A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps.
Virtual colonoscopy is a new method of imaging the colon in which thin-section, helical computed tomography (CT) is used to generate high-resolution, two-dimensional axial images. Three-dimensional images of the colon simulating those obtained with conventional colonoscopy are then reconstructed off-line. We compared the performance of virtual and conventional colonoscopy for the detection of colorectal polyps. We prospectively studied 100 patients at high risk for colorectal neoplasia (60 men and 40 women; mean age, 62 years). We performed virtual colonoscopy immediately before conventional colonoscopy. We inserted a rectal tube and insufflated the colon with air to the maximal level that the patient could tolerate. We administered 1 mg of glucagon intravenously immediately before CT scanning to minimize the degree of smooth-muscle spasm and peristalsis and to reduce the patient's discomfort. The entire colon was clearly seen by virtual colonoscopy in 87 patients and by conventional colonoscopy in 89. Fifty-one patients had normal findings on conventional colonoscopy. In the other 49, we identified a total of 115 polyps and 3 carcinomas. Virtual colonoscopy identified all 3 cancers, 20 of 22 polyps that were 10 mm or more in diameter (91 percent), 33 of 40 that were 6 to 9 mm (82 percent), and 29 of 53 that were 5 mm or smaller (55 percent). There were 19 false positive findings of polyps and no false positive findings of cancer. Of the 69 adenomatous polyps, 46 of the 51 that were 6 mm or more in diameter (90 percent) and 12 of the 18 that were 5 mm or smaller (67 percent) were correctly identified by virtual colonoscopy. Although discomfort was not specifically recorded, none of the patients requested that virtual colonoscopy be stopped because of discomfort or pain. In a group of patients at high risk for colorectal neoplasia, virtual and conventional colonoscopy had similar efficacy for the detection of polyps that were 6 mm or more in diameter.


Recent advances in the pathogenesis of syndromic autisms.
Background. Current advances in genetic technology continue to expand the list of medical conditions associated with autism. Clinicians have to identify specific autistic-related syndromes, and to provide tailored counseling. The aim of this study is to elucidate recent advances in autism research that offer important clues into pathogenetic mechanisms of syndromic autism and relevant implications for clinical practice. Data Sources. The PubMed database was searched with the keywords "autism" and "chromosomal abnormalities," "metabolic diseases," "susceptibility loci." Results. Defined mutations, genetic syndromes, and metabolic diseases account for up to 20% of autistic patients. Metabolic and mitochondrial defects may have toxic effects on the brain cells, causing neuronal loss and altered modulation of neurotransmission systems. Alterations of the neocortical excitatory/inhibitory balance and perturbations of interneurons' development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in Fragile X-Syndrome and Tuberous Sclerosis Complex. Chromosomal abnormalities and potential candidate genes are strongly implicated in the disruption of neural connections, brain growth, and synaptic/dendritic morphology. Conclusion. Metabolic testing may be appropriate if specific symptoms are present. High-resolution chromosome analysis may be recommended if a specific diagnosis is suspected because of obvious dysmorphisms. Identifying cryptic chromosomal abnormalities by whole genome microarray analysis can increase the understanding of the neurobiological pathways to autism.


Constant-load cycle endurance performance: test-retest reliability and validity in patients with COPD.
The purpose of this study was to evaluate the rest-retest reliability and validity of a constant-load endurance exercise test on a cycle ergometer with a workload of 75% of maximal work capacity (W(max)) in patients with moderate to severe chronic obstructive pulmonary disease (COPD). In 60 patients with COPD (FEV(1) 40 +/- 15% pred), exercise endurance time was measured with a constant-load endurance exercise tests at 75% of W(max), on two different occasions. In a subgroup of 20 patients, test-retest reliability of the measurement of end-exercise ventilatory and metabolic responses was assessed. Validity of the cycle endurance test was assessed comparing endurance time and total work performed during the cycle endurance test to peak oxygen uptake (VO(2peak)) and the 12-minute walking distance (12MWD). Test and retest assessments of cycle endurance time did not differ statistically significantly (P =.40). Highly significant intraclass correlation coefficients (ICC > or = 0.85; P <.001) were found between test and retest of assessment of endurance time as well as of end-exercise ventilatory and metabolic responses. In addition, statistically significant correlation coefficients were found between VO(2peak) and endurance time (r = 0.50; P =.001) and total work performed (r = 0.72; P <.001) during the constant-load cycle test. Significant correlation coefficients of the same magnitude were found between 12MWD and endurance time (r = 0.58; P =.001) and total work performed (r = 0.72; P <.001) during the constant-load cycle test. It is concluded that constant-load exercise testing on a cycle ergometer with a workload of 75% of maximal work capacity is a reliable and valid method to assess exercise endurance in patients with COPD.


Oxidative phosphorylation in Escherichia coli K12. Mutations affecting magnesium ion- or calcium ion-stimulated adenosine triphosphatase.
1. Two mutants of Escherichia coli K 12 were isolated which, although able to grow on glucose, are unable to grow with succinate or d-lactate as the sole source of carbon. 2. Genetic mapping of these mutants showed that they both contain a mutation in a gene (designated uncA) mapping at about minute 73.5 on the E. coli chromosome. 3. The uncA(-) alleles were transferred by bacteriophage-mediated transduction into another strain of E. coli and the transductants compared with the parent strain to determine the nature of the biochemical lesion in the mutants. 4. The mutants gave low aerobic growth yields when grown on limiting concentrations of glucose, but oxidase activities in membranes from both the mutants and the normal strain were similar. 5. Measurement of P/O ratios with d-lactate as substrate indicated that a mutation in the uncA gene causes uncoupling of phosphorylation associated with electron transport. 6. Determination of the Mg(2+),Ca(2+)-stimulated adenosine triphosphatase activities in the mutant and normal strains indicated that the uncA gene is probably the structural gene for Mg(2+),Ca(2+)-stimulated adenosine triphosphatase. 7. Mg(2+),Ca(2+)-stimulated adenosine triphosphatase therefore appears to be essential for oxidative phosphorylation in E. coli.


Ex Vivo Expansion and CRISPR-Cas9 Genome Editing of Primary Human Natural Killer Cells.
Natural killer (NK) cells are potent innate immune cells that provide the surveillance and elimination of infected, stressed, and malignant cells. The unique immune recognition mechanisms and functions of NK cells make them an attractive cell type for immunology research and adoptive immunotherapy. However, primary NK cells are challenging to culture ex vivo and lack efficient genetic tools, hindering the research of NK cells and the development of NK cell therapeutics. Here we describe methods for the freeze-thaw process, feeder-free ex vivo expansion, CRISPR-Cas9 genome editing, and functional characterizations of primary human NK cells. Our protocol enables ∼30-fold and ∼2000-fold average expansion rates from 1 × 107 cryopreserved NK cells in 14 and 28 days, respectively. We also detail methods for CRISPR gene knockout and knockin by nucleofection of Cas9 ribonucleoproteins (RNP) and DNA repair templates. Gene knockout by Cas9 RNP nucleofection can be multiplexed to simultaneously target three genes. The CRISPR-edited cells can be cryopreserved and rethawed with high viability for future studies. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Thawing of natural killer cells Basic Protocol 2: Ex vivo expansion of natural killer cells Basic Protocol 3: Cryopreservation of expanded natural killer cells Basic Protocol 4: Characterization of natural killer cells: Flow cytometry and surface marker analysis Basic Protocol 5: Cytotoxicity and degranulation assays Basic Protocol 6: Preparation of homology-directed repair templates Basic Protocol 7: Nucleofection of CRISPR-Cas9 ribonucleoproteins Basic Protocol 8: Genotyping of gene-edited natural killer cells Basic Protocol 9: Phenotyping of gene-edited natural killer cells.


Haemagglutination by parvovirus B19.
Human parvovirus B19 is a member of the autonomous parvoviridae but in contrast to other members of the genus has not been shown to agglutinate red blood cells. We now report that the virus agglutinates red cells of primate origin, though with plasma-derived virus this activity is masked by the presence of an IgM-like inhibitor. This observation is consistent with the presence on the erythroid precursor target cell of a specific receptor for parvovirus B19.


Dynamic prediction and identification of cases at risk of relapse following completion of low-intensity cognitive behavioural therapy.
Objective: Low-intensity cognitive behavioural therapy (LiCBT) can help to alleviate acute symptoms of depression and anxiety, but some patients relapse after completing treatment. Little is known regarding relapse risk factors, limiting our ability to predict its occurrence. Therefore, this study aimed to develop a dynamic prediction tool to identify cases at high risk of relapse. Method: Data from a longitudinal cohort study of LiCBT patients was analysed using a machine learning approach (XGBoost). The sample included n = 317 treatment completers who were followed-up monthly for 12 months (n = 223 relapsed; 70%). An ensemble of XGBoost algorithms was developed in order to predict and adjust the estimated risk of relapse (vs maintained remission) in a dynamic way, at four separate time-points over the course of a patient's journey. Results: Indices of predictive accuracy in a cross-validation design indicated adequate generalizability (AUC range = 0.72-0.84; PPV range = 71.2-75.3%; NPV range = 56.0-74.8%). Younger age, unemployment, (non-)linear treatment responses, and residual symptoms were identified as important predictors. Discussion: It is possible to identify cases at risk of relapse and predictive accuracy improves over time as new information is collected. Early identification coupled with targeted relapse prevention could considerably improve the longer-term effectiveness of LiCBT.


