Mortality risk factors in chronic haemodialysis patients with infective endocarditis.

BACKGROUND: It is well documented that infective endocarditis (IE) is strongly associated with morbidity and mortality in haemodialysis (HD) patients. Less clear are the mortality risk factors for IE, particularly in an urban African-American dialysis population. METHODS: IE patients were identified from the medical records for the period from January 1999 to February 2004 and confirmed by Duke criteria. The patients were classified as 'survivors' and 'non-survivors' depending on in-hospital mortality, and risk factors for IE mortality were determined by comparing the two cohorts. Survivors were followed as out-patients with death as the endpoint. RESULTS: A total of 52 patients with 54 episodes of IE were identified. A catheter was the HD access in 40 patients (74%). Mitral valve (50%) was the commonest valve involved, and Gram-positive infections accounted for 87% of IE. In-hospital mortality was high (37%) and valve replacement was required for 13 IE episodes (24%). On logistic regression analyses, mitral valve disease [P = 0.002; odds ratio (OR) = 15.04; 95% confidence interval (CI) = 2.70-83.61] and septic embolism (P = 0.0099; OR = 9.56; 95% CI = 1.72-53.21) were significantly associated with in-hospital mortality. Using the Cox proportional hazards model, mitral valve involvement (P = 0.0008; hazard ratio 4.05; 95% CI = 1.78-9.21) and IE related to drug-resistant organisms such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus sp. (P = 0.016; hazard ratio 2.43; 95% CI = 1.18-5.00) were associated with poor outcome after hospital discharge. CONCLUSIONS: IE was associated with high mortality in our predominantly African-American dialysis population, when the mitral valve was involved, or septic emboli occurred and if MRSA or VRE were the causal organisms.     

Infectious complications in renal transplant recipients

Post-kidney transplant infection is the most common life-threatening complication of long-term immunosuppressive therapy. Optimal immunosuppression, in which a balance is maintained between prevention of rejection and avoidance of infection, is the most challenging aspect of posttransplantation care. The study of infectious complications in immunologically compromised recipients is changing rapidly, particularly in the fields of prophylactic and preemptive strategies, molecular diagnostic methods, and antimicrobial agents. In addition, emerging pathogens such as BK polyomavirus and West Nile flavivirus infections and the introduction of newer immunosuppressive agents that constantly change the risk profiles for opportunistic infections has added layers of complexity to this burgeoning field. Although remarkable progress has been made in these disciplines, comprehensive understanding of the clinical manifestations of infections remains limited, and the standardization of prophylaxis, diagnosis, and treatment of most infections is yet inadequately defined. The long-term goal for optimal care of transplant recipients, with respect to infection, is the prevention and/or early recognition and treatment of infections while avoiding drug-related toxicities.     

Sustained attention in mild Alzheimer's disease

The vigilance decrement in perceptual sensitivity was examined in 10 patients with mild Alzheimer's disease (AD) and 20 age-matched controls. A visual high-event rate digit-discrimination task lasting 7.2 min. (six 1.2 min blocks) was presented at different levels of stimulus degradation. Previous studies have shown that sensitivity decrements (d') over time at high-stimulus degradation result from demands on effortful processing. For all degradation levels, the overall level of vigilance (d') was lower in AD patients than in controls. All participants showed sensitivity decrement over blocks, with greater decrement at higher degradation levels. AD patients exhibited greater sensitivity decrement over time at the highest degradation level they all could perform relative to control participants. There were no concomitant changes in either response bias (C) or response times. The results indicate that mild AD patients have overall lower levels of vigilance under conditions that require both automatic and effortful processing. Mild AD patients also exhibit a deficit in the maintenance of vigilance over time under effortful processing conditions. Although the sample of AD patients was small, results further suggest that both possible and probable AD patients had greater sensitivity decrement over time at the highest degradation level than did control participants, but only probable AD patients had lower overall levels of vigilance. In the possible AD patients as a group, the decrement in vigilance occurred in the absence of concurrent deficits on standard attentional tasks, such as the Stroop and Trail Making tests, suggesting that deficits in vigilance over time may appear earlier than deficits in selective attention.     

Once-daily budesonide inhalation powder (Pulmicort Turbuhaler®) improves health-related quality of life in adults previously receiving inhaled corticosteroids

In the treatment of asthma, the conventional measures used to monitor a patient's progress and health status do not address the impact of functional impairments associated with the disease that may affect the patient's daily life. Unlike those measures, health-related quality of life (HRQL) reflects the physical, psychological, and social difficulties a patient perceives on a day-to-day basis. This study was conducted to determine the effects of once-daily budesonide inhalation powder via the Pulmicort Turbuhaler on the HRQL in adult patients with asthma previously treated with other inhaled corticosteroids. A total of 184 patients 18 to 70 years of age who previously received inhaled corticosteroids were enrolled in this double-blind, placebo-controlled, parallel-group, multicenter study. Patients were randomly assigned to budesonide 400 microg once daily or to placebo for 12 weeks. Each patient's HRQL was assessed at randomization and at weeks 4 and 12 with the Asthma Quality of Life Questionnaire (AQLQ). More patients receiving budesonide than those receiving placebo reported statistically significant (P < or = .05) improvements in HRQL at weeks 4 and 12. With the exception of the domain pertaining to exposure to environmental stimuli, differences from placebo in overall AQLQ scores and individual domain scores were clinically important (> or = 0.5 units). In addition, 2.4 patients needed to be treated with once-daily budesonide for 1 patient to demonstrate clinically important improvement. Budesonide 400 microg administered once daily via the Pulmicort Turbuhaler provides statistically significant and clinically important HRQL benefit in adult patients with asthma previously receiving inhaled corticosteroids.     

