Computational insights into the photodeactivation dynamics of phosphors for OLEDs: a perspective.
A detailed molecular-level understanding of both the photoluminescence and electroluminescence properties of transition-metal (TM) complexes used as emitters in organic light-emitting diodes (OLEDs) is vital to pave the way to the next generation of OLEDs materials. In this Perspective, we present recent ab initio and density-functional theory (DFT) results, including or not spin-orbit couplings (SOCs), focused on disentangling competing photodeactivation mechanisms of radiative and non-radiative nature in target Pt(ii) and Ir(iii) complexes. These complexes are the most widespread organo-transition metal compounds for OLEDs applications. We address their photodeactivation dynamics, their temperature-dependent photoluminescence kinetics and some unusual photophysical properties (such as, e.g., dual photoluminescence or non-Kasha emissive behaviour). In addition, we discuss the pending questions regarding the photophysics of these systems, which will require the interplay between theoretical and experimental efforts.


Use of anti-depressants and the risk of fracture of the hip or femur.
Anti-depressants are used largely, but have serious side effects. We show that both selective serotonin re-uptake inhibitors (SSRIs) and tricyclic anti-depressants (TCAs) increase the risk of hip/femur fracture and that this risk is time related and depends on the degree of serotonin transporter inhibition. This should be considered when prescribing anti-depressants to patients. Anti-depressants are known to have serious side effects. We examined the association between the use of anti-depressants and the risk of hip/femur fractures with a special focus on the relation with the degree of 5-hydroxytryptamine transporter (5-HTT) inhibition and the duration of use. A case-control study was conducted within the Dutch PHARMO-RLS database. Cases (n = 6,763) were adult patients with a first hip/femur fracture during the study period. For each case, four controls (n = 26341) were matched by age, gender and geographic region. The risk of hip/femur fracture increased with current use of SSRIs (adjusted odds ratio (OR(adj)) 2.35 [95% confidence interval (CI) 1.94-2.84]) and TCAs (ORadj 1.76 [95% CI 1.45-2.15]). The risk of hip/femur fracture declined rapidly after discontinuation of use. The risk of hip/femur fracture increased as the degree of 5-HTT inhibition of all anti-depressants increased from OR(adj) 1.64 [95% CI 1.14-2.35] for drugs with low 5-HTT inhibition to OR(adj) 2.31 [95% CI 1.94-2.76] for those with high 5-HTT inhibiting properties. Current use of both SSRIs and TCAs increase hip/femur fracture risk. Further studies are needed to elucidate the mechanistic pathways and the relation with the underlying pathophysiology. Until then, the elevated fracture risk should be considered when prescribing anti-depressants.


Linking functional molecular variation with environmental gradients: myosin gene diversity in a crustacean broadly distributed across variable thermal environments.
To investigate the molecular basis of temperature adaptation in natural populations we used the candidate gene approach, targeting the myosin heavy chain (MyHC) gene. The functional effects of genetic variation in MyHC have been well characterised, and changes in the flexibility of the surface loops 1 and 2, caused by modulations in length, amino acid composition and charge can play an important role in thermal acclimation in fish. However, the extent that MyHC diversity is influenced by natural thermal gradients is largely unknown. Sequence variation in MyHC cDNA was examined in 7 species of gammarid amphipod with broad latitudinal distributions and differing intertidal thermal habitats in the NE Atlantic and Arctic Oceans. A high degree of diversity was detected in the loop 1 nucleotide sequences, although not all are likely to be functional transcripts, and their deduced amino acid sequences indicated no differences in the length and charge of loop 1 and associated binding kinetics. Four isoforms for loop 2 were detected which differed in sequence length and charge distribution, suggesting functional differences in sliding velocities and ATPase activities. While all species, and indeed most individuals, expressed multiple loop 2 isoforms, analysis of the two species with the greatest number of sequenced clones revealed that G. duebeni, a high-shore species with the highest thermal tolerance, expressed a greater diversity of forms than G. oceanicus, a low intertidal species more sensitive to temperature change. Latitude further influenced MyHC loop 2 diversity in G. duebeni, as the number of isoforms increased in the northern populations. Species-specific variations in MyHC diversity were observed, irrespective of phylogenetic associations revealed by analysis of the mitochondrial cytochrome oxidase 1 (CO1) gene. Overall, it appears that the temporal temperature variations associated with higher intertidal habitat may be a greater selective agent for MyHC isoform diversity in gammarid muscles than broad spatial changes with latitude.


Thiocolchicoside exhibits anticancer effects through downregulation of NF-κB pathway and its regulated gene products linked to inflammation and cancer.
The discovery of new uses for older, clinically approved drugs is one way to expedite drug development for cancer. Thiocolchicoside, a semisynthetic colchicoside from the plant Gloriosa superba, is a muscle relaxant and used to treat rheumatologic and orthopedic disorders because of its analgesic and anti-inflammatory mechanisms. Given that activation of the transcription factor NF-κB plays a major role in inflammation and tumorigenesis, we postulated that thiocolchicoside would inhibit NF-κB and exhibit anticancer effects through the modulation of NF-κB-regulated proteins. We show that thiocolchicoside inhibited proliferation of leukemia, myeloma, squamous cell carcinoma, breast, colon, and kidney cancer cells. Formation of tumor colonies was also suppressed by thiocolchicoside. The colchicoside induced apoptosis, as indicated by caspase-3 and poly(ADP-ribose) polymerase cleavage, and suppressed the expression of cell survival [e.g., Bcl-2, X-linked inhibitor of apoptosis (XIAP), MCL-1, bcl-xL, cIAP-1, cIAP-2, and cFLIP] proteins. Cell proliferation biomarkers such as c-MYC and phosphorylation of phosphoinositide 3-kinase and glycogen synthase kinase 3β were also blocked by thiocolchicoside. Because most cell survival and proliferation gene products are regulated by NF-κB, we studied the effect of thiocolchicoside on this transcription factor and found that thiocolchicoside inhibited NF-κB activation, degradation of inhibitory κBα (IκBα), IκBα ubiquitination, and phosphorylation, abolished the activation of IκBα kinase, and suppressed p65 nuclear translocation. This effect of thiocolchicoside on the NF-κB pathway led to inhibition of NF-κB reporter activity and cyclooxygenase-2 promoter activity. Our results indicate that thiocolchicoside exhibits anticancer activity through inhibition of NF-κB and NF-κB-regulated gene products, which provides novel insight into a half-century old drug.


Distribution of economic benefits from ecotourism: a case study of Wolong Nature Reserve For Giant Pandas in China.
Ecotourism is widely promoted as a conservation tool and actively practiced in protected areas worldwide. Theoretically, support for conservation from the various types of stakeholder inside and outside protected areas is maximized if stakeholders benefit proportionally to the opportunity costs they bear. The disproportional benefit distribution among stakeholders can erode their support for or lead to the failure of ecotourism and conservation. Using Wolong Nature Reserve for Giant Pandas (China) as an example, we demonstrate two types of uneven distribution of economic benefits among four major groups of stakeholders. First, a significant inequality exists between the local rural residents and the other types of stakeholder. The rural residents are the primary bearers of the cost of conservation, but the majority of economic benefits (investment, employment, and goods) in three key ecotourism sectors (infrastructural construction, hotels/restaurants, and souvenir sales) go to other stakeholders. Second, results show that the distribution of economic benefits is unequal among the rural residents inside the reserve. Most rural households that benefit from ecotourism are located near the main road and potentially have less impact on panda habitat than households far from the road and closer to panda habitats. This distribution gap is likely to discourage conservation support from the latter households, whose activities are the main forces degrading panda habitats. We suggest that the unequal distribution of the benefits from ecotourism can be lessened by enhancing local participation, increasing the use of local goods, and encouraging relocation of rural households closer to ecotourism facilities.


GAD1 is a biomarker for benign and malignant prostatic tissue.
Tissue-specific markers are useful for identification of tumour type in advanced cancers of unknown origin. This study investigated the expression of glutamate decarboxylase 1 (GAD1) in prostate and control tissue compared with the established prostate-specific markers prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA). A tissue microarray was constructed of 36 prostate adenocarcinomas, eight benign prostate samples and benign and malignant control tissues from urinary bladder, lung and rectum. Immunohistochemistry for GAD1, PSA and PSMA was performed. The products of staining intensity and extent were analysed. The GAD1 antibody was validated by Western blot. Real-time polymerase chain reaction (RT-PCR) was performed on malignant and benign samples from each tissue type. GAD1 and PSA immunostains were significantly stronger in malignant and benign prostatic tissue than in controls. PSMA was stronger in prostate cancer than in urothelial and rectal cancer but had a lower specificity than GAD1 and PSA. GAD1 expression decreased with increasing Gleason score. RT-PCR confirmed the presence of mRNA for GAD1, PSA and PSMA in prostate samples. GAD1 is expressed in benign and malignant prostatic tissue and may serve as a highly prostate-specific tissue biomarker.


