Thioflavin-based molecular probes for application in Alzheimer's disease: from in silico to in vitro models.

Alzheimer's disease (AD) is a neurological disease of confusing causation with no cure or prevention available. The definitive diagnosis is made postmortem, in part through the presence of amyloid-beta plaques in the brain tissue, which can be done with the small molecule thioflavin-T (ThT). Plaques are also found to contain elevated amounts of metal ions Cu(ii) and Zn(ii) that contribute to the neurotoxicity of amyloid-beta (Aß). In this paper, we report in silico, in vitro, and ex vivo studies with ThT-derived metal binders 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT) and their respective iodinated counterparts, HBXI and HBTI. They exhibit low cytotoxicity in a neuronal cell line, potential blood-brain barrier penetration, and interaction with Aß fibrils from senile plaques present in human and transgenic mice AD models. Molecular modelling studies have also been undertaken to understand the prospective ligand-Aß complexes as well as to rationalize the experimental findings. Overall, our studies demonstrate that HBX, HBT, HBXI, and HBTI are excellent agents for future use in in vivo models of AD, as they show in vitro efficacy and biological compatibility. In addition to this, we present the glycosylated form of HBX (GBX), which has been prepared to take advantage of the benefits of the prodrug approach. Overall, the in vitro and ex vivo assays presented in this work validate the use of the proposed ThT-based drug candidate series as chemical tools for further in vivo development.

Changing practice habits of King County obstetricians.

In 1987, all practicing King County, Washington obstetricians (N = 181) were surveyed to determine the impact of rising malpractice premium rates and the threat of litigation on their obstetric practices. Six percent of respondents anticipated closing their practices over the next year, which means an additional 520 deliveries will have to be absorbed into existing obstetric practices. Of the 71% who increased their professional fees in 1986, 90% attributed the increase to higher malpractice premiums and increased risk of litigation.

In vitro growth of renal cell carcinoma after preoperative renal infarction.

Renal cell carcinoma tissue was cultured from 2 patients who underwent embolization of the tumor before surgery and from 2 patients who did not have the tumor embolized. A combination of small Gelfoam particles and polyvinyl alcohol foam particles (250-590 mu diameter) was used to devascularize maximally the tumors that were embolized. The tumor cells from all 4 patients grew in short-term tissue cultures and demonstrated histology and growth properties characteristic of tumor cells. Successful embolization of renal cell carcinomas may not completely infarct the primary tumor, and local tumor growth may continue.

Reliability of two measures of life stress among outpatients at a Veterans Hospital.

To measure test-retest reliability, 38 Veterans Administration clinic patients completed a modification of the Sarason Life Experience Survey (LES) twice within several weeks. Summary scores were found to be more reliable than scores on individual questions. Patients attending the Mental Hygiene Clinic responded less reliably than other patients. The "stress ladder"--a simple summary score measure--was found to be the most reliable measure of all.

Early femoral component loosening in DF-80 total hip arthroplasty.

Forty-seven DF-80 total hip arthroplasties performed in 40 patients were evaluated to determine the incidence and causes of early femoral component loosening. With an average 37.1-month follow-up period, 48.9% of the femoral components developed bone cement-bone radiolucent lines worrisome for stem loosening. Twenty-three percent of the stems had subsided and 4.3% had been revised. Radiolucent lines were apparent very early (average, 8.8 months). Statistical analysis revealed positive correlations between the use of the larger (45-mm) offset stem and both the appearance of radiolucent lines and stem loosening. Being male and tall also were associated with stem loosening. The causes for early DF-80 femoral component loosening could not be defined with certainty. The results of this study and a review of the literature suggest that failure may be a result of early biologic weakening of the proximal cement-bone interface combined with a stem design that maintains proximal bone loading. Metal debris did not appear to be a factor in loosening of this titanium alloy stem.

Methotrexate in the treatment of corticosteroid-dependent asthma. A double-blind crossover study.

To test our previous observation that methotrexate reduces corticosteroid requirements of patients with severe asthma, we studied 14 patients with corticosteroid-dependent bronchial asthma in a 24-week randomized double-blind crossover trial comparing a low dosage of methotrexate (15 mg per week) with placebo. At base line the mean dosage of prednisone was 173.5 mg per week (range, 70 to 420). On the average, 36.5 percent less prednisone was required when patients received methotrexate than when they received placebo (P = 0.01). Measurement of forced vital capacity and forced expiratory volume in one second showed that there was no deterioration in the condition of patients in whom the dosage of prednisone was reduced. The patients' subjective assessment of breathing ability indicated significant improvement (P = 0.01). The adverse effects of methotrexate were limited to transient nausea in three patients and an evanescent rash in one patient. Nine patients are still receiving methotrexate 3 to 10 months after the study's conclusion. The dosages of steroids have been further reduced in each of these patients, and prednisone has been discontinued in four. We conclude from this preliminary study that the use of methotrexate allows a significant reduction in the use of corticosteroids in patients with severe asthma without deterioration of pulmonary function.