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Cloning, heterologous expression and antigenicity of a schistosome cercarial protease. A gene coding for the 30 kDa Schistosoma mansoni cercarial protease was amplified using the polymerase chain reaction (PCR) from genomic DNA templates. Cloning and sequencing of several independent PCR clones revealed the presence of an intron additional to the one described in the original cloning of the gene. The 3 exons were cloned into expression vectors so that they could be expressed as separate glutathione-S-transferase (GST) translational fusions. Recombinant bacteria carrying these expression plasmids expressed the fusion proteins at high levels. Western blotting of bacterial lysates with sera raised against the native S. mansoni cercarial protease showed that all 3 exons were recognized. Thus we have produced recombinant bacteria capable of providing large amounts of an S. mansoni antigen for immunological studies and evaluation as a candidate vaccine.
The effects of FaRPs on the motility of isolated muscle strips from the liver fluke, Fasciola hepatica. The effects of a range of FMRFamide-related peptides (FaRPs) on isometric contractility were tested using isolated muscle strips from the liver fluke, F. hepatica. The neuropeptides tested were the molluscan FaRPs, FMRFamide and FLRFamide, the turbellarian FaRPs, RYIRFamide and GYIRFamide, the cestode peptides, NPF and GNFFRFamide, and the nematode FaRPs, AF-1 (KNEFIRFamide), AF-2 (KHEYLRFamide), AF-8 (KSAYMRFamide), and PF-4 (KPNFIRFamide). Dose-response experiments were undertaken at a concentration range of 5 nM-5 microM for all of the neuropeptides tested. FMRFamide and AF-8 caused statistically significant increases in the amplitude and frequency of contractions at concentrations of 0.5 microM and 5 microM. FLRFamide and AF-2 also caused significant increases in contraction frequency at concentrations of 0.5 microM and 5 microM, although a significant increase in amplitude of contraction was observed only at a concentration of 5 microM. GYIRFamide increased both amplitude and frequency significantly at concentrations of 50 nM, 0.5 microM and 5 microM. RYIRFamide significantly increased frequency of contractions at concentrations of 0.5 microM and 5 microM, but failed to have a significant effect on contraction amplitude. AF-1 at a concentration of 5 microM increased contraction amplitude, but failed to have an effect on frequency at any of the concentrations used. PF-4 caused a statistically significant increase in both the amplitude and frequency of contractions at a concentration of 5 microM. NPF and GNFFRFamide had no effect on the in vitro motility of F. hepatica over the range of concentrations tested. The results are discussed in the light of possible structure-activity relationships in the FaRPs tested.
Comparative analysis of the distribution of bradykinin-, GYIRFamide- and neuropeptide F-like immunoreactivities in the monogenean, Diclidophora merlangi. An indirect immunocytochemical technique combined with confocal scanning laser microscopy has been used to demonstrate immunoreactivities to the nonapeptide, RPPGFSPFR (bradykinin, BK) and the endogenous flatworm regulatory peptide, GYIRFamide in the nervous system of the monogenean, Diclidophora merlangi. In addition, a simultaneous double-labelling technique was employed to examine possible co-localization of GYIRFamide- and neuropeptide F (NPF) immunoreactivities, using antisera to the C-terminal nonapeptide-amide of NPF (Moniezia expansa, FAIIGRPRF. NH2). BK immunostaining was restricted to a small population of nerve cells and associated fibres within the ventral nerve cords and to 2 pairs of nerve cells innervating the cirrus and the pharynx, respectively. No immunopositive nerve cells and fibres were identified within the brain or in association with the female reproductive apparatus. In contrast, GYIRFamide staining was abundant throughout the central and peripheral nervous systems, and appeared similar to the staining pattern revealed using an FMRFamide antiserum. GYIRFamide immunoreactivity was localized to nerve cells and fibres within the paired cerebral ganglia and the longitudinal ventral, dorsal and lateral nerve cords and their numerous interconnecting transverse commissures. The plexuses of the buccal suckers, pharynx and clamps of the haptor were strongly immunopositive for GYIRFamide, as were nerve cells innervating the ootype, the oviduct and the vitelline reservoir of the reproductive apparatus. Double-labelling experiments indicated an apparent co-localization of GYIRFamide and NPF immunoreactivities.
Effect of praziquantel and liposome-incorporated praziquantel on peritoneal macrophage activation in mice infected with Mesocestoides corti tetrathyridia (Cestoda). The activation of peritoneal macrophage effector functions after therapy with free PZQ and PZQ incorporated in liposomes (lip.PZQ) was studied in the Mesocestoides corti-mouse model system. Each drug formulation was administered to an infected group of mice in 6 daily doses from day 14 p.i. Phagocytic activity of macrophages increased significantly after the administration of both drug formulations, more after lip.PZQ with an earlier peak observed for PZQ (day 3) than for lip.PZQ (day 6). Empty liposomes had no significant effect. The average counts of ingested particles in phagocytosing cells were significantly higher only after lip.PZQ administration. The pattern of changes in phagocytic activity correlated with the reduction of parasite numbers in the peritoneal cavity, with the highest observed on day 6 after therapy with lip.PZQ. Phagocytosis of lip.PZQ in vivo stimulated significantly the respiratory burst in peritoneal macrophages, with the highest concentration of superoxide anions recorded on day 1 after the last dose, whereas therapy with PZQ itself did not increase this process significantly. The capacity for the respiratory burst declined in all groups with progressing infection. It is proposed that the phagocytic activity of peritoneal macrophages after therapy was stimulated indirectly as a consequence of activation of the specific immune response. The larvicidal effect of lip.PZQ on the tetrathyridia in the peritoneal cavity was synergistic with the phagocytic activity and might be the result of double action of drug and superoxide anions generated during the respiratory burst stimulated by this drug formulation.
Mechanisms of specificity of association between the nematode Steinernema scapterisci and its symbiotic bacterium. We suggest a new mechanism for the maintenance of specificity of the association between the entomopathogenic nematode Steinernema scapterisci and its symbiotic bacteria. We evaluated the development and reproduction of infective and non-infective juvenile S. scapterisci in monoxenic combinations with its symbiotic bacteria, Xenorhabdus sp. 'S' and with the bacterial symbiont of Steinernema carpocapsae and Steinernema riobravis. Although development of non-infective stages occurred on all Xenorhabdus spp., the development of infective juveniles to the 4th stage ('dauer' recovery) was significantly delayed and reduced with X. nematophilus and Xenorhabdus sp. 'R', the bacterial symbionts of S. carpocapsae and S. riobravis, respectively. 'Dauer' recovery improved significantly when the cultures of X. nematophilus and Xenorhabdus sp. 'R' were supplemented with cell-free filtrates from Xenorhabdus sp. 'S'. The infective juvenile S. scapterisci produced in all 3 cultures were virulent to Galleria mellonella larvae, confirming successful retention of Xenorhabdus from other steinernematids in their intestine. In fact, S. scapterisci infective juveniles containing X. nematophilus or Xenorhabdus sp. 'R' were more virulent to G. mellonella than those containing their natural symbiont, Xenorhabdus sp. 'S'. We believe that this is the first demonstration of the symbiont-specific exit of infective juveniles from the 'dauer' phase which represents the finest level of specificity of bacteria-nematode association. This is also the first report of successful isolation of the natural symbiont of S. scapterisci.
Neutral lipids and the assessment of infectivity in entomopathogenic nematodes: observations on four Steinernema species. An 8-point visual index was developed for Oil Red O staining of neutral lipids in infective juveniles (IJs) of Steinernema carpocapsae (A11), S. riobravis (Biosys 355), S. feltiae (UK76) and S. glaseri (NC). The visual index was found to be a reliable and rapid method for determining the relative neutral lipid content of individual IJs and was validated quantitatively by gas chromatography. The relationship between neutral lipid utilization and infectivity of IJs stored in distilled water at 25 degrees C was also investigated and the first quantitative results on neutral lipid utilization in entomopathogenic nematodes are reported. Neutral lipid contents of freshly harvested IJs of S. carpocapsae, S. riobravis. S. feltiae and S. glaseri were 31, 31, 24 and 26% dry wt, respectively. Steinernema carpocapsae showed a sigmoidal pattern for neutral lipid utilization while S. riobravis used neutral lipids at an almost constant rate. Survivorship of these two species ranged between 120 and 135 days, whereas S. feltiae and S. glaseri lived > 450 days and had a slower rate of lipid utilization during a 260 day storage period. Oil Red O staining showed that individual IJs in each population utilized lipids at different rates, even though they had the same initial lipid index. The infectivity of S. riobravis, S. feltiae and S. glaseri declined with lipid utilization. In contrast, S. carpocapsae maintained a high level of infectivity even at relatively low lipid levels. Therefore, neutral lipid content was found to be a suitable indicator of infectivity for S. riobravis, S. feltiae and S. glaseri but not for S. carpocapsae.
Genome sizes of the entomopathogenic nematodes Steinernema carpocapsae and Heterorhabditis bacteriophora (Nematoda:Rhabditida). There is currently no information on the genome size and complexity in the entomoparasitic nematodes Steinernema and Heterorhabditis. DNA reassociation kinetics were used to determine the genome size and complexity in 2 species: Steinernema carpocapsae and Heterorhabditis bacteriophora. C0t curves derived from renaturation kinetics of denatured DNA indicate that the genomes of these entomoparasitic rhabditids are different both in size and complexity. Genome sizes were estimated at 2.3 x 10(8) bp for S. carpocapsae and 3.9 x 10(7) bp for H. bacteriophora and repetitive DNA contents were found to represent 39% and 51% of these respective genomes.
Problems of reproducibility--does geologically ancient DNA survive in amber-preserved insects? Apparently ancient DNA has been reported from amber-preserved insects many millions of years old. Rigorous attempts to reproduce these DNA sequences from amber- and copal-preserved bees and flies have failed to detect any authentic ancient insect DNA. Lack of reproducibility suggests that DNA does not survive over millions of years even in amber, the most promising of fossil environments.
Hemispheric specialization for global and local processing: the effect of stimulus category. Neuropsychological evidence indicates that the global aspect of complex visual scenes is preferentially processed by the right hemisphere, and local aspects are preferentially processed by the left hemisphere. Using letter-based hierarchical stimuli (Navon figures), we recently demonstrated, in a directed-attention task, lateralized neural activity (assessed by positron emission tomography) in the left prestriate cortex during local processing, and in the right prestriate cortex during global processing. Furthermore, temporal-parietal cortex was critically activated bilaterally in a divided-attention task that involved varying the number of target switches between local and global levels of letter-based hierarchical stimuli. Little is known about whether such stimulus categories influence such hemispheric lateralization. We now present data on brain activity, derived from positron emission tomography, in normal subjects scanned during either local or global processing of object-based hierarchical stimuli. We again observe attentional modulation of neural activity in prestriate cortex. There is now greater right-sided activation for local processing and greater left-sided activation for global processing, which is the opposite of that seen with letter-based stimuli. The results suggest that the relative differential hemispheric activations in the prestriate areas during global and local processing are modified by stimulus category.
Pattern formation triggered by rare events: lessons from the spread of rabies. Understanding of large-scale spatial pattern formation is a key to successful management in ecology and epidemiology. Neighbourhood interactions between local units are known to contribute to large-scale patterns, but how much do they contribute and what is the role of regional interactions caused by long-distance processes? How much long-distance dispersal do we need to explain the patterns that we observe in nature? There seems to be no way to answer these questions empirically. Therefore, we present a modelling approach that is a combination of a grid-based model describing local interactions and an individual-based model describing dispersal. Applying our approach to the spread of rabies, we show that in addition to local rabies dynamics, one long-distance infection per 14000 km2 per year is sufficient to reproduce the wave-like spread of this disease. We conclude that even rare ecological events that couple local dynamics on a regional scale may have profound impacts on large-scale patterns and, in turn, dynamics. Furthermore, the following results emerge: (i) Both neighbourhood infection and long-distance infection are needed to generate the wave-like dispersal pattern of rabies; (ii) randomly walking rabid foxes are not sufficient to generate the wave pattern; and (iii) on a scale of less than 100 km x 100 km, temporal oscillations emerge that are independent from long-distance dispersal.
