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.

Rare heterozygous variants in paediatric steroid resistant nephrotic syndrome - a population-based analysis of their significance.

Genetic testing in nephrotic syndrome may identify heterozygous predicted-pathogenic variants (HPPVs) in autosomal recessive (AR) genes that are known to cause disease in the homozygous or compound heterozygous state. In such cases, it can be difficult to define the variant's true significance and questions remain about whether a second pathogenic variant has been missed during analysis or whether the variant is an incidental finding. There are now known to be over 70 genes associated with nephrotic syndrome, the majority inherited as an AR trait. Knowledge of whether such HPPVs occur with equal frequency in patients compared to the general population would assist interpretation of their significance. Exome sequencing was performed on 187 Steroid-Resistant Nephrotic Syndrome (SRNS) paediatric patients recruited to a UK rare disease registry plus originating from clinics at Evelina, London. 59 AR podocytopathy linked genes were analysed in each patient and a list of HPPVs created. We compared the frequency of detected HPPVs with a 'control' population from the gnomAD database containing exome data from approximately 50,000 individuals. A bespoke filtering process was used for both patients and controls to predict 'likely pathogenicity' of variants. In total 130 Caucasian SRNS patients were screened across 59 AR genes and 201 rare heterozygous variants were identified. 17/201 (8.5%) were assigned as 'likely pathogenic' (HPPV) using our bespoke filtering method. Comparing each gene in turn, for SRNS patients with a confirmed genetic diagnosis, in 57 of the 59 genes we found no statistically significant difference in the frequency of these HPPVs between patients and controls (In genes ARHGDIA and TP53RK, we identified a significantly higher number of HPPVs in the control population compared with the patients when filtering was performed with 'high stringency' settings only). In the SRNS patients without a genetics diagnosis confirmed, there was no statistically significant difference identified in any gene between patient and control. In children with SRNS, we propose that identification of HPPV in AR podocytopathy linked genes is not necessarily representative of pathogenicity, given that the frequency is similar to that seen in controls for the majority. Whilst this may not exclude the presence of genetic kidney disease, this type of heterozygous variant is unlikely to be causal and each result must be interpreted in its clinical context.

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.

Hair cell distribution and orientation in goldfish otolith organs.

Structurally diverse sensory regions occur in the otolith organs of the goldfish inner ear. Scanning electron microscopy reveals regional distinctions based on three criteria. (1) Hair cells have different sizes of apical bundles, based on thickness. In all three maculae, two central regions have hair cells with bundles significantly thicker than those in surrounding regions. (2) Hair cell population density varies, with regional aggregations present. The central regions with thick bundles have two to three times the density of surrounding regions with thin bundles, and contain 40-80% of the total hair cell number in each macula. (3) Hair cell orientation maps show that each macula has two oppositely oriented cell populations that can be separated completely, not by a zone of interspersion, but apparently by a single unbroken line. The lagena is like the utricle in having hair cells with the kinocilium on the side of the cell toward the opposition line, but in the saccule the kinocilia face away from the line, and the small macula neglecta consists of two completely separate, oppositely oriented patches. The opposition line does not divide each macula simply down its midline; instead, the line divides the regions with thich bundles into nearly equal opposing areas, except for a remarkably abrupt large loop in the line in the anterior part of the saccule. The regional structural diversity in these organs may relate to localized functional diversity of responses to tilt, vibration and sound.

Methicillin-resistant Staphylococcus aureus outbreak at a Veterans' Affairs Medical Center: importance of carriage of the organism by hospital personnel.

The reported prevalence of nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) by hospital personnel averages 2.5%. From August 1985 to September 1987, 155 patients at our Veterans' Affairs Medical Center (VAMC) were colonized or infected with MRSA. In December 1986, only two (2.1%) of 94 healthcare workers were identified as nasal carriers. Prompted by a sharp increase in the number of patients with MRSA in early 1987, contact tracing identified 450 employees, of whom 36 (8%) were nasal carriers. Thirty-five percent of surgical residents (7 of 20) were nasal carriers. Prior to being identified as a nasal carrier, one surgical resident was associated with the inter-hospital spread of the VAMC MRSA strain to the burn unit of the affiliated university hospital. Three family members of two employee carriers were also found to harbor the epidemic strain. All 36 carriers were decolonized with various antimicrobial combinations. Vigorous infection control measures were effective in controlling the epidemic. The frequency of MRSA carriage by hospital personnel at our medical center during the epidemic proved higher than previously appreciated. Thus, healthcare workers may comprise a sizable MRSA reservoir. During an MRSA epidemic, infection control should attempt to identify and decolonize this hospital reservoir, as these individuals can disseminate MRSA both within the hospital as well as into the community.

