query: Whole brain radiotherapy increases the occurrence of new brain metastases.

title: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.

text:
CONTEXT In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone.
 OBJECTIVE To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death.
 DESIGN, SETTING, AND PATIENTS Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003.
 INTERVENTIONS Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients).
 MAIN OUTCOME MEASURES The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death.
 RESULTS The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation.
 CONCLUSIONS Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used.
 TRIAL REGISTRATION umin.ac.jp/ctr Identifier: C000000412.

title: Value of whole brain re-irradiation for brain metastases--single centre experience.

text:
AIMS There is controversy in published studies regarding the role of repeat whole brain radiation (WBRT) for previously irradiated brain metastases. The aim of our retrospective study was to document the practice at Princess Margaret Hospital with respect to the re-irradiation of patients with progressive or recurrent brain metastatic disease after initial WBRT.    MATERIALS AND METHODS A comprehensive computerised database was used to identify patients treated for brain metastases with more than one course of WBRT between 1997 and 2003. Seventy-two patients were treated with WBRT for brain metastases and retreated with WBRT at a later date. The records of these patients were reviewed.
 RESULTS The median age was 56.5 years. The most common primary sites were lung (51 patients) and breast (17 patients). The most frequent dose used for the initial radiotherapy was 20 Gy/5 fractions (62 patients). The most common doses of re-irradiation were 25 Gy/10 fractions (22 patients), 20 Gy/10 fractions (12 patients), 15 Gy/5 fractions (11 patients) and 20 Gy/8 fractions (10 patients). Thirty-one per cent of patients experienced a partial clinical response after re-irradiation, as judged by follow-up clinical notes; 27% remained stable; 32% deteriorated after re-irradiation. Patients who had Eastern Cooperative Oncology Group performance status 0-1 at the time of retreatment lived longer. In responders, the mean duration of response was 5.1 months. The median survival after re-irradiation was 4.1 months. One patient was reported as having memory impairment and pituitary insufficiency after 5 months of progression-free survival.
 CONCLUSION Repeat radiotherapy may be a useful treatment in carefully selected patients. With increased survival and better systemic options for patients with metastatic disease, more patients may be candidates for consideration of repeat WBRT for recurrent brain metastases, but prospective studies are needed to more clearly document their outcomes.

title: Surgical Resection for Patients with Solid Brain Metastases: Current Status

text: Brain metastases occur in up to 40% of patients with cancer. Their management has been revolutionized in the last decade by three developments: improved imaging and detection of metastases, better treatment of systemic disease with the result that metastases occur more often; and improved surgical techniques including image-guided surgery to treat metastatic lesions. Class 1 data suggest that surgery is a better treatment for metastases than whole brain radiation. Other data suggest that metastases even in eloquent cortex can be removed safely. The complication rate is low and the recurrence rate is less than 10%. In general, indications for surgery include a mass with an unknown primary; a symptomatic mass including one in eloquent areas; a mass with considerable edema requiring high dose steroids; a mass greater than 3 cm; or patient preference when radiosurgery may also be an option. The question of radiosurgery or whole brain radiation as adjunct to surgical removal requires further evaluation.

title: Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer.

text:
PURPOSE Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine.    EXPERIMENTAL DESIGN Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease.
 RESULTS Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions.
 CONCLUSIONS This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

title: A Whole Brain Staining, Embedding, and Clearing Pipeline for Adult Zebrafish to Visualize Cell Proliferation and Morphology in 3-Dimensions

text: The field of macro-imaging has grown considerably with the appearance of innovative clearing methods and confocal microscopes with lasers capable of penetrating increasing tissue depths. The ability to visualize and model the growth of whole organs as they develop from birth, or with manipulation, disease or injury, provides new ways of thinking about development, tissue-wide signaling, and cell-to-cell interactions. The zebrafish (Danio rerio) has ascended from a predominantly developmental model to a leading adult model of tissue regeneration. The unmatched neurogenic and regenerative capacity of the mature central nervous system, in particular, has received much attention, however tools to interrogate the adult brain are sparse. At present there exists no straightforward methods of visualizing changes in the whole adult brain in 3-dimensions (3-D) to examine systemic patterns of cell proliferation or cell populations of interest under physiological, injury, or diseased conditions. The method presented here is the first of its kind to offer an efficient step-by-step pipeline from intraperitoneal injections of the proliferative marker, 5-ethynyl-2'-deoxyuridine (EdU), to whole brain labeling, to a final embedded and cleared brain sample suitable for 3-D imaging using optical projection tomography (OPT). Moreover, this method allows potential for imaging GFP-reporter lines and cell-specific antibodies in the presence or absence of EdU. The small size of the adult zebrafish brain, the highly consistent degree of EdU labeling, and the use of basic clearing agents, benzyl benzoate, and benzyl alcohol, makes this method highly tractable for most laboratories interested in understanding the vertebrate central nervous system in health and disease. Post-processing of OPT-imaged adult zebrafish brains injected with EdU illustrate that proliferative patterns in EdU can readily be observed and analyzed using IMARIS and/or FIJI/IMAGEJ software. This protocol will be a valuable tool to unlock new ways of understanding systemic patterns in cell proliferation in the healthy and injured brain, brain-wide cellular interactions, stem cell niche development, and changes in brain morphology.

title: The cost effectiveness of stereotactic radiosurgery versus surgical resection in the treatment of solitary metastatic brain tumors.

