Indoor aerosols: from personal exposure to risk assessment.
Motivated by growing considerations of the scale, severity, and risks associated with human exposure to indoor particulate matter, this work reviewed existing literature to: (i) identify state-of-the-art experimental techniques used for personal exposure assessment; (ii) compare exposure levels reported for domestic/school settings in different countries (excluding exposure to environmental tobacco smoke and particulate matter from biomass cooking in developing countries); (iii) assess the contribution of outdoor background vs indoor sources to personal exposure; and (iv) examine scientific understanding of the risks posed by personal exposure to indoor aerosols. Limited studies assessing integrated daily residential exposure to just one particle size fraction, ultrafine particles, show that the contribution of indoor sources ranged from 19% to 76%. This indicates a strong dependence on resident activities, source events and site specificity, and highlights the importance of indoor sources for total personal exposure. Further, it was assessed that 10-30% of the total burden of disease from particulate matter exposure was due to indoor-generated particles, signifying that indoor environments are likely to be a dominant environmental factor affecting human health. However, due to challenges associated with conducting epidemiological assessments, the role of indoor-generated particles has not been fully acknowledged, and improved exposure/risk assessment methods are still needed, together with a serious focus on exposure control.


Comparative biomechanics of the Pan and Macaca mandibles during mastication: finite element modelling of loading, deformation and strain regimes.
The mechanical behaviour of the mandibles of Pan and Macaca during mastication was compared using finite element modelling. Muscle forces were calculated using species-specific measures of physiological cross-sectional area and scaled using electromyographic estimates of muscle recruitment in Macaca. Loading regimes were compared using moments acting on the mandible and strain regimes were qualitatively compared using maps of principal, shear and axial strains. The enlarged and more vertically oriented temporalis and superficial masseter muscles of Pan result in larger sagittal and transverse bending moments on both working and balancing sides, and larger anteroposterior twisting moments on the working side. The mandible of Pan experiences higher principal strain magnitudes in the ramus and mandibular prominence, higher transverse shear strains in the top of the symphyseal region and working-side corpus, and a predominance of sagittal bending-related strains in the balancing-side mandible. This study lays the foundation for a broader comparative study of Hominidae mandibular mechanics in extant and fossil hominids using finite element modelling. Pan's larger and more vertical masseter and temporalis may make it a more suitable model for hominid mandibular biomechanics than Macaca.


Cytokine- and Ig-producing T cells in mucosal effector tissues: analysis of IL-5- and IFN-gamma-producing T cells, T cell receptor expression, and IgA plasma cells from mouse salivary gland-associated tissues.
The present study has focused on the analysis of cytokine- and Ig-producing mononuclear cells (MC) that reside in the salivary glands and their associated tissues (SGAT) in the oral region. The SGAT are located under the mandibular area and consist of submandibular glands, periglandular lymph nodes, and cervical lymph nodes. MC were isolated from individual SGAT and examined for T cell subsets and TCR expression, in comparison with T cells obtained from other mucosa-associated and systemic tissues. Forty to fifty percent of MC in submandibular glands were CD3+ T cells, equally divided into CD4+ CD8- and CD4- CD8+ T cell subsets. On the other hand, the intestinal lamina propria and Peyer's patches possessed a approximately 2 to 3:1 ratio of CD4+ CD8- to CD4- T cells. A high frequency of CD4- CD8- (double negative) (DN) T cells (approximately 6 to 10%) was also isolated from submandibular glands. In contrast, approximately 70 to 90% of MC in periglandular lymph nodes and cervical lymph nodes were CD3+ T cells and like the peripheral lymph nodes consisted of fivefold higher numbers of CD4+ CD8- than CD4- CD8+ T cells, with low numbers of DN cells (less than 5%). When expression of gamma/delta and alpha/beta TCR was examined in individual T cell subsets of submandibular glands, the CD4- CD8+ and DN T cell fractions contained 25% and 100% gamma/delta TCR+ cells, respectively. On the other hand, essentially all CD4+ CD8- T cells in SGAT as well as CD4- CD8+ cells in periglandular lymph nodes and cervical lymph nodes were alpha/beta TCR+ T cells. When cytokine production was examined by using IFN-gamma- and IL-5-specific enzyme-linked immunospot assays, the CD3+ CD4+ CD8- T cells in submandibular glands contained T cells spontaneously producing IFN-gamma and IL-5. Further, IL-5 spot-forming cells (SFC) were two- to threefold greater in number, compared with IFN-gamma SFC. The periglandular lymph node T cells contained cytokine producing cells with a ratio of 2:1 for IL-5 and IFN-gamma SFC cells, whereas cervical lymph node T cells did not produce cytokines unless stimulated with T cell mitogens. When the isotype distribution of Ig-producing cells was examined among SGAT, submandibular glands contained large numbers of IgA-producing cells, with few IgM- and IgG-producing cells, a pattern similar to that of the lamina propria. Further, elevated numbers of IgA-secreting cells were also seen in periglandular lymph nodes but not in cervical lymph nodes.(ABSTRACT TRUNCATED AT 400 WORDS)


Thyroid hormones and lipid metabolism in a group of patients over seventy.
Numerous studies have suggested a marked correlation between thyroid functionality indices and lipid metabolism. In this trial we assessed the functional parameters of 165 individuals over 70, 87 women and 78 men, correlating the serum values of T3, T4, FT4, TSH with cholesterol, triglycerides, HDL, Apo-A and Apo-B levels. The correlation was performed over the whole population studied and subsequently, after dividing the population by sex and age (3 age groups: A, 70-75; B, 76-80; C, over 80) in the individual groups. In the population as a whole, we have observed a statistically significant correlation between T4/cholesterol (P=0.0001); T3/cholesterol (P=0.06); T4/triglycerides (P=0.0001); T3/triglycerides (P=0.09); T4/HDL (P=0.0001); T4/Apo-A (P= 0.02); T3/Apo-A (P=0.008); T4/Apo-B (P=0.0001). Analysis by gender shows a statistically significance between the female and male sexes in the correlation between T3/cholesterol (P=0.001); T3/triglycerides (P=0.06); T4/cholesterol (P=0.0001) and T4/triglycerides (P=0.0001). When the data were analyzed by age, in Group A (75-80) there was no statistically significant correlation, whereas in Group B (76-80) there has been an increase in significance in the correlation between T3/cholesterol (P=0.006); T3/triglycerides (P=0.001); T3/Hdl (P=0.08); T3/Apo-A (P=0.0001); T3/Apo-B (P=0.08); T4/cholesterol (P=0.00001) and ); T4/Apo-A (P=0.0001). On the other hand in the Group C age group (over 80) this significance is considerably lower. Maybe this decrease of correlations should be attributed to a global savings of the older organisms, or to a process of natural selection.


Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutagenesis.
UV-damaged DNA-binding activity (UV-DDB) is deficient in some xeroderma pigmentosum group E individuals due to mutation of the p48 gene, but its role in DNA repair has been obscure. We found that UV-DDB is also deficient in cell lines and primary tissues from rodents. Transfection of p48 conferred UV-DDB to hamster cells, and enhanced removal of cyclobutane pyrimidine dimers (CPDs) from genomic DNA and from the nontranscribed strand of an expressed gene. Expression of p48 suppressed UV-induced mutations arising from the nontranscribed strand, but had no effect on cellular UV sensitivity. These results define the role of p48 in DNA repair, demonstrate the importance of CPDs in mutagenesis, and suggest how rodent models can be improved to better reflect cancer susceptibility in humans.


Connectome-wide Mega-analysis Reveals Robust Patterns of Atypical Functional Connectivity in Autism.
Neuroimaging studies of functional connectivity (FC) in autism have been hampered by small sample sizes and inconsistent findings with regard to whether connectivity is increased or decreased in individuals with autism, whether these alterations affect focal systems or reflect a brain-wide pattern, and whether these are age and/or sex dependent. The study included resting-state functional magnetic resonance imaging and clinical data from the EU-AIMS LEAP (European Autism Interventions Longitudinal European Autism Project) and the ABIDE (Autism Brain Imaging Data Exchange) 1 and 2 initiatives of 1824 (796 with autism) participants with an age range of 5-58 years. Between-group differences in FC were assessed, and associations between FC and clinical symptom ratings were investigated through canonical correlation analysis. Autism was associated with a brainwide pattern of hypo- and hyperconnectivity. Hypoconnectivity predominantly affected sensory and higher-order attentional networks and correlated with social impairments, restrictive and repetitive behavior, and sensory processing. Hyperconnectivity was observed primarily between the default mode network and the rest of the brain and between cortical and subcortical systems. This pattern was strongly associated with social impairments and sensory processing. Interactions between diagnosis and age or sex were not statistically significant. The FC alterations observed, which primarily involve hypoconnectivity of primary sensory and attention networks and hyperconnectivity of the default mode network and subcortex with the rest of the brain, do not appear to be age or sex dependent and correlate with clinical dimensions of social difficulties, restrictive and repetitive behaviors, and alterations in sensory processing. These findings suggest that the observed connectivity alterations are stable, trait-like features of autism that are related to the main symptom domains of the condition.


On the contribution of Angola to the initial spread of HIV-1.
Angola borders and has long-term links with Democratic Republic of Congo (DRC) as well as high levels of Human Immunodeficiency Virus (HIV) genetic diversity, indicating a potential role in the initial spread of the HIV-1 pandemic. Herein, we analyze 564 C2V3 and 354 pol publicly available sequences from DRC, Republic of Congo (RC) and Angola to better understand the initial spread of the virus in this region. Phylogeographic analyses were performed with the BEAST software. While our results pinpoint the origin of the pandemic to Kinshasa (DRC) around 1906, the introduction of HIV-1 to Angola could have occurred early between the 1910s and 1940s. Furthermore, most of the HIV-1 migrations out of Kinshasa were directed not only to Lubumbashi and Mbuji-Mayi (DRC), but also to Luanda and Brazzaville. Kinshasa census records corroborate these findings, indicating that the early exportation of the virus to Angola might be related to the high number of Angolans in Kinshasa at that time, originated mostly from the North of Angola. In summary, our results place Angola at the epicenter of the early HIV dissemination, together with DRC and RC.


