Access to free or low-cost tuberculosis treatment for migrants and refugees along the Thailand-Myanmar border in Tak province, Thailand.
In Tak province, Thailand migrants and refugees from Myanmar navigate a pluralistic healthcare system to seek Tuberculosis (TB) care from a variety of government and non-governmental providers. This multi-methods qualitative study examined access to TB, TB/HIV and multidrug-resistant tuberculosis (MDR-TB) treatment with an emphasis on barriers to care and enabling factors. In the summer and fall of 2014, we conducted 12 key informant interviews with public health officials and TB treatment providers. We also conducted 11 focus group discussions with migrants and refugees who were receiving TB, TB/HIV and MDR-TB treatment in Tak province as well as non-TB patients. We analyzed these data through thematic analysis using both predetermined and emergent codes. As a second step in the qualitative analysis, we explored the barriers and enabling factors separately for migrants and refugees. We found that refugees face fewer barriers to accessing TB treatment than migrants. For both migrants and refugees, legal status plays an important intermediary role in influencing the population's ability to access care and eligibility for treatment. Our results suggest that there is a large geographical catchment area for migrants who seek TB treatment in Tak province that extends beyond provincial boundaries. Migrant participants described their ability to seek care as linked to the financial and non-financial resources required to travel and undergo treatment. Patients identified language of health services, availability of free or low cost services, and psychosocial support as important health system characteristics that affect accessibility. Access to TB treatment for migrants and refugees occurs at the interface of health system accessibility, population ability and legal status. In Tak province, migrant patients draw upon their social networks and financial resources to navigate a pathway to treatment. We revised a conceptual framework for access to healthcare to incorporate legal status and the cyclical pathways through which migrants access TB treatment in this region. We recommend that organizations continue to collaborate to provide supportive services that help migrants to access and continue TB treatment.


Filarial Infection or Antigen Administration Improves Glucose Tolerance in Diet-Induced Obese Mice.
Helminths induce type 2 immune responses and establish an anti-inflammatory milieu in their hosts. This immunomodulation was previously shown to improve diet-induced insulin resistance which is linked to chronic inflammation. In the current study, we demonstrate that infection with the filarial nematode Litomosoides sigmodontis increased the eosinophil number and alternatively activated macrophage abundance within epididymal adipose tissue (EAT) and improved glucose tolerance in diet-induced obese mice in an eosinophil-dependent manner. L. sigmodontis antigen (LsAg) administration neither altered the body weight of animals nor adipose tissue mass or adipocyte size, but it triggered type 2 immune responses, eosinophils, alternatively activated macrophages, and type 2 innate lymphoid cells in EAT. Improvement in glucose tolerance by LsAg treatment remained even in the absence of Foxp3+ regulatory T cells. Furthermore, PCR array results revealed that LsAg treatment reduced inflammatory immune responses and increased the expression of genes related to insulin signaling (Glut4, Pde3b, Pik3r1, and Hk2) and fatty acid uptake (Fabp4 and Lpl). Our investigation demonstrates that L. sigmodontis infection and LsAg administration reduce diet-induced EAT inflammation and improve glucose tolerance. Helminth-derived products may, therefore, offer new options to improve insulin sensitivity, while loss of helminth infections in developing and developed countries may contribute to the recent increase in the prevalence of type 2 diabetes.


Spatial effects on species persistence and implications for biodiversity.
Natural ecosystems are characterized by striking diversity of form and functions and yet exhibit deep symmetries emerging across scales of space, time, and organizational complexity. Species-area relationships and species-abundance distributions are examples of emerging patterns irrespective of the details of the underlying ecosystem functions. Here we present empirical and theoretical evidence for a new macroecological pattern related to the distributions of local species persistence times, defined as the time spans between local colonizations and extinctions in a given geographic region. Empirical distributions pertaining to two different taxa, breeding birds and herbaceous plants, analyzed in a framework that accounts for the finiteness of the observational period exhibit power-law scaling limited by a cutoff determined by the rate of emergence of new species. In spite of the differences between taxa and spatial scales of analysis, the scaling exponents are statistically indistinguishable from each other and significantly different from those predicted by existing models. We theoretically investigate how the scaling features depend on the structure of the spatial interaction network and show that the empirical scaling exponents are reproduced once a two-dimensional isotropic texture is used, regardless of the details of the ecological interactions. The framework developed here also allows to link the cutoff time scale with the spatial scale of analysis, and the persistence-time distribution to the species-area relationship. We conclude that the inherent coherence obtained between spatial and temporal macroecological patterns points at a seemingly general feature of the dynamical evolution of ecosystems.


A vibration-insensitive optical cavity and absolute determination of its ultrahigh stability.
We use the three-cornered-hat method to evaluate the absolute frequency stabilities of three different ultrastable reference cavities, one of which has a vibration-insensitive design that does not even require vibration isolation. An Nd:YAG laser and a diode laser are implemented as light sources. We observe approximately 1 Hz beat note linewidths between all three cavities. The measurement demonstrates that the vibration-insensitive cavity has a good frequency stability over the entire measurement time from 100 ms to 200 s. An absolute, correlation-removed Allan deviation of 1.4 x 10(-15) at s of this cavity is obtained, giving a frequency uncertainty of only 0.44 Hz.


The Effects of Adjuvant Endocrine Treatment on Serum Leptin, Serum Adiponectin and Body Composition in Patients with Breast Cancer: The Izmir Oncology Group (IZOG) Study.
A limited number of studies have been conducted on the effects of hormonal therapy with tamoxifen (TMX) or aromatase inhibitors (AIs) on plasma levels of leptin and adiponectin, as well as body composition in breast cancer (BC) patients. Therefore, we aimed to analyze the relationship between adipocytokines and body composition as well as the effects of TMX and AIs on plasma adiponectin, leptin, leptin/adiponectin ratio (LAR) and body composition. Patients were treated with either TMX or AI according to their menopausal status after adjuvant radiotherapy. Changes in body composition and serum leptin and adiponectin levels were evaluated. We recorded the type of hormonal therapy, BMI, waist/hip ratio (WHR), leptin and adiponectin levels at study entry, and after 6 and 12 months. From baseline to the 6- and 12-month follow-ups, there were statistically significant increases in WHR (p = 0.003), fat mass (p = 0.041), and serum leptin (p < 0.001) and adiponectin levels (p < 0.001). The changes in body composition and serum leptin and adiponectin levels were similar in TMX and AI groups. A statistically significant decrease was found in total body water and LAR (p < 0.001). Although weight and body fat percentage increased, such increases were not statistically significant. A positive correlation was found between baseline BMI and serum leptin levels. This correlation was maintained at 6 and 12 months. The negative correlation found between serum adiponectin levels at baseline and baseline BMI did not last throughout the study. In this study, increased leptin and adiponectin levels and a decreased LAR were found in both AI and TMX groups. These changes might have occurred through both mechanisms of hormonal therapy and body composition changes. Therefore, AIs and TMX may exert their protective effects for BC patients by decreasing LAR rather than affecting leptin or adiponectin alone.


Fgf signalling controls diverse aspects of fin regeneration.
Studies have shown that fibroblast growth factor (Fgf) signalling is necessary for appendage regeneration, but its exact function and the ligands involved during regeneration have not yet been elucidated. Here, we performed comprehensive expression analyses and identified fgf20a and fgf3/10a as major Fgf ligands in the wound epidermis and blastema, respectively. To reveal the target cells and processes of Fgf signalling, we performed a transplantation experiment of mesenchymal cells that express the dominant-negative Fgf receptor 1 (dnfgfr1) under control of the heat-shock promoter. This mosaic knockdown analysis suggested that Fgf signalling is directly required for fin ray mesenchyme to form the blastema at the early pre-blastema stage and to activate the regenerative cell proliferation at a later post-blastema stage. These results raised the possibility that the early epidermal Fgf20a and the later blastemal Fgf3/10a could be responsible for these respective processes. We demonstrated by gain-of-function analyses that Fgf20a induces the expression of distal blastema marker junbl, and that Fgf3 promotes blastema cell proliferation. Our study highlights that Fgfs in the wound epidermis and blastema have distinct functions to regulate fin regeneration cooperatively.


Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation.
Recent studies have suggested that bone marrow cells might possess a much broader differentiation potential than previously appreciated. In most cases, the reported efficiency of such plasticity has been rather low and, at least in some instances, is a consequence of cell fusion. After myocardial infarction, however, bone marrow cells have been suggested to extensively regenerate cardiomyocytes through transdifferentiation. Although bone marrow-derived cells are already being used in clinical trials, the exact identity, longevity and fate of these cells in infarcted myocardium have yet to be investigated in detail. Here we use various approaches to induce acute myocardial injury and deliver transgenically marked bone marrow cells to the injured myocardium. We show that unfractionated bone marrow cells and a purified population of hematopoietic stem and progenitor cells efficiently engraft within the infarcted myocardium. Engraftment was transient, however, and hematopoietic in nature. In contrast, bone marrow-derived cardiomyocytes were observed outside the infarcted myocardium at a low frequency and were derived exclusively through cell fusion.


