Modeling parents and nurses' relationships.
Over the past 20 years, the transition to parenting has been widely investigated as much in nursing as in psychology. The challenges of this developmental period, such as developing parenting efficacy, and the resources available to one or both parents have been explored. Different factors have been found to influence parents' perceived efficacy, such as the quality of social support, the quality of the marital relationship, and the level of stress and anxiety. Little attention has been paid, however, to the influence of nurses' relationships with parents on parents' development of parenting efficacy, especially with multiparous parents. This information is needed to better understand nurses' contribution to parenting development. A model of the primary variables of interest -- perceived parenting efficacy, critical events, and nurses' collaborative and help-giving practices -- is presented.


Using the singlet oxygen scavenging property of carotenoid in photodynamic molecular beacons to minimize photodamage to non-targeted cells.
We recently introduced the concept of photodynamic molecular beacons (PMB) for selective control of photodynamic therapy (PDT). The PMB consists of a peptide linker that is sequence specific to a cancer-associated protease. A photosensitizer (PS) and a singlet oxygen (1O2) quencher are conjugated to the opposite ends of this linker. Proximity of the PS and quencher can efficiently inhibit 1O2 generation. In the presence of a targeted protease, the substrate sequence is cleaved and the PS and quencher will separate so that the PS can be photo-activated. There are two ways to optimize the PMB selectivity to cancer cells. The first is to increase the protease specificity to targeted cells and the second is to minimize the phototoxicity of intact (uncleaved) PMBs in non-targeted (normal) cells. Carotenoids (CARs) are well known in nature for their role in quenching excited states of PS and in directly scavenging 1O2. The purpose of this study is to evaluate whether the CAR with dual quenching modes (PS excited states deactivation and 1O2 scavenging) can be used to minimize the photodamage of intact PMBs to non-targeted cells. Thus, we synthesized a beacon (PPC) with a caspase-3 cleavable peptide linking a PS and a CAR quencher. It was confirmed that CAR deactivates the PS excited states and also directly scavenges 1O2. Moreover, the in vitro PDT response showed that CAR completely shuts off the photodynamic effect in non-targeted HepG(2) cells, while PS without CAR (control) remains highly potent even at a much lower (30-fold) dose.


Satisfaction of Vietnamese patients and their families with refugee and mainstream mental health services.
The study examined levels of satisfaction with mainstream mental health services and specialized mental health services for refugees among Vietnamese psychiatric patients and their relatives. Demographic, diagnostic, symptomatic, and service-related issues that might influence satisfaction were investigated. Eighty-six Vietnamese patients were identified from case notes of mainstream inpatient services (N = 31), mainstream community services (N = 7), and a specialized refugee treatment unit (N = 48). During an interview, a scale measuring satisfaction with treatment as well as measures of anxiety, depression, and posttraumatic stress disorder was administered to them. A modified satisfaction scale was administered to 56 relatives. Patients and relatives were, on average, moderately satisfied with treatment. Patients expressed greater satisfaction with the specialized treatment unit for refugees than with mainstream services, a finding that was not influenced by diagnostic differences or symptom levels at the time patients responded. Further analyses controlling for multiple comparisons revealed that the extent of the information provided and the ease of negotiating changes in treatment were the most salient variables in distinguishing satisfaction levels across the two types of treatment centers. Patients' fluency in English and their relatives' level of education were inversely associated with satisfaction scores, tentatively suggesting that the greater the ability of patients and their families to evaluate services, the less likely they were to express satisfaction with treatment. Specialized mental health services for refugees may be more acceptable to refugee populations than their mainstream counterparts, perhaps because better communication with patients and their families is possible in the specialized services. Patients and families who are in a position to evaluate services fully are more likely to be critical of treatments offered.


Comparison of diabetic and non-diabetic patients referred for coronary angiography.
To evaluate whether diabetic patients differ from non-diabetic patients when referred for coronary angiography regarding previous history, indication for and findings at coronary angiography, use of medication, exercise test results and mortality. Data were prospectively collected on patients referred for consideration of coronary revascularization to seven of the eight public Swedish heart centers that performed approximately 92% of all bypass operations in Sweden in 1994. 2762 patients were included of whom 406 (15%) had a history of diabetes mellitus. There was no difference in age or sex in the two groups. Chronic stable angina was the most common indication (73% in both groups) and only 3% were admitted due to silent ischemia. Diabetic patients had more severe symptoms (Canadian Cardiovascular Society III-IV) than non-diabetic patients (66% vs. 58%, p<0.01). They more frequently used ACE-inhibitors (33% vs. 19%, p<0.0001) and calcium channel blockers (47% vs. 40%, p<0.01) and more often had a diagnosis of arterial hypertension than non-diabetic patients (50% vs. 33%, p<0.0001). Diabetic patients more often had depressed myocardial function (EF<35%); 12% and 8%, respectively (p<0.01), and more extensive coronary artery disease (left main/3-VD; 48% vs. 37%, p<0.001). The mortality during the subsequent 21 months was 7.9% among diabetic patients and 3.6% among non-diabetic patients (p<0.001). Among patients being referred for coronary angiography in Sweden, 15% were patients with a history of diabetes. They differed from patients without such a history by more often having severe symptoms and a higher prevalence of left main/triple vessel disease. Coronary angiography may thus be underused in diabetic patients with chest pain.


Demographic and socioeconomic determinants of COVID-19 across Oman - A geospatial modelling approach.
Local, bivariate relationships between coronavirus 2019 (COVID-19) infection rates and a set of demographic and socioeconomic variables were explored at the district level in Oman. To limit multicollinearity a principal component analysis was conducted, the results of which showed that three components together could explain 65% of the total variance that were therefore subjected to further study. Comparison of a generalized linear model (GLM) and geographically weighted regression (GWR) indicated an improvement in model performance using GWR (goodness of fit=93%) compared to GLM (goodness of fit=86%). The local coefficient of determination (R2) showed a significant influence of specific demographic and socioeconomic factors on COVID-19, including percentages of Omani and non-Omani population at various age levels; spatial interaction; population density; number of hospital beds; total number of households; purchasing power; and purchasing power per km2. No direct correlation between COVID- 19 rates and health facilities distribution or tobacco usage. This study suggests that Poisson regression using GWR and GLM can address unobserved spatial non-stationary relationships. Findings of this study can promote current understanding of the demographic and socioeconomic variables impacting the spatial patterns of COVID-19 in Oman, allowing local and national authorities to adopt more appropriate strategies to cope with this pandemic in the future and also to allocate more effective prevention resources.


Abnormal captopril renogram with a technetium-99m-labeled hippuran analog.
A case of renovascular hypertension is presented in which the [131I]hippuran renogram was initially normal, but became strikingly abnormal upon administration of the angiotensin converting enzyme (ACE) inhibitor captopril. The patient presented with fibromuscular dysplasia of the renal arteries, which was shown by hippuran renography to be functionally significant on the right side. She became normotensive after angioplasty of the right renal artery. Hypertension recurred a year later, at which time the renogram was normal without captopril, but showed functionally significant left renal artery stenosis with captopril challenge. Both the conventional agent, [131I]hippuran, and an experimental new 99mTc-labeled hippuran analog, [99mTc]MAG3, were used. Angiography confirmed progression of disease on the left side, which was successfully treated by angioplasty. Functionally significant unilateral renal artery stenosis was thus demonstrated first on the right side and then, 1 yr later, on the left side, using hippuran and [99mTc]MAG3. Anatomic progression of disease was documented by angiography.


Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk.
Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal-Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.


Fluorimetric Techniques for the Assessment of Sperm Membranes.
Standard spermiograms describing sperm quality are mostly based on the physiological and visual parameters, such as ejaculate volume and concentration, motility and progressive motility, and sperm morphology and viability. However, none of these assessments is good enough to predict the semen quality. Given that maintenance of sperm viability and fertilization potential depends on membrane integrity and intracellular functionality, evaluation of these parameters might enable a better prediction of sperm fertilization competence. Here, we describe three feasible methods to evaluate sperm quality using specific fluorescent probes combined with fluorescence microscopy or flow cytometry analyses. Analyses assessed plasma membrane integrity using 4',6-diamidino-2-phenylindole (DAPI) and propidium iodide (PI), acrosomal membrane integrity using fluorescein isothiocyanate-conjugated Pisum sativum agglutinin (FITC-PSA) and mitochondrial membrane integrity using 5,5',6,6'-tetra-chloro-1,1',3,3'-tetraethylbenzimidazolyl carbocyanine iodide (JC-1). Combinations of these methods are also presented. For instance, use of annexin V combined with PI fluorochromes enables assessing apoptosis and calculating the proportion of apoptotic sperm (apoptotic index). We believe that these methodologies, which are based on examining spermatozoon membranes, are very useful for the evaluation of sperm quality.


Lymphoepithelial cyst of the pancreas.
A rare case of lymphoepithelial cyst of the pancreas is reported. Microscopically the cyst content consisted of keratinous material and the walls were lined by mature squamous epithelium surrounded by dense lymphoid tissue. Immunohistochemistry showed diffuse reactivity for CD20 and CD3 in the lymphoid tissue and uniform positivity for cytokeratins in the squamous epithelium. Although the histogenesis of lymphoepithelial cysts of the pancreas is not understood, awareness of this lesion is helpful in differentiating it from other pancreatic cystic lesions.


