An empirical approach for defining acceptable levels of risk: a case study in team sports.

OBJECTIVES: To determine acceptable levels of risk in sport and to compare these with values used in occupational settings. DESIGN: Cross-sectional, questionnaire-based study. SETTINGS: Seven soccer and 11 rugby union teams. SUBJECTS: 140 male athletes and 108 male and 100 female spectators associated with soccer and rugby union teams. MAIN OUTCOMES: Views on acceptable frequencies with which athletes sustain acute injuries of various levels of severity. RESULTS: The responses of athletes and spectators were similar, although spectators consistently indicated a higher acceptable frequency of injury than athletes. There were no significant differences in responses as a function of respondents' gender and age. The results confirmed an inverse relationship between the acceptable frequency of occurrence and the severity of injury, although the relationships identified by the risk-averse and risk-taking minorities within the sample population were widely different. CONCLUSION: The mean frequency-severity risk relationship identified by athletes and spectators in soccer and rugby was similar to the relationship routinely used for risk assessments in industry and commerce.

A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation.

Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the polycystic kidney and hepatic disease (PKHD1) gene encoding the protein fibrocystin/polyductin. The aim of our study was to produce a mouse model of ARPKD in which there was no functional fibrocystin/polyductin to study the pathophysiology of cystic and fibrocystic disease in renal and non-renal tissues. Exon 2 of the gene was deleted and replaced with a neomycin resistance cassette flanked by loxP sites, which could be subsequently removed by Cre-lox recombinase. Homozygous Pkhd1(del2/del2) mice were viable, fertile and exhibited hepatic, pancreatic, and renal abnormalities. The biliary phenotype displayed progressive bile duct dilatation, resulting in grossly cystic and fibrotic livers in all animals. The primary cilia in the bile ducts of these mutant mice had structural abnormalities and were significantly shorter than those of wild-type (WT) animals. The Pkhd1(del2/del2) mice often developed pancreatic cysts and some exhibited gross pancreatic enlargement. In the kidneys of affected female mice, there was tubular dilatation of the S3 segment of the proximal tubule (PT) starting at about 9 months of age, whereas male mice had normal kidneys up to 18 months of age. Inbreeding the mutation onto BALBc/J or C57BL/6J background mice resulted in females developing PT dilatation by 3 months of age. These inbred mice will be useful resources for studying the mechanisms underlying the pathogenesis of ARPKD.

The 2000 canine distemper epidemic in Caspian seals (Phoca caspica): pathology and analysis of contributory factors.

More than 10,000 Caspian seals (Phoca caspica) were reported dead in the Caspian Sea during spring and summer 2000. We performed necropsies and extensive laboratory analyses on 18 seals, as well as examination of the pattern of strandings and variation in weather in recent years, to identify the cause of mortality and potential contributory factors. The monthly stranding rate in 2000 was up to 2.8 times the historic mean. It was preceded by an unusually mild winter, as observed before in mass mortality events of pinnipeds. The primary diagnosis in 11 of 13 seals was canine distemper, characterized by broncho-interstitial pneumonia, lymphocytic necrosis and depletion in lymphoid organs, and the presence of typical intracytoplasmic inclusion bodies in multiple epithelia. Canine distemper virus infection was confirmed by phylogenetic analysis of reverse transcriptase-polymerase chain reaction products. Organochlorine and zinc concentrations in tissues of seals with canine distemper were comparable to those of Caspian seals in previous years. Concurrent bacterial infections that may have contributed to the mortality of the seals included Bordetella bronchiseptica (4/8 seals), Streptococcus phocae (3/8), Salmonella dublin (1/8), and S. choleraesuis (1/8). A newly identified bacterium, Corynebacterium caspium, was associated with balanoposthitis in one seal. Several infectious and parasitic organisms, including poxvirus, Atopobacter phocae, Eimeria- and Sarcocystis-like organisms, and Halarachne sp. were identified in Caspian seals for the first time.

Mathematical models to assess strategies for the control of gastrointestinal roundworms in cattle 1. Construction.