Registry-derived stage (RD-Stage) for capturing cancer stage at diagnosis for endometrial cancer.
Capture of cancer stage at diagnosis is important yet poorly reported by health services to population-based cancer registries. In this paper we describe current completeness of stage information for endometrial cancer available in Australian cancer registries; and develop and validate a set of rules to enable cancer registry medical coders to calculate stage using data available to them (registry-derived stage or 'RD-Stage'). Rules for deriving RD-stage (Endometrial carcinoma) were developed using the American Joint Commission on Cancer (AJCC) TNM (tumour, nodes, metastasis) Staging System (8th Edition). An expert working group comprising cancer specialists responsible for delivering cancer care, epidemiologists and medical coders reviewed and endorsed the rules. Baseline completeness of data fields required to calculate RD-Stage, and calculation of the proportion of cases for whom an RD stage could be assigned, was assessed across each Australian jurisdiction. RD-Stage (Endometrial cancer) was calculated by Victorian Cancer Registry (VCR) medical coders and compared with clinical stage recorded by the patient's treating clinician and captured in the National Gynae-Oncology Registry (NGOR). The necessary data completeness level for calculating RD-Stage (Endometrial carcinoma) across various Australian jurisdictions varied from 0 to 89%. Three jurisdictions captured degree of spread of cancer, rendering RD-Stage unable to be calculated. RD-Stage (Endometrial carcinoma) could not be derived for 64/485 (13%) cases and was not captured for 44/485 (9%) cases in NGOR. At stage category level (I, II, III, IV), there was concordance between RD-Stage and NGOR captured stage in 393/410 (96%) of cases (95.8%, Kendall's coefficient = 0.95). A lack of consistency in data captured by, and data sources reporting to, population-based cancer registries meant that it was not possible to provide national endometrial carcinoma stage data at diagnosis. In a sample of Victorian cases, where surgical pathology was available, there was very good concordance between RD-Stage (Endometrial carcinoma) and clinician-recorded stage data available from NGOR. RD-Stage offers promise in capturing endometrial cancer stage at diagnosis for population epidemiological purposes when it is not provided by health services, but requires more extensive validation.


Individual differences in posterior cortical volume correlate with proneness to pride and gratitude.
Proneness to specific moral sentiments (e.g. pride, gratitude, guilt, indignation) has been linked with individual variations in functional MRI (fMRI) response within anterior brain regions whose lesion leads to inappropriate behaviour. However, the role of structural anatomical differences in rendering individuals prone to particular moral sentiments relative to others is unknown. Here, we investigated grey matter volumes (VBM8) and proneness to specific moral sentiments on a well-controlled experimental task in healthy individuals. Individuals with smaller cuneus, and precuneus volumes were more pride-prone, whereas those with larger right inferior temporal volumes experienced gratitude more readily. Although the primary analysis detected no associations with guilt- or indignation-proneness, subgenual cingulate fMRI responses to guilt were negatively correlated with grey matter volumes in the left superior temporal sulcus and anterior dorsolateral prefrontal cortices (right >left). This shows that individual variations in functional activations within critical areas for moral sentiments were not due to grey matter volume differences in the same areas. Grey matter volume differences between healthy individuals may nevertheless play an important role by affecting posterior cortical brain systems that are non-critical but supportive for the experience of specific moral sentiments. This may be of particular relevance when their experience depends on visuo-spatial elaboration.


The Role of Episodic Postprandial Peptides in Exercise-Induced Compensatory Eating.
Prolonged physical activity gives rise to variable degrees of body weight and fat loss, and is associated with variability in appetite control. Whether these effects are modulated by postprandial, peptides is unclear. We examined the role of postprandial peptide response in compensatory eating during 12 weeks of aerobic exercise and in response to high-fat, low-carbohydrate (HFLC) and low-fat, high-carbohydrate (LFHC) meals. Of the 32 overweight/obese individuals, 16 completed 12 weeks of aerobic exercise and 16 nonexercising control subjects were matched for age and body mass index. Exercisers were classified as responders or nonresponders depending on net energy balance from observed compared with expected body composition changes from measured energy expenditure. Plasma samples were collected before and after meals to compare profiles of total and acylated ghrelin, insulin, cholecystokinin, glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY) between HFLC and LFHC meals, pre- and postexercise, and between groups. No differences between pre- and postintervention peptide release. Responders had greater suppression of acylated ghrelin (P < 0.05) than nonresponders, as well as higher postprandial levels of GLP-1 (P < 0.001) and total PYY (P < 0.001) compared with nonresponders and control subjects. No impact on postprandial peptide release was found after 12 weeks of aerobic exercise. Responders to exercise-induced weight loss showed greater suppression of acylated ghrelin and greater release of GLP-1 and total PYY at baseline. Therefore, episodic postprandial peptide profiles appear to form part of the pre-existing physiology of exercise responders and suggest differences in satiety potential may underlie exercise-induced compensatory eating.


The effect of ZD1839 (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin, on apoptosis in SCC-15 cells.
The aim of this study was to determine the effect of ZD1839 on growth and apoptosis in SCC-15 (a human head and neck cancer cell line) lone, or in combination with cisplatin. High expression of the epidermal growth factor receptor has been implicated in the development of squamous cell carcinomas of head and neck. ZD1839 ('Iressa') is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. Here, growth arrest was observed with 3.64 microm ZD1839. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (sMTT) viability assay revealed a significant decrease (P < 0.001) in the percentage of surviving cells upon treatment with ZD1839 and cisplatin compared with cisplatin or ZD1839 on their own. Combined therapy of 3.64 microm ZD1839 for 24 h, prior to administration of 100 microm cisplatin, significantly (P < 0.001) and additively increased the cytotoxicity effect of cisplatin. p53-independent apoptosis was seen with cisplatin treatment, a novel finding. These data support the use of ZD1839 in anti-cancer therapy, and particularly in combination therapy. Cisplatin may induce p53-independent apoptosis. Over-expression of Bcl-2 in head and neck squamous cell carcinoma tumour cell lines is unlikely to be a general mechanism to protect these cells from apoptosis.


Holography and coherent diffraction with low-energy electrons: A route towards structural biology at the single molecule level.
The current state of the art in structural biology is led by NMR, X-ray crystallography and TEM investigations. These powerful tools however all rely on averaging over a large ensemble of molecules. Here, we present an alternative concept aiming at structural analysis at the single molecule level. We show that by combining electron holography and coherent diffraction imaging estimations concerning the phase of the scattered wave become needless as the phase information is extracted from the data directly and unambiguously. Performed with low-energy electrons the resolution of this lens-less microscope is just limited by the De Broglie wavelength of the electron wave and the numerical aperture, given by detector geometry. In imaging freestanding graphene, a resolution of 2Å has been achieved revealing the 660.000 unit cells of the graphene sheet from a single data set. Once applied to individual biomolecules the method shall ultimately allow for non-destructive imaging and imports the potential to distinguish between different conformations of proteins with atomic resolution.


Effect of deep cervical flexor muscles training using pressure biofeedback on pain and disability of school teachers with neck pain.
[Purpose] The job of secondary school teachers involves a lot of head down posture as frequent reading, assignment correction, computer use and writing on a board put them at risk of developing occupational related neck pain. Available studies of neck pain experienced by teachers are limited. The purpose of this study was to determine whether training of deep cervical flexor muscles with pressure biofeedback has any significant advantage over conventional training for pain and disability experienced by school teachers with neck pain. [Subjects] Thirty teachers aged 25-45 years with neck pain and poor craniocervical flexion test participated in this study. [Methods] A pretest posttest experimental group design was used in which experimental group has received training with pressure biofeedback and conventional exercises while control group received conventional exercises only. Measurements of dependent variables were taken at baseline, and after 2 and 4 weeks of training. Pain intensity was assessed using a numeric pain rating scale and functional disability was assessed using the neck disability index. [Results] The data analysis revealed that there was significant improvement in pain and disability in both the groups and the results were better in the experimental group. [Conclusion] Addition of pressure biofeedback for deep cervical flexor muscles training gave a better result than conventional exercises alone. Feedback helps motor learning which is the set of processes associated with practice or experience leading to permanent changes in ability to respond.


Reduced gray matter volume in the anterior cingulate, orbitofrontal cortex and thalamus as a function of mild depressive symptoms: a voxel-based morphometric analysis.
Studies investigating structural brain abnormalities in depression have typically employed a categorical rather than dimensional approach to depression [i.e., comparing subjects with Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined major depressive disorder (MDD) v. healthy controls]. The National Institute of Mental Health, through their Research Domain Criteria initiative, has encouraged a dimensional approach to the study of psychopathology as opposed to an over-reliance on categorical (e.g., DSM-based) diagnostic approaches. Moreover, subthreshold levels of depressive symptoms (i.e., severity levels below DSM criteria) have been found to be associated with a range of negative outcomes, yet have been relatively neglected in neuroimaging research. To examine the extent to which depressive symptoms--even at subclinical levels--are linearly related to gray matter volume reductions in theoretically important brain regions, we employed whole-brain voxel-based morphometry in a sample of 54 participants. The severity of mild depressive symptoms, even in a subclinical population, was associated with reduced gray matter volume in the orbitofrontal cortex, anterior cingulate, thalamus, superior temporal gyrus/temporal pole and superior frontal gyrus. A conjunction analysis revealed concordance across two separate measures of depression. Reduced gray matter volume in theoretically important brain regions can be observed even in a sample that does not meet DSM criteria for MDD, but who nevertheless report relatively elevated levels of depressive symptoms. Overall, these findings highlight the need for additional research using dimensional conceptual and analytic approaches, as well as further investigation of subclinical populations.


