The influence of glucocorticoids on lipid and lipoprotein metabolism and atherosclerosis.
Glucocorticoids have multiple therapeutic uses, but their impact on lipid metabolism and cardiovascular disease risk is not always considered during long-term treatment. Genetic variations, environmental factors and the reasons for glucocorticoid treatment all influence the lipid profile and atherosclerosis. Responses to glucocorticoid treatment may therefore be variable and unpredictable. Despite the frequency with which pharmacological doses of glucocorticoids are used, surprisingly few publications examine their effects on lipid metabolism and atherosclerosis. Patients managed with glucocorticoids should have their cardiovascular risk assessed, especially if long-term treatment is planned. While some apparent favourable changes have been reported in high-density lipoprotein metabolism, very-low-density lipoprotein and low-density lipoprotein responses seem unfavourable. The impact of glucocorticoids on atherosclerosis, which is often viewed as an inflammatory process, is unclear. Glucocorticoid treatment should be undertaken for appropriate indications, but in some instances special attention should be given to management of dyslipidaemia, as long-term survivors of treatment are likely to encounter atherosclerosis.


An In Vivo Evaluation of the Fit of Zirconium-Oxide Based, Ceramic Single Crowns with Vertical and Horizontal Finish Line Preparations.
Different types of tooth preparations influence the marginal precision of zirconium-oxide based ceramic single crowns. In this in vivo study, the marginal fits of zirconium-oxide based ceramic single crowns with vertical and horizontal finish lines were compared. Forty-six teeth were chosen in eight patients indicated for extraction for implant placement. CAD/CAM technology was used for the production of 46 zirconium-oxide-based ceramic single crowns: 23 teeth were prepared with vertical finishing lines, 23 with horizontal finishing lines. One operator accomplished all clinical procedures. The zirconia crowns were cemented with glass ionomer cement. The teeth were extracted 1 month later. Marginal gaps along vertical planes were measured for each crown, using a total of four landmarks for each tooth by means of a microscope at 50× magnification. On conclusion of microscopic assessment, ESEM evaluation was completed on all specimens. The comparison of the gap between the two types of preparation was performed with a nonparametric test (two-sample Wilcoxon rank-sum test) with a level of significance fixed at p < 0.05. All data were analyzed with STATA12. In the group with horizontal finish line preparations, the median value of the gap was 35.45 μm (Iqr, 0.33); for the vertical finish line group, the median value of the gap was 35.44 μm (Iqr, 0.40). The difference between the two groups was not statistically significant (two-sample Wilcoxon rank-sum test, p = 0.0872). Within the limitations of this study, the gaps of the zirconium-oxide-based ceramic CAD/CAM crowns with vertical and horizontal finish line preparations were not different.


[Prevalence of Trypanosoma cruzi infection in opossum (Didelphis albiventris) in Santiago del Estero, Argentina].
The opossum of the genus Didelphis is one of the principal wild reservoirs of Trypanosoma cruzi and is widely distributed in the Western Hemisphere. Didelphis albiventris is the most common marsupial in Amamá and Trinidad, two communities in the province of Santiago del Estero, Argentina. The D. albiventris population is replaced every year, and the opossum normally has two reproductive periods, one at the beginning of the spring and another at the beginning of the summer. The two litters are weaned, and they leave the mother's marsupial pouch to join the population, the first (G1) at the beginning of the summer and the second (G2) at the beginning of the fall. Between 1988 and 1991 409 D. albiventris opossums were studied, and xenodiagnoses showed that 35% of them were infected with T. cruzi. Annual cycles of renewed infection were observed, with prevalences that ranged between 22% and 43%. The acquisition of the parasite occurred over the entire year, from the summer through the spring. The prevalence of infection increased with age. The G1 individuals tended to present higher prevalences than the G2 individuals, probably from being exposed to transmission for a longer period of time. In the first two (younger) age categories for the opossums, G2 individuals showed higher prevalences than did the G1 individuals. This indicates a significant increase in transmission intensity during the fall. Opossums should be regarded as a potential source of T. cruzi entry to the domestic transmission cycle.


Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads to Lipodystrophy and Insulin Resistance.
Sphingolipids have been implicated in the etiology of chronic metabolic diseases. Here, we investigated whether sphingolipid biosynthesis is associated with the development of adipose tissues and metabolic diseases. SPTLC2, a subunit of serine palmitoyltransferase, was transcriptionally upregulated in the adipose tissues of obese mice and in differentiating adipocytes. Adipocyte-specific SPTLC2-deficient (aSPTLC2 KO) mice had markedly reduced adipose tissue mass. Fatty acids that were destined for the adipose tissue were instead shunted to liver and caused hepatosteatosis. This impaired fat distribution caused systemic insulin resistance and hyperglycemia, indicating severe lipodystrophy. Mechanistically, sphingosine 1-phosphate (S1P) was reduced in the adipose tissues of aSPTLC2 KO mice, and this inhibited adipocyte proliferation and differentiation via the downregulation of S1P receptor 1 and decreased activity of the peroxisome proliferator-activator receptor γ. In addition, downregulation of SREBP (sterol regulatory element-binding protein)-1c prevented adipogenesis of aSPTLC2 KO adipocytes. Collectively, our observations suggest that the tight regulation of de novo sphingolipid biosynthesis and S1P signaling plays an important role in adipogenesis and hepatosteatosis.


A mutation in the fibroblast growth factor receptor 1 gene causes fully penetrant normosmic isolated hypogonadotropic hypogonadism.
Kallmann syndrome (KS) consists of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia/hyposmia. Currently, the fibroblast growth factor receptor 1 (FGFR1) gene is the only known autosomal dominant cause of KS, which is also associated with synkinesia, midfacial defects, and dental agenesis. Mutations in FGFR1 typically demonstrate reduced penetrance, variable expressivity, and until recently have been exclusively identified in families with anosmia. The purpose of this study was to determine whether FGFR1 mutations were present in a unique family with autosomal dominant, fully penetrant, normosmic IHH. The study is a review of detailed clinical findings, dynamic endocrine studies, and performance of a molecular analysis of the FGFR1 gene. The study was carried out in an academic medical center. All four affected individuals have complete IHH with full penetrance but no anosmia/hyposmia, and they have none of the FGFR1-associated anomalies. In addition, no other family member has anosmia. Inverventions: Interventions included detailed phenotype characterization including history, physical exam, smell testing, dynamic pituitary testing, brain imaging, and molecular analysis. Outcome was measured by the determination of the severity of IHH, olfactory function, and sequence of the FGFR1 gene. The same heterozygous nonsense mutation, Arg622X, was present in all four affected members, but not in three unaffected members or 100 controls. The mutation is predicted to encode a truncated protein or result in nonsense-mediated decay. Our findings indicate that mutations in the FGFR1 gene can cause normosmic, fully penetrant, complete IHH with little or no variable expressivity, and without the other FGFR1-associated anomalies typically found in KS.


Weight management and determinants of weight change in patients with coronary artery disease.
To study the effects of a comprehensive secondary prevention programme on weight loss and to identify determinants of weight change in patients with coronary artery disease (CAD). We performed a secondary analysis focusing on the subgroup of overweight CAD patients (BMI ≥27 kg/m2) in the Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists-2 (RESPONSE-2) multicentre randomised trial. We evaluated weight change from baseline to 12-month follow-up; multivariable logistic regression with backward elimination was used to identify determinants of weight change. Intervention patients (n=280) lost significantly more weight than control patients (n=257) (-2.4±7.1 kg vs -0.2±4.6 kg; p<0.001). Individual weight change varied widely, with weight gain (≥1.0 kg) occurring in 36% of interventions versus 41% controls (p=0.21). In the intervention group, weight loss of ≥5% was associated with higher age (OR 2.94), lower educational level (OR 1.91), non-smoking status (OR 2.92), motivation to start with weight loss directly after the baseline visit (OR 2.31) and weight loss programme participation (OR 3.33), whereas weight gain (≥1 kg) was associated with smoking cessation ≤6 months before or during hospitalisation (OR 3.21), non-Caucasian ethnicity (OR 2.77), smoking at baseline (OR 2.70), lower age (<65 years) (OR 1.47) and weight loss programme participation (OR 0.59). The comprehensive secondary prevention programme was, on average, effective in achieving weight loss. However, wide variation was observed. As weight gain was observed in over one in three participants in both groups, prevention of weight gain may be as important as attempts to lose weight. NTR3937.


Effects of Cannabidiol on Diabetes Outcomes and Chronic Cerebral Hypoperfusion Comorbidities in Middle-Aged Rats.
Diabetes and aging are risk factors for cognitive impairments after chronic cerebral hypoperfusion (CCH). Cannabidiol (CBD) is a phytocannabinoid present in the Cannabis sativa plant. It has beneficial effects on both cerebral ischemic diseases and diabetes. We have recently reported that diabetes interacted synergistically with aging to increase neuroinflammation and memory deficits in rats subjected to CCH. The present study investigated whether CBD would alleviate cognitive decline and affect markers of inflammation and neuroplasticity in the hippocampus in middle-aged diabetic rats submitted to CCH. Diabetes was induced in middle-aged rats (14 months old) by intravenous streptozotocin (SZT) administration. Thirty days later, the diabetic animals were subjected to sham or CCH surgeries and treated with CBD (10 mg/kg, once a day) during 30 days. Diabetes exacerbated cognitive deficits induced by CCH in middle-aged rats. Repeated CBD treatment decreased body weight in both sham- and CCH-operated animals. Cannabidiol improved memory performance and reduced hippocampal levels of inflammation markers (inducible nitric oxide synthase, ionized calcium-binding adapter molecule 1, glial fibrillary acidic protein, and arginase 1). Cannabidiol attenuated the decrease in hippocampal levels of brain-derived neurotrophic factor induced by CCH in diabetic animals, but it did not affect the levels of neuroplasticity markers (growth-associated protein-43 and synaptophysin) in middle-aged diabetic rats. These results suggest that the neuroprotective effects of CBD in middle-aged diabetic rats subjected to CCH are related to a reduction in neuroinflammation. However, they seemed to occur independently of hippocampal neuroplasticity changes.


CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons.
CRISPR/Cas9-based functional genomics have transformed our ability to elucidate mammalian cell biology. However, most previous CRISPR-based screens were conducted in cancer cell lines rather than healthy, differentiated cells. Here, we describe a CRISPR interference (CRISPRi)-based platform for genetic screens in human neurons derived from induced pluripotent stem cells (iPSCs). We demonstrate robust and durable knockdown of endogenous genes in such neurons and present results from three complementary genetic screens. First, a survival-based screen revealed neuron-specific essential genes and genes that improved neuronal survival upon knockdown. Second, a screen with a single-cell transcriptomic readout uncovered several examples of genes whose knockdown had strikingly cell-type-specific consequences. Third, a longitudinal imaging screen detected distinct consequences of gene knockdown on neuronal morphology. Our results highlight the power of unbiased genetic screens in iPSC-derived differentiated cell types and provide a platform for systematic interrogation of normal and disease states of neurons. VIDEO ABSTRACT.


A live measles-vectored COVID-19 vaccine induces strong immunity and protection from SARS-CoV-2 challenge in mice and hamsters.
Several COVID-19 vaccines have now been deployed to tackle the SARS-CoV-2 pandemic, most of them based on messenger RNA or adenovirus vectors.The duration of protection afforded by these vaccines is unknown, as well as their capacity to protect from emerging new variants. To provide sufficient coverage for the world population, additional strategies need to be tested. The live pediatric measles vaccine (MV) is an attractive approach, given its extensive safety and efficacy history, along with its established large-scale manufacturing capacity. We develop an MV-based SARS-CoV-2 vaccine expressing the prefusion-stabilized, membrane-anchored full-length S antigen, which proves to be efficient at eliciting strong Th1-dominant T-cell responses and high neutralizing antibody titers. In both mouse and golden Syrian hamster models, these responses protect the animals from intranasal infectious challenge. Additionally, the elicited antibodies efficiently neutralize in vitro the three currently circulating variants of SARS-CoV-2.


Trends and Determinants of Comprehensive Knowledge of HIV among Adolescents and Young Adults in Nigeria: 2003 - 2013.
This study examined comprehensive knowledge of HIV (CKH) and its determinants among young people aged 15-24 years in Nigeria between 2003 and 2013. Secondary analysis was conducted on three rounds of NDHS 2003, 2008 and 2013 data. CKH increased significantly between 2003 and 2013, but the level reached in 2013 fell short of the global expectation for young people. Its significant determinants included gender, age, educational attainment, place and region of residence, household wealth status and uptake of HIV test. There is need to sustain all on-going effective youth-focused interventions and programmes to meet the comprehensive knowledge needs for all young people in Nigeria.


A 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 h in severe Alzheimer's dementia.
The 24-week, prospective, randomized, double-blind ACTION study investigated the efficacy, safety, and tolerability of 13.3 versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). Patients had probable AD and Mini-Mental State Examination scores ≥3-≤12. Primary outcome measures were as follows: Severe Impairment Battery (SIB) and AD Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Secondary outcomes were as follows: ADCS-Clinical Global Impression of Change (ADCS-CGIC), 12-item Neuropsychiatric Inventory (NPI-12), and safety/tolerability. Of 1014 patients screened, 716 were randomized to 13.3 mg/24 h (N = 356) or 4.6 mg/24 h (N = 360) patch. Baseline characteristics/demographics were comparable. Completion rates were as follows: 64.3% (N = 229) with 13.3 mg/24 h and 65.0% (N = 234) with 4.6 mg/24 h patch. The 13.3 mg/24 h patch was significantly superior to 4.6 mg/24 h patch on cognition (SIB) and function (ADCS-ADL-SIV) at Week 16 (P < 0.0001 and P = 0.049, respectively) and 24 (primary endpoint; P < 0.0001 and P = 0.025). Significant between-group differences (Week 24) were observed on the ADCS-CGIC (P = 0.0023), not NPI-12 (P = 0.1437). A similar proportion of the 13.3 mg/24 h and 4.6 mg/24 h patch groups reported adverse events (AEs; 74.6% and 73.3%, respectively) and serious AEs (14.9% and 13.6%). The 13.3 mg/24 h patch demonstrated superior efficacy to 4.6 mg/24 h patch on SIB and ADCS-ADL-SIV, without marked increase in AEs, suggesting higher-dose patch has a favorable benefit-to-risk profile in severe AD.


Effects of 1,25-Dihydroxyvitamin D3 on the Prevention of Chronic Obstructive Pulmonary Disease (COPD) in Rats Exposed to Air Pollutant Particles Less than 2.5 Micrometers in Diameter (PM2.5).
BACKGROUND This study aimed to investigate the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on airway changes in chronic obstructive pulmonary disease (COPD) rats exposed to air pollutant particles less than 2.5 micrometers in diameter (PM2.5), and to evaluate the mechanisms. MATERIAL AND METHODS Three groups were included in this study: a normal group, a COPD model group, and a COPD with 1,25(OH)2D3 treatment group. In each group, the rats were divided into four subgroups: control and different doses of PM2.5 (1.6, 8 and 40 mg/kg body weight). Apoptosis in lung tissue was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The expression of c-Jun N-terminal kinase 1 (JNK1) and mucin 5AC (MUC5AC) were detected by real-time polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence staining. RESULTS Compared with corresponding subgroups in normal group, the apoptotic rates in COPD group were significantly increased. By contrast, 1,25(OH)2D3 treatment group significantly reduced COPD-induced apoptosis in lung tissue. Upon the dose increase of PM2.5, the apoptotic rate was also elevated in each group. Compared with the corresponding control in each group, PM2.5 increased apoptosis in a dose-dependent manner. Importantly, 1,25(OH)2D3 also prevented apoptosis in COPD rats exposed to PM2.5. Mechanically, the expression of MUC5AC and JNK1 in COPD group was significantly upregulated, compared with corresponding subgroups in the normal group. Treatment with 1,25(OH)2D3 reduced expression of MUC5AC and JNK1 in COPD rats. It was found that the expression of MUC5AC and JNK1 was elevated with the dose increase of PM2.5 in each group. Consistently, 1,25(OH)2D3 also reduced the expression of MUC5AC and JNK1 in COPD rats exposed to PM2.5. CONCLUSIONS 1,25(OH)2D3 prevented lung injury in COPD rats with or without PM2.5 exposure. Our results suggest that 1,25(OH)2D3 is useful to mitigate the injury caused by COPD.


Response of Bacillus subtilis to nitric oxide and the nitrosating agent sodium nitroprusside.
We examined the effects of nitric oxide (NO) and sodium nitroprusside (SNP) on Bacillus subtilis physiology and gene expression. In aerobically growing cultures, cell death was most pronounced when NO gas was added incrementally rather than as a single bolus, suggesting that the length of exposure was important in determining cell survival. DNA microarrays, Northern hybridizations, and RNA slot blot analyses were employed to characterize the global transcriptional response of B. subtilis to NO and SNP. Under both aerobic and anaerobic conditions the gene most highly induced by NO was hmp, a flavohemoglobin known to protect bacteria from NO stress. Anaerobically, NO also induced genes repressed by the Fe(II)-containing metalloregulators, Fur and PerR, consistent with the known ability of NO to nitrosylate the Fe(II) center in Fur. In support of this model, we demonstrate that NO fails to induce PerR-regulated genes under growth conditions that favor the formation of PerR:Mn(II) rather than PerR:Fe(II). Aerobically, NO gas induced hmp, the sigmaB general stress regulon, and, to a lesser extent, the Fur and PerR regulons. Surprisingly, NO gas induced the sigmaB regulon via the energy branch of the sigmaB regulatory cascade while induction by SNP was mediated by the environmental stress branch. This emphasizes that NO and SNP elicit genetically distinct stress responses.


Rapid and continuous monitoring of cerebral perfusion by magnetic resonance line scan assessment with arterial spin tagging.
A new approach is presented for rapid and continuous monitoring of cerebral perfusion which is based upon line-scan MR column imaging with arterial spin tagging (AST) of endogenous water. Spin tagging of arterial water protons is accomplished using adiabatic fast passage inversion, followed by acquisition of the perfusion sensitive MR signal from a column placed at the desired level through the brain using line scan localization techniques. A perfusion sensitive line scan is followed by a non-perfusion sensitive line scan, and perfusion is calculated pixel-by-pixel from the intensity difference of the two lines. Continuous perfusion measurements are reported with temporal resolution of 10 s in pixels of volume 0.027 cm3 or less. Examples of the methodology are given during hypercapnic challenge induced with carbon dioxide, and during an ischemic event induced by reversible middle cerebral artery occlusion. The method is also used to characterize the signal response as a function of arterial inversion time and post inversion acquisition delay. These methods permit rapid and continuous monitoring of cerebral perfusion with high spatial resolution, and can be interleaved with MR measurements of diffusion and T1 to follow the progression of cerebral events during physiological or pharmacological intervention.


Reversal of antipsychotic-associated weight gain.
Given growing concern about weight gain associated with treatment with antipsychotic agents, we performed a retrospective chart review of patients who reversed weight gain associated with antipsychotic treatment to determine the prevalence of reversal and both the course and methods used. Prevalence of weight gain reversal was determined by surveying clinicians. Of 53 patients who gained >/= 20 lb (9 kg) during antipsychotic treatment, an initial sample of 12 patients (23%) who subsequently lost >/= 10 lb (5 kg) was identified. These 12 patients were combined with additional patients, identified by the authors, who met the same criteria for reversal of antipsychotic-associated weight gain to form a total sample of 35 patients. Course and methods of weight loss were determined by reviewing these patients' charts. Information about interventions and both antipsychotic and other medications was collected. At the point of maximum weight gain, the total sample of 35 patients had gained a mean of 29.36 kg (64.73 lb) over a mean of 33 months. At the point of greatest weight loss (56 months), these patients were a mean of 10.86 kg (23.94 lb) over their baseline weight. The most recent weight for patients (63 months) indicated they were 14.81 kg (32.65 lb) over baseline. The most frequent weight loss interventions were regular dietician visits (42.9% [N = 15]), self-directed diet (28.6% [N = 10]), and weight loss as a treatment goal (25.7% [N = 9]). The least frequent interventions were no intervention (5.7% [N = 2]), psychiatrist addressing weight loss (5.7% [N = 2]), and surgery (2.9% [N = 1]). No significant change in medications prescribed was found. Some patients who gain weight while taking antipsychotic medications are able to stop gaining and lose weight over time, largely through behavioral interventions. While patients' weight fluctuated, this group sustained a loss of approximately half their initial gain. Dietary interventions appear promising and should be explored further to prevent and reverse weight gain.