The activation of effect codes in response preparation: new evidence from an indirect priming paradigm.
Evidence for the anticipation of environmental effects as an integral part of response planning comes mainly from experiments in which the effects were physically presented. Thus, in these studies it cannot be excluded that effect codes were activated during response preparation only because the effects were displayed as external stimuli before response execution. In order to provide more clear-cut evidence for the anticipation of response effects in action planning, we performed a series of three experiments using a new paradigm, where displaying effect codes before the response was avoided. Participants first learned arbitrary effects of key-pressing responses. In the following test phase they were instructed to execute a response only if a Go stimulus was presented after a variable stimulus onset asynchrony (SOA). The Go stimulus was either compatible or incompatible with the effect, but independent of the response. In Experiment 1 we tested the paradigm with two responses and two effects. We found a significant compatibility effect: If the Go stimulus was compatible with the response effect, responses were initiated faster than in incompatible trials. In Experiment 2 response effects were only present in the acquisition phase, but not in the test phase. The compatibility effect disappeared, indicating that the results of Experiment 1 were indeed related to the anticipation of the forthcoming response effects. In Experiment 3 we extended this paradigm by using a larger number of stimuli and response alternatives. Again we found a robust compatibility effect, which can only be explained if the effect representations are active before response execution. The compatibility effects in Experiments 1 and 3 did not depend on the SOA. The fact that the Go stimulus affected response preparation at any time indicates that the role of effect anticipation is not limited to response selection.


Morphological and biochemical characterization of influenza vaccines commercially available in the United Kingdom.
Four vaccines are available in the United Kingdom against influenza virus. All are subunit vaccines, defined as either split-virion or purified surface antigen vaccine; there are two of each distinct type available. Both vaccine types are less reactogenic than whole inactivated virus, with antigenicity induced by viral surface glycoproteins. Here, each of the four vaccines has been characterized by electron microscopy and SDS-PAGE analysis, giving a unique vaccine profile. Three vaccines contain internal viral nucleoprotein which, in the presence of residual haemagglutinin, may induce an influenza A virus cross-reactive cytotoxic T-cell response and thus be of value to vaccine efficacy. Residual lipid was present in three vaccines and recent evidence suggests that pyrogenicity is correlated with the presence of viral lipid with clusters of surface glycoproteins. By a combination of electron microscopic evidence and biochemical characterization, it has been possible to resolve compositional differences, not only between vaccine type, but also between each individual currently available vaccine. Hence, there is the possibility that the morphological differences characterized here may be contributory to potential reactogenic effects subsequent to vaccination.


Hormonal implications of the hypocholesterolemic effect of intake of field beans (Vicia faba L.) by young men with hypercholesterolemia.
This study examined the hypocholesterolemic effect and hormonal changes resulting from 30 d of supplementation with Vicia faba L. (field bean) flour of diets of young men (aged 18-21 y; n = 40) with borderline-high or high serum cholesterol values. All subjects (groups A-D) consumed the same basic diet. Additionally, volunteers in the control group (A) consumed 90 g control flour/d whereas those in the three bean groups received either 90 g cooked field bean flour (groups B and C) or 90 g raw field bean flour (group D) daily. Groups A and B included volunteers with borderline-high cholesterol values [5.2-6.2 mmol total cholesterol/L and 3.4-4.1 mmol low-density-lipoprotein (LDL) cholesterol/L]. Subjects in groups C and D had high serum cholesterol concentrations (total cholesterol > 6.2 mmol/L and LDL cholesterol > 4.1 mmol/L). After 30 d, serum glucose, insulin, triacylglycerol, total, LDL-cholesterol, and very-low-density-lipoprotein (VLDL)-cholesterol values were significantly lower than initial values in all subjects who consumed diets containing field bean flour (P < or = 0.0001, except for LDL-cholesterol concentrations in group C, for which P < or = 0.0007). Legume intake also resulted in a significant increase (P < or = 0.0001) in glucagon and high-density-lipoprotein cholesterol. Neither cortisol nor thyroid hormone values changed significantly. The results suggest that the hypocholesterolemic effect of field bean intake depends at least partly on a concomitant increase in glucagon and decrease in insulin values. The more marked reduction in triacylglycerol and VLDL-cholesterol concentrations in subjects who consumed raw field beans indicates a coparticipation of their thermolabile components.


Patient Experiences at Enhanced-Service Pharmacies in Iowa.
As payment systems are evolving, the role of community pharmacists has expanded from simply dispensing prescriptions to actively providing care to patients. Little is known about patients' experiences with enhanced pharmacy services under the pay-forperformance model. In Iowa, Wellmark implemented its Value-Based Pharmacy Program (VBPP) where pharmacists receive capitation for performance on a set of quality measurements. Therefore, the objective of this study was to evaluate the quality of services and pharmacies from patients' perspective in VBPP. A structured interview guide developed from the service quality model was used for this study. We conducted telephone interviews with patients from 6 community pharmacies participating in VBPP between December 2017 and January 2018. Patients who were aged between 21 and 90 years, had Wellmark prescription drug coverage, were currently on at least three medications with one or more of the medications for a chronic condition and had received enhanced pharmacy services were invited for the study. The semi-structured interview transcripts were coded and analyzed using an inductive approach of thematic analysis. Interviews were completed by 25 patients. Most of them were female and the average age was 59. More than half of the patients were taking at least five medications for chronic conditions. A majority of the patients received medication synchronization and immunization. A total of 13 themes across the service quality dimensions were identified. Patients thought their pharmacists were reliable, responsive, knowledgeable and trustworthy when they provided services. Pharmacy services were accessible and perceived as high quality. Privacy was not a big concern for most patients. Patients had a somewhat limited view regarding how pharmacists helped them maintain health. Patients' perceptions of enhanced pharmacy services and pharmacies were generally positive while their understanding of pharmacists' clinical role was limited.


The Yersinia pestis type III secretion system: expression, assembly and role in the evasion of host defenses.
Yersinia pestis, the etiologic agent of plague, utilizes a type III secretion system (T3SS) to subvert the defenses of its mammalian hosts. T3SSs are complex nanomachines that allow bacterial pathogens to directly inject effector proteins into eukaryotic cells. The Y. pestis T3SS is not expressed during transit through the flea vector, but T3SS gene expression is rapidly thermoinduced upon entry into a mammalian host. Assembly of the T3S apparatus is a highly coordinated process that requires the homo- and hetero-oligomerization over 20 Yersinia secretion (Ysc) proteins, several assembly intermediates and the T3S process to complete the assembly of the rod and external needle structures. The activation of effector secretion is controlled by the YopN/TyeA/SycN/YscB complex, YscF and LcrG in response to extracellular calcium and/or contact with a eukaryotic cell. Cell contact triggers the T3S process including the secretion and assembly of a pore-forming translocon complex that facilitates the translocation of effector proteins, termed Yersinia outer proteins (Yops), across the eukaryotic membrane. Within the host cell, the Yop effector proteins function to inhibit bacterial phagocytosis and to suppress the production of pro-inflammatory cytokines.


Evaluating the physiological reserves of older patients with cancer: the value of potential biomarkers of aging?
Aging of an individual entails a progressive decline of functional reserves and loss of homeostasis that eventually lead to mortality. This process is highly individualized and is influenced by multiple genetic, epigenetic and environmental factors. This individualization and the diversity of factors influencing aging result in a significant heterogeneity among people with the same chronological age, representing a major challenge in daily oncology practice. Thus, many factors other than mere chronological age will contribute to treatment tolerance and outcome in the older patients with cancer. Clinical/comprehensive geriatric assessment can provide information on the general health status of individuals, but is far from perfect as a prognostic/predictive tool for individual patients. On the other hand, aging can also be assessed in terms of biological changes in certain tissues like the blood compartment which result from adaptive alterations due to past history of exposures, as well as intrinsic aging processes. There are major signs of 'aging' in lymphocytes (e.g. lymphocyte subset distribution, telomere length, p16INK4A expression), and also in (inflammatory) cytokine expression and gene expression patterns. These result from a combination of the above two processes, overlaying genetic predispositions which contribute significantly to the aging phenotype. These potential "aging biomarkers" might provide additional prognostic/predictive information supplementing clinical evaluation. The purpose of the current paper is to describe the most relevant potential "aging biomarkers" (markers that indicate the biological functional age of patients) which focus on the biological background, the (limited) available clinical data, and technical challenges. Despite their great potential interest, there is a need for much more (validated) clinical data before these biomarkers could be used in a routine clinical setting. This manuscript tries to provide a guideline on how these markers can be integrated in future research aimed at providing such data.


Sumanene: an efficient π-bowl for dihydrogen storage.
Density functional theory calculations at the M06L/6-311++G(d,p) level show that sumanene (Su), a polycyclic aromatic π-bowl, and its anionic forms possess high dihydrogen binding affinity. The dihydrogen rich systems such as Su(H2)40, Su-(H2)40, and Su2-(H2)40 show interaction energy (Eint) values of 51.7, 63.0 and 87.6 kcal mol-1, respectively. The ion-pair complexes of anionic, dianionic and trianionic sumanenes with K+ also have a significant H2 binding capacity with Eint values of 61.6 kcal mol-1 for Su-K+(H2)47, 77.1 kcal mol-1 for Su2-(K+)2(H2)51 and 132.6 kcal mol-1 for Su3-(K+)3(H2)51. The charge delocalization in the complex increases substantially with an increase in the amount of H2 adsorbed, which parallels with a declining trend in the magnitude of the molecular electrostatic potential (MESP) minimum (Vmin) for Su, Su-, Su2-, Su-K+, Su2-(K+)2, and Su3-(K+)3. Also, using quantum theory of atoms in molecules (QTAIM) analysis, sumaneneH2 noncovalent interactions and secondary dihydrogen interactions within the complex are established by locating bond critical points (bcp). The structured network of noncovalent bonds in the complex accounts for the stability of the complex. Further, by replacing K+ with lighter metals such as Li+ or Na+, a 66-74% increase in Eint is observed for anion-M+ and dianion-(M+)2 ion pairs. Our results prove that sumanene systems possess significant dihydrogen binding affinity, which can be employed in developing efficient hydrogen storage systems.


