Topological mirror images in protein structure computation: an underestimated problem.
When calculating three-dimensional structures from NMR data, alternative solutions with very large RMS deviation can be obtained. Sometimes local or global inversions of the protein folding can be observed. We call these different solutions topological mirror images, as they keep the correct amino acid chirality. They are observed when the number of restraints is insufficient and represent different solutions from the same scalar information. Therefore they are common in small peptides where the NMR data are often limited and the secondary structure is not very well defined. They can also be observed in large molecules in regions of higher flexibility. In our experience the observation of topological mirror images is independent of the efficiency of sampling of the algorithm used. We present four examples of proteins with different size and folding. We also discuss ways to distinguish among the different solutions.


Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions.
1. The long-term level of arterial pressure is dependent on the relationship between arterial pressure and the urinary output of salt and water, which, in turn, is affected by a number of factors, including renal sympathetic nerve activity (RSNA). In the present brief review, we consider the mechanisms within the brain that can influence RSNA, focusing particularly on hypothalamic mechanisms. 2. The paraventricular nucleus (PVN) in the hypothalamus has major direct and indirect connections with the sympathetic outflow and there is now considerable evidence that tonic activation of the PVN sympathetic pathway contributes to the sustained increased level of RSNA that occurs in conditions such as heart failure and neurogenic hypertension. The tonic activity of PVN sympathetic neurons, in turn, depends upon the balance of excitatory and inhibitory inputs. A number of neurotransmitters and neuromodulators are involved in these tonic excitatory and inhibitory effects, including glutamate, GABA, angiotensin II and nitric oxide. 3. The dorsomedial hypothalamic nucleus (DMH) also exerts a powerful influence over sympathetic activity, including RSNA, via synapses with sympathetic nuclei in the medulla and, possibly, also other brainstem regions. The DMH sympathetic pathway is an important component of the phasic sympathoexcitatory responses associated with acute stress, but there is no evidence that it is an important component of the central pathways that produce long-term changes in arterial pressure. Nevertheless, it is possible that repeated episodic activation of this pathway could lead to vascular hypertrophy and, thus, sustained changes in vascular resistance and arterial pressure. 4. Recent studies have reactivated the old debate concerning the possible role of the baroreceptor reflex in the long-term regulation of sympathetic activity. Therefore, central resetting of the baroreceptor-sympathetic reflex may be an important component of the mechanisms causing sustained changes in RSNA. However, little is known about the cellular mechanisms that could cause such resetting.


Influencing Factors of Sexual Intimacy and Satisfaction among Women within 1 Year after Mastectomy.
The purpose of this study was to identify the levels of body image, sexual intimacy, and sexual satisfaction, and to explore factors affecting sexual intimacy and satisfaction among women within one year of mastectomy. The present study was a cross-sectional survey and involved 101 women who had undergone mastectomy at a University hospital of D city, Korea. Measurement included the scales of body image, sexual intimacy, and sexual satisfaction. Mean age of the subjects was 51 years. Scores of the body image, sexual intimacy, and sexual satisfaction were 59.62, 90.69, and 69.04, respectively. Body image, sexual intimacy, and sexual satisfaction were significantly related to each other. Sexual intimacy was higher when women were of young age (β=-.32), had a shorter period since surgery (β=-.24), and with higher levels of body image (β=.37). Sexual satisfaction was higher when women had higher levels of body image (β=.19) and greater levels of sexual intimacy (β=.74). Higher levels of body image and greater levels of sexual intimacy were identified as the significant factors influencing sexual satisfaction among these women. Future research with a mixed-method research is needed to gain a deep understanding of the sexuality between women and their husbands.


Induced new mutation of D1 serine-268 in soybean photosynthetic cell cultures produced atrazine resistance, increased stability of S2QB- and S3QB- states, and increased sensitivity to light stress.
We have isolated several herbicide-resistant cell lines from photosynthetic cell suspensions of soybean (Glycine max) that possessed different levels of herbicide resistance, photosystem II activity, and chlorophyll a/b ratio. We have further studied the STR7 mutant, which showed the highest level of resistance to atrazine as well as a cross-resistance to 3-(3,4-dichlorophenyl)-1, 1-dimethylurea (50- and 3-fold, respectively, compared with the wild type). Sequencing of the psbA gene (coding for the D1 polypeptide of photosystem II) from this mutant revealed a single change, serine-268 to proline, in the D1 protein. To our knowledge, this substitution has not previously been described in any photosynthetic organism. In addition to affecting atrazine resistance, this single amino acid change caused a decrease in the electron transfer rate between the secondary acceptors QA and QB and a stabilization of the S2QB- and S3QB- states. The mutant also showed a larger antenna size, an increase in non-QB-reducing centers, and a higher sensitivity to light stress. The unusual stability of the S2QB- and S3QB- states indicates that STR7 belongs to a new class of QB-site mutants.


Management of non-genital herpes simplex virus infections in immunocompetent patients.
Non-genital herpes simplex virus in immunocompetent hosts causes a variety of primary infections--gingivostomatitis, keratoconjunctivitis, herpetic whitlow, and encephalomyelitis. Recurrent infections with orolabialis are very common, but are usually mild and self-limiting. Cutaneous complications of herpes simplex virus infections include eczema herpeticum and erytherma multiforme. Systemic treatment with acyclovir is indicated in encephalomyelitis, progressive eczema herpeticum, and frequent severe erythema multiforme. Chronic, suppressive acyclovir treatment may be helpful in severe recurrent infections or those complicated by erythema multiforme/dissemination. Many primary and recurrent infections can be treated with simple topical therapy to control secondary infection. There is no evidence that systemic treatment affects viral latency or recurrent infections following discontinuation of treatment.


Regulation of prostaglandin biosynthesis in vivo by glutathione.
Intraperitoneal administration of urate crystals to mice reduced subsequent macrophage conversion of arachidonic acid (AA) to prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid for up to 6 h. In contrast, levels of 12-hydroxyheptadecatrienoic acid (12-HHT) were markedly elevated. This metabolic profile was previously observed in vitro when recombinant cyclooxygenase (COX) enzymes were incubated with reduced glutathione (GSH). Analysis of peritoneal GSH levels revealed a fivefold elevation after urate crystal administration. The GSH synthesis inhibitor L-buthionine-[S,R]-sulfoximine partially reversed the urate crystal effect on both GSH elevation and PG synthesis. Moreover, addition of exogenous GSH to isolated peritoneal macrophages shifted AA metabolism from PGs to 12-HHT. Urate crystal administration reduced COX-1, but induced COX-2 expression in peritoneal cells. The reduction of COX-1 may contribute to the attenuation of PG synthesis after 1 and 2 h, but PG synthesis remained inhibited up to 6 h, when COX-2 levels were high. Overall, our results indicate that elevated GSH levels inhibit PG production in this model and provide in vivo evidence for the role of GSH in the regulation of PG biosynthesis.