Open surgical repair for chronic type B aortic dissection: a systematic review.
The treatment of chronic type B aortic dissection (CBAD) remains complicated. Thoracic endovascular aortic repair (TEVAR) has supplanted open surgical repair (OSR) as the preferred surgical treatment for CBAD. Despite TEVAR's superior short-term results, much less is understood about its long-term outcomes. As much of the understanding of OSR originates from historical report, contemporary series, with modern surgical techniques and technologies, may present an alternative to TEVAR. The present systematic review will assess the short- and long-term outcomes of historic and contemporary series of OSR for CBAD. Electronic searches were performed using six databases from their inception to March 2014. Relevant studies with OSRs for chronic type B dissection were identified. Data were extracted by two independent reviewers and analyzed according to predefined clinical endpoints. Studies were sub-classified into the pre-endovascular (historic series) and endovascular era (contemporary series) depending on whether the majority of cases were performed after 1999. Nineteen studies were identified for inclusion for quantitative analysis. Pooled short-term mortality was 11.1% overall, and 7.5% in the nine contemporary studies. Stroke, spinal cord ischemia, renal dysfunction, and reoperation for bleeding were 5.9%, 4.9%, 8.1%, and 8.1%, respectively, for the contemporary series. Absolute late reintervention was identified in 13.3% of patients overall, and in 11.3% of patients in the contemporary series. Aggregated survival at 1-, 3-, 5-, and 10-years of all patients were 82.1%, 74.1%, 66.3%, and 50.8%, respectively. OSR for chronic type B dissection in the contemporary era offers acceptable results. Management approaches should be considered carefully, taking into account both short-term and long-term complications. More research is required to clarify specific indications for OSR and TEVAR in chronic type B dissections.


Coagulopathy, Venous Thromboembolism, and Anticoagulation in Patients with COVID-19.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic, and patients with the infection are referred to as having COVID-19. Although COVID-19 is commonly considered a respiratory disease, there is clearly a thrombotic potential that was not expected. The pathophysiology of the disease and subsequent coagulopathy produce an inflammatory, hypercoagulable, and hypofibrinolytic state. Several observational studies have demonstrated surprisingly high rates of venous thromboembolism (VTE) in both general ward and intensive care patients with COVID-19. Many of these observational studies demonstrate high rates of VTE despite patients being on standard, or even higher intensity, pharmacologic VTE prophylaxis. Fibrinolytic therapy has also been used in patients with acute respiratory distress syndrome. Unfortunately, high quality randomized controlled trials are lacking. A literature search was performed to provide the most up-to-date information on the pathophysiology, coagulopathy, risk of VTE, and prevention and treatment of VTE in patients with COVID-19. These topics are reviewed in detail, along with practical issues of anticoagulant selection and duration. Although many international organizations have produced guidelines or consensus statements, they do not all cover the same issues regarding anticoagulant therapy for patients with COVID-19, and they do not all agree. These statements and the most recent literature are combined into a list of clinical considerations that clinicians can use for the prevention and treatment of VTE in patients with COVID-19.


B cell exchange across the blood-brain barrier in multiple sclerosis.
In multiple sclerosis (MS) pathogenic B cells likely act on both sides of the blood-brain barrier (BBB). However, it is unclear whether antigen-experienced B cells are shared between the CNS and the peripheral blood (PB) compartments. We applied deep repertoire sequencing of IgG heavy chain variable region genes (IgG-VH) in paired cerebrospinal fluid and PB samples from patients with MS and other neurological diseases to identify related B cells that are common to both compartments. For the first time to our knowledge, we found that a restricted pool of clonally related B cells participated in robust bidirectional exchange across the BBB. Some clusters of related IgG-VH appeared to have undergone active diversification primarily in the CNS, while others have undergone active diversification in the periphery or in both compartments in parallel. B cells are strong candidates for autoimmune effector cells in MS, and these findings suggest that CNS-directed autoimmunity may be triggered and supported on both sides of the BBB. These data also provide a powerful approach to identify and monitor B cells in the PB that correspond to clonally amplified populations in the CNS in MS and other inflammatory states.


Fabrication of tissue-engineered cell sheets by automated cell culture equipment.
Most cells for regenerative medicine are currently cultured manually. In order to promote the widespread use of regenerative medicine, it will be necessary to develop automated culture techniques so that cells can be produced in greater quantities at lower cost and with more stable quality. In the field of regenerative medicine technology, cell sheet therapy is an effective tissue engineering technique whereby cells can be grafted by attaching them to a target site. We have developed automated cell culture equipment to promote the use of this cell sheet regenerative treatment. This equipment features a fully closed culture vessel and circuit system that avoids contamination with bacteria and the like from the external environment, and it was designed to allow 10 cell sheets to be simultaneously cultured in parallel. We used this equipment to fabricate 50 sheets of human oral mucosal epithelial cells in five automated culture tests in this trial. By analyzing these sheets, we confirmed that 49 of the 50 sheets satisfied the quality standards of clinical research. To compare the characteristics of automatically fabricated cell sheets with those of manually fabricated cell sheets, we performed histological analyses using immunostaining and transmission electron microscopy. The results confirmed that cell sheets fabricated with the automated cell culture are differentiated in the same way as cultures fabricated manually.


Development of anti-TNF therapy for rheumatoid arthritis.
The aetiology of systemic, autoimmune, chronic inflammatory diseases--such as rheumatoid arthritis--is not known, and their pathogenesis is complex and multifactorial. However, progress in the characterization of intercellular mediators--proteins that are now known as cytokines--has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-alpha), has an important role in the pathogenesis of rheumatoid arthritis. This discovery heralded a new era of targeted and highly effective therapeutics for rheumatoid arthritis and, subsequently, other chronic inflammatory diseases.


Soil moisture depletion under simulated drought in the Amazon: impacts on deep root uptake.
*Deep root water uptake in tropical Amazonian forests has been a major discovery during the last 15 yr. However, the effects of extended droughts, which may increase with climate change, on deep soil moisture utilization remain uncertain. *The current study utilized a 1999-2005 record of volumetric water content (VWC) under a throughfall exclusion experiment to calibrate a one-dimensional model of the hydrologic system to estimate VWC, and to quantify the rate of root uptake through 11.5 m of soil. *Simulations with root uptake compensation had a relative root mean square error (RRMSE) of 11% at 0-40 cm and < 5% at 350-1150 cm. The simulated contribution of deep root uptake under the control was c. 20% of water demand from 250 to 550 cm and c. 10% from 550 to 1150 cm. Furthermore, in years 2 (2001) and 3 (2002) of throughfall exclusion, deep root uptake increased as soil moisture was available but then declined to near zero in deep layers in 2003 and 2004. *Deep root uptake was limited despite high VWC (i.e. > 0.30 cm(3) cm(-3)). This limitation may partly be attributable to high residual water contents (theta(r)) in these high-clay (70-90%) soils or due to high soil-to-root resistance. The ability of deep roots and soils to contribute increasing amounts of water with extended drought will be limited.


BAFF augments IgA2 and IL-10 production by TLR7/8 stimulated total peripheral blood B cells.
Class-switching of B cells to IgA can be induced via both T-cell-dependent and T-cell-independent mechanisms. IgA is most predominantly produced mucosally and is important for combating infections and allergies. In contrast to mice, humans have two forms of IgA; IgA1 and IgA2 with diverse tissue distribution. In early life, IgA levels might be sub-optimal especially during the fall season when bacterial and viral infections are more common. Therefore, we investigated using human B cells whether T-cell-independent factors -promoting cell survival, class switching and immunoglobulin secretion- BAFF, APRIL, IL-10 and retinoic acid can boost IgA production in the context of viral or bacterial infection. To this end total and naive peripheral blood B cells were stimulated with these factors for 6 days in the presence or absence of TLR7/8 agonist R848 (mimicking viral infection) or TLR9 agonist CpG-ODN (mimicking bacterial infection). We show that BAFF significantly augments IgA2 production in TLR7/8 stimulated mature, but not naïve B cells. In addition, BAFF augments IL-10 production and viability in TLR7/8 and TLR9 stimulated mature B cells. These data warrant further investigation of its role in immune regulation both in the periphery and mucosal tissues in early life or during disease.


Incidence and morbidity of craniocervical arterial dissections in atraumatic subarachnoid hemorrhage patients who underwent aneurysmal repair.
No studies have assessed the incidence of craniocervical arterial dissections (CCADs) and its association to mortality in hospitalized patients with a primary diagnosis of atraumatic subarachnoid hemorrhage (SAH) requiring aneurysmal repair. We hypothesize that the incidence of CCADs in these patients has increased over time as well as its association to mortality. We conducted a 9 year retrospective assessment of the incidence of CCADs in patients hospitalized with a primary diagnosis of an SAH requiring repair and the effect of CCAD on mortality. Using the Nationwide Inpatient Sample (NIS), we queried records from 2003 to 2011 for an ICD-9 (International Classification of Diseases-9) code corresponding to admissions for atraumatic SAH. Demographical data, incidence of CCADs, type of aneurysmal repair, length of hospital stay, and hospital mortality were recorded. Multivariate logistical regression models were fitted to assess for the impact of CCAD on inhospital mortality and morbidity. During the period 2003-2011, of the NIS reported 18,260 patients who required aneurysmal SAH repair, 9737 (53.32%) underwent endovascular coiling and 8523 (46.48%) had surgical clipping. There were 131 patients in the cohort with reported CCADs: 94 (71.75%) of these patients had received endovascular coiling repair and 37 (28.25%) had undergone surgical clipping repair. Patients who underwent endovascular coiling had a higher rate of CCADs in this cohort (OR 2.94; 95% CI 2.00 to 4.31, p<0.0001). The incidence of CCADs in this population increased by an average rate of 9.4% per year (OR 1.14; 95% CI 1.06 to 1.23, p<0.0006), from 0.49% in 2003 to 1.10% in 2011. The diagnosis of CCAD added 3 and 6 more days to median length of hospitalization stay for surgical clipping and endovascular coiling, respectively. The unadjusted rate of mortality was 8.4% in the CCADs subgroup, and the presence of CCAD was not a predictor of mortality in our multivariate regression model (OR 0.68; 95% CI 0.36 to 1.27, p=0.2244). Our study indicates an annual increase in the incidence of CCADs in patients admitted with SAH who require aneurysmal repair. More than two-thirds of these patients that developed CCADs had undergone endovascular coiling repair. A diagnosis of CCAD increased the length of hospital stay but had no statistically significant association with mortality in this patient population.


