Toll-like receptor-4 signaling mediates pulmonary neutrophil sequestration in response to gram-positive bacterial enterotoxin

BACKGROUND: Toll-like receptors (TLRs) serve as mediators of innate immune responses to pathogen-associated molecular patterns (PAMPs) which include lipopolysaccharide (LPS) and staphylococcal enterotoxin B (SEB). TLR-4 is thought to act as the primary effector of LPS recognition and TLR-2 is thought to mediate responses to Gram-positive bacterial proteins. Chemokines such as macrophage inflammatory protein (MIP-2) are peptides that are responsible for lung neutrophil (PMN) sequestration following an infectious or inflammatory insult. Given the Gram-positive origin of SEB, we hypothesized that mice with altered TLR-4 signaling would exhibit no difference in lung PMN sequestration following SEB when compared to wild-type mice. METHODS: Wild-type and TLR-4 mutant mice were administered intratracheal saline, LPS (Escherichia coli 0.1 mg/kg), or SEB (1 mg/kg). After 24 h, lung PMN accumulation was determined by myeloperoxidase (MPO) assay and bronchoalveolar lavage fluid cell count (BALfcc). Total lung and BALf MIP-2 was measured by enzyme-linked immunosorbent assay. RESULTS: There was an increase in lung PMN accumulation (by both MPO and BALfcc) and MIP-2 following LPS and SEB in wild-type mice compared to saline-treated controls. In contrast, TLR-4 mice failed to exhibit an increase in lung MIP-2 or PMN accumulation following either LPS or SEB compared to wild-type mice. CONCLUSIONS: TLR-4 mutant mice are unresponsive to intratracheal LPS. SEB elicited an increase in lung MIP-2 and PMN accumulation in wild-type mice. However, TLR-4 mutant mice were protected from this process. This suggests that TLR-4 signaling may mediate the responses to other PAMPs in addition to LPS.     

Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer

PURPOSE: High-dose (400 mg.) oral ketoconazole 3 times daily with replacement doses of hydrocortisone has become a standard treatment option for patients with advanced prostate cancer which progresses after androgen deprivation. However, toxicity can hinder the ability to deliver treatment and the cost of the regimen can be substantial. Therefore, a prospective phase II study was conducted to assess the efficacy and safety of a regimen of low dose (200 mg.) oral ketoconazole 3 times daily with replacement doses of hydrocortisone in men with androgen independent prostate cancer. MATERIALS AND METHODS: The study included 28 patients with progressive prostate cancer despite anorchid levels of testosterone and ongoing testicular androgen suppression. Treatment consisted of low dose ketoconazole and replacement doses of oral hydrocortisone (20 mg. every morning and 10 mg. at bedtime). At the time of disease progression patients were treated with high dose ketoconazole and continued on the same dose of hydrocortisone. Adrenal androgen levels were measured, and baseline and followup levels correlated with clinical outcome. RESULTS: Overall, 13 (46%) of 28 patients had a prostate specific antigen decrease of more than 50% (95% confidence interval 27.5% to 66.1%). Median duration of prostate specific antigen decrease for all responders was 30+ weeks and 5 patients continue to exhibit a response, ranging from 36+ to 53+ weeks. In general, therapy was well tolerated. There were no grade 4 toxicities. Grade 3 toxicities included hepatotoxicity in 1 patient and depression in 2. The most common toxicities were nausea (29% grades 1 and 2), dry skin (18% grade 1) and fatigue (14% grade 1). Four (14%) patients discontinued low dose ketoconazole due to toxicities. Of the 16 patients who received high dose ketoconazole after disease progression with low dose ketoconazole, 3 were removed from treatment due to toxicity and no patient responded to high dose ketoconazole. There was no difference in the distribution of pretreatment endocrine values between responders and nonresponders, and the magnitude of change in adrenal androgen levels was not associated with response to therapy, although a potential association could easily have been missed due to small sample size. CONCLUSIONS: The regimen of low dose ketoconazole with replacement doses of hydrocortisone is well tolerated and has moderate activity in patients with progressive androgen independent prostate cancer.     

Morbidity and mortality of gastrectomy for cancer in Department of Veterans Affairs Medical Centers

BACKGROUND: The purpose of this study was to define risk factors that predict 30-day morbidity and mortality after gastrectomy for cancer in Veterans Affairs (VA) Medical Centers. METHODS: The VA National Surgical Quality Improvement Program prospectively collected data on 708 patients undergoing gastrectomy for cancer in 123 participating VA medical centers from 1991 to 1998. Independent variables included 68 preoperative patient characteristics and 12 intraoperative variables; the dependent variables were 21 defined adverse outcomes and death. Predictive models for 30-day morbidity and mortality were constructed by using stepwise logistic regression analysis. RESULTS: The 30-day morbidity rate was 33.3% (236 of 708). The overall 30-day mortality rate was 7.6% (54 of 708). Significant positive predictors of morbidity (P <.05) included current pneumonia, American Society of Anesthesiologists class IV (threat to life), partially dependent functional status, dyspnea on minimal exertion, preoperative transfusion, extended operative time, and increasing age. Significant positive predictors of mortality (P <.05) included do not resuscitate status, prior stroke, intraoperative transfusion, preoperative weight loss, preoperative transfusion, and elevated preoperative alkaline phosphatase level. CONCLUSIONS: Risk factors predicting morbidity and mortality rates at VA hospitals after gastrectomy for gastric cancer are reported by using a prospectively collected, multi-institutional database. Assigning relative weights to factors associated with adverse outcomes may help improve patient care.     

