The relationship between obesity, hyperglycemia symptoms, and health-related quality of life among Hispanic and non-Hispanic white children and adolescents.
The current study was conducted to evaluate the effects of overweight, hyperglycemia symptoms, Hispanic ethnicity, and language barriers on health-related quality of life (HRQoL) among children and adolescents. Parents'/guardians of a population based sample of 5530 children between ages 3 and 18 were administered the parents' version of the KINDL survey instrument to assess HRQoL in children and adolescents. Multiple linear regression analysis was used to assess relationships between HRQoL, body mass index, and hyperglycemia symptoms categories. The mean age of children was 10.6 (SD = 4.3). The mean KINDL total score was 79.7 (SD = 11.6) and the mean physical functioning score was 81.9 (SD = 20.3). Male children exhibited better physical health as compared to the female children (p < 0.001). Overweight children had lower overall HRQoL (p = 0.008). However, the association was not significant for the four of the six subscales including the physical health domain. Children with hyperglycemia symptoms and a family history of diabetes also had significantly lower overall and physical health HRQoL (p < 0.05). Children diagnosed with diabetes and in lower income strata also had significantly lower overall HRQoL (p < 0.05). No significant association between the Hispanic ethnicity and HRQoL was observed. However, those who reported mostly speaking Spanish exhibited significantly lower overall HRQoL (p = 0.001). Results suggest that overweight may reduce overall quality of life among children, though it does not directly influence physical functioning. However, hyperglycemia symptoms may affect both overall health and physical functioning. Findings also suggest the need for developing programs directed at overcoming language barriers that may face Spanish-speaking children or their parents. Furthermore, targeting children who have hyperglycemia symptoms with public information campaigns may be more appropriate than targeting overweight children.


Effector-independent voluntary timing: behavioural and neuroimaging evidence.
We investigated effector-independent aspects of voluntary motor timing, using behavioural measurements and functional magnetic resonance imaging. Two types of temporal pattern were investigated; one isochronous, the other a metric, rhythmic sequence of six temporal intervals. Each pattern was performed using tapping movements with the left or right index fingers, or rhythmic speech on one syllable. Deviations from the ideal temporal pattern in the rhythmic sequence tasks were consistent between the three different effectors, within subjects. This suggests that the same representation of the rhythm was used to time the movements with all effectors. To reveal brain regions involved in such effector-independent timing, we localized the overlap in brain activity when the rhythmic sequence was performed with the different effectors. Activity was found in the mesial and lateral premotor cortices, posterior and anterior regions of the superior temporal gyrus and the inferior frontal cortex. Subcortical activations were in the left globus pallidus, the vermis and bilaterally in the cerebellar hemispheres (lobule VI) and the thalamus. The overlap in activity between the isochronous tasks included the same set of brain regions, except for the basal ganglia and the thalamus. Rhythmic sequences had significantly higher activity in mesial premotor cortex, the left superior temporal gyrus and the cerebellum, than had isochronous movements. These findings reveal a set of brain regions likely to be involved in effector-independent representations of temporal patterns in voluntary motor timing. A subset of these regions plays important roles for the organization of rhythmic sequences of several intervals.


Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.
Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.


Informed consent in the psychosis prodrome: ethical, procedural and cultural considerations.
Research focused on the prodromal period prior to the onset of psychosis is essential for the further development of strategies for early detection, early intervention, and disease pre-emption. Such efforts necessarily require the enrollment of individuals who are at risk of psychosis but have not yet developed a psychotic illness into research and treatment protocols. This work is becoming increasingly internationalized, which warrants special consideration of cultural differences in conceptualization of mental illness and international differences in health care practices and rights regarding research participation. The process of identifying and requesting informed consent from individuals at elevated risk for psychosis requires thoughtful communication about illness risk and often involves the participation of family members. Empirical studies of risk reasoning and decisional capacity in young people and individuals with psychosis suggest that most individuals who are at-risk for psychosis can adequately provide informed consent; however ongoing improvements to tools and procedures are important to ensure that this work proceeds with maximal consideration of relevant ethical issues. This review provides a discussion of these issues in the context of international research efforts.


Quality of reporting in abstracts of RCTs published in emergency medicine journals: a systematic survey of the literature suggests we can do better.
We investigated the association between the publication of the Consolidated Standards of Reporting Trials extension for abstracts (CONSORT-EA) and other variables of interest on the quality of reporting of abstracts of randomised controlled trials (RCTs) published in emergency medicine (EM) journals. We performed a survey of the literature, comparing the quality of reporting before (2005-2007) with after (2014-2015) the publication of the dedicated CONSORT-EA in 2008. The quality of reporting was measured as the sum of items of the CONSORT-EA checklist reported in each abstract, ranging from 0 to 15. The main explanatory variable was the period of publication: pre-CONSORT-EA versus post-CONSORT-EA public. Other explanatory variables were journal's endorsement of the CONSORT statement, number of centres participating in the study, study's sample size, type of intervention, significance of results, source of funding and study setting. We analysed the data using generalised estimation equations, performing a univariate and a multivariable analysis. We retrieved 844 articles, and randomly selected 60 per period for review, after stratifying for journal. The mean (SD) number of items reported was 6.4 (1.9) in the period before and 6.9 (1.8) in the period after the publication of the CONSORT-EA, with an adjusted mean difference (aMD) of 0.47 (95% CI -0.13 to 1.06). Abstracts of trials of pharmacological interventions had a significantly larger mean number of reported items than those of trials of non-pharmacological interventions (aMD 1.59; 95% CI 0.94 to 2.24). The quality of reporting in abstracts of RCTs published in EM journals is low and was not significantly impacted by the publication of a dedicated CONSORT-EA.


Preoperative administration of epoetin alfa to reduce transfusion requirements in elderly patients having primary total hip or knee reconstruction.
Avoidance of allogeneic blood transfusion is challenging in elderly patients with multiple comorbid conditions, who need major elective orthopaedic surgery. We conducted a study comparing the safety and efficacy of preoperative recombinant human erythropoietin (epoetin alfa) in patients having major elective orthopaedic surgery and in matched historical control patients. Patients aged 70 years or more undergoing primary total knee arthroplasty (TKA) or total hip arthroplasty (THA) were given two or three doses, respectively, of epoetin alfa (40,000 IU). They also received oral iron for 14 or 21 days. Epoetin alfa increased hemoglobin (Hb) and hematocrit (HCT) levels before surgery; 74% of control patients required blood transfusion, compared with 12.5% of patients receiving epoetin alfa. No serious adverse event was attributed to study treatment. These data indicate that epoetin alfa is safe and effective and reduces the need for allogeneic blood transfusion in elderly patients having elective total joint replacement.


Viruses isolated from Panamanian sloths.
Seven virus strains were isolated in Vero cells from whole blood samples from 80 wild-caught sloths, Bradypus variegatus and Choloepus hoffmanni, from Central Panamá. Four strains of at least two different serotypes are related to Changuinola virus; two of these were associated with prolonged or recrudescent viremias. One strain is an antigenic subtype of Punta Toro virus, and another, described here as Bradypus-4 virus, is a new, antigenically ungrouped virus. A second new virus from sloths, Utive virus, forms an antigenic complex within the Simbu serogroup with Utinga and Pintupo viruses. Tests on sequential plasma samples from radio-marked free-ranging sloths and from recently captured animals maintained in captivity showed that both species develop neutralizing antibodies following naturally acquired virus infections. Antibodies against the Changuinola and Simbu serogroup viruses are widespread in both sloth species and are especially prevalent in Choloepus, but are virtually absent in all other wild vertebrate species tested.


Case study for the assessment of the biogeophysical effects of a potential afforestation in Europe.
A regional-scale sensitivity study has been carried out to investigate the climatic effects of forest cover change in Europe. Applying REMO (regional climate model of the Max Planck Institute for Meteorology), the projected temperature and precipitation tendencies have been analysed for summer, based on the results of the A2 IPCC-SRES emission scenario simulation. For the end of the 21st century it has been studied, whether the assumed forest cover increase could reduce the effects of the greenhouse gas concentration change. Based on the simulation results, biogeophysical effects of the hypothetic potential afforestation may lead to cooler and moister conditions during summer in most parts of the temperate zone. The largest relative effects of forest cover increase can be expected in northern Germany, Poland and Ukraine, which is 15-20% of the climate change signal for temperature and more than 50% for precipitation. In northern Germany and France, potential afforestation may enhance the effects of emission change, resulting in more severe heavy precipitation events. The probability of dry days and warm temperature extremes would decrease. Large contiguous forest blocks can have distinctive biogeophysical effect on the climate on regional and local scale. In certain regions of the temperate zone, climate change signal due to greenhouse gas emission can be reduced by afforestation due to the dominant evaporative cooling effect during summer. Results of this case study with a hypothetical land cover change can contribute to the assessment of the role of forests in adapting to climate change. Thus they can build an important basis of the future forest policy.


Gastric neuroendocrine neoplasms and related precursor lesions.
Gastric neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours showing different clinicopathological features and behaviour, implying a wide spectrum of therapeutic options. They are currently classified using the 2010 WHO classification of digestive neuroendocrine neoplasms into G1-neuroendocrine tumours (NETs), G2-NETs, neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs). However, most gastric NENs are composed of ECL-cells (ECL-cell NETs) that can be preceded by ECL-cell hyperplastic and dysplastic lesions, whose oncologic potential has not yet been completely elucidated. ECL-cell NETs differ considerably in terms of prognosis depending on the proliferative status and clinicopathological background. The integration of both aspects in the diagnostic pathway may help to better classify tumours in different prognostic categories, especially when diagnosing them in small bioptic specimens. NECs are all poorly differentiated, highly aggressive carcinomas, while MANECs can show different morphological features that are directly associated with different prognoses. Precursor lesions of such carcinomas are not entirely understood. In this review, the clinicopathological features of gastric NENs and related precursor lesions will be described to give the reader a comprehensive overview on this topic.