Investigation of iso-propylchaetominine anticancer activity on apoptosis, cell cycle and Wnt signaling pathway in different cancer models.
Dysregulation of the Wnt signaling pathway contributes to the development of many cancer types. Natural compounds produced with biotechnological systems have been the focus of research for being a new drug candidate both with unlimited resources and cost-effective production. In this study, it was aimed to reveal the effects of isopropylchaetominine on cytotoxic, cytostatic, apoptotic and Wnt signaling pathways in brain, pancreatic and prostate cancer. The IC50 values of isopropylchaetominine in U-87 MG, PANC1, PC3 and LNCaP cells were calculated as 91.94 μM, 41.68 μM, 54.54 μM and 7.86 μM in 72nd h, respectively. The metabolite arrests the cell cycle in G0/G1 phase in each cancer cells. Iso-propylchaetominine induced a 4.3-fold and 1.9-fold increase in apoptosis in PC3 and PANC1 cells, respectively. The toxicity of isopropylchaetominine in healthy fibroblast cells was assessed using the annexin V method, and no significant apoptotic activity was observed between the groups treated with the active substance and untreated. In U-87 MG, PANC1, PC3, and LNCaP cells under treatment with isopropylchaetominin, the expression levels of DKK3, TLE1, AES, DKK1, FRZB, DAB2, AXIN1/2, PPARD, SFRP4, APC and SOX17 tumor suppressor genes increased significantly. Decreases in expression of Wnt1, Wnt2, Wnt3, Wnt4, Wnt5, Wnt6, Wnt10, Wnt11, FRZ2, FRZ3, FRZ7, TCF7L1, BCL9, PYGO, CCND2, c-MYC, WISP1 and CTNNB1 oncogenic genes were detected. All these result shows that isopropylchaetominine can present promising new treatment strategy in different cancer types.


Integrin beta 4 (ITGB4) and its tyrosine-1510 phosphorylation promote pancreatic tumorigenesis and regulate the MEK1-ERK1/2 signaling pathway.
Pancreatic cancer is the fourth leading cause of cancer death, with a 5-year survival rate of only 1-4%. Integrin-mediated cell adhesion is critical for the initiation, progression, and metastasis of cancer. In this study we investigated the role of integrin b4 (ITGB4) and its phosphorylation at tyrosine Y1510 (p-ITGB4-Y1510) in the tumorigenesis of pancreatic cancer. We analyzed the expression of ITGB4 and p-ITGB4-Y1510 in pancreatic cancer tissue and cell lines using immunohistochemistry, Western blot, or semi-quantitative reverse transcription PCR. ITGB4 and p-ITGB4-Y1510 were highly expressed in pancreatic cancer (n = 176) compared with normal pancreatic tissue (n = 171). High p-ITGB4-Y1510 expression correlated with local invasion and distant metastasis of pancreatic cancer, and high ITGB4 was significantly associated with poor survival of patients. Inhibition of ITGB4 by siRNA significantly reduced migration and invasion of PC-1.0 and AsPC-1 cells. Overexpression of the mutant ITGB4-Y1510A (a mutation of tyrosine to alanine at 1510 position) in PC-1.0 and AsPC-1 cells not only blocked the ITGB4 phosphorylation at Y1510 but also suppressed the expression of ITGB4 (p < 0.05 vs. wild-type ITGB4). The transfection of PC-1.0 and AsPC-1 cells with ITGB4-Y1510A significantly decreased the level of p-mitogen-activated protein kinase kinase (MEK)1 (T292) and p-extracellular signal-regulated kinase (ERK)1/2 but did not affect the level of p-MEK1 (T386) and p-MEK2 (T394). Overall, our study showed that ITGB4 and its phosphorylated form promote cell migration and invasion in pancreatic cancer and that p-ITGB4-Y1510 regulates the downstream MEK1-ERK1/2 signaling cascades. Targeting ITGB4 or its phosphorylation at Y1510 may be a novel therapeutic option for pancreatic cancer.


Role of dopamine in the regulation of blood pressure and the renin--angiotensin--aldosterone system in conscious rats.
1. In conscious rats, intracerebroventricular injection of dopamine resulted in a decrease in blood pressure, whereas injection of metoclopramide, the dopamine antagonist, produced an increase in blood pressure. The central depressor effect of dopamine was attenuated by a subpressor pretreatment with intraventricular metoclopramide, but not by phentolamine. 2. Intravenous administration of dopamine increase blood pressure. This increase in blood pressure was almost completely abolished by intravenous phentolamine. Metoclopramide, when injected intravenously, did not reduce any change in blood pressure. 3. Plasma renin activity and plasma aldosterone concentration were decreased by intraventricular injection of dopamine, and increased by that of metoclopramide. In contrast, intravenous administration of metoclopramide increased plasma aldosterone concentration without changing plasma renin activity. Plasma concentrations of potassium, sodium and corticosterone were not affected by these treatments. 4. These results suggest that the dopaminergic system in the brain, but not in the systemic circulation, is involved in the regulation of blood pressure. It is also suggested that the central dopaminergic system participates in the regulation of aldosterone secretion by changes in the renin--angiotensin axis, whereas the peripheral dopaminergic modulation of aldosterone secretion appears to occur independently of the renin--angiotensin system.


Gain model for microchannel plates.
It is shown that microchannel plates (MCPs) tend to act as if they were discrete stage electron multipliers with a fixed number of stages or dynodes if a plausible assumption is made regarding the behavior of the secondary electrons emitted from the semiconducting sidewalls of tubular channel electron multipliers under the grazing incidence conditions predominantly encountered in these multipliers. The shape of the resultant predicted gain-voltage transfer characteristic for the MCP fits well with experimental data, confirming the assumption made and permitting the use of curve matching techniques to determine such important MCP parameters as the average number of active dynodes, the gain per stage, the crossover potential for the MCP wall material, the transit time through the multiplier, etc.


Evaluation of the new Ocuton S tonometer.
To evaluate the intra- and interobserver variability of the Ocuton S tonometer, its correlation with Goldmann tonometry, the reliability of self-tonometry and the safety of the instrument. Thirty-five healthy subjects and 45 patients with primary open-angle glaucoma (POAG), aged from 38 to 80 years (mean age: 64.6 +/- 12.2 years), underwent tonometry with the Ocuton S tonometer in one eye chosen at random. The intra- and interobserver variability between two operators (kappa coefficient), the Ocuton S/Goldmann correlation and the reliability of self-tonometry were evaluated by performing two tonometries on each patient in subgroups. Each tonometry was considered as the mean of three consecutive measurements. Central ultrasonic pachymetry, keratometry and corneal biomicroscopy were also evaluated. The intra- and interobserver variability ranged from 0.38 to 0.66. The difference between the means of intraocular pressure (IOP) with the Ocuton S (24.4 +/- 4.7 mmHg) and the Goldmann tonometer (18.1 +/- 4.7 mmHg) was statistically significant (p < 0.0001). Linear regression analysis revealed a good Ocuton S/Goldmann correspondence (r = 0.88, p = 0.0001). However, IOP values detected with the Ocuton were consistently overestimated, compared to those detected with the Goldmann tonometer. The correlation between corneal thickness and IOP was statistically significant both for the Goldmann (r = 0.510, p = 0.021) and for the Ocuton S tonometer (r = 0.520, p = 0.019). No correlation was found between keratometry and IOP. The mean measurement obtained by self-tonometry (21.9 +/- 3.6 mmHg) showed no statistically significant difference when compared to the mean measurement obtained by an expert operator (21.3 +/- 3.4 mmHg). The Ocuton S tonometer is a safe instrument that can be used easily by the patient. However, in comparison to the Goldmann tonometer, it overestimates IOP and requires further technical and methodological refinements in order to ensure greater reliability.


Obesity, hypertension, and migration: a meta-analysis of populations of the South Asian diaspora.
The effects of migration on human health have been a topic of interest for demographers and human biologists. Even if migrants to a new region achieve a higher standard of living in their new place of residence, their improved living conditions may not be associated with better health. Part of the difficulty of understanding the health consequences of migration is the complications in trying to control for variables that may affect health, such as gender, age, and urban or rural environment of migrants and nonmigrants. In this paper we report results of a meta-analysis of the body mass index (BMI) and blood pressure (BP) of people of South Asian descent, by comparing nonmigrants who inhabit the subcontinent, with migrants who moved to various places around the globe. Our results indicate that BMI almost always increases to a significant level upon migration and that an increase in BMI is most pronounced in female migrants. Our results also show that BP does not always increase in migrant communities and that it is actually lower in some migrant samples than it is in comparable nonmigrant groups. Therefore, our results show that BP and the BMI do not behave in the same manner following a migration event. We propose that the BMI changes experienced by migrants are likely to reflect different activity levels and diet in the new homeland. However, the BP changes experienced by migrants are likely to reflect stress broadly defined. Such stress may be increased or decreased, depending on the specific migration experience. We propose that the BMI and BP measure two different dimensions of the migration experience.


Diverse roles for the posteromedial thalamus in sensory-evoked cortical plasticity.
The posteromedial thalamus (POm) has extensive recurrent connectivity with the whisker-related primary somatosensory cortex (wS1) of rodents. However, its functional contribution to somatosensory processing in wS1 remains unclear. This article reviews several recent findings, which begin to elucidate the role of POm in sensory-evoked plasticity and discusses their implications for somatosensory processing.