The rise and fall of the craniocervical junction relative to the hard palate: a lifetime story.
Endoscopic approaches to the anterior craniocervical junction are increasing in frequency. Choice of oral versus endoscopic endonasal approach to the odontoid often depends on the relationship of the C1-2 complex to the hard palate. However, it is not known how this relevant anatomy changes with age. We hypothesize that there is a dynamic relationship of C-2 and the hard palate, which changes with age, and potentially affects the choice of surgical approach. The aim of this study was to characterize the relationship of C-2 relative to the hard palate with respect to age and sex. Emergency department billing and trauma records from 2008 to 2014 were reviewed for patients of all ages who underwent cervical or maxillofacial CT as part of a trauma evaluation for closed head injury. Patients who had a CT scan that allowed adequate visualization of the hard palate, opisthion, and upper cervical spine (C-1 and C-2) were included. Patients who had cervical or displaced facial/skull base fractures, a history of rheumatoid arthritis, or craniofacial anomalies were excluded. The distance from McGregor's palatooccipital line to the midpoint of the inferior endplate of C-2 (McL-C2) was measured on midsagittal CT scans. Patients were grouped by decile of age and by sex. A 1-way ANOVA was performed with each respective grouping. Ultimately, 483 patients (29% female) were included. The mean age was 46 ± 24 years. The majority of patients studied were in the 2nd through 8th decades of life (85%). Significant variation was found between McL-C2 and decile of age (p < 0.001) and sex (p < 0.001). The mean McL-C2 was 27 mm in the 1st decade of life compared with the population mean of 37 mm. The mean McL-C2 was also noted to be smaller in females (mean difference 4.8 mm, p < 0.0001). Both decile of age (p = 0.0009) and sex (p < 0.0001) were independently correlated with McL-C2 on multivariate analysis. The relationship of C-2 and the hard palate significantly varies with respect to age and sex, descending relative to the hard palate a full centimeter on average in adulthood. These findings may have relevance in determining optimal surgical approaches for addressing pathology involving the anterior craniocervical junction.


From single-use to multi-use: Study of consumers' behavior toward consumption of reusable containers.
This study advances the theory of planned behavior (TPB) to identify the mechanism that underlies the consumption of reusable containers. A questionnaire including context, motivation, subjective norms, attitudes, perceived behavioral control, intentions and behavior items was developed and pre-tested on 180 students in a Canadian and a Chinese university respectively. Subsequently, the questionnaire was implemented in the form of an online survey and 1221 effective responses were collected from Western (n = 549) and Asian (n = 672) consumers. The findings revealed that the context and motivation variables are important antecedents to several TPB constructs. Context strongly impacts perceived behavioral control and motivations as well as attitudes. Motivation is clearly distinct from intentions and has a significant influence on both attitudes and intentions. In addition to the standard variables of perceived behavioral control, subjective norms and attitudes, motivation does have a significant impact on intentions. Furthermore, there are cultural differences in the way context impacts intentions and behavior in that Asians (Westerners) are influenced by context to increase reusable containers consumption through motivation (attitudes). Attitude is a significantly stronger predictor of intentions for Westerners than Asians.


Malabsorption and intestinal adaptation after one anastomosis gastric bypass compared with Roux-en-Y gastric bypass in rats.
The technically easier one-anastomosis (mini) gastric bypass (MGB) is associated with similar metabolic improvements and weight loss as the Roux-en-Y gastric bypass (RYGB). However, MGB is controversial and suspected to result in greater malabsorption than RYGB. In this study, we compared macronutrient absorption and intestinal adaptation after MGB or RYGB in rats. Body weight and food intake were monitored and glucose tolerance tests were performed in rats subjected to MGB, RYGB, or sham surgery. Carbohydrate, protein, and lipid absorption was determined by fecal analyses. Intestinal remodeling was evaluated by histology and immunohistochemistry. Peptide and amino acid transporter mRNA levels were measured in the remodeled intestinal mucosa and those of anorexigenic and orexigenic peptides in the hypothalamus. The MGB and RYGB surgeries both resulted in a reduction of body weight and an improvement of glucose tolerance relative to sham rats. Hypothalamic orexigenic neuropeptide gene expression was higher in MGB rats than in RYGB or sham rats. Fecal losses of calories and proteins were greater after MGB than RYGB or sham surgery. Intestinal hyperplasia occurred after MGB and RYGB with increased jejunum diameter, higher villi, and deeper crypts than in sham rats. Peptidase and peptide or amino acid transporter genes were overexpressed in jejunal mucosa from MGB rats but not RYGB rats. In rats, MGB led to greater protein malabsorption and energy loss than RYGB. This malabsorption was not compensated by intestinal overgrowth and increased expression of peptide transporters in the jejunum.


Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments.
Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, thus ranking among the major causes of disability and morbidity worldwide. To date, genetic and environmental determinants of MDD remain mostly unknown. Here, we investigated whether and how the Plasminogen Activator Inhibitor-1 (PAI-1) may contribute to MDD. We first examined the phenotype of PAI-1 knockout (PAI-1-/-) and wild-type (PAI-1+/+) male mice with a range of behavioral tests assessing depressive-like behaviors (n = 276). We next investigated the mechanisms relating PAI-1 to MDD using molecular, biochemical and pharmacological analyzes. We demonstrate here that PAI-1 plays a key role in depression by a mechanism independent of the tissue-type Plasminogen Activator (tPA) - Brain-Derived Neurotrophic Factor (BDNF) axis, but associated with impaired metabolisms of serotonin and dopamine. Our data also reveal that PAI-1 interferes with therapeutic responses to selective serotonin reuptake inhibitors (escitalopram, fluoxetine). We thus highlight a new genetic preclinical model of depression, with the lack of PAI-1 as a factor of predisposition to MDD. Altogether, these original data reveal that PAI-1 should be now considered as a key player of MDD and as a potential target for the development of new drugs to cure depressive patients resistant to current treatments.


Comparison of Brachial Vein Versus Internal Jugular Vein Approach for Access to the Right Side of the Heart With or Without Myocardial Biopsy.
Right heart catheterization (RHC) and endomyocardial biopsy are mainstay procedures for patients with heart failure and heart transplantation. Approaches are predominantly neck (internal jugular) or leg (femoral vein). We describe a novel arm (brachial/basilica vein) approach. Over 5.5 years, 1,130 right-sided cardiac procedures in 276 patients were analyzed retrospectively and divided into either neck or arm approach. Comparative analyses of procedural success, time, safety, efficacy, and cost were performed. Patient preference was assessed for those who had both neck and arm approaches. In patients receiving RHC (174 neck and 121 arm cases) and in those receiving RHC + biopsy (594 neck and 141 arm cases), mean elapsed and fluoroscopic times (minutes), respectively, were 60 ± 20 versus 62 ± 19 and 3.43 ± 3.8 versus 4.99 ± 5.2 (RHC neck vs arm, respectively), and 55 ± 19 versus 63 ± 17 and 4.14 ± 3.4 versus 5.22 ± 2.6 (RHC + biopsy neck vs arm, respectively). Procedural complications were low (n = 7, 0.6%) and restricted to the neck approach. Patients surveyed preferred the arm approach. In conclusion, RHC and endomyocardial biopsy through the brachial vein can be performed safely, timely, effectively, and at equivalent cost compared with a neck approach. We advocate that an arm approach be the preferred method for these procedures.


Cryopreserved or Fresh Mesenchymal Stromal Cells: Only a Matter of Taste or Key to Unleash the Full Clinical Potential of MSC Therapy?
Mesenchymal stromal cells (MSCs) harbor great therapeutic potential for numerous diseases. From early clinical trials, success and failure analysis, bench-to-bedside and back-to-bench approaches, there has been a great gain in knowledge, still leaving a number of questions to be answered regarding optimal manufacturing and quality of MSCs for clinical application. For treatment of many acute indications, cryobanking may remain a prerequisite, but great uncertainty exists considering the therapeutic value of freshly thawed (thawed) and continuously cultured (fresh) MSCs. The field has seen an explosion of new literature lately, outlining the relevance of the topic. MSCs appear to have compromised immunomodulatory activity directly after thawing for clinical application. This may provide a possible explanation for failure of early clinical trials. It is not clear if and how quickly MSCs recover their full therapeutic activity, and if the "cryo stun effect" is relevant for clinical success. Here, we will share our latest insights into the relevance of these observations for clinical practice that will be discussed in the context of the published literature. We argue that the differences of fresh and thawed MSCs are limited but significant. A key issue in evaluating potency differences is the time point of analysis after thawing. To date, prospective double-blinded randomized clinical studies to evaluate potency of both products are lacking, although recent progress was made with preclinical assessment. We suggest refocusing therapeutic MSC development on potency and safety assays with close resemblance of the clinical reality.


The influence of convergence angle and dentin micromorphology on shear bond strength of adhesive resin luting cement.
To determine the influence of convergence angles and axial planes on shear bond strength between dentin and adhesive composite resin luting cement, and its relation to dentin micromorphology. The four axial planes of 60 intact extracted mandibular molars were prepared at either 4 or 20 degrees to the longitudinal tooth axis. A Teflon cylindrical mold (1.6 mm) was filled with Rely X-ARC, bonded to Single Bond treated dentin surface and tested for shear bond strength after 7 days. Three SEM micrographs (5000X magnification) were taken from each surface after removing the bonding layer. The tubule circumference was marked using Adobe Photoshop. Micromorphology parameters were analyzed with the MATLAB program. A Mixed Effect Linear Model and linear regression were performed to analyze the influence of tubule density, tubule area, tubule circumference, and residual dentin thickness on shear bond strength. The shear bond strength was not significantly different between axial planes (p > 0.05), but was significantly higher at 4 degrees than at 20 degrees (p = 0.009). A significant positive correlation was found between shear bond strength and tubule area (R = 0.43, p = 0.003) or tubule circumference (R = 0.42, p = 0.003), confirming the importance of resin penetration into the tubules. No correlation was found between shear bond strength and tubule density (R = 0.22, p > 0.05) or residual dentin thickness (R = -0.22, p > 0.05). More round and more elliptic tubule orifices characterized dentin prepared at 4 and 20 degrees, respectively. Regional variations in tubule cross-section appearance can modify the bond strength of adhesive resin luting cements.


