Minneapolis VA Medical Center

BACKGROUND: Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol. METHODS: We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. RESULTS: The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006). We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. CONCLUSIONS: Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

The body mass index (BMI) is the metric currently in use for defining anthropometric height/weight characteristics in adults and for classifying (categorizing) them into groups. The common interpretation is that it represents an index of an individual's fatness. It also is widely used as a risk factor for the development of or the prevalence of several health issues. In addition, it is widely used in determining public health policies.The BMI has been useful in population-based studies by virtue of its wide acceptance in defining specific categories of body mass as a health issue. However, it is increasingly clear that BMI is a rather poor indicator of percent of body fat. Importantly, the BMI also does not capture information on the mass of fat in different body sites. The latter is related not only to untoward health issues but to social issues as well. Lastly, current evidence indicates there is a wide range of BMIs over which mortality risk is modest, and this is age related. All of these issues are discussed in this brief review.

Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.

Among 75 urosepsis isolates of Escherichia coli, 29 virulence factor (VF) genes were detected by use of a novel polymerase chain reaction (PCR) assay. Compared with probe hybridization, the PCR assay's specificity was 100% and sensitivity 97.1%. fyuA (yersiniabactin: overall prevalence, 93%), traT (serum resistance, 68%), and a pathogenicity-associated island marker (71%) occurred in most strains from both compromised and noncompromised hosts. Present in <20% of strains each were sfaS, focG (F1C fimbriae), afa/dra, bmaE (M fimbriae), gafD (G fimbriae), cnf1, cdtB (cytolethal distending toxin), cvaC (colicin V), and ibeA (invasion of brain endothelium). Different VFs were variously confined to virulence-associated phylogenetic group B2 (as defined by multilocus enzyme electrophoresis); concentrated in group B2, but with spread beyond; or concentrated outside of group B2. These findings provide novel insights into the VFs of extraintestinal pathogenic E. coli and demonstrate the new PCR assay's utility for molecular epidemiological studies.

OBJECTIVE: To examine the association between registered nurse (RN) staffing and patient outcomes in acute care hospitals. STUDY SELECTION: Twenty-eight studies reported adjusted odds ratios of patient outcomes in categories of RN-to-patient ratio, and met inclusion criteria. Information was abstracted using a standardized protocol. DATA SYNTHESIS: Random effects models assessed heterogeneity and pooled data from individual studies. Increased RN staffing was associated with lower hospital related mortality in intensive care units (ICUs) [odds ratios (OR), 0.91; 95% confidence interval (CI), 0.86-0.96], in surgical (OR, 0.84; 95% CI, 0.80-0.89), and in medical patients (OR, 0.94; 95% CI, 0.94-0.95) per additional full time equivalent per patient day. An increase by 1 RN per patient day was associated with a decreased odds ratio of hospital acquired pneumonia (OR, 0.70; 95% CI, 0.56-0.88), unplanned extubation (OR, 0.49; 95% CI, 0.36-0.67), respiratory failure (OR, 0.40; 95% CI, 0.27-0.59), and cardiac arrest (OR, 0.72; 95% CI, 0.62-0.84) in ICUs, with a lower risk of failure to rescue (OR, 0.84; 95% CI, 0.79-0.90) in surgical patients. Length of stay was shorter by 24% in ICUs (OR, 0.76; 95% CI, 0.62-0.94) and by 31% in surgical patients (OR, 0.69; 95% CI, 0.55-0.86). CONCLUSIONS: Studies with different design show associations between increased RN staffing and lower odds of hospital related mortality and adverse patient events. Patient and hospital characteristics, including hospitals' commitment to quality of medical care, likely contribute to the actual causal pathway.

