Personality differences between internal medicine and surgical residents in an Asian population.

PURPOSE: Personality traits often have an impact on the way individuals relate to each other as colleagues and the patients we treat. It is often perceived that distinct personality exist between different specialties and may help predict success during one's training and career. METHODS: Objective of the study was to compare the personality between surgical and medical residents. Thirty-five medical residents and 35 surgical residents completed the Revised NEO Personality Inventory, a validated measure of personality traits. A score was generated for each of the 5 major character traits namely: neuroticism(N), extraversion(E), openness(O), conscientiousness(C), agreeableness(A). Each of these traits were subdivided into 6 component facets. This was compared with sociodemographic characteristics. RESULTS: Medical residents displayed higher scores in the area of overall Agreeableness, with a mean score of 47.4 vs 40.5. Within Agreeableness facets, medical residents also displayed higher scores of straightforwardness, altruism and modesty. Surgical residents displayed higher scores in terms of overall Extraversion (52.4 vs 45.4). Within the Extraversion facets, surgical residents were also more assertive and excitement-seeking. There was no difference in the overall neuroticism domain; however, within the neuroticism facets, surgical residents had statistically higher mean scores in angry hostility and impulsiveness. Gender stratification did not result in any statistically significant difference. CONCLUSION: There are fundamental differences between personalities of medical and surgical residents. Detailed analysis of each individual's data could be useful, with proper assistance and coaching, for residents in learning more about their personalities and how these impact their clinical practice. This can be beneficial in future career counselling and the development of a more holistic medical practitioner.

Distribution of IL-1ß immunoreactive cells in pancreatic biopsies from living volunteers with new-onset type 1 diabetes: comparison with donors without diabetes and with longer duration of disease.

AIMS/HYPOTHESIS: Although IL-1ß is considered a key mediator of beta cell destruction, its cellular expression in islets during early type 1 diabetes remains unclear. We compared its expression in rare pancreatic biopsies from new-onset living volunteers with its expression in cadaveric pancreas sections from non-diabetic autoantibody-positive and -negative individuals and those with long-standing disease. METHODS: Pancreatic biopsy sections from six new-onset living volunteers (group 1) and cadaveric sections from 13 non-diabetic autoantibody-negative donors (group 2), four non-diabetic autoantibody-positive donors (group 3) and nine donors with diabetes of longer duration (0.25-12 years of disease; group 4) were triple-immunostained for IL-1ß, insulin and glucagon. Intra- and peri-islet IL-1ß-positive cells in insulin-positive and -negative islets and in random exocrine fields were enumerated. RESULTS: The mean number of IL-1ß-positive cells per islet from each donor in peri- and intra-islet regions was <1.25 and <0.5, respectively. In all study groups, the percentage of islets with IL-1ß cells in peri- and/or intra-islet regions was highly variable and ranged from 4.48% to 17.59% in group 1, 1.42% to 44.26% in group 2, 7.93% to 17.53% in group 3 and 3.85% to 42.86% in group 4, except in a single case where the value was 75%. In 25/32 donors, a higher percentage of islets showed IL-1ß-positive cells in peri-islet than in intra-islet regions. In sections from diabetic donors (groups 1 and 4), a higher mean number of IL-1ß-positive cells occurred in insulin-positive islets than in insulin-negative islets. In group 2, 70-90% of islets in 3/13 sections had weak-to-moderate IL-1ß staining in alpha cells but staining was virtually absent or substantially reduced in the remaining groups. The mean number of exocrine IL-1ß-positive cells in group 1 was lower than in the other groups. CONCLUSIONS/INTERPRETATION: At onset of type 1 diabetes, the low number of islet-associated IL-1ß-positive cells may be insufficient to elicit beta cell destruction. The variable expression in alpha cells in groups 2-4 suggests their cellular heterogeneity and probable physiological role. The significance of a higher but variable number of exocrine IL-1ß-positive cells seen in non-diabetic individuals and those with long-term type 1 diabetes remains unclear.

An immunohistochemical study of nitrotyrosine expression in pancreatic islets of cases with increasing duration of type 1 diabetes and without diabetes.

