Polarized Proteins in Endothelium and Their Contribution to Function.

Protein localization in endothelial cells is tightly regulated to create distinct signaling domains within their tight spatial restrictions including luminal membranes, abluminal membranes, and interendothelial junctions, as well as caveolae and calcium signaling domains. Protein localization in endothelial cells is also determined in part by the vascular bed, with differences between arteries and veins and between large and small arteries. Specific protein polarity and localization is essential for endothelial cells in responding to various extracellular stimuli. In this review, we examine protein localization in the endothelium of resistance arteries, with occasional references to other vessels for contrast, and how that polarization contributes to endothelial function and ultimately whole organism physiology. We highlight the protein localization on the luminal surface, discussing important physiological receptors and the glycocalyx. The protein polarization to the abluminal membrane is especially unique in small resistance arteries with the presence of the myoendothelial junction, a signaling microdomain that regulates vasodilation, feedback to smooth muscle cells, and ultimately total peripheral resistance. We also discuss the interendothelial junction, where tight junctions, adherens junctions, and gap junctions all convene and regulate endothelial function. Finally, we address planar cell polarity, or axial polarity, and how this is regulated by mechanosensory signals like blood flow.

No Change in Social Decision-Making Following Transcranial Direct Current Stimulation of the Right Temporoparietal Junction.

The right temporoparietal junction (rTPJ) is thought to play an important role in social cognition and pro-social decision-making. One way to explore this link is through the use of transcranial direct current stimulation (tDCS), a non-invasive brain stimulation method that is able to modulate cortical activity. The aim of this research was therefore to determine whether anodal tDCS to the rTPJ altered response to a social decision-making task. In this study, 34 healthy volunteers participated in a single-center, double-blinded, sham-controlled crossover design. Subjects received 20 min of active/sham anodal tDCS to the rTPJ before undertaking the Ultimatum Game (UG), a neuroeconomics paradigm in which participants are forced to choose between monetary reward and punishing an opponent's unfairness. Contrary to expectations, we found no significant difference between anodal and sham stimulation with regard to either the total number or reaction time of unfair offer rejections in the UG. This study draws attention to methodological issues in tDCS studies of the rTPJ, and highlights the complexity of social decision-making in the UG.

Etiopathogenesis of Nephrolithiasis in Ulcerative Colitis Patients with the Ileal Pouch Anal Anastomosis.

BACKGROUND: Our previous study showed that nephrolithiasis is a common complication in ulcerative colitis patients after ileal pouch anal anastomosis (IPAA). However, the pathogenesis of nephrolithiasis in IPAA patients has not been studied. The aim of this study was to compare urine and serum metabolic compositions in IPAA patients with nephrolithiasis and controls with IPAA and no nephrolithiasis. METHODS: Using cross-sectional study design, serum and 24-hour urine metabolic compositions were compared between IPAA patients with nephrolithiasis (the study group) and those without (the control group). Urinary supersaturation of calcium oxalate, calcium phosphate, and uric acid was calculated. RESULTS: A total of 40 patients were enrolled in the study. There were no significant differences in serum electrolytes, vitamin D, parathyroid hormone, and kidney function tests between the study (n = 20) and control groups (n = 20). Patients in the study group were found to have a significantly higher 24-hour urine supersaturation of calcium oxalate (8.8 versus 5.0, P = 0.037) and calcium phosphate (0.61 versus 0.27, P = 0.028) as compared with controls. Nineteen (95%) patients in the study group were symptomatic due to nephrolithiasis with several requiring procedural intervention for treatment, including ureteroscopy in 3 (15%) patients, lithotripsy in 5 (25%) patients, and percutaneous surgery in 1 (5%) patient. CONCLUSIONS: Ulcerative colitis-IPAA patients are at risk for the development of calcium oxalate and calcium phosphate stones. Nephrolithiasis is symptomatic in a majority of the patients and frequently requires procedural intervention for treatment.

Factor structure and construct validity of the temporal experience of pleasure scales.

