Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry.

Peripheral Neuropathy and Nerve Dysfunction in Individuals at High Risk for Type 2 Diabetes: The PROMISE Cohort.

Objective: Emerging evidence suggests that peripheral neuropathy begins in the early stages of diabetes pathogenesis. Our objective was to describe the prevalence of peripheral neuropathy and nerve dysfunction according to glucose tolerance and metabolic syndrome status and examine how these conditions are associated with neurological changes in individuals at risk for type 2 diabetes.

Research Design And Methods: We studied 467 individuals in the longitudinal PROMISE (Prospective Metabolism and Islet Cell Evaluation) cohort.

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.

Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set.

Objective: Corneal confocal microscopy is a novel diagnostic technique for the detection of nerve damage and repair in a range of peripheral neuropathies, in particular diabetic neuropathy. Normative reference values are required to enable clinical translation and wider use of this technique. We have therefore undertaken a multicenter collaboration to provide worldwide age-adjusted normative values of corneal nerve fiber parameters.

Uric acid as a biomarker and a therapeutic target in diabetes.

Diabetic nephropathy is a long-standing microvascular complication of diabetes mellitus and is the leading cause of end stage renal disease in developed countries. Current therapeutic strategies used to prevent or delay diabetic nephropathy exert limited clinical protective effects and can have serious adverse effects. Thus, identification of new pharmacologic agents that protect against the initiation and progression of complications of diabetes is of the utmost importance.

Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk.

Corneal confocal microscopy predicts 4-year incident peripheral neuropathy in type 1 diabetes.

Objective: This study determined if deficits in corneal nerve fiber length (CNFL) assessed using corneal confocal microscopy (CCM) can predict future onset of diabetic peripheral neuropathy (DPN).

Research Design And Methods: CNFL and a range of other baseline measures were compared between 90 nonneuropathic patients with type 1 diabetes who did or did not develop DPN after 4 years. The receiver operator characteristic (ROC) curve was used to determine the capability of single and combined measures of neuropathy to predict DPN.

Resistance Exercise in Already-Active Diabetic Individuals (READI): study rationale, design and methods for a randomized controlled trial of resistance and aerobic exercise in type 1 diabetes.

The Resistance Exercise in Already Active Diabetic Individuals (READI) trial aimed to examine whether adding a 6-month resistance training program would improve glycemic control (as reflected in reduced HbA₁c) in individuals with type 1 diabetes who were already engaged in aerobic exercise compared to aerobic training alone. After a 5-week run-in period including optimization of diabetes care and low-intensity exercise, 131 physically active adults with type 1 diabetes were randomized to two groups for 22weeks: resistance training three times weekly, or waiting-list control. Both groups maintained the same volume, duration and intensity of aerobic exercise throughout the study as they did at baseline.

Ecological conditions of ponds situated on blast furnace slag deposits located in South Gare Site of Special Scientific Interest (SSSI), Teesside, UK.

Slag, a by-product from the iron and steel industry, has a range of applications within construction and is used in wastewater treatment. Historically considered a waste material, little consideration was given to the environmental impacts of its disposal. South Gare (a Site of Special Scientific Interest) located at the mouth of the Tees estuary, UK, formed on slag deposits used to create a sea wall and make the land behind permanent.

Electrophysiologic testing in diabetic neuropathy.

Electrophysiologic studies provide objective data concerning nerve and muscle function. This information enables the diagnosis of disease states and monitoring of disease progression. This chapter describes the changes in electrophysiologic function in both prediabetes and diabetes and discusses the utility of this testing in patients with diabetes.

Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus.

Plasma uric acid (PUA) is associated with metabolic, cardiovascular, and renal abnormalities in patients with type 2 diabetes but is less well understood in type 1 diabetes (T1D). Our aim was to compare PUA levels and fractional uric acid excretion (FEUA) in patients with T1D vs. healthy controls (HC) during euglycemia and hyperglycemia.

The role of 11-cis-retinyl esters in vertebrate cone vision.

A cycle of cis-to-trans isomerization of the chromophore is intrinsic to vertebrate vision where rod and cone photoreceptors mediate dim- and bright-light vision, respectively. Daylight illumination can greatly exceed the rate at which the photoproduct can be recycled back to the chromophore by the canonical visual cycle. Thus, an additional supply pathway(s) must exist to sustain cone-dependent vision.

Measurement of cooling detection thresholds for identification of diabetic sensorimotor polyneuropathy in type 1 diabetes.