Comparison of efficacy of tray-delivered carbamide and hydrogen peroxide for at-home bleaching: a systematic review and meta-analysis.
The aim of the study was to compare the color change produced by tray-delivered carbamide peroxide [CP] versus hydrogen peroxide products [HP] for at-home bleaching through a systematic review and meta-analysis. MEDLINE via PubMeb, Scopus, Web of Science, Latin American and Caribbean Health Sciences Literature database (LILACS), Brazilian Library in Dentistry (BBO), and Cochrane Library and Grey literature were searched without restrictions. The abstracts of the International Association for Dental Research (IADR) and unpublished and ongoing trial registries were also searched. Dissertations and theses were explored using the ProQuest Dissertations and Periodicos Capes Theses databases. We included randomized clinical trials that compared tray-delivered CP versus HP for at-home dental bleaching. The color change in shade guide units (SGU) and ΔE were the primary outcomes, and tooth sensitivity and gingival irritation were the secondary outcomes. The risk of bias tool of the Cochrane Collaboration was used for quality assessment. After duplicate removal, 1379 articles were identified. However, only eight studies were considered to be at "low" risk of bias in the key domains of the risk bias tool and they were included in the analysis. For ΔE, the standardized mean difference was -0.45 (95 % CI -0.69 to -0.21), which favored tray-delivered CP products (p < 0.001). The color change in ΔSGU (p = 0.70), tooth sensitivity (p = 0.83), and gingival irritation (p = 0.62) were not significantly different between groups. Tray-delivered CP gels showed a slightly better whitening efficacy than HP-based products in terms of ΔE, but they were similar in terms of ΔSGU. Both whitening systems demonstrated equal level of gingival irritation and tooth sensitivity. Tray-delivered CP gels have a slightly better whitening efficacy than HP-based products in terms of ΔE. This should be interpreted with caution as the data of ΔSGU did not show statistical difference between the products.


Water-borne and plasma corticosterone are not correlated in spotted salamanders.
Water-borne hormone measurement is a noninvasive method suitable for amphibians of all sizes that are otherwise difficult to sample. For this method, containment-water is assayed for hormones released by the animal. Originally developed in fish, the method has expanded to amphibians, but requires additional species-specific validations. We wanted to determine physiological relevance of water-borne corticosterone in spotted salamanders (Ambystoma maculatum) by comparing concentrations to those taken using established corticosterone sampling methods, such as plasma. Using a mixture of field and laboratory studies, we compared water-borne corticosterone levels to other traditional methods of sampling corticosterone for spotted salamander larvae, metamorphs, and adults. Despite multiple attempts, and detecting differences between age groups, we found no correlations between water-borne and plasma corticosterone levels in any age group. Water-borne sampling measures a rate of release; whereas plasma is the concentration circulating in the blood. The unique units of measurement may inherently prevent correlations between the two. These two methods may also require different interpretations of the data and the physiological meaning. We also note caveats with the method, including how to account for differences in body size and life history stages. Collectively, our results illustrate the importance of careful validation of water-borne hormone levels in each species in order to understand its physiological significance.


Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation.
Chronic atrial fibrillation is associated with a shortening of the atrial action potential duration and atrial refractory period. To test the hypothesis that these changes are mediated by changes in the density of specific atrial K+ currents, we compared the density of K+ currents in left and right atrial myocytes and the density of delayed rectifier K+ channel alpha-subunit proteins (Kv1.5 and Kv2.1) in left and right atrial appendages from patients (n = 28) in normal sinus rhythm with those from patients (n = 15) in chronic atrial fibrillation (AF). Contrary to our expectations, nystatin-perforated patch recordings of whole-cell K+ currents revealed significant reductions in both the inactivating (ITO) and sustained (IKsus) outward K+ current densities in left and right atrial myocytes isolated from patients in chronic AF, relative to the ITO and IKsus densities in myocytes isolated from patients in normal sinus rhythm. Quantitative Western blot analysis revealed that although there was no change in the expression of the Kv2.1 protein, the expression of Kv1.5 protein was reduced by > 50% in both the left and the right atrial appendages of AF patients. The finding that Kv1.5 expression is reduced in parallel with the reduction in delayed rectifier K+ current density is consistent with recent suggestions that Kv1.5 underlies the major component of the delayed rectifier K+ current in human atrial myocytes, the ultrarapid delayed rectifier K+ current, IKur. The unexpected finding of reduced voltage-gated outward K+ current densities in atrial myocytes from AF patients demonstrates the need to further examine the details of the electrophysiological remodeling that occurs during AF to enable more effective and safer therapeutic strategies to be developed.


Impact of a probiotic fermented milk in the gut ecosystem and in the systemic immunity using a non-severe protein-energy-malnutrition model in mice.
Malnutrition affects the immune response, causing a decrease of defence mechanisms and making the host more susceptible to infections. Probiotics can reconstitute the intestinal mucosa and stimulate local and systemic immunity. The aim of this work was evaluate the effects of a probiotic fermented milk as a complement of a re-nutrition diet, on the recovery of the intestinal barrier, and mucosal and systemic immune functions in a murine model of non-severe protein-energy-malnutrition. Its potential protection against Salmonella enterica serovar Typhimurium (S. Typhimurium) infection was also analyzed. Mice were undernourished and divided into 3 groups according to the dietary supplement received during re-nutrition (milk, probiotic fermented milk or its bacterial free supernatant) and compared to well-nourished and malnourished mice. They were sacrificed previous to the re-nutrition and 5 days post re-nutrition. The phagocytic activity of macrophages from spleen and peritoneum and the changes in the intestinal histology and microbiota were evaluated. Different immune cell populations and cytokine productions were analyzed in the small intestine tissues. The effect of the re-nutrition supplements on the systemic immunity using OVA antigen and against an infection with S. Typhimurium was also studied. Probiotic fermented milk was the most effective re-nutrition diet that improved the intestinal microbiota. Its administration also increased the number of IgA+ cells, macrophages and dendritic cells. The production of different cytokine (IFN-γ, TNF-α, IL-12) by these cells and the phagocytic activity in peritoneum and spleen was also increased. This re-nutrition diet also stimulated the systemic immune response against OVA antigen which was diminished after the malnutrition period and also improved the host response against S. Typhimurium, decreasing the spread of pathogenic bacteria to the liver and the spleen. The importance of the metabolites released during milk fermentation was also demonstrated through the analysis of the bacterial free supernatant obtained from the probiotic fermented milk, but the whole product showed the best effects in the parameters evaluated in this study. The administration of probiotic fermented milk as a dietary supplement during the re-nutrition process in a murine immunodeficiency model by malnutrition could be a good adjuvant diet to improve the gut and systemic immune response for the protection against Salmonella infection.


Cannabinoids as therapeutic agents for ablating neuroinflammatory disease.
Cannabinoids have been reported to alter the activities of immune cells in vitro and in vivo. These compounds may serve as ideal agents for adjunct treatment of pathological processes that have a neuroinflammatory component. As highly lipophilic molecules, they readily access the brain. Furthermore, they have relatively low toxicity and can be engineered to selectively target cannabinoid receptors. To date, two cannabinoid receptors have been identified, characterized and designated CB(1) and CB(2). CB(1) appears to be constitutively expressed within the CNS while CB(2) apparently is induced during inflammation. The inducible nature of expression of CB(2) extends to microglia, the resident macrophages of the brain that play a critical role during early stages of inflammation in that compartment. Thus, the cannabinoid-cannabinoid receptor system may prove therapeutically manageable in ablating neuropathogenic disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, HIV encephalitis, closed head injury, and granulomatous amebic encephalitis.


HIV/AIDS and older adults in Cameroon: Emerging issues and implications for caregiving and policy-making.
The burden of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) on the elderly population in three divisions within the Northwest Region of Cameroon was examined. Data for this paper were extracted from a larger study which had been conducted concerning the burden of HIV infection and AIDS on the older adults in the Northwest Region of Cameroon. Using in-depth interviews (IDIs) and focus group discussions (FGDs), data were collected from 36 participants who were purposively selected from the three divisions which had been chosen randomly. 6 FGD sessions were held with 30 women aged 60 years and above and who were affected by HIV infection and AIDS, while IDIs sessions were held with 6 male community leaders. The results revealed that HIV infection and AIDS has added another dimension to the role of older persons. HIV infection and AIDS affects older people in diverse ways, as they have to look after themselves, their sick children and are often also left to look after their grandchildren orphaned by HIV infection and AIDS. These emerging issues in their lives make them vulnerable to health, social, economic and psychological challenges, and place a burden on them as caregivers instead of being cared for in their old age. Apart from increased direct expenditures, taking care of victims of HIV infection and AIDS requires older people to stay away from social, religious and community activities. The results showed that the loss of a child to HIV infection and AIDS affects the economic/financial well-being, participation in social/religious interactions as well as the community activities of older people participants. The implications of these findings for caregiving and social policy are discussed.


