The development of new therapeutics for Alzheimer's disease.

Existing treatments for Alzheimer's disease (AD) fail to address the underlying pathology of the disease; they merely provide short-lived symptomatic relief. Consequently, the progression of AD is unrelenting, leading to a continual decrease in cognitive abilities. Recent advances in understanding the genetic factors that predispose to AD, as well as in biomarker development, have brought with them the promise of earlier and more reliable diagnosis of this disease. As improvements continue to be made in these areas, the shortcomings of current AD treatments appear all the more acute because opportunities for early intervention are hindered by a lack of "curative" or even disease-modifying drugs. This State of the Art report reviews existing AD therapeutics and highlights recent progress made in the design and development of drugs that are aimed at disrupting AD disease progression by inhibition of the protein misfolding of ß-amyloid (Aß) into neurotoxic oligomeric aggregates.

Epilepsy and antiepileptic drug use in elderly people as risk factors for dementia.

OBJECTIVE: To assess the role of epilepsy and antiepileptic drugs (AEDs) as risk factors for probable Alzheimer's disease (AD) and for all dementias in the Canadian Study of Health and Aging (CSHA). A secondary objective was to isolate the effect of the AED phenytoin on the development of dementia and AD. METHODS: The cohort consists of 5376 participants aged 65 years or older with no evidence of dementia, defined as Modified Mini-Mental State (3MS) score > or =78. Primary exposure was self-report or clinical diagnosis of epilepsy at baseline (n=39), or self-report of AED therapy (n=67). Primary outcomes were development of dementia, defined as 3MS<78, or AD, determined by clinical examination using standard criteria, during a 5-year follow-up period. People whose 3MS score remained > or =78 served as the comparison group. RESULTS: People reporting AED use at baseline had an age, sex and baseline 3MS adjusted odds ratio (OR) of 2.11 (95% CI 1.11 to 4.01) for developing dementia compared to those not taking AEDs at baseline. The association remained significant using only phenytoin as the exposure. No significant association was found between AED use and development of AD, nor between epilepsy and development of either AD or dementia. CONCLUSIONS: Older adults taking AEDs are at a significantly higher relative risk of developing dementia than those not taking AEDs. Further investigation of this finding is warranted.

Sheared poloidal flow driven by mode conversion in tokamak plasmas.

A two-dimensional integral full-wave model is used to calculate poloidal forces driven by mode conversion in tokamak plasmas. In the presence of a poloidal magnetic field, mode conversion near the ion-ion hybrid resonance is dominated by a transition from the fast magnetosonic wave to the slow ion cyclotron wave. The poloidal field generates strong variations in the parallel wave spectrum that cause wave damping in a narrow layer near the mode conversion surface. The resulting poloidal forces in this layer drive sheared poloidal flows comparable to those in direct launch ion Bernstein wave experiments.

Functional effects of polymorphisms of house dust mite allergens.

BACKGROUND: Sequence polymorphisms have been found in cDNA clones of commercial house dust mites. Here we report on the polymorphisms of Der p 1 found in environmental mites and the effect of the polymorphisms on T cell proliferation. METHODS: Sequences were obtained from DNA amplified from single mites by PCR. Synthetic peptides were used to stimulate peripheral blood cells. RESULTS: The polymorphism was limited to a few residues, but regional differences were detected in mites in Wagga. T cells were specific for the polymorphisms, so that in 16 of 17 responses, stimulation was achieved with one form of the peptide. This included peptides with Ala and Val at position 124 in the immunodominant 110-133 region. Peptide 45-63 also stimulated frequently, but only with Tyr at position 50 and not His, a residue only found in commercial mites. CONCLUSIONS: Polymorphisms of Der p 1 are found in the environment and have a profound effect on polyclonal T cell stimulation to frequently recognised epitopes.

Assessment of antigenicity and genetic variation of glycoprotein B of murine cytomegalovirus.

An analysis of linear antibody-binding sites of the glycoprotein B (gB) molecule of murine cytomegalovirus (MCMV) and of genetic variation within these regions was performed. To achieve this, a series of overlapping fragments spanning the entire coding sequence of the gB gene of the K181 strain of MCMV was expressed in E. coli as fusion proteins with glutathione S-transferase (GST) using the pGEX expression system. Four antibody-binding regions were mapped to locations spanning amino acid residues 17-79 (BS), 155-278 (BE2), 809-926 (SS) and 347-508 (BB and EE), based on reactivity in Western blot analysis of GST-gB fusion proteins with murine polyclonal antiserum raised against MCMV. Only the antibody-binding region BE2 (155-278) elicited an antiserum that exhibited complement-dependent neutralizing activity, and immunization of mice with the fusion protein BE2 led to moderate but significant reductions in the level of MCMV replication in the spleen. Polyclonal antisera raised against the GST-gB fusion proteins detected purified virion proteins of 105 kDa (anti-BS and anti-BE2) and 52 kDa (anti-SS) and are therefore likely to recognize the N-terminal and C-terminal portions of the gB molecule, respectively. The antibody-binding region within amino acid residues 17-79 was found to be MCMV strain-specific, whereas antibody-binding regions within residues 155-278 and 809-926 were found to be conserved among MCMV field isolates. Comparative sequence analysis of the corresponding regions of MCMV gB revealed a level and extent of sequence of sequence heterogeneity consistent with these findings.

