Effect of Caregiver Training on the Neurodevelopment of HIV-Exposed Uninfected Children and Caregiver Mental Health: A Ugandan Cluster-Randomized Controlled Trial.
Early childhood development programs typically combine healthy nutrition and cognitive stimulation in an integrated model. We separately delivered these 2 components in a cluster-randomized controlled trial to evaluate their comparative effectiveness in promoting healthy child development and caregiver mental health. This is the first study to do so for HIV-affected children and their infected mothers. Two hundred twenty-one HIV-exposed but uninfected child (2-3 years old) and caregiver dyads in 18 geographic clusters in Eastern Uganda were randomized by cluster to receive biweekly individualized sessions of either (1) Mediational Intervention for Sensitizing Caregivers (MISC) training emphasizing cognitive stimulation or (2) Uganda Community Based Association for Child Welfare (UCOBAC) program that delivered health and nutrition training. Children were evaluated at baseline, 6 months, 1 year (training conclusion), and 1-year posttraining with the Mullen Scales of Early Learning (MSEL), the Color-Object Association Test for memory, the Early Childhood Vigilance Test of attention, and the Behavior Rating Inventory of Executive Function (BRIEF-parent). The Caldwell Home Observation for the Measurement of the Environment (HOME) was completed by observers to gauge caregiving quality after training. Caregiver depression/anxiety (Hopkins Symptom Checklist-25) and functionality (list of activities of daily living) were also evaluated. Data collectors were blinded to trial arm assignment. Mediational Intervention for Sensitizing Caregivers resulted in significantly better quality of caregiving compared with UCOBAC midintervention with an adjusted mean difference (MadjDiff) of 2.34 (95% confidence interval [CI]: 1.54-3.15, p < .01), postintervention (MadjDiff = 2.43, 95% CI: 1.61-3.25, p < .01), and at 1-year follow-up (MadjDiff = 2.07, 95% CI: 1.23-2.90, p < .01). MISC caregivers reported more problems on the BRIEF for their child at 1-year posttraining only (p < .01). Caregiving quality (HOME) was significantly correlated with MSEL composite performance 1-year posttraining for both the MISC and the UCOBAC trial arms. Likewise, physical growth was significantly related to child development outcomes even though it did not differ between trial arms. Even though MISC demonstrated an advantage of improving caregiving quality, it did not produce better child cognitive outcomes compared with health and nutrition training. clinicaltrials.gov Identifier: NCT01640561.


Assessing the tolerability and efficacy of first-line chemotherapy in elderly patients with metastatic HER2-ve breast cancer.
In metastatic breast cancer (MBC), there is no consensus regarding the optimal regimen sequence and whether adults >65 years old (OA) are at increased risk from chemotherapy toxicity. Treatment decisions are often driven by the ability to tolerate treatment and maintain the quality of life. This study was designed to assess current practice in an oncology hospital in the UK. Retrospective data were collected about treatments used for 87 OA with MBC in a single centre between 2009 and 2016 to assess the tolerability and efficacy of first-line chemotherapy. Student's T-tests and Kaplan-Meier statistical methods were applied. 70% of patients were commenced on standard dose (SD) of chemotherapy; 84% (21/25) of the anthracycline group (AG), 65% (20/31) of the capecitabine group (CG), 48% (10/21) of the taxane group (TG) and 100% (10/10) of other agents. 32% of patients had dose reductions; 16% in AG, 19% in TG and 58% in CG. Overall 30% of patients received six cycles of SD of chemotherapy; 36% in AG, 29% in CG and 14% in TG. 23% of patients suffered ≥grade 3 toxicity; 28% in AG, 29% in CG and 10% in TG. There were four treatment-related deaths; two in AG and one in both CG and TG. 61% of the CG received 6+ cycles with a mean on treatment time of 445 days (1-2,150). There was no statistical significance in progression- free survival (PFS) between groups. The median PFS for all patients was 244 days (87-381). Performance status, haemoglobin and estimated glomerular filtration rates prior to starting chemotherapy were all useful in predicting PFS. A relevant number of patients required dose reduction but dose-reduced chemotherapy was tolerated well. Anthracycline-based regimens were used in patients who had not received adjuvant chemotherapy. Capecitabine required the most dose reductions. Taxanes were generally started at reduced doses, resulting in fewer grade 3+ toxicities. As well as age, underlying physiological reserve, current performance status and co-morbidities should guide physicians who should consider lower starting doses in OA and recognise that dose reductions may be required to improve tolerability. The PFS of all regimens were similar in this study. This study highlights the need for further research to define the optimal first-line chemotherapy and starting dose in OA with MBC.


The innate resistance of Trypanosoma copemani to human serum.
Trypanosoma copemani is known to be infective to a variety of Australian marsupials. Characterisation of this parasite revealed the presence of stercorarian-like life-cycle stages in culture, which are similar to T. rangeli and T. cruzi. The blood incubation infectivity test (BIIT) was adapted and used to determine if T. copemani, like T. cruzi and T. rangeli, has the potential to grow in the presence of human serum. To eliminate any effects of anticoagulants on the complement system and on human high density lipoprotein (HDL), only fresh whole human blood was used. Trypanosoma copemani was observed by microscopy in all human blood cultures from day 5 to day 19 post inoculation (PI). The mechanism for normal human serum (NHS) resistance in T. copemani is not known. The results of this study show that at least one native Australian trypanosome species may have the potential to be infective for humans.


Relation of physical activity to prevalence of nonalcoholic Fatty liver disease independent of cardiometabolic risk.
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance and has been linked with increased cardiovascular risk. Although physical activity (PA) and lifestyle modification are often recommended in patients at cardiovascular risk, the benefit across the cardiometabolic risk spectrum is unclear. We aimed to evaluate the relation of PA and NAFLD independent of metabolic syndrome (MS) or obesity. We evaluated 5,743 healthy Brazilian subjects (43 ± 10 years, 79% men) without clinical coronary heart disease from December 2008 to December 2010. NAFLD was diagnosed using ultrasounds, and self-reported PA was assessed using the International Physical Activity Questionnaire scale. In a multivariate logistic regression adjusted for cardiometabolic risk factors, we evaluated for an independent association of NAFLD and PA. In the total study population, NAFLD prevalence was 36% (n = 2,075), obesity 23% (1,300), and MS 20% (1,152). NAFLD was more prevalent in subjects with MS (74%) than those without (26%) and in those obese (73%) than in those nonobese (25%). Overall, 1,305 (23%) subjects reported low activity, 1,990 (35%) moderate activity, and 2,448 (42%) high activity. NAFLD prevalence was lower at higher levels of reported PA (low 45%, moderate 38%, and high 30%, p <0.001). After adjusting for risk factors, subjects with high activity had lower odds of having NAFLD. The favorable association was independent of obesity or MS. In conclusion, PA presents a dose-response association with NAFLD independent of the MS or obesity. Our results are compatible with the idea that benefits of PA are relevant to everyone regardless of cardiometabolic risk.


Characterisation of peroxidation products arising from culinary oils exposed to continuous and discontinuous thermal degradation processes.
High-resolution NMR analysis has been used, for the first time, to identify, putatively, two new secondary aldehydic lipid oxidation products in culinary oils. The impact of heating and cooling times on the thermal stability, fatty acid composition and lipid oxidation product (LOP) concentrations have been analysed for continuous and discontinuous heating periods (180 °C). The susceptibility of the selected oils to thermal oxidation for the different heating episodes has been evaluated via the detection and determination of LOPs, particularly cytotoxic and genotoxic aldehydes. The identities and quantities of these LOPs evolved throughout a 2.0 hour period. Results acquired indicated that sunflower oil was more resistant to discontinuous oxidation than rapeseed and olive oils, however overall discontinuous heating resulted in more LOPs.


Geographical ecology of the palms (Arecaceae): determinants of diversity and distributions across spatial scales.
The palm family occurs in all tropical and sub-tropical regions of the world. Palms are of high ecological and economical importance, and display complex spatial patterns of species distributions and diversity. This review summarizes empirical evidence for factors that determine palm species distributions, community composition and species richness such as the abiotic environment (climate, soil chemistry, hydrology and topography), the biotic environment (vegetation structure and species interactions) and dispersal. The importance of contemporary vs. historical impacts of these factors and the scale at which they function is discussed. Finally a hierarchical scale framework is developed to guide predictor selection for future studies. Determinants of palm distributions, composition and richness vary with spatial scale. For species distributions, climate appears to be important at landscape and broader scales, soil, topography and vegetation at landscape and local scales, hydrology at local scales, and dispersal at all scales. For community composition, soil appears important at regional and finer scales, hydrology, topography and vegetation at landscape and local scales, and dispersal again at all scales. For species richness, climate and dispersal appear to be important at continental to global scales, soil at landscape and broader scales, and topography at landscape and finer scales. Some scale-predictor combinations have not been studied or deserve further attention, e.g. climate on regional to finer scales, and hydrology and topography on landscape and broader scales. The importance of biotic interactions - apart from general vegetation structure effects - for the geographic ecology of palms is generally underexplored. Future studies should target scale-predictor combinations and geographic domains not studied yet. To avoid biased inference, one should ideally include at least all predictors previously found important at the spatial scale of investigation.


Smoking and drinking habits five years after baseline in the JACC study.
Observing longitudinal changes in smoking and drinking habits is important for evaluating the risk of incidence and death from cancer or other diseases in a cohort study. Smoking and drinking habits at baseline and about five years later among 18,312 males and 28,338 females were obtained from the baseline and interim surveys in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study) sponsored by Monbusho (Ministry of Education, Science, Sports and Culture of Japan). Changes in smoking and drinking habits between the two surveys were observed. Odds ratios for quitting these habits at interim survey were estimated. Percentages of current smokers at baseline and interim surveys were 51.0% and 45.5% in males, and 5.2% and 4.8% in females, respectively. Percentages of current drinkers at baseline and interim surveys were 78.0% and 73.2% in males, and 29.5% and 23.5% in females, respectively. The number of cigarettes per day among male current smokers and the usual amount of alcohol consumed on each occasion among current drinkers decreased between the two surveys. Odds ratios for smoking cessation increased with age at baseline and decreased with the number of cigarettes per day at baseline. Odds ratios for drinking cessation increased with age at baseline and decreased with the usual amount of alcohol consumed on each occasion at baseline. The decrease in smoking and drinking habits was observed during the five-year follow-up period. Higher age and lower levels of exposure were associated with quitting smoking or drinking.