A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy

Investigational New Drugs - Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral,...     

Acetylcholine affects the spatial scale of attention: evidence from Alzheimer's disease

Location precues were used to manipulate the spatial scale of attention in visual search for a target in an array of letters in patients with dementia of the Alzheimer type (DAT) and in age-matched older controls. Cue size varied in the amount of spatial precision conferred. Scopolamine, a muscarinic antagonist, decreased overall arousal and broadened spatial attention after a precise precue (small and valid) to target location for DAT patients but not for controls, suggesting a selective effect for attentional impairment induced by cholinergic blockade. In contrast, physostigmine, a cholinesterase inhibitor, did not alter the distribution of spatial attention relative to no-drug baseline testing for patients. Results support a differential role for cholinergic mechanisms in the modulation of the spatial scale of visual attention.     

Effects of apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle-aged adults: results From the National Institute of Mental Health's BIOCARD study

The cognitive consequences of the apolipoprotein E-epsilon4 (APOE-epsilon4) allele were examined in middle age, before likely onset of symptoms of Alzheimer's disease. The authors identified 3 cognitive processes--visuospatial attention, spatial working memory, and the effect of visuospatial attention on working memory--and devised "behavioral assays" of the integrity of components of these processes. Redirecting visuospatial attention, retention of memory for location, and attentional modulation of memory of target location were affected by APOE genotype. Visuospatial attention showed additive effects of epsilon4 gene dose; each additional epsilon4 allele inherited further slowed disengagement from invalidly cued space. In contrast, working memory performance was affected only in epsilon4 homozygotes. Effect sizes for the APOE gene were moderate to large, ranging from 14% to 24%. Effects of APOE genotype on component processes of cognition in healthy, middle-aged adults is consistent with the emergence in adulthood of an APOE-epsilon4 cognitive phenotype.     

Mitochondria-dependent reactive oxygen species-mediated programmed cell death induced by 3,3'-diindolylmethane through inhibition of F0F1-ATP synthase in unicellular protozoan parasite Leishmania donovani

Mitochondria are the principal site for the generation of cellular ATP by oxidative phosphorylation. F0F1-ATP synthase, a complex V of the electron transport chain, is an important constituent of mitochondria-dependent signaling pathways involved in apoptosis. In the present study, we have shown for the first time that 3,3'-diindolylmethane (DIM), a DNA topoisomerase I poison, inhibits mitochondrial F0F1-ATP synthase of Leishmania donovani and induces programmed cell death (PCD), which is a novel insight into the mechanism in protozoan parasites. DIM-induced inhibition of F0F1-ATP synthase activity causes depletion of mitochondrial ATP levels and significant stimulation of mitochondrial reactive oxygen species (ROS) production, followed by depolarization of mitochondrial membrane potential (DeltaPsi(m)). Because DeltaPsi(m) is the driving force for mitochondrial ATP synthesis, loss of DeltaPsi(m) results in depletion of cellular ATP level. The loss of DeltaPsi(m) causes the cellular ROS generation and in turn leads to the oxidative DNA lesions followed by DNA fragmentation. In contrast, loss of DeltaPsi(m) leads to release of cytochrome c into the cytosol and subsequently activates the caspase-like proteases, which lead to oligonucleosomal DNA cleavage. We have also shown that mitochondrial DNA-depleted cells are insensitive to DIM to induce PCD. Therefore, mitochondria are necessary for cytotoxicity of DIM in kinetoplastid parasites. Taken together, our study indicates for the first time that DIM-induced mitochondrial dysfunction by inhibition of F0F1-ATP synthase activity leads to PCD in Leishmania spp. parasites, which could be exploited to develop newer potential therapeutic targets.     

Budesonide turbuhaler delivered once daily improves health-related quality of life in adult patients with non-steroid-dependent asthma.

Budesonide inhalation powder via the dry-powder multidose inhaler Turbuhaler (budesonide Turbuhaler) has been shown to improve lung function and symptoms in adults with asthma. In this double-blind, placebo-controlled, multicenter trial, we evaluated the effects of once-daily budesonide Turbuhaler on health-related quality of life (HRQL) in 177 adults (aged 18-70 years) with non-steroid-dependent asthma. Patients were randomized to receive budesonide Turbuhaler (400 micrograms) once daily or placebo for 12 weeks. HRQL was assessed at baseline and weeks 4 and 12 using the Asthma Quality of Life Questionnaire (AQLQ). In addition to assessment based on the four AQLQ domains (activity limitations, asthma symptoms, emotional function, and response to exposure to environmental stimuli), AQLQ overall scores were analyzed for both treatment groups. Compared with placebo, patients using budesonide Turbuhaler once daily had statistically significant (p < 0.001) improvements from baseline to weeks 4 and 12 in AQLQ overall scores. Statistically significant improvements from baseline to weeks 4 and 12 in all four individual domains also were observed in the budesonide Turbuhaler group compared with placebo. Differences between the two treatment groups in mean changes from baseline in AQLQ overall, asthma symptoms, and emotional function reached the level required for patients to achieve a minimal important difference of change (> or = 0.5 U) at week 12. A retrospective analysis of the data showed that approximately 70% of patients treated with budesonide Turbuhaler experienced a minimal important difference of change in AQLQ overall scores. Overall, improvements in AQLQ correlated significantly (p < or = 0.04) with improvements in forced expiratory volume in 1 second, morning peak expiratory flow measurements, asthma symptoms, and breakthrough bronchodilator use at the study end. Thus, patients with corticosteroid-na?ve asthma can experience improved HRQL when using budesonide Turbuhaler.