text: Solitary metastatic brain tumors are the most common intracranial neoplasms encountered by neurosurgeons. Surgical resection of brain metastasis with whole brain radiotherapy (WBR) significantly increases survival in comparison with WBR alone. Stereotactic radiosurgery (SR) seems to provide results that are similar to those of surgical resection. To analyze the economic efficiency of these different treatments, we compared the results of surgical resection and SR as reported in the medical literature between 1974 and 1994. We included studies in which: 1) at least 75% of patients received WBR; 2) study dates were in the computed tomography era (after 1975); 3) operative morbidity, mortality, and median survival were reported; 4) study dates were not included in a more recent update or review; 5) tumor histologies were reported; and 6) the cobalt-60 gamma unit was used for SR. Three surgical resection studies and one SR study met all entry requirements. The WBR baseline was developed from two prospective, randomized trials and used for incremental cost effectiveness analysis. We developed a model of typical resource usage for uncomplicated procedures, reported complications, and subsequent craniotomies (for recurrent tumor or radiation necrosis) for both treatment options. Costs were estimated from the societal viewpoint using the 1992 Medicare Provider Analysis and Review database with average cost:charge ratios for surgery and WBR. A survey of capital and operating costs from five sites was used for radiosurgery. Our analysis revealed that radiosurgery had a lower uncomplicated procedure cost ($20,209 versus $27,587), a lower average complication cost per case ($2,534 versus $2,874), and a lower total cost per procedure ($22,743 versus $30,461), was more cost effective ($24,811 versus $32,149 per life year), and had a better incremental cost effectiveness ($40,648 versus $52,384 per life year) than surgical resection. A sensitivity analysis revealed that large changes in key assumptions would be required to change the analysis outcome. Equalization of the incremental cost effectiveness of the two treatments would require one of the following: 1) a 38.7% reduction in SR annual case volume, 2) a 34.7% increase in SR procedure cost, 3) a 18.8% reduction in surgical resection procedure cost, 4) a 240.5% increase in SR morbidity cost, 5) a 12.7% reduction in SR median survival, 6) a 16.8% increase in surgical resection median survival. Elimination of all surgical resection morbidity cost would still result in superior incremental cost effectiveness for SR.(ABSTRACT TRUNCATED AT 400 WORDS)

title: β-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis.

text: A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of β-catenin remained uninfluenced. Consistently, β-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. β-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.

title: Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases

text: Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

title: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.

text:
BACKGROUND Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety.
 METHODS Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival.
 RESULTS A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.
 CONCLUSIONS The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.

title: An Excitatory Loop with Astrocytes Contributes to Drive Neurons to Seizure Threshold

text: Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca2+ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca2+ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca2+ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca2+ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron-astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures.

title: Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma

text:
BACKGROUND HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma.
 RESULTS We observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively.
 CONCLUSIONS Based on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma.

title: Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer.

text:
OBJECTIVE To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases.
 DATA SOURCES Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies. Foreign language papers were included.    STUDY SELECTION Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity.
 RESULTS 95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted > or = 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates.
 CONCLUSIONS In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.

title: Neuronal replacement from endogenous precursors in the adult brain after stroke

text: In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.

title: Excitotoxic brain injury in adult zebrafish stimulates neurogenesis and long-distance neuronal integration.

text: Zebrafish maintain a greater capacity than mammals for central nervous system repair after injury. Understanding differences in regenerative responses between different vertebrate species may shed light on mechanisms to improve repair in humans. Quinolinic acid is an excitotoxin that has been used to induce brain injury in rodents for modeling Huntington's disease and stroke. When injected into the adult rodent striatum, this toxin stimulates subventricular zone neurogenesis and neuroblast migration to injury. However, most new neurons fail to survive and lesion repair is minimal. We used quinolinic acid to lesion the adult zebrafish telencephalon to study reparative processes. We also used conditional transgenic lineage mapping of adult radial glial stem cells to explore survival and integration of neurons generated after injury. Telencephalic lesioning with quinolinic acid, and to a lesser extent vehicle injection, produced cell death, microglial infiltration, increased cell proliferation, and enhanced neurogenesis in the injured hemisphere. Lesion repair was more complete with quinolinic acid injection than after vehicle injection. Fate mapping of her4-expressing radial glia showed injury-induced expansion of radial glial stem cells that gave rise to neurons which migrated to injury, survived at least 8 weeks and formed long-distance projections that crossed the anterior commissure and synapsed in the contralateral hemisphere. These findings suggest that quinolinic acid lesioning of the zebrafish brain stimulates adult neural stem cells to produce robust regeneration with long-distance integration of new neurons. This model should prove useful for elucidating reparative mechanisms that can be applied to restorative therapies for mammalian brain injury.

title: Transcriptional regulation of neuronal genes and its effect on neural functions: expression and function of forkhead transcription factors in neurons.

text: Forkhead box transcription factor, class O (FOXO) is a mammalian homologue of DAF-16, which is known to regulate the lifespan of Caenorhabditis elegans and includes subfamilies of forkhead transcription factors such as AFX, FKHRL1, and FKHR. FKHR is phosphorylated on three sites (Thr-24, Ser-256, and Ser-319) in a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner, thereby inhibiting death signals. We here documented dephosphorylation of FKHR following transient forebrain ischemia with its concomitant translocation into the nucleus in neurons in gerbil and mouse brains. The activation of FKHR preceded delayed neuronal death in the vulnerable hippocampal regions following ischemic brain injury. The FKHR activation was accompanied by an increase in DNA binding activity for FKHR-responsive element on the Fas ligand promoter. We also defined FKHR-induced downstream targets such as Fas ligand and Bim in brain ischemia. Therefore, we propose a new strategy to rescue neurons from delayed neuronal death by promoting the survival signaling. Sodium orthovanadate, a protein tyrosine phosphatase inhibitor, up-regulated Akt activity in the brain and in turn rescue neurons from delayed neuronal death by inhibiting FKHR-dependent or -independent death signals in neurons.

text: The preceding editions made "The Rat Brain in Stereotaxic Coordinates" the second most cited book in science. This Fifth Edition is the result of years of research providing the user with the drawings of the completely new set of coronal sections, now from one rat, and with significantly improved resolution by adding a third additional section level as compared to earlier editions. Numerous new nuclei and structures also have been identified. The drawings are presented in two color, providing a much better contrast for use, and the accompanying CD-ROM contains all of the drawings from the atlas as well as the corresponding color micrographs (which are not included in the book). Affordable, comprehensive, compact, and convenient, the Fifth Edition continues the legacy of this major neuroscience publication and is a guide to all students and scientists who study the rat brain. It contains 161 coronal diagrams based on a single brain and includes a CD-ROM featuring all of the drawings from the book, plus the accompanying color micrographs that are not in the printed atlas. The delineations are drawn entirely new from a new set of sections. The diagrams are spaced at constant 120 m intervals resulting in the high resolution and convenience of use. The drawings use blue color lines and black labels to facilitate extraction of information. The stereotaxic grid was derived using the same techniques that produced the widely praised stereotaxic grid of the previous editions. Over 1000 structures are identified, a number for the first time in this edition.

title: Optogenetics reveal delayed afferent synaptogenesis on grafted human-induced pluripotent stem cell-derived neural progenitors.