Adaptive changes in Plasmodium transmission strategies following chloroquine chemotherapy. Both theory and data suggest that malaria parasites divert resources from within-host replication to the production of transmission stages (gametocytes) when conditions deteriorate. Increased investment into transmission stages should therefore follow subcurative treatment with antimalarial drugs, but relevant clinical studies necessarily lack adequate control groups. We therefore carried out controlled experiments to test this hypothesis, using a rodent malaria (Plasmodium chabaudi) model. Infections treated with a subcurative dose of the antimalarial chloroquine showed an earlier peak and a greater rate of gametocyte production relative to untreated controls. These alterations led to correlated changes in infectivity to mosquitoes, with the consequence that chloroquine treatment had no effect on the proportion of mosquitoes infected. Treatment of human malaria commonly does not result in complete parasite clearance. If surviving parasites produce compensatory increases in their rate of gametocyte production similar to those reported here, such treatment may have minimal effect on decreasing, and may actually increase, transmission. Importantly, if increased investment in transmission is a generalized stress response, the effect might be observed following a variety of antimalarial treatments, including other drugs and potential vaccines. Similar parasite life history counter-adaptations to intervention strategies are likely to occur in many disease-causing organisms.
The biochemical basis of synaptic plasticity and neurocomputation: a new theory. The recent finding that dendritic spines (on which 90% of all excitatory synapses on pyramidal cells are formed) are not permanent structures but are continually being formed and adsorbed has implications for the present theoretical basis of neurocomputation, which is largely based on the concept of fixed nerve nets. This evidence would tend to support the recent theories of Edelman, Freeman, Globus, Pribram and others that neuronal networks in the brain operate mainly as nonlinear dynamic, chaotic systems. This paper presents a hypothesis of a possible neurochemical mechanism underlying this synaptic plasticity based on reactive oxygen species and toxic 0-semiquinones derived from catecholamines (i) by the enzyme prostaglandin H synthetase induced by glutamatergic NMDA receptor activation and (ii) by reactive nitrogen species derived from nitric oxide in a low ascorbate environment. A key factor in this neuromodulation may be the fact that catecholamines are potent antioxidants and free radical scavengers and are thus able to affect the redox mediated balance at the glutamate receptors between synapse formation and synapse removal that may be a key factor in neurocomputational plasticity. But catecholamines are also easily oxidized to neurotoxic 0-semiquinones and this may be relevant to the pathology of several diseases including schizophrenia. The relationship between dopamine release and positive reinforcement is relevant to this hypothesis.
A novel neuropeptide-endocrine interaction controlling ecdysteroid production in ixodid ticks. Ixodid (hard) ticks are blood-feeding arthropods that require a blood meal to complete each stage of development. However, the hormonal events coordinating aspects of feeding and development are only poorly understood. We have delineated a new neuropeptide-endocrine interaction in the adult tick, Amblyomma hebraeum, that stimulates the synthesis of the moulting hormones, the ecdysteroids. In adult female ticks, ecdysteroid synthesis could be demonstrated in integumental tissue incubated in vitro with a synganglial (central nervous system) extract, but not in its absence. Stimulation by the synganglial extract is both time- and dose-dependent, but is completely abolished by trypsin treatment, suggesting that the activity is due to a peptide/protein. Integumental tissue ecdysteroidogenesis is also stimulated by elevation of the cAMP concentration using forskolin and 3-isobutyl-l-methyl-xanthine, or by 8-bromo-cAMP. This suggests the involvement of at least a cAMP second messenger system in the neuropeptide-ecdysteroidogenesis axis, without precluding a role for other second messengers as well. Despite involving a quite different steroidogenic tissue, the foregoing system has some parallels with the known prothoracicotropic hormone (neuropeptide)-prothoracic gland endocrine axis of insects.
A quantitative comparison of mechanoelectrical transduction in vestibular and auditory hair cells of neonatal mice. Vestibular hair cells (VHCs) and cochlear outer hair cells (OHCs) of neonatal mice were stimulated by a fluid jet directed at their stereociliary bundles. Relations between the force exerted by the jet, bundle displacement, and the resulting transducer current were studied. The mean maximum transducer conductance in VHCs (2.6 nS) was about half that of the OHCs (5.5 nS), with the largest recorded values being 4.1 nS and 9.2 nS, respectively. In some OHCs activity of a single, 112 pS transducer channel was observed, allowing an estimate of the maximum number of channels: up to 36 in VHCs and 82 in OHCs, corresponding to about one transducer channel per tip link. The VHC bundles required about 330 nm of tip displacement to activate 90% of the maximum transducer conductance, compared to 150 nm for the OHC bundles. This corresponded to 2 deg of rotation about their pivots for both, due to the greater length of the VHC bundles. The VHC bundles' translational stiffness was one-seventh of that of the OHCs. Conversion to rotational stiffness almost abolished this difference. Rotation of the hair bundle rather than translation determines the gating of the transducer channels, independent of bundle height or origin of the cells.
Collision-induced dissociation of polyprotonated oligonucleotides produced by electrospray ionization. The efficient production of polyprotonated oligonucleotides, studied at n < or = 19, occurs from water/propan-2-ol solutions over an ammonium acetate concentration range between 2.5 and 40 mm and a pH range from 5 to 11. Average charge-state levels observed were approximately half of those found in mass spectra of polyanionic oligonucleotides, reflecting differences in sites of ionization: heterocyclic bases for protonation and phosphodiester backbone for deprotonation. Collision-induced dissociation mass spectra show three principal reaction paths: (1) release of protonated bases, with abundances dictated largely by base proton affinity; (2) phosphodiester chain cleavage at C3'-O3' indicative of sequence in the 3'-->5' direction; and (3) chain cleavage concomitant with base loss giving furan-type ions indicative of sequence in the 5'-->3' direction, analogous to reactions of polyanionic oligonucleotides. Thymine residues undergo very little protonation, resulting in characteristic absence of phosphodiester cleavage on the 3' side of T sites, producing mass-ladder gaps representing dinucleotides.
Profiling peptide adducts of oxidized N-acetyldopamine by electrospray mass spectrometry. Phenolic and catecholamine polymers are common constituents of many biological systems. Cross-linking of polyphenols with other phenols, peptides, proteins and carbohydrates results in the synthesis of complex natural products which are not easily characterized. Electrospray mass spectrometry (ES-MS) and tandem mass spectrometry (ES-MS/MS) were used to identify polymers of oxidized N-acetyldopamine (NADA) and peptide adducts with oxidized NADA. Following incubation with mushroom tyrosinase, NADA adducts of trityrosine were identified. It was not possible to locate the site of NADA binding to this tripeptide. Compounds formed by incubation of N-acetylhistidine and N-acetyllysine with oxidized NADA, previously characterized using classical chemical techniques, were confirmed using ES-MS/MS. The peptide angiotensin (DRVYIHPFHL) was used as a model substrate to determine whether the site(s) to which oxidized NADA bound could be determined. The lot of angiotensin used was contaminated with a peptide of mass 14 u greater than angiotensin, and it was found that the H in position 9 of the contaminant peptide was modified. ES-MS/MS of the angiotensin and the contaminant peptide following incubation with oxidized NADA revealed that the C-terminal aspartic acid was the primary amino acid to which NADA adducts were covalently bound, but other residues were also modified. Femto-molar sensitivity for analysis of complex mixtures of catecholamine-peptide adducts will facilitate structural elucidation of natural products not amenable to characterization using other spectroscopic techniques.
Effect of cyclodextrins on the hydrolysis of an oxazolidine prodrug of (1R,2S)-(-)-ephedrine-cis-2-(4-methoxyphenyl)-3, 4-dimethyl-5-phenyloxazolidine. Molecular complexes of an oxazolidine prodrug of (-)-ephedrine, cis-2-(4-methoxyphenyl)-3,4-dimethyl-5-phenyloxazolidine, with alpha-, beta-, dimethyl-beta- (DM-beta-) and hydroxypropl-beta- (HP-beta-) cyclodextrins (CDs) were examined using ionspray mass spectrometry. The results suggest, under our experimental conditions, a 1:1 stoichiometric complex between the prodrug and all CDs. Apart from the putative inclusion complexation, the stabilization effect of CDs on the prodrug in an aqueous solution was studied. beta-, DM-beta- and HP-beta-CD exhibited a retardation effect on the rate of hydrolysis of the prodrug. Conversely, alpha-CD did not alter the rate of hydrolysis even at excess concentrations. Presumably, the larger cavity diameter of beta-CDs may permit a greater depth of penetration of the prodrug, resulting in its shielding from hydrolysis. The observations in this work indicate that mass spectrometry could be a rapid and informative analytical method to aid in the preliminary evaluation of the potential utility of CDs in enhancement of drug stability.
Influence of solvents and detergents on matrix-assisted laser desorption/ionization mass spectrometry measurements of proteins and oligonucleotides. The effect of solvents was found to be critical for sample preparation in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). For proteins and oligonucleotides the use of 2-propanol/water as a solvent for different matrices can significantly improve the quality of spectra. This effect is demonstrated with proteins ranging in molecular weight from 12 to 150 kDa and with a special 19-mer oligonucleotide. A comparison of MALDI-MS using of 2-propanol as matrix solvent and high-performance capillary electrophoresis resulted in identical relative peak intensities for a p(dT)12-18 oligonucleotide mixture. Additionally, the effect of detergents for characterization of high molecular weight proteins in very dilute solutions was studied with this solvent. It was found that Triton X-100, up to a concentration of 1%, was highly compatible with MALDI measurements and even could improve the quality of spectra. Use of detergents for cell profiling has extended the detectable mass range to about m/z 75,000.
Isolation and characterization of proteins from human lymphocyte nuclei using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and post-source decay analysis. The cell nucleus plays an essential role in all aspects of cell function, including DNA replication, gene transcription, RNA processing and cell division. Within the cell nucleus there are many proteins and peptides that have regulatory roles. Although several higher molecular weight protein components (> 30 kDa) have been identified and characterized, limited information is available for the lower molecular weight components. Nuclei from human peripheral blood lymphocytes were isolated and rapidly characterized by employing a strategy using reversed-phase high-performance liquid chromatography, tryptic digestion, and post-source decay analysis of matrix-assisted laser desorption/ionization (MALDI) ions in combination with database searches. Database searches utilizing molecular weight, proteolytic digest fragments, and peptide sequence results identified known proteins. The results illustrate the usefulness of MALDI as a tool in the characterization of low abundance proteins in the cell nucleus.
A highly specific method for the characterization of glycation and glyco-oxidation products of globins. A new method, based on matrix-assisted laser desorption/ionization (MALDI) measurements, has been developed for the evaluation of the glycation level of globins, a relevant parameter for diabetes control. It shows high levels of reproducibility and specificity, allowing the different glycated and glyco-oxidized products of both alpha- and beta-globins to be distinguished. Such specificity is reflected in its possible diagnostic use not only for the control of diabetes, but also for the occurrence of 'oxidative stress'. The comparison, for the same samples, of the obtained MALDI data with the related HbA1c values, determined by a high performance liquid chromatographic method, allowed it to be established that HbA1c percentages are not, as usually retained, related to the simply glycated beta-globin, but to the whole pool of glycated and glyco-oxidized alpha- and beta-globins.
Mass spectrometry in the study of non-enzymatic glyco-oxidation of proteins. Studies that have been performed by MALDI mass spectrometry in the field of non-enzymatic protein glyco-oxidation are briefly reviewed. The results obtained by in vitro and in vivo experiments demonstrate the power of this technique, which is able to give information on the number of sugar molecules condensed on specific proteins and, consequently, represents a new and specific diagnostic tool in diabetes control.