Chromosomal analysis of sperm from men with idiopathic infertility using sperm karyotyping and fluorescence in situ hybridization.

OBJECTIVE: To determine if idiopathic infertile men having oligozoospermia, asthenozoospermia, or teratozoospermia have an elevated risk of transmitting chromosomal abnormalities to their offspring. DESIGN: Sperm chromosomal complements from five somatically normal infertile men were assayed using the human sperm-hamster oocyte fusion system and the disomy frequencies for chromosomes 1, 12, and the sex chromosomes were determined using fluorescence in situ hybridization. SETTING: Infertile men and normal donors were volunteers in an academic research environment. PATIENTS: Five men with the appropriate semen characteristics were recruited among patients concerned about their infertility. INTERVENTIONS: Sperm fused with hamster oocytes resulting in sperm chromosomes or the sperm nuclei were prepared for fluorescence in situ hybridization. MAIN OUTCOME MEASURE: Structural and numerical abnormalities assessed by sperm karyotypes and the disomy frequency determined by fluorescence in situ hybridization analysis. RESULTS: The infertile men showed increased frequencies of numerical abnormalities and total abnormalities as determined by sperm karyotyping. Analysis of sperm nuclei by fluorescence in situ hybridization indicated a significant increase in the frequency of disomy for chromosome 1 and XY disomy. CONCLUSIONS: Sperm from infertile men may contain an increased frequency of chromosomal abnormalities.

Collecting duct carcinoma of the kidney: a case report and review of the literature.

Collecting duct carcinoma of the kidney is unique and rarely reported. The histological and ultrastructural characteristics of this tumor are well described in the pathological literature. However, there are few reports documenting the clinical presentation and long-term prognosis in patients with this unusual malignancy. Collecting duct carcinoma arises from the epithelium of the collecting tubules within the medulla and secondarily invades the renal cortex. The tumor occurs in a younger age group than is typical for renal cell carcinoma and most patients appear to have metastatic disease at presentation. We describe a case of this uncommon tumor and review the literature.

Bone mineral content at three sites in normal perimenopausal women.

Bone mineral content (BMC) in 217 healthy white women between the ages of 40 and 55 years was measured using single- and dual-photon absorptiometry. The sites measured included the distal radius, midradius, proximal femur, and lumbar spine. The relationship between BMC and age was constant over the age range studied when the confounding effect of menopause was controlled. Women with low body mass indices (BMIs) had significantly lower BMC than women with average or greater than average BMIs. More active women had higher BMC than less active women at both appendicular and axial sites. A trend suggesting that women with higher calcium intake may have higher BMC was statistically significant only at the midradial site. A trend of postmenopausal women having lower BMC than pre- or perimenopausal women was also statistically significant only at the midradial site. Only modest correlations were found between the various sites. These correlations are too weak to allow accurate clinical predictions of BMC at axial sites from the BMC at an appendicular site in individual patients.

An evaluation of the bending stiffness of various tibial fixation methods.

The relative stiffness of human tibial fixation by plaster casts, intramedullary rods, external fixators, and dynamic compression plates was compared to the stiffness of the intact tibia. Four-point bending was performed on each specimen, first intact, and then after sequential instrumentation, thus allowing each specimen to serve as its own control. The mean stiffnesses obtained for the bone-device complexes, as a percentage of the intact tibial stiffness, were 113 +/- 9% for the delta frame fixator, 57 +/- 14% for the dynamic compression plate, 28 +/- 2% for the unilateral external fixator (UEF) with stainless steel sidebar, 18 +/- 1% for the UEF with aluminum sidebar, 7 +/- 2% for the flexible intramedullary (IM) rods, and 6 +/- 2% for the cast. Even relatively flexible unilateral external fixators are much stiffer than cast or IM rod fixation, methods that usually lead to satisfactory union by secondary healing. If secondary union with callus formation is desirable, modifications of the external fixator may be necessary to provide more flexible fixation. This study may be one of the first attempts to quantitate the stiffness of tibial fixation in a standard cast and compare it with other devices.