Mural art therapy for young offenders hospitalised with a mental illness.
To describe a mural art therapy project completed within an adolescent unit of a secure forensic psychiatric hospital. The planning, implementation and consecutive stages of the mural art therapy project are described. Pertinent themes are identified. A cohort of adolescent forensic inpatients was engaged in a group therapeutic process involving collaboration, design and the completion of an art mural. The participants generally approved of the project and identified themes of gaining a sense of achievement, empowerment, teamwork, involvement and ownership. The art mural transformed and improved the visual and spatial environment of the Adolescent unit courtyard. Mural art therapy was acceptable to young offenders hospitalised with mental illness, which has relevance for adolescent psychiatric units and youth detention centres.


Aldosterone in renal disease.
Blockade of the renin-angiotensin-aldosterone system has proved effective in retarding the progression of renal disease in the remnant kidney model, as well as other experimental diseases, and most importantly, in a range of progressive human renal diseases. Attention has focused on the role of angiotensin II in propagating progression both by its hemodynamic and non-hemodynamic actions. Recent evidence, predominantly in the remnant kidney model, indicates that the drugs used to block this hormone system, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, also lower aldosterone levels. Aldosterone as well as angiotensin II thus appears to be instrumental in sustaining the hypertension and fibroproliferative destruction of the residual kidney.


Aggregate availability of doctors in India: 2014-2030.
The current belief of availability of doctors in India is based on the registration stock of doctors accumulated since the early 20th century. This has not been adjusted to attrition of the strength occurring due to retirement, emigration, etc. To estimate the number of practicing doctors currently available in India and will be available in 2030 after adjustments made for attrition of the stock. The paper used Medical Council of India's historical data (1960-2015) on registration stock of doctors obtained from the Indian medical registers available on its website and other data on emigration of doctors accessed from Organization for Economic Cooperation and Development and destination country sources. The paper found that there were only 4.8 practicing doctors per 10,000 population available in India in 2014, in contrast to the belief of having 7 doctors per 10,000 people. Rest of the registered doctors have either retired or emigrated from the country to practice abroad. It is estimated that the country would be able to achieve a ratio of about 6.9 practicing doctors per 10,000 people only by 2030. Given these findings of the current availability of doctors per 10,000 people and their growth prospects over the next 15-year period, it looks like an impossible task to achieve even a moderate doctor-population ratio of 1:1000 by 2030. Therefore, a genuine commitment to provide equitable healthcare to the rural population must innovate and experiment a special cadre of practitioners for rural areas on a pan-India basis.


Computerized neurocognitive testing within 1 week of sport-related concussion: meta-analytic review and analysis of moderating factors.
The purpose of this study is to perform a meta-analysis assessing the effects of sport-related concussion as measured by computerized neurocognitive tests (NCT) 1-week post injury. Thirty-seven studies involving 3960 participants between 2000 and 2011 were included. Hedge's g provides an adjusted effect size for smaller sample sizes and was calculated for overall and cognitive task effects, and subgroup analyses were conducted for age, type of NCT, and sport. Concussions had a low negative effect (g = -0.16; p < .001) across all groups, outcomes, and time points. Code substitution (g = -0.27; p < .05), visual memory (g = -0.25; p < .05), processing speed (g = -0.18; p < .05), and memory (g = -0.21; p < .05) tasks demonstrated negative effects for concussion. Younger adolescents had lower (g = -0.29; p < .05) NCT performance than older adolescents (g = -0.01) and college aged athletes (g = -0.11). ImPACT studies (g = -0.19; p < .05) demonstrated a negative effect for concussion as did those involving contact sports (g = -0.20; p < .05). A low to moderate overall effect size of concussion on neurocognitive performance was supported. Subgroup analyses revealed different effect sizes for specific cognitive tasks, types of NCTs, age, and type of sport.


Emerging role of uterine natural killer cells in establishing pregnancy.
Normal pregnancy has been considered as a controlled state of inflammation at an early stage of blastocyst implantation that subsequently develops systemically. Till recent past most popular hypotheses regarding status of immune system in pregnancy were dominated by the Th1 and Th2 hypothesis, in which the fetus avoids maternal rejection through a bias towards T-helper (Th2) cytokine production. Recent findings have shown that predominant immune interactions in the human deciduas are between the placental trophoblast and maternal uterine natural killer (uNK) cells rather than the T cells. Thus NK cells are emerging as important players in the uterine immune response to invasive forms of placenta, as in cases of hemochorial placenta. In humans there is a lack of evidence for T-cell responses to trophoblast cells; therefore it was thought that uterine NK cells are the key factors by which the maternal immune system recognizes trophoblast cells. In this review we are trying to summarize the role of uNK cells in the maintenance of normal pregnancy in humans.


Renovascular hypertension and ischemic nephropathy.
Renovascular disease remains among the most prevalent and important causes of secondary hypertension and renal dysfunction. Many lesions reduce perfusion pressure including fibromuscular diseases and renal infarction, but most are caused by atherosclerotic disease. Epidemiologic studies establish a strong association between atherosclerotic renal-artery stenosis (ARAS) and cardiovascular risk. Hypertension develops in patients with renovascular disease from a complex set of pressor signals, including activation of the renin-angiotensin system (RAS), recruitment of oxidative stress pathways, and sympathoadrenergic activation. Although the kidney maintains function over a broad range of autoregulation, sustained reduction in renal perfusion leads to disturbed microvascular function, vascular rarefaction, and ultimately development of interstitial fibrosis. Advances in antihypertensive drug therapy and intensive risk factor management including smoking cessation and statin therapy can provide excellent blood pressure control for many individuals. Despite extensive observational experience with renal revascularization in patients with renovascular hypertension, recent prospective randomized trials fail to establish compelling benefits either with endovascular stents or with surgery when added to effective medical therapy. These trials are limited and exclude many patients most likely to benefit from revascularization. Meaningful recovery of kidney function after revascularization is limited once fibrosis is established. Recent experimental studies indicate that mechanisms allowing repair and regeneration of parenchymal kidney tissue may lead to improved outcomes in the future. Until additional staging tools become available, clinicians will be forced to individualize therapy carefully to optimize the potential benefits regarding both blood pressure and renal function for such patients.


Starvation for different nutrients in Escherichia coli results in differential modulation of RpoS levels and stability.
Levels of RpoS increase upon glucose starvation in Escherichia coli, which leads to the transcription of genes whose products combat a variety of stresses. RpoS stability is a key level of control in this process, as SprE (RssB)-mediated degradation is inhibited under glucose starvation. Starvation for ammonia or phosphate also results in increased stress resistance and induction of RpoS-dependent genes. However, we demonstrate that RpoS levels following ammonia starvation are only slightly increased compared to growing cells and are 10-fold below the levels observed under glucose or phosphate limitation. This difference is largely due to regulated proteolysis of RpoS, as its stability in ammonia-starved cells is intermediate between that in logarithmic-phase cells and glucose-starved cells. Use of an rpoS construct that is devoid of the gene's native transcriptional and translational control regions reveals that stability differences are sufficient to explain the different levels of RpoS observed in logarithmic phase, ammonia starvation, and glucose starvation. Under phosphate starvation, however, rpoS translation is increased. The cellular response to nutrient limitation is much more complex than previously appreciated, as there is not simply one response that is activated by starvation for any essential nutrient. Our data support the hypothesis that SprE activity is the key level at which ammonia and glucose starvation signals are transmitted to RpoS, and they suggest that carbon source and/or energy limitation are necessary for full inactivation of the SprE pathway.


Emergency medicine resident crisis resource management ability: a simulation-based longitudinal study.
Simulation has been identified as a means of assessing resident physicians' mastery of technical skills, but there is a lack of evidence for its utility in longitudinal assessments of residents' non-technical clinical abilities. We evaluated the growth of crisis resource management (CRM) skills in the simulation setting using a validated tool, the Ottawa Crisis Resource Management Global Rating Scale (Ottawa GRS). We hypothesized that the Ottawa GRS would reflect progressive growth of CRM ability throughout residency. Forty-five emergency medicine residents were tracked with annual simulation assessments between 2006 and 2011. We used mixed-methods repeated-measures regression analyses to evaluate elements of the Ottawa GRS by level of training to predict performance growth throughout a 3-year residency. Ottawa GRS scores increased over time, and the domains of leadership, problem solving, and resource utilization, in particular, were predictive of overall performance. There was a significant gain in all Ottawa GRS components between postgraduate years 1 and 2, but no significant difference in GRS performance between years 2 and 3. In summary, CRM skills are progressive abilities, and simulation is a useful modality for tracking their development. Modification of this tool may be needed to assess advanced learners' gains in performance.


Congenital brain anomalies associated with the hypoplastic left heart syndrome.
This study details the type, frequency, and clinical presentation of developmental brain anomalies in 41 infants with the hypoplastic left heart syndrome encountered during a 52-month interval. Overall, 29% of the infants had either a major or minor central nervous system abnormality. Overt central nervous system malformations, including 3 cases of agenesis of the corpus callosum and 1 case of holoprosencephaly, were seen in 4 infants (10%). Micrencephaly (brain weight at autopsy more than 2 SDs below the mean for age) was found in 27% of the infants. An immature cortical mantle was seen in 21% of the study group. Seven infants (17%) had specific recognizable patterns of malformation. The absence of dysmorphic physical features did not preclude overt or subtle central nervous system malformations. Conversely, the presence of dysmorphic features did not reliably indicate an underlying brain anomaly. Infants who had hypoplastic left heart syndrome as one of multiple nonneurologic malformations were more likely to have micrencephaly than those infants with hypoplastic left heart syndrome as an isolated abnormality. Occurrence of developmental neuropathology was elevated in those infants with hypoplastic left heart syndrome who did not have a recognizable pattern of malformation but who were small for gestational age, microcephalic, or had ocular abnormalities. Infants with hypoplastic left heart syndrome deserve careful genetic, opthalmologic, and neurologic evaluations, imaging of their intracranial anatomy, and long-term neurologic follow-up.


