Vitamin K2 Ameliorates Damage of Blood Vessels by Glucocorticoid: a Potential Mechanism for Its Protective Effects in Glucocorticoid-induced Osteonecrosis of the Femoral Head in a Rat Model.
Glucocorticoid has been reported to decrease blood vessel number and harm the blood supply in the femoral head, which is recognized to be an important mechanism of glucocorticoid-induced osteonecrosis of the femoral head (ONFH). To prevent glucocorticoid-induced ONFH, medication that promotes both bone formation and angiogenesis would be ideal. Vitamin K2 has been revealed to play an important role in bone metabolism; however, few studies have focused on the effect of Vitamin K2 on new vascular formation. Thus, this study aimed to investigate whether Vitamin K2 promoted new blood vessel formation in the presence of glucocorticoids, both in vitro and in vivo. The effect of Vitamin K2 on viability, migration, in vitro tube formation, and VEGF, vWF, CD31, KDR, Flt and PDGFB in EAhy926 incubated with or without dexamethasone were elucidated. VEGF, TGF-β and BMP-2, angiogenesis-related proteins secreted by osteoblasts, were also detected in the osteoblast-like cell line of MG63. In addition, blood vessels of the femoral head in rats administered with or without methylprednisolone and Vitamin K2 were evaluated using angiography and CD31 staining. In vitro studies showed that Vitamin K2 significantly protected endothelial cells from dexamethasone-induced apoptosis, promoted endothelial cell migration and in vitro tube formation. Angiogenesis-related proteins both in EAhy926 and MG63 were also upregulated by Vitamin K2 when cotreated with dexamethasone. In vivo studies showed enhanced blood vessel volume and CD31-positive staining cells in rats cotreated with VK2 and methylprednisolone compared to rats treated with methylprednisolone only. Collectively, Vitamin K2 has the ability to promote angiogenesis in vitro and to ameliorate vessels of the femoral head in glucocorticoid-treated rats in vivo, indicating that Vitamin K2 is a promising drug that may be used to prevent steroid-induced ONFH.


The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression.
During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is a defining subunit of the hematopoiesis-specific BAF (SWI/SNF) chromatin-remodeling complex, and it is mutated in multiple cancers and neurological disorders. We uncovered that hematopoiesis-specific Dpf2-KO mice developed leukopenia, severe anemia, and lethal systemic inflammation characterized by histiocytic and fibrotic tissue infiltration resembling a clinical hyperinflammatory state. Dpf2 loss impaired the polarization of macrophages responsible for tissue repair, induced the unrestrained activation of Th cells, and generated an emergency-like state of HSC hyperproliferation and myeloid cell-biased differentiation. Mechanistically, Dpf2 deficiency resulted in the loss of the BAF catalytic subunit BRG1 from nuclear factor erythroid 2-like 2-controlled (NRF2-controlled) enhancers, impairing the antioxidant and antiinflammatory transcriptional response needed to modulate inflammation. Finally, pharmacological reactivation of NRF2 suppressed the inflammation-mediated phenotypes and lethality of Dpf2Δ/Δ mice. Our work establishes an essential role of the DPF2-BAF complex in licensing NRF2-dependent gene expression in HSCs and immune effector cells to prevent chronic inflammation.


Microbiome in the Gut-Skin Axis in Atopic Dermatitis.
The microbiome is vital for immune system development and homeostasis. Changes in microbial composition and function, termed dysbiosis, in the skin and the gut have recently been linked to alterations in immune responses and to the development of skin diseases, such as atopic dermatitis (AD). In this review, we summarize the recent findings on the gut and skin microbiome, highlighting the roles of major commensals in modulating skin and systemic immunity in AD. Although our understanding of the gut-skin axis is only beginning, emerging evidence indicates that the gut and skin microbiome could be manipulated to treat AD.


TP53 and IDH2 Somatic Mutations Are Associated With Inferior Overall Survival After Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome.
Next-generation sequencing has identified somatic mutations that are prognostic of cancer. We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen. The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P = .03) and IDH2 mutations (HR, 4.74; 95% CI, 1.33-16.91; P = .02) as predictors of inferior 3-year overall survival. This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy.


Outcome of daily cisplatin with thoracic chemoradiotherapy in advanced non-small cell lung cancer patients with comorbid disorders: a pilot study.
Lung cancer is the most common cancer in males worldwide. The principal mode of treatment in the early stage of non-small cell lung cancer (NSCLC) is surgery. However, five-year survival is only about 15% for all stages. The aim is to investigate the effect of daily low dose cisplatin concurrently with radiation therapy in advanced NSCLC patients with poor performance status. Ten patients diagnosed as inoperable Stage IIIB NSCLC with comorbid disease were assessed retrospectively in Bezmialem Vakif University, Faculty of Medicine, Department of Radiation Oncology, between 2011 to 2013. ECOG performance status was between 3 and 4. Cisplatin was administered at 6 mg/m2 daily, for 5 days a week concurrently with radiotherapy using 160-200 cGy daily fractions, 54 Gy being the lowest and 63 Gy being the highest dose. Complete response at the primary tumour site was obtained in 20% patients. Grade I esophagitis was seen 70 percent of patients, and the grade II haematological toxicity rate was 20%. Median survival time was 7 months. Median survival time was reasonable, despite the patients ECOG performance status of 3-4, which is similar to groups even without comorbid disorders in comparison to other published papers in the literature. Acceptable toxicity, high response rates and quality of life of patients are the other favourable features.


A study of evolutionary multiagent models based on symbiosis.
Multiagent Systems with Symbiotic Learning and Evolution (Masbiole) has been proposed and studied, which is a new methodology of Multiagent Systems (MAS) based on symbiosis in the ecosystem. Masbiole employs a method of symbiotic learning and evolution where agents can learn or evolve according to their symbiotic relations toward others, i.e., considering the benefits/losses of both itself and an opponent. As a result, Masbiole can escape from Nash Equilibria and obtain better performances than conventional MAS where agents consider only their own benefits. This paper focuses on the evolutionary model of Masbiole, and its characteristics are examined especially with an emphasis on the behaviors of agents obtained by symbiotic evolution. In the simulations, two ideas suitable for the effective analysis of such behaviors are introduced; "Match Type Tile-world (MTT)" and "Genetic Network Programming (GNP)". MTT is a virtual model where tile-world is improved so that agents can behave considering their symbiotic relations. GNP is a newly developed evolutionary computation which has the directed graph type gene structure and enables to analyze the decision making mechanism of agents easily. Simulation results show that Masbiole can obtain various kinds of behaviors and better performances than conventional MAS in MTT by evolution.


Coffee and tea consumption and risk of pre- and postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study.
Specific coffee subtypes and tea may impact risk of pre- and post-menopausal breast cancer differently. We investigated the association between coffee (total, caffeinated, decaffeinated) and tea intake and risk of breast cancer. A total of 335,060 women participating in the European Prospective Investigation into Nutrition and Cancer (EPIC) Study, completed a dietary questionnaire from 1992 to 2000, and were followed-up until 2010 for incidence of breast cancer. Hazard ratios (HR) of breast cancer by country-specific, as well as cohort-wide categories of beverage intake were estimated. During an average follow-up of 11 years, 1064 premenopausal, and 9134 postmenopausal breast cancers were diagnosed. Caffeinated coffee intake was associated with lower risk of postmenopausal breast cancer: adjusted HR=0.90, 95% confidence interval (CI): 0.82 to 0.98, for high versus low consumption; Ptrend=0.029. While there was no significant effect modification by hormone receptor status (P=0.711), linear trend for lower risk of breast cancer with increasing caffeinated coffee intake was clearest for estrogen and progesterone receptor negative (ER-PR-), postmenopausal breast cancer (P=0.008). For every 100 ml increase in caffeinated coffee intake, the risk of ER-PR- breast cancer was lower by 4% (adjusted HR: 0.96, 95% CI: 0.93 to 1.00). Non-consumers of decaffeinated coffee had lower risk of postmenopausal breast cancer (adjusted HR=0.89; 95% CI: 0.80 to 0.99) compared to low consumers, without evidence of dose-response relationship (Ptrend=0.128). Exclusive decaffeinated coffee consumption was not related to postmenopausal breast cancer risk, compared to any decaffeinated-low caffeinated intake (adjusted HR=0.97; 95% CI: 0.82 to 1.14), or to no intake of any coffee (HR: 0.96; 95%: 0.82 to 1.14). Caffeinated and decaffeinated coffee were not associated with premenopausal breast cancer. Tea intake was neither associated with pre- nor post-menopausal breast cancer. Higher caffeinated coffee intake may be associated with lower risk of postmenopausal breast cancer. Decaffeinated coffee intake does not seem to be associated with breast cancer.


MODIFIED ALVARADO SCORE IN CHILDREN WITH DIAGNOSIS OF APPENDICITIS.
Appendicitis is one of the most common abdominal emergency. Some predictive scoring systems are recommended to decrease the rate of negative appendectomy. To evaluate sensitivity, specificity, positive predictive value, and negative predictive value of modified Alvarado score in children who underwent appendectomy. Four hundred children with initial diagnosis of appendicitis were randomly selected from patients who underwent appendectomy. Modified Alvarado score was used for evaluation of the appendicitis, that was confirmed using histology. Of modified Alvarado score components, anorexia; nausea and vomiting and rebound tenderness were significantly more common in children with positive appendectomy in contrast to patients with negative appendectomy. Sensitivity, specificity, positive predictive value, and negative predictive value for modified Alvarado score were: 91.3%; 38.4%; 87.7%; and 51.2% respectively. Alvarado score has high sensitivity but low specificity for diagnosis of acute appendicitis in children.