Mathematical models were constructed to simulate the effect of Ostertagia ostertagi infections on the growth of young cattle. The equations are based on System Dynamics using the DYSMAP 2 software package in their construction. A pasture and animal growth model simulates the growth of pasture and the influences of management and climate on it; cattle feed intake and conversion into energy for maintenance and liveweight gain; the effect of the parasite burden on feed intake and utilization of energy. This model was then combined with one of the life cycle of O. ostertagi in order to determine the effect of worm burdens on animal growth rate in a range of farm conditions, such as stocking rate, grazing history of the pasture, and rainfall. By converting the resultant liveweight gain into a monetary value, an economic assessment of alternative worm control strategies can be made. In this paper the construction of the models with equations and assumptions is given in detail.

Mathematical models to assess strategies for the control of gastrointestinal roundworms in cattle 2. Validation.

A computer model of the population biology of Ostertagia ostertagi in young cattle and the effect of the parasite on animal growth has been constructed. It was validated against results from field trials where worm populations and rate of growth of cattle treated with anthelmintics were compared to similar groups of untreated animals. A close correlation between observed and predicted values for faecal egg and pasture larval counts was seen in the cattle which had been treated with an oxfendazole pulse release bolus at turnout. Timings and peak values were less accurately predicted in the untreated cattle. Although predictions for live weight gain during the grazing season indicated that the model may be overestimating the potential growth rate of cattle, it is considered that the model provides a suitable tool for comparing the effectiveness of different worming programmes under farm conditions. The computer simulation also allowed examination of the underlying influences and interactions between parasitological factors, such as numbers of immature and adult worms, and animal and pasture factors, such as sward height, grass consumption and feed conversion, in the parasite's influence on animal performance.

Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects.

A high level of polycystin-1 expression is detected in kidneys of all patients with autosomal dominant polycystic kidney disease (ADPKD). Mice that overexpress polycystin-1 also develop renal cysts. Whether overexpression of polycystin-1 is necessary for cyst formation is still unclear. Here, we report the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotypic characterization in comparison with the del34 mutants that carry a 'truncation mutation' in Pkd1. We show that null homozygotes develop the same, but more aggressive, renal and pancreatic cystic disease as del34/del34. Moreover, we report that both homozygous mutants develop polyhydramnios, hydrops fetalis, spina bifida occulta and osteochondrodysplasia. Heterozygotes also develop adult-onset pancreatic disease. We show further that del34 homozygotes continue to produce mutant polycystin-1, thereby providing a possible explanation for increased immunoreactive polycystin-1 in ADPKD cyst epithelia in the context of the two-hit model. Our data demonstrate for the first time that loss of polycystin-1 leads to cyst formation and defective skeletogenesis, and indicate that polycystin-1 is critical in both epithelium and chondrocyte development.

Analysis of cyanobacterial toxins by physicochemical and biochemical methods.

Cyanobacteria (blue-green algae) produce a wide range of low molecular weight metabolites that include potent neurotoxins, hepatotoxins, and cytotoxins. The accumulation of such toxins in freshwaters, and in brackish and marine waters presents hazards to human and animal health by a range of exposure routes. A review is presented of developments in the detection and analysis of cyanobacterial toxins, other than bioassays, including application of physicochemical, immunoassays, and enzyme-based methods. Analytical requirements are considered with reference to recently derived guideline levels for the protection of health and to the availability, or otherwise, of purified, quantitative cyanobacterial toxin standards.

Diagnostic accuracy of paediatric echocardiograms interpreted by individuals other than paediatric cardiologists.

OBJECTIVE: To assess the diagnostic error rate among echocardiograms undertaken by individuals other than paediatric cardiologists in our referral area. METHODOLOGY: External group: The charts and echocardiographic results of all patients who had undergone outside echocardiograms between January 1996 and December 1999 were reviewed (110). Age at echocardiography, diagnostic complexity, presence of any diagnostic errors and the severity of any diagnostic errors were identified. Internal group: To assess our own error rate, the initial echocardiographic diagnoses of 100 patients undergoing cardiac catheterisation or corrective surgery were compared with the post-catheterisation or postoperative diagnoses. Age and diagnostic complexity were also assessed in the control group. RESULTS: Diagnostic errors occurred in 47/110 patients (44%) of the externally studied group (of which 24% were either major or life threatening) as opposed to 3/100 of the internally studied group, despite the internally studied group being of increased diagnostic complexity. Errors were more common and of increased severity in infants less than 1 month of age but extended throughout all age groups. Major and life threatening errors increased with increasing diagnostic complexity. In the externally studied group, 8/47 errors were patients inappropriately designated as normal. Four of these patients required cardiac surgery or interventional cardiac catheterisation. CONCLUSIONS: This study suggests an unacceptably high error rate in paediatric echocardiographic diagnoses by non-paediatric cardiologists throughout all age groups. Such errors are more likely in younger infants and with increasing diagnostic complexity.

