Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial.

Several case reports have implicated Ginkgo biloba in clinically adverse bleeding disorders. Ginkgo biloba has been reported to increase pain-free walking distance among patients with peripheral artery disease (PAD). Standard PAD therapy includes 325 mg/day aspirin. The objective of this study was to examine potential adverse effects of concomitant aspirin and Ginkgo biloba on platelet function. Ginkgo biloba (EGb 761, 300 mg/day) was compared with placebo for effects on measures of platelet aggregation among adults consuming 325 mg/day aspirin in a randomized, double-blind, placebo-controlled, parallel design trial of 4-week duration. Participants were adults, age 69 +/- 10 years, with PAD or risk factors for cardiovascular disease. Outcome measures included platelet function analysis (PFA-100 analyzer) using ADP as an agonist (n = 26 placebo; n = 29 ginkgo), and platelet aggregation using ADP, epinephrine, collagen and ristocetin as agonists (n = 21 placebo; n = 23 ginkgo). Participants kept daily logs of bleeding or bruising episodes. There were no clinically or statistically significant differences between treatment groups for any agonists, for either PFA-100 analysis or platelet aggregation. Reports of bleeding or bruising were infrequent and similar for both study groups. In conclusion, in older adults with PAD or cardiovascular disease risk, a relatively high dose of Ginkgo biloba combined with 325 mg/day daily aspirin did not have a clinically or statistically detectable impact on indices of coagulation examined over 4 weeks, compared with the effect of aspirin alone. No adverse bleeding events were observed, although the trial was limited to a small sample size.     

THE EFFECT OF HYPERTENSIVE EPISODES AND CARDIAC HYPERTROPHY ON THE CANINE CARDIAC BAROREFLEX

1. Left ventricular (LV) hypertrophy has been implicated in the reduction of baroreflex sensitivity present in hypertension. The aim of the current study was to investigate the mean arterial pressure-heart rate reflex (MAP-HR) in a model which induced left ventricular hypertrophy but no sustained blood pressure elevation. 2. Five mongrel dogs were exposed to transient blood pressure elevation of between 20 and 30 mmHg, through hindlimb compression using a pneumatic pressure suit, for 7 h per day, 6 days per week for 6 weeks. Resting blood pressure was not altered by the 6 week hindlimb compression intervention. 3. Echocardiographically determined LV mass (mean ± s.e.m.) was 116.0 ± 7.4 g prior to hindlimb compression (baseline) and elevated to 125.4 ± 8.1 g (P= 0.003) after 6 weeks of compression. A reduction in the early (E) to late (A) transmitral diastolic flow ratio (E/A) from 1.80 ± 0.06 at baseline to 1.54 ± 0.09 (P = 0.037) after the 6 week intervention suggested that cardiac compliance was reduced. 4. The maximum gain of the MAP-HR reflex, studied using the ‘steady-state’ drug technique, when blood pressure was normal, showed a trend for reduction from 3.85 ± 0.43 beats/min per mmHg at baseline to 3.10 ± 0.45 beats/min per mmHg (P= 0.067) after 6 weeks of compression. This gain reduction became significant after β-adrenoceptor blockade with propranolol (3.13 ± 0.55 vs 2.32 ± 0.25 beats/min per mmHg; P= 0.039). Covariant analysis showed a significant inverse correlation between LV mass and maximum gain (r= 0.96; P<0.001) during the 6 week compression period. 5. The MAP-HR reflex changes in this model mimic those present in hypertension and implicate cardiac hypertrophy as one possible mediator.     

Psychiatric morbidity among people aged 85+ in 1987. A follow-up study at two and a half years: Associations with changes in psychiatric morbidity

This article reports findings from a longitudinal survey of very elderly people living at home in London. The research aimed to identify social, psychological and physical characteristics associated with positive ageing and successful survival in the community in later life and its converse—negative ageing—as well as the associated policy implications. Associations with psychiatric morbidity, measured using the General Health Questionnaire, among sample members without cognitive impairment between the baseline interviews in 1987 and at follow-up, two and a half years later in 1990, are reported. Twenty-five per cent of survivors scored over the threshold of the GHQ in 1987 and 30% scored over the threshold in 1990. Half of those with a score over the threshold in 1990 also scored over the threshold in 1987. Hierarchical regression (using residualized change analysis) was used to estimate the effects of the independent variables on changes in psychiatric morbidity. The most significant predictor of psychiatric morbidity (GHQ score) in 1990 was baseline GHQ score, followed by health and functional status scores. Health and functional status were also the strongest predictors of baseline (1987) GHQ scores. The uniqueness of the study lies in the collection of follow-up data on a sample of very elderly people, given that most surveys are corss-sectional and contain too few people aged 85+ to merit separate analysis. It contributes to the small body of literature on outcome of depression. The lack of consistent associations with recovery from psychiatric morbidity in the literature enhances the importance of studies aiming to identify factors associated with different outcomes.     

Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment.