Peroxynitrite-induced nitration of cellular proteins has been shown to associate with various human pathologies. The expression of pancreatic nitrotyrosine and its cellular source relative to insulitis were analysed in cases with increasing duration of type 1 diabetes and compared with non-diabetic autoantibody-negative and -positive cases. Pancreatic tail sections from non-diabetic autoantibody-negative cases (Group 1; n = 7), non-diabetic autoantibody-positive cases (Group 2; n = 6), recently diagnosed cases (Group 3; n = 6), 0.25-5 years of diabetes (Group 4; n = 8) and 7-12 years of diabetes (Group 5; n = 6) were immunostained sequentially for nitrotyrosine, insulin and leucocytes. Nitrotyrosine expression was observed in selective beta cells only. In group 1, the percentage of insulin-positive islets with nitrotyrosine ranged from 7.6 to 58.8%. In group 2, it was minimally expressed in 2 cases and was present in 4.7-19.3% of insulin-positive islets in 3 cases and in all islets in 1 case. In group 3, it was absent in 1 case and in the remaining 5 cases, the values were 17.4-85.7%. In group 4, nitrotyrosine was absent in 6 cases and positive in 1.8 and 22.2% of insulin-positive islets in 2 cases. In group 5, the values were 60% (1 case) and 100% (2 cases), being absent in 3 cases, consistent with insulin-negativity. This case analysis shows that nitrotyrosine immunostaining is independent of the presence and severity of insulitis. Variable nitrotyrosine expression is present in some non-diabetic cases. Its increased expression in beta cells of recent-onset and long-standing disease requires further studies to determine whether beta cell nitration plays a pathogenic role during T1D.

A first reported case of clear cell carcinoma associated with delayed extrusion of midurethral tape.

We present the first reported case of clear cell carcinoma associated with a midurethral tape (MUT), the possible hypotheses and the management pitfalls we encountered. We report a 58-year-old woman who presented with symptoms of urinary tract infection and acute retention of urine associated with vaginal tape exposure 10 years after placement of an inside-out transobturator tape. She subsequently had a partial transobturator tape excision and a diagnostic cystoscopy, which revealed inflammatory changes within the urethra. Postoperatively, her symptoms persisted and the vaginal epithelium healed poorly. A biopsy of the friable tissue reported clear cell carcinoma. Imaging showed a locally invasive periurethral mass and bony and lymphatic metastases. This was treated with palliative radiation therapy. She was still receiving palliative care 5 months after the initial surgery.

Analysis of peri-islet CD45-positive leucocytic infiltrates in long-standing type 1 diabetic patients.

AIMS/HYPOTHESIS: The role of peri-islet CD45-positive leucocytes, as one component of insulitis, in beta cell death during human type 1 diabetes remains unclear. We undertook a case study, comparing and quantifying leucocytes in the peri- and intra-islet areas in insulin-positive and -negative islets, to assess whether peri-islet leucocytes are pathogenic to beta cells during type 1 diabetes. METHODS: Pancreatic sections from 12 diabetic patients (0.25-12 years of disease) and 13 non-diabetic individuals with and without autoantibodies were triple-immunostained for islet leucocytes, insulin and glucagon cells. Islets were graded for insulitis, enumerated and mapped for the spatial distribution of leucocytes in peri- and intra-islet areas in relation to insulin- and glucagon-immunopositive cells. RESULTS: In the non-diabetic autoantibody-negative group, the percentage of islets with insulitis was either absent or <1% in five out of eight cases and ranged from 1.3% to 19.4% in three cases. In the five non-diabetic autoantibody-positive cases, it varied from 1.5% to 16.9%. In the diabetic group, it was <1% in one case and 1.1-26.9% in 11 cases, with insulitis being absent in 68% of insulin-positive islets. Peri-islet leucocytes were more numerous than intra-islet leucocytes in islets with insulin positivity. Increasing numbers of exocrine leucocytes in non-diabetic autoantibody-positive and diabetic donors were also present. CONCLUSIONS/INTERPRETATION: The prominence of peri-islet leucocytes in insulin-positive islets in most long-standing diabetic individuals suggests that they may be pathogenic to residual beta cells. Increasing numbers of leucocytes in the exocrine region may also participate in the pathogenesis of type 1 diabetes.

Postoperative risk of chronic kidney disease in radical nephrectomy and donor nephrectomy patients: a comparison and analysis of predictive factors.

