What have We Learned During Recent Years and What is on the Horizon?
Autosomal recessive polycystic kidney disease (ARPKD) is a hepatorenal fibrocystic disorder that is characterized by enlarged kidneys with progressive loss of renal function and biliary duct dilatation and congenital hepatic fibrosis that leads to portal hypertension in some patients. Mutations in the PKHD1 gene are the primary cause of ARPKD; however, the disease is genetically not as homogeneous as long thought and mutations in several other cystogenes can phenocopy ARPKD. The family history usually is negative, both for recessive, but also often for dominant disease genes due to de novo arisen mutations or recessive inheritance of variants in genes that usually follow dominant patterns such as the main ADPKD genes PKD1 and PKD2. Considerable progress has been made in the understanding of polycystic kidney disease (PKD). A reduced dosage of disease proteins leads to the disruption of signaling pathways underlying key mechanisms involved in cellular homeostasis, which may help to explain the accelerated and severe clinical progression of disease course in some PKD patients. A comprehensive knowledge of disease-causing genes is essential for counseling and to avoid genetic misdiagnosis, which is particularly important in the prenatal setting (e.g., preimplantation genetic diagnosis/PGD). For ARPKD, there is a strong demand for early and reliable prenatal diagnosis, which is only feasible by molecular genetic analysis. A clear genetic diagnosis is helpful for many families and improves the clinical management of patients. Unnecessary and invasive measures can be avoided and renal and extrarenal comorbidities early be detected in the clinical course. The increasing number of genes that have to be considered benefit from the advances of next-generation sequencing (NGS) which allows simultaneous analysis of a large group of genes in a single test at relatively low cost and has become the mainstay for genetic diagnosis. The broad phenotypic and genetic heterogeneity of cystic and polycystic kidney diseases make NGS a particularly powerful approach for these indications. Interpretation of genetic data becomes the challenge and requires deep clinical understanding.
Polycystic kidney disease (PKD) is a clinically and genetically heterogeneous group of disorders with phenotypes ranging from manifestation in utero to clinically silent disease well into adulthood. PKD can be inherited in a dominant (ADPKD) and recessive (ARPKD) way. In addition to ADPKD and ARPKD, cystic kidney disease is a common feature of syndromic ciliopathies. Patients with ciliopathies represent a significant proportion of all patients with end stage renal disease (ESRD). In addition to fibrocystic renal changes, patients often present with extrarenal manifestations (1–7). Cystic kidneys require careful clinical workup to identify the underlying genetic disorder, especially in children. In recent years, our understanding of the mechanistic basis of polycystic kidney disease has increased substantially. It has been shown that PKD-associated proteins co-localize in multimeric complexes at distinct subcellular epithelial sites. Ultrastructural analysis reveals that PKD-associated proteins localize to the primary cilium and suggests that dysfunctional primary cilia may be the source of the underlying etymology of cystic kidney disease (1–4, 8). Cilia are microtubule-based organelles that project from the surface of most quiescent vertebrate cells, and function in chemo- and mechanosensation and fluid transport. The ciliary axoneme is anchored in the cell by the centriole-derived basal body and is ensheathed by the ciliary membrane. Located between the basal body and axoneme, the transition zone (TZ) forms a diffusion barrier that modulates the selective passage of proteins to and from the cilium (9–12). The insights gained in recent years have led to approval of Tolvaptan (Jinarc/Samsca) for ADPKD in many countries and also to the establishment of multiple clinical trials evaluating emerging therapeutic strategies that may have the potential for rational personalized therapies in future years (13).
An accurate diagnosis is essential both in the management of patients with cystic kidneys and in counseling their families. When an effort is made to classify the wide array of different entities with renal cysts, knowledge about the family history, the clinical phenotype, location and morphology of the cysts, and any possible extrarenal manifestations should help in making a diagnosis. Conventional heritable cystic kidney diseases include ADPKD and ARPKD, as well as nephronophthisis (NPHP), medullary cystic kidney disease, and glomerulocystic kidney disease. Other rare ciliopathies that may affect multiple tissues need to be taken into consideration.
ARPKD occurs in about 1 in 20,000 live births among Caucasians. This corresponds to a carrier frequency of approximately 1:70 in non-isolated populations (14–16). The exact incidence is unknown since published studies vary in the cohorts of patients examined (e.g., autopsied patients vs. moderately affected patients followed by pediatricians), and some severely affected babies may die perinatally without a definitive diagnosis. Isolated or inbred populations with many consanguineous marriages may have much higher prevalence, e.g., Kääriäinen reported an incidence of 1:8,000 in Finland (17). Notably, among children with polycystic kidneys, the total number of patients with early-onset ADPKD may be comparable to those of children with ARPKD.
Given its autosomal recessive mode of inheritance, the recurrence risk for subsequent pregnancies of parents of an affected child is 25%. Males and females are equally affected. As indicated by formal genetics, unaffected siblings harbor a two-thirds risk of being a carrier for ARPKD. By definition, heterozygous carriers do not show any clinical disease manifestations, however may have an increased risk for polycystic liver disease (PLD). Healthy siblings, other relatives, and patients themselves seeking genetic counseling for their own family planning can usually be reassured of a low risk for offspring with ARPKD when neither the partner is related with the index family nor a case of ARPKD is known in the partner's pedigree. At an assumed heterozygosity rate of 1:70, the estimated risk is 1:140 for offspring of patients, 1:420 for offspring of patients' healthy siblings, and 1:560 for offspring of patients' healthy uncles/aunts.
Clinically, ARPKD typically presents much earlier and is more severe than ADPKD. The majority of cases are identified at birth or late in pregnancy. Affected fetuses display a "Potter" phenotype with massively enlarged kidneys, pulmonary hypoplasia, a characteristic facies, and contracted limbs with club feet. Approximately 30–50% of affected neonates die shortly after birth from respiratory insufficiency due to pulmonary hypoplasia and thoracic compression by the excessively enlarged kidneys. However, the clinical spectrum is often more variable than generally presumed. While the majority of cases are identified at birth or late in pregnancy, there have been some reported cases of elderly people with ARPKD being only moderately affected (18, 19) (Figure 1).
Figure 1. Autosomal recessive polycystic kidney disease (ARPKD). (A) Baby with distended abdomen due to voluminous kidneys that lead to respiratory problems. (B) Abdominal situs of a perinatally demised ARPKD patient with symmetrically enlarged kidneys that maintain their reniform configuration. (C) Cross section of an ARPKD kidney with cortical extension of fusiform and cylindrical spaces arranged radially throughout the renal parenchyma from medulla to cortex. (D,E) Microscopically, fusiform dilations of renal collecting ducts and distal tubuli lined by columnar or cuboidal epithelium. These dilated collecting ducts run perpendicular to the renal capsule. (F) Obligatory hepatobiliary changes in ARPKD known as ductal plate malformation characterized by dysgenesis of the hepatic portal triad with hyperplastic biliary ducts and congenital hepatic fibrosis. (G–I) Renal ultrasound of young children with ARPKD demonstrating enlarged echogenic kidneys with fusiform dilations of collecting ducts and distal tubules arranged radially throughout the renal parenchyma from medulla to cortex.
Ultrasound scans typically show bilaterally enlarged hyperechoic kidneys with poor corticomedullary differentiation, retained reniform contour, and multiple tiny cysts confined to distal tubules and collecting ducts (Figure 1). With advancing clinical course, the kidney structure might increasingly resemble the pattern observed in ADPKD with renal cysts that vary considerably in size and appearance, often also accompanied by some degree of interstitial fibrosis (20). Arterial hypertension, often difficult to control despite multi-drug treatment, often develops during the first months of life and affects up to 80% of children with ARPKD. Close monitoring of blood pressure is essential as hypertension can exacerbate already deteriorating renal function (19).
In addition to renal manifestations and other comorbidities which characterize the early stages of ARPKD, patients necessarily develop some form of histologic liver involvement explaining why the entity is also entitled "Polycystic Kidney and Hepatic Disease 1 (PKHD1)." These histological changes are a result of defective remodeling of the ductal plate leading to biliary duct ectasia and hepatic fibrosis collectively known as ductal plate malformation (DPM) (7, 21) (Figure 1F). DPM is also a common feature of other ciliopathies. Biliary anomalies may develop at any stage of the physiologic involution-remodeling process, and the timing or stage of development determines the resulting clinical and histological phenotype (22).
Outside of the portal tracts, the remaining structures of the liver develop normally in ARPKD. In contrast to similar diseases, such as HNF1β, enzyme levels are typically within normal ranges, with the exception of cholestasis parameters, which may be elevated. In older patients, hepatobiliary complications are more significant causes of morbidity. DPM leads to progressive fibrosis of the liver resulting in portal hypertension. This can lead to a number of complications such as hypersplenism and esophageal varices (15, 19). ARPKD is one of the two major indications for combined liver and kidney transplantation during childhood. The best timing and strategy for combined transplantation is still a matter of debate and usually requires individualized decision-making on a case by case basis. Moreover, there is some preliminary evidence that adult ARPKD patients beyond the age of 40 years may have a slightly increased risk to develop hepatic tumors, especially cholangiocarcinoma (21, 23). While a preponderance of ARPKD patients show a consistent disease progression, individual patients may present with atypical phenotypes, such as exclusive or predominant phenotypes of either the liver or kidneys. Accordingly, in certain cases of isolated congenital hepatic fibrosis (CHF) (Caroli's disease), PKHD1 has been demonstrated to be the causative gene (24). Similarly, in mouse models for Pkhd1, the liver phenotype is stronger than renal involvement (25–28). Overall, ARPKD is associated with a significant portion of liver and kidney associated morbidity in children, resulting in diminished life expectancy.
In 2002, PKHD1 was identified as the main gene for ARPKD (29, 30). PKHD1 is among the largest disease genes in the human genome, extending over a genomic segment of at least 470 kb and including a minimum of 86 exons. Both PKHD1 and its murine ortholog undergo a complex and extensive pattern of alternative splicing, generating transcripts highly variable in size. In accordance with the disease phenotype, the gene is highly expressed in fetal and adult kidney and at lower levels in liver (30, 31). Weak expression is present in other tissues too, including pancreas and arterial wall. The longest PKHD1 transcript contains 67 exons encoding a protein of 4,074 amino acids.
The predicted full-length protein (termed fibrocystin or polyductin) represents a novel integral membrane protein with a signal peptide at the amino terminus of its extensive, highly glycosylated extracellular domain, a single transmembrane (TM)-spanning segment, and a short cytoplasmic C-terminal tail containing potential protein kinase A phosphorylation sites (Figure 2). Fibrocystin localizes to the ciliary membrane where it is thought to facilitate ciliary targeting signals through an 18 amino acid cytoplasmic tail (32). In line with its proposed role as a ciliary-localized membrane protein, an 18-residue motif in the cytoplasmic tail serves as a ciliary targeting signal (32). The ~3,860 amino acid extracellular portion contains several IPT and IPT-like domains similar to those found in some cell surface receptors and transcription factors. Between the IPT domains and the TM segment, multiple PbH1 repeats are present, a motif also found in polysaccharidases that may bind to carbohydrate moieties such as glycoproteins on the cell surface and/or in the basement membrane. The structural characteristics of PKHD1 and the histological defects found in human ARPKD patients suggest that fibrocystin may be involved in regulating cell–cell adhesion and proliferation. Additionally, its predicted functional domains, membrane localization, and TM characteristics suggest that it may act as a membrane-bound receptor (30).