Electrical Grounding Improves Vagal Tone in Preterm Infants.
Low vagal tone (VT) is a marker of vulnerability to stress and the risk of developing necrotizing enterocolitis in preterm infants. Electric fields produced by equipment in the neonatal intensive care unit (NICU) induce an electric potential measurable on the skin in reference to ground. An electrical connection to ground reduces the skin potential and improves VT in adults. We aimed to measure the electric field strengths in the NICU environment and to determine if connecting an infant to electrical ground would reduce the skin potential and improve VT. We also wished to determine if the skin potential correlated with VT. Environmental magnetic flux density (MFD) was measured in and around incubators. Electrical grounding (EG) was achieved with a patch electrode and wire that extended to a ground outlet. We measured the skin potential in 26 infants and heart rate variability in 20 infants before, during, and after grounding. VT was represented by the high-frequency power of heart rate variability. The background MFD in the NICU was below 0.5 mG, but it ranged between 1.5 and 12.7 mG in the closed incubator. A 60-Hz oscillating potential was recorded on the skin of all infants. With EG, the skin voltage dropped by about 95%. Pre-grounding VT was inversely correlated with the skin potential. VT increased by 67% with EG. After grounding, the VT fell to the pre-grounding level. The electrical environment affects autonomic balance. EG improves VT and may improve resilience to stress and lower the risk of neonatal morbidity in preterm infants.


Mechanical Thrombectomy in Wake-Up Strokes: A Case Series Using Alberta Stroke Program Early CT Score (ASPECTS) for Patient Selection.
There is lack of published studies on mechanical thrombectomy with stent retrievers for wake-up stroke (WUS). To report the outcomes of WUS patients with large vessel occlusions, selected for intervention based on Alberta Stroke Program Early CT Score (ASPECTS) and treated with stent retrievers or primary aspiration thrombectomy. Data were collected retrospectively for each consecutive WUS patient undergoing mechanical thrombectomy with a stent retriever or primary aspiration catheter between February 2015 and September 2016. ASPECTS ≥ 6 was used as the primary imaging criterion for offering thrombectomy in these WUS patients. Main outcomes were the in-hospital improvement in the National Institutes of Health Stroke Scale (NIHSS) and the occurrence of symptomatic hemorrhage. Twelve patients were included in this study; 11 were treated with stent retrievers and 1 was treated with primary aspiration thrombectomy alone. Successful recanalization was achieved in 100% of the patients (33% thrombolysis in cerebral infarction [TICI] 2B and 67% TICI 3). Every patient experienced a reduction in the NIHSS during hospitalization, with a mean NIHSS decrease of 11.1 ± 5.1 points. There was a trend for a larger reduction in the NIHSS in patients with TICI 3 compared to TICI 2B recanalization. There was no symptomatic intracranial hemorrhage in our cohort. For patients with WUS, careful selection of patients using ASPECTS may allow for safe interventions, with low risk of clinical deterioration, and no-periprocedural mortality. All our patients demonstrated a reduction in their NIHSS after the thrombectomy and clinical improvement.


Circulating catecholamines and systolic time intervals in labile and sustained hypertension.
1. Average supine circulating total catecholamine concentrations were found to be higher than the normal range in about 50% of patients with labile hypertension and in about 30% of patients with sustained essential hypertension. 2. These higher resting concentrations were mainly due to an increase in adrenaline in labile hypertension and to an increase in noradrenaline in sustained hypertension. 3. Patients with elevated catecholamine concentrations were also characterized by a higher heart rate, by an increased myocardial contractility and by greater hypotensive response after treatment with beta-adrenoreceptor blocking agents. 4. These studies suggest the existence of sub-groups of hypertensive patients with increased sympathetic tone.


Diabetes mellitus-induced lower urinary tract symptoms and hepatic steatosis in an older male.
Diabetes mellitus type 2 (DM-2) is one of the important causes of low-grade chronic inflammation (meta inflammation) seen in almost all tissues in the body. Other possible mechanisms involved in the development of lower urinary tract symptoms (LUTS) with DM-2 are the hypertonicity of the peripheral sympathetic nerves and hyperinsulinemia effects on the autonomous nervous system activity. These further suggests that abnormalities in glucose homeostasis influence the hyperproliferation of the prostate cells resulting in benign prostatic hyperplasia (BPH). Similarly, hepatic steatosis, a form of non-alcoholic fatty liver disease (NAFLD) prevalence among patients with DM-2, is as high as 75%. NAFLD has no symptoms in most diabetic patients. In this study, we present a case of a 64-year-old Black male who had worsening urinary urgency and hesitancy for 4 months, with increasing abdominal girth. Patient was found to have symptoms, diagnostic studies, and physical exam findings indicative of BPH and fatty liver disease. He was treated with hepato-protective medications, tighter control of his blood glucose levels, and blood pressure meds for 13 months. Upon follow-up, most of his symptoms were resolved. Timeline of BPH resolution and decrease in liver size following treatment suggest that DM-2 has a strong correlation with the development of BPH and fatty liver disease in most patients living with diabetes. Men with type 2 diabetes mellitus (DM-2) tend to have significantly lower serum PSA level, lower testosterone levels, and larger prostate volume compared to non-diabetic male patients. Patients with DM-2 have higher prevalence of hepatic steatosis, liver cirrhosis, and end-stage liver failure. The role of metformin in reducing hepatic steatosis as stated by several studies is yet to be validated as our patient has been on metformin for 22 years for the management of DM-2 with fatty liver disease.


Polymorphonuclear leukocyte function in cattle with left displaced abomasum with or without concurrent infections.
Cattle submitted to the University of Minnesota for surgical correction of left displaced abomasum (LDA) were examined for the in vitro phagocytic and bactericidal activities of their polymorphonuclear leukocytes (PMN). The PMN from cattle with LDA with or without concurrent infection had depressed phagocytic function when compared with PMN from healthy animals (controls). Those with concurrent infection had phagocytic activities lower than those in the group of cattle with LDA without any concurrent infection, and the former group was also observed to have depressed intracellular killing. Cattle with LDA complicated by infection were the only group in which phagocytic function was altered during surgical correction of LDA (and recovery). Treatment of PMN from both groups of affected cattle with levamisole in vitro enhanced intracellular killing, but had no effect on phagocytosis.


Six-month mortality and cardiac catheterization in non-ST-segment elevation myocardial infarction patients with anemia.
It is unknown how anemia influences the invasive management of patients with non-ST-segment elevation myocardial infarction (NSTEMI) and associated mortality. We investigated whether receipt of cardiac catheterization relates to 6-month death rates among patients with different severity of anemia. We used data from the population-based Worcester Heart Attack Study, which included 2634 patients hospitalized with confirmed NSTEMI, from three percutaneous coronary intervention-capable medical centers in the Worcester (Massachusetts, U.S.A.) metropolitan area, during five biennial periods between 1997 and 2005. Severity of anemia was categorized using admission hematocrit levels: less than or equal to 30.0% (moderate-to-severe anemia), 30.1-39.0% (mild anemia), and more than 39.0% (no anemia). Propensity matching and conditional logistic regression adjusting for hospital use of aspirin, heparin, and plavix compared 6-month postadmission all-cause mortality rates in relation to cardiac catheterization during NSTEMI hospitalization. Compared with patients without anemia, patients with anemia were less likely to undergo cardiac catheterization {adjusted odds ratio (AOR) 0.79 [95% confidence interval (CI): 0.67-0.95] for mild anemia and 0.45 (95% CI: 0.42-0.49) for moderate-to-severe anemia}. After propensity matching, cardiac catheterization was associated with lower 6-month death rates only in patients without anemia [AOR 0.26 (95% CI: 0.09-0.79)] but not in patients with mild anemia [AOR 0.55 (95% CI: 0.25-1.23)]. The small number of patients rendered data inconclusive for patients with moderate-to-severe anemia. Anemia at the time of hospitalization for NSTEMI was associated with lower utilization of cardiac catheterization. However, cardiac catheterization use was associated with a decreased risk of dying at 6 months after hospital admission only in patients without anemia.


Field observations of the developing legal recreational cannabis economy in Washington State.
Washington State legalized the sale of recreational cannabis in 2012. This paper describes the unfolding of the market regulatory regime in an eastern portion of the state, including field descriptions to illustrate the setting. We made observations and conducted interviews of the local supply chain comprising a producer/processor, analytic facility, and retail establishments as well as querying the state director of the regulatory board. Interviews and observations of facilities suggest an overwhelming concern for black market diversion drives state regulatory efforts. The ongoing dialogue between market actors and the state has resulted in a more equitable distribution of profits at different stages in the process. State safety regulations have thus far been shifted to independent laboratories. Banks and insurance companies have slowly begun making inroads into the industry, despite federal prohibition. The law was conceived as a social justice remedy, but the bulk of the legal and regulatory activity surrounds cannabis marketplace management. This has been characterized by concerns for black market diversion, producer/processor profits, and a hands-off approach to safety regulation. Minor cannabis violations as a pathway to criminal justice system involvement have been reduced substantially but disproportionate enforcement upon racial/ethnic minorities continues.


Semiparametric Theory for Causal Mediation Analysis: efficiency bounds, multiple robustness, and sensitivity analysis.
Whilst estimation of the marginal (total) causal effect of a point exposure on an outcome is arguably the most common objective of experimental and observational studies in the health and social sciences, in recent years, investigators have also become increasingly interested in mediation analysis. Specifically, upon evaluating the total effect of the exposure, investigators routinely wish to make inferences about the direct or indirect pathways of the effect of the exposure not through or through a mediator variable that occurs subsequently to the exposure and prior to the outcome. Although powerful semiparametric methodologies have been developed to analyze observational studies, that produce double robust and highly efficient estimates of the marginal total causal effect, similar methods for mediation analysis are currently lacking. Thus, this paper develops a general semiparametric framework for obtaining inferences about so-called marginal natural direct and indirect causal effects, while appropriately accounting for a large number of pre-exposure confounding factors for the exposure and the mediator variables. Our analytic framework is particularly appealing, because it gives new insights on issues of efficiency and robustness in the context of mediation analysis. In particular, we propose new multiply robust locally efficient estimators of the marginal natural indirect and direct causal effects, and develop a novel double robust sensitivity analysis framework for the assumption of ignorability of the mediator variable.