Relationship between novel isoforms, functionally important domains, and subcellular distribution of CD164/endolyn.

Functional analyses have indicated that the human CD164 sialomucin may play a key role in hematopoiesis by facilitating the adhesion of human CD34(+) cells to the stroma and by negatively regulating CD34(+)CD38(lo/-) cell proliferation. We have identified three novel human CD164 variants derived by alternative splicing of bona fide exons from a single genomic transcription unit. The predominant CD164(E1-6) isoform, encoded by six exons, is a type I transmembrane protein containing two extracellular mucin domains (I and II) interrupted by a cysteine-rich non-mucin domain. The 103B2/9E10 and 105A5 epitopes, which specify ligand binding characteristics, are located on the exon 1-encoded mucin domain I. Three human CD164(E1-6) mRNA species, exhibiting differential polyadenylation site usage, are differentially expressed in hematopoietic and non-hematopoietic tissues. This study provides additional evidence that human CD164(E1-6) represents the ortholog of murine MGC-24v and rat endolyn. Comparative analysis of murine MGC-24v/CD164(E1-6) with human CD164(E1-6) revealed two potential splice variants and a similar genomic structure. Whereas the human CD164 gene is located on chromosome 6q21, the mouse gene occurs in a syntenic region on chromosome 10B1-B2. By confocal microscopy, human CD164 in CD34(+)CD38(+) hematopoietic progenitor (KG1B) and epithelial cell lines appears to be localized primarily in endosomes and lysosomes, with low concentrations at the cell surface. However, in a minority of KG1B cells, CD164 is more prominently expressed at the plasma membrane and in the recycling endosomes, suggesting that its distribution is regulated in cells of hematopoietic origin.

The first fluorescent sensor for boronic and boric acids with sensitivity at sub-micromolar concentrations--a cautionary tale.

The first reported fluorescent sensor for boronic and boric acids is actually not a sensor for boronic and boric acids but rather is a sensor for protons; the system is also not the first fluorescent sensor since Alizarin has been used as a fluorescent sensor for boric acids since 1936.

A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype.

Three founder transgenic mice were generated with a 108 kb human genomic fragment containing the entire autosomal dominant polycystic kidney disease (ADPKD) gene, PKD1, plus the tuberous sclerosis gene, TSC2. Two lines were established (TPK1 and TPK3) each with approximately 30 copies of the transgene. Both lines produced full-length PKD1 mRNA and polycystin-1 protein that was developmentally regulated, similar to the endogenous pattern, with expression during renal embryogenesis and neonatal life, markedly reduced at the conclusion of renal development. Tuberin expression was limited to the brain. Transgenic animals from both lines (and the TPK2 founder animal) often displayed a renal cystic phenotype, typically consisting of multiple microcysts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation, characteristic of ADPKD, were also seen. All animals with two copies of the transgenic chromosome developed cysts and, in total, 48 of the 100 transgenic animals displayed a cystic phenotype. To test the functionality of the transgene, animals were bred with the Pkd1(del34) knockout mouse. Both transgenic lines rescued the embryonically lethal Pkd1(del34/del34) phenotype, demonstrating that human polycystin-1 can complement for loss of the endogenous protein. The rescued animals were viable into adulthood, although more than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd1(del34/+) animals. The TPK mice have defined a minimal area that appropriately expresses human PKD1. Furthermore, this model indicates that over-expression of normal PKD1 can elicit a disease phenotype, suggesting that the level of polycystin-1 expression may be relevant in the human disease.

Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue.