The contact hypothesis and the virtual revolution: Does face-to-face interaction remain central to improving intergroup relations?
Research on the contact hypothesis has traditionally prioritized the role of positive, direct, face-to-face interactions in shaping intergroup prejudices, but it has recently expanded to study indirect vicarious, negative, and online contact experiences. In the majority of studies though, there has been little direct comparison of the relationship between these different forms of contact and prejudice. The present research set out to compare the amount and effects of negative, online, and vicarious contact in the context of positive, face-to-face and direct contact in two studies. Study 1 comprised a national cross-sectional survey of relations between White and Black UK residents (n = 1014), and Study 2 comprised a national longitudinal survey of relations between Catholic and Protestant residents of Northern Ireland (n = 1030). The results of both studies indicated that positive face-to-face contact occurred more frequently and had a comparatively stronger relationship with prejudice than other forms of contact. However, they also indicated the effects of online, negative and vicarious forms of contact existed independently of those of direct, positive face-to-face contact. Moreover, online negative contact generally had a stronger relationship to prejudice than negative contact experienced face-to-face. Exploratory mediation analyses suggested the affective pathways from contact to prejudice may vary for different forms of contact.


[The specific features of immune disorders in acute severe brain injury].
Fifty-three patients aged 17-65 years who had severe brain injury (SBI) were examined and randomized to 2 groups: 1) 16 patients without complications; 2) 37 patients developed pneumonia (35.2%), bronchitis (32.4%), meningitis (10.8%), meningitis concurrent with pneumonia (8.1%), bedsores concurrent with bronchitis (13.5%) on days 4-7. The authors studied the immune status: the subpopulation composition of lymphocytes (CD+, a marker of adult lymphocytes; CD+, a marker of T helper/inductor cells, CD8+, a marker of cytotoxic lymphocytes, CD16+, a marker of natural killer cells, CD20+, a marker of B lymphocytes) by the indirect immunofluorescence technique using monoclonal antibodies; the functional activity of lymphocytes from the expression of activation antigens, such as CD71+, CD25+, HLA-DR; serum immunoglobulins (IgG, IgA, and IgM) by the immunoturbidimetric technique using the test systems (Spinreakt, Spain). A control group included 23 apparently healthy individuals. Immunosuppression developing as significant T lymphopenia due to lower CD4+ and CD8+ lymphocytes, as well as impaired humoral immunity with inadequate IgG generation was detected in the acute phase of SBI. The indicators reflecting the development of secondary pyoseptic complications were elevated CD3+, CD4+, and CD8+ lymphocytes on day 7 and the higher lymphocytic expression of the activation antigens CD25+ and CD71+. The findings show that the diagnostic markers, such as CD3+, CD4+, CD8+, CD25+, and CD71+ lymphocytes, should be included into a comprehensive examination of patients with SBI.


Pulmonary function, exercise capacity and physical activity participation in adults following burn.
To determine the relationship between pulmonary function, aerobic exercise capacity and physical activity participation in adults following burn. Eight burn injured males aged 20-55 years (%TBSA 33.3±18.7, 5.1 years±1.8 post injury), and 30 healthy adult controls participated. Pulmonary function was assessed during rest via spirometry. A graded exercise test measuring peak oxygen consumption (VO(2peak)) and oxygen saturation (S(p)O(2)) was conducted, and physical activity was assessed via the Older Adult Exercise Status Inventory (OA-EI). No significant correlation was observed between resting pulmonary function, aerobic capacity and physical activity participation for burn injured patients or controls. Two burn injured patients presented with obstructive ventilatory defects, and one displayed a restrictive ventilatory defect. Burn injured patients had a significantly lower VO(2peak) (p<0.001) and time to fatigue (p=0.026), and a greater degree of oxygen desaturation (p=0.063, Effect Size=1.02) during a graded exercise test. Burn injured patients reported significantly less participation in leisure-related activity>9 METs (p=0.01), and significantly greater participation in work-related activity (p=0.038), than healthy controls. Compromised lung function, decreased aerobic capacity and reduced participation in leisure-related physical activity may still exist in some adults, even up to 5 years post injury. Limitations and long term outcomes of cardiopulmonary function and physical fitness need to be considered in the prescription of exercise rehabilitation programmes following burn.


Emergence of male-biased genes on the chicken Z-chromosome: sex-chromosome contrasts between male and female heterogametic systems.
There has been extensive traffic of male-biased genes out of the mammalian and Drosophila X-chromosomes, and there are also reports of an under-representation of male-biased genes on the X. This may reflect an adaptive process driven by natural selection where an autosomal location of male-biased genes is favored since male genes are only exposed to selection one-third of the time when X-linked. However, there are several alternative explanations to "out-of-the-X" gene movement, including mutational bias and a means for X-linked genes to escape meiotic sex chromosome inactivation (MSCI) during spermatogenesis. As a critical test of the hypothesis that genomic relocation of sex-biased genes is an adaptive process, I examined the emergence, and loss, of genes on the chicken Z-chromosome, i.e., a female heterogametic system (males ZZ, females ZW). Here, the analogous prediction would be an emergence of male-biased genes onto, not a loss from, the Z-chromosome because Z is found more often in males than autosomes are. I found that genes expressed in testis but not in ovary are highly over-represented among genes that have emerged on the Z-chromosome during avian evolution. Moreover, genes with male-biased expression are similarly over-represented among new Z-chromosomal genes. Interestingly, genes with female-biased expression have more often moved from than to the Z-chromosome. These observations show that male and female heterogametic organisms display opposing directionalities in the emergence and loss of sex-biased genes on sex chromosomes. This is consistent with theoretical models on the evolution of sexually antagonistic genes in which new mutations are at least partly dominant.


Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study.
Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.


Gastroesophageal reflux and altered motility in lung transplant rejection.
Lung transplantation has become an effective therapeutic option for selected patients with end stage lung disease. Long-term survival is limited by chronic rejection manifest as bronchiolitis obliterans syndrome (BOS). The aspiration of gastric contents has been implicated as a causative or additive factor leading to BOS. Gastroesophageal reflux (GER) and altered foregut motility are common both before and after lung transplantation. Further, the normal defense mechanisms against reflux are impaired in the allograft. Recent studies using biomarkers of aspiration have added to previous association studies to provide a growing body of evidence supporting the link between rejection and GER. Further, the addition of high-resolution manometry (HRM) and impedance technology to characterize bolus transit and the presence and extent of reflux regardless of pH might better identify at-risk patients. Although additional prospective studies are needed, fundoplication appears useful in the prevention or treatment of post-transplant BOS. This review will highlight the existing literature on the relationship of gastroesophageal reflux and altered motility to lung transplant rejection, particularly BOS. The article will conclude with a discussion of the evaluation and management of patients undergoing lung transplantation at our center.


SPAK-mediated NCC regulation in response to low-K+ diet.
The NaCl cotransporter (NCC) of the renal distal convoluted tubule is stimulated by low-K(+) diet by an unknown mechanism. Since recent work has shown that the STE20/SPS-1-related proline-alanine-rich protein kinase (SPAK) can function to stimulate NCC by phosphorylation of specific N-terminal sites, we investigated whether the NCC response to low-K(+) diet is mediated by SPAK. Using phospho-specific antibodies in Western blot and immunolocalization studies of wild-type and SPAK knockout (SPAK(-/-)) mice fed a low-K(+) or control diet for 4 days, we found that low-K(+) diet strongly increased total NCC expression and phosphorylation of NCC. This was associated with an increase in total SPAK expression in cortical homogenates and an increase in phosphorylation of SPAK at the S383 activation site. The increased pNCC in response to low-K(+) diet was blunted but not completely inhibited in SPAK(-/-) mice. These findings reveal that SPAK is an important mediator of the increased NCC activation by phosphorylation that occurs in the distal convoluted tubule in response to a low-K(+) diet, but other low-potassium-activated kinases are likely to be involved.


Managing Cutaneous Tuberculosis: A Case Report.
Tuberculosis (TB) continues to be a prevalent disease worldwide; an estimated one third of the world's population is infected and 2015 data from the World Health Organization show 10 million people had an active infection. Although TB often is cited as a disease that most commonly occurs in underdeveloped countries, the evolution of drug-resistant forms of TB and infection sensitivity of immunocompromised individuals have made this disease a focal point for indus- trialized countries as well. When TB is spread, it commonly affects the lungs, but it can infect any organ of the body. An uncommon version - cutaneous TB - affects < 2% of all individuals with an active form of TB. This study describes a 34-year-old man with multiple comorbidities, including peripheral vascular disease and a remote history of travel to Latin America who presented to a wound care clinic with a 2-year history of painful shallow necrotic ulcers on his right lower limb and previous treatments that included a positive response to antibiotics. Once TB was con rmed via 2 posi- tive Quantiferon Gold tests, the patient received therapy (directly observed by the state health department) that included pyrazinamide, rifampin, ethambutol, isoniazid, and undocumented vitamin B6. Treatment for the TB-related lesions, con- comitant cellulitis, and a Stage 2 pressure injury under his rst right metatarsal head was initiated as well. The patient received local wound care for 40 days that included sharp debridement, of oading for the pressure injury, and pain relief before treatment at the wound care clinic and daily as prescribed by his primary care provider. All wounds were securely covered with collagen dressings followed by silicone-bordered bandages. Local wound care was provided for 40 days, with biweekly follow-up for an additional 30 days. The wounds resolved and the patient was discharged from the wound care clinic but remained on the caseload for 30 days in the event his pain increased or the wounds recurred. Cutaneous TB, uncommon and challenging, should be a consideration in patients with an increased likelihood of occurrence.


Osteonecrosis of the femoral head in a family with hyperlipoproteinemia.
A family of four generations has been identified as having hyperlipoproteinemia as well as radiologic evidence of active or healed osteonecrosis of the femoral head. Sixteen family members were available for complete clinical, radiologic, and laboratory examination. Six living and two deceased members were found to have both conditions. Hyperlipoproteinemia should be considered in the differential diagnosis of the idiopathic osteonecrosis of the femoral head; some common pathogenetic factor may underlie these two conditions when they coexist in a familial pattern.