Large Terrestrial Bird Adapting Behavior in an Urbanized Zone.
Wildlife living within urban ecosystems have to adapt or perish. Red-legged Seriema, a large terrestrial bird, are rare in urban ecosystems, however, they have been reported in a medium-sized Brazilian city. We investigated the reasons for this occurrence as well as their behavior. We assessed the distribution of Seriemas (including fledglings), free-ranging cats, and cat-feeding points provided by humans, and past records of Seriemas in the study area. We discovered that Seriemas are sharing spatial resources with cats without apparent conflicts, and intraspecific competition was important to define the spatial distribution of Seriemas. This species is able to use human-made structures to improve territory defense and opportunistic foraging. Direct and indirect human food provisioning is helping them to survive in the studied area, but is also facilitating the domestication process, which may cause future conflicts with humans and cats. Although Seriemas have inhabited the studied urban area for years, they are still adapting their behaviors for urban life, as they have not yet perceived the dangers of automotive traffic. Our study corroborates that wild species may adapt to urban areas driven by human contact, but it also acts as a trap for the adaptive process.


Definition of erythroid cell-positive blood transcriptome phenotypes associated with severe respiratory syncytial virus infection.
Biomarkers to assess the risk of developing severe respiratory syncytial virus (RSV) infection are needed. We conducted a meta-analysis of 490 unique profiles from six public RSV blood transcriptome datasets. A repertoire of 382 well-characterized transcriptional modules was used to define dominant host responses to RSV infection. The consolidated RSV cohort was stratified according to four traits: "interferon response" (IFN), "neutrophil-driven inflammation" (Infl), "cell cycle" (CC), and "erythrocytes" (Ery). We identified eight prevalent blood transcriptome phenotypes, of which three Ery+ phenotypes comprised higher proportions of patients requiring intensive care. This finding confirms on a larger scale data from one of our earlier reports describing an association between an erythrocyte signature and RSV disease severity. Further contextual interpretation made it possible to associate this signature with immunosuppressive states (late stage cancer, pharmacological immunosuppression), and with a population of fetal glycophorin A+ erythroid precursors. Furthermore, we posit that this erythrocyte cell signature may be linked to a population of immunosuppressive erythroid cells previously described in the literature, and that overabundance of this cell population in RSV patients may underlie progression to severe disease. These findings outline potential priority areas for biomarker development and investigations into the immune biology of RSV infection. The approach that we developed and employed here should also permit to delineate prevalent blood transcriptome phenotypes in other settings.


The value of 18F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study.
Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions. Diagnosis of underlying disease may be improved by 18F-fluorodesoxyglucose positron emission tomography (18F-FDG-PET). Prospective study to test diagnostic utility of 18F-FDG-PET/CT in a large cohort of patients with FUO or IUO and to define parameters that increase the likelihood of diagnostic 18F-FDG-PET/CT. Patients with FUO or IUO received 18F-FDG-PET/CT scanning in addition to standard diagnostic work-up. 18F-FDG-PET/CT results were classified as helpful or non-helpful in establishing final diagnosis. Binary logistic regression was used to identify clinical parameters associated with a diagnostic 18F-FDG-PET/CT. 240 patients were enrolled, 72 with FUO, 142 with IUO and 26 had FUO or IUO previously (exFUO/IUO). Diagnosis was established in 190 patients (79.2%). The leading diagnoses were adult-onset Still's disease (15.3%) in the FUO group, large vessel vasculitis (21.1%) and polymyalgia rheumatica (18.3%) in the IUO group and IgG4-related disease (15.4%) in the exFUO/IUO group. In 136 patients (56.7% of all patients and 71.6% of patients with a diagnosis), 18F-FDG-PET/CT was positive and helpful in finding the diagnosis. Predictive markers for a diagnostic 18F-FDG-PET/CT were age over 50 years (p=0.019), C-reactive protein (CRP) level over 30 mg/L (p=0.002) and absence of fever (p=0.001). 18F-FDG-PET/CT scanning is helpful in ascertaining the correct diagnosis in more than 50% of the cases presenting with FUO and IUO. Absence of intermittent fever, higher age and elevated CRP level increase the likelihood for a diagnostic 18F-FDG-PET/CT.


Clinical application of array-based comparative genomic hybridization for the identification of prognostically important genetic alterations in chronic lymphocytic leukemia.
Genomic aberrations have increasingly gained attention as prognostic markers in B-cell chronic lymphocytic leukemia (CLL). Fluorescence in situ hybridization (FISH) has improved the detection rate of genomic alterations in CLL from approximately 50% using conventional cytogenetics to greater than 80%. More recently, array comparative genomic hybridization (CGH) has gained popularity as a clinical tool that can be applied to detect genomic gains and losses of prognostic importance in CLL. Array CGH and FISH are particularly useful in CLL because genomic gains and losses are key events with both biologic and prognostic significance, while balanced translocations have limited prognostic value. Although FISH has a higher technical sensitivity, it requires separate, targeted hybridizations for the detection of alterations at genomic loci of interest. Array CGH, on the other hand, has the ability to provide a genome-wide survey of genomic aberrations with a single hybridization reaction. Array CGH is expanding the known genomic regions of importance in CLL and allows these regions to be evaluated in the context of a genome-wide perspective. Ongoing clinical trials are evaluating the use of genomic aberrations as tools for risk-stratifying patients for therapy, thus increasing the need for reliable and high-yield methods to detect these genomic changes. In this review, we consider the use of array CGH as a clinical tool for the identification of genomic alterations with prognostic significance in CLL, and suggest ways to integrate this test into the clinical molecular diagnostic laboratory work flow.


Longitudinal Association Between Hearing Loss, Vision Loss, Dual Sensory Loss, and Cognitive Decline.
To better understand the role of sensory loss as a potentially modifiable risk factor for cognitive decline, this study examined cognitive decline in relation to single modality hearing or vision loss and dual sensory loss. Longitudinal secondary data analysis. The Health and Retirement Study (HRS) and its supplement: The Aging, Demographics, and Memory Study (ADAMS). Individuals aged 73 and older (N = 295). Hearing loss was defined by an inability to hear sounds of 25 dB at frequencies between 0.5 and 4.0 kHz in either ear. Vision loss was defined as having corrected binocular vision worse than 20/40. Dual sensory loss was defined as having both hearing and vision loss. We used one time point of hearing and vision data objectively measured in ADAMS Wave C (June 2006-May 2008) and five waves of cognitive function data measured by the HRS version of the Telephone Interview for Cognitive Status in HRS (2006-2014). Multilevel mixed models were used. Among the participants, 271 completed a hearing assessment and 120 had hearing loss; 292 completed a vision assessment and 115 had vision loss; 52 had dual sensory loss. Older adults with hearing loss had a significantly faster rate of cognitive decline as they aged compared to those with normal hearing (β = -0.16, P < .05). No significant association was found between vision loss and the rate of cognitive decline (β = -0.06, P = .41). Older adults who had dual sensory loss likewise had a significantly faster rate of cognitive decline as they age (β = -0.23, P < .05) compared to those with no sensory loss. Older adults with hearing loss and dual sensory loss have faster rates of cognitive decline than those with normal sensory function.


Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease.
Mutations in distant regulatory elements can have a negative impact on human development and health, yet because of the difficulty of detecting these critical sequences, we predominantly focus on coding sequences for diagnostic purposes. We have undertaken a comparative sequence-based approach to characterize a large noncoding region deleted in patients affected by Van Buchem (VB) disease, a severe sclerosing bone dysplasia. Using BAC recombination and transgenesis, we characterized the expression of human sclerostin (SOST) from normal (SOST(wt)) or Van Buchem (SOST(vbDelta) alleles. Only the SOST(wt) allele faithfully expressed high levels of human SOST in the adult bone and had an impact on bone metabolism, consistent with the model that the VB noncoding deletion removes a SOST-specific regulatory element. By exploiting cross-species sequence comparisons with in vitro and in vivo enhancer assays, we were able to identify a candidate enhancer element that drives human SOST expression in osteoblast-like cell lines in vitro and in the skeletal anlage of the embryonic day 14.5 (E14.5) mouse embryo, and discovered a novel function for sclerostin during limb development. Our approach represents a framework for characterizing distant regulatory elements associated with abnormal human phenotypes.


Relationship between parental psychopathology, parenting strategies and child mental health--findings from the GB national study.
Parental and child psychiatric disorders have been found to be associated, and this association can be mediated by other psychosocial variables, including parenting attitudes and strategies. As most previous studies included clinical samples, the purpose of this study was to establish the relationship between parental psychopathology and parenting strategies with child psychiatric disorders in a national survey population. The sample included 10,438 children of 5-15 years and their parents, from representative UK households. Families were assessed on child psychiatric diagnosis, parental psychopathology, family functioning, and socioeconomic status. Parenting strategies included using rewards, physical and non-physical punishments towards their child. Parental psychopathology scores (OR 3.99, 95% CI 3.13-5.09) and non-physical punishment (OR 1.50, 95% CI 1.27-1.76) were associated with child psychiatric disorders. This association was particularly prominent among children with conduct disorders: parental psychopathology scores (OR 3.13, 95% CI 2.28-4.30) and non-physical punishment (OR 3.19, 95% CI 2.55-3.97). Absence of child psychopathology was associated with a combination of rewarding and non-punitive parenting strategies. Although parents in the general population may be using less physical strategies than in the past, non-physical punishment is strongly related to mental health problems in children. Enhancement of positive parenting through universal and targeted interventions is an important preventive strategy.