Exogenous heparin induces fibronectin overexpression parallel to angiogenesis in the extracellular matrix of the chick embryo chorioallantoic membrane. Heparin (HE) was injected into the allantoic sac of chick embryo eggs on the 5th day of incubation. After 48 h, a morphometric analysis of angiogenic response and an immunohistochemical investigation of fibronectin (FN) and type IV collagen immunoreactivity in developing vasculature were performed in order to verify whether HE-related choriollantoic membrane (CAM) angiogenic activity was associated with overexpression of FN and/or type IV collagen changes in CAM extracellular matrix. Data to be presented show a close relationship between HE treatment, angiogenic processes, and overexpression of FN, but not of type IV collagen in CAM extracellular matrix. They agree with other studies proving a facilitating role of FN in angiogenic processes.
Collagen type VI is a component of the extracellular matrix microfibril network of the prostatic stroma. Stroma-epithelium relationships are of great relevance in prostatic morphogenesis and physiology. However, little knowledge exists about either stromal cells or extracellular matrix composition and arrangement in this system. Ultrastructural analysis revealed the existence of a microfibrillar system which occupies large areas of the rat prostatic stroma. In this work, we have applied immunocytochemistry and an ATP treatment for the ultrastructural identification of collagen type VI microfibrils, aiming at examining its participation in the prostatic microfibrillar network. Immunocytochemistry was also extended to a human case of prostatic nodular hyperplasia. Both methods succeeded in identifying collagen type VI in the rat ventral prostate. Collagen type VI is evenly distributed throughout the stroma but mainly associated with the basal lamina, collagen fibrils, and around the stromal cells. The use of ATP treatment allowed for the discrimination between collagen type VI and elastin-associated microfibrils, and demonstrated that these two classes of microfibrils establish an extended, mixed, and open network. The same aspects of association with the basal lamina, with stromal cells (particularly with smooth muscle cells), and with fibrillar components of the stroma were observed in the human tissue. We suggest that the collagen type VI and elastin-associated microfibril system may be involved in the control of some aspects of cellular behavior and may also play a structural role, maintaining the organ integrity after the deformations occurring under smooth muscle contraction.
The polycystic ovarian (PCO) condition: apoptosis and epithelialization of the ovarian antral follicles are aspects of cystogenesis in the dehydroepiandrosterone (DHEA)-treated rat model. This investigation was designed to study apoptosis and epithelialization during cystogenesis of the dehydroepiandrosterone rat model. Using in situ DNA 3'- end-labeling with non-radioactive digoxigenindidesoxy-UTP (dig-ddUTP), apoptosis is initially seen in cumulus granulosa cells and other granulosa cells facing the antrum. During cystogenesis, apoptosis systematically progresses from the cumulus towards the mural granulosa layer. In contrast, granulosa cells of atretic follicles undergo apoptosis in a random manner. The outer layer of mural granulosa cells during cystogenesis escapes apoptosis. Granulosa cells contain vimentin. However, the outer mural granulosa cell layer that lines the cyst acquires keratin. In addition to being associated with each other via gap junctions, the outer layer of granulosa cells acquire tight junctions. With the characterization of the transformation of the outer mural granulosa cells into a characteristic epithelium and the orderly progression of apoptosis, we further the understanding of the multifaceted process of cystogenesis of the ovarian antral follicle.
Ultrastructure of cholesterol gallstones as observed by electron microscopy after freeze-fracturing. The ultrastructure of cholesterol gallstones (mixed type) was studied in detail for the first time under the transmission electron microscope after freeze-fracturing. Gallstones consisted essentially of cholesterol crystals, some impurities, and fluid. In accord with the theoretical 3.4 nm bilayered structure of cholesterol crystals, 3-4 nm periodicity of crystal layering was observed. However, gallstone cholesterol crystals were not perfect and often showed structural defects. Between crystals, complete edge-to-surface, edge-to-edge and surface-to-surface adhesions, and overall block-like aggregations were found. These may represent the structural basis for the stability of cholesterol crystal aggregation. The easy breakdown of cholesterol gallstones by extracorporeal shock wave lithotripsy is discussed in relation to their ultrastructure.
Immunohistochemical localization of serotonin, galanin, cholecystokinin, and methionine-enkephalin in adrenal medullary cells of the chicken. The identification of adrenaline- (A) and noradrenaline- (NA) containing cells in the adrenal medulla of the chicken and colocalization of serotonin and neuropeptides with A or NA in medullary cells were investigated with the use of immunohistochemical methods. Antisera against tyrosine hydroxylase and phenylethanolamine-N-methyltransferase were used as markers for catecholamine- and A-synthesizing cells, respectively. About 70% of catecholamine-synthesizing cells also exhibited immunoreactivity for phenylethanolamine-N-methyltransferase antiserum. Therefore, these cells are A-containing ones and the rest of cells seem to be NA-containing cells. Immunoreactivity with serotonin antiserum was observed in almost all medullary cells. Galanin-immunoreactivity was also found throughout the adrenal medulla, but was stronger in A-containing cells than in NA-containing ones. Cholecystokinin-immunoreactivity was restricted to A-containing cells. Methionine-enkephalin-immunoreactivity was seen in both A- and NA-containing cells, but in about half of medullary cells. From these results, it is suggested that serotonin, galanin, cholecystokinin, and methionine-enkephalin may be co-released with A and/or NA from adrenal medullary cells of the chicken.
Conditions for the culture of bovine embryonic myogenic cells. The objective of this experiment was to determine the growth characteristics of bovine embryonic muscle cells and to optimize the growth conditions for these cells using commercially-prepared media and sera. In the first study, the growth of muscle cells isolated from the hindlimb was determined by measuring DNA content. The DNA concentration was lowest (P < 0.001) at 24 h post-plating and increased to a maximum at approximately 60 h. The slopes of creatine kinase activity and fusion index curves were similar to the DNA; however, the creatine kinase activity achieved a maximum at 140 h post-plating, while the fusion index reached maximum at 120 h. In the second study, cells were cultured on different substrata, either plastic, gelatin, or collagen. There were no differences (P > 0.05) in the cell growth rates for any of the three substrata. In the third study, cells were grown in 10% fetal bovine serum (FBS) and either a balanced salt solution (BSS; 30 mM Hepes, 10 mM glucose, 120 mM NaCl, 2.5 mM Na2HPO4, and 3 mM KCl), McCoy's 5A, Dulbecco's Minimal Essential Medium/Ham's F12 (DMEM/F12), or 70% DMEM/20% M-199. Cell numbers adhering to the plate at 26 h post-plating were different (P > 0.001) between each medium (DMEM/M-199 > McCoy's 5A > DMEM/F12 > BSS). Cell proliferation rates for each treatment medium were greatest for DMEM/M-199, followed by McCoy's 5A, DMEM/F12, and BSS. Cell differentiation was highest (P < 0.05) in the DMEM/F12, followed by McCoy's 5A, DMEM/M-199, and BSS. In the final study, the cells were treated with different sources of serum added at 10% to DMEM/M-199. The sera consisted of FBS, newborn calf serum (NCS), horse serum (HS) and iron-supplemented calf serum (Fe(2+)-CS). The cells were added to each well at 10(4) cells. At 24 h post-plating, the serum-free, NCS, and FBS-treated cell numbers were greater (P < 0.05) than the cells treated with HS or Fe(2+)-CS, which may reflect the efficient adherence to the surface or faster adaptation to the serum by the cells. The proliferation rate was greatest (P < 0.001) for the cells treated with Fe(2+)-CS, followed by FBS = NCS, HS, and no serum. Therefore, the muscle cells obtained from bovine embryos grow and differentiate similar to muscle cells from other species. The optimal growth medium for growing these cells in vitro is DMEM/M-199 plus 10% Fe(2+)-CS, while the optimal differentiation medium is McCoy's 5A.
Impala, Aepyceros melampus, platelets: count, morphology, and morphometric observations. There is little published information regarding the platelets of impala (Aepyceros melampus). In this study we determined the platelet counts of 12 healthy adult male impalas and describe the morphology of the platelets. The platelet counts of the animals are high. Although the platelets appear to be extremely small, they have the characteristic ultrastructure of the platelets of the family Bovidae. They have few but prominent alpha-granules. Other cytoplasmic inclusions are the dense bodies, microtubules, mitochondria, and glycogen. There is no surface-connecting canalicular system present.
Determination of the unit size of the corneal endothelial cell mosaic from Fourier component image analysis. Scanning electron micrographs were taken of the central region of the corneal endothelium of cows (Holstein). The cells were outlined and an image overlay generated of approximately 100 cells. Via a Windows-based scanning system, the overlay was subjected to a two-dimensional Fourier transform on a Unix-based system. A custom algorithm was developed (IRIS) to sequentially analyse the Fourier transform pattern. The transform and resultant harmonics spectrum were compared to those obtained from artificial cell mosaics generated from uniform sized symmetrical hexagons. The position, width, and height of the 1st harmonic component of the frequency distribution appears to be derived from average cell-cell border distances across the image. The radial position of the 1st harmonic is inversely related to the unit cell size in the mosaic, i.e. the dominant cell size. The application of such techniques to cell mosaic analyses is discussed.
Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Markers for the division-competent cells in mammary gland epithelium are important to the understanding of normal and neoplastic mammary epithelial growth and architectural maintenance, but have been difficult to reveal. Using the presence of condensed chromosomes as an indicator of division competence, we have described morphological markers in the nucleus and cytoplasm that reliably characterize two sets of structurally-distinct, division-competent cells in murine (i.e. mouse and rat) mammary epithelium. The markers, based, in part, on cell size, nuclear and cytoplasmic staining characteristics, and distinctive morphological features of the nucleus and cytoplasm allow classification of the division-competent cells into two categories: 'large light cells' and 'small light cells'. Based on the degree of cytoplasmic organelle differentiation, the small light cells are the least differentiated cells in the epithelium, and the large light cells appear, structurally and functionally, to be in the early stages of secretory differentiation. We demonstrate, using statistical analysis of cell counts (per unit area of epithelium) from four stages of mammary epithelial growth, that there are, in fact, three division-competent cell populations in the rat mammary epithelium, and that the large light cell is a direct precursor to terminally differentiated cells, both secretory and myoepithelial. Using our results we synthesize a morphological model of cell mitosis and the progression of epithelial differentiation in murine mammary gland from a stem cell through two progenitors.
Body image disturbances and their change with videofeedback in anorexia nervosa. Disturbance in the way the body is experienced is a diagnostic criterion for anorexia nervosa, and impedes recovery. A method relatively free of external prompts, to reduce the potential for experimentally induced biases, evaluated body image distortions (BID) in 18 patients with anorexia nervosa soon after admission to an inpatient unit, and 18 normal controls, before and after a videofeedback session. The BID were assessed in the affective and self/social domains by visual analogue scales in which the instructional set oriented subjects to (a) the sensation of fatness (Affective Response, AR), and (b) size compared with other young women (Comparative Size Response, CSR). The AR and CSR were significantly greater than normal in anorexia but decreased significantly with videofeedback, while values for controls were stable. The AR and CSR were only partially independent, indicating overlap of the domains. In anorexia only, the responses were related to two DSM-IV diagnostic criteria for anorexia, fear of gaining weight and health-weight concerns, as well as to drive for thinness and body dissatisfaction. Fear of gaining weight occupied a central position in determining the magnitudes of BID and the other measures, including anxiety and depression.
Underprediction of pain in children undergoing ear piercing. Ear piercing is a brief, standard, painful stimulus which is submitted to voluntarily, offering a unique opportunity for research on children's anticipation of pain in a naturalistic context. Self-ratings on visual analogue scales of fear, predicted pain, and experienced pain were collected, as each ear was pierced in turn, from 32 girls aged 5-11 yr. Of these, 69% underpredicted their pain on the first ear. These underpredictors of pain on the first ear expected and reported significantly greater pain when the second ear was pierced than did overpredictors or children who accurately predicted the pain for the first ear. Fear scores taken before the first ear was pierced did not significantly predict pain for the second ear. Younger children made less accurate predictions and were more likely to use the extremes of the scale. The results, which are consistent with those of previous studies of prediction of pain and anxiety, have implications for preparation of children for brief procedural pain: they support recommendations to encourage children to expect realistic rather than minimal amounts of pain.