Compression of strings with approximate repeats.
We describe a model for strings of characters that is loosely based on the Lempel Ziv model with the addition that a repeated substring can be an approximate match to the original substring; this is close to the situation of DNA, for example. Typically there are many explanations for a given string under the model, some optimal and many suboptimal. Rather than commit to one optimal explanation, we sum the probabilities over all explanations under the model because this gives the probability of the data under the model. The model has a small number of parameters and these can be estimated from the given string by an expectation-maximization (EM) algorithm. Each iteration of the EM algorithm takes O(n2) time and a few iterations are typically sufficient. O(n2) complexity is impractical for strings of more than a few tens of thousands of characters and a faster approximation algorithm is also given. The model is further extended to include approximate reverse complementary repeats when analyzing DNA strings. Tests include the recovery of parameter estimates from known sources and applications to real DNA strings.


Elevation leads to altruistic behavior.
Feelings of elevation, elicited by witnessing another person perform a good deed, have been hypothesized to motivate a desire to help others. However, despite growing interest in the determinants of prosocial behavior, there is only limited evidence that elevation leads to increases in altruistic behavior. In two experiments, we tested the relationship between elevation and helping behavior. Prior to measuring helping behavior, we measured elevation among participants in an elevation-inducing condition and control conditions in order to determine whether witnessing altruistic behavior elicited elevation. In Experiment 1, participants experiencing elevation were more likely to volunteer for a subsequent unpaid study than were participants in a neutral state. In Experiment 2, participants experiencing elevation spent approximately twice as long helping the experimenter with a tedious task as participants experiencing mirth or a neutral emotional state. Further, feelings of elevation, but not feelings of amusement or happiness, predicted the amount of helping. Together, these results provide evidence that witnessing another person's altruistic behavior elicits elevation, a discrete emotion that, in turn, leads to tangible increases in altruism.


Epstein-Barr and other viral mimicry of autoantigens, myelin and vitamin D-related proteins and of EIF2B, the cause of vanishing white matter disease: massive mimicry of multiple sclerosis relevant proteins by the Synechococcus phage.
The Epstein-Barr virus expresses proteins containing numerous short consensi (identical pentapeptides at least, or longer gapped consensi) that are identical to those in 16 multiple sclerosis autoantigens or in the products of multiple sclerosis susceptibility genes. Other viruses implicated in multiple sclerosis also display such mimicry and the Synechococcus phage was identified as a novel and major contributor to this phenomenon. Cyanobacteria hosts of Synechococcus phage favor temperate climes, in line with multiple sclerosis distribution, and bacterial and phage ecology accords closely with multiple sclerosis epidemiology. Bovine, ovine or canine viral proteins were also identified as autoantigen homologues, in line with epidemiological data linking multiple sclerosis to cattle density, sheep contact and dog ownership. Viral proteins align with known autoantigens, other myelin and vitamin D-related proteins and the translation initiation factor EIF2B, which is implicated in vanishing white matter disease. These data suggest that the autoantigens in multiple sclerosis, which causes demyelination in animal models, may be generated by antibodies raised to viral protein homologues. Multiple autoantibodies may cause multiple sclerosis via protein knockdown and immune activation. Their selective removal may be of clinical benefit as already suggested by promising results using plasmapheresis or immunoadsorption in certain multiple sclerosis patients.


Symptomatic Citrus trees reveal a new pathogenic lineage in Fusarium and two new Neocosmospora species.
The diversity of fusaria in symptomatic Citrus trees in Greece, Italy and Spain was evaluated using morphological and molecular multi-locus analyses based on fragments of the calmodulin (CAM), intergenic spacer region of the rDNA (IGS), internal transcribed spacer region of the rDNA (ITS), large subunit of the rDNA (LSU), RNA polymerase largest subunit (RPB1), RNA polymerase second largest subunit (RPB2), translation elongation factor 1-alpha (EF-1α) and beta-tubulin (TUB) genes. A total of 11 species (six Fusarium spp., and five Neocosmospora spp.) were isolated from dry root rot, crown, trunk or twig canker or twig dieback of citrus trees. The most commonly isolated species were Fusarium sarcochroum, F. oxysporum and Neocosmospora solani. Three new Fusarium species are described, i.e., F. citricola and F. salinense belonging to the newly described F. citricola species complex; and F. siculi belonging to the F. fujikuroi species complex. Results of pathogenicity tests showed this new complex to include prominent canker causing agents affecting several Citrus spp. In addition, two new species are described in Neocosmospora, named N. croci and N. macrospora, the latter species being clearly differentiated from most members of this genus by producing large, up to nine-septate sporodochial conidia.


Translating global recommendations on HIV and infant feeding to the local context: the development of culturally sensitive counselling tools in the Kilimanjaro Region, Tanzania.
This paper describes the process used to develop an integrated set of culturally sensitive, evidence-based counselling tools (job aids) by using qualitative participatory research. The aim of the intervention was to contribute to improving infant feeding counselling services for HIV positive women in the Kilimanjaro Region of Tanzania. Formative research using a combination of qualitative methods preceded the development of the intervention and mapped existing practices, perceptions and attitudes towards HIV and infant feeding (HIV/IF) among mothers, counsellors and community members. Intervention Mapping (IM) protocol guided the development of the overall intervention strategy. Theories of behaviour change, a review of the international HIV/IF guidelines and formative research findings contributed to the definition of performance and learning objectives. Key communication messages and colourful graphic illustrations related to infant feeding in the context of HIV were then developed and/or adapted from existing generic materials. Draft materials were field tested with intended audiences and subjected to stakeholder technical review. An integrated set of infant feeding counselling tools, referred to as 'job aids', was developed and included brochures on feeding methods that were found to be socially and culturally acceptable, a Question and Answer Guide for counsellors, a counselling card on the risk of transmission of HIV, and an infant feeding toolbox for demonstration. Each brochure describes the steps to ensure safer infant feeding using simple language and images based on local ideas and resources. The brochures are meant to serve as both a reference material during infant feeding counselling in the ongoing prevention of mother to child transmission (pMTCT) of HIV programme and as take home material for the mother. The study underscores the importance of formative research and a systematic theory based approach to developing an intervention aimed at improving counselling and changing customary feeding practices. The identification of perceived barriers and facilitators for change contributed to developing the key counselling messages and graphics, reflecting the socio-economic reality, cultural beliefs and norms of mothers and their significant others.


Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor Runx1.
Microglia are the immune cells of the nervous system, where they act as resident macrophages during inflammatory events underlying many neuropathological conditions. Microglia derive from primitive myeloid precursors that colonize the nervous system during embryonic development. In the postnatal brain, microglia are initially mitotic, rounded in shape (amoeboid), and phagocytically active. As brain development proceeds, they gradually undergo a transition to a surveillant nonphagocytic state characterized by a highly branched (ramified) morphology. This ramification process is almost recapitulated in reverse during the process of microglia activation in the adult brain, when surveillant microglia undergo a ramified-to-amoeboid morphological transformation and become phagocytic in response to injury or disease. Little is known about the mechanisms controlling amoeboid microglial cell proliferation, activation, and ramification during brain development, despite the critical role of these processes in the establishment of the adult microglia pool and their relevance to microglia activation in the adult brain. Here we show that the mouse transcription factor Runx1, a key regulator of myeloid cell proliferation and differentiation, is expressed in forebrain amoeboid microglia during the first two postnatal weeks. Runx1 expression is then downregulated in ramified microglia. Runx1 inhibits mouse amoeboid microglia proliferation and promotes progression to the ramified state. We show further that Runx1 expression is upregulated in microglia following nerve injury in the adult mouse nervous system. These findings provide insight into the regulation of postnatal microglia activation and maturation to the ramified state and have implications for microglia biology in the developing and injured brain.


Selectivity of face aftereffects for expressions and anti-expressions.
Adapting to a facial expression can alter the perceived expression of subsequently viewed faces. However, it remains unclear whether this adaptation affects each expression independently or transfers from one expression to another, and whether this transfer impedes or enhances responses to a different expression. To test for these interactions, we probed the basic expressions of anger, fear, happiness, sadness, surprise, and disgust, adapting to one expression and then testing on all six. Each expression was varied in strength by morphing it with a common neutral facial expression. Observers determined the threshold level required to correctly identify each expression, before or after adapting to a face with a neutral or intense expression. The adaptation was strongly selective for the adapting category; responses to the adapting expression were reduced, while other categories showed little consistent evidence of either suppression or facilitation. In a second experiment we instead compared adaptation to each expression and its anti-expression. The latter are defined by the physically complementary facial configuration, yet appear much more ambiguous as expressions. In this case, for most expressions the opposing faces produced aftereffects of opposite sign in the perceived expression. These biases suggest that the adaptation acts in part by shifting the perceived neutral point for the facial configuration. This is consistent with the pattern of renormalization suggested for adaptation to other facial attributes, and thus may reflect a generic level of configural coding. However, for most categories aftereffects were stronger for expressions than anti-expressions, pointing to the possible influence of an additional component of the adaptation at sites that explicitly represent facial expressions. At either level our results are consistent with other recent work in suggesting that the six expressions are defined by dimensions that are largely independently normalized by adaptation, possibly because the facial configurations conveying different expressions vary in independent ways.