To die or not to die: an overview of apoptosis and its role in disease.
The death of cells in tissues of humans and other multicellular organisms is neither always abnormal nor always detrimental. Although necrosis ensues at the sites of massive cellular injury, most cells in the body die through a more subtle, noninflammatory, energy-dependent form of cell death called apoptosis. The number of cells in tissues is determined by the homeostatic balance between proliferation of new cells and death of senescent cells; the rates of proliferation and apoptosis vary widely from tissue to tissue. Recent research into the molecular mechanisms of apoptosis has revealed that apoptosis is a genetically programmed process that can become deranged when the components of the cellular apoptotic machinery are mutated or present in inappropriate quantities. Dysregulation of apoptosis is associated with the pathogenesis of a wide array of diseases: cancer, neurodegeneration, autoimmunity, heart disease, and other disorders. Products of genes involved in the regulation and execution of apoptosis are potentially excellent targets for diagnosis and therapeutic intervention in disease processes, and they offer renewed hope for cures and treatments for a wide array of maladies.


Clinical and economic analysis of the 2009 H1N1 influenza pandemic among pregnant Korean women.
Unlike Western countries, the 2009 pandemic influenza infection among pregnant women was reported as mild in a previous interim study in South Korea. However, several mortalities were reported thereafter, suggesting that nationwide data were lacking. This case-control study covers the entire 2009 pandemic inf luenza period, from May 2009 to February 2010. The clinical and economic data of pregnant (case) and age-matched non-pregnant (control) women with influenza A (H1N1) pdm09 virus (H1N1pdm09) infection were retrospectively collected from nine hospitals in South Korea. A total of 130 pregnant women with H1N1pdm09 infection were identified. The mean age of the pregnant women was 31.1 years (range, 19 to 41) and mean gestational age was 18.4 weeks (range, 3 to 40). Both case and control groups were similar in terms of age (p = 0.43) and comorbidities (p = 0.18). The overall rate of complications was comparable between the two groups (p = 0.648). However, mortality was reported only among the cases, so mean economic per capita burden is estimated to be higher for pregnant women compared to the control (4,821,992 Korean won [KRW] vs. 351,233 KRW, p = 0.31). Obstetric complications were observed in 12 cases, including preterm labor (n = 7), low birth-weight (n = 3), miscarriage (n = 1), stillbirth (n = 1), and cleft lip (n = 1). Although statistically insignificant, the detrimental impact of influenza A H1N1pdm09 on pregnancy can be serious in some complicated cases in South Korea. Thus, the strong recommendation of influenza vaccination should be maintained for pregnant women as a high priority.


Significance of supernumerary ribs in rodent developmental toxicity studies: postnatal persistence in rats and mice.
Pregnant Sprague-Dawley rats and Swiss-Webster mice were gavaged with bromoxynil at 15 and 96.4 mg/kg/day, respectively, on Days 6-15 of gestation. The frequency of supernumerary ribs (SNR), which are here defined as any degree of ossification lateral to the first lumbar vertebrae, was determined in fetuses at term and offspring on Postnatal Days 6, 20, and 40. Bromoxynil induced significant increases in the incidence of SNR in fetuses of both species. In rats, SNR occurred in 62% of treated fetuses as compared to 14% in controls; in mice these values were 45% and 11%, respectively. The postnatal incidence and persistence of SNR was species dependent. In the rat, postnatal SNR incidence in treated animals did not differ significantly from controls. In contrast, in mice the bromoxynil-induced elevated incidence of SNR persisted through Day 40 (42.3% in treated vs 0% in controls). Analysis of SNR was also done on the basis of their length (greater or less than 1/2 the length of the 13th rib). In the mouse, the incidence of smaller SNR was much lower on Day 40 as compared to Day 20; in contrast the incidence of larger SNR persisted through Day 40. In the rat, the incidence of larger SNR was too small to draw conclusions as to the postnatal fate of these structures. As in the mouse, however, the incidence of smaller SNR was significantly lower by Day 40. The significance of SNR in developmental toxicity remains problematic. The impact of this anomaly on animals is difficult to assess.(ABSTRACT TRUNCATED AT 250 WORDS)


Adherence in the CAPRISA 004 tenofovir gel microbicide trial.
High adherence is key to microbicide effectiveness. Here we provide a description of adherence interventions and the adherence rates achieved in the CAPRISA 004 Tenofovir gel trial. Adherence support for the before-and-after dosing strategy (BAT 24) was provided at enrolment and at each monthly study visit. This initially comprised individual counselling and was replaced midway by a structured theory-based adherence support program (ASP) based on motivational interviewing. The 889 women were followed for an average of 18 months and attended a total of 17,031 monthly visits. On average women reported five sex acts and returned 5.9 empty applicators per month. The adherence rate based on applicator count in relation to all reported sex acts was 72.2 % compared to the 82.0 % self-reported adherence during the last sex act. Adherence support activities, which achieve levels of adherence similar to or better than those achieved by the CAPRISA 004 ASP, will be critical to the success of future microbicide trials.


Recommended best practices for collecting, analyzing, and reporting microplastics in environmental media: Lessons learned from comprehensive monitoring of San Francisco Bay.
Microplastics are ubiquitous and persistent contaminants in the ocean and a pervasive and preventable threat to the health of marine ecosystems. Microplastics come in a wide variety of shapes, sizes, and plastic types, each with unique physical and chemical properties and toxicological impacts. Understanding the magnitude of the microplastic problem and determining the highest priorities for mitigation require accurate measures of microplastic occurrence in the environment and identification of likely sources. The field of microplastic pollution is in its infancy, and there are not yet widely accepted standards for sample collection, laboratory analyses, quality assurance/quality control (QA/QC), or reporting of microplastics in environmental samples. Based on a comprehensive assessment of microplastics in San Francisco Bay water, sediment, fish, bivalves, stormwater, and wastewater effluent, we developed recommended best practices for collecting, analyzing, and reporting microplastics in environmental media. We recommend factors to consider in microplastic study design, particularly in regard to site selection and sampling methods. We also highlight the need for standard QA/QC practices such as collection of field and laboratory blanks, use of methods beyond microscopy to identify particle composition, and standardized reporting practices, including suggested vocabulary for particle classification.


sFlt-1 in Chronic Kidney Disease: Friend or Foe?
Placental growth factor (PlGF) and its receptor, fms-like tyrosine kinase-1 (Flt-1), are important regulators involved in angiogenesis, atherogenesis, and inflammation. This review article focuses on the function of PlGF/Flt-1 signaling and its regulation by soluble Flt-1 (sFlt-1) in chronic kidney disease (CKD). Elevation of circulating sFlt-1 and downregulation of sFlt-1 in the vascular endothelium by uremic toxins and oxidative stress both exacerbate heart failure and atherosclerosis. Circulating sFlt-1 is inconsistent with sFlt-1 synthesis, because levels of matrix-bound sFlt-1 are much higher than those of circulating sFlt-1, as verified by a heparin loading test, and are drastically reduced in CKD.


Using an e-Health Intervention to Reduce Prolonged Sitting in UK Office Workers: A Randomised Acceptability and Feasibility Study.
Low-cost workplace interventions are required to reduce prolonged sitting in office workers as this may improve employees' health and well-being. This study aimed to assess the acceptability and feasibility of an e-health intervention to reduce prolonged sitting among sedentary UK-based office workers. Secondary aims were to describe preliminary changes in employee health, mood and work productivity after using an e-health intervention. Healthy, university office workers (n = 14) completed this study. An 8 week randomised crossover design was used, consisting of two trials: Intervention (computer-based prompts) and Control. Eligibility and retention rates were recorded to assess the feasibility of the trial and interviews were conducted following the intervention to explore its acceptability. Sitting, standing and stepping were objectively assessed prior to and during week 8 of each trial. Before and after each trial, measurements of vascular function, cerebrovascular function, mood and work productivity were obtained. This study had eligibility and retention rates of 54.5% and 77.8%, respectively. Participants expressed a lack of autonomy and disruption to their workflow when using the e-health intervention, raising concerns over its acceptability and long-term implementation. Preliminary data indicate that the intervention may improve the patterning of activity accrued during work hours, with increases in the number of standing and stepping bouts completed, in addition to improving vascular function. This e-health intervention is feasible to deliver in a cohort of university office workers. However, adaptations to its implementation, such as personalised settings, are needed to increase acceptability before larger trials can be conducted.


Prevalence of Panulirus argus Virus 1 (PaV1) and habitation patterns of healthy and diseased Caribbean spiny lobsters in shelter-limited habitats.
Caribbean spiny lobsters Panulirus argus are socially gregarious, preferring shelters harboring conspecifics over empty shelters. In laboratory trials, however, healthy lobsters strongly avoided shelters harboring lobsters infected with the highly pathogenic Panulirus argus Virus 1 (PaV1). Because PaV1 is transmitted by contact, this behavior may thwart its spread in wild lobsters. In a field experiment conducted from 1998 to 2002 in a shelter-poor reef lagoon (Puerto Morelos, Mexico), densities of juvenile P. argus increased significantly on sites enhanced with artificial shelters (casitas) but not on control sites. Because PaV1 emerged in this location during 2000, we reexamined these data to assess whether casitas could potentially increase transmission of PaV1. In 2001, PaV1 prevalence was 2.5% and the cohabitation level (percentage of healthy lobsters cohabiting with diseased lobsters) was similar between natural shelters (3.5%) and casitas (2.4 %). The relative lobster densities in casita sites and control sites did not change significantly before (1998-1999) or after (2001-2002) the disease emergence. In late 2006, data from casita sites showed a significant increase in prevalence (10.9%) and cohabitation level (29.4%), but no significant changes in lobster density. In May 2006, casitas were deployed on shelter-poor sites within Chinchorro Bank, 260 km south of Puerto Morelos. In late 2006, prevalence and cohabitation level were 7.4 and 21.7%, respectively. Our results are inconclusive as to whether or not casitas increase PaV1 transmission, but suggest that across shelter-poor habitats, lobsters make a trade-off between avoiding diseased conspecifics and avoiding predation risk.


