Octopamine is involved in TRP- induced thermopreference responses in American cockroach.
Insects' thermoregulatory processes depend on thermosensation and further processing of thermal information in the nervous system. It is commonly known that thermosensation involves thermoreceptors, including members of the TRP receptor family, but the involvement of neurotransmitters in thermoregulatory pathways remains unstudied. We conducted test to determine whether octopamine, a biogenic amine that acts as a neurotransmitter and neurohormone in insects, is involved in TRP-induced thermoregulatory responses in Periplaneta americana. We used capsaicin, an activator of the heat-sensitive TRP channel, Painless, to induce thermoregulatory response in cockroaches. Then, we evaluated the behavioural (thermal preferences and grooming), physiological (heart rate) and biochemical responses of insects to capsaicin, octopamine and phentolamine - octopaminergic receptor blocker. Capsaicin, similar to octopamine, increased cockroaches' grooming activity and heart rate. Moreover, octopamine level and protein kinase A (PKA) activity significantly increased after capsaicin treatment. Blocking octopaminergic receptors with phentolamine diminished cockroaches' response to capsaicin - thermoregulatory behaviour, grooming and heart rate were abolished. The results indicate that octopamine is a neurotransmitter secreted in insects after the activation of heat receptors.


Reading with central scotomas: is there a binocular gain?
The purpose of this study was to compare reading performance under binocular versus monocular viewing conditions in patients with bilateral age-related macular degeneration (AMD). Twenty-two patients with AMD participated. Distance acuity, reading acuity, and contrast sensitivity were recorded binocularly and monocularly with the better eye. An infrared eye tracker recorded eye movements during reading. Reading speed and reading eye movement parameters, including number of fixations and regressions, fixation duration, and number of saccades to find the next line, were calculated for both viewing conditions. The difference between binocular and monocular performance (binocular gain) was computed. Regression analysis was used to determine whether intraocular differences in distance and reading acuity and contrast sensitivity were predictive of binocular gain. Reading speed when using both eyes was highly correlated with the reading speed for the better eye. There was a small, but not significant, advantage of binocular viewing (6.9 words/minute, p = 0.33). No significant difference was detected in any eye movement parameters when comparing both eyes with the better eye. Although some patients showed either positive or negative binocular gain, the amount of gain was not predicted by intraocular differences in acuity or contrast sensitivity. Overall, there was no significant difference between binocular and monocular reading performance in patients with AMD.


Characterization of aggression-provoked renin from an unknown source in male mice.
1. In male mice without kidneys and submaxillary, as well as sublingual, glands aggressive behaviour causes a vast release of renin [J. Bing & K. Poulsen (1979) Acta Physiologica Scandinavica, 107, 251-256]. 2. This resulted in about an 800-fold increase in plasma renin concentration from the control level of 0.52 (range 0.15-0.8) Goldblatt unit (G.U.) x 10(-3)/ml to 430 (range 300-500) G.U. x 10(-3)/ml after aggression. 3. The aggression-provoked renin fulfil all the criteria so far studied for being active renin, identical with normal mouse plasma renin and pure submaxillary mouse renin. 4. It generates angiotensin I with renin substrate and Km (1.2 mumol/l) is the same. It is neutralized by pepstatin but not by inhibitors of metallo-, thiol and serine proteinases, indicating that it is an aspartate proteinase (acidic proteinase). 5. It is a 40 000-mol.wt. renin, which has full enzymatic activity with a specific enzymatic activity of 0.32 G.U./micrograms, identical with that of normal plasma renin. 6. Its enzymatic activity is neutralized by a specific antibody against pure submaxillary renin. It is measureable in the direct renin radioimmunoassay with a dilution curve which parallels that of the standards. It demonstrates complete antigenic identity with pure submaxillary renin in crossed immunoelectrophoresis. 7. Its origin is unknown.


Early predictors of bladder recovery and urodynamics after spinal cord injury.
Our purpose was to determine if intact perianal (S4-5) pin sensation (PPS) and bulbocavernosus (S2-4) reflex (BCR) shortly after spinal cord injury (SCI) are predictive of bladder function recovery. Twenty-eight SCI patients (aged 18-68 years, Frankel Classification A-D, spinal injury level C4-T12), admitted within 72 hours of injury, underwent evaluation of initial PPS and BCR. The presence of intact PPS and BCR were correlated with the patient's voiding function and urodynamic evaluation results 1 year postinjury. Of the 28 patients within 72 hours of SCI, PPS was intact in 17 (60%) and absent in 11(40%), while 15 patients (54%) demonstrated a positive BCR and 13 (46%) did not. One year after SCI, no patient with absent PPS voided unassisted, while of the 17 patients with preserved PPS, 11 (65%) were voiding spontaneously. Of these 11 patients, urodynamic evaluation revealed detrusor areflexia in 1 (9%), normal detrusor function in 2 (18%), and detrusor hyperreflexia in 8 (73%), with 3 of these 8 patients (38%) also demonstrating detrusor-sphincter dyssynergia. At 1 year postinjury, only 2 of 13 patients (15%) with an absent BCR voided spontaneously, while 9 of 15 patients (60%) with an intact BCR were able to void. Although PPS and BCR are moderately sensitive in predicting the return of spontaneous voiding, they cannot predict detrusor hyperreflexia and sphincter dyssynergia. Therefore, urodynamic study remains an essential component of initial urologic evaluation after SCI.


Renal pathology in pre-eclampsia.
Pre-eclampsia affects the kidney both functionally and morphologically. Renal haemodynamics decrease and urinary protein excretion increases, in part due to lesions affecting the glomerulus, where a combination of changes produces a characteristic appearance and permits differentiation of pre-eclamptic nephropathy from other glomerular alterations associated with hypertension in pregnancy. In pre-eclampsia the glomerulus is diffusely enlarged and bloodless, due not to proliferation, but to hypertrophy of the intracapillary cells. These alterations, best described ultrastructurally, include hypertrophy of the cytoplasmic organelles in endothelial and occasionally mesangial cells, particularly the lysosomes, which undergo marked enlargement and vacuolization (due to accumulation of free neutral lipids). These reactive changes have been termed 'glomerular capillary endotheliosis'. Other lesions, observed occasionally, include subendothelial and mesangial electron-dense deposits, as well as interposition of mesangial cell cytoplasm or mesangial matrix along an otherwise normal basement membrane. Some investigators have described immunohistological findings (presence of IgM, IgG and fibrin) which they believe specific for pre-eclampsia, and others have claimed the disease may cause focal segmental glomerulosclerosis (FSGS). We believe the immunohistological findings are non-specific and insudative, and that FSGS when present predates the pre-eclamptic complication. Finally, the renal lesions appear fully reversible and the disease has no remote cardiorenal effects on its patients.


Bone mineral density and the risk of breast cancer: the Rotterdam Study.
Estrogens play an important role in the development of breast cancer, but studies on serum levels of estrogens have shown inconsistent results. Bone mineral density is considered to be a marker for lifetime estrogen exposure. Some studies have suggested that a higher bone mass is associated with an increase in breast cancer risk. We investigated the association between bone mineral density (BMD), as measured at the lumbar spine and femoral neck, and the risk of breast cancer in women age 55 or older in the Rotterdam Study, a population-based cohort study in the Netherlands. Information on baseline lumbar spine and femoral neck BMD, as measured by DEXA (Lunar DPX-L), and cancer incidence was available for 3,107 women. The Rotterdam Cancer Registry provided information on follow-up of incident cancer. After an average follow-up time of 6.5 years, 74 new cases of breast cancer occurred. Z-scores of lumbar spine and femoral neck BMD were divided into tertiles and risk estimates for breast cancer were computed by the Cox proportional hazards model, using the middle tertile as a reference. Breast cancer risk in the upper tertile of lumbar spine BMD was doubled compared to the reference after adjustment for age, body mass index, and age at menopause (hazards ratio = 2.1 [1.1-3.7]), whereas risk estimates for women in the lower tertile did not significantly differ from the reference (hazards ratio = 1.5 [0.8-2.9]). Women with either a low intertrochanteric or femoral neck BMD appeared to have a somewhat decreased breast cancer risk, although this was not statistically significant. The results of this study suggest that in elderly women an association between especially lumbar spine BMD and incident breast cancer exists. Stimulating effects of estrogen on both trabecular bone and mammary cells may be responsible.


BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension (2017 Grover Conference Series).
Despite the discovery more than 15 years ago that patients with hereditary pulmonary arterial hypertension (HPAH) inherit BMP type 2 receptor ( BMPR2) mutations, it is still unclear how these mutations cause disease. In part, this is attributable to the rarity of HPAH and difficulty obtaining tissue samples from patients with early disease. However, in addition, limitations to the approaches used to study the effects of BMPR2 mutations on the pulmonary vasculature have restricted our ability to determine how individual mutations give rise to progressive pulmonary vascular pathology in HPAH. The importance of understanding the mechanisms by which BMPR2 mutations cause disease in patients with HPAH is underscored by evidence that there is reduced BMPR2 expression in patients with other, more common, non-hereditary form of PAH, and that restoration of BMPR2 expression reverses established disease in experimental models of pulmonary hypertension. In this paper, we focus on the effects on endothelial function. We discuss some of the controversies and challenges that have faced investigators exploring the role of BMPR2 mutations in HPAH, focusing specifically on the effects different BMPR2 mutation have on endothelial function, and whether there are qualitative differences between different BMPR2 mutations. We discuss evidence that BMPR2 signaling regulates a number of responses that may account for endothelial abnormalities in HPAH and summarize limitations of the models that are used to study these effects. Finally, we discuss evidence that BMPR2-dependent effects on endothelial metabolism provides a unifying explanation for the many of the BMPR2 mutation-dependent effects that have been described in patients with HPAH.