Antibody inhibition of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 reduces rapid exocytosis in insulin-secreting cells.
SNARE-proteins (soluble NSF-attachment protein receptor) are important for Ca(2+)-dependent exocytosis. We have used capacitance measurements and confocal imaging to dissect the role of synaptosomal protein of 25 kDa (SNAP-25) and syntaxin 1 in rapid exocytosis in insulin-secreting pancreatic beta-cells. Following immunoneutralization of syntaxin 1 and SNAP-25, exocytosis was strongly reduced and associated with a marked reduction in the size of the readily releasable pool (RRP) by 65% and 86% in the presence of the anti-SNAP-25 and anti-syntaxin 1 antibodies respectively. The size of the immediately releasable pool (IRP), a subset of RRP in close association with the voltage-dependent Ca(2+)-channels, was reduced to an equal extent. The reduction in IRP correlated with slowed release kinetics and the time constant (tau) increased from a control value of 16 to 36 ms and 51 ms after inclusion of anti-SNAP-25 and anti-syntaxin 1 antibodies respectively in the pipette solution. We further show that SNAP-25 and syntaxin 1 aggregate in clusters along the plasma membrane. The size of these clusters was estimated to be approximately 300 nm and every beta-cell contained approximately 400 SNAP-25/syntaxin 1 clusters. Whereas the inhibitory action of the anti-syntaxin 1 antibody on exocytosis could be attributed almost entirely to suppression of the voltage-dependent Ca(2+)-current (-40%), the effect of the anti-SNAP-25 antibody was not mediated by decreased Ca(2+)-entry and is more likely due to a direct interference with the exocytotic machinery. Our data are consistent with the concept that both syntaxin 1 and SNAP-25 are required for rapid exocytosis in beta-cells.


The impact of acculturation on the use of traditional Chinese medicine in newly diagnosed Chinese cancer patients.
This study assessed the impact of acculturation on the prevalence of traditional Chinese medicine and other complementary and alternative medicine (TCM/CAM) use in newly diagnosed Chinese cancer patients. The individual determinants of TCM/CAM use among patients were also investigated. A consecutive sample of Chinese cancer patients treated at the British Columbia Cancer Agency was surveyed at admission using a 15-item questionnaire. Items included TCM/CAM use, sociodemographics, as well as medical and cultural factors. Data were analyzed using bivariate methods including Pearson's X (2) test and Student's t test. As well, multiple logistic regression was used to obtain the final causal model. Of the 230 respondents, 57% completed the survey in Chinese and 94% were immigrants. The average age was 59. Participants had a mean disease duration of approximately 2 months and 79% had already received at least one conventional treatment. Overall, TCM/CAM was used by 47% of respondents. Herbal remedies, vitamins/minerals, and prayer were the most commonly used therapies. Multivariable analysis showed that prior TCM/CAM use (p < 0.001), having received conventional treatment(s) (p = 0.029), and being less acculturated (p = 0.028) were associated with TCM/CAM use. Prevalence and type of use were found to vary as a function of the degree of acculturation. Health care practitioners would be well advised to discuss TCM/CAM use with their patients, especially those who are less acculturated to Western society, since they are the most likely users of TCM/CAM.


Vertebral fractures predict subsequent fractures.
This population-based study documents an increase in most types of fractures following the occurrence of a clinically recognized vertebral fracture among 820 Rochester, Minnesota, residents. During 4349 person-years of follow-up, 896 new fractures were observed. Relative to incidence rates in the community, there was a 2.8-fold increase in the risk of any fracture, which was greater in men (standardized incidence ratio (SIR), 4.2; 95% CI, 3.2-5.3) than women (SIR, 2.7; 95% CI, 2.4-3.0). The estimated cumulative incidence of any fracture after 10 years was 70%. The greatest increase in risk was for subsequent fractures of the axial skeleton, in particular a 12.6-fold increase (95% CI, 11-14) in additional vertebral fractures. There was a lesser increase in most limb fractures, including a 2.3-fold increase (95% CI, 1.8-2.9) in hip fractures and a 1.6-fold increase (95% CI, 1.01-2.4) in distal forearm fractures. There was a slightly greater association with distal forearm fractures among those whose first vertebral fracture occurred before age 70 years but a similar relationship with hip fractures, including cervical and intertrochanteric hip fractures separately, regardless of age at the initial vertebral fracture. There was also an equivalent increase in subsequent fracture risk whether the initial vertebral fracture was attributed to severe or moderate trauma. These data show that vertebral fractures represent an important risk factor for fractures in general, not just those of the spine and hip.


Characterization of lymphocyte responsiveness in early experimental syphilis. I. In vitro response to mitogens and Treponema pallidum antigens.
Lymphoid cells from spleens and lymph nodes of rabbits infected with T. pallidum respond by proliferation to concanavalin A (Con A) and T. pallidum antigens. Spleen cell responsiveness to treponemal antigens appears 6 days after infection, is 100 to 600 fold higher than the response of uninfected control rabbits, and is maintained throughout the 31-day observation period. Specifically responding cells in the inguinal and popliteal lymph nodes of infected animals are demonstrable on day 10, and the magnitude of the response increases throughout the observation period. Specific responsiveness to T. pallidum antigens in vitro is enhanced in purified T cell populations and is abolished by treatment with goat anti-rabbit thymocyte serum and complement. The response of spleen and lymph node cells to Con A is unaffected during syphilitic infection. These results are consistent with a role for T cell-mediated specific immunity to treponemal antigens early after infection and do not support a hypothesis of depressed cellular immunity during syphilitic infection.


Potentiation of excitatory serotonergic responses by MK-801 in the medial prefrontal cortex.
New atypical antipsychotics show a greater affinity to serotonergic rather than to dopamine receptors, suggesting that serotonin (5-HT) has a major role in the pathophysiology and treatment of schizophrenia. The goal of this study was to characterise the response of pyramidal neurons in the medial prefrontal cortex (mPFC) to 5-HT and NMDA before and after administration of the NMDA receptor antagonist, MK-801 (dizocilpine), a well-validated pharmacological model of psychosis. mPFC pyramidal (glutamatergic) neurons were recorded in urethane-anaesthetised rats. The responses to NMDA and 5-HT were assessed using in vivo electrophysiology and microiontophoresis. The 5-HT2A/2C antagonist ritanserin and the 5-HT1A antagonist WAY100635 were used to block 5-HT responses. MK-801 decreased the NMDA-induced excitatory responses and increased NMDA-evoked burst activity among mPFC pyramidal neurons. Three subpopulations of pyramidal cells were identified according to their responses to 5-HT: excitation (33%), inhibition (40%) and non-response (27%). The inhibitory responses were blocked by WAY100635 in 100% of cases, but not by ritanserin; the excitatory responses were blocked by ritanserin in 75% of cases, but not by WAY100635. The administration of MK-801 potentiated the firing rate of excitatory responses but did not modify the inhibitory responses induced by microiontophoretic application of 5-HT. These results suggest that MK-801 modifies 5-HT synapses in the mPFC by potentiating the excitatory 5-HT2A/2C responses and attenuating NMDA excitations. These data indicate that 5-HT excitatory transmission is selectively impaired at the mPFC level in this pharmacological model of schizophrenia.


Exploring the Potential of Emerging Technologies to Meet the Care and Support Needs of Older People: A Delphi Survey.
Some emerging technologies have potential to address older people's care and support needs. However, there is still a gap in the knowledge on the potential uses of these technologies in some care domains. Therefore, a two-round Delphi survey was conducted to establish a consensus of opinion from a group of health and social technology experts (n = 21) on the potential of 10 emerging technologies to meet older people's needs in five care and support domains. Experts were also asked to provide reasons for their choices in free-text spaces. The consensus level was set at 70%. Free-text responses were analyzed using thematic analysis. Voice activated devices was the technology that reached experts consensus in all assessed care domains. Some technologies (e.g., Artificial intelligence (AI) enabled apps and wearables and Internet of things (IoT) enabled homes) also show potential to support basic self-care and access to healthcare needs of older people. However, most of the remaining technologies (e.g., robotics, exoskeletons, virtual and augmented reality (VR/AR)) face a range of technical and acceptability issues that may hinder their adoption by older people in the near future. Findings should encourage the R & D community to address some of the identified challenges to improve the adoption of emerging technologies by older people.