The insect reservoir of biodiversity for viruses and for antiviral mechanisms.
Insects are the most diverse group of animals. They can be infected by an extraordinary diversity of viruses. Among them, arthropod-borne viruses (arboviruses) can be transmitted to humans. High-throughput sequencing of small RNAs from insects provides insight into their virome, which may help understand the dynamics of vector borne infectious diseases. Furthermore, investigating the mechanisms that restrict viral infections in insects points to genetic innovations that may inspire novel antiviral strategies.


β2-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans.
Acute exercise preferentially mobilizes cytotoxic T-cells, NK-cells and non-classical monocytes to the bloodstream under the influence of hemodynamic forces and/or β2-adrenergic receptor (β2-AR) signaling. However, the relative contribution of these mechanisms to the redeployment of the most exercise-responsive cell types is largely unknown. We determined the lymphocyte and monocyte subtypes mobilized to blood during exercise via β2-AR signaling whilst controlling for β1-AR mediated reductions in hemodynamic forces. In a randomized, double blind, complete cross-over design, 14 healthy cyclists exercised for 30-minutes at +10% of blood lactate threshold after ingesting: (1) a placebo, (2) a β1-preferential antagonist (10 mg bisoprolol), or (2) a non-preferential β1 + β2-antagonist (80 mg nadolol) across three trials separated by >7-days. Bisoprolol was administered to reduce hemodynamic forces (heart rate and blood pressure) during exercise to levels comparable with nadolol but without blocking β2-ARs. The mobilization of total NK-cells, terminally differentiated (CD57+) NK-cells, central memory, effector memory and CD45RA+ effector memory CD8+ T-cells; non-classical monocytes; and γδ T-cells were significantly blunted or abrogated under nadolol compared to both bisoprolol and placebo, indicating that the exercise-induced mobilization of these cell types to the blood is largely influenced by β2-AR signaling. Nadolol failed to inhibit the mobilization of classical monocytes, CD4+ T-cells (and their subsets) or naïve CD8+ T-cells, indicating that these cell types are mobilized with exercise independently of the β2-AR. We conclude that the preferential mobilization of NK-cells, non-classical monocytes and differentiated subsets of CD8+ T-cells with exercise is largely dependent on catecholamine signaling through the β2-AR. These findings provide mechanistic insights by which distinct lymphocyte and monocyte subtypes are preferentially mobilized to protect the host from anticipated injury or infection in response to an acute stress response.


Monocot plastid phylogenomics, timeline, net rates of species diversification, the power of multi-gene analyses, and a functional model for the origin of monocots.
We present the first plastome phylogeny encompassing all 77 monocot families, estimate branch support, and infer monocot-wide divergence times and rates of species diversification. We conducted maximum likelihood analyses of phylogeny and BAMM studies of diversification rates based on 77 plastid genes across 545 monocots and 22 outgroups. We quantified how branch support and ascertainment vary with gene number, branch length, and branch depth. Phylogenomic analyses shift the placement of 16 families in relation to earlier studies based on four plastid genes, add seven families, date the divergence between monocots and eudicots+Ceratophyllum at 136 Mya, successfully place all mycoheterotrophic taxa examined, and support recognizing Taccaceae and Thismiaceae as separate families and Arecales and Dasypogonales as separate orders. Only 45% of interfamilial divergences occurred after the Cretaceous. Net species diversification underwent four large-scale accelerations in PACMAD-BOP Poaceae, Asparagales sister to Doryanthaceae, Orchidoideae-Epidendroideae, and Araceae sister to Lemnoideae, each associated with specific ecological/morphological shifts. Branch ascertainment and support across monocots increase with gene number and branch length, and decrease with relative branch depth. Analysis of entire plastomes in Zingiberales quantifies the importance of non-coding regions in identifying and supporting short, deep branches. We provide the first resolved, well-supported monocot phylogeny and timeline spanning all families, and quantify the significant contribution of plastome-scale data to resolving short, deep branches. We outline a new functional model for the evolution of monocots and their diagnostic morphological traits from submersed aquatic ancestors, supported by convergent evolution of many of these traits in aquatic Hydatellaceae (Nymphaeales).


Determination of the proteolytic cleavage sites of the amyloid precursor-like protein 2 by the proteases ADAM10, BACE1 and γ-secretase.
Regulated intramembrane proteolysis of the amyloid precursor protein (APP) by the protease activities α-, β- and γ-secretase controls the generation of the neurotoxic amyloid β peptide. APLP2, the amyloid precursor-like protein 2, is a homolog of APP, which shows functional overlap with APP, but lacks an amyloid β domain. Compared to APP, less is known about the proteolytic processing of APLP2, in particular in neurons, and the cleavage sites have not yet been determined. APLP2 is cleaved by the β-secretase BACE1 and additionally by an α-secretase activity. The two metalloproteases ADAM10 and ADAM17 have been suggested as candidate APLP2 α-secretases in cell lines. Here, we used RNA interference and found that ADAM10, but not ADAM17, is required for the constitutive α-secretase cleavage of APLP2 in HEK293 and SH-SY5Y cells. Likewise, in primary murine neurons knock-down of ADAM10 suppressed APLP2 α-secretase cleavage. Using mass spectrometry we determined the proteolytic cleavage sites in the APLP2 sequence. ADAM10 was found to cleave APLP2 after arginine 670, whereas BACE1 cleaves after leucine 659. Both cleavage sites are located in close proximity to the membrane. γ-secretase cleavage was found to occur at different peptide bonds between alanine 694 and valine 700, which is close to the N-terminus of the predicted APLP2 transmembrane domain. Determination of the APLP2 cleavage sites enables functional studies of the different APLP2 ectodomain fragments and the production of cleavage-site specific antibodies for APLP2, which may be used for biomarker development.


Structural definition and substrate specificity of the S28 protease family: the crystal structure of human prolylcarboxypeptidase.
The unique S28 family of proteases is comprised of the carboxypeptidase PRCP and the aminopeptidase DPP7. The structural basis of the different substrate specificities of the two enzymes is not understood nor has the structure of the S28 fold been described. The experimentally phased 2.8 A crystal structure is presented for human PRCP. PRCP contains an alpha/beta hydrolase domain harboring the catalytic Asp-His-Ser triad and a novel helical structural domain that caps the active site. Structural comparisons with prolylendopeptidase and DPP4 identify the S1 proline binding site of PRCP. A structure-based alignment with the previously undescribed structure of DPP7 illuminates the mechanism of orthogonal substrate specificity of PRCP and DPP7. PRCP has an extended active-site cleft that can accommodate proline substrates with multiple N-terminal residues. In contrast, the substrate binding groove of DPP7 is occluded by a short amino-acid insertion unique to DPP7 that creates a truncated active site selective for dipeptidyl proteolysis of N-terminal substrates. The results define the structure of the S28 family of proteases, provide the structural basis of PRCP and DPP7 substrate specificity and enable the rational design of selective PRCP modulators.


History and current status of the National Notifiable Diseases Surveillance System.
The National Notifiable Diseases Surveillance System (NNDSS) has origins dating more than a century ago and continues to serve today as a timely source of national data. Both the history and the current status of the NNDSS illustrate the collaborative effort required among persons at all levels of the medical and public health systems. The evolution of the list of conditions considered nationally notifiable demonstrates the responsiveness of the system to changing priorities. The NNDSS has also evolved with the development of technology; it currently uses computers for the collection of data rather than letters or telegrams. These fundamental factors--partnerships, shifting priorities, and rapidly changing technology--will continue to characterize and to influence the practice of public health surveillance as it evolves during the 21st century.


Cross-Domain Semi-Supervised Learning Using Feature Formulation.
Semi-Supervised Learning (SSL) traditionally makes use of unlabeled samples by including them into the training set through an automated labeling process. Such a primitive Semi-Supervised Learning (pSSL) approach suffers from a number of disadvantages including false labeling and incapable of utilizing out-of-domain samples. In this paper, we propose a formative Semi-Supervised Learning (fSSL) framework which explores hidden features between labeled and unlabeled samples to achieve semi-supervised learning. fSSL regards that both labeled and unlabeled samples are generated from some hidden concepts with labeling information partially observable for some samples. The key of the fSSL is to recover the hidden concepts, and take them as new features to link labeled and unlabeled samples for semi-supervised learning. Because unlabeled samples are only used to generate new features, but not to be explicitly included in the training set like pSSL does, fSSL overcomes the inherent disadvantages of the traditional pSSL methods, especially for samples not within the same domain as the labeled instances. Experimental results and comparisons demonstrate that fSSL significantly outperforms pSSL-based methods for both within-domain and cross-domain semi-supervised learning.


Changes in local cerebral blood flow following bilateral carotid occlusion in spontaneously hypertensive and normotensive rats.
Local blood flow in the cortex and thalamus was measured by the hydrogen clearance method in spontaneously hypertensive rats (SHR) and normotensive rats (NTR) before and after bilateral carotid occlusion. There were no differences in the resting blood flow values between SHR and NTR. Following carotid occlusion cortical blood flow in SHR was markedly reduced to 17% of the resting level at 1 h and, further, to less than 10% at 3--5 h period, while in NTR it decreased only to 36--38% during 5 h occlusion. Thalamic blood flow in SHR was decreased to 39% at 1 hr and to below 20% at 3--5 h, while in NTR it remained approximately 40% of the resting level during 5 h occlusion. The blood flow reduction in either cortex or thalamus after carotid occlusion was much greater in SHR than in NTR. This difference was highly significant. The increased cerebral vascular resistance caused by persistent hypertension may play an important role in a greater reduction of blood flow in SHR after carotid occlusion. Relation of the blood flow reduction to the brain metabolism is discussed.