BACKGROUND: Whether elective surgical repair of small abdominal aortic aneurysms improves survival remains controversial. METHODS: We randomly assigned patients 50 to 79 years old with abdominal aortic aneurysms of 4.0 to 5.4 cm in diameter who did not have high surgical risk to undergo immediate open surgical repair of the aneurysm or to undergo surveillance by means of ultrasonography or computed tomography every six months with repair reserved for aneurysms that became symptomatic or enlarged to 5.5 cm. Follow-up ranged from 3.5 to 8.0 years (mean, 4.9). RESULTS: A total of 569 patients were randomly assigned to immediate repair and 567 to surveillance. By the end of the study, aneurysm repair had been performed in 92.6 percent of the patients in the immediate-repair group and 61.6 percent of those in the surveillance group. The rate of death from any cause, the primary outcome, was not significantly different in the two groups (relative risk in the immediate-repair group as compared with the surveillance group, 1.21; 95 percent confidence interval, 0.95 to 1.54). Trends in survival did not favor immediate repair in any of the prespecified subgroups defined by age or diameter of aneurysm at entry. These findings were obtained despite a low total operative mortality of 2.7 percent in the immediate-repair group. There was also no reduction in the rate of death related to abdominal aortic aneurysm in the immediate-repair group (3.0 percent) as compared with the surveillance group (2.6 percent). Eleven patients in the surveillance group had rupture of abdominal aortic aneurysms (0.6 percent per year), resulting in seven deaths. The rate of hospitalization related to abdominal aortic aneurysm was 39 percent lower in the surveillance group. CONCLUSIONS: Survival is not improved by elective repair of abdominal aortic aneurysms smaller than 5.5 cm, even when operative mortality is low.

A consensus conference on cardio-renal syndromes (CRS) was held in Venice Italy, in September 2008 under the auspices of the Acute Dialysis Quality Initiative (ADQI). The following topics were matter of discussion after a systematic literature review and the appraisal of the best available evidence: definition/classification system; epidemiology; diagnostic criteria and biomarkers; prevention/protection strategies; management and therapy. The umbrella term CRS was used to identify a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. Different syndromes were identified and classified into five subtypes. Acute CRS (type 1): acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. Chronic cardio-renal syndrome (type 2): chronic abnormalities in heart function (CHF-CHD) leading to kidney injury and/or dysfunction. Acute reno-cardiac syndrome (type 3): acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. Chronic reno-cardiac syndrome (type 4): chronic kidney disease leading to heart injury, disease, and/or dysfunction. Secondary CRS (type 5): systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. Consensus statements concerning epidemiology, diagnosis, prevention, and management strategies are discussed in the paper for each of the syndromes.

CONTEXT: Limited data are available to assess whether endovascular repair of abdominal aortic aneurysm (AAA) improves short-term outcomes compared with traditional open repair. OBJECTIVE: To compare postoperative outcomes up to 2 years after endovascular or open repair of AAA in a planned interim report of a 9-year trial. DESIGN, SETTING, AND PATIENTS: A randomized, multicenter clinical trial of 881 veterans (aged > or = 49 years) from 42 Veterans Affairs Medical Centers with eligible AAA who were candidates for both elective endovascular repair and open repair of AAA. The trial is ongoing and this report describes the period between October 15, 2002, and October 15, 2008. INTERVENTION: Elective endovascular (n = 444) or open (n = 437) repair of AAA. MAIN OUTCOME MEASURES: Procedure failure, secondary therapeutic procedures, length of stay, quality of life, erectile dysfunction, major morbidity, and mortality. RESULTS: Mean follow-up was 1.8 years. Perioperative mortality (30 days or inpatient) was lower for endovascular repair (0.5% vs 3.0%; P = .004), but there was no significant difference in mortality at 2 years (7.0% vs 9.8%, P = .13). Patients in the endovascular repair group had reduced median procedure time (2.9 vs 3.7 hours), blood loss (200 vs 1000 mL), transfusion requirement (0 vs 1.0 units), duration of mechanical ventilation (3.6 vs 5.0 hours), hospital stay (3 vs 7 days), and intensive care unit stay (1 vs 4 days), but required substantial exposure to fluoroscopy and contrast. There were no differences between the 2 groups in major morbidity, procedure failure, secondary therapeutic procedures, aneurysm-related hospitalizations, health-related quality of life, or erectile function. CONCLUSIONS: In this report of short-term outcomes after elective AAA repair, perioperative mortality was low for both procedures and lower for endovascular than open repair. The early advantage of endovascular repair was not offset by increased morbidity or mortality in the first 2 years after repair. Longer-term outcome data are needed to fully assess the relative merits of the 2 procedures. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00094575.