Blockade of insulin receptor substrate-1 inhibits corneal lymphangiogenesis.
To analyze whether insulin receptor substrate (IRS-1) is involved in lymphatic vessel development and whether IRS-1 blockade can inhibit lymphangiogenesis in vivo. The impact of IRS-1 blockade by GS-101 (Aganirsen), an antisense oligonucleotide against IRS-1, on lymphatic endothelial cell (LEC) proliferation was assessed by ELISA. Furthermore, the effect of IRS-1 blockade on prolymphangiogenic growth factor expression by LECs and macrophages (peritoneal exudate cells) was tested by real-time PCR. The mouse model of inflammatory corneal neovascularization was used to analyze the effect of IRS-1 blockade in vivo: after corneal suture placement, mice were treated with GS-101 eye drops (twice daily afterwards for 1 week, 5 μL per drop; 50, 100, or 200 μM). Afterward, corneal wholemounts were prepared and stained for blood and lymphatic vessels. Blockade of IRS-1 by GS-101 inhibited LEC proliferation dose dependently. GS-101 led to decreased VEGF-A expression levels in LECs, whereas VEGF-C, VEGF-D, and VEGFR3 showed no significant change. In macrophages, VEGF-A expression levels were also inhibited by IRS-1 blockade. Additionally, GS-101 strongly inhibited macrophage-derived VEGF-C, VEGF-D, and VEGFR3 expression. In vivo, corneal hemangiogenesis was significantly inhibited when used at a concentration of 200 μM (by 17%; P < 0.01). Corneal lymphangiogenesis was significantly inhibited when used at a dose of 100 μM (by 21%; P < 0.01), and the highest used dose (200 μM) showed an even stronger inhibition (by 28%; P < 0.001). Blockade of IRS-1 inhibits not only hemangiogenesis but also lymphangiogenesis. To the authors' knowledge, this is the first evidence that IRS-1 is involved in the molecular pathway leading to lymphangiogenesis.


Exploring personalized searches using tag-based user profiles and resource profiles in folksonomy.
With the increase in resource-sharing websites such as YouTube and Flickr, many shared resources have arisen on the Web. Personalized searches have become more important and challenging since users demand higher retrieval quality. To achieve this goal, personalized searches need to take users' personalized profiles and information needs into consideration. Collaborative tagging (also known as folksonomy) systems allow users to annotate resources with their own tags, which provides a simple but powerful way for organizing, retrieving and sharing different types of social resources. In this article, we examine the limitations of previous tag-based personalized searches. To handle these limitations, we propose a new method to model user profiles and resource profiles in collaborative tagging systems. We use a normalized term frequency to indicate the preference degree of a user on a tag. A novel search method using such profiles of users and resources is proposed to facilitate the desired personalization in resource searches. In our framework, instead of the keyword matching or similarity measurement used in previous works, the relevance measurement between a resource and a user query (termed the query relevance) is treated as a fuzzy satisfaction problem of a user's query requirements. We implement a prototype system called the Folksonomy-based Multimedia Retrieval System (FMRS). Experiments using the FMRS data set and the MovieLens data set show that our proposed method outperforms baseline methods.


Beta-blockade in burns.
A significant proportion of the mortality and morbidity of severe burns is attributable to the ensuing hypermetabolic response that typically lasts for at least 9-12 months post-injury. This is associated with impaired wound healing, increased infection risks, erosion of lean body mass, hampered rehabilitation and delayed reintegration of burn survivors into society. The endocrine status is markedly altered during this period with an initial and then sustained increase in proinflammatory 'stress' hormones such as cortisol and other glucocorticoids, and catecholamines including epinephrine and norepinephrine by the adrenal medulla and cortex. These hormones exert catabolic effects leading to muscle wasting, the intensity of which depends upon the percentage of total body surface area (TBSA) involved, as well as the time elapsed since initial injury. Pharmacological and non-pharmacological strategies may be used to reverse the catabolic effect of thermal injury. Of these, beta-adrenergic blockade with propranolol has been the most efficacious anti-catabolic therapy in the treatment of burns. The underlying mechanism of action of propranolol is still unclear, however its effect appears to occur due to an increased protein synthesis in the face of a persistent protein breakdown and reduced peripheral lipolysis. This article aims to review the current understanding of catecholamines in postburn muscle wasting and focuses on the clinical and metabolic effects of beta-blockade in severe burns.


Epithelium percentage estimation facilitates epithelial quantitative protein measurement in tissue specimens.
The rapid advancement of high-throughput tools for quantitative measurement of proteins has demonstrated the potential for the identification of proteins associated with cancer. However, the quantitative results on cancer tissue specimens are usually confounded by tissue heterogeneity, e.g. regions with cancer usually have significantly higher epithelium content yet lower stromal content. It is therefore necessary to develop a tool to facilitate the interpretation of the results of protein measurements in tissue specimens. Epithelial cell adhesion molecule (EpCAM) and cathepsin L (CTSL) are two epithelial proteins whose expressions in normal and tumorous prostate tissues were confirmed by measuring staining intensity with immunohistochemical staining (IHC). The expressions of these proteins were measured by ELISA in protein extracts from OCT embedded frozen prostate tissues. To eliminate the influence of tissue heterogeneity on epithelial protein quantification measured by ELISA, a color-based segmentation method was developed in-house for estimation of epithelium content using H&E histology slides from the same prostate tissues and the estimated epithelium percentage was used to normalize the ELISA results. The epithelium contents of the same slides were also estimated by a pathologist and used to normalize the ELISA results. The computer based results were compared with the pathologist's reading. We found that both EpCAM and CTSL levels, measured by ELISA assays itself, were greatly affected by epithelium content in the tissue specimens. Without adjusting for epithelium percentage, both EpCAM and CTSL levels appeared significantly higher in tumor tissues than normal tissues with a p value less than 0.001. However, after normalization by the epithelium percentage, ELISA measurements of both EpCAM and CTSL were in agreement with IHC staining results, showing a significant increase only in EpCAM with no difference in CTSL expression in cancer tissues. These results were obtained with normalization by both the computer estimated and pathologist estimated epithelium percentage. Our results show that estimation of tissue epithelium percentage using our color-based segmentation method correlates well with pathologists' estimation of tissue epithelium percentages. The epithelium contents estimated by color-based segmentation may be useful in immuno-based analysis or clinical proteomic analysis of tumor proteins. The codes used for epithelium estimation as well as the micrographs with estimated epithelium content are available online.


Pegylated interferon alpha - 2a is clinically effective and tolerable in myeloproliferative neoplasm patients treated off clinical trial.
Polycythemia vera, essential thrombocytosis, and myelofibrosis are chronic Philadelphia-negative myeloproliferative neoplasms that are characterized by clonal hematopoiesis, splenomegaly, risk of hemorrhagic and thrombotic sequelae, and profound symptom burden. We review the outcomes of 75 myeloproliferative neoplasm patients treated with pegylated interferon alpha 2a off study at an academic medical center. In the 56 treated polycythemia vera and essential thrombocytosis patients, a complete or partial response was obtained in 78.6% of patients per ELN/IWG-MRT revised criteria, with >80% of polycythemia vera patients becoming phlebotomy independent and 60% of essential thrombocytosis patients having platelet normalization with therapy. In the 19 treated myelofibrosis patients, stable disease was seen in 63.2% of patients. Vascular events occurred in 2/75 (2.6%) of treated patients while on therapy. Grade 3 toxicity was uncommon with leukopenia noted in 1 patient (1.3%). The most common adverse event overall was grade 1 fatigue in 18.7%. This retrospective single center analysis demonstrates pegylated interferon alpha 2a is active and well-tolerated therapy outside the support of a clinical trial. These results substantiate the previously reported efficacy of pegylated interferon alpha 2a in myeloproliferative neoplasms. Further prospective and randomized clinical trial data is required to better delineate pegylated interferon alpha 2a's use in myeloproliferative disease, with emphasis placed on comprehensive molecular characterization, allelic burden quantification, and measurement of histologic response.


Microgravity experiments on phase change of self-rewetting fluids.
A series of microgravity experiments on self-rewetting fluids has been conducted at the 10-second drop shaft of the Japan Microgravity Center (JAMIC). In all the experiments, 1.5 wt% of 1-butanol aqueous solution were employed as a self-rewetting fluid. The objective of the first experiment was to observe the boiling behavior of two-dimensional adjacent dual vapor bubbles with the aid of a two-wavelength interferometer and tracer particles. A significant difference was observed between a self-rewetting fluid and a normal fluid (CFC-113 in this experiment) in bubble interaction and flow developed along vapor/bubble interface. The second experiment focused on the flow at the bubble/heater contact area and around the three-phase interline, visualized with tracer particles. Differing behavior among three fluids, 1-butanol aqueous solution, CFC-113, and ethanol aqueous solution, was observed. The last microgravity experiment was a demonstration of wickless heat pipes containing three different fluids as a working fluid, 1-butanol aqueous solution, water, and ethanol aqueous solution. The temperature variation of working fluid in the heat pipe was monitored, and the liquid flow returning from the condensation region to the evaporation region was visualized by tracer particles. In addition to microgravity experiments, the performance of conventional heat pipes with 1-butanol aqueous solution was evaluated on the ground, and compared with water heat pipes. Our preliminary results are presented.