Vertical and horizontal variations in the physiological diversity of the aerobic chemoheterotrophic bacterial microflora in deep southeast coastal plain subsurface sediments.
Aerobic chemoheterotrophic bacteria were isolated from surface soils and coastal plain subsurface (including deep aquifer) sediments (depths to 265 m) at a study site near Aiken, S.C., by plating on concentrated and dilute media. Morphologically distinct colonies were purified, and their responses to 21 selected physiological tests were determined. These isolates were quite diverse; 626 physiologically distinct types (i.e., types with a unique pattern of responses to the 21 tests) were detected among the 1,112 isolates obtained. Physiologically distinct types were isolated on concentrated and dilute media (only 11% overlap between the groups); isolates from surface soils and subsurface sediments were also quite different (only 3% overlap). The surface soil isolates more readily utilized all but 1 of 12 carbon sources offered, and a significantly larger proportion of them hydrolyzed esculin and gelatin. Only 4% of the subsurface isolates fermented glucose, even though 82% of them could use it aerobically. l-Malate and d-gluconate were utilized by at least 75% of the subsurface isolates, and seven other carbon sources were used by at least 40% of them. Subsurface isolates from different geological formations (depths) and, to a lesser extent, from the same geological formation at different boreholes differed distinctly in their group responses to certain physiological tests. Moreover, sediments from different depths and boreholes contained physiologically distinct types of bacteria. Thus, considerable bacterial diversity was observed in coastal plain subsurface sediments, even within defined geological formations.


Importance of secondary structure in the signal sequence for protein secretion.
Mutant Escherichia coli strains in which export of the LamB protein (coded for by the lamB gene) to the outer membrane of the cell is prevented have been described previously. One of these mutant strains contains a small (12-base pair) deletion mutation within the region of the lamB gene that codes for the NH2-terminal signal sequence. In this mutant strain, export but not synthesis of the LamB protein is blocked. We have isolated pseudorevertants that restore export of functional LamB protein to the outer membrane. DNA sequence analysis showed that two of the revertants contain a point mutation in addition to the original deletion. These point mutations lead to amino acid substitutions within the signal sequence. Our results indicate that these secondary mutations efficiently suppress the export defect caused by the deletion mutation. Analysis of the secondary structure of the wild-type, mutant, and pseudorevertant LamB signal sequences suggests that the secondary mutations restore export by allowing the formation of a stable alpha-helical conformation in the central, hydrophobic region of the signal sequence.


Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis.
The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.


HEALTHIER, WEALTHIER, AND WISER: A DEMONSTRATION OF COMPOSITIONAL CHANGES IN AGING COHORTS DUE TO SELECTIVE MORTALITY.
The gradual changes in cohort composition that occur as a result of selective mortality processes are of interest to all aging research. We present the first illustration of changes in the distribution of specific cohort characteristics that arise purely as a result of selective mortality. We use data on health, wealth, education, and other covariates from two cohorts (the AHEAD cohort, born 1900-23 and the HRS cohort, born 1931-41) included in the Health and Retirement Survey, a nationally representative panel study of older Americans spanning nearly two decades (N=14,466). We calculate sample statistics for the surviving cohort at each wave. Repeatedly using only baseline information for these calculations so that there are no changes at the individual level (what changes is the set of surviving respondents at each specific wave), we obtain a demonstration of the impact of mortality selection on the cohort characteristics. We find substantial changes in the distribution of all examined characteristics across the nine survey waves. For instance, the median wealth increases from about $90,000 to $130,000 and the number of chronic conditions declines from 1.5 to 1 in the AHEAD cohort. We discuss factors that influence the rate of change in various characteristics. The mortality selection process changes the composition of older cohorts considerably, such that researchers focusing on the oldest old need to be aware of the highly select groups they are observing, and interpret their conclusions accordingly.


A novel method for structure-based prediction of ion channel conductance properties.
A rapid and easy-to-use method of predicting the conductance of an ion channel from its three-dimensional structure is presented. The method combines the pore dimensions of the channel as measured in the HOLE program with an Ohmic model of conductance. An empirically based correction factor is then applied. The method yielded good results for six experimental channel structures (none of which were included in the training set) with predictions accurate to within an average factor of 1.62 to the true values. The predictive r2 was equal to 0.90, which is indicative of a good predictive ability. The procedure is used to validate model structures of alamethicin and phospholamban. Two genuine predictions for the conductance of channels with known structure but without reported conductances are given. A modification of the procedure that calculates the expected results for the effect of the addition of nonelectrolyte polymers on conductance is set out. Results for a cholera toxin B-subunit crystal structure agree well with the measured values. The difficulty in interpreting such studies is discussed, with the conclusion that measurements on channels of known structure are required.


gespeR: a statistical model for deconvoluting off-target-confounded RNA interference screens.
Small interfering RNAs (siRNAs) exhibit strong off-target effects, which confound the gene-level interpretation of RNA interference screens and thus limit their utility for functional genomics studies. Here, we present gespeR, a statistical model for reconstructing individual, gene-specific phenotypes. Using 115,878 siRNAs, single and pooled, from three companies in three pathogen infection screens, we demonstrate that deconvolution of image-based phenotypes substantially improves the reproducibility between independent siRNA sets targeting the same genes. Genes selected and prioritized by gespeR are validated and shown to constitute biologically relevant components of pathogen entry mechanisms and TGF-β signaling. gespeR is available as a Bioconductor R-package.


Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types.
Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.


Emissive Single-Crystalline Boroxine-Linked Colloidal Covalent Organic Frameworks.
The synthesis of periodic two-dimensional (2D) polymers and characterization of their optoelectronic behaviors are challenges at the forefront of polymer chemistry and materials science. Recently, we showed that layered 2D polymers known as 2D covalent organic frameworks (COFs) can be synthesized as single crystals by preparing COF particles as colloidal suspensions. Here we expand this approach from the condensation of boronic acids and catechols to the dehydrative trimerization of polyboronic acids. The resulting boroxine-linked colloids are the next class of 2D COFs to be obtained as single-crystalline particles, as demonstrated here for four 2D COFs and one 3D COF. Colloidal stabilization enables detailed structural analysis by synchrotron X-ray diffraction and high-resolution transmission electron microscopy. Solution fluorescence spectroscopy revealed that the COF crystallites are highly emissive compared to their respective monomer solutions. Excitation-emission matrix fluorescence spectroscopy indicated that the origin of this enhanced emission can be attributed to through-space communication of chromophores between COF sheets. These observations will motivate the development of colloidal COF systems as a platform to organize functional aromatic systems into precise and predictable assemblies with emergent properties.


Effects of glucan on immunosuppressive actions of mercury.
Global cycling of mercury results in the presence of mercury salts in the environment. The well-established negative effects of mercury on the immune system led us to the study whether natural immunomodulator glucan can overcome the immunosuppressive effects of mercury. Two types of mercury, thimerosal and mercury acetate, were administered in a dose of 2-8 mg/L of drinking water to mice. After 2 weeks, all mice exhibited profound suppression of both cellular (phagocytosis, natural killer cell activity, mitogen-induced proliferation, and expression of CD markers) and humoral (antibody formation and secretion of interleukin-6, interleukin-12, and interferon-gamma) responses. The mice were then fed with a diet containing a standard dose of glucan. Our results showed that simultaneous treatment with mercury and glucan resulted in significantly lower immunotoxic effects of mercury, which suggests that glucans can be successfully used as a natural remedy of low-level exposure to mercury.


Genome-Resolved Meta-Omics Ties Microbial Dynamics to Process Performance in Biotechnology for Thiocyanate Degradation.
Remediation of industrial wastewater is important for preventing environmental contamination and enabling water reuse. Biological treatment for one industrial contaminant, thiocyanate (SCN-), relies upon microbial hydrolysis, but this process is sensitive to high loadings. To examine the activity and stability of a microbial community over increasing SCN- loadings, we established and operated a continuous-flow bioreactor fed increasing loadings of SCN-. A second reactor was fed ammonium sulfate to mimic breakdown products of SCN-. Biomass was sampled from both reactors for metagenomics and metaproteomics, yielding a set of genomes for 144 bacteria and one rotifer that constituted the abundant community in both reactors. We analyzed the metabolic potential and temporal dynamics of these organisms across the increasing loadings. In the SCN- reactor, Thiobacillus strains capable of SCN- degradation were highly abundant, whereas the ammonium sulfate reactor contained nitrifiers and heterotrophs capable of nitrate reduction. Key organisms in the SCN- reactor expressed proteins involved in SCN- degradation, sulfur oxidation, carbon fixation, and nitrogen removal. Lower performance at higher loadings was linked to changes in microbial community composition. This work provides an example of how meta-omics can increase our understanding of industrial wastewater treatment and inform iterative process design and development.