BACKGROUND: Despite recommendations for annual vaccination against influenza, more than half of elderly Americans do not receive this vaccine. In a serial cohort study, we assessed the efficacy and cost effectiveness of influenza vaccine administered to older persons living in the community. METHODS: Using administrative data bases, we studied men and women over 64 years of age who were enrolled in a large health maintenance organization in the Minneapolis-St. Paul area. We examined the rate of vaccination and the occurrence of influenza and its complications in each of three seasons: 1990-1991, 1991-1992, and 1992-1993. Outcomes were adjusted for age, sex, diagnoses indicating a high risk, use of medications, and previous use of health care services. RESULTS: Each cohort included more than 25,000 persons 65 years of age or older. Immunization rates ranged from 45 percent to 58 percent. Although the vaccine recipients had more coexisting illnesses at base line than those who did not receive the vaccine, during each influenza season vaccination was associated with a reduction in the rate of hospitalization for pneumonia and influenza (by 48 to 57 percent, P < or = 0.002) and for all acute and chronic respiratory conditions (by 27 to 39 percent, P < or = 0.01). Vaccination was also associated with a 37 percent reduction (P = 0.04) in the rate of hospitalization for congestive heart failure during the 1991-1992 season, when influenza A was epidemic. The costs of hospitalization for all types of illness studied were lower in the vaccinated group during 1991-1992 (range of reduction, 47 to 66 percent; P < 0.005) and for acute and chronic respiratory conditions and congestive heart failure in 1990-1991 (reductions of 37 percent and 43 percent, respectively; P < or = 0.05). Direct savings per year averaged $117 per person vaccinated (range, $21 to $235), with cumulative savings of nearly $5 million. Vaccination was also associated with reductions of 39 to 54 percent in mortality from all causes during the three influenza seasons (P < 0.001). CONCLUSIONS: For elderly citizens living in the community, vaccination against influenza is associated with reductions in the rate of hospitalization and in deaths from influenza and its complications, as compared with the rates in unvaccinated elderly persons, and vaccination produces direct dollar savings.

Nitric oxide (NO) is a small, gaseous, paramagnetic radical with a high affinity for interaction with ferrous hemoproteins such as soluble guanylate cyclase and hemoglobin. Interest in NO measurement increased exponentially with the discovery that NO or a related compound is the endothelium-derived relaxing factor (EDRF). In addition to being a potent endogenous vasodilator, NO has a role in inflammation, thrombosis, immunity, and neurotransmission. Measurement of NO is important as many of its effects (e.g., vasodilatation, inhibition of platelet aggregation) are similar to those of other substances produced by the endothelium, such as prostacyclin. NO is formed in small amounts in vivo and is rapidly destroyed by interaction with oxygen, making measurement difficult. A computerized search of the past five year's literature found NO measurements reported in fewer than 50 of 955 articles dealing with EDRF. Inhibitors of NO synthesis such as the arginine analogs or agents that inactivate NO, such as reduced hemoglobin, are commonly used as specific probes for NO, in vivo and in vitro; however, none of the NO inhibitors is completely specific. The most widely used assays use one of three strategies to detect NO: 1) NO is "trapped" by nitroso compounds, or reduced hemoglobin, forming a stable adduct that is detected by electron paramagnetic resonance (EPR) (detection threshold approximately 1 nmol); 2) NO oxidizes reduced hemoglobin to methemoglobin, which is detected by spectrophotometry (detection threshold approximately 1 nmol); 3) NO interacts with ozone producing light, "chemiluminescence" (detection threshold approximately 20 pmol). These assays can be performed to exclusively detect NO, or by adding acid and reducing agents to the sample, can measure NO and related oxides of nitrogen such as nitrite. Several new amperometric microelectrode assays offer the potential to measure smaller amounts of NO (10(-20) M), permitting NO measurement in intact issues and from single cells. This review describes the pharmacology and toxicology of NO and reviews the major techniques for measuring NO in biological models.