Feelings of pleasure felt in the moment of goal attainment (consummatory pleasure) are thought to be dissociable from feelings of desire connected with the motivated approach of goals (anticipatory pleasure). The Temporal Experience of Pleasure Scales (TEPS; Gard, Gard, Kring, & John, 2006) was developed to assess individual differences in these distinct processes. Recently, an independent evaluation of the psychometric characteristics of a Chinese-translated TEPS suggested a more complex factor structure (Chan et al., 2012). This study aimed to reexamine the factor structure and convergent and divergent validity of the TEPS in two previously unexamined multiethnic samples. University students in the United Kingdom (N = 294) completed the TEPS and university students in Australia (N = 295) completed the TEPS as well as a battery of conceptually related questionnaires. A confirmatory factor analysis of Gard et al.'s (2006) 2-factor model produced inadequate fit, which model-modification indexes suggested might be due to item cross-loadings. This issue was examined further using an exploratory factor analysis, which revealed a clear 2-factor solution despite cross-loadings among some items. Finally, mixed evidence for convergent-divergent validity was obtained, in terms of relationships between the TEPS and measures of anhedonia, approach-motivation, and positive emotion.

Clarifying the Relation Between Extraversion and Positive Affect.

This article clarifies two sources of ambiguity surrounding the relation between extraversion and positive affect. First, positive affect is defined differently across major models of the structure of affect. Second, no previous research has examined potentially diverging associations of lower-order aspects of extraversion (i.e., assertiveness and enthusiasm) with positive affect. Australian (Study 1: N = 437, 78% female, Mage = 20.41) and American (Study 2: N = 262, 39% female, Mage = 33.86) participants completed multiple measures of extraversion and positive affect. Correlations were employed to examine relations among these measures. In both studies, extraversion was most clearly associated with positive affect as conceptualized within a major factor model of affect-specifically, as positive activation (Watson & Tellegen, 1985)-rather than the valence-based conceptualization of positive affect provided by a circumplex model of affect (Russell, 1980). This was also the case for the assertiveness and enthusiasm aspects of extraversion. Our findings clarify the nature of the positive affective component of extraversion, which is best described in terms of both positive valence and high activation.

Equivalent beneficial effects of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in a large randomized trial in treatment-resistant major depression.

Repetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. Recent studies have produced conflicting results as to whether unilateral rTMS is more or less effective than sequentially applied bilateral rTMS. To address this we conducted a trial comparing sequential bilateral rTMS to right-sided unilateral rTMS using a priming protocol. Patients with treatment-resistant depression (n = 179) were enrolled in a two-arm randomized controlled trial across a 4-wk time period. The primary outcome assessment was the Hamilton Depression Rating Scale. Overall, there was a substantial response rate of >50% (and a 40% remission rate); however, there were no significant differences in clinical response between the two treatment groups. rTMS was well tolerated with a very low discontinuation rate. There was no relationship between response in the current trial and previous response, or non-response, to electroconvulsive therapy. We found no significant differences in clinical response between sequential bilateral rTMS and right-sided unilateral rTMS applied with a priming protocol. The results of this study do not support superior efficacy of bilateral rTMS and instead suggest that other approaches should be explored to increase treatment efficacy.

Microbial utilisation of biochar-derived carbon.

Whilst largely considered an inert material, biochar has been documented to contain a small yet significant fraction of microbially available labile organic carbon (C). Biochar addition to soil has also been reported to alter soil microbial community structure, and to both stimulate and retard the decomposition of native soil organic matter (SOM). We conducted a short-term incubation experiment using two (13)C-labelled biochars produced from wheat or eucalypt shoots, which were incorporated in an aridic arenosol to examine the fate of the labile fraction of biochar-C through the microbial community. This was achieved using compound specific isotopic analysis (CSIA) of phospholipid fatty acids (PLFAs). A proportion of the biologically-available fraction of both biochars was rapidly (within three days) utilised by gram positive bacteria. There was a sharp peak in CO2 evolution shortly after biochar addition, resulting from rapid turnover of labile C components in biochars and through positive priming of native SOM. Our results demonstrate that this CO2 evolution was at least partially microbially mediated, and that biochar application to soil can cause significant and rapid changes in the soil microbial community; likely due to addition of labile C and increases in soil pH.