Evolution of the primate trypanolytic factor APOL1.
ApolipoproteinL1 (APOL1) protects humans and some primates against several African trypanosomes. APOL1 genetic variants strongly associated with kidney disease in African Americans have additional trypanolytic activity against Trypanosoma brucei rhodesiense, the cause of acute African sleeping sickness. We combined genetic, physiological, and biochemical studies to explore coevolution between the APOL1 gene and trypanosomes. We analyzed the APOL1 sequence in modern and archaic humans and baboons along with geographic distribution in present day Africa to understand how the kidney risk variants evolved. Then, we tested Old World monkey, human, and engineered APOL1 variants for their ability to kill human infective trypanosomes in vivo to identify the molecular mechanism whereby human trypanolytic APOL1 variants evade T. brucei rhodesiense virulence factor serum resistance-associated protein (SRA). For one APOL1 kidney risk variant, a two-residue deletion of amino acids 388 and 389 causes a shift in a single lysine residue that mimics the Old World monkey sequence, which augments trypanolytic activity by preventing SRA binding. A second human APOL1 kidney risk allele, with an amino acid substitution that also restores sequence alignment with Old World monkeys, protected against T. brucei rhodesiense due in part to reduced SRA binding. Both APOL1 risk variants induced tissue injury in murine livers, the site of transgenic gene expression. Our study shows that both genetic variants of human APOL1 that protect against T. brucei rhodesiense have recapitulated molecular signatures found in Old World monkeys and raises the possibility that APOL1 variants have broader innate immune activity that extends beyond trypanosomes.


Optical interferometry for measurement of the geometric dimensions of industrial parts.
We describe an instrument for the measurement of surface flatness, parallelism, and size (thickness) of plane-parallel parts in a single measurement to 1sigma gauge capability of 0.02, 0.03, and 0.06 microm, respectively. A low-coherence IR profiler viewing both sides of the part simultaneously, believed to be novel, accommodates a wide variety of industrial surface finishes, including machined, ground, or lapped parts, with a 75-mm field of view and 15,000 pixels per side. A heterodyne laser displacement gauge together with an integrated zeroing system allows for a range of part sizes from 0 to 100 mm.


Optimization of Small-Scale Production of Zika Virus Envelope Glycoprotein by Transient Expression in HEK293 Cells for ELISA.
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus, which has recently caused global epidemics with its association with congenital Zika syndrome such as severe microcephaly. The recombinant ZIKV envelope (Env) glycoprotein is useful for immunological applications such as serodiagnosis of ZIKV infection and for monitoring immune responses in preclinical and clinical ZIKV vaccine developments. In this chapter, we describe the optimization of production of Zika virus envelope glycoprotein in Human Embryonic Kidney (HEK 293T) cells by small-scale expression followed by large-scale protein production. Small-scale expression of HEK 293T cells allows screening of a large number of vectors simultaneously to select the vectors with best secretory profiles for scale-up in Expi293 mammalian system to maximize the protein yield followed by purification for research and clinical applications.


Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL).
The Philadelphia chromosome (Ph1) is a translocation between chromosomes 9 and 22 that is found in chronic myelogenous leukemia (CML) and a subset of acute lymphocytic leukemia patients (ALL). In CML, this results in the expression of a chimeric 8.5-kilobase BCR-ABL transcript that encodes the P210BCR-ABL tyrosine kinase. The Ph1 chromosome in ALL expresses a distinct ABL-derived 7-kilobase messenger RNA that encodes the P185ALL-ABL protein. Since the expression of different oncogene products may play a role in the distinctive presentation of Ph1-positive ALL versus CML, it is necessary to understand the molecular basis for the expression of P185ALL-ABL. Both P210BCR-ABL and P185ALL-ABL are recognized by an antiserum directed to BCR determinants in the amino-terminal region of both proteins. Antisera to BCR determinants proximal to the BCR-ABL junction in CML immunoprecipitated P210BCR-ABL but not P185ALL-ABL. Nucleotide sequence analysis of complementary DNA clones made from RNA from the Ph1-positive ALL SUP-B15 cell line, and S1 nuclease protection analysis confirmed the presence of BCR-ABL chimeric transcripts in Ph1-positive ALL cells. In Ph1-positive ALL, ABL sequences were joined to BCR sequences approximately 1.5 kilobases 5' of the CML junction. P185ALL-ABL represents the product of a BCR-ABL fusion gene in Ph1-positive ALL that is distinct from the BCR-ABL fusion gene of CML.


Effectiveness of current hygiene practices on minimization of Listeria monocytogenes in different mushroom production-related environments.
The commercial production of Agaricus bisporus is a three stage process: 1) production of compost, also called "substrate"; 2) production of casing soil; and 3) production of the mushrooms. Hygiene practices are undertaken at each stage: pasteurization of the substrate, hygiene practices applied during the production of casing soil, postharvest steam cookout, and disinfection at the mushroom production facilities. However, despite these measures, foodborne pathogens, including Listeria monocytogenes, are reported in the mushroom production environment. In this work, the presence of L. monocytogenes was evaluated before and after the application of hygiene practices at each stage of mushroom production with swabs, samples of substrate, casing, and spent mushroom growing substrates. L. monocytogenes was not detected in any casing or substrate sample by enumeration according to BS EN ISO 11290-2:1998. Analysis of the substrate showed that L. monocytogenes was absent in 10 Phase II samples following pasteurization, but was then present in 40% of 10 Phase III samples. At the casing production facility, 31% of 59 samples were positive. Hygiene improvements were applied, and after four sampling occasions, 22% of 37 samples were positive, but no statistically significant difference was observed (p > .05). At mushroom production facilities, the steam cookout process inactivated L. monocytogenes in the spent growth substrate, but 13% of 15 floor swabs at Company 1 and 19% of 16 floor swabs at Company 2, taken after disinfection, were positive. These results showed the possibility of L. monocytogenes recontamination of Phase III substrate, cross-contamination at the casing production stage and possible survival after postharvest hygiene practices at the mushroom growing facilities. This information will support the development of targeted measures to minimize L. monocytogenes in the mushroom industry.


The use of complementary/preventive medicine to prevent prostate cancer recurrence/progression following definitive therapy: part I--lifestyle changes.
The number one cause of death in the United States and in most countries around the world is cardiovascular disease. The number one or number two cause of death in prostate cancer patients is also cardiovascular disease. These observations do not serve to belittle the impact of prostate cancer, but are a reminder that the ultimate goal of healthy lifestyle recommendations is to reduce the burden of both of these major causes of death, especially after definitive prostate therapy. Patients need to be encouraged to know their cholesterol levels and other cardiovascular markers including blood pressure, as well as being aware of their prostate-specific antigen values. Patients should not smoke, they should reduce their intake of saturated and trans fats, increase their consumption of a diversity of fruit and vegetables, consume moderate quantities of dietary soy or flaxseed, increase their consumption of fish or fish oils and other omega-3 fatty acids, as well as maintaining a healthy weight, getting at least 30 min/day of physical activity, and lifting weights several times a week. When in doubt it is important for the clinician and patient to realize that what is healthy for the heart is generally found to be healthy for the prostate. Many of these lifestyle changes, when accomplished on a regular basis, may dramatically reduce the risk of overall early mortality. Despite the simplistic and moderate recommendations in this manuscript, research suggests that few individuals are currently following these suggestions. Clinicians need to constantly emphasize these basic changes in order to truly impact the overall health of any patient following definitive prostate therapy.


Field survey of health perception and complaints of Pennsylvania residents in the Marcellus Shale region.
Pennsylvania Marcellus Shale region residents have reported medical symptoms they believe are related to nearby Unconventional Natural Gas Development (UNGD). Associations between medical symptoms and UNGD have been minimally explored. The objective of this descriptive study is to explore whether shale region Pennsylvania residents perceive UNGD as a health concern and whether they attribute health symptoms to UNGD exposures. A questionnaire was administered to adult volunteers with medical complaints in a primary-care medical office in a county where UNGD was present. Participants were asked whether they were concerned about health effects from UNGD, and whether they attributed current symptoms to UNGD or to some other environmental exposure. There were 72 respondents; 22% perceived UNGD as a health concern and 13% attributed medical symptoms to UNGD exposures. Overall, 42% attributed one or more of their medical symptoms to environmental causes, of which UNGD was the most frequent. A medical record review conducted on six participants who attributed their medical symptoms to UNGD revealed that only one of these records documented both the symptoms in question and the attribution to UNGD. The results of this pilot study suggest that there is substantial concern about adverse health effects of UNGD among Pennsylvania Marcellus Shale residents, and that these concerns may not be adequately represented in medical records. Further efforts to determine the relationship between UNGD and health are recommended in order to address community concerns.


eRepo-ORP: Exploring the Opportunity Space to Combat Orphan Diseases with Existing Drugs.
About 7000 rare, or orphan, diseases affect more than 350 million people worldwide. Although these conditions collectively pose significant health care problems, drug companies seldom develop drugs for orphan diseases due to extremely limited individual markets. Consequently, developing new treatments for often life-threatening orphan diseases is primarily contingent on financial incentives from governments, special research grants, and private philanthropy. Computer-aided drug repositioning is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Here, we present eRepo-ORP, a comprehensive resource constructed by a large-scale repositioning of existing drugs to orphan diseases with a collection of structural bioinformatics tools, including eThread, eFindSite, and eMatchSite. Specifically, a systematic exploration of 320,856 possible links between known drugs in DrugBank and orphan proteins obtained from Orphanet reveals as many as 18,145 candidates for repurposing. In order to illustrate how potential therapeutics for rare diseases can be identified with eRepo-ORP, we discuss the repositioning of a kinase inhibitor for Ras-associated autoimmune leukoproliferative disease. The eRepo-ORP data set is available through the Open Science Framework at https://osf.io/qdjup/.


