Comprehensive questionnaire for assessment of Dhat syndrome: development and use in patient population.

Introduction: Dhat syndrome is a culture-bound syndrome, characterized by the core belief of loss of semen accompanied by symptoms of general weakness, lack of energy and concentration, impaired sexual functions, and vague somatic troubles, often associated with an anxious or dysphoric mood state. Although many studies have described the clinical picture of Dhat syndrome, there is lack of availability of an instrument which can comprehensively assess patients presenting with Dhat syndrome.

Aim: The aim of this article is to develop a questionnaire that can comprehensively assess Dhat syndrome and guide the clinicians in managing such patients.

Characterization of critical reagents in ligand-binding assays: enabling robust bioanalytical methods and lifecycle management.

The effective management of validated ligand-binding assays used for PK, PD and immunogenicity assessments of biotherapeutics is vital to ensuring robust and consistent assay performance throughout the lifetime of the method. The structural integrity and functional quality of critical reagents is often linked to ligand-binding assay performance; therefore, physicochemical and biophysical characterization coupled with assessment of assay performance can enable the highest degree of reagent quality. The implementation of a systematic characterization process for monitoring critical reagent attributes, utilizing detailed analytical techniques such as LC-MS, can expedite assay troubleshooting and identify deleterious trends.

Fatal agranulocytosis associated with psychotropic medication use.

Purpose: A patient's death due to severe hematologic adverse effects of the concomitant use of four psychotropic medications is reported.

Summary: A 40-year-old Caucasian woman with a 9-year history of depression and anxiety (managed with alprazolam) was admitted to a psychiatric hospital for the treatment of acute psychotic symptoms. After nine days, the patient was discharged home on a regimen of lamotrigine, mirtazapine, quetiapine, and venlafaxine.

Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia.

Complement components and their receptors are found within and around amyloid β (Aβ) cerebral plaques in Alzheimer's disease (AD). Microglia defend against pathogens through phagocytosis via complement component C3 and/or engagement of C3 cleavage product iC3b with complement receptor type 3 (CR3, Mac-1). Here, we provide direct evidence that C3 and Mac-1 mediate, in part, phagocytosis and clearance of fibrillar amyloid-β (fAβ) by murine microglia in vitro and in vivo.

Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists.

A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth.

Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations.

Substantial evidence has accumulated in support of the hypothesis that elevated cholesterol levels increase the risk of developing Alzheimer disease (AD). As a result, much work has investigated the potential use of lipid-lowering agents, particularly statins, as preventive or therapeutic agents for AD. Although epidemiology and preclinical statin research (described in part I of this review) have generally supported an adverse role of high cholesterol levels regarding AD, human studies of statins (reviewed herein) show highly variable outcomes, making it difficult to draw firm conclusions.

Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies.

During the last 2 decades, evidence has accumulated that a high cholesterol level may increase the risk of developing Alzheimer disease (AD). With the global use of statins to treat hypercholesterolemia, this finding has led to the anticipation that statins could prove useful in treating or preventing AD. However, the results of work on this topic are inconsistent: some studies find beneficial effects, but other studies do not.

Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab.

Preclinical and clinical studies conducted in the mid-1990s reported strong association and causality between the T-cell helper (T(H)) 1 inductor cytokine interleukin (IL)-12 and numerous immune-mediated disorders, which spurred the development of therapeutic agents targeting IL-12 function. One of the first to enter the clinic, ustekinumab, is a human monoclonal antibody (mAb) that binds to the p40 subunit of IL-12. Subsequent to the generation of ustekinumab, it was discovered that IL-23 also contains the p40 subunit.

Laparoscopic Management of a Rare Case of Spontaneous Adnexal Torsion in an Adolescent.

The occurrence of spontaneous torsion of normal ovary and fallopian tube in an adolescent is very rare. We report a case of a 14-year-old post-menarche teenager who presented as acute abdomen. Here, we discuss the differential diagnosis of acute pain abdomen, importance of immediate diagnostic laparoscopy and prompt decision for de torsion of the ovarian pedicle and mesoalphinx to salvage the fallopian tube and ovary, which has a bearing on future reproduction.

Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors.