Asthma-COPD overlap 2015: now we are six.
The overlap between asthma and COPD is increasingly recognised. This review examines the new insights, treatment and remaining knowledge gaps for asthma-COPD overlap. A systematic literature review of cluster analyses of asthma and COPD was performed. Articles from 2009 to the present dealing with prevalence, morbidity and treatment of asthma-COPD overlap were identified and reviewed. Asthma-COPD overlap was consistently recognised in studies using a variety of different study designs and sampling. The prevalence was approximately 20% in patients with obstructive airways diseases. Asthma-COPD overlap was associated with increased morbidity and possibly an increased mortality and comorbidity. There was evidence of a heterogeneous pattern of airway inflammation that included eosinophilic (in adult asthma), neutrophilic or mixed patterns (in severe asthma and COPD). Systemic inflammation was present in asthma-COPD overlap and resembled that of COPD. Within asthma-COPD overlap, there is evidence of different subgroups, and recognition using bronchodilator responsiveness has not been successful. Guidelines generally recommend a serial approach to assessment, with treatment recommendations dominated by an asthma paradigm. Research is needed into key clinical features that impact outcome, mechanisms and treatment approaches in asthma-COPD overlap. Identifying and treating disease components by multidimensional assessment shows promise. Asthma-COPD overlap has drawn attention to the significant heterogeneity that exists within obstructive airway diseases. It should be replaced by novel approaches that identify and manage the components of this heterogeneity, such as multidimensional assessment and treatment. Future research is needed to test these novel and personalised approaches.


Loss of Trop2 causes ErbB3 activation through a neuregulin-1-dependent mechanism in the mesenchymal subtype of HNSCC.
In head and neck squamous cell cancer (HNSCC), four intrinsic subtypes (or groups) have been identified, and each one possesses a unique biology that will require specific treatment strategies. We previously reported that mesenchymal (group 2) tumors exhibit reduced levels of Trop2 expression. In this study, we investigated the functional role of Trop2 in HNSCC and find that loss results in autocrine activation of the EGFR family member ErbB3 via neuregulin-1. Trop2 localizes to both the cell surface and cytosol of HNSCC cells and forms a complex with neuregulin-1, which is predominantly cytosolic. Inactivation of Trop2 increases the concentration of neuregulin-1 at the cell surface where it is cleaved to activate ErbB3. In primary HNSCC, detection of ErbB3 activation was limited to Trop2 negative tumors. An analysis of the Cancer Genome Atlas (TCGA) HNSCC dataset confirms enrichment for ErbB3 activity in mesenchymal tumors. Notably, Trop2 loss triggers sensitivity to anti-ErbB3 antibodies, which results in reduced proliferation and tumorigenic growth of Trop2 negative HNSCC cancer cells. These results uncover a molecular mechanism by which tumor cells control the amount of cell-surface neuregulin-1 available for cleavage and ErbB3 activation. Moreover, we demonstrate that Trop2 is a potential surrogate biomarker to identify tumors with ErbB3 activation and may therefore respond to anti-ErbB3 therapeutics.


Patient-specific factors modulate leukocyte response in dimethyl fumarate treated MS patients.
Determine if patient-specific factors modulate absolute lymphocyte count (ALC), neutrophil count (ANC), and/or Neutrophile-lymphocyte ratio (NLR) in Dimethyl Fumarate (DMF) treated patients. A retrospective study of patients who initiated DMF between 2013-2018. A multicenter study of two MS clinics: Charlottesville, VA (UVA) and Dallas, TX (DaVA). 103 patients (67-UVA, 36-DaVA) met eligibility. At baseline, the DaVa population was younger (mean±sd: 38.6±9.0 vs 42.2±12.5, p 0.152) and had a higher proportion of males (61% vs. 35%), consistent with a veteran cohort. Pre-treatment, all other laboratory parameters were similar between the two groups. On treatment there was a 30% lowering of mean ALC, with 3% having grade-3 lymphopenia (ALC < 500). Sustained neutropenia occurred in 3.9% of patients and was more common in males. Over 50% of patients had a high NLR at baseline, with a further 44% increase in NLR on-treatment. Age was significantly predictive of lymphopenia, with grade-3 lymphopenia found in 33% of patients ≥ 55 years. Neutropenia was more common in males. Serum BG (sBG) has modest correlation to leukocyte parameters. BMI was not correlated with any leukocyte-related outcomes. Patient-specific factors, specifically-age, sex, and serum blood glucose, modulate leukocyte response and ratios in DMF treated MS patients. Age appears to be a relevant predictor of lymphopenia and should be a factor in treatment decision making. Neutropenia, independent of lymphopenia, can occur and males may be at increased risk. High sBG may impact leukocyte count and ratios in MS patients and merits further study, particularly in patients with diabetes. NLR is abnormal in MS and increased with DMF-treatment, the clinical implications of this will require further study.


Delayed presentation and late testing for HIV: demographic and behavioral risk factors in a multicenter study in Italy.
Ensuring timely access to care for persons with HIV is an important public health goal. To identify factors associated with delayed presentation to medical care after testing HIV-positive or with late HIV testing, we studied 968 patients at their first HIV care visit, enrolled in a multicenter study in Italy from 1997-2000. Patients completed a questionnaire on HIV-testing history, sexual behavior, and drug use behavior. Delayed presenters were patients with >6 months between their first HIV-positive test and presentation for HIV care; late testers were patients with CD4 count < 200 /mm or clinically defined AIDS at their first HIV-positive test. Among the study patients, 255 (26.3%) were delayed presenters, and 280 (28.9%) were late testers. In multinomial logistic regression analysis, injection drug use significantly increased (odds ratio [OR]= 5.04) the probability of delayed presentation but reduced (OR = 0.55) the chance of late testing. A previous HIV-negative test was associated with a reduced risk of both delayed presentation (OR = 0.39) and late testing (OR = 0.36). Unemployment was positively associated with delayed presentation and increasing age with late testing, whereas HIV counseling at the time of first positive HIV test strongly (OR = 0.42) reduced the odds of delayed presentation. Interventions aimed at promoting timely access to care of HIV-infected persons should consider differentiated programs for delayed presentation and late testing.


Why are social sciences and humanities needed in the works of IPBES? A systematic review of the literature.
Despite the increased attention, which has been given to the issue of involving knowledge and experts from the social sciences and humanities (SSH) into the products and works of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES), little is known on what the expectations towards the involvement of SSH in IPBES actually are. The aim of this paper is to close this gap by identifying the range of possible SSH contributions to IPBES that are expected in the literature, and discuss the inherent challenges of and concrete ways to realize these contributions in the particular institutional setting of IPBES. We address these two points by: firstly, assessing the literature dealing with IPBES and building a typology describing the main ways in which contributions from SSH to IPBES have been conceived between 2006 and 2017. We discuss these expected contributions in light of broader debates on the role of SSH in nature conservation and analyse some of the blind spots and selectivities in the perception of how SSH could substantially contribute to the works of IPBES. Then, secondly, by looking at one particular example, economics and its use in the first thematic assessment on pollinators, pollination and food production, we will concretely illustrate how works in a given discipline could contribute in many different and unprecedented ways to the works of IPBES and help identify paths for enhancing the conservation of biodiversity. Finally, we propose a range of practical recommendations as to how to increase the contribution of SSH in the works of IPBES.


Minimizing potential resistance: the molecular view.
The major contribution of molecular biology to the study of antibiotic resistance has been the elucidation of nearly all biochemical mechanisms of resistance and the routes for dissemination of genetic information among bacteria. In this review, we consider the potential contribution of molecular biology to counteracting the evolution of resistant bacteria. In particular, we emphasize the fact that fundamental approaches have had direct practical effects on minimizing potential resistance: by improving interpretation of resistance phenotypes, by providing more adequate human therapy, by fostering more prudent use of antibiotics, and by allowing the rational design of new drugs that evade existing resistance mechanisms or address unexploited targets.


Neuromagnetic response to body motion and brain connectivity.
Visual detection of body motion is of immense importance for daily-life activities and social nonverbal interaction. Although neurobiological mechanisms underlying visual processing of human locomotion are being explored extensively by brain imaging, the role of structural brain connectivity is not well understood. Here we investigate cortical evoked neuromagnetic response to point-light body motion in healthy adolescents and in patients with early periventricular lesions, periventricular leukomalacia (PVL), that disrupt brain connectivity. In a simultaneous masking paradigm, participants detected the presence of a point-light walker embedded in a few sets of spatially scrambled dots on the joints of a walker. The visual sensitivity to camouflaged human locomotion was lower in PVL patients. In accord with behavioral data, root-mean-square (RMS) amplitude of neuromagnetic trace in response to human locomotion was lower in PVL patients at latencies of 180-244 msec over the right temporal cortex. In this time window, the visual sensitivity to body motion in controls, but not in PVL patients, was inversely linked to the right temporal activation. At later latencies of 276-340 msec, we found reduction in RMS amplitude in PVL patients for body motion stimuli over the right frontal cortex. The findings indicate that disturbances in brain connectivity with the right temporal cortex, a key node of the social brain, and with the right frontal cortex lead to disintegration of the neural network engaged in visual processing of body motion. We suspect that reduced cortical response to body motion over the right temporal and frontal cortices might underlie deficits in visual social cognition.


Personality disorder services in England: findings from a national survey.
Aims and method We aimed to evaluate the availability and nature of services for people affected by personality disorder in England by conducting a survey of English National Health Service (NHS) mental health trusts and independent organisations. Results In England, 84% of organisations reported having at least one dedicated personality disorder service. This represents a fivefold increase compared with a 2002 survey. However, only 55% of organisations reported that patients had equal access across localities to these dedicated services. Dedicated services commonly had good levels of service use and carer involvement, and engagement in education, research and training. However, a wider multidisciplinary team and a greater number of biopsychosocial interventions were available through generic services. Clinical implications There has been a substantial increase in service provision for people affected by personality disorder, but continued variability in the availability of services is apparent and it remains unclear whether quality of care has improved.