BACKGROUND: The mutational mechanism responsible for cyst formation in polycystic kidney disease 1 gene (PKD1) remains controversial, with data indicating a two-hit mechanism, but also evidence of polycystin-1 expression in cystic tissue. METHODS: To investigate this apparent paradox, we analyzed polycystin-1 expression in cystic renal or liver tissue from 10 patients with truncating PKD1 mutations (including one early-onset case) and 2 patients with severe disease associated with contiguous deletions of TSC2 and PKD1, using monoclonal antibodies (mAbs) to both extreme N-(7e12) and C-terminal (PKS-A) regions of the protein. Truncation of the C-terminal epitope from the putative mutant proteins in each case allowed exclusive assessment of the nontruncated protein with PKS-A. RESULTS: In adult PKD1 tissue, the majority of cysts (approximately 80%) showed polycystin-1 expression, although staining was absent in a variable but significant minority (approximately 20%), in spite of the normal expression of marker proteins. Unlike adult PKD1, however, negative cysts were rarely found in infantile PKD1 or TSC2/PKD1 deletion cases. CONCLUSIONS: If a two-hit mutational mechanism is operational, these results suggest that the majority of somatic mutations in adult PKD1 are likely to be missense changes. The low level of polycystin-1-negative cysts in the three "early-onset" cases, however, suggests that a somatic PKD1 mutation may not always be required for cyst formation.

Coordinate expression of the autosomal dominant polycystic kidney disease proteins, polycystin-2 and polycystin-1, in normal and cystic tissue.

A second gene for autosomal dominant polycystic kidney disease (ADPKD), PKD2, has been recently identified. Using antisera raised to the human PKD2 protein, polycystin-2, we describe for the first time its distribution in human fetal tissues, as well as its expression in adult kidney and polycystic PKD2 tissues. Its expression pattern is correlated with that of the PKD1 protein, polycystin-1. In normal kidney, expression of polycystin-2 strikingly parallels that of polycystin-1, with prominent expression by maturing proximal and distal tubules during development, but with a more pronounced distal pattern in adult life. In nonrenal tissues expression of both polycystin molecules is identical and especially notable in the developing epithelial structures of the pancreas, liver, lung, bowel, brain, reproductive organs, placenta, and thymus. Of interest, nonepithelial cell types such as vascular smooth muscle, skeletal muscle, myocardial cells, and neurons also express both proteins. In PKD2 cystic kidney and liver, we find polycystin-2 expression in the majority of cysts, although a significant minority are negative, a pattern mirrored by the PKD1 protein. The continued expression of polycystin-2 in PKD2 cysts is similar to that seen by polycystin-1 in PKD1 cysts, but contrasts with the reported absence of polycystin-2 expression in the renal cysts of Pkd2+/- mice. These results suggest that if a two-hit mechanism is required for cyst formation in PKD2 there is a high rate of somatic missense mutation. The coordinate presence or loss of both polycystin molecules in the same cysts supports previous experimental evidence that heterotypic interactions may stabilize these proteins.

Comparative toxicity of four microcystins of different hydrophobicities to the protozoan, Tetrahymena pyriformis.

Microcystins (MC) are a group of over 60 cyclic heptapeptide hepatotoxins produced by cyanobacteria. The 1-octanol/water partition coefficients (log P) of MC-LR, -LY, -LW and -LF have been estimated by HPLC to be 2.16, 2.92, 3.46 and 3.56, respectively. Their in vivo toxicities to Tetrahymena pyriformis was also investigated. Twenty-four hour LC50 values followed the order MC-LR > -LY > -LW approximately -LF. The LC50 values of MC-LR and -LY were significantly reduced in the presence of 1% (v/v) dimethylsulphoxide, although no significant effect occurred with MC-LW or -LF. Tetrahymena pyriformis respiration rates were inhibited by MC-LR in both a time- and dose-dependent manner. Increasing log P of the MC used caused a significantly greater inhibition of respiration. Population growth rate and maximum culture density were inhibited by all MC variants in proportion to log P. Positive correlations between all toxicological endpoints and log P occurred, with the most hydrophobic toxin, MC-LF, being 1.4 to 3.5 times more toxic than MC-LR. MC-LW had a similar toxicity to MC-LF, while MC-LY toxicity was intermediate between that of MC-LR and -LF. Implications of this positive relationship between in vivo toxicity and hydrophobicity for the toxicity of MC to aquatic organisms, and the potential for using log P as a descriptor in a quantitative structure-activity relationship for MC, are discussed.