Measurement of regional bronchial arterial blood flow and bronchovascular resistance in dogs.
Little is known about normal variations and control of bronchial blood flow and bronchovascular resistance. We have used the reference-flow technique and 15-microns-diameter microspheres to measure bronchial blood flow under physiological conditions. Dogs (n = 13) were anesthetized and ventilated, and their chests were opened. A ligature was placed loosely around the left main pulmonary artery, and the left atrium was cannulated. In six dogs three sets of microspheres were injected simultaneously into the left atrium, and in another seven dogs the three sets of microspheres were injected sequentially at 0.5-h intervals. Prior to each injection measurements of pulmonary arterial, left atrial, and aortic pressures, cardiac output, and blood gases were made. Five seconds after injection the left main pulmonary artery was transiently occluded to prevent recirculation. After the final injection, dogs were killed, the lungs were removed, and the parenchyma was stripped off the large and small airways of the left lung. Knowing the radioactivity in the trachea, bronchi, parenchyma, and in the reference flow blood and also the aortic and left atrial pressures, we calculated bronchial blood flow (ml X min-1 X g dry lung-1) and bronchovascular resistance (cmH2O X ml-1 X min X 100 g dry lung). Results showed that there were no significant differences between the three measurements of bronchial blood flow when microspheres were injected simultaneously or sequentially. Bronchial blood flow to the left lung was 0.4% of cardiac output; 55% of the total flow went to lung parenchyma and 45% to trachea and bronchi. Expressed as flow/g dry lung the greatest flow was to the airways.


Public Health Approach to Addressing the Needs of Children Affected by Congenital Zika Syndrome.
We have learned much about the short-term sequelae of congenital Zika virus (ZIKV) infection since the Centers for Disease Control and Prevention activated its ZIKV emergency response in January 2016. Nevertheless, gaps remain in our understanding of the full spectrum of adverse health outcomes related to congenital ZIKV infection and how to optimize health in those who are affected. To address the remaining knowledge gaps, support affected children so they can reach their full potential, and make the best use of available resources, a carefully planned public health approach in partnership with pediatric health care providers is needed. An essential step is to use population-based data captured through surveillance systems to describe congenital Zika syndrome. Another key step is using collected data to investigate why some children exhibit certain sequelae during infancy and beyond, whereas others do not, and to describe the clustering of anomalies and the timing of when these anomalies occur, among other research questions. The final critical step in the public health framework for congenital Zika syndrome is an intervention strategy with evidence-based best practices for longer-term monitoring and care. Adherence to recommended evaluation and management procedures for infants with possible congenital ZIKV infection, including for those with less obvious developmental and medical needs at birth, is essential. It will take many years to fully understand the effects of ZIKV on those who are congenitally infected; however, the lifetime medical and educational costs as well as the emotional impact on affected children and families are likely to be substantial.


Temporal evolution of concentration and microstructure of colloidal films during vertical drying: a lattice Boltzmann simulation study.
We study the temporal and structural development of colloid films during vertical drying using the lattice Boltzmann (LB) simulation. The dispersed particles moving in Brownian motion have excluded volume and hydrodynamic interactions in the film. The concentrated colloidal film formed by solvent evaporation is modeled as an uniaxial compression of colloids with a planar moving interface. The simulation studies are carried out over a wide range of Péclet number (Pe), the relative ratio between the evaporation rate and the diffusion rate of colloids. The results clearly demonstrate a temporal variation of colloid concentration as the evaporation rate increases. In the case of high Pe, the increase of colloid concentration in the top layer creates structural features that can be distinguished along the height of the film, and eventually can induce a large tensile stress in the layer. However, surprisingly, the colloids are maximally crystallized in the case of moderate Pe. The LB simulation results are further compared with those from previous studies of the Brownian Dynamics (BD) simulation and the continuum model for the evaporation film. The LB and BD results match well both at low and high Pe limits. The qualitatively significant differences between LB and BD simulations at a moderate Pe indicate that hydrodynamic interactions (HIs) play an important role in this Pe. The presence of HIs induces a greater reduction of diffusion than under geometrical restriction alone, and the effect is conspicuous when particles are driven both by diffusion and by advection.


Downregulated long noncoding RNA MEG3 is associated with poor prognosis and promotes cell proliferation in gastric cancer.
Long noncoding RNAs (lncRNAs) have emerged recently as major players in governing fundamental biological processes, and many of which are altered in expression and likely to have a functional role in tumorigenesis. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes a lncRNA associated with various human cancers. However, its biological role and clinical significance in gastric cancer development and progression are unknown. In this study, to investigate the lncRNA MEG3 expression in gastric cancer, quantitative reverse-transcription polymerase chain reaction was conducted. We found that MEG3 levels were markedly decreased in gastric cancer tissues compared with adjacent normal tissues. Its expression level was significantly correlated with TNM stages, depth of invasion, and tumor size. Moreover, patients with low levels of MEG3 expression had a relatively poor prognosis. Furthermore, knockdown of MEG3 expression by siRNA could promote cell proliferation, while ectopic expression of MEG3 inhibited cell proliferation, promoted cell apoptosis, and modulated p53 expression in gastric cancer cell lines. By 5-aza-CdR treatment, we also observed that MEG3 expression can be modulated by DNA methylation. Our findings present that MEG3 downexpression can be identified as a poor prognostic biomarker in gastric cancer and regulate cell proliferation and apoptosis in vitro.


The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo.
Despite recent advances in the development of novel therapies against castration-resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product, sphingosine-1-phosphate, can promote proliferation, drug resistance, angiogenesis, and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this first-in-class inhibitor in castration-resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor, while lysosomal acidification increased. ABC294640 also induced a greater than 3-fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides. In vivo, ABC294640 diminished the growth rate of TRAMP-C2 xenografts in syngeneic hosts and elevated dihydroceramides within tumors as visualized by MALDI imaging mass spectroscopy. The plasma of ABC294640-treated mice contained significantly higher levels of C16- and C24:1-ceramides (but not dihydro-C16-ceramide) compared with vehicle-treated mice. In summary, our results suggest that ABC294640 may reduce the proliferative capacity of castration-resistant prostate cancer cells through inhibition of both sphingosine kinase 2 and dihydroceramide desaturase, thereby providing a foundation for future exploration of this small-molecule inhibitor for the treatment of advanced disease.


Defensive spending on tap water substitutes: the value of reducing perceived health risks.
We examine factors that explain consumer spending on tap water substitutes using information from a national survey undertaken with a representative set of Canadian respondents. We develop a model to predict the percentage of households that undertake such spending for the purpose of reducing perceived health risks from tap water consumption. Using results from the model we estimate the magnitude of defensive expenditures to be over half a billion dollars (2010 US$) per year for Canada, as a whole. This is equivalent to approximately $48 per household per year or about $19 per person per year. Residents of Ontario, the province in which an Escherichia coli incident took place in 2000, have the highest willingness-to-pay of approximately $60 per household per year.


Interventions Targeting the Prescribing and Monitoring of Vancomycin for Hospitalized Patients: A Systematic Review Protocol.
Vancomycin remains one of our essential antibiotics after fifty years of treating serious infections such as methicillin-resistant Staphylococcus aureus. Vancomycin, unlike many other antibiotic agents, requires individualized dosing and monitoring of serum drug levels to ensure it is efficacious, to minimize toxicity, and to limit the development of antibiotic resistance. These issues have led to numerous vancomycin clinical practice guidelines being published in recent years including several key national guidelines. Significant resources are invested during the development of such guidelines; however, there is often little or no information about how such guidelines or other vancomycin practice improvement initiatives should be implemented. The aim of this systematic review is to identify and evaluate the effect of interventions using education, guideline implementation, and dissemination of educational resources that have sought to improve therapeutic drug monitoring and dosing of vancomycin. A systematic review of the literature will be conducted for RCTs and observational studies where a vancomycin guideline or practice improvement initiative has been implemented. Electronic databases to be searched are PubMed, Medline, CINAHL, EMBASE and the Cochrane Library of Systematic Reviews. The population will be patients who have had intravenous vancomycin prescribed and monitored in hospital. The interventions will be education, implementation of guidelines or protocols, dissemination of educational materials (printed or electronic) or multifaceted interventions of the above. The comparator will be patients who have had standard-care prescribing and monitoring of vancomycin. Outcomes will be changes in prescribing and ordering of vancomycin serum tests, and serum levels attained in patients as well as reported nephrotoxicity. Two reviewers will be involved in the quality assessment and extraction of data. The Scottish Intercollegiate Guidelines Network checklist for RCTs will be used. Studies that are not randomized will be assessed for quality using the validated ROBINS-I (risk of bias in non-randomized studies of interventions) tool. This systematic review will identify interventions that have been used to implement guidelines and clinical practice initiatives for vancomycin. The findings of this review may be informative to those involved with the implementation of vancomycin clinical practice guidelines. Systematic review registration: PROSPERO: CRD42016049147.


Bayesian nonparametric centered random effects models with variable selection.
In a linear mixed effects model, it is common practice to assume that the random effects follow a parametric distribution such as a normal distribution with mean zero. However, in the case of variable selection, substantial violation of the normality assumption can potentially impact the subset selection and result in poor interpretation and even incorrect results. In nonparametric random effects models, the random effects generally have a nonzero mean, which causes an identifiability problem for the fixed effects that are paired with the random effects. In this article, we focus on a Bayesian method for variable selection. We characterize the subject-specific random effects nonparametrically with a Dirichlet process and resolve the bias simultaneously. In particular, we propose flexible modeling of the conditional distribution of the random effects with changes across the predictor space. The approach is implemented using a stochastic search Gibbs sampler to identify subsets of fixed effects and random effects to be included in the model. Simulations are provided to evaluate and compare the performance of our approach to the existing ones. We then apply the new approach to a real data example, cross-country and interlaboratory rodent uterotrophic bioassay.