Heterogeneity in Fanconi anemia: evidence for 2 new genetic subtypes.
Fanconi anemia (FA) is an autosomal recessive syndrome featuring diverse symptoms including progressive bone marrow failure and early occurrence of acute myeloid leukemia. Nine genetic subtypes have been described for FA (A, B, C, D1, D2, E, F, G, and L), all of which have been connected to distinct disease genes, except B. Here we report on 8 unrelated FA patients who were excluded from the known subtypes on the basis of phenotypic correction or genetic data. Four of these cell lines failed to complement each other in somatic cell hybrids and therefore represent a new group, termed FA-I. The remaining cell lines complemented group FA-I but did not complement each other, thus representing a second new group, FA-J. Both FA-I and -J cell lines were capable of forming an FA multiprotein core complex. This complex is required for activation of the FANCD2 protein by mono-ubiquitination, a key downstream event in the FA pathway. In FA-I cells FANCD2 was not mono-ubiquitinated, indicating a defect upstream in the FA pathway, whereas in FA-J cells FANCD2 was mono-ubiquitinated, indicating a downstream defect. Our results suggest that the FA pathway of genome stabilization may be controlled by at least 11 different genes, including FANCI and FANCJ.


A gastrointestinal locally activating Janus kinase inhibitor to treat ulcerative colitis.
In this study, we integrated machine learning (ML), structure-tissue selectivity-activity-relationship (STAR), and wet lab synthesis/testing to design a gastrointestinal (GI) locally activating JAK inhibitor for ulcerative colitis treatment. The JAK inhibitor achieves site-specific efficacy through high local GI tissue selectivity while minimizing the requirement for JAK isoform specificity to reduce systemic toxicity. We used the ML model (CoGT) to classify whether the designed compounds were inhibitors or noninhibitors. Then we used the regression ML model (MTATFP) to predict their IC50 against related JAK isoforms of predicted JAK inhibitors. The ML model predicted MMT3-72, which was retained in the GI tract, to be a weak JAK1 inhibitor, while MMT3-72-M2, which accumulated in only GI tissues, was predicted to be an inhibitor of JAK1/2 and TYK2. ML docking methods were applied to simulate their docking poses in JAK isoforms. Application of these ML models enabled us to limit our synthetic efforts to MMT3-72 and MMT3-72-M2 for subsequent wet lab testing. The kinase assay confirmed MMT3-72 weakly inhibited JAK1, and MMT3-72-M2 inhibited JAK1/2 and TYK2. We found that MMT3-72 accumulated in the GI lumen, but not in GI tissue or plasma, but released MMT3-72-M2 accumulated in colon tissue with minimal exposure in the plasma. MMT3-72 achieved superior efficacy and reduced p-STAT3 in DSS-induced colitis. Overall, the integration of ML, the structure-tissue selectivity-activity-relationship system, and wet lab synthesis/testing could minimize the effort in the optimization of a JAK inhibitor to treat colitis. This site-specific inhibitor reduces systemic toxicity by minimizing the need for JAK isoform specificity.


Proteomics Screen Identifies Class I Rab11 Family Interacting Proteins as Key Regulators of Cytokinesis.
The 14-3-3 protein family orchestrates a complex network of molecular interactions that regulates various biological processes. Owing to their role in regulating the cell cycle and protein trafficking, 14-3-3 proteins are prevalent in human diseases such as cancer, diabetes, and neurodegeneration. 14-3-3 proteins are expressed in all eukaryotic cells, suggesting that they mediate their biological functions through evolutionarily conserved protein interactions. To identify these core 14-3-3 client proteins, we used an affinity-based proteomics approach to characterize and compare the human and Drosophila 14-3-3 interactomes. Using this approach, we identified a group of Rab11 effector proteins, termed class I Rab11 family interacting proteins (Rab11-FIPs), or Rip11 in Drosophila We found that 14-3-3 binds to Rip11 in a phospho-dependent manner to ensure its proper subcellular distribution during cell division. Our results indicate that Rip11 plays an essential role in the regulation of cytokinesis and that this function requires its association with 14-3-3 but not with Rab11. Together, our results suggest an evolutionarily conserved role for 14-3-3 in controlling Rip11-dependent protein transport during cytokinesis.


Pathogenesis and therapy of rheumatoid arthritis.
Rheumatoid arthritis is a chronic disabling disease affecting at least 1% of the population on a worldwide basis. Research aimed at understanding the pathogenesis of this disease led to the identification of TNFalpha as a major pro-inflammatory cytokine expressed in the inflamed joints of patients with rheumatoid arthritis. Subsequently, in vitro studies provided evidence to suggest that TNFalpha played an important role in driving the expression of additional pro-inflammatory cytokines, such as IL-1, GM-CSF, IL-6, and IL-8, in synovial cell cultures. Another important finding that confirmed the pathological significance of TNFalpha was that mice genetically engineered to overexpress TNFalpha spontaneously developed arthritis. Subsequently, the therapeutic effect TNFalpha blockade was tested in animal models prior to clinical trials in human patients, which provided unequivocal verification of the validity of TNFalpha as a therapeutic target. Anti-TNFalpha therapy is now accepted as a fully-validated treatment modality for rheumatoid arthritis.


Seasonal ammonia losses from spray-irrigation with secondary-treated recycled water.
This work examines ammonia volatilization associated with agricultural irrigation employing recycled water. Effluent from a secondary wastewater treatment plant was applied using a center pivot irrigation system on a 12 ha agricultural site in Palmdale, California. Irrigation water was captured in shallow pans and ammonia concentrations were quantified in four seasonal events. The average ammonia loss ranged from 15 to 35% (averaging 22%) over 2-h periods. Temporal mass losses were well-fit using a first-order model. The resulting rate constants correlated primarily with temperature and secondarily with wind speed. The observed application rates and timing were projected over an entire irrigation season using meteorological time series data from the site, which yielded volatilization estimates of 0.03 to 0.09 metric tons NH(3)-N/ha per year. These rates are consistent with average rates (0.04 to 0.08 MT NH(3)-N/ha per year) based on 10 to 20 mg NH(3)-N/L effluent concentrations and a 22% average removal. As less than 10% of the treated effluent in California is currently reused, there is potential for this source to increase, but the increase may be offset by a corresponding reduction in synthetic fertilizers usage. This point is a factor for consideration with respect to nutrient management using recycled water.


Transfection of pancreatic islets using polyvalent DNA-functionalized gold nanoparticles.
Transplantation of pancreatic islets is an effective treatment for select patients with type 1 diabetes. Improved cellular therapy results may be realized by altering the gene expression profile of transplanted islets. Current viral and nonviral vectors used to introduce nucleic acids for gene regulation hold promise, but safety and efficacy shortcomings motivate the development of new transfection strategies. Polyvalent gold nanoparticles (AuNPs) densely functionalized with covalently immobilized DNA oligonucleotides (AuNP-DNA) are new single entity transfection and gene regulating agents (ie, not requiring lipids, polymers, or viral vectors for cell entry) able to enter cells with high efficiency and no evidence of toxicity. We hypothesize that AuNP-DNA conjugates can efficiently transfect pancreatic islets with no impact on viability or functionality, and can function to regulate targeted gene expression. AuNPs were surface-functionalized with control and antisense DNA oligonucleotides. Purified murine and human islets were exposed to AuNP-DNA conjugates for 24 hours. Islet AuNP-DNA uptake, cell viability, and functionality were measured. Furthermore, the ability of antisense AuNP-DNA conjugates to regulate gene expression was measured using murine islets expressing eGFP. Collectively, fluorescent confocal microscopy, transmission electron microscopy, mass spectrometry, and flow cytometry revealed substantial penetration of the AuNP-DNA conjugates into the inner core of the islets and within islet cells. No change in cellular viability occurred and the insulin stimulation index was unchanged in treated versus untreated islets. Transplantation of AuNP-DNA treated islets cured diabetic nude mice. Functionally, antisense eGFP AuNP-DNA conjugates reduced eGFP expression in MIP-eGFP islets. Polyvalent AuNP-DNA conjugates may represent the next generation of nucleic acid-based therapeutic agents for improving pancreatic islet engraftment, survival, and long-term function.


Birth Hospital Length of Stay and Rehospitalization During COVID-19.
To determine if birth hospitalization length of stay (LOS) and infant rehospitalization changed during the coronavirus disease 2019 (COVID-19) era among healthy, term infants. Retrospective cohort study using Epic's Cosmos data from 35 health systems of term infants discharged ≤5 days of birth. Short birth hospitalization LOS (vaginal birth <2 midnights; cesarean birth <3 midnights) and, secondarily, infant rehospitalization ≤7 days after birth hospitalization discharge were compared between the COVID-19 (March 1 to August 31, 2020) and prepandemic eras (March 1 to August 31, 2017, 2018, 2019). Mixed-effects models were used to estimate adjusted odds ratios (aORs) comparing the eras. Among 202 385 infants (57 110 from the COVID-19 era), short birth hospitalization LOS increased from 28.5% to 43.0% for all births (vaginal: 25.6% to 39.3%, cesarean: 40.1% to 61.0%) during the pandemic and persisted after multivariable adjustment (all: aOR 2.30, 95% confidence interval [CI] 2.25-2.36; vaginal: aOR 2.12, 95% CI 2.06-2.18; cesarean: aOR 3.01, 95% CI 2.87-3.15). Despite shorter LOS, infant rehospitalizations decreased slightly during the pandemic (1.2% to 1.1%); results were similar in adjusted analysis (all: aOR 0.83, 95% CI 0.76-0.92; vaginal: aOR 0.82, 95% CI 0.74-0.91; cesarean: aOR 0.87, 95% CI 0.69-1.10). There was no change in the proportion of rehospitalization diagnoses between eras. Short infant LOS was 51% more common in the COVID-19 era, yet infant rehospitalization within a week did not increase. This natural experiment suggests shorter birth hospitalization LOS among family- and clinician-selected, healthy term infants may be safe with respect to infant rehospitalization, although examination of additional outcomes is needed.