Incidence and Predictors of Acute Kidney Injury in Patients Undergoing Elective Hepatic Resection for Malignant Tumors: A 3-year Prospective Observational Study.
Acute kidney injury (AKI) is common in patients undergoing major surgeries, and leads to the need for renal replacement therapy and increased morbidity, intensive care unit (ICU) and hospital length of stay (LOS), cost, and mortality. We evaluated the incidence and predictors of postoperative AKI in patients undergoing hepatic resections and their short-term outcomes. This prospective observational study was conducted over a 3-year period in 180 patients undergoing elective hepatic resections for a variety of indications. We used the Acute Kidney Injury Network criteria to determine the incidence of AKI at 72 hours. Perioperative variables contributing to the development of AKI and the short-term postoperative outcomes of patients were evaluated. Postoperative AKI occurred in 29.4% of patients. Persistent renal dysfunction was seen in five patients. Development of AKI was associated with hepatic failure (18.5 vs 5.5%, p < 0.005), prolonged ICU (2 vs 1 days, p < 0.001) and hospital LOS (11 vs 8 days, p < 0.004), and increased ICU and hospital mortality (9.6 vs 1.4%, p < 0.02). Age [OR (odds ratio) 1.033, 95% CI (confidence interval) 1.003-1.065, p = 0.03], BMI (body mass index) (OR 1.131, 95% CI 1.043-1.227, p = 0.003), and need for postoperative ventilation (OR 3.456, 95% CI 1.593-7.495, p = 0.002) were independent predictors of AKI. AKI after elective hepatic resection occurred in nearly one-third of our patients. Persistent renal dysfunction was seen in five patients. Age, BMI, and need for postoperative ventilation were independent predictors of postoperative AKI. (CTRI reg. No.: CTRI/2016/06/007044). Joshi M, Milmile R, Dhakane P, Bhosale SJ, Kulkarni AP. Incidence and Predictors of Acute Kidney Injury in Patients Undergoing Elective Hepatic Resection for Malignant Tumors: A 3-year Prospective Observational Study. Indian J Crit Care Med 2021;25(4):398-404.


Metrics of retinal image quality predict visual performance in eyes with 20/17 or better visual acuity.
The purpose of this study is to determine the ability of single-value metrics of retinal image quality of the eye to predict visual performance as measured by high (HC) and low (LC) -contrast acuity at photopic (P) and mesopic (M) light levels in eyes with 20/17 and better visual acuity. Forty-nine normal subjects in good health ranging in age from 21.8 to 62.6 with 20/17 or better monocular high-contrast logarithm of the minimum angle of resolution (logMAR) acuity served as subjects. Wavefront error through the 10th Zernike radial order over a 7-mm pupil was measured on each test eye using a custom-built Shack/Hartmann wavefront sensor. For each eye, 31 different single-value retinal image quality metrics were calculated. Visual acuity was measured using HC (95%) and LC (11%) logMAR at photopic (270 cd/m) and mesopic (0.75 cd/m) light levels. To determine the ability of each metric of retinal image quality to predict each type of logMAR acuity (P HC, P LC, M HC, and M LC), each acuity measure was regressed against each optical quality metric. The ability of the metrics of retinal image quality to predict logMAR acuity improved as luminance and/or contrast is lowered. The best retinal image quality metric (logPFSc) accounted for 2.6%, 15.1%, 27.6%, and 40.0% of the variance in P HC, P LC, M HC, and M LC logMAR acuity, respectively. In eyes with 20/17 and better P HC acuity, P HC logMAR acuity is insensitive to variations in retinal image quality compared with M LC logMAR acuity. Retinal image quality becomes increasingly predictive of logMAR acuity as contrast and/or luminance is decreased. Everyday life requires individuals to function over a large range of contrast and luminance levels. Clinically, the impact of retinal image quality as a function of luminance and contrast is readily measurable in a time-efficient manner with M LC logMAR acuity charts.


Prognostic utility of glycosyltransferase expression in breast cancer.
The post-translational modification of proteins, including glycosylation, is known to differ between normal and tumour cells. In this study, the expression profile of two glycosyltranferases, UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-6 (ppGalNAc-T6) and alpha6-sialyl-transferase-I (ST6GalNAc-I) was assessed, in a cohort of women with breast cancer. Breast cancer tissues (n=127) and normal background tissues (n=33) were collected immediately after excision during surgery. Following RNA extraction, reverse transcription was carried out and transcript levels were determined using real-time quantitative PCR and normalized against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Transcript levels within the breast cancer specimens were compared to the normal background tissues and analyzed against conventional pathological parameters and clinical outcome over a 10 year follow-up period. Significantly higher levels of ppGalNAc-T6 were found in the breast cancer specimens compared to the background tissue (p=0.015). There was a non-significant trend for levels to increase with the Nottingham Prognostic Index (NPI) and TNM stage and those who died from breast cancer. ST6GalNAc-I expression was associated with better prognosis, reaching significance when comparing patients who remained disease free to those with distant recurrence (p=0.0096). The relationship approached significance when comparing NPI 2 to NPI 3 (p=0.058) and disease free patients to non-disease free patients (p=0.052) or those who died of breast cancer (p=0.060). For both enzymes a significant association with ductal type was found. Expression of ppGalNAc-T6 is significantly higher in breast cancer compared to 'normal'/benign breast tissue samples. ST6GalNAc-I expression in breast cancer is associated with better prognosis.


Direct Observation of the Statics and Dynamics of Emergent Magnetic Monopoles in a Chiral Magnet.
In the three-dimensional (3D) Heisenberg model, topological point defects known as spin hedgehogs behave as emergent magnetic monopoles, i.e., quantized sources and sinks of gauge fields that couple strongly to conduction electrons, and cause unconventional transport responses such as the gigantic Hall effect. We observe a dramatic change in the Hall effect upon the transformation of a spin hedgehog crystal in a chiral magnet MnGe through combined measurements of magnetotransport and small-angle neutron scattering (SANS). At low temperatures, well-defined SANS peaks and a negative Hall signal are each consistent with expectations for a static hedgehog lattice. In contrast, a positive Hall signal takes over when the hedgehog lattice fluctuates at higher temperatures, with a diffuse SANS signal observed upon decomposition of the hedgehog lattice. Our approach provides a simple way to both distinguish and disentangle the roles of static and dynamic emergent monopoles on the augmented Hall motion of conduction electrons.


A systematic review and meta-analysis of set-shifting ability in eating disorders.
The aim was to critically appraise and synthesize the literature relating to set-shifting ability in eating disorders. PsycINFO, Medline, and Web of Science databases were searched to December 2005. Hand searching of eating-disorder journals and relevant reference sections was also undertaken. The 15 selected studies contained both eating disorder and healthy control groups, and employed at least one of the following six neuropsychological measures of set-shifting ability; Trail Making Test (TMT), Wisconsin Card Sort Test (WCST), Brixton task, Haptic Illusion, CatBat task, or the set-shifting subset of the Cambridge Neuropsychological Test Automated Battery (CANTAB). The outcome variable was performance on the set-shifting aspect of the task. Pooled standardized mean differences (effect sizes) were calculated. TMT, WCST, CatBat and Haptic tasks had sufficient sample sizes for meta-analysis. These four tasks yielded acceptable pooled standardized effect sizes (0.36; TMT -1.05; Haptic) with moderate variation within studies (as measured by confidence intervals). The Brixton task showed a small pooled mean difference, and displayed more variation between sample results. The effect size for CANTAB set shifting was 0.17. Problems in set shifting as measured by a variety of neuropsychological tasks are present in people with eating disorders.


Characteristics of neurones projecting from the supraoesophageal ganglion in the shadow reflex pathway of the barnacle.
Barnacles respond to decreases in light intensity (shadows). Previous evidence indicates that the first stages of the visual pathway within the supraoesophageal ganglion comprise a limited number of neurones: a single pair of second-order neurones (I-cells), a pair of third-order projection neurones (A-cells), and at least five other projection neurones (four A-like shadow-excited cells and one shadow-inhibited cell) whose spikes may be recorded extracellularly from the circum-oesophageal connective nerve. Here we present evidence that information in this pathway diverges at the A-cell stage. Destruction of both A-cells by intense illumination of cells injected with carboxyfluorescein abolishes all shadow-evoked activity in the connectives and also the ability of shadows to influence motor neurones in the ventral ganglion. In addition, we have located the somata of these previously unidentified projection neurones, injected them with carboxyfluorescein, and observed that they have distinct branching patterns different from that of the A-cell. We name these cells 'alpha' (alpha), 'beta' (beta) and 'gamma' (gamma) cells. Simultaneous impalements show that A-cells drive at least one of the beta-cells but not vice versa. The same observation has not yet been made with regard to alpha- or gamma-cells. Depolarizing an I-cell does not readily drive a beta-cell impaled simultaneously. These observations support our conclusion that information diverges from the A-cells and not from the second-order I-cells to the other projection neurones in this ganglion.


A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade.
Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.


Evidence for a negative association between schizophrenia and a polymorphism in the insulin receptor substrate-3 (IRS-3) gene.
Since there are clear indications that schizophrenia is a systemic disorder, we sought for a common molecular basis for schizophrenia abnormalities in brain and body. Our hypothesis was that an impaired insulin and insulin-like growth factor signalling in cells might underlie changes in both brain and body in schizophrenia. In this regard, the insulin receptor substrates 1-4, linking both the insulin and insulin-like growth factor-1 receptors with intracellular pathways, might be of interest to study genetically. In the present study, we chose to study the insulin receptor substrate-3 (IRS-3) gene as a candidate gene in schizophrenia. The IRS-3 gene of 93 patients with the diagnosis of schizophrenia according to DSM-IV criteria and 57 healthy control subjects was screened for DNA sequence variations, followed by case-control analyses of total 10 detected polymorphisms. The A/G genotype of the single nucleotide polymorphism (SNP) rs117078492 in the IRS-3 gene occurred in 5.3% of the control subjects compared with in 0% of the patients (p=0.05). Similarly, the haplotypes 5 and 3X, constructed from polymorphisms in the IRS-3 gene and including the A allele of this A/G SNP, occurred only in the control subjects and not in the patients (5.3% vs 0%, p=0.05). Our findings suggest that individuals carrying the A allele of this A/G SNP in the IRS-3 gene as well as the estimated haplotypes 5 or 3X including this A allele, have a protection against schizophrenia development.