Construction of polyfunctional coatings assisted by gallic acid to facilitate co-immobilization of diverse biomolecules.
Designing a multifunctional surface based on the coimmobilization of two or more diverse biomolecules with synergic action is very important in certain cases. In this work, a facile method by two-step aimed to construct a polyfunctional coating containing -COOH, -NH2, and phenol/quinine groups was reported. The first-step was to introduce amine groups onto target modified-surface by coating with plasma polymerized allylamine (PPAam), followed by the second-step conjugation of gallic acid (3,4,5-trihydroxybenzoic acid) onto the PPAam surface. The density of -COOH, -NH2, and phenol/quinone groups could be regulated easily by adjusting the reaction time of GA conjugation, making it possible to coimmobilize two or three diverse molecules. This has been shown by the successful coimmobilization of anti-CD34 antibody and vascular endothelial growth factor (VEGF). The surface coimmobilized with the anti-CD34 antibody and VEGF presented significant enhancement in the capture of endothelial progenitor cells (EPCs) and the growth of human umbilical vein endothelial cells (HUVECs). These data suggest the huge potential of such polyfunctional coating for tailoring the desired interfacial properties of materials through selectively conjugating two or more diverse bioactive molecules with synergic action.


High-Throughput Automation of Endosomolytic Polymers for mRNA Delivery.
In recent years, there has been an increasing interest in designing delivery systems to enhance the efficacy of RNA-based therapeutics. Here, we have synthesized copolymers comprised of dimethylaminoethyl methacrylate (DMAEMA) or diethylaminoethyl methacrylate (DEAEMA) copolymerized with alkyl methacrylate monomers ranging from 2 to 12 carbons, and developed a high throughput workflow for rapid investigation of their applicability for mRNA delivery. The structure activity relationship revealed that the mRNA encapsulation efficiency is improved by increasing the cationic density and use of shorter alkyl side chains (2-6 carbons). Minimal cytotoxicity was observed when using DEAEMA-co-BMA (EB) polyplexes up to 18 h after dosing, independent of a poly(ethylene glycol) (PEG) first block. The lowest molecular weight polymer (EB10,250) performed best, exhibiting greater transfection than polyethyenimine (PEI) based upon the number of cells transfected and mean intensity. Conventional investigations into the performance of polymeric materials for mRNA delivery is quite tedious, consequently limiting the number of materials and formulation conditions that can be studied. The high throughput approach presented here can accelerate the screening of polymeric systems and paves the way for expanding this generalizable approach to assess various materials for mRNA delivery.


Nestin is essential for zebrafish brain and eye development through control of progenitor cell apoptosis.
Nestin is expressed in neural progenitor cells (NPC) of developing brain. Despite its wide use as an NPC marker, the function of nestin in embryo development is unclear. As nestin is conserved in zebrafish and its predicted sequence is clustered with the mammalian nestin orthologue, we used zebrafish as a model to investigate its role in embryogenesis. Injection of nestin morpholino (MO) into fertilized eggs induced time- and dose-dependent brain and eye developmental defects. Nestin morphants exhibited characteristic morphological changes including small head, small eyes and hydrocephalus. Histological examinations show reduced hind- and mid-brain size, dilated ventricle, poorly organized retina and underdeveloped lens. Injection of control nestin MO did not induce brain or eye changes. Nestin MO injection reduced expression of ascl1b (achaete-scute complex-like 1b), a marker of NPCs, without affecting its distribution. Nestin MO did not influence Elavl3/4 (Embryonic lethal, abnormal vision, Drosophila-like 3/4) (a neuronal marker), or otx2 (a midbrain neuronal marker), but severely perturbed cranial motor nerve development and axon distribution. To determine whether the developmental defects are due to excessive NPC apoptosis and/or reduced NPC proliferation, we analyzed apoptosis by TUNEL assay and acridine orange staining and proliferation by BrdU incorporation, pcna and mcm5 expressions. Excessive apoptosis was noted in hindbrain and midbrain cells. Apoptotic signals were colocalized with ascl1b. Proliferation markers were not significantly altered by nestin MO. These results suggest that nestin is essential for zebrafish brain and eye development probably through control of progenitor cell apoptosis.


[Nitrate prescriptions in primary care--are we over-prescribing? A pilot intervention].
Nitrates vasodilate coronary arteries that are already compensatory dilated due to ischemia and increase the coronary blood flow. In the short term, the use of nitrates, after myocardial infraction has advantages, while prolonged use can even be associated with an increase in sudden death. To characterize patients treated with nitrates in a primary care clinic and examine whether a lecture concerning benefits and harms of nitrates will cause discontinuation of their use. An interventional study performed in one primary care clinic. The clinic physician attended a Lecture on nitrates, including benefits and harms. The outcome measure was the number of patients that stopped using nitrates. The last stage included interviews with patients concerning their symptoms, six months after intervention. Of the 8794 patients treated in the clinic, 284 (3.2%) were treated with nitrates; 166 of the patients were using nitrates on a regular basis; 75 (26.4%) of those using nitrates did not have a clinical indication for chronic use. Nitrates were discontinued in 40 patients (53.5% of those taking nitrates with no indication). Of the patients who stopped taking nitrates, 26 (65%) remained asymptomatic after 6 months. We found that there was over-prescription of nitrates and that the family physician, based on anamnesis and data from the medical file, can stop nitrate treatment to about 10% of these patients without any significant harm. A family physician can stop nitrate treatment based on anamnesis and data from the medical file.


Syntheses, structures and reactions of a series of beta-diketiminatoyttrium compounds.
This paper describes the synthesis and selected reactions of a series of crystalline mono(beta-diiminato)yttrium chlorides 3a, 3b, 4a, 4b, 5a, 5b, 5c and 9. The X-ray structure of each has been determined, as well as of [YCl(L4)(2)] (6), [Y(L1)(2)OBu(t)] (7) and [Y{CH(SiMe(3))(2)}(thf)(mu-Cl)(2)Li(OEt(2))(2)(mu-Cl)](2) (8). The N,N'-kappa(2)-beta-diiminato ligands were [{N(R)C(Me)}(2)CH](-) [R = C(6)H(4)Pr(i)-2 (L1); R = C(6)H(4)Bu(t)-2 (L2); R = C(6)H(3)Pr(i)(2)-2,6 (L3)], [{N(SiMe(3))C(Ph)}(2)CH)](-) (L4) and [{N(C(6)H(3)Pr(i)(2)-2,6)C(H)}(2)CPh](-) (L5). Equivalent portions of Li[L(x)] and YCl(3) in Et(2)O under mild conditions yielded [Y(mu-Cl)(L(x))(mu-Cl)(2)Li(OEt(2))(2)](2) [L(x) = (L1(3a)) or (L1(3b))] and [Y(mu-Cl)(L3)(mu-Cl)Li(OEt(2))(2)(mu-Cl)](2) (4a) or its thf (instead of Et(2)O) equivalent 4b. Each of the Li(OEt(2))(2)Cl(2) moieties is bonded in a terminal (3) or bridging (4) mode with respect to the two Y atoms; the difference is attributed to the greater steric demand of L3 than L1 or L2. Under slightly more forcing conditions, YCl(3) and Li(L2) (via 3b) gave the lithium-free complex [YCl(2)(L2)(thf)(2)] (5b). Two isoleptic compounds 5a and 5c (having in place of L2 in 5b, L3 and L5, respectively) were obtained from YCl(3) and an equivalent portion of K[L3] and Na[L5], respectively; under the same conditions using Na[L4], the unexpected product was [YCl(L4)(2)] (6) (i.e. incorporating only one half of the YCl(3)). A further unusual outcome was in the formation of 8 from 3a and 2 Li[CH(SiMe(3))(2)]. Compound [Y(L5){N(H)C(6)H(3)Pr(i)(2)-2,6}(thf)(mu(3)-Cl)(2)K](2).4Et(2)O (9), obtained from and K[N(H)C(6)H(3)Pr(i)(2)-2,6], is noteworthy among group 3 or lanthanide metal (M) compounds for containing MClKCl (M = Y) moieties.


Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer.
Inactivation of the P16 (INK4A)/retinoblastoma (RB) or TP53 biochemical pathway is frequent event in most human cancers. Recent evidence has shown that P14ARF binds to MDM2 leading to an increased availability of wild type TP53 protein. Functional studies also support a putative tumor suppressor gene function for p14ARF suggesting that p14ARF or p53 inactivation may be functionally equivalent in tumorigenesis. To study the relative contribution of each pathway in tumorigenesis, we analysed and compared alterations of the p16, p14ARF and p53 genes in 38 primary non-small cell lung cancers (NSCLCs) (19 adenocarcinomas and 19 squamous carcinoma). The p16 tumor suppressor gene was inactivated in 22 of 38 (58%) tumors. Twelve of these samples (31%) had homozygous deletions by microsatellite analysis; eight of them (21%) had p16 promoter hypermethylation detected by Methylation Specific PCR (MSP) and the remaining two (5%) harbored a point mutation in exon 2 by sequence analysis. The absence of P16 protein in every case was confirmed by immunohistochemistry. Fourteen of the 22 tumors with p16 inactivation also inactivated the p14ARF gene (12 with homozygous deletions extending into INK4a/ARF and two with exon 2 mutations). Mutations of p53 were found in 18 (47%) of the tumors and nine of them (50%) harbored p14ARF inactivation. Thus, an inverse correlation was not found between p14ARF and p53 genetic alterations (P=0.18; Fisher Exact Test). Our data confirm that the p16 gene is frequently inactivated in NSCLC. Assuming that 9p deletion occurs first, the common occurrence of p53 and p14ARF alterations suggests that p14ARF inactivation is not functionally equivalent to abrogation of the TP53 pathway by p53 mutation.


