contralateral (non-operated) uterine horns. We discuss why the incidence of oromandibulofacial limb hypogenesis syndrome is low following chorionic villus sampling, and propose a possible aetiology for the limb abnormalities seen in this condition.