Cohort profile: Study on Zika virus infection in Brazil (ZIKABRA study).
Zika virus (ZIKV) has been detected in blood, urine, semen, cerebral spinal fluid, saliva, amniotic fluid, and breast milk. In most ZIKV infected individuals, the virus is detected in the blood to one week after the onset of symptoms and has been found to persist longer in urine and semen. To better understand virus dynamics, a prospective cohort study was conducted in Brazil to assess the presence and duration of ZIKV and related markers (viral RNA, antibodies, T cell response, and innate immunity) in blood, semen, saliva, urine, vaginal secretions/menstrual blood, rectal swab and sweat. The objective of the current manuscript is to describe the cohort, including an overview of the collected data and a description of the baseline characteristics of the participants. Men and women ≥ 18 years with acute illness and their symptomatic and asymptomatic household contacts with positive reverse transcriptase-polymerase chain reaction test for ZIKV in blood and/or urine were included. All participants were followed up for 12 months. From July 2017 to June 2019, a total of 786 participants (284 men, 502 women) were screened. Of these, 260 (33.1%) were enrolled in the study; index cases: 64 men (24.6%), 162 (62.3%) women; household contacts: 12 men (4.6%), 22 (8.5%) women. There was a statistically significant difference in age and sex between enrolled and not enrolled participants (p<0.005). Baseline sociodemographic and medical data were collected at enrollment from all participants. The median and interquartile range (IQR) age was 35 (IQR; 25.3, 43) for men and 36.5 years (IQR; 28, 47) for women. Following rash, which was one of the inclusion criteria for index cases, the most reported symptoms in the enrollment visit since the onset of the disease were fever, itching, arthralgia with or without edema, non-purulent conjunctivitis, headache, and myalgia. Ten hospitalizations were reported by eight patients (two patients were hospitalized twice) during follow up, after a median of 108 days following symptom onset (range 7 to 266 days) and with a median of 1.5 days (range 1 to 20 days) of hospital stay. A total of 4,137 visits were performed, 223 (85.8%) participants have attended all visits and 37 (14.2%) patients were discontinued.


Genotypic and phenotypic traits that distinguish neonatal meningitis-associated Escherichia coli from fecal E. coli isolates of healthy human hosts.
Neonatal meningitis Escherichia coli (NMEC) is one of the top causes of neonatal meningitis worldwide. Here, 85 NMEC and 204 fecal E. coli isolates from healthy humans (HFEC) were compared for possession of traits related to virulence, antimicrobial resistance, and plasmid content. This comparison was done to identify traits that typify NMEC and distinguish it from commensal strains to refine the definition of the NMEC subpathotype, identify traits that might contribute to NMEC pathogenesis, and facilitate choices of NMEC strains for future study. A large number of E. coli strains from both groups were untypeable, with the most common serogroups occurring among NMEC being O18, followed by O83, O7, O12, and O1. NMEC strains were more likely than HFEC strains to be assigned to the B2 phylogenetic group. Few NMEC or HFEC strains were resistant to antimicrobials. Genes that best discriminated between NMEC and HFEC strains and that were present in more than 50% of NMEC isolates were mainly from extraintestinal pathogenic E. coli genomic and plasmid pathogenicity islands. Several of these defining traits had not previously been associated with NMEC pathogenesis, are of unknown function, and are plasmid located. Several genes that had been previously associated with NMEC virulence did not dominate among the NMEC isolates. These data suggest that there is much about NMEC virulence that is unknown and that there are pitfalls to studying single NMEC isolates to represent the entire subpathotype.


Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial.
Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86-1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. UK National Institute for Health Research Health Technology Assessment programme (10/57/49).


A genetic variant in SLC6A20 is associated with Type 2 diabetes in white-European and Chinese populations.
To investigate whether polymorphisms in SLC6A20 are associated with susceptibility to Type 2 diabetes. In the Rotterdam Study, a prospective, population-based cohort (n = 5974), 22 tagging polymorphisms with minor allele frequencies>0.05 across SLC6A20 were studied. Replication studies were performed in an independent Dutch case-control study (DiaGene-Rotterdam Study 2 n = 3133), and in a Chinese Han case-control population (n = 2279). A meta-analysis of the results was performed. In the Rotterdam study, the minor alleles of rs13062383, rs10461016 and rs2286489 increased the risk of Type 2 diabetes (hazard ratio 1.37, 95% CI 1.15-1.63, hazard ratio 1.30 95% CI 1.09-1.54 and hazard ratio 1.20, 95% CI 1.07-1.35, respectively). In the DiaGene/Rotterdam Study 2, the A allele of rs13062383 increased the risk of Type 2 diabetes (odds ratio 1.45, 95% CI 1.19-1.76). In the Chinese Han study, the rs13062383 A allele also increased the risk of Type 2 diabetes (odds ratio 1.21, 95% CI 1.03-1.42). Meta-analysis showed a highly significant association of rs13062383 with Type 2 diabetes (odds ratio 1.35, 95% CI 1.21-1.47; P = 3.3 × 10⁻⁸). In conclusion, rs13062383 in SLC6A20 increased the susceptibility to Type 2 diabetes in populations with different genetic backgrounds.


Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule.
There is a genetic contribution to fetal alcohol spectrum disorders (FASD), but the identification of candidate genes has been elusive. Ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain. Pharmacologic inhibition or genetic knockdown of ERK2 did not alter L1 adhesion, but markedly decreased ethanol inhibition of L1 adhesion in NIH/3T3 cells and NG108-15 cells. Likewise, leucine replacement of S1248, an ERK2 substrate on the L1 cytoplasmic domain, did not decrease L1 adhesion, but abolished ethanol inhibition of L1 adhesion. Stable transfection of NIH/3T3 cells with human L1 resulted in clonal cell lines in which L1 adhesion was consistently sensitive or insensitive to ethanol for more than a decade. ERK2 activity and S1248 phosphorylation were greater in ethanol-sensitive NIH/3T3 clonal cell lines than in their ethanol-insensitive counterparts. Ethanol-insensitive cells became ethanol sensitive after increasing ERK2 activity by transfection with a constitutively active MAP kinase kinase 1. Finally, embryos from two substrains of C57BL mice that differ in susceptibility to ethanol teratogenesis showed corresponding differences in MAPK activity. Our data suggest that ERK2 phosphorylation of S1248 modulates ethanol inhibition of L1 adhesion by inside-out signaling and that differential regulation of ERK2 signaling might contribute to genetic susceptibility to FASD. Moreover, identification of a specific locus that regulates ethanol sensitivity, but not L1 function, might facilitate the rational design of drugs that block ethanol neurotoxicity.


Neural process reconstruction from sparse user scribbles.
We present a novel semi-automatic method for segmenting neural processes in large, highly anisotropic EM (electron microscopy) image stacks. Our method takes advantage of sparse scribble annotations provided by the user to guide a 3D variational segmentation model, thereby allowing our method to globally optimally enforce 3D geometric constraints on the segmentation. Moreover, we leverage a novel algorithm for propagating segmentation constraints through the image stack via optimal volumetric pathways, thereby allowing our method to compute highly accurate 3D segmentations from very sparse user input. We evaluate our method by reconstructing 16 neural processes in a 1024 x 1024 x 50 nanometer-scale EM image stack of a mouse hippocampus. We demonstrate that, on average, our method is 68% more accurate than previous state-of-the-art semi-automatic methods.


Primary pleural synovial sarcoma presenting as a multiloculated cyst in an adolescent.
Primary pleural synovial sarcoma (PPSS) is a rare pleural malignancy with a grave prognosis. Most cases present as a well-circumscribed mass with foci of haemorrhage and necrosis. We present an unusual case in a Nepalese boy that presented as a multiloculated cyst mimicking hydatid disease. The diagnosis was confirmed by histology and cytogenetic analysis.