Duration of immunity after rabies vaccination in dogs: The Rabies Challenge Fund research study.
A prospective study of 65 research beagles kept in a rabies-free environment was undertaken to determine the duration of immunity after they received licensed rabies vaccines. The eventual goal was to extend mandated rabies booster intervals to 5 or 7 years and help reduce the risk of vaccine-associated adverse events. Three groups of dogs were vaccinated with 1 of 2 commercial rabies vaccines or saline at 12 and 15 weeks of age. Beginning 5 years 5 months later, vaccinated and unvaccinated dogs were challenged with virulent rabies virus and observed for 90 days over a series of 3 trials. Humoral and cellular immune responses were examined by serology and flow cytometry. Brain tissue from all challenged dogs was tested for rabies virus. Challenge trial 1 was confounded due to insufficiently virulent virus. In trials 2 and 3 virulent challenge provided 100% mortality in controls. Vaccinate survival was 80% (4/5) after 6 years 7 months, 50% (6/12) after 7 years 1 month, and 20% (1/5) after 8years 0 months. Antibody responses 12 days post-challenge correlated strongly with survival. In a separate non-challenge trial, administration of either a recombinant or a killed rabies vaccine demonstrated memory antibody responses 6 years 1 month after initial vaccination compared with unvaccinated controls. Our data demonstrated that i) duration of immunity to rabies in vaccinated dogs extends beyond 3 years; ii) immunologic memory exists even in vaccinated dogs with serum antibody titer < 0.1 IU/mL; and iii) non-adjuvanted recombinant rabies vaccine induces excellent antibody responses in previously vaccinated dogs 14 days after administration.


Vitamin B6 treatment in acute neuroleptic-induced akathisia: a randomized, double-blind, placebo-controlled study.
Treatment strategies for acute neuroleptic-induced akathisia (NIA) contain anticholinergic (antimuscarinic) agents, dopamine agonists, gamma-aminobutyric acid (GABA)-ergic agents, beta-blockers, benzodiazepines, and serotonin antagonists. Nevertheless, many patients who suffer from acute akathisia fail to respond to treatment. In earlier studies, vitamin B6 was found to be effective in the treatment of neuroleptic-induced movement disorders. The purpose of this study was to evaluate the efficacy of vitamin B6 in the treatment of acute NIA. This is the first report of B6 as a treatment for NIA. This study was conducted in 2 mental health centers from February 2003 to November 2003. Twenty schizophrenia and schizoaffective inpatients with a DSM-IV diagnosis of NIA were randomly divided to receive vitamin B6 600 mg/day b.i.d. (N = 10) or placebo (N = 10) twice a day for 5 days in a double-blind design. The Barnes Akathisia Scale (BAS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impressions scale (CGI) were used to assess the severity of NIA and psychotic symptoms. The BAS assessment was made at baseline and every day during the study. The BPRS and CGI were completed at baseline and at the end of the study. The vitamin B6-treated patients in comparison with the placebo group showed a significant improvement on the subjective-awareness of restlessness (p = .0004), subjective-distress (p = .01), and global (p = .004) subscales of the BAS. The objective subscale did not demonstrate significant positive results (p = .079), but there was a trend of symptom amelioration in the vitamin B6 group. A reduction of at least 2 points on the BAS global subscale was noted in 8 patients in the vitamin B6 group (80%), and in only 3 patients in the placebo group (30%) (p = .037). Our preliminary results indicate that high doses of vitamin B6 may be useful additions to the available treatments for NIA, perhaps due to its combined effects on various neurotransmitter systems.


The influence of bilingualism on statistical word learning.
Statistical learning is a fundamental component of language acquisition, yet to date, relatively few studies have examined whether these abilities differ in bilinguals. In the present study, we examine this issue by comparing English monolinguals with Chinese-English and English-Spanish bilinguals in a cross-situational statistical learning (CSSL) task. In Experiment 1, we assessed the ability of both monolinguals and bilinguals on a basic CSSL task that contained only one-to-one mappings. In Experiment 2, learners were asked to form both one-to-one and two-to-one mappings, and were tested at three points during familiarization. Overall, monolinguals and bilinguals did not differ in their learning of one-to-one mappings. However, bilinguals more quickly acquired two-to-one mappings, while also exhibiting greater proficiency than monolinguals. We conclude that the fundamental SL mechanism may not be affected by language experience, in accord with previous studies. However, when the input contains greater variability, bilinguals may be more prone to detecting the presence of multiple structures.


Effect of Aerobic Exercise-induced Weight Loss on the Components of Daily Energy Expenditure.
Exercise usually results in less weight loss than expected. This suggests increased energy intake and/or deceased expenditure counteract the energy deficit induced by exercise. The aim of this study was to evaluate changes in components of daily energy expenditure (doubly labeled water and room calorimetry) after 24 wk of exercise training with two doses of aerobic exercise. This was an ancillary study in 42 (29 women, 13 men) sedentary, middle-age (47.8 ± 12.5 yr) individuals with obesity (35 ± 3.7 kg·m-2) enrolled in the Examination of Mechanisms of Exercise-induced Weight Compensation study. Subjects were randomized to three groups: healthy living control group (n = 13), aerobic exercise that expended 8 kcal·kg-1 of body weight per week (8 KKW, n = 14), or aerobic exercise that expended 20 kcal per kilogram of weight per week (20 KKW, n = 15). Total daily energy expenditure (TDEE) was measured in free-living condition by doubly labeled water and in sedentary conditions in a metabolic chamber over 24 h (24EE). Energy intake was calculated over 14 d from TDEE before and after the intervention using the intake-balance method. Significant weight loss occurred with 20 KKW (-2.1 ± 0.7 kg, P = 0.04) but was only half of expected. In the 20 KKW group free-living TDEE increased by ~4% (P = 0.03), which is attributed to the increased exercise energy expenditure (P = 0.001), while 24EE in the chamber decreased by ~4% (P = 0.04). Aerobic exercise at 8 KKW did not induce weight change, and there was no significant change in any component of EE. There was no significant change in energy intake for any group (P = 0.53). Structured aerobic exercise at a dose of 20 KKW produced less weight loss than expected possibly due to behavioral adaptations leading to reduced 24EE in a metabolic chamber without any change in energy intake.


The role of early and sufficient isolated venovenous ultrafiltration in heart failure patients with pulmonary and systemic congestion.
Hypervolemia, present in at least 70% of patients with decompensated heart failure, results in renal dysfunction due to increased renal venous pressure, impaired renal autoregulation, and decreased renal blood flow that are associated with increased morbidity and mortality. Loop diuretics, widely used in congested patients, result in the production of hypotonic urine and neurohormonal activation. In contrast, ultrafiltration (UF) removes isotonic fluid without increasing renin secretion by the macula densa. Simplified devices that permit us to perform UF with peripheral venous access, adjustable blood flows, and small extracorporeal blood volumes make this therapy feasible at most hospitals and in less acute care settings. Conflicting results on the effects of UF in heart failure patients underscore the challenges of patient selection and choice of fluid removal rates. Unfavorable outcomes in patients undergoing UF in the midst of cardiorenal syndrome type 1 are in contrast with the sustained benefits of UF initiated before unsuccessful use of high-dose intravenous (IV) diuretics. UF rates should be based on a precise knowledge of the degree of hypervolemia and careful assessment of blood volume changes, so that extracellular fluid gradually refills the intravascular space and volume depletion is avoided. Poor outcomes are likely to occur if fluid removal rates are not tailored to individual patients' clinical characteristics. A large trial is ongoing to determine if a strategy of early UF, initiated before renal function is worsened by other therapies, is superior to IV diuretics in reducing 90-day heart-failure-related hospitalizations in patients with pulmonary and systemic congestion.


A novel storage system for cryoEM samples.
We present here a new CryoEM grid boxes storage system designed to simplify sample labeling, tracking and retrieval. The system is based on the crystal pucks widely used by the X-ray crystallographic community for storage and shipping of crystals. This system is suitable for any cryoEM laboratory, but especially for large facilities that will need accurate tracking of large numbers of samples coming from different sources.


On Having a Goal: Goals as Representations or Behavior.
The present article discusses the concepts of having a goal and of goal-directed behavior from a behavior-analytic perspective. In clinical psychology as well as in the study of human behavior at large, goals delineate an important area of investigation when it comes to health, well-being, and behavioral change. While concepts like goals and goal-directed behavior may be more frequently used outside the theoretical boundaries of behavior analysis, we argue that by incorporating recent behavior analytic research on verbal behavior, new and fruitful ways open up for approaching the phenomenon of having a goal. A behavior-analytic approach thereby may increase both precision in understanding and the potential for influencing essential aspects of human behavior. This analysis starts with the concept of rule-governed behavior and develops that analysis by using the concept of derived relational responding.


[The prediction of the outcomes of severe odontogenic inflammatory diseases of the maxillofacial area taking into account biorhythms].
Time course of laboratory parameters is assessed in 31 patients with severe maxillofacial inflammations, hospitalized in intensive care wards. The patients were followed up for 4 to 42 days. Routine blood and urine analyses were monitored. Wave-like fluctuations in all laboratory parameters with periodicity of about a week (biorhythms) were detected. In lethal outcomes, the rhythms were disordered (desynchronized) and counterphases were detected. A grave course of inflammation is for the first time graphically represented critical periods of the diseases are determined; this will help planning the rational terms for monitoring the homeostasis, predict the disease outcome, and improve the treatment of such patients.


Selective functional integration between anterior temporal and distinct fronto-mesolimbic regions during guilt and indignation.
It has been hypothesized that the experience of different moral sentiments such as guilt and indignation is underpinned by activation in temporal and fronto-mesolimbic regions and that functional integration between these regions is necessary for the differentiated experience of these moral sentiments. A recent fMRI study revealed that the right superior anterior temporal lobe (ATL) was activated irrespective of the context of moral feelings (guilt or indignation). This region has been associated with context-independent conceptual social knowledge which allows us to make fine-grained differentiations between qualities of social behaviours (e.g. "critical" and "faultfinding"). This knowledge is required to make emotional evaluations of social behaviour. In contrast to the context-independent activation of the ATL, there were context-dependent activations within different fronto-mesolimbic regions for guilt and indignation. However, it is unknown whether functional integration occurs between these regions and whether regional patterns of integration are distinctive for the experience of different moral sentiments. Here, we used fMRI and psychophysiological interaction analysis, an established measure of functional integration to investigate this issue. We found selective functional integration between the right superior ATL and a subgenual cingulate region during the experience of guilt and between the right superior ATL and the lateral orbitofrontal cortex for indignation. Our data provide the first evidence for functional integration of conceptual social knowledge representations in the right superior ATL with representations of different feeling contexts in fronto-mesolimbic regions. We speculate that this functional architecture allows for the conceptually differentiated experience of moral sentiments in healthy individuals.


Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system.
We studied the survival of 195 patients with agnogenic myeloid metaplasia (AMM) diagnosed between 1962 and 1992 in an attempt to stratify patients into risk groups. Median survival was 42 months. Adverse prognostic factors for survival were age > 60 years, hepatomegaly, weight loss, low hemoglobin level (Hb), low or very high leukocyte count (WBC), high percentage of circulating blasts, male sex, and low platelet count. A new scoring system based on two adverse prognostic factors, namely Hb < 10 g/dL and WBC < 4 or > 30 x 10(9)/L, was able to separate patients in three groups with low (0 factor), intermediate (1 factor), and high (2 factors) risks, associated with a median survival of 93, 26, and 13 months, respectively. An abnormal karyotype (32 cases of 94 tested patients) was associated with a short survival, especially in the low-risk group (median survival of 50 v 112 months in patients with normal karyotype). The prognostic factors for acute conversion were WBC > 30 x 10(9)/L and abnormal karyotype. Thus, hemoglobin level and leukocyte count provide a simple prognostic model for survival in AMM, and the adverse prognostic value of abnormal karyotype may be related to a higher rate of acute conversion.


The role of n-3 polyunsaturated fatty acids in human heart failure.
n-3 polyunsaturated fatty acids (PUFA) have been proposed as potential treatments for human heart failure. The cardioprotective effects of n-3 PUFA are supported by extensive cell culture, animal and human studies. Animal studies with n-3 PUFA have shown marked improvements in many independent risk factors for heart failure, including obesity, type II diabetes, insulin resistance, hypertension and inflammation. However, the evidence from observational studies, randomised controlled trials and meta-analyses that these benefits on risk factors lead to improvements in the symptoms of heart failure in patients is much less convincing. Further, most studies have used marine n-3 PUFA; the role of the plant-derived PUFA, α-linolenic acid (ALA), is even less clear. This discontinuity of scientific evidence from animal to human studies suggests that future studies should focus on defining the optimal dosage range and the efficacy of n-3 PUFA compared to standard treatments using standardised study designs. Further studies on ALA would seem justified.


An outbreak of Bacillus cereus food poisoning resulting from contaminated vegetable sprouts.
In an outbreak of gastrointestinal illness caused by consumption of home-grown raw vegetable sprouts contaminated by Bacillus cereus, victims developed symptoms after an incubation period of 6-15 hours. Four persons initially experienced nausea and vomiting, and this was followed in 3 cases by abdominal cramps and diarrhea. Bacteriologic investigation indicated that B. cereus on unsprouted seeds proliferated during germination in a commercially sold seed sprouting kit and reached levels in excess of 10(7) per gram. B. cereus isolated from the incriminated sprouts exhibited enterotoxigenic activity when tested by the ligated rabbit ileal loop technique, the dermal reaction in guinea pigs, and the rabbit skin capillary permeability test. The diversity of symptoms and incubation periods attributed to B. cereus requires analysis for this often overlooked organism whenever food-borne gastroenteritis is suspected.


Quality-of-life, health service use, and costs associated with syncope.
Syncope is a prevalent condition that is associated with high morbidity, health service use, and costs. Syncope negatively impacts multiple domains of quality-of-life, including physical health, mental health, and functional status. The morbidity associated with recurrent syncope is equivalent to chronic conditions such as severe rheumatoid arthritis and low back pain. Frequency of syncope events is related to worse morbidity, suggesting that effective diagnosis and management can improve quality-of-life. There is a high incidence of health service use associated with syncope, including 740,000 annual emergency department visits and 460,000 hospital admissions in the United States. Rates of admission and inpatient diagnostic testing are characterized by high variance and low clinical utility. Finally, the evaluation of syncope is associated with high costs. Hospital costs associated with the inpatient evaluation of syncope exceed $2.4 billion per year in the United States. Improved diagnostic and treatment algorithms are urgently needed to improve patient quality-of-life, reduce health service use, and lower costs related to the evaluation of syncope.


Evaluation of irregular menses in perimenarcheal girls: a pilot study.
Acyclic vaginal bleeding in girls within three years of menarche is most commonly attributed to an immature hypothalamic-pituitary-ovarian axis. Assuming this diagnosis may preclude the practitioner from performing more definitive studies and thereby diagnosing other, treatable causes of menstrual irregularities. A retrospective chart review of 178 girls presenting to an inner-city hospital-based adolescent clinic within three years of menarche was performed. Personal and family medical and menarcheal history was assessed, and findings on physical and laboratory examination performed were evaluated. Of the 178 girls still perimenarcheal at presentation, 47 were the focus of this study. Of these, 39 had no significant findings on physical examination, while 3 had signs of functional ovarian hyperandrogenism (FOH) including obesity, hirsutism, and moderate acne with corresponding LH/FSH ratios>3, although pelvic ultrasound examination revealed normal ovaries. Four of the 39 patients with normal physical exams had LH/FSH testing done, and 1 of the 4 had an abnormal LH/FSH ratio, indicating possible FOH. Two of the 47 patients were pregnant. Other laboratory abnormalities included microcytic, hypochromic anemia in patients, and an elevated Erythrocyte Sedimentation Rate in a patient later diagnosed with a rheumatologic disorder. Those perimenarcheal girls presenting with irregular menses and findings including obesity, acne, or pallor, were likely to have treatable causes of menstrual irregularities. In one of the four girls with a normal physical examination, hormonal testing indicated possible FOH, thus suggesting that hormonal evaluation of perimenarcheal girls with menstrual irregularities may be justified, as it may reveal previously unsuspected pathology.


Acid hydrolysis of saponin-rich extracts of quinoa, lentil, fenugreek and soybean to yield sapogenin-rich extracts and other bioactive compounds.
Typical hydrolysis times of saponins generally do not take into consideration the effect of time on the degradation of the target compounds, namely sapogenins. When producing natural extracts, it should be borne in mind that conducting hydrolysis to yield a target compound might also affect the final composition of the extracts in terms of other bioactive compounds. In our study, saponin-rich extracts from fenugreek, quinoa, lentil, and soybean were produced and their acid hydrolysis to give sapogenin-rich extracts was conducted over different periods (0-6 h). The disappearance of saponins and appearance of sapogenins was analyzed using high-performance liquid chromatography-diode array detection-mass spectrometry (HPLC-DAD-MS) and gas chromatography-mass spectrometry (GC-MS), respectively. The impact of hydrolysis on the phytosterols and tocopherol in the extracts was also evaluated. Fenugreek showed the highest saponin content (169 g kg-1 ), followed by lentil (20 g kg-1 ), quinoa (15 g kg-1 ), and soybean (13 g kg-1 ). Hydrolysis for 1 h caused the complete disappearance of saponins and the greatest release of sapogenins. Hydrolyzed fenugreek and quinoa extracts contained the highest amounts of sapogenins and minor fractions of phytosterols and tocopherol. Hydrolyzed extracts of lentil and soybean contained a major fraction of phytosterols and a low fraction of sapogenins. In all cases, sapogenins decreased after 1 h of hydrolysis, phytosterols slightly decreased, and tocopherol was unaffected. Standards of diosgenin and oleanolic acid also showed this decreasing pattern under acid hydrolysis conditions. Hydrolysis times of 1 h for saponin-rich extracts from the assayed seeds guarantee the maximum transformation to sapogenin-rich extracts, along with phytosterols and tocopherol. Fenugreek and quinoa seeds are preferred for this. © 2018 Society of Chemical Industry.


Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD).
In a substantial number of patients with systemic mastocytosis (SM), an associated clonal haematological non-mast cell lineage disease (AHNMD) is detectable. Although most of these patients display KIT mutations, especially KIT(D816V), little is known about their exact frequency and their distribution in AHNMD subtypes. We examined 48 patients with SM-AHNMD for the presence of mutant KIT in the SM and AHNMD components of the disease. Mast cells and AHNMD cells were obtained from immunostained bone marrow sections by laser microdissection and examined by melting point analysis of nested-PCR products. KIT(D816V) was found in AHNMD cells in the vast majority of patients with SM-chronic myelomonocytic leukaemia (CMML, 89%). Unexpectedly, KIT(D816V) was far less frequently detectable in AHNMD cells in patients with SM-myeloproliferative neoplasm (MPN, 20%) and SM-acute myeloid leukaemia (AML, 30%). None of the patients with lymphoproliferative AHNMDs displayed KIT codon 816 mutations in AHNMD cells (0/8). In FIP1L1/PDGFRA-positive chronic eosinophilic leukaemia (CEL), neither the SM nor the CEL component of the disease exhibited the KIT mutation. Our findings demonstrate that KIT codon 816 mutations are variably present in AHNMD cells in patients with SM-AHNMD, depending on the subtype of AHNMD. The high frequency of KIT(D816V) in neoplastic mast cells and leukaemic myelomonocytic cells in SM-CMML may point to a common precursor in these patients, and may have implications for the biology of the disease and the development of KIT-targeting therapies.