Identification of a human homologue of the sea urchin receptor for egg jelly: a polycystic kidney disease-like protein.

Previous studies have shown sequence similarity between a region of the autosomal dominant polycystic kidney disease (ADPKD) protein, polycystin-1 and a sea urchin sperm glycoprotein involved in fertilization, the receptor for egg jelly (suREJ). We have analysed sequence databases for novel genes encoding PKD/REJ-like proteins and found a significant region of homology to a large open reading frame in genomic sequence from human chromosome 22. Northern analysis showed that this is a functional gene [termed the polycystic kidney disease and receptor for egg jelly related gene ( PKDREJ )], but unlike polycystin-1, has a very restricted expression pattern; the approximately 8 kb transcript was found exclusively in testis, coincident with the timing of sperm maturation. The PKDREJ transcript was cloned by screening a testis cDNA library and RT-PCR which revealed a 7660 bp mRNA terminating with a 900 bp 3'UTR and a polyA tail. Comparison with genomic sequence showed that PKDREJ is intronless; sequencing the mouse orthologue revealed a similar structure. The predicted human PKDREJ protein has 2253 amino acids (calculated molecular mass 255 kDa) and sequence similarity over approximately 2000 amino acids with polycystin-1, corresponding to the predicted membrane associated region and the area of homology ( approximately 1000 amino acids) with the suREJ protein (the REJ module). The suREJ protein binds the glycoprotein coat of the egg (egg jelly), triggering the acrosome reaction, which transforms the sperm into a fusogenic cell. The sequence similarity and expression pattern suggests that PKDREJ is a mammalian equivalent of the suREJ protein and therefore may have a central role in human fertilization.

Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil.

BACKGROUND: After a drought in February, 1996, all 126 patients in a haemodialysis unit in Caruaru, north-east Brazil, developed signs and symptoms of acute neurotoxicity and subacute hepatotoxicity following the use of water from a lake with massive growth of cyanobacteria (blue-green algae). 60 patients died. METHODS: Besides recording clinical details and outcome at follow-up, we arranged laboratory, radiological, and histological investigations on the patients and toxicological studies of serum and haemodialysis water filters. FINDINGS: The acute presentation was with malaise, myalgia and weakness, nausea and vomiting, and tender hepatomegaly, with a range of neurological symptoms from tinnitus, vertigo, headaches, and deafness to blindness and convulsions. Liver injury ranged from abnormal liver-function test results to rapidly progressive and fatal hepatic failure. Biochemical investigations revealed gross hyperbilirubinaemia, abnormal liver enzyme activities, and hypertriglyceridaemia, but there was no evidence of haemolysis or microangiopathy. Histology revealed a novel acute toxic hepatitis with diffuse panlobular hepatocyte necrosis, neutrophil infiltration, canalicular cholestasis, and regenerative multinucleate hepatocytes. Samples of serum, dialysis filters, and water-treatment columns contained microcystins, the highly toxic low-molecular-weight hepatotoxins produced by cyanobacteria. INTERPRETATION: Cyanobacteria present water-borne hazards to health via drinking water and recreational water. Haemodialysis presents an additional high-risk exposure route: when they enter directly into the circulation, microcystins can lead to fatal clinical syndromes ranging from acute neurotoxic illness to subacute liver failure.

Colorimetric protein phosphatase inhibition assay of laboratory strains and natural blooms of cyanobacteria: comparisons with high-performance liquid chromatographic analysis for microcystins.