Hormone signalling via G-protein: regulation of phosphatidylinositol 4,5-bisphosphate hydrolysis by Gq.
Heterotrimeric GTP-dependent regulatory proteins (G-proteins) mediate modulation by many cell surface receptors. Activation of the G-proteins promotes dissociation of their alpha and beta gamma subunits. The similarity of behaviour of beta gamma subunits derived from a variety of G-proteins has led to their use as affinity reagents for the analysis of the more unique alpha subunits. The evolution of these uses is presented. One of the more insightful results was the isolation of a new class of G-protein alpha subunits (the alpha q subfamily) which have been shown to regulate the activity of a phospholipase C (PLC) specific for phosphatidylinositols. The experimental evidence leading to this conclusion is discussed. The activation by alpha q increases the apparent Vmax of the beta isoform of phosphatidylinositol-specific phospholipase C (PLC beta) and can be modulated by beta gamma subunits.


Dissecting the transcriptional regulatory properties of human chromosome 16 highly conserved non-coding regions.
Non-coding DNA conservation across species has been often used as a predictor for transcriptional enhancer activity. However, only a few systematic analyses of the function of these highly conserved non-coding regions (HCNRs) have been performed. Here we use zebrafish transgenic assays to perform a systematic study of 113 HCNRs from human chromosome 16. By comparing transient and stable transgenesis, we show that the first method is highly inefficient, leading to 40% of false positives and 20% of false negatives. When analyzed in stable transgenic lines, a great majority of HCNRs were active in the central nervous system, although some of them drove expression in other organs such as the eye and the excretory system. Finally, by testing a fraction of the HCNRs lacking enhancer activity for in vivo insulator activity, we find that 20% of them may contain enhancer-blocking function. Altogether our data indicate that HCNRs may contain different types of cis-regulatory activity, including enhancer, insulators as well as other not yet discovered functions.


The big data challenges of connectomics.
The structure of the nervous system is extraordinarily complicated because individual neurons are interconnected to hundreds or even thousands of other cells in networks that can extend over large volumes. Mapping such networks at the level of synaptic connections, a field called connectomics, began in the 1970s with a the study of the small nervous system of a worm and has recently garnered general interest thanks to technical and computational advances that automate the collection of electron-microscopy data and offer the possibility of mapping even large mammalian brains. However, modern connectomics produces 'big data', unprecedented quantities of digital information at unprecedented rates, and will require, as with genomics at the time, breakthrough algorithmic and computational solutions. Here we describe some of the key difficulties that may arise and provide suggestions for managing them.


Controlling the phase matching conditions of optical parametric chirped-pulse amplification using partially deuterated KDP.
Using a partially deuterated KDP crystal for an optical parametric amplifier, we demonstrated ultrabroadband optical parametric chirped-pulse amplification of more than 250 nm bandwidth at a center wavelength of 1050 nm. We numerically show how to control the broadband phase matching conditions at different wavelengths to match center wavelengths of suitable broadband seed sources by adjusting the deuteration level in partially deuterated KDP.


Prognostic factors for chronic post-surgical pain after lung or pleural surgery: a protocol for a systematic review and meta-analysis.
Chronic post-surgical pain (CPSP) after lung or pleural surgery is a common complication and associated with a decrease in quality of life, long-term use of pain medication and substantial economic costs. An abundant number of primary prognostic factor studies are published each year, but findings are often inconsistent, methods heterogeneous and the methodological quality questionable. Systematic reviews and meta-analyses are therefore needed to summarise the evidence. The reporting of this protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist. We will include retrospective and prospective studies with a follow-up of at least 3 months reporting patient-related factors and surgery-related factors for any adult population. Randomised controlled trials will be included if they report on prognostic factors for CPSP after lung or pleural surgery. We will exclude case series, case reports, literature reviews, studies that do not report results for lung or pleural surgery separately and studies that modified the treatment or prognostic factor based on pain during the observation period. MEDLINE, Scopus, Web of Science, Embase, Cochrane, CINAHL, Google Scholar and relevant literature reviews will be searched. Independent pairs of two reviewers will assess studies in two stages based on the PICOTS criteria. We will use the Quality in Prognostic Studies tool for the quality assessment and the CHARMS-PF checklist for the data extraction of the included studies. The analyses will all be conducted separately for each identified prognostic factor. We will analyse adjusted and unadjusted estimated measures separately. When possible, evidence will be summarised with a meta-analysis and otherwise narratively. We will quantify heterogeneity by calculating the Q and I2 statistics. The heterogeneity will be further explored with meta-regression and subgroup analyses based on clinical knowledge. The quality of the evidence obtained will be evaluated according to the Grades of Recommendation Assessment, Development and Evaluation guideline 28. Ethical approval will not be necessary, as all data are already in the public domain. Results will be published in a peer-reviewed scientific journal. CRD42021227888.


Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies.
Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association. Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69-0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58-1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73-2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67-4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence. In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients. NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.


HIV testing within general practices in Europe: a mixed-methods systematic review.
Late diagnosis of HIV infection remains a key challenge in Europe. It is acknowledged that general practitioners (GPs) may contribute greatly to early case finding, yet there is evidence that many diagnostic opportunities are being missed. To further promote HIV testing in primary care and to increase the utility of available research, the existing evidence has been synthesised in a systematic review adhering to the PRISMA guidelines. The databases PubMed, Scopus and Embase were searched for the period 2006-2017. Two authors judged independently on the eligibility of studies. Through a mixed-methods systematic review of 29 studies, we provide a description of HIV testing in general practices in Europe, including barriers and facilitators. The findings of the study show that although various approaches to target patients are used by GPs, most tests are still carried out based on the patient's request. Several barriers obstruct HIV testing in general practice. Included are a lack of communication skills on sexual health, lack of knowledge about HIV testing recommendations and epidemic specificities, difficulties with using the complete list of clinical HIV indicator diseases and lack of experience in delivering and communicating test results. The findings also suggest that the provision of specific training, practical tools and promotion programmes has an impact on the testing performance of GPs. GPs could have an increased role in provider-initiated HIV-testing for early case finding. To achieve this objective, solutions to the reported barriers should be identified and testing criteria adapted to primary healthcare defined. Providing guidance and training to better identify priority groups for HIV testing, as well as information on the HIV epidemic's characteristics, will be fundamental to increasing awareness and testing by GPs.


Frequency domain optical reflectometer.
A correlation reflectometer operating in the frequency domain is described. It is shown that such an instrument is well adapted to detecting weak discrete reflections. The detection of end reflections in a 2.2-km length of fiber whose end is index matched is demonstrated. A round-trip range of over 70 dB is obtained with a 1-mW optical source power. The method shows promise for characterizing the reflective properties of optical fiber elements, such as tapers, microbends, and splices, and may be useful in fault location.


Unilateral rotation in baseball fielder causes low back pain contralateral to the hitting side.
Low back pain (LBP) often occurs in baseball players;however, the characteristics of the location of their LBP with respect to their throwing and hitting sides have not been clarified. In order to clarify the left-right asymmetry of LBP that occurs in baseball players, we surveyed 247 university baseball players using an LBP questionnaire. The main investigational items were:throwing and hitting side, position at the time of LBP experience, and LBP location. Based upon the indication of their throwing and hitting side, subjects were classified into unilateral rotational (UR) or bilateral rotational (BR) types. Subjects were also classified into categories of LBP location as described by ipsilateral or contralateral to dominant side of throwing or hitting. Chi-square test or Fisher exact test were used to compare LBP location side by rotational type (UR/BR) in all subjects and by position (pitcher/fielder). We found that among fielders, LBP occurring contralateral to the hitting side in UR was significantly more frequent than that in BR. We conclude that LBP occurred in baseball fielders with a left-right asymmetry, which suggests that high frequency unilateral rotation causes the lumbar region contralateral to the dominant hitting side to be subject to a high load. J. Med. Invest. 65:56-59, February, 2018.


Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials.
Statin therapy is effective for the prevention of coronary heart disease and stroke in patients with mild-to-moderate chronic kidney disease, but its effects in individuals with more advanced disease, particularly those undergoing dialysis, are uncertain. We did a meta-analysis of individual participant data from 28 trials (n=183 419), examining effects of statin-based therapy on major vascular events (major coronary event [non-fatal myocardial infarction or coronary death], stroke, or coronary revascularisation) and cause-specific mortality. Participants were subdivided into categories of estimated glomerular filtration rate (eGFR) at baseline. Treatment effects were estimated with rate ratio (RR) per mmol/L reduction in LDL cholesterol. Overall, statin-based therapy reduced the risk of a first major vascular event by 21% (RR 0·79, 95% CI 0·77-0·81; p<0·0001) per mmol/L reduction in LDL cholesterol. Smaller relative effects on major vascular events were observed as eGFR declined (p=0·008 for trend; RR 0·78, 99% CI 0·75-0·82 for eGFR ≥60 mL/min per 1·73 m(2); 0·76, 0·70-0·81 for eGFR 45 to <60 mL/min per 1·73 m(2); 0·85, 0·75-0·96 for eGFR 30 to <45 mL/min per 1·73 m(2); 0·85, 0·71-1·02 for eGFR <30 mL/min per 1·73 m(2) and not on dialysis; and 0·94, 0·79-1·11 for patients on dialysis). Analogous trends by baseline renal function were seen for major coronary events (p=0·01 for trend) and vascular mortality (p=0·03 for trend), but there was no significant trend for coronary revascularisation (p=0·90). Reducing LDL cholesterol with statin-based therapy had no effect on non-vascular mortality, irrespective of eGFR. Even after allowing for the smaller reductions in LDL cholesterol achieved by patients with more advanced chronic kidney disease, and for differences in outcome definitions between dialysis trials, the relative reductions in major vascular events observed with statin-based treatment became smaller as eGFR declined, with little evidence of benefit in patients on dialysis. In patients with chronic kidney disease, statin-based regimens should be chosen to maximise the absolute reduction in LDL cholesterol to achieve the largest treatment benefits. UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Community Biomed Programme, Australian National Health and Medical Research Council, Australian National Heart Foundation.