In Alzheimer's disease (AD), dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal long-term potentiation (LTP) can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field EPSPs and whole-cell recordings in wild-type mouse hippocampal slices.

Detection of low-affinity anti-drug antibodies and improved drug tolerance in immunogenicity testing by Octet(®) biolayer interferometry.

We assessed the utility of the FortéBio Octet(®) system for detection of anti-drug antibodies (ADAs) against an investigational therapeutic human IgG1 monoclonal antibody (mAb), CNTO X. To understand the relative merits of this technology, key performance requirements were compared with two popularly accepted ADA detection methods, a step-wise bridging ELISA and a Meso Scale Discovery (MSD) homogeneous (single step binding) bridging ECLIA. When used to detect 13 monoclonal ADAs of varying affinities and one polyclonal ADA, all three methods demonstrated their greatest apparent sensitivity to the polyclonal sample (1, 6, and 130 ng/mL, respectively for ECLIA, ELISA, and Octet).

Improved oral bioavailability in rats of SR13668, a novel anti-cancer agent.

Purpose: SR13668, a bis-indole with potent activity in vitro and in vivo against various cancers and promising cancer chemopreventive activity, was found to have very low oral bioavailability, <1%, in rats during pilot pharmacokinetic studies. The objective of these studies was to better understand the source of low oral exposure and to develop a formulation that could be used in preclinical development studies.

Methods: An automated screening system for determining solubility in lipid-based vehicles, singly and in combination, was used to identify formulations that might enhance absorption by improving solubility of SR13668, and these results were confirmed in vivo using Sprague-Dawley rats.

Composite ganglioneuroma-paraganglioma of the filum terminale.

Extraadrenal paragangliomas are most commonly found in the carotid body and are also found with lower frequency in the CNS. These lesions are derived from the sympathoadrenal lineage of neural crest cells. Here, the authors report a rare case of a composite paraganglioma with ganglioneuromatous components found at the filum terminale in a patient who presented with a brief history of low-back pain and paresthesias in the inguinal region.

The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia.

The molecular pathways leading to Alzheimer-type dementia are not well understood, but the amyloid beta-protein is believed to be centrally involved. The quantity of amyloid beta-protein containing plaques does not correlate well with clinical status, suggesting that if amyloid beta-protein is pathogenic it involves soluble non-plaque material. Using 43 brains from the Newcastle cohort of the population-representative Medical Research Council Cognitive Function and Ageing Study, we examined the relationship between biochemically distinct forms of amyloid beta-protein and the presence of Alzheimer-type dementia.

Lack of racial differences in the pharmacokinetics of subcutaneous golimumab in healthy Japanese and Caucasian male subjects.

This phase 1 study evaluated the single-dose pharmacokinetics and safety of subcutaneous golimumab, a human anti-tumor necrosis factor-alpha monoclonal antibody, in healthy Japanese and Caucasian subjects. Eligible subjects were males, aged 20 to 45 years, weighing 50 to 90 kg with a body mass index of 19 to 30 kg/m(2). Japanese and Caucasian subjects were matched by body weight and dose group.

Influence of formulation factors on tablet formulations with liquid permeation enhancer using factorial design.

For a drug with low bioavailability, a matrix tablet with liquid permeation enhancer (Labrasol) was formulated. Factorial design was used to evaluate the effect of three formulation factors: drug percentage, polymer type (Methocel K100M or Eudragit L 100-55), and tablet binder percentage (Plasdone S-630) on tablet characteristics. Tablets were prepared by direct compression and characterized.

Alzheimer's disease: synaptic dysfunction and Abeta.

Synapse loss is an early and invariant feature of Alzheimer's disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid beta-protein (Abeta) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Abeta are mediators of synaptic compromise.

Biochemical and immunohistochemical analysis of an Alzheimer's disease mouse model reveals the presence of multiple cerebral Abeta assembly forms throughout life.

The amyloid beta-protein (Abeta) is believed to play a causal role in Alzheimer's disease, however, the mechanism by which Abeta mediates its effect and the assembly form(s) of Abeta responsible remain unclear. Several APP transgenic mice have been shown to accumulate Abeta and to develop cognitive deficits. We have studied one such model, the J20 mouse.