Cancer-related fatigue: a brief overview of current nursing perspectives and experiences.
Cancer-related fatigue (CRF) has often been called the "sixth vital sign" and was the focus of a symposium at the Oncology Nursing Society's 32nd Annual Congress, where nurses discussed CRF's impact on patients. Despite this dialogue, current nursing perspectives and practice still need to be determined. The definition of CRF as a multidimensional symptom will be considered in this article. CRF may create psychological, functional, cognitive, and socioeconomic issues in patients. Challenges for effective management will be considered.


Differential effects of ibotenic acid lesions of the hippocampus and blockade of N-methyl-D-aspartate receptor-dependent long-term potentiation on contextual processing in rats.
The contextual specificity of appetitive conditioned responding was examined in rats undergoing chronic intracerebroventricular infusion of 15 or 30 mM D-2-amino-5-phosphonopentanoic acid (D-AP5) or with excitotoxic hippocampal lesions. The magnitude of conditioned responding by control rats and rats infused with D-AP5 to a conditioned stimulus (CS) trained in Context A was attenuated when the same stimulus was presented in Context B. By contrast, hippocampal-lesioned rats displayed comparable levels of responding to the CS when presented in either Context A or B. Subsequent in vivo electrophysiological investigations showed that the D-AP5 concentrations were effective in blocking long-term potentiation (LTP) in the dentate gyrus. Results indicate that rats are capable of processing contextual information in the absence of N-methyl-D-aspartate (NMDA) receptor-dependent LTP and demonstrate an important dissociation between the effects of hippocampal lesions and the blockade of NMDA receptors in the hippocampus.


Serological evidence of Rift Valley fever virus among humans in Mersin province of Turkey.
Rift Valley fever virus (RVFV) is a vector-borne pathogen that causes serious outbreaks among livestock, and severe symptoms and mortality in humans. The virus is known to be widespread throughout African countries and Arabian peninsula. The aim of the present study was to investigate the seroprevalence of RVFV infection among human populations of Mersin province, Turkey. A region-wide serological survey was conducted on humans residing in rural and urban areas of Mersin province located in the subtropical mediterranean region of Turkey from July 2011- January 2014. Plasma samples were tested for the presence of anti-RVFV antibodies using commercially available indirect immunofluorescence assay. The overall past infections were detected in 48 (4.9%) of the 977 human blood samples. The RVF virus- specific IgG positivity was detected in 33 (4.9%) of the 677 blood samples obtained from the urban area and in 15 (5%) of the 300 samples obtained from the rural area. There was no statistically significant difference in the distribution of RVFV IgG positivity rates between urban and rural areas (p = 0.933); though difference was significant between the rural areas (p = 0.029). The study confirmed for the first time, the presence of the RVFV antibody in the urban and rural areas of mediterranean province of Mersin in Turkey, suggesting wide circulation of RVFV in the human population.


Evaluation of left pulmonary artery sling, associated cardiovascular anomalies, and surgical outcomes using cardiovascular computed tomography angiography.
We evaluated the prevalence, image appearance, associated cardiovascular anomalies, and surgical outcomes of left pulmonary artery sling (LPAS) using cardiovascular computed tomography angiography (CCTA). A retrospective search of patients from our database between October 2007 and December 2014 identified 52,200 patients with congenital heart diseases (CHD) referred for CCTA, echocardiography, or magnetic resonance imaging. Clinical information, CCTA findings, associated cardiovascular anomalies, and surgical outcomes were analyzed. We showed a hospital-based prevalence of 71 patients with LPAS (0.14%, 71/52,200) among CHD patients. Of these, 47 patients with CCTA examinations were assessed further. Most patients (40/47, 85%) had associated cardiovascular anomalies, of which ventricular septal defects (22/47, 47%), atrial septal defects (20/47, 43%), patent ductus arteriosus (16/47, 34%), persistent left superior vena cava (14/47, 30%), and abnormal branching of the right pulmonary artery (ABRPA) (14/47, 30%) were most commonly identified. In total, 28 patients underwent LPA reanastomosis and/or tracheoplasty in our center, and 5 died. LPAS had a hospital-based prevalence of 0.14% among CHD patients. ABRPA is not uncommon and must be recognized. CCTA is a feasible method for demonstrating LPAS and its associated cardiovascular anomalies for an optimal pre-operative assessment of LPAS.


Motor radiculopathy.
A 48-year-old immunosuppressed woman presented to a rheumatology follow-up clinic after suffering from herpes zoster infection. She had manifestations of foot drop 3 months after the initial infection. She was diagnosed with motor radiculopathy following herpes zoster infection that was effectively managed by physiotherapy and amitriptyline.


H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation.
Natural killer (NK) cells are unique players in innate immunity and, as such, an attractive target for immunotherapy. NK cells display immune memory properties in certain models, but the long-term status of NK cells following systemic inflammation is unknown. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory-like properties, showing increased production of IFNγ upon specific secondary stimulation. The NK cell memory response is detectable for at least 9 weeks and contributes to protection from E. coli infection upon adoptive transfer. Importantly, we reveal a mechanism essential for NK cell memory, whereby an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erases the enhancer and abolishes NK cell memory. Thus, NK cell memory develops after endotoxemia in a histone methylation-dependent manner, ensuring a heightened response to secondary stimulation.


Bilateral axillary skin fold flaps used for dorsal thoracic skin wound closure in a dog.
A 10-year-old greyhound-cross dog was presented with a large, chronic skin wound extending over the interscapular region. The substantial skin defect was closed by making use of bilateral axillary skin fold flaps. It was possible to elevate the 2 skin flaps sufficiently to allow them to meet at the dorsal midline and thus facilitate complete closure of a large and awkwardly positioned wound. Small dorsal areas of the skin flaps underwent necrosis, but the resulting defects were closed without difficulty in a subsequent procedure. To the author's knowledge, this is the 1st clinical report of the use of bilateral axillary skin fold flaps in this fashion and describes an additional use of a versatile skin flap procedure.


Whole-brain white matter organization, intelligence, and educational attainment.
General cognitive ability, sometimes referred to as intelligence, is associated with educational attainment throughout childhood. Most studies that have explored the neural correlates of intelligence in childhood focus on individual brain regions. This analytical approach is designed to identify restricted sets of voxels that overlap across participants. By contrast, we explored the relationship between white matter connectome organization, intelligence, and education. In both a sample of typically-developing children (N = 63) and a sample of struggling learners (N = 139), the white matter connectome efficiency was strongly associated with intelligence and educational attainment. Further, intelligence partially mediated the relationship between connectome efficiency and educational attainment. In contrast, a canonical voxel-wise analysis failed to identify any significant relationships. The results emphasize the importance of distributed brain network properties for cognitive or educational ability in childhood. Our findings are interpreted in the context of a developmental theory, which emphasizes the interaction between different subsystems over developmental time.


Mixed infection with Porphyromonas gingivalis and Fusobacterium nucleatum in a murine lesion model: potential synergistic effects on virulence.
These studies determined the characteristics of tissue destruction in a murine abscess model elicited by mixed infection with the periodontopathogens Fusobacterium nucleatum and Porphyromonas gingivalis. The interbacterial effects of this synergism, the kinetics of the relationship of the bacterial interaction, and the characteristics of the bacteria required for the tissue destruction were studied. Infection of mice with P. gingivalis and F. nucleatum strains elicited lesions of various sizes as a function of infective dose. Primary infection with F. nucleatum plus P. gingivalis at various ratios (i.e., <1:1) resulted in a significantly greater lesion size (P < 0.001) compared with that resulting from primary infection with P. gingivalis alone. At F. nucleatum/P. gingivalis ratios of > or = 1:1, spreading lesion formation and progression were significantly (P < 0.001) decreased, suggesting that bacterial interaction (i.e., coaggregation) may have inhibited the spread of the P. gingivalis infection to a site distant from the initial injection. Infection with F. nucleatum and P. gingivalis simultaneously (at different sites) or F. nucleatum administered within 4 h prior to or 1 h following P. gingivalis infection significantly enhanced the ability of P. gingivalis to form large phlegmonous lesions. Chemical inhibition of the P. gingivalis trypsin-like protease activity or the use of a trypsin-negative P. gingivalis strain abrogated tissue destruction either alone or in combination with F. nucleatum. Therefore, it was possible to examine aspects of virulence of these pathogens in a murine lesion model by either altering bacterial ratios, manipulating the time of infection, or targeting vital bacterial virulence factors.


Treatment of active psoriatic arthritis with the PPARgamma ligand pioglitazone: an open-label pilot study.
Psoriatic arthritis (PsA) is an inflammatory joint disease, in which early neovascularization of affected skin and synovial tissue represents an important pathogenetic step in the disease process. Activation of the peroxisome proliferator activated receptor gamma (PPARgamma) showed anti-inflammatory effects in several in vitro and in vivo models (e.g. collagen-induced arthritis) by inhibition of angiogenesis and suppression of proinflammatory cytokines. Therefore, we studied the use of pioglitazone, a PPARgamma agonist originally developed for the treatment of diabetes, in patients with PsA. Ten patients with active PsA, seven males and three females, who showed at least two tender and two swollen joints despite stable treatment with an NSAID, were enrolled in this open-label study. All patients received a daily dose of 60 mg pioglitazone while continuing their current NSAID therapy. The primary endpoint was the PsARC (Psoriatic Arthritis Response Criterion); the secondary endpoints included the ACR20 response and improvement in the Psoriasis Area and Severity Index (PASI) in patients with more than 2% skin involvement. Patients were evaluated for endpoints at baseline and after 12 weeks. After 12 weeks, six of 10 patients met the PsARC. The ACR20 response was achieved in five patients. The mean percentage reduction in PASI was 38%, with a clinically meaningful PASI 50 response in two of six patients. Median tender joint count (interquartile range) decreased from 12.0 (8.0-18.0) to 4.0 (2.0-10.0), and the median swollen joint count from 5.0 (4.0-8.0) to 2.0 (1.0-7.0) (P<0.05 for both). Median Health Assessment Questionnaire score changed from 1.0 (0.375-1.375) to 0.75 (0.375-1.0) (P<0.05). Three patients had to be withdrawn from the study due to inefficacy and side-effects. Major side-effects were oedema of the lower extremities and increase in weight. Treatment with a PPARgamma agonist appears to be a promising therapeutic principle in PsA, but the use of PPARgamma ligands might be limited by side-effects such as increase in weight and fluid retention.