text: Reprogramming of somatic cells into pluripotency stem cell state has opened new opportunities in cell replacement therapy and disease modeling in a number of neurological disorders. It still remains unknown, however, to what degree the grafted human-induced pluripotent stem cells (hiPSCs) differentiate into a functional neuronal phenotype and if they integrate into the host circuitry. Here, we present a detailed characterization of the functional properties and synaptic integration of hiPSC-derived neurons grafted in an in vitro model of hyperexcitable epileptic tissue, namely organotypic hippocampal slice cultures (OHSCs), and in adult rats in vivo. The hiPSCs were first differentiated into long-term self-renewing neuroepithelial stem (lt-NES) cells, which are known to form primarily GABAergic neurons. When differentiated in OHSCs for 6 weeks, lt-NES cell-derived neurons displayed neuronal properties such as tetrodotoxin-sensitive sodium currents and action potentials (APs), as well as both spontaneous and evoked postsynaptic currents, indicating functional afferent synaptic inputs. The grafted cells had a distinct electrophysiological profile compared to host cells in the OHSCs with higher input resistance, lower resting membrane potential, and APs with lower amplitude and longer duration. To investigate the origin of synaptic afferents to the grafted lt-NES cell-derived neurons, the host neurons were transduced with Channelrhodopsin-2 (ChR2) and optogenetically activated by blue light. Simultaneous recordings of synaptic currents in grafted lt-NES cell-derived neurons using whole-cell patch-clamp technique at 6 weeks after grafting revealed limited synaptic connections from host neurons. Longer differentiation times, up to 24 weeks after grafting in vivo, revealed more mature intrinsic properties and extensive synaptic afferents from host neurons to the lt-NES cell-derived neurons, suggesting that these cells require extended time for differentiation/maturation and synaptogenesis. However, even at this later time point, the grafted cells maintained a higher input resistance. These data indicate that grafted lt-NES cell-derived neurons receive ample afferent input from the host brain. Since the lt-NES cells used in this study show a strong propensity for GABAergic differentiation, the host-to-graft synaptic afferents may facilitate inhibitory neurotransmitter release, and normalize hyperexcitable neuronal networks in brain diseases, for example, such as epilepsy.

title: An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex.

text: The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function. To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex. We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain. For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase. This dataset will provide a powerful new resource for understanding the development and function of the brain. To ensure the widespread distribution of these datasets, we have created a user-friendly website (http://web.stanford.edu/group/barres_lab/brain_rnaseq.html) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain.

title: Whole-body MR vascular screening detects unsuspected concomitant vascular disease in coronary heart disease patients

text: Coronary heart disease (CHD) patients often show atherosclerotic vascular disease in other vascular territories. We evaluated how often whole-body MR imaging detects concomitant arterial pathologies in CHD patients, and how often these pathologies were not known to the patients previously. Of 4,814 participants in the population-based Heinz Nixdorf Recall Study, 327 reported CHD (i.e., previous coronary bypass surgery, angioplasty); of those, 160 patients (mean age 66.4 years) were examined using MR of the brain, the heart (excluding the coronary arteries), and whole-body MR angiography. The prevalence of each vascular pathology was assessed, correlated to the others and compared to patients’ histories. Of the 160 CHD patients, 16 (10%) showed MR signs of stroke, and 77 (48.1%) had a stenosis >50% in at least one extracerebral peripheral artery (other than the coronaries), including 28 (17.5%) with relevant renal artery stenoses, and 20 (12.5%) with relevant extracerebral internal carotid artery stenoses. False negative histories were reported in 12 of 81 cases with myocardial infarctions, and in 11 of 16 cases with cerebrovascular infarctions. This whole-body atherosclerosis MR screening program allows previously unknown concomitant vascular disease to be detected in coronary heart disease patients. Its prospective value should be assessed in further studies.

title: Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area.

text: PURPOSE OF REVIEW The availability of a growing number of immunomodulatory medications over the past few years has been associated with various JC virus (JCV)-associated brain syndromes in patients with autoimmune diseases, including multiple sclerosis, Crohn's disease, and psoriasis that had not been previously recognized as predisposing factors for progressive multifocal leukoencephalopathy. This review covers the three novel syndromes discovered in the last decade that are caused by JCV infection of neurons and meningeal cells.    RECENT FINDINGS For more than 30 years, JCV was thought to exclusively infect oligodendrocytes and astrocytes in the white matter of the brain of immunosuppressed individuals. We now recognize that JCV-infected glial cells are frequently located at the gray-white matter junction or exclusively within the gray matter causing demyelination in the cortex. Mutations in JCV can trigger a change in tropism leading to involvement of other cell types, such as neurons and meningeal cells, causing clinically distinct entities. These new features of JCV infection provide challenges for clinicians taking care of affected patients and investigators studying the biology of this polyomavirus, its pathogenesis, and tropism.    SUMMARY We hope that increasing awareness of these syndromes will lead to early diagnosis, and pave the way for new avenues of research to better understand all aspects of JCV pathogenesis and develop efficient therapies for our patients. However, we need to remain vigilant and open to the possibility that additional JC variants or yet unknown polyomaviruses may also be associated with neurological diseases.


query: Women are more susceptible to death due to pneumonia when compared to men.

title: Gender-dependent differences in outcome after the treatment of infection in hospitalized patients.

text:
CONTEXT While it is established that management strategies and outcomes differ by gender for many diseases, its effect on infection has not been adequately studied.
 OBJECTIVE To investigate the role of gender among hospitalized patients treated for infection.
 DESIGN Observational cohort study conducted during a 26-month period from December 1996 through January 1999.
 SETTING University-affiliated hospital.
 PARTICIPANTS A total of 892 patients in the surgical units of the hospital with 1470 consecutive infectious episodes (782 in men and 688 in women).
 MAIN OUTCOME MEASURES Mortality during hospitalization by gender for infection episodes overall and for specific infectious sites, including lung, peritoneum, bloodstream, catheter, urine, surgical site, and skin/soft tissue.
 RESULTS Among all infections, there was no significant difference in mortality based on gender (men, 11.1% vs women, 14.2%; P = .07). After logistic regression analysis, factors independently associated with mortality included higher APACHE (Acute Physiology and Chronic Health Evaluation) II score, older age, malignancy, blood transfusion, and diagnosis of infection more than 7 days after admission, but not gender (female odds ratio [OR] for death, 1.32; 95% confidence interval [CI], 0.90-1.94; P = .16). Mortality was higher in women for lung (men, 18% vs women, 34%; P = .002) and soft tissue (men, 2% vs women, 10%; P < or = .05) infection; for other infectious sites, mortality did not differ by gender. Factors associated with mortality due to pneumonia by logistic regression included higher APACHE II score, malignancy, diabetes mellitus, diagnosis of infection more than 7 days after admission, older age, transplantation, and female gender (OR for death, 2.25; 95% CI, 1.17-4.32; P = .02).
 CONCLUSIONS Although gender may not be predictive of mortality among all infections, women appear to be at increased risk for death from hospital-acquired pneumonia, even after controlling for other comorbidities.