INTRODUCTION: To compare baseline renal function and identify predictive factors in patients undergoing radical nephrectomy (RN) or donor nephrectomy (DN) and their risk of subsequent chronic kidney disease (CKD) after surgery. MATERIALS AND METHODS: A retrospective review of patients with no baseline CKD undergoing RN (n = 88) and DN (n = 58) from 2000 to 2008 was performed. Baseline and postoperative renal function (eGFR) was determined using the Modification of Diet in Renal Disease (MDRD) formula. CKD was defined as eGFR < 60 mL/min/1.73 m2 according to the National Kidney Foundation guidelines. RESULTS: Before surgery, patients undergoing RN and DN had a mean eGFR (+/- SD) of 83.5 +/- 17.4 and 92.9 +/- 17.0 mL/min/1.73 m2 respectively (p = 0.002). Patients with RN had significantly greater morbidities including hypertension (47.7%), diabetes (14.8%) and ischemic heart disease (12.5%) than DN (5.2%, 0% and 1.7% respectively) (all p < 0.05). Median follow up was 3.5 years. The relative hazard of developing CKD post RN compared with DN was 1.91 (95% CI 1.01 to 3.61, p = 0.040). The median time to CKD was 77 months (range 2-107) for RN and 100 months (range 11-105) for DN. Age, gender, comorbidities, radical nephrectomy and baseline kidney function were individual risk factors for CKD post nephrectomy. However, preoperative eGFR was the only independent prognostic factor on multi-variable analysis. CONCLUSIONS: Patients undergoing RN are distinctly different from kidney donors in terms of age, renal function and comorbidities. RN is not an independent predictive factor for CKD but the lower baseline renal function in RN patients significantly accelerates renal senescence in the uninephrectomy state.

Successful endourological management of the 'forgotten' stent in a transplanted kidney.

BACKGROUND: Ureteric stents are used to prevent urological complications like ureteric fistulas and obstruction in kidney transplants. Despite its advantages, complications arising from delayed removal of a double J (DJ) stent include urinary tract infections, stone encrustation, and migration of the DJ stent [Sansalone et al.: Transplant Proc 2005;37:2511-2515]. Encrustation of the stent makes removal difficult and risks injury to the transplanted kidney. CASE PRESENTATION: We report a case of retained DJ stent for 19 years presenting with recurrent urinary tract infections. A radiograph revealed a retained ureteric stent extending from the right iliac fossa transplant kidney to the urinary bladder with multiple foci of large calcification along its length. Two sessions of extracorporeal shockwave lithotripsy along the stent were performed after a percutaneous nephrostomy tube had been placed in the transplanted kidney. Subsequently, the retained DJ stent was removed endoscopically after laser lithotripsy to remnant calcifications. Remnant stone fragments were removed with another session of ureteroscopy and laser lithotripsy. The patient achieved complete stent and stone clearance with a functioning graft. CONCLUSION: This case illustrates that significant stone encrustation of the retained stent in a transplanted kidney can be treated successfully with a combination of endourological techniques.

Extramammary breast cancer of the vulva.

A woman in her 70s was seen in the gynaecology outpatient clinic with a swelling on the right side of the vulva. Surgical excision of the lesion revealed unexpectedly an extensive ductal carcinoma in situ with a focus of a grade 2 invasive ductal carcinoma arising in extramammary breast tissue of the vulva. Postoperative staging studies showed normal breasts, with no evidence of disease elsewhere. The patient underwent a wider excision of the right vulva and sentinel node biopsy of the right inguinal region, which revealed no further disease. The patient is currently taking adjuvant hormonal therapy and has remained disease free at 2-year follow-up. This case underscores the importance of considering rare presentations of vulvar malignancies and the necessity for a multidisciplinary approach in managing such cases.

Understanding Patients' Experiences and Perspectives of Tele-Prehabilitation: A Qualitative Study to Inform Service Design and Delivery.