Leisure time physical activity among older adults with long-term spinal cord injury.
Cross-sectional. To describe participation in leisure time physical activity (LTPA) (amount, intensity and type) among older adults with long-term spinal cord injury (SCI), and to investigate the associations with sociodemographics, injury characteristics and secondary health conditions (SHCs). Home settings in southern Sweden. Data from the Swedish Aging with Spinal Cord Injury Study (SASCIS). The physical activity recall assessment for people with SCI was used to assess LTPA among 84 men and 35 women (mean age 63.5 years, mean time since injury 24 years, injury levels C1-L5, American Spinal Injury Association Impairment Scale A-D). Associations were analyzed statistically using hierarchical multivariable regression. Twenty-nine percent reported no LTPA, whereas 53% performed moderate-to-heavy intensity LTPA. The mean minutes per day of total LTPA was 34.7 (±41.5, median 15, range 0-171.7) and of moderate-to-heavy LTPA 22.5 (±35.1, median 5.0, range 0-140.0). The most frequently performed activities were walking and wheeling. Sociodemographics, injury characteristics and SHCs (bowel-related and bladder-related problems, spasticity and pain) explained 10.6% and 13.4%, respectively, of the variance in total and moderate-to-heavy LTPA. Age and wheelchair use were significantly, negatively associated with total LTPA. Women, wheelchair users and employed participants performed significantly less moderate-to-heavy LTPA than men, those using walking devices/no mobility device and unemployed participants. Many older adults with long-term SCI do not reach the amount or intensity of LTPA needed to achieve fitness benefits. Research is needed on how to increase LTPA and to identify modifiable factors that could enhance their participation.


Health, wellbeing, and disability among older people infected or affected by HIV in Uganda and South Africa.
To describe and compare the health status, emotional wellbeing, and functional status of older people in Uganda and South Africa who are HIV infected or affected by HIV in their families. Data came from the general population cohort and Entebbe cohort of the Medical Research Council/Uganda Virus Research Institute, and from the Africa Centre Demographic Information System through cross-sectional surveys in 2009/10 using instruments adapted from the World Health Organization (WHO) Study on Global Ageing and Adult Health (SAGE). Analysis was based on 932 people aged 50 years or older (510 Uganda, 422 South Africa). Participants in South Africa were slightly younger (median age - 60 years in South Africa, 63 in Uganda), and more were currently married, had no formal education, were not working, and were residing in a rural area. Adjusting for socio-demographic factors, older people in South Africa were significantly less likely to have good functional ability [adjusted odds ratio (aOR) 0.72, 95% CI 0.53-0.98] than those in Uganda, but were more likely to be in good subjective wellbeing (aOR 2.15, 95% CI 1.60-2.90). South Africans were more likely to be obese (aOR 5.26, 95% CI 3.46-8.00) or to be diagnosed with hypertension (aOR 2.77, 95% CI 2.06-3.73). While older people's health problems are similar in the two countries, marked socio-demographic differences influence the extent to which older people are affected by poorer health. It is therefore imperative when designing policies to improve the health and wellbeing of older people in sub-Saharan Africa that the region is not treated as a homogenous entity.


Planning for sustainable tourism in southern Pulau Banggi: an assessment of biophysical conditions and their implications for future tourism development.
A priori assessments of a site's biophysical and socio-economic capacity for accommodating tourism are less common than tourism impact studies. A priori evaluations can provide a contextual understanding of ecological, economic and socio-cultural forces, which shape the prospects for sustainable tourism development at the host destination, and can avert adverse impacts of tourism. We conduct an a priori assessment of the biophysical environment of Pulau Banggi, in the Malaysian state of Sabah for sustainable tourism development. We characterise baseline conditions of the island's marine biodiversity, seasonality, and infrastructure. We then evaluate how existing biophysical conditions will influence options for sustainable tourism development. In particular, we suggest conditions, if there are any, which constitute a limit to future tourism development in terms of compatibility for recreation and resilience to visitor impacts. We find that the biggest constraint is the lack of adequate water and sanitation infrastructure. Blast fishing, although occurring less than once per hour, can potentially destroy the major attraction for tourists. We conclude that while Pulau Banggi possesses natural qualities that are attractive for ecotourism, financial and institutional support must be made available to provide facilities and services that will enable local participation in environmental protection and enhance prospects for future sustainable tourism.


Production and characterization of lignocellulosic biomass-derived activated carbon.
The goal of this work is to establish the technical feasibility of producing activated carbon from pulp mill sludges. KOH chemical activation of four lignocellulosic biomass materials, two sludges from pulp mills, one sludge for a linerboard mill, and cow manure, were investigated experimentally, with a focus on the effects of KOH/biomass ratio (1/1, 1.5/1 and 2/1), activation temperature (400-600 °C) and activation time (1 to 2 h) on the development of porosity. The activation products were characterized for their physical and chemical properties using a surface area analyzer, scanning electron microscopy and Fourier transform infrared spectroscopy. Experiments were carried out to establish the effectiveness of the lignocellulosic biomass-derived activated carbon in removing methylene blue (MB), a surrogate of large organic molecules. The results show that the activated carbon are highly porous with specific surface area greater than 500 m²/g. The yield of activated carbon was greater than the percent of fixed carbon in the dry sludge, suggesting that the activation process was able to capture a substantial amount of carbon from the organic matter in the sludge. While 400 °C was too low, 600 °C was high enough to sustain a substantial rate of activation for linerboard sludge. The KOH/biomass ratio, activation temperature and time all play important roles in pore development and yield control, allowing optimization of the activation process. MB adsorption followed a Langmuir isotherm for all four activated carbon, although the adsorption capacity of NK-primary sludge-derived activated carbon was considerably lower than the rest, consistent with its lower specific surface area.


[Demonstration of an engagement process towards cell death by apoptosis in lymphocytes of HIV infected patients].
Peripheral blood lymphocytes from AIDS patients or from infected asymptomatic individuals display a rapid loss of viability upon culture in a survival medium. Cellular death occurs following endonucleosomal DNA fragmentation (apoptosis), which is preceeded by chromatin condensation and lower staining with orange acridine. This phenomenon is accelerated by compounds known to activate lymphocytes (such as ionophores) and is partly or entirely suppressed by addition of a cytokine crude preparation, enriched in IL2. All together, these results suggest that in vivo a significant fraction of patients' lymphocytes is engaged towards a preapoptosis process resulting from abnormal activation.


Assembly of Outer Membrane β-Barrel Proteins: the Bam Complex.
The major class of integral proteins found in the outer membrane (OM) of E. coli and Salmonella adopt a β-barrel conformation (OMPs). OMPs are synthesized in the cytoplasm with a typical signal sequence at the amino terminus, which directs them to the secretion machinery (SecYEG) located in the inner membrane for translocation to the periplasm. Chaperones such as SurA, or DegP and Skp, escort these proteins across the aqueous periplasm protecting them from aggregation. The chaperones then deliver OMPs to a highly conserved outer membrane assembly site termed the Bam complex. In E. coli, the Bam complex is composed of an essential OMP, BamA, and four associated OM lipoproteins, BamBCDE, one of which, BamD, is also essential. Here we provide an overview of what we know about the process of OMP assembly and outline the various hypotheses that have been proposed to explain how proteins might be integrated into the asymmetric OM lipid bilayer in an environment that lacks obvious energy sources. In addition, we describe the envelope stress responses that ensure the fidelity of OM biogenesis and how factors, such as phage and certain toxins, have coopted this essential machine to gain entry into the cell.


Correlates of objectively measured overweight/obesity and physical activity in Kenyan school children: results from ISCOLE-Kenya.
Childhood overweight/obesity and inadequate physical activity burden Western countries, and now, pose a growing threat to the health of children in low and middle income countries. Behavioural transitions toward more sedentary lifestyles coupled with increased consumption of high calorie foods has resulted in rising proportions of overweight/obesity and decreasing levels of physical activity in school-aged children. The objective of this study was to determine the prevalence and to investigate factors associated with overweight/obesity and physical activity in Kenyan children aged 9 to 11 years. Body composition and physical activity measures of participating children were accomplished by anthropometric assessment, accelerometry, and administration of questionnaires related to diet and lifestyle, and the school and neighbourhood environments. Data collection was conducted in the city of Nairobi as part of a larger International Study of Childhood Obesity, Lifestyle and Environment. A total of 563 participants (46.5% boys, 53.5% girls) were included in the analyses. Of these, 3.7% were underweight, 14.4% were overweight, and 6.4% were obese based on WHO cut-points. Mean daily sedentary time was 398 minutes, time spent in light physical activity was 463 minutes, and time spent in moderate-to-vigorous physical activity was 36 minutes based on activity cut-points developed by Treuth et al. Only 12.6% of participating children were meeting the recommendation of ≥ 60 minutes of daily moderate-to-vigorous physical activity, and 45.7% of participants used active transportation to/from school. Increasing parental education level, total annual household income, and attending a private rather than public school were associated positively with being overweight/obese and negatively with meeting physical activity guidelines. This study provided the evidence for an existing prevalence of childhood overweight/obesity in Nairobi. Children were spending a considerable amount of time in sedentary and light intensity physical activity, with few meeting physical activity guidelines. Higher socioeconomic status and parental education attainment were associated with a higher likelihood of children being overweight/obese and a lower likelihood of children meeting the physical activity recommendations. Interventions and strategies should be attentive to the potential health consequences of lifestyle transitions resulting from urbanisation and economic prosperity.


Interaction of EGFR to δ-catenin leads to δ-catenin phosphorylation and enhances EGFR signaling.
Expression of δ-catenin reportedly increases during late stage prostate cancer. Furthermore, it has been demonstrated that expression of EGFR is enhanced in hormone refractory prostate cancer. In this study, we investigated the possible correlation between EGFR and δ-catenin in prostate cancer cells. We found that EGFR interacted with δ-catenin and the interaction decreased in the presence of EGF. We also demonstrated that, on one hand, EGFR phosphorylated δ-catenin in a Src independent manner in the presence of EGF and on the other hand, δ-catenin enhanced protein stability of EGFR and strengthened the EGFR/Erk1/2 signaling pathway. Our findings added a new perspective to the interaction of EGFR to the E-cadherin complex. They also provided novel insights to the roles of δ-catenin in prostate cancer cells.