Detection of retroviral super-infection from non-invasive samples.
While much attention has been focused on the molecular epidemiology of retroviruses in wild primate populations, the correlated question of the frequency and nature of super-infection events, i.e., the simultaneous infection of the same individual host with several strains of the same virus, has remained largely neglected. In particular, methods possibly allowing the investigation of super-infection from samples collected non-invasively (such as faeces) have never been properly compared. Here, we fill in this gap by assessing the costs and benefits of end-point dilution PCR (EPD-PCR) and multiple bulk-PCR cloning, as applied to a case study focusing on simian foamy virus super-infection in wild chimpanzees (Pan troglodytes). We show that, although considered to be the gold standard, EPD-PCR can lead to massive consumption of biological material when only low copy numbers of the target are expected. This constitutes a serious drawback in a field in which rarity of biological material is a fundamental constraint. In addition, we demonstrate that EPD-PCR results (single/multiple infection; founder strains) can be well predicted from multiple bulk-PCR clone experiments, by applying simple statistical and network analyses to sequence alignments. We therefore recommend the implementation of the latter method when the focus is put on retroviral super-infection and only low retroviral loads are encountered.


Mucorales-Specific T Cells in Patients with Hematologic Malignancies.
Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during high-dose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD): 2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.


Toxicity of two carbamide peroxide products used in nightguard vital bleaching.
This study evaluated the effects of two generic classes of 10% carbamide-peroxide (CP) oxygenating agents (currently under clinical assessment for nightguard vital tooth bleaching) for lethality and genetic mutation after oral administration to mice, and for cellular cytotoxicity to mouse fibroblasts in vitro. The single dose LD50 values for a non-carbopol-containing CP (Gly-Oxide) and a carbopol-containing CP (Proxigel) in mice were found to be 143.8 mg/kg and 87.2 mg/kg, respectively. Genotoxicity, as measured by the Mouse Micronucleus test for mutagenicity, was negative for both 10% CP agents in comparison with positive and negative controls. Cytotoxicity as measured in the L929 fibroblast lysis assay resulted in 50% killing of L929 fibroblasts at 0.62 for the non-carbopol-containing CP and 1.88 mmol/L for the carbopol-containing CP. Both 10% CP agents were compared with seven widely-used dental products in the L929 fibroblast lysis assay and found to be no more toxic than these products.


Quality of life in patients with postural tachycardia syndrome.
To quantify quality of life and identify demographic and clinical correlates of functioning in a well-characterized sample of patients with postural tachycardia syndrome (POTS). Prospective patients were those seen at the Mayo Clinic Autonomic Disorders Laboratory from September 2000 to June 2001. Neurologists made diagnoses of POTS according to established criteria. Patients completed a questionnaire packet that included measures of quality of life (36-Item Short-Form Health Survey [SF-36]) and symptom severity (Autonomic Symptom Profile). Additional clinical information was abstracted from medical records. Ninety-four patients (89% female; mean age, 34.2 years) were enrolled in the study. Patients with POTS reported impairment across multiple domains on the SF-36. Physical functioning, role functioning, bodily pain, general health, vitality, and social functioning were all significantly impaired compared with a healthy population (P<.01 for all) and similar to that reported by patients with other chronic, disabling conditions. Hierarchical regression analyses revealed that symptom severity (beta = -.36, P<.001) and disability status (beta = -36, P<.001) were independent predictors of SF-36 physical component scores, with the full model accounting for 54% of the variance (P<.001). None of the variables examined accounted for a significant amount of the variance in SF-36 mental component scores. Patients with POTS experience clear limitations across multiple domains of quality of life, including physical, social, and role functioning. Treatment should address the multiple and varied impairments experienced by these patients and may require a multidisciplinary approach. Future research must further delineate factors, both disease related and psychosocial, that predict functioning and adjustment in this population.


Sequential alterations in catabolic and anabolic gene expression parallel pathological changes during progression of monoiodoacetate-induced arthritis.
Chronic inflammation is one of the major causes of cartilage destruction in osteoarthritis. Here, we systematically analyzed the changes in gene expression associated with the progression of cartilage destruction in monoiodoacetate-induced arthritis (MIA) of the rat knee. Sprague Dawley female rats were given intra-articular injection of monoiodoacetate in the knee. The progression of MIA was monitored macroscopically, microscopically and by micro-computed tomography. Grade 1 damage was observed by day 5 post-monoiodoacetate injection, progressively increasing to Grade 2 by day 9, and to Grade 3-3.5 by day 21. Affymetrix GeneChip was utilized to analyze the transcriptome-wide changes in gene expression, and the expression of salient genes was confirmed by real-time-PCR. Functional networks generated by Ingenuity Pathways Analysis (IPA) from the microarray data correlated the macroscopic/histologic findings with molecular interactions of genes/gene products. Temporal changes in gene expression during the progression of MIA were categorized into five major gene clusters. IPA revealed that Grade 1 damage was associated with upregulation of acute/innate inflammatory responsive genes (Cluster I) and suppression of genes associated with musculoskeletal development and function (Cluster IV). Grade 2 damage was associated with upregulation of chronic inflammatory and immune trafficking genes (Cluster II) and downregulation of genes associated with musculoskeletal disorders (Cluster IV). The Grade 3 to 3.5 cartilage damage was associated with chronic inflammatory and immune adaptation genes (Cluster III). These findings suggest that temporal regulation of discrete gene clusters involving inflammatory mediators, receptors, and proteases may control the progression of cartilage destruction. In this process, IL-1β, TNF-α, IL-15, IL-12, chemokines, and NF-κB act as central nodes of the inflammatory networks, regulating catabolic processes. Simultaneously, upregulation of asporin, and downregulation of TGF-β complex, SOX-9, IGF and CTGF may be central to suppress matrix synthesis and chondrocytic anabolic activities, collectively contributing to the progression of cartilage destruction in MIA.


Exploring heterogeneity in clinical trials with latent class analysis.
Case-mix is common in clinical trials and treatment effect can vary across different subgroups. Conventionally, a subgroup analysis is performed by dividing the overall study population by one or two grouping variables. It is usually impossible to explore complex high-order intersections among confounding variables. Latent class analysis (LCA) provides a framework to identify latent classes by observed manifest variables. Distal clinical outcomes and treatment effect can be different across these classes. This paper provides a step-by-step tutorial on how to perform LCA with R. A simulated dataset is generated to illustrate the process. In the example, the classify-analyze approach is employed to explore the differential treatment effects on distal outcomes across latent classes.


Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia.
The early course of neuropsychological dysfunction in schizophrenia and the impact of treatment on these deficits need to be better specified. A sample of 45 patients with schizophrenia underwent five neuropsychological evaluations from prior to treatment with antipsychotic treatment through a 2-year follow-up period. A comparison sample of 33 matched healthy individuals underwent neuropsychological evaluations at similar time points. At baseline, a generalized deficit across cognitive domains was evident for the schizophrenia sample. After 6 weeks of treatment, patients showed modest improvements in visual memory and visual perception, but a decline in verbal memory. Verbal memory performance returned to baseline levels by the 6-month follow-up while deficits in other neuropsychological domains persisted throughout the 2-year period. Relatively static and generalized neuropsychological dysfunction, evident from illness onset, is consistent with neurodevelopmental rather than neurodegenerative models of schizophrenia.


Performance of freestanding inpatient rehabilitation hospitals before and after the rehabilitation prospective payment system.
Inpatient rehabilitation hospitals provide important services to patients to restore physical and cognitive functioning. Historically, these hospitals have been reimbursed by Medicare under a cost-based system; but in 2002, Medicare implemented a rehabilitation prospective payment system (PPS). Despite the implementation of a PPS for rehabilitation, there is limited published research that addresses the operating and financial performance of these hospitals. We examined operating and financial performance in the pre- and post-PPS periods for for-profit and nonprofit freestanding inpatient rehabilitation hospitals to test for pre- and post-PPS differences within the ownership groups. We identified freestanding inpatient rehabilitation hospitals from the Centers for Medicare and Medicaid Services Health Care Cost Report Information System database for the first two fiscal years under PPS. We excluded facilities that had fiscal years less than 270 days, facilities with missing data, and government facilities. We computed average values for performance variables for the facilities in the two consecutive fiscal years post-PPS. For the pre-PPS period, we collected data on these same facilities and, once facilities with missing data and fiscal years less than 270 days were excluded, computed average values for the two consecutive fiscal years pre-PPS. Our final sample of 140 inpatient rehabilitation facilities was composed of 44 nonprofit hospitals and 96 for-profit hospitals both pre- and post-PPS. We utilized a pairwise comparison test (t-test comparison) to measure the significance of differences on each performance variable between pre- and post-PPS periods within each ownership group. Findings show that both nonprofit and for-profit freestanding inpatient rehabilitation hospitals reduced length of stay, increased discharges, and increased profitability. Within the for-profit ownership group, the percentage of Medicare discharges increased and operating expense per adjusted discharge decreased. Findings suggest that managers of these hospitals have adapted their administrative practices to conform with the financial incentives of the rehabilitation PPS. Managers must continue to control costs, increase discharges, and reduce length of stay to remain financially viable under the rehabilitation PPS.


Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention?
As part of the National Institute of Mental Health Epidemiologic Catchment Area study, 7954 respondents were questioned at baseline and 1 year later about sleep complaints and psychiatric symptoms using the Diagnostic Interview Schedule. Of this community sample, 10.2% and 3.2% noted insomnia and hypersomnia, respectively, at the first interview. Forty percent of those with insomnia and 46.5% of those with hypersomnia had a psychiatric disorder compared with 16.4% of those with no sleep complaints. The risk of developing new major depression was much higher in those who had insomnia at both interviews compared with those without insomnia (odds ratio, 39.8; 95% confidence interval, 19.8 to 80.0). The risk of developing new major depression was much less for those who had insomnia that had resolved by the second visit (odds ratio, 1.6; 95% confidence interval, 0.5 to 5.3). Further research is needed to determine if early recognition and treatment of sleep disturbances can prevent future psychiatric disorders.


Characterizing linkage disequilibrium in pig populations.
Knowledge of the extent and range of linkage disequilibrium (LD), defined as non-random association of alleles at two or more loci, in animal populations is extremely valuable in localizing genes affecting quantitative traits, identifying chromosomal regions under selection, studying population history, and characterizing/managing genetic resources and diversity. Two commonly used LD measures, r(2) and D', and their permutation based adjustments, were evaluated using genotypes of more than 6,000 pigs from six commercial lines (two terminal sire lines and four maternal lines) at ~4,500 autosomal SNPs (single nucleotide polymorphisms). The results indicated that permutation only partially removed the dependency of D' on allele frequency and that r(2) is a considerably more robust LD measure. The maximum r(2) was derived as a function of allele frequency. Using the same genotype dataset, the extent of LD in these pig populations was estimated for all possible syntenic SNP pairs using r(2) and the ratio of r(2) over its theoretical maximum. As expected, the extent of LD highest for SNP pairs was found in tightest linkage and decreased as their map distance increased. The level of LD found in these pig populations appears to be lower than previously implied in several other studies using microsatellite genotype data. For all pairs of SNPs approximately 3 centiMorgan (cM) apart, the average r(2) was equal to 0.1. Based on the average population-wise LD found in these six commercial pig lines, we recommend a spacing of 0.1 to 1 cM for a whole genome association study in pig populations.


Determinants of waterpipe use amongst adolescents in Northern Sweden: a survey of use pattern, risk perception, and environmental factors.
Determinants of waterpipe use in adolescents are believed to differ from those for other tobacco products, but there is a lack of studies of possible social, cultural, or psychological aspects of waterpipe use in this population. This study applied a socioecological model to explore waterpipe use, and its relationship to other tobacco use in Swedish adolescents. A total of 106 adolescents who attended an urban high-school in northern Sweden responded to an anonymous questionnaire. Prevalence rates for waterpipe use were examined in relation to socio-demographics, peer pressure, sensation seeking behavior, harm perception, environmental factors, and depression. Thirty-three percent reported ever having smoked waterpipe (ever use), with 30% having done so during the last 30 days (current use). Among waterpipe ever users, 60% had ever smoked cigarettes in comparison to 32% of non-waterpipe smokers (95% confidence interval 1.4-7.9). The odds of having ever smoked waterpipe were three times higher among male high school seniors as well as students with lower grades. Waterpipe ever users had three times higher odds of having higher levels of sensation-seeking (95% confidence interval 1.2-9.5) and scored high on the depression scales (95% confidence interval 1.6-6.8) than non-users. The odds of waterpipe ever use were four times higher for those who perceived waterpipe products to have pleasant smell compared to cigarettes (95% confidence interval 1.7-9.8). Waterpipe ever users were twice as likely to have seen waterpipe use on television compared to non-users (95% confidence interval 1.1-5.7). The odds of having friends who smoked regularly was eight times higher for waterpipe ever users than non-users (95% confidence interval 2.1-31.2). The current study reports a high use of waterpipe in a select group of students in northern Sweden. The study adds the importance of looking at socioecological determinants of use, including peer pressure and exposure to media marketing, as well as mental health among users.


Fetuin A/nutritional status predicts cardiovascular outcomes and survival in hemodialysis patients.
Fetuin A - a predictor of cardiovascular (CV) outcomes in dialysis patients - is correlated with over-nutrition in the general population. Whether fetuin A and nutritional status interact with each other to alter CV outcomes and survival in hemodialysis (HD) patients remains unknown. We performed a prospective study on 388 prevalent HD patients. We used the geriatric nutritional risk index (GNRI) for the evaluation of nutritional status. Study outcomes included the occurrence of CV event, CV death, and all-cause mortality during follow-up; interactions between parameters for predicting outcomes were assessed by the interaction terms in a Cox regression model. Overall, 131 patients experienced CV events and 92 patients died, with 51 CV deaths. HD patients with higher fetuin A levels had lower numbers of CV events (adjusted hazard ratio [HR], 0.9; 0.81-0.99) and all-cause mortality (adjusted HR, 0.97; 0.91-0.99). However, patients with higher GNRI had lower all-cause mortality (adjusted HR, 0.79; 0.51-0.98, for every 10-unit increase). Fetuin A levels and GNRI showed a significant interaction in the prediction of CV events (adjusted HR, 1.01; 1.008-1.02) but not for all-cause or CV mortality. In patients with poor nutritional status, higher fetuin A levels were associated with fewer CV events; however, in contrast, in subjects with better nutritional status, higher fetuin A levels appeared to lead to a higher number of CV events. Fetuin A showed a remarkable interaction with nutritional status in evaluating the risks of CV morbidities in prevalent HD patients.


Identification of seven hydrophobic clusters in GCN4 making redundant contributions to transcriptional activation.
GCN4 is a transcriptional activator in the bZIP family that regulates amino acid biosynthetic genes in the yeast Saccharomyces cerevisiae. The N-terminal 100 amino acids of GCN4 contains a potent activation function that confers high-level transcription in the absence of the centrally located acidic activation domain (CAAD) delineated in previous studies. To identify specific amino acids important for activation by the N-terminal domain, we mutagenized a GCN4 allele lacking the CAAD and screened alleles in vivo for reduced expression of the HIS3 gene. We found four pairs of closely spaced phenylalanines and a leucine residue distributed throughout the N-terminal 100 residues of GCN4 that are required for high-level activation in the absence of the CAAD. Trp, Leu, and Tyr were highly functional substitutions for the Phe residue at position 45. Combined with our previous findings, these results indicate that GCN4 contains seven clusters of aromatic or bulky hydrophobic residues which make important contributions to transcriptional activation at HIS3. None of the seven hydrophobic clusters is essential for activation by full-length GCN4, and the critical residues in two or three clusters must be mutated simultaneously to observe a substantial reduction in GCN4 function. Numerous combinations of four or five intact clusters conferred high-level transcription of HIS3. We propose that many of the hydrophobic clusters in GCN4 act independently of one another to provide redundant means of stimulating transcription and that the functional contributions of these different segments are cumulative at the HIS3 promoter. On the basis of the primacy of bulky hydrophobic residues throughout the activation domain, we suggest that GCN4 contains multiple sites that mediate hydrophobic contacts with one or more components of the transcription initiation machinery.


Social, institutional, and knowledge mechanisms mediate diverse ecosystem service benefits from coral reefs.
Ecosystem services are supplied by nature but, by definition, are received by people. Ecosystem service assessments, intended to influence the decisions people make regarding their interactions with nature, need to understand how people benefit from different ecosystem services. A critical question is therefore, What determines the distribution of ecosystem service benefits between different sections of society? Here, we use an entitlements approach to examine how people perceive ecosystem service benefits across 28 coral reef fishing communities in four countries. In doing so, we quantitatively show that bundles of benefits are mediated by key access mechanisms (e.g., rights-based, economic, knowledge, social, and institutional). We find that specific access mechanisms influence which ecosystem services people prioritize. Social, institutional, and knowledge mechanisms are associated with the largest number and diversity of benefits. However, local context strongly determines whether specific access mechanisms enable or constrain benefits. Local ecological knowledge enabled people to prioritize a habitat benefit in Kenya, but constrained people from prioritizing the same benefit in Madagascar. Ecosystem service assessments, and their resultant policies, need to include the broad suite of access mechanisms that enable different people to benefit from a supply of ecosystem services.


Deterministic characterization of phase noise in biomolecular oscillators.
On top of the many external perturbations, cellular oscillators also face intrinsic perturbations due the randomness of chemical kinetics. Biomolecular oscillators, distinct in their parameter sets or distinct in their architecture, show different resilience with respect to such intrinsic perturbations. Assessing this resilience can be done by ensemble stochastic simulations. These are computationally costly and do not permit further insights into the mechanistic cause of the observed resilience. For reaction systems operating at a steady state, the linear noise approximation (LNA) can be used to determine the effect of molecular noise. Here we show that methods based on LNA fail for oscillatory systems and we propose an alternative ansatz. It yields an asymptotic expression for the phase diffusion coefficient of stochastic oscillators. Moreover, it allows us to single out the noise contribution of every reaction in an oscillatory system. We test the approach on the one-loop model of the Drosophila circadian clock. Our results are consistent with those obtained through stochastic simulations with a gain in computational efficiency of about three orders of magnitude.