A Research Agenda for Advancing Non-pharmacological Management of Chronic Musculoskeletal Pain: Findings from a VHA State-of-the-art Conference.
Chronic pain is widely prevalent among Veterans and can have serious negative consequences for functional status and quality of life among other domains. The Veterans Health Administration (VHA) convened a state-of-the-art (SOTA) conference to develop research priorities for advancing the science and clinical practice of non-pharmacological management of chronic musculoskeletal pain. In this perspective article, we present the methods and consensus recommendations for research priorities emanating from the SOTA. In the months leading up to the SOTA, a core group of researchers defined four areas of focus: psychological/behavioral therapies; exercise/movement therapies; manual therapies; and models for delivering multi-modal pain care and divided into workgroups. Each workgroup, in their respective areas of focus, identified seminal studies capturing the state of the evidence. Herein, we present consensus recommendations ranging from efficacy to effectiveness to implementation/dissemination research depending on the state of the evidence as assessed by participants, including commentary on common elements across workgroups and future areas of innovation in study design, measurement, and outcome ascertainment.


[Rhabdomyolysis secondary to gluteal compartment syndrome after bariatric surgery: case report.].
Bariatric surgery has become a common procedure and several complications have been reported. The objective of this report is to present a case of gluteal compartment syndrome that evolved to acute renal failure after bariatric surgery and to discuss the diagnosis, and the prophylactic and therapeutic measures. A 42 years old male patient, white, with a body mass index (BMI) of 43, physical status ASA II, who underwent bariatric surgery of the duodenal switch type, under general anesthesia associated with epidural anesthesia. There were no complications during the procedure. The anesthetic-surgical procedure lasted 3 hours and 30 minutes. On postoperative day one the patient developed lumbosacral and gluteal pain, besides paresthesia in the lower limbs in the distribution of the sciatic nerve. On physical exam, the buttocks were slightly pale, tight, swollen, and painful to palpation and to movement. A diagnosis of gluteal compartment syndrome was made; it evolved to rhabdomyolysis and acute renal failure. The renal function improved and the patient did not present any motor or sensitive deficits. Patients with morbid obesity undergoing bariatric surgery may present gluteal compartment syndrome as a complication. When it is not diagnosed and treated promptly, it may evolve to rhabdomyolysis and acute renal failure, which represents a serious life-threatening situation.


Race and recession: Effects of economic scarcity on racial discrimination.
When the economy declines, existing racial disparities typically expand, suggesting that economic scarcity may promote racial discrimination. To understand this pattern, we examined the effect of perceived scarcity on resource allocations to Black and White American recipients, and tested whether this effect depends on a decision maker's motivation to respond without prejudice. We proposed that scarcity would lead to increased discrimination among those with relatively low internal motivation but not those high in internal motivation. Indeed, we found that when resources were framed as scarce (vs. abundant or a control condition), low-motivation participants allocated less to Black than White recipients, whereas high-motivation participants allocated more to Black than White recipients (Studies 1 and 2). This pattern was strongest when decisions could be made deliberatively (Study 3), and anti-Black allocation bias emerged even in a non-zero-sum context (Studies 4 and 5), suggesting a strategic bias directed against Black recipients rather than in favor of White recipients. These findings indicate that the psychological perception of scarcity can produce racial bias in the distribution of economic resources, depending on the motivations of the decision maker-an effect that may contribute to the increase in racial disparities observed during economic stress. (PsycINFO Database Record


Mineral Metabolism Disturbances and Arteriovenous Fistula Maturation.
The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.


Substandard and counterfeit antimicrobials: recent trends and implications to key public health interventions in developing countries.
The objective of this review is to produce evidence on the prevalence and trends in the availability of substandard and counterfeit antimicrobials in the global market and its consequences on key public health interventions in developing countries Review of various literatures collected through the internet and other sources. Literature search using PubMed and Medline databases and Google search engine was conducted to identify related publications on the subject. Relevant published and unpublished literature was also consulted as additional source of information. During the past few decades, the trade of substandard and counterfeit medicines has increased substantially. Past experiences indicate that almost any kind of medicine can be counterfeited. In developing countries, primary targets are those antimicrobials that are commonly used in the treatment of life-threatening conditions including malaria, tuberculosis and HIV/AIDS. The findings in this review support the strong contention that substandard and counterfeit antimicrobials are available in the developing world in very high proportions. This is becoming one of the major causes of treatment failures leading to excessive mortality and morbidity. Moreover, it is implicated for contributing to the development of drug resistant organisms in many infectious diseases of public health significance such as malaria, tuberculosis and HIV/AIDS. If trends in the prevalence of counterfeit/substandard drugs continue at the current scale, there is a huge threat to interventions underway on major killer diseases in the developing world. So, public health interventions in developing countries should include quality control of antimicrobials as an integral part of program implementation. The national drug regulatory authorities in those countries should also be strengthened to enhance their capacity in enforcing regulations pertaining the registration, production, distribution and use of antimicrobial drugs.


SLCO1B1 variants and statin-induced myopathy--a genomewide study.
Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants. The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy. We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. (Current Controlled Trials number, ISRCTN74348595.)


Phylogenetic Distribution and Diversity of Bacterial Pseudo-Orthocaspases Underline Their Putative Role in Photosynthesis.
Orthocaspases are prokaryotic caspase homologs - proteases, which cleave their substrates after positively charged residues using a conserved histidine - cysteine (HC) dyad situated in a catalytic p20 domain. However, in orthocaspases pseudo-variants have been identified, which instead of the catalytic HC residues contain tyrosine and serine, respectively. The presence and distribution of these presumably proteolytically inactive p20-containing enzymes has until now escaped attention. We have performed a detailed analysis of orthocaspases in all available prokaryotic genomes, focusing on pseudo-orthocaspases. Surprisingly we identified type I metacaspase homologs in filamentous cyanobacteria. While genes encoding pseudo-orthocaspases seem to be absent in Archaea, our results show conservation of these genes in organisms performing either anoxygenic photosynthesis (orders Rhizobiales, Rhodobacterales, and Rhodospirillales in Alphaproteobacteria) or oxygenic photosynthesis (all sequenced cyanobacteria, except Gloeobacter, Prochlorococcus, and Cyanobium). Contrary to earlier reports, we were able to detect pseudo-orthocaspases in all sequenced strains of the unicellular cyanobacteria Synechococcus and Synechocystis. In silico comparisons of the primary as well as tertiary structures of pseudo-p20 domains with their presumably proteolytically active homologs suggest that differences in their amino acid sequences have no influence on the overall structures. Mutations therefore affect most likely only the proteolytic activity. Our data provide an insight into diversification of pseudo-orthocaspases in Prokaryotes, their taxa-specific distribution, and allow suggestions on their taxa-specific function.


Amyloid-beta alters trafficking of internalized acetylcholinesterase and dextran.
Amyloid-beta (Aβ), the main peptide constituent of senile plaques, is a suspected pathogenic mediator in Alzheimer's Disease (AD). Plaques also contain acetylcholinesterase (AChE), which may promote Aβ toxicity. We previously found that Aβ increased AChE levels in neuron-like N1E.115 neuroblastoma cells by reducing AChE degradation and surface shedding. Here we show that Aβ also alters the intracellular fate of surface AChE. When surface AChE was tagged with FITC-conjugated Fasciculin II (FasII), fluorescence gradually accumulated in intracellular particles. In the presence of extracellular Aβ this accumulation increased and shifted from the juxtanuclear zone to more peripheral cytoplasm. The cytoplasmic FasII-positive structures were positive for Lysosomal-Associated Membrane Protein 1, identifying them as late endosomes and early lysosomes. Thus, surface AChE trafficked into the lysosomal compartment, but further transport was impaired. Aβ also affected the transport or disposition of fluorescent dextran, an index of pinocytosis, and caused a 60% increase in intracellular accumulation similar to the lysosomotropic effects of chloroquine. On the other hand, Aβ caused no apparent changes in clathrin- and caveolae-mediated endocytosis. Overall it appears that selective alteration of endocytic mechanisms and an accumulation of organelles containing improperly processed substrates might contribute to the neuronal damage associated with age and disease-related accumulation of neurotoxic Aβ in the human brain.


Personalized medicine in psoriasis: developing a genomic classifier to predict histological response to Alefacept.
Alefacept treatment is highly effective in a select group patients with moderate-to-severe psoriasis, and is an ideal candidate to develop systems to predict who will respond to therapy. A clinical trial of 22 patients with moderate to severe psoriasis treated with alefacept was conducted in 2002-2003, as a mechanism of action study. Patients were classified as responders or non-responders to alefacept based on histological criteria. Results of the original mechanism of action study have been published. Peripheral blood was collected at the start of this clinical trial, and a prior analysis demonstrated that gene expression in PBMCs differed between responders and non-responders, however, the analysis performed could not be used to predict response. Microarray data from PBMCs of 16 of these patients was analyzed to generate a treatment response classifier. We used a discriminant analysis method that performs sample classification from gene expression data, via "nearest shrunken centroid method". Centroids are the average gene expression for each gene in each class divided by the within-class standard deviation for that gene. A disease response classifier using 23 genes was created to accurately predict response to alefacept (12.3% error rate). While the genes in this classifier should be considered as a group, some of the individual genes are of great interest, for example, cAMP response element modulator (CREM), v-MAF avian musculoaponeurotic fibrosarcoma oncogene family (MAFF), chloride intracellular channel protein 1 (CLIC1, also called NCC27), NLR family, pyrin domain-containing 1 (NLRP1), and CCL5 (chemokine, cc motif, ligand 5, also called regulated upon activation, normally T expressed, and presumably secreted/RANTES). Although this study is small, and based on analysis of existing microarray data, we demonstrate that a treatment response classifier for alefacept can be created using gene expression of PBMCs in psoriasis. This preliminary study may provide a useful tool to predict response of psoriatic patients to alefacept.


