Summary of the recommendations on sexual dysfunctions in men.

Introduction: Sexual health is an integral part of overall health. Sexual dysfunction can have a major impact on quality of life and psychosocial and emotional well-being.

Aim: To provide evidence-based, expert-opinion consensus guidelines for clinical management of sexual dysfunction in men.

Pharmacological chaperone for the structured domain of human prion protein.

In prion diseases, the misfolded protein aggregates are derived from cellular prion protein (PrP(C)). Numerous ligands have been reported to bind to human PrP(C) (huPrP), but none to the structured region with the affinity required for a pharmacological chaperone. Using equilibrium dialysis, we screened molecules previously suggested to interact with PrP to discriminate between those which did not interact with PrP, behaved as nonspecific polyionic aggregates or formed a genuine interaction.

Open conformation of adipokinetic hormone receptor from the malaria mosquito facilitates hormone binding.

Insect flight requires rapid mobilization of energy reserves during flight, which is mediated and regulated by hormonal control via adipokinetic hormones. The structure of the G-protein receptors to which these hormones bind, are crucial in understanding many of the physiological processes in which they play a central role. To date no 3D structure of an insect G-protein coupled receptor (GPCR) is available.

The H187R mutation of the human prion protein induces conversion of recombinant prion protein to the PrP(Sc)-like form.

Prion diseases are associated with a conformational switch in the prion protein (PrP) from its normal cellular form (denoted PrP(C)) to a disease-associated "scrapie" form (PrP(Sc)). A number of PrP(Sc)-like conformations can be generated by incubating recombinant PrP(C) at low pH, indicating that protonation of key residues is likely to destabilize PrP(C), facilitating its conversion to PrP(Sc). Here, we examine the stability of human PrP(C) with pH and find that PrP(C) fold stability is significantly reduced by the protonation of two histidine residues, His187 and His155.

Spontaneous generation of mammalian prions.

Prions are transmissible agents that cause lethal neurodegeneration in humans and other mammals. Prions bind avidly to metal surfaces such as steel wires and, when surface-bound, can initiate infection of brain or cultured cells with remarkable efficiency. While investigating the properties of metal-bound prions by using the scrapie cell assay to measure infectivity, we observed, at low frequency, positive assay results in control groups in which metal wires had been coated with uninfected mouse brain homogenate.

PRNP allelic series from 19 years of prion protein gene sequencing at the MRC Prion Unit.

Mutation of the human prion protein gene (PRNP) open reading frame (ORF) accounts for almost all reported familial concurrence of prion disease. The more common mutations globally: octapeptide repeat insertions, P102L, D178N, E200K, and V210I have occurred in large multigenerational pedigrees and display autosomal dominant inheritance, however, many rare genetic changes have been reported that are of uncertain pathogenicity. Based on 19 years of PRNP sequencing at the MRC Prion Unit, London, and analysis of 3664 samples from patients referred with suspected prion disease and healthy populations, we present novel allele combinations, healthy control population data, results of screening the PRNP ORF in DNA from the entire referral series and the CEPH human genome diversity cell line panel.

A highly sensitive immunoassay for the detection of prion-infected material in whole human blood without the use of proteinase K.

Background: The causal association of variant Creutzfeldt-Jakob disease (vCJD) with bovine spongiform encephalopathy has raised significant concerns for public health. Assays for vCJD infection are vital for the application of therapeutics, for the screening of organ donations, and to maintain a safe blood supply. Currently the best diagnostic tools for vCJD depend upon the detection of disease-associated prion protein (PrP(Sc) ), which is distinguished from normal background PrP (PrP(C) ) by proteinase K (PK) digestion, which can also degrade up to 90% of the target antigen.

Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that specifically affects motor neurons and leads to a progressive and ultimately fatal loss of function, resulting in death typically within 3 to 5 years of diagnosis. The disease starts with a focal centre of weakness, such as one limb, and appears to spread to other parts of the body. Mutations in superoxide dismutase 1 (SOD1) are known to cause disease and it is generally accepted they lead to pathology not by loss of enzymatic activity but by gain of some unknown toxic function(s).

Cardiovascular aspects of sexual medicine.

Introduction: Erectile dysfunction (ED) is common and considered to be predominantly of vascular origin.

Aim: To evaluate the link between ED and coronary artery disease (CAD) and provide a consensus report regarding evaluation and management.

Methods: A committee of eight experts from six countries was convened to review the worldwide literature concerning ED and CAD and provide a guideline for management.

The legs at odd angles (Loa) mutation in cytoplasmic dynein ameliorates mitochondrial function in SOD1G93A mouse model for motor neuron disease.