[Colonization properties of opportunistic bacteria isolated from children with pneumonia].
Evaluation of phenotypes and pathogenicity factors of 476 opportunistic bacteria isolated from respiratory samples of 973 children with community-acquired pneumonia and 36 children without respiratory infection symptoms. Quantitative method of tracheal aspirate and nasopharyngeal swab seeding into certified nutrient media was used, identification was carried out according to standard techniques. Adhesive, "anti-interferon", anti-lysozyme and inherent bactericidal activity of Escherichia coli and Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter spp. were established to ensure in combination with known aggression factors their colonization advantage compared with other pneumopathogens. Adhesion indexes of Gram-negative bacteria lower than 2.5 are shown as markers of invasive strains. Anti-lysozyme activity level lower than 2.14 microg/ml and lack of "anti-interferon" activity characterize non-invasive opportunistic bacteria strains. The detected phenotypic features of opportunistic bacteria may be used in clinical practice for evaluatio of etiologic importance of microorganisms isolated from tracheal aspirate in pneumonia patients.


A general dynamic force distribution algorithm for multifingered grasping.
A general dynamic force distribution (DFD) algorithm for multifingered grasping is presented. Based on the convexity and cone property of contact constraints, the optimal internal force is defined. Determination of the contact force is divided into two phases: (1) determine the direction of the optimal internal force during grasp planning and (2) determine the manipulation force and compensation factor during task manipulation. The total computation cost consists of off-line numerical iterations and on-line analytical computations. Only the latter is related to the real-time control. The algorithm can directly deal with the nonlinear and/or coupled constraints and well overcome the temporal discontinuity.


Understanding the Metabolic Capacity of Antarctic Fishes to Acclimate to Future Ocean Conditions.
Antarctic fishes have evolved under stable, extreme cold temperatures for millions of years. Adapted to thrive in the cold environment, their specialized phenotypes will likely render them particularly susceptible to future ocean warming and acidification as a result of climate change. Moving from a period of stability to one of environmental change, species persistence will depend on maintaining energetic equilibrium, or sustaining the increased energy demand without compromising important biological functions such as growth and reproduction. Metabolic capacity to acclimate, marked by a return to metabolic equilibrium through physiological compensation of routine metabolic rate (RMR), will likely determine which species will be better poised to cope with shifts in environmental conditions. Focusing on the suborder Notothenioidei, a dominant group of Antarctic fishes, and in particular four well-studied species, Trematomus bernacchii, Pagothenia borchgrevinki, Notothenia rossii, and N. coriiceps, we discuss metabolic acclimation potential to warming and CO2-acidification using an integrative and comparative framework. There are species-specific differences in the physiological compensation of RMR during warming and the duration of acclimation time required to achieve compensation; for some species, RMR fully recovered within 3.5 weeks of exposure, such as P. borchgrevinki, while for other species, such as N. coriiceps, RMR remained significantly elevated past 9 weeks of exposure. In all instances, added exposure to increased PCO2, further compromised the ability of species to return RMR to pre-exposure levels. The period of metabolic imbalance, marked by elevated RMR, was underlined by energetic disturbance and elevated energetic costs, which shifted energy away from fitness-related functions, such as growth. In T. bernacchii and N. coriiceps, long duration of elevated RMR impacted condition factor and/or growth rate. Low growth rate can affect development and ultimately the timing of reproduction, severely compromising the species' survival potential and the biodiversity of the notothenioid lineage. Therefore, the ability to achieve full compensation of RMR, and in a short-time frame, in order to avoid long term consequences of metabolic imbalance, will likely be an important determinant in a species' capacity to persist in a changing environment. Much work is still required to develop our understanding of the bioenergetics of Antarctic fishes in the face of environmental change, and a targeted approach of nesting a mechanistic focus in an ecological and comparative framework will better aid our predictions on the effect of global climate change on species persistence in the polar regions.


[Surgical treatment of congenital lung malformations in pediatric patients].
To determine the main congenital lung malformations treated and the principal diagnostic methods employed, as well as the indications for surgical treatment and the results obtained, at a referral facility for pediatric thoracic surgery. We reviewed the medical charts of 52 patients anatomopathologically diagnosed with congenital lung malformations and who had been submitted to pulmonary resection between January of 1997 and December of 2006. Exclusion criteria were age > 12 years and incomplete clinical data. The final sample comprised 35 patients. In this sample, the mean age was 31 months, and there was a predominance of males (n = 21). The anatomopathological findings were cystic adenomatoid malformation (n = 14), congenital lobar emphysema (n = 13), pulmonary sequestration (n = 8) and arteriovenous malformation (n = 1). The most common type of lung resection was left lower lobectomy (in 25.71%) followed by different types of segmentectomy (in 22.85%), left upper lobectomy (in 22.85%), right upper lobectomy (in 14.28%), right lower lobectomy (in 8.57%) and middle lobectomy (in 5.71%). Of the 35 patients, 34 (97.14%) were submitted to closed pleural drainage, with a mean duration of thoracic drainage of 3.9 days. Ten patients (28.5%) presented with postoperative complications. There were no deaths in our sample. Pulmonary resection for the treatment of congenital lung malformations is a safe procedure, presenting low morbidity and no mortality at a referral facility for pediatric thoracic surgery.


Exposure Definition in Case-Control Studies of Cervical Cancer Screening: A Systematic Literature Review.
The first step in evaluating the effectiveness of cervical screening is defining exposure to screening. Our aim was to describe the spectrum of screening exposure definitions used in studies of the effectiveness of cervical screening. This systematic review included case-control studies in a population-based screening setting. Outcome was incidence of cervical cancer. Three electronic databases were searched from January 1, 2012 to December 6, 2018. Articles prior to 2012 were identified from a previous review. The qualitative synthesis focused on describing screening exposure definitions reported in the literature and the methodologic differences that could have an impact on the association between screening and cervical cancer. Forty-one case-control studies were included. Six screening exposure definitions were identified. Cervical cancer risk on average decreased by 66% when screening exposure was defined as ever tested, by 77% by time since last negative test, and by 79% after two or more previous tests. Methodologic differences included composition of the reference group and whether diagnostic and/or symptomatic tests were excluded from the analysis. Consensus guidelines to standardize exposure definitions are needed to ensure evaluations of cervical cancer screening can accurately measure the impact of transitioning from cytology to human papillomavirus-based screening and to allow comparisons between programs.


Genetic influences on heart rate variability.
Heart rate variability (HRV) is the variation of cardiac inter-beat intervals over time resulting largely from the interplay between the sympathetic and parasympathetic branches of the autonomic nervous system. Individual differences in HRV are associated with emotion regulation, personality, psychopathology, cardiovascular health, and mortality. Previous studies have shown significant heritability of HRV measures. Here we extend genetic research on HRV by investigating sex differences in genetic underpinnings of HRV, the degree of genetic overlap among different measurement domains of HRV, and phenotypic and genetic relationships between HRV and the resting heart rate (HR). We performed electrocardiogram (ECG) recordings in a large population-representative sample of young adult twins (n=1060 individuals) and computed HRV measures from three domains: time, frequency, and nonlinear dynamics. Genetic and environmental influences on HRV measures were estimated using linear structural equation modeling of twin data. The results showed that variability of HRV and HR measures can be accounted for by additive genetic and non-shared environmental influences (AE model), with no evidence for significant shared environmental effects. Heritability estimates ranged from 47 to 64%, with little difference across HRV measurement domains. Genetic influences did not differ between genders for most variables except the square root of the mean squared differences between successive R-R intervals (RMSSD, higher heritability in males) and the ratio of low to high frequency power (LF/HF, distinct genetic factors operating in males and females). The results indicate high phenotypic and especially genetic correlations between HRV measures from different domains, suggesting that >90% of genetic influences are shared across measures. Finally, about 40% of genetic variance in HRV was shared with HR. In conclusion, both HR and HRV measures are highly heritable traits in the general population of young adults, with high degree of genetic overlap across different measurement domains.


Rational design of a secreted enzymatically inactive mutant of extracellular superoxide dismutase.
Extracellular superoxide dismutase (SOD3) is a secreted enzyme that regulates levels of extracellular superoxide and protects the extracellular matrix from degradation by reactive species. The SOD3 protein contains a heparin-binding domain and resides in a microenvironment rich in other heparin-bound growth factors, raising the possibility that SOD3 may have some biological role independent of its catalytic activity. To begin to address this, we designed and created enzymatically inactive mutant constructs targeting either the copper coordinating (i.e. H96 and H98) or superoxide channeling (i.e. N180 and R186) amino acid residues of SOD3. All constructs expressed equal quantities of immature intracellular SOD proteins, but only the N180A, R186A, and combination N180A/R186A mutants produced fully processed and secreted extracellular protein. Furthermore, while SOD activity was significantly inhibited in the single N180A and R186A mutants, the activity was completely abrogated in the N180A/R186A double mutant. Overall, the use of this novel tool may have broad reaching impacts into various fields of biology and medicine, and will aid in the delineation of cellular processes that are regulated by solely the SOD3 protein, its reactive oxygen species substrates and products, or the combination of both.


Improving patient access to hepatitis C antiviral medicines in Switzerland: Understanding the financial risks for community pharmacies.
As observed in other countries, some patients may experiment difficulties in obtaining their hepatitis C antiviral medicines (HCVm) in Swiss community pharmacies. There is a lack of data related to access to HCVm at the patient level and notably related to the potential financial risks for the community pharmacies. (a) To evaluate the potential financial risks for community pharmacist associated with the delivery of HCVm in the Swiss healthcare system; (b) to explore the attitudes and experiences of community pharmacists related to these risks and their consequences for the patients. A three-step approach was chosen as follows: (a) estimation of costs, incomes, and gross financial results directly related to 3-month treatment with Harvoni based on the drug delivery process (data from 68 patients over 2 years); (b) sensitivity analyses; (c) exploration of local community pharmacists' attitudes and experiences related to the delivery of HCVm in the canton of Vaud (Western Switzerland). Two main risks were identified: (a) Incomes do not always cover costs; (b) reimbursement issues could lead to an increase in the requirement for working capital. According to the survey, 23% (14/60) of pharmacies refused to deliver HCVm to at least one patient, and these patients had to find a solution mostly on their own. The scenario analysis clarifies the causes of the possible refusal to deliver HCVm. With the growing number of high-priced medicines, the healthcare systems should have a clear strategy to encourage their delivery by community pharmacies by ensuring seamless and collaborative care for patients. The community pharmacists could be accountable to provide such services-if they get the education, training, and remuneration.