An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets.
Analysis and interpretation of functional MRI (fMRI) data have traditionally been based on identifying areas of significance on a thresholded statistical map of the entire imaged brain volume. This form of analysis can be likened to a "fishing expedition." As we become more knowledgeable about the structure-function relationships of different brain regions, tools for a priori hypothesis testing are needed. These tools must be able to generate region of interest masks for a priori hypothesis testing consistently and with minimal effort. Current tools that generate region of interest masks required for a priori hypothesis testing can be time-consuming and are often laboratory specific. In this paper we demonstrate a method of hypothesis-driven data analysis using an automated atlas-based masking technique. We provide a powerful method of probing fMRI data using automatically generated masks based on lobar anatomy, cortical and subcortical anatomy, and Brodmann areas. Hemisphere, lobar, anatomic label, tissue type, and Brodmann area atlases were generated in MNI space based on the Talairach Daemon. Additionally, we interfaced these multivolume atlases to a widely used fMRI software package, SPM99, and demonstrate the use of the atlas tool with representative fMRI data. This tool represents a necessary evolution in fMRI data analysis for testing of more spatially complex hypotheses.


Detection of antigens specific for B-lymphoid cultured cell lines with human alloantisera.
Human sera were tested for cytotoxicity to pairs of long-term tissue-cultured cell lines. Each pair had been derived from the same individual and one of the pairs possessed the characteristics of either "T" or "B" cells. The alloantisera used were HL-A-typing reagents or sera obtained from Amish multiparas. Selected cytotoxicity was found against the B-cell lines by direct testing. Cytotoxicity was abolished by absorption with B-cell line but not by absorption with the T-cell lines. The results suggest that a group of allotypic antigens may be expressed exculsively on human B cells.


Predictors of fast and ultrafast shunt failure in pediatric hydrocephalus: a Hydrocephalus Clinical Research Network study.
The primary objective of this study was to use the prospective Hydrocephalus Clinical Research Network (HCRN) registry to determine clinical predictors of fast time to shunt failure (≤ 30 days from last revision) and ultrafast time to failure (≤ 7 days from last revision). Revisions (including those due to infection) to permanent shunt placements that occurred between April 2008 and November 2017 for patients whose entire shunt experience was recorded in the registry were analyzed. All registry data provided at the time of initial shunt placement and subsequent revision were reviewed. Key variables analyzed included etiology of hydrocephalus, age at time of initial shunt placement, presence of slit ventricles on imaging at revision, whether the ventricles were enlarged at the time of revision, and presence of prior fast failure events. Univariable and multivariable analyses were performed to find key predictors of fast and ultrafast failure events. A cohort of 1030 patients with initial shunt insertions experienced a total of 1995 revisions. Of the 1978 revision events with complete records, 1216 (61.5%) shunts remained functional for more than 1 year, and 762 (38.5%) failed within 1 year of the procedure date. Of those that failed within 1 year, 423 (55.5%) failed slowly (31-365 days) and 339 (44.5%) failed fast (≤ 30 days). Of the fast failures, 131 (38.6%) were ultrafast (≤ 7 days). In the multivariable analysis specified a priori, etiology of hydrocephalus (p = 0.005) and previous failure history (p = 0.011) were independently associated with fast failure. Age at time of procedure (p = 0.042) and etiology of hydrocephalus (p = 0.004) were independently associated with ultrafast failure. These relationships in both a priori models were supported by the data-driven multivariable models as well. Neither the presence of slit ventricle syndrome nor ventricular enlargement at the time of shunt failure appears to be a significant predictor of repeated, rapid shunt revisions. Age at the time of procedure, etiology of hydrocephalus, and the history of previous failure events seem to be important predictors of fast and ultrafast shunt failure. Further work is required to understand the mechanisms of these risk factors as well as mitigation strategies.


Population-based mammography screening below age 50: balancing radiation-induced vs prevented breast cancer deaths.
Exposure to ionizing radiation at mammography screening may cause breast cancer. Because the radiation risk increases with lower exposure age, advancing the lower age limit may affect the balance between screening benefits and risks. The present study explores the benefit-risk ratio of screening before age 50. The benefits of biennial mammography screening, starting at various ages between 40 and 50, and continuing up to age 74 were examined using micro-simulation. In contrast with previous studies that commonly used excess relative risk models, we assessed the radiation risks using the latest BEIR-VII excess absolute rate exposure-risk model. The estimated radiation risk is lower than previously assessed. At a mean glandular dose of 1.3 mGy per view that was recently measured in the Netherlands, biennial mammography screening between age 50 and 74 was predicted to induce 1.6 breast cancer deaths per 100,000 women aged 0-100 (range 1.3-6.3 extra deaths at a glandular dose of 1-5 mGy per view), against 1121 avoided deaths in this population. Advancing the lower age limit for screening to include women aged 40-74 was predicted to induce 3.7 breast cancer deaths per 100,000 women aged 0-100 (range 2.9-14.4) at biennial screening, but would also prevent 1302 deaths. The benefits of mammography screening between age 40 and 74 were predicted to outweigh the radiation risks.


A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation.
V(D)J recombination of Ig and TCR loci is a stepwise process during which site-specific DNA double-strand breaks (DSBs) are made by RAG1/RAG2, followed by DSB repair by nonhomologous end joining. Defects in V(D)J recombination result in SCID characterized by absence of mature B and T cells. A subset of T-B-NK+ SCID patients is sensitive to ionizing radiation, and the majority of these patients have mutations in Artemis. We present a patient with a new type of radiosensitive T-B-NK+ SCID with a defect in DNA ligase IV (LIG4). To date, LIG4 mutations have only been described in a radiosensitive leukemia patient and in 4 patients with a designated LIG4 syndrome, which is associated with chromosomal instability, pancytopenia, and developmental and growth delay. The patient described here shows that a LIG4 mutation can also cause T-B-NK+ SCID without developmental defects. The LIG4-deficient SCID patient had an incomplete but severe block in precursor B cell differentiation, resulting in extremely low levels of blood B cells. The residual D(H)-J(H) junctions showed extensive nucleotide deletions, apparently caused by prolonged exonuclease activity during the delayed D(H)-J(H) ligation process. In conclusion, different LIG4 mutations can result in either a developmental defect with minor immunological abnormalities or a SCID picture with normal development.


Cost of illness and disease burden in The Netherlands due to infections with Shiga toxin-producing Escherichia coli O157.
Infections with Shiga toxin-producing Escherichia coli O157 (STEC O157) are associated with hemorrhagic colitis, hemolytic uremic syndrome (HUS), and end-stage renal disease (ESRD). In the present study, we extend previous estimates of the burden of disease associated with STEC O157 with estimates of the associated cost of illness in The Netherlands. A second-order stochastic simulation model was used to calculate disease burden as disability-adjusted life years (DALYs) and cost of illness (including direct health care costs and indirect non-health care costs). Future burden and costs are presented undiscounted and discounted at annual percentages of 1.5 and 4%, respectively. Annually, approximately 2.100 persons per year experience symptoms of gastroenteritis, leading to 22 cases of HUS and 3 cases of ESRD. The disease burden at the population level was estimated at 133 DALYs (87 DALYs discounted) per year. Total annual undiscounted and discounted costs of illness due to STEC O157 infection for the Dutch society were estimated at €9.1 million and €4.5 million, respectively. Average lifetime undiscounted and discounted costs per case were both €126 for diarrheal illness, both €25,713 for HUS, and €2.76 million and €1.22 million, respectively, for ESRD. The undiscounted and discounted costs per case of diarrheal disease including sequelae were €4,132 and €2,131, respectively. Compared with other foodborne pathogens, STEC O157 infections result in relatively low burden and low annual costs at the societal level, but the burden and costs per case are high.


Comparison of the accuracy of impedance plethysmography and compression ultrasonography in outpatients with clinically suspected deep vein thrombosis. A two centre paired-design prospective trial.
Impedance plethysmography (IPG) and compression ultrasonography (CUS) have been reported to be highly accurate for the diagnosis of deep vein thrombosis (DVT) in symptomatic patients. In many centres CUS has become the method of choice. However, direct comparisons of the accuracy of IPG to CUS have not been performed. To determine the test of choice we performed a two centre prospective comparison of IPG and CUS, with venography, and determined how the size and distribution of thrombi influenced the accuracy of each test. 495 symptomatic outpatients with suspected DVT had evaluable venograms. The prevalence of DVT was 27% (130/495), 84% (109) of which were proximal. The sensitivity of IPG and CUS for proximal vein thrombosis was 77% and 90% respectively (p = .002). The specificity of IPG was 93% whereas the specificity of CUS was 98% (p = 0.04). There were significant differences in accuracy between the two centres as a consequence of differences in the size and location of thrombi The majority of proximal thrombi not detected by IPG and CUS involved less than 5 cm of the distal half of the popliteal vein and most of these thrombi occurred in one centre. Exclusion of these thrombi from the analysis increases the sensitivity of CUS to 99% (86/87) and IPG to 91% (72/79), for proximal thrombi (P = .019). The positive predictive value of CUS was strongly influenced by the number of abnormal venous segments (three sites were examined); 100% (80/80) if two or three sites were abnormal, but only 68% if a single site was involved. We conclude that: 1) CUS is more accurate than the IPG for the diagnosis of DVT in symptomatic outpatients, and this relationship holds true regardless of the size or location of the DVT, 2) the sensitivities of IPG and CUS are much lower for small proximal DVT, and 3) confirmatory venography is warranted if the abnormality with CUS is limited to one venous segment.


Risk of Arterial Ischemic Events After Intracerebral Hemorrhage.
Background and Purpose- The risk of arterial ischemic events after intracerebral hemorrhage (ICH) is poorly understood given the lack of a control group in prior studies. This study aimed to evaluate the risk of acute ischemic stroke and myocardial infarction (MI) among patients with and without ICH. Methods- We performed a retrospective cohort study using claims data from Medicare beneficiaries from 2008 to 2014. Our exposure was acute ICH, identified using validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. Our primary outcome was a composite of acute ischemic stroke and MI, whereas secondary outcomes were ischemic stroke alone and MI alone. We used Cox regression analysis to compute hazard ratios during 1-month intervals after ICH. Sensitivity analyses entailed exclusion of patients with atrial fibrillation and valvular heart disease. Results- Among 1 760 439 Medicare beneficiaries, 5924 had ICH. The 1-year cumulative incidence of an arterial ischemic event was 5.7% (95% CI, 4.8-6.8) in patients with ICH and 1.8% (95% CI, 1.7-1.9) in patients without ICH. After adjusting for potential confounders, the risk of an arterial ischemic event remained significantly increased for the first 6 months after ICH and was especially high in the first month (hazard ratio, 6.7 [95% CI, 5.0-8.6]). In secondary analysis, the risk of ischemic stroke was increased in the first 6 months after ICH (hazard ratio, 6.1 [95% CI, 3.5-9.3]) but the risk of MI was not (hazard ratio, 1.6 [95% CI, 0.3-2.9]). In sensitivity analyses excluding patients with atrial fibrillation and valvular heart disease, the association between ICH and arterial ischemic events was similar to that of the primary analysis. Conclusions- In a large population-based cohort, we found that elderly patients with ICH had a substantially increased risk of ischemic stroke in the first 6 months after diagnosis. Further exploration of this risk is needed to determine optimal secondary prevention strategies for these patients.


