A novel likely pathogenic CLCN5 variant in Dent's disease.

BACKGROUND: The majority of cases of Dent's disease are caused by pathogenic variants in the CLCN5 gene, which encodes a voltage-gated chloride ion channel (ClC-5), resulting in proximal tubular dysfunction. We present three members of the same family and one unrelated paediatric patient with the same insertion-deletion CLCN5 variant. The identification of these patients and positive familial segregation led to the re-classification of this variant from one of unknown significance to one of likely pathogenicity. CASE PRESENTATION: A 41 year old male presented with end stage kidney failure, proteinuria and haematuria. Whole genome sequencing identified an insertion-deletion variant in CLCN5, resulting in a missense change (c.1744_1745delinsAA p.(Ala582Lys)). His brother and nephew, who both exhibited renal impairment, haematuria, proteinuria, glycosuria and nephrocalcinosis, were found to have the same variant. In addition, genetic testing of an unrelated paediatric patient who presented with proteinuria and hypercalciuria, demonstrated the same variant. CONCLUSIONS: The identification of this novel variant in four individuals with features of Dent's disease, has led to the re-classification of the variant to one of likely pathogenicity. As a result, our patients and any future patients with the same variant can be offered a likely diagnosis, without the need for kidney biopsy, and their family members can be offered genetic screening.

Biology of the eyelash hair follicle: an enigma in plain sight.

Because of their crucial impact on our perception of beauty, eyelashes constitute a prime target for the cosmetic industry. However, when compared with other hair shafts and the mini-organs that produce them [eyelash hair follicles (ELHFs)], knowledge on the biology underlying growth and pigmentation of eyelashes is still rudimentary. This is due in part to the extremely restricted availability of human ELHFs for experimental study, underappreciation of their important sensory and protective functions and insufficient interest in understanding why they are distinct from scalp hair follicles (HFs) (e.g. ELHFs produce shorter hair shafts, do not possess an arrector pili muscle, have a shorter hair cycle and undergo greying significantly later than scalp HFs). Here we synthesize the limited current knowledge on the biology of ELHFs, in humans and other species, their role in health and disease, the known similarities with and differences from other HF populations, and their intrinsic interethnic variations. We define major open questions in the biology of these intriguing mini-organs and conclude by proposing future research directions. These include dissecting the molecular and cellular mechanisms that underlie trichomegaly and the development of in vitro models in order to interrogate the distinct molecular controls of ELHF growth, cycling and pigmentation and to probe novel strategies for the therapeutic and cosmetic manipulation of ELHFs beyond prostaglandin receptor stimulation.

Extracellular matrix and matrix metalloproteinases in sciatic nerve.

Although matrix metalloproteinases (MMPs) are increasingly being implicated in several pathologies of the nervous system, it is not yet clear what role they play in normal neurobiological processes. We review the expression of extracellular matrix (ECM) components as well as MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the peripheral nervous system. We explore the expression of certain MMPs and the four TIMPs at the mRNA level in the postnatal mouse sciatic nerve. In addition, we have used substrate gel and in situ zymography to determine levels of MMP-2 and -9 and TIMP activity in rat sciatic nerve after crush and during regeneration. A rapid and transient increase in MMP-9 localised at and immediately distal to the site of injury was observed, whereas an increase in MMP-2 activity was delayed, prolonged, and extended proximal and distal to the injury site. This activity coincides with periods of axonal elongation, suggesting that it could act to facilitate axonal extension along the nerve matrix. We also detected multiple species of gelatinolytic inhibitory activity, including TIMP-1 and -3 in control and injured nerve. These activities probably act to prevent uncontrolled gelatinolytic activity, maintaining nerve integrity at the level essential for axonal regrowth.

Renin gene expression in fetal kidneys of pregnancies complicated by twin-twin transfusion syndrome.

Twin-twin transfusion syndrome (TTTS) complicates one in five monochorionic pregnancies and is generally associated with high mortality and morbidity. One twin (the recipient) grows appropriately and has polyhydramnios while the other (the donor) may have a reduced growth velocity and severe oligohydramnios. The disparities in amniotic fluid volumes represent differences in fetal urine output. These differences occur secondary to hemodynamic changes, in which the vascular arrangement of placental anastomoses in TTTS leads to unidirectional flow from the donor to the recipient twin. A better understanding of the pathophysiology may contribute to improved management of this morbid condition. We studied three consecutive prospectively diagnosed stillborn twin pairs affected by early-onset TTTS. Renin gene expression was studied in sections of fetal kidneys with immunocytochemistry using a renin antiserum and with in situ hybridization using riboprobes complementary to renin mRNA, and renin-secreting cells (RCC) were counted. The overall maturation of the renal cortex was assessed by the percentage of immature glomeruli. The donor twin kidneys were smaller than those of the recipients, but the maturation of the renal cortex was not significantly different (28.2% immature glomeruli in the donor and 24.4% in the recipient kidney). The donor kidney showed increased renin gene expression with hyperplastic juxtaglomerular apparatuses (JGAs) that contained excess RCCs (median 20.02 [25th-75th centiles, 5.4, 25.1 RCCs per 100 glomeruli]). In contrast, the recipient kidney was virtually devoid of these cells (0.04 [0, 0.36] RCCs per 100 glomeruli; P < 0.05). In the donor kidney, increased renin release may, by a local action, contribute to renal vasoconstriction and oliguria. Increased renin and/or angiotensin II in the blood passing through the placental anastomoses may, by an endocrine action, suppress renin synthesis in the recipient kidney, thereby increasing renal blood flow and causing polyuria and polyhydramnios. These changes in the renal RAS could thus contribute to the pathogenesis of TTTS. The renal renin changes noted here may represent a contributory or compensating mechanism, the success of which may dictate the overall survival of the twin pregnancy and allow better understanding of the pathophysiology and perhaps therapy that may be employed in this condition.