Eye tracking a self-moved target with complex hand-target dynamics.
Previous work has shown that the ability to track with the eye a moving target is substantially improved when the target is self-moved by the subject's hand compared with when being externally moved. Here, we explored a situation in which the mapping between hand movement and target motion was perturbed by simulating an elastic relationship between the hand and target. Our objective was to determine whether the predictive mechanisms driving eye-hand coordination could be updated to accommodate this complex hand-target dynamics. To fully appreciate the behavioral effects of this perturbation, we compared eye tracking performance when self-moving a target with a rigid mapping (simple) and a spring mapping as well as when the subject tracked target trajectories that he/she had previously generated when using the rigid or spring mapping. Concerning the rigid mapping, our results confirmed that smooth pursuit was more accurate when the target was self-moved than externally moved. In contrast, with the spring mapping, eye tracking had initially similar low spatial accuracy (though shorter temporal lag) in the self versus externally moved conditions. However, within ∼5 min of practice, smooth pursuit improved in the self-moved spring condition, up to a level similar to the self-moved rigid condition. Subsequently, when the mapping unexpectedly switched from spring to rigid, the eye initially followed the expected target trajectory and not the real one, thereby suggesting that subjects used an internal representation of the new hand-target dynamics. Overall, these results emphasize the stunning adaptability of smooth pursuit when self-maneuvering objects with complex dynamics.


pQCT- and Ultrasound-based Muscle and Fat Estimate Errors after Resistance Exercise.
Resistance exercise increases blood flow, induces osmotic and hydrostatic fluid shifts during and immediately after exercise, and may trigger inflammatory responses for several days in the working muscle. The resultant muscle swelling can subsequently affect muscle size and quality assessments. However, the effects of muscle swelling on x-ray attenuation of adipose estimate errors are unknown. Peripheral quantitative computed tomography (pQCT) and ultrasonography were used to assess muscle and adipose tissue properties of both upper arms before, 24, 48, and 72 h after unilateral resistance exercise. Recreationally active participants (n = 17) completed the exercise while their contralateral limb served as a control. Resistance exercise resulted in a significant increase in pQCT-derived muscle cross-sectional area (includes intermuscular adipose tissue [IMAT] area), muscle area (excludes IMAT area) and IMAT area, and ultrasound-derived muscle thickness at 24, 48, and 72 h. A significant decrease in pQCT-derived muscle density was also detected as well as an increase in ultrasound-derived echo intensity at 48 and 72 h. The changes in muscle area, IMAT area, and muscle density were significantly correlated with changes in echo intensity, whereas the changes in muscle cross-sectional area and IMAT area were significantly correlated with changes in muscle thickness. Unaccustomed resistance exercise can cause errors in pQCT- and ultrasound-based muscle and adipose estimates for at least 72 h. These errors are the result of muscle swelling likely caused by muscle blood flow and inflammation-dependent fluid shifts in muscle. These findings may have implications for measurements in other inflammatory conditions.


11β-Hydroxysteroid dehydrogenase 1: translational and therapeutic aspects.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.


A survey of U.S. physicians and their partners regarding the impact of work-home conflict.
Work-home conflicts (WHC) threaten work-life balance among physicians, especially those in dual career relationships. In this study, we analyzed factors associated with WHC for physicians and their employed partners. We surveyed 89,831 physicians from all specialty disciplines listed in the Physician Masterfile. Of the 7,288 (27.7 %) physicians who completed the survey, 1,644 provided the e-mail contact information of their partner. We surveyed these partners and 891 (54 %) responded. Burnout, quality of life (QOL), and depression were measured using validated instruments in both surveys. Satisfaction with career, work-life balance, and personal relationships, as well as experience of WHC were also evaluated. WHC within the previous 3 weeks were commonly experienced by physicians and their employed partners (44.3 % and 55.7 %, respectively). On multivariate analysis, greater work hours for physicians and their employed partners were independently associated with WHC (OR 1.31 and 1.23 for each additional 10 h, respectively, both p < 0.0001). Physicians and partners who had experienced a recent WHC were more likely to have symptoms of burnout (47.1 % vs. 26.6 % for physicians with and without WHC; 42.4 % vs. 23.8 % for partners with and without WHC, both p < 0.0001). WHC are commonly experienced by physicians and their employed partners. These conflicts may be a major contributor to personal distress for physicians and their partners.


Is Intra-Arterial Treatment for Acute Ischemic Stroke Less Effective in Women than in Men?
Stroke etiology and outcome after ischemic stroke differ between men and women. We examined if sex modifies the effect of intra-arterial treatment (IAT) in a randomized clinical trial of IAT for acute ischemic stroke in the Netherlands (MR CLEAN). The primary outcome was the score on the modified Rankin scale at 90 days. We tested for interaction between sex and treatment and estimated the treatment effect by sex with multiple ordinal logistic regression with adjustment for prognostic factors. All 500 patients were included in the analysis; 292 (58.4%) were men. The treatment effect (adjusted common odds ratio) was 2.39 [95% confidence interval (CI) 1.55-3.68] in men and 0.99 (95% CI 0.60-1.66) in women (pinteraction = 0.016). In women, mortality was higher in the intervention group than in the control group (24 vs. 15%, p = 0.07). Serious adverse events occurred more often in women than in men undergoing intervention. There were no differences in neuro-imaging outcomes. Contrary to other studies, we found a significant interaction between sex and treatment effect in the MR CLEAN trial. Pooled analyses of all published thrombectomy trials did not confirm this finding. In MR CLEAN, women seem to have a slightly more unfavorable profile, causing higher mortality and more serious adverse events, but insufficient to explain the absence of an overall effect. This suggests a play of chance and makes it clear that IAT should not be withheld in women.


Effect of insulin glargine and n-3FA on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events: the glucose reduction and atherosclerosis continuing evaluation study (ORIGIN-GRACE).
To evaluate the effects of insulin glargine and n-3 polyunsaturated fatty acid (n-3FA) supplements on carotid intima-media thickness (CIMT). We enrolled 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes in a randomized multicenter 2 × 2 factorial design trial. Participants received open-label insulin glargine (targeting fasting glucose levels ≤ 5.3 mmol/L [95 mg/dL]) or standard glycemic care and double-blind therapy with a 1-g capsule of n-3FA or placebo. The primary trial outcome was the annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments. Secondary outcomes were the annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation, respectively. Baseline followed by annual ultrasounds were obtained during a median follow-up of 4.9 years. Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups. In people with CV disease and/or CV risk factors and dysglycemia, insulin glargine used to target normoglycemia modestly reduced CIMT progression, whereas daily supplementation with n-3FA had no effect on CIMT progression.


Genetic profiling of the oral microbiota associated with severe early-childhood caries.
The determination of the composition of the microbial community in the oral cavity is usually based on cultivation methods; however, nearly half of the bacteria in the saliva and the dental plaque are not cultivable. In this study, we evaluated the difference in oral microbial diversity between children with severe early-childhood caries (S-ECC) and caries-free (CF) controls by means of a cultivation-independent approach called denaturing gradient gel electrophoresis (DGGE). Pooled dental plaque samples were collected from 20 children aged 2 to 8 years. Total microbial genomic DNA was isolated from those subjects, and a portion of the 16S rRNA gene locus was PCR amplified by using universal primers. We observed that the mean species richness of the bacterial population was greater in the CF children (n = 12) (42 +/- 3.7) than in the S-ECC children (n = 8) (35 +/- 4.3); the difference was statistically significant (P = 0.005). The overall diversity of plaque samples as measured by the Shannon index was 3.5 for the S-ECC group and 3.7 for the CF group (P = 0.004). Differences in DGGE profiles were distinguished on the basis of a cluster analysis. Sequence analysis of excised DGGE bands consisted of 2.7 phylotypes, on average. After adjusting for the number of observed bands, we estimated that the S-ECC group exhibited 94.5 total phylotypes and that the CF group exhibited 113.4. These results suggest that the microbial diversity and complexity of the microbial biota in dental plaque are significantly less in S-ECC children than in CF children.


Pathophysiology of diabetes. A review of selected recent developments and their impact on treatment.
Recent developments in epidemiology, physiology, anatomy and molecular biology have greatly increased our knowledge of the aetiology and immunological mechanisms involved in diabetes mellitus. This understanding has, in turn, facilitated progress in the diagnosis and treatment of the disease. It is generally accepted that both genetic and environmental factors have a role in the pathogenesis of insulin- and non-insulin-dependent diabetes mellitus. The contribution of insulin resistance or decreased insulin secretion to the pathogenesis of non-insulin-dependent diabetes remains controversial but it is likely that both have a role to play. Counterregulatory hormones, principally adrenaline (epinephrine) and glucagon, prevent blood glucose levels falling to extreme levels by antagonising the effect of insulin hypoglycaemia, and inducing hepatic glucose production. Patients with insulin-dependent diabetes frequently exhibit impaired glucose counterregulation and, although its aetiology is uncertain in some patients, intensification of insulin therapy per se has been implicated. Secondary failure of oral hypoglycaemic agents in patients with non-insulin-dependent diabetes is a major and often inevitable problem, necessitating combined use of sulphonylurea and insulin in most patients. Recently, new treatments for patients with diabetes have been developed, including insulin analogues administered by a variety of novel methods, pancreatic grafts and transplantation of islet cells. Although promising, the clinical viability of these techniques remains to be demonstrated.


Who runs public health? A mixed-methods study combining qualitative and network analyses.
Persistent health inequalities encourage researchers to identify new ways of understanding the policy process. Informal relationships are implicated in finding evidence and making decisions for public health policy (PHP), but few studies use specialized methods to identify key actors in the policy process. We combined network and qualitative data to identify the most influential individuals in PHP in a UK conurbation and describe their strategies to influence policy. Network data were collected by asking for nominations of powerful and influential people in PHP (n = 152, response rate 80%), and 23 semi-structured interviews were analysed using a framework approach. The most influential PHP makers in this conurbation were mid-level managers in the National Health Service and local government, characterized by managerial skills: controlling policy processes through gate keeping key organizations, providing policy content and managing selected experts and executives to lead on policies. Public health professionals and academics are indirectly connected to policy via managers. The most powerful individuals in public health are managers, not usually considered targets for research. As we show, they are highly influential through all stages of the policy process. This study shows the importance of understanding the daily activities of influential policy individuals.