Addressing sexual health needs: a comparison of a one-stop shop with separate genitourinary medicine and family planning services.
Little evidence is available on the extent to which one-stop shops address users' sexual health needs and the extent to which they identify additional needs users may not have identified. As part of the One-Stop Shop Evaluation, a questionnaire was designed to compare the reasons for users' visits and the reported outcomes of visits at a one-stop shop with the experiences of users in separate genitourinary medicine (GUM) and contraceptive clinics. The difference in the proportions of those attending the one-stop shop and those attending the control sites services for a sexually transmitted infection (STI)-related reason who were diagnosed with an STI was minimal, but those attending for an STI-related reason in the one-stop shop were more likely to receive an additional contraceptive outcome. Women attending for a contraceptive-related reason at the one-stop shop were more likely to have an STI screen than those attending the control sites for the same reason, but there was little difference in the proportions amongst this group receiving an STI diagnosis or receiving treatment. When focusing on women attending for a pregnancy-related reason, one-stop shop users were more likely to have received contraceptive advice or supplies. It was not possible in our evaluation to determine the relative effectiveness of the one-stop shop in comparison to the traditional GUM and contraceptive clinics in improving sexual health status, however the one-stop shop was more likely to address additional sexual health needs that service users may not have previously identified.


Does practicing a wide range of joint angle configurations lead to higher flexibility in a manual obstacle-avoidance target-pointing task?
Flexibility in motor actions can be defined as variability in the use of degrees of freedom (e.g., joint angles in the arm) over repetitions while keeping performance (e.g., fingertip position) stabilized. We examined whether flexibility can be increased through enlarging the joint angle range during practice in a manual obstacle-avoidance target-pointing task. To establish differences in flexibility we partitioned the variability in joint angles over repetitions in variability within (GEV) and variability outside the solution space (NGEV). More GEV than NGEV reflects flexibility; when the ratio of the GEV and NGEV is higher, flexibility is higher. The pretest and posttest consisted of 30 repetitions of manual pointing to a target while moving over a 10 cm high obstacle. To enlarge the joint angle range during practice participants performed 600 target-pointing movements while moving over obstacles of different heights (5-9 cm, 11-15 cm). The results indicated that practicing movements over obstacles of different heights led participants to use enlarged range of joint angles compared to the range of joint angles used in movements over the 10 cm obstacle in the pretest. However, for each individual obstacle neither joint angle variance nor flexibility were higher during practice. We also did not find more flexibility after practice. In the posttest, joint angle variance was in fact smaller than before practice, primarily in GEV. The potential influences of learning effects and the task used that could underlie the results obtained are discussed. We conclude that with this specific type of practice in this specific task, enlarging the range of joint angles does not lead to more flexibility.


Asymmetry of visual sensory mechanisms: electrophysiological, structural, and psychophysical evidences.
Psychophysical visual field asymmetries are widely documented and have been attributed to anatomical anisotropies both at the retinal and cortical levels. This debate on whether such differences originate within the retina itself or are due to higher visual processing may be illuminated if concomitant anatomical, physiological, and psychophysical measures are taken in the same individuals. In the current study, we have focused on the study of objective functional and structural asymmetries at the retinal level and examined their putative correlation with visual performance asymmetries. Forty healthy participants (80 eyes; 13 male and 27 female subjects) were included in this study. Objective functional/structural asymmetries were probed using the multifocal electroretinogram (mfERG) technique and optical coherence tomography (OCT), respectively. A nasal/temporal pattern of asymmetry (nasal visual hemifield disadvantage) was found for all methods (retinal thickness, contrast sensitivity, and mfERG P1 amplitude). Furthermore, superior/inferior asymmetries could be documented only with psychophysics and structural measures. These patterns likely arise at different levels of the retina as inferred by partly independent correlation patterns. We conclude that patterns of structural/functional asymmetries arise at different levels of visual processing with a strong retinal contribution.


Studying the assembly of multicomponent protein and ribonucleoprotein complexes using surface plasmon resonance.
The assembly of large macromolecular complexes is an important aspect of cellular organization and metabolism. Interactions involving such complexes in principle follow the same rules as the interactions between single proteins or other macromolecules and can therefore be investigated using similar approaches. We have developed protocols employing standard surface plasmon resonance technology that allow the investigation of interactions involving complex macromolecular structures. The principal experimental challenges arise from the possibility of parallel reactions where partially assembled or dissociated subcomplexes form a significant proportion of the molecule population and from an increased likelihood of unspecific binding events owing to the larger surface and statistically higher number of charged areas on multisubunit assemblies. Ways to experimentally avoid or, where this is not possible, to control for these complications are discussed.


Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors.
Owing to the emergence of resistant virus, next generation non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles have been developed to treat HIV infection. Crystal structures of HIV-1 RT complexed with benzophenones optimized for inhibition of HIV mutants that were resistant to the prototype benzophenone GF128590 indicate factors contributing to the resilience of later compounds in the series (GW4511, GW678248). Meta-substituents on the benzophenone A-ring had the designed effect of inducing better contacts with the conserved W229 while reducing aromatic stacking interactions with the highly mutable Y181 side chain, which unexpectedly adopted a "down" position. Up to four main-chain hydrogen bonds to the inhibitor also appear significant in contributing to resilience. Structures of mutant RTs (K103N, V106A/Y181C) with benzophenones showed only small rearrangements of the NNRTIs relative to wild-type. Hence, adaptation to a mutated NNRTI pocket by inhibitor rearrangement appears less significant for benzophenones than other next-generation NNRTIs.


2023 American College of Rheumatology and American Association of Hip and Knee Surgeons Clinical Practice Guideline for the Optimal Timing of Elective Hip or Knee Arthroplasty for Patients With Symptomatic Moderate-to-Severe Osteoarthritis or Advanced Symptomatic Osteonecrosis With Secondary Arthritis for Whom Nonoperative Therapy Is Ineffective.
To develop evidence-based consensus recommendations for the optimal timing of hip and knee arthroplasty to improve patient-important outcomes including, but not limited to, pain, function, infection, hospitalization, and death at 1 year for patients with symptomatic and radiographic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis of the hip or knee who have previously attempted nonoperative therapy, and for whom nonoperative therapy was ineffective, and who have chosen to undergo elective hip or knee arthroplasty (collectively referred to as TJA). We developed 13 clinically relevant population, intervention, comparator, outcomes (PICO) questions. After a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence (high, moderate, low, or very low), and evidence tables were created. A Voting Panel, including 13 physicians and patients, discussed the PICO questions until consensus was achieved on the direction (for/against) and strength (strong/conditional) of the recommendations. The panel conditionally recommended against delaying TJA to pursue additional nonoperative treatment including physical therapy, nonsteroidal antiinflammatory drugs, ambulatory aids, and intraarticular injections. It conditionally recommended delaying TJA for nicotine reduction or cessation. The panel conditionally recommended delay for better glycemic control for patients who have diabetes mellitus, although no specific measure or level was identified. There was consensus that obesity by itself was not a reason for delay, but that weight loss should be strongly encouraged, and the increase in operative risk should be discussed. The panel conditionally recommended against delay in patients who have severe deformity or bone loss, or in patients who have a neuropathic joint. Evidence for all recommendations was graded as low or very low quality. This guideline provides evidence-based recommendations regarding the optimal timing of TJA in patients who have symptomatic and radiographic moderate-to-severe osteoarthritis or advanced symptomatic osteonecrosis with secondary arthritis for whom nonoperative therapy was ineffective to improve patient-important outcomes, including pain, function, infection, hospitalization, and death at 1 year. We acknowledge that the evidence is of low quality primarily due to indirectness and hope future research will allow for further refinement of the recommendations.


TScratch: a novel and simple software tool for automated analysis of monolayer wound healing assays.
Cell migration plays a major role in development, physiology, and disease, and is frequently evaluated in vitro by the monolayer wound healing assay. The assay analysis, however, is a time-consuming task that is often performed manually. In order to accelerate this analysis, we have developed TScratch, a new, freely available image analysis technique and associated software tool that uses the fast discrete curvelet transform to automate the measurement of the area occupied by cells in the images. This tool helps to significantly reduce the time needed for analysis and enables objective and reproducible quantification of assays. The software also offers a graphical user interface which allows easy inspection of analysis results and, if desired, manual modification of analysis parameters. The automated analysis was validated by comparing its results with manual-analysis results for a range of different cell lines. The comparisons demonstrate a close agreement for the vast majority of images that were examined and indicate that the present computational tool can reproduce statistically significant results in experiments with well-known cell migration inhibitors and enhancers.


Fragmentation of intra-peptide and inter-peptide disulfide bonds of proteolytic peptides by nanoESI collision-induced dissociation.
Characterisation and identification of disulfide bridges is an important aspect of structural elucidation of proteins. Covalent cysteine-cysteine contacts within the protein give rise to stabilisation of the native tertiary structure of the molecules. Bottom-up identification and sequencing of proteins by mass spectrometry most frequently involves reductive cleavage and alkylation of disulfide links followed by enzymatic digestion. However, when using this approach, information on cysteine-cysteine contacts within the protein is lost. Mass spectrometric characterisation of peptides containing intra-chain disulfides is a challenging analytical task, because peptide bonds within the disulfide loop are believed to be resistant to fragmentation. In this contribution we show recent results on the fragmentation of intra and inter-peptide disulfide bonds of proteolytic peptides by nano electrospray ionisation collision-induced dissociation (nanoESI CID). Disulfide bridge-containing peptides obtained from proteolytic digests were submitted to low-energy nanoESI CID using a quadrupole time-of-flight (Q-TOF) instrument as a mass analyser. Fragmentation of the gaseous peptide ions gave rise to a set of b and y-type fragment ions which enabled derivation of the sequence of the amino acids located outside the disulfide loop. Surprisingly, careful examination of the fragment-ion spectra of peptide ions comprising an intramolecular disulfide bridge revealed the presence of low-abundance fragment ions formed by the cleavage of peptide bonds within the disulfide loop. These fragmentations are preceded by proton-induced asymmetric cleavage of the disulfide bridge giving rise to a modified cysteine containing a disulfohydryl substituent and a dehydroalanine residue on the C-S cleavage site.