BACKGROUND: Until recently, there has been no practical alternative to the use of calcineurin inhibitors (CIs) as primary immunosuppressants in lung transplantation (LTx) and heart transplantation (HTx). Sirolimus (SRL) is a novel powerful immunosuppressant without renal toxicity, a common post-transplant problem associated with CI therapy. METHODS: SRL was used in 20 LTx and 5 HTx recipients >90 days post-transplant, where serious renal impairment was limiting CI dosing. Patients started on 2 to 5 mg/day orally at a median of 1,185 days post-transplant. Dosage adjustments were made according to trough levels, toxicity and perceived efficacy. With SRL initiation, 48% ceased CI therapy and the remainder decreased their dose substantively. RESULTS: After 30 days, 4 of 5 dialyzed patients ceased dialysis and 15 of 20 patients with an elevated serum creatinine (Cr) (mean Cr 0.29 mmol/liter) improved their Cr. The direction of change in Cr at 30 days predicted longer term Cr. The starting Cr did not predict the 30-day or long-term value. There were two bouts of acute and one bout of chronic rejection. There were 35 infectious complications in 16 patients and 24 episodes of potential SRL-related toxicity in 17 patients. These events generally responded to dose reduction or temporary cessation and were level-related. Fifteen recipients presently remain on the drug. None of the 7 deaths could be directly related to toxicity. CONCLUSION: SRL is a useful alternative immunosuppressant, allowing significant CI withdrawal in transplant recipients with renal impairment. Whether the resulting improvement in Cr can be maintained in the long term probably depends on the balance between the extent of acute and chronic renal damage.     

Costello syndrome: Clinical phenotype,genotype, and management guidelines

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence‐based guidelines due to the lack of data for this rare condition.     

Monoclonal antibodies against membrane proteins of the rat glomerulus. Immunochemical specificity and immunofluorescence distribution of the antigens.

Monoclonal antibodies (MAbs) were generated to detergent-solubilized glomerular extracts to identify new epithelial and endothelial membrane proteins and to study the possible role of the corresponding antigens in the formation of immune deposits. Triton X-114 extracts of isolated glomeruli were subjected to phase separation, and the resultant detergent and aqueous phases were used to immunize mice. Monoclonal antibodies were prepared by standard techniques, and hybridomas secreting antibodies (IgGs) that recognize glomerular cell surface antigens were selected by enzyme immunoassay (EIA) and indirect immunofluorescence. The IgGs of 13 MAbs selected for study recognized antigens of different molecular weights (45-350 kd) by immunoprecipitation and immunoblotting and had different distributions in the glomerulus and in other renal structures by immunofluorescence. Several proved to recognize known antigens--ie, podocalyxin (MAbs 1A, 5A, 11A, and 20A), gp330 (20B), and dipeptidylpeptidase IV (26C). Others recognized antigens not previously characterized that fell into four groups: 1) those that were detected mainly in glomeruli; 2) those present in both glomeruli and peritubular capillaries; 3) those present in both glomeruli and tubule epithelia; and 4) those detected in all these sites. The pattern of glomerular staining also varied, but most of the antigens appeared to be expressed on either the endothelium or the epithelium, or on both. 27A IgG was specific for podocytes and weakly precipitated a 103-kd protein. 7A and 13A IgG precipitated a 120-kd protein and stained glomeruli as well as the basal aspects of distal tubules. 23A IgG recognized a more-than 350-kd antigen that appeared to be specific for endothelial cells in rat kidney and in all other organs studied. 14A IgG precipitated a 150-kd protein and stained glomeruli, proximal tubule brush borders, and endothelial and epithelial cells in rat kidney and in several other organs. 4B and 9B IgG gave a granular cytoplasmic staining in all cells. When injected intravenously into rats, all of the MAbs except 4B and 9B rapidly bound to glomeruli, demonstrating that the respective antigens are exposed at the cell surface and represent potential targets for antibody-mediated immune injury. It is concluded that selective detergent extraction of glomeruli is a useful approach for generation of antibodies that recognize native, nondenatured membrane components of glomerular endothelial and epithelial cells.     

Basement membrane heparan sulfate proteoglycan is the main proteoglycan synthesized by glomerular epithelial cells in culture.

The production and distribution of basement membrane-type heparan sulfate proteoglycans (BM HSPG) were investigated in a mouse glomerular epithelial cell line. Confluent cell monolayers were radiolabeled with [35S]sulfate or [35S]cysteine. Proteoglycans were isolated from the medium and cell layers by ion exchange chromatography and their nature determined by enzyme digestion (chondroitinase ABC) or degradative treatment (nitrous acid). It was found that more than 80% of the proteoglycans in both the cell layer and medium were heparan sulfate proteoglycans (HSPG) based on their susceptibility to nitrous acid degradation. More than half of the HSPG in the cell layer could be precipitated with an antiserum that specifically recognizes BM HSPG; only 10% of those released into the medium were precipitated with this antiserum. When immunoprecipitates of [35S] sulfate-labeled proteoglycans were analyzed by SDS-PAGE, the mature proteoglycans ran as a broad band at the top of the gel. When immunoprecipitates of [35S]cysteine-labeled proteoglycans were similarly analyzed, a 250 kd precursor core protein band was seen in addition to the mature proteoglycan. When BM HSPG were localized by immunofluorescence and immunoelectron microscopy (immunoperoxidase), they were found intracellularly in biosynthetic compartments (ER and Golgi cisternae) and extracellularly in deposits of basement membrane-like matrix located beneath and between the cells. These results indicate that l) BM HSPG are the predominant type of proteoglycans made by glomerular epithelial cells in culture; 2) these HSPG are assembled into a loosely organized matrix that is deposited beneath and between the cells; and 3) this cell type produces a higher proportion of BM HSPG than other cultured epithelial cells studied previously.