Somatodendritic ion channel expression in substantia nigra pars compacta dopaminergic neurons across postnatal development.
Dopaminergic neurons of the substantia nigra pars compacta (SNc) are involved in the control of movement, sleep, reward, learning, and nervous system disorders and disease. To date, a thorough characterization of the ion channel phenotype of this important neuronal population is lacking. Using immunohistochemistry, we analyzed the somatodendritic expression of voltage-gated ion channel subunits that are involved in pacemaking activity in SNc dopaminergic neurons in 6-, 21-, and 40-day-old rats. Our results demonstrate that the same complement of somatodendritic ion channels is present in SNc dopaminergic neurons from P6 to P40. The major developmental changes were an increase in the dendritic range of the immunolabeling for the HCN, T-type calcium, Kv4.3, delayed rectifier, and SK channels. Our study sheds light on the ion channel subunits that contribute to the somatodendritic delayed rectifier (Kv1.3, Kv2.1, Kv3.2, Kv3.3), A-type (Kv4.3) and calcium-activated SK (SK1, SK2, SK3) potassium currents, IH (mainly HCN2, HCN4), and the L- (Cav1.2, Cav1.3) and T-type (mainly Cav3.1, Cav3.3) calcium currents in SNc dopaminergic neurons. Finally, no robust differences in voltage-gated ion channel immunolabeling were observed across the population of SNc dopaminergic neurons for each age examined, suggesting that differing levels of individual ion channels are unlikely to distinguish between specific subpopulations of SNc dopaminergic neurons. This is significant in light of previous studies suggesting that age- or region-associated variations in the expression profile of voltage-gated ion channels in SNc dopaminergic neurons may underlie their vulnerability to dysfunction and disease.


Evaluation of the effects of the low-level laser therapy on swelling, pain, and trismus after removal of impacted lower third molar.
In current study we aimed to examine the effect of a low-level laser therapy on the pain, mouth opening and swelling of patients whose impacted 3rd molar tooth was extracted in addition measurement volumetrically to the edema with 3dMD face system. It was surveyed 15 patients who had bilateral symmetric lower 3rd molars. Surgical sides of patients were randomly separated into two groups: the study group and the control group. It was applied extra oral low-level laser therapy (LLLT, 0.3 W, 40 s, 4 J/cm(2)) to the study group (n = 15) after the surgical operation and on the 2nd day. Only routine postoperative recommendation (ice application) was made in the control (n = 15) group. The maximum mouth opening, pain level and facial swelling evaluated. 3dMD Face® (3dMD, Atlanta, GA) Photogrammetric System was used to evaluate volumetric changes of the swelling. There was no statistically significant difference in the edema and interincisal opening between the groups and the pain level in the laser group was significantly lower than in the control group on the 7(th) postoperative day. Although there were decreasing trismus, swelling, and pain level, with this LLLT, there was significant difference only in the 7th day pain level in the laser group compared with the control group.


12-Month peak alpha frequency is a correlate but not a longitudinal predictor of non-verbal cognitive abilities in infants at low and high risk for autism spectrum disorder.
Although studies of PAF in individuals with autism spectrum disorder (ASD) report group differences and associations with non-verbal cognitive ability, it is not known how PAF relates to familial risk for ASD, and whether similar associations with cognition in are present in infancy. Using a large multi-site prospective longitudinal dataset of infants with low and high familial risk for ASD, metrics of PAF at 12 months were extracted and growth curves estimated for cognitive development between 12-36 months. Analyses tested whether PAF 1) differs between low and high risk infants, 2) is associated with concurrent non-verbal/verbal cognitive ability and 3) predicts developmental change in non-verbal/verbal ability. Moderation of associations between PAF and cognitive ability by familial risk status was also tested. No differences in 12-month PAF were found between low and high risk infants. PAF was associated with concurrent non-verbal cognitive ability, but did not predict change in non-verbal cognitive over development. No associations were found between PAF and verbal ability, along with no evidence of moderation. PAF is not related to familial risk for ASD, and is a neural marker of concurrent non-verbal cognitive ability, but not verbal ability, in young infants at low and high risk for ASD.


Improving nurses' knowledge of continuous ST-segment monitoring.
Continuous ST-segment monitoring can result in detection of myocardial ischemia, but in clinical practice, continuous ST-segment monitoring is conducted incorrectly and underused by many registered nurses (RNs). Many RNs are unable to correctly institute ST-segment monitoring guidelines because of a lack of education. To evaluate whether an educational intervention, provided to 32 RNs, increases knowledge and correct clinical decision making (CDM) for the use of continuous ST-segment monitoring. At a single institution, an ST-segment monitoring class was provided to RNs in 2 cardiovascular units. Knowledge and correct CDM instruments were used for a baseline pretest and subsequent posttest after ST-segment monitoring education. Statistical significance between pretest and posttest scores for knowledge and correct CDM practice was noted with dependent t tests (P = .0001). Many RNs responsible for electrocardiographic monitoring are not aware of evidence-based ST-segment monitoring practice guidelines and cannot properly place precordial leads needed for ST-segment monitoring. Knowledge and correct CDM with ST-segment monitoring can be improved with focused education.


Immunological effect of administration of sequential doses of Haemophilus influenzae type b and pneumococcal conjugate vaccines in the same versus alternating limbs in the routine infant immunisation schedule: an open-label randomised controlled trial.
The use of different limbs for the administration of sequential doses of an intradermal rabies vaccine was shown to result in reduced vaccine immunogenicity. We aimed to assess whether this phenomenon also occurs with routine infant vaccines. In this open-label, randomised, controlled study, eligible healthy infants 6-12 weeks of age recruited through five clinical trials units (four in the UK and one in Malta) were randomly assigned in a 1:1 ratio to two vaccination groups: consistent limb or alternating limb. Infants in the consistent limb group received the diphtheria-tetanus-acellular pertussis-inactived polio-Haemophilus influenzae type b combined vaccine (DTaP-IPV-Hib) at 2, 3, and 4 months of age, and the pneumococcal conjugate vaccine (PCV13) at 2, 4, and 12 months, all administered to the right leg. Infants in the alternating limb group received DTaP-IPV-Hib in the left leg at 2 months and in the right leg at 3 and 4 months; and PCV13 in the left leg at 2 months, in the right leg at 4 months, and in the left arm at 12 months. All infants in both groups received the combined H influenzae type b and capsular group C Neisseria meningitidis tetanus toxoid conjugate vaccine (Hib-MenC-TT), administered in the left leg at 12 months. Randomisation was achieved by randomly generated codes, with permuted block size of 30, and was stratified by study site. Group allocation was not masked from study staff and parents of participants after enrolment, but group allocation was masked from laboratory staff assessing blood samples. The current study was a prespecified secondary objective of a parent phase 4 trial that assessed the induction of immunity following varying schedules of vaccination with glyco-conjugate capsular group C Neisseria meningitidis (Men C) vaccines in infancy. The objective of the current study was to compare the immunogenicity and reactogenicity of vaccines delivered in either consistent or alternating limbs. Immunogenicity was assessed by comparing serum IgG geometric mean concentrations at 5, 12, 13, and 24 months, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01129518. Between July 5, 2010, and Aug 1, 2013, we enrolled 509 infants and randomly allocated them to the consistent limb group (n=254) or the alternating limb group (n=255). Anti-H influenzae type b anti-polyribosylribitol phosphate IgG geometric mean concentrations were lower in the consistent limb group than in the alternating limb group at 5 months (consistent limb 0·41 μg/mL [95% CI 0·31-0·54] vs alternating limb 0·61 μg/mL [0·45-0·82]; p=0·0268) and at 12 months (0·35 μg/mL [0·28-0·43] vs 0·50 μg/mL [0·40-0·62]; p=0·0136). Anti-tetanus toxoid antibody IgG geometric mean concentrations were lower in the consistent limb group (1·63 IU/mL [95% CI 1·40-1·90]) than in the alternating limb group (2·30 IU/mL [1·97-2·68]) at 13 months (p=0·0008) and at 24 months (0·44 IU/mL [0·37-0·52] vs 0·61 IU/mL [0·51-0·73]; p=0·0074). Anti-pneumococcal IgG geometric mean concentrations were similar between both groups at all timepoints. The proportions of participants who had adverse events did not differ between the two groups. Use of different (alternating) limbs for sequential doses of routine infant vaccines does not reduce, and might enhance, immunogenicity. The underlying mechanism for this finding warrants further research. NIHR Oxford Biomedical Research Centre and GlaxoSmithKline Biologicals.


Clinician Perspectives of an Avatar-Directed Scheduling and Memory App.
Effective strategies are needed to address the need for scheduling support in the unique setting of a home rehabilitation service, providing home based therapy, as well as telerehabilitation. One approach is an electronic avatar-directed scheduling and memory aid in the form of an app. The aim of this study is to investigate clinician perspectives on the use of this type of technology. In this mixed method study a total of sixteen clinicians from various disciplines based at a metropolitan hospital in Adelaide (SA, Australia) participated in 2 semi-structured focus groups aimed to explore experiences and attitudes towards scheduling support in the form of an avatar-directed app, perceptions on the usefulness of the app, as well as acceptability. Thematic analysis was undertaken on focus groups' transcripts. Self-reported technology proficiency, perceived usefulness (PU), and perceived ease of use (PEOU) were assessed quantitatively. Summary statistics were used to analyse the quantitative data and Spearman's correlation was used to explore the relationship between participant characteristics and individual and mean scores for PU and PEOU. Four themes emerged from the focus groups: effectiveness versus efficiency, patient empowerment, practicality and ease of use, and likability of the avatar. Clinicians experienced time constraints, and welcomed technology that could assist with reliable scheduling of appointments and therapy sessions. They liked the concept of the avatar and found the app interesting, novel and fun. However, although the app was reasonably easy to use, the setting up was problematic and time consuming. Clinicians did not see the app as beneficial to their patients, and felt that the technology did not add value to the delivery of care. The older, more experienced, clinicians found the app more difficult to use, but neither the level of technological competency, nor gender, was found to be associated with PU or PEOU. Although clinicians appreciated the concept of an avatar-directed scheduling and memory app, they did not see it as a useful tool in the provision of scheduling assistance in this particular setting providing short-term rehabilitation services. Clinicians felt time-poor and emphasized the importance of a time-efficient solution. Perceived lack of usefulness in this context and poor likeability of the avatar highlight the need for clinician involvement in the design process before an app can be successfully implemented in a clinical setting.