Risk factors for nephrolithiasis in patients with ileal pouches.

BACKGROUND AND AIMS: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become a standard of care in patients with ulcerative colitis (UC). Nephrolithiasis is common in patients with inflammatory bowel disease (IBD), but has never been studied as a complication of IPAA. We aimed to assess the risk factors for nephrolithiasis in patients with IPAA. METHODS: Using an IRB-approved, prospectively maintained pouch registry, we identified 1221 patients between 2000 and 2010. Those with post-IPAA nephrolithiasis served as the study group whereas IPAA patients without nephrolithiasis served as the controls. Demographic and clinical variables were analyzed using multivariable logistic regression to identify risk factors. RESULTS: There were a total of 218 IPAA patients: 81 with nephrolithiasis (37%) and 137 without (63%). Of the 81 patients in the study group, 17 were excluded due to limited clinical data. Three risk factors were found to be associated with nephrolithiasis: the presence of extra-intestinal manifestations (odd's ratio [OR]=2.9, 95% confidence interval [CI]: 1.4, 5.8, p=0.003), no use of antibiotics (OR=3.2, 95% CI: 1.5, 6.5, p=0.002) and low serum bicarbonate level (OR=0.87, 95% CI: 0.77, 0.99, p=0.038). CONCLUSION: Nephrolithiasis was a common finding in our patients with IPAA. As pouch patients with nephrolithiasis can develop adverse clinical complications, those with at least one of the risk factors we identified may need to be monitored more closely and possibly receive prophylactic treatment with oral bicarbonate.

A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression.

OBJECTIVE: A substantive body of research has demonstrated the efficacy of repetitive transcranial magnetic stimulation treatment (rTMS) in patients with depression. However, the parameters needed to optimize therapeutic efficacy remain unclear. The aim of this study was to investigate whether there is an advantage in efficacy of sequential bilateral rTMS compared to standard high-frequency left sided rTMS. METHOD: Sixty seven patients with treatment resistant depression were included in a randomised double-blind sham controlled trial of sequential bilateral rTMS compared to standard high-frequency left sided rTMS and sham rTMS over a three-week period. The study also included a further three week comparison of the two active treatment conditions. The primary outcome variable was scores on the 17-item Hamilton Depression Rating Scale (HAMD). RESULTS: In the three-week double-blind phase of the trial there was a greater antidepressant response to unilateral left sided rTMS compared with sham or bilateral rTMS. Across the full six weeks of active rTMS, there was also a consistent pattern of improved response in unilateral left compared to bilateral treatment. Response rates were low in both active groups. CONCLUSIONS: This study does not support the hypothesis that sequential bilateral rTMS is more effective than unilateral high-frequency left-sided rTMS.

Nephrolithiasis: treatment, causes, and prevention.

Factors that promote stone formation include low daily urine volumes; saturation of the urine with calcium, oxalate, calcium phosphate, uric acid, or cystine; acidic urine; and bacterial infection. The author identifies the mechanisms of stone formation and outlines management aimed at preventing recurrences.

Clinical evaluation of the longevity and durability of an impressionless intraoral appliance (iNterra) system.

OBJECTIVE: To clinically evaluate the durability of an impressionless intraoral appliance (iNterra) system, fabricated using a direct/indirect technique. METHODS: Fifty-three (53) appliances were fabricated using the technique and followed for a median observation period of 301 days. Appliances were evaluated by calibrated operators for adaptation to teeth, retention, stability, and paresthesia, as reported by subjects, in addition to wear. RESULTS: All restorations (100%) were rated acceptable for adaptation to teeth, retention, and stability at placement. At the longest recalls, 96.2% of appliances survived without fracture. A similar percentage (96.0%) were rated acceptable for adaptation to teeth, retention, and stability. Paresthesia (reversible malodor) was reported in one (1.9%) case. In terms of wear, 98.1% of appliances delivered were rated as "no wear evident" or "evident but acceptable wear." CONCLUSION: Overall, the evaluators agreed that the impressionless system offered procedural efficiency advantages, was clinically viable, and should be a valuable option to practitioners considering appliance therapy to control parafunctional behavior.