Laminin-5 gamma 2 chain and matrix metalloproteinase-2 may trigger colorectal carcinoma invasiveness through formation of budding tumor cells.
Tumor budding has been reported to be significantly associated with lymph node or distant metastasis in colorectal carcinomas. We attempted to elucidate the contributing factors for the formation of budding tumor cells. Fifty T1 colorectal carcinomas were immunostained using several antibodies against adhesion-related molecules, and the associations between tumor budding and clinicopathological factors were examined. Univariate analysis revealed that predominant histology, lymphatic permeation, depth of invasion, width of invasion, CD44 variant 6 expression, laminin-5 gamma 2 chain expression and stromal MMP-2 expression were associated with tumor budding. Multivariate analysis showed that lymphatic permeation, laminin-5 gamma 2 chain expression and stromal MMP-2 expression were independently and significantly associated with tumor budding. Furthermore, laminin-5 gamma 2 chain and stromal MMP-2 expression patterns were significantly associated with locoregional failure. These results suggest that laminin-5 gamma 2 chain and MMP-2 may contribute synergistically to the formation of budding tumor cells.


The heparin-binding hemagglutinin protein of Mycobacterium tuberculosis is a nucleoid-associated protein.
Nucleoid-associated proteins (NAPs) regulate multiple cellular processes such as gene expression, virulence, and dormancy throughout bacterial species. NAPs help in the survival and adaptation of Mycobacterium tuberculosis (Mtb) within the host. Fourteen NAPs have been identified in Escherichia coli; however, only seven NAPs are documented in Mtb. Given its complex lifestyle, it is reasonable to assume that Mtb would encode for more NAPs. Using bioinformatics tools and biochemical experiments, we have identified the heparin-binding hemagglutinin (HbhA) protein of Mtb as a novel sequence-independent DNA-binding protein which has previously been characterized as an adhesion molecule required for extrapulmonary dissemination. Deleting the carboxy-terminal domain of HbhA resulted in a complete loss of its DNA-binding activity. Atomic force microscopy showed HbhA-mediated architectural modulations in the DNA, which may play a regulatory role in transcription and genome organization. Our results showed that HbhA colocalizes with the nucleoid region of Mtb. Transcriptomics analyses of a hbhA KO strain revealed that it regulates the expression of ∼36% of total and ∼29% of essential genes. Deletion of hbhA resulted in the upregulation of ∼73% of all differentially expressed genes, belonging to multiple pathways suggesting it to be a global repressor. The results show that HbhA is a nonessential NAP regulating gene expression globally and acting as a plausible transcriptional repressor.


Mechanism of crosstalk inhibition of IL-6 signaling in response to LPS and TNFalpha.
Negative regulation of cytokine signaling is critical for the generation of the appropriate cellular outcome in response to signals, and can be modulated by other concomitant extracellular stimuli ("crosstalk"). Using both genetic and pharmacological manipulations we have investigated the mechanisms by which the pro-inflammatory stimuli, lipopolysaccharide (LPS) and Tumor necrosis factor alpha (TNFalpha), negatively regulate interleukin-6 (IL-6) signaling in primary mouse macrophages. Analysis of suppressor of cytokine signalling 3 (SOCS3)-deficient macrophages reveal that SOCS3 is necessary but surprisingly, not sufficient for the complete crosstalk inhibition of IL-6 signaling induced by LPS and TNFalpha. Analysis of macrophages from gp130 (Y757F) mutant mice suggest that SH2 domain-containing tyrosine phosphatase (SHP2) activity does not explain the residual inhibitory effect of these pro-inflammatory stimuli. In addition, p38 mitogen-activated protein kinase (p38) activation also negatively regulates IL-6 signaling independent of its parallel and necessary action to induce SOCS3 expression. Finally, we have identified an additional, novel mechanism of crosstalk inhibition: a reduction in total cellular levels of gp130 following stimulation with LPS and TNFalpha.


Bronchiolitis obliterans syndrome: alloimmune-dependent and -independent injury with aberrant tissue remodeling.
Long-term success in lung transplantation continues to be challenged by chronic graft dysfunction, which is manifest as bronchiolitis obliterans syndrome (BOS). The mechanisms of BOS involve both immune-mediated pathways (rejection, autoimmune-like mechanisms), and alloimmune-independent pathways (infection, aspiration, ischemia, primary graft failure), which lead to a fibroproliferative responses. BOS correlates histologically with obliterative bronchiolitis in terminal bronchioles and evidence of aberrant remodeling in the airway epithelium, vasculature, stroma, and lymphoid system. A potentially important mechanism that supports the progressive and therapy-resistant nature of BOS is a continuous cycle of ongoing injury and aberrant remodeling. Namely, anatomical and functional abnormalities induce and exacerbate immune-mediated and alloimmune-independent pathways through various mechanisms (e.g., epithelial remodeling decreases mucociliary clearance that exacerbates aspiration-related injury). From this viewpoint, we review current therapeutic strategies and revisit the role of transplant surgeons in attenuating the initial transplant-related injuries to prevent the lung grafts from entering the remodeling-injury cycle.


Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.
Recent investigation suggests that a reversible glutamatergically mediated thalamocortical-striatal dysfunction may serve as a reliable pathophysiological and treatment response marker for obsessive-compulsive disorder (OCD). We postulated that N-methyl- d-aspartate (NMDA) receptors were involved in OCD, and specifically that polymorphisms in the 3' untranslated region of GRIN2B (glutamate receptor, ionotropic, N-methyl- d-aspartate 2B) were associated with OCD in affected families. The objective of this investigation was to test the association between GRIN2B variants and transmission of the OCD trait using a family-based design. Using the Family Based Association Test (FBAT), we tested for association with OCD diagnosis in 130 families, and also performed a haplotype analysis. FBAT was additionally used in a subset of 98 families to test for association with the quantitative phenotype of lifetime OCD symptom severity. RESULTS. Under a non-additive model of inheritance, the 5072T/G variant was significantly associated with OCD even after correcting for the number of models tested ( P=0.014). In addition, there was a significant positive association with OCD diagnosis ( P=0.002) for the 5072G-5988T haplotype under the recessive model. Although preliminary and requiring replication in larger samples, these results provide evidence that GRIN2B may be associated with susceptibility to OCD. Coupled with basic neuroscience and clinical neuroimaging findings in patients with OCD, our results provide new and converging support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.