ZnO dense nanowire array on a film structure in a single crystal domain texture for optical and photoelectrochemical applications.
A single crystal domain texture quality (a unique in-plane and out-of-plane crystalline orientation over a large area) ZnO nanostructure of a dense nanowire array on a thick film has been homogeneously synthesized on a-plane sapphire substrates over large areas through a one-step chemical vapor deposition (CVD) process. The growth mechanism is clarified: a single crystal [02(-)1] oriented ZnAl(2)O(4) buffer layer was formed at the ZnO film and the a-plane sapphire substrate interface via a diffusion reaction process during the CVD process, providing improved epitaxial conditions that enable the synthesis of the high crystalline quality ZnO nanowire array on a film structure. The high optoelectronic quality of the ZnO nanowire array on a film sample is evidenced by the free exitonic emissions in the low-temperature photoluminescence spectroscopy. A carrier density of ~10(17) cm(-3) with an n-type conductivity of the ZnO nanowire array on a film sample is obtained by electrochemical impedance analysis. Finally, the ZnO nanowire array on a film sample is demonstrated to be an ideal template for a further synthesis of a single crystal quality ZnO-ZnGa(2)O(4) core-shell nanowire array on a film structure. The fabricated ZnO-ZnGa(2)O(4) sample revealed an enhanced anticorrosive ability and photoelectrochemical performance when used as a photoanode in a photoelectrochemical water splitting application.


Next-generation sequencing of HIV-1 RNA genomes: determination of error rates and minimizing artificial recombination.
Next-generation sequencing (NGS) is a valuable tool for the detection and quantification of HIV-1 variants in vivo. However, these technologies require detailed characterization and control of artificially induced errors to be applicable for accurate haplotype reconstruction. To investigate the occurrence of substitutions, insertions, and deletions at the individual steps of RT-PCR and NGS, 454 pyrosequencing was performed on amplified and non-amplified HIV-1 genomes. Artificial recombination was explored by mixing five different HIV-1 clonal strains (5-virus-mix) and applying different RT-PCR conditions followed by 454 pyrosequencing. Error rates ranged from 0.04-0.66% and were similar in amplified and non-amplified samples. Discrepancies were observed between forward and reverse reads, indicating that most errors were introduced during the pyrosequencing step. Using the 5-virus-mix, non-optimized, standard RT-PCR conditions introduced artificial recombinants in a fraction of at least 30% of the reads that subsequently led to an underestimation of true haplotype frequencies. We minimized the fraction of recombinants down to 0.9-2.6% by optimized, artifact-reducing RT-PCR conditions. This approach enabled correct haplotype reconstruction and frequency estimations consistent with reference data obtained by single genome amplification. RT-PCR conditions are crucial for correct frequency estimation and analysis of haplotypes in heterogeneous virus populations. We developed an RT-PCR procedure to generate NGS data useful for reliable haplotype reconstruction and quantification.


Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy.
The efficacy and mechanisms of therapeutic action are largely described by atomic bonds and interactions local to drug binding sites. Here we introduce global connectivity analysis as a high-throughput computational assay of therapeutic action--inspired by the Google page rank algorithm that unearths most "globally connected" websites from the information-dense world wide web (WWW). We execute short timescale (30 ps) molecular dynamics simulations with high sampling frequency (0.01 ps), to identify amino acid residue hubs whose global connectivity dynamics are characteristic of the ligand or mutation associated with the target protein. We find that unexpected allosteric hubs--up to 20 Å from the ATP binding site, but within 5 Å of the phosphorylation site--encode the Gibbs free energy of inhibition (ΔG(inhibition)) for select protein kinase-targeted cancer therapeutics. We further find that clinically relevant somatic cancer mutations implicated in both drug resistance and personalized drug sensitivity can be predicted in a high-throughput fashion. Our results establish global connectivity analysis as a potent assay of protein functional modulation. This sets the stage for unearthing disease-causal exome mutations and motivates forecast of clinical drug response on a patient-by-patient basis. We suggest incorporation of structure-guided genetic inference assays into pharmaceutical and healthcare Oncology workflows.


Ethnomedicinal Value of Antidiabetic Plants in Bangladesh: A Comprehensive Review.
The use of conventional drugs to treat metabolic disorders and the pathological consequences of diabetes further increases the complications because of the side effects, and is sometimes burdensome due to relatively higher costs and occasionally painful route of administration of these drugs. Therefore, shifting to herbal medicine may be more effective, economical, have fewer side effects and might have minimal toxicity. The present review amasses a list of ethnomedicinal plants of 143 species belonging to 61 families, from distinctive domestic survey literature, reported to have been used to treat diabetes by the ethnic and local people of Bangladesh. Leaves of the medicinal plants were found leading in terms of their use, followed by fruits, whole plants, roots, seeds, bark, stems, flowers, and rhizomes. This review provides starting information leading to the search for and use of indigenous botanical resources to discover bioactive compounds for novel hypoglycemic drug development.


The Sense of Smell Impacts Metabolic Health and Obesity.
Olfactory inputs help coordinate food appreciation and selection, but their role in systemic physiology and energy balance is poorly understood. Here we demonstrate that mice upon conditional ablation of mature olfactory sensory neurons (OSNs) are resistant to diet-induced obesity accompanied by increased thermogenesis in brown and inguinal fat depots. Acute loss of smell perception after obesity onset not only abrogated further weight gain but also improved fat mass and insulin resistance. Reduced olfactory input stimulates sympathetic nerve activity, resulting in activation of β-adrenergic receptors on white and brown adipocytes to promote lipolysis. Conversely, conditional ablation of the IGF1 receptor in OSNs enhances olfactory performance in mice and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals.


Theoretical analysis of the two-electron transfer reaction and experimental studies with surface-confined cytochrome c peroxidase using large-amplitude Fourier transformed AC voltammetry.
A detailed analysis of the cooperative two-electron transfer of surface-confined cytochrome c peroxidase (CcP) in contact with pH 6.0 phosphate buffer solution has been undertaken. This investigation is prompted by the prospect of achieving a richer understanding of this biologically important system via the employment of kinetically sensitive, but background devoid, higher harmonic components available in the large-amplitude Fourier transform ac voltammetric method. Data obtained from the conventional dc cyclic voltammetric method are also provided for comparison. Theoretical considerations based on both ac and dc approaches are presented for cases where reversible or quasi-reversible cooperative two-electron transfer involves variation in the separation of their reversible potentials, including potential inversion (as described previously for solution phase studies), and reversibility of the electrode processes. Comparison is also made with respect to the case of a simultaneous two-electron transfer process that is unlikely to occur in the physiological situation. Theoretical analysis confirms that the ac higher harmonic components provide greater sensitivity to the various mechanistic nuances that can arise in two-electron surface-confined processes. Experimentally, the ac perturbation with amplitude and frequency of 200 mV and 3.88 Hz, respectively, was employed to detect the electron transfer when CcP is confined to the surface of a graphite electrode. Simulations based on cooperative two-electron transfer with the employment of reversible potentials of 0.745 ± 0.010 V, heterogeneous electron transfer rate constants of between 3 and 10 s(-1) and charge transfer coefficients of 0.5 for both processes fitted experimental data for the fifth to eighth ac harmonics. Imperfections in theory-experiment comparison are consistent with kinetic and thermodynamic dispersion and other nonidealities not included in the theory used to model the voltammetry of surface-confined CcP.


Combining PLS regression with portable NIR spectroscopy to on-line monitor quality parameters in intact olives for determining optimal harvesting time.
This study presents a systematized method for predicting water content, fat content and free acidity in olive fruits by on-line NIR Spectroscopy combined with chemometric techniques (PCA, LDA and PLSR). Three cultivar varieties of Olea europaea - Hojiblanca cv., Picual cv. and Arbequina cv. - were monitored. Five olive cultivation areas of Southern Spain (Andalucia) and Southern Portugal (Alentejo) were studied in 2011 and 2012. 465 olive samples were collected during the ripening process (non-mature olives) and compared with other 203 samples of mature olives collected at the final ripening stage. NIR spectra were measured directly in the olive fruits in the wavelength region from 1000 to 2300 nm in reflectance mode. The reference analyses were performed on the olive paste by oven drying for the moisture, by mini-Soxhlet extraction for the fat content and by acid titration of the oil extracted from the olive paste. Calibrations and predictive models were developed by Partial Least Square Regression (PLSR) previous Principal Component and Linear Discriminant analyses (PCA and LDA) were employed as exploratory and clean-up tools of data sets. The final models obtained for the total samples showed acceptable statistics of prediction with R(2)=0.88, RMSEV%=4.88 and RMSEP%=4.98 for water content, R(2)=0.76, RMSECV%=19.5 and RMSEP%=20.0 for fat content and R(2)=0.83, RMSECV%=36.8 and RMSEP%=38.8 for free acidity. Regression coefficients were better for only one maturity state (ripe period) than for olive fruit with different composition (ripening period). All models obtained were applied to predict LQPs on a new set of samples with satisfactory results, a good prediction potential of the models.


When do anomalies begin?
An anomaly in science is an observed fact that is difficult to explain in terms of the existing conceptual framework. Anomalies often point to the inadequacy of the current theory and herald a new one. It is argued here that certain scientific anomalies are recognized as anomalies only after they are given compelling explanations within a new conceptual framework. Before this recognition, the peculiar facts are taken as givens or are ignored in the old framework. Such a "retrorecognition" phenomenon reveals not only a significant feature of the process of scientific discovery but also an important aspect of human psychology.


Tethered aminohydroxylation: dramatic improvements to the process.
[reaction: see text] Changing the identity of the N leaving group on a hydroxylamine-based reoxidant gives a dramatic improvement to the tethered aminohydroxylation reaction. Using OCOC6F5 as a leaving group means that only 1 mol % of osmium is required and yields as high as 98% can be obtained. Acyclic homoallylic alcohols were substrates considered too unreactive for effective use in the tethered aminohydroxylation reaction; improved reaction conditions mean that they have now become viable substrates for oxidation.