Looming vulnerability to spreading contamination in subclinical OCD. The present study examined the hypothesis, stimulated by the looming vulnerability model of anxiety (Riskind, in press, Behaviour Research and Therapy), that subclinical OCD is associated with a subjective sense of looming vulnerability. One-hundred and four undergraduates rated vignettes of common, everyday situations involving exposure to possible dirt, germs, or contamination. Participants in a subclinical obsessional group had a far higher sense of looming vulnerability to spreading contamination than did those in a control group. Results verified that the subjective sense of looming vulnerability still had separate, distinct and significant contributions to fear-of-contamination symptoms, with the effects of cognitive appraisals of other aspects of threat (such as probability of harm, or lack of control) removed. In contrast, these other cognitive appraisals had no significant associations with symptoms that proved to be independent of the subjective sense of looming vulnerability. A path analysis further explored the dependency of these other cognitive appraisals on looming vulnerability. This analysis found that part of the effects of the subjective sense of looming vulnerability on fears may be indirect and mediated via correlated effects of other cognitive appraisals.
Covariation bias for phylogenetic versus ontogenetic fear-relevant stimuli. In the present study, two groups of 21 subjects with either high or low fear of both snakes (or spiders) and damaged electrical outlets/appliances participated in a two phase experiment. After reading a description of an illusory correlation experiment, subjects were asked to imagine themselves participating in it. They rated their expectations for the number of occasions on which slides of snakes, electrical outlets, and flowers would be followed by either a shock, tone, or nothing. As predicted, both high and low-fear subjects reported an expectancy bias for both phylogenetic and ontogenetic fear-relevant stimuli and shock. In the second phase subjects were actually exposed to the random slide/outcome presentation. Only high-fear subjects demonstrated a covariation bias which was specific to phylogenetic fear-relevant slides and shock, indicating all other biases were effectively attenuated.
Excessive responsibility in obsessional concerns: a fine-grained experimental analysis. Excessive responsibility has been suggested as a central cognitive variable associated with Obsessive-Compulsive Disorder (OCD) (Rachman, 1993, Behaviour Research and Therapy, 31, 149-154; Salkovskis, 1985, Behaviour Research and Therapy, 23, 571-583; Salkovskis, 1989, Behaviour Research and Therapy, 27, 677-682; Salkovskis, 1995, Current controversies in the anxiety disorders). Several studies using questionnaires (e.g. Rhéaume, Freeston, Dugas, Letarte & Ladouceur, 1995, Behaviour Research and Therapy, 33, 785-794) and experimental manipulations (Ladouceur et al., 1995, Behaviour Research and Therapy, 33, 937-946; Lopatka & Rachman, 1995, Behaviour Research and Therapy, 33, 673-684) have shown evidence for such a link between responsibility and obsessive-compulsive symptoms. Responsibility has been defined as the belief of possessing a pivotal power to provoke or preventing crucial negative consequences (Salkovskis et al., 1992 cited in Salkovskis, 1995, Current controversies in the anxiety disorders). This definition emphasizes two related cognitive distortions: personal influence and potential negative consequences. The respective roles of each component and their potential interaction need to be clarified. The present study tests the effects of an experimental manipulation of both influence and negative consequences on perceived responsibility and checking behavior during a classification task. Seventy-seven subjects were divided into four experimental conditions: the Combined condition, the Influence condition, the Negative Consequences condition and the Control condition. After the experimental manipulation, subjects from each condition had to classify capsules in semi-transparent bottles. Results showed that personal influence is the best predictor of perceived responsibility. Although increased potential negative consequences were sufficient to trigger hesitations, combined influence and negative consequences were necessary to produce modifications. These results are consistent with the results obtained by the questionnaires (e.g. Rhéaume, Ladouceur, Freeston & Letarte, 1995a, Behaviour Research and Therapy, 33, 159-169) and previous manipulations (e.g. Ladouceur et al., 1995).
Scholastic impairments among traumatized adolescents. This investigation sought to determine if exposure to exceptional stress is associated with academic deficits or whether academic deficits are specifically associated with post-traumatic stress disorder (PTSD). In order to address these questions, the Metropolitan Achievement Test (MAT) as well as a measure of intelligence were administered to three groups of Lebanese adolescents. The first group met diagnostic criteria for PTSD. The second group had been exposed to qualitatively and quantitatively similar stressors but did not meet diagnostic criteria for PTSD. The third group consisted of nontraumatized controls. Data analysis using IQ as a covariate determined that the MAT scores of the PTSD subjects were significantly lower than the scores of the stress exposed PTSD negatives and controls. No significant differences were observed when the MAT scores of the stress exposed PTSD negatives and controls were compared.
Expectancy variables predicting tolerance and avoidance of pain in chronic pain patients. Previous research on anxiety and some recent reports on chronic pain suggest that the response to aversive stimuli may be influenced by expectations rather than actual experience. This study examined the contributions of four expectancy-related variables to the tolerance and avoidance of pain: pain expectancy, response expectancy, self-efficacy expectancy, and danger expectancy. Chronic pain sufferers volunteered to undergo cold pressor pain on two trials (the first for practice, and the second to determine tolerance) and then faced the prospect of a third trial (to determine avoidance). It was found that expected tolerance (or response expectancy) significantly predicted actual tolerance, whereas expected danger significantly predicted avoidance. These findings are in partial agreement with previous research. Among the clinical implications are that chronic pain sufferers generally associate pain with damage and they predict their pain tolerance well; they do not necessarily escape from a compulsory activity that produces pain, but given the chance they would rather avoid it in the first place.
Primary obsessional slowness: long-term findings. Cases of slowness among patients who spent large amounts of time to perform daily activities were first reported in 1974, and described as primary obsessional slowness (POS). It was observed that it was neither obsessive thoughts nor compulsions that directly hindered their daily activities. However, in more than 20 years following the original report, the diagnostic independence of POS remains controversial, some insisting that obsessional slowness can be explained as secondary. The authors experienced four cases in Japan which share the same characteristics as the original cases. Long-term observation and treatment has led us to support the diagnostic independence of POS. Slowness remained after other accompanying symptoms of obsessive-compulsive disorder had been successfully treated, showing that the slowness of our patients was not secondary.
Information processing in anxiety and depression. Performance on explicit and implicit memory tasks was compared among non-clinical participants (N = 47) who reported low anxiety and low depression, high anxiety and low depression, or high anxiety and high depression. No differences were found among the groups in explicit memory. Differences in our measure of implicit memory were attributable to higher anxiety, regardless of depression. Increased implicit memory was specific to personally relevant information. The study highlights the need for further exploration of information processing in mixed anxiety and depression.
The Blood-Injection Symptom Scale (BISS): assessing a structure of phobic symptoms elicited by blood and injections. Assessments for blood-injury-injection phobia measure feared stimuli and overt behaviours, but they have not systematically addressed the symptoms of fear and faintness. The Blood-Injection Symptom Scale (BISS) was developed to overcome this omission. An exploratory factor analysis grouped symptoms triggered by blood and injections into three internally consistent factors (faintness, anxiety and tension). A confirmatory factor analysis replicated the factor structure in a new sample. To test the construct validity of the BISS, an attempt was made to reproduce Ost's (1992, Journal of Abnormal Psychology, 101, 68-74) finding that fear was stronger among people with concerns about injections, while faintness was stronger among people with concerns about blood. A community sample of 80 individuals with concerns (i.e. fear or fainting) about blood or injections completed the BISS. Controlling faintness, individuals with concerns about injections reported more fear than people with concerns about blood. In contrast, controlling for fear, the latter reported more symptoms of faintness. These data suggest that the BISS generates stable and internally consistent subscales useful in the measurement of symptoms elicited by blood and injections.
Measurement of antecedents to drug and alcohol use: psychometric properties of the Inventory of Drug-Taking Situations (IDTS). The development, factor structure, and validity of the Inventory of Drug-Taking Situations (IDTS) is described. This 50-item self-report questionnaire, which is an extension of the Inventory of Drinking Situations (Annis, 1982. Inventory of drinking situations; Annis, Graham & Davis, 1987, Inventory of drinking situations (IDS): User's guide), is designed to assess the situational antecedents to use of a wide range of drugs of abuse. The IDTS consists of 8 subscales that measure a client's substance use in the 8 situations identified in the work of Marlatt (1978, Alcoholism: New directions in behavioral research and treatment): Unpleasant Emotions, Physical Discomfort, Pleasant Emotions, Testing Personal Control, Urges and Temptations to Use, Conflict with Others, Social Pressure to Use, and Pleasant Times with Others. Reliability, factor structure and validity of the IDTS were assessed on 699 clients admitted to the Addiction Research Foundation's treatment facility in Toronto. The IDTS was shown to have reliable subscales. The IDTS total score correlated with self-ratings of the severity of the clients' substance use problem, and with retrospective reports of frequency of use (drugs) and quantity of use (alcohol), years of usage, and severity of dependence. Confirmatory factor analysis was used to test the fit of the data to Marlatt's model of substance use situations, as well as to several alternative models. The goodness-of-fit indicators suggested that the best fit for the data was an 8-factor model corresponding to the 8 subscales based on the Marlatt categories. Evidence was presented that the 8 subscales can be further grouped into 3 second-order factors: (1) negative situations, (2) positive situations, and (3) temptation situations. The negative situation subscales of Unpleasant Emotions, Conflict with Others and Physical Discomfort were found to be correlated with the SCL-90R Depression scale. Interpersonal Sensitivity scale and Somatization scale respectively. The positive social situation subscales of Pleasant Times with Others and Social Pressure to Use were found to be negatively correlated with percentage of time using alone, and positively correlated with pressure from friends and family to use. On the States of Change Readiness and Treatment Eagerness Scales (SOCRATES), clients at the precontemplation stage of change had relatively flat, undifferentiated IDTS profiles (i.e. little scatter of subscale scores), whereas clients in the determination stage had the most differentiation in their IDTS subscale scores. Excellent comparability was found for alcohol clients between the IDS and the IDTS. Evidence was also presented for adequate comparability between the computer and paper and pencil administrative formats of the IDTS.
The evolution of adjustment issues in HIV/AIDS. The issues of emotional adjustment to AIDS have been inextricably linked to medical advances in fundamental knowledge about the human immunodeficiency virus and its potential therapies. In 1987 patients were struggling with the advantages and disadvantages "to do or not to do AZT (zidovudine)," whereas the choices imposed by combination therapies and the protease inhibitors in 1997 are fundamentally different and are occurring in an evolving context created by a number of striking medical advances, expanding populations, the availability of environmental support, and changing public sentiments. As the psychiatric treatment of HIV-positive individuals shifts increasingly from "AIDS specialists" to the wider therapeutic community, it is important that the therapist who has had relatively little experience with this population not assume that contemporary issues and concerns of the seropositive patient, or the patient with AIDS, are essentially those discussed widely in the earlier years of the epidemic. Patients living with this virus for a number of years have traveled a long and arduous journey and will experience more empathy from a therapist who has some knowledge of that path. Awareness of the evolution of emotional adjustment, counseling, and ethical issues of AIDS should amplify the general fund of knowledge required for good clinical management of the person living with AIDS.
Contemporary treatment of schizophrenia. Over the past decade the treatment of schizophrenia has changed in each of its biopsychosocial domains. Advances in neuroscience, particularly in the knowledge of the receptor site, led to increased effectiveness of antipsychotic medication. Development of more sophisticated psychoeducational and rehabilitative techniques enhanced the chances for fuller recovery. Evolution from therapeutic community to continuum of care replaced the traditional inpatient setting with a range of more ambulatory-based alternatives. Comprehensive treatment matches these changes with the phase of illness and is reinforced with a flexible and supportive psychotherapy that emphasizes medication compliance and educational and problem-solving tasks.
A psychoeducational program for patients with trauma-related disorders. The authors describe the development and implementation of a psychoeducational program for patients with a wide range of trauma-related symptoms and disorders. The psychoeducational intervention is designed to facilitate coping, promote self-understanding, and enhance reflectiveness. Using attachment theory as the overarching conceptual framework, the authors educate patients about the nature of trauma, the effects of trauma on development, trauma-related psychiatric disorders, and a range of treatment approaches to trauma. They describe groups for adult inpatients and adults in partial hospital treatment, and for adolescents in either inpatient, residential, or outpatient treatment.