BACKGROUND: Neurohormones are considered markers of heart failure progression. We examined whether changes in brain natriuretic peptide (BNP) and norepinephrine (NE) over time are associated with corresponding changes in mortality and morbidity in the Valsartan Heart Failure Trial. METHODS AND RESULTS: Plasma BNP and NE were measured before randomization and during follow-up in approximately 4300 patients in the Valsartan Heart Failure Trial. The relation between baseline BNP and NE and all-cause mortality and first morbid event (M&M) was analyzed in subgroups, with values above and below the median, and by quartiles. The change and percent change from baseline to 4 and 12 months in BNP and NE were also analyzed by quartiles for subsequent M&M. Risk ratios for M&M were calculated using a Cox proportional hazard model. Risk ratio of M&M for patients with baseline BNP or NE above the median was significantly higher than that for patients with values below the median. Baseline BNP and NE in quartiles also showed a quartile-dependent increase in M&M. BNP had a stronger association with M&M than NE. Patients with the greatest percent decrease in BNP and NE from baseline to 4 and 12 months had the lowest whereas patients with greatest percent increase in BNP and NE had the highest M&M. CONCLUSIONS: Not only are plasma BNP and NE important predictors of heart failure M&M, but changes in these neurohormones over time are associated with corresponding changes in M&M. These data further reinforce their role as significant surrogate markers in HF and underscore the importance of including their measurement in HF trials.

While multiple theories have been put forth regarding the origin of schizophrenia, by far the vast majority of evidence points to the neurodevelopmental model in which developmental insults as early as late first or early second trimester lead to the activation of pathologic neural circuits during adolescence or young adulthood leading to the emergence of positive or negative symptoms. In this report, we examine the evidence from brain pathology (enlargement of the cerebroventricular system, changes in gray and white matters, and abnormal laminar organization), genetics (changes in the normal expression of proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis), environmental factors (increased frequency of obstetric complications and increased rates of schizophrenic births due to prenatal viral or bacterial infections), and gene-environmental interactions (a disproportionate number of schizophrenia candidate genes are regulated by hypoxia, microdeletions and microduplications, the overrepresentation of pathogen-related genes among schizophrenia candidate genes) in support of the neurodevelopmental model. We relate the neurodevelopmental model to a number of findings about schizophrenia. Finally, we also examine alternate explanations of the origin of schizophrenia including the neurodegenerative model.

Nitric oxide (NO)-induced relaxation is associated with increased levels of cGMP in vascular smooth muscle cells. However, the mechanism by which cGMP causes relaxation is unknown. This study tested the hypothesis that activation of Ca-sensitive K (KCa) channels, mediated by a cGMP-dependent protein kinase, is responsible for the relaxation occurring in response to cGMP. In rat pulmonary artery rings, cGMP-dependent, but not cGMP-independent, relaxation was inhibited by tetraethylammonium, a classical K-channel blocker, and charybdotoxin, an inhibitor of KCa channels. Increasing extracellular K concentration also inhibited cGMP-dependent relaxation, without reducing vascular smooth muscle cGMP levels. In whole-cell patch-clamp experiments, NO and cGMP increased whole-cell K current by activating KCa channels. This effect was mimicked by intracellular administration of (Sp)-guanosine cyclic 3',5'-phosphorothioate, a preferential cGMP-dependent protein kinase activator. Okadaic acid, a phosphatase inhibitor, enhanced whole-cell K current, consistent with an important role for channel phosphorylation in the activation of NO-responsive KCa channels. Thus NO and cGMP relax vascular smooth muscle by a cGMP-dependent protein kinase-dependent activation of K channels. This suggests that the final common pathway shared by NO and the nitrovasodilators is cGMP-dependent K-channel activation.

BACKGROUND: A standard phenotype of frailty was associated with an increased risk of adverse outcomes including mortality in a recent study of older adults. However, the predictive validity of this phenotype for fracture outcomes and across risk subgroups is uncertain. METHODS: To determine whether a standard frailty phenotype was independently associated with risk of adverse health outcomes in older women and to evaluate the consistency of associations across risk subgroups defined by age and body mass index (BMI), we ascertained frailty status in a cohort of 6724 women>or=69 years and followed them prospectively for incident falls, fractures, and mortality. Frailty was defined by the presence of three or more of the following criteria: unintentional weight loss, weakness, self-reported poor energy, slow walking speed, and low physical activity. Incident recurrent falls were defined as at least two falls during the subsequent year. Incident fractures (confirmed with x-ray reports), including hip fractures, and deaths were ascertained during an average of 9 years of follow-up. RESULTS: After controlling for multiple confounders such as age, health status, medical conditions, functional status, depressive symptoms, cognitive function, and bone mineral density, frail women were subsequently at increased risk of recurrent falls (multivariate odds ratio=1.38, 95% confidence interval [CI], 1.02-1.88), hip fracture (multivariate hazards ratio [MHR]=1.40, 95% CI, 1.03-1.90), any nonspine fracture (MHR=1.25, 95% CI, 1.05-1.49), and death (MHR=1.82, 95% CI, 1.56-2.13). The associations between frailty and these outcomes persisted among women>or=80 years. In addition, associations between frailty and an increased risk of falls, fracture, and mortality were consistently observed across categories of BMI, including BMI>or=30 kg/m2. CONCLUSION: Frailty is an independent predictor of adverse health outcomes in older women, including very elderly women and older obese women.