Higher tobramycin concentration and vibrating mesh technology can shorten antibiotic treatment time in cystic fibrosis.
Poor adherence to recommended therapy in cystic fibrosis (CF) is often because of the time demands of therapy. Tobramycin (TOBI®, 300 mg at 60 mg/ml) inhaled from the PARI LC PLUS® nebulizer requires about 20 min. This study determined if equivalent levels of pulmonary deposition could be achieved in shorter time using 1.5 ml of 100 mg/ml tobramycin solution delivered by an investigational eFlow® nebulizer. Sixteen males with stable CF, 8 children and 8 adults, and an FEV(1) > 45% predicted inhaled both preparations on two occasions with (99m) Tc-DTPA added to the tobramycin. Blood samples were taken for quantification of tobramycin in the serum. The PARI LC PLUS® delivered 45.4 (39.3-51.6), mean and 95% CI, mg to the lungs in 17.0 ± 2.5 min (mean ± SD) with serum levels of 1,089 ± 388 µg/L. The investigational eFlow® delivered 46.3(40.3-51.7) mg in 4.0 ± 1.0 min with blood levels of 909 ± 458 µg/L. Only the time of delivery was significantly different with P < 0.0001 (paired t-test). Tolerability of the treatment was comparable for both inhalation regimes, but the shorter treatment was preferred by all patients. These results demonstrate the possibility of delivering equivalent levels of tobramycin much faster into the lungs of CF patients when using eFlow®, a very efficient electronic nebulizer.


"A Vegetarian vs. Conventional Hypocaloric Diet: The Effect on Physical Fitness in Response to Aerobic Exercise in Patients with Type 2 Diabetes." A Parallel Randomized Study.
It has been shown that it is possible to modify macronutrient oxidation, physical fitness and resting energy expenditure (REE) by changes in diet composition. Furthermore, mitochondrial oxidation can be significantly increased by a diet with a low glycemic index. The purpose of our trial was to compare the effects of a vegetarian (V) and conventional diet (C) with the same caloric restriction (-500 kcal/day) on physical fitness and REE after 12 weeks of diet plus aerobic exercise in 74 patients with type 2 diabetes (T2D). An open, parallel, randomized study design was used. All meals were provided for the whole study duration. An individualized exercise program was prescribed to the participants and was conducted under supervision. Physical fitness was measured by spiroergometry and indirect calorimetry was performed at the start and after 12 weeks Repeated-measures ANOVA (Analysis of variance) models with between-subject (group) and within-subject (time) factors and interactions were used for evaluation of the relationships between continuous variables and factors. Maximal oxygen consumption (VO2max) increased by 12% in vegetarian group (V) (F = 13.1, p < 0.001, partial η² = 0.171), whereas no significant change was observed in C (F = 0.7, p = 0.667; group × time F = 9.3, p = 0.004, partial η² = 0.209). Maximal performance (Watt max) increased by 21% in V (F = 8.3, p < 0.001, partial η² = 0.192), whereas it did not change in C (F = 1.0, p = 0.334; group × time F = 4.2, p = 0.048, partial η² = 0.116). Our results indicate that V leads more effectively to improvement in physical fitness than C after aerobic exercise program.


Identification of an 80kD protein associated with the alpha 3 beta 1 integrin as a proteolytic fragment of the alpha 3 subunit: studies with human keratinocytes.
We have characterised a protein of approximately 80kD previously observed to co-immunoprecipitate with the alpha 3 beta 1 integrin in lysates of surface labelled human epidermalkeratinocytes. The 80kD protein only appeared when keratinocytes were harvested with trypsin/EDTA prior to lysis and a protein of similar molecular mass could be immunoprecipitated from human dermal fibroblasts following treatment of the cells with trypsin/EDTA. N terminal sequencing established that the 80kD protein had homology with the alpha 3 integrin subunit. Peptide-mass fingerprinting was used to confirm that the protein comprised the amino terminus of alpha 3 and established that the site of cleavage was after amino acid 629. The 80kD fragment could be coimmunoprecipitated with alpha 3 beta 1 using an antibody to the cytoplasmic domain of the alpha 3 subunit, showing that the fragment remained complexed with intact alpha 3 beta 1. When antibodies to the cytoplasmic and extracellular domains of alpha 3 were used to label human epidermis by immunofluorescence, the staining patterns were indistinguishable and there is therefore no evidence that proteolysis of alpha 3 plays a role in keratinocyte detachment from the basement membrane during terminal differentiation. Whether the 80kD fragment has any effects, positive or negative, on alpha 3 beta 1-mediated adhesion remains to be determined.


Differential N-Glycosylation Patterns in Lung Adenocarcinoma Tissue.
To decrease the mortality of lung cancer, better screening and diagnostic tools as well as treatment options are needed. Protein glycosylation is one of the major post-translational modifications that is altered in cancer, but it is not exactly clear which glycan structures are affected. A better understanding of the glycan structures that are differentially regulated in lung tumor tissue is highly desirable and will allow us to gain greater insight into the underlying biological mechanisms of aberrant glycosylation in lung cancer. Here, we assess differential glycosylation patterns of lung tumor tissue and nonmalignant tissue at the level of individual glycan structures using nLC-chip-TOF-MS. Using tissue samples from 42 lung adenocarcinoma patients, 29 differentially expressed (FDR < 0.05) glycan structures were identified. The levels of several oligomannose type glycans were upregulated in tumor tissue. Furthermore, levels of fully galactosylated glycans, some of which were of the hybrid type and mostly without fucose, were decreased in cancerous tissue, whereas levels of non- or low-galactosylated glycans mostly with fucose were increased. To further assess the regulation of the altered glycosylation, the glycomics data was compared to publicly available gene expression data from lung adenocarcinoma tissue compared to nonmalignant lung tissue. The results are consistent with the possibility that the observed N-glycan changes have their origin in differentially expressed glycosyltransferases. These results will be used as a starting point for the further development of clinical glycan applications in the fields of imaging, drug targeting, and biomarkers for lung cancer.


The elimination of Chagas' disease from Brazil.
On 9 June 2006 the Pan American Health Organization (PAHO) presented the Minister of Health of Brazil with the International Elimination of Transmission of Chagas' Disease Certificate. This act was the culmination of an intensive process that began in 1991 with the Southern Cone Initiative, a joint agreement between the governments of Argentina, Bolivia, Brazil, Chile, Paraguay, Uruguay and Peru, to control Chagas' disease by the elimination of the main vector, Triatoma infestans. This initiative has been highly successful and the prevalence area of the vector diminished rapidly in the last years. As a consequence, the current seroprevalence in children aged between 0 and 5 years is of the order of 10(-5), a clear indication that transmission, if it is occurring, is only accidental. In this review I calculate the basic reproduction number, R0, for Chagas' disease and demonstrate that its relatively low value (1.25) explains why vectorial transmission was interrupted relatively easily. In addition, I used a mathematical model to forecast how long the remaining cases of the disease, as well as the additional vertically transmitted cases will last.


The Drosophila fl(2)d gene, required for female-specific splicing of Sxl and tra pre-mRNAs, encodes a novel nuclear protein with a HQ-rich domain.
The Drosophila gene female-lethal(2)d [fl(2)d] interacts genetically with the master regulatory gene for sex determination, Sex-lethal. Both genes are required for the activation of female-specific patterns of alternative splicing on transformer and Sex-lethal pre-mRNAs. We have used P-element-mediated mutagenesis to identify the fl(2)d gene. The fl(2)d transcription unit generates two alternatively spliced mRNAs that can encode two protein isoforms differing at their amino terminus. The larger isoform contains a domain rich in histidine and glutamine but has no significant homology to proteins in databases. Several lines of evidence indicate that this protein is responsible for fl(2)d function. First, the P-element insertion that inactivates fl(2)d interrupts this ORF. Second, amino acid changes within this ORF have been identified in fl(2)d mutants, and the nature of the changes correlates with the severity of the mutations. Third, all of the phenotypes associated with fl(2)d mutations can be rescued by expression of this cDNA in transgenic flies. Fl(2)d protein can be detected in extracts from Drosophila cell lines, embryos, larvae, and adult animals, without apparent differences between sexes, as well as in adult ovaries. Consistent with a possible function in posttranscriptional regulation, Fl(2)d protein has nuclear localization and is enriched in nuclear extracts.


Attitudes and perceptions of health professionals towards management of hypothyroidism in general practice: a qualitative interview study.
To explore the attitudes and perceptions of health professionals towards management of hypothyroidism that contributes to the suboptimal treatment of hypothyroidism in general practice. A qualitative interview study using semistructured interviews. Sixteen participants were interviewed between March and August 2016 comprising nine general practitioners (GPs), four pharmacists, two practice nurses and one nurse practitioner. General practice and community pharmacies in the counties of Northumberland, Tyne and Wear, Stockton-on-Tees and North Cumbria, North of England, UK. A grounded-theory approach was used to generate themes from interviews, which were underpinned by the theory of planned behaviour to give explanation to the data. Although health professionals felt that hypothyroidism was easy to manage, GPs and nurses generally revealed inadequate knowledge of medication interactions and levothyroxine pharmacokinetics. Pharmacists felt limited in the advice that they provide to patients due to lack of access to patient records. Most GPs and nurses followed local guidelines, and relied on blood tests over clinical symptoms to adjust levothyroxine dose. The information exchanged between professional and patient was usually restricted by time and often centred on symptoms rather than patient education. Health professionals felt that incorrect levothyroxine adherence was the main reason behind suboptimal treatment, although other factors such as comorbidity and concomitant medication were mentioned. Enablers perceived by health professionals to improve the management of hypothyroidism included continuity of care, blood test reminders, system alerts for interfering medications and prescription renewal, and accessible blood tests and levothyroxine prescriptions for patients. There is a significant health professional behavioural component to the management of hypothyroidism. Addressing the differences in patient and professional knowledge and perceptions could reduce the barriers to optimal treatment, while continuity of care and increased involvement of pharmacists and practice nurses would help to promote optimal thyroid replacement.


Tenofovir-based preexposure prophylaxis for HIV infection among African women.
Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection. We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly. Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). We observed no significant differences in the frequencies of other adverse events. None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.).