Microcystins are cyclic heptapeptide hepatotoxins commonly produced by bloom-forming genera of cyanobacteria. These toxins are potent and specific inhibitors of protein phosphatases 1 and 2A. We have optimised a rapid, simple and sensitive colorimetric protein phosphatase 1 inhibition assay, utilising the activity of protein phosphatase 1 as expressed in a recombinant strain of Escherichia coli, towards the chromogenic substrate, p-nitrophenyl phosphate. A standard curve for the inhibition of protein phosphatase 1 by microcystin-LR was constructed with an IC50 of about 38 ng ml-1 and a limit of detection of 10-20 ng ml-1. Twenty-three laboratory-grown strains and 25 natural bloom samples of cyanobacteria were analysed by high-performance liquid chromatography for microcystins and by the protein phosphatase 1 inhibition assay. Agreement for the microcystin contents of the samples detected by high-performance liquid chromatography and the protein phosphatase 1 inhibition assay showed good correlation (R2 > 0.93, P < 0.0001). The suitability of the colorimetric protein phosphatase 1 inhibition assay as a screen for cyanobacterial microcystins is discussed.

Cyanobacterial toxins: occurrence, modes of action, health effects and exposure routes.

Cyanobacterial toxins are produced by terrestrial- fresh-, brackish- and sea-water cyanobacteria of cosmopolitan occurrence. These toxins present acute and chronic hazards to human and animal health and are responsible for isolated, sporadic animal fatalities (mammals, fish, birds) each year. Human health problems are associated with the ingestion of, and contact with cyanobacterial blooms and their toxins. Modes of action of cyanobacterial neurotoxins, hepatotoxins and skin irritants are considered. Recent indications of the accumulation of cyanobacterial toxins in fish, their effect on crop plants and their association with the deaths of human dialysis patients are discussed. These findings and events indicate an incomplete understanding of the exposure routes of these natural toxins and the need for greater awareness of their occurrence and properties among users of waterbodies which are prone to cyanobacterial bloom development.

Cloning and characterization of a functional human homolog of Escherichia coli endonuclease III.

Repair of oxidative damage to DNA bases is essential to prevent mutations and cell death. Endonuclease III is the major DNA glycosylase activity in Escherichia coli that catalyzes the excision of pyrimidines damaged by ring opening or ring saturation, and it also possesses an associated lyase activity that incises the DNA backbone adjacent to apurinic/apyrimidinic sites. During analysis of the area adjacent to the human tuberous sclerosis gene (TSC2) in chromosome region 16p13.3, we identified a gene, OCTS3, that encodes a 1-kb transcript. Analysis of OCTS3 cDNA clones revealed an open reading frame encoding a predicted protein of 34.3 kDa that shares extensive sequence similarity with E. coli endonuclease III and a related enzyme from Schizosaccharomyces pombe, including a conserved active site region and an iron/sulfur domain. The product of the OCTS3 gene was therefore designated hNTH1 (human endonuclease III homolog 1). The hNTH1 protein was overexpressed in E. coli and purified to apparent homogeneity. The recombinant protein had spectral properties indicative of the presence of an iron/sulfur cluster, and exhibited DNA glycosylase activity on double-stranded polydeoxyribonucleotides containing urea and thymine glycol residues, as well as an apurinic/apyrimidinic lyase activity. Our data indicate that hNTH1 is a structural and functional homolog of E. coli endonuclease III, and that this class of enzymes, for repair of oxidatively damaged pyrimidines in DNA, is highly conserved in evolution from microorganisms to human cells.

Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney.

Polycystic kidney disease 1 (PKD1) is the major locus of the common genetic disorder autosomal dominant polycystic kidney disease. We have studied PKD1 mRNA, with an RNase protection assay, and found widespread expression in adult tissue, with high levels in brain and moderate signal in kidney. Expression of the PKD1 protein, polycystin, was assessed in kidney using monoclonal antibodies to a recombinant protein containing the C terminus of the molecule. In fetal and adult kidney, staining is restricted to epithelial cells. Expression in the developing nephron is most prominent in mature tubules, with lesser staining in Bowman's capsule and the proximal ureteric bud. In the nephrogenic zone, detectable signal was observed in comma- and S-shaped bodies as well as the distal branches of the ureteric bud. By contrast, uninduced mesenchyme and glomerular tufts showed no staining. In later fetal (>20 weeks) and adult kidney, strong staining persists in cortical tubules with moderate staining detected in the loops of Henle and collecting ducts. These results suggest that polycystin's major role is in the maintenance of renal epithelial differentiation and organization from early fetal life. Interestingly, polycystin expression, monitored at the mRNA level and by immunohistochemistry, appears higher in cystic epithelia, indicating that the disease does not result from complete loss of the protein.