Eyasi Plateau Paleontological Expedition, Laetoli, Tanzania, fossil specimen database 1998-2005.
The Eyasi Plateau Paleontological Expedition (EPPE) Laetoli specimen database contains 13716 records of plant and animal fossils (ca. 28248 specimens) collected by EPPE field teams working at Laetoli, Tanzania between 1998 and 2005. This dataset is a digital version of the original hard-copy specimen catalog, and it documents the discovery, stratigraphic provenience and taxonomic diversity of Plio-Pleistocene fauna and flora in northern Tanzania between 4.4 Ma and >200 ka. Laetoli is renowned for the discovery of important hominin fossils, including the lectotype for Australopithecus afarensis, one of our early hominin ancestors, the first record of Paranthropus aethiopicus outside Kenya-Ethiopia, and an early record of our own species Homo sapiens. This database is one of the few publicly available palaeoanthropological fossil datasets and serves as an example for expanding open access to primary fossil occurrence data in palaeoanthropology. The taxonomic identifications appearing in this dataset are the original field identifications and are provisional. Any taxonomic analysis employing this dataset should refer to updated taxonomic identifications published by specialists.


Climate factors influencing coccidioidomycosis seasonality and outbreaks.
Although broad links between climatic factors and coccidioidomycosis have been established, the identification of simple and robust relationships linking climatic controls to seasonal timing and outbreaks of the disease has remained elusive. Using an adaptive data-oriented method for estimating date of exposure, in this article I analyze hypotheses linking climate and dust to fungal growth and dispersion, and evaluate their respective roles for Pima County, Arizona. Results confirm a strong bimodal disease seasonality that was suspected but not previously seen in reported data. Dispersion-related conditions are important predictors of coccidioidomycosis incidence during fall, winter, and the arid foresummer. However, precipitation during the normally arid foresummer 1.5-2 years before the season of exposure is the dominant predictor of the disease in all seasons, accounting for half of the overall variance. Cross-validated models combining antecedent and concurrent conditions explain 80% of the variance in coccidioidomycosis incidence. .


Iatrogenic dissection during neurointerventional procedures: a retrospective analysis.
Retrospective analysis of patients suffering iatrogenic dissection during neurointervention is reported. The circumstances surrounding the occurrence, early detection, clinical course and management options are discussed. 18 iatrogenic dissections over 11 years were retrospectively analyzed. Data were gathered from patient records, run sheets, morbidity records and imaging studies. All procedures were done by operators trained to operate according to institution standards. Total cases were 6981, with 3925 angiograms and 3056 interventions. Incidence was 0.26%, with 0.25% during diagnostic and 0.26% during intervention. 1031 pediatric cases had no dissections. Beyond 35 years, dissection rate increased to 0.35%. There was no difference between men and women. Carotid dissection was more common than vertebral. Most were minimal intimal tear (67%) and others flow limiting (33%). All cases were managed with heparin in the acute stage and later with aspirin and Plavix or Coumadin, except in two cases. Cases having >70% luminal narrowing with poor intracranial cross circulation were stented. None presented with neurologic deficits acutely or on follow-up. 94% of patients were followed for a variable period, with variable imaging modalities, being a retrospective study. Angiogram, MRI brain with MR angiography (MRA), Doppler ultrasonogram and CT angiograms were used for follow-up. There was good outcome in 94% of the followed-up cases. Iatrogenic dissection is a random event with a benign clinical course. Early detection and aggressive management result in excellent outcome. Angiography is the best modality to follow-up. Non-invasive imaging like MRI with MRA and duplex ultrasonography are good tools to follow dissections.


Alginate controls heartburn in patients with erosive and nonerosive reflux disease.
To evaluate the effect of a novel alginate-based compound, Faringel, in modifying reflux characteristics and controlling symptoms. In this prospective, open-label study, 40 patients reporting heartburn and regurgitation with proven reflux disease (i.e., positive impedance-pH test/evidence of erosive esophagitis at upper endoscopy) underwent 2 h impedance-pH testing after eating a refluxogenic meal. They were studied for 1 h under basal conditions and 1 h after taking 10 mL Faringel. In both sessions, measurements were obtained in right lateral and supine decubitus positions. Patients also completed a validated questionnaire consisting of a 2-item 5-point (0-4) Likert scale and a 10-cm visual analogue scale (VAS) in order to evaluate the efficacy of Faringel in symptom relief. Tolerability of the treatment was assessed using a 6-point Likert scale ranging from very good (1) to very poor (6). Faringel decreased significantly (P < 0.001), in both the right lateral and supine decubitus positions, esophageal acid exposure time [median 10 (25th-75th percentil 6-16) vs 5.8 (4-10) and 16 (11-19) vs 7.5 (5-11), respectively] and acid refluxes [5 (3-8) vs 1 (1-1) and 6 (4-8) vs 2 (1-2), respectively], but increased significantly (P < 0.01) the number of nonacid reflux events compared with baseline [2 (1-3) vs 3 (2-5) and 3 (2-4) vs 6 (3-8), respectively]. Percentage of proximal migration decreased in both decubitus positions (60% vs 32% and 64% vs 35%, respectively; P < 0.001). Faringel was significantly effective in controlling heartburn, based on both the Likert scale [3.1 (range 1-4) vs 0.9 (0-2); P < 0.001] and VAS score [7.1 (3-9.8) vs 2 (0.1-4.8); P < 0.001], but it had less success against regurgitation, based on both the Likert scale [2.6 (1-4) vs 2.2 (1-4); P = not significant (NS)] and VAS score [5.6 (2-9.6) vs 3.9 (1-8.8); P = NS]. Overall, the tolerability of Faringel was very good 5 (2-6), with only two patients reporting modest adverse events (i.e., nausea and bloating). Our findings demonstrate that Faringel is well-tolerated and effective in reducing heartburn by modifying esophageal acid exposure time, number of acid refluxes and their proximal migration.


Offspring sex preference in frontier America.
Analysis of the fertility histories of women born between 1850 and 1900, as given in the Utah Population Database (UPDB), reveals the effect of the number, as well as the sex composition, of previous children on birth-stopping and birth-spacing decisions. Specifically, agricultural and Church of Jesus Christ of Latter-day Saints (LDS) households—two sub-populations that might have placed different values on male and female children for economic, social, and/or cultural reasons—showed a distinct preference for male children, as expressed by birth stopping after the birth of a male child and shorter birth intervals in higher-parity births when most previous children were female. Remarkably, women in both the early "natural fertility" and the later contraceptive eras used spacing behavior to achieve a desired sex mix. Although the LDS population had relatively high fertility rates, it had the same preferences for male children as the non-LDS population did. Farmers, who presumably had a need for family labor, were more interested in the quantity than in the sex mix of their children.


Enhancement of light extraction efficiency of OLEDs using Si₃N₄-based optical scattering layer.
An optical scattering layer, consisting of a Si3N4 nano-pillar array and a spin-coated hydrogen silsesquioxane (HSQ) planarization layer, was introduced to an organic light-emitting diode (OLED) substrate to increase the out-coupling efficiency. After plasma enhanced chemical vapor deposition (PECVD) of the Si3N4 layer, the nano-pillar array was created using nanoimprint lithography and reactive ion etching. As the Si3N4 pillar array has a refractive index of 2.0, photons generated in the organic layer are scattered by the Si3N4 structures and thus have a higher chance of being emitted from the device. The spin-coated HSQ planarization layer produces a flat substrate, which is essential for depositing a uniform organic material layer and assuring the electric conductivity of the transparent conducting oxide (TCO) layer. In this study, Si3N4 nano-structures with a height of 100 or 300 nm were used to enhance the out-coupling efficiency of the OLED devices. Although the electrical conductivity of the TCO layer deposited on the light scattering layer was slightly degraded, the OLED devices formed with the light scattering layer exhibited a higher luminous power at given electrical power. Consequently, the use of a planarized 300-nm-thick Si3N4 layer increased the external quantum efficiency of the OLED device by 50% at 10,000 cd/m2 compared to the reference OLED device fabricated on a flat glass substrate.


Natural Products Combating Neurodegeneration: Parkinson's Disease.
Parkinson's disease (PD) is characterized by neurodegeneration and a progressive functional impairment of the midbrain nigral dopaminergic neurons. The cause remains unknown; however, several pathological processes and central factors, such as protein aggregation, mitochondrial dysfunction, iron accumulation, neuroinflammation and oxidative stress, have been reported. The current treatment method primarily targets symptoms by using anti-Parkinson drugs such as levodopa, carbidopa, dopamine (DA) agonists, monoamine oxidase type B inhibitors and anticholinergics to replace DA. When drug therapy is not satisfactory, surgical treatments are recommended. Unfortunately, the existing conventional strategies that target PD are associated with numerous side effects and possess an economic burden. Therefore, novel therapeutic approaches that regulate the pathways leading to neuronal death and dysfunction are necessary. For many years, nature has provided the primary resource for the discovery of potential therapeutic agents. Remarkably, many natural products from medicinal plants, fruits and vegetables have been demonstrated to be efficacious anti-Parkinson agents. These products possess neuroprotective properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding iron accumulation, protein misfolding and the maintenance of proteasomal degradation, as well as mitochondrial homeostasis. The aim of this review is to report the available anti-Parkinson agents based on natural products and delineate their therapeutic actions, which act on various pathways. Overall, this review emphasizes the types of natural products that are potential future resources in the treatment of PD as novel regimens or supplementary agents.


An in vitro assay using overexpressed yeast SRP demonstrates that cotranslational translocation is dependent upon the J-domain of Sec63p.
The signal recognition particle (SRP) is required for co-translational targeting of polypeptides to the endoplasmic reticulum (ER). Once at the membrane, the precursor interacts with a complex proteinaceous machinery that mediates its translocation across the bilayer. Genetic studies in yeast have identified a number of genes whose products are involved in this complex process. These mutants offer a potentially valuable resource with which to analyze the biochemical role played by each component in the pathway. However, such analyses have been hampered by the failure to reconstitute an efficient in vitro assay for SRP-dependent translocation. We report the construction of two multicopy vectors that allow overexpression of all seven gene products required to make SRP in the yeast Saccharomyces cerevisiae. The overexpressed subunits assemble into intact and functional SRP particles, and we further demonstrate that in vitro reconstitution of co-translational translocation is greatly enhanced using cytosol from the overexpression strain. We use this assay to demonstrate that Sec63p is required for co-translational translocation in vitro and specifically identify the "J-domain" of Sec63p as crucial for this pathway.