Rational planning of operating lists: a prospective comparison of 'booking to the mean' vs. 'probabilistic case scheduling' in urology.
The efficient use of operating theatres requires accurate case scheduling. One common method is 'booking to the mean'. Here, the mean times for individual operations are summed to approximate the time allocated to the list. An alternative approach is 'probabilistic scheduling'. Here, the means and standard deviation of the individual case times are combined to estimate the probability that the planned list will finish on time. This study assessed how probabilistic booking would have changed list utilisation, over-running and case cancellations in 60 urology lists during eight months that had been 'booked to the mean'. Booking to the mean resulted in 53/60 (88%) lists over-running and correctly predicted the finish times in just 13% of lists. Out of 264 patients, 36 (14%) were cancelled on the day due to over-runs in 24/60 (40%) lists. In contrast, probabilistic scheduling correctly predicted an over-run or under-run in 77% of lists, which would have allowed the case mix to be adjusted to prevent cancellation and optimise utilisation.


Michaelis-Menten kinetics at high enzyme concentrations.
The total quasi-steady state approximation (tQSSA) for the irreversible Michaelis-Menten scheme is derived in a consistent manner. It is found that self-consistency of the initial transient guarantees the uniform validity of the tQSSA, but does not guarantee the validity of the linearization in the original derivation of Borghans et al. (1996, Bull. Math. Biol., 58, 43-63). Moreover, the present rederivation yielded the noteworthy result that the tQSSA is at least roughly valid for any substrate and enzyme concentrations. This reinforces and extends the original assertion that the parameter domain for which the tQSSA is valid overlaps the domain of validity of the standard quasi-steady state approximation and includes the limit of high enzyme concentrations. The criteria for the uniform validity of the original (linearized) tQSSA are corrected, and are used to derive approximate solutions that are uniformly valid in time. These approximations overlap and extend the domains of validity of the standard and reverse quasi-steady state approximations.


Nasolabial morphologic changes after a Le Fort I osteotomy: a three-dimensional anthropometric study.
After a Le Fort I osteotomy, nasal and labial changes are sometimes undesirable. The aim of this study was to perform a three-dimensional evaluation of the morphologic changes of the nose and lips after a Le Fort I osteotomy with a three-dimensional laser scanner.Twelve female patients who underwent a Le Fort I osteotomy with bilateral sagittal split ramus osteotomy (mean age, 24.2 y) were selected. Three-dimensional facial morphology was measured immediately after surgery and 6 months after surgery with a three-dimensional laser scanner. Analysis of the three-dimensional data was performed with three-dimensional image analyzing software. The evaluation was performed by (1) linear and angular analyses of landmarks, (2) three-dimensional curvature, and (3) visual qualitative analysis using superimposing mapping images. The results were compared control with data taken from volunteers (mean age, 24.5 y).Lateral expansion of nasal alae was commonly observed after surgery. The labial changes were mainly due to movements of the jawbone, and obvious flattening was not detected in this study. There was no relationship between the nasal changes and maxillary advancement.The nasal morphologic changes after a Le Fort I osteotomy consist mainly of a widening of the nasal alae caused by the release of the muscle insertion and their retraction. This change was not influenced by the direction of maxillary movements.


Mind the gut: genomic insights to population divergence and gut microbial composition of two marine keystone species.
Deciphering the mechanisms governing population genetic divergence and local adaptation across heterogeneous environments is a central theme in marine ecology and conservation. While population divergence and ecological adaptive potential are classically viewed at the genetic level, it has recently been argued that their microbiomes may also contribute to population genetic divergence. We explored whether this might be plausible along the well-described environmental gradient of the Baltic Sea in two species of sand lance (Ammodytes tobianus and Hyperoplus lanceolatus). Specifically, we assessed both their population genetic and gut microbial composition variation and investigated not only which environmental parameters correlate with the observed variation, but whether host genome also correlates with microbiome variation. We found a clear genetic structure separating the high-salinity North Sea from the low-salinity Baltic Sea sand lances. The observed genetic divergence was not simply a function of isolation by distance, but correlated with environmental parameters, such as salinity, sea surface temperature, and, in the case of A. tobianus, possibly water microbiota. Furthermore, we detected two distinct genetic groups in Baltic A. tobianus that might represent sympatric spawning types. Investigation of possible drivers of gut microbiome composition variation revealed that host species identity was significantly correlated with the microbial community composition of the gut. A potential influence of host genetic factors on gut microbiome composition was further confirmed by the results of a constrained analysis of principal coordinates. The host genetic component was among the parameters that best explain observed variation in gut microbiome composition. Our findings have relevance for the population structure of two commercial species but also provide insights into potentially relevant genomic and microbial factors with regards to sand lance adaptation across the North Sea-Baltic Sea environmental gradient. Furthermore, our findings support the hypothesis that host genetics may play a role in regulating the gut microbiome at both the interspecific and intraspecific levels. As sequencing costs continue to drop, we anticipate that future studies that include full genome and microbiome sequencing will be able to explore the full relationship and its potential adaptive implications for these species.


Evaluation of the Interstitial Histological Lesions in Pulmonary Langerhans Cell Histiocytosis.
Pulmonary Langerhans cell histiocytosis is a cystic lung disease characterized by the proliferation of parenchymal dendritic cells. The disease can become chronic or even cause pulmonary fibrosis. Our aim in this study was to investigate the typical histological findings and interstitial fibrosis in pulmonary Langerhans cell histiocytosis cases. In the study, cases that had undergone diagnostic resection were screened. Smoking, histological stage (subacute, subacute-chronic), and cystic and eosinophilic granulomas were confirmed in the cases. In addition to emphysema, chronic nonspecific bronchiolitis, interstitial fibrosis (subpleural-paraseptal fibrosis, peribronchial fibrosis, fibrotic nonspecific interstitial pneumonia), honeycomb-type fibrocysts, and unexpected lesions were investigated. Descriptive and comparative (Fisher exact test) statistical analyses were used in the study (p < 0.05). A total of 27 cases were detected; age distribution was 17-68 (36.4). Smoking was present in 15 (55.5%) cases. Six (22.2%) cases were subacute, and 21 (7.7%) cases were subacute-chronic histological stage. A cystic lesion was present in 22 (81.4%) cases. All cases had emphysema accompanying the underlying lesions. Chronic nonspecific bronchiolitis was detected in 14 (51.8%) cases. Interstitial fibrosis was detected in 8 (29.6%) patients. Compared to interstitial fibrosis and nonfibrosis, there was no significant difference between being younger than 39 years, gender, smoking, and histological stage (p=0.41; 1; 0.69; 0.63, respectively). There is a risk of developing interstitial fibrosis patterns and honeycomb-type fibrocysts in the progression of pulmonary Langerhans cell histiocytosis. Histopathological evaluation can play an important role in the detection of risk groups.


Effective targeting of the tumor microenvironment for cancer therapy.
The tumor microenvironment is an emerging source of novel therapeutic targets in cancer. The glycosaminoglycan hyaluronan (HA) accumulates in 20-30% of tumors and is often associated with poor prognosis. We developed a digitized, semiquantitative scoring system for tumor-associated HA content, then grouped tumors (from animal models or patients) according to the degree of HA accumulation (HA+1,2,3). The antitumor response to HA-depletion by pegylated PH20 hyaluronidase (PEGPH20) was then characterized as a function of HA accumulation. Semiquantitative grouping of tumors demonstrated that HA accumulation predicts the response of tumors in animal models to PEGPH20. Prospective analysis of HA content was used to predict response to PEGPH20 of squamous cell-type explants from patients with non-small cell lung cancer in nude mice. Measurement of HA is a viable biomarker approach for predicting antitumor response in animal models to the HA-depleting agent, PEGPH20.


Influence of Anthropogenic Climate Change on Planetary Wave Resonance and Extreme Weather Events.
Persistent episodes of extreme weather in the Northern Hemisphere summer have been shown to be associated with the presence of high-amplitude quasi-stationary atmospheric Rossby waves within a particular wavelength range (zonal wavenumber 6-8). The underlying mechanistic relationship involves the phenomenon of quasi-resonant amplification (QRA) of synoptic-scale waves with that wavenumber range becoming trapped within an effective mid-latitude atmospheric waveguide. Recent work suggests an increase in recent decades in the occurrence of QRA-favorable conditions and associated extreme weather, possibly linked to amplified Arctic warming and thus a climate change influence. Here, we isolate a specific fingerprint in the zonal mean surface temperature profile that is associated with QRA-favorable conditions. State-of-the-art ("CMIP5") historical climate model simulations subject to anthropogenic forcing display an increase in the projection of this fingerprint that is mirrored in multiple observational surface temperature datasets. Both the models and observations suggest this signal has only recently emerged from the background noise of natural variability.


Broadband miniature fiber optic ultrasound generator.
This paper presents the design, fabrication and characterization of a broadband miniature fiber optic ultrasound generator based on photoacoustic (PA) ultrasound generation principle for biomedical ultrasound imaging and ultrasound non-destructive test (NDT) applications. A novel PA generation material, gold nanocomposite, was synthesized by directly reducing gold nanoparticles within polydimethylsiloxane (PDMS) through a one-pot protocol. The fiber optic ultrasound generator was fabricated by coating the gold nanocomposite on the tip of the optical fiber. The efficiency of the PA generation using gold nanocomposite was increased 10(5) compared to using aluminum thin film and 10(3) compared to using graphite mixed within epoxy. The ultrasound profile and the acoustic distribution have been characterized. The amplitude of the generated ultrasound signal was as high as 0.64 MPa and the bandwidth was more than 20 MHz. This paper also demonstrated its capability for ultrasound imaging of a tissue specimen.