E2A proteins maintain the hematopoietic stem cell pool and promote the maturation of myelolymphoid and myeloerythroid progenitors.
Hematopoiesis is a tightly controlled process maintained by a small pool of hematopoietic stem cells (HSCs). Here, we demonstrate that the LT-HSC, MPP, premegakaryocytic/erythroid, Pre CFU-E, Pre GM, MkP, and granulocyte-macrophage compartments were all significantly reduced in E2A-deficient bone marrow. Despite a severe depletion of erythroid progenitors, the erythrocyte and megakaryocyte compartments were equivalent in E2A-deficient bone marrow as compared with wild-type mice. E2A-deficient HSCs also failed to efficiently maintain the HSC pool on serial transplantation, and we demonstrate that the E2A proteins regulate cell cycle progression of HSCs by regulating the expression of p21(Cip1), p27(Kip1), and the thrombopoietin receptor, known regulators of HSC self-renewal activity. Based on these observations, we propose that the E2A proteins promote the developmental progression of the entire spectrum of early hematopoietic progenitors and to suppress an erythroid specific program of gene expression in alternative cell lineages. Last, the data mechanistically link E2A, cell cycle regulators, and the maintenance of the HSC pool in a common pathway.


A new DNA sensor system for specific and quantitative detection of mycobacteria.
In the current study, we describe a novel DNA sensor system for specific and quantitative detection of mycobacteria, which is the causative agent of tuberculosis. Detection is achieved by using the enzymatic activity of the mycobacterial encoded enzyme topoisomerase IA (TOP1A) as a biomarker. The presented work is the first to describe how the catalytic activities of a member of the type IA family of topoisomerases can be exploited for specific detection of bacteria. The principle for detection relies on a solid support anchored DNA substrate with dual functions namely: (1) the ability to isolate mycobacterial TOP1A from crude samples and (2) the ability to be converted into a closed DNA circle upon reaction with the isolated enzyme. The DNA circle can act as a template for rolling circle amplification generating a tandem repeat product that can be visualized at the single molecule level by fluorescent labelling. This reaction scheme ensures specific, sensitive, and quantitative detection of the mycobacteria TOP1A biomarker as demonstrated by the use of purified mycobacterial TOP1A and extracts from an array of non-mycobacteria and mycobacteria species. When combined with mycobacteriophage induced lysis as a novel way of effective yet gentle extraction of the cellular content from the model Mycobacterium smegmatis, the DNA sensor system allowed detection of mycobacteria in small volumes of cell suspensions. Moreover, it was possible to detect M. smegmatis added to human saliva. Depending on the composition of the sample, we were able to detect 0.6 or 0.9 million colony forming units (CFU) per mL of mycobacteria, which is within the range of clinically relevant infection numbers. We, therefore, believe that the presented assay, which relies on techniques that can be adapted to limited resource settings, may be the first step towards the development of a new point-of-care diagnostic test for tuberculosis.


Characterization of rat follistatin-related gene: effects of estrous cycle stage and pregnancy on its messenger RNA expression in rat reproductive tissues.
Follistatin-related gene (FLRG) was first identified as a target of a chromosomal translocation in a human B-cell leukemia. Because FLRG protein binds to activins and bone morphogenetic proteins, FLRG is postulated to be a regulator of these growth factors. However, physiological aspects of FLRG are unclear. To elucidate the physiology of FLRG, we examined expression of FLRG in reproductive tissues of the rat. FLRG mRNA was abundantly expressed in the placenta. FLRG mRNA was also expressed in the ovary, uterus, testis, lung, adrenal gland, pituitary, kidney, small intestine, and heart. During the second half of pregnancy, expression of FLRG in the placenta continuously increased, whereas follistatin mRNA levels decreased from Day 12 to Day 14 and remained low thereafter. FLRG was also expressed in decidua. Levels of decidual FLRG mRNA remained low from Day 12 to Day 16 and then noticeably increased until Day 20. In contrast, follistatin mRNA was highly expressed in the decidua on Day 12, continuously decreased until Day 16, and then remained at relatively low levels thereafter. During the rat estrous cycle, levels of ovarian FLRG mRNA fluctuated diurnally, with highest levels during daytime, and did not change relative to the day of the estrous cycle. The present results suggest that FLRG may play a role in the regulation of reproductive events.


Prenatal Omega-3 and Omega-6 Polyunsaturated Fatty Acids and Childhood Atopic Dermatitis.
Atopic dermatitis is a common childhood disease, potentially influenced by prenatal nutritional exposures such as polyunsaturated fatty acids (PUFAs). In a racially diverse cohort, we hypothesized that childhood atopic dermatitis would be associated with higher prenatal omega-6 (n-6) and lower omega-3 (n-3) PUFAs. We included mother-child dyads, births 2006 to 2011, enrolled in the University of Tennessee Health Sciences Center Conditions Affecting Neurocognitive Development in Early Childhood cohort. Primary exposures included second trimester plasma n-3 and n-6 PUFA status and the ratio of the two (n-6:n-3). We assessed child current atopic dermatitis symptoms in the previous 12 months at age approximately 4 to 6 years. We investigated the association between PUFA exposures and atopic dermatitis using multivariable logistic regression, adjusting for potential confounders. We assessed for effect modification by maternal prenatal smoking, atopic disease history, and child sex. Among 1131 women, 67% were African American and 42% had an atopic disease history; 17% of children had atopic dermatitis. Higher prenatal n-6 PUFAs were associated with increased relative odds of child atopic dermatitis (adjusted odds ratio: 1.25; confidence interval: 1.01-1.54 per interquartile range difference), and interaction models demonstrated that this association was seen in dyads in which the women had a history of atopic disease. Neither prenatal n-3 PUFAs nor n-6:n-3 were associated with child atopic dermatitis. In this racially diverse cohort, higher second trimester n-6 PUFAs were associated with atopic dermatitis in children of women with atopy. PUFAs may represent a modifiable risk factor for atopic dermatitis, particularly in individuals with a familial predisposition.


Do the competition rules of synchronized swimming encourage undesirable levels of hypoxia?
Recent anecdotal reports that some synchronized swimmers have become dizzy or disorientated towards the end of their performance, and in the worst cases fainted underwater, have caused concern. However, the rules of synchronized swimming encourage slow performance of compulsory figures, and an analysis of the competition placings and duration of underwater sequences showed that the highest rankings were gained by slowly performed compulsory figures and free programmes containing a long underwater sequence. The combination of breath-holding and the vigorous exercise involved suggests that some of the symptoms complained of by the swimmers might be due to hypoxia. We therefore studied the alveolar gas tensions in nine members of the Great Britain National Squad immediately following the performance of set figures and the initial underwater sequence of their free routine in a swimming-bath. All were cyanosed after the underwater sequences of the free routine and reported being mildly confused. The mean(s.d.) alveolar PO2 at this stage was 5.07(1.1) KPa, while three girls had an alveolar PO2 below 4 KPa, the lowest being 3.67 KPa. These gas tensions suggest that potentially dangerous levels of hypoxia may develop during competitive synchronized swimming and that prolonged underwent sequences should not be encouraged.


Application of a plasmin generation assay to define pharmacodynamic effects of tranexamic acid in women undergoing cesarean delivery.
Essentials Tranexamic acid (TXA) is an antifibrinolytic drug used to reduce bleeding. Assaying plasmin generation (PG) in plasma detects clinically relevant TXA levels in vitro and ex vivo. 3.1-16.2 µg/mL TXA half-maximally inhibits PG in plasma from women undergoing cesarean delivery. PG velocity shows the strongest dose-relationship at low TXA concentrations (≤10 µg/mL). ABSTRACT: Background Tranexamic acid (TXA) is used to reduce bleeding. TXA inhibits plasmin(ogen) binding to fibrin and reduces fibrinolysis. TXA antifibrinolytic activity is typically measured by clot lysis assays; however, effects on plasmin generation (PG) are unclear due to a lack of tools to measure PG in plasma. Aims Develop an assay to measure PG kinetics in human plasma. Determine effects of TXA on PG and compare with fibrinolysis measured by rotational thromboelastometry (ROTEM). Methods We characterized effects of plasminogen, tissue plasminogen activator, fibrinogen, and α2 -antiplasmin on PG in vitro. We also studied effects of TXA on PG in plasma from 30 pregnant women administered intravenous TXA (5, 10, or 15 mg/kg) during cesarean delivery. PG was measured by calibrated fluorescence. PG parameters were compared with TXA measured by mass spectrometry and ROTEM of whole blood. Results The PG assay is specific for plasmin and sensitive to tissue plasminogen activator, fibrin(ogen), and α2 -antiplasmin. Addition of TXA to plasma in vitro dose dependently prolonged the clot lysis time and delayed and reduced PG. For all doses of TXA administered intravenously, the PG assay detected delayed time-to-peak (≤3 hours) and reduced the velocity, peak, and endogenous plasmin potential (≤24 hours) in plasma samples obtained after infusion. The PG time-to-peak, velocity, and peak correlated significantly with TXA concentration and showed less variability than the ROTEM lysis index at 30 minutes or maximum lysis. Conclusions The PG assay detects pharmacologically relevant concentrations of TXA administered in vitro and in vivo, and demonstrates TXA-mediated inhibition of PG in women undergoing cesarean delivery.


Associations of perceived work strain with nicotine dependence in a community sample.
Little is known about work strain and smoking, and even less about work strain and nicotine dependence. To investigate the relations of perceived work strain with nicotine dependence among an adult general population sample. Cross sectional survey with a probability sample of residents of a northern German area with 4075 participants, aged 18-64 years (participation rate 70.2%). The current study is based on 2549 participants who were working 15 or more hours per week. Face to face at-home computer aided interviews (World Health Organization Composite International Diagnostic Interview) were carried out. Work strain, defined as high work demand and low work control, was assessed with a questionnaire. Nicotine dependence was diagnosed according to the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association. In addition, the Fagerström Test for Nicotine Dependence (FTND) was used. Subjects with work strain had an odds ratio of 1.6 (95% CI 1.2 to 2.3) for nicotine dependence compared to those who had no work strain. In a general linear model, higher work strain was associated with a stronger relation between work demand and work control and the FTND. The findings were adjusted for alcohol use disorders, occupational status, age, and sex. Perceived work strain is related to nicotine dependence in this general adult population.