title: Pathology of postprimary tuberculosis in humans and mice: contradiction of long-held beliefs.

text: Tuberculosis remains one of the world's leading infectious causes of death. Approximately 80% of all disease is due to postprimary (secondary) tuberculosis in the lung. Unfortunately, tissues of developing lesions are seldom available and there are no recognized models of postprimary tuberculosis. In the preantibiotic era when tissues were more abundant, several investigators described early postprimary tuberculosis as a lipid pneumonia quite different from the caseating granulomas commonly described today. We used histopathologic, immunohistochemical and acid fast stains to examine tissues from several people with untreated primary and postprimary tuberculosis and compared the findings with those of mice with reactivation tuberculosis. The results confirmed that developing postprimary tuberculosis begins as a lipid pneumonia accompanied by bronchial obstruction in which infection is restricted to foamy alveolar macrophages. Cavities result from a combination of caseation of tuberculous pneumonia and microvascular occlusion characteristic of delayed type hypersensitivity (DTH). Reactivation tuberculosis in the mouse begins as a similar tuberculous lipid pneumonia with bronchial obstruction and evidence for participation of DTH. Developing necrosis in both species is associated with localization of organisms within lipid droplets. These results suggest that reactivation tuberculosis in mice is a valuable model of developing human postprimary tuberculosis.

title: Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events.

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OBJECTIVE To assess whether sex differences exist in the angiographic severity, management and outcomes of acute coronary syndromes (ACS).
 METHODS The study comprised 7638 women and 19 117 men with ACS who underwent coronary angiography and were included in GRACE (Global Registry of Acute Coronary Events) from 1999-2006. Normal vessels/mild disease was defined as <50% stenosis in all epicardial vessels; advanced disease was defined as >or=one vessel with >or=50% stenosis.
 RESULTS Women were older than men and had higher rates of cardiovascular risk factors. Men and women presented equally with chest pain; however, jaw pain and nausea were more frequent among women. Women were more likely to have normal/mild disease (12% vs 6%, p<0.001) and less likely to have left-main and three-vessel disease (27% vs 32%, p<0.001) or undergo percutaneous coronary intervention (65% vs 68%, p<0.001). Women and men with normal and mild disease were treated less aggressively than those with advanced disease. Women with advanced disease had a higher risk of death (4% vs 3%, p<0.01). After adjustment for age and extent of disease, women were more likely to have adverse outcomes (death, myocardial infarction, stroke and rehospitalisation) at six months compared to men (odds ratio 1.24, 95% confidence interval 1.14 to 1.34); however, sex differences in mortality were no longer statistically significant.
 CONCLUSIONS Women with ACS were more likely to have cardiovascular disease risk factors and atypical symptoms such as nausea compared with men, but were more likely to have normal/mild angiographic coronary artery disease. Further study regarding sex differences related to disease severity is warranted.

title: Migraine and cardiovascular disease: systematic review and meta-analysis.

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OBJECTIVE To evaluate the association between migraine and cardiovascular disease, including stroke, myocardial infarction, and death due to cardiovascular disease.
 DESIGN Systematic review and meta-analysis.
 DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies and reviews published until January 2009. Selection criteria Case-control and cohort studies investigating the association between any migraine or specific migraine subtypes and cardiovascular disease. Review methods Two investigators independently assessed eligibility of identified studies in a two step approach. Disagreements were resolved by consensus. Studies were grouped according to a priori categories on migraine and cardiovascular disease.
 DATA EXTRACTION Two investigators extracted data. Pooled relative risks and 95% confidence intervals were calculated.
 RESULTS Studies were heterogeneous for participant characteristics and definition of cardiovascular disease. Nine studies investigated the association between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidence interval 1.31 to 2.29). Additional analyses indicated a significantly higher risk among people who had migraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90 to 1.69; meta-regression for aura status P=0.02). Furthermore, results suggested a greater risk among women (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11). Age less than 45 years, smoking, and oral contraceptive use further increased the risk. Eight studies investigated the association between migraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due to cardiovascular disease (1.03, 0.79 to 1.34). Only one study investigated the association between women who had migraine with aura and myocardial infarction and death due to cardiovascular disease, showing a twofold increased risk.
 CONCLUSION Migraine is associated with a twofold increased risk of ischaemic stroke, which is only apparent among people who have migraine with aura. Our results also suggest a higher risk among women and risk was further magnified for people with migraine who were aged less than 45, smokers, and women who used oral contraceptives. We did not find an overall association between any migraine and myocardial infarction or death due to cardiovascular disease. Too few studies are available to reliably evaluate the impact of modifying factors, such as migraine aura, on these associations.

title: How much alcohol and how often? Population based case-control study of alcohol consumption and risk of a major coronary event.

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OBJECTIVE To quantify the effects of quantity and frequency of alcohol consumption on risk of acute myocardial infarction and coronary death.
 DESIGN Case-control study.
 SETTING Lower Hunter region of New South Wales, Australia, 1983-94.    SUBJECTS Men and women aged 35-69 years.
 MAIN OUTCOME MEASURE Acute myocardial infarction or coronary death.
 RESULTS Alcohol consumption patterns were compared between 11,511 cases of acute myocardial infarction or coronary death and 6077 controls randomly selected from the same study population. After adjusting for the effects of age, smoking, and medical history, men and women who consumed one or two drinks of alcohol on five or six days a week had a reduction in risk of a major coronary event compared with men and women who were non-drinkers (odds ratios: men 0.31 (95% confidence interval 0.22 to 0.45); women 0.33 (0.18 to 0.59)). A similar reduction in risk was found after excluding non-drinkers who were formerly moderate to heavy drinkers. An acute protective effect of alcohol consumption was also found for regular drinkers who consumed one or two drinks in the 24 hours preceding the onset of symptoms (odds ratios: men 0.74 (0.51 to 1.09); women 0.43 (0.20 to 0.95)).
 CONCLUSIONS Frequency and quantity of alcohol consumption are important in assessing the risk of a major coronary event. Risk is lowest among men who report one to four drinks daily on five or six days a week and among women who report one or two drinks daily on five or six days a week.