Effects of hydrogen-rich saline on aquaporin 1, 5 in septic rat lungs.
Aquaporin 1(AQP1) and AQP5 have an important role in eliminating extravascular lung water, an increase of which contributes to lung injury in patients with sepsis and its consequent mortality. It has been reported that hydrogen-rich saline (HRS) has protective effects against sepsis-related lung injury. In this study, we hypothesized that the protective effect occurred by preserving the expression of AQP1 and AQP5. To test this hypothesis, male Sprague-Dawley rats received intratracheal administration of lipopolysaccharide (LPS) followed by intraperitoneal injection of HRS. Lung function, wet-to-dry weight ratio, and histopathology scores were determined. The expression of AQP1 and AQP5 at the messenger RNA and protein levels, as well as the involved pathways, was explored by quantitative polymerase chain reaction and Western blot. LPS significantly impaired lung function and downregulated the expression of AQP1 and AQP5 in the rat lung, all of which were attenuated by HRS treatment. Moreover, HRS treatment inhibited LPS-induced activation of p38 mitogen-activated protein kinase and jun N-terminal kinase, which is associated with LPS-induced downregulation of AQP1 and AQP5.


The effects of two weeks of recombinant growth hormone administration on the response of IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP) during a single bout of high resistance exercise in resistance trained young men.
Recombinant human growth hormone (rhGH) is used by some athletes and body builders with the aim of enhancing performance, building muscle and improving physique. Detection of the misuse of rhGH has proved difficult for a number of reasons. One of these is the effect of preceding exercise. In this randomised, double blind placebo-controlled study, we determined the effects of rhGH administration in male amateur athletes on two candidate markers of rhGH abuse, IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP), following a bout of weightlifting exercise. Sixteen men entered a four-week general weight training programme to homogenise their activity profile. They then undertook repeated bouts of standardised leg press weightlifting exercise (AHRET-acute heavy resistance exercise test). Blood samples were taken before and up to one hour after the AHRET. After the first laboratory visit (Test 1), the subjects were randomly assigned to receive daily injections of either rhGH (0.1 IU kg(-1) day(-1)) or placebo for two weeks. The AHRET was repeated after the two-week dosing period (Test 2) and a further test was undertaken following a one-week washout (Test 3). There was no effect of exercise on either IGF-I or P-III-NP in any test. Both markers were markedly elevated at Test 2 (p<0.001), with P-III-NP remaining elevated at Test 3 in the GH administration group (p<0.05). Application of the GH-2000 discriminant function positively identified GH administration in 17 of 40 blood samples taken at Test 2 from the rhGH group and none from the placebo group. The data show that rhGH results in elevated levels of IGF-I and P-III-NP in well-trained individuals and that leg press weightlifting exercise does not affect these markers. The GH-2000 discriminant function identified four of eight subjects taking rhGH with no false positive results.


Exonuclease I of Saccharomyces cerevisiae functions in mitotic recombination in vivo and in vitro.
We previously described a 5'-3' exonuclease required for recombination in vitro between linear DNA molecules with overlapping homologous ends. This exonuclease, referred to as exonuclease I (Exo I), has been purified more than 300-fold from vegetatively grown cells and copurifies with a 42-kDa polypeptide. The activity is nonprocessive and acts preferentially on double-stranded DNA. The biochemical properties are quite similar to those of Schizosaccharomyces pombe Exo I. Extracts prepared from cells containing a mutation of the Saccharomyces cerevisiae EXO1 gene, a homolog of S. pombe exo1, had decreased in vitro recombination activity and when fractionated were found to lack the peak of activity corresponding to the 5'-3' exonuclease. The role of EXO1 on recombination in vivo was determined by measuring the rate of recombination in an exo1 strain containing a direct duplication of mutant ade2 genes and was reduced sixfold. These results indicate that EXO1 is required for recombination in vivo and in vitro in addition to its previously identified role in mismatch repair.


Temporal patterns and oscillatory voltage perturbation during an electrochemical process.
The response of electrodissolution dynamics of nickel in sulfuric acid electrolyte was studied and categorized using efficient signal processing techniques. Time-frequency and phase analysis revealed complex dynamical patterns in anodic currents observed in the system. These patterns which respond to three-dimensional changes in the electrolyte and surface conditions, have a multitude of spatio-temporal properties which proved sensitive to oscillatory voltage perturbations, allowing signal recognition through distinct response patterns. Experimental work included studies on identification of control parameters, characterization of subsequent temporal patterns and examination of system response to information in the form of oscillatory voltage perturbations. Various data processing and pattern recognition techniques revealed the complexity and dynamics of these distinctive responses, which illustrate the capacity of the system to store information, with varying memory lengths. These patterns can be recalled upon excitation with particular perturbation cues.


Merkel cell carcinoma with sarcomatous differentiation: is it a poor prognostic factor?
Poor prognostic factors in Merkel cell carcinoma include male sex, advanced stage at diagnosis, large tumor size (>5 mm), diffuse growth pattern, heavy lymphocytic infiltrate, and high mitotic rate. To date only six cases of Merkel cell carcinoma with sarcomatous or pseudosarcomatous differentiation and poor prognosis have been documented. We present a new case of Merkel cell carcinoma with sarcomatous differentiation. The immunohistochemical staining patterns reflected the morphologic differentiation of the epithelial and sarcomatous pattern. After two months of follow-up, there were no signs of local recurrence or metastases. In all cases of merkelomas with sarcomatous differentiation described to date, lymph node metastases have been found, except in the presented case. However, larger series of cases will be required to determine if sarcomatous differentiation represents another negative prognostic factor.


Effects of soft tissue mobilization (Rolfing pelvic lift) on parasympathetic tone in two age groups.
The effects of a soft tissue mobilization procedure, the Rolfing pelvic lift, on parasympathetic tone was studied in healthy adult men. Parasympathetic tone was assessed 1) by quantifying the amplitude of the respiratory sinus arrhythmia from the heart rate pattern and 2) by measuring heart rate. Heart rate patterns were assessed during the pelvic lift and during the durational touch and baseline control conditions. Two groups of healthy subjects were tested: Group 1 contained 20 subjects aged 26 to 41 years, and Group 2 contained 10 subjects aged 55 to 68 years. In Group 1, the pelvic lift elicited a somatovisceral-parasympathetic reflex characterized by a significant increase in parasympathetic tone relative to durational touch and baseline conditions. Group 2 did not exhibit a parasympathetic change during the pelvic lift. The results of this study contribute to our understanding of pelvic mobilization techniques and may help to explain why these techniques have been clinically successful in treating myofascial pain syndromes and other musculoskeletal dysfunctions characterized by reduced parasympathetic tone and excessive sympathetic activity.


Extraction, isolation and characterization of bioactive compounds from plants' extracts.
Natural products from medicinal plants, either as pure compounds or as standardized extracts, provide unlimited opportunities for new drug leads because of the unmatched availability of chemical diversity. Due to an increasing demand for chemical diversity in screening programs, seeking therapeutic drugs from natural products, interest particularly in edible plants has grown throughout the world. Botanicals and herbal preparations for medicinal usage contain various types of bioactive compounds. The focus of this paper is on the analytical methodologies, which include the extraction, isolation and characterization of active ingredients in botanicals and herbal preparations. The common problems and key challenges in the extraction, isolation and characterization of active ingredients in botanicals and herbal preparations are discussed. As extraction is the most important step in the analysis of constituents present in botanicals and herbal preparations, the strengths and weaknesses of different extraction techniques are discussed. The analysis of bioactive compounds present in the plant extracts involving the applications of common phytochemical screening assays, chromatographic techniques such as HPLC and, TLC as well as non-chromatographic techniques such as immunoassay and Fourier Transform Infra Red (FTIR) are discussed.


Salivary Clear Cell Carcinoma Clinicopathologic Characteristics and Outcomes: A Population-Based Analysis.
Salivary clear cell carcinoma is an uncommon, low-grade malignancy for which limited data describing predictive clinicopathologic factors and treatment outcomes exist because of rarity. The authors queried the Surveillance, Epidemiology, and End Results database from 1982 to 2014. Multivariate Cox and Kaplan-Meier analyses were performed to determine disease-specific survival (DSS) and predictive clinicopathologic factors. One hundred ninety-eight patients with salivary clear cell carcinoma were included. Overall incidence was 0.011 per 100 000 individuals, with no significant annual percentage change across years (-0.93%, P = .632). Five-, 10-, and 20-year DSS rates were 81.3% (n = 117), 69.6% (n = 94), and 55.3% (n = 68), respectively. Men (hazard ratio, 4.74; P = .0087) and patients with regional (hazard ratio, 5.59; P = .018) or distant (hazard ratio, 8.9; P = .01) metastases carried a worse prognosis. Five-year DSS was greater in patients with localized disease (96.36%, P < .0001) than those with regional or distant metastases. Treatment with surgery alone had better 10-year DSS (86.3%) compared with treatment with combination radiation and surgery (57.6%) or radiation monotherapy (18.75%, P < .0001). Salivary clear cell carcinoma carries an overall good prognosis. Patients with localized disease and those treated with surgery alone have more favorable prognoses. Male patients and those with regional or distant metastatic disease at time of presentation carry a worse prognosis. N/A.