BACKGROUND: Tele-prehabilitation is a behaviour change intervention that facilities the modification of unhealthy lifestyle behaviours. Understanding patients' experiences of tele-prehabilitation provides important insights into service improvement. In this study, we aimed to describe our patients' perceptions of tele-prehabilitation and capture their capabilities, opportunities, and motivations to participate. This was a qualitative study to inform our service design and delivery. METHODS: Following purposive sampling, 22 qualitative semistructured interviews were conducted with patients in the community that had completed tele-prehabilitation. Interviews were recorded and transcribed. Deductive content analysis was used to map the identified themes against theoretical determinants of health behaviour change. RESULTS: We conducted 22 interviews. Our patients described their overall experience of tele-prehabilitation as positive and provided important insights that impacted their capabilities, opportunities, and motivations to engage with our service. Our team provided them the capabilities and self-efficacy to engage by personalising multimodal plans and setting goals. The remote delivery of our service was a recurring positive theme in providing flexibility and widening accessibility to participation. A missed opportunity was the potential for peer support through shared experiences with other patients. Patients showed greater motivation to participate for immediate perioperative benefit compared to long-term health gains. CONCLUSION: Patients' experiences and perspectives of tele-prehabilitation can be enhanced by incorporating the findings from this qualitative study into service redesign and delivery. We recommend: (1) applying holistic principles in care and goal-setting, (2) delivering a combination of home-based and in-centre programmes, and (3) engaging with patients at the start of their cancer journey when they are most motivated. In turn, this can result in more effective uptake, improve adherence to interventions, and greater satisfaction.

Anion exchanger 1 in red blood cells and kidney: Band 3's in a pod.

The bicarbonate/chloride exchanger 1 (AE1, Band 3) is abundantly expressed in the red blood cell membrane, where it is involved in gas exchange and functions as a major site of cytoskeletal attachment to the erythrocyte membrane. A truncated kidney isoform (kAE1) is highly expressed in type A intercalated cells of the distal tubules, where it is vital for urinary acidification. Recently, kAE1 has emerged as a novel physiologically significant protein in the kidney glomerulus. This minireview will discuss the known interactions of kAE1 in the podocytes and the possible mechanisms whereby this important multispanning membrane protein may contribute to the function of the glomerular filtration barrier and prevent proteinuria.

Impact of Kidney Disease Outcomes Quality Initiative guidelines on the prevalence of chronic kidney disease after living donor nephrectomy.

PURPOSE: We evaluated the prevalence of chronic kidney disease stage 3 or worse based on the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines after living kidney donation at a single institution. MATERIALS AND METHODS: The collected data of 86 consecutive patients who underwent uneventful donor nephrectomy between 1987 and 2008 were evaluated retrospectively. Estimated glomerular filtration rate was determined using the Modification of Diet in Renal Disease from serum creatinine levels collected before and after surgery in kidney donor followup clinics. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 ml/minute/1.73 m(2) according to the Kidney Disease Outcomes Quality Initiative guidelines. Cox regression analyses were then used to determine the impact of predictors on the development of chronic kidney disease. RESULTS: All donors (mean age 41.2, SD 9.9 years) had a mean preoperative estimated glomerular filtration rate of 88.7 ml/min/1.73 m(2) (SD 16.3). Median followup was 6.4 years (range 0.9 to 21.0). Progression to stage 3 or worse chronic kidney disease was seen in 24.4% (95% CI 15.2-33.7) of patients. There were 2 patient deaths secondary to cancer and none required dialysis. Multivariable analysis showed that preoperative estimated glomerular filtration rate less than 82 ml/minute/1.73 m(2) was an independent risk factor for post-donation chronic kidney disease. For every 1 ml/minute/1.73 m(2) increase in baseline estimated glomerular filtration rate, the hazard of postoperative chronic kidney disease was reduced by 7% (HR 0.93, 95% CI 0.89-0.97, p = 0.001). CONCLUSIONS: Kidney Disease Outcomes Quality Initiative stage 3 chronic kidney disease or worse occurs in 24.4% of kidney donors. Long-term prospective studies and closer followup of donors are needed to identify its implications, given the associated risk of cardiovascular diseases with chronic kidney disease in the general population.

Anion exchanger 1 interacts with nephrin in podocytes.