The place of physical activity in the time budgets of 10- to 13-year-old Australian children.
Low physical activity has been associated with increased fatness and deceased fitness. This observational study aimed to describe the magnitude, composition, and time-distribution of moderate-to-vigorous physical activity (MVPA) in Australian children. A total of 1132 10 to 13 year old schoolchildren completed a 24-h activity recall diary on 2 to 4 occasions. MVPA was defined as any activity requiring ≥3METs, including sport, play, active transport, chores, and other activities. MVPA was higher in boys than girls (173 vs 140 min/day; P<.0001), higher on nonschool days than school days (166 vs 143 min/day; P<.0001), and decreased with age (9 min/day per year of age). MVPA consisted of structured sport (37%), active transport (26%), unstructured play (24%), and chores/miscellaneous activities (13%). Every hour of MVPA was associated with a reduction in screen time (26.5 min), non-screen-based sedentary pastimes (8 min), and sleep (5.5 min). The least active quartile of children were more likely to be girls (OR=3.4), have higher screen time, and sleep more. From 4:00-6:30 PM on school days there were large differences in participation between high-active and low-active children. Findings suggest MVPA interventions should target girls, screen time and focus on the after-school period.


Effect of chemical dehairing on the prevalence of Escherichia coli O157:H7 and the levels of aerobic bacteria and enterobacteriaceae on carcasses in a commercial beef processing plant.
The objective of this experiment was to test the hypothesis that cleaning cattle hides by removing hair and extraneous matter before hide removal would result in improved microbiological quality of carcasses in commercial beef processing plants. To test this hypothesis, we examined the effect of chemical dehairing of cattle hides on the prevalence of Escherichia coli O157:H7 and the levels of aerobic bacteria and Enterobacteriaceae on carcasses. Samples from 240 control (conventionally processed) and 240 treated (chemically dehaired before hide removal) hides (immediately after stunning but before treatment) and preevisceration carcasses (immediately after hide removal) were obtained from four visits to a commercial beef processing plant. Total aerobic plate counts (APC) and Enterobacteriaceae counts (EBC) were not (P > 0.05) different between cattle designated for chemical dehairing (8.1 and 5.9 log CFU/100 cm2 for APC and EBC, respectively) and cattle designated for conventional processing (8.0 and 5.7 log CFU/100 cm2 for APC and EBC, respectively). However, E. coli O157:H7 hide prevalence was higher (P < 0.05) for the control group than for the treated group (67% versus 88%). In contrast to hides, the bacterial levels were lower (P < 0.05) on the treated (3.5 and 1.4 log CFU/100 cm2 for APC and EBC) than the control (5.5 and 3.2 log CFU/100 cm2 for APC and EBC) preevisceration carcasses. Prevalence of E. coli O157:H7 was lower (P > 0.05) on treated than on control preevisceration carcasses (1% versus 50%). These data indicate that chemical dehairing of cattle hides is an effective intervention to reduce the incidence of hide-to-carcass contamination with pathogens. The data also imply that any effective hide intervention process incorporated into beef processing procedures would significantly reduce carcass contamination by E. coli O157:H7.


Fundamental and intensive care of acute pancreatitis.
Patients who have been diagnosed as having acute pancreatitis should be, on principle, hospitalized. Crucial fundamental management is required soon after a diagnosis of acute pancreatitis has been made and includes monitoring of the conscious state, the respiratory and cardiovascular system, the urinary output, adequate fluid replacement and pain control. Along with such management, etiologic diagnosis and severity assessment should be conducted. Patients with a diagnosis of severe acute pancreatitis should be transferred to a medical facility where intensive respiratory and cardiovascular management as well as interventional treatment, blood purification therapy and nutritional support are available. The disease condition in acute pancreatitis changes every moment and even symptoms that are mild at the time of diagnosis may become severe later. Therefore, severity assessment should be conducted repeatedly at least within 48 h following diagnosis. An adequate dose of fluid replacement is essential to stabilize cardiovascular dynamics and the dose should be adjusted while assessing circulatory dynamics constantly. A large dose of fluid replacement is usually required in patients with severe acute pancreatitis. Prophylactic antibiotic administration is recommended to prevent infectious complications in patients with severe acute pancreatitis. Although the efficacy of intravenous administration of protease inhibitors is still a matter of controversy, there is a consensus in Japan that a large dose of a synthetic protease inhibitor should be given to patients with severe acute pancreatitis in order to prevent organ failure and other complications. Enteral feeding is superior to parenteral nutrition when it comes to the nutritional support of patients with severe acute pancreatitis. The JPN Guidelines recommend, as optional continuous regional arterial infusion and blood purification therapy.


Rapid, specific detection of alphaviruses from tissue cultures using a replicon-defective reporter gene assay.
We established a rapid, specific technique for detecting alphaviruses using a replicon-defective reporter gene assay derived from the Sindbis virus XJ-160. The pVaXJ expression vector containing the XJ-160 genome was engineered to form the expression vectors pVaXJ-EGFP expressing enhanced green fluorescence protein (EGFP) or pVaXJ-GLuc expressing Gaussia luciferase (GLuc). The replicon-defective reporter plasmids pVaXJ-EGFPΔnsp4 and pVaXJ-GLucΔnsp4 were constructed by deleting 1139 bp in the non-structural protein 4 (nsP4) gene. The deletion in the nsP4 gene prevented the defective replicons from replicating and expressing reporter genes in transfected BHK-21 cells. However, when these transfected cells were infected with an alphavirus, the non-structural proteins expressed by the alphavirus could act on the defective replicons in trans and induce the expression of the reporter genes. The replicon-defective plasmids were used to visualize the presence of alphavirus qualitatively or detect it quantitatively. Specificity tests showed that this assay could detect a variety of alphaviruses from tissue cultures, while other RNA viruses, such as Japanese encephalitis virus and Tahyna virus, gave negative results with this system. Sensitivity tests showed that the limit of detection (LOD) of this replicon-defective assay is between 1 and 10 PFU for Sindbis viruses. These results indicate that, with the help of the replicon-defective alphavirus detection technique, we can specifically, sensitively, and rapidly detect alphaviruses in tissue cultures. The detection technique constructed here may be well suited for use in clinical examination and epidemiological surveillance, as well as for rapid screening of potential viral biological warfare agents.


Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease.
Although multiple myeloma (MM) is a unique entity, a marked heterogeneity is actually observed among the patients, which has been first related to immunoglobulin (Ig) types and light chain subtypes and more recently to chromosomal abnormalities. To further investigate this genetic heterogeneity, we analyzed gene expression profiles of 92 primary tumors according to their Ig types and light chain subtypes with DNA microarrays. Several clusters of genes involved in various biologic functions such as immune response, cell cycle control, signaling, apoptosis, cell adhesion, and structure significantly discriminated IgA- from IgG-MM. Genes associated with inhibition of differentiation and apoptosis induction were up-regulated while genes associated with immune response, cell cycle control, and apoptosis were down-regulated in IgA-MM. According to the expression of the 61 most discriminating genes, BJ-MM represented a separate subgroup that did not express either the genes characteristic of IgG-MM or those of IgA-MM at a high level. This suggests that transcriptional programs associated to the switch could be maintained up to plasma cell differentiation. Several genes whose products are known to stimulate bone remodeling discriminate between kappa- and lambda-MM. One of these genes, Mip-1alpha, was overexpressed in the kappa subgroup. In addition, we established a strong association (P =.0001) between kappa subgroup expressing high levels of Mip-1alpha and active myeloma bone disease. This study shows that DNA microarrays enable us to perform a molecular dissection of the bioclinical diversity of MM and provide new molecular tools to investigate the pathogenesis of malignant plasma cells.


Revitalizing the drug pipeline: AntibioticDB, an open access database to aid antibacterial research and development.
The current state of antibiotic discovery, research and development is insufficient to respond to the need for new treatments for drug-resistant bacterial infections. The process has changed over the last decade, with most new agents that are in Phases 1-3, or recently approved, having been discovered in small- and medium-sized enterprises or academia. These agents have then been licensed or sold to large companies for further development with the goal of taking them to market. However, early drug discovery and development, including the possibility of developing previously discontinued agents, would benefit from a database of antibacterial compounds for scrutiny by the developers. This article describes the first free, open-access searchable database of antibacterial compounds, including discontinued agents, drugs under pre-clinical development and those in clinical trials: AntibioticDB (AntibioticDB.com). Data were obtained from publicly available sources. This article summarizes the compounds and drugs in AntibioticDB, including their drug class, mode of action, development status and propensity to select drug-resistant bacteria. AntibioticDB includes compounds currently in pre-clinical development and 834 that have been discontinued and that reached varying stages of development. These may serve as starting points for future research and development.


Informed consent for interventions in stable coronary artery disease: problems, etiologies, and solutions.
The objective of this review was to determine whether patients undergoing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) (1) understand the aims of the proposed intervention, and (2) whether they are offered alternative and potentially more effective therapies, as required for the process of informed consent. We performed a systematic review of Medline for observational studies of patient understanding and perceptions of coronary revascularization and of the consent process. Data extraction was of patient perceptions of expected symptomatic and prognostic benefits of PCI and CABG, and the proportion of patients offered potential alternative treatments. Eight studies were identified, of which seven were relevant to PCI and three to CABG. On average, 55% of patients correctly believed that PCI would improve symptoms, while 78% erroneously believed that PCI would extend life expectancy and 71% erroneously believed PCI would prevent future myocardial infarction. On average, over 80% of patients correctly identified that CABG would improve symptoms, reduce the risk of myocardial infarction and extend life expectancy. In the three studies that examined whether alternative therapies were discussed, 68% of PCI patients and 59% of CABG patients reported no such discussion. In conclusion, a large proportion of patients undergoing coronary interventions do not appear to understand the rationale for treatment and have erroneous perceptions regarding expected benefits. Moreover, patients are frequently not offered potentially more effective alternative therapies. This raises important questions about the adequacy of the current informed consent process. We recommend a multidisciplinary team approach as the most obvious way to remedy current practice.


Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer.
Glucose-regulated protein 78 (GRP78) has been implicated in the protection of tumor cells from cytotoxic damage and apoptosis and thus assists cells in survival under oxygen-deprivation and nutrient-stress conditions. However, its expression and potential role in gastric cancer development and progression have not been reported. In the present study, we determined the level of GRP78 expression in the primary tumor in 86 cases of resected gastric cancer by using immunohistochemistry and analyzed the relationships between GRP78 and clinicopathological characteristics. We found that GRP78 was overexpressed in the tumor specimens when compared with the expression in adjacent tumor-free gastric mucosa. Furthermore, the level of GRP78 expression in both primary tumors and metastatic lymph nodes was inversely correlated with patient survival. Overexpression of GRP78 was directly correlated with Sp1 expression and increased lymph node metastasis. Knocking down GRP78 expression inhibited tumor cell invasion in vitro and growth and metastasis in a xenograft nude mouse model. Therefore, our data imply that dysregulated expression of GRP78 may contribute to the development and progression of gastric cancer.


Virtual slide telepathology enables an innovative telehealth rapid breast care clinic.
An innovative telemedicine-enabled rapid breast care service is described that bundles telemammography, telepathology, and teleoncology services into a single day process. The service is called the UltraClinics Process. Since the core services are at four different physical locations a challenge has been to obtain STAT second opinion readouts on newly diagnosed breast cancer cases. In order to provide same day QA re-review of breast surgical pathology cases, a DMetrix DX-40 ultrarapid virtual slide scanner (DMetrix, Inc., Tucson, AZ) was installed at the participating laboratory. Glass slides of breast cancer and breast hyperplasia cases were scanned the same day the slides were produced by the University Physicians Healthcare Hospital histology laboratory. Virtual slide telepathology was used for STAT quality assurance readouts at University Medical Center, 6 miles away. There was complete concurrence with the primary diagnosis in 139 (90.3%) of cases. There were 4 (2.3%) major discrepancies, which would have resulted in a different therapy and 3 (1.9%) minor discrepancies. Three cases (1.9%) were deferred for immunohistochemistry. In 2 cases (1.3%), the case was deferred for examination of the glass slides by the reviewing pathologists at University Medical Center. We conclude that the virtual slide telepathology QA program found a small number of significant diagnostic discrepancies. The virtual slide telepathology program service increased the job satisfaction of subspecialty pathologists without special training in breast pathology, assigned to cover the general surgical pathology service at a small satellite university hospital.


All-optical modulation-transparent wavelength multicasting in a highly nonlinear fiber Sagnac loop mirror.
An all-optical wavelength multicasting scheme using four-wave mixing (FWM) in a highly nonlinear fiber (HNLF) Sagnac loop mirror has been demonstrated. This proposed scheme has the advantage that even when the wavelength of a multicast channel overlaps with the pump-pump generated idler, clear eye diagram can still be observed. Six and ten 10-Gb/s multicast channels, compliant with the ITU grid, are successfully obtained by using two- and three-pump lasers, respectively. Multicasting of on-off shift keying (OOK) and differential phase-shift keying (DPSK) signals are both successfully demonstrated. The maximum power penalty of the multicast channels is less than 3.5 dB. Furthermore, compared with the non-loop configuration, up to 1.2 dB power penalty improvement can be achieved in this proposed Sagnac loop configuration.


Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.
Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease. Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 μM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms. Our in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals. We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.


The combined action of omega-3 polyunsaturated fatty acids and grape proanthocyanidins on a rat model of diet-induced metabolic alterations.
It has been suggested that food components such as ω-3 polyunsaturated fatty acids (ω-3 PUFAs) and (poly)phenols counteract diet-induced metabolic alterations by common or complementary mechanisms. To examine the effects of a combination of ω-3 PUFAs and (poly)phenols on such alterations, adult Wistar-Kyoto rats were fed an obesogenic high-fat high-sucrose diet supplemented, or not, for 24 weeks with: eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) 1 : 1 (16.6 g kg(-1) feed); proanthocyanidin-rich grape seed extract (GSE, 0.8 g kg(-1) feed); or EPA/DHA 1 : 1 + GSE. Body weight, feed intake, and plasma glucose were evaluated every 6 weeks, while adipose tissue weight, insulin, glucagon, ghrelin, leptin, adiponectin, cholesterol, and triglycerides were evaluated at the end of the experiment. ω-3 PUFAs reduced plasma leptin and cholesterol levels, but did not modify diet-induced perigonadal fat or plasma insulin levels; while GSE increased plasma triglyceride levels. The combined action of ω-3 PUFAs and the proanthocyanidins reduced plasma insulin and leptin, as well as partially prevented perigonadal fat accumulation. While separate supplementation with ω-3 PUFAs or grape proanthocyanidins may not counteract all the key metabolic changes induced by a high-energy-dense diet, the combination of both supplements reverts altered insulin, leptin and triglyceride levels to normal.


Primary evidence of seton therapy at Tarban Creek, New South Wales, 1839.
We aimed to find and explore the earliest available New South Wales asylum medical records to identify any management or therapeutic data that might be of interest to the psychiatric field. The earliest known existing records of New South Wales asylum data are from Tarban Creek Asylum. After almost two centuries the preserved records allow insight into treatment used in early colonial Australia, including the scarcely remembered seton therapy. This finding highlights the importance of preserving historical records. It also demonstrates the necessity and/or evolving wish within the colony to care for patients with perceived mental health difficulties based on a shared medical culture inherited from techniques used in Britain.


Anesthetic neuroprotection: antecedents and an appraisal of preclinical and clinical data quality.
Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.


Pandemic Nightmares: COVID-19 Lockdown Associated With Increased Aggression in Female University Students' Dreams.
The COVID-19 pandemic and its associated stressors have impacted the daily lives and sleeping patterns of many individuals, including university students. Dreams may provide insight into how the mind processes changing realities; dreams not only allow consolidation of new information, but may give the opportunity to creatively "play out" low-risk, hypothetical threat simulations. While there are studies that analyze dreams in high-stress situations, little is known of how the COVID-19 pandemic has impacted dreams of university students. The aim of this study was to explore how the dream content of students was affected during the university COVID-19 lockdown period (March-July, 2020). Using online survey methods, we analyzed dream recall content (n = 71) using the Hall-Van de Castle dream coding system and Fisher's exact tests for sex comparisons. Preliminary results indicate that female students experienced more nightmares as compared to male students. Dream analysis found that, relative to normative American College Student (ACS) samples generated pre-COVID-19, women were more likely to experience aggressive interactions in their dream content, including increased physical aggression. Results indicate that university students did experience changes in dream content due to the pandemic lockdown period, with women disproportionally affected. These findings can aid universities in developing support programs for students by bringing forth an understanding of students' concerns and anxieties as they process the "new normal" of social distancing.


Dissociation of normal feature analysis and deficient processing of letter-strings in dyslexic adults.
Neuroimaging studies have revealed that the functional organization of reading differs between developmentally dyslexic and non-impaired individuals. However, it is not clear how early in the reading process the differences between fluent and dyslexic readers start to emerge. We studied cortical activity of ten dyslexic adults using magnetoencephalography (MEG), as they silently read words or viewed symbol-strings which were clearly visible or degraded with Gaussian noise. This method has previously been used to dissociate between analysis of local features and pre-lexical word processing in fluent adult readers. Signals peaking around 100 ms after stimulus onset and originating in the postero-medial extrastriate cortex were associated with increasing local luminance contrast in the noise patches. These early visual responses were similar in dyslexic and non-impaired readers. In contrast, the letter-string-specific responses peaking around 150 ms predominantly in the left inferior occipito-temporal cortex in fluent readers were undetectable in dyslexic readers. Thus, while the early visual processing seems intact in dyslexic adults, the pattern of cortical activation starts to differ from that of fluent readers at the point where letter-string-specific signals first emerge during reading.


Glomerulosclerosis is transmitted by bone marrow-derived mesangial cell progenitors.
We found that ROP Os/+ (Os/+) mice had diffuse glomerulosclerosis and glomerular hypertrophy and that their mesangial cells (the vascular smooth muscle cells of the glomerulus) displayed an apparent sclerosing phenotype. Since mesangial cells are the major source of scar tissue in glomerulosclerosis, we postulated that the sclerosis phenotype was carried by mesangial cell progenitors and that this phenotype could be derived from the bone marrow (BM). Therefore, we transplanted BM from Os/+ mice into congenic ROP +/+ mice (+/+ mice), which have normal glomeruli. We found that glomeruli of +/+ recipients of Os/+ marrow contained the Os/+ genotype, were hypertrophied, and contained increased extracellular matrix. Clones of recipient glomerular mesangial cells with the donor genotype were found in all +/+ recipients that developed mesangial sclerosis and glomerular hypertrophy, whereas +/+ recipients of +/+ BM had normal glomeruli. Thus, the sclerotic (Os/+) or normal (+/+) genotype and phenotype were present in, and transmitted by, BM-derived progenitors. These data show that glomerular mesangial cell progenitors are derived from the BM and can deliver a disease phenotype to normal glomeruli. Glomerular lesions may therefore be perpetuated or aggravated, rather than resolved, by newly arriving progenitor cells exhibiting a disease phenotype.