Depression in the context of late-life transitions. Late-life transitions shape feelings, yet these transitions are often overlooked when considering the mental state of older persons. The author discusses late-life transitions and how change in late life can present a challenge for growth. An understanding of these developments is necessary for mental health professionals trying to assess and treat depression in the elderly. Accurate assessment of depressive symptoms in late life requires a multifaceted, age-adjusted understanding of the unique characteristics of life's later years. Such an understanding can be fostered by learning to appreciate the patina that develops from decades of living. Properly focused treatment can promote further maturation in response to the vagaries of life. Change can be fostered by an openness to the possibility of late-life development.
Fear and anxiety in children and adolescents. The author reviews fears and anxiety in children and adolescents. In particular, the nature and prevalence of fears and anxiety disorders, including panic disorder, are described. This is followed by a description of comorbidity and gender differences, and the stability or chronicity of these disorders. Factors believed to contribute to the development of childhood fear and anxiety are outlined, and finally the treatments for these disorders are reviewed.
Anxiety disorders in primary care: a life-span perspective. From a family-oriented life-span perspective, the authors highlight issues involved in recognition, assessment, and treatment of anxiety disorders. After reviewing prevalence rates for these disorders in child, adult, and geriatric groups, they discuss cross-generational transmission of illness and identify cross-cutting themes, such as comorbidity of anxiety and depression, relationship between anxiety disorders and quality of life, and links among disability, adversity, and anxiety. They also discuss issues specific to childbearing, motherhood, and bereavement, and conclude with a brief summary of treatment approaches.
Panic disorder and addiction: the clinical issues of comorbidity. Panic disorder and addiction are occasionally comorbid--4.5% of addicted patients have panic disorder, and 16% of panic disorder patients are comorbid for addiction to alcohol and other drugs. Despite these relatively low rates of comorbidity, the treatment of these two disorders is commonly confounded by issues of comorbidity, as many physicians avoid using benzodiazepines to treat panic disorder out of inappropriate fear of addiction, and not a few physicians treat panic disorder thinking that they will thereby end comorbid addiction. Sound clinical practice calls for clear identification of both panic disorder and addiction and fully effective treatments of the diseases from which the patients suffer.
Panic disorder across the life span: a differential diagnostic approach to treatment resistance. There has been significant progress over the past 30 years in our understanding of the treatment of panic disorder. There are now several different classes of pharmacological treatments, as well as cognitive-behavioral treatments that have been shown to have efficacy in treating panic disorder. Despite the increase in the knowledge base, many patients are only partially responsive or unresponsive to initial treatment efforts. A differential diagnostic approach to reviewing possible causes for treatment failure is presented. These causes include coexisting psychiatric disorders, unrecognized medical factors, environmental stressors, and others. Additionally, a review of factors specifically related to elderly and to very young treatment-resistant panic disorder patients is presented, along with some suggestions for evaluation and treatment. Based on the limited literature and clinical experience, practical clinical suggestions for approaching identified factors are presented.
Discussion and overview: what can we learn if we view panic disorder across the life span and across different presentations and contexts? The author reviews new understanding of the etiology of panic disorder, particularly as it involves factors across the life span and across multiple presentations. In light of this perspective, he discusses treatment implications. He also emphasizes the necessity of increased efforts at case finding, and concludes by suggesting directions for future clinical and research strategies.
Troglitazone: a new antihyperglycemic agent. Troglitazone is the first of a new family of antihyperglycemic drugs. We review its use in clinical practice.
Approach to adult patients with recurrent infections. Recurrent infections often reflect underlying abnormalities, either anatomic or immunologic. In this paper we review how to recognize the underlying disorders in a variety of recurrent infections.
Chronic hepatitis C: a clinical overview. Recent advances in analyzing hepatitis C virus (HCV) have improved understanding of how it causes chronic liver disease, although the exact rate of disease progression and factors influencing its natural history are not entirely known. Tests for HCV fall into two categories: serologic and virologic. Interferon has shown limited efficacy in treating chronic HCV infection, and various strategies are being tried to improve its efficacy. HCV-related cirrhosis and liver failure have become one of the most common indications for liver transplantation in the United States.
A live-virus "suicide" vaccine for human immunodeficiency virus. A vaccine that uses a live, attenuated human immunodeficiency virus (HIV) may offer the best hope of a vaccine against acquired immunodeficiency syndrome (AIDS). A recent improvement should increase the safety of the live-virus approach: a "suicide gene" inserted into the viral RNA, which causes infected cells to die when treated with ganciclovir. We envision using this strategy not only to prevent AIDS, but also to treat it.
Coronary stent placement as a bridge to coronary artery bypass surgery in an unstable, anemic Jehovah's Witness patient: a case report and review of bloodless surgery techniques. Bloodless cardiac surgery would be optimal for all patients undergoing major or complex heart surgery; however, for Jehovah's Witnesses it involves a religious law and is fundamentally mandated. In this context, we review a case of unstable angina with associated anemia requiring catheterization and definitive intervention in a Jehovah's Witness patient. Coronary stenting to stabilize the acute coronary syndrome is described with definitive total revascularization performed by coronary artery bypass graft surgery after utilizing erythropoietin and aggressive blood conservation techniques.
The outcome of triplet pregnancies at Hartford Hospital--1989-1996. The advent of artificial induction of ovulation has increased the incidence of triplet pregnancies. Although the outcome of triplet pregnancies has improved through advanced technology, several studies have suggested that triplets conceived by artificial induction of ovulation have worse prenatal and perinatal outcomes than those conceived naturally. Our study examined the outcome of 14 sets of triplets conceived at Hartford Hospital between 1989 and 1996. Five of 14 sets of triplets were conceived by artificial methods and nine of 14 were conceived naturally. The mean gestational age was 31.8 weeks for artificially conceived infants vs 29.7 weeks for naturally conceived infants. Average weight at birth was 1.625 kg in the artificially conceived study group and 1.377 kg in the naturally conceived group. Time spent in the neonatal intensive care unit was 4.67 weeks for the artificially conceived study group and 3.57 weeks for the naturally conceived group. It is concluded that there was no difference in outcome in the triplets conceived by artificial induction of ovulation vs natural conception. Maternal age and sex of triplets were important factors determining perinatal outcomes of triplets.
Pica: are you hungry for the facts? Pica, the persistent and compulsive ingestion of particular food items or nonnutritive substances, has been associated with iron deficiency, zinc deficiency, geophagia, mental deficiency, developmental delay, and a family history of pica. Nutritional, sensory physiologic, psychosocial, and cultural theories have been advanced to explain this phenomenon, but the etiology of pica is poorly understood. Pica, secondary to iron deficiency, is relatively common and remits after iron therapy. Complications of pica include abdominal problems (sometimes necessitating surgery), lead poisoning, hypokalemia, hyperkalemia, mercury poisoning, phosphorus intoxication, and dental injury. Pica is an underdiagnosed problem that can be caused by a variety of disorders and can lead to serious complications.
Trends in cancer incidence in Connecticut. The population-based Connecticut Tumor Registry was used to examine recent trends (1980-84 to 1990-94) in average annual age-standardized incidence rates (ASRs) for invasive cancers. Noteworthy were the increase for lung cancer in women (but a decline in men), the sharp increase for prostate cancer (but little change in female breast cancer), increases for melanoma of skin (both sexes) and non-Hodgkin's lymphoma (especially in males), and declines for colon and rectum (both sexes). Reducing cancer incidence rates will require expanded primary prevention efforts, involving mainly behavioral or life-style changes, with an important role for primary-care physicians.
The birth of the RCMI Clinical Research Center is a joint venture of the University of Hawaii and Kapiolani Health. Hawaii established a Clinical Research Center with collaboration from the University of Hawaii Pacific Biomedical Research Center, the John A. Burns School of Medicine and Kapiolani Health via a five year award from the Research Centers in Minority Institutions of the National Institutes of Health. Support offered includes consultative services for protocol design; epidemiological and biostatistical analysis; design of study forms; and data and specimen collection and analysis.
Violence in medical facilities: a review of 40 incidents. Workplace violence has become an increasing problem in the United States. This paper reviews 40 such incidents of non-patient violence occurring in medical facilities. Areas of study include categories of violence, weapons used, number of persons killed or wounded, precipitant for the violent act, and the presence of psychopathology. Additional variables such as suicide, drug and alcohol use, stalking, and hostage-taking are also examined. The results indicate that workplace violence in medical settings differs considerably from incidents in other work environments, particularly with respect to motivation, psychiatric diagnoses, weapons used, and stalking. Intervention and management strategies in health care institutions may, therefore, need to be modified in order to deal with violence. An examination of the data allows development of a profile for violence in medical settings and the identification of risk factors. Security issues for hospitals, clinics, and physician offices are also discussed.
Wilms' tumor in an adult: a case report and review of the literature. Wilms' tumor in an adult is extremely rare, with less than 250 cases reported in the world literature. Treatment guidelines for pediatric Wilms' tumor are well established; those for adults are not. This article presents the case of a 19-year-old male diagnosed with Wilms' tumor after complaints of hematuria. He was categorized as Stage IV after nephrectomy and received post-operative radiotherapy and chemotherapy consisting of Vincristine, Adriamycin, and Actinomycin-D. Two years later he was found to have metastases to brain and lungs. He was treated with radiotherapy and bone marrow transplantation, and died of septic shock. The literature regarding Wilms' tumor in adults is reviewed, and current therapy is discussed.
Alzheimer's disease: new horizons in diagnosis and treatment. We are in the midst of an explosion in research in Alzheimer's disease. Advances in our scientific understanding of genetic factors and pathogenesis are leading to enhanced diagnostic capabilities and new presymptomatic and symptomatic therapies. Estrogen therapy in postmenopausal females and NSAIDs show early promise, while AChE inhibitors keep getting better. Armed with knowledge and new diagnostic and therapeutic tools, we can finally begin to fight this devastating disease.
Rubber and plastic ammunition lethal injuries: the Israeli experience. Rubber and plastic ammunition was used by the Israeli Defence Forces between the years 1987 and 1993 (Intifada) almost exclusively as a deterrent to aggression by the Palestinian civilian population in the occupied territories of Gaza, Judea and Samaria. While designed to avoid the serious wounds and deaths caused by the use of conventional military ammunition, the firing of rubber and plastic bullets has resulted in extensive injuries and more than 20 deaths. The data from the autopsies of 17 of these victims, mostly teenagers, were analysed. Ten of the victims died from injuries inflicted by Improved Rubber Bullets, while the other seven succumbed to injuries caused by Plastic Bullets. In most instances, the cause of death was related to injuries to the brain. Ballistic features of non-conventional bullets are discussed, and suggestions to curtail the serious injuries and fatalities arising from their use are given, with emphasis on firing from a safe range. British and South African experience with this type of ammunition is compared with our observations.
Physical restraint of patients in a psychiatric hospital. Use of physical restraint occurs within British psychiatric hospitals yet there has been little evaluative research on current practice. The present study aims to describe a group of disturbed in-patients who had required physical restraint at some point during the course of their stay in hospital and to classify the reasons for its use. Cases were identified using Case Register data and information obtained from patients' records. In the 48 episodes of physical restraint identified, patients were predominantly schizophrenic (60%), male (67%) and had been restrained because of physical violence to others (44%) or because they were attempting to abscond (31%). Although the majority of patients were compulsorily detained prior to the use of physical restraint, three remained informal. The findings are discussed in the context of the legal justifications for use of restraint. Further research on current practice is required to enable formulation of clear guidelines.
Assessment of the perceived need for a psychiatric service to a magistrates' court. One approach to diversion from custody of mentally disordered offenders is to provide a psychiatric liaison service to local magistrates' courts. We aimed to establish whether such a scheme was needed locally. Questionnaires for the bench, defence solicitors and bail information officers, enquiring as to the perceived need for a psychiatric assessment, social service care and specialist bail provision, were distributed for all those appearing in a magistrates' court who had been held overnight in police custody. Responses were received for 223 individuals. An immediate psychiatric report was considered necessary for 4.9% of cases. In 2.2% of cases it was thought that remand in custody could have been avoided if such an opinion had been available. In 8% of cases it was thought that remand in custody could have been avoided if specialist bail provision were available. We conclude that availability of a specialist bail provision would lead to a greater number of diversions from custody than providing a psychiatric service to this magistrates' court.