Primary squamous cell carcinoma of the terminal ileum.

A case of squamous cell carcinoma of the terminal ileum with no underlying duplication or inflammatory disorder is described. The neoplasm seemed to have originated from the surface epithelium, invading the wall and metastasising to the regional lymph nodes. The 65 year old patient was free of disease three years after having had the tumour removed. Previous reports of squamous carcinoma of the small intestine have been associated with intestinal duplication or metastatic disease from distant sites.

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.

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.

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.

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.

An experiment in psychiatric community care in north Staffordshire: the experience of working with relatives of mentally-ill people.

This paper describes the changing nature of the relationship between the consumers and providers of services, following the transition from a hospital to a community-based service. One aspect of this change, the development of a relatives' group, is considered in more detail. Those attitudes and approaches which help or hinder staff working with relatives are discussed.

Retention of generalized hair cell patterns in the inner ear of the primitive flatfish Psettodes.

Flatfish are a group of uniquely asymmetrical vertebrates, lying always on one side. This postural control depends on the vestibular receptors of the inner ear. From the most primitive living flatfish, orientations of sensory hair cells in the inner ear were mapped by scanning electron microscopy. The maps of the three otolith organs, the three semicircular cristae, and the macula neglecta (newly discovered here for flatfish) show patterns that are very similar to those in many upright teleosts, particularly perches. Thus, peripheral sensory structure does not require modification for the unusual postural control of flatfish.

Social class, underprivileged areas and psychiatric disorder in the city of Stoke-on-Trent.

A survey of psychiatric disorder, based on hospital inpatient records, was conducted in the City of Stoke-on-Trent, England for the year 1983. This was used to test the hypothesis that areas of lower social class and greatest underprivilege would display higher rates of inpatient admissions for psychiatric disorder than the more privileged areas of the city. The results confirmed a significant positive correlation between extent of underprivilege of an area and rates of inpatient admissions. The link between lower social class and mental disorder was not directly demonstrated.

Detection of clear air turbulence by water vapor emission anomalies: weighting functions and sensitivities.

It has been demonstrated by Kuhn et al. [Science 196, 1099 (1977)] that clear air turbulence (CAT) ahead of an aircraft can be sensed by a forward-looking IR radiometer tilted at a small elevation angle and detecting in the water vapor rotational emission band. An increase in the radiometer signal due to the upward transfer of moist air by turbulence provides several minutes warning of impending CAT. In this paper the radiance changes due to a model water vapor anomaly are calculated. The corresponding weighing function and its dependence on wavelength, altitude, and viewing angle are investigated. Consideration of the radiative transfer equation indicates that a weighting function which gives the change in transmittance with total water path is the most useful for the calculation of the water vapor emission changes due to CAT. The water vapor emission in the strongly absorbing rotational band and along a slant path in both the troposphere and stratosphere comes mainly from atomspheric layers close to the detector. It is thus possible to describe the water vapor emission in terms of an isothermal slant path to a good approximation.

Variation in lengths of ciliary bundles on hair cells along the macula of the sacculus in two species of teleost fishes.

The sacculus is one of the end-organs of the inner ear. In many teleost fishes the sacculus is considered the major auditory organ. We have used scanning electron microscopy to examine the lengths of the ciliary bundles on hair cells in the sensory macula of the sacculus in two diverse species of teleosts. The data are presented in a form allowing direct comparison with recent data on a wide range of tetrapod auditory organs. In goldfish, the ciliary bundles are significantly longer in the caudal part of the macula than in the rostral part, but the kissing gourami shows nearly uniform ciliary bundle heights along its entire length. Based on limited data from the literature, the part of the macula responsive to lower frequencies is the part containing these taller bundles in goldfish, suggesting a parallel with the gradient of ciliary bundles and frequency response found in tetrapods.