Evaluation of the Metricheck device and the gloved hand for the diagnosis of clinical endometritis in dairy cows.
The objective of this study was to compare 2 surrogate vaginal examination methods (i.e., gloved hand and a vaginal device) with vaginoscopy as a reference method for diagnosing clinical endometritis in dairy cows. Holstein-Friesian cows (n = 1,002) in 2 commercial dairy herds in Germany were examined for endometritis at 21 to 27 d in milk (DIM) by using 1 of 3 vaginal diagnostic methods. Vaginal examinations were performed either with a speculum (reference method), a vaginal device (Metricheck, Simcro, New Zealand), or a gloved hand. Vaginal discharge adhering to the diagnostic tool was classified according to a vaginal discharge score ranging from 0 to 3 (where 0 = translucent mucus, 1 = mucus containing flecks of white or off-white pus, 2 = less than 50% white or off-white mucopurulent material, and 3 = greater than 50% white or yellow pus that may be sanguineous). Cows with vaginal discharge scores of 1 to 3 received 500 microg of cloprostenol after examination and again 14 d later (35 to 41 DIM). The prevalence of endometritis in both herds was 40.6 and 40.3%, respectively. With the Metricheck device, significantly more cows were diagnosed as affected with endometritis than by examination with a speculum or a gloved hand (47.5 vs. 36.9 and 36.8%). Binary logistic regression for the risk of conception after first AI as an outcome variable, with vaginal discharge score, diagnostic method, and farm as covariates, revealed a significant effect of degree of endometritis, but not of the diagnostic methods. Survival analyses for the hazard of insemination and pregnancy within 200 DIM, respectively, revealed a significant effect of degree of endometritis, herd, and parity, but not of the diagnostic tool. It can be concluded that any one of the 3 vaginal examination methods can be used interchangeably, without a negative effect on reproductive performance.


Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. I. A dose-response study.
This multicenter, double-blind, placebo-controlled, dose-response study was conducted in patients with primary hypercholesterolemia to examine the effects of pravastatin, a selective inhibitor of HMG-CoA reductase, on plasma lipids and lipoproteins. A total of 306 patients on cholesterol-lowering diets received twice daily doses of 5 mg, 10 mg, 20 mg pravastatin, or placebo for 12 weeks. Marked reductions in low density lipoprotein (LDL) cholesterol and total cholesterol were observed after 1 week of treatment; maximum lipid-lowering effects occurred at 4 weeks and were sustained for the duration of the trial. At week 12, pravastatin treatment resulted in dose-dependent mean reductions from baseline in LDL cholesterol of 17.5%, 22.9%, and 30.8% for the 3 doses tested (P less than or equal to 0001 compared with baseline and placebo). The reduction in LDL cholesterol was log-linear with respect to dose; each doubling of dose reduced LDL cholesterol an additional 6.5%. Dose-dependent reductions in total cholesterol from 12.9% to 23.3% also occurred (P less than or equal to 0.001). Triglycerides decreased by as 15.4% (P less than or equal to 0.001) and high-density lipoprotein (HDL) cholesterol increased approximately 7% (P less than or equal to 0.01), but these effects were not dose-dependent. No patient receiving pravastatin was discontinued during the 12-week trial. Transient episodes of rash and headache occurred. Slight increases in mean serum levels of ASAT and ALAT occurred, and 2% of both placebo- and pravastatin-treated patients reported myalgia although there was no clinically significant elevation of creatine kinase. These data indicate that pravastatin favorably affects all lipid parameters and is well tolerated.


Patterns of abdominal injury in 37 387 disaster patients from the Wenchuan earthquake.
Due to lack of sufficient data it is difficult to understand fully the pattern of abdominal injury after an earthquake. This study aimed to evaluate the pattern of abdominal injury by analysing the data of trauma patients with abdominal injury incurred during the 2008 Wenchuan earthquake. We retrospectively reviewed the medical records of 37387 inpatients. Among them, 883 (2.36%) cases of abdominal injury were deemed eligible and enrolled for analysis. The data analysed included demographics, category of abdominal injury, associated injury type, cause of injury, treatment and clinical outcome, as well as risk factors for death. Abdominal injury was often accompanied with multiple injuries. Injury of the abdominal wall was the most frequent type of earthquake-related abdominal injury (32%). The spleen was the most commonly injured abdominal organ (18%). Of the 883 patients evaluated, 221 cases received operations and 41 cases died. The highest death rate was found in patients with haemorrhagic shock (28/41, 68.3%) caused by intra-abdominal bleeding. Abdominal injuries are relatively uncommon in earthquake disasters and often present with associated injuries. A timely and complete diagnosis of both abdominal as well as associated injuries is of primary importance in the treatment of patients with abdominal injuries. Knowledge of different types of abdominal injury, and their relative proportions, prevalence of associated injuries, risk factors and final clinical outcomes observed in this study may be of valuable reference in dealing with major earthquake events in the future.


Spousal Caregivers Are Caregiving Alone In The Last Years Of Life.
Caregiving in the last years of life is associated with increased depression and negative health outcomes for surviving spouses, many of whom are themselves in poor health. Yet it is unclear how often spouses are caregiving alone, how they differ from supported spouses, and whether lack of support affects postbereavement outcomes. We hypothesized that spouses who were solo caregivers-that is, the only caregivers (paid or unpaid) who provided assistance with a spouse's self-care or household activities-would experience more depression after bereavement than supported spouses would. Using information from the Health and Retirement Study, we found that 55 percent of the spouses of community-dwelling married people with disability were solo caregivers. Solo caregiving was even common among people who cared for spouses with dementia and those with adult children living close by. Bereavement outcomes did not differ between solo and supported caregiving spouses. Caregiving spouses are often isolated and may benefit from greater support, particularly during the final years before bereavement. While some state and federal policy proposals aim to systematically recognize and assess caregivers, further innovations in care delivery and reimbursement are needed to adequately support seriously ill older adults and their caregivers. Ultimately, the focus of serious illness care must be expanded from the patient to the family unit.


Mind-body medicine for multiple sclerosis: a systematic review.
Background. Mind-body therapies are used to manage physical and psychological symptoms in many chronic health conditions. Objective. To assess the published evidence for using mind-body techniques for symptom management of multiple sclerosis. Methods. MEDLINE, PsycINFO, and Cochrane Clinical Trials Register were searched from inception to March 24, 2012. Eleven mind-body studies were reviewed (meditation, yoga, biofeedback, hypnosis, relaxation, and imagery). Results. Four high quality trials (yoga, mindfulness, relaxation, and biofeedback) were found helpful for a variety of MS symptoms. Conclusions. The evidence for mind-body medicine in MS is limited, yet mind-body therapies are relatively safe and may provide a nonpharmacological benefit for MS symptoms.


Effects of weight loss on regional fat distribution and insulin sensitivity in obesity.
Weight loss (WL) decreases regional depots of adipose tissue and improves insulin sensitivity, two parameters that correlate before WL. To examine the potential relation of WL-induced change in regional adiposity to improvement in insulin sensitivity, 32 obese sedentary women and men completed a 4-month WL program and had repeat determinations of body composition (dual-energy X-ray absorptiometry and computed tomography) and insulin sensitivity (euglycemic insulin infusion). There were 15 lean men and women who served as control subjects. VO2max was unaltered with WL (39.2 +/- 0.8 vs. 39.8 +/- 1.1 ml x fat-free mass [FFM](-1) x min(-1)). The WL intervention achieved significant decreases in weight (100.2 +/- 2.6 to 85.5 +/- 2.1 kg), BMI (34.3 +/- 0.6 to 29.3 +/- 0.6 kg/m2), total fat mass (FM) (36.9 +/- 1.5 to 26.1 +/- 1.3 kg), percent body fat (37.7 +/- 1.3 to 31.0 +/- 1.5%), and FFM (59.2 +/- 2.3 to 55.8 +/- 2.0 kg). Abdominal subcutaneous and visceral adipose tissue (SAT and VAT) were reduced (494 +/- 19 to 357 +/- 18 cm2 and 157 +/- 12 to 96 +/- 7 cm2, respectively). Cross-sectional area of low-density muscle (LDM) at the mid-thigh decreased from 67 +/- 5 to 55 +/- 4 cm2 after WL. Insulin sensitivity improved from 5.9 +/- 0.4 to 7.3 +/- 0.5 mg x FFM(-1) x min(-1) with WL. Rates of insulin-stimulated nonoxidative glucose disposal accounted for the majority of this improvement (3.00 +/- 0.3 to 4.3 +/- 0.4 mg x FFM(-1) x min(-1)). Serum leptin, triglycerides, cholesterol, and insulin all decreased after WL (P < 0.01). After WL, insulin sensitivity continued to correlate with generalized and regional adiposity but, with the exception of the percent decrease in VAT, the magnitude of improvement in insulin sensitivity was not predicted by the various changes in body composition. These interventional weight loss data underscore the potential importance of visceral adiposity in relation to insulin resistance and otherwise suggest that above a certain threshold of weight loss, improvement in insulin sensitivity does not bear a linear relationship to the magnitude of weight loss.


Rural dentists of the future: dental school enrollment strategies.
The purpose of this study was to determine the relationship, if any, of a dental student's 1) state of residency and 2) gender to his or her practice location in a rural Nebraska community after graduation. Previous research has demonstrated that dental students generally locate their practices near their place of rearing and that male graduates are more likely than female graduates to locate in rural areas. Dental student data for all University of Nebraska Medical Center College of Dentistry graduates from 1989 to 2008 (n=879) were analyzed. Descriptive and quantitative analyses were performed utilizing SPSS software (version 17.0). Chi-square and odds ratio analyses were also conducted. In contrast to previous research, women dentists who remained in the state after graduation were more likely to locate their practice in a rural community than were male dentists: 59 percent and 48.5 percent, respectively. Nonresidents who remained in the state after graduation were also more likely to locate in a rural community than were residents: 69 percent and 51 percent, respectively. Dental schools may find this information useful as state officials and policymakers look to dental schools for leadership in addressing dental workforce needs, especially in rural/underserved areas.