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute approximately 10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15-20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord.

Modification of superoxide dismutase 1 (SOD1) properties by a GFP tag--implications for research into amyotrophic lateral sclerosis (ALS).

Background: Since the discovery that mutations in the enzyme SOD1 are causative in human amyotrophic lateral sclerosis (ALS), many strategies have been employed to elucidate the toxic properties of this ubiquitously expressed mutant protein, including the generation of GFP-SOD1 chimaeric proteins for studies in protein localization by direct visualization using fluorescence microscopy. However, little is known about the biochemical and physical properties of these chimaeric proteins, and whether they behave similarly to their untagged SOD1 counterparts.

Methodology/principal Findings: Here we compare the physicochemical properties of SOD1 and the effects of GFP-tagging on its intracellular behaviour.

Discrimination between prion-infected and normal blood samples by protein misfolding cyclic amplification.

Background: Diagnosis of prion disease from blood samples requires the detection of minute quantities of misfolded protein (PrP(Sc)) against a high background of correctly folded material (PrP(C)). Protein misfolding cyclic amplification (PMCA) is a technique that can amplify small amounts of seed PrP(Sc) to a level detectable by conventional methods. Application of PMCA to the testing of whole blood samples enhances the ability to detect PrP(Sc) and allows antemortem detection of prion infection and could facilitate blood screening.

Cost-effectiveness of pentostatin compared with cladribine in the management of hairy cell leukemia in the United Kingdom.

Objective: This article assesses the cost-effectiveness of pentostatin compared with cladribine in the management of hairy cell leukemia (HCL) in the United Kingdom.

Methods: A systematic literature search for papers on HCL was performed using MEDLINE, EMBASE, Current Contents, NHS Economic Evaluation Database, and the Cochrane computerized database. Search terms were HCL plus 1 of the following: incidence, prevalence, epidemiology, cladribine, interferon, pentostatin, rituximab, splenectomy, utility, quality of life, cost-effectiveness, cost-utility, resource utilization, economic, or cost.

Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk.

To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.

The R1441C mutation alters the folding properties of the ROC domain of LRRK2.

LRRK2 is a 250 kDa multidomain protein, mutations in which cause familial Parkinson's disease. Previously, we have demonstrated that the R1441C mutation in the ROC domain decreases GTPase activity. Here we show that the R1441C alters the folding properties of the ROC domain, lowering its thermodynamic stability.

G to C transition at position -173 of MIF gene of the recipient is associated with reduced relapse rates after allogeneic stem cell transplantation.

Pro-inflammatory and dendritic cell-activating properties of macrophage migration inhibitory factor (MIF) suggest a potentially important role for MIF in alloantigen-specific immune responses after allogeneic stem cell transplantation (allo-SCT). We tested whether MIF -173 G/C gene polymorphism of donor or patient had impacts on the outcomes after allo-SCT. Four hundred and fifty-four donor-patient pairs were genotyped and mortality, relapse, and development of complications were analyzed.

Regulatory T-cell suppression of CD8+ T-cell-mediated graft-versus-host reaction requires their presence during priming.

Background: Despite the promising therapeutic potential of regulatory T cells (Treg) in animal studies of graft-versus-host disease (GVHD), little is known about their effect on human GVHD. Whether Treg are capable of ameliorating GVHD tissue damage has never been demonstrated in humans. It is also unknown whether Treg modulation of GVH histopathologic damage relies on their presence during effector T-cell priming, or whether allogeneic Treg are safe to use clinically.

Aspirin acetylates nitric oxide synthase type 3 in platelets thereby increasing its activity.

Aims: Acute administration of aspirin increases nitric oxide (NO) synthesis by platelets, an effect not shared by other non-steroidal anti-inflammatory drugs. The aim of the present study was to determine the mechanism by which aspirin acutely increases the activity of NO synthase type 3 (NOS-3), the predominant NOS isoform expressed by platelets, and specifically whether this occurs through an increase in its acetylation.

Methods And Results: Platelets isolated from the blood of healthy human subjects were exposed in vitro to vehicle or aspirin at different concentrations (5 micromol/L-4 mmol/L).

Conformational properties of beta-PrP.

Prion propagation involves a conformational transition of the cellular form of prion protein (PrPC) to a disease-specific isomer (PrPSc), shifting from a predominantly alpha-helical conformation to one dominated by beta-sheet structure. This conformational transition is of critical importance in understanding the molecular basis for prion disease. Here, we elucidate the conformational properties of a disulfide-reduced fragment of human PrP spanning residues 91-231 under acidic conditions, using a combination of heteronuclear NMR, analytical ultracentrifugation, and circular dichroism.