A multifaceted architectural framework of the mouse claustrum complex.

Accurate anatomical characterizations are necessary to investigate neural circuitry on a fine scale, but for the rodent claustrum complex (CLCX), this has yet to be fully accomplished. The CLCX is generally considered to comprise two major subdivisions, the claustrum (CL) and the dorsal endopiriform nucleus (DEn), but regional boundaries to these areas are debated. To address this, we conducted a multifaceted analysis of fiber- and cytoarchitecture, genetic marker expression, and connectivity using mice of both sexes, to create a comprehensive guide for identifying and delineating borders to CLCX, including an online reference atlas. Our data indicated four distinct subregions within CLCX, subdividing both CL and DEn into two. Additionally, we conducted brain-wide tracing of inputs to CLCX using a transgenic mouse line. Immunohistochemical staining against myelin basic protein (MBP), parvalbumin (PV), and calbindin (CB) revealed intricate fiber-architectural patterns enabling precise delineations of CLCX and its subregions. Myelinated fibers were abundant dorsally in CL but absent ventrally, whereas PV expressing fibers occupied the entire CL. CB staining revealed a central gap within CL, also visible anterior to the striatum. The Nr2f2, Npsr1, and Cplx3 genes expressed specifically within different subregions of the CLCX, and Rprm helped delineate the CL-insular border. Furthermore, cells in CL projecting to the retrosplenial cortex were located within the myelin sparse area. By combining own experimental data with digitally available datasets of gene expression and input connectivity, we could demonstrate that the proposed delineation scheme allows anchoring of datasets from different origins to a common reference framework.

Mice are a highly tractable model for studying the claustrum complex (CLCX). However, without a consensus on how to delineate the CLCX in rodents, comparing results between studies is challenging. It is therefore important to expand our anatomical knowledge of the CLCX, to match the level of detail needed to study its functional properties. To improve and expand upon preexisting delineation schemes, we used the combinatorial expression of several markers to create a comprehensive guide to delineate the CLCX and its subregions, including an online reference atlas. This anatomical framework will allow researchers to anchor future experimental data into a common reference space. We demonstrated the power of this new structural framework by combining our own experimental data with digitally available data on gene expression and input connectivity of the CLCX.

Human lesions and animal studies link the claustrum to perception, salience, sleep and pain.

The claustrum is the most densely interconnected region in the human brain. Despite the accumulating data from clinical and experimental studies, the functional role of the claustrum remains unknown. Here, we systematically review claustrum lesion studies and discuss their functional implications. Claustral lesions are associated with an array of signs and symptoms, including changes in cognitive, perceptual and motor abilities; electrical activity; mental state; and sleep. The wide range of symptoms observed following claustral lesions do not provide compelling evidence to support prominent current theories of claustrum function such as multisensory integration or salience computation. Conversely, the lesions studies support the hypothesis that the claustrum regulates cortical excitability. We argue that the claustrum is connected to, or part of, multiple brain networks that perform both fundamental and higher cognitive functions. As a multifunctional node in numerous networks, this may explain the manifold effects of claustrum damage on brain and behaviour.

In search of common developmental and evolutionary origin of the claustrum and subplate.

The human claustrum, a major hub of widespread neocortical connections, is a thin, bilateral sheet of gray matter located between the insular cortex and the striatum. The subplate is a largely transient cortical structure that contains some of the earliest generated neurons of the cerebral cortex and has important developmental functions to establish intra- and extracortical connections. In human and macaque some subplate cells undergo regulated cell death, but some remain as interstitial white matter cells. In mouse and rat brains a compact layer is formed, Layer 6b, and it remains underneath the cortex, adjacent to the white matter. Whether Layer 6b in rodents is homologous to primate subplate or interstitial white matter cells is still debated. Gene expression patterns, such as those of Nurr1/Nr4a2, have suggested that the rodent subplate and the persistent subplate cells in Layer 6b and the claustrum might have similar origins. Moreover, the birthdates of the claustrum and Layer 6b are similarly precocious in mice. These observations prompted our speculations on the common developmental and evolutionary origin of the claustrum and the subplate. Here we systematically compare the currently available data on cytoarchitecture, evolutionary origin, gene expression, cell types, birthdates, neurogenesis, lineage and migration, circuit connectivity, and cell death of the neurons that contribute to the claustrum and subplate. Based on their similarities and differences we propose a partially common early evolutionary origin of the cells that become claustrum and subplate, a likely scenario that is shared in these cell populations across all amniotes.

Chronic social isolation exerts opposing sex-specific consequences on serotonin neuronal excitability and behaviour.