Motivational Affordance and Risk-Taking Across Decision Domains.
We propose a motivational affordance account to explain both stability and variability in risk-taking propensity in major decision domains. We draw on regulatory focus theory to differentiate two types of motivation (prevention, promotion) that play a key role in predicting risk-taking. Study 1 demonstrated that prevention motivation is negatively associated with risk-taking across six key decision domains, including health/safety, ethics, recreation, gambling, investment, and social. In contrast, promotion motivation is positively associated with risk-taking in the social and investment domains. Study 2 replicated the same pattern and provided direct evidence that promotion motivation is a strong predictor of risk-taking only in domains where there is true potential for gains. Study 3 manipulated promotion (vs. prevention) motivation experimentally to demonstrate that motivational affordance is a critical mechanism for understanding risk-taking behaviors.


Impact of antihypertensive therapy on postmenopausal osteoporosis: effects of the angiotensin converting enzyme inhibitor moexipril, 17beta-estradiol and their combination on the ovariectomy-induced cancellous bone loss in young rats.
No data are available on whether angiotensin converting enzyme (ACE) inhibition affects the skeleton, though this might be of clinical relevance when antihypertensive therapy is initiated, particularly in hypertensive women after menopause who typically suffer from a concomitant rapid onset of osteoporosis. In the present study we investigated the effects of the new ACE inhibitor moexipril, 17beta-estradiol and their combination on the bone turnover in ovariectomized Sprague-Dawley rats, an established animal model for studying human postmenopausal osteoporosis. We studied 119 12-week-old virgin female Sprague-Dawley rats. Seven rats were killed on day 0 as basal controls. The remaining rats were divided into sham-ovariectomy or ovariectomy groups. Vehicle, moexipril at 10 mg/kg per day alone (orally), 17beta-estradiol at 10 mu g/kg per day alone (subcutaneously) or both were administered to both groups immediately after the operation for 14 (short-term effects) or 56 (long-term effects) days. A stereology computer program was used for measurements. Static histomorphometric measurements, using a stereology computer program, were taken on double-fluorescent labeled undecalcified proximal tibial metaphyseal (cancellous bone site) and tibial shaft (cortical bone site) sections. Ovariectomy induced dramatically cancellous bone loss due to increased bone turnover, with resorption exceeding formation. Moexipril had no effect on the cancellous bone site in either ovariectomized or sham-operated rats. 17beta-Estradiol treatment added extra cancellous bone in the sham-operated rats and prevented cancellous bone loss in the ovariectomized rats by inhibiting bone resorption. The combination of moexipril and 17beta-estradiol gave similar results to those of 17beta-estradiol alone. Comparable results were observed in the cortical bone site. The results of this study show that ACE inhibition by moexipril has no effect on the skeleton when given alone and that it does not hamper the osteoprotective effects of 17beta-estradiol. These findings are relevant for the use of antihypertensive therapy in postmenopausal women treated or not with hormone replacement therapy.


Early evidence of San material culture represented by organic artifacts from Border Cave, South Africa.
Recent archaeological discoveries have revealed that pigment use, beads, engravings, and sophisticated stone and bone tools were already present in southern Africa 75,000 y ago. Many of these artifacts disappeared by 60,000 y ago, suggesting that modern behavior appeared in the past and was subsequently lost before becoming firmly established. Most archaeologists think that San hunter-gatherer cultural adaptation emerged 20,000 y ago. However, reanalysis of organic artifacts from Border Cave, South Africa, shows that the Early Later Stone Age inhabitants of this cave used notched bones for notational purposes, wooden digging sticks, bone awls, and bone points similar to those used by San as arrowheads. A point is decorated with a spiral groove filled with red ochre, which closely parallels similar marks that San make to identify their arrowheads when hunting. A mixture of beeswax, Euphorbia resin, and possibly egg, wrapped in vegetal fibers, dated to ∼40,000 BP, may have been used for hafting. Ornaments include marine shell beads and ostrich eggshell beads, directly dated to ∼42,000 BP. A digging stick, dated to ∼39,000 BP, is made of Flueggea virosa. A wooden poison applicator, dated to ∼24,000 BP, retains residues with ricinoleic acid, derived from poisonous castor beans. Reappraisal of radiocarbon age estimates through bayesian modeling, and the identification of key elements of San material culture at Border Cave, places the emergence of modern hunter-gatherer adaptation, as we know it, to ∼44,000 y ago.


Defensive responses of cuttlefish to different teleost predators.
We evaluated cuttlefish (Sepia officinalis) responses to three teleost predators: bluefish (Pomatomus saltatrix), summer flounder (Paralichthys dentatus), and black seabass (Centropristis striata). We hypothesized that the distinct body shapes, swimming behaviors, and predation tactics exhibited by the three fishes would elicit markedly different antipredator responses by cuttlefish. Over the course of 25 predator-prey behavioral trials, 3 primary and 15 secondary defense behaviors of cuttlefish were shown to predators. In contrast, secondary defenses were not shown during control trials in which predators were absent. With seabass-a benthic, sit-and-pursue predator-cuttlefish used flight and spent more time swimming in the water column than with other predators. With bluefish-an active, pelagic searching predator-cuttlefish remained closely associated with the substrate and relied more on cryptic behaviors. Startle (deimatic) displays were the most frequent secondary defense shown to seabass and bluefish, particularly the Dark eye ring and Deimatic spot displays. We were unable to evaluate secondary defenses by cuttlefish to flounder-a lie-and-wait predator-because flounder did not pursue cuttlefish or make attacks. Nonetheless, cuttlefish used primary defense during flounder trials, alternating between cryptic still and moving behaviors. Overall, our results suggest that cuttlefish may vary their behavior in the presence of different teleost predators: cryptic behaviors may be more important in the presence of active searching predators (e.g., bluefish), while conspicuous movements such as swimming in the water column and startle displays may be more prevalent with relatively sedentary, bottom-associated predators (e.g., seabass).


Molecular epidemiology and emergence of worldwide epidemic clones of Neisseria meningitidis in Taiwan.
Meningococcal disease is infrequently found in Taiwan, a country with 23 million people. Between 1996 and 2002, 17 to 81 clinical cases of the disease were reported annually. Reported cases dramatically increased in 2001-2002. Our record shows that only serogroup B and W135 meningococci have been isolated from patients with meningococcal disease until 2000. However, serogroup A, C and Y meningococci were detected for the first time in 2001 and continued to cause disease through 2002. Most of serogroup Y meningococcus infections localized in Central Taiwan in 2001, indicating that a small-scale outbreak of meningococcal disease had occurred. The occurrence of a meningococcal disease outbreak and the emergence of new meningococcal strains are of public health concern. Neisseria meningitidis isolates from patients with meningococcal disease from 1996 to 2002 were collected and characterized by serogrouping, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The genetic relatedness and clonal relationship between the isolates were analyzed by using the PFGE patterns and the allelic profiles of the sequence types (STs). Serogroups A, B, C, W135, Y, and non-serogroupable Neisseria meningitidis were, respectively, responsible for 2%, 50%, 2%, 35%, 9%, and 2% of 158 culture-confirmed cases of meningococcal disease in 1996-2002. Among 100 N. meningitidis isolates available for PFGE and MLST analyses, 51 different PFGE patterns and 30 STs were identified with discriminatory indices of 0.95 and 0.87, respectively. Of the 30 STs, 21 were newly identified and of which 19 were found in serogroup B isolates. A total of 40 PFGE patterns were identified in 52 serogroup B isolates with the patterns distributed over several distinct clusters. In contrast, the isolates within each of the serogroups A, C, W135, and Y shared high levels of PFGE pattern similarity. Analysis of the allelic profile of the 30 STs suggested the serogroup B isolates be assigned into 5 clonally related groups/ clonal complexes and 7 unique clones. The ST-41/44 complex/Lineage 3, and the ST-3439 and ST-3200 groups represented 79% of the serogroup B meningococci. In contrast, isolates within serogroups A, serogroup W135 (and C), and serogroup Y, respectively, simply belonged to ST-7, ST-11, and ST-23 clones. Our data suggested that serogroup B isolates were derived from several distinct lineages, most of which could either be indigenous or were introduced into Taiwan a long time ago. The serogroup A, W135 (and C), and Y isolates, respectively, belonged to the ST-7, ST-11, and ST-23, and the represented clones that are currently the major circulating clones in the world and are introduced into Taiwan more recently. The emergence of serogroup A, C and Y strains contributed partly to the increase in cases of meningococcal disease in 2001-2002.


Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors.
Approximately 3% of all human T-lymphotropic virus type 1 (HTLV-1)-infected persons will develop a disabling inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis, against which there is currently no efficient treatment. As correlation exists between the proviral load (PVL) and the clinical status of the carrier, it is thought that diminishing the PVL could prevent later occurrence of the disease. We have conducted a study combining valproate, an inhibitor of histone deacetylases, and azidothymidine, an inhibitor of reverse transcriptase, in a series of baboons naturally infected with simian T-lymphotropic virus type 1 (STLV-1), whose PVL was equivalent to that of HTLV-1 asymptomatic carriers. We show that the combination of drugs caused a strong decrease in the PVL and prevented the transient rise in PVL that is seen after treatment with histone deacetylases alone. We then demonstrate that the PVL decline was associated with an increase in the STLV-1-specific cytotoxic T-cell population. We conclude that combined treatment with valproate to induce viral expression and azidothymidine to prevent viral propagation is a safe and effective means to decrease PVL in vivo. Such treatments may be useful to reduce the risk of HAM/TSP in asymptomatic carriers with a high PVL.