Delivering HIV services to vulnerable populations: a review of CARE Act-funded research

This article summarizes key findings from evaluation and research studies that have received financial support from the HIV/AIDS Bureau of the Health Resources and Services Administration or from Ryan White Comprehensive AIDS Resources Emergency (CARE) Act grantees. These studies suggest that the CARE Act has improved but not equalized service accessibility, quality, and outcomes for different populations living with HIV disease. Evaluations of access to highly active antiretroviral therapy (HAART) found that uninsured patients, women, people of color, and injection drug users waited much longer than others to receive the new therapies. These disparities were not uniform across study sites, suggesting that clinic characteristics and geographic location have a major influence on prescribing patterns. Once patients gained access to HAART, health insurance status made little difference in clinical outcomes.     

Dietary and nondietary determinants of vitamin K biochemical measures in men and women

Few epidemiological studies that rely on the food frequency questionnaire (FFQ) for dietary assessment have measured biomarkers of vitamin K intake to independently confirm associations between self-reported dietary vitamin K intake and disease risk. Associations were examined between two sensitive biomarkers of vitamin K status, plasma phylloquinone and serum percent undercarboxylated osteocalcin (%ucOC), and self-reported usual phylloquinone intake as estimated from a FFQ. The influence of other dietary and nondietary factors on plasma phylloquinone concentrations was also examined. Dietary phylloquinone intake was estimated using a FFQ in 369 men and 468 women of the Framingham Offspring Study. The prevalence of high %ucOC concentrations (>/= 20%), suggestive of a low vitamin K status, was 44% in men and 54% in women, respectively. After multivariate adjustment, the odds of a high %ucOC was 2.5 greater for women (odds ratio: 2.5; 95% confidence interval [CI]: 1.2-5.1) and almost three times greater for men (odds ratio: 2.8; 95% CI: 1.3-5.9) in the lowest dietary phylloquinone intake quintile category compared to the highest quintile category. Fasting triglyceride concentrations, smoking status and season were associated with plasma phylloquinone concentrations, independent of dietary phylloquinone intake. Phylloquinone and green vegetable intake was linearly associated with plasma phylloquinone, after adjustment for potential confounding factors. There were limitations in the use of the FFQ to predict plasma phylloquinone, evident in an observed plateau effect and required nondietary adjustment factors. Despite these caveats, these findings support the use of a FFQ for a relative assessment of vitamin K status in population-based studies.     

Clinical information systems for primary care: more than just an electronic medical record

Massachusetts General Hospital Senior Health has integrated a computer-based clinical information system into all aspects of its patient care. This technology includes a longitudinal medical record but has broader functionality that encourages communication, education, and quality improvement activities. Care of geriatric patients is often challenging because of the complex nature of their clinical presentations. The case presented here, a patient at risk for stroke, illustrates how a clinical information system can facilitate quality care. The benefits, as well as difficulties, experienced as the system was integrated into the program's clinical practice are also described.     

Bright light,dark and melatonin can promote circadian adaptation in night shift workers

The circadian rhythms of shift workers do not usually phase shift to adapt to working at night and sleeping during the day. This misalignment results in a multitude of negative symptoms including poor performance and reduced alertness during night work and poor daytime sleep at home. After an introduction to circadian principles, we discuss the efficacy of appropriately timed bright light exposure (natural and artificial) and exogenous melatonin administration for producing circadian adaptation to night work. Interventions that generate alternative 24h light/dark patterns that facilitate appropriate circadian phase shifting are discussed. Such interventions include minimizing night workers' exposure to the external light/dark cycle, and the use of intermittent and moving patterns of bright light at work. The efficacy of melatonin in phase shifting circadian rhythms in the field is also addressed and compared to that of bright light. We present sleep/light exposure schedules that could produce circadian adaptation in permanent night workers. We conclude this review by discussing the impact of individual differences on possible circadian interventions and issues associated with the use of bright light interventions in the field.     

The dialectic of friendship for people with psychiatric disabilities

In the psychiatric literature, the meaning and importance of friendship has remained largely unexplored, subsumed under the rubric of social support or viewed as a component of community integration. Twenty-one qualitative interviews were conducted with individuals suffering from psychiatric disabilities focusing on the meaning of friendship as they described it. Analysis revealed the contrasts, contradiction and paradox of friendship for this group of people. The ongoing struggles of people with psychiatric disabilities regarding the need to connect with others and have friends, and conversely, the need to be alone and to withdraw from others, was highlighted.