Duplication of chromosome 2 in association with ventriculomegaly - a case report.

This is a case report of the prenatal diagnosis of a de novo interstitial duplication of chromosome 2 (46,XX,dup(2)(p13p21) de novo) with an associated phenotypic abnormality. This chromosomal duplication is rare, only one has previously been described prenatally. Postnatal reports of similar duplications in this region have described associated dysmorphic features and significant neurodevelopmental delay. In our case, the only ultrasound finding was moderately severe ventriculomegaly. At post-mortem, ventriculomegaly was confirmed and there was associated macrocephaly (head circumference above the 97th centile) with no dysmorphic features seen.

Effect of a boil water notice on behaviour in the management of a water contamination incident.

In late 1998, the water supply of 878 households was affected by possible sewage contamination. A notice was issued to advise residents of the need to boil their water. This provided an opportunity to assess to what extent the boil water notice led people to avoid activities that might put them at risk of waterborne infection. A postal questionnaire sent to 350 randomly selected households in the affected area asked about timing and mode of receipt of the notice, risk behaviour (boiling water, brushing teeth, washing dishes, drinks for pets, preparation of food), and subsequent changes in drinking water consumption habits. Eighty-one per cent of the households surveyed engaged in behaviour likely to increase the risk of waterborne infection. Comments were collected from consumers on how to improve the management of future water contamination incidents.

Structure and function in the saccule of the goldfish (Carassius auratus): a model of diversity in the non-amniote ear.

The vertebrate inner ear is comprised of a remarkable diversity of cell types, including several types of sensory hair cells. In amniotes (reptiles, birds, and mammals), the morphological and physiological characteristics that distinguish these cell types have been well documented, while cellular variation in the ears of non-amniotes (all other vertebrate groups) has remained underrecognized. Since non-amniotes have become increasingly popular models for developmental and genetic research, a more comprehensive understanding of structure and function in the inner ears of these species is warranted. This paper first reviews the large body of data describing the morphology and physiology of hair cells and afferent neurons in the inner ear of the goldfish (Carassius auratus). In particular, we examine the structure of the goldfish saccule, an endorgan that has been the subject of numerous investigations on audition. New data on the structural variation of synaptic bodies in saccular hair cells are also presented, and the functional implications of these data are discussed. Finally, we conclude that hair cell structure varies along the length of the goldfish saccule in a manner consistent with known physiological characteristics of the endorgan. The saccule provides an excellent model for investigating structure-function relationships in the vertebrate inner ear, as well as the development of auditory and vestibular sensory epithelia.

Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations.

The increased or inappropriate expression of genes with oncogenic properties through specific chromosome translocations is an important event in the pathogenesis of B-cell lymphoproliferative diseases. Recent studies have found deletions or translocations of chromosome 7q to be the most common cytogenetic abnormality observed in SLVL, a leukemic variant of SMZL, with the q21-q22 region being most frequently affected. In three patients with translocations between chromosomes 2 and 7, the cloning of the breakpoints at 7q21 revealed that each was located within a small region of DNA 3.6 kb upstream of the transcription start site of cyclin dependent kinase 6 (CDK6). In each case the translocation event was consistent with aberrant VJ recombination between the immunoglobulin light chain region (Ig kappa) on chromosome 2p12 and DNA sequences at 7q21, resembling the heptamer recombination site. The t(7;21) breakpoint in an additional patient with splenic marginal zone lymphoma (SMZL), resided 66 kb telomeric to the t(2;7) breakpoints juxtaposing CDK6 to an uncharacterized transcript. In two of the SLVL patient samples, the CDK6 protein was found to be markedly over expressed. These results suggest that dysregulation of CDK6 gene expression contributes to the pathogenesis of SLVL and SMZL.

Prenatal diagnosis of mosaicism for partial trisomy 8: a case report including fetal pathology.

A case of prenatally diagnosed partial trisomy 8 is described. The 'syndrome' is associated with skeletal and cardiac anomalies, as well as hepatic calcification. Differing proportions of 47,XY, +der(8) and 46 XY were present in the different fetal tissues sampled. The highest proportion of 47,XY,+der(8) cells was found in the placenta.