Knowledge-driven binning approach for rare variant association analysis: application to neuroimaging biomarkers in Alzheimer's disease.
Rapid advancement of next generation sequencing technologies such as whole genome sequencing (WGS) has facilitated the search for genetic factors that influence disease risk in the field of human genetics. To identify rare variants associated with human diseases or traits, an efficient genome-wide binning approach is needed. In this study we developed a novel biological knowledge-based binning approach for rare-variant association analysis and then applied the approach to structural neuroimaging endophenotypes related to late-onset Alzheimer's disease (LOAD). For rare-variant analysis, we used the knowledge-driven binning approach implemented in Bin-KAT, an automated tool, that provides 1) binning/collapsing methods for multi-level variant aggregation with a flexible, biologically informed binning strategy and 2) an option of performing unified collapsing and statistical rare variant analyses in one tool. A total of 750 non-Hispanic Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort who had both WGS data and magnetic resonance imaging (MRI) scans were used in this study. Mean bilateral cortical thickness of the entorhinal cortex extracted from MRI scans was used as an AD-related neuroimaging endophenotype. SKAT was used for a genome-wide gene- and region-based association analysis of rare variants (MAF (minor allele frequency) < 0.05) and potential confounding factors (age, gender, years of education, intracranial volume (ICV) and MRI field strength) for entorhinal cortex thickness were used as covariates. Significant associations were determined using FDR adjustment for multiple comparisons. Our knowledge-driven binning approach identified 16 functional exonic rare variants in FANCC significantly associated with entorhinal cortex thickness (FDR-corrected p-value < 0.05). In addition, the approach identified 7 evolutionary conserved regions, which were mapped to FAF1, RFX7, LYPLAL1 and GOLGA3, significantly associated with entorhinal cortex thickness (FDR-corrected p-value < 0.05). In further analysis, the functional exonic rare variants in FANCC were also significantly associated with hippocampal volume and cerebrospinal fluid (CSF) Aβ1-42 (p-value < 0.05). Our novel binning approach identified rare variants in FANCC as well as 7 evolutionary conserved regions significantly associated with a LOAD-related neuroimaging endophenotype. FANCC (fanconi anemia complementation group C) has been shown to modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. Our results warrant further investigation in a larger independent cohort and demonstrate that the biological knowledge-driven binning approach is a powerful strategy to identify rare variants associated with AD and other complex disease.


Romiplostim Treatment in Adults with Immune Thrombocytopenia of Varying Duration and Severity.
Romiplostim is recommended for the second- and third-line treatment of primary immune thrombocytopenia (ITP). We conducted a large, single-arm study (clinicaltrials.gov; NCT00508820) with broad entry criteria to evaluate the safety of romiplostim in adult ITP. Patients (n = 407) with ITP lasting 0.03-57.14 years and low platelet counts (median 14.0 × 10 9 /l) or uncontrolled bleeding received romiplostim for up to 4 years. The rates of treatment-related, serious adverse events, serious hemorrhage events, thromboembolic events and fatal events were similar to those reported in previous romiplostim trials (0.2, 0.4, 0.2 and 0.1/100 patient-weeks, respectively). Bone marrow reticulin was observed in 4 patients, but biopsies were not routinely performed so the true incidence of this event cannot be determined. Type I collagen (nonserious, unrelated) was reported in 1 patient who likely had myelodysplastic syndrome. No new class of adverse events was reported. Platelet responses were achieved by >90% of the patients, typically within 1-2 weeks of the initiation of romiplostim treatment. From week 8, median platelet counts were >100 × 10 9 /l; 47% of the patients received rescue medications (the use decreased over time). This study confirms and extends the tolerability/efficacy findings of previous romiplostim clinical studies. It was performed on a large ITP population, which is likely more representative of clinical practice.


Potential blood pressure thresholds and outcome in acute intracerebral hemorrhage.
Little is known about the relationships between different systolic blood pressure (SBP) thresholds and their outcomes in acute intracerebral hemorrhage (ICH). We aimed to determine the associations of potential systolic blood pressure (SBP) thresholds with hematoma growth (HG) and clinical outcome in patients with acute ICH. 117 patients with acute (<6 h) spontaneous supratentorial ICH underwent blood pressure monitoring at 15 min interval over the first 24 h. SBP thresholds of 140, 150, 160, 170, 180, 190, and 200 mm Hg were assessed by means of the percentage of 24-hour values exceeding each threshold (SBP load). HG at 24 h, early neurological deterioration (END), 24-hour and 90-day mortality, and poor outcome were recorded. SBP 170, 180, 190, and 200 loads were significantly correlated with the amount of both absolute and relative hematoma enlargement at 24 h. In multivariate analyses, SBP 170 load was related to HG and END, while SBP 160 load was associated with mortality at 24 h. No thresholds were independently related to outcomes at 90 days. In patients with acute ICH, SBP lowering to at least less than 160 mm Hg threshold may be needed to minimize the deleterious effect of high SBP on 24-hour outcomes.


Lanthanide derivatives comprising arylhydrazones of β-diketones: cooperative E/Z isomerization and catalytic activity in nitroaldol reaction.
Two complexes [KLa(HL(1))2{(CH3)2NCHO}2(H2O)3] (1) and [Sm(H2O)9](E-H2L(2))3·2H2O (2) were synthesized by the reaction of lanthanum(III) and samarium(III) nitrates with potassium 3-(2-(2,4-dioxopentan-3-ylidene)hydrazinyl)-2-hydroxy-5-nitrobenzenesulfonate (KH2L(1)) and potassium (E,Z)-5-chloro-3-(2-(1,3-dioxo-1-phenylbutan-2-ylidene)hydrazinyl)-2-hydroxybenzenesulfonate (KH2L(2)), respectively. Both complexes were fully characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy, ESI-MS and single-crystal X-ray diffraction. Cooperative E,Z→E isomerization of KH2L(2), induced by resonance assisted hydrogen bonding and ionic interactions, occurs upon the interaction with Sm(III). Catalytic activities of KH2L(1,2) and their lanthanide derivatives were evaluated in the Henry reaction of nitroethane with a variety of aromatic and aliphatic aldehydes. Good yields (up to 91%) and diastereoselectivities (syn/anti 3 : 1) were observed in the reactions catalyzed by 1 in water.


Occurrence of multiple ribonucleotide reductase classes in gamma-proteobacteria species.
Ribonucleotide reductase (RNR) is central to de novo synthesis of deoxyribonucleotides and essential for all living cells. Three classes have been described; class I is oxygen dependent and represented by two subclasses, Ia (NrdAB) and Ib (NrdEF); class II (NrdJ) is indifferent to oxygen; and class III (NrdDG) is oxygen sensitive. More than one class can be found in an organism, reflecting the oxygen status of its environment. We have investigated, by using PCR and Southern blot, the occurrence of the different classes among species of the gamma-Proteobacteria. Class III are present in all species tested, but the presence of the other classes varies. Some species contain one unique additional enzyme, class Ia, Ib, or II, whereas others contain two additional enzymes, class Ia and Ib, or class Ia and II.


DNR directives are established early in mechanically ventilated intensive care unit patients.
Setting treatment goals in the intensive care unit (ICU) often involves resuscitation decisions. Our objective was to study the rate of establishing do-not-resuscitate (DNR) directives, determinants, and outcomes of those directives for mechanically ventilated patients. In a multicentre observational study, we included consecutive adults with no DNR directives within 24 hr of ICU admission who were mechanically ventilated for at least 48 hr. We identified the rate with which DNR directives were established, and factors associated with these directives. Among 765 patients, DNR directives were established for 231 (30.2%) patients; 143 (62.1%) of these were established within the first week. Factors independently associated with a DNR directive were: patient age [> or = 75 yr (hazard ratio [HR] 2.3, 95% confidence interval 1.5-3.4], 65 to 74 yr (HR 1.8, 1.2-2.7), 50 to 64 yr (HR 1.4, 1.0-2.2) relative to < 50 yr); medical rather than surgical diagnosis (HR 1.8, 1.3-2.5); multiple organ dysfunction score (HR 1.7 for each five-point increment, 1.4-2.0); physician prediction of ICU survival [< 10% (HR 15.0, 6.7-33.6)], 10 to 40% [(HR 5.0, 2.3-11.2), 41 to 60% (HR 4.0, 1.8-9.0) relative to > 90%]; and physician perception of patient preference to limit life support (no advanced life support [(HR 5.8, 3.6-9.4) or partial advanced life support (HR 3.2, 2.2-4.6) compared to full measures]. One third of mechanically ventilated patients had DNR directives established early during their ICU stay after the first 24 hr of admission. The strongest predictors of DNR directives were physician prediction of low probability of survival, physician perception of patient preference to limit life support, organ dysfunction, medical diagnosis and age.