title: Combined Impact of Health Behaviours and Mortality in Men and Women: The EPIC-Norfolk Prospective Population Study

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BACKGROUND There is overwhelming evidence that behavioural factors influence health, but their combined impact on the general population is less well documented. We aimed to quantify the potential combined impact of four health behaviours on mortality in men and women living in the general community.
 METHODS AND FINDINGS We examined the prospective relationship between lifestyle and mortality in a prospective population study of 20,244 men and women aged 45-79 y with no known cardiovascular disease or cancer at baseline survey in 1993-1997, living in the general community in the United Kingdom, and followed up to 2006. Participants scored one point for each health behaviour: current non-smoking, not physically inactive, moderate alcohol intake (1-14 units a week) and plasma vitamin C >50 mmol/l indicating fruit and vegetable intake of at least five servings a day, for a total score ranging from zero to four. After an average 11 y follow-up, the age-, sex-, body mass-, and social class-adjusted relative risks (95% confidence intervals) for all-cause mortality(1,987 deaths) for men and women who had three, two, one, and zero compared to four health behaviours were respectively, 1.39 (1.21-1.60), 1.95 (1.70--2.25), 2.52 (2.13-3.00), and 4.04 (2.95-5.54) p < 0.001 trend. The relationships were consistent in subgroups stratified by sex, age, body mass index, and social class, and after excluding deaths within 2 y. The trends were strongest for cardiovascular causes. The mortality risk for those with four compared to zero health behaviours was equivalent to being 14 y younger in chronological age.
 CONCLUSIONS Four health behaviours combined predict a 4-fold difference in total mortality in men and women, with an estimated impact equivalent to 14 y in chronological age.

title: Cost-effectiveness of options for the diagnosis of high blood pressure in primary care: a modelling study.

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BACKGROUND The diagnosis of hypertension has traditionally been based on blood-pressure measurements in the clinic, but home and ambulatory measurements better correlate with cardiovascular outcome, and ambulatory monitoring is more accurate than both clinic and home monitoring in diagnosing hypertension. We aimed to compare the cost-effectiveness of different diagnostic strategies for hypertension.
 METHODS We did a Markov model-based probabilistic cost-effectiveness analysis. We used a hypothetical primary-care population aged 40 years or older with a screening blood-pressure measurement greater than 140/90 mm Hg and risk-factor prevalence equivalent to the general population. We compared three diagnostic strategies-further blood pressure measurement in the clinic, at home, and with an ambulatory monitor-in terms of lifetime costs, quality-adjusted life years, and cost-effectiveness.
 FINDINGS Ambulatory monitoring was the most cost-effective strategy for the diagnosis of hypertension for men and women of all ages. It was cost-saving for all groups (from -£56 [95% CI -105 to -10] in men aged 75 years to -£323 [-389 to -222] in women aged 40 years) and resulted in more quality-adjusted life years for men and women older than 50 years (from 0·006 [0·000 to 0·015] for women aged 60 years to 0·022 [0·012 to 0·035] for men aged 70 years). This finding was robust when assessed with a wide range of deterministic sensitivity analyses around the base case, but was sensitive if home monitoring was judged to have equal test performance to ambulatory monitoring or if treatment was judged effective irrespective of whether an individual was hypertensive.
 INTERPRETATION Ambulatory monitoring as a diagnostic strategy for hypertension after an initial raised reading in the clinic would reduce misdiagnosis and save costs. Additional costs from ambulatory monitoring are counterbalanced by cost savings from better targeted treatment. Ambulatory monitoring is recommended for most patients before the start of antihypertensive drugs.
 FUNDING National Institute for Health Research and the National Institute for Health and Clinical Excellence.

title: Peripheral arterial disease in the elderly: The Rotterdam Study.

text: To assess the age- and sex-specific prevalence of peripheral arterial disease (PAD) and intermittent claudication (IC) in an elderly population, we performed a population-based study in 7715 subjects (40% men, 60% women) aged 55 years and over. The presence of PAD and IC was determined by measuring the ankle-arm systolic blood pressure index (AAI) and by means of the World Health Organization/Rose questionnaire, respectively. PAD was considered present when the AAI was <0.90 in either leg. The prevalence of PAD was 19.1% (95% confidence interval, 18.1% to 20.0%): 16.9% in men and 20.5% in women. Symptoms of IC were reported by 1.6% (95% confidence interval, 1.3% to 1.9%) of the study population (2.2% in men, 1.2% in women). Of those with PAD, 6.3% reported symptoms of IC (8.7% in men, 4.9% in women), whereas in 68.9% of those with IC an AAI below 0.90 was found. Subjects with an AAI <0.90 were more likely to be smokers, to have hypertension, and to have symptomatic or asymptomatic cardiovascular disease compared with subjects with an AAI of 0.90 or higher. The authors conclude that the prevalence of PAD in the elderly is high whereas the prevalence of IC is rather low, although both prevalences clearly increase with advancing age. The vast majority of PAD patients reports no symptoms of IC.

title: Vegetarian dietary patterns and mortality in Adventist Health Study 2.