The central role of the multifunctional protein nephrin within the macromolecular complex forming the glomerular slit diaphragm is well established, but the mechanisms linking the slit diaphragm to the cytoskeleton and to the signaling pathways involved in maintaining the integrity of the glomerular filter remain incompletely understood. Here, we report that nephrin interacts with the bicarbonate/chloride transporter kidney anion exchanger 1 (kAE1), detected by yeast two-hybrid assay and confirmed by immunoprecipitation and co-localization studies. We confirmed low-level glomerular expression of kAE1 in human and mouse kidneys by immunoblotting and immunofluorescence microscopy. We observed less kAE1 in human glomeruli homozygous for the NPHS1(FinMaj) nephrin mutation, whereas kAE1 expression remained unchanged in the collecting duct. We could not detect endogenous kAE1 expression in NPHS1(FinMaj) podocytes in primary culture, but heterologous re-introduction of wild-type nephrin into these podocytes rescued kAE1 expression. In kidneys of Ae1(-/-) mice, nephrin abundance was normal but its distribution was altered along with the reported kAE1-binding protein integrin-linked kinase (ILK). Ae1(-/-) mice had increased albuminuria with glomerular enlargement, mesangial expansion, mesangiosclerosis, and expansion of the glomerular basement membrane. Glomeruli with ILK-deficient podocytes also demonstrated altered AE1 and nephrin expression, further supporting the functional interdependence of these proteins. These data suggest that the podocyte protein kAE1 interacts with nephrin and ILK to maintain the structure and function of the glomerular basement membrane.

The Feasibility and Effects of a Telehealth-Delivered Home-Based Prehabilitation Program for Cancer Patients during the Pandemic.

Patients awaiting cancer treatment were classified as "vulnerable" and advised to shield to protect themselves from exposure to coronavirus during the pandemic. These measures can negatively impact patients. We sought to establish the feasibility and effects of a telehealth-delivered home-based prehabilitation program during the pandemic. Eligible patients were referred from multiple centers to a regional prehabilitation unit providing home-based prehabilitation. The enrolled patients received telehealth-delivered prehabilitation prior to surgery and/or during non-surgical cancer treatment, which included personalized training exercises, dietary advice, medical optimization therapies, and psychological support. The primary outcome was to investigate the feasibility of our program. The secondary outcome was to investigate the relationship between our program and patient-reported outcomes (PROs). The patients completed two questionnaires (the EQ-5D-3L and the FACIT-Fatigue Scale) pre- and post-intervention. A total of 182 patients were referred during the study period. Among the 139 (76%) patients that were enrolled, 100 patients completed the program, 24 patients have still to complete, and 15 have discontinued. A total of 66 patients were able to return completed questionnaires. These patients were recruited from colorectal, urology, breast, and cardiothoracic centers. The patients significantly improved their self-perceived health (p = 0.001), and fatigue (p = 0.000). Home-based prehabilitation is a feasible intervention. The PROs improved post-intervention.

The Feasibility of Prehabilitation as Part of the Breast Cancer Treatment Pathway.

BACKGROUND: There is compelling support for implementing prehabilitation to optimize perioperative risk factors and to improve postoperative outcomes. However, there is limited evidence studying the application of multimodal prehabilitation for patients with breast cancer. OBJECTIVE: To determine the feasibility of multimodal prehabilitation as part of the breast cancer treatment pathway. DESIGN: This was a prospective, cohort observational study. Breast cancer patients undergoing surgery were recruited. They were assigned to an intervention or control group according to patient preference. SETTING: UK prehabilitation center. PARTICIPANTS: A total of 75 patients were referred during the study period. Forty eight patients (64%) did not participate; 20 of those opted to be in the control group. Twenty four patients engaged with prehabilitation and returned completed questionnaires. In total, 44 patients were included in the analysis. INTERVENTIONS: The program consisted of supervised exercise, nutritional advice, smoking cessation, and psychosocial support. OUTCOME MEASURES: Feasibility was determined by the center's ability to deliver the program. This was measured by the number of patients who wanted to access the service, compared with those able to. Service uptake, patient satisfaction, and project costs were recorded. Patient-reported outcomes (PROs) and the use of healthcare resources were also evaluated. RESULTS: A total of 61 patients (81%) wanted to participate; 24 (32%) were able to partake and return questionnaires. Reasons for nonparticipation included surgery within weeks, full-time commitments, and transportation difficulties. A total of 25 (93%) prehabilitation patients recorded high satisfaction with the program. There was a significant reduction in anxiety among prehabilitation patients. There were no significant improvements in the other PROs. There were no changes to hospital length of stay, readmissions, and complications. CONCLUSIONS: Multimodal prehabilitation is a feasible intervention. Logistical challenges need to be addressed to improve engagement. These results are limited and would require a larger sample to confirm the findings. Work on a thorough cost-benefit analysis is also required.