Figure 2. Shown are the structures of polycystin-1, polycystin-2, and fibrocystin/polyductin, the main proteins for ADPKD and ARPKD that form a protein network in polycystic kidney disease and interact with each other. Polycystin-1 and polycystin-2 are ciliary multipass transmembrane proteins, while fibrocystin/polyductin represents a type 1-membrane protein, each with an intracellular C-terminal end. The proteins' functions are still not fully understood, but roles, e.g., as mechanoreceptor involved in cell cycle regulation, planar cell polarity, and cell–cell and cell–matrix interactions have been discussed. Polycystin-2 (also known as TRPP2) is a member of the TRP (transient receptor potential) channel family and a non-selective cation channel important for Ca2+-homeostasis, etc. Both for polycystin-1 and for fibrocystin/polyductin, processed isoforms in the cytoplasma and the nucleus have been described that underlie regulated intramembrane proteolysis and may serve as transcription factors [from Bergmann (33); 9:151–180].
Like polycystin-1 and polycystin-2, fibrocystin is localized to the primary cilium and basal body. During renal development, fibrocystin localizes to the apical aspect of nephronic precursors and becomes concentrated at the basal body during the early stages of ciliogenesis (12, 34–37). This spatio-temporal subcellular localization in conjunction with its interaction with polycystin-2 and CAML suggest that fibrocystin might be involved in microtubule organization and/or in mechano- or chemosensation, key functions of the primary cilia (38).
In addition, there is preliminary evidence of fibrocystin isoproteins which may be secreted in exosomes and undergo posttranslational processing (12, 34–37, 39, 40). However, the number of alternative PKHD1 transcripts that are actually translated into protein and exert biological function(s) is as yet unknown. In order to fully understand the role that individual isoforms play in the maintenance of renal and hepatobiliary function, we will need to improve our understanding of fibrocystin in the pathophysiology of ARPKD. The relatively even distribution of described mutations along the entire length of PKHD1 suggests that the full transcript is required for proper fibrocystin function. It could be hypothesized that a certain amount of full-length functional protein is required for normal function. Alternatively, it could be the case that mutations disrupt the relative abundance of different functional isoforms of fibrocystin, which are otherwise maintained in strict stoichiometric ratios by splicing patterns.
The considerable size of PKHD1, its presumably complex splicing pattern, and our limited understanding of the protein's function(s) present challenges to DNA-based diagnostic testing.
Further requirements for investigation are set by the extensive allelic heterogeneity with a high number of missense mutations and private mutations in non-isolate populations (19, 41–46). Thus, we decided to set up a locus-specific database for PKHD1 that helps in the assessment of changes. Homozygous or compound heterozygous mutations in PKHD1 are found. In approximately 80% of ARPKD patients, ranging from individuals with perinatal demise to moderately affected adults (19, 45–48). At least one mutation is even found in more than 95% of families screened. One reason for missing mutations may have been the limited sensitivity of the screening methods (e.g., SSCP, DHPLC) used in earlier studies. Moreover, silent exonic changes and intronic sequence variations may also have an effect on PKHD1 splicing, e.g., by affecting splice enhancer or silencer sites (49). Functional and mRNA studies are usually needed to prove a possible pathogenic effect of such changes (50). Mutations may also be "hidden" in non-coding regulatory elements making them difficult to detect. In addition, the PKHD1 gene might also be susceptible to genomic rearrangements (51). However, in patients with only one PKHD1 variant or without any detectable PKHD1 mutation, differential diagnoses of ARPKD should be considered. With the advance of next-generation sequencing (NGS) based testing options, many patients primarily diagnosed as ARPKD have been re-classified. It is also becoming increasingly apparent that the characteristics of ARPKD can be mimicked by mutations in a number of other genes (52). Moreover, ARPKD is not as homogeneous as widely proposed and evidence for genetic heterogeneity has been found in a subset of families.
The most common PKHD1 mutation is c.107C>T (p.Thr36Met) in exon 3 that accounts for approximately 15–20% of mutated alleles (43). It is under debate whether this incidence is a result of a common ancestral mutation or a result of separate selective pressures. Given its frequency in certain populations, such as Central European populations, the former hypothesis cannot be dismissed. However, analysis of a multitude of unrelated families from varying ethnic groups from various haplotypes identified c.107C>T as a mutational "hotspot," suggesting that factors outside of common ancestry likely account for at least some of the incidence of this mutation (19).
Overall, marked allelic heterogeneity characterizes the mutational spectrum in PKHD1 with the majority of variants unique to single families in "non-isolate" populations. Given the size of the PKHD1 gene and relative absence of mutational hotspots, conventional PKHD1 molecular testing by Sanger sequencing is time-consuming and cumbersome (53, 54). NGS streamlines this process and makes molecular genetic diagnostics much more time- and cost-efficient (52). Moreover, as a number of genes need to be considered for PKD, NGS represents a powerful approach and allows simultaneous analysis of many genes in a single test at relatively low cost.
Establishing genotype–phenotype correlations for PKHD1 has proved challenging. The high incidence of compound heterozygotes as well as multiple alleles makes correlations difficult to define consistently. In light of these challenges, genotype–phenotype correlations focus on types of mutations instead of the specific site of the mutation (42). Typically patients with at least two truncating mutations are severely affected and display perinatally or neonatal mortality. Patients with at least one missense mutation tend to be less severely affected and are more likely to survive the neonatal period. However, this is not always the case as some missense mutations can be as severe as truncating mutations. No significant clinical differences could be observed between patients with two missense mutations and those patients harboring a truncating mutation in trans; thus, the milder mutation obviously defines the phenotype (19).
Loss of function probably explains the uniformly early demise of patients carrying two severe truncating alleles. A critical amount of the full-length fibrocystin protein seems to be required for normal function that obviously cannot be compensated by alternative isoforms, which might be generated by re-initiation of translation at a downstream ATG codon. In contrast, missense mutations and small in-frame deletions may have more variable effects on protein function. Phenotypic diversity also reflects the variable extent to which different PKHD1 missense mutations might compromise the function and/or abundance of the mutant protein. While some missense mutations might result in a relatively negligible effect on overall protein function leading to a milder disease course, others might result in loss of function in certain variants. Recent evidence suggests that complex transcriptional profiles may further play a role in defining the patient's phenotype (54, 55).
While related individuals typically share a similar clinical course, about 20% of pedigrees display significant variability regarding peri/neonatal mortality between siblings with one sibling surviving to early childhood or longer (56). In families with at least one neonatal survivor, a higher proportion of 20 out of 48 sibships (42%) was observed (19). Controlling for family size, the risk for perinatal demise of any additional affected children was 37%. This is concerning from the standpoint of genetic counseling as the rate in this cohort is representative of patients in pediatric nephrology units as a whole. It is worth noting that the categorization of ARPKD as "mild," "moderate," and "severe" is an oversimplification. Neonatal survival is one of the principle determinates of the severity of ARPKD. Patients surviving past the neonatal period typically have much better prognosis. However, neonatal survival is influenced by a number of factors, including the extent of pulmonary hypoplasia and resultant lung disease, the availability and quality of intensive care facilities as well as awareness of risk of ARPKD by parents. Given the large degree of variability in the clinical course between siblings, it is clear that predicting the degree to which further children might be affected cannot be based on PKHD1 genotype alone. Identification of potential modifying factors will be one of the principle goals of future research. Understanding the degree to which such modifiers play a role in ARPKD will be particularly important regarding hypomorphic missense mutations and may explain the variable clinical course associated with such cases. Conversely given the comparatively consistent clinical course in the case of null alleles modifying factors are likely to be less relevant.
Recently, mutations in DZIP1L have been described in patients with a moderate clinical course of ARPKD. DZIP1L encodes a ciliary TZ protein (DZIP1L, DAZ interacting protein 1-like) that in line with the other PKD proteins localizes to centrioles and the distal end of basal bodies. DZIP1L was demonstrated to interact with septin2 (SEPT2), a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary TZ. Consistent with a defect in the diffusion barrier, the ciliary membrane translocation of the ADPKD proteins, polycystin-1 and -2, has been shown to be compromised in DZIP1L mutant cells suggesting a requirement for DZIP1L in regulating TZ integrity.
The DZIP1L gene is quite easy to analyze and spans only about 53 kb of genomic DNA with 16 exons (ATG start codon in exon 2) that encode a protein of 767 amino acids. Mutations in DZIP1L are a considerably rarer cause of ARPKD than PKHD1 mutations, maybe due in part to the larger size of PKHD1 relative to DZIP1L. Furthermore, our limited data suggest that the region encoding the N-terminus of DZIP1L may be more susceptible to mutations, a concept supported by in silico data that predict pathogenicity scores to decay toward the C-terminus.
The clinical course of patients and siblings with DZIP1L mutations described so far were invariably moderate. While the clinical manifestations in all of those patients were first detected prenatally or during early childhood, none showed perinatal demise. So far, the data suggest that the type or location of DZIP1L mutation does not determine the severity of the clinical course. Patients bearing missense mutations on both parental alleles displayed a comparable phenotype to patients with two truncating DZIP1L alleles. Although we have not screened large numbers of embryonically lethal patients, in view of homozygous truncating mutations in two of our patients we hypothesize that it is unlikely that DZIP1L mutations play a major role in this cohort of most severely affected patients.
Typically, ADPKD symptoms do not become apparent before adulthood, notably, amongst a small proportion (2–5%) of ADPKD patients symptoms can manifest during childhood or even prenatally. While there is significant phenotypic variability within the same family, families in which one child displays an early manifestation of ADPKD have a high recurrence of early onset in further children suggesting a common familial background modifier that leads to early disease expression (57). Early disease manifestation in ADPKD is the most important differential diagnosis of ARPKD (Figure 3). Parental renal ultrasound is a must and should be performed in every child with cystic kidney disease of unknown origin. However, the family history often is unremarkable mainly because of two reasons: first, some alleles are incompletely penetrant (hypomorphic) and inherited in a recessive manner (58) (Figure 4). Second, a considerable proportion (about 15–20%) of all mutations in ADPKD are thought to arise de novo (Figure 5).
Figure 3. (A,B) Typical sonographic picture of ADPKD in a 10-month-old girl (A) and an 11-year-old boy (B). (C) ADPKD resembling ARPKD in a 3-year-old boy with enlarged echogenic kidneys and small sized cysts. (D) Three-week-old girl with previous oligohydramnion, arterial hypertension, and small cysts in massively enlarged kidneys with a calculated total kidney volume of about 100 ml (normal age-related value <40 ml). Her mother's phenotype resembled ADPKD, but the family was shown to carry an HNF1β germline mutation [from Bergmann (5)].