Is universal screening for lead in children indicated? An analysis of lead results in Augusta, Georgia in 1997.

Pediatricians have a dilemma about whether they should do universal or targeted screening for lead in children. In order to determine whether we should continue our institution's present policy of universal screening, we analyzed 962 lead samples obtained by routine screening in the calendar year 1997, 83 children (8.6%) had elevated levels (over 10 mcg/dl) by capillary samples; of the 57 children who had follow up tests by venipuncture, 35 had abnormal levels making the incidence of elevated leads in our screened children 3.6%. Most of the abnormal levels were in African-American children living in two downtown zip codes. Based on recent AAP recommendations, in our community, targeted screening should replace universal screening.

Substance abuse and dependence in physicians: the Missouri Physicians' Health Program.

Substance abuse and dependence (alcohol and drugs) are behavioral disorders and treatable medical diseases. There is growing concern in the medical community for physicians impaired by these diseases. The Missouri Physicians' Health Program has been established to help impaired physicians return to healthy personal and professional lives. This confidential voluntary program of early referral, intervention, treatment, monitoring, and advocacy has been highly successful. The average recovery rate in this study of 146 participants was 94%.

Prenatal diagnosis of cerebral arteriovenous malformation using color Doppler ultrasonography: case report and review of the literature.

Aneurysms of the vein of Galen are rare, representing less than 1% of all intracranial arteriovenous malformations. In the fetus, however, almost all cerebral arterial malformations involve the vein of Galen, usually presenting in the neonatal period with severe cardiac failure leading to neonatal death. In this report we present a case of arteriovenous malformation involving the vein of Galen detected prenatally at 35 weeks with the use of color Doppler ultrasonography. The literature is reviewed in an attempt to delineate the role of prenatal ultrasonography in the diagnosis and its impact on perinatal outcome.

Widespread colonization of personnel at a Veterans Affairs medical center by methicillin-resistant, coagulase-negative Staphylococcus.

A serial prospective survey of nasal colonization of hospital personnel by methicillin-resistant coagulase-negative staphylococci (MRCNS) was conducted at a Veterans Affairs medical center on three occasions over a 16-month period. The epidemiological typing systems used to assess relatedness included antimicrobial susceptibility profiles; biotyping; phage typing; plasmid profiles; restriction fragment length polymorphism (RFLP) analysis with ribosomal RNA; and plasmid hybridization with a 1.68-MD plasmid as the DNA probe. Forty-three percent of all personnel and 62% of all nurses were colonized with MRCNS. Nurses on the wards (72%) and in the intensive care unit (73%) were significantly more likely to be colonized with MRCNS than nurses who had less contact with patients or those who worked in the operating room. The molecular epidemiological typing systems indicated some degree of relatedness among the strains. Specifically, riboprobe analysis revealed a Dice coefficient of > 90%. However, each typing system detected dissimilarity among strains. Further studies are needed to determine the role that such human reservoirs of MRCNS serve in horizontal transmission to and subsequent infection of hospitalized patients.

Angiosarcoma in congenital hereditary lymphoedema (Milroy's disease)--diagnostic beacons and a review of the literature.

In cases of congenital lymphoedema the finding of ulceration, violaceous nodules or papules, or apparent traumatic ecchymoses should act as a diagnostic beacon warning of dangers. A case is reported of a high-grade angiosarcoma developing in a patient with congenital hereditary lymphoedema (Milroy's disease). This is the second paper to report this complication, the third case report and the first case in which the diagnosis is substantiated by immunohistochemistry and lectin histochemistry. A review of cases of angiosarcoma complicating congenital hereditary and non-hereditary lymphoedema is also presented.

Zebrafish inner ear sensory surfaces are similar to those in goldfish.

The inner ear of the zebrafish (Brachydanio rerio) is very similar to that of the goldfish in its structural details, including the distribution and orientation of mechanosensory hair cell populations. Both species have been used in studying different aspects of the acoustic startle response. These structural similarities suggest that the zebrafish is a valid representative model for understanding peripheral hearing specializations in otophysan fishes.

Damage and regeneration of hair cell ciliary bundles in a fish ear following treatment with gentamicin.

Sensory hair cells in the striolar regions of the utricle and lagena of a teleost fish, the oscar (Astronotus ocellatus), were damaged following intramuscular injections of gentamicin sulfate. In order to determine whether fish can regenerate hair cells, the time course of damage and recovery was followed over a period of four weeks by scanning electron microscopy. Maximum loss of ciliary bundles occurred at about day 10 after the first of four daily injections of gentamicin (20 mg/kg) in 4-6 cm long fish. The striolar regions were almost totally denuded of ciliary bundles, and there was evidence of considerable hair cell loss. The time course for damage was longer in larger fish, but the recovery of the ciliary bundles appeared to be complete about 10 days after maximal damage was seen in both the smaller and larger fish. These data indicate that Astronotus is able to repair damage to hair cells for an extended period of time post-embryonically.