Relationship of adherence to pediatric asthma morbidity among inner-city children.
Morbidity from asthma among children is one of the most important US health concerns. This study examines the relationship of baseline nonadherence to subsequent asthma morbidity among inner-city children. A multisite, prospective, longitudinal panel study was conducted of 1199 children who were aged 4 to 9 years and had asthma and their caregivers, most of whom were parents, in emergency departments and clinics at 8 research centers in 7 US metropolitan inner-city areas. Nine morbidity indicators were collected at 3, 6, and 9 months after baseline, including hospitalizations, unscheduled visits, days of wheeze/cough, and days of reduced activities. Children whose caregivers scored high on a new measure, Admitted Nonadherence, experienced significantly worse morbidity on 8 of the 9 measures. Children who scored high on a new Risk for Nonadherence measure experienced significantly worse morbidity on all 9 morbidity measures. Multiple and logistic regressions found that the adherence measures had independent significant effects on morbidity. Combining the measures improved estimates of morbidity: children whose caregivers were poor on either adherence measure had worse morbidity than those with good adherence on both, eg, rate of hospitalization was twice as high, they missed more than twice as much school, had poorer overall functioning, and experienced more days of wheezing and more restricted days of activity. Risk for Nonadherence and Admitted Nonadherence independently and jointly predicted subsequent asthma morbidity. Targeting risks for nonadherence may be an effective intervention strategy. Most risks can be controlled by physicians through reducing the complexity of asthma regimens, communicating effectively with caregivers about medication use, and correcting family misconceptions about asthma medication side effects.


Comparison of Composition and Anticaries Effect of Galla Chinensis Extracts with Different Isolation Methods.
Galla chinensis water extract (GCE) has been demonstrated to inhibit dental caries by favorably shifting the demineralization/remineralization balance of enamel and inhibiting the biomass and acid formation of dental biofilm. The present study focused on the comparison of composition and anticaries effect of Galla chinensis extracts with different isolation methods, aiming to improve the efficacy of caries prevention. The composition of water extract (GCE), ethanol extract (eGCE) and commercial tannic acid was compared. High performance liquid chromatography coupled to electrospray ionization-time of flight-mass spectrometry (HPLC-ESI-TOF-MS) analysis was used to analyze the main ingredients. In vitro pH-cycling regime and polymicrobial biofilms model were used to assess the ability of different Galla chinensis extracts to inhibit enamel demineralization, acid formation and biofilm formation. All the GCE, eGCE and tannic acid contained a high level of total phenolics. HPLC-ESI-TOF-MS analysis showed that the main ingredients of GCE were gallic acid (GA), while eGCE mainly contained 4-7 galloylglucopyranoses (GGs) and tannic acid mainly contained 5-10 GGs. Furthermore, eGCE and tannic acid showed a better effect on inhibiting enamel demineralization, acid formation and biofilm formation compared to GCE. Galla chinensis extracts with higher tannin content were suggested to have higher potential to prevent dental caries.


Creation of a neovagina by the Vecchietti procedure in a patient with corrected high imperforate anus.
Vaginal atresia is often associated with high imperforate anus. Because the commonly used methods of surgical vaginal creation (eg, McIndoe, intestinal segment interposition) may adversely affect urinary and fecal continence, the less-invasive Vecchietti procedure was selected for a young adult with a successfully corrected high imperforate anus. A 21-year-old was born with a high imperforate anus, vaginal atresia, right hemi-uterus, and left renal agenesis. A colostomy was done at birth, a pull-through procedure at 9 months, and a stoma closure 3 months later. At age 13, an obstructed and dilated right hemiuterus and fallopian tube were resected. A laparoscopic version of the Vecchietti procedure was used for creation of a neovagina. After the patient had been in the hospital for 2 days, traction was gradually advanced every other day in the office. At 2 weeks postoperatively, the bead was removed revealing a 7-cm vagina. Further elongation was achieved using the Frank method, while continence remained intact. The Vecchietti procedure is an attractive, minimally invasive alternative for creation of a neovagina in patients at risk for compromise to their vesico-anorectal continence.


Evaluation of three different methods of distance learning for postgraduate diagnostic imaging education: A pilot study.
Objective : The purpose of this study was to evaluate the perceived effectiveness and learning potential of 3 Web-based educational methods in a postgraduate radiology setting. Methods : Three chiropractic radiology faculty from diverse geographic locations led mini-courses using asynchronous discussion boards, synchronous Web conferencing, and asynchronous voice-over case presentations formatted for Web viewing. At the conclusion of each course, participants filled out a 14-question survey (using a 5-point Likert scale) designed to evaluate the effectiveness of each method in achieving specified course objectives and goals and their satisfaction when considering the learning potential of each method. The mean, standard deviation, and percentage agreements were tabulated. Results : Twenty, 15, and 10 participants completed the discussion board, Web conferencing, and case presentation surveys, respectively. All educational methods demonstrated a high level of agreement regarding the course objective (total mean rating >4.1). The case presentations had the highest overall rating for achieving the course goals; however, all but one method still had total mean ratings >4.0 and overall agreement levels of 70%-100%. The strongest potential for interactive learning was found with Web conferencing and discussion boards, while case presentations rated very low in this regard. Conclusions : The perceived effectiveness in achieving the course objective and goals was high for each method. Residency-based distance education may be a beneficial adjunct to current methods of training, allowing for international collaboration. When considering all aspects tested, there does not appear to be a clear advantage to any one method. Utilizing various methods may be most appropriate.


Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes.
In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.


Recessive dystonia-ataxia syndrome in a Turkish family caused by a COX20 (FAM36A) mutation.
DYTCA is a syndrome that is characterized by predominant dystonia and mild cerebellar ataxia. We examined two affected siblings with healthy, consanguineous, Turkish parents. Both patients presented with a combination of childhood-onset cerebellar ataxia, dystonia, and sensory axonal neuropathy. In the brother, dystonic features were most pronounced in the legs, while his sister developed torticollis. Routine diagnostic investigations excluded known genetic causes. Biochemical analyses revealed a mitochondrial respiratory chain complex IV and a coenzyme Q10 deficiency in a muscle biopsy. By exome sequencing, we identified a homozygous missense mutation (c.154A >C; p.Thr52Pro) in both patients in exon 2 of the COX20 (FAM36A) gene, which encodes a complex IV assembly factor. This variant was confirmed by Sanger sequencing, was heterozygous in both parents, and was absent from 427 healthy controls. The exact same mutation was recently reported in a patient with ataxia and muscle hypotonia. Among 128 early-onset dystonia and/or ataxia patients, we did not detect any other patient with a COX20 mutation. cDNA sequencing and semi-quantitative analysis were performed in fibroblasts from one of our homozygous mutation carriers and six controls. In addition to the exchange of an amino acid, the mutation led to a shift in splicing. In conclusion, we extend the phenotypic spectrum of a recently identified mutation in COX20 to a recessively inherited, early-onset dystonia-ataxia syndrome that is characterized by reduced complex IV activity. Further, we confirm a pathogenic role of this mutation in cerebellar ataxia, but this mutation seems to be a rather rare cause.


Choice of resolution by functional trait or taxonomy affects allometric scaling in soil food webs.
Belowground organisms often display a shift in their mass-abundance scaling relationships due to environmental factors such as soil chemistry and atmospheric deposition. Here we present new empirical data that show strong differences in allometric scaling according to whether the resolution at the local scale is based on a taxonomic or a functional classification, while only slight differences arise according to soil environmental conditions. For the first time, isometry (an inverse 1:1 proportion) is recognized in mass-abundance relationships, providing a functional signal for constant biomass distribution in soil biota regardless of discrete trophic levels. Our findings are in contrast to those from aquatic ecosystems, in that higher trophic levels in soil biota are not a direct function of increasing body mass.


Different Escherichia coli B2-ST131 clades (B and C) producing extended-spectrum β-lactamases (ESBL) colonizing residents of Portuguese nursing homes.
ESBL-producing Enterobacteriaceae and particularly Escherichia coli ST131 isolates producing CTX-M enzymes are commonly found colonizing the intestine of nursing home (NH) residents, but ST131 subclonal structure has been scarcely explored in this vulnerable population. Our goal was to perform a pilot study to assess the faecal carriage rate and epidemiological features of ESBL- and/or carbapenemase-producing Enterobacteriaceae (ESBL-E and CPE, respectively) among NH residents. For this purpose, faecal samples from residents at 4 different NHs in the North of Portugal (representing 9·5% of the residents' population, July 2014) were screened for ESBL-E and/or CPE by phenotypic and genotypic methods. Clonal structure and plasmid typing of ESBL-producing E. coli (ESBL-Ec) was performed by PCR and sequencing. Four ESBL-Ec isolates (2 CTX-M-15/2 CTX-M-14) were found in 20% of the samples, all belonging to the pandemic clonal lineage B2-ST131-O25b:H4. Two different clades were identified, the C2/H30-Rx-virotype C producing CTX-M-15 and an atypical B/H22-like-virotype D5 (producing CTX-M-14 and fluoroquinolone-resistant), firstly described in Portugal. This pilot study highlights the role of NH residents as a source of different ST131 clades, besides emphasizing the importance of E. coli B2-ST131 subtyping in different clinical settings, and understanding the transmission dynamics of the different variants.


Dependence of the DPOAE amplitude pattern on acoustical biasing of the cochlear partition.
Distortion product otoacoustic emissions (DPOAEs) were recorded from guinea pigs in response to simultaneous increases in the levels of high frequency primary tones in the presence of a low frequency biasing tone of 30 Hz at 120 dB SPL. The DPOAE amplitudes plotted as functions of the biasing tone phase angle show distinctive repeatable minima, which are identical to the amplitude notches observed for the distortion products at the output of a single saturating non-linearity. The number of the amplitude minima grows with increasing order of the DPOAE, a feature that is also reproduced by the model. The model of DPOAE generation due to a single saturating non-linearity does not explain the experimentally observed asymmetry of the response of the DPOAEs to rising and falling half cycles of the biasing tone. This asymmetry is attributed to a hypothetical mechanism, which adjusts the operating point of the outer hair cell's mechanoelectrical transducer. Experimental data were consistent with a hypothesis that, for the parameters of stimulation used in this study, both lower and upper sideband DPOAEs are dominated by emission generated from a single and spatially localized place in the cochlea.