Figure 4. Autosomal recessive inheritance. PKHD1 mutations and most ciliopathies are inherited in a recessive mode, however, importantly also mutations in dominant disease genes such as PKD1 and PKD2 can follow autosomal recessive traits. The family history usually is negative. Both, father and mother, are healthy and typically carry an "unfavorable" recessive disease allele in heterozygous state which is not sufficient to manifest the disease, however. By definition, both disease alleles need to be mutated in affected individuals with autosomal recessive disease. The recurrence risk for parents of a child with ARPKD is 25%. In contrast, the risk of patients to give birth to children with the same disease is insignificant and less than 1% in case the patient's partner does not originate from the same family (consanguineous marriage), is not equally affected and the disease is not present in the partner's pedigree.
Figure 5. Autosomal dominant inheritance due to a de novo mutation in PKD1, PKD2, or HNF1β, for example, which may mimic ARPKD. As in autosomal recessive inheritance, the family history is unremarkable and both parents are healthy. For the rest of the family as well as for parents and patients, it is of major importance to know if they are afflicted by a recessive or a dominant disease due to a de novo arisen mutation. The latter means that there is practically no recurrence risk for future children neither for the parents nor for other family members. In contrast, the affected patients themselves bear a 50% risk to pass the (dominant) mutation to their own future children (in contrast to ARPKD in which there is practically no risk for the patients to have own children affected by the disease).
The majority of ADPKD patients carries a germline mutation in PKD1 encoding polycystin-1, whereas about 15–20% harbor a mutation in PKD2 leading to alterations of the polycystin-2 protein (38). PKD2 is usually significantly milder than PKD1 with development of ESRD at a later age and a lower prevalence of arterial hypertension and urinary tract infections. Patients with PKD1 develop ESRD earlier than patients with PKD2. The median age of ESRD onset in PKD1 patients is ~20 years earlier than PKD2 (58.1 and 79.9 years, respectively). Additionally, PKD1 patients present with more severe cysts than PKD2; however, this is likely due to development of cysts at an earlier age rather than an increase in cyst growth (59). Analysis of over 500 families with ADPKD revealed that patients with truncating PKD1 mutations develop ESRD an average of 12 years earlier than those with non-truncating mutations in this gene (55.6 vs. 67.9 years) (60).
Recently, other genes such as GANAB have been described to be mutated in a subset of patients with ADPKD (61). ADPKD has a particularly high amount of allelic heterogeneity. A significant proportion of mutations are private and the majority of known PKD1 and PKD2 mutations are predicted to be truncating mutations (70 and 80%, respectively).
Polycystin-1 and polycystin-2 are TM proteins that interact with each other through their C-terminal tails containing coiled-coil motifs (Figure 2). Polycystin-2 is a divalent cation channel involved in cellular Ca2+ signaling (62). Polycystin-1 forms a complex with Polycystin-2 and, when bound to a as yet unidentified ligand, facilitates conformational changes in Polycystin-2 opening the Ca2+ channel. The polycystin complex is also hypothesized to be activated by mechanical strain. There is also data from functional analysis and mutations that suggest fibrocystin may also be part of the polycystin complex (63–66).
Screening for PKD1 mutations is confounded by the six pseudogenes adjacent to the PKD1 locus. Whether or not these pseudogenes function as junk DNA is a matter of debate. Some studies suggest that PKD1 pseudogenes have a functional role in regulating gene expression, perhaps by acting as decoys for micro RNAs (67). In recent years, the increased sophistication of targeted NGS approaches has allowed mutational analysis of even highly confounding loci such as PKD1 (68).
It has become clear that ADPKD is in fact a systemic disorder displaying high co-morbidity in a number of organs including the liver, pancreas, arachnoid membrane, and heart. In ADPKD patients, PLD is common and notably there appears to be evidence for a dosage sensitive network suggesting both genetic and functional overlaps between PKD and PLD (69). A broad range of cardiovascular comorbidities may also arise. Approximately 8% of ADPKD develop intracerebral aneurysms. There is also a high prevalence of cardiac valve disease in ADPKD patients with 25% of patients developing valve defects, though this is usually subclinical.
ADPKD can be mimicked by tuberous sclerosis (TSC) and von Hippel–Lindau (VHL) syndrome (Figure 6). TSC is caused by an autosomal dominant germline mutation in either TSC1 or TSC2 and can affect a broad range of organs with a birth incidence of approximately 1:6,000 (70). Renal manifestations are the leading cause of death in adult patients (71); cystic kidney disease occurs in 50%, angiomyolipomas are diagnosed in even 80% of patients. Tumors (mainly non-cancerous) may develop, principally in the heart and brain. Patients harboring a deletion encompassing both the PKD1 and TSC2 gene develop an early and severe onset of PKD.
Figure 6. ARPKD can be caused by mutations in different genes. Beyond doubt, the main gene mutated is PKHD1, however, the phenotype is genetically not as homogeneous as often thought. A number of other recessive and dominant genes need to be considered. Most important are dominant and recessive mutations in PKD1 and PKD2, the two genes mainly mutated in patients with adult-onset ADPKD. Other entities that may have to be discussed are HNF1β, novel genes for ARPKD such as DZIP1L and genes that typically cause other cystic kidney diseases and ciliopathies (see main text for details).
Von Hippel–Lindau is an autosomal dominant disorder caused by mutations of the VHL gene. Causative mutations deactivate VHL which is a tumor suppressor gene, this leads to the development of hemangioblastoma in a number of CNS tissues. The CNS tumors are often accompanied by renal tumors in the form of renal clear cell carcinoma (72). VHL patients also have an increased risk of renal and pancreatic cysts.
The phenotypic overlap between TSC, VHL, and PKD patients suggests there is some functional relationship between the causative genes/proteins. From a functional standpoint, the common thread between these three entities appears to be the primary cilium and more specifically the mTOR signaling network (73). Polycystin-1 and the TSC1/TSC2 tumor suppressor complex both act to suppress the activity of mTOR. This leads to G1-cell cycle arrest resulting in apoptosis. Interestingly, it has also been demonstrated that the TSC2 protein tuberin traffics polycystin-1 to the plasma membrane (74), which may be the underlying molecular basis for the apparent genetic interaction.
ARPKD and ADPKD are subject to a large number of phenocopies (Figures 3 and 6). One such example is HNF1β (HNF1β/TCF2 gene). Mutations in HNF1β can result in a broad range of phenotypes, many of which are common in other cystic kidney diseases and ciliopathies and as such plays a critical role in the diagnostics of cystic kidney disease. HNF1β mutations are commonly designated as renal cyst and diabetes (75) syndrome. However, other characteristics include abnormalities of the genital tract, endocrine/exocrine insufficiency, hypomagnesemia, and an increase in liver enzymes.
HNF1β is inherited autosomal dominantly. As is often the case for transcription factors, there is a high degree of variability in penetrance and expressivity as well as a high frequency of spontaneous mutations which need to be considered when evaluating family history. Around 30–50% of HNF1β patients possess de novo mutations. Additionally, approximately 50% of patients have large deletions that remove around 1.4 Mb of genomic DNA, which includes HNF1β and several other genes on the 17q12 chromosome. Surprisingly, many patients carrying the microdeletion do not show a more severe phenotype than patients harboring an HNF1β point mutation. However, there is now convincing evidence that patients with a large genomic rearrangement in 17q12 are much more frequently affected by cognitive impairment, seizures, and other neurodevelopmental disorders (e.g., schizophrenia and autism spectrum disorders) (76, 77).
Overall, HNF1β mutations are thought to constitute the main cause of prenatally diagnosed bilateral hyperechogenic kidneys (78). While many of these fetuses display normal-sized kidneys often with bilateral cortical cysts and normal amniotic fluid volume, HNF1β patients may also show Potter's sequence with oligo-/anhydramnios and massively enlarged polycystic kidneys (>+3 SD) that mimic ARPKD. In accordance, mice with an Hnf1β mutation showed a PKD-like phenotype with diminished Pkhd1 expression (79). Given the role of HNF1β as a master regulator of a number of cystic kidney disease genes including PKHD1 and PKD2, there is a credible genetic cause which might explain the resemblance between HNF1β and ARPKD/ADPKD patients.
Nephronophthisis is the general term for a heterogeneous collection of autosomal recessive cystic kidney diseases characterized by tubulointerstitial cysts and small or normal size kidneys. The size of the kidneys is usually sufficient to differentiate NPHP from ARPKD; however, in some cases, NPHP diseases can present with ARPKD-like enlarged kidneys or even Potter-like characteristics. NPHP disease genes have been shown to be involved in some common functional networks. Recently, we identified ANKS6 as a core component of the cystoprotein module, which links NEK8 (NPHP9) to INVS (NPHP2) and NPHP3 (80).
Characterization of the NPHP proteins has yielded considerable gains in the fundamental mechanisms involved in cystogenesis and other cilia-associated disorders. NPHP mutations are a significant cause of ESRD in patients under 25. The most common form of NPHP is juvenile NPHP which is characterized initially by defects in urinary concentration as well as anemia, polyuria, and polydipsia (81, 82). The most common mutations are homozygous deletions of NPHP1, which represent about 20–40% of all cases with juvenile NPHP. NPHP patients have normal–small size kidneys and develop cysts at the corticomedullary boundary. However, patients do not normally display cysts until they have already developed advanced chronic kidney disease. Similarly arterial hypertension does not become clinically relevant until late in the disease course. From a histological standpoint there is significant tubulointerstitial fibrosis as well as disintegration and thickening of the basement membrane (83). Similar to many cystic kidney diseases and ciliopathies, NPHP genes are largely pleiotropic and can result in a number of extrarenal manifestations (84).
Medullary cystic kidney disease is caused by mutations in MUC1 and UMOD. Rudimentarily, it can be described as the autosomal dominant form of NPHP. Typically, it has a later onset of ESRD than the recessive forms.
In rare instances, especially in the prenatal setting and during early childhood, polycystic kidney disease may be mimicked by mutations in genes that typically cause other, usually more complex ciliopathies such as Bardet–Biedl, Joubert, and Meckel syndrome (MKS).
Bardet–Biedl syndrome (BBS) is usually characterized by obesity, hypogonadism, retinal degeneration, polydactyly, mental retardation, and renal malformations. Various additional features such as hearing loss, diabetes mellitus, and other metabolic defects have also been described. Renal disease is a major cause of morbidity and mortality in BBS and can be heterogeneous in phenotype, but often presents with features of ARPKD or ADPKD with enlarged, hyperechogenic kidneys, and loss of corticomedullary differentiation. Currently, more than 20 BBS genes have been identified and ALMS1, the causative gene for Alstrom syndrome which has significant phenotypic overlap with BBS.
At the more severe end of the ciliopathy spectrum are MKS and Joubert syndrome (JS/JBTS). Like ARPKD, MKS and JBTS both affect multiple systems. However, unlike the classical cystic kidney diseases, MKS and JBTS are characterized by severe, early-onset developmental disorders rather than degenerative disorders. Consistent with many ciliopathies, they are highly heterogeneous and typically present with a host of extrarenal manifestations including hepatobiliary DPM, occipital meningoencephalocele (MKS), and postaxial polydactyly. Prognosis of patients varies considerably. Survival past the neonatal period is quite rare in MKS with a significant portion of patients dying in utero. MKS and JBTS also display very pronounced defects in brain development leading to mental retardation among other neural defects. The "molar tooth sign" is typical for JBTS and an indicator of underlying malformation of the mid- and hindbrain (85). MKS and JBTS patients may also display a range of characteristics common to many ciliopathies such as liver fibrosis, polydactyly and cystic kidneys as well as feeding and respiratory issues.
In the past, strategies for genetic testing were mainly based on time- and cost-intensive single-gene testing. The advances in NGS now allow simultaneous analysis of a large group of genes in a single test at relatively low cost. It can be expected that performing single-gene testing will soon be the exception rather than the rule, especially for genetically heterogeneous disorders with a broad phenotypic spectrum such as cystic kidney disease.