The therapeutic and preventive effect of RRR-alpha-vitamin E succinate on prostate cancer via induction of insulin-like growth factor binding protein-3.
Insulin-like growth factor binding protein-3 (IGFBP-3) is a well-known antiproliferative and proapoptotic molecule in prostate cancer, suggesting that targeting IGFBP-3 might produce clinical benefits. In prostate cancer cells, RRR-alpha-vitamin E succinate (VES) inhibits cell proliferation and induces apoptosis, yet the mechanisms remain to be elucidated. We hypothesize that the protective effects of VES in prostate cancer are mediated by IGFBP-3 up-regulation. Using prostate cancer models, the involvement of IGFBP-3 in the anticancer effect of VES was investigated. IGFBP-3 mRNA and protein were determined by real-time PCR and Western blotting in prostate cancer cells, xenografted tumors of nude mice, and prostate tumors of transgenic adenocarcinoma mouse prostate (TRAMP) mice. The serum levels of IGFBP-3 were assessed by ELISA. The importance of IGFBP-3 in VES-mediated antitumor effects was confirmed by small interfering RNA knockdown strategy. We found that VES induced IGFBP-3 mRNA and protein levels in human prostate cancer cell lines. Knockdown of IGFBP-3 by small interfering RNA attenuated VES-induced IGFBP-3 expression and VES-mediated antiproliferative and proapoptotic functions. Furthermore, administration of VES resulted in a significant therapeutic effect on LNCaP and PC3 xenografts and a preventive effect on tumorigenic progression in the TRAMP model without overt toxicity. Notably, the therapeutic and preventive efficacy of VES correlated with increased accumulation of IGFBP-3 in mouse serum as well as in the xenograft tumors and TRAMP prostate samples. Consequently, reduced proliferation and induced apoptosis were witnessed. VES mediates its therapeutic and preventive effects against prostate cancer at least partially through up-regulating IGFBP-3, which inhibits cell proliferation and promotes cell apoptosis.


Continual Learning Through Synaptic Intelligence.
While deep learning has led to remarkable advances across diverse applications, it struggles in domains where the data distribution changes over the course of learning. In stark contrast, biological neural networks continually adapt to changing domains, possibly by leveraging complex molecular machinery to solve many tasks simultaneously. In this study, we introduce intelligent synapses that bring some of this biological complexity into artificial neural networks. Each synapse accumulates task relevant information over time, and exploits this information to rapidly store new memories without forgetting old ones. We evaluate our approach on continual learning of classification tasks, and show that it dramatically reduces forgetting while maintaining computational efficiency.


Helicobacter pylori targets dendritic cells to induce immune tolerance, promote persistence and confer protection against allergic asthma.
The bacterial pathogen Helicobacter pylori is predominantly known for its tight association with peptic ulcer disease and gastric cancer. However, recent evidence suggests that chronic infection with H. pylori may also be beneficial to the host by conferring protection against allergies, asthma and inflammatory bowel diseases. The protective effects of H. pylori depend on highly suppressive regulatory T-cells. In this addendum, we summarize results showing that H. pylori infection efficiently re-programs dendritic cells (DCs) toward a tolerance-promoting phenotype; their "tolerogenic" activity requires inflammasome activation and the secretion of interleukin-18. H. pylori-experienced DCs fail to induce T-cell effector functions, but efficiently induce FoxP3 expression in naive T-cells in vitro and in vivo. The experimental depletion of DCs breaks tolerance and results in improved infection control, but also in aggravated T-cell-driven immunopathology. In summary, we propose that H. pylori evades adaptive immune responses by re-programming DCs in favor of tolerance over immunity.


KRLMM: an adaptive genotype calling method for common and low frequency variants.
SNP genotyping microarrays have revolutionized the study of complex disease. The current range of commercially available genotyping products contain extensive catalogues of low frequency and rare variants. Existing SNP calling algorithms have difficulty dealing with these low frequency variants, as the underlying models rely on each genotype having a reasonable number of observations to ensure accurate clustering. Here we develop KRLMM, a new method for converting raw intensities into genotype calls that aims to overcome this issue. Our method is unique in that it applies careful between sample normalization and allows a variable number of clusters k (1, 2 or 3) for each SNP, where k is predicted using the available data. We compare our method to four genotyping algorithms (GenCall, GenoSNP, Illuminus and OptiCall) on several Illumina data sets that include samples from the HapMap project where the true genotypes are known in advance. All methods were found to have high overall accuracy (> 98%), with KRLMM consistently amongst the best. At low minor allele frequency, the KRLMM, OptiCall and GenoSNP algorithms were observed to be consistently more accurate than GenCall and Illuminus on our test data. Methods that tailor their approach to calling low frequency variants by either varying the number of clusters (KRLMM) or using information from other SNPs (OptiCall and GenoSNP) offer improved accuracy over methods that do not (GenCall and Illuminus). The KRLMM algorithm is implemented in the open-source crlmm package distributed via the Bioconductor project (http://www.bioconductor.org).


Achieving horizontal equity: must we have a single-payer health system?
The question posed in this article is whether single-payer health care systems are more likely to provide equal treatment for equal need (horizontal equity) than are multipayer systems. To address this question, we compare access to primary and specialty health care services across selected neighborhoods, grouped by average household income, in a single-payer system (the English NHS), a multiple-payer system with universal coverage (French National Health Insurance), and the U.S. multiple-payer system characterized by large gaps in health insurance coverage. We find that Paris residents, including those with low incomes, have better access to health care than their counterparts in Inner London and Manhattan. This finding casts doubt on the notion that the number of payers influences the capacity of a health care system to provide equitable access to its residents. The lesson is to worry less about the number of payers and more about the system's ability to assure access to primary and specialty care services.


Structural basis for differential neutralization of ebolaviruses.
There are five antigenically distinct ebolaviruses that cause hemorrhagic fever in humans or non-human primates (Ebola virus, Sudan virus, Reston virus, Taï Forest virus, and Bundibugyo virus). The small handful of antibodies known to neutralize the ebolaviruses bind to the surface glycoprotein termed GP₁,₂. Curiously, some antibodies against them are known to neutralize in vitro but not protect in vivo, whereas other antibodies are known to protect animal models in vivo, but not neutralize in vitro. A detailed understanding of what constitutes a neutralizing and/or protective antibody response is critical for development of novel therapeutic strategies. Here, we show that paradoxically, a lower affinity antibody with restricted access to its epitope confers better neutralization than a higher affinity antibody against a similar epitope, suggesting that either subtle differences in epitope, or different characteristics of the GP₁,₂ molecules themselves, confer differential neutralization susceptibility. Here, we also report the crystal structure of trimeric, prefusion GP₁,₂ from the original 1976 Boniface variant of Sudan virus complexed with 16F6, the first antibody known to neutralize Sudan virus, and compare the structure to that of Sudan virus, variant Gulu. We discuss new structural details of the GP₁-GP₂ clamp, thermal motion of various regions in GP₁,₂ across the two viruses visualized, details of differential interaction of the crystallized neutralizing antibodies, and their relevance for virus neutralization.


Soluble receptor-mediated targeting of mouse hepatitis coronavirus to the human epidermal growth factor receptor.
The mouse hepatitis coronavirus (MHV) infects murine cells by binding of its spike (S) protein to murine CEACAM1a. The N-terminal part of this cellular receptor (soR) is sufficient for S binding and for subsequent induction of the conformational changes required for virus-cell membrane fusion. Here we analyzed whether these characteristics can be used to redirect MHV to human cancer cells. To this end, the soR domain was coupled to single-chain monoclonal antibody 425, which is directed against the human epidermal growth factor receptor (EGFR), resulting in a bispecific adapter protein (soR-425). The soR and soR-425 proteins, both produced with the vaccinia virus system, were able to neutralize MHV infection of murine LR7 cells. However, only soR-425 was able to target MHV to human EGFR-expressing cancer cells. Interestingly, the targeted infections induced syncytium formation. Furthermore, the soR-425-mediated infections were blocked by heptad repeat-mimicking peptides, indicating that virus entry requires the regular S protein fusion process. We conclude that the specific spike-binding property of the CEACAM1a N-terminal fragment can be exploited to direct the virus to selected cells by linking it to a moiety able to bind a receptor on those cells. This approach might be useful in the development of tumor-targeted coronaviruses.


Association of CPAP bacterial colonization with chronic rhinosinusitis.
The purpose of our study was to investigate whether bacterial colonization of the continuous positive air-way pressure (CPAP) machine reservoirs occurred, and if so, if it was related to the development of chronic rhinosinusitis (CRS). Prospective cohort study. London Health Sciences Center (LHSC). Regular CPAP users with obstructive sleep apnea (OSA). N/A. Patient demographics were recorded and they were asked to fill out the chronic sinusitis survey (CSS) form. Patients then had their CPAP machines swabbed. An ANOVA was used to determine if the presence of microbacterial colonization was related to CSS scores. In total, 72 patients were included in the study. There was no significant difference in any of the scores between the group with positive cultures and the group without positive cultures. Having a positive culture in the cpap reservoir does not seem to lead to an increased symptomatology of crs: although the reservoirs often become colonized, there seems to be no clinical impact.


Differences in the Gambling Behavior of Online and Non-online Student Gamblers in a Controlled Laboratory Environment.
Although research suggests that approximately 1 in 4 college students report having gambled online, few laboratory-based studies have been conducted enlisting online student gamblers. Moreover, it is unclear the extent to which differences in gambling behavior exist between online and non-online student gamblers. The current study examined if online gamblers would play more hands, commit more errors, and wager more credits than non-online student gamblers in a controlled, laboratory environment. Online (n = 19) and non-online (n = 26) student gamblers played video poker in three separate sessions and the number of hands played, errors committed, and credits wagered were recorded. Results showed that online student gamblers played more hands and committed more errors playing video poker than non-online student gamblers. The results from the current study extend previous research by suggesting that online gamblers engage in potentially more deleterious gambling behavior (e.g., playing more hands and committing more errors) than non-online gamblers. Additional research is needed to examine differences in the gambling behavior of online and non-online gamblers in a controlled, laboratory environment.