Maternal tobacco use and its preimplantation effects on fertility: more reasons to stop smoking.
There are numerous health concerns regarding tobacco smoke. Yet, only recently have researchers extensively explored the association between tobacco smoke and a woman's inability to conceive. Whether exposure occurs in utero, during pregnancy, or throughout the reproductive years, it can affect all facets of fertility and lead to diminished ovarian function and earlier menopause. This review analyzes the literature concerning the delay or absence of conception in some women exposed to cigarette smoke and provides a detailed examination of the potential reproductive targets of the mutagenic and toxic components of tobacco. A negative influence on ovarian steroidogenesis and gametogenesis, oocyte maturity, ovulation, oocyte cumulus complex pick-up, gamete and embryo transport by the oviduct, fertilization, and implantation could all play a role. Assisted reproductive technology, or more specifically, in vitro fertilization, has allowed us to more thoroughly analyze successful pregnancy cycles and the negative consequences of smoking. Objective measurements of tobacco compounds and their metabolites in follicular fluid correlate with subjective measures of ovarian, gamete, and embryo quality in smokers and in those exposed to passive smoke. Regardless, there is an abundance of literature accumulating and more than enough reasons to tell patients to stop smoking.


In search of an unknown primary tumour presenting with extracervical metastases: the diagnostic performance of FDG-PET.
A retrospective study was carried out to determine the performance of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unknown primary tumours presenting with metastases external to the neck. All patients referred to an academic PET centre (July, 1997 to December, 2000) presenting with an extracervical metastasis and no prior systemic therapy were eligible. The minimum follow-up period was 11 months. From 63 eligible cases, known metastases were FDG avid in all but one neuroendocrine process. PET scans were retrospectively classified as positive for a primary tumour (n=29), i.e. revealing at least one anatomical site suspected to be the primary tumour. This was confirmed in 16, either by histology (n=10) or radiological and clinical follow-up (n=6). There were four false positive cases. In nine patients, the primary tumour was never confirmed. Of the remaining 33 negative PET scans the primary tumour was clinically not found in 18. Follow-up and additional pathology investigations demonstrated the primary tumour in 15. A survey on clinical usefulness of PET (response rate 83%) suggested that PET positively contributed to diagnostic understanding in 29 of 52 evaluable cases. Applied late in the diagnostic trajectory, approximately four patients need to be scanned by PET in order to find one primary tumour. However, in addition to direct demonstration of unknown primaries, there appears to be a positive effect on the diagnostic work-up of these patients of a similar magnitude.


Inflammation induces α1-adrenoceptor expression in peripheral blood mononuclear cells of patients with complex regional pain syndrome.
Persistent regional and systemic inflammation may promote pain and hyperalgesia in complex regional pain syndrome (CRPS). In this study, we investigated whether stimulation of α1-adrenoceptors (α1-AR) on peripheral blood mononuclear cells (PBMC) might contribute to this inflammatory state. PBMC were isolated from venous blood collected from 21 CRPS patients and 21 sex and age-matched controls. Lipopolysaccharide (LPS), a bacterial toxin, was administered to cultured PBMC for 24 h to trigger inflammation. Exposure to LPS resulted in heightened gene expression of α1-AR subtype B (α1B-AR) in PBMC of CRPS patients relative to controls. Interleukin (IL)-1β and IL-6 levels did not change when the α1-AR agonist phenylephrine was administered to naïve PBMC. However, α1-AR stimulation following LPS treatment increased IL-6 mRNA and protein levels in PBMC of patients and controls. To investigate the possible consequence of heightened IL-6 levels on immunoglobulin G antibody production, PBMC were stimulated with CD40 ligand and IL-21 to generate plasmablasts (B cells that secrete antibodies). This response was similar in patients and controls. Adding IL-6 to the cell culture medium increased plasmablast differentiation in controls and antibody production both in patients and controls. These findings suggest that the inflammatory cascade associated with elevated levels of IL-6 may generate α1B-AR expression in CRPS PBMC. A reciprocal interaction between heightened α1-AR expression in PBMC and IL-6 secretion may contribute to systemic inflammation and antibody production in CRPS.


Medium-term Results After Femoral Head Resection and Subtrochanteric Valgus Osteotomy in Children and Adolescents With Neuromuscular Disorders.
Various salvage surgical procedures for painful hip dislocation in adolescent patients with cerebral palsy exist. To date, no significant differences among these surgical techniques have been described. In our institution the McHale procedure is the standard of care for painful chronically dislocated hips with or without deformity of the femoral head in patients with cerebral palsy. This study focuses on mid-term results after surgical treatment. Surgical reports and patient charts were analyzed retrospectively. All x-rays were evaluated and migration of the proximal femur and heterotopic ossification according to Brooker were recorded. In addition, we conducted a telephone interview with the caretakers with special reference to pain preoperatively and postoperatively and after implant removal, sitting tolerance, range of motion, mobility, quality of life, and personal hygiene. Fifty-two patients (65 hips) with a mean age of 13.5 ± 3.6 years (range: 4 to -20 y) were included. Mean surgery time was 178.4 ± 63.4 minutes (range: 45 to 380 min) and mean follow-up was 45.17 ± 30.6 months (range: 12 to 204 mo). A significant difference between preoperative and postoperative pain levels was found, P <0.001. Personal hygiene ( P =0.02) and quality of life ( P =0.013) improved significantly. Eighty-five percent of the caregivers would have the surgery performed on their child again and 81% of the caregivers would recommend the surgery to others. The removal of implants leads to a significant improvement in pain ( P =0.011). A total of 22 complications in 65 McHale procedures (33.9%) were related to the procedures. A significant reduction in pain and a significant improvement of hygiene as well as quality of life can be achieved with the McHale procedure in painful chronically dislocated hips in patients with cerebral palsy. Overall, the procedure is predominantly experienced as helpful by the caregivers and recommended to others. The removal of the implants improves pain significantly, but complications may occur in one third of the patients. IV.


Think positive! Resolving human motion ambiguity in the presence of disease threat.
Recently, approach-avoidance tendencies and visual perception biases have been increasingly studied using bistable point-light walkers (PLWs). Prior studies have found a facing-the-viewer bias when one is primed with general threat stimuli (e.g. angry faces), explained by the "error management theory", as failing to detect a threat as approaching is riskier than the opposite. Importantly, no study has explored how disease threat - linked to the behavioural immune system - might affect this bias. This study aimed to explore whether disease-signalling cues can alter how we perceive the motion direction of ambiguous PLWs. Throughout 3 experiments, participants indicated the motion direction of a bistable PLW previously primed with a control or disease-signalling stimuli - that is, face with a surgical mask (Experiment 1), sickness sound (Experiment 2), or face with a disease cue (Experiment 3). Results showed that sickness cues do not significantly modulate the perception of approach-avoidance behaviours. However, a pattern emerged in Experiments 2 and 3, suggesting that sickness stimuli led to more facing away percepts. Unlike other types of threat, this implies that disease-related threat stimuli might trigger a distinct perceptual bias, indicating a preference to avoid a possible infection source. Nonetheless, this finding warrants future investigations.