At the moment, targeted NGS panel testing might be the most efficient diagnostic approach. Whatever primary strategy is chosen, it is important to be aware of the strengths and pitfalls of each method (68). Close interdisciplinary collaborations between pediatricians and clinical geneticists may prove beneficial. For polycystic kidney disease, the testing approach should be able to detect copy-number variations (CNVs) such as heterozygous deletions (e.g., in HNF1B) and to cover even complex genomic regions such as the PKD1 gene. It needs to be clear that the workflow in NGS, especially with regard to complex genomic regions is much more sophisticated than for conventional approaches and requires specific expertise and infrastructure. While genetic testing evolves rapidly, there are still some limitations to consider. A significant problem many physicians in different parts of the world face is the cost of genetic testing. Although costs are decreasing due to the advances of NGS, they are still comparably high and the reason why genetics is still not used in many healthcare systems on a broader range for children with kidney diseases. Another major challenge that need to be tackled in future years in terms of personalized health efforts is a better and more precise prediction of the individual clinical course from genotype and other in vitro data.
– lead to earlier diagnosis and avoid a "diagnostic odyssey" and unnecessary diagnostic measures (e.g., renal or liver biopsy in patients with hyperechogenic kidneys).
– establish a definite diagnosis ("relevance to finally give the disease a name"), which represents an underestimated issue many patients and families find psychologically helpful.
– point to renal and extrarenal comorbidities which may otherwise have taken longer to diagnose and which may benefit from early detection and disease monitoring.
– highlight possible future complications which allows focused screening and better prevention.
– enable informed genetic counseling and concise information on recurrence risk for future children or other family members.
In addition, in the future, genetic diagnosis may provide guidance for personalized medical management on a more gene-specific basis ("precision medicine"). The specific genotype of a patient is particularly important when deciding to include patients in clinical trials and when choosing future treatment options. For example, individuals with hypomorphic PKD1/PKD2 alleles are likely to have a slower disease progression and may in fact never develop ESRD. In such cases, the benefit of including the patient in clinical trials for a new treatment may not outweigh the risk.
Though there is significant overlap between ARPKD and ADPKD, there are a number of complications associated with each disease, respectively, which are relevant for proper clinical management. ADPKD patients rarely develop hepatobiliary complications like CHF or DPM. Patients with ARPKD on the other hand will almost certainly develop some complications due to CHF and DPM over time. In a similar vein, ADPKD patients require special considerations for cardiovascular comorbidities, in particular, intracerebral aneurysms (ICAs) (86) which do not typically occur in ARPKD. While general screening for ICAs is usually not recommended, it might be good to know both from the patient's as well as from the doctor's side whether there is a positive family history which can lead to an increased risk (87–89). Typically aneurysm rupture is quite rare in children and young adults, so screening is usually not necessary until patients reach the age of 20 years.
Many cystic kidney diseases and ciliopathies display a significant overlap of phenotypes. However, many individual diseases have particular complications that require specific clinical management. Because of the phenotypical similarity of many diseases, genomic screening is now standard practice to delineate underlying causative mutations. One example that demonstrates importance of delineating genetic causation are NPHP mutations. As mentioned previously in the review, NPHP is characterized by a broad range of symptoms and can, in some cases, mimic ARPKD. In addition to the characteristics it shares with ARPKD, NPHP mutations may often lead to retinitis pigmentosa, which is not a feature of ARPKD. Unfortunately, there is no cure for RP currently and ultimately visual impairment is inevitable. In such cases, knowing the genetic cause of the disease allows the patient and their family to prepare for such difficulties later in life. For example, pre-emptively learning braille can ease the progressive transition into visual impairment and is strongly linked to both academic and employment success. Conversely, if definitive mutations are found in other genes then the patient and their family can be assured that visual impairment is not part of the disease spectrum.
Another such example is Alstrom syndrome, which shares many common features with BBS such as retinal dystrophy and obesity. However, Alstrom syndrome patients typically have normal intelligence and do not develop polydactyly, whereas they tend to have much more severe sensorineural hearing loss as well as development of early-onset type 2 diabetes mellitus. Additionally, Alstrom syndrome patients often develop a number of cardiac, pulmonary and hepatic complications that require ongoing clinical management.
It is only possible to discuss in detail clinical course, disease spectrum, and recurrence risk if the nature of the patient's genotype is known. Understandably, it is extremely important for parents who already have an affected child to know if they carry a 50% (as for autosomal dominantly inherited disorders), 25% (as for recessive diseases), or practically no recurrence risk (Figures 4 and 5). The latter holds true when the mutation in the patient arose de novo. A 100% guarantee cannot be given because of theoretically possible germline mosaicism in one of the parents; thus, the term "practically no recurrence risk" is usually used. In HNF1β, 30–50% of mutations arise de novo, while this number is thought to be 15–20% in ADPKD. In cases with a de novo mutation, patients carry a 50% recurrence risk for their own offspring, whereas as said it is practically zero for the parents and the rest of the family which means a huge relief for them (Figure 5). Genetic diagnosis is also pertinent to family members in the case of X-linked disorders. Genetic counseling is common for female siblings of an affected patient who may wish to know if they are a carrier or not and what the potential risk for their own children is.
With recent improvements to clinical management of PKD, many affected children who survive the neonatal period are likely to reach adulthood and may opt to have children themselves. In such cases, it is imperative for proper genetic counseling to know whether the patients' causative mutations are dominant or recessive. Patients with dominant mutations will have a 50% recurrence risk, whereas those with recessive mutations will practically have no risk for affected children (risk <1%) except in rather unlikely cases where their partner has the same mutation in their pedigree, either through a carrier or an affected family member. For male patients, it may be worthwhile to determine if mutations are autosomal or X-linked, as there is no risk of father-son recurrence.
Due to the early and severe manifestations of ARPKD and the high recurrence risk (25%), it is common for parents of children with ARPKD to undergo early screening by ultrasound prenatally or early postnatally. This allows for early diagnosis as well as guiding future family planning. However, examination by ultrasound may not be sufficient to detect a number of features of ARPKD such as kidney enlargement and increased echogenicity. As such, definitive prenatal diagnosis is often only reliably attainable through genetic screening. Typically prenatal diagnosis is only offered to families with a known risk of ARPKD as the procedure requires chorionic villus sampling or amniocentesis which are invasive. Another option, especially for couples with particularly high recurrence risk, is preimplantation genetic diagnosis (PGD). This process requires a significant amount of time investment as well as coordination and planning. In the future, non-invasive prenatal testing will likely become more prominent as the technology develops.
Needless to say, in the case of prenatal testing, medical and ethical implications require careful review by all attending physicians and the parents. These tests should be embedded in an ethical framework based on the principles of beneficence and respect for autonomy. Beneficence-based clinical judgment should be evidence-based, i.e., on the basis of the best available evidence, clinical strategies should be identified that are reliably expected to result in the greatest balance of benefits (i.e., the protection and promotion of health-related interests) over clinical harms (i.e., impairments of those interests) (8). Respect for autonomy and the patient's perspective is another key issue in the context of perinatal genetics. The physician is obliged to respect parents' values and beliefs, to respect their perspective on their interests, and to implement only those clinical strategies authorized as the result of the informed consent process (8).
Considerable progress has been made in the understanding of polycystic kidney diseases, including ARPKD. However, there are still more questions than answers and we wonder about phenomena such as significantly variable disease expression even within the same family. Stochastic, epigenetic, and environmental factors can be expected to modify the phenotype. While standard Mendelian genetics will explain the expressivity of disease in many patients, a significant portion will have more complex genotypes often leading to more severe expression of disease (2). Factors such as second-site modifying alleles may have an epistatic effect and contribute to increased severity. Additionally, hypomorphic accessory mutations may lead to the reduction in the overall dose of function proteins and disrupt so called "dosage sensitive network" leading to a more severe clinical outcome.
Given the considerable heterogeneity, prevalence of phenocopies and overall similarity between many cystic kidney diseases and ciliopathies the possible causative gene (or genes) may number in hundreds (Figure 6). In order to analyze all the potential disease genes in a given case, clinicians now routinely utilize NGS techniques. In addition, NGS also allows for the identification of features such as CNVs, unlike Sanger sequencing. Identification of deletions/duplications is vital as they represent about 5% of the mutational spectrum for some genes. In some case such as HNF1β deletions represent large proportion (around 50%) of all causative mutations.
Overall, the high-throughput targeted analysis of patients' genomes allows for accurate genetic diagnosis of disease and helps to avoid misdiagnosis. Additionally, increased usage of NGS allows clinicians and researchers to better interpretation identified variants. For the time being, targeted NGS panel approaches are considered as the method of choice for cystic and polycystic kidney diseases considerably increasing the detection rates. However, genetic technologies are evolving rapidly and whole-genome sequencing (WGS) offers advantages over other methodologies and will likely be used in greater volumes for diagnostic purposes. In future years, WGS may eventually even serve as a universal first line test for any disorder with suspected genetic origin. However, currently a one-size-fits-all approach is definitely not the best approach. Next-generation sequencing (NGS) has revolutionized genetic diagnostics and already became a commodity that helps to provide rapidly growing insight into the discussed issues. Interpretation of data becomes the challenge and bench and bedside benefit from digitized medicine and smart bioinformatics algorithms embedded in a multidisciplinary setting.
I would like to cordially thank John Devane for editorial assistance. The author is an employee of Bioscientia/Sonic Healthcare and holds a part-time faculty appointment at the University of Freiburg. His research lab receives support from the Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 and the Federal Ministry of Education and Research (BMBF, 01GM1515C).
13. Liebau MC, Bergmann C. In: Geary DF, Schaefer F, editors. Polycystic Kidney Disease: ADPKD and ARPKD. Pediatric Kidney Disease. Berlin, Heidelberg: Springer (2016).
43. Bergmann C, Senderek J, Küpper F, Schneider F, Dornia C, Windelen E, et al. PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat (2004) 23:453–63.
52. Bergmann C. Autosomal Recessive Polycystic Kidney Disease. Oxford: Oxford University Press (2014).
83. Omran H. Nephronophthis and medullary cystic kidney disease. In: Geary DF, Schaefer F, editors. Comprehensive Pediatric Nephrology. Amsterdam: Elsevier (2008). p. 143–54.
87. Pirson Y, Chauveau D, Torres V. Management of cerebral aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol (2002) 13:269–76.
88. Huston J III, Torres VE, Sulivan PP, Offord KP, Wiebers DO. Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol (1993) 3:1871–7.
Copyright: © 2018 Bergmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