Single-unit recording studies of posterior parietal neurons have indicated a similarity of neuronal activation to that observed in the dorsolateral prefrontal cortex in relation to performance of delayed saccade tasks. A key issue addressed in the present study is whether the different classes of neuronal activity observed in these tasks are encountered more frequently in one or the other area or otherwise exhibit region-specific properties. The present study is the first to directly compare these patterns of neuronal activity by alternately recording from parietal area 7ip and prefrontal area 8a, under the identical behavioral conditions, within the same hemisphere of two monkeys performing an oculomotor delayed response task. The firing rate of 222 posterior parietal and 235 prefrontal neurons significantly changed during the cue, delay, and/or saccade periods of the task. Neuronal responses in the two areas could be distinguished only by subtle differences in their incidence and timing. Thus neurons responding to the cue appeared earliest and were more frequent among the task-related neurons within parietal cortex, whereas neurons exhibiting delay-period activity accounted for a larger proportion of task-related neurons in prefrontal cortex. Otherwise, the task-related neuronal activities were remarkably similar. Cue period activity in prefrontal and parietal cortex exhibited comparable spatial tuning and temporal duration characteristics, taking the form of phasic, tonic, or combined phasic/tonic excitation in both cortical populations. Neurons in both cortical areas exhibited sustained activity during the delay period with nearly identical spatial tuning. The various patterns of delay-period activity-tonic, increasing or decreasing, alone or in combination with greater activation during cue and/or saccade periods-likewise were distributed to both cortical areas. Finally, similarities in the two populations extended to the proportion and spatial tuning of presaccadic and postsaccadic neuronal activity occurring in relation to the memory-guided saccade. The present findings support and extend evidence for a faithful duplication of receptive field properties and virtually every other dimension of task-related activity observed when parietal and prefrontal cortex are recruited to a common task. This striking similarity attests to the principal that information shared by a prefrontal region and a sensory association area with which it is connected is domain specific and not subject to hierarchical elaboration, as is evident at earlier stages of visuospatial processing.

OBJECTIVES: To compare the validity of a parsimonious frailty index (components: weight loss, inability to rise from a chair, and poor energy (Study of Osteoporotic Fractures (SOF) index)) with that of the more complex Cardiovascular Health Study (CHS) index (components: unintentional weight loss, low grip strength, poor energy, slowness, and low physical activity) for prediction of adverse outcomes in older men. DESIGN: Prospective cohort study. SETTING: Six U.S. centers. PARTICIPANTS: Three thousand one hundred thirty-two men aged 67 and older. MEASUREMENTS: Frailty status categorized as robust, intermediate stage, or frail using the SOF index and criteria similar to those used in CHS index. Falls were reported three times for 1 year. Disability (>or=1 new impairments in performing instrumental activities of daily living) ascertained at 1 year. Fractures and deaths ascertained during 3 years of follow-up. Analysis of area under the receiver operating characteristic curve (AUC) statistics compared for models containing the SOF index versus those containing the CHS index. RESULTS: Greater evidence of frailty as defined by either index was associated with greater risk of adverse outcomes. Frail men had a higher age-adjusted risk of recurrent falls (odds ratio (OR)=3.0-3.6), disability (OR=5.3-7.5), nonspine fracture (hazard ratio (HR)=2.2-2.3), and death (HR=2.5-3.5) (P<.001 for all models). AUC comparisons revealed no differences between models with the SOF index and models with the CHS index in discriminating falls (AUC=0.63, P=.97), disability (AUC=0.68, P=.86), nonspine fracture (AUC=0.63, P=.90), or death (AUC=0.71 for model with SOF index and 0.72 for model with CHS index, P=.19). CONCLUSION: The simple SOF index predicts risk of falls, disability, fracture, and mortality in men as well as the more-complex CHS index.