Triage tool inter-rater reliability: a comparison of live versus paper case scenarios.
Published studies of triage scale inter-rater reliability assessment have been conducted mostly using paper case scenarios. To determine if this method of inter-rater reliability assessment generated significantly different measures from those generated from live triage cases. This was a multicenter, prospective, observational cohort study of a population-based random sample of patients triaged at 2 emergency departments during a period of 4 months. All patients presenting to the emergency department within the study periods were simultaneously and independently triaged using a 5-level triage acuity scale by 2 to 3 research triage nurses blinded to each other's assessment and to the study objective. After 6 months, the same nurses were asked to assign triage scores to paper case scenarios of the same patients that they had each previously triaged. Each of the 9 research nurses triaged approximately 90 cases. The inter-rater reliabilities as measured by an intraclass correlation coefficient were 0.9 (95% CI = 0.87 to 93) for the live triage assessments and 0.76 (95% CI = 0.73 to 0.79) for the paper case scenarios. The mean triage score assigned to the live cases was significantly less than that assigned to the paper-based cases (3.17; 95% CI = 3.08 to 3.26) (p < 0.001). There is moderate to high agreement between live cases and paper case scenarios, and the inter-rater reliabilities, although significantly different, are acceptable in both cases. It is impossible to determine which triage setting provides a more accurate triage score but paper case scenarios generally receive lower triage scores than live cases.


[Acanthamoeba keratitis treated with propamidine and polyhexamethyl biguanide (PHMB)].
The diagnosis of acanthamoeba keratitis has increased since 1985 due to the massive use of contact lenses and a better knowledge of the disease by ophthalmologists. The use of biassociated therapy has resulted in a better prognosis and lower complication rate. To report patients with acanthamoeba keratitis treated with the association of propamidine (Brolene) and polyhexamethylbiguanide (PHMB) 0.02%. Retrospective analysis of 27 patients (31 eyes) with acanthamoeba keratitis (bilateral in four cases), diagnosed by culture, biopsy or characteristic clinical features. Ninety six percent of patients used rigid contact lenses. Acanthamoeba cultures were positive in 71% of cases. The delay in the diagnosis was between 1 and 5 months. Early treatment was possible in 29% of patients. Infection was irradicated in all cases with the biassociated therapy. A tectonic keratoplasty to treat a trophic perforation was done in eight eyes. No patient required therapeutic keratoplasty to resolve the infection. Visual acuity at the end of follow up was better than 20/40 in nine patients and in eight it was in the range of count fingers or less. In patients with the clinical picture of acanthamoeba keratitis, early or late antiamoebic treatment is warranted even in the absence of positive cultures. The visual results of the treatment are highly dependent on the precocity of treatment. Prevention is imperative and is based on a strict contact lens hygiene.


Characterization of the surface organization of nanostructured hybrid organic-inorganic materials by time-of-flight secondary ion mass spectrometry
Time-of-flight secondary ion mass spectrometry (TOF-SIMS) has been used to analyse the surface composition of organic-inorganic hybrid solids obtained by a sol-gel process. Gels of type O(1.5)Si-R-SiO(1. 5), obtained from bis-silylated precursors (R'O)(3)-R-Si(OR')(3) (R' = Me, Et and R = (-CH(2))(n)-, n = 1, 2, 6, 10, 12;--CH=CH-; (-CH(2))(3)NH(CH(2))(3)-; 1, 1'-ferrocenyl; (CH(2))(n)-Ph-(CH(2))(n)- with Ph = 1,4-phenylene and n = 0, 1, 2; Ph = 1,3,5-phenyl and n = 0) were analysed. The results were highly dependent on the nature of the organic group. When the organic group was small or 'rigid', the main peaks detected corresponded to SiOH and SiOR' residual groups. Fragment ions from the organic group were poorly detected in this case. When the organic group was larger and more 'flexible', characteristic mass fragment ions were detected at higher relative intensities, indicative of a different organization of the organic units in the solid. TOF-SIMS clearly showed the differences between the xerogels derived from mono- and bis-silylated organic precursors : the organic group is present at the surface of mono-silylated xerogels, whereas for bis-silylated ones, the organization is dependent on the length and the flexibility of the organic units. These TOF-SIMS results are in agreement with other features already reported. Copyright 1999 John Wiley & Sons, Ltd.


Development and Validation of a New Protocol for Detecting and Recovering Clostridium difficile from Meat Samples.
There is no recommended protocol for detecting and isolating Clostridium difficile present in food samples. Here, we have evaluated the recovery of C. difficile in meat samples after incubating them in various enrichment broths. The media were as follows: cycloserine-cefoxitin fructose broth supplemented with taurocholic acid, d-cycloserine, cefoxitin, and lysozyme; cycloserine-cefoxitin mannitol broth with taurocholate and lysozyme; and cycloserine-cefoxitin fructose broth supplemented with taurocholic acid, C. difficile moxalactam norfloxacin selective supplement, and lysozyme. Samples were inoculated with various strains and quantities of C. difficile and then enriched in the different broths for 1, 4, and 7 days. C. difficile was isolated on agar plates and detected with quantitative real-time PCR (qPCR). The procedure using enrichment in cycloserine-cefoxitin fructose broth supplemented with taurocholic acid, d-cycloserine, cefoxitin, and lysozyme and incubation for 4 days for qPCR detection and 7 days for isolation (plating on C. difficile agar base with added C. difficile selective supplement and 7% [v/v] defibrinated horse blood after alcoholic shock and centrifugation) was validated. Samples of different kinds of meat and meat preparation were contaminated and used for validation of the chosen protocol. The sensitivity of detection with qPCR was 100%, and the sensitivity of the isolation method was 96%.


Dimensions of depression, mania and psychosis in the general population.
In order to investigate whether correlated but separable symptom dimensions that have been identified in clinical samples also have a distribution in the general population, the underlying structure of symptoms of depression, mania and psychosis was studied in a general population sample of 7072 individuals. Data were obtained from the three measurements of the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Symptoms of depression, mania and the positive symptoms of psychosis were assessed using the Composite International Diagnostic Interview. Confirmatory factor-analysis was used to test statistically the fit of hypothesized models of one, two, three or seven dimensions. The seven-dimensional model comprising core depression, sleep problems, suicidal thoughts, mania, paranoid delusions, first-rank delusions and hallucinations fitted the data best, whereas the unidimensional model obtained the poorest fit. This pattern of results could be replicated at both follow-up measurements. The results were similar for the subsamples with and without a lifetime DSM-III-R diagnosis. The seven dimensions were moderately to strongly correlated, with correlations ranging from 0.18 to 0.73 (mean 0.45). In the general population, seven correlated but separable dimensions of experiences exist that resemble dimensions of psychopathology seen in clinical samples with severe mental illness. The substantial correlations between these dimensions in clinical and non-clinical samples may suggest that there is aetiological overlap between the different dimensions regardless of level of severity and diagnosable disorder.