Spatiotemporal Epidemiology of Tuberculosis in Thailand from 2011 to 2020.
Tuberculosis is a leading cause of infectious disease globally, especially in developing countries. Better knowledge of spatial and temporal patterns of tuberculosis burden is important for effective control programs as well as informing resource and budget allocation. Studies have demonstrated that TB exhibits highly complex dynamics in both spatial and temporal dimensions at different levels. In Thailand, TB research has been primarily focused on surveys and clinical aspects of the disease burden with little attention on spatiotemporal heterogeneity. This study aimed to describe temporal trends and spatial patterns of TB incidence and mortality in Thailand from 2011 to 2020. Monthly TB case and death notification data were aggregated at the provincial level. Age-standardized incidence and mortality were calculated; time series and global and local clustering analyses were performed for the whole country. There was an overall decreasing trend with seasonal peaks in the winter. There was spatial heterogeneity with disease clusters in many regions, especially along international borders, suggesting that population movement and socioeconomic variables might affect the spatiotemporal distribution in Thailand. Understanding the space-time distribution of TB is useful for planning targeted disease control program activities. This is particularly important in low- and middle-income countries including Thailand to help prioritize allocation of limited resources.


A novel granulocyte-derived peptide with lipopolysaccharide-neutralizing activity.
Rabbit CAP18 (cationic antimicrobial protein, 18 kDa) is a leukocyte protein identified and purified using as an assay its capacity to bind and inhibit various activities of LPS. Oligonucleotide probes designed from the putative N-terminal protein sequence were used to obtain the corresponding cDNA from a rabbit bone marrow cDNA library. Examination of the cDNA sequence revealed that the protein fragment of the putative N-terminus was actually a 37-amino-acid C-terminal fragment. This fragment, designated CAP18(106-142), inhibits many activities of LPS. In the present studies, synthetic CAP18(106-142) is shown to: 1) bind to erythrocytes coated with diverse strains of LPS; 2) inhibit LPS-induced release of cytokines (TNF, IL-1, IL-6) and nitric oxide from macrophages; 3) inhibit LPS-induced LAL coagulation and 4) protect mice from LPS lethality. CAP18(106-142) may have therapeutic utility for conditions associated with elevated concentrations of LPS.


Peripheral artery disease, calf skeletal muscle mitochondrial DNA copy number, and functional performance.
In people without lower extremity peripheral artery disease (PAD), mitochondrial DNA copy number declines with aging, and this decline is associated with declines in mitochondrial activity and functional performance. However, whether lower extremity ischemia is associated with lower mitochondrial DNA copy number and whether mitochondrial DNA copy number is associated with the degree of functional impairment in people with PAD is unknown. In people with and without PAD, age 65 years and older, we studied associations of the ankle-brachial index (ABI) with mitochondrial DNA copy number and associations of mitochondrial DNA copy number with functional impairment. Calf muscle biopsies were obtained from 34 participants with PAD (mean age: 73.5 years (SD 6.4), mean ABI: 0.67 (SD 0.15), mean 6-minute walk distance: 1191 feet (SD 223)) and 10 controls without PAD (mean age: 73.1 years (SD 4.7), mean ABI: 1.14 (SD 0.07), mean 6-minute walk distance: 1387 feet (SD 488)). Adjusting for age and sex, lower ABI values were associated with higher mitochondrial DNA copy number, measured in relative copy number (ABI<0.60: 914, ABI 0.60-0.90: 731, ABI 0.90-1.50: 593; p trend=0.016). The association of mitochondrial DNA copy number with the 6-minute walk distance and 4-meter walking velocity differed significantly between participants with versus without PAD ( p-value for interaction=0.001 and p=0.015, respectively). The correlation coefficient between mitochondrial DNA copy number and the 6-minute walk distance was 0.653 ( p=0.056) among people without PAD and -0.254 ( p=0.154) among people with PAD and ABI < 0.90. In conclusion, lower ABI values are associated with increased mitochondrial DNA copy number. Associations of mitochondrial DNA copy number with the 6-minute walk distance and 4-meter walking velocity significantly differed between people with versus without PAD, with stronger positive associations observed in people without PAD than in people with PAD. The cross-sectional and exploratory nature of the analyses precludes conclusions regarding causal inferences. ClinicalTrials.gov Identifier: NCT02246660.


Inspiratory muscle training lowers the oxygen cost of voluntary hyperpnea.
The purpose of this study was to determine if inspiratory muscle training (IMT) alters the oxygen cost of breathing (Vo(2RM)) during voluntary hyperpnea. Sixteen male cyclists completed 6 wk of IMT using an inspiratory load of 50% (IMT) or 15% placebo (CON) of maximal inspiratory pressure (Pi(max)). Prior to training, a maximal incremental cycle ergometer test was performed to determine Vo(2) and ventilation (V(E)) at multiple workloads. Pre- and post-training, subjects performed three separate 4-min bouts of voluntary eucapnic hyperpnea (mimic), matching V(E) that occurred at 50, 75, and 100% of Vo(2 max). Pi(max) was significantly increased (P < 0.05) by 22.5 ± 8.7% from pre- to post-IMT and remained unchanged in the CON group. The Vo(2RM) required during the mimic trial corresponded to 5.1 ± 2.5, 5.7 ± 1.4, and 11.7% ± 2.5% of the total Vo(2) (Vo(2T)) at ventilatory workloads equivalent to 50, 75, and 100% of Vo(2 max), respectively. Following IMT, the Vo(2RM) requirement significantly decreased (P < 0.05) by 1.5% (4.2 ± 1.4% of Vo(2T)) at 75% Vo(2 max) and 3.4% (8.1 ± 3.5% of Vo(2T)) at 100% Vo(2 max). No significant changes were shown in the CON group. IMT significantly reduced the O(2) cost of voluntary hyperpnea, which suggests that a reduction in the O(2) requirement of the respiratory muscles following a period of IMT may facilitate increased O(2) availability to the active muscles during exercise. These data suggest that IMT may reduce the O(2) cost of ventilation during exercise, providing an insight into mechanism(s) underpinning the reported improvements in whole body endurance performance; however, this awaits further investigation.


Chronic choline supplementation improves cognitive and motor performance via modulating oxidative and neurochemical status in rats.
Choline, an essential nutrient, accounts for multiple functions in the body and brain. While its beneficial effects on healthy adults are not clear, choline supplementation is important during pregnancy for brain development, in elderly patients for support of cognitive performance and in patients with neurological disorders to reduce memory deficits. Thus, the aim of this study is to investigate whether choline administration in healthy adult rats beneficially impacts cognitive and locomotor performance, and associated oxidative and neurochemical outcomes. Two groups, control and choline, received tap water and choline bitartrate, respectively at the dose equivalent to adequate intake for five weeks. Food intake and body weight were monitored daily. Behavioral analysis comprising assessment of cognitive performance (by novel object recognition, passive avoidance and Morris Water Maze test) and locomotor performance (by Open field, Kondziela's inverted screen and beam walking test) were performed. Following testing, rats were decapitated and brain samples were collected for estimation of acetylcholine, redox profile and monoamine measurements. The results showed that chronic choline administration significantly improves cognitive and locomotor performance accompanied by a reduction in oxidative stress, enhanced cholinergic neurotransmission and monoamine levels in the brain of healthy adult rats. Hence, chronic choline intake was found to improve behavioral, oxidative and neurochemical outcomes in the normal population, so it can be suggested that choline tablets can be used as a safe and effective supplement for improving the neurological health of normal individuals and that they might also be beneficial in preventing cognitive and motor disorders later in life.


The impact of smoking and other substance use by urban women on the birthweight of their infants.
The impact of maternal smoking and other substance use during pregnancy on infant birthweight is demonstrated in a sample of 766 urban women, using data collected in the Washington, D.C. Metropolitan Area Drug Study (DC*MADS). Women residing and giving birth in the District of Columbia were interviewed in 1992. A multivariable linear regression model was used to quantify the association between birthweight and the mother's use of cigarettes, alcohol, or illicit drugs during pregnancy, while controlling for possible confounding variables. The analysis focused on factors, including prenatal care and substance use during pregnancy that may contribute to low birthweight infants born to this sample of urban, predominantly black women. A woman's use of cigarettes, marijuana, and heroin during pregnancy was related to infant birthweight, but her use of alcohol and cocaine during pregnancy was not significantly related. Smoking during pregnancy was a strong predictor for low birthweight, suggesting that targeting more smoking cessation programs for pregnant women, particularly those who may also be illicit drug users, could help reduce adverse health consequences for low birthweight infants.


[Analysis of the work process in health research laboratories: a proposal for investigation]
This article presents a proposal for analyzing the work process involved in building technoscientific knowledge in the health field, focusing on the work developed by research laboratory technicians in the Oswaldo Cruz Foundation. Beginning with an in-depth description of the technicians' laboratory activities, we discuss the relationship between the various stages of work and the different actors, the technicians' value as actors in the process of building knowledge, and various actors' perceptions of how essential this work is. We attempt to outline the context in which the work processes in health sciences laboratories were incorporated into an analysis of the work process in health. By establishing a dialogue with the sociology of science, we present our proposal as an attempt to introduce new social sciences approaches for analyzing the work process, specifically as applicable to an analysis of work in the health field.


Acute Administration of Methionine Affects Performance of Swiss Mice in Learning and Memory Paradigms.
Methionine, an essential amino acid, plays an essential role in the central nervous system CNS development. It serves as a crucial intermediate in the methylation, trans-sulfuration and amino- phosphorylationpathways,necessary for the synthesis of nucleic acids, phospholipids, hormones, neurotransmitters, antioxidants, polyamines, catecholamines and other biogenic amines. The effect of methionine on learning and memory in mice was investigated using Morris water maze (MWM), Elevated plus maze(EPM) and Y maze (YM). Animals were administered with distilled water (control), methionine (1,700mg/kg); folate (3mg/kg) or methionine (1700mg/kg) plus folate (3mg/kg) for 14 days. Escape latency and time spent in target quadrants; transfer latency and percentage spontaneous alternations were measured in the MWM, EPM and YM respectively. The animals were anaesthetized with inhalational chloroform and their brains subsequently harvested, homogenized and assayed for acetylcholinesterase24 hours after the experiment.Folate significantly(p<0.05) increased transfer latency (53.33 ± 12.62) as compared to control (20.1 ± 5.01) and reduced spontaneous alternations significantly (25.0 ± 8.9) when compared to control (44.33 ± 3.07). When folate was combined with methionine there was also a significant increase in transfer latency (43.0 ± 14.39) when compared with control (20.1 ± 5.01). Folate-methionine combination also significantly reduced spontaneous alternations (20.4 ± 8.4) as compared to the control (44.33 ± 3.07) much more than folate alone. Acetylcholinesterase activities in all groups were not statistically significant. It can be concluded that acute methionine administration has some benefits in memory enhancement. However, a short course folate supplementation impairslearning and working memory especially when combined with methioninewhich may be as a result of sudden overwhelming of the methylation cycle, leading to homocysteinemia which is pro-dementia.


