From the Cover: Rhythmic ring–ring stacking drives the circadian oscillator clockwise

The oscillator of the circadian clock of cyanobacteria is composed of three proteins, KaiA, KaiB, and KaiC, which together generate a self-sustained ∼24-h rhythm of phosphorylation of KaiC. The mechanism propelling this oscillator has remained elusive, however. We show that stacking interactions between the CI and CII rings of KaiC drive the transition from the phosphorylation-specific KaiC–KaiA interaction to the dephosphorylation-specific KaiC–KaiB interaction. We have identified the KaiB-binding site, which is on the CI domain. This site is hidden when CI domains are associated as a hexameric ring. However, stacking of the CI and CII rings exposes the KaiB-binding site. Because the clock output protein SasA also binds to CI and competes with KaiB for binding, ring stacking likely regulates clock output. We demonstrate that ADP can expose the KaiB-binding site in the absence of ring stacking, providing an explanation for how it can reset the clock.     

Prevalence of hair shedding among women

Hair shedding in female patients is a frequent complaint in dermatological, endocrinological, and gynecological consults. Previously, the Sinclair Hair Shedding Scale was developed to assess normal versus excessive hair shedding in female pattern hair loss (FPHL) subjects. However, the prevalence of hair shedding in females not suffering from FPHL is unknown. To gain better understanding of hair shedding in the general population, we recruited 300 subjects visiting a public hospital for conditions other than alopecia. Of the 300 subjects recruited, 263 did not suffer from FPHL. Among those subjects, approximately 40% reported experiencing excessive hair shedding (as defined by the Sinclair Hair Shedding Scale) on hair washing days. In comparison, in our subject population, approximately 60% of subjects with FPHL reported excessive hair shedding on hair washing days. To best of our knowledge, this is the first study to quantify the prevalence of hair shedding in women. While, no treatment currently exists for this condition, we hope that this study would encourage physicians and researchers to address this frequent concern.     

Perfusion MR imaging of extracranial tumor angiogenesis

Dynamic contrast-enhanced MRI (DCE-MRI) using small molecular weight gadolinium chelates enables noninvasive imaging characterization of tissue vascularity. Depending on the technique used, data reflecting tissue perfusion (blood flow, blood volume, mean transit time), microvessel permeability surface area product, and extracellular leakage space can be obtained. Insights into these physiological processes can be obtained from inspection of kinetic enhancement curves or by the application of complex compartmental modeling techniques. Combining morphologic and kinetic features can increase the accuracy of clinical diagnoses. Potential clinical applications include screening for malignant disease, lesion characterization, monitoring lesion response to treatment, and assessment of residual disease. Newer applications include prognostication, pharmacodynamic assessments of antivascular anticancer drugs, and predicting efficacy of treatment. For dynamic MRI to enter into widespread clinical practice, it will be necessary to develop standardized approaches to measurement and robust analysis approaches.     

Haematuria and acute kidney injury in elderly patients admitted to hospital with supratherapeutic warfarin anticoagulation

Background and objectives

Warfarin-related nephropathy is reported to occur with an INR >3.0 as a result of glomerular bleeding. There is a lack of prospective studies examining the effect of supratherapeutic warfarin anticoagulation on haematuria and acute kidney injury (AKI). Older patients may be susceptible due to greater warfarin use, prevalence of kidney disease and comorbidities. The objective of this study was to determine the incidence and nature of haematuria and AKI in older patients on warfarin and to determine any association with high INR levels.

Design, setting, participants and measurements

This was a prospective, observational study of 150 elderly patients receiving warfarin anticoagulation who were acutely hospitalised in a tertiary hospital. AKI was assessed using RIFLE criteria. Urinalysis was performed to quantify haematuria, characterise erythrocyte morphology and measure the albumin–creatinine ratio. Positive cases received follow-up at 4–6 weeks to determine resolution.

Results

An INR >3.0 was found in 54 % of patients. Pre-admission antibiotic use increased the risk of excessive anticoagulation. The incidence of isolated AKI, isolated haematuria and both was 18.7, 13.3 and 12 %, respectively. Factors associated with a higher risk of haematuria were an INR >4.0, non-urinary infection, catheterisation and albuminuria. Most cases of AKI were mild, and there was no demonstrable correlation between the admission INR and AKI. Admission with heart failure was significantly associated with an increased risk of persistent kidney impairment at follow-up.

Conclusions

Supratherapeutic warfarin anticoagulation was associated with an increased risk of haematuria, but not with AKI. The majority of cases of haematuria were transient.     

Cell therapy for type 1 diabetes

ABSTRACT

Introduction

Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction of insulin-producing β-cells. Islet or whole-pancreas transplantation is limited by the shortage of donors and need for chronic immune suppression. Novel strategies are needed to prevent β-cell loss and to rescue production of endogenous insulin.