[Comparative study of the reaction kinetics of cytochrome P-450 reduction by NADPH-cytochrome P-450 reductase and dithionite].
The reactions of NADPH- or dithionite-dependent reduction of cytochrome P-450 were studied using a stopped flow technique. It was found that the kinetic curves for both reactions may be fitted by a sum of the two exponents. The arrhenius plots for the fast phase rate constants are linear for both reactions. On the contrary, the breaks on the corresponding plots for the slow phase rate constants are observed at 22 and 33 degrees C for cytochrome P-450 reduction by dithionite and at 31 degrees C for NADPH-dependent reduction of cytochrome P-450. The coincidence of the values of the rate constants and activation energy (56 +/- 5 kJ/mol) for the fast phase of NADPH-dependent reduction of cytochrome P-450 with values of catalytic constants and activation energy for demethylation of tertiary amines suggests that the first electron transfer process from NADPH-cytochrome P-450 reductase to cytochrome P-450 may be the rate-limiting step. A diverse character of the kinetic parameters for the two cytochrome P-450 reduction reactions is indicative of different nature of biphasity of these processes.


Paget's disease: important features for the general practitioner.
Because many features of Paget's disease (osteitis deformans) initially manifest intraorally or in the head and neck, the dentist frequently makes the initial diagnosis. This article provides a review of Paget's disease, and includes current thoughts regarding etiology and a discussion of newer successful therapeutic modalities.


Congenital Giant Teratoma Arising from the Hard Palate: A Rare Clinical Presentation.
Teratomas are rare tumours which originate from all 3 germs cell layers namely endoderm, mesoderm and ectoderm, with varying proportions of each component. The most common site of teratoma is in the sacro-coccygeal region. Teratomas are generally benign and have well appreciable clinical and histopathological features. Incidence of congenital teratoma is 1 in 4000. In head and neck region congenital teratomas usually associated with other anomalies like cystic hygroma and cleft palate with an incidence of 1 in 400. The approximately reported incidence of palatal teratoma is 1 in 35000 to 40000 live-births. Upper airway difficulty causes anticipated functional problems at hypopharynx. The prognosis of palatal teratoma mostly depends on the risk and extent of neonatal respiratory distress. We present a rare case of congenital teratoma arising from the hard palate in a new born girl. The outcome in this case was bad due to the large mass causing respiratory difficulty and bleeding from the ruptured cystic areas leading to hypovolemic shock. After two hours of delivery, baby expired.


Cells encapsulated in alginate: a potential system for delivery of recombinant proteins to malignant brain tumours.
Growth and progression of malignant brain tumours occurs in a micromilieu consisting of both tumour and normal cells. Several proteins have been identified with the potential of interfering directly with tumour cells or with the neovascularisation process, thereby inhibiting tumour growth. A continuous delivery of such inhibitory proteins to the tumour microenvironment by genetically engineered cells could theoretically be of considerable therapeutic importance. In this study we have investigated the growth characteristics of cells encapsulated in alginate, which represents a potential delivery system for recombinant proteins that may have antitumour effects. Three different cell lines, NHI 3T3, 293 and BT4C were encapsulated in alginate, which is an immuno-isolating substance extracted from brown seaweed. The encapsulated cells were observed at specific intervals during a 4-month period after in vitro propagation and as transplants into the cortex of BD-IX rats. Morphological studies showed that encapsulated cells proliferated and formed spheroids within the alginate in the in vitro cultures and after implantation into the brain. Even after 4 months in vivo a substantial amount of living cells were observed within the alginate beads. A vigorous infiltration of mononuclear cells was observed in the brain bordering the alginate beads, one week after implantation. However, there was a gradual decrease of mononuclear cells at the border zone beyond the first week of implantation. The majority of inflammatory cells were reactive microglia and invading monocytes, as verified by immunohistochemistry. The data further shows that alginate encapsulated cells can be frozen in liquid N2 and will retain their viability and proliferative capacity.


The safety of the electroconvulsive therapy-aripiprazole combination: four case reports.
In clinical practice, a proportion of patients with psychotic or mood disorders are treated with electroconvulsive therapy (ECT) while receiving concomitantly antipsychotic and/or other psychotropic agents. Aripiprazole is a second-generation antipsychotic that seems to have a favorable side-effect profile. However, to the best of our knowledge, there are, as yet, no available reports on the safety of ECT-aripiprazole combination. We report the cases of 4 female inpatients--3 suffering from major depression and 1 from schizophrenia--who underwent ECT--1 of them twice--while receiving aripiprazole (10-15 mg/d), as part of their regimen. In all cases, the combination was well tolerated and only minimal side effects were reported.


Testosterone and alcohol use among adolescent male twins: testing between-family associations in within-family comparisons.
We examined associations of testosterone (T) and alcohol use in adolescent twin brothers, conducting both between- and within-family analyses. The twins completed semi-structured interviews, provided two saliva samples to assay T, and reported their drinking patterns and pubertal development. We adjusted T levels for diurnal/seasonal effects and association with pubertal maturation. In analyses of twins as individuals, higher T levels characterized boys reporting ever drinking, more frequent intoxication, high density drinking, more alcohol symptoms, and diagnosed alcohol dependency on interview. Adjusting for pubertal development, only associations with symptom count and diagnosis remained significant. The association with frequent intoxication replicated among drinking-discordant twin brothers, effectively ruling out between-family confounds, but that association was not significant after adjustment for pubertal development. The phenotypic correlation between T and pubertal maturation is largely genetic, inviting study of the magnitude and meaning of linkages between testosterone and symptoms of alcoholism on follow-up in early adulthood.


Cre recombinase-mediated site-specific modification of a cellular genome using an integrase-defective retroviral vector.
Retroviral integrase is an enzyme responsible for the integration of retroviruses. A single mutation in the integrase core domain can severely compromise its integration ability, leading to the accumulation of circular retroviral cDNA in the nuclei of infected cells. We therefore attempted to use those cDNA as substrates for Cre recombinase to perform a recombinase-mediated cassette exchange (RMCE), thereby targeting retroviral vectors to a predetermined site. An expression unit containing a promoter, an ATG codon and marker genes (hygromycin resistance gene and red fluorescent protein gene) flanked by wild-type and mutant loxP sites was first introduced into cellular chromosome to build founder cell lines. We then constructed another plasmid for the production of integrase-defective retroviral vectors (IDRV), which contains an ATG-deficient neomycin resistance gene and green fluorescent protein gene, flanked by a compatible pair of loxPs. After providing founder cells with Cre and infecting with IDRV later, effective RMCE occurred, resulting in the appearance of G418-resistant colonies and a change in the color of fluorescence from red to green. Southern blot and PCR analyses on selected clones further confirmed site-specific recombination. The successful substitution of the original viral integration machinery with a non-viral mechanism could expand the application of retroviral vectors.