Repetitive and non-repetitive violent offending behaviour in male patients in a maximum security mental hospital--clinical and neuroimaging findings. OBJECTIVE To examine if different violent offending behaviours are associated with different clinical and neuroimaging profiles. METHOD Thirty-nine schizophrenic and schizoaffective offenders from a maximum security mental hospital-20 repetitive violent offenders (RVOs) and 19 non-repetitive violent offenders (NRVOs)-were selected for clinical and neuroimaging assessments. RESULTS Both groups had positive family history of mental illness and violence. Age, diagnosis, duration of illness, victim profiles and use of weapons at the time of the index offence were similar. RVOs had a higher prevalence of early parental separation, juvenile conduct problem, previous convictions of crimes not involving violence, impulsive suicide attempts, delusion of their lives being threatened at the time of the index offence and electroencephalographic (EEG) abnormalities localized to temporal lobes. NRVOs had a higher prevalence of sexual inexperience and command hallucinations to kill at the time of the index offence. Asymmetric gyral patterns at the temporo-parietal region were particularly common in RVOs and absent in NRVOs. Non-specific white matter changes in magnetic resonance imaging (MRI) and generalized cortical hypometabolism in positron emission tomography (PET) were present in both groups. CONCLUSIONS Different structural and metabolic changes in the brain were associated with different violent offending behaviours. The complex interaction between violent behaviour, clinical features and neuroimaging findings in schizophrenia requires further studies.
Gender-based differences in the treatment of young offenders by the police and the children's court in New South Wales, Australia. It has been consistently reported that young males commit crimes with an average frequency five times greater than their female peers. Most data supporting this view are derived from juvenile court and police statistics. Studies using data derived from self-reported behaviour suggest that the true relative frequency may be closer to 2:1. Police and juvenile justice data for the year 1994-5 in New South Wales, Australia, were analysed in an attempt to determine whether court and police statistics might reflect a form of selection bias, where the likelihood of arrest, trial and/or sentence is a function of gender, rather than frequency and nature of offence. The results suggest that the 5:1 gender ratio reflects a strong component of gender bias in the workings of the juvenile justice system in New South Wales. If suspected of a given crime, young males are more likely to be denied bail and (if found guilty) to be given a harsher sentence than young females suspected (or found guilty) of the same crime. Overall, if found guilty of an offence, boys were four times more likely than girls to receive a custodial sentence. Therefore, boys are selectively denied access to alternate rehabilitation resources which are made available to girls who are in trouble with the law. The juvenile justice system in New South Wales requires careful examination and reform if such apparently deeply entrenched biases are to be eliminated.
Sudden unexplained death in a psychiatric patient--a case report: the role of phenothiazines and physical restraint. Psychotropic drug use has long been associated with sudden unexplained and unexpected death in psychiatric patients despite controversies surrounding the issue. Physical restraint following violent episodes in psychiatric in-patients is also associated with neurally mediated sudden cardiac death. A case where these two mechanisms have jointly resulted in sudden death is reported. The literature on the subject is reviewed and the measures which may be useful in reducing the incidence of such deaths are discussed. The need for accurate and detailed reporting of such cases is emphasized.
Self-mutilation with needles. Two cases of self-mutilation with needles are reported. One of the deceased suffered from chronic schizophrenia and committed suicide by plastic bag suffocation. At autopsy several needles were detected grown into the connective tissue of chest or abdominal organs. In the other case a knitting needle was used for repeated manipulations at the forehead leading to a defect of the skin and the skull. At least one vessel was injured leading to an extensive haemorrhage in the left hemisphere of the brain. The forensic and etiologic aspects of the cases are discussed.
The role of the peridomiciliary area in the elimination of Triatoma infestans from rural Argentine communities. The purpose of this study was to identify the origin of Triatoma infestans reinfestation and study its dynamics following spraying with deltamethrin inside and around 94 houses in three rural communities in northwestern Argentina. The effectiveness of the spraying was evaluated immediately after the houses were sprayed and two months later. In addition, five residual peridomiciliary foci were found and sprayed, as well as three preexisting ones that had not been sprayed. To monitor reinfestation, biosensors were placed in the houses and each family was also asked to capture triatomines and keep them in plastic bags; in addition, triatomines were searched for in and around houses, using an aerosol that dislodged them from their hiding places. Selective sprayings were carried out only where a colony of T. infestans was found. During the 30 months of follow-up, the percentage of houses in which any T. infestans were captured varied between 3% and 9%. In six houses, T. infestans were captured during more than one evaluation. The number of peridomiciliary areas found to be infested (19) was double the number of infested houses (9). Colonies of T. infestans were found only in the peridomiciliary areas, where the number of T. infestans captured was six times higher than in the houses. Chickens were the host most frequently associated with peridomiciliary foci. This area was the origin and principal source of reinfestation. To reduce the speed of reinfestation and the frequency with which sprayings are needed, the following environmental and chemical control methods must be combined in the peridomiciliary area: reduce the number of hiding places of triatomines; restrict the raising of birds to structures that cannot be colonized by triatomines; apply an insecticide that is less likely to be degraded by exposure to the elements, or perform a second spraying 6 to 12 months after the first; and employ a device for early detection of the presence of T. infestans around houses.
Factors favoring houseplant container infestation with Aedes aegypti larvae in Marília, São Paulo, Brazil. Since reinvasion of São Paulo State by the Aedes aegypti (L.) mosquito in 1985, flower pots and vases have been important larval habitats despite educational messages focusing on their control. The objectives of this study were to characterize flower pots and vases as larval habitats with respect to the quantities present and infested, the types of plants involved, and the specific locations of the mosquito larvae; to explore local names for houseplants; and to examine factors affecting acceptance of control measures. The results showed an average of more than four potential plant-related larval habitats per premises, of which only 0.4% were occupied by the vector. Plant-related containers represented 31% of all the containers with Aedes aegypti larvae. Although a sample of 126 respondents was able to list 105 different houseplant names, 49% of the positive plants were of two types: ferns and the ornamental plant Dieffenbachia avoena. The public's apparent unwillingness to accept recommended anti-aegypti control measures involving houseplants seems related to the relative rarity of aegypti larvae in the very common houseplant containers, the control program's poor credibility as a source of information about plants, and a perception that the recommended control measures are harmful to plants. An intervention currently being planned for dengue control will use educational material that refers specifically to those plants whose containers are most commonly found to harbor aegypti larvae; it will also utilize information sources such as botanists with greater credibility regarding plants; and it will set out alternative plant care recommendations that are more likely to appeal as beneficial to the plants and that will stand a better chance of being accepted.
Highways for protein delivery to the mitochondria. Messenger RNA (mRNA) localisation is one of the prime mechanisms to ensure protein localisation in the cytoplasm of polarised embryonic cells, and has been well-studied in the development of Xenopus and Drosophila embryos. But what of other cells? Here, we discuss whether the directed transport of mRNA out of the nucleus, following cytoplasmic highways to a specified organelle in the cytoplasm, might also contribute to the exquisite fidelity of protein targeting observed in all eukaryotic cells.
ATP-dependent proteases that also chaperone protein biogenesis. The ATP-dependent proteases Clp and FtsH from bacteria, as well as mitochondrial homologs of FtsH and Lon from yeast, may act as chaperones; they mediate not only proteolysis, but also the insertion of proteins into membranes and the disassembly or oligomerization of protein complexes. The coordination of such processes with selective proteolysis may function in the quality control of protein biogenesis.
Silencers and locus control regions: opposite sides of the same coin. Whether or not genes are in an active or a repressed state in a cell depends on the relative effect of gene silencers and locus control regions (LCRs). Here, we suggest that these elements act as binary switches; the state that prevails (activated or repressed) probably depends on a competition between protein complex formation and the stability of the complexes formed at either of the two elements.
Histone acetylation: chromatin in action. Histone acetylation acts as a landmark and determinant for chromatin function. Active roles in the transcription and assembly of chromatin have been discovered for histone acetyltransferases and deacetylases. This review highlights these roles and discusses their significance for the maintenance of cell differentiation.
Pre-mRNA splicing: the discovery of a new spliceosome doubles the challenge. A rare class of pre-mRNA introns with non-canonical consensus sequences has been identified in metazoan genes. The novel, low-abundance spliceosome that excises these introns contains one small nuclear ribonucleoprotein (snRNP) in common with the major spliceosome (U5) and four snRNPs that are distinct from, but structurally and functionally analogous to U1, U2 and U4-U6. The architecture of RNA components at the presumptive core of the AT-AC splicesome supports current models of the spliceosomal active center and raises tantalizing questions about spliceosome evolution.
Methods and reagents. Degraded DNA and gel tornados. Methods and reagents is a unique monthly column that highlights current discussions in the newsgroup bionet.molbio.methds-reagnts, available on the Internet. This month's column discusses a case of inexplicable DNA degradation and tornados seen in agarose gels. For details on how to partake in the newsgroup, see the accompanying box.
Eosinophil lysis and free granules: an in vivo paradigm for cell activation and drug development. Release of cytotoxic granule proteins from activated eosinophil granules is considered to be a key pathogenic mechanism in eosinophilic diseases. Degenerated eosinophils and extracellular eosinophil granules have been repeatedly depicted. The present overview describes evidence that eosinophil lysis and distribution of free eosinophil granules (as opposed to 'classical degranulation') is an important mechanism by which eosinophils affect their surroundings. Here, Carl Persson and Jonas Erjefält summarize how recent reports on the induction of eosinophil lysis in vivo provide a new paradigm for eosinophil activation and thus constitute a novel basis for pharmacological manipulations in eosinophilic diseases.
Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription. Calcineurin is a calcium (Ca2+)/calmodulin (CaM)-dependent protein phosphatase that has been shown to regulate the activity of ion channels, neurotransmitter and hormone release, synaptic plasticity and gene transcription. At glutamatergic synapses, the inhibition of calcineurin with immunosuppressant drugs has been reported to enhance both the presynaptic release of glutamate and postsynaptic responsiveness. Several other ligand- and voltage-gated ion channels are negatively regulated by calcineurin. Hormone release in insulin-secreting pancreatic beta cells and pituitary corticotrope tumour (AtT20) cells is also negatively regulated by calcineurin. In this article, Jerrel Yakel discusses the evidence that calcineurin plays a vital role in regulating neuronal excitability and hormone release.
Where is the locus in opioid withdrawal? Identification of neuroadaptations in specific brain regions that generate withdrawal is crucial for understanding and perhaps treating opioid dependence. It has been widely proposed that the locus coeruleus (LC) is the nucleus that plays the primary causal role in the expression of the opioid withdrawal syndrome. MacDonald Christie, John Williams, Peregrine Osborne and Clare Bellchambers believe that this view and the interpretation of the literature on which it is based are at best controversial. Here, they suggest an alternative view in which regions close to the LC such as the periaqueductal grey, as well as other brain structures which are independent of the LC noradrenergic system, play a more important role in the expression of the opioid withdrawal syndrome.
Epidemiology of Helicobacter pylori infection in Barbados. The epidemiology of Helicobacter pylori infection in Barbadian patients and controls was studied. H. pylori was isolated from biopsies from 50/100 (50%) adult patients undergoing endoscopy for investigation of upper gastrointestinal tract symptoms. Urease was detected in biopsies from 54 patients and gastritis was detected by histology in 71 patients. Serology was performed using a commercial ELISA method. Using an IgG concentration of 10 U/ml as a threshold, antibodies were detected in 78% of 100 patients undergoing endoscopy, 72% of 230 blood donors and 22% of 50 children. The mean antibody concentration was significantly higher in patients (92 U/ml) than in blood donors (49 U/ml) or in children (9.5 U/ml). Culture-positive patients (120 U/ml) had higher IgG concentrations than culture-negative patients (64 U/ml). Using isolation of H. pylori or a positive biopsy urease test as a measure of true prevalence of infection, the sensitivity of serology was 96%, the specificity 42%, positive predictive value 67% and negative predictive value 90%. Seroprevalence increased with age, to a peak of more than 90% in blood donors aged 50-59 years and in patients aged over 60 years. The epidemiology of H. pylori in Barbados is similar to that in developed countries, where few children are infected, but resembles other developing countries in the high seroprevalence observed in middle-aged adults. Our results confirm the utility of serology for detecting H. pylori by a non-invasive technique.