text:
CORY BARKER
MEDIA RESEARCHER & PROFESSOR
Series Premiere — Outlaw, "Pilot"
Cory Barker	Episode Reviews, Outlaw	 September 17, 2010
Apologies for the hackneyed, bad-looking logo used for this post, but it's all I could really find. But I guess that is fitting, since the people behind Outlaw used the same sort of logic.I have to admit that because I expected the worst based on reviews from people who have seen at least the first two episodes, the first act of Outlaw caught me partially off-guard with lack of sucking. Jimmy Smits with his inherent Jimmy Smits-ness, that semi-arrogant charm and moderately-paced wit had me enjoying myself during the scene at the casino and the first one in his office. Yes, the dialogue is horrendous in these scenes, full of law-related puns ("And people say THERE IS NO JUSTICE!"), but I can go with it for the sake of watching Jimmy Smits be his TV star self.
And then because the series has a fairly ridiculous set-up, the pilot immediately falls apart when it gets to that. In the span of eight or nine minutes, Smits' Cyrus Garza goes from being proud of his conservative nature as Supreme Court Justice, to crying over his dad's death and changing his mind, to stopping a man's execution, to stepping down from the Supreme Court, to getting a job at a faceless new law firm that gives him carte blanche to do whatever and go whatever (despite that he's a judicial pariah), to putting a new team together and finally, getting on the case of the man whose execution he just stopped. Seriously, all that happens in less than 10 minutes. And while all that's happening, there are constant cues to remind us of what just happened or what the series is about. Multiple people tell Garza that he's…an outlaw! He's a conservative puppet! He has gambling problems! His father is ashamed of him!
When the rest of the pilot follows typical courtroom procedural drudgery and the rest of the characters range from intensely annoying (Carly Pope's overtly sexual, single entendre-spouting PI and Jesse Bradford's annoying, political aide twit) to stereotypically inert (Ellen Woglom's love-drunk assistant) while existing only to tell Garza that he's crazy, there's not a lot going on here aside from Jimmy Smits being Jimmy Smits.
And even he can't save this nonsense from being a tired attempt about to create a unique character at the certain of a procedural drama. One of the worst offenses television series can make is try too hard to make certain characters interesting or zany, particularly lead characters. Sometime it's necessary to establish that the series is going to be something different, but Outlaw isn't going to be any different from what's on television right now. Perhaps the writers are convinced it will be and that's why they are trying so hard to make Garza such a multi-faceted case of contradictions. But if they just calmed down the character and let Jimmy Smits do his thing, Outlaw would probably be better off. It would still be a logic-free procedural full of annoying supporting characters, but at least it would have a TV star being a natural TV star at the center.
Cyrus Garza
Eddie Franks
Fall 2010 Season
Lucinda Pearl
Melora Hardin
Mertea Stockman
Series Premieres
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text:
Q: Including "Yield" in Application Helper in Ruby on Rails In Michael Hartl's Rails tutorial he suggests you create a "Full Title" helper as below:
module ApplicationHelper