The use of vaccine antigen characterization, for example by MATS, to guide the introduction of meningococcus B vaccines.
Current concepts of vaccines against serogroup B meningococci (MenB) are mainly based on genetically variable protein antigens. Vaccine efficacy studies for meningococcal disease in developed countries are hampered by the low incidence. Licensure must therefore exclusively rely on clinical trials and laboratory investigation of meningococcal strains. In contrast to capsule polysaccharide vaccines, serum bactericidal assays for technical reasons are limited in their practicability as the surrogate of protection provided by MenB vaccines. Therefore, assays are required for reliable laboratory based assessment of expression of those specific antigen variants that are predicted to be targeted by bactericidal antibodies elicited by the vaccine. The MATS ELISA (MATS, meningococcal antigen typing system) reported recently is an example for such an assay. The paper discusses the pre- and post-licensure application of MATS, the role of reference laboratories, concepts of sustained provision of the assay, external quality assessment, and laboratory twinning.


Lipid coated liquid crystal droplets for the on-chip detection of antimicrobial peptides.
We describe a novel biosensor based on phospholipid-coated nematic liquid crystal (LC) droplets and demonstrate the detection of Smp43, a model antimicrobial peptide (AMP) from the venom of North African scorpion Scorpio maurus palmatus. Mono-disperse lipid-coated LC droplets of diameter 16.7 ± 0.2 μm were generated using PDMS microfluidic devices with a flow-focusing configuration and were the target for AMPs. The droplets were trapped in a bespoke microfluidic trap structure and were simultaneously treated with Smp43 at gradient concentrations in six different chambers. The disruption of the lipid monolayer by the Smp43 was detected (<6 μM) at concentrations well within its biologically active range, indicated by a dramatic change in the appearance of the droplets associated with the transition from a typical radial configuration to a bipolar configuration, which is readily observed by polarizing microscopy. This suggests the system has feasibility as a drug-discovery screening tool. Further, compared to previously reported LC droplet biosensors, this LC droplet biosensor with a lipid coating is more biologically relevant and its ease of use in detecting membrane-related biological processes and interactions has the potential for development as a reliable, low-cost and disposable point of care diagnostic tool.


Recruited brown adipose tissue as an antiobesity agent in humans.
Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron emission tomography and computed tomography, we previously reported that BAT decreases with age and thereby accelerates age-related accumulation of body fat in humans. Thus, the recruitment of BAT may be effective for body fat reduction. In this study, we examined the effects of repeated stimulation by cold and capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT activity. Acute cold exposure at 19°C for 2 hours increased energy expenditure (EE). Cold-induced increments of EE (CIT) strongly correlated with BAT activity independently of age and fat-free mass. Daily 2-hour cold exposure at 17°C for 6 weeks resulted in a parallel increase in BAT activity and CIT and a concomitant decrease in body fat mass. Changes in BAT activity and body fat mass were negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks increased CIT. These results demonstrate that human BAT can be recruited even in individuals with decreased BAT activity, thereby contributing to body fat reduction.


Analyzing In Silico the Relationship Between the Activation of the Edema Factor and Its Interaction With Calmodulin.
Molecular dynamics (MD) simulations have been recorded on the complex between the edema factor (EF) of Bacilllus anthracis and calmodulin (CaM), starting from a structure with the orthosteric inhibitor adefovir bound in the EF catalytic site. The starting structure has been destabilized by alternately suppressing different co-factors, such as adefovir ligand or ions, revealing several long-distance correlations between the conformation of CaM, the geometry of the CaM/EF interface, the enzymatic site and the overall organization of the complex. An allosteric communication between CaM/EF interface and the EF catalytic site, highlighted by these correlations, was confirmed by several bioinformatics approaches from the literature. A network of hydrogen bonds and stacking interactions extending from the helix V of of CaM, and the residues of the switches A, B and C, and connecting to catalytic site residues, is a plausible candidate for the mediation of allosteric communication. The greatest variability in volume between the different MD conditions was also found for cavities present at the EF/CaM interface and in the EF catalytic site. The similarity between the predictions from literature and the volume variability might introduce the volume variability as new descriptor of allostery.


An optothermally generated surface bubble and its applications.
Under laser illumination, a solid-state surface or nanostructure can turn into a micro/nano heating source with the so-called optothermal effect. This effect allows for non-invasive control of heat at the micro/nanoscale. In the presence of a liquid, a surface bubble can be generated on top of the solid surface or nanostructure at a temperature much higher than the boiling point of the liquid. The high temperature and the fluid flow associated with the optothermally generated surface bubble enable many intriguing applications, ranging from the micro/nano-manipulation of fluids, particles, cells, and light to the synthesis of micro/nano-structures under ambient conditions. In this review article, we present the fundamentals, recent developments, and future perspectives in this emerging field.


Characteristics of increased urine flow during a dry saturation dive at 31 ATA.
Three male divers were subjected to a 7-day dry saturation dive at 31 ATA (New Seatopia). Urine samples were collected for measurements of electrolytes and creatinine for glomerular filtration rate (GFR) 5 times daily, at 3-h intervals during daytime (0700-2200 h) and once at night (2200-0700 h). Collections were taken for 2 days before (predive 1 ATA air), 7 days during 31 ATA exposure, and during 10 days of decompression and for 2 days at postdive 1 ATA air. Blood samples were taken after overnight fasting at each of the dive periods for measurements of atrial natriuretic factor (ANF), electrolytes, and other blood constituents. Compression to 31 ATA resulted in a twofold increase in urine flow accompanied by increases in excretion of osmotic substances (+40%) and sodium (+54%), and a reduction in urine osmolality (-32%). The increase in urine volume was greater (P less than 0.05) at night than day with no change in GFR between day and night, confirming the earlier findings. However, no change in plasma ANF was observed in spite of a sustained increase in daily sodium and water excretion at high pressure. These results suggest that the hyperbaric diuresis-natriuresis may not be directly mediated by the ANF release.


Major Histocompatibility Complex Class II (DRB3) Genetic Diversity in Spanish Morucha and Colombian Normande Cattle Compared to Taurine and Zebu Populations.
Bovine leukocyte antigens (BoLA) have been used as disease markers and immunological traits in cattle due to their primary role in pathogen recognition by the immune system. A higher MHC allele diversity in a population will allow presenting a broader peptide repertoire. However, loss of overall diversity due to domestication process can decrease a population's peptide repertoire. Within the context of zebu and taurine cattle populations, BoLA-DRB3 genetic diversity in Spanish Morucha and Colombian Normande cattle was analyzed and an approach to estimate functional diversity was performed. Sequence-based typing was used for identifying 29, 23, 27, and 28 alleles in Spanish Morucha, Nariño-, Boyacá-, and Cundinamarca-Normande cattle, respectively. These breeds had remarkably low heterozygosity levels and the Hardy-Weinberg principle revealed significant heterozygote deficiency. FST and DA genetic distance showed that Colombian Normande populations had greater variability than other phenotypically homogeneous breeds, such as Holstein. It was also found that Spanish Morucha cattle were strongly differentiated from other cattle breeds. Spanish Morucha had greater divergence in the peptide-binding region regarding other cattle breeds. However, peptide-binding region covariation indicated that the potential peptide repertoire seemed equivalent among cattle breeds. Despite the genetic divergence observed, the extent of the potential peptide repertoire in the cattle populations studied appears to be similar and thus their pathogen recognition potential should be equivalent, suggesting that functional diversity might persist in the face of bottlenecks imposed by domestication and breeding.


The effect of postoperative enoxaparin on risk for reoperative hematoma.
The risk of postoperative bleeding is the chief concern expressed by plastic surgeons who do not use pharmacologic prophylaxis against venous thromboembolism. The Plastic Surgery Foundation-funded Venous Thromboembolism Prevention Study examined whether receipt of postoperative enoxaparin prophylaxis changed 60-day reoperative hematoma rates. In 2009, the study's network sites uniformly adopted a "best practice" clinical protocol to provide postoperative enoxaparin to adult plastic surgery patients at risk for perioperative venous thromboembolism. Historical control patients (2006 to 2008) received no chemoprophylaxis for 60 days after surgery. Retrospective chart review identified demographic and surgery-specific risk factors that potentially contributed to bleeding risk. The primary study outcome was 60-day reoperative hematoma. Stratified analyses examined reoperative hematoma in the overall population and among high-risk patients. Multivariable logistic regression controlled for identified confounders. Complete data were available for 3681 patients (2114 controls and 1567 enoxaparin patients). Overall, postoperative enoxaparin did not change the reoperative hematoma rate when compared with controls (3.38 percent versus 2.65 percent, p = 0.169). Similar results were seen in subgroup analyses for breast reconstruction (5.25 percent versus 4.21 percent, p = 0.737), breast reduction (7.04 percent versus 8.29 percent, p = 0.194), and nonbreast plastic surgery (2.20 percent versus 1.46 percent, p = 0.465). In the regression model, independent predictors of reoperative hematoma included breast surgery, microsurgical procedure, and post-bariatric surgery body contouring. Receipt of postoperative enoxaparin was not an independent predictor (odds ratio, 1.16; 95 percent CI, 0.77 to 1.76). Postoperative enoxaparin does not produce a clinically relevant or statistically significant increase in observed rates of reoperative hematoma. Risk: II.