Adult myeloid leukaemia, geology, and domestic exposure to radon and gamma radiation: a case control study in central Italy.
To investigate whether indoor randon or gamma radiation might play a part in myeloid leukaemia as suggested by studies based on crude geographical or geological data for exposure assessment. For six months randon and gamma radiation was measured with solid state nuclear track detectors and thermoluminescent dosimeters in dwellings of 44 adult male cases of acute myeloid leukaemia and 211 controls (all subjects deceased). Conditional logistic regression ORs (ORs) and 95% confidence intervals (95% CIs) were estimated for quartiles of radon and gamma radiation and for municipality and dwelling characteristics. The risk of leukaemia was associated with an increasing urbanisation index (p value for trend = 0.008). An increased OR was found among those living in more modern houses (OR 3.0, 95% CI 1.4 to 6.6). Confirming the findings of a previous study in the same area, geological features bore a positive association with myeloid leukemia, even by adjusting for level of urbanisation. Contrary to expectations from the previous study, however, no association appeared between myeloid leukaemia and radon and gamma radiation; for the highest quartiles of exposure, ORs were 0.56 (95% CI 0.2 to 1.4) and 0.52 (95% CI 0.2 to 1.4), respectively. Considering only subjects who had lived > or = 20 years in the monitored home and adjusting for urbanisation, there was still no effect of exposure to radiation. In view of the limited numbers, the results do not in general refute a possible risk of myeloid leukaemia from exposure to indoor radon or gamma radiation, but decrease the credibility of such a relation in the area studied and also of other studies suggesting an effect without monitoring indoor radiation. Some other fairly strong determinants have appeared--that is, level of urbanisation and living in modern houses--that might need further consideration.


Seed storage protein variation in Arachis species.
Seventy-two accessions, representing 22 species from sections Arachis, Erectoides, Extranervosae, and Triseminalae of the genus Arachis, were screened for seed storage protein polymorphism. Variation was detected between sections, between genome types, between species, and in some cases between different accessions of the same species or different seeds of the same accession. Arachis duranensis and one accession of A. cardenasii were found to have identical protein patterns. The greatest dissimilarity was found between species of the section Extranervosae and species of the section Triseminalae. Those of section Erectoides showed much similarity with some species of section Arachis. Protein polymorphism was shown to distinguish the two subspecies of A. hypogaea (fastigiata and hypogaea) in 27 of 28 cases. The seed protein profile of A. monticola was a combination of seed protein profiles from the two A. hypogaea subspecies. The relatedness between the various species was calculated and those that had the greatest similarity with A. hypogaea were A. spegazzinii and A. batizocoi.


Finite-size effects in biomimetic smectic films.
Thin stacks of lipid multibilayers supported on rigid silicon and mica substrates are found to exhibit finite-size effects. Using neutron diffraction we find that the repeat spacing (d) of stacks containing up to a few tens of bilayers depends on their thickness (D), with d increasing with decreasing D. Differences in d are larger in the low-temperature Lbeta' phase consisting of rigid bilayers than in the high-temperature Lalpha phase where the bilayers are more flexible. Various scenarios that may be responsible for this counterintuitive observation are discussed.


Harnessing tumor immunogenomics: Tumor neoantigens in ovarian cancer and beyond.
Ovarian cancer is a major cause of death among gynecological cancers due to its highly aggressive nature. Immunotherapy has emerged as a promising avenue for ovarian cancer treatment, offering targeted approaches with reduced off-target effects. With the advent of next-generation sequencing, it has become possible to identify genomic alterations that can serve as potential targets for immunotherapy. Furthermore, immunogenomics research has revealed the importance of genetic alterations in shaping the cancer immune responses. However, the heterogeneity of immunogenicity and the low tumor mutation burden pose challenges for neoantigen-based immunotherapies. Further research is needed to identify neoantigen-specific tumor-infiltrating lymphocytes (TIL) and establish guidelines for patient inclusion criteria in TIL-based therapy. The study of neoantigens and their implications in ovarian cancer immunotherapy holds great promise, and efforts focused on personalized treatment strategies, refined neoantigen selection, and optimized therapeutic combinations will contribute to improving patient outcomes in the future.


Sexual trafficking in the United States: a domestic problem with transnational dimensions.
The trafficking of young women and children for prostitution and other forms of sexual exploitation is one of the most significant human rights abuses in contemporary society. In keeping with the social work profession's commitment to social justice, this article examines the issue of sexual trafficking in the United States. The transnational scope of the problem is discussed along with the means that traffickers use to recruit, transport, and initiate victims from around the world into the sex industry in the United States. Some legislative responses to the problem are discussed, and a number of suggestions are offered to help social workers advocate on behalf of some of the most vulnerable and oppressed people in the global community.


The use of biologics and small molecules in pregnant patients with rheumatic diseases.
Biological agents have radically changed the prognosis of rheumatic patients. Current evidence demonstrates that tight disease control during pregnancy is mandatory to minimize adverse outcome risk. As the new therapeutic tools are pivotal to maintain appropriate disease activity, it is timely to review available evidence about the safety of biologics and small molecules in pregnancy. Areas covered: A comprehensive literature review has been performed, reporting available data about the passage into breast milk, rate of pregnancy loss and fetal malformations, and long-term complications due to in utero exposure to biological agents and small molecules. Expert commentary: Data about the safety of agents against tumor necrosis factor in pregnancy are reassuring. Even rituximab, tocilizumab, belimumab, ustekinumab, secukinumab, and abatacept have not been associated with an increased rate of fetal abnormalities or adverse pregnancy outcome. Experience with small molecules is too small to draw any conclusion. Even if further data are warranted to define the possible long-term effects of in utero biologic exposure on the infant immune system development, it is reasonable to speculate that in the next future the use of biologics during pregnancy will continue to expand, at least when maternal benefit justifies the potential risk to the fetus.


Conformational Equilibrium of Cinchonidine in C6D12 Solution. Alternative NMR/DFT Approach.
1H NMR and 13C NMR chemical shifts as well as conformation dependent vicinal 1H-1H spin-spin coupling constants for cinchonidine in a dilute C6D12 solution have been measured. These data have been interpreted in detail exploiting the results of the extensive quantum chemistry calculations of molecular geometry and NMR parameters of the molecule, performed using the density functional theory (DFT) B3LYP/6-311++G(2d,p) polarizable continuum model (PCM) level of theory. The experimental values of NMR parameters for cinchonidine have been reproduced very well in terms of parameters calculated for key conformers of this molecule. Simultaneously, the analysis has provided us with a lot of information on conformational equilibrium of cinchonidine in the investigated solution. These findings remain in general agreement with the conclusions of other works, based on NOESY spectra or other physicochemical data. Thus, a careful quantitative interpretation of easily measurable NMR chemical shifts can be an independent and valuable source of structural information even in such complex cases as cinchonidine in solution.


