Alcohol consumption and markers of inflammation in women with preclinical rheumatoid arthritis.

Objective: To examine the association between alcohol consumption and markers of inflammation in preclinical rheumatoid arthritis (RA).

Methods: We studied 174 incident RA cases with stored blood collected 1-16 years prior to RA symptoms (preclinical RA), from the Nurses' Health Study. Alcohol intake was measured using a detailed food frequency questionnaire administered every 4 years, prior to blood collection.

Translating research discoveries into clinical tests.

In the past decade, mutations in many genes have been discovered to underlie the myriad of inherited renal and other genetic diseases. Once these genes are identified as etiologic in a disease, the development of a clinical test becomes possible. However, clinical tests are not yet available for all identified disease genes.

Characterization of protein targets of mammalian thioredoxin reductases.

Mammalian thioredoxin reductases (TRs) are members of the pyridine nucleotide-disulfide oxidoreductase family. The main function of these enzymes is to maintain thioredoxins (Trxs) in the reduced state. The accessibility and high reactivity of selenocysteine in the C-terminal tetrapeptide allows mammalian TRs to couple to a range of substrates from proteins, such as Trx, to small molecules, such as selenite and hydroperoxides.

Intramolecular Aldol reaction of N-acylated (2-aminophenyl)-alpha-oxoacetic acids: rapid access to tri- and tetracyclic 1,2-dihydroquinolin-2(1H)-ones.

A four-step synthesis of tri- and tetracyclic 1,2-dihydroquinolin-2(1H)-ones via acylation of various substituted isatins with readily available N-Boc-protected aminoacids followed by an intramolecular aldol reaction and cyclization has been developed. The final products were obtained in moderate to excellent overall yields.

Teaching about health disparities using a social determinants framework.

The intersection of two trends in health intervention has the potential to fundamentally change the practice of medicine. First, research into the social determinants of health is revealing the mechanisms by which living conditions cause disease. Second, the restructuring of primary care around preventive interventions represents the convergence point of medicine and public health.

Amyloid-beta immunotherapy for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients; however, none of them modify disease progression.

Identification and validation of lupus nephritis cases using administrative data.

Large administrative databases such as Medicaid billing databases could be used to study care and outcomes of lupus nephritis if these patients could be correctly identified from claims data. We aimed to develop and validate an algorithm for the correct identification of cases of lupus nephritis using ICD-9 billing codes. We used the Research Patient Data Resource query tool at our institution to identify patients with potential lupus nephritis.

Discovery of notch-sparing gamma-secretase inhibitors.

Overwhelming evidence supports a central role for the amyloid beta-peptide (Abeta) in the pathogenesis of Alzheimer's disease (AD), and the proteases that produce Abeta from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting gamma-secretase, which generates the C-terminus of Abeta; however, gamma-secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter gamma-secretase activity to reduce Abeta production without affecting the proteolysis of Notch.

Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.

Understanding the origin of myofibroblasts in kidney is of great interest because these cells are responsible for scar formation in fibrotic kidney disease. Recent studies suggest epithelial cells are an important source of myofibroblasts through a process described as the epithelial-to-mesenchymal transition; however, confirmatory studies in vivo are lacking. To quantitatively assess the contribution of renal epithelial cells to myofibroblasts, we used Cre/Lox techniques to genetically label and fate map renal epithelia in models of kidney fibrosis.

Hypertension in the developing world: challenges and opportunities.

Hypertension is a major public health problem and a leading cause of death and disability in developing countries. One-quarter of the world's adult population has hypertension, and this is likely to increase to 29% by 2025. Modeled projections indicate an increase to 1.

Abdominal obesity and peripheral vascular disease in men and women: a comparison of waist-to-thigh ratio and waist circumference as measures of abdominal obesity.

Objective: Abdominal obesity is associated with coronary heart disease (CHD) but its relationship to peripheral vascular disease (PVD) is under-researched. This study is to evaluate the association of PVD with two measures of abdominal obesity, waist-to-thigh ratio (WTR) and waist circumference (WC).

Methods And Results: The study population consisted of 5057 adults aged 40 years or older who participated in NHANES 1999-2002.

Autologous chondrocyte implantation for joint preservation in patients with early osteoarthritis.

Unlabelled: Young patients with early osteoarthritis wishing to remain functionally active have limited treatment options. Existing studies examining the use of autologous chondrocyte implantation (ACI) have included patients with early degenerative changes; however, none specifically investigated the outcome of ACI with this challenging problem. We prospectively followed 153 patients (155 knees) for up to 11 years after treatment with ACI for early-stage osteoarthritis.

Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci.

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.

Endothelin-1 raises excitability and reduces potassium currents in sensory neurons.