Assessing Niche Shifts and Conservatism by Comparing the Native and Post-Invasion Niches of Major Forest Invasive Species.
Invasive species experience biotic and abiotic conditions that may (or may not) resemble their native environment. We explored the methodology of determining climatic niches and compared the native and post-invasion niches of four invasive forest pests to determine if these species experienced shifts or changes in their new climatic niches. We used environmental principle components analysis (PCA-env) method to quantify climatic niche shifts, expansions, and temporal changes. Furthermore, we assessed the effect of variable selection in the delineation and comparison of niche space. We found that variable selection influenced the delineation and overlap of each niche, whereas the subset of climatic variables selected from the first two PCA-env axes explained more variance in environmental conditions than the complete set of climatic variables for all four species. Most focal species showed climatic niche shifts in their invasive range and had not yet fully occupied the available niche within the invaded range. Our species varied the proportion of niche overlap between the native and invasive ranges. By comparing native and invasive niches, we can help predict a species' potential range expansion and invasion potential. Our results can guide monitoring and help inform management of these and other invasive species.


Evaluation of near infra-red interactance as a method for predicting body composition.
The ability of near infra-red interactance (NIRI) to predict body composition, as measured by whole-body densitometry, was assessed in a group of 29 healthy volunteers; 15 m, 14 f, aged 18-40 years, body mass index (BMI) 18.3-28.5 kg/m2. The results were compared with those obtained by five other predictive methods: whole-body impedance/resistance, skinfold thicknesses, and methods based on weight and height or BMI. The correlation between densitometry and the alternative methods, including NIRI, were found to be remarkably similar, both with respect to fat (r = 0.90-0.92, s.e.e. = 2.12-2.47 kg), and fat-free mass (r = 0.96-0.97, s.e.e. = 2.13-2.71 kg). Percentage body fat (densitometry) correlated better with the near infrared measurements made in the biceps area than with those made in the triceps or thigh areas, or with a combination of measurements made at two or three sites. The 95 per cent limits of agreement between NIRI and densitometry for the estimation of body constituents were slightly greater than those between densitometry and the other methods. NIRI was also found to underestimate body fat increasingly as the degree of adiposity increased. This under-estimation was found to be particularly marked (16 per cent body weight) in a small and separate group of grossly obese women, BMI greater than 50 kg/m2, whose body composition was assessed by total body potassium as well as by densitometry. This study suggests that, in the healthy group of subjects examined, NIRI has little or no advantage over other simple methods in predicting body composition measured by classical whole-body densitometry.


The long-term effects of laser photocoagulation treatment in patients with diabetic retinopathy: the early treatment diabetic retinopathy follow-up study.
To evaluate the long-term natural history and effects of laser photocoagulation treatment in patients with diabetic retinopathy. Follow-up study of the 214 surviving patients enrolled originally at the Johns Hopkins Clinical Center for the Early Treatment Diabetic Retinopathy Study (ETDRS), which was a clinical trial designed to evaluate the role of laser photocoagulation and aspirin treatment in patients with diabetic retinopathy. Early Treatment Diabetic Retinopathy Study patients enrolled in the Johns Hopkins Clinical Center had complete eye examinations, including best-corrected visual acuity measurements, fundus photographs, and medical questionnaires throughout the 7-year study. They had the same examinations at the final long-term follow-up visit at the National Eye Institute, National Institutes of Health, 13 to 19.5 years after the initial laser photocoagulation (median, 16.7 years). The major outcomes were mortality and the rates of moderate and severe vision loss. The secondary outcomes were progression of diabetic retinopathy and need for other eye surgery. Of the 214 patients who were alive at the end of the original ETDRS in 1989, 130 (61%) were deceased at the time of the re-examination. Of the 84 who were alive, 71 (85%) were examined at their long-term follow-up visit at the National Institutes of Health. At the long-term follow-up examination, 42% had visual acuity of 20/20 or better, and 84% had visual acuity of 20/40 or better in the better eye. Compared with baseline, 20% of patients had moderate vision loss (loss of 3 lines or more vision) in the better eye at follow-up. Only one patient had visual acuity of 20/200 bilaterally. He had visual acuity loss secondary to age-related macular degeneration. No patient had severe vision loss (worse than 5/200). All the initially untreated eyes of patients who had severe nonproliferative diabetic retinopathy or worse by the time of the ETDRS closeout visit of the original study received scatter photocoagulation treatment. Focal photocoagulation was performed in 43% bilaterally and 22% unilaterally. Cataract surgery was performed in 31% of the patients, vitrectomy in 17%, and glaucoma surgery in one patient. As previously reported, the mortality rate of patients with diabetic retinopathy is much higher than that of the general population. For those who survived, aggressive follow-up, with treatment when indicated, seems to be associated with maintenance of good long-term visual acuity for most patients. The need for laser scatter photocoagulation with long-term follow-up seems to be high.


Internet Usage by Women with Eating Disorders during Illness and Recovery.
Internet usage may have both positive and negative impacts on people with eating disorders. In research to date, most of the focus has been put on the harms connected with platforms that support people in continuing their disorder. Less studied have been the benefits of other technology platforms used by people with eating disorders. When these different platforms were investigated, users were rarely interviewed about their experience. To fill this gap, we conducted 30 interviews with participants aged 16 to 28, all female, living in the Czech Republic. The interviews focused on their experiences with the harmful and helpful impacts of the internet on the course of their eating disorders. The data were analyzed via thematic analysis. The results provided insight into the participants' experience with the following online environments: 1) nonprofessional pro-eating disorder platforms; 2) nonprofessional pro-recovery platforms; 3) social networking sites (SNS); 4) platforms for counting calories and setting weight goals; 5) platforms about food, exercise, and lifestyle; and 6) platforms providing professional help. The participants noted many benefits these platforms could provide; however, their ability to achieve the benefits was affected by their motivation for treatment. As a result, even platforms designed to support recovery could be used for illness maintenance. The results are discussed in the context of research on the changing motivations for recovery in people with eating disorders and the theory of different processes connected to the course of the eating disorders according to the differential interactivity of digital platforms.


Structural features of the diatom photosystem II-light-harvesting antenna complex.
In photosynthesis, light energy is captured by pigments bound to light-harvesting antenna proteins (LHC) that then transfer the energy to the photosystem (PS) cores to initiate photochemical reactions. The LHC proteins surround the PS cores to form PS-LHC supercomplexes. In order to adapt to a wide range of light environments, photosynthetic organisms have developed a large variety of pigments and antenna proteins to utilize the light energy efficiently under different environments. Diatoms are a group of important eukaryotic algae and possess fucoxanthin (Fx) chlorophyll a/c proteins (FCP) as antenna which have exceptional capabilities of harvesting blue-green light under water and dissipate excess energy under strong light conditions. We have solved the structure of a PSII-FCPII supercomplex from a centric diatom Chaetoceros gracilis by cryo-electron microscopy, and also the structure of an isolated FCP dimer from a pennate diatom Phaeodactylum tricornutum by X-ray crystallography at a high resolution. These results revealed the oligomerization states of FCPs distinctly different from those of LHCII found in the green lineage organisms, the detailed binding patterns of Chl c and Fxs, a huge pigment network, and extensive protein-protein, pigment-protein, and pigment-pigment interactions within the PSII-FCPII supercomplex. These results therefore provide a solid structural basis for examining the detailed mechanisms of the highly efficient energy transfer and quenching processes in diatoms.


The differential characterization of GPR55 receptor in human peripheral blood reveals a distinctive expression in monocytes and NK cells and a proinflammatory role in these innate cells.
G protein-coupled receptor 55 (GPR55) is activated by endogenous, plant-derived and synthetic cannabinoids. Recent studies reported a broad tissue distribution for GPR55 and found prominent roles for this receptor in inflammatory pain, gut and bone physiology, as well as cancer. However, little is known about the expression and function of GPR55 in immune cells. To address this question, we performed a detailed characterization of GPR55 in different human innate and adaptive immune populations using polychromatic flow cytometry and we found that monocytes and NK cells expressed remarkable levels of this receptor compared to several cells of adaptive immunity. GPR55 activation by the specific agonist O-1602 boosted IL-12 and TNF-α production, and decreased endocytic activity, in LPS-activated monocytes. In addition, it increased CD69 activation marker expression, granzyme B and CD107a-dependent cytotoxicity and IFN-γ and TNF-α production in NK cells activated by both IL-2 and IL-12. These over-stimulatory effects of GPR55 were antagonized by its selective antagonist cannabidiol. Altogether, our data thus unveil a proinflammatory role for GPR55 in innate immunity that may be important for the design of new immune therapeutic strategies.


Listeria monocytogenes infection of HD11, chicken macrophage-like cells.
Listeria monocytogenes can be carried by and infect poultry, although the clinical disease in birds is rare. Escape from macrophage phagocytosis is a key step in pathogenesis for L. monocytogenes. Therefore, we investigated the infection of the chicken macrophage-like cell line HD11 with 2 strains of L. monocytogenes EGD-e and Scott A. After infection, L. monocytogenes was quantified by spread plating and HD11 was quantified with trypan blue exclusion stain before enumeration. The standard macrophage killing protocols require washing the cell monolayers 3 times with PBS, which was found to negatively influence HD11 monolayers. Maximum bacterial densities within macrophages were not different between the 2 Listeria strains. HD11 required more than 11 h to effectively reduce intracellular L. monocytogenes Scott A, and Scott A was more susceptible to HD11 killing than EGD-e. It appears that Listeria infection initially causes attenuation of HD11 growth, and infected HD11 cells do not begin to lyse until at least 11 h post infection. These results suggest that there are subtle strain to strain differences in response to HD11 macrophage phagocytosis. The long lead-time required for HD11 to kill L. monocytogenes cells means that there is sufficient time available for chicken macrophages to circulate in the blood and transfer the intracellular Listeria to multiple tissues.