Methods to assess students' acquisition, application and integration of basic science knowledge in an innovative competency-based curriculum.

BACKGROUND: The Cleveland Clinic Lerner College of Medicine was designed to encourage medical students to pursue careers as physician investigators. Our faculty decided that assessment should enhance learning and adopted only formative assessments to document student performance in relation to nine broad-based competencies. No grades are used to judge student performance throughout the 5-year program. Instead, assessments are competency-based, relate directly to performance standards, and are stored in e-Portfolios to track progress and document student achievement. The class size is limited to 32 students a year. AIMS: Schools with competency-based curricula must provide students with formative feedback to identify performance gaps and monitor progress. We describe a systematic approach to assess medical knowledge using essay-type questions (CAPPs) and multiple choice questions (SAQs) to provide medical students with weekly, formative feedback about their abilities to acquire, apply and integrate basic and clinical science concepts. METHOD: Processes for developing performance standards, creating assessment items, training faculty, reporting student performance and monitoring outcomes are described. A case study of a Year 1 course is presented with specific examples of CAPPs and SAQs to illustrate how formative assessment data are interpreted and reported in students' e-Portfolios. RESULTS: Preliminary evidence suggests that CAPPs and SAQs have a positive impact on students' education, a justifiable cost in light of obtained benefits and growing acceptance among stakeholders. Two student cohorts performed significantly above the population mean on USMLE Step 1, which suggests that these assessment methods have not disadvantaged students. More evidence is needed to assess the reliability and validity of these tools for formative purposes. CONCLUSIONS: Using assessment data for formative purposes may encourage application and integration of knowledge, help students identify performance gaps, foster student development of learning plans and promote student responsibility for learning. Discussion provides applications for institutions with larger classes to consider.

Performance of the Cockcroft-Gault and modification of diet in renal disease equations in estimating GFR in ill hospitalized patients.

BACKGROUND: Estimating glomerular filtration rate (GFR) in severely ill inpatients is clinically important for therapeutic interventions and prognosis, but notoriously difficult to do accurately. The Modification of Diet in Renal Disease (MDRD) equation and Cockcroft-Gault (CG) formula are widely used to estimate renal function in sick hospitalized patients; however, neither method has been validated in this setting. METHODS: Iodine 125-iothalamate clearances (iGFR) performed in 107 sick inpatients with renal dysfunction were compared with estimated GFRs (eGFRs) from the 6- and 4-variable MDRD (MDRD eGFR) and CG (CG eGFR) equations. RESULTS: Mean serum creatinine (SCr) level was 3.5 +/- 2.0 mg/dL (309 +/- 177 micromol/L), and mean iGFR was 17.1 +/- 17.9 mL/min/1.73 m2 (0.29 +/- 0.30 mL/s/1.73 m2). Six-variable MDRD eGFR was 22.5 +/- 17.4 mL/min/1.73 m2 (0.38 +/- 0.29 mL/s/1.73 m2), 4-variable MDRD eGFR was 23.9 +/- 16.3 mL/min/1.73 m2 (0.40 +/- 0.27 mL/s/1.73 m2), and CG eGFR was 26.0 +/- 17.1 mL/min/1.73 m2 (0.43 +/- 0.29 mL/s/1.73 m2). Blood urea nitrogen (BUN)/SCr ratios greater than 20 were seen in 58% of patients. Overall, the CG and MDRD equations overestimated iGFR, with poor agreement. Overestimation of at least 25% of measured iGFR was seen in 63%, 67%, and 70% of all inpatients when using the 6-variable MDRD, 4-variable MDRD, and CG equations, respectively. Accuracy of eGFR within 50% of measured iGFR was 55% for the 6-variable MDRD equation, 49% for the 4-variable MDRD equation, and 40% for the CG formula. The performance of both methods deteriorated further in patients with a BUN/SCr ratio greater than 20. CONCLUSION: Estimation equations are performed poorly compared with iGFR and are not reliable measures of actual level of function in sick hospitalized patients, especially those with a high BUN/SCr ratio. Although use of the 6-variable MDRD equation provides a better estimation of GFR, it still is unsuitable for clinical application in this population.

Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease.

The performance of the Modification of Diet in Renal Disease (MDRD) and the Cockcroft-Gault (CG) equations as compared with measured (125)I-iothalamate GFR (iGFR) was analyzed in patients with chronic kidney disease (CKD) and in potential kidney donors. All outpatients (n = 1285) who underwent an iGFR between 1996 and 2003 were considered for analysis. Of these, 828 patients had CKD and 457 were potential kidney donors. Special emphasis was put on the calibration of the serum creatinine measurements. In CKD patients with GFR <60 ml/min per 1.73 m(2), the MDRD equation performed better than the CG formula with respect to bias (-0.5 versus 3.5 ml/min per 1.73 m(2), respectively) and accuracy within 30% (71 versus 60%, respectively) and 50% (89 versus 77%, respectively). Similar results are reported for 249 CKD patients with diabetes. In the kidney donor group, the MDRD equation significantly underestimated the measured GFR when compared with the CG formula, with a bias of -9.0 versus 1.9 ml/min per 1.73 m(2), respectively (P < 0.01), and both the MDRD and CG equations overestimated the strength of the association of GFR with measured serum creatinine. The present data add further validation of the MDRD equation in outpatients with moderate to advanced kidney disease as well as in those with diabetic nephropathy but suggest that its use is problematic in healthy individuals. This study also emphasizes the complexity of laboratory calibration of serum creatinine measurements, a determining factor when estimating GFR in both healthy individuals and CKD patients with preserved GFR.

Evaluation of hyponatremia: a little physiology goes a long way.

Hyponatremia is common in hospitalized patients. By taking a careful and logical approach, one can promptly recognize the causative factor or factors in nearly all cases. Most cases of hyponatremia are due to impaired renal water excretion, and recognizing the cause and pathophysiologic process makes it possible to provide focused individualized care and avoid mistreatment.

Preventing kidney stones: calcium restriction not warranted.

The traditional wisdom on preventing calcium stones, the most common form of kidney stone, has been to advise patients to limit dietary calcium. Research has proved this wrong, however. Normal dietary calcium intake, along with reduced salt and protein, is now advised. This paper also summarizes the diagnosis and treatment of the less-common forms of kidney stones-struvite, uric acid, and cystine.

Increased urinary albumin excretion in children from families with Balkan nephropathy.

Balkan nephropathy (BN) has not been described in children. However, some previous studies have revealed abnormalities of the urinary tract in children from families with BN. In the present study, urinary excretion of albumin was studied in 703 healthy children, age 9-13 years, from endemic and non-endemic settlements around the South Morava River. Since BN is an environmentally induced disease, with possible seasonal variation of toxicant(s), children were studied three times a year: spring, autumn, and winter. After a water load of 15 ml/kg body weight, a 3-h urine sample was collected, from 7 to 10 a.m. Albumin excretion in urine was highest in children from families with BN in all three periods investigated. It was significantly different from excretion in children from the city, and in autumn it was also different ( P<0.01) from children in non-endemic families. Correlation analysis of albumin excretion with some urinary markers of tubular nephrotoxicity shows the highest correlation with both beta(2)-microglobulin and N-acetyl-beta-D-glucosaminidase in endemic villages in autumn. If the upper limit of albumin excretion is set at 8.5 mg/mmol creatinine, then in autumn increased albumin excretion was found in 15 of 229 children from endemic settlements and in only 5 of 454 children from non-endemic areas ( P<0.0001). Evidence is presented that in autumn children from families with BN excreted significantly more albumin than those from non-endemic families but living in the same settlements, or from children living outside of the endemic region in the city of Nis.