Cannabis use before age 15 and subsequent executive functioning.
Many studies have suggested that adolescence is a period of particular vulnerability to neurocognitive effects associated with substance misuse. However, few large studies have measured differences in cognitive performance between chronic cannabis users who started in early adolescence (before age 15) with those who started later. To examine the executive functioning of individuals who started chronic cannabis use before age 15 compared with those who started chronic cannabis use after 15 and controls. We evaluated the performance of 104 chronic cannabis users (49 early-onset users and 55 late-onset users) and 44 controls who undertook neuropsychological tasks, with a focus on executive functioning. Comparisons involving neuropsychological measures were performed using generalised linear model analysis of variance (ANOVA). The early-onset group showed significantly poorer performance compared with the controls and the late-onset group on tasks assessing sustained attention, impulse control and executive functioning. Early-onset chronic cannabis users exhibited poorer cognitive performance than controls and late-onset users in executive functioning. Chronic cannabis use, when started before age 15, may have more deleterious effects on neurocognitive functioning.


Brain anomalies in children exposed prenatally to a common organophosphate pesticide.
Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9-11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure × IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose-response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain.


Possible seizure suppression via deep brain stimulation of the thalamic ventralis oralis posterior nucleus.
Surgical treatment of intractable epilepsy with deep brain stimulation (DBS) has been shown to be of therapeutic benefit in some patients and with the recent publication of a randomised control study its use is likely to increase in the future. We describe a patient who developed a focal epileptic seizure within a few seconds of momentarily turning off the DBS stimulator in the nucleus ventralis oralis posterior, with which she was successfully treated for tremor. The seizure was the result of a newly diagnosed primary brain tumor. We suggest that the nucleus ventralis oralis posterior may be another thalamic target of DBS in epilepsy.


Tissue specificity of enzyme expression regulated by diffusible factors: evidence in Drosophila hybrids.
Pairs of hybridizable species of Hawaiian picture-winged Drosophila differ qualitatively in the distributions of specific enzymes in their tissues. An examination of the patterns of enzyme expression in the hybrids showed that, in three instances, absence of an enzyme from a specific tissue was dominant to presence. Since other developmental features indicated that both parental genomes were functioning, these results suggest that, in these cases, the pattern differences in the parental species were due to diffusible factors that affected expression of the relevant structural genes rather than to differences in the genes themselves or in cis-acting regulatory sites.


Alterations in source-sink patterns by modifications of source strength.
Bean plants, trimmed to a simplified "double source, double sink" translocation system (the paired primary leaves serving as the double source and the paired lateral leaflets of the immature first trifoliate leaf as the double sink) were used to study the magnitude and short-term time course of change in the allocation ratio (partition ratio) of assimilates translocated from the labeled primary leaf to its respective "near" and "far leaflet" sinks in response to an increase or decrease in the source strength of the opposite primary leaf (the "control" leaf). If the rates of net photosynthesis in the two primary leaves were similar, assimilates from the labeled source leaf partitioned to the leaflet sinks in the ratio of 5:1 or higher, the dominant sink being the leaflet "nearer" to the labeled source leaf. If the rate of net photosynthesis in the control leaf was increased substantially above that of the labeled source leaf, the rate of translocation from the labeled source to either the near leaflet sink or far leaflet sink remained unaffected, despite, presumably, a higher translocation rate from the control leaf, and hence a higher phloem pressure gradient (or increased cross-sectional area) in the transport pathway from the control leaf to the leaflet sinks. If the control leaf was excised, thus reducing the source leaf area by about a half, the translocation rate from the remaining source leaf rapidly doubled, the partition ratio becoming equal to unity. If the control leaf was darkened, the partition ratio adjusted to an intermediate value. Although export rates from the labeled source leaf were increased either by excising or darkening the control leaf, the rate of net photosynthesis in the labeled leaf remained constant.


Review of the medicinal effects of tualang honey and a comparison with manuka honey.
Tualang honey (TH) is a Malaysian multifloral jungle honey. In recent years, there has been a marked increase in the number of studies published in medical databases regarding its potential health benefits. The honey is produced by the rock bee (Apis dorsata), which builds hives on branches of tall Tualang trees located mainly in the north-western region of Peninsular Malaysia. This review collates the results of the various studies of TH that range from research on tissue culture to randomised control clinical trials. Findings thus far show that, TH has antimicrobial, anti-inflammatory, antioxidant, antimutagenic, antitumor, and antidiabetic properties, in addition to wound-healing attributes. Some of its properties are similar to the well-researched Manuka honey (New Zealand and/or Australian monofloral honey). Distinct differences include higher phenolics, flavonoids, and 5-(hydroxymethyl) furfural (HMF). Compared with Manuka honey, TH is also more effective against some gram-negative bacterial strains in burn wounds.


Patient Satisfaction with In-Home Telerehabilitation After Total Knee Arthroplasty: Results from a Randomized Controlled Trial.
Background and Introduction: Telerehabilitation after total knee arthroplasty (TKA) is supported by strong evidence on the effectiveness of such intervention and from a cost-benefit point of view. Satisfaction of patients toward in-home telerehabilitation after TKA has not yet been examined thoroughly in large-scale clinical trials. This study aims to compare satisfaction level of patients following in-home telerehabilitation (TELE) after TKA to one of the patients following a usual face-to-face home visit (STD) rehabilitation. Secondarily, to determine if any clinical or personal variables were associated to the level of satisfaction. This study was embedded in a multicenter randomized controlled trial with 205 patients randomized into two groups. Rehabilitation intervention was the same for both groups; only approach for service delivery differed (telerehabilitation or home visits). Participants were assessed at baseline (before TKA), at hospital discharge, and at 2 and 4 months postdischarge (E4) using functional outcomes. Patient satisfaction was measured using the validated Health Care Satisfaction Questionnaire (HCSQ) at E4. Characteristics of all participants were similar at baseline. Satisfaction level of both groups did not differ and was very high (over 85%). It was neither correlated to personal characteristics nor to improvements of functional level from preoperative to E4. Satisfaction was rather found associated to walking and stair-climbing performances. These results, in conjunction with evidences of clinical effectiveness and cost benefits demonstrated in the same sample of patients, strongly support the use of telerehabilitation to improve access to rehabilitation services and efficiency of service delivery after TKA.


Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2.
The segregation of COL1A1 and COL1A2, the two genes which encode the chains of type I collagen, was analyzed in 38 dominant osteogenesis imperfecta (OI) pedigrees by using polymorphic markers within or close to the genes. This was done in order to estimate the consistency of linkage of OI genes to these two loci. None of the 38 pedigrees showed evidence of recombination between the OI gene and both collagen loci, suggesting that the frequency of unlinked loci in the population must be low. From these results, approximate 95% confidence limits for the proportion of families linked to the type I collagen genes can be set between .91 and 1.00. This is high enough to base prenatal diagnosis of dominantly inherited OI on linkage to these genes even in families which are too small for the linkage to be independently confirmed to high levels of significance. When phenotypic features were compared with the concordant collagen locus, all eight pedigrees with Sillence OI type IV segregated with COL1A2. On the other hand, Sillence OI type I segregated with both COL1A1 (17 pedigrees) and COL1A2 (7 pedigrees). The concordant locus was uncertain in the remaining six OI type I pedigrees. Of several other features, the presence or absence of presenile hearing loss was the best predictor of the mutant locus in OI type I families, with 13 of the 17 COL1A1 segregants and none of the 7 COL1A2 segregants showing this feature.


Typing of group A streptococci by random amplified polymorphic DNA analysis.
Random amplified polymorphic DNA (RAPD) analysis was evaluated in comparison with restriction endonuclease analysis (REA) of genomic DNA and serotyping in the typing of 160 epidemiologically unrelated group A streptococci (GAS). Amplification of genomic DNA of GAS was performed with a single primer with an arbitrarily selected nucleotide sequence of 12 nucleotides. In total, 31 RAPD patterns and 15 REA patterns were observed among the isolates studied. The results of RAPD analysis were in accordance with the results of REA for 86% of the isolates, as both methods identified 15 different strains among 138 isolates. However, RAPD analysis differentiated 16 additional strains among 22 isolates. RAPD analysis was somewhat better than REA for differentiation of isolates of the same and different serotypes. However, not all of the serotypes were differentiated by RAPD analysis either. In conclusion, RAPD analysis provides a practical alternative for genomic typing of GAS. It can be recommended for the typing of GAS, especially if used in parallel with serotyping.