Lifestyle in Curaçao. Smoking, alcohol consumption, eating habits and exercise. The Curaçao Health Study was carried out among a randomized sample (n = 2248, response rate = 85%) of the adult non-institutionalized population in order to assess aspects of lifestyle that may pose health risks. Factors examined were tobacco and alcohol use, eating habits and exercise behaviour. Outcome variables were cross-tabulated by gender, age and socioeconomic status. 17.1% of the participants were smokers and 20.5% were regular drinkers, including 6.3% of the men who consumed alcohol excessively (4 or more glasses of alcohol a day). 75% of the participants did not exercise regularly, 37% did not eat vegetables daily, and half did not eat fruit daily. Other poor eating habits were the addition of extra sugar and salt to prepared food by 33% and 20% of the participants, respectively. On the whole, men had less healthy lifestyles than women, with the exception of exercise behaviour. People of high socioeconomic status (SES) drank less alcohol, and exercised more often than those of low SES. Considering the high prevalence of diabetes mellitus and hypertension in the Caribbean, research on lifestyle factors in other Caribbean countries is required to facilitate the development of regional prevention and intervention programmes.
Scanning electron microscopy of the jejunum in children with protein-energy malnutrition. Samples of jejunum from seven children dying from severe oedematous malnutrition were fixed with intralumenal glutaraldehyde in combination with external immersion, using a rapid autopsy protocol. Selected areas were post-fixed in osmium tetroxide, dehydrated with an ethanol series and critical point dried. After mounting on aluminium stubs, specimens were sputter-coated with a thin layer of gold and palladium. Scanning electron microscopy showed patterns ranging from subtotal villous atrophy, through partial villous atrophy with low ridges, to longer, taller ridges with cerebriform convolutions. In one case, villous height had been interpreted as normal on light microscopy. The scanning electron microscope revealed that the mucosa in this case was composed of ridges and leaf forms. Processing for scanning electron microscopy is simple. The specimens can be viewed and photographed in a relatively short time. In addition, the three-dimensional record provides clarification of ambiguities which often arise from routine histological sections.
Kidney function in phasic insulin dependent diabetes mellitus in Jamaica. In Jamaica, malnutrition related diabetes mellitus (MRDM) presents the clinical picture of phasic insulin dependence. This study was undertaken to investigate nephropathic changes associated with this group of patients. Fourteen phasic insulin dependent diabetes mellitus (PIDDM) patients were compared with 10 insulin dependent (IDDM) and 10 non-insulin dependent (NIDDM) diabetes mellitus patients, and 10 normal controls. Each group was matched for age, sex, body mass index (BMI) and, in the case of the diabetic patient controls, duration of diabetes. Urinary microalbumin concentration was significantly (p < 0.05) higher in the PIDDM group (mean +/- SD: 153 +/- 48.3 mg/dl) than in the groups of NIDDM (35.7 +/- 9.6 mg/dl) or IDDM (38.6 +/- 15.8 mg/dl) patients. Serum urea and creatinine concentrations (mean +/- SE 7.6 +/- 1.0 mmol/l and 130.0 +/- 20.3 mumol/l, respectively) were higher in the PIDDM patients than in the NIDDM and IDDM groups. Confounding factors such as hypertension and urinary tract infections were excluded as causes for these differences. We conclude that PIDDM patients have more severe renal dysfunction than NIDDM patients and, since glycosylated haemoglobin concentrations are comparable in these groups, we attribute this to a renal insult due to malnutrition predating the onset of the PIDDM.
Invasive streptococcal infections. Report of four cases occurring in Trinidad. Many countries are reporting a resurgence of virulent streptococcal strains but there is little information from the Caribbean. Four cases of severe invasive streptococcal infections, three of them fatal, are reported. The portal of entry was infected scabatic lesions in one patient and infected mosquito bites in another patient who developed cellulitis and gangrene; but no portal of entry was detected in the other patients. Group A beta haemolytic Streptococcus (GAS) was isolated from the blood of three patients, one of them GAS M type 3, which had the genome for streptococcal pyrogenic exotoxins A (SPeA) and B (SPeB). GAS M type 72, which had the genome for SPeB and SPeC, were isolated from the tissues (but not from the blood) of the patient who developed cellulitis and who was the sole survivor. Physicians in the Caribbean must be alerted to the presence of these virulent streptococcal strains, and must be prepared to manage serious invasive disease.
Cardiac fibroma presenting as sudden death in a six-month-old infant. Cardiac fibroma is a rare benign tumour which occurs predominantly in infancy and childhood. We present the case of a six-month-old female infant who died suddenly at home and was found at autopsy to have a large cardiac fibroma in the ventricular septum. The tumour was apparently asymptomatic although there was evidence of mild cardiac failure. Death was thought to be due to a fatal arrhythmia.
The 'internal clocks' of circadian and interval timing. Animals engage in a startlingly diverse array of behaviours that depend critically on the time of day or the ability to time short intervals. Timing intervals on the scale of many hours to around a day is mediated by the circadian timing system, while in the range of seconds to hours a different system, known as interval timing, is used. Recent research has illuminated some of the neural mechanisms underlying the 'internal clocks' of these two different timing systems in both animals and humans. Therapeutic applications for humans with impairments in either timing system may ultimately result from these endeavours.
Stable isotope methods for studying nutrient mineral metabolism in humans. Stable isotopes are safe, versatile, scientifically rigorous tools for studying nutrient metabolism in humans. They can be used to follow the metabolism of nutrient minerals from specific foods or diets, including the determination of efficiency of absorption and the effects of dietary constituents on absorption, and to investigate fundamental aspects of nutritional biochemistry. In this article we describe stable isotope methods and the results of some recent nutrient mineral metabolism studies in humans.
Alternative forms of the critical power test for ramp exercise. The critical power test provides estimates of two important parameters characterizing work performance; anaerobic work capacity (AWC) and critical power (CP). The CP concept has recently been adapted to a test procedure involving ramp exercise. Just as the constant power format of the CP test can be expressed in several mathematically equivalent forms, so too can the ramp format. This communication illustrates these forms and tests the various AWC and CP estimates so obtained. It is found that three of the four forms provide equivalent estimates for both AWC and CP. It is concluded that provided either endurance time or total work performed is taken as the dependent variable, researchers can expect consistent estimates for both AWC and CP.
Physiological model of CO2 output during incremental exercise. In this study, a physiological model to explain the pathway of CO2 output during incremental exercise was examined by referring to experimental data. Since CO2 output (VCO2) shows multiple correlations with mixed venous CO2 pressure (PvCO2) and arterial CO2 pressure (PaCO2), the increase in the difference between PvCO2 and PaCO2 was considered to be involved in the increase in VCO2. In order to better understand the influence of CO2 pressure, VCO2 was divided into the expiratory CO2 phase (non-lactic VCO2), which was unrelated to lactic acid increase and the expiratory CO2 phase (excess VCO2), which was related to lactic acid increase. As a result, the non-lactic VCO2 significantly correlated to PvCO2. When non-lactic VCO2 was zero, the value of PvCO2 was 43.7 mmHg. This was higher than the resting PaCO2 value. On the other hand, as PaCO2 showed an almost constant value in the low load phase and showed a low value in the high load phase, it was believed that the low value of PaCO2 was related to the excess VCO2 that appeared in the high load phase. The CO2 excess, which was obtained by adding excess VCO2 in terms of the lapse of exercise time, correlated significantly with an increase in lactate in the blood. Based on the results, a model was constructed to illustrate the pathway of CO2 output. The key points of the model were as follows: (1) the use of the blood CO2 dissociation curve as the vector to transport CO2 from tissue to lungs, (2) the standard value of PaCO2 was established in order to divide non-lactic VCO2 and excess VCO2, (3) the dextroversion of the blood CO2 dissociation curve due to lactic acid was connected to excess VCO2, and (4) a decrease in PaCO2 was related to excess VCO2 derived from tissue.
A single metric for quantifying biomechanical stress in repetitive motions and exertions. The relative effects of repetition, force and posture were studied in order to investigate how continuous biomechanical measurements can be combined into a single metric corresponding to subjective discomfort. A full factorial experiment was conducted involving repetitive wrist flexion from a neutral posture to a given angle against a controlled force. Seven subjects performed the task using two paces (20 and 4 motions/min), two force levels (15 and 45 N) and two angles (15 and 45 degrees) for 1 h each. Discomfort was reported on a 10 cm visual analogue scale anchored between 'no discomfort' and 'very high discomfort'. Repeated measures analysis of variance showed that all main effects were statistically significant (p < 0.05) and no significant interactions were observed. A linear regression model was fitted to the data and used for generating frequency weighted digital filters that shape continuous recordings of repetitive motions and exertions into an output proportional to relative discomfort. The resulting high-pass digital filter had a 22 dB/decade attenuation slope. A simulated industrial task used for validating the model involved repetitively transferring pegs across a horizontal bar and inserting them into holes against a controlled resistance. Angular wrist data were recorded using an electrogoniometer and filtered. Six subjects performed the task of the three conditions consisting of (1) 15 wrist flexion, 15 N resistance and 6 motions min, (2) 15 wrist flexion. 45 N resistance and 12 motions/min, and (3) 45 degrees wrist flexion, 45 N resistance and 15 motions/min. Subjective discomfort was reported after performing the task for 1 h. Pearson correlations between subjective discomfort ratings and the integrated filtered biomechanical data for individual subjects ranged from 0.90 to 1.00. The pooled correlation across subjects was 0.67. This approach may be useful for physical stress exposure assessment and for design of tasks involving repetitive motions and exertions.
Load knowledge affects low-back loading and control of balance in lifting tasks. This study investigated the effect of the presence or absence of load knowledge on the low-back loading and the control of balance in lifting tasks. Low-back loading was quantified by the net sagittal plane torque at the lumbo-sacral joint. The control of balance was studied by the position of the centre of gravity relative to the base of support, the horizontal and vertical momentum of the centre of gravity and the angular momentum of the whole body. In a first experiment, 8 male subjects lifted a rather heavy load (22% of body mass), using a leglift and a backlift, while they were familiar with the load mass. To counteract the threat to balance, imposed by picking up a load in front of the body, the subjects performed specific preparations, based upon the known load mass; prior to load pick-up, profound changes in the horizontal and angular momentum were found. The preparations were technique specific. Preserving balance seemed easier while picking up a load with a backlift than with a leglift. In the second experiment, 25 male subjects lifted a 6 kg box, which they expected to be 16 kg, because, in a series of lifts, the load mass was changed from 16 to 6 kg without their knowledge. Despite the 10 kg difference in actual load mass, the net torque at the lumbo-sacral joint was not different between lifting 6 and 16 kg, until 150 ms after box lift-off. Moreover, lifting of the overestimated load mass caused a disturbance of balance in 92% of the trials. The postural reactions aimed at regaining balance were not accompanied by an increased low-back loading. It was concluded that the absence of load knowledge, and the following overestimation of the load mass to be lifted, lead to an increased mechanical load on the lumbar spine and to an increased risk of losing balance in lifting tasks. Both events may contribute to a higher risk of low-back injury in manual materials handling tasks.
Isometric muscle strength of Chinese young males in Taiwan. This paper represents the results of an anthropometric measurement of the isometric muscle strength of Chinese young males in Taiwan aged from 16 to 20 years. The study uses a sample of 120 male students and measures four types of muscle strength: (1) right arm strength in exerting pull, push, adduction, abduction, lift, and press directions with five elbow angles (60, 90, 120, 150 and 180 degrees) in seated posture; (2) grip strength of both hands; (3) backlift strength: and (4) chest expanding strength. The obtained data are analysed and listed. Comparisons are made between the results of this study and those from domestic and foreign studies available in the literature. In general, their pattern is similar, but values obtained in this study are relatively smaller than those obtained in western countries.