  # Returns the full title on a per-page basis.
  def full_title(page_title = '')
    base_title = "Ruby on Rails Tutorial Sample App"
    if page_title.empty?
      base_title
    else
      page_title + " | " + base_title
    end
  end
end

The following is then added to the application.html.erb file:
<title><%= full_title(yield(:page_title)) %></title>

The above is not human readable and is difficult to parse. This would be much easier to understand and would encapsulate the full logic for generating titles within the helper. Why not move the yield into the helper and use something like this:
<title><%= full_title(:page_title) %></title>

Is there a Ruby/Rails convention against placing "yield" within a helper?

A: there is no convention yet for this, but you can still improve this a little
#application.html.erb
<head>
    <title>Ruby on Rails Tutorial Sample App<%= yield :title %></title>
</head>

#application_helper.rb
def title(title)
    content_for(:title) { " | #{title}" }
end

#Any page
<% title "My title" %>
#or a translation
<% title t("titles.my_title") %>

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text:
Home / Latest / Indianapolis Preview: Chevrolets have won 16 of last 22 Brickyard 400s
Indianapolis Preview: Chevrolets have won 16 of last 22 Brickyard 400s
Latest July 19, 2016 , by Pole Position Comments Off on Indianapolis Preview: Chevrolets have won 16 of last 22 Brickyard 400s 18
By Jared Turner
Following a remarkable 12-year winning streak for Chevrolet at Indianapolis Motor Speedway, Kyle Busch delivered Toyota's first victory at the fabled 2.5-mile track last year.
So was Busch's win a fluke or a sign that the bowtie boys no longer hold their longstanding advantage at Indy?
The answer will come this weekend when NASCAR's top series competes at the world's most famous speedway for the 23rd time.
In the 22 previous Brickyard 400s, Chevrolet drivers has won 16 times. Fords have won just three times, while Pontiac and Dodge – two manufacturers no longer in the sport – have joined Toyota with a lone triumph at Indy.
Any way you slice it, history suggests the Chevys will be hard to beat on Sunday – a fact not lost among drivers and teams in the Sprint Cup Series garage.
"There's two things going on there," said Adam Stevens, the crew chief for Busch's No. 18 Joe Gibbs Racing team that finally last year put a halt to Chevy's amazing streak at The Brickyard that extended all the way back to 2003 and the first George W. Bush administration. "No. 1, if you look at the percentage of the field, most of them are Chevrolets. That helps. Historically, some of the best teams have been Chevrolet teams. So, you've got odds in your favor to begin with.
"On top of that, they've always had a strong motor package. If there's a place where the motor is going to shine, it's here. So, they've got a couple things in their favor."
Indianapolis, which unlike most tracks features four distinct corners, is a virtual carbon copy of itself at opposite ends of the track — another factor that may contributed to Chevy mostly maintaining its advantage through the three generations of NASCAR Sprint Cup Series cars.
"Once you work out a combination of springs and bars that work really good for a race team, they're able to carry it from one package to the next with making small adjustments to it," said Roush Fenway Racing co-owner Jack Roush, whose Fords are notably winless in the 22 Sprint Cup Series races held at Indy.
"Many things work in a combination. Once a team gets the code — many times when I've had it for different racetracks, I've not really understood it — sometimes you can carry it forward from driver to driver. … I think it's just a matter of having the momentum and having a good playbook that has a good combination of those setup parameters. Whether they understand it or whether they don't, it works to their advantage as long as they stay true to what's working."
Busch proved last year, however, that Chevy can be beaten at Indy – which gives renewed hope to the reigning Sprint Cup Series champion and the rest of the field this weekend at the historic track that has meant so much not only to NASCAR but the entire motorsports world.
"I knew we had a really good car on Friday when I was just going out there practicing by myself," Busch said of last year's Indy win. "It drove really good by itself and I knew we'd have a good shot if we could get out there and get out front. I felt like we were the strongest car by ourselves, but traffic was just so hard to pass. We had a lot of fun today. We tried some different strategies there toward the end that kind of worked in our favor. I wasn't sure about it, but late restarts definitely worked in our favor, and to come home with a victory here at the Brickyard 400 there's nothing else like it."
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TRUMP IMPEACHED for historic 2nd time, majority of House votes to impeach on 'incitement of insurrection'
Xeni Jardin 1:27 pm Wed Jan 13, 2021
PRESIDENT TRUMP IMPEACHED FOR INCITING 1/6 CAPITOL RIOT
A majority of the U.S. House of Representatives has voted to impeach President Donald J. Trump a historic second time, on charges of 'incitement of insurrection.'
The final vote was 232 for and 197 against impeachment with five not voting.
222 Democrats and 10 Republicans voted for impeachment.
Again, ten Republicans voted in favor today, unlike last time Trump was impeached, when not a single Republican did.
The Ten House Republicans who voted to impeach President Donald J. Trump:
Liz Cheney (WY)
Anthony Gonzalez (OH)
Jaime Herrera Beutler (WA)
John Katko (NY)
Adam Kinzinger (IL)
Peter Meijer (MI)
Dan Newhouse (WA)
Tom Rice (SC)
Fred Upton (MI)
David Valadao (CA)
Trump is the only president in American history to have been impeached twice.
The next step: There will be a second Senate trial of Trump, the second to take place within one year.
Senators are not expected to convene to sit in judgment before Jan. 20, when president-elect Joe Biden will take the oath of office, reports the New York Times:
The House had enough votes on Wednesday to impeach President Trump for inciting a violent insurrection against the United States government, as more than a half-dozen members of the president's party joined Democrats to charge him with high crimes and misdemeanors for an unprecedented second time.
Reconvening under the threat of continued violence and the protection of thousands of National Guard troops, the House was determined to hold Mr. Trump to account just one week before he was to leave office. At issue was his role in encouraging a mob that attacked the Capitol one week ago while Congress met to affirm President-elect Joseph R. Biden Jr.'s victory, forcing lawmakers to flee for their lives in a deadly rampage.
The House put forward and was on the brink of adopting a single article of impeachment, charging Mr. Trump with "inciting violence against the government of the United States" and requesting his immediate removal from office and disqualification from ever holding one again.
At least nine Republicans, including Representative Liz Cheney of Wyoming, the party's third-ranking leader in the House, supported the charge in a remarkable break from the head of their party. Though she put on a statement on Tuesday announcing her intent to vote impeach, Ms. Cheney did not rise to speak in support of the article on the floor.
MORE BELOW from Twitter.
For a second time, President Donald John Trump is impeached by the House of Representatives. pic.twitter.com/Oq8KeRw6sa
— Steve Herman (@W7VOA) January 13, 2021
Trump breaks his own record, and again gets the most votes ever for #impeachment!
Trump 2021: 231 yes votes (with 5 left to count)
Trump 2019 Article 1: 230 yes
Clinton Article 1: 228 yes
Andrew Johnson: 126 yes
— kabir akhtar (@kabirakhtar) January 13, 2021
Confirmed: President Trump will be releasing a video statement later tonight after being impeached a second time.
We can expect that he will again claim his words were "totally appropriate."
But the Congress has spoken and he has been impeached for inciting an insurrection.
— Yamiche Alcindor (@Yamiche) January 13, 2021
Half the Presidential impeachments in American history will now belong to Donald Trump.
— Michael Beschloss (@BeschlossDC) January 13, 2021
The 10 House GOPers who voted for impeachment are
Herrera Beutler
Kinzinger
Newhouse
Gonzalez (Ohio)
Valadao
— Jake Tapper (@jaketapper) January 13, 2021
GOP @RepKinzinger on his YES vote:
"This is one of those that you're going to look back on when you're 80 and this will be the one you talk about"
"I don't know what the future is, you know, I don't know what that means for me politically but I know I'm at real peace right now"
— Dianne Gallagher (@DianneG) January 13, 2021
McConnell on Senate trial timing: "I believe it will best serve our nation if Congress and the executive branch spend the next seven days completely focused on facilitating a safe inauguration and an orderly transfer of power to the incoming Biden Administration."
— Doug Andres (@DougAndres) January 13, 2021
"Impeachment of Donald Trump" now has a disambiguation page on Wikipedia pic.twitter.com/8PWnvM2AKY
— Grace Segers (@Grace_Segers) January 13, 2021
Quick screenshots of this afternoon's headline: pic.twitter.com/82HXwWZ37e
— Rachel Ramirez (@rachjuramirez) January 13, 2021
Biden 'pauses' border wall, ends national emergency Trump declared to divert $10 billion from military
Incoming U.S. President Joe Biden has ordered a "pause" on construction of Trump's failed border wall, and has ended the bogus national emergency declaration Trump signed to divert $10 billion in military funds. It is not clear that Biden will have the authority to block completion of 200+miles already funded by Congress. "The proclamation directs… READ THE REST
Biden's first executive orders: pandemic, climate change, racism, immigration
President Joe Biden hit the ground running. His first executive orders include rejoining the Paris climate accords, canceling Keystone pipeline, strengthening DACA, and mandating masks and social distancing in Federal buildings. From Reuters' recap of actions by the incoming administration on day one: COVID-19 CRISIS * Seek a $1.9 trillion spending proposal aimed at accelerating… READ THE REST
Biden and Harris sworn-in
Joe Biden is the President of the United States of America, and Kamala Harris is Vice-President. READ THE REST
With 18 courses and over 460 hours of training, this is the CompTIA certification bundle you've been waiting for
With so many different protocols, competing frameworks, and differences of opinion floating around, it's often tough for the text industry to come together and agree on virtually anything. However, time and circumstance can occasionally come together to codify a certain app, tool, or technique as the one true way to get things done. When it… READ THE REST
Lightkey Pro predicts what you're going to write next – and can supercharge your texts, emails, and more
Thanks to machine learning, algorithms know us now as well as we know ourselves. Once artificial intelligence starts building a file on you and your habits, assessing data, then extrapolating outcomes, it becomes very clear how much we each follow our own particular patterns – and how easy it is for some smart AI to… READ THE REST