Hydrogen sulfide is gaining acceptance as an endogenously produced modulator of tissue function. The present paradigm of H(2)S (diprotonated, gaseous form of hydrogen sulfide) as a tissue messenger consists of H(2)S being released from the desulfhydration of l-cysteine at a rate sufficient to maintain whole tissue hydrogen sulfide concentrations of 30 microM to >100 microM, and these tissue concentrations serve a messenger function. Utilizing physiological concentrations of l-cysteine and aerobic conditions, we found that catabolism of hydrogen sulfide by mouse liver and brain homogenates exceeded the rate of enzymatic release of this compound such that measureable hydrogen sulfide release was less with tissue-containing vs. tissue-free buffers. Analyses of the gas space over rapidly homogenized mouse brain and liver indicated that in situ tissue hydrogen sulfide concentrations were only about 15 nM. Human alveolar air measurements indicated negligible free H(2)S concentrations in blood. We conclude rapid tissue catabolism of hydrogen sulfide maintains whole tissue brain and liver concentrations of free hydrogen sulfide that are three orders of magnitude less than conventionally accepted values and only 1/5,000 of the hydrogen sulfide concentration (100 microM) required to alter cellular function in vitro. For hydrogen sulfide to serve as an endogenously produced messenger, tissue production and catabolism must result in intracellular microenvironments with a sufficiently high hydrogen sulfide concentration to activate a local signaling mechanism, while whole tissue concentrations remain very low.

OBJECTIVE: To investigate the efficacy and safety of prostate-specific antigen (PSA) testing to screen for prostate cancer. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic search of Cochrane Central Register of Controlled Trials, Web of Science, Embase, Scopus, OpenGrey, LILACS, and Medline, and search of scientific meeting abstracts and trial registers to April 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing PSA screening with usual care in men without a diagnosis of prostate cancer. DATA EXTRACTION: Rapid Recommendation) provided input on the design and interpretation of the systematic review, including selection of outcomes important to patients. We used a random effects model to obtain pooled incidence rate ratios (IRR) and, when feasible, conducted subgroup analyses (defined a priori) based on age, frequency of screening, family history, ethnicity, and socioeconomic level, as well as a sensitivity analysis based on the risk of bias. The quality of the evidence was assessed with the GRADE approach. RESULTS: Five randomised controlled trials, enrolling 721 718 men, were included. Studies varied with respect to screening frequency and intervals, PSA thresholds for biopsy, and risk of bias. When considering the whole body of evidence, screening probably has no effect on all-cause mortality (IRR 0.99, 95% CI 0.98 to 1.01; moderate certainty) and may have no effect on prostate-specific mortality (IRR 0.96, 0.85 to 1.08; low certainty). Sensitivity analysis of studies at lower risk of bias (n=1) also demonstrates that screening seems to have no effect on all-cause mortality (IRR 1.0, 0.98 to 1.02; moderate certainty) but may have a small effect on prostate-specific mortality (IRR 0.79, 0.69 to 0.91; moderate certainty). This corresponds to one less death from prostate cancer per 1000 men screened over 10 years. Direct comparative data on biopsy and treatment related complications from the included trials were limited. Using modelling, we estimated that for every 1000 men screened, approximately 1, 3, and 25 more men would be hospitalised for sepsis, require pads for urinary incontinence, and report erectile dysfunction, respectively. CONCLUSIONS: At best, screening for prostate cancer leads to a small reduction in disease-specific mortality over 10 years but has does not affect overall mortality. Clinicians and patients considering PSA based screening need to weigh these benefits against the potential short and long term harms of screening, including complications from biopsies and subsequent treatment, as well as the risk of overdiagnosis and overtreatment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42016042347.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest. SEARCH STRATEGY: A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to June 2004. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported remission or survival by allocation. Fifty-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 of these studies reported the one-year survival outcome. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alfa versus controls, and for two randomized studies of the value of initial nephrectomy prior to interferon-alfa in fit patients with metastases detected at the time of diagnosis. MAIN RESULTS: Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. It has been established that reduced dose interleukin-2 given by intravenous bolus or by subcutaneous injection provides equivalent survival to high dose interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two recent randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms: despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival by 4.8 months over interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of bevacizumab, an anti-vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo therapy though frequency of remissions or survival were not improved. AUTHORS' CONCLUSIONS: interferon-alfa provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.