Evaluation of Patch Test Findings in Patients With Anogenital Dermatitis.
Contact dermatitis in the anogenital area is associated with sleep disturbance and dyspareunia and can profoundly affect quality of life. The literature on anogenital contact dermatitis and culprit allergens is limited. The last large-scale study on common, relevant allergens in patients with anogenital dermatitis was published in 2008. To characterize patients with anogenital dermatitis referred for patch testing by the North American Contact Dermatitis Group, to identify common allergens, and to explore sex-associated differences between anogenital dermatitis and allergens. A retrospective, cross-sectional analysis was conducted of the North American Contact Dermatitis Group database among 28 481 patients who underwent patch testing from January 1, 2005, to December 31, 2016, at outpatient referral clinics in the United States and Canada. Patch testing for allergens. Currently relevant allergic patch test reactions in patients with anogenital dermatitis. Of 28 481 patients tested during the study period, 832 patients (336 men and 496 women; mean [SD] age, 50.1 [26.5] years) had anogenital involvement and 449 patients (177 men and 272 women; mean [SD] age, 49.6 [17.4] years) had anogenital dermatitis only. Compared with those without anogenital involvement, there were significantly more male patients in the group with anogenital dermatitis (177 [39.4%] vs 8857 of 27 649 [32.0%]; relative risk, 1.37; 95% CI, 1.14-1.66; P < .001). In the group with anogenital involvement, female patients were significantly less likely than male patients to have allergic contact dermatitis as a final diagnosis (130 [47.8%] vs 107 [60.5%]; relative risk, 0.78; 95% CI, 0.64-0.94; P = .01), whereas a final diagnosis of other dermatoses (eg, lichen planus, lichen sclerosus, or lichen simplex chronicus) was more frequent for female patients than for male patients (67 [24.6%] vs 28 [15.8%]; relative risk, 1.54; 95% CI, 1.02-2.31; P = .03). Of the 449 patients in the group with anogenital involvement only, 227 (50.6%) had 1 or more relevant reaction with patch testing. Allergens that were statistically significantly more common in patients with anogenital involvement compared with those without anogenital involvement included medicaments such as dibucaine (10 of 250 patients tested [4.0%] vs 32 of 17 494 patients tested [0.2%]; relative risk, 22.74; 95% CI, 11.05-46.78; P < .001) and preservatives such as methylchloroisothiazolinone and methylisothiazolinone (30 of 449 patients tested [6.7%] vs 1143 of 27 599 patients tested [4.1%]; relative risk, 1.61; 95% CI, 1.14-2.41; P = .008). A total of 152 patients met the definition for anogenital allergic contact dermatitis, which is defined as anogenital involvement only, allergic contact dermatitis as the only diagnosis, and 1 or more positive reaction of current clinical relevance. For patients with anogenital involvement only who were referred for patch testing, male patients were more likely to have allergic contact dermatitis, whereas female patients were more likely to have other dermatoses. Common allergens or sources consisted of those likely to contact the anogenital area. For individuals with anogenital involvement suspected of having allergic contact dermatitis, reactions to preservatives, fragrances, medications (particularly topical anesthetics), and topical corticosteroids should be tested.


Health care utilization by people with disabilities: A longitudinal analysis of the Korea Welfare Panel Study (KoWePS).
Health care is important for people with disabilities in terms of maintaining basic functional status and promoting health. However, empirical studies on health care utilization by this population in South Korea are rare. The purpose of this study was to examine the characteristics of people with disabilities and to evaluate the relationship between the presence and severity of disabilities and health care utilization. We analyzed the 2005-2011 Korea Welfare Panel Study data, and the final sample included 38,598 observations over seven years. Health care utilization was measured by health screening attendance, number of outpatient physician visits, and inpatient days. To examine the impact of disabilities on health care utilization, random-effects logistic regression and negative binomial regression models were adopted. About 3.3% of the sample had physical disabilities, as defined by the Korean disability registration system. In the sample, the prevalence of chronic diseases and percentage of poor self-rated health were higher in people with disabilities than in people without disabilities. The results of the regression analyses showed that people with severe disabilities had a lower probability of health screening attendance, and they also had significantly longer inpatient stays for health care services. These findings imply poor accessibility of preventive or outpatient health care services for people with severe disabilities in Korea, and suggest that barriers should be removed. Further studies are necessary for effective health care provision to meet the complex needs of people with disabilities.


Differential roles of regulatory light chain and myosin binding protein-C phosphorylations in the modulation of cardiac force development.
Phosphorylation of myosin regulatory light chain (RLC) by myosin light chain kinase (MLCK) and myosin binding protein-C (cMyBP-C) by protein kinase A (PKA) independently accelerate the kinetics of force development in ventricular myocardium. However, while MLCK treatment has been shown to increase the Ca(2+) sensitivity of force (pCa(50)), PKA treatment has been shown to decrease pCa(50), presumably due to cardiac troponin I phosphorylation. Further, MLCK treatment increases Ca(2+)-independent force and maximum Ca(2+)-activated force, whereas PKA treatment has no effect on either force. To investigate the structural basis underlying the kinase-specific differential effects on steady-state force, we used synchrotron low-angle X-ray diffraction to compare equatorial intensity ratios (I(1,1)/I(1,0)) to assess the proximity of myosin cross-bridge mass relative to actin and to compare lattice spacings (d(1,0)) to assess the inter-thick filament spacing in skinned myocardium following treatment with either MLCK or PKA. As we showed previously, PKA phosphorylation of cMyBP-C increases I(1,1)/I(1,0) and, as hypothesized, treatment with MLCK also increased I(1,1)/I(1,0), which can explain the accelerated rates of force development during activation. Importantly, interfilament spacing was reduced by 2 nm (3.5%) with MLCK treatment, but did not change with PKA treatment. Thus, RLC or cMyBP-C phosphorylation increases the proximity of cross-bridges to actin, but only RLC phosphorylation affects lattice spacing, which suggests that RLC and cMyBP-C modulate the kinetics of force development by similar structural mechanisms; however, the effect of RLC phosphorylation to increase the Ca(2+) sensitivity of force is mediated by a distinct mechanism, most probably involving changes in interfilament spacing.


Barriers in the Delivery of Emergency Obstetric and Neonatal Care in Post-Conflict Africa: Qualitative Case Studies of Burundi and Northern Uganda.
Maternal and neonatal mortality and morbidity rates are particularly grim in conflict, post-conflict and other crisis settings, a situation partly blamed on non-availability and/or poor quality of emergency obstetric and neonatal care (EmONC) services. The aim of this study was to explore the barriers to effective delivery of EmONC services in post-conflict Burundi and Northern Uganda, in order to provide policy makers and other relevant stakeholders context-relevant data on improving the delivery of these lifesaving services. This was a qualitative comparative case study that used 42 face-to-face semi-structured in-depth interviews and 4 focus group discussions for data collection. Participants were 32 local health providers and 37 staff of NGOs working in the area of maternal health. Data was analysed using the framework approach. The availability, quality and distribution of EmONC services were major challenges across the sites. The barriers in the delivery of quality EmONC services were categorised into two major themes; human resources-related challenges, and systemic and institutional failures. While some of the barriers were similar, others were unique to specific sites. The common barriers included shortage of qualified staff; lack of essential installations, supplies and medications; increasing workload, burn-out and turnover; and poor data collection and monitoring systems. Barriers unique to Northern Uganda were demoralised personnel and lack of recognition; poor referral system; inefficient drug supply system; staff absenteeism in rural areas; and poor coordination among key personnel. In Burundi, weak curriculum; poor harmonisation and coordination of training; and inefficient allocation of resources were the unique challenges. To improve the situation across the sites, efforts are ongoing to improve the training and recruitment of more staff; harmonise and strengthen the curriculum and training; increase the number of EmONC facilities; and improve staff supervision, monitoring and support. Post-conflict health systems face different challenges in the delivery of EmONC services and as such require context-specific interventions to improve the delivery of these services.


Noradrenergic modulation of cholinergic nucleus basalis neurons demonstrated by in vitro pharmacological and immunohistochemical evidence in the guinea-pig brain.
The effects of noradrenalin were tested upon electrophysiologically characterized cholinergic nucleus basalis neurons in guinea-pig brain slices. According to their previously established intrinsic membrane properties, the cholinergic cells were distinguished by the presence of low-threshold Ca2+ spikes and transient outward rectification that endowed them with the capacity to fire in low-threshold bursts in addition to a slow tonic discharge. A subset of the electrophysiologically identified cholinergic cells that responded to noradrenalin had been filled with biocytin (or biotinamide) and documented in previously published reports as choline acetyltransferase (ChAT)-immunoreactive. The noradrenalin-responsive, biocytin-filled/ChAT+cells were mapped in the present study and shown to be distributed within the substantia innominata amongst a large population of ChAT+ cells. Slices from another subset of noradrenalin-responsive, electrophysiologically identified cholinergic cells were stained for dopamine-beta-hydroxylase to visualize the innervation of the biocytin-filled neurons by noradrenergic fibres. These biocytin-filled neurons were surrounded by a moderate plexus of varicose noradrenergic fibres and were ostensibly contacted by a small to moderate number of noradrenergic boutons abutting their soma and dendrites. Applied in the bath, noradrenalin produced membrane depolarization and a prolonged tonic spike discharge. This excitatory action was associated with an increase in membrane input resistance, suggesting that it occurred through reduction of a K+ conductance. These effects persisted when synaptic transmission was eliminated (by tetrodotoxin or low Ca2+/high Mg2+) and were therefore clearly postsynaptic. The excitatory effect of noradrenalin was blocked by the alpha 1-adrenergic receptor antagonist prazosin and not by the alpha 2-antagonist yohimbine, and it was mimicked by the alpha 1-agonist L-phenylephrine but not by the alpha 2-agonists clonidine and UK14.304, indicating mediation by an alpha 1-adrenergic receptor. There was also evidence for a contribution by a beta-adrenergic receptor to the effect, since the beta-antagonist propranolol partially attenuated the effect of noradrenalin, and the beta-agonist isoproterenol produced, like noradrenalin, alone or when applied in the presence of the alpha 1-antagonist prazosin, membrane depolarization and an increase in tonic spike discharge. These results indicate that through a predominant action upon alpha 1-adrenergic receptors, but with the additional participation of beta-adrenergic receptors, noradrenalin depolarizes and excites cholinergic neurons. This action would tend to drive the cholinergic cells into a tonic mode of firing and to stimulate or increase the rate of repetitive spike discharge for prolonged periods.(ABSTRACT TRUNCATED AT 400 WORDS)


Mutations in trans-acting factors affecting mRNA decapping in Saccharomyces cerevisiae.
The decay of several yeast mRNAs occurs by a mechanism in which deadenylation precedes decapping and subsequent 5'-to-3' exonucleolytic decay. In order to identify gene products required for this process of mRNA turnover, we screened a library of temperature-sensitive strains for mutants with altered mRNA degradation. We identified seven mutations in four genes that inhibited mRNA turnover. Two mutations were alleles of the XRN1 5'-to-3' exoribonuclease known to degrade mRNAs following decapping. One mutation defined a new gene, termed DCP1, which in subsequent work was demonstrated to encode a decapping enzyme or a necessary component of a decapping complex. The other mutations defined two additional genes, termed MRT1 and MRT3 (for mRNA turnover). Mutations in the MRT1 and MRT3 genes slow the rate of deadenylation-dependent decapping, show transcript-specific effects on mRNA decay rates, and do not affect the rapid turnover of an mRNA containing an early nonsense codon, which is degraded by a deadenylation-independent decapping mechanism. Importantly, cell extracts from mrt1 and mrt3 strains contain normal levels of the decapping activity required for mRNA decay. These observations suggest that the products of the MRT1 and MRT3 genes function to modulate the rates of decapping that occur following deadenylation.