A randomised trial of the effect and cost-effectiveness of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with screen-detected type 2 diabetes: the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION-Europe) study.
Intensive treatment (IT) of cardiovascular risk factors can halve mortality among people with established type 2 diabetes but the effects of treatment earlier in the disease trajectory are uncertain. To quantify the cost-effectiveness of intensive multifactorial treatment of screen-detected diabetes. Pragmatic, multicentre, cluster-randomised, parallel-group trial. Three hundred and forty-three general practices in Denmark, the Netherlands, and Cambridge and Leicester, UK. Individuals aged 40-69 years with screen-detected diabetes. Screening plus routine care (RC) according to national guidelines or IT comprising screening and promotion of target-driven intensive management (medication and promotion of healthy lifestyles) of hyperglycaemia, blood pressure and cholesterol. The primary end point was a composite of first cardiovascular event (cardiovascular mortality/morbidity, revascularisation and non-traumatic amputation) during a mean [standard deviation (SD)] follow-up of 5.3 (1.6) years. Secondary end points were (1) all-cause mortality; (2) microvascular outcomes (kidney function, retinopathy and peripheral neuropathy); and (3) patient-reported outcomes (health status, well-being, quality of life, treatment satisfaction). Economic analyses estimated mean costs (UK 2009/10 prices) and quality-adjusted life-years from an NHS perspective. We extrapolated data to 30 years using the UK Prospective Diabetes Study outcomes model [version 1.3; (©) Isis Innovation Ltd 2010; see www.dtu.ox.ac.uk/outcomesmodel (accessed 27 January 2016)]. We included 3055 (RC, n = 1377; IT, n = 1678) of the 3057 recruited patients [mean (SD) age 60.3 (6.9) years] in intention-to-treat analyses. Prescription of glucose-lowering, antihypertensive and lipid-lowering medication increased in both groups, more so in the IT group than in the RC group. There were clinically important improvements in cardiovascular risk factors in both study groups. Modest but statistically significant differences between groups in reduction in glycated haemoglobin (HbA1c) levels, blood pressure and cholesterol favoured the IT group. The incidence of first cardiovascular event [IT 7.2%, 13.5 per 1000 person-years; RC 8.5%, 15.9 per 1000 person-years; hazard ratio 0.83, 95% confidence interval (CI) 0.65 to 1.05] and all-cause mortality (IT 6.2%, 11.6 per 1000 person-years; RC 6.7%, 12.5 per 1000 person-years; hazard ratio 0.91, 95% CI 0.69 to 1.21) did not differ between groups. At 5 years, albuminuria was present in 22.7% and 24.4% of participants in the IT and RC groups, respectively [odds ratio (OR) 0.87, 95% CI 0.72 to 1.07), retinopathy in 10.2% and 12.1%, respectively (OR 0.84, 95% CI 0.64 to 1.10), and neuropathy in 4.9% and 5.9% (OR 0.95, 95% CI 0.68 to 1.34), respectively. The estimated glomerular filtration rate increased between baseline and follow-up in both groups (IT 4.31 ml/minute; RC 6.44 ml/minute). Health status, well-being, diabetes-specific quality of life and treatment satisfaction did not differ between the groups. The intervention cost £981 per patient and was not cost-effective at costs ≥ £631 per patient. Compared with RC, IT was associated with modest increases in prescribed treatment, reduced levels of risk factors and non-significant reductions in cardiovascular events, microvascular complications and death over 5 years. IT did not adversely affect patient-reported outcomes. IT was not cost-effective but might be if delivered at a reduced cost. The lower than expected event rate, heterogeneity of intervention delivery between centres and improvements in general practice diabetes care limited the achievable differences in treatment between groups. Further follow-up to assess the legacy effects of early IT is warranted. ClinicalTrials.gov NCT00237549. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 64. See the NIHR Journals Library website for further project information.


Chasing Jenner's vaccine: revisiting cowpox virus classification.
Cowpox virus (CPXV) is described as the source of the first vaccine used to prevent the onset and spread of an infectious disease. It is one of the earliest described members of the genus Orthopoxvirus, which includes the viruses that cause smallpox and monkeypox in humans. Both the historic and current literature describe "cowpox" as a disease with a single etiologic agent. Genotypic data presented herein indicate that CPXV is not a single species, but a composite of several (up to 5) species that can infect cows, humans, and other animals. The practice of naming agents after the host in which the resultant disease manifests obfuscates the true taxonomic relationships of "cowpox" isolates. These data support the elevation of as many as four new species within the traditional "cowpox" group and suggest that both wild and modern vaccine strains of Vaccinia virus are most closely related to CPXV of continental Europe rather than the United Kingdom, the homeland of the vaccine.


When is it appropriate to stop non-vitamin K antagonist oral anticoagulants before catheter ablation of atrial fibrillation? A multicentre prospective randomized study.
Although a recent expert consensus statement has recommended periprocedural uninterrupted (UI) non-vitamin K antagonist oral anticoagulants (NOACs) during catheter ablation of atrial fibrillation (AF) as a Class I indication, there have been no clear randomized trials. We investigated the safety and efficacy of UI, procedure day single-dose skipped (SDS), and 24-hour skipped (24S) NOACs in patients undergoing AF ablation. In this prospective, open-label, randomized multicentre trial, 326 patients (75% male, 58 ± 11 years old) scheduled for AF catheter ablation were randomly assigned in a 1:1:1 ratio to UI, SDS, and 24S at three tertiary hospitals. Bridging with low molecular weight heparin was carried out in the patients with persistent AF who were assigned to the 24S group. Dabigatran, rivaroxaban, and apixaban were assigned in order after randomization. The primary endpoint was the incidence of bleeding events within 1 month after ablation. The secondary endpoints included thrombo-embolic and other procedure-related complications. The intra-procedural heparin requirement was higher in the 24S group than others (P < 0.001), and the mean activated clotting time was comparable among the groups (P = 0.139). The incidence of major bleeding up to 1 month after ablation and a post-procedural reduction in the haemoglobin levels did not significantly differ among the treatment groups and different NOACs (P > 0.05). There were no fatal events or thrombo-embolic complications in all the three groups. In patients undergoing AF ablation, UI NOACs and SDS or double dose skipped NOACs had a comparable efficacy and safety, regardless of the type of NOAC.


Development of a multilocus sequence typing tool for high-resolution genotyping of Enterocytozoon bieneusi.
Thus far, genotyping of Enterocytozoon bieneusi has been based solely on DNA sequence analysis of the internal transcribed spacer (ITS) of the rRNA gene. Both host-adapted and zoonotic (human-pathogenic) genotypes of E. bieneusi have been identified. In this study, we searched for microsatellite and minisatellite sequences in the whole-genome sequence database of E. bieneusi isolate H348. Seven potential targets (MS1 to MS7) were identified. Testing of the seven targets by PCR using two human-pathogenic E. bieneusi genotypes (A and Peru10) led to the selection of four targets (MS1, MS3, MS4, and MS7). Further analysis of the four loci with an additional 24 specimens of both host-adapted and zoonotic E. bieneusi genotypes indicated that most host-adapted genotypes were not amplified by PCR targeting these loci. In contrast, 10 or 11 of the 13 specimens of the zoonotic genotypes were amplified by PCR at each locus. Altogether, 12, 8, 7, and 11 genotypes of were identified at MS1, MS3, MS4, and MS7, respectively. Phylogenetic analysis of the nucleotide sequences obtained produced a genetic relationship that was similar to the one at the ITS locus, with the formation of a large group of zoonotic genotypes that included most E. bieneusi genotypes in humans. Thus, a multilocus sequence typing tool was developed for high-resolution genotyping of E. bieneusi. Data obtained in the study should also have implications for understanding the taxonomy of Enterocytozoon spp., the public health significance of E. bieneusi in animals, and the sources of human E. bieneusi infections.


Schistosomiasis in women: manifestations in the upper reproductive tract.
Female genital schistosomiasis (FGS) is a neglected disease entity which may give rise to considerable suffering among women of child-bearing age in areas where schistosomiasis (especially due to Schistosoma haematobium) is prevalent. The close relation between the vessels in genital organs and the urinary bladder enables the parasite to easily change location to virtually any organs in the female pelvic area. Symptoms concur with the anatomical location of worm pairs and their ova. Lesions of the lower female genital tract can easily be investigated by cytology, histology or direct demonstration of eggs in scrapings or biopsies whereas schistosomiasis of the upper genital tract is clinically indecipherable and less accessible for examination. In the literature there are references to FGS as a cause of infertility, complications of pregnancy, menstrual disorders, problems related to sexual intercourse, diagnostic similarities to STDs and cancer, unspecified complaints related to blood loss, chronic abdominal pain, social segregation and related psychological problems. The diagnosis of female upper genital schistosomiasis is difficult and the authors point out possible diagnostic procedures which might be helpful for further understanding of this complex entity.


OligoArray 2.0: design of oligonucleotide probes for DNA microarrays using a thermodynamic approach.
There is a substantial interest in implementing bioinformatics technologies that allow the design of oligonucleotides to support the development of microarrays made from short synthetic DNA fragments spotted or in situ synthesized on slides. Ideally, such oligonucleotides should be totally specific to their respective targets to avoid any cross-hybridization and should not form stable secondary structures that may interfere with the labeled probes during hybridization. We have developed OligoArray 2.0, a program that designs specific oligonucleotides at the genomic scale. It uses a thermodynamic approach to predict secondary structures and to calculate the specificity of targets on chips for a unique probe in a mixture of labeled probes. Furthermore, OligoArray 2.0 can adjust the oligonucleotide length, according to user input, to fit a narrow T(m) range compatible with hybridization requirements. Combined with on chip oligonucleotide synthesis, this program makes it feasible to perform expression analysis on a genomic scale for any organism for which the genome sequence is known. This is without relying on cDNA or oligonucleotide libraries. OligoArray 2.0 was used to design 75 764 oligonucleotides representing 26 140 transcripts from Arabidopsis thaliana. Among this set, we provide at least one specific oligonucleotide for 93% of these transcripts.


The effects of antidepressants appear to be rapid and at environmentally relevant concentrations.
The effects of antidepressants on wildlife are currently raising some concern because of an increased number of publications indicating biological effects at environmentally relevant concentrations (<100 ng/L). These results have been met with some scepticism because of the higher concentrations required to detect effects in some species and the perceived slowness to therapeutic effects recorded in humans and other vertebrates. Because their mode of action is thought to be by modulation of the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates that possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. The authors highlight studies on the effects of antidepressants, particularly on crustacean and molluskan groups, showing that they are susceptible to a wide variety of neuroendocrine disruptions at environmentally relevant concentrations. Interestingly, some effects observed in these species can be observed within minutes to hours of exposure. For example, exposure of amphipod crustaceans to several selective serotonin reuptake inhibitors can invoke changes in swimming behavior within hours. In mollusks, exposure to selective serotonin reuptake inhibitors can induce spawning in male and female mussels and foot detachment in snails within minutes of exposure. In the light of new studies indicating effects on the human brain from selective serotonin reuptake inhibitors using magnetic resonance imaging scans, the authors discuss possible reasons for the discrepancy in former results in relation to the read-across hypothesis, variation in biomarkers used, modes of uptake, phylogenetic distance, and the affinity to different targets and differential sensitivity to receptors.