High-Throughput Analysis of Arabidopsis Stem Vibrations to Identify Mutants With Altered Mechanical Properties.
Mechanical properties are rarely used as quantitative indices for the large-scale mutant screening of plants, even in the model plant Arabidopsis thaliana. The mechanical properties of plant stems generally influence their vibrational characteristics. Here, we developed Python-based software, named AraVib, for the high-throughput analysis of free vibrations of plant stems, focusing specifically on Arabidopsis stem vibrations, and its extended version, named AraVibS, to identify mutants with altered mechanical properties. These programs can be used without knowledge of Python and require only an inexpensive handmade setting stand and an iPhone/iPad with a high-speed shooting function for data acquisition. Using our system, we identified an nst1 nst3 double-mutant lacking secondary cell walls in fiber cells and a wrky12 mutant displaying ectopic formation of secondary cell wall compared with wild type by employing only two growth traits (stem height and fresh weight) in addition to videos of stem vibrations. Furthermore, we calculated the logarithmic decrement, the damping ratio, the natural frequency and the stiffness based on the spring-mass-damper model from the video data using AraVib. The stiffness was estimated to be drastically decreased in nst1 nst3, which agreed with previous tensile test results. However, in wrky12, the stiffness was significantly increased. These results demonstrate the effectiveness of our new system. Because our method can be applied in a high-throughput manner, it can be used to screen for mutants with altered mechanical properties.


Two-dimensional optical architecture for time-delay beam forming in a phased-array antenna.
We propose and experimentally demonstrate a new two-dimensional optical architecture based on polarization switching by N spatial light modulators that provides 2(N) time delays to a phased-array antenna of p x p radiating elements. Moreover the 0 to 2pi phase of the microwave signals is optically controlled by a liquid-crystal spatial light modulator that operates in the birefringent mode. The microwave signal originates from the coherent detection of a dual-frequency laser beam obtained with an acousto-optic frequency shifter. Preliminary experimental results obtained at a microwave frequency f = 1.85 GHz are presented.


Mechanisms of spermidine-induced autophagy and geroprotection.
Aging involves the systemic deterioration of all known cell types in most eukaryotes. Several recently discovered compounds that extend the healthspan and lifespan of model organisms decelerate pathways that govern the aging process. Among these geroprotectors, spermidine, a natural polyamine ubiquitously found in organisms from all kingdoms, prolongs the lifespan of fungi, nematodes, insects and rodents. In mice, it also postpones the manifestation of various age-associated disorders such as cardiovascular disease and neurodegeneration. The specific features of spermidine, including its presence in common food items, make it an interesting candidate for translational aging research. Here, we review novel insights into the geroprotective mode of action of spermidine at the molecular level, as we discuss strategies for elucidating its clinical potential.


Comparison of LASIK and surface ablation by using propensity score analysis: a multicenter study in Korea.
We compared the 3-year outcomes with regard to efficacy, stability, and safety of LASIK and surface ablation performed at multiple centers in Korea. The charts of 5109 eyes that underwent LASIK or surface ablation, including LASEK, epi-LASIK, and photorefractive keratectomy (PRK), at multiple centers between 2002 and 2005 were reviewed. Of these, 577 LASIK-treated eyes and 577 propensity score-matched surface-ablated eyes were included in this cohort study. A standardized case report form (CRF) was completed based on a review of the 3-year follow-up chart. The CRF included the preoperative, surgical, and postoperative data for the refractive error, uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), IOP, corneal thickness, keratometry, corneal topography, Schirmer test, and tear breakup time (TBUT). The efficacy index calculated after 3 years and the postoperative spherical equivalents measured at 3 months or 3 years did not differ between the LASIK and surface ablation groups. Although myopic regression was observed in the surface ablation group through postoperative years 1 and 2, this difference did not affect the visual acuity significantly. Surface ablation did carry a higher cumulative incidence of corneal haze. LASIK and surface ablation produced similar postoperative visual efficacy after corneal healing. The outcome predictability did not differ between the 2 groups, but myopic regression was observed more frequently in the surface ablation group. Corneal haze after surface ablation is much more common than reported previously.


Hyperoxic Exposure of Immature Mice Increases the Inflammatory Response to Subsequent Rhinovirus Infection: Association with Danger Signals.
Infants with a history of prematurity and bronchopulmonary dysplasia have a high risk of asthma and viral-induced exacerbations later in life. We hypothesized that hyperoxic exposure, a predisposing factor to bronchopulmonary dysplasia, modulates the innate immune response, producing an exaggerated proinflammatory reaction to viral infection. Two- to 3-d-old C57BL/6J mice were exposed to air or 75% oxygen for 14 d. Mice were infected intranasally with rhinovirus (RV) immediately after O2 exposure. Lung mRNA and protein expression, histology, dendritic cells (DCs), and airway responsiveness were assessed 1-12 d postinfection. Tracheal aspirates from premature human infants were collected for mRNA detection. Hyperoxia increased lung IL-12 expression, which persisted up to 12 d postexposure. Hyperoxia-exposed RV-infected mice showed further increases in IL-12 and increased expression of IFN-γ, TNF-α, CCL2, CCL3, and CCL4, as well as increased airway inflammation and responsiveness. In RV-infected, air-exposed mice, the response was not significant. Induced IL-12 expression in hyperoxia-exposed, RV-infected mice was associated with increased IL-12-producing CD103(+) lung DCs. Hyperoxia also increased expression of Clec9a, a CD103(+) DC-specific damaged cell-recognition molecule. Hyperoxia increased levels of ATP metabolites and expression of adenosine receptor A1, further evidence of cell damage and related signaling. In human preterm infants, tracheal aspirate Clec9a expression positively correlated with the level of prematurity. Hyperoxic exposure increases the activation of CD103(+), Clec9a(+) DCs, leading to increased inflammation and airway hyperresponsiveness upon RV infection. In premature infants, danger signal-induced DC activation may promote proinflammatory airway responses, thereby increasing respiratory morbidity.


Hearing faces: how the infant brain matches the face it sees with the speech it hears.
Speech is not a purely auditory signal. From around 2 months of age, infants are able to correctly match the vowel they hear with the appropriate articulating face. However, there is no behavioral evidence of integrated audiovisual perception until 4 months of age, at the earliest, when an illusory percept can be created by the fusion of the auditory stimulus and of the facial cues (McGurk effect). To understand how infants initially match the articulatory movements they see with the sounds they hear, we recorded high-density ERPs in response to auditory vowels that followed a congruent or incongruent silently articulating face in 10-week-old infants. In a first experiment, we determined that auditory-visual integration occurs during the early stages of perception as in adults. The mismatch response was similar in timing and in topography whether the preceding vowels were presented visually or aurally. In the second experiment, we studied audiovisual integration in the linguistic (vowel perception) and nonlinguistic (gender perception) domain. We observed a mismatch response for both types of change at similar latencies. Their topographies were significantly different demonstrating that cross-modal integration of these features is computed in parallel by two different networks. Indeed, brain source modeling revealed that phoneme and gender computations were lateralized toward the left and toward the right hemisphere, respectively, suggesting that each hemisphere possesses an early processing bias. We also observed repetition suppression in temporal regions and repetition enhancement in frontal regions. These results underscore how complex and structured is the human cortical organization which sustains communication from the first weeks of life on.


Differences in monocyte subsets are associated with short-term survival in patients with septic shock.
Sepsis is characterized by dynamic changes of the immune system resulting in deregulated inflammation and failure of homoeostasis and can escalate to septic shock. Circulating monocytes and other innate immune cells are among the first ones to recognize and clear pathogens. Monocytes have an important role in sepsis and septic shock and have been studied as potential diagnostic markers. In total, forty-two patients with septic shock were recruited and blood samples obtained within first 12 hours of ICU admission. We showed that frequency of classical and intermediate monocytes assessed at the time of admission to the intensive care unit are significantly distinct in patients with septic shock who survived longer that five days from those who died. These parameters correlate significantly with differences in serum levels of inflammatory cytokines MCP-1, IL-6, IL-8, IL-10, and IL-18, and with the proportion of helper and cytotoxic T cells. The described changes in frequency of monocyte subsets and their activation status may predict short-term septic shock survival and help with fast identification of the group of vulnerable patients, who may profit from tailored therapy.


FATAL RANAVIRUS INFECTION IN A GROUP OF ZOO-HOUSED MELLER'S CHAMELEONS (TRIOCEROS MELLERI).
A group of five juvenile Meller's chameleons (Trioceros melleri) experienced 100% mortality over a period of 1 mo due to ranavirus infection. The index case was found dead without premonitory signs. The three subsequent cases presented with nonspecific clinical signs (lethargy, decreased appetite, ocular discharge) and were ultimately euthanatized. The final case died after initially presenting with skin lesions. Postmortem examination revealed thin body condition in all five animals and mild coelomic effusion and petechiae affecting the tongue and kidneys of one animal. Microscopically, all animals had multifocal necrosis of the spleen, liver, and kidney; four of five animals had necrosis of the nasal cavity; and two of five had necrosis of adrenal tissue, bone marrow, and skin. Numerous basophilic intracytoplasmic inclusions were present in the liver of all animals and nasal mucosa of three of the five animals. Consensus polymerase chain reaction for herpesvirus and adenovirus were negative, whereas ranavirus quantitative polymerase chain reaction was positive. Virus isolation followed by whole genome sequencing and Bayesian phylogenetic analysis classified the isolates as a strain of frog virus 3 (FV3) most closely related to an FV3 isolate responsible for a previous outbreak in the zoo's eastern box turtle (Terrapene carolina carolina) group. This case series documents the first known occurrence of ranavirus-associated disease in chameleons and demonstrates the potential for interspecies transmission between chelonian and squamate reptiles.


Dental age in patients with Down syndrome.
The aim of this research was to evaluate dental age in 102 patients with Down Syndrome, using panoramic radiographs. A software program developed by the Discipline of Radiology, School of Dentistry of São José dos Campos, São Paulo State University (UNESP), was used. A table of mineralization chronology of permanent teeth among Brazilians conceived by Nicodemo, Moraes and Medici Filho was used within the software. Statistical analysis of the results showed that 70.91% of the males and 61.21% of the females presented advanced dental age. Only 32.09% of the males and 38.79% of the females presented delayed dental age. Regarding the differences between the dental and chronological ages, two thirds of the males and females presented dental age with differences of up to 12 months, which means that they can be considered to be within normal standards, whereas only 18.87% of the males and 10.21% of the females presented dental age outside normal standards, with differences of over 24 months. In conclusion, the majority of the patients with Down Syndrome were considered to be within the normal standards of mineralization chronology.