Socioeconomic status and risk factors for complications in young people with type 1 or type 2 diabetes: a cross-sectional study.

INTRODUCTION: Young people with type 2 diabetes (T2D) develop complications earlier than those with type 1 diabetes (T1D) of comparable duration, but it is unclear why. This apparent difference in phenotype could relate to relative inequality. RESEARCH DESIGN AND METHODS: Cross-sectional study of young people referred to secondary diabetes services in Auckland, Aotearoa-New Zealand (NZ): 731 with T1D and 1350 with T2D currently aged <40 years, and diagnosed between 15 and 30 years. Outcome measures were risk factors for complications (glycemic control, urine albumin/creatinine ratio (ACR), cardiovascular disease (CVD) risk) in relation to a validated national index of deprivation (New Zealand Deprivation Index (NZDep)). RESULTS: Young people with T2D were an average 3 years older than those with T1D but had a similar duration of diabetes. 71% of those with T2D were of Maori or Pasifika descent, compared with 24% with T1D (p<0.001). T1D cases were distributed evenly across NZDep categories. 78% of T2D cases were living in the lowest four NZDep categories (p<0.001). In both diabetes types, body mass index (BMI) increased progressively across the NZDep spectrum (p<0.002), as did mean glycated hemoglobin (HbA1c) (p<0.001), the prevalence of macroalbuminuria (p≤0.01), and CVD risk (p<0.001). Adjusting for BMI, diabetes type, and duration and age, multiple logistic regression revealed deprivation was the strongest risk factor for poorly controlled diabetes (defined as HbA1c >64 mmol/mol, >8%); OR 1.17, 95% CI 1.13 to 1.22, p<0.0001. Ordinal logistic regression showed each decile increase in NZDep increased the odds of a higher ACR by 11% (OR 1.11, 95% CI 1.06 to 1.16, p<0.001) following adjustment for BMI, blood pressure, diabetes type and duration, HbA1c, and smoking status. Multiple linear regression indicated a 4% increase in CVD risk for every decile increase in NZDep, regardless of diabetes type. CONCLUSIONS: The apparent more aggressive phenotype of young-onset T2D is at least in part explicable by relative deprivation.

CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease.

Renal tubular reabsorption is important for extracellular fluid homeostasis and much of this occurs via the receptor-mediated endocytic pathway. This pathway is disrupted in Dent's disease, an X-linked renal tubular disorder that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure. Dent's disease is due to mutations of CLC-5, a chloride/proton antiporter, expressed in endosomes and apical membranes of renal tubules. Loss of CLC-5 function alters receptor-mediated endocytosis and trafficking of megalin and cubilin, although the underlying mechanisms remain to be elucidated. Here, we report that CLC-5 interacts with kinesin family member 3B (KIF3B), a heterotrimeric motor protein that facilitates fast anterograde translocation of membranous organelles. Using yeast two-hybrid, glutathione-S-transferase pull-down and coimmunoprecipitation assays, the COOH terminus of CLC-5 and the coiled-coil and globular domains of KIF3B were shown to interact. This was confirmed in vivo by endogenous coimmunoprecipitation of CLC-5 and KIF3B and codistribution with endosomal markers in mouse kidney fractions. Confocal live cell imaging in kidney cells further demonstrated association of CLC-5 and KIF3B, and transport of CLC-5-containing vesicles along KIF3B microtubules. KIF3B overexpression and underexpression, using siRNA, had reciprocal effects on whole cell chloride current amplitudes, CLC-5 cell surface expression, and endocytosis of albumin and transferrin. Clcn5(Y/-) mouse kidneys and isolated proximal tubular polarized cells showed increased KIF3B expression, whose effects on albumin endocytosis were dependent on CLC-5 expression. Thus, the CLC-5 and KIF3B interaction is important for CLC-5 plasma membrane expression and for facilitating endocytosis and microtubular transport in the kidney.

Mutational analysis of CLC-5, cofilin and CLC-4 in patients with Dent's disease.

BACKGROUND/AIMS: Dent's disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. METHODS: Eighteen probands with Dent's disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. RESULTS: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. CONCLUSIONS: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent's disease in this patient cohort.