Objective: Compared to recently-studied novel morphological measures, conventional small nerve fiber functional tests have not been systematically studied for identification of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine and compare the diagnostic performance of cooling detection thresholds (CDT) in a cross-sectional type 1 diabetes cohort.

Research Design And Methods: 136 subjects with type 1 diabetes and 52 healthy volunteers underwent clinical and electrophysiological examination for DSP classification concomitantly with the Toronto Clinical Neuropathy Score (TCNS) and three small fiber function tests: CDT, heart rate variability (HRV), and laser doppler imaging of axon-mediated neurogenic flare responses to cutaneous heating (LDIFLARE).

Retinal regeneration following OCT-guided laser injury in zebrafish.

Purpose: Establish a focal injury/regeneration model in zebrafish using laser photocoagulation guided by optical coherence tomography (OCT).

Methods: Adult zebrafish were imaged by OCT and confocal scanning laser ophthalmoscopy (cSLO) in room air through a contact lens. Using a beam combiner, 532-nm laser photocoagulation was applied using the OCT C-scan image for targeting.

Sodium-glucose cotransporter 2 inhibition in type 1 diabetes: simultaneous glucose lowering and renal protection?

Diabetic nephropathy is the most common cause of end-stage renal disease requiring chronic dialysis or renal transplantation, resulting in high morbidity, mortality and societal costs to Canadians. Unfortunately, glycemic targets are often not achieved, and existing medications that block the renin-angiotensin-aldosterone system only offer partial protection against the development of renal and cardiovascular complications. As a consequence, in type 1 diabetes mellitus, 20% of patients treated with angiotensin-converting enzyme inhibition still have progressive nephropathy over 10 years.

Sensor-augmented pump and multiple daily injection therapy in the United States and Canada: post-hoc analysis of a randomized controlled trial.

Objective: Effectiveness of advanced technologies for diabetes management may differ depending on national healthcare models or population characteristics. In the setting of a cross-national trial, we aimed to compare efficacy of sensor-augmented pump (SAP) therapy in the United States (US) and Canada.

Methods: In the clinical trial Sensor-Augmented Pump Therapy for A1C Reduction (STAR 3), 329 adults with type 1 diabetes were randomly allocated to either SAP or glargine-based multiple daily injection (MDI) therapy at 26 US sites (n=271) and 4 Canadian sites (n=58).

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS).

The Par-PrkC polarity complex is required for cilia growth in zebrafish photoreceptors.

Specification and development of the apical membrane in epithelial cells requires the function of polarity proteins, including Pard3 and an atypical protein kinase C (PrkC). Many epithelial cells possess microtubule-based organelles, known as cilia, that project from their apical surface and the membrane surrounding the cilium is contiguous with the apical cell membrane. Although cilia formation in cultured cells required Pard3, the in vivo requirement for Pard3 in cilia development remains unknown.

Fasting blood glucose--a missing variable for GFR-estimation in type 1 diabetes?

Objective: Estimation of glomerular filtration rate (eGFR) is one of the current clinical methods for identifying risk for diabetic nephropathy in subjects with type 1 diabetes (T1D). Hyperglycemia is known to influence GFR in T1D and variability in blood glucose at the time of eGFR measurement could introduce bias in eGFR. We hypothesized that simultaneously measured blood glucose would influence eGFR in adults with T1D.

myosin 7aa(-/-) mutant zebrafish show mild photoreceptor degeneration and reduced electroretinographic responses.

Mutations in myosin VIIa (MYO7A) cause Usher Syndrome 1B (USH1B), a disease characterized by the combination of sensorineural hearing loss and visual impairment termed retinitis pigmentosa (RP). Although the shaker-1 mouse model of USH1B exists, only minor defects in the retina have been observed during its lifespan. Previous studies of the zebrafish mariner mutant, which also carries a mutation in myo7aa, revealed balance and hearing defects in the mutants but the retinal phenotype has not been described.

Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial.

Objective: Adjunctive-to-insulin therapy with sodium-glucose cotransporter 2 (SGLT2) inhibition may improve glycemic control in type 1 diabetes (T1D).

Research Design And Methods: We evaluated the glycemic efficacy and safety of empagliflozin 25 mg daily in 40 patients treated for 8 weeks in a single-arm open-label proof-of-concept trial (NCT01392560).

Results: Mean A1C decreased from 8.