Strengthening the public health system.
Although the American public health system has made major contributions to life expectancy for residents of this country over the past century, the system now faces more complex health problems that require comprehensive approaches and increased capacity, particularly in local and State public health agencies. To strengthen the public health system, concerted action is needed to meet these five critical needs: First, the knowledge base of public health workers needs to be supplemented through on-the-job training and continuing education programs. To this end, self-study courses will be expanded, and a network of regional training centers will be established throughout the country. Second, communities need dynamic leadership from public health officials and their agencies. To enhance leadership skills and expand the leadership role of public health agencies, focused personal leadership development activities, including a Public Health Leadership Institute, and national conferences will provide a vision of the future role of public health agencies. Third, local and State public health agencies need access to data on the current health status of the people in their communities and guidance from the nation's public health experts. To improve access to information resources, state-of-the-art technologies will be deployed to create integrated information and communication systems linking all components of the public health system. Fourth, local and State agencies need disease prevention and health promotion plans that target problems and develop strategies and the capacity to address them. To provide communities with structured approaches to this process, planning tools have been developed and distributed, and technical assistance will be provided to local and State health agencies to involve each community in planning,priority setting, and constituency building.Finally, public health agencies need adequate resources to fund prevention programs. To improve the use of existing Federal support and enhance the availability of new community resources, grant programs will be modified, and innovative approaches to local resource enhancement will be developed and shared.Activities in these five key areas are designed to improve the infrastructure of the public health system and its capacity to carry out effectively the core functions of public health assessment, policy development, and assurance of the availability of the benefits of public health. If the nation is to achieve the health objectives for the year 2000, the public health system-the individuals and institutions that, when working effectively together, promote and protect the health of the people-must be strengthened.


XRCC1 co-localizes and physically interacts with PCNA.
X-ray Repair Cross Complementing 1 (XRCC1) is thought to function as a scaffolding protein in both base excision repair and single-strand break repair (SSBR), since it interacts with several proteins participating in these related pathways and has no known enzymatic activity. Moreover, studies indicate that XRCC1 possesses discrete G1 and S phase-specific functions. To further define the contribution of XRCC1 to DNA metabolism, we determined the in vivo localization pattern of this protein and searched for novel protein interactors. We report here that XRCC1 co-localizes with proliferating cell nuclear antigen (PCNA) at DNA replication foci, observed exclusively in the S phase of undamaged HeLa cells. Furthermore, fluorescence resonance energy transfer (FRET) analysis and co-immunoprecipitation indicate that XRCC1 and PCNA are in a complex and likely physically interact in vivo. In vitro biochemical analysis demonstrated that these two proteins associate directly, with the interaction being mediated by residues between amino acids 166 and 310 of XRCC1. The current evidence suggests a model where XRCC1 is sequestered via its interaction with PCNA to sites of DNA replication factories to facilitate efficient SSBR in S phase.


The two faces of Janus kinases and their respective STATs in mammary gland development and cancer.
Since its discovery as "just another kinase" more than twenty years ago, the family of JAK tyrosine kinases and their respective Signal Transducers and Activators of Transcription (STATs) has been a center of attention in the areas of signal transduction, development, and cancer. The subsequent designation of JAKs as Janus kinases after the mythical two-faced Roman God of the doorways accurately portrays the analogous and sometimes contrasting molecular and biological characteristics of these tyrosine kinases. The two "faces" of JAKs are their structurally similar kinase and pseudo-kinase domains. As essential parts of various transmembrane receptor complexes, these tyrosine kinases function at cellular gateways and relay signals from growth factors to their respective intracellular targets. The multifaceted nature of JAKs becomes evident from their ability to activate specific STATs during distinct phases of normal mammary gland development. Studies in breast cancer cells and genetically engineered mouse models also show that JAK/STAT signaling possesses a "two-faced" role during breast cancer initiation and progression. This review will highlight recent findings about important biological functions of JAKs and STATs during normal mammogenesis, with particular emphasis on the Jak2/Stat5 pathway as well as Jak1/2/Stat3 signaling complexes. In addition, we will discuss how the importance of these signaling networks changes during carcinogenesis. With JAK inhibitors currently under development to treat myeloproliferative disorders, determining the essential functions of JAKs at particular stages of disease initiation and progression is of critical importance to predict the efficacy of these agents for targeted therapies against breast cancer.


High-resolution confocal detection of nanometric displacement by use of a 2 x 1 optical fiber coupler.
A novel high-resolution confocal measurement of nanometric displacement that uses a simple 2 x 1 optical fiber coupler is presented. The basic principle is to detect interferometrically the change in the phase difference between two adjacent input fibers of the coupler that results from the nonuniform wave-front curvature of the reflected light. Measurement of subnanometer axial modulation, which permits high-resolution displacement sensing by optical means, is demonstrated.


The Economic Burden of Out-of-Pocket Expenses for Plastic Surgery Procedures.
Health insurance reimbursement structure has evolved, with patients becoming increasingly responsible for their health care costs through rising out-of-pocket expenses. High levels of cost sharing can lead to delays in access to care, influence treatment decisions, and cause financial distress for patients. Patients undergoing the most common outpatient reconstructive plastic surgery operations were identified using Truven MarketScan databases from 2009 to 2017. Total cost of the surgery paid to the insurer and out-of-pocket expenses, including deductible, copayment, and coinsurance, were calculated. Multivariable generalized linear modeling with log link and gamma distribution was used to predict adjusted total and out-of-pocket expenses. All costs were inflation-adjusted to 2017 dollars. The authors evaluated 3,165,913 outpatient plastic and reconstructive surgical procedures between 2009 and 2017. From 2009 to 2017, total costs had a significant increase of 25 percent, and out-of-pocket expenses had a significant increase of 54 percent. Using generalized linear modeling, procedures performed in outpatient hospitals conferred an additional $1999 in total costs (95 percent CI, $1978 to $2020) and $259 in out-of-pocket expenses (95 percent CI, $254 to $264) compared with office procedures. Ambulatory surgical center procedures conferred an additional $1698 in total costs (95 percent CI, $1677 to $1718) and $279 in out-of-pocket expenses (95 percent CI, $273 to $285) compared with office procedures. For outpatient plastic surgery procedures, out-of-pocket expenses are increasing at a faster rate than total costs, which may have implications for access to care and timing of surgery. Providers should realize the increasing burden of out-of-pocket expenses and the effect of surgical location on patients' costs when possible.


The Role of Decreased Hip IR as a Cause of Low Back Pain in a Golfer: a Case Report.
Among golf injuries, low back pain (LBP) is the most common compliant for both professional and amateur golfers. Hip rotational range of motion (ROM) might be related to LBP in those who repeatedly place specific activity rotational demands on the hip in one direction. Coordination of timing of movement (neural control) between the hip and lumbopelvic region during trunk movements is critical for normal mechanics. Altered timing can contribute to areas of high tissue loading and can lead to LBP symptoms seen during active lower limb movement tests. Patient was a 42-year-old male recreational golfer who presented with low back pain and decreased hip internal rotation ROM. With the use of manual physical therapy to increase hip ROM and lumbar stabilization therapeutic exercises, the patient was able to return to pain-free golf and to better his handicap by three strokes. Significant improvement was seen in his Oswestry outcome score, and a (-) prone instability test was noted. It is recommended to address hip ROM limitations in those experiencing low back pain while golfing. Rapid spinal rotation may produce large spinal loads, but this is likely not the major contributor to low back pain in golfers. Mechanical factors may play a larger role.


Apathy in schizophrenia as a deficit in the generation of options for action.
Negative symptoms are a core feature of schizophrenia and have been grouped into 2 factors: a motivational factor, which we refer to as apathy, and a diminished expression factor. Recent studies have shown that apathy is closely linked to functional outcome. However, knowledge about its mechanisms and its relation to decision-making is limited. In the current study, we examined whether apathy in schizophrenia is associated with predecisional deficits, that is, deficits in the generation of options for action. We applied verbal protocol analysis to investigate the quantity of options generated in ill-structured real world scenarios in 30 patients with schizophrenia or schizoaffective disorder and 21 healthy control participants. Patients generated significantly fewer options than control participants and clinical apathy ratings correlated negatively with the quantity of generated options. We show that the association between measures of psychopathology and option generation is most pronounced in regard to apathy symptoms and that it is only partially mediated by deficits in verbal fluency. This study provides empirical support for dysfunctional option generation as a possible mechanism for apathy in schizophrenia. Our data emphasize the potential importance of predecisional stages in the development and persistence of apathy symptoms in neuropsychiatric disorders and might also inform the development of novel treatment options in the realm of cognitive remediation.


Factors influencing early referral, early diagnosis and management in patients with diffuse cutaneous systemic sclerosis.
To gain insight into clinical practice regarding referral, early diagnosis and other aspects of the management of patients with dcSSc in Europe and the USA. Semi-structured interviews were conducted with 84 rheumatologists (or internal medicine physicians) and 40 dermatologists in different countries (the UK, France, Germany, Italy, Spain and the USA). Physicians were asked to identify key steps in the patient pathway relating to patient presentation, diagnosis and referral, in addition to other treatment and follow-up processes. The interviewed physicians reported that late presentation with dcSSc was common, with some patients presenting to primary care physicians after symptoms had persisted for up to 1 year. Awareness of dcSSc is reported to vary widely among primary care physicians. Final diagnosis, generally following guideline-based recommendations, was by rheumatologists in most cases (or internal medicine physicians in France) and they remained responsible for global patient management, with lesser involvement in diagnosis and management by dermatologists. Specialist centres were not well defined and did not exist in all countries. Patients and primary healthcare providers can be unaware of the symptoms of dcSSc, therefore presentation and referral to specialist care are often late. Thus, improved awareness among patients and primary care physicians is necessary to facilitate earlier referral and diagnosis. Once referred, more consistent use of the modified Rodnan skin score at diagnosis and follow-up may help to monitor disease progression. Furthermore, establishing specialist centres may help to promote such changes and improve patient care.