Social isolation raises the risk for mood disorders associated with serotonergic disruption. Yet, the underlying mechanisms by which the stress of social isolation increases risk are not well understood. Men and women are differently vulnerable; however, this modulating role of sex is challenging to study in humans under carefully controlled conditions. Therefore, we investigated this question in mice of both sexes, asking how the long-term stress of social isolation (from weaning into adulthood) affects the excitability of serotonin neurons in the dorsal raphe nucleus as well as mouse behaviour. The electrophysiological experiments and the first set of behavioural tests were conducted in young adult mice, with additional behavioural assays completed as the mice matured to assess the stability of their behavioural phenotype. We found that social isolation exerted seemingly-opposite effects in male and female mice, relative to their respective group-housed littermate controls. This distinctive pattern was observed for the effect of social isolation on the control of serotonergic neuron excitability via the SK family of calcium-activated potassium channels. Furthermore, we observed a similar and consistent pattern on tests relevant to assessing the efficacy of anti-depressant medicines, including the forced swim test, the novelty-suppressed feeding test, and the sucrose preference test. These findings underscore the concept that stress-elicited illness manifests distinctly in males and females and that treatments aimed at restoring serotonergic function may require a sex-specific approach. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels.

The activity of serotonin (5-HT) neurons is critical for mood regulation. In a mouse model of chronic social isolation, a known risk factor for depressive illness, we show that 5-HT neurons in the dorsal raphe nucleus are less responsive to stimulation. Probing the responsible cellular mechanisms pinpoints a disturbance in the expression and function of small-conductance Ca2+-activated K+ (SK) channels and reveals an important role for both SK2 and SK3 channels in normal regulation of 5-HT neuronal excitability. Chronic social isolation renders 5-HT neurons insensitive to SK2 blockade, however inhibition of the upregulated SK3 channels restores normal excitability. In vivo, we demonstrate that inhibiting SK channels normalizes chronic social isolation-induced anxiety/depressive-like behaviors. Our experiments reveal a causal link for the first time between SK channel dysregulation and 5-HT neuron activity in a lifelong stress paradigm, suggesting these channels as targets for the development of novel therapies for mood disorders.

Outcomes After Post-Traumatic AKI Requiring RRT in United States Military Service Members.

BACKGROUND AND OBJECTIVES: Mortality and CKD risk have not been described in military casualties with post-traumatic AKI requiring RRT suffered in the Iraq and Afghanistan wars. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective case series of post-traumatic AKI requiring RRT in 51 military health care beneficiaries (October 7, 2001-December 1, 2013), evacuated to the National Capital Region, documenting in-hospital mortality and subsequent CKD. Participants were identified using electronic medical and procedure records. RESULTS: Age at injury was 26±6 years; of the participants, 50 were men, 16% were black, 67% were white, and 88% of injuries were caused by blast or projectiles. Presumed AKI cause was acute tubular necrosis in 98%, with rhabdomyolysis in 72%. Sixty-day all-cause mortality was 22% (95% confidence interval [95% CI], 12% to 35%), significantly less than the 50% predicted historical mortality (P<0.001). The VA/NIH Acute Renal Failure Trial Network AKI integer score predicted 60-day mortality risk was 33% (range, 6%-96%) (n=49). Of these, nine died (mortality, 18%; 95% CI, 10% to 32%), with predicted risks significantly miscalibrated (P<0.001). The area under the receiver operator characteristic curve for the AKI integer score was 0.72 (95% CI, 0.56 to 0.88), not significantly different than the AKI integer score model cohort (P=0.27). Of the 40 survivors, one had ESRD caused by cortical necrosis. Of the remaining 39, median time to last follow-up serum creatinine was 1158 days (range, 99-3316 days), serum creatinine was 0.85±0.24 mg/dl, and eGFR was 118±23 ml/min per 1.73 m(2). No eGFR was <60 ml/min per 1.73 m(2), but it may be overestimated because of large/medium amputations in 54%. Twenty-five percent (n=36) had proteinuria; one was diagnosed with CKD stage 2. CONCLUSIONS: Despite severe injuries, participants had better in-hospital survival than predicted historically and by AKI integer score. No patient who recovered renal function had an eGFR<60 ml/min per 1.73 m(2) at last follow-up, but 23% had proteinuria, suggesting CKD burden.

Report of the first peritoneal dialysis program in Guyana, South America.