Finding novel relationships with integrated gene-gene association network analysis of Synechocystis sp. PCC 6803 using species-independent text-mining.
The increasing move towards open access full-text scientific literature enhances our ability to utilize advanced text-mining methods to construct information-rich networks that no human will be able to grasp simply from 'reading the literature'. The utility of text-mining for well-studied species is obvious though the utility for less studied species, or those with no prior track-record at all, is not clear. Here we present a concept for how advanced text-mining can be used to create information-rich networks even for less well studied species and apply it to generate an open-access gene-gene association network resource for Synechocystis sp. PCC 6803, a representative model organism for cyanobacteria and first case-study for the methodology. By merging the text-mining network with networks generated from species-specific experimental data, network integration was used to enhance the accuracy of predicting novel interactions that are biologically relevant. A rule-based algorithm (filter) was constructed in order to automate the search for novel candidate genes with a high degree of likely association to known target genes by (1) ignoring established relationships from the existing literature, as they are already 'known', and (2) demanding multiple independent evidences for every novel and potentially relevant relationship. Using selected case studies, we demonstrate the utility of the network resource and filter to (i) discover novel candidate associations between different genes or proteins in the network, and (ii) rapidly evaluate the potential role of any one particular gene or protein. The full network is provided as an open-source resource.


Morphological characterization of the seminiferous cycle in the goat (Capra hircus): a histological and ultrastructural study.
The cycle of spermatogenesis/seminiferous cycle was investigated in the goat testis using both light and electron microscopy techniques. Using the various cell associations and the accompanying changes in spermatid shape and location, the cycle was divided into eight (8) successive stages. The cycle began with the accomplishment of spermiation (stage 1) and ended with apical migration and close attachment of late maturation phase spermatids at the Sertoli cell apex accompanied by adluminal retention of residual bodies with dense staining inclusions (stage 8). The early stages of the cycle (stages 1-4) were therefore characterized by the presence of only one generation of spermatids, the second one appearing only after the division of secondary spermatocytes in stage 4. Consequently, stages 5-8 had two generations of spermatids; Golgi or cap phase as well as maturation phase spermatids. Although stages 5 to 7 appeared as distinct entities, stages 6 and 7 were rather short-lived and considered as continuations of stage 5. Therefore, the 8 stages of the cycle in the goat were further condensed into 6 main divisions. The duration of each stage was estimated by the frequency of occurrence in sections. Among these, stage 1 had the highest frequency (34%) followed by stages 5-7 (27%). Stages 8 and 4 had the shortest frequency (up to 9%) while stages 2 and 3 had 13% and 12% respectively. These results indicate that, like most domestic species, goats have a cycle of 8 stages with 6 main divisions, the longest being stage 1.


Human immunodeficiency virus type 1 pharmacogenomics in clinical practice: relevance of HIV-1 drug resistance testing (Part 2).
Throughout most of the past century, physicians could offer patients no treatments for infections caused by viruses. The experience with treatment of infection by human immunodeficiency virus (HIV) has changed the way healthcare workers deal with viral infections and has triggered a growing rate of discovery and use of antiviral agents, the first fruits of the expanding genomics revolution. HIV treatment also provides an informative paradigm for pharmacogenomics because control of infection and its consequences is limited by the development of viral drug resistance and by host factors. This report summarizes studies published to date on the significance of testing of HIV-1 resistance to antiretroviral drugs. The only Food and Drug Administration-approved kit is commercially available through Visible Genetics, Inc., for HIV drug resistance testing by genotypic sequencing. Genotyping sequencing alone is most likely an adequate test to assist in the therapeutic decision-making process in cases of previous regimen failure, treatment-naïve patients in areas of high prevalence of transmitted resistant virus, and pregnant women. However, in exceptional cases of highly complex mutation patterns and extensive cross-resistance, it may be useful to obtain a phenotype test, because that result may more easily identify drugs to which the virus is least resistant. There are no published clinical trial results on the usefulness of the so-called virtual phenotype over genotypic sequencing alone. The paradigm of viral pharmacogenomics in the form of HIV genotypic sequencing has been not only useful to the treatment of other viral diseases but also important to the real-life implementation of the growing discipline of genomics or molecular medicine. The application of this paradigm to the thousands of potential therapeutic targets that have become available through the various human genome projects will certainly gradually change the landscape of diagnosis and management of many diseases, including cancer.


Safety of Rotational Atherectomy Using the Radial Access in Patients With Severe Aortic Stenosis.
Despite frequent percutaneous coronary intervention (PCI) in calcified vessels of older patients, rotational atherectomy (RA) has not been endorsed in patients with severe aortic stenosis (AS) due to safety concerns and lack of data. We explored periprocedural safety and mortality in severe AS patients undergoing RA. Prospective anonymized clinical, echocardiographic, procedural and outcome data of patients undergoing RA PCI between January 2012 and July 2018 were retrospectively extracted from the institutional coronary database. Patients with severe AS undergoing RA PCI were 1:1 propensity matched with patients undergoing RA PCI in the absence of AS. Outcomes of interest were RA related periprocedural complications, 30-day and 1-year mortality. A prespecified subgroup analysis examined the influence of transcatheter aortic valve replacement on mortality following RA PCI. A total of 544 patients underwent RA PCI; 478 without AS and 66 with AS. Propensity matching yielded 35 matched pairs with improved balance in covariates of interest and no significant differences in baseline characteristics postmatching. In the matched cohort (n = 70) slow flow/no-reflow, coronary dissection, perforation, and hemodynamic instability were rare and not significantly different. Survival analyses revealed significantly higher 30-day (Log-Rank p = 0.02) and 1-year mortality (Log rank p = 0.02, HR 5.24 [95% CI 1.13 to 24.28]) in the severe AS group; driven by a fivefold increase in the hazard of death among patients who did not undergo transcatheter aortic valve replacement HR 4.98 [95% CI 1.03 to 24.1]. In conclusion, our study of 70 patients undergoing radial RA PCI suggests that it can be safely performed in patients with severe AS. Long-term outcomes after RA in patients with severe AS are determined by the presence of the valve disease and other co-morbidities.


A framework for assessing the impact of chemical exposures on neurodevelopment in ECHO: Opportunities and challenges.
The Environmental influences on Child Health Outcomes (ECHO) Program is a research initiative funded by the National Institutes of Health that capitalizes on existing cohort studies to investigate the impact of early life environmental factors on child health and development from infancy through adolescence. In the initial stage of the program, extant data from 70 existing cohort studies are being uploaded to a database that will be publicly available to researchers. This new database will represent an unprecedented opportunity for researchers to combine data across existing cohorts to address associations between prenatal chemical exposures and child neurodevelopment. Data elements collected by ECHO cohorts were determined via a series of surveys administered by the ECHO Data Analysis Center. The most common chemical classes quantified in multiple cohorts include organophosphate pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, environmental phenols (including bisphenol A), phthalates, and metals. For each of these chemicals, at least four ECHO cohorts also collected behavioral data during infancy/early childhood using the Child Behavior Checklist. For these chemicals and this neurodevelopmental assessment (as an example), existing data from multiple ECHO cohorts could be pooled to address research questions requiring larger sample sizes than previously available. In addition to summarizing the data that will be available, the article also describes some of the challenges inherent in combining existing data across cohorts, as well as the gaps that could be filled by the additional data collection in the ECHO Program going forward.


Pathological role of regulatory T cells in the initiation and maintenance of eczema herpeticum lesions.
It remains unknown why the occurrence of eczema herpeticum (EH) caused by an extensive disseminated cutaneous infection with HSV-1 or HSV-2 is associated with the exacerbation of atopic dermatitis lesions after withdrawal of treatment. Although regulatory T cells (Tregs) limit the magnitude of HSV-specific T cell responses in mice, their role in the induction and resolution of EH has not been defined. We initially investigated the frequencies, phenotype, and function of Tregs in the peripheral blood of atopic dermatitis with EH (ADEH) patients at onset and after clinical resolution, atopic dermatitis patients without EH, and healthy controls. Tregs with the skin-homing phenotype and the activated/induced phenotype were expanded at onset and contracted upon resolution. Treg-suppressive capacity was retained in ADEH patients and, the expanded Tregs suppressed IFN-γ production from HSV-1-specific CD8(+) and CD4(+) T cells. The increased frequency of CD14(dim)CD16(+) proinflammatory monocytes (pMOs) was also observed in the blood and EH skin lesions. Thus, pMOs detected in ADEH patients at onset were characterized by an increased ability to produce IL-10 and a decreased ability to produce proinflammatory cytokines, unlike their normal counterparts. Our coculture study using Tregs and pMOs showed that the pMOs can promote the expansion of inducible Tregs. Tregs were detected frequently in the vicinity of HSV-expressing and varicella zoster virus-expressing CD16(+) monocytes in the EH lesions. Expansions of functional Tregs, together with pMOs, initially required for ameliorating excessive inflammation occurring after withdrawal of topical corticosteroids could, in turn, contribute to the initiation and progression of HSV reactivation, resulting in the onset of EH.