Legal briefing: The unbefriended: making healthcare decisions for patients without surrogates (Part 2).
This issue's "Legal Briefing" column continues coverage of recent legal developments involving medical decision making for unbefriended patients. These patients have neither decision-making capacity nor a reasonably available surrogate to make healthcare decisions on their behalf. This topic has been the subject of recent articles in JCE. It has been the subject of major policy reports. Indeed, caring for the unbefriended has even been described as the "single greatest category of problems" encountered in bioethics consultation. Moreover, the scope of the problem continues to expand, especially with rapid growth in the elderly population and with an increased prevalence of dementia. Unfortunately, most U.S.jurisdictions have failed to adopt effective healthcare decision-making systems or procedures for the unbefriended. "Existing mechanisms to address the issue of decision making for the unbefriended are scant and not uniform." Most providers are "muddling through on an ad hoc basis." Still, over the past several months, a number of state legislatures have finally addressed the issue. These developments and a survey of the current landscape are grouped into the following 14 categories. The first two categories define the problem of medical decision making for the unbefriended.The remaining 12 describe different solutions to the problem. The first six categories were covered in Part 1 of this article; the last eight categories are covered in this issue (Part 2). 1. Who are the unbefriended? 2. Risks and problems of the unbefriended. 3. advance care planning, diligent searching, and careful capacity assessment. 4. Decision-making mechanisms and standards. 5. Emergency exception to informed consent. 6. Expanded default surrogate lists: close friends. 7. Private guardians. 8. Volunteer guardians. 9. Public guardians. 10. Temporary and emergency guardians. 11. Attending physicians. 12. Other clinicians, individuals, and entities. 13. Institutional committees. 14. External committees.


Responding the "Wrong Way": The Emotion Work of Caring for a Family Member With Dementia.
Although it is generally acknowledged that the changing behaviors of some people living with dementia can be emotionally exhausting for family members, there has been little research on how carers actually interpret and manage their emotional responses when interacting with persons with dementia in context and over time. Applying the concept of emotion work, this analysis examines when and where carers feel they are responding "the right way" to their kin and when and where they resist normative emotions around family care. Semi-structured qualitative interviews (N = 20) and diaries (N = 11) were conducted with, and collected from, family carers in Manitoba, Canada to explore how they negotiate their emotions and emotional displays when caring for a family member whose behaviors are changing. Carers expressed feelings of frustration, anger, and resentment and identified putting on a positive attitude, putting the person with dementia first, protecting the person with dementia, and avoiding conflict and arguing as the "right way" to respond to these feelings. They identified challenges responding the "right way," however, in relation to household chores, and situations that also involved isolation, fear, verbal aggression, and fatigue. Programs and policies must recognize the complex emotion work of family carers. There is a need for more nuanced education materials, support with household tasks, inclusion of carers' emotional needs in transition planning, and support for carers to exit the caring role when necessary.


Serum IgM in retinitis pigmentosa: a genetic study.
Because of a published report that serum immunoglobulin M (IgM) was elevated in some cases of retinitis pigmentosa (RP), a genetic study was undertaken to determine if a particular pattern of inheritance was associated with elevated IgM. Seventy-five RP patients in 37 families were ascertained and classified by pattern of inheritance into six groups. Serum IgM was quantitated by the radial immunodiffusion technique. Fifty-one controls were also studied. Methods of adjusting the IgM values for sex, age, and race were derived, but only a sex adjustment was used, since no effect of age on IgM was found in this sample, and there were few data on race. There was no signifcant difference in mean IgM levels between RP patients and controls. The variance of the RP group was slightly greater than that of the controls. One-way analysis of variance of the six genetic categories of RP and controls was performed on the raw data and on the data after log transformation. The F-ratio was not significant, indicating that there was no difference in serum IgM levels among the seven groups. Possible reasons for the discrepancy in results between this study and the previous report are presented.


Implementing telehealth to support medical practice in rural/remote regions: what are the conditions for success?
Telehealth, as other information and communication technologies (ICTs) introduced to support the delivery of health care services, is considered as a means to answer many of the imperatives currently challenging health care systems. In Canada, many telehealth projects are taking place, mostly targeting rural, remote or isolated populations. So far, various telehealth applications have been implemented and have shown promising outcomes. However, telehealth utilisation remains limited in many settings, despite increased availability of technology and telecommunication infrastructure. A qualitative field study was conducted in four remote regions of Quebec (Canada) to explore perceptions of physicians and managers regarding the impact of telehealth on clinical practice and the organisation of health care services, as well as the conditions for improving telehealth implementation. A total of 54 respondents were interviewed either individually or in small groups. Content analysis of interviews was performed and identified several effects of telehealth on remote medical practice as well as key conditions to ensure the success of telehealth implementation. According to physicians and managers, telehealth benefits include better access to specialised services in remote regions, improved continuity of care, and increased availability of information. Telehealth also improves physicians' practice by facilitating continuing medical education, contacts with peers, and access to a second opinion. At the hospital and health region levels, telehealth has the potential to support the development of regional reference centres, favour retention of local expertise, and save costs. Conditions for successful implementation of telehealth networks include the participation of clinicians in decision-making, the availability of dedicated human and material resources, and a planned diffusion strategy. Interviews with physicians and managers also highlighted the importance of considering telehealth within the broader organisation of health care services in remote and rural regions. This study identified core elements that should be considered when implementing telehealth applications with the purpose of supporting medical practice in rural and remote regions. Decision-makers need to be aware of the specific conditions that could influence telehealth integration into clinical practices and health care organisations. Thus, strategies addressing the identified conditions for telehealth success would facilitate the optimal implementation of this technology.


Severe hypoglycaemia in adults with insulin-treated diabetes: impact on healthcare resources.
To assess resource utilization associated with severe hypoglycaemia across three insulin regimens in a large phase 3a clinical programme involving people with Type 1 diabetes treated with basal-bolus insulin, people with Type 2 diabetes treated with multiple daily injections and people with Type 2 diabetes treated with basal-oral therapy. Data relating to severe hypoglycaemia events (defined as episodes requiring external assistance) from the insulin degludec and insulin degludec/insulin aspart programme (15 trials) were analysed using descriptive statistics. Comparators included insulin glargine, biphasic insulin aspart, insulin detemir and sitagliptin. Mealtime insulin aspart was used in some regimens. This analysis used the serious adverse events records, which documented the use of ambulance/emergency teams, a hospital/emergency room visit ≤ 24 h, or a hospital visit > 24 h. In total, 536 severe hypoglycaemia events were analysed, of which 157 (29.3%) involved an ambulance/emergency team, 64 (11.9%) led to hospital/emergency room attendance of ≤ 24 h and 36 (6.7%) required hospital admission (> 24 h). Although there were fewer events in people with Type 2 diabetes compared with Type 1 diabetes, once a severe episode occurred, the tendency to utilize healthcare resources was higher in Type 2 diabetes vs. Type 1 diabetes. A higher proportion (47.6%) in the basal-oral therapy group required hospital treatment for > 24 h versus the Type 1 diabetes (5.0%) and Type 2 diabetes multiple daily injections (5.3%) groups. This analysis suggests that severe hypoglycaemia events often result in emergency/ambulance calls and hospital treatment, incurring a substantial health economic burden, and were associated with all insulin regimens.


Familial hemiplegic migraine.
Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with aura, where hemiplegia occurs during the aura phase. Mutation screening of families with FHM has revealed a range of different mutations. The mutated FHM genes code for ion transport proteins. Animal and cellular studies have associated the mutated FHM genes with disturbed ion homeostasis, altered cellular excitability and altered neurotransmitter release. Abnormal cortical excitability due to dysfunctional ion-channels might facilitate cortical spreading depression (CSD) and thereby migraine aura and migraine headache. Genotyped FHM patients offer us the chance to study the interplay between genotype and phenotype and may be regarded as a genetic migraine model. FHM studies might open for a better understanding of the molecular migraine pathology, and potentially help to unravel the pathogenesis of the more common migraine forms. We have therefore studied genotyped FHM patients to understand the effect of genotype on the response to migraine provoking substances. We show here that two known migraine triggers failed to induce more migraine aura or migraine headache in FHM-patients than in healthy controls, thus indicating that the FHM genotype does not confer hypersensitivity to these migraine triggers. This has implications for our understanding of the headache mechanisms and raises the question whether FHM share neurobiological background with the common types of migraine. The aims of the present thesis were to test the hypothesis that FHM mutations might be associated with hypersensitivity to known migraine triggers and, thereby, share pathophysiological pathways with the common types of migraine, but our results disprove this hypothesis. Thus, FHM seems very different from MO and MA, both genetically and pathophysiologically. The fact that FHM genes regulate ion homeostasis cannot be extrapolated to the common types of migraine.


The future of public health informatics: alternative scenarios and recommended strategies.
In October 2013, the Public Health Informatics Institute (PHII) and Institute for Alternative Futures (IAF) convened a multidisciplinary group of experts to evaluate forces shaping public health informatics (PHI) in the United States, with the aim of identifying upcoming challenges and opportunities. The PHI workshop was funded by the Robert Wood Johnson Foundation as part of its larger strategic planning process for public health and primary care. During the two-day workshop, nine experts from the public and private sectors analyzed and discussed the implications of four scenarios regarding the United States economy, health care system, information technology (IT) sector, and their potential impacts on public health in the next 10 years, by 2023. Workshop participants considered the potential role of the public health sector in addressing population health challenges in each scenario, and then identified specific informatics goals and strategies needed for the sector to succeed in this role. Participants developed recommendations for the public health informatics field and for public health overall in the coming decade. These included the need to rely more heavily on intersectoral collaborations across public and private sectors, to improve data infrastructure and workforce capacity at all levels of the public health enterprise, to expand the evidence base regarding effectiveness of informatics-based public health initiatives, and to communicate strategically with elected officials and other key stakeholders regarding the potential for informatics-based solutions to have an impact on population health.