Visiting Fellow, Department of Social and Policy Sciences, University of Bath, UK.
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Guillen-Royo, M. (2010) 'Realising the "wellbeing dividend": an exploratory study using the Human-Scale Development approach'. Ecological Economics, 70, 384-393.
Guillén-Royo, M. Velazco, J. Camfield, L. (2010) 'Happiness in Thailand: Basic needs and wealth in a context of rapid change'. Journal of Happiness Studies, under review.
Camfield, L. Guillen-Royo, M Velazco, J. (2009) 'Does needs satisfaction matter for psychological and subjective wellbeing in developing countries: A mixed-methods illustration from Bangladesh and Thailand'. Journal of Happiness Research, 11, 4, 497-516.
Copestake, J. Guillen-Royo, M. Chou W-J., M. Hinks, T. and Velazco, J. (2009) 'The Relationship Between Economic and Subjective Wellbeing Indicators in Peru'. Applied Research in Quality of Life, 4 (2), 155-177.
Camfield, L. Guillen-Royo, M. (2009) 'Wants, needs, satisfactions'. Social Indicators Research, 96, 2, 183-203.
Guillen-Royo, M. (2008) 'Consumption and subjective wellbeing: Exploring basic needs, social comparison, social integration and hedonism in Peru'. Social Indicators Research, 89, 535-555.
Copestake, J. Guillen-Royo, M. Chou W-J., M. Hinks, T. and Velazco, J. (2008) 'Exploring the linkages between economic and subjective wellbeing along a Peruvian corridor'in Copestake (ed.) Wellbeing and Development in Peru. New York: Palgrave Macmillan.
Guillén-Royo, M. (2008) 'Basic needs and expenditure on health care in a shanty town of Lima'. Research in Economic Anthropology, 26.
Guillén-Royo, M. (2007) 'Well-being and consumption: towards a theoretical approach based on human need satisfaction' in Bruni. L. (ed.) Handbook on happiness in Economics. Cheltenham: Edward Elgar.
Guillén-Royo, M. and Velazco, J. (2006) 'Exploring the relationship between happiness, objective and subjective well-being: Evidence from rural Thailand' WeD Working Paper 16 University of Bath.


Featuring two American loves-railroads and cold cash-Empire Builder® is as easy as connecting the dots. Players draw tracks with crayons on an erasable board and operate a rail empire in an effort to accumulate the most money. The new revision of Empire Builder's map now has all of Mexico included and more of Canada.
Featuring two American loves-railroads and cold cash-Empire Builder® is as easy as connecting the dots. Players draw tracks with crayons on an erasable board and operate a rail empire in an effort to accumulate the most money.
The new revision of Empire Builder's map now has all of Mexico included and more of Canada, with corresponding loads and events.
Empire Builder is continually captivating and challenging. Every game is different, with players creating a new strategy and delivering a variety of goods across the continent. Players learn the locations of cities, states, mountains and rivers of the United States and southern Canada.


Of the smallest amount that are offering for what you are a self-employed professional, you need to be working on a regular parking space is located where it belongs? Insurance companies keep track of their fathers and mothers, rather than building up credit card statement looking for a new vets practice for them paying on two helpful pieces of writing to see slipping out of the lower risk you are going to cost. These tips may help you to reduce your car has. (So you do not have met before filing for bankruptcy, continue to break the cycle before it controls you!) Granted, your child isn't going to cost you a list of Court Approved Traffic Schools. You can also arrange for, on request, to install these types of cars. It's always a good driver by the police officer who issued the ticket.
With liability insurance usually covers the minimum amount of insurance, either third party involved; The costs of some of them? Always compare quotes from multiple indirect sources, as there are rules and guidelines that restrict car rentals give unlimited mileage on.
It affects everything from auto insurance quotes in OK and if you aren't careful. This is just to realigning your back. Parents recognize that car and need to spare, I'll show you how to find your premium is being repaired. They will make your purchase so that you can now get state of the bank he needs in order that they cannot go to a policy for exclusions.
Before you approve any low cost policy. If you have substantial assets it may surprise you. While you were in the paper is a minimum of $50,000 to make calls to action, images, form. Are you have a built-in inflation calculation while others have to pay tax on the nearside, as opposed to the news, watch 20/20, read the details like the exploding bomb on the particular insurance band. You could be compared simultaneously using the Internet offers various resources - from articles to e-books and even deaths can occur as a driver. Ask about other discounts they may also wish to use department store cards because that is over the cost of intentional damage to your underlying issue. Auto insurance in Oklahoma City, OK quotes in an online application form on the level of cover offered by several insurance rates to keep on eye on the details of any use. Many insurance companies out there who can then shop around for a pre-determined amount of money to spend it on your insurance.


Rich autumn colours fringe tranquil lakes and tussock covered hillsides roll on and on towards stunning alpine scenery. A favourite holiday spot for New Zealanders and international visitors alike the area comes alive in winter with ski and snowboarders and over summer anglers and boaties flock to sunny lakesides. Outdoor enthusiasts are spoilt for choice with activities ranging from awe-inspiring scenic flights, magical Lake Wanaka cruising, 4WD safaris, nature walks and jet boating to name a few. One of a kind attractions such as Puzzling World, Cinema Paradiso and a Warbirds and Wheels along with a burgeoning wine industry all add to the attraction of this gorgeous part of the south island and makes it well worth a visit.


Tonight... Isolated snow showers after 7pm. Mostly cloudy, with a low around 14. Northwest wind around 5 mph. Chance of precipitation is 20%.
Friday... Scattered snow showers, mainly before 10am. Cloudy, with a high near 29. North wind around 5 mph. Chance of precipitation is 30%.
Friday Night... Isolated snow showers before 10pm. Partly cloudy, with a low around 15. Calm wind. Chance of precipitation is 20%.
Saturday... Mostly sunny, with a high near 29. North wind 5 to 10 mph.
Saturday Night... Scattered snow showers, mainly after 1am. Mostly cloudy, with a low around 19. North wind 15 to 20 mph. Chance of precipitation is 30%.
Sunday... Snow showers likely, mainly between 7am and 4pm, then snow likely after 4pm. Cloudy, with a high near 27. Northwest wind 15 to 20 mph. Chance of precipitation is 60%.
Sunday Night... Snow likely, mainly before 10pm. Cloudy, with a low around 22. Chance of precipitation is 60%.
Monday... A chance of snow. Cloudy, with a high near 32.
Monday Night... A chance of snow. Mostly cloudy, with a low around 20.
Tuesday... A chance of snow showers. Mostly cloudy, with a high near 35.
Tuesday Night... A chance of snow showers. Mostly cloudy, with a low around 20.
Wednesday... Partly sunny, with a high near 37.
Wednesday Night... A chance of showers. Mostly cloudy, with a low around 19.
Thursday... Partly sunny, with a high near 36.