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IMPORTANCE Some evidence suggests vegetarian dietary patterns may be associated with reduced mortality, but the relationship is not well established.
 OBJECTIVE To evaluate the association between vegetarian dietary patterns and mortality.
 DESIGN Prospective cohort study; mortality analysis by Cox proportional hazards regression, controlling for important demographic and lifestyle confounders.
 SETTING Adventist Health Study 2 (AHS-2), a large North American cohort.
 PARTICIPANTS A total of 96,469 Seventh-day Adventist men and women recruited between 2002 and 2007, from which an analytic sample of 73,308 participants remained after exclusions.    EXPOSURES Diet was assessed at baseline by a quantitative food frequency questionnaire and categorized into 5 dietary patterns: nonvegetarian, semi-vegetarian, pesco-vegetarian, lacto-ovo-vegetarian, and vegan.
 MAIN OUTCOME AND MEASURE The relationship between vegetarian dietary patterns and all-cause and cause-specific mortality; deaths through 2009 were identified from the National Death Index.
 RESULTS There were 2570 deaths among 73,308 participants during a mean follow-up time of 5.79 years. The mortality rate was 6.05 (95% CI, 5.82-6.29) deaths per 1000 person-years. The adjusted hazard ratio (HR) for all-cause mortality in all vegetarians combined vs nonvegetarians was 0.88 (95% CI, 0.80-0.97). The adjusted HR for all-cause mortality in vegans was 0.85 (95% CI, 0.73-1.01); in lacto-ovo-vegetarians, 0.91 (95% CI, 0.82-1.00); in pesco-vegetarians, 0.81 (95% CI, 0.69-0.94); and in semi-vegetarians, 0.92 (95% CI, 0.75-1.13) compared with nonvegetarians. Significant associations with vegetarian diets were detected for cardiovascular mortality, noncardiovascular noncancer mortality, renal mortality, and endocrine mortality. Associations in men were larger and more often significant than were those in women.
 CONCLUSIONS AND RELEVANCE Vegetarian diets are associated with lower all-cause mortality and with some reductions in cause-specific mortality. Results appeared to be more robust in males. These favorable associations should be considered carefully by those offering dietary guidance.

title: Angina with "normal" coronary arteries: sex differences in outcomes.

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BACKGROUND Several studies have demonstrated that women with nonobstructive coronary disease have a high rate of subsequent investigations, rehospitalizations for recurrent chest pain, and repeat coronary angiography. The sex specificity of this finding is unclear. We therefore undertook an evaluation of sex differences in rehospitalization for acute coronary syndrome (ACS) or chest pain in patients with "angiographically normal" coronaries.
 METHODS A retrospective cohort study using prospectively collected angiographic and clinical data on all patients in British Columbia, Canada, presenting for their first cardiac catheterization with suspected ischemic heart disease but angiographically normal coronaries.
 RESULTS Among 32,856 patients, 7.1% of men versus 23.3% of women were angiographically normal (P < .001). Among angiographically normal patients, women were older and more likely to present with hypertension, prior stroke, chronic obstructive pulmonary disease, and peripheral vascular disease than men, but Canadian Cardiovascular Society class of angina did not vary by sex. Within 1 year, 1.0% died, (19 women, 18 men, P = .27) and 0.6% had a stroke (13 women, 9 men, P = .91). Readmission to hospital for ACS or chest pain requiring catheterization was significantly higher in women compared to men (adjusted OR 4.06; 95% CI 1.15-14.31).
 CONCLUSIONS In a contemporary, population-based cohort presenting for cardiac catheterization for suspected ischemia, women with angiographically normal coronaries were >4 times more likely to be readmitted to hospital for ACS/chest pain within 180 days compared to men. The observed sex difference has important social and economic implications and suggests that traditional diagnostic methods may not be optimal for women.

title: Sex-based differences in the effect of digoxin for the treatment of heart failure.

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BACKGROUND The Digitalis Investigation Group trial reported that treatment with digoxin did not decrease overall mortality among patients with heart failure and depressed left ventricular systolic function, although it did reduce hospitalizations slightly. Even though the epidemiologic features, causes, and prognosis of heart failure vary between men and women, sex-based differences in the effect of digoxin were not evaluated.
 METHODS We conducted a post hoc subgroup analysis to assess whether there were sex-based differences in the effect of digoxin therapy among the 6800 patients in the Digitalis Investigation Group study. The presence of an interaction between sex and digoxin therapy with respect to the primary end point of death from any cause was evaluated with the use of Mantel-Haenszel tests of heterogeneity and a multivariable Cox proportional-hazards model, adjusted for demographic and clinical variables.
 RESULTS There was an absolute difference of 5.8 percent (95 percent confidence interval, 0.5 to 11.1) between men and women in the effect of digoxin on the rate of death from any cause (P=0.034 for the interaction). Specifically, women who were randomly assigned to digoxin had a higher rate of death than women who were randomly assigned to placebo (33.1 percent vs. 28.9 percent; absolute difference, 4.2 percent, 95 percent confidence interval, -0.5 to 8.8). In contrast, the rate of death was similar among men randomly assigned to digoxin and men randomly assigned to placebo (35.2 percent vs. 36.9 percent; absolute difference, -1.6 percent; 95 percent confidence interval, -4.2 to 1.0). In the multivariable analysis, digoxin was associated with a significantly higher risk of death among women (adjusted hazard ratio for the comparison with placebo, 1.23; 95 percent confidence interval, 1.02 to 1.47), but it had no significant effect among men (adjusted hazard ratio, 0.93; 95 percent confidence interval, 0.85 to 1.02; P=0.014 for the interaction).
 CONCLUSIONS The effect of digoxin therapy differs between men and women. Digoxin therapy is associated with an increased risk of death from any cause among women, but not men, with heart failure and depressed left ventricular systolic function.

title: Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship.

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IMPORTANCE The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear.
 OBJECTIVE To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity.
 DESIGN, SETTING, AND PARTICIPANTS We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661,137 men and women (median age, 62 years; range, 21-98 years) and 116,686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years.    EXPOSURES Leisure time moderate- to vigorous-intensity physical activity.
 MAIN OUTCOMES AND MEASURES The upper limit of mortality benefit from high levels of leisure time physical activity.
 RESULTS Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer.
 CONCLUSIONS AND RELEVANCE Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.

title: Treatment outcome of an unselected cohort of tuberculosis patients in relation to human immunodeficiency virus serostatus in Zomba Hospital, Malawi.

text: There is little information about treatment outcome in patients with smear-negative pulmonary tuberculosis (PTB) or extrapulmonary tuberculosis (EPTB) treated under routine programme conditions in subsaharan Africa. A prospective study was carried out to determine treatment outcome in an unselected cohort of TB patients admitted to Zomba General Hospital, Malawi. Eight hundred and twenty-seven adult TB patients (451 men and 376 women) were registered between 1 July and 31 December 1995. Standardized treatment outcomes of treatment completion, death, default, and transfer to another district were assessed in relation to type of TB, human immunodeficiency virus (HIV) serostatus, age and gender. Two hundred and fifty-four patients (31%) died by the end of treatment, half of the deaths occurring in the first month. Death rates were 19% among 386 patients with smear-positive PTB, 46% among 211 patients with smear-negative PTB, and 37% among 230 patients with EPTB; 77% of the patients were HIV seropositive. Among new patients, HIV-positive patients had higher death rates than HIV-negative patients (hazard ratio [HR] 2.5; 95% confidence interval [95% CI] 1.6-3.8). Smear-negative patients had the highest death rates (HR 3.9; 95% CI 2.7-5.5 compared to smear-positive patients), followed by EPTB patients (HR 2.6, 95% CI 1.8-3.7 compared to smear-positive patients). Death rates increased with age but were similar in men and women. Adult patients in Malawi with smear-negative PTB and EPTB have low treatment completion and high death rates, related to high levels of HIV infection. National TB control programmes in areas of high HIV prevalence should no longer ignore treatment outcomes in patients with smear-negative PTB or EPTB.