Association between participation in social activity and physical fitness in community-dwelling older Japanese adults.
Purpose This study aimed to examine the relationship between participation in social activity and both, composite and individual measures of physical fitness in community-dwelling older adults.Methods This study was conducted using baseline data from the Sasaguri Genkimon Study (SGS), a longitudinal cohort study conducted in 2011. Participants were 1,365 community-dwelling men and women aged 65 years or above, who did not require certified nursing care and who resided in Sasaguri, a town located east of the Fukuoka metropolitan area. Participation in social activity was assessed by asking participants whether they engaged in any of eight social activities. Physical fitness tests assessed participants' handgrip strength and knee extension strength as measures of muscle strength, and their one-leg standing time, 5-m maximum gait speed, and 5-repetition sit-to-stand rate as measures of their physical performance. Multiple linear regression and logistic regression analyses were conducted to assess the relationship between participation in social activity and each measure of physical fitness, adjusting for sex; age; body mass index; socioeconomic status; solitary living; exercise, habitual drinking and smoking; accelerometer-measured, moderate-to-vigorous physical activity; cognitive function; instrumental activities of daily living; distress; social network; and comorbidities.Results A total of 83.6% of the participants were engaged in at least one social activity. After adjusting for potential confounders, engagement in social activity was positively associated with a higher composite physical fitness score, faster gait speed and 5-repetition sit-to-stand rate, and longer one-leg standing time (P=0.008, P=0.030, P=0.034, and P=0.009, respectively).Conclusion Participation in social activity was significantly associated with physical fitness, specifically those related to locomotive function. These associations were independent of various confounders including socioeconomic status, and comorbidities.


[Possibilities of modern imaging technologies in early diagnosis of Alzheimer disease].
Recent advances in neuroimaging technology and image analysis algorithms have significantly contributed to a better understanding of spatial and temporal aspects of brain change associated with Alzheimer Disease. The current review will demonstrate how functional (fMRI) and structural magnetic resonance imaging (MRI) techniques may be used to identify distinct patterns of brain change associated with disease progression and also increased risk for Alzheimer Disease. Moreover, Positron Emission Tomography (PET) based measures of glucosemetabolism (Fluorodeoxyglucose, FDG) and Amyloid-beta plaque density (11-C-Pittsburgh Compound B, PiB and 18-F) will be reviewed regarding their diagnostic value for assessing the individual degree of Alzheimer -pathology and thus complement the information provided by MRI and other clinical measures.


Intrastriatal transplantation of adenovirus-generated induced pluripotent stem cells for treating neuropathological and functional deficits in a rodent model of Huntington's disease.
Induced pluripotent stem cells (iPSCs) show considerable promise for cell replacement therapies for Huntington's disease (HD). Our laboratory has demonstrated that tail-tip fibroblasts, reprogrammed into iPSCs via two adenoviruses, can survive and differentiate into neuronal lineages following transplantation into healthy adult rats. However, the ability of these cells to survive, differentiate, and restore function in a damaged brain is unknown. To this end, adult rats received a regimen of 3-nitropropionic acid (3-NP) to induce behavioral and neuropathological deficits that resemble HD. At 7, 21, and 42 days after the initiation of 3-NP or vehicle, the rats received intrastriatal bilateral transplantation of iPSCs. All rats that received 3-NP and vehicle treatment displayed significant motor impairment, whereas those that received iPSC transplantation after 3-NP treatment had preserved motor function. Histological analysis of the brains of these rats revealed significant decreases in optical densitometric measures in the striatum, lateral ventricle enlargement, as well as an increase in striosome size in all rats receiving 3-NP when compared with sham rats. The 3-NP-treated rats given transplants of iPSCs in the 7- or 21-day groups did not exhibit these deficits. Transplantation of iPSCs at the late-stage (42-day) time point did not protect against the 3-NP-induced neuropathology, despite preserving motor function. Transplanted iPSCs were found to survive and differentiate into region-specific neurons in the striatum of 3-NP rats, at all transplantation time points. Taken together, these results suggest that transplantation of adenovirus-generated iPSCs may provide a potential avenue for therapeutic treatment of HD.


An impactor origin for lunar magnetic anomalies.
The Moon possesses strong magnetic anomalies that are enigmatic given the weak magnetism of lunar rocks. We show that the most prominent grouping of anomalies can be explained by highly magnetic extralunar materials from the projectile that formed the largest and oldest impact crater on the Moon: the South Pole-Aitken basin. The distribution of projectile materials from a model oblique impact coincides with the distribution of magnetic anomalies surrounding this basin, and the magnetic properties of these materials can account for the intensity of the observed anomalies if they were magnetized in a core dynamo field. Distal ejecta from this event can explain the origin of isolated magnetic anomalies far from this basin.


Fluid and electrolyte considerations in diuretic therapy for hypertensive patients with chronic obstructive pulmonary disease.
When a patient with chronic obstructive pulmonary disease (COPD) requires medical therapy for systemic hypertension, a number of special considerations may affect the choice of antihypertensive drug and subsequent management. Thiazide diuretics have no adverse effect on airway function and are the agents of choice for initial therapy. beta-Antagonists are usually considered first-line agents in antihypertensive therapy, but even relatively cardioselective ones may increase airway resistance in patients with obstructive lung diseases, and they should be used with caution, if at all, in such patients. Although potassium-wasting diuretics are the preferred agents for treating hypertension in patients with COPD, they may worsen carbon dioxide retention in hypoventilating patients and potentiate hypokalemia in those receiving corticosteroids. In addition, beta-agonists may substantially lower serum potassium levels in patients already rendered hypokalemic by diuretics. Patients with COPD receiving potassium-wasting diuretics who have chronic respiratory acidosis or are receiving corticosteroids or beta-agonists should undergo close monitoring of electrolyte levels and be considered for therapy with potassium supplements or, preferably, potassium-sparing agents.


Preventing weight gain: the baseline weight related behaviors and delivery of a randomized controlled intervention in community based women.
Women aged 25-45 years represent a high risk group for weight gain and those with children are at increased risk because of weight gain associated with pregnancy and subsequent lifestyle change. Average self-reported weight gain is approximately 0.60 kg per year, and weight gain is associated with increased risk of chronic disease. There are barriers to reaching, engaging and delivering lifestyle interventions to prevent weight gain in this population. This study investigated the baseline weight related behaviors and feasibility of recruiting and delivering a low intensity self-management lifestyle intervention to community based women with children in order to prevent weight gain, compared to standard education. The recruitment and delivery of the cluster-randomized controlled intervention was in conjunction with 12 primary (elementary) schools. Baseline data collection included demographic, anthropometric, behavioral and biological measures. Two hundred and fifty community based women were randomized as clusters to intervention (n = 127) or control (n = 123). Mean age was 40.4 years (SD 4.7) and mean BMI 27.8 kg/m2 (SD 5.6). All components of this intervention were successfully delivered and retention rates were excellent, 97% at 4 months.Nearly all women (90%) reported being dissatisfied with their weight and 72% attempted to self-manage their weight. Women were more confident of changing their diet (mean score 3.2) than physical activity (mean score 2.7). This population perceived they were engaging in prevention behaviors, with 71% reporting actively trying to prevent weight gain, yet they consumed a mean of 68 g fat/day (SD30 g) and 27 g saturated fat/day (SD12 g) representing 32% and 13% of energy respectively. The women had a high rate of dyslipidemia (33%) and engaged in an average of 9187 steps/day (SD 3671). Delivery of this low intensity intervention to a broad cross-section of community based women with children is feasible. Women with children are engaging in lifestyle behaviours which do not confer adequate health benefits. They appear to be motivated to attend prevention programs by their interest in weight management. Interventions are required to strengthen and sustain current attempts at achieving healthy lifestyle behaviours in women to prevent weight gain.


The use of astrocytes in culture as model systems for evaluating neurotoxic-induced-injury.
The prevailing thought that astrocytes function predominantly as passive metabolic or even physical support for neurons has faded over the last 20 years. Today these stellar shaped cells are credited with an expanded role, playing key functions in CNS development, homeostasis, and pathology. In probing their expanded roles, primary astrocyte culture systems have proven to be an indispensable tool. Astrocytes have been implicated in both a defensive and facilitatory capacity for many toxic injuries. Evidence for a protective role of astrocytes in modulating CNS toxicity is afforded by observations that the toxicity of glutamate to cortical neurons is diminished upon astrocytic enrichment of the cell culture (Rosenberg and Aizenman, 1989). In cultures of rat cerebral cortex in which astrocyte proliferation is stringently suppressed, glutamate neurotoxicity occurs at low glutamate concentrations similar to those which are normally found in the extracellular space in the hippocampus. In the presence of excess astrocytes, concentrations of glutamate one-hundred fold higher are required to produce equivalent neurotoxicity (Rosenberg and Aizenman, 1989). Astrocytes can facilitate the action of neurotoxins via a modulating process which takes place within the astrocyte or by a direct cytotoxic effect. Whereas primary astrocyte cultures remain unaffected by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Marini et al., 1989), they function prominently in the selective destruction of dopaminergic neurons of the nigrostriatal pathway in humans, other primates and rodents (Davis et al. 1979; Langston et al., 1983; Burns et al., 1983; Langston et al., 1984; Heikkila et al., 1984; Jarvis and Wagner, 1985). Thus, while MPTP by itself is not toxic to cerebellar cells in co-culture with cerebellar astrocytes, MPTP is toxic to the granule cells (Marini et al, 1989). This is thought to be due to an astrocyte-mediated conversion of MPTP to its highly polar and toxic metabolite, 1-methyl-4-phenylpyridinium ion (MPP+; Chiba et al. 1984). There is compelling evidence that astrocytes respond directly or indirectly to a number of other neurotoxins. Direct cytotoxic effects on astrocytes constitute the major morphologic feature in hyperammonemia (Norenberg, 1981), a condition implicated as an etiologic factor in several CNS disorders. In addition, a predisposition of astrocytes for methylmercury uptake (Aschner et al., 1990 a,b) offers a possible explanation for the observed neurotoxicity of this heavy metal, since a direct toxic effect on astrocytes would result in failure of astrocyte homeostatic functions, indirectly resulting in neuronal impairment, injury and death.