Anti-inflammatory and antioxidant effects of infliximab in a rat model of intestinal ischemia/reperfusion injury.
The aim of this study was to investigate the possible protective effects of infliximab on oxidative stress, cell proliferation and apoptosis in the rat intestinal mucosa after ischemia/reperfusion (I/R). A total of 30 male Wistar albino rats were divided into three groups: sham, I/R and I/R+ infliximab; each group comprised 10 animals. Sham group animals underwent laparotomy without I/R injury. I/R groups after undergoing laparotomy, 1 hour of superior mesenteric artery ligation occurred, which was followed by 1 hour of reperfusion. In the infliximab group, 3 days before I/R, infliximab (3 mg/kg) was administered intravenously. All animals were killed at the end of reperfusion and intestinal tissues samples were obtained for biochemical and histopathological investigation in all groups. To date, no biochemical and histopathological changes have been reported regarding intestinal I/R injury in rats due to infliximab treatment. Infliximab treatment significantly decreased the elevated tissue malondialdehyde levels and increased reduced superoxide dismutase and glutathione peroxidase enzyme activities in intestinal tissues samples. I/R caused severe histopathological injury including mucosal erosions, inflammatory cell infiltration, necrosis, hemorrhage, and villous congestion. Infliximab treatment significantly attenuated the severity of intestinal I/R injury, inhibiting I/R-induced apoptosis, and cell proliferation. Because of its anti-inflammatory and antioxidant effects, infliximab pretreatment may have protective effects on the experimental intestinal I/R model of rats.


Ammonia-oxidizing bacterial community composition in estuarine and oceanic environments assessed using a functional gene microarray.
The relationship between environmental factors and functional gene diversity of ammonia-oxidizing bacteria (AOB) was investigated across a transect from the freshwater portions of the Chesapeake Bay and Choptank River out into the Sargasso Sea. Oligonucleotide probes (70-bp) designed to represent the diversity of ammonia monooxygenase (amoA) genes from Chesapeake Bay clone libraries and cultivated AOB were used to construct a glass slide microarray. Hybridization patterns among the probes in 14 samples along the transect showed clear variations in amoA community composition. Probes representing uncultivated members of the Nitrosospira-like AOB dominated the probe signal, especially in the more marine samples. Of the cultivated species, only Nitrosospira briensis was detected at appreciable levels. Discrimination analysis of hybridization signals detected two guilds. Guild 1 was dominated by the marine Nitrosospira-like probe signal, and Guild 2's largest contribution was from upper bay (freshwater) sediment probes. Principal components analysis showed that Guild 1 was positively correlated with salinity, temperature and chlorophyll a concentration, while Guild 2 was positively correlated with concentrations of oxygen, dissolved organic carbon, and particulate nitrogen and carbon, suggesting that different amoA sequences represent organisms that occupy different ecological niches within the estuarine/marine environment. The trend from most diversity of AOB in the upper estuary towards dominance of a single type in the polyhaline region of the Bay is consistent with the declining importance of AOB with increasing salinity, and with the idea that AO-Archaea are the more important ammonia oxidizers in the ocean.


Experimental allergic encephalomyelitis: the effect of 6-mercaptopurine.
1. 6-Mercaptopurine (6-MP) prevents experimental allergic encephalomyelitis (EAE) during the period of drug administration in both rabbits and guinea pigs. The disease is suppressed even when treatment is started as late as the 5th day after antigenic stimulation in guinea pigs and the 12th day in rabbits. 2. After discontinuation of 6-MP treatment, there is a latent period before the disease is noted. The length of this latent period is not modified by the duration of 6-MP treatment. 3. The effect of 6-MP on EAE is not the result of leukopenia, non-specific toxicity and debilitation, anti-inflammatory activity, or mere masking of clinical signs of the disease. It is, rather, the result of 6-MP's specific anti-immunologic activity. 4. The effects of 6-MP on antibody production, delayed hypersensitivity, and EAE are compared. This provides indirect evidence for the importance of circulating antibody in the pathogenesis of EAE. 5. The important considerations in the use of 6-MP are discussed and the possible usefulness of 6-MP in human neurologic diseases is considered.


Is Sjögren's syndrome dry eye similar to dry eye caused by other etiologies? Discriminating different diseases by dry eye tests.
Dry Eye Disease (DED) is part of several conditions, including Sjögren's syndrome (SS) and no single test to diagnosis DED. The present study intends to evaluate whether a set of signs and symptoms of DED can distinguish: a) SS from other non-overlapping systemic diseases related to DED; b) primary and secondary SS. 182 consecutive patients with DED were evaluated under five groups: SS, graft-versus-host disease (GVHD), Graves' orbitopathy (GO), diabetes mellitus (DM), glaucoma under treatment with benzalkonium chloride medications (BAK). Twenty-four healthy subjects were included as control group (CG). The evaluation consisted of Ocular Surface Disease Index (OSDI), Schirmer test (ST), corneal fluorescein staining (CFS) and tear film break up time (TFBUT). Indeed, a subset of DED patients (n = 130), classified as SS1, SS2 and nonSS (NSS) by the American-European Criteria were compared. Quadratic discriminant analysis (QDA) classified the individuals based on variables collected. The area under Receiver Operating Characteristics (ROC) curve evaluated the classification performance in both comparisons. Comparing SS with other diseases, QDA showed that the most important variable for classification was OSDI, followed by TFBUT and CFS. Combined, these variables were able to correctly classify 62.6% of subjects in their actual group. At the discretion of the area under the ROC curve, the group with better classification was the control (97.2%), followed by DM (95.5%) and SS (92.5%). DED tests were different among the NSS, SS1 and SS2 groups. The analysis revealed that the combined tests correctly classified 54.6% of the patients in their groups. The area under the ROC curve better classified NSS (79.5%), followed by SS2 (74.4%) and SS1 (69.4%). Diseases that causes DED, and also SS1, SS2 and NSS are distinguishable conditions, however a single ocular tools was not able to detect the differences among the respective groups.


A stress inducible SUMO conjugating enzyme gene (SaSce9) from a grass halophyte Spartina alterniflora enhances salinity and drought stress tolerance in Arabidopsis.
SUMO (Small Ubiquitin related Modifier) conjugation is a post translational regulatory process found in all eukaryotes, mediated by SUMO activating enzyme, SUMO conjugating enzyme, and SUMO ligase for the attachment of SUMO to its target protein. Although the mechanism for regulation of SUMO conjugation pathway genes under abiotic stress has been studied to certain extent, the role of SUMO conjugating enzyme in improving abiotic stress tolerance to plant is largely unexplored. Here, we have characterized a SUMO conjugating enzyme gene 'SaSce9' from a halophytic grass Spartina alterniflora and investigated its role in imparting abiotic stress tolerance. SaSce9 gene encodes for a polypeptide of 162 amino acids with a molecular weight of ~18 kD and isoelectric point 8.43. Amino acid sequence comparisons of SaSce9 with its orthologs from other plant species showed high degree (~85-93%) of structural conservation among each other. Complementation analysis using yeast SCE mutant, Ubc9, revealed functional conservation of SaSce9 between yeast and S. alterniflora. SaSce9 transcript was inducible by salinity, drought, cold, and exogenously supplied ABA both in leaves and roots of S. alterniflora. Constitutive overexpression of SaSce9 in Arabidopsis through Agrobacterium mediated transformation improved salinity and drought tolerance of Arabidopsis. SaSce9 overexpressing Arabidopsis plants retained more chlorophyll and proline both under salinity and drought stress. SaSce9 transgenic plants accumulated lower levels of reactive oxygen under salinity stress. Expression analysis of stress responsive genes in SaSce9 Arabidopsis plants revealed the increased expression of antioxidant genes, AtSOD and AtCAT, ion antiporter genes, AtNHX1 and AtSOS1, a gene involved in proline biosynthesis, AtP5CS, and a gene involved in ABA dependent signaling pathway, AtRD22. These results highlight the prospect of improving abiotic stress tolerance in plants through genetic engineering of the sumoylation pathway. The study provides evidence that the overexpression of SaSce9 in plant can improve salinity and drought stress tolerance by protecting the plant through scavenging of ROS, accumulation of an osmolyte, proline, and expression of stress responsive genes. In addition, this study demonstrates the potential of the halophyte grass S. alterniflora as a reservoir of abiotic stress related genes for crop improvement.


Identification, Characterization, and Distribution of Southern rice black-streaked dwarf virus in Vietnam.
A novel dwarf and twisting syndrome first observed on rice in Nghe An Province, Vietnam, in 2009 has spread rapidly to the other 19 provinces of North and Central Vietnam. Infected rice plants showed stunting, darkening of leaves, twisting of leaf tips, and splitting of leaf margins. At a later stage, white waxy enations that eventually turned black were observed on the underside of leaf blades, leaf sheaths, and culms. The disease also infected maize after rice was harvested. Infected maize plants were stunted and dark green with small enations along the minor veins on the back of leaves. The disease agent has now been identified as Southern rice black-streaked dwarf virus (SRBSDV) recently reported from Southern China. Typical fijivirus viroplasms containing crystalline arrayed spherical virions approximately 70 to 75 nm in diameter were observed under the electron microscope in ultrathin sections of infected rice leaves. The virus was transmitted to rice and maize seedlings by the white-backed planthopper (Sogatella furcimera). A one-step reverse transcription-polymerase chain reaction (RT-PCR) protocol was used to confirm the presence of SRBSDV in 477 samples of rice or maize from 29 provinces among 5 agroecological regions in North and Central Vietnam. Rice black-streaked dwarf virus was not detected in these samples. Partial sequences of RNA segments 4 and 10 from several isolates showed very low genetic divergences between isolates from Vietnam and China, suggesting a common origin, and phylogenetic analysis confirmed the placement of SRBSDV as a distinct virus within subgroup 2 of the genus Fijivirus.