title: Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study

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OBJECTIVES To quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and to derive a diagnostic tool.
 DESIGN Diagnostic study performed between 2007 and 2010. Participants had their history taken, underwent physical examination and measurement of C reactive protein (CRP) and procalcitonin in venous blood on the day they first consulted, and underwent chest radiography within seven days.
 SETTING Primary care centres in 12 European countries.
 PARTICIPANTS Adults presenting with acute cough.
 MAIN OUTCOME MEASURES Pneumonia as determined by radiologists, who were blind to all other information when they judged chest radiographs.
 RESULTS Of 3106 eligible patients, 286 were excluded because of missing or inadequate chest radiographs, leaving 2820 patients (mean age 50, 40% men) of whom 140 (5%) had pneumonia. Re-assessment of a subset of 1675 chest radiographs showed agreement in 94% (κ 0.45, 95% confidence interval 0.36 to 0.54). Six published "symptoms and signs models" varied in their discrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95% confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net reclassification improvement 28%). In the 1556 patients classified according to symptoms, signs, and CRP >30 mg/L as "low risk" (<2.5%) for pneumonia, the prevalence of pneumonia was 2%. In the 132 patients classified as "high risk" (>20%), the prevalence of pneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnostic information. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted in proportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk group respectively.
 CONCLUSIONS A clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation. Addition of CRP concentration at the optimal cut off of >30 mg/L improved diagnostic information, but measurement of procalcitonin concentration did not add clinically relevant information in this group.

title: Epidemiology of Staphylococcus aureus blood and skin and soft tissue infections in the US military health system, 2005-2010.

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CONTEXT Rates of hospital-onset methicillin-resistant Staphylococcus aureus (MRSA) infections are reported as decreasing, but recent rates of community-onset S. aureus infections are less known.
 OBJECTIVES To characterize the overall and annual incidence rates of community-onset and hospital-onset S. aureus bacteremia and skin and soft tissue infections (SSTIs) in a national health care system and to evaluate trends in the incidence rates of S. aureus bacteremia and SSTIs and the proportion due to MRSA.
 DESIGN, SETTING, AND PARTICIPANTS Observational study of all Department of Defense TRICARE beneficiaries from January 2005 through December 2010. Medical record databases were used to identify and classify all annual first-positive S. aureus blood and wound or abscess cultures as methicillin-susceptible S. aureus or MRSA, and as community-onset or hospital-onset infections (isolates collected >3 days after hospital admission).
 MAIN OUTCOME MEASURES Unadjusted incidence rates per 100,000 person-years of observation, the proportion of infections that was due to MRSA, and annual trends for 2005 through 2010 (examined using the Spearman rank correlation test or the Mantel-Haenszel χ2 test for linear trend).
 RESULTS During 56 million person-years (nonactive duty: 47 million person-years; active duty: 9 million person-years), there were 2643 blood and 80,281 wound or abscess annual first-positive S. aureus cultures. Annual incidence rates varied from 3.6 to 6.0 per 100,000 person-years for S. aureus bacteremia and 122.7 to 168.9 per 100,000 person-years for S. aureus SSTIs. The annual incidence rates for community-onset MRSA bacteremia decreased from 1.7 per 100,000 person-years (95% CI, 1.5-2.0 per 100,000 person-years) in 2005 to 1.2 per 100,000 person-years (95% CI, 0.9-1.4 per 100,000 person-years) in 2010 (P = .005 for trend). The annual incidence rates for hospital-onset MRSA bacteremia also decreased from 0.7 per 100,000 person-years (95% CI, 0.6-0.9 per 100,000 person-years) in 2005 to 0.4 per 100,000 person-years (95% CI, 0.3-0.5 per 100,000 person-years) in 2010 (P = .005 for trend). Concurrently, the proportion of community-onset SSTI due to MRSA peaked at 62% in 2006 before decreasing annually to 52% in 2010 (P < .001 for trend).
 CONCLUSION In the Department of Defense population consisting of men and women of all ages from across the United States, the rates of both community-onset and hospital-onset MRSA bacteremia decreased in parallel, while the proportion of community-onset SSTIs due to MRSA has more recently declined.

title: Serum Soluble Corin is Decreased in Stroke.

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BACKGROUND AND PURPOSE Soluble corin was decreased in coronary heart disease. Given the connections between cardiac dysfunction and stroke, circulating corin might be a candidate marker of stroke risk. However, the association between circulating corin and stroke has not yet been studied in humans. Here, we aimed to examine the association in patients wtith stroke and community-based healthy controls.
 METHODS Four hundred eighty-one patients with ischemic stroke, 116 patients with hemorrhagic stroke, and 2498 healthy controls were studied. Serum soluble corin and some conventional risk factors of stroke were examined. Because circulating corin was reported to be varied between men and women, the association between serum soluble corin and stroke was evaluated in men and women, respectively.
 RESULTS Patients with ischemic and hemorrhagic stroke had a significantly lower level of serum soluble corin than healthy controls in men and women (all P values, <0.05). In multivariate analysis, men in the lowest quartile of serum soluble corin were more likely to have ischemic (odds ratio [OR], 4.90; 95% confidence interval, 2.99-8.03) and hemorrhagic (OR, 17.57; 95% confidence interval, 4.85-63.71) stroke than men in the highest quartile. Women in the lowest quartile of serum soluble corin were also more likely to have ischemic (OR, 3.10; 95% confidence interval, 1.76-5.44) and hemorrhagic (OR, 8.54; 95% confidence interval, 2.35-31.02) stroke than women in the highest quartile. ORs of ischemic and hemorrhagic stroke were significantly increased with the decreasing levels of serum soluble corin in men and women (all P values for trend, <0.001).
 CONCLUSIONS Serum soluble corin was decreased in patients with stroke compared with healthy controls. Our findings raise the possibility that serum soluble corin may have a pathogenic role in stroke.

title: Body-mass index and mortality in Korean men and women.