INTRODUCTION: In 2008, we initiated the first Guyanese comprehensive kidney replacement program, comprising hemodialysis (HD), peritoneal dialysis (PD), vascular access procedures, and living-donor kidney transplantation. The government of Guyana, US-based philanthropists, US-based physicians, and Guyanese caregivers teamed up to form a public-private partnership. This pilot program was free of cost to the patients. METHODS: From July 2010 to the time of writing, we placed 17 patients with end-stage kidney disease on PD, which was used as a bridge to living-donor kidney transplantation. During the same period, we placed 12 primary arteriovenous fistulae. RESULTS: The 17 patients who received a PD catheter had a mean age of 43.6 years and a mean follow-up of 5.3 months. In that group, 2 deaths occurred (from multi-organ failure) within 2 weeks of catheter placement, and 2 patients were switched to HD because of inadequate clearance. Technical issues were noted in 2 patients, and 3 patients developed peritonitis (treated with intravenous antibiotics). An exit-site abscess in 1 patient was drained under local anesthesia. The peritonitis rate was 0.36 episodes per patient-year. Of the 17 patients who received PD, 4 underwent living-donor kidney transplantation. CONCLUSIONS: In Guyana, PD is a safe and cost-effective option; it may be equally suitable for similar developing countries. In Guyana, PD was used as a bridge to living-donor kidney transplantation. We have been able to sustain this program since 2008 by making incremental gains and nurturing the ongoing public-private partnership.

Association of prescription of oral sodium polystyrene sulfonate with sorbitol in an inpatient setting with colonic necrosis: a retrospective cohort study.

BACKGROUND: Colonic necrosis has been reported after sodium polystyrene sulfonate (SPS)/sorbitol use, but the incidence and relative risk (RR) are not established. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 123,391 adult inpatients at a tertiary medical center. PREDICTOR: Receipt of SPS prescriptions (exposed) or a prescription other than SPS (unexposed internal comparison group) between September 1, 2001, and October 31, 2010. OUTCOMES: The main outcome measure was tissue-confirmed diagnosis of colonic necrosis, considered SPS-associated if SPS was prescribed 30 or fewer days before tissue accession date. MEASUREMENTS: Demographics, serum chemistry test results, hospital location, and International Classification of Diseases, Ninth Revision diagnostic codes. RESULTS: SPS was prescribed to 2,194 inpatients. 82 inpatient colonic necrosis cases were identified. 3 received oral SPS (1 gram per 4 milliliters of 33% sorbitol) 30 or fewer days before the colonic necrosis accession date (3.7% of inpatient colonic necrosis cases). The data were linked with 123,391 individuals who received inpatient prescriptions between the same dates. Colonic necrosis incidence was 0.14% (95% CI, 0.03%-0.40%) in those prescribed SPS versus 0.07% (95% CI, 0.05-0.08%) in those not prescribed SPS (RR, 2.10; 95% CI, 0.68-6.48; P = 0.2). The number needed to harm was 1,395 (95% CI, 298-5,100). Subgroup analysis (age >65 years; estimated glomerular filtration rate, <30 mL/min/1.73 m(2), intensive care unit admission, or surgical ward status) did not show significant associations. Sample-size analysis indicated that 4,974 SPS-treated individuals older than 65 years and a comparison group 10 times larger would be required for rigorous multivariate analysis of SPS-associated colonic necrosis risk. LIMITATIONS: Individuals with colonic necrosis admitted to non-Department of Defense hospitals would not have been ascertained. Only individuals who had colonic biopsy or surgical tissue submitted for pathologic review could be ascertained as having colonic necrosis. CONCLUSIONS: SPS-associated colonic necrosis is rare, and inpatient SPS/sorbitol prescription was not associated significantly with an increased RR of colonic necrosis in this retrospective cohort analysis. Multivariate analysis would require retrospective clinical cohorts from larger or more than one hospital system(s).

Asymptomatic autoantibodies associate with future anti-glomerular basement membrane disease.

The pathophysiology of anti-glomerular basement membrane (anti-GBM) disease before clinical presentation is unknown. The presence of anti-GBM, anti-proteinase 3 (PR3), and anti-myeloperoxidase (MPO) antibodies associate with the disease at the time of diagnosis, but little is known about the presence of these autoantibodies before diagnosis. We used serum samples from the Department of Defense Serum Repository to conduct a case-control study involving 30 patients diagnosed with anti-GBM disease and 30 healthy controls matched for the age, gender, race, and age of the serum samples. We analyzed a maximum of three samples from each subject: the most recent sample before diagnosis, the penultimate sample before diagnosis, and the oldest sample available; the average time between the most recent sample and diagnosis was 195 days (range, 4 to 1346 days). Elevated anti-GBM levels (≥3 U/ml) were present in four patients, all less than 1 year before diagnosis but in no controls. Detectable anti-GBM antibody levels (≥1 U/ml but <3 U/ml) in a single serum sample before diagnosis were more frequent in cases than controls (70% versus 17%, P < 0.001). Only study patients had detectable anti-GBM levels in multiple samples before diagnosis (50% versus 0%, P < 0.001). Almost all patients had detectable anti-PR3 and/or anti-MPO that preceded the onset of disease. Among patients with a clear antecedent antibody, anti-PR3 or anti-MPO always became detectable before the anti-GBM antibody. In summary, our data describe the subclinical formation of autoantibodies, which improves our understanding of the pathophysiology of anti-GBM disease.