Unveiling a VEGF-mimetic peptide sequence in the IQGAP1 protein.
The ability to modulate angiogenesis by chemical tools has several important applications in different scientific fields. With the perspective of finding novel proangiogenic molecules, we searched peptide sequences with a chemical profile similar to that of the QK peptide, a well described VEGF mimetic peptide. We found that residues 1617-1627 of the IQGAP1 protein show molecular features similar to those of the QK peptide sequence. The IQGAP1-derived synthetic peptide was analyzed by NMR spectroscopy and its biological activity was characterized in endothelial cells. These studies showed that this IQGAP1-derived peptide has a biological activity similar to that of VEGF and could be considered as a novel tool for reparative angiogenesis.


Retinal graft-mediated pupillary responses in rats: restoration of a reflex function in the mature mammalian brain.
We have shown previously that fetal retinae transplanted to neonatal rat brains are capable of making the pretectal connections necessary for driving a pupillary reflex in response to light. At birth, the rat brain is still developing and presents a favorable environment for fiber outgrowth and synaptogenesis. A remaining question is whether such grafts will also establish functional connections within the less plastic mature brain. Fetal retinae taken from Sprague-Dawley rats at embryonic day 13 or 14 were implanted in the pretectal region of mature host rats ranging in age from 6 to 11 weeks. The contralateral host eye was removed to reduce afferent competition within the pretectum between the optic input of graft and host. The remaining host optic nerve was cut before testing to eliminate all remaining host visual input. Beginning 1 month after transplantation, the retinae were surgically exposed and illuminated. In 6 of 24 animals, illumination elicited an obvious pupilloconstriction response in the host eye. The magnitude of this graft-mediated response varied between animals. Two animals produced very brisk responses, comparable to the best results seen following transplantation into neonatal hosts. In these cases, the degree of constriction was clearly dependent on the level of graft illumination. The 4 other animals produced responses that were less brisk. All 6 animals with clear-cut graft-mediated pupillary responses had well-formed grafts containing numerous rosettes and ganglion cells. In addition to these 6 animals, 9 others showed extremely small or variable pupillary changes on graft illumination. The remaining 9 animals showed no stimulus-associated pupillary activity. Grafts in this group tended to be poorly formed or were located outside the pretectal area. These results show that transplanted retinae are capable of making specific functional connections with the mature brain, since an appropriate visual reflex can be elicited by illuminating the graft in the absence of host visual input.


Supporting family caregivers of Veterans: Participant perceptions of a federally-mandated caregiver support program.
To understand patients' and caregivers' experiences with and perceptions of a federally-mandated program within the Department of Veterans Affairs (VA) that provides educational and monetary support to family caregivers of post-9/11 Veterans. Twenty-six Veterans and their family caregivers were recruited to participate in individual and dyadic interviews. Interviews lasted between 60 and 90 min and took place between August 2016 and July 2018 in Oregon and Louisiana. Interviews were recorded, transcribed and coded by multiple team members. Recurrent themes and categories were identified through close examination of coded text and comparison within and across transcripts. Three main themes emerged in the data: 1) appreciation of the caregiver program for validating and compensating family caregiver work; 2) perception that some caregiving activities are less visible, and thus go unrecognized and uncompensated; 3) concern about loss of benefits. Implications and policy recommendations for programs to support family caregivers, both within the VA and in the context of the broader national movement to support family caregivers, are discussed.


The Evolutionary Landscape of Colorectal Tumorigenesis: Recent Paradigms, Models, and Hypotheses.
Using colorectal cancer as a model, we review some of the insights into cancer evolution afforded by cancer sequencing. These include nonlinear and neutral evolution; polyclonality of driver mutations and parallel evolution in adenomas, although these are rare in carcinomas; the ability of mutational processes to shape evolution against the force of selection; the presence of rare driver genes that function in the same signaling pathways as the longstanding canonical drivers; and the existence of selective windows that constrain the functional effects of cancer driver mutations within limits. Many of these nascent evolutionary paradigms are potentially important for treating colorectal cancers as well as understanding their development.


Individual differences in highly skilled visual perceptual-motor striking skill.
Expertise studies into visual perceptual-motor skills have mainly focused their investigation upon group comparisons rather than individual comparisons. This study investigated the pick-up of visual information to time weight transfer and bat kinematics within an exemplar group of striking sport experts using an in situ temporal occlusion paradigm. Highly skilled cricket batsmen faced bowlers and attempted to strike delivered balls, whilst their vision was either temporally occluded through occlusion glasses prior to ball bounce or not occluded (control condition). A chronometric analysis was conducted on trials in the occlusion condition to quantify the pick-up of visual information to time biomechanical variables. Results indicated that initiation of weight transfer and bat downswing, as well as bat downswing completion, was significantly different between some individual batsmen. No significant difference was found between individual batsmen for time of weight transfer completion. Unexpectedly, it was found that achievement of the goal to strike delivered balls, that is, the frequency of bat-ball contacts was not significantly different between batsmen. Collectively, the findings indicate that individual differences exist in the coordination pattern of a complex whole body visual perceptual-motor skill, but these different patterns are used to achieve a similar outcome, which is known as motor equivalence.


Mitochondria-localising DNA-binding biscyclometalated phenyltriazole iridium(iii) dipyridophenazene complexes: syntheses and cellular imaging properties.
Two new biscyclometalated complexes [Ir(ptzR)2(dppz)]+ (dppz = dipyridophenazene; ptzRH = 4-phenyl-1-benzyl-1,2,3-triazole (1+) and 4-phenyl-1-propyl-1,2,3-triazole (2+)) have been prepared. The hexafluorophosphate salts of these complexes have been fully characterized and, in one case, the X-ray structure of a nitrate salt was obtained. The DNA binding properties of the chloride salts of the complexes were investigated, as well as their cellular uptake by A2780 and MCF7 cell lines. Both complexes display an increase in the intensity of phosphorescence upon titration with duplex DNA, indicating the intercalation of the dppz ligand and, given that they are monocations, the complexes exhibit appreciable DNA binding affinity. Optical microscopy studies reveal that both complexes are taken up by live cancer cell lines displaying cytosol based luminescence. Colocalization studies with commercial probes show high Pearson coefficients with mitotracker dyes confirming that the new complexes specifically localize on mitochondria.


Large-scale, high-resolution neurophysiological maps underlying FMRI of macaque temporal lobe.
Maps obtained by functional magnetic resonance imaging (fMRI) are thought to reflect the underlying spatial layout of neural activity. However, previous studies have not been able to directly compare fMRI maps to high-resolution neurophysiological maps, particularly in higher level visual areas. Here, we used a novel stereo microfocal x-ray system to localize thousands of neural recordings across monkey inferior temporal cortex (IT), construct large-scale maps of neuronal object selectivity at subvoxel resolution, and compare those neurophysiology maps with fMRI maps from the same subjects. While neurophysiology maps contained reliable structure at the sub-millimeter scale, fMRI maps of object selectivity contained information at larger scales (>2.5 mm) and were only partly correlated with raw neurophysiology maps collected in the same subjects. However, spatial smoothing of neurophysiology maps more than doubled that correlation, while a variety of alternative transforms led to no significant improvement. Furthermore, raw spiking signals, once spatially smoothed, were as predictive of fMRI maps as local field potential signals. Thus, fMRI of the inferior temporal lobe reflects a spatially low-passed version of neurophysiology signals. These findings strongly validate the widespread use of fMRI for detecting large (>2.5 mm) neuronal domains of object selectivity but show that a complete understanding of even the most pure domains (e.g., faces vs nonface objects) requires investigation at fine scales that can currently only be obtained with invasive neurophysiological methods.


IMPULS: Impulsivity-Focused Group Intervention to Reduce Binge Eating Episodes in Patients with Binge Eating Disorder - A Randomised Controlled Trial.
Impulsivity is a risk factor for binge eating disorder, and binge eating (BE) equates to impulsive eating behaviour. Hence, we developed IMPULS, a cognitive behavioural group intervention focusing on impulsive eating. We randomised 41 patients to the IMPULS group and 39 to the control group. The IMPULS group participated in the IMPULS treatment, while both groups completed weekly self-observations. We compared both groups concerning BE episodes in the past 4 weeks at the end of treatment (primary outcome). As secondary outcomes, we investigated eating pathology, depression, general impulsivity and body mass index (BMI) at the end of treatment and in a 3-month follow-up. The primary outcome failed, because BE episodes in the past 4 weeks were reduced in both groups at the end of treatment. At follow-up, the IMPULS group showed further improvement, contrary to the control group. The BE days/episodes in the 2 months before were overall reduced in both groups. Eating pathology was reduced in the IMPULS group at the end of treatment and partly in both groups at the follow-up. Depression was only reduced in the IMPULS group. General impulsivity and BMI did not change. The IMPULS study has a negative primary outcome. However, secondary outcomes indicate that the IMPULS treatment might be promising, as BE, eating pathology and depression were reduced in the IMPULS group. The initially reduced BE in the control group might represent a short-term effect from the self-observations. General impulsivity and BMI might need a longer time or more intensive treatment to change.


Signal recognition particle (SRP) and SRP receptor: a new paradigm for multistate regulatory GTPases.
The GTP-binding proteins or GTPases comprise a superfamily of proteins that provide molecular switches in numerous cellular processes. The "GTPase switch" paradigm, in which a GTPase acts as a bimodal switch that is turned "on" and "off" by external regulatory factors, has been used to interpret the regulatory mechanism of many GTPases for more than two decades. Nevertheless, recent work has unveiled an emerging class of "multistate" regulatory GTPases that do not adhere to this classical paradigm. Instead of relying on external nucleotide exchange factors or GTPase activating proteins to switch between the on and off states, these GTPases have the intrinsic ability to exchange nucleotides and to sense and respond to upstream and downstream factors. In contrast to the bimodal nature of the GTPase switch, these GTPases undergo multiple conformational rearrangements, allowing multiple regulatory points to be built into a complex biological process to ensure the efficiency and fidelity of the pathway. We suggest that these multistate regulatory GTPases are uniquely suited to provide spatial and temporal control of complex cellular pathways that require multiple molecular events to occur in a highly coordinated fashion.