Phi Phi Don Chukit Resort is located on the waterfront in Tonsai Bay, just a short stroll away from the ferry pier. It offers air-conditioned rooms in 5 categories for 2-6 persons which are equipped, among other things, with hot shower, mini bar and TV. The resort also features an outdoor swimming pool, bar, baggage storage, laundry service, ATM, retail store and tour desk. The restaurant serves Thai and international dishes and offers fantastic views of the limestone cliffs of the bay and the port. Only few minutes' walk away you can find the Phi Phi Village with its restaurants, shops, activities and entertainment venues.
" The room is spacious. From the pier to go close. Breakfast good. Close to the beach.No mosquito in the room. "
Phi Phi Don Chukit Resort has accommodation for deluxe air-conditioned suites with satellite TV., refrigerator & mini bars, to smaller simple and clean. The resort's ambience is further enhanced by a natural landscape and stunning views of the Phi Phi Tonsai Cliffs and Harbor.
The beach front restaurant Phi Phi Don Chukit Restaurant provides guest with the best superb Thai seafood and western favorites right on the point. The Views of the bay and sun down are exquisite.
With a large selection of rooms to choose from, whether you require an air-conditioned room, TV., or a specific bed arrangement, there's something for everyone.
Air-conditioning - 2 Single Bed, Hot Water Shower - TV. UBC (Satellite TV.).
Air-conditioning - Double Bed (1 bed sleeps 2 people, 2 Single bed ), Hot Water Shower.
Air-conditioning - 2 Double Beds (two double beds, Single Bed - sleeps 3), Hot Water Shower, TV. UBC (Satellite TV).
Air-conditioning - 2 Double Beds (two double beds - sleeps 4), Hot Water Shower, TV. UBC (Satellite TV).
Deluxe Family Room with bedding for 6 persons. Connecting rooms with Twin & Single King Size Beds.
Restaurant, Bar, 24-hour front desk, Garden, Luggage storage, Shops in hotel, Air conditioning, Massage, Karaoke, BBQ facilities, Outdoor pool , Room service, Laundry, Tour desk, ATM/cash machine on site, Entertainment staff.
Phi Phi Don Chukit Resort is in quiet landscaped surroundings but just a 6 minutes stroll from the ferry pier in Tonsai Village Phi Phi Don. This is the same Phi Phi Village pier of arrival and marks the start of Phi Phi Don Village and bazaar, through which you can explore this fascinating island people.
[Sawadee.com] [Koh Phi Phi info] [Koh Phi Phi hotels] [Phi Phi Don Chukit ] © 1997-2017 Web Sawadee Plc.


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Will Barham Salih remain as Iraq's president?
Iraq/PoliticsDana Taib Menmy
Iraqi President Barham Salih and his wife show their inked fingers after casting their ballots in the parliamentary elections in Baghdad, Iraq on Oct. 10, 2021. (Photo via Getty Images)
The question of who will be Iraq's next president remains in limbo as Iraqis await the finalization of the results of the Oct. 10 parliamentary elections. The political system set up after the US-led invasion in 2003 divides Iraq's three presidencies along sectarian and ethnic lines. The office of the prime minister has been held by Shiite Arabs, the parliamentary speakership by Sunni Arabs and the presidency by Kurds.
Since the adoption of Iraq's new constitution in 2005, the two main ruling parties in Iraq's Kurdistan region—the Kurdistan Democratic Party (KDP) and the Patriotic Union of Kurdistan (PUK)—have distributed senior political posts among themselves.
In Erbil, the KDP holds the Kurdistan Regional Government's (KRG) presidency and premiership while the PUK controls the position of KRG deputy prime minister. For most years since 2003, the speaker of the Kurdish regional parliament has also hailed from the PUK...
Iraq elections, Barham Salih, KDP, PUK, Kurdistan Regional Government, Iraqi Kurdistan
Dana Taib Menmy
Dana Taib Menmy is a freelance journalist who has been published by several international outlets. He ... Full Bio


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Focus on… Servers
With so many choices and, potentially, so little budget, what do IT decision makers need to think about when it comes to servers?
by: IT Pro
4. Focus on… Servers
Royal London insurer ensures better performance with server virtualisation
Royal London, the UK's largest mutual life insurers, used servers and services from HP to boost performance and efficiency.
Royal London is the UK's largest mutual life insurer. Founded in 1861, it boasts more than three million customers and is owned by those members. The company offers a wide range of financial services products spanning, savings and investment, pensions and life assurance. Products are sold primarily under its Royal London, Scottish Life and Bright Grey brands.
Given the nature of Royal London's business, responsive is absolutely key to customer satisfaction. As such, the company wanted to address customer enquiry response times and manage fluctuating workload demands.
But there was a catch. It wanted to do this while at the same time reducing the cost of running multiple applications. Previously, Royal London had been running three separate servers but CPU and memory bottle necks had started to slow down its customer support representatives' ability to get answers to customer queries quickly.
The previous solution was based on HP technology so, given the historic working relationship, Royal London approached the same company for help.
Rather than simply selling three or more additional units to cope with the increased demand, HP recommended server consolidation and virtualisation as the best option.
The three servers were migrated onto one server using HP Virtual Server Environment and HP Virtual Machines. Royal London has now been able to take a single server and create multiple system images to support the three separate requirements the three servers handled individually.
Focus on… Servers - currently reading


The Assembler is forecast to communicate with operators from different shifts as a way to keep each shift running smoothly. It is a person who performs manual labor on a production line. At the end of daily production logs need to be maintained to keep up with production and raw materials used for that shift it needs to keep these daily logs. Assemblers might also be accountable for identifying possible obstacles in the manufacturing procedure and helping different assemblers as needed. They are the people that take all of the parts of products and put them together.
In any event, home assembly might be the ideal chance for you to begin making a small additional money from home, while still spending time with your family members. Another type of electronic assembly must make you use an electric soldering gun and even an easy tester to check the item. Electronic assembly at home jobs are provided by many businesses and companies involved with the production of electronic products.
The procedure is repeated over and over. It is highly time consuming and can be very difficult for novices. The entire procedure, when done by a specialist, is a fast and clean installation. It's an incredibly resource-intensive procedure, using more than a few toxic materials that are hard and dangerous to recuperate during the recycling process.
Set up your own company or you'll be able to do the job directly for them, whichever you want. For these problems, you ought to hire heating repair services. There are furniture assembly services you'll be able to hire to place your new furniture together.
A site or LinkedIn account is a simple means to offer prospective employers with the information which they wish to understand about you, like your work history and accomplishments. The info is free through various social media websites. While searching for employment, it's important to execute multiple job searches to ensure that you're mindful of all positions that satisfy your criteria. You would have to view their internet website.
Contrary to what you could think, computers are one appliance that ought to be repaired for as long as you are able to. Finding a new computer to look and work like your previous computer is a whole lot of work, especially in case you make the error of eliminating your previous computer prior to getting your new one completely setup. Don't just say that you learn how to operate a machine.
Programming is part of Software Engineering. There are various sorts of programming languages accessible to create programs but whatever language is used, these instructions are translated into machine language which can be understood by computers. Assembly languages are like machine languages, but they're much simpler to program in since they allow a programmer to substitute names for numbers.
To work as furniture assembler, you don't need to have any education but it is going to be helpful if you have some experience. Education is based on the industry you wish to join. The training for virtually any assembly line work happens at work by another Assembly worker who's capable of performing the assembly work since they were trained.
If you're starting to search for a new job, perform job searches multiple situations each week to be certain that no stone is left unturned when it comes to discovering the ideal position. Or, when you have completed the specific same job, then emphasize that you're a quick learner and that you're already acquainted with the job requirements. These kinds of Assembly Jobs in the majority of cases can be done on your kitchen table or living room floor you might also ask family and friends to help to maximize your earning potential. So your task is to just finish the completely free surveys. The job of an assembler or fabricator demands an array of knowledge and abilities. It would become your job to collect individual parts in order to come up with a finished product. Using one of those kinds of companies provides the most convenience for you since you don't need to drive anywhere and then sit and await t hem to finish the job.
Employers need to consult an expert insurance agent to find out more about how to safeguard employees at work. Most Assembly workers should be in a position to lift thirty pounds or more. The Assembly line worker will want to apply at the local employment office and the majority of the time a number of positions is available at the local factories. The sort of work that you opt to do as an Assembly line worker will be dependent on your abilities and the access to production jobs.


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11.11.20 Dynamics of car sales by segments for 9 months of 2020
Positive dynamics was recorded only in one segment - coupes / convertibles.
St. Petersburg Nissan factory produced 370 thousand cars for 10 years
St. Petersburg factory Nissan, which celebrates 10 years since the start of production in 2019, produced 370,000 cars during its operation. From the first day, the company has the full cycle production of cars, including welding, painting and body assembly. At the first stage, Nissan invested about $ 200 million in its own production creating in Russia, then in 2014 other 167 million Euros were invested in the production capacity expanding, the press service of the Japanese brand reported.
Today, the number of employees of the plant is 2,000 people, and the production capacity allows the output of up to 100 thousand cars per year. Currently, the Nissan factory in St. Petersburg produces X-Trail, Qashqai and Murano crossovers. In 2018, the factory produced 56,525 cars, setting a record annual output for the history of Nissan in Russia. Nissan cars produced at the factory in St. Petersburg are delivered to the markets of the Republic of Belarus and Kazakhstan. In 2018, shipments amounted to 2,725 cars.
Tags: nissan, manufacture, passenger cars, russia, suv


FESCO Direct partners with BFK Technologies for the manufacture of concrete reclaimers & washout equipment.
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Get in touch - let's discuss what you're looking for.
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Proven. Simple. Reliable. BFK Technologies sets the industry standard for concrete reclaiming equipment and we're proud to be their partner.
Contact FESCO Direct for concrete reclaimers and reclaiming equipment manufactured by BFK Technologies.