Large-scale label-free proteomics analysis of occupational poisoned patients of 1-bromopropane, workers exposed to 1-bromopropane and healthy individuals.
1-Bromopropane (1-BP) is an increasingly used chemical solvent for cleaning metals and gradually replacing spraying adhesives. Workers exposed to 1-BP (WBP) showed nervous system dysfunction and other symptoms. This study focused on the proteomic change between healthy individuals (HIs), WBP and poisoned patients with 1-BP (PBP). Total proteins from serum samples were isolated, and high-abundance proteins were filtered out. Large-scale label-free proteomics platform was utilized for protein identification and quantitative comparison, followed by biological function analysis by bioinformatics tools. Compared to HI, 99 proteins were up-regulated and 55 proteins were down-regulated in WBP; 59 proteins were up-regulated and 94 proteins were down-regulated in PBP. With WBP as control, 63 proteins were up-regulated and 127 proteins were down-regulated in PBP. These differently expressed proteins were mainly involved in the immune response, neuron system regulation, blood coagulation, wound healing, endopeptidase activity, lipid metabolic process and apoptosis. The proteomic profiling change of HI, WBP and PBP provides a comprehensive view on 1-BP poison through immune response, signal transduction, metabolism, coagulation and response to stress. This study expanded our understanding on early development and maintenance and provided more potential protein markers for diagnosis of 1-BP poisoning.


Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease.
Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.


Genetic structure among sorghum landraces as revealed by morphological variation and microsatellite markers in three agroclimatic regions of Burkina Faso.
Diversity among 124 sorghum landraces from 10 villages surveyed in 3 regions of Burkina Faso covering different agroecological zones was assessed by 28 agromorphological traits and 29 microsatellite markers. 94.4% of the landraces collected belonged to the botanical race guinea (consisting of 96.6% guinea gambicum and 3.4% guinea margaritiferum), 74.2% had white kernels, 13.7% had orange and 12.1% had red kernels. Compared to the "village nested within zone" factor, the "variety nested within village within zone" factor predominately contributed to the diversity pattern for all nine statistically analysed quantitative traits. The multivariate analyses performed on ten morphological traits identified five landrace groups, and of these, the red kernel sorghum types appeared the most homogenous. 2 to 17 alleles were detected per locus with a mean 4.9 alleles per locus and a gene diversity (He) of 0.37. Landraces from the sub-Sahelian zone had the highest gene diversity (He = 0.38). Cluster analysis revealed that the diversity was weakly stratified and could not be explained by any biophysical criteria. One homogenous guinea margaritiferum group was distinguished from other guinea landraces. The red kernel type appeared to be genetically distinct from all other guinea landraces. The kernel colour was the principal structuring factor. This is an example of a homogeneous group of varieties selected for a specific use (for local beer preparation), mainly grown around the households in compound fields, and presenting particular agromorphological and genetic traits. This is the most original feature of sorghum diversity in Burkina Faso and should be the focus of special conservation efforts.


Genetics and Crime: Integrating New Genomic Discoveries Into Psychological Research About Antisocial Behavior.
Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.


PRMT4 is involved in insulin secretion via the methylation of histone H3 in pancreatic β cells.
The relationship between protein arginine methyltransferases (PRMTs) and insulin synthesis in β cells is not yet well understood. In the present study, we showed that PRMT4 expression was increased in INS-1 and HIT-T15 pancreatic β cells under high-glucose conditions. In addition, asymmetric dimethylation of Arg17 in histone H3 was significantly increased in both cell lines in the presence of glucose. The inhibition or knockdown of PRMT4 suppressed glucose-induced insulin gene expression in INS-1 cells by 81.6 and 79% respectively. Additionally, the overexpression of mutant PRMT4 also significantly repressed insulin gene expression. Consistently, insulin secretion induced in response to high levels of glucose was decreased by both PRMT4 inhibition and knockdown. Moreover, the inhibition of PRMT4 blocked high-glucose-induced insulin gene expression and insulin secretion in primary pancreatic islets. These results indicate that PRMT4 might be a key regulator of high-glucose-induced insulin secretion from pancreatic β cells via H3R17 methylation.


Effect of catechol-O-methyltransferase (rs4680) single-nucleotide polymorphism on opioid-induced hyperalgesia in adults with chronic pain.
The catechol-O-methyltransferase Val158Met polymorphism has been associated with alterations in pain perception, but the influence of the polymorphism on pain perception in patients with chronic pain receiving daily opioid therapy has not been previously reported. The primary aim of this study was to investigate the effects of the catechol-O-methyltransferase Val158Met polymorphism on heat pain perception in a cohort of adults receiving daily opioid therapy for chronic pain. Adults with chronic pain consecutively admitted to an outpatient pain rehabilitation program who met inclusion criteria and were receiving daily opioid therapy were recruited for study participation (N = 142). Individuals were genotyped for catechol-O-methyltransferase Val158Met (rs4680), and the polymorphism was analyzed using an additive and codominant genotype models. The distribution of the Val158Met genotypes was 25% for Val/Val, 41% for Val/Met and 34% for Met/Met (Hardy-Weinberg, P > 0.05). A main effect of genotype was observed for heat pain perception ( P = 0.028). Under the codominant model of allele effects, exploratory post hoc pairwise comparisons adjusted for morphine equivalent dose and pain catastrophizing demonstrated that individuals with the Val/Met genotype were hyperalgesic compared to individuals with the Val/Val ( P = 0.039) and Met/Met ( P = 0.023) genotypes. No significant association was observed between heat pain perception and genotype under the additive model of allele effects. Among patients with chronic pain who were receiving daily opioids, the Val/Met genotype was associated with hyperalgesia using a measure of heat pain perception that has been previously indicative of opioid-induced hyperalgesia in other heterogeneous samples of adults with chronic pain. This study contributes to the emerging understanding of how catechol-O-methyltransferase activity affects pain perception in the context of daily opioid use, and these findings may be useful in the design of future trials aimed at investigating the potential efficacy of ß-2 adrenergic receptor antagonism for opioid-induced hyperalgesia.


To determine how obstetricians and gynecologists (OB/GYNs) perceive the gynecologic health effects of obesity and to identify perceived obstacles to counseling. OB/GYNs with 3 St. Louis health systems were emailed a 46-question survey regarding physicians' role in counseling women on the health risks of obesity and barriers faced in achieving this counseling. Differences between respondents' gender, age, practice type, years in practice, and body mass index were assessed using Chi-square or Fisher's exact tests as appropriate. Of 318 OB/GYNs emailed, 134 completed surveys, including 82 generalists and 52 subspecialists. 93% of respondents believed it was necessary to educate patients on health risks of obesity. 90% and 75%, respectively, cited diagnoses of endometrial hyperplasia and cancer as teachable moments for counseling. The most frequently cited barriers to successful counseling were lack of time, referral services, and patient tools/information. Most did not believe they had adequate reimbursement (65%), training (53%) or educational resources (50%) to counsel patients. Survey answers differed by practice setting, gender, and provider age. Although most OB/GYN providers consider obesity counseling important, execution is hindered by perceived barriers that differ by provider gender, age, and practice type. For OB/GYNs, more effective weight management counseling will require better training and practice-specific strategies. Based on survey responses, better reimbursement combined with increased resources for appropriate referrals and cancer prevention counseling are needed in order to improve weight management implementation in OB/GYN. •The majority of OB/GYNs believe obesity counseling is important•Perceptions of obesity counseling differ based on provider/practice characteristics.•Lack of time, referral services, and patient tools are the biggest cited barriers to counseling.•Improved obesity counseling could improve downstream OB/GYN morbidities.


Editor's Highlight: Pregnancy Alters Aflatoxin B1 Metabolism and Increases DNA Damage in Mouse Liver.
Pregnancy is a complex physiological state, in which the metabolism of endogenous as well as exogenous agents is ostensibly altered. One exogenous agent of concern is the hepatocarcinogen aflatoxin B1 (AFB1), a foodborne fungal toxin, that requires phase I metabolic oxidation for conversion to its toxic and carcinogenic form, the AFB1-8,9-exo-epoxide. The epoxide interacts with cellular targets causing toxicity and cell death; these targets include the covalent modification of DNA leading to mutations that can initiate malignant transformation. The main detoxification pathway of the AFB1-epoxide involves phase II metabolic enzymes including the glutathione-S-transferase (GST) family. Pregnancy can modulate both phase I and II metabolism and alter the biological potency of AFB1. The present work investigated the impact of pregnancy on AFB1 exposure in mice. A single IP dose of 6 mg/kg AFB1 was administered to pregnant C57BL/6 J mice at gestation day 14 and matched non-pregnant controls. Pregnant mice accumulated 2-fold higher AFB1-N7-guanine DNA adducts in the liver when compared with nonpregnant controls 6 h post-exposure. Enhanced DNA adduct formation in pregnant animals paralleled elevated hepatic protein expression of mouse CYP1A2 and mouse homologs of human CYP3A4, phase I enzymes capable of bioactivating AFB1. Although phase II enzymes GSTA1/2 showed decreased protein expression, GSTA3, the primary enzymatic protection against the AFB1-epoxide, was unaffected at the protein level. Taken together, our results reveal that pregnancy may constitute a critical window of susceptibility for maternal health, and provide insight into the biochemical factors that could explain the underlying risks.