Rumen Fluid Metabolomics Analysis Associated with Feed Efficiency on Crossbred Steers.
The rumen has a central role in the efficiency of digestion in ruminants. To identify potential differences in rumen function that lead to differences in average daily gain (ADG), rumen fluid metabolomic analysis by LC-MS and multivariate/univariate statistical analysis were used to identify differences in rumen metabolites. Individual feed intake and body-weight was measured on 144 steers during 105 d on a high concentrate ration. Eight steers with the greatest ADG and 8 steers with the least-ADG with dry matter intake near the population average were selected. Blood and rumen fluid was collected from the 16 steers 26 d before slaughter and at slaughter, respectively. As a result of the metabolomics analysis of rumen fluid, 33 metabolites differed between the ADG groups based on t-test, fold changes and partial least square discriminant analysis. These metabolites were primarily involved in linoleic and alpha-linolenic metabolism (impact-value 1.0 and 0.75, respectively; P < 0.05); both pathways were down-regulated in the greatest-ADG compared with least-ADG group. Ruminal biohydrogenation might be associated with the overall animal production. The fatty acids were quantified in rumen and plasma using targeted MS to validate and evaluate the simple combination of metabolites that effectively predict ADG.


Dietary flavonoid and lignan intake and breast cancer risk according to menopause and hormone receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.
Evidence on the association between dietary flavonoids and lignans and breast cancer (BC) risk is inconclusive, with the possible exception of isoflavones in Asian countries. Therefore, we investigated prospectively dietary total and subclasses of flavonoid and lignan intake and BC risk according to menopause and hormonal receptor status in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 334,850 women, mostly aged between 35 and 70 years from ten European countries. At baseline, country-specific validated dietary questionnaires were used. A flavonoid and lignan food composition database was developed from the US Department of Agriculture, the Phenol-Explorer and the UK Food Standards Agency databases. Cox regression models were used to analyse the association between dietary flavonoid/lignan intake and the risk of developing BC. During an average 11.5-year follow-up, 11,576 incident BC cases were identified. No association was observed between the intake of total flavonoids [hazard ratio comparing fifth to first quintile (HRQ5-Q1) 0.97, 95 % confidence interval (CI): 0.90-1.04; P trend = 0.591], isoflavones (HRQ5-Q1 1.00, 95 % CI: 0.91-1.10; P trend = 0.734), or total lignans (HRQ5-Q1 1.02, 95 % CI: 0.93-1.11; P trend = 0.469) and overall BC risk. The stratification of the results by menopausal status at recruitment or the differentiation of BC cases according to oestrogen and progesterone receptors did not affect the results. This study shows no associations between flavonoid and lignan intake and BC risk, overall or after taking into account menopausal status and BC hormone receptors.


Changes in atmospheric carbon-14 attributed to a variable sun.
The (14)C production rate in the upper atmosphere changes with time because the galactic cosmic-ray flux responsible for (14)C production is modulated by the changes in solar wind magnetic properties. The resulting changes in the atmospheric (14)C level are recorded in tree rings and are used to calculate past (14)C production rates from a carbon reservoir model that describes terrestrial carbon exchange between the atmosphere, ocean, and biosphere. These past (14)C production rate changes are compared with (14)C production rates determined from 20th-century neutron flux measurements, and a theory relating (14)C production and solar variability, as given by geomagnetic Aa indices and sunspot numbers, is developed. This theory takes into account long-term solar changes that were previously neglected. The 860-year (14)C record indicates three episodes when sunspots apparently were absent: A.D. 1654 to 1714 (Maunder minimum), 1416 to 1534 (Spörer minimum), and 1282 to 1342 (Wolf minimum). A less precisely defined minimum occurred near A.D. 1040. The part of this record after A.D. 1645 correlates well with the basic features of the historical record of sunspot numbers. The magnitude of the calculated (14)C production rates points to a further increase in cosmic-ray flux when sunspots are absent. This flux was greatest during the Spörer minimum. A record of approximate sunspot numbers and Aa indices for the current millennium is also presented.


Induction of apoptosis by Acanthopanax senticosus HARMS and its component, sesamin in human stomach cancer KATO III cells.
Antitumor effect of the stem bark of Acanthopanax senticosus HARMS (ASH) from Hokkaido (Japanese name: Ezoukogi) on human stomach cancer KATO III cells was investigated. The extract of the stem bark of ASH prepared with hot water was dissolved in distilled water and used for the assay of antitumor effect on the KATO III cells. The exposure of KATO III cells to ASH led to both growth inhibition and induction of apoptosis. Morphological change showing apoptotic bodies was observed in the cells treated with ASH. The fragmentation by ASH of DNA to oligonucleosomal-sized fragments that are characteristics of apoptosis was observed to be concentration- and time-dependent. We have investigated which component in ASH is effective on the induction of apoptosis. Among chlorogenic acid, syringaresinol di-o-beta-D glucoside, syringin, and sesamin, components of the n-butanol extract prepared from ASH, sesamin suppressed the growth and induced apoptosis in the cells. These findings suggest that growth inhibition by ASH results from the apoptosis induced by sesamin, a component of ASH.


Red luminescence and ferromagnetism in europium oxynitridosilicates with a β-K2SO4 structure.
The new compounds LaSrSiO3N and LaBaSiO3N activated with Eu(2+) are orange-red light-emitting luminescent materials under excitation in the UV-blue range. They represent the first examples of stoichiometric alkaline earth oxynitridosilicates with a β-K2SO4 structure. The isostructural compound LaEuSiO3N is ferromagnetic with a Curie temperature of 3 K and also shows red luminescence (λmax = 705 nm) under excitation at 405 nm.


The origin of man: a chromosomal pictorial legacy.
Man, gorilla, and chimpanzee likely shared an ancestor in whom the fine genetic organization of chromosomes was similar to that of present man. A comparative analysis of high-resolution chromosomes from orangutan, gorilla, chimpanzee, and man suggests that 18 or 23 pairs of chromosomes of modern man are virtually identical to those of our "common hominoid ancestor", with the remaining pairs slightly different. From this lineage, gorilla separated fist, and three major chromosomal rearrangements presumably occurred in a progenitor of chimpanzee and man before the final divergence of these tow species. A precursor of the hominoid ancestor and orangutan is also assumed.


G protein regulation of ion channels and abscisic acid signaling in Arabidopsis guard cells.
The phytohormone abscisic acid (ABA) promotes plant water conservation by decreasing the apertures of stomatal pores in the epidermis through which water loss occurs. We found that Arabidopsis thaliana plants harboring transferred DNA insertional mutations in the sole prototypical heterotrimeric GTP-binding (G) protein alpha subunit gene, GPA1, lack both ABA inhibition of guard cell inward K(+) channels and pH-independent ABA activation of anion channels. Stomatal opening in gpa1 plants is insensitive to inhibition by ABA, and the rate of water loss from gpa1 mutants is greater than that from wild-type plants. Manipulation of G protein status in guard cells may provide a mechanism for controlling plant water balance.


Topical diclofenac: clinical effectiveness and current uses in osteoarthritis of the knee and soft tissue injuries.
Diclofenac is a commonly used non-steroidal anti-inflammatory drug (NSAID) for symptom control in osteoarthritis (OA) of the knee and soft tissue injuries. Although treatment with oral diclofenac is associated with serious adverse effects involving both the gastrointestinal and renal systems, these adverse effects are thought to be limited with topical diclofenac formulations without loss of efficacy. The aim of this review is to explore the available evidence in relation to the pharmacokinetics, efficacy and reported adverse effects of the topical diclofenac formulations available. In the majority of studies examined, topical diclofenac formulations with sodium lotion, lecithin or epolamine gel, patch or plaster were either superior or equivalent to oral diclofenac formulations or placebo. Topical diclofenac significantly reduced pain and morning stiffness and improved physical function and patient global assessment without major adverse effects reported in patients with OA of the knee; and provided significant pain relief in patients with sports and soft tissue injuries involving the ankle, knee or shoulder. In the majority of studies, the predominant adverse effect involved pruritus or rash at the site of application, or nausea. The principle outcome of these studies is that topical diclofenac is a safe and practical alternative as a method of treatment in OA of the knee or as an alternative treatment for sports and soft tissue injury.


Lung volume reduction surgery vs medical treatment: for patients with advanced emphysema.
To contribute to the knowledge on the therapeutic value of lung volume reduction surgery (LVRS). Two similar, independently conceived and conducted, multicenter, randomized clinical trials. The Canadian Lung Volume Reduction (CLVR) study and the Overholt-Blue Cross Emphysema Surgery Trial (OBEST). Using a fixed-effects meta-analysis, the 6-month results produced by the addition of LVRS to optimal medical therapy were compared to those obtained from optimal medical therapy alone. Patients were required to have severe emphysema, marked airflow limitation (ie, FEV(1), 15 to 40% predicted), hyperinflation (total lung capacity [TLC], > 120% predicted), CO(2), < 55 mm Hg, and measurable dyspnea (chronic respiratory disease questionnaire [CRDQ] scores </= 4 for the CLVR study, or Medical Research Council dyspnea scale >/= 1 for the OBEST). Optimal medical therapy included pulmonary rehabilitation in both arms of both studies. The CLVR study randomized 58 patients and the OBEST randomized 35 patients for a total of 93 patients. Of these, 54 patients were randomized to undergo surgery, and 39 patients were randomized to receive medical treatment. The 6-month mortality rate (including operative mortality) in the surgical and medical cohorts was similar (5.6% vs 5.1%, respectively). A comparison of the medical and surgical arms of the combined CLVR study/OBEST population showed that LVRS was associated with a higher FEV(1) (167 mL or 24% predicted; 95% confidence interval [CI], 29 to 304; p = 0.017), lower residual volume (-1,342 mL or 24.5% predicted; 95% CI, -1,844 to -840; p < 0.001), lower TLC (-1,044 mL or 13% predicted; 95% CI, -1483 to -605; p < 0.001), and higher 6-min walk distance (148.8 feet; 95% CI, 24.3 to 273.2; p = 0.019). Each domain of the CRDQ showed statistically significant improvement in the surgical arm of the study, but not in the medical arm. The summary physical component scale of the Medical Outcomes Study 36-item short form (SF-36) was also more favorable in the LVRS cohort (6.9; 95% CI, 2.86 to 10.90; p < 0.001). The summary mental component scale of the SF-36 did not show a statistically significant difference between the two groups. Six months after randomization, LVRS produced better palliation than optimal medical therapy in patients with advanced emphysema.