Retreatment tuberculosis cases. Factors associated with drug resistance and adverse outcomes. STUDY OBJECTIVE Risk factors associated with treatment failure and multidrug-resistant tuberculosis (MDR-TB) were examined among HIV-seronegative patients who were previously treated for tuberculosis (TB). DESIGN Prospective, cohort study of patients referred to the study hospital for retreatment of TB between March 1986 and March 1990. PATIENTS The patients belonged to three groups, according to outcomes following their previous treatment: 37 patients who abandoned treatment or suffered relapse after completion of therapy (group A), 91 patients who failed to respond to the first-line drug regimen (group B), and 78 patients who failed to respond to the second-line drug regimen (group C). RESULTS Patients with Mycobacterium tuberculosis strains resistant to rifampin and isoniazid were found in 2 (6%) in group A, 29 (33%) in group B, and 49 (65%) in group C. Cure was achieved in 77% in group A, 54% in group B, and 36% in group C. Death occurred in none of the patients in group A, 8% in group B, and 24% in group C. In a multivariate logistic regression analysis, unfavorable response (failure to sterilize sputum culture, death, and abandonment) was significantly associated with infection with a multidrug-resistant M tuberculosis strain (p = 0.0002), cavitary disease (p = 0.0029), or irregular use of medications (p < 0.0001). CONCLUSIONS These observations show that a previous treatment outcome and current clinical and epidemiologic histories can be used to predict the development of MDR-TB and adverse outcomes in patients undergoing retreatment for TB. Such information may be useful for identifying appropriate patient candidates for programs such as directly observed therapy.
Noncompliance with directly observed therapy for tuberculosis. Epidemiology and effect on the outcome of treatment. STUDY OBJECTIVES To describe the epidemiology and clinical consequences of noncompliance with directly observed therapy (DOT) for treatment of tuberculosis. DESIGN Retrospective review. SETTING An urban tuberculosis control program that emphasizes DOT. PATIENTS All patients treated with outpatient DOT from 1984 to 1994. MEASUREMENTS AND RESULTS We defined noncompliance as follows: (1) missing > or = 2 consecutive weeks of DOT; (2) prolongation of treatment > 30 days due to sporadic missed doses; or (3) incarceration for presenting a threat to public health. Poor outcomes of therapy were defined as a microbiologic or clinical failure of initial therapy, relapse, or death due to tuberculosis. Fifty-two of 294 patients (18%) who received outpatient DOT fulfilled one or more criteria for noncompliance. Using multivariate logistic regression, risk factors for noncompliance were alcohol abuse (odds ratio, 3.0; 95% confidence interval, 1.2 to 7.5; p = 0.02) and homelessness (odds ratio, 3.2; 95% confidence interval, 1.5 to 7.2; p = 0.004). Noncompliant patients had poor outcomes from the initial course of therapy more often than compliant patients: 17 of 52 (32.7%) vs 8 of 242 (3.3%); relative risk was 9.9; 95% confidence interval was 4.5 to 21.7 (p < 0.001). CONCLUSIONS In an urban tuberculosis control program, noncompliance with DOT was common and was closely associated with alcoholism and homelessness. Noncompliance was associated with a 10-fold increase in the occurrence of poor outcomes from treatment and accounted for most treatment failures. Innovative programs are needed to deal with alcoholism and homelessness in patients with tuberculosis.
The utility of a single sputum specimen in the diagnosis of tuberculosis. Comparison between HIV-infected and non-HIV-infected patients. STUDY OBJECTIVES (1) To assess the utility of a single sputum specimen in the evaluation of HIV-infected patients who are suspected of having tuberculosis (TB). (2) To identify radiographic findings that discriminate between HIV-infected patients with TB and those with pneumonia of other causes. DESIGN Retrospective cohort analysis. PATIENTS All patients evaluated at Harborview Medical Center, Seattle, between January 1986 and July 1994 in whom culture of respiratory secretions grew Mycobacterium tuberculosis or Mycobacterium avium-complex. Patients who were coinfected with HIV formed the primary study group. Their chest radiographs were then compared with those of a matched group of patients with pneumonia of other causes. MEASUREMENTS AND RESULTS We identified 164 patients with TB, 20 of whom were HIV infected. The initial sputum specimen grew M tuberculosis in all HIV-infected patients and 99% of non-HIV-infected patients. Seventy percent of HIV-infected and 71% of non-HIV-infected patients had at least one positive smear. Most of these patients tested positive on their initial smear, and no significant difference was found between HIV-positive and HIV-negative patients (79% and 90%, respectively [p = 0.34]). The addition of a second sputum smear identified all HIV-infected patients and all but one in non-HIV-infected patients who were ultimately determined to be smear positive. A total of 27 HIV-infected patients had a positive acid-fast bacilli sputum smear during the study period, 14 of which were attributable to TB (specificity = 52%). The only radiographic findings that discriminated between HIV-infected patients with TB and those with pneumonia of other causes were the presence of cavitation or a miliary pattern (p = 0.014). CONCLUSIONS A single sputum specimen was sufficient to establish the diagnosis in all HIV-infected patients with pulmonary TB. A single negative sputum smear made the diagnosis of TB significantly less likely. However, a minimum of two smears were necessary to achieve an acceptable early diagnostic yield. The presenting chest radiograph failed to discriminate between HIV-infected patients with TB and pneumonia of other causes in most cases.
Empiric treatments impair the diagnostic yield of BAL in HIV-positive patients. OBJECTIVE To investigate the influence of empiric treatments prior to fiberoptic bronchoscopy (FOB) on the diagnostic yield of BAL in HIV-positive patients with respiratory symptoms. METHOD We studied 123 consecutive FOBs with BAL in HIV-positive patients; 101 of these patients (82%) had received previous antimicrobial treatment from 1 to 60 days. Diagnostic yield of BAL for Pneumocystis carinii, Mycobacterium tuberculosis, and bacterial pneumonia was compared between patients with and without previous empiric treatments. RESULTS A diagnosis was obtained in 85 patients (69%), of whom 17 (20%) had multiple infections. Diagnostic yield was higher in patients without previous treatment, 91% (20/22) compared with 64% (65/101), p < 0.03. Diagnostic yield was also higher for bacterial pneumonia: seven isolations from 22 patients not receiving previous empiric treatment (32%), compared with 11 of those who had (11%; p < 0.02). The duration of empiric treatment against P carinii in patients in whom it was isolated was significantly shorter than in those in whom P carinii was not detected (3.5 +/- 1.8 days compared with 5.2 +/- 2.4 days; p = 0.003). FOB permitted a change in treatment in 62% of patients with a final diagnosis. CONCLUSION This study demonstrates that empiric treatments prior to FOB significantly impair the diagnostic yield of BAL in detecting common pathogens in HIV-infected patients with respiratory symptoms.
Utility of lactate dehydrogenase vs radiographic severity in the differential diagnosis of Pneumocystis carinii pneumonia. STUDY OBJECTIVES In patients with HIV infection, serum lactate dehydrogenase (LDH) level is commonly stated to be more elevated in Pneumocystis carinii pneumonia (PCP) than in non-PCP. We hypothesized that LDH level reflects radiographic extent and severity of pneumonia rather than P carinii infection specifically and therefore is not useful in the differential diagnosis of lung infections in AIDS. DESIGN We compared radiographic features and LDH values in 93 sequential patients with HIV infection and a new hospital admission for pneumonia (53 PCP and 40 non-PCP) after excluding all patients with other potential causes for elevated LDH levels. The chest radiograph was graded using a quantitative scale (0 to 24) to assess radiographic extent and severity of pneumonia by two independent observers in blinded fashion. The relationship between radiographic score and hospital admission LDH level was analyzed by linear regression and Bayesian analysis was applied to different LDH ranges to calculate the clinical value of LDH measurements. SETTING Tertiary care teaching hospital and regional AIDS referral center. RESULTS Mean LDH level was higher in the PCP group (1.217 +/- 88 U/L compared with 776 +/- 55 U/L; p < 0.001), as was mean radiographic score (12.4 +/- 0.6 for PCP compared with 6.3 +/- 0.5 for non-PCP; p < 0.001). For the whole sample of 93, LDH level was significantly related to chest radiographic score (r = 0.43, p < 0.0001). Significant overlap occurred between the two groups at all levels of LDH such that no cutoff level could be established that impacted significantly on posttest probability of PCP, whereas a radiographic score of > 12 yielded a 96% posttest probability of PCP. CONCLUSIONS Serum LDH level reflects the degree of radiographic abnormality and is elevated in both PCP and non-PCP pneumonia to an extent that limits its utility in differentiating the two processes in hospitalized patients. The extent of radiographic involvement more clearly distinguishes the two conditions.
Alveolar damage in AIDS-related Pneumocystis carinii pneumonia. OBJECTIVE Pneumocystis carinii pneumonia is the most common and serious of the pulmonary complications of AIDS. Despite this, many basic aspects in the pathogenesis of HIV-associated P carinii pneumonia are unknown. We therefore undertook a light and electron microscopic study of transbronchial biopsy specimens to compare pathologic features of P carinii pneumonia and other HIV-related lung diseases. DESIGN AND PATIENTS Thirty-seven consecutive HIV-infected patients undergoing a diagnostic bronchoscopy. RESULTS P carinii pneumonia was characterized by an increase in inflammation, edema, exudate, fibrosts, type II pneumocyte proliferation, and cellular infiltration of the alveolar wall when compared with other lung diseases (all p < 0.05). Electron microscopy showed apposition of the trophozoite to the type I pneumocyte. Erosion of type I pneumocytes was observed in 13 of 15 patients with P carinii pneumonia, whereas none without P carinii pneumonia had this finding (p < 0.05). Erosion of the type II pneumocyte was not observed. CONCLUSION Inflammation, interstitial fibrosis, and alveolar epithelial erosion are characteristic features of P carinii pneumonia. The changes may form the pathologic basis for the respiratory failure seen in patients with P carinii pneumonia. Electron microscopy did not show any diagnostie advantage over conventional light microscopy using routine stains.
Aerosol delivery during continuous nebulization. BACKGROUND AND OBJECTIVES Continuous administration of aerosolized beta 2-agonists has been suggested as an effective treatment for severe reversible airways disease. To facilitate continuous therapy and avoid a feed system for small-volume nebulizers (SVNs), a large-volume medication nebulizer (Vortran HEART) was developed. The goal of this study was to determine actual drug delivery of the HEART and conventional SVNs for both adult and pediatric breathing patterns. DESIGN Output studies were conducted on comparable samples of CIS-US AeroTech II and Hospitak PowerMist SVNs and Vortran HEART large-volume continuous nebulizers. To duplicate clinical aerosol delivery via an aerosol mask, drug particles were inhaled through the mouth of a model of a human face for two test breathing patterns (adult = tidal volume (Vt) of 500 mL, 20 breaths/min, duty cycle of 40%; pediatric = VT of 100 mL, 35 breaths/min, duty cycle of 40%), generated by a ventilator. Radiolabeled particles of saline solution, confirmed to behave identically to albuterol, were collected on absolute filters at the mouth of the face to measure the actual mass of albuterol particles delivered to the airway opening. RESULTS The AeroTech II and PowerMist SVNs delivered 5.14 and 3.74 mg/h, respectively, for the adult breathing pattern and 2.97 and 2.48 mg/h, respectively, for the pediatric breathing pattern. Drug delivery rates of the HEART were a function of drug concentration and ranged from 0.87 to 3.48 mg/h for the adult breathing pattern. For the pediatric breathing pattern, drug delivery rate was a function of drug concentration and inspired minute ventilation and ranged from 0.41 to 1.83 mg/h. CONCLUSION Our data demonstrate that drug delivery to the patient, expressed as inhaled mass over time, is similar for continuous nebulization (HEART system) and intermittently filled SVNs. In addition, for all nebulizers, the influence of the pediatric breathing pattern needs to be considered. Continuous nebulization permits the redistribution of health-care personnel and may reduce the costs of therapy.

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