Exposure to endothelin-1 (ET-1, 50 nM) of sensory neurons, acutely isolated from rat dorsal root ganglia (DRG), results in an increase in the number of action potentials elicited by a linear ramp of stimulating current. The changes are complete in 5 min after ET-1 treatment and do not reverse in 5-10 min after ET-1's removal. Neither the resting potential, nor the threshold potential for the first or second action potentials, nor their rate-of-rise or decay, are changed by ET-1 exposure, but the slow depolarizations which occur before the first and second action potentials during the current ramp are increased by ca.

One-pot synthesis of alpha-carbolines via sequential palladium-catalyzed aryl amination and intramolecular arylation.

A one-pot synthesis of alpha-carbolines via a palladium-catalyzed aryl amination followed by intramolecular arylation is described. 2,3-Dichloro- and 2,3-dibromopyridines have been shown to react with readily available anilines to obtain various substituted alpha-carbolines in moderate to excellent yields.

The speed of free will.

Do voluntary and task-driven shifts of attention have the same time course? In order to measure the time needed to voluntarily shift attention, we devised several novel visual search tasks that elicited multiple sequential attentional shifts. Participants could only respond correctly if they attended to the right place at the right time. In control conditions, search tasks were similar but participants were not required to shift attention in any order.

Psychopathology predicts the outcome of medial branch blocks with corticosteroid for chronic axial low back or cervical pain: a prospective cohort study.

Background: Comorbid psychopathology is an important predictor of poor outcome for many types of treatments for back or neck pain. But it is unknown if this applies to the results of medial branch blocks (MBBs) for chronic low back or neck pain, which involves injecting the medial branch of the dorsal ramus nerves that innervate the facet joints. The objective of this study was to determine whether high levels of psychopathology are predictive of pain relief after MBB injections in the lumbar or cervical spine.

Lux vs. wavelength in light treatment of Seasonal Affective Disorder.

Objective: Published dosing guidelines for treatment of Seasonal Affective Disorder (SAD) refer to photopic lux, which is not appropriate for short-wavelength light. Short wavelengths are most potent for many non-visual responses to light. If SAD therapy were similarly mediated, standards utilizing lux risk overestimating necessary dose.

N-Glycan Moieties in Neonatal Fc Receptor Determine Steady-state Membrane Distribution and Directional Transport of IgG.

The neonatal Fc receptor (FcRn) is a major histocompatibility complex class I-related molecule known to protect IgG and albumin from catabolism and transport IgG across polarized epithelial cells in a bidirectional manner. Previous studies have shown species-specific differences in ligand binding, IgG transport direction, and steady-state membrane distribution when expressed in polarized epithelial cells. We hypothesized that these differences may be due to the additional N-glycans expressed on the rat FcRn, because N-glycans have been proposed to function as apical targeting signals, and that two of the N-glycan moieties have been shown to contribute to the IgG binding of rat FcRn.

Selective amyloid-beta lowering agents.

The amyloid-beta peptide (Abeta), implicated in the pathogenesis of Alzheimer's disease (AD), is produced through sequential proteolysis of the Abeta precursor protein (APP) by beta- and gamma-secretases. Thus, blocking either of these two proteases, directly or indirectly, is potentially worthwhile toward developing AD therapeutics. beta-Secretase is a membrane-tethered pepsin-like aspartyl protease suitable for structure-based design, whereas gamma-secretase is an unusual, heterotetrameric membrane-embedded aspartyl protease.

Endothelin receptors and pain.

Unlabelled: The endogenous endothelin (ET) peptides participate in a remarkable variety of pain-relatedprocesses. Pain that is elevated by inflammation, by skin incision, by cancer, during a Sickle Cell Disease crisis and by treatments that mimic neuropathic and inflammatory pain and are all reduced by local administration of antagonists of endothelin receptors. Many effects of endogenously released endothelin are simulated by acute, local subcutaneous administration of endothelin, which at very high concentrations causes pain and at lower concentrations sensitizes the nocifensive reactions to mechanical, thermal and chemical stimuli.

Targeted therapy for neuro-oncology: reviewing the menu.

Targeted therapy against cancer shows not only promise, but also limits. No matter how specific the target, many pathways and cell types can be affected, some unexpectedly. A tumor is heterogeneous and plastic; it can evade a targeting agent or an attack mechanism.

Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney.

Understanding the origin of scar-producing myofibroblasts is vital in discerning the mechanisms by which fibrosis develops in response to inflammatory injury. Using a transgenic reporter mouse model expressing enhanced green fluorescent protein (GFP) under the regulation of the collagen type I, alpha 1 (coll1a1) promoter and enhancers, we examined the origins of coll1a1-producing cells in the kidney. Here we show that in normal kidney, both podocytes and pericytes generate coll1a1 transcripts as detected by enhanced GFP, and that in fibrotic kidney, coll1a1-GFP expression accurately identifies myofibroblasts.