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BACKGROUND Obesity is associated with diverse health risks, but the role of body weight as a risk factor for death remains controversial.
 METHODS We examined the association between body weight and the risk of death in a 12-year prospective cohort study of 1,213,829 Koreans between the ages of 30 and 95 years. We examined 82,372 deaths from any cause and 48,731 deaths from specific diseases (including 29,123 from cancer, 16,426 from atherosclerotic cardiovascular disease, and 3362 from respiratory disease) in relation to the body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters).
 RESULTS In both sexes, the average baseline BMI was 23.2, and the rate of death from any cause had a J-shaped association with the BMI, regardless of cigarette-smoking history. The risk of death from any cause was lowest among patients with a BMI of 23.0 to 24.9. In all groups, the risk of death from respiratory causes was higher among subjects with a lower BMI, and the risk of death from atherosclerotic cardiovascular disease or cancer was higher among subjects with a higher BMI. The relative risk of death associated with BMI declined with increasing age.
 CONCLUSIONS Underweight, overweight, and obese men and women had higher rates of death than men and women of normal weight. The association of BMI with death varied according to the cause of death and was modified by age, sex, and smoking history.

title: Prevalence of the Metabolic Syndrome Among Us Adults: Findings From the Third National Health and Nutrition Examination Survey

text: Metabolic syndrome is diagnosed when three or more of the following criteria are met: abdominal obesity (waist circumference more than 102 cm in men and 88 cm in women); hypertriglyceridemia of 150 mg/dl or above; a high-density lipoprotein (HDL) cholesterol level less than 40 mg/dl in men or 50 mg/dl in women; blood pressure of 130/85 mm Hg or higher; or fasting glucose of at least 110 mg/dl. Individuals with metabolic syndrome are likelier than others to develop diabetes and cardiovascular disease and have increased mortality from all causes (and from cardiovascular disease in particular). The investigators attempted to determine the prevalence of the syndrome in the United States by analyzing data on 8814 men and women 20 years of age or older who took part in the Third National Health and Nutrition Examination Survey in the years 1988 to 1994. This is a cross-sectional health survey of a sample of the noninstitutionalized civilian American population. The overall age-adjusted prevalence of metabolic syndrome was 23.7%. The prevalence rose from 6.7% in persons 20 to 29 years of age to 42% in those aged 70 years and more. There was virtually no gender-related difference in prevalence rates for the combined racial groups. Metabolic syndrome was most prevalent in Mexican Americans and least prevalent in whites, African Americans, and "others. " Among both African Americans and Mexican Americans, women had higher prevalence rates than men. Extrapolating from age-specific prevalence rates and US census counts from the year 2000, 47 million US residents have metabolic syndrome. Considering its prevalence, it seems important to estimate the direct medical costs of metabolic syndrome. In the great majority of cases the critical causes are improper nutrition and insufficient physical activity, emphasizing the importance of controlling obesity and encouraging physical activity in the United States.

title: Association between smoking and risk of bladder cancer among men and women.

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CONTEXT Previous studies indicate that the population attributable risk (PAR) of bladder cancer for tobacco smoking is 50% to 65% in men and 20% to 30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking. During the last 30 years, incidence rates have remained stable in the United States in men (123.8 per 100,000 person-years to 142.2 per 100,000 person-years) and women (32.5 per 100,000 person-years to 33.2 per 100,000 person-years); however, changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer.
 OBJECTIVE To evaluate the association between tobacco smoking and bladder cancer.
 DESIGN, SETTING, AND PARTICIPANTS Men (n = 281,394) and women (n = 186,134) of the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study cohort completed a lifestyle questionnaire and were followed up between October 25, 1995, and December 31, 2006. Previous prospective cohort studies of smoking and incident bladder cancer were identified by systematic review and relative risks were estimated from fixed-effects models with heterogeneity assessed by the I(2) statistic.
 MAIN OUTCOME MEASURES Hazard ratios (HRs), PARs, and number needed to harm (NNH).
 RESULTS During 4,518,941 person-years of follow-up, incident bladder cancer occurred in 3896 men (144.0 per 100,000 person-years) and 627 women (34.5 per 100,000 person-years). Former smokers (119.8 per 100,000 person-years; HR, 2.22; 95% confidence interval [CI], 2.03-2.44; NNH, 1250) and current smokers (177.3 per 100,000 person-years; HR, 4.06; 95% CI, 3.66-4.50; NNH, 727) had higher risks of bladder cancer than never smokers (39.8 per 100,000 person-years). In contrast, the summary risk estimate for current smoking in 7 previous studies (initiated between 1963 and 1987) was 2.94 (95% CI, 2.45-3.54; I(2) = 0.0%). The PAR for ever smoking in our study was 0.50 (95% CI, 0.45-0.54) in men and 0.52 (95% CI, 0.45-0.59) in women.
 CONCLUSION Compared with a pooled estimate of US data from cohorts initiated between 1963 and 1987, relative risks for smoking in the more recent NIH-AARP Diet and Health Study cohort were higher, with PARs for women comparable with those for men.

title: The prevalence and clustering of four major lifestyle risk factors in an English adult population.

text:
BACKGROUND The aim of this study was to examine the clustering of four major lifestyle risk factors (smoking, heavy drinking, lack of fruit and vegetables consumption, and lack of physical activity), and to examine the variation across different socio-demographic groups in the English adult population.
 METHODS The study population was derived from the 2003 Health Survey for England (n=11,492). Clustering was examined by comparing the observed and expected prevalence of the different possible combinations. A multinomial multilevel regression model was conducted to examine the socio-demographic variation in the clustering of the four risk factors.
 RESULTS The study found that, when using British health recommendations, a majority of the English population have multiple lifestyle risk factors at the same time. Clustering was found at both ends of the lifestyle spectrum and was more pronounced for women than for men. Overall, multiple risk factors were more prevalent among men, lower social class households, singles, and people who are economically inactive, but less prevalent among home owners and older age groups.
 CONCLUSIONS The clustering of multiple risk factors provides support for multiple-behavior interventions as opposed to single-behavior interventions.