Overexpression of a High-Affinity Nitrate Transporter OsNRT2.1 Increases Yield and Manganese Accumulation in Rice Under Alternating Wet and Dry Condition.
Nitrate and manganese (Mn) are necessary elements for the growth and development of rice in paddy soil. Under physiological conditions, we previously reported that the uptake of Mn in roots can be improved by the addition of external nitrate but not ammonium. To investigate the mechanism(s) of this phenotype, we produced plant lines overexpressing OsNRT2.1 and assessed Mn uptake under alternating wet and dry (AWD) and waterlogged (WL) conditions. Under AWD condition, we observed a 31% reduction in grain yields of wild type (WT) plants compared to WL condition. Interestingly, the overexpression of OsNRT2.1 could recover this loss, as OsNRT2.1 transgenic lines displayed higher grain yields than WT plants. We also observed 60% higher grain Mn in the transgenic lines in AWD condition and approximately 30% higher Mn in the grain of transgenic lines in WL condition. We further found that the overexpression of OsNRT2.1 did not alter Mg and Fe in the seeds in either growth condition. The reasons for the increased Mn content in OsNRT2.1 transgenic seeds in AWD condition could be explained by the elevated expression of OsNRAMP family genes including OsNRAMP3, OsNRAMP5, and OsNRAMP6 in node I, the panicle-neck, and the flag leaves. The mechanism(s) underpinning the upregulation of these genes requires further investigation. Taken together, our results provide a new function of OsNRT2.1 in improving rice yields and grain Mn accumulation during water-saving cultivation patterns. This represents a new strategy for maintaining yield and improving food quality in a sustainable agricultural system.


Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?
The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI). Data from all patients with BRAF-mutant metastatic melanoma with a highly elevated serum LDH at baseline (≥2× upper limit of normal) receiving first-line targeted therapy between 2012 and 2019 in the Netherlands were collected. Patients were stratified according to response status to targeted therapy and change in LDH at start of subsequent treatment with ICI. Differences in overall survival (OS) between the subgroups were compared using log-rank tests. After a median follow-up of 35.1 months, median OS of the total study population (n = 360) was 4.9 months (95% CI 4.4-5.4). Of all patients receiving subsequent treatment with ICI (n = 113), survival from start of subsequent treatment was significantly longer in patients who had normalized LDH and were still responding to targeted therapy compared to those with LDH that remained elevated (median OS 24.7 vs. 1.1 months). Our study suggests that introducing ICI upon response to targeted therapy with normalization of LDH could be an effective strategy in obtaining long-term survival in advanced melanoma patients with initial highly elevated serum LDH.


Adolescent fiber intake and mammographic breast density in premenopausal women.
To date, there is limited and inconsistent epidemiologic evidence for associations of adolescent diet with mammographic breast density, a strong and consistent predictor of breast cancer. We investigated the association of adolescent fiber intake with mammographic density in premenopausal women. This study included 743 cancer-free premenopausal women (mean age, 44.9 years) within the Nurses' Health Study II cohort. Percent breast density, absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique. Adolescent and adult diet were assessed with a food frequency questionnaire; energy-adjusted nutrient intakes were estimated for each food item. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between quartiles of adolescent fiber intake and each of the breast density measures, adjusted for potential confounders. Associations were examined separately for total fiber intake; fiber from fruits, vegetables, legumes, and cereal; and food sources of fiber (fruits, vegetables, and nuts). In multivariable analyses, total fiber intake during adolescence was not associated with percent breast density (p for trend = 0.64), absolute dense area (p for trend = 0.80), or non-dense area (p for trend = 0.75). Similarly, neither consumption of fiber from fruits, vegetables, legumes, or cereal nor specific sources of fiber intake (fruits, vegetables, or nuts) during adolescence were associated with any of the mammographic density phenotypes. Our findings do not support the hypothesis that adolescent fiber intake is associated with premenopausal mammographic breast density.


Mental Health Consequences for Healthcare Workers During the COVID-19 Pandemic: A Scoping Review to Draw Lessons for LMICs.
Background: The COVID-19 pandemic has had a significant impact on the mental health of healthcare workers (HCWs) particularly in low and middle-income countries (LMICs). This scoping review provides a summary of current evidence on the mental health consequences of COVID on HCWs. Methods: A scoping review was conducted searching PubMed and Embase for articles relevant to mental health conditions among HCWs during COVID-19. Relevant articles were screened and extracted to summarize key outcomes and findings. Results: A total of fifty-one studies were included in this review. Depressive symptoms, anxiety symptoms, psychological trauma, insomnia and sleep quality, workplace burnout and fatigue, and distress were the main outcomes reviewed. Most studies found a high number of symptoms endorsed for depression, anxiety, and other conditions. We found differences in symptoms by sex, age, and HCW role, with female, younger-aged, frontline workers, and non-physician workers being affected more than other subgroups. Conclusion: This review highlights the existing burden of mental health conditions reported by HCWs during COVID-19. It also demonstrates emerging disparities among affected HCW subgroups. This scoping review emphasizes the importance of generating high quality evidence and developing informed interventions for HCW mental health with a focus on LMICs.


Asynchronous, all-optical signal processing based on the self-frequency shift of a gigahertz Raman soliton.
Ultrafast asynchronous all-optical signal processing is experimentally demonstrated. It is based on the intensity-dependent, self-frequency shift of a gigahertz Raman soliton. We demonstrate error-free, asynchronous, all-optical, bit-by-bit, self-signal recognition and demultiplexing from contended optical packets without use of an optical buffer, control pulse, or bit-phase synchronization. Fourfold, contended, 9.95-Gbit/s optical packets are transmitted through a conventional repeater span of 80 km and simultaneously demultiplexed to multiwavelength 9.95-Gbit/s optical packets with 0.5-dB processing sensitivity. Furthermore, we successfully accomplish demultiplexing from overlapping signals in contended optical packets with better than 3-dB recognition sensitivity. We confirm the capability of realizing a 3x cascade operation from bit-error-rate measurements.


Capturing and testing perceptual-cognitive expertise: a comparison of stationary and movement response methods.
Numerous methods have been used to study expertise and performance. In the present article, we compare the cognitive thought processes of skilled soccer players when responding to film-based simulations of defensive situations involving two different experimental conditions. Participants either remained stationary in a seated position (n = 10) or were allowed to move (n = 10) in response to life-size film sequences of 11 versus 11 open-play soccer situations viewed from a player's perspective. Response accuracy and retrospective verbal reports of thinking were collected across the two task conditions. In the movement-based response group, participants generated a greater number of verbal report statements, including a higher proportion of evaluation, prediction, and action planning statements, than did participants in the stationary group. Findings suggest that the processing strategies employed during performance differ depending on the nature of the response required of participants. Implications for behavioral methods and experimental design are discussed.


Arthropod- and host-specific Borrelia burgdorferi bbk32 expression and the inhibition of spirochete transmission.
Antisera to BBK32 (a Borrelia burgdorferi fibronectin-binding protein) and BBK50, two Ags synthesized during infection, protect mice from experimental syringe-borne Lyme borreliosis. Therefore, B. burgdorferi bbk32 and bbk50 expression within Ixodes scapularis ticks and the murine host, and the effect of BBK32 and BBK50 antisera on spirochetes throughout the vector-host life cycle were investigated. bbk32 and bbk50 mRNA and protein were first detected within engorged ticks, demonstrating regulated expression within the vector. Then bbk32 expression increased in mice at the cutaneous site of inoculation. During disseminated murine infection, bbk32 and bbk50 were expressed in several murine tissues, and mRNA levels were greatest in the heart and spleen at 30 days. BBK32 antisera protected mice from tick-borne B. burgdorferi infection and spirochete numbers were reduced by 90% within nymphs that engorged on immunized mice. Moreover, 75% of these ticks did not retain spirochetes upon molting, and subsequent B. burgdorferi transmission by adult ticks was impaired. Larval acquisition of B. burgdorferi by I. scapularis was also inhibited by BBK32 antisera. These data demonstrate that bbk32 and bbk50 are expressed during tick engorgement and that BBK32 antisera can interfere with spirochete transmission at various stages of the vector-host life cycle. These studies provide insight into mechanisms of immunity to Lyme borreliosis and other vector-borne diseases.


Genetically determined fungal pathogen tolerance and soil variation influence ectomycorrhizal traits of loblolly pine.
Selection on genetically correlated traits within species can create indirect effects on one trait by selection on another. The consequences of these trait correlations are of interest because they may influence how suites of traits within species evolve under differing selection pressures, both natural and artificial. By utilizing genetic families of loblolly pine either tolerant (t) or susceptible (s) to two different suites of pathogenic fungi responsible for causing either pine decline or fusiform rust disease, we investigated trait variation and trait correlations within loblolly pine (Pinus taeda L.) by determining how ectomycorrhizal (EM) colonization relates to pathogen susceptibility. We detected interactions between susceptibility to pathogenic fungi and soil inoculation source on loblolly pine compatibility with the EM fungi Thelephora, and on relative growth rate of loblolly pine. Additionally, we detected spatial variation in the loblolly pine-EM fungi interaction, and found that variation in colonization rates by some members of the EM community is not dictated by genetic variation in the host plant but rather soil inoculation source alone. The work presented here illustrates the potential for indirect selection on compatibility with symbiotic EM fungi as a result of selection for resistance to fungal pathogens. Additionally, we present evidence that the host plant does not have a single "mycorrhizal trait" governing interactions with all EM fungi, but rather that it can interact with different fungal taxa independently. Synthesis. An understanding of the genetic architecture of essential traits in focal species is crucial if we are to anticipate and manage the results of natural and artificial selection. As demonstrated here, an essential but often overlooked symbiosis (that between plants and mycorrhizal fungi) may be indirectly influenced by directed selection on the host plant.


Scattering polarization by anisotropic biomolecules.
The full polarization properties of anisotropic biomolecule optical scattering are investigated theoretically. By using a simple ellipsoid model of a single biomolecule, the scattering fields and Mueller matrices are derived from fundamental electromagnetism theory. The energy of scattered photons is not necessarily equal to that of the incident laser beam. This theory can be generally applied to the experiments of fluorescence, Raman scattering, and second-harmonic generation. Fitting of a single tetramethylrhodamine-labeled lipid molecule's anisotropic imaging experiment is demonstrated. This theory has provided a fundamental simulation analysis tool of understanding and developing the optical polarimetric sensing science and technology of the anisotropic biomolecules and biomedium. The medium dielectric constant of the model ellipsoid provides a theoretic background for correlating the optical polarization properties of a biomolecule to its microscopic electronic structure.


Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study.
The profile of cognitive and behavioral variation observed in individuals with fragile X syndrome (FXS), the most common known cause of inherited intellectual impairment, suggests aberrant functioning of specific brain systems. Research investigating animal models of FXS, characterized by limited or lack of fragile X mental retardation protein, (FMRP), has linked brain dysfunction to deficits in the cholinergic and glutamatergic systems. Thus, we sought to examine in vivo levels of neurometabolites related to cholinergic and glutamatergic functioning in males and females with FXS. The study participants included 18 adolescents and young adults with FXS, and a comparison group of 18 individuals without FXS matched for age, sex and general intellectual functioning. Proton magnetic resonance spectroscopy (MRS) was used to assess neurometabolite levels in the caudate nucleus, a region known to be greatly enlarged and involved in abnormal brain circuitry in individuals with FXS. A general linear model framework was used to compare group differences in metabolite concentration. We observed a decrease in choline (P = 0.027) and in glutamate + glutamine (P = 0.032) in the caudate nucleus of individuals with FXS, relative to individuals in the comparison group. This study provides evidence of metabolite differences in the caudate nucleus, a brain region of potential importance to our understanding of the neural deficits underlying FXS. These metabolic differences may be related to aberrant receptor signaling seen in animal models. Furthermore, identification of the specific neurometabolites involved in FXS dysfunction could provide critical biomarkers for the design and efficacy tracking of disease-specific pharmacological treatments.


Relationship between football playing ability and selected performance measures.
The relationships between football playing ability (FPA) and selected anthropometric and performance measures were determined among NCAA Division I-A football players (N = 40). Football playing ability (determined by the average of coaches' rankings) was significantly correlated with vertical jump (VJ) in all groups (offense, defense, and position groups of wide receiver-defensive back, offensive linemen-defensive linemen, and running back-tight end-linebacker). Eleven of 50 correlations (groups by variables), or 22%, were important for FPA. Five of the 11 relationships were related to VJ. Forward stepwise regression equations for each group explained over half of the criterion variable, FPA, as indicated by the R(2) values for each model. Vertical jump was the prime predictor variable in the equations for all groups. The findings of this study are discussed in relation to the specificity hypothesis. Strength and conditioning programs that facilitate the capacity for football players to develop forceful and rapid concentric action through plantar flexion of the ankle, as well as extension of the knee and hip, may be highly profitable.


Photoinduced structural distortions and singlet-triplet intersystem crossing in Cu(i) MLCT excited states monitored by optically gated fluorescence spectroscopy.
Copper(i) phenanthroline complexes represent viable earth-abundant alternatives to the ubiquitous Ru(ii) tris-bipyridine photosensitizers owing to their similar metal-to-ligand charge transfer (MLCT) properties. A well-established complication of Cu(i) phenanthroline complexes is that they can undergo significant photo-induced structural rearrangements, leading to excited states that are highly susceptible to exciplex formation and short-lived. In this work, a comprehensive analysis of the photo-induced structural distortions and singlet-triplet intersystem crossing dynamics of a series of four sterically encumbered Cu(i) phenanthroline chromophores has been conducted, namely, [Cu(dsbp)2]+ (dsbp = 2,9-di-sec-butyl-1,10-phenanthroline), [Cu(dsbtmp)2]+ (dsbtmp = 2,9-di-sec-butyl-3,4,7,8-tetramethyl-1,10-phenanthroline), [Cu(dipp)2]+ (dipp = 2,9-di-isopropyl-1,10-phenanthroline), and [Cu(diptmp)2]+ (diptmp = 2,9-di-isopropyl-3,4,7,8-tetramethyl-1,10-phenanthroline). Upconverted fluorescence decay kinetics were measured at wavelengths along the blue side of the photoluminescence spectrum. The experimental results displayed strong wavelength dependence of the singlet emission, with rapid sub-picosecond decay dominating at higher energies. At lower emission energies, increasing contribution of a longer decay component was revealed. This wavelength dependence is a signature of the excited state structural rearrangement of the phenanthroline ligands which concomitantly lower the excited state energy. The obtained time constants were in excellent agreement with those measured in the complementary ultrafast transient absorption experiments. The sub-picosecond component (prompt fluorescence) is associated with the photo-induced structural rearrangement that lowers the energy of the singlet excited state. The longer decay component represents the lifetime of the S1 excited state, and thus the time-scale of singlet-triplet intersystem crossing. Lastly, the observed dual emission was further characterized by constructing picosecond time-resolved emission spectra from the measured kinetic data. These qualitative luminescence spectra capture the resulting emission from both the S1 initial state and the S1 flattened state, providing further insight into the energy-lowering excited state distortion across the series.


Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer.
Basal-like breast cancer (BLBC) is an aggressive disease that lacks a clinically approved targeted therapy. Traditional chemotherapy is effective in BLBC, but it spares the cancer stem cell (CSC)-like population, which is likely to contribute to cancer recurrence after the initial treatment. Dual specificity phosphatase-4 (DUSP4) is a negative regulator of the mitogen-activated protein kinase (MAPK) pathway that is deficient in highly aggressive BLBCs treated with chemotherapy, leading to aberrant MAPK activation and resistance to taxane-induced apoptosis. Herein, we investigated how DUSP4 regulates the MAP-ERK kinase (MEK) and c-jun-NH2-kinase (JNK) pathways in modifying CSC-like behavior. DUSP4 loss increased mammosphere formation and the expression of the CSC-promoting cytokines interleukin (IL)-6 and IL-8. These effects were caused in part by loss of control of the MEK and JNK pathways and involved downstream activation of the ETS-1 and c-JUN transcription factors. Enforced expression of DUSP4 reduced the CD44(+)/CD24(-) population in multiple BLBC cell lines in a MEK-dependent manner, limiting tumor formation of claudin-low SUM159PT cells in mice. Our findings support the evaluation of MEK and JNK pathway inhibitors as therapeutic agents in BLBC to eliminate the CSC population.


Variation in care for patients presenting with hip fracture in six high-income countries: A cross-sectional cohort study.
Hip fractures are costly and common in older adults, but there is limited understanding of how treatment patterns and outcomes might differ between countries. We performed a retrospective serial cross-sectional cohort study of adults aged ≥66 years hospitalized with hip fracture between 2011 and 2018 in the US, Canada, England, the Netherlands, Taiwan, and Israel using population-representative administrative data. We examined mortality, hip fracture treatment approaches (total hip arthroplasty [THA], hemiarthroplasty [HA], internal fixation [IF], and nonoperative), and health system performance measures, including hospital length of stay (LOS), 30-day readmission rates, and time-to-surgery. The total number of hip fracture admissions between 2011 and 2018 ranged from 23,941 in Israel to 1,219,696 in the US. In 2018, 30-day mortality varied from 3% (16% at 1 year) in Taiwan to 10% (27%) in the Netherlands. With regards to processes of care, the proportion of hip fractures treated with HA (range 23%-45%) and THA (0.2%-10%) differed widely across countries. For example, in 2018, THA was used to treat approximately 9% of patients in England and Israel but less than 1% in Taiwan. Overall, IF was the most common surgery performed in all countries (40%-60% of patients). IF was used in approximately 60% of patients in the US and Israel, but only 40% in England. In 2018, rates of nonoperative management ranged from 5% of patients in Taiwan to nearly 10% in England. Mean hospital LOS in 2018 ranged from 6.4 days (US) to 18.7 days (England). The 30-day readmission rate in 2018 ranged from 8% (in Canada and the Netherlands) to nearly 18% in England. The mean days to surgery in 2018 ranged from 0.5 days (Israel) to 1.6 days (Canada). We observed substantial between-country variation in mortality, surgical approaches, and health system performance measures. These findings underscore the need for further research to inform evidence-based surgical approaches.


Evaluation of miCRovascular rarefaction in vascUlar Cognitive Impairment and heArt faiLure (CRUCIAL): Study protocol for an observational study.
Microvascular rarefaction, the functional reduction in perfused microvessels and structural reduction of microvascular density, seems to be an important mechanism in the pathophysiology of small blood vessel related disorders including vascular cognitive impairment (VCI) due to cerebral small vessel disease and heart failure with preserved ejection fraction (HFpEF). Both diseases share common risk factors including hypertension, diabetes mellitus, obesity, and ageing; in turn, these co-morbidities are associated with microvascular rarefaction. Our consortium aims to investigate novel non-invasive tools to quantify microvascular health and rarefaction in both organs, as well as surrogate biomarkers for cerebral and/or cardiac rarefaction (via sublingual capillary health, vascular density of the retina, and RNA content of circulating extracellular vesicles), and to determine whether microvascular density relates to disease severity. The clinical research program of CRUCIAL consists of four observational cohort studies. We aim to recruit 75 VCI patients, 60 HFpEF patients, 60 patients with severe aortic stenosis (AS) undergoing surgical aortic valve replacement as a pressure overload HFpEF model, and 200 elderly participants with mixed comorbidities to serve as controls. Data collected will include medical history, physical examination, cognitive testing, advanced brain and cardiac MRI, ECG, echocardiography, sublingual capillary health, optical coherence tomography angiography (OCTa), extracellular vesicles RNA analysis and myocardial remodelling-related serum biomarkers. The AS cohort undergoing surgery will also have myocardial biopsy for histological microvascular assessment. CRUCIAL will examine the pathophysiological role of microvascular rarefaction in VCI and HFpEF using advanced brain and cardiac MRI techniques. Furthermore, we will investigate surrogate biomarkers for non-invasive, faster, easier, and cheaper assessment of microvascular density since these are more likely to be disseminated into widespread clinical practice. If microvascular rarefaction is an early marker of developing small vessel diseases, then measuring rarefaction may allow pre-clinical diagnosis, with implications for screening, risk stratification, and prevention. Further knowledge of the relevance of microvascular rarefaction and its underlying mechanisms may provide new avenues for research and therapeutic targets.