Obesity in pregnancy: infant health service utilisation and costs on the NHS.
To estimate the direct healthcare cost of infants born to overweight or obese mothers to the National Health Service in the UK. Retrospective prevalence-based study. Combined linked anonymised electronic data sets on a cohort of mother-child pairs enrolled on the Growing Up in Wales: Environments for Healthy Living (EHL) study. Infants were categorised according to maternal early-pregnancy body mass index (BMI): healthy weight mother (18.5≤BMI<25 kg/m(2); n=342), overweight mother (25≤BMI≤29.9 kg/m(2); n=157) and obese mother (BMI≥30; n=110). 609 singleton pregnancies with available health service records and an antenatal maternal BMI. Total health service utilisation and direct healthcare costs for providing these services in the year 2012-2013. Costs are calculated as cost of the infant (no maternal costs considered) and are related to health service usage from birth to age 1 year. A strong association existed between healthcare usage cost and BMI (p<0.001). Mean total costs were 72% higher among children born to obese mothers (rate ratio (RR) 1.72, 95% CI 1.71 to 1.73) compared with infants born to healthy weight mothers. Higher costings were attributed to a significantly greater number (RR 1.39, 95% CI 1.04 to 1.84) and duration (RR 1.55, 95% CI 1.37 to 1.74) of inpatient visits and a higher number of general practitioner visits (RR 1.10, 95% CI 1.03 to 1.16). Total mean additional resource cost was estimated at £65.13 for infants born to overweight mothers and £1138.11 for infants born to obese mothers, when compared with infants of healthy weight mothers. Increasingly infants born to mothers with high BMIs consume additional health service resources in the first year of life; this was apparent across inpatient and general practitioner services. Considering both maternal and infant health service use, interventions that cost less than £2310 per person in reducing obesity early pregnancy could be cost-effective.


Proton pump inhibitor use is associated with hip fracture development: a nationwide population-based cohort study.
Effect of proton pump inhibitor (PPI) use on the risk of hip fracture is controversial. This study aimed to clarify the association between PPI use and hip fracture risk using a large cohort. This study recruited participants from the nationwide cohort (n = 1,025,340). After exclusion of participants who had hip fractures or were aged less than 40 years during the baseline period (2002 to 2004), 371,806 participants were followed to 2013. Participants prescribed PPIs for more than 90 days during baseline period were defined as users. Fracture cases were defined when participants were hospitalized with claims of a hip fracture. During 4,159,343 person-years of follow-up, fractures developed more often in PPI users than in nonusers (relative risk [RR], 1.787; 95% confidence interval [CI], 1.260 to 2.534; p = 0.002). The results persisted after adjusting for age, sex, and many drugs relevant to osteoporosis or influential in bone health. Furthermore, fracture risk associated with PPI use increased with duration of use (p trend < 0.001). The fully adjusted RRs of hip fracture development were 1.350 (95% CI, 1.203 to 1.515) for 1- to 90-day users, 1.487 (95% CI, 0.957 to 2.311) for 91- to 180-day users, and 1.771 (95% CI, 0.931 to 3.368) for > 180-day users. The positive association between PPI use and fracture was also confirmed in a subgroup with health screening data where further adjustment for body mass index, smoking status, alcohol consumption, and physical activity was available (adjusted RR, 2.025; 95% CI, 1.151 to 3.564, p = 0.014). PPI use is associated with hip fracture development.


Combining biochemical and imaging markers to improve diagnosis and characterization of mild traumatic brain injury in the acute setting: results from a pilot study.
Mild traumatic brain injury (mTBI) is a significant healthcare burden and its diagnosis remains a challenge in the emergency department. Serum biomarkers and advanced magnetic resonance imaging (MRI) techniques have already demonstrated their potential to improve the detection of brain injury even in patients with negative computed tomography (CT) findings. The objective of this study was to determine the clinical value of a combinational use of both blood biomarkers and MRI in mTBI detection and their characterization in the acute setting (within 24 hours after injury). Nine patients with mTBI were prospectively recruited from the emergency department. Serum samples were collected at the time of hospital admission and every 6 hours up to 24 hours post injury. Neuronal (Ubiquitin C-terminal Hydrolase-L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels were analyzed. Advanced MRI data were acquired at 9 ± 6.91 hours after injury. Patients' neurocognitive status was assessed by using the Standard Assessment of Concussion (SAC) instrument. The median serum levels of UCH-L1 and GFAP on admission were increased 4.9 folds and 10.6 folds, respectively, compared to reference values. Three patients were found to have intracranial hemorrhages on SWI, all of whom had very high GFAP levels. Total volume of brain white matter (WM) with abnormal fractional anisotropy (FA) measures of diffusion tensor imaging (DTI) were negatively correlated with patients' SAC scores, including delayed recall. Both increased and decreased DTI-FA values were observed in the same subjects. Serum biomarker level was not correlated with patients' DTI data nor SAC score. Blood biomarkers and advanced MRI may correlate or complement each other in different aspects of mTBI detection and characterization. GFAP might have potential to serve as a clinical screening tool for intracranial bleeding. UCH-L1 complements MRI in injury detection. Impairment at WM tracts may account for the patients' neurocognitive symptoms.


Caveolin-1 regulates cancer cell metabolism via scavenging Nrf2 and suppressing MnSOD-driven glycolysis.
Aerobic glycolysis is an indispensable component of aggressive cancer cell metabolism. It also distinguishes cancer cells from most healthy cell types in the body. Particularly for this reason, targeting the metabolism to improve treatment outcomes has long been perceived as a potentially valuable strategy. In practice, however, our limited knowledge of why and how metabolic reprogramming occurs has prevented progress towards therapeutic interventions that exploit the metabolic peculiarities of tumors. We recently described that in breast cancer, MnSOD upregulation is both necessary and sufficient to activate glycolysis. Here, we focused on determining the molecular mechanisms of MnSOD upregulation. We found that Caveolin-1 (Cav-1) is a central component of this mechanism due to its suppressive effects of NF-E2-related factor 2 (Nrf2), a transcription factor upstream of MnSOD. In transformed MCF10A(Er/Src) cells, Cav-1 loss preceded the activation of Nrf2 and its induction of MnSOD expression. Consistently, with previous observations, MnSOD expression secondary to Nrf2 activation led to an increase in the glycolytic rate dependent on mtH2O2 production and the activation of AMPK. Moreover, rescue of Cav-1 expression in a breast cancer cell line (MCF7) suppressed Nrf2 and reduced MnSOD expression. Experimental data were reinforced by epidemiologic nested case-control studies showing that Cav-1 and MnSOD are inversely expressed in cases of invasive ductal carcinoma, with low Cav-1 and high MnSOD expression being associated with lower 5-year survival rates and molecular subtypes with poorest prognosis.


Ultrasound techniques in the evaluation of the mediastinum, part 2: mediastinal lymph node anatomy and diagnostic reach of ultrasound techniques, clinical work up of neoplastic and inflammatory mediastinal lymphadenopathy using ultrasound techniques and how to learn mediastinal endosonography.
Ultrasound imaging has gained importance in pulmonary medicine over the last decades including conventional transcutaneous ultrasound (TUS), endoscopic ultrasound (EUS), and endobronchial ultrasound (EBUS). Mediastinal lymph node (MLN) staging affects the management of patients with both operable and inoperable lung cancer (e.g., surgery vs. combined chemoradiation therapy). Tissue sampling is often indicated for accurate nodal staging. Recent international lung cancer staging guidelines clearly state that endosonography should be the initial tissue sampling test over surgical staging. Mediastinal nodes can be sampled from the airways [endobronchial ultrasound combined with transbronchial needle aspiration (EBUS-TBNA)] or the esophagus [endoscopic ultrasound fine needle aspiration (EUS-FNA)]. EBUS and EUS have a complementary diagnostic yield and in combination virtually all MLNs can be biopsied. Additionally endosonography has an excellent yield in assessing granulomas in patients suspected of sarcoidosis. The aim of this review in two integrative parts is to discuss the current role and future perspectives of all ultrasound techniques available for the evaluation of mediastinal lymphadenopathy and mediastinal staging of lung cancer. A specific emphasis will be on learning mediastinal endosonography. Part 1 deals with an introduction into ultrasound techniques, MLN anatomy and diagnostic reach of ultrasound techniques and part 2 with the clinical work up of neoplastic and inflammatory mediastinal lymphadenopathy using ultrasound techniques and how to learn mediastinal endosonography.


Differential effects of pH and inositol hexaphosphate on the spectroscopic properties of the alpha and beta subunits in methemoglobins M Milwaukee and A.
The effect of pH and inositol hexaphosphate on the electron spin resonance spectra of the alpha-hemes (g = 6.0) and the beta-hemes (g = 6.7) has been measured in methemoglobin M Milwaukee and compared with that of methemoglobin A (g = 6.0). The beta-hemes are found to be comparatively insensitive to both effectors while the alpha-hemes behave in a manner similar to the heme groups of methemoglobin A. Binding of inositol hexaphosphate enhances the high spin ESR signal of the alpha-hemes in both methemoglobins. Comparison of the optical properties of methemoglobins A and M Milwaukee over the pH range from 5.0 to 8.1 shows that inositol hexaphosphate has a differential effect on the subunit types in these two methemoglobins. At low pH the spectral changes observed upon inositol hexaphosphate binding arise primarily from the beta-hemes, while at neutral and alkaline pH these changes arise from both subunit types. The beta-heme spectral changes appear to be pH independent while those arising from the alpha-hemes are strongly pH dependent. It is concluded that it is the hydroxymet form of the alpha-hemes which undergoes spectral change upon inositol hexaphosphate binding to the beta-subunits. In methemoglobin A the spin state and paramagnetic susceptibility increase only in the neutral and alkaline pH ranges upon inositol hexaphosphate binding (Gupta, R.K. and Mildvan, R.S. (1975) J. Biol. Chem. 250, 246; Perutz, M.F., Sanders, J.K.M., Chenery, D.H., Noble, R.W., Penelly, R.R., Fung, L.W.-M., Ho, C., Giannini, I., Porschke, D. and Winkler, H. (1978) Biochemistry 17, 3640). Therefore the hydroxymet form of the alpha-hemes which is responsible for the observed spectral changes must also be responsible for these increases in the magnetic properties of methemoglobin A. Inositol hexaphosphate can bind to methemoglobin at alkaline pH if the beta-hemes are in the high spin form.