Assessment of racial disparities in chronic kidney disease stage 3 and 4 care in the department of defense health system.

BACKGROUND AND OBJECTIVES: Racial disparities in provision of healthcare are widespread in the United States but have not been specifically assessed in provision of chronic kidney disease (CKD) care. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective cohort study of the clinical database used in a Department of Defense (DOD) medical system. Beneficiaries studied were DOD-eligible beneficiaries with CKD stage 3 (n = 7729) and 4 (n = 589) using the modified Modification of Diet in Renal Disease (MDRD)-estimated GFR formula but requiring manual correction for Black race. Compliance with selected Kidney Disease Outcomes Quality Initiative (KDOQI) CKD recommended targets (monitoring of recommended laboratory data, prescription of recommended medications, and referral to nephrology) was assessed over a 12-mo period, stratified by CKD stage. Logistic regression analysis was used to assess whether race (White, Black, or other) was independently associated with provider compliance with targets, adjusted for demographic factors and burden of comorbid conditions. RESULTS: Among the targets, only monitoring of LDL cholesterol was significantly less common among Blacks. For all other measures, compliance was either not significantly different or significantly higher for Black compared with White beneficiaries. However, patients categorized as "Other" race were in general less likely to achieve targets than Whites, and at stage 3 CKD significantly less likely to achieve targets for monitoring of phosphorous, hemoglobin, and vitamin D. CONCLUSIONS: In the DOD health system, provider compliance with selected CKD stage 3 and 4 targets was not significantly lower for Black beneficiaries than for Whites, with the exception of LDL cholesterol monitoring. Patients classified as Other race were generally less likely to achieve targets than Whites, in some patients significantly so.

Association of oral sodium phosphate purgative use with acute kidney injury.

Oral sodium phosphate (OSP) is a commonly used purgative before colonoscopy. There have been numerous reports of acute phosphate nephropathy attributed to the use of OSP. This study evaluated the association between the use of OSP and acute kidney injury (AKI) in an observational, retrospective, cohort study. Of 9799 patients who underwent colonoscopy and had serum creatinine values recorded within 365 days before and after the procedure, AKI, defined as > or =50% increase in baseline serum creatinine, was identified in 114 (1.16%). After adjustment for significant covariates in a multiple logistic regression model, the use of OSP was associated with increased risk for AKI (odds ratio 2.35; 95% confidence interval 1.51 to 3.66; P < 0.001) with an adjusted number need to harm of 81. Age was also independently associated with AKI in this cohort; therefore, until larger, prospective studies define the population at risk for acute phosphate nephropathy, the use of polyethylene glycol-based purgatives should be considered for older patients and possibly for those with comorbid medical conditions.

Body mass index and peritoneal dialysis: "exceptions to the exception" in reverse epidemiology?

Until recently, it was not apparent whether apparent paradoxical associations of body mass index (BMI), lipids, and blood pressure with survival observed in hemodialysis (HD) patients, which contradict observations from the general population, also applied to peritoneal dialysis (PD) patients. Studies of survival in PD patients must account for differences in adjusted survival relative to HD patients, namely, early equivalent to superior survival, but after about 1-2 years, inferior survival. Several recent observational studies have analyzed the association between BMI and survival in PD patients from different perspectives and using different patient populations. In general, these studies found that any survival advantage associated with obesity is significantly less likely in PD than HD patients. Among PD patients, those who are obese can be said to have equivalent survival to PD patients with normal BMI. Studies of lipids and blood pressure in PD patients also yield conflicting associations with survival. Obese patients, especially if diabetic, may have increased risk of death after starting on PD compared to HD, although firm conclusions are premature given the limitations of current evidence. At present, the levels of lipids and blood pressure which are best associated with survival in PD patients are not well-defined.

Use of beta-blockers and aspirin after myocardial infarction by patient renal function in the Department of Defense health care system.