Cross-sectional comparison of coronary artery calcium scores between Caucasian men in the United States and Japanese men in Japan: the multi-ethnic study of atherosclerosis and the Shiga epidemiological study of subclinical atherosclerosis.
The incidence of coronary heart disease in the United States has declined, and prevalences of several coronary disease risk factors have become comparable to those in Japan. Therefore, the burden of coronary atherosclerosis may be closer among younger persons in the 2 countries. We aimed to compare prevalences of coronary atherosclerosis, measured with coronary artery calcium scores, between men in the 2 countries by age group (45-54, 55-64, or 65-74 years). We used community-based samples of Caucasian men in the United States (2000-2002; n = 1,067) and Japanese men in Japan (2006-2008; n = 832) aged 45-74 years, stratifying them into groups with 0, 1, 2, or ≥3 of the following risk factors: current smoking, overweight, diabetes, dyslipidemia, and hypertension. We calculated adjusted odds ratios of US Caucasian men's having Agatston scores of ≥10, ≥100, and ≥400 with reference to Japanese men. Overall, the odds of Caucasian men having each Agatston cutoff point were greater. The ethnic difference, however, became smaller in younger age groups. For example, adjusted odds ratios for Caucasian men's having an Agatston score of ≥100 were 2.05, 2.43, and 3.86 among those aged 45-54, 55-64, and 65-74 years, respectively. Caucasian men in the United States had a higher burden of coronary atherosclerosis than Japanese men, but the ethnic difference was smaller in younger age groups.


Lipopolysaccharide-mediated hepatic glutathione depletion and progressive mitochondrial damage in mice: protective effect of glutathione monoethyl ester.
Overproduction of reactive oxygen intermediates (ROI) may have an important role in the pathophysiology of lipopolysaccharide-mediated liver-injury. This study examined the role of cytosolic and mitochondrial glutathione in protecting hepatocytes from oxidative stress during exposure to lipopolysaccharide. In addition, the possible participation of changes of inner mitochondrial membrane permeability in lipopolysaccharide-induced hepatotoxicity was investigated. The changes of hepatic glutathione content following lipopolysaccharide challenge (2 mg/kg) were measured in mice by reverse-phase high-performance liquid chromatography. Glutathione depletion and a glutathione-rich state were produced by intraperitoneal administration of a specific inhibitor of gamma-glutamyl cysteine synthetase, buthionine sulfoximine (3 mmol/kg), and by administration of glutathione monoethyl ester (10 mmol/kg), respectively. Intracellular ROI generation and the mitochondrial membrane potential were quantified by flow cytometry. Changes of inner mitochondrial membrane permeability in hepatocytes were assessed by radioactive sucrose entrapment. There was increased production of ROI along with depletion of cellular and mitochondrial glutathione in the liver after lipopolysaccharide administration. There was also a change of inner mitochondrial membrane permeability in hepatocytes, with the loss of coupled functions. Buthionine sulfoximine decreased the hepatic antioxidant capacity, worsened mitochondrial function, and reduced the survival rate of the mice. In contrast, glutathione monoethyl ester improved all of these parameters. Glutathione may have an important role in cellular defenses against lipopolysaccharide-induced liver damage in mice, and excessive oxidative stress may precipitate the mitochondrial membrane permeability transition in hepatocytes and lead to cell death.


T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10.
The development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a multistep process and can be clinico-pathologically divided into Helicobacter pylori-associated gastritis, low-grade tumors, and high-grade tumors. The molecular events underlying this progression are largely unknown. However, identification of the genes involved in MALT lymphoma-specific t(11;18)(q21;q21) and t(1;14)(p22;q32) has provided fresh insights into the pathogenesis of this disease. T(11;18)(q21;q21) results in a chimeric transcript between the API2 and the MALT1 genes, whereas t(1;14) (p22;q32) causes aberrant nuclear BCL10 expression. Significantly, nuclear BCL10 expression also occurs frequently in MALT lymphomas without t(1;14)(p22;q32), suggesting an important role for BCL10 in lymphoma development. Thirty-three cases of H pylori gastritis, 72 MALT lymphomas, and 11 mucosal diffuse large B-cell lymphomas (DLBCL) were screened for t(11;18)(q21;q21) by reverse transcription-polymerase chain reaction followed by sequencing. BCL10 expression in lymphoma cases was examined by immunohistochemistry. The API2--MALT1 fusion transcript was not detected in H pylori gastritis and mucosal DLBCL but was found in 25 of 72 (35%) MALT lymphomas of various sites. Nuclear BCL10 expression was seen in 28 of 53 (53%) of MALT lymphomas. Of the gastric cases, the largest group studied, the frequency of both t(11;18)(q21;q21) and nuclear BCL10 expression was significantly higher in tumors that showed dissemination to local lymph nodes or distal sites (14 of 18 = 78% and 14 of 15 = 93%, respectively) than those confined to the stomach (3 of 29 = 10% and 10 of 26 = 38%). Furthermore, t(11;18)(q21;q21) closely correlated with BCL10 nuclear expression. These results indicate that both t(11;18)(q21;q21) and BCL10 nuclear expression are associated with advanced MALT lymphoma and that their oncogenic activities may be related to each other. (Blood. 2001;98:1182-1187)


Mitochondrial function and apoptotic susceptibility in aging skeletal muscle.
During aging, skeletal muscle undergoes sarcopenia, a condition characterized by a loss of muscle cell mass and alterations in contractile function. The origin of these decrements is unknown, but evidence suggests that they can be partly attributed to mitochondrial dysfunction. To characterize the nature of this dysfunction, we investigated skeletal muscle contractile properties, subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial biogenesis and function, as well as apoptotic susceptibility in young (6 months old) and senescent (36 months old) Fischer 344 Brown Norway rats. Muscle mass and maximal force production were significantly lower in the 36-month group, which is indicative of a sarcopenic phenotype. Furthermore, contractile activity in situ revealed greater fatigability in the 36-month compared to the 6-month animals. This decrement could be partially accounted for by a 30% lower mitochondrial content in fast-twitch muscle from 36-month animals, as well as lower protein levels of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha. Enzyme activities and glutamate-induced oxygen consumption rates in isolated SS and IMF mitochondria were similar between age groups. However, mitochondrial reactive oxygen species (ROS) production during state 3 respiration was approximately 1.7-fold greater in mitochondria isolated from 36-month compared to 6-month animals, and was accompanied by a 1.8-fold increase in the DNA repair enzyme 8-oxoguanine glycosylase 1 in fast-twitch muscle. Basal rates of release of cytochrome c and endonuclease G in SS mitochondria were 3.5- to 7-fold higher from senescent animals. These data suggest that the age-related sarcopenia and muscle fatigability are associated with enhanced ROS production, increased mitochondrial apoptotic susceptibility and reduced transcriptional drive for mitochondrial biogenesis.


Tobacco Product Use Among Adults - United States, 2017.
Cigarette smoking harms nearly every organ of the body and causes adverse health consequences, including heart disease, stroke, and multiple types of cancer (1). Although cigarette smoking among U.S. adults has declined considerably, tobacco products have evolved in recent years to include various combustible, noncombustible, and electronic products (1,2). To assess recent national estimates of tobacco product use among U.S. adults aged ≥18 years, CDC, the Food and Drug Administration (FDA), and the National Institutes of Health's National Cancer Institute analyzed data from the 2017 National Health Interview Survey (NHIS). In 2017, an estimated 47.4 million U.S. adults (19.3%) currently used any tobacco product, including cigarettes (14.0%; 34.3 million); cigars, cigarillos, or filtered little cigars (3.8%; 9.3 million); electronic cigarettes (e-cigarettes) (2.8%; 6.9 million); smokeless tobacco (2.1%; 5.1 million); and pipes, water pipes, or hookahs (1.0%; 2.6 million). Among current tobacco product users, 86.7% (41.1 million) smoked combustible tobacco products, and 19.0% (9.0 million) used ≥2 tobacco products. By univariate analyses, the prevalence of current use of any tobacco product was higher among males than among females; adults aged <65 years than among those aged ≥65 years; non-Hispanic American Indian/Alaska Natives, whites, blacks, or multiracial adults than among Hispanics or non-Hispanic Asians; adults who lived in the South or Midwest than among those in the West or Northeast; adults who had a general educational development certificate (GED) than among those with other levels of education; adults who earned an annual household income of <$35,000 than among those with those with higher income; lesbian, gay, or bisexual adults than among heterosexual/straight adults; and adults who were divorced/separated/widowed or single/never married/not living with a partner than among those who were married/living with a partner. Prevalence was also higher among those who were uninsured, insured by Medicaid, or had some other public insurance than among those with private insurance or Medicare only; those who had a disability/limitation than among those who did not; and those who had serious psychological distress than among those who did not. Full implementation of evidence-based tobacco control interventions that address the diversity of tobacco products used by U.S. adults, in coordination with regulation of tobacco product manufacturing, marketing, and sales, can reduce tobacco-related disease and death in the United States (1-3).