Identifying youth-friendly service practices associated with adolescents' use of reproductive healthcare services in post-conflict Burundi: a cross-sectional study.
Very little is known about reproductive health service (RHS) availability and adolescents' use of these services in post-conflict settings. Such information is crucial for targeted community interventions that aim to improve quality delivery of RHS and outcomes in post-conflict settings. The objectives of this study therefore was to examine the density of RHS availability; assess spatial patterns of RHC facilities; and identify youth-friendly practices associated with adolescents' use of services in post-conflict Burundi. A cross-sectional survey was conducted from a full census of all facilities (n = 892) and provider interviews in Burundi. Surveyed facilities included all public, private, religious and community association owned-centers and hospitals. At each facility efforts were made to interview the officer-in-charge and a group of his/her staff. We applied both geospatial and non-spatial analyses, to examine the density of RHS availability and density, and to explore the association between youth-friendly practices and adolescents' use of RHS in post-conflict Burundi. High spatial patterning of distances of RHC facilities was observed, with facilities clustered predominantly in districts exhibiting persistent violence. But, use of services remained undeterred. We further found a stronger association between use of RHS and facility and programming characteristics. Community outreach, designated check-in/exam rooms, educational materials (posters, print, and pictures) in waiting rooms, privacy and confidentiality were significantly associated with adolescents' use of RHS across all facility types. Cost was associated with use only at religious facilities and youth involvement at private facilities. No significant association was found between provider characteristics and use of RHS at any facility. Our findings indicate the need to improve youth-friendly service practices in the provision of RHS to adolescents in Burundi and suggest that current approaches to provider training may not be adequate for improving these vital practices. Our mixed methods approach and results are generalizable to other countries and post-conflict settings. In post-conflict settings, the methods can be used to identify service availability and spatial patterns of RHC facilities to plan for targeted service interventions, to increase demand and uptake of services by youth and young adults.


Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities.
The mechanisms of pathology for the family of polyglutamine disease proteins are unknown; however, recently it was shown that several of these proteins inhibit transcription suggesting that transcriptional repression may be a potential mechanism for pathology. In the present study we use cell transfections, in vitro binding, co-immunoprecipitations, and reporter assays to show that the polyglutamine disease protein, ataxin-3, interacts with the major histone acetyltransferases cAMP-response-element binding protein (CREB)-binding protein, p300, and p300/CREB-binding protein-associated factor and inhibits transcription by these coactivators. Importantly, endogenous ataxin-3 is co-immunoprecipitated with each of these coactivators in non-transfected cells. The C-terminal polyglutamine-containing domain of ataxin-3 inhibits coactivator-dependent transcription and is required for binding coactivators. The N-terminal domain of ataxin-3 inhibits histone acetylation by p300 in vitro and inhibits transcription in vivo. Histone binding and blocking access of coactivators to acetylation sites on histones appears to be the mechanism of inhibition. Together, our data provide a novel mechanism of transcriptional regulation by ataxin-3 that involves targeting histones, coactivators, and an independent mode of direct repression of transcription, and suggests that its physiological function and possibly pathological effects are linked to its interactions with these proteins.


Demographic and Spatiotemporal Patterns of Avian Influenza Infection at the Continental Scale, and in Relation to Annual Life Cycle of a Migratory Host.
Since the spread of highly pathogenic avian influenza (HPAI) H5N1 in the eastern hemisphere, numerous surveillance programs and studies have been undertaken to detect the occurrence, distribution, or spread of avian influenza viruses (AIV) in wild bird populations worldwide. To identify demographic determinants and spatiotemporal patterns of AIV infection in long distance migratory waterfowl in North America, we fitted generalized linear models with binominal distribution to analyze results from 13,574 blue-winged teal (Anas discors, BWTE) sampled in 2007 to 2010 year round during AIV surveillance programs in Canada and the United States. Our analyses revealed that during late summer staging (July-August) and fall migration (September-October), hatch year (HY) birds were more likely to be infected than after hatch year (AHY) birds, however there was no difference between age categories for the remainder of the year (winter, spring migration, and breeding period), likely due to maturing immune systems and newly acquired immunity of HY birds. Probability of infection increased non-linearly with latitude, and was highest in late summer prior to fall migration when densities of birds and the proportion of susceptible HY birds in the population are highest. Birds in the Central and Mississippi flyways were more likely to be infected compared to those in the Atlantic flyway. Seasonal cycles and spatial variation of AIV infection were largely driven by the dynamics of AIV infection in HY birds, which had more prominent cycles and spatial variation in infection compared to AHY birds. Our results demonstrate demographic as well as seasonal, latitudinal and flyway trends across Canada and the US, while illustrating the importance of migratory host life cycle and age in driving cyclical patterns of prevalence.


Effects of betel nut on cardiovascular risk factors in a rat model.
Areca nut (commonly known as betel nut) chewing has been shown to be associated with metabolic syndrome and cardiovascular disease (CVD). The mechanism by which betel nut ingestion could lead to development of CVD is not precisely known; however, dyslipidemia, hyperhomocysteinemia, hypertriglyceridemia and inflammation could be some of the potential risk factors. This study was undertaken to investigate the effects of two dosages of betel nut on homocysteinemia, inflammation and some of the components of metabolic syndrome, such as hypertriglyceridemia, low HDL-cholesterol, obesity and fasting hyperglycemia in a rat model. Thirty-six adult female Sprague Dawley rats, aged 10-12 weeks were divided into three equal groups. Group-1 served as the control group (n = 12) and received water, whereas groups 2 and 3 were given water suspension of betel nut orally in two dosages, 30 mg and 60 mg, respectively for a period of 5 weeks. At the end of the fifth week, the animals were weighed and sacrificed, blood was collected and liver, kidney, spleen and stomach were removed for histological examination.Plasma/serum was analyzed for glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, homocysteine, folate, vitamin B12 and N-acetyl-β-D-glucosaminidase (NAG) - a marker of inflammation. When the mean concentration values of 3 groups were compared using one way ANOVA followed by Tukey's HSD-test, there was a significant increase in the concentration of total cholesterol (p = 0.04) in the group receiving 30 mg/day betel nut compared to the control group. However, administration of a higher dose of betel nut (60 mg/day) had no significant effect on the serum concentrations of glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, and NAG. Histological examination of spleen revealed a dose-dependent extramedullary hematopoiesis. No other remarkable change in the tissues (liver, kidney and stomach) was observed.Mean serum/plasma levels of folate, vitamin B12 and homocysteine were not found to be significantly different in all the groups. Betel nut ingestion had no effect on the mean body weights of rats. Low dosage of betel nut is found to be associated with hypercholesterolemia. However, betel nut ingestion is not associated with hyperhomocysteinemia, hypertriglyceridemia, hyperglycemia, inflammation and increase in body weight in a rat model.


The Site of the Inhibition of the Shikimate Pathway by Glyphosate: I. INHIBITION BY GLYPHOSATE OF PHENYLPROPANOID SYNTHESIS IN BUCKWHEAT (FAGOPYRUM ESCULENTUM MOENCH) .
The nonselective herbicide glyphosate (n-[phosphonomethyl]glycine) inhibited the light-induced accumulation of phenylpropanoid substances (chlorogenic acid, procyanidin, rutin, anthocyanin) in etiolated buckwheat hypocotyls 90% at 1 millimolar. Structurally related compounds, such as n,n-bis[phosphonomethyl]glycine, aminomethylphosphonate, methylglycine, and iminodiacetate, had little or no inhibiting effects. Of all amino acids tested, only l-phenylalanine reversed the inhibition, and partial reversal of anthocyanin synthesis was achieved with chorismate, phenylpyruvate, trans-cinnamate, p-coumarate, and naringenin. Phenylalanine concentrations were reduced in glyphosate-treated hypocotyls, and glyphosate effectively reduced the high level of phenylalanine that was caused by the phenylalanine ammonia-lyase inhibitor l-alpha-aminooxy-beta-phenylpropionate. Glyphosate had no significant effect on the time course of phenylalanine ammonia-lyase activity in hypocotyls incubated either in the dark or in the light. Under appropriate feeding conditions, glyphosate inhibited the incorporation of [(14)C]shikimate into all three aromatic amino acids, and radioactive shikimate accumulated in the tissue. The results lead to the conclusion that glyphosate interferes with the shikimate pathway at or prior to the formation of chorismate.


A Nationwide Survey in Japan of Palliative Radiotherapy for Bleeding in Gastrointestinal and Genitourinary Tumor Patients.
In end-stage cancer, bleeding may markedly influence the patient's quality of life, and radiotherapy plays an important role in the control of the bleeding. In particular, there is no clear evidence of the benefit of palliative radiotherapy for cancers including gastric, rectal, and bladder cancers. A clarification of the current status of palliative radiotherapy for bleeding is needed. A survey was conducted by the palliative radiotherapy working group of the Japanese Radiation Oncology Study Group (JROSG), focusing on annual cases of radiotherapy for tumors of the upper and lower gastrointestinal tracts and genitourinary organs (excluding the uterus) and applicable fractionated doses for three hypothetical patients. A total of 54 radiation oncologists at 43 facilities answered. Most of the facilities reported that they conducted hemostatic irradiation for less than one patient per year, though the median annual number of patients treated with radiotherapy in these facilities was 594. The most frequently observed doses per fraction for two of the hypothetical cases were 3.0 and 2.0 Gy. On the other hand, in each case, the numbers of fractions reported varied markedly among the respondents, ranging from 20 Gy in five fractions to over 30 fractions. Especially in gastric cancer, hemostatic irradiation is rarely performed in most facilities in Japan. An optimal dose fractionation has not been established. Thirty Gy in 10 fractions is one of the most frequently used regimens, but re-bleeding was observed in approximately one-third of the patients.