BACKGROUND: Whether the previously reported underutilization of standard-of-care medications in the management of patients with acute myocardial infarction (AMI) persists in more recent years or differs by ward of admission has not been reported. METHODS: We performed a retrospective cross-sectional study of patients hospitalized with a discharge diagnosis of incident AMI to a Department of Defense hospital (Walter Reed Army Medical Center, Washington, DC) from 2001 through 2004. Use of beta-blockers and aspirin at the time of discharge after AMI was assessed according to Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rate (eGFR) in milliliters per minute per 1.73 m2, stratified by admission to the coronary care unit (CCU) versus other wards. Adjusted odds ratios for discharge beta-blocker and aspirin therapy were calculated by using logistic regression. RESULTS: Among 431 patients, overall discharge use of beta-blockers was 86.8%, and aspirin, 86.8%, both significantly greater after CCU admission than admission to other wards (93%, aspirin use; 91.7%, beta-blocker use; P < 0.001 and P < 0.001). In logistic regression, CCU admission was the only independent factor associated with either beta-blocker or aspirin use; MDRD eGFR was not associated significantly with beta-blocker and aspirin use regardless of admission to the CCU or non-CCU. CONCLUSION: Future studies of disparities in use of standard-of-care medications after AMI according to renal function should account for the primary site of admission, particularly CCU versus others. In addition, legitimate contraindications to the use of beta-blockers and aspirin may be subtle, including appropriate end-of-life decisions.

Body mass index, dialysis modality, and survival: analysis of the United States Renal Data System Dialysis Morbidity and Mortality Wave II Study.

BACKGROUND: The impact of obesity on survival in end-stage renal disease (ESRD) patients as related to dialysis modality (i.e., a direct comparison of hemodialysis with peritoneal dialysis) has not been assessed adjusting for differences in medication use, follow-up > or =2 years, or accounting for changes in dialysis modality. METHODS: We performed a retrospective cohort study of the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Wave II Study (DMMS) patients who started dialysis in 1996, and were followed until October 31 2001. Cox regression analysis was used to model adjusted hazard ratios (AHR) for mortality for categories of body mass index (BMI), both as quartiles and as > or =30 kg/m2 vs. lower. Because such a large proportion of peritoneal dialysis patients changed to hemodialysis during the study period (45.5%), a sensitivity analysis was performed calculating survival time both censoring and not censoring on the date of change from peritoneal dialysis to hemodialysis. RESULTS: There were 1675 hemodialysis and 1662 peritoneal dialysis patients. Among hemodialysis patients, 5-year survival for patients with BMI > or =30 kg/m2 was 39.8% vs. 32.3% for lower BMI (P < 0.01 by log-rank test). Among peritoneal dialysis patients, 5-year survival for patients with BMI >/=30 kg/m2 was 38.7% vs. 40.4% for lower BMI (P > 0.05 by log-rank test). In adjusted analysis, BMI > or = 30 kg/m2 was associated with improved survival in hemodialysis patients (AHR 0.89; 95% CI 0.81, 0.99; P= 0.042) but not peritoneal dialysis patients (AHR = 0.99; 95% CI, 0.86, 1.15; P= 0.89). Results were not different on censoring of change from peritoneal dialysis to hemodialysis. CONCLUSION: We conclude that any survival advantage associated with obesity among chronic dialysis patients is significantly less likely for peritoneal dialysis patients, compared to hemodialysis patients.

International use of an academic nephrology World Wide Web site: from medical information resource to business tool.

BACKGROUND: Studies of the use of the World Wide Web to obtain medical knowledge have largely focused on patients. In particular, neither the international use of academic nephrology World Wide Web sites (websites) as primary information sources nor the use of search engines (and search strategies) to obtain medical information have been described. METHODS: Visits ("hits") to the Walter Reed Army Medical Center (WRAMC) Nephrology Service website from April 30, 2000, to March 14, 2001, were analyzed for the location of originating source using Webtrends, and search engines (Google, Lycos, etc.) were analyzed manually for search strategies used. RESULTS: From April 30, 2000 to March 14, 2001, the WRAMC Nephrology Service website received 1,007,103 hits and 12,175 visits. These visits were from 33 different countries, and the most frequent regions were Western Europe, Asia, Australia, the Middle East, Pacific Islands, and South America. The most frequent organization using the site was the military Internet system, followed by America Online and automated search programs of online search engines, most commonly Google. The online lecture series was the most frequently visited section of the website. Search strategies used in search engines were extremely technical. CONCLUSIONS: The use of "robots" by standard Internet search engines to locate websites, which may be blocked by mandatory registration, has allowed users worldwide to access the WRAMC Nephrology Service website to answer very technical questions. This suggests that it is being used as an alternative to other primary sources of medical information and that the use of mandatory registration may hinder users from finding valuable sites. With current Internet technology, even a single service can become a worldwide information resource without sacrificing its primary customers.