Prognostic factors and disease-specific survival among immigrants diagnosed with cutaneous malignant melanoma in Sweden.
Little is known about cutaneous malignant melanoma (CMM) among immigrants in Europe. We aimed to investigate clinical characteristics and disease-specific survival among first- and second-generation immigrants in Sweden. This nationwide population-based study included 27,235 patients from the Swedish Melanoma Register diagnosed with primary invasive CMM, 1990-2007. Data were linked to nationwide, population-based registers followed up through 2013. Logistic regression and Cox regression models were used to determine the association between immigrant status, stage and CMM prognosis, respectively. After adjustments for confounders, first generation immigrants from Southern Europe were associated with significantly more advanced stages of disease compared to Swedish-born patients [Stage II vs. I: Odds ratio (OR) = 2.37, 95% CI = 1.61-3.50. Stage III-IV vs I: OR = 2.40, 95% CI = 1.08-5.37]. The ORs of stage II-IV versus stage I disease were increased among men (OR = 1.9; 95% CI = 1.1-3.3; p = 0.020), and women (OR = 4.8; 95% CI = 2.6-9.1; p < 0.001) in a subgroup of immigrants from former Yugoslavia compared to Swedish-born patients. The CMM-specific survival was significantly decreased among women from former Yugoslavia versus Swedish-born women [hazard ratio (HR)=2.2; 95% CI = 1.1-4.2; p = 0.043]. After additional adjustments including stage, the survival difference was no longer significant. No survival difference between the second generation immigrant group and Swedish-born patients were observed. In conclusion, a worse CMM-specific survival in women from former Yugoslavia was associated with more advanced stages of CMM at diagnosis. Secondary prevention efforts focusing on specific groups may be needed to further improve the CMM prognosis.


Diet-induced weight loss: the effect of dietary protein on bone.
High-protein (>30% of energy from protein or >1.2 g/kg/day) and moderately high-protein (22% to 29% of energy from protein or 1.0 to 1.2 g/kg/day) diets are popular for weight loss, but the effect of dietary protein on bone during weight loss is not well understood. Protein may help preserve bone mass during weight loss by stimulating insulin-like growth factor 1, a potent bone anabolism stimulator, and increasing intestinal calcium absorption. Protein-induced acidity is considered to have minimal effect on bone resorption in adults with normal kidney function. Both the quantity and predominant source of protein influence changes in bone with diet-induced weight loss. Higher-protein, high-dairy diets may help attenuate bone loss during weight loss.


Support vector machine classification and characterization of age-related reorganization of functional brain networks.
Most of what is known about the reorganization of functional brain networks that accompanies normal aging is based on neuroimaging studies in which participants perform specific tasks. In these studies, reorganization is defined by the differences in task activation between young and old adults. However, task activation differences could be the result of differences in task performance, strategy, or motivation, and not necessarily reflect reorganization. Resting-state fMRI provides a method of investigating functional brain networks without such confounds. Here, a support vector machine (SVM) classifier was used in an attempt to differentiate older adults from younger adults based on their resting-state functional connectivity. In addition, the information used by the SVM was investigated to see what functional connections best differentiated younger adult brains from older adult brains. Three separate resting-state scans from 26 younger adults (18-35 yrs) and 26 older adults (55-85) were obtained from the International Consortium for Brain Mapping (ICBM) dataset made publically available in the 1000 Functional Connectomes project www.nitrc.org/projects/fcon_1000. 100 seed-regions from four functional networks with 5mm(3) radius were defined based on a recent study using machine learning classifiers on adolescent brains. Time-series for every seed-region were averaged and three matrices of z-transformed correlation coefficients were created for each subject corresponding to each individual's three resting-state scans. SVM was then applied using leave-one-out cross-validation. The SVM classifier was 84% accurate in classifying older and younger adult brains. The majority of the connections used by the classifier to distinguish subjects by age came from seed-regions belonging to the sensorimotor and cingulo-opercular networks. These results suggest that age-related decreases in positive correlations within the cingulo-opercular and default networks, and decreases in negative correlations between the default and sensorimotor networks, are the distinguishing characteristics of age-related reorganization.


Does Celiac Disease Influence Survival in Sepsis? A Nationwide Longitudinal Study.
Individuals with celiac disease (CD) are at increased risk of sepsis. The aim of this study was to examine whether CD influences survival in sepsis of bacterial origin. Nationwide longitudinal registry-based study. Through data on small intestinal biopsies from Sweden's 28 pathology departments, we identified 29,096 individuals with CD (villous atrophy, Marsh stage III). Each individual with CD was matched with five population-based controls. Among these, 5,470 had a record of sepsis according to the Swedish Patient Register (1,432 celiac individuals and 4,038 controls). Finally we retrieved data on mortality in sepsis patients through the Swedish Cause of Death Registry. CD was associated with a 19% increase in overall mortality after sepsis (95% confidence interval (CI) = 1.09-1.29), with the highest relative risk occurring in children (adjusted hazard ratio (aHR) = 1.62; 95%CI = 0.67-3.91). However, aHR for death from sepsis was lower (aHR = 1.10) and failed to reach statistical significance (95%CI = 0.72-1.69). CD did not influence survival within 28 days after sepsis (aHR = 0.98; 95%CI = 0.80-1.19). Although individuals with CD seem to be at an increased risk of overall death after sepsis, that excess risk does not differ from the general excess mortality previously seen in celiac patients in Sweden. CD as such does not seem to influence short-term or sepsis-specific survival in individuals with sepsis and therefore is not an independent risk factor for poor prognosis in sepsis.


COVID-19-related conspiracy beliefs and their relationship with perceived stress and pre-existing conspiracy beliefs.
Previous studies have down that erroneous Conspiracy Theory (CT) beliefs develop more strongly in people who have underlying conspiratorial reasoning styles and psychopathological traits and particularly when they are faced with stressful external events (Swami et al., 2013; van Prooijen, 2018). In this study, we test this proposition by examining the individual differences associated with the development of COVID-19-related CT beliefs during the pandemic. A total of 660 adults completed a survey that captured COVID-related CT beliefs and broader conspiracy beliefs, education, perceived stress and attitudes towards government responses. The results showed that COVID-19 related CT beliefs were: strongly related to broader CT beliefs, higher in those with lower levels of education; and, positively (although weakly) correlated with more negative attitudes towards government responses. However, no relationship was found between COVID-19 beliefs and self-reported stress. These findings hold implications for why some people are more likely to be resistant to public health interventions relating to COVID-19. The findings encourage more detailed exploration of the causes and sources of CTs and, in particular, the role of social media use and other information sources in the development and perpetuation of health-related CT beliefs.


RELAx - REstricted versus Liberal positive end-expiratory pressure in patients without ARDS: protocol for a randomized controlled trial.
Evidence for benefit of high positive end-expiratory pressure (PEEP) is largely lacking for invasively ventilated, critically ill patients with uninjured lungs. We hypothesize that ventilation with low PEEP is noninferior to ventilation with high PEEP with regard to the number of ventilator-free days and being alive at day 28 in this population. METHODS/DESIGN: The "REstricted versus Liberal positive end-expiratory pressure in patients without ARDS" trial (RELAx) is a national, multicenter, randomized controlled, noninferiority trial in adult intensive care unit (ICU) patients with uninjured lungs who are expected not to be extubated within 24 h. RELAx will run in 13 ICUs in the Netherlands to enroll 980 patients under invasive ventilation. In all patients, low tidal volumes are used. Patients assigned to ventilation with low PEEP will receive the lowest possible PEEP between 0 and 5 cm H2O, while patients assigned to ventilation with high PEEP will receive PEEP of 8 cm H2O. The primary endpoint is the number of ventilator-free days and being alive at day 28, a composite endpoint for liberation from the ventilator and mortality until day 28, with a noninferiority margin for a difference between groups of 0.5 days. Secondary endpoints are length of stay (LOS), mortality, and occurrence of pulmonary complications, including severe hypoxemia, major atelectasis, need for rescue therapies, pneumonia, pneumothorax, and development of acute respiratory distress syndrome (ARDS). Hemodynamic support and sedation needs will be collected and compared. RELAx will be the first sufficiently sized randomized controlled trial in invasively ventilated, critically ill patients with uninjured lungs using a clinically relevant and objective endpoint to determine whether invasive, low-tidal-volume ventilation with low PEEP is noninferior to ventilation with high PEEP. ClinicalTrials.gov , ID: NCT03167580 . Registered on 23 May 2017.


Evaluation of nutrient retention in vegetated filter strips using the SWAT model.
Nutrient fluxes in stream basins need to be controlled to achieve good water quality status. In stream basins with intensive agricultural activities, nutrients predominantly come from diffuse sources. Therefore, best management practices (BMPs) are increasingly implemented to reduce nutrient input to streams. The objective of this study is to evaluate the impact of vegetated filter strip (VFS) application as an agricultural BMP. For this purpose, SWAT is chosen, a semi-distributed water quality assessment model that works at the watershed scale, and applied on the Nif stream basin, a small-sized basin in Western Turkey. The model is calibrated with an automated procedure against measured monthly discharge data. Nutrient loads for each sub-basin are estimated considering basin-wide data on chemical fertilizer and manure usage, population data for septic tank effluents and information about the land cover. Nutrient loads for 19 sub-basins are predicted on an annual basis. Average total nitrogen and total phosphorus loads are estimated as 47.85 t/yr and 13.36 t/yr for the entire basin. Results show that VFS application in one sub-basin offers limited retention of nutrients and that a selection of 20-m filter width is most effective from a cost-benefit perspective.