Nonmonotonic strain dependence of lattice thermal conductivity in monolayer SiC: a first-principles study.
An increasing number of two-dimensional (2D) materials have already been achieved experimentally or predicted theoretically, which have potential applications in nano- and opto-electronics. Various applications of electronic devices are closely related to their thermal transport properties. In this work, the strain dependence of phonon transport in monolayer SiC with a perfect planar hexagonal honeycomb structure is investigated by solving the linearized phonon Boltzmann equation. It is found that the room-temperature lattice thermal conductivity (κL) of monolayer SiC is two orders of magnitude lower than that of graphene. The low κL is due to small group velocities and short phonon lifetimes, which can also be explained by the polarized covalent bond due to large charge transfer from Si to C atoms. In a considered strain range, it is proved that the SiC monolayer is mechanically and dynamically stable. With increased tensile strain, the κL of the SiC monolayer shows an unusual nonmonotonic up-and-down behavior, which is due to the competition between the change of phonon group velocities and phonon lifetimes of low frequency phonon modes. At low strain values (<8%), the phonon lifetime enhancement induces the increased κL, while at high strain values (>8%) the reduction of group velocities as well as the decrease of the phonon lifetimes are the major mechanisms responsible for decreased κL. Our works further enrich the studies on the phonon transport properties of 2D materials with a perfect planar hexagonal honeycomb structure, and motivate further experimental studies.


Meta-analysis of the likelihood of FOXC1 expression in early- and late-stage tumors.
Aberrations in the expression of the transcription factor forkhead box C1 (FOXC1) have been linked to a number of malignancies. Here, we characterized the relationship between FOXC1 and cancer progression by conducting a meta-analysis of studies that reported the frequency of FOXC1 expression in tumors of different stages (T1, T2, T3, T4). Relevant articles were retrieved from the Medline database by searching for the terms "FOXC1" and "cancer"; then, the retrieved articles were reviewed individually, and studies that were of multivariate cohort design, evaluated FOXC1 expression via immunohistochemical staining, and assessed the relationship between FOXC1 expression and cancer T-stage were included in our meta-analysis. Our search terms identified 128 studies, 5 of which met all inclusion criteria. A total of 850 tumor samples were evaluated in the 5 studies; 452 samples were from early-stage (T1-T2) tumors, and 398 were from late-stage (T3-T4) tumors. FOXC1 was expressed in 60.7% (516/850) of all samples, in 54.6% (247/452) of early-stage tumor samples, and in 67.5% (269/398) of late-stage tumor samples. When calculated relative to early-stage samples, the pooled risk for FOXC1 expression in late-stage samples was 1.238 (95% CI = 1.061-1.444, p = 0.007). The results from our meta-analysis of 5 studies indicate that FOXC1 is 23.8% more likely to be expressed in late-stage tumors than in early-stage tumors.


Integration of rotational angiography enables better dose planning in Gamma Knife radiosurgery for brain arteriovenous malformations.
OBJECTIVEIn Gamma Knife radiosurgery (GKS) for arteriovenous malformations (AVMs), CT angiography (CTA), MRI, and digital subtraction angiography (DSA) are generally used to define the nidus. Although the AVM angioarchitecture can be visualized with superior resolution using rotational angiography (RA), the efficacy of integrating RA into the GKS treatment planning process has not been elucidated.METHODSUsing data collected from 25 consecutive patients with AVMs who were treated with GKS at the authors' institution, two neurosurgeons independently created treatment plans for each patient before and after RA integration. For all patients, MR angiography, contrasted T1 imaging, CTA, DSA, and RA were performed before treatment. The prescription isodose volume before (PIVB) and after (PIVA) RA integration was measured. For reference purposes, a reference target volume (RTV) for each nidus was determined by two other physicians independent of the planning surgeons, and the RTV covered by the PIV (RTVPIV) was established. The undertreated volume ratio (UVR), overtreated volume ratio (OVR), and Paddick's conformal index (CI), which were calculated as RTVPIV/RTV, RTVPIV/PIV, and (RTVPIV)2/(RTV × PIV), respectively, were measured by each neurosurgeon before and after RA integration, and the surgeons' values at each point were averaged. Wilcoxon signed-rank tests were used to compare the values obtained before and after RA integration. The percentage change from before to after RA integration was calculated for the average UVR (%ΔUVRave), OVR (%ΔOVRave), and CI (%ΔCIave) in each patient, as ([value after RA integration]/[value before RA integration] - 1) × 100. The relationships between prior histories and these percentage change values were examined using Wilcoxon signed-rank tests.RESULTSThe average values obtained by the two surgeons for the median UVR, OVR, and CI were 0.854, 0.445, and 0.367 before RA integration and 0.882, 0.478, and 0.463 after RA integration, respectively. All variables significantly improved after compared with before RA integration (UVR, p = 0.009; OVR, p < 0.001; CI, p < 0.001). Prior hemorrhage was significantly associated with larger %ΔOVRave (median 20.8% vs 7.2%; p = 0.023) and %ΔCIave (median 33.9% vs 13.8%; p = 0.014), but not %ΔUVRave (median 4.7% vs 4.0%; p = 0.449).CONCLUSIONSIntegrating RA into GKS treatment planning may permit better dose planning owing to clearer visualization of the nidus and, as such, may reduce undertreatment and waste irradiation. Further studies examining whether the observed RA-related improvement in dose planning also improves the radiosurgical outcome are needed.


Prevalence and risk factors of bowel symptoms in Korean patients with ulcerative colitis in endoscopic remission: a retrospective study.
Many patients with ulcerative colitis (UC) in clinical remission frequently complain of bowel symptoms such as increased stool frequency (SF) and rectal bleeding (RB). However, studies on these patient-reported outcomes in patients with inactive UC are limited, especially in Korea. Therefore, we investigated the prevalence and risk factors of bowel symptoms in Korean patients with inactive UC. We investigated the prevalence of bowel symptoms in patients with endoscopically quiescent UC between June 1989 and December 2016 using a well-characterized referral center-based cohort. The Mayo clinic score (MCS) was used to evaluate bowel symptoms at the most recent visit near the date of endoscopy. Clinical characteristics of the patients were compared based on the presence or absence of bowel symptoms. Overall, 741 patients with endoscopically quiescent UC were identified, of whom 222 (30%) and 48 (6.5%) had an SF and RB subscore of ≥ 1, respectively. Patients with bowel symptoms (SF + RB ≥ 1; n = 244 [32.9%]) had higher rates of left-sided colitis (E2) or extensive colitis (E3) than patients without bowel symptoms (SF + RB = 0; n = 497 [67.1%]; P = 0.002). Multivariate analysis revealed that female sex (odds ratio [OR]: 1.568; 95% confidence interval [CI]: 1.023-2.402; P = 0.039) and E2 or E3 (OR 1.411; 95% CI 1.020-1.951; P = 0.038) were the significant risk factors for increased SF. This study revealed that one-third of patients with endoscopically quiescent UC reported increased SF. Female sex and disease extent may be associated with bowel symptoms.


Report of the Council on Scientific Affairs: preventing needlestick injuries in health care settings.
Needlestick injuries continue to pose a significant risk to health care workers; however, appropriate use of needlestick prevention devices, especially in comprehensive prevention programs, can significantly reduce the incidence of such injuries. Cost analyses indicate that use of these devices will be cost-effective in the long term. To provide more scientific and cost data on the efficacy of needlestick prevention devices, recording of needlestick injuries must be improved. Federal law now requires the use of safety-engineered sharps devises to protect health care workers, and state-level legislation on the use and evaluation of needlestick prevention devices is under consideration. Health care employers should evaluate the implementation of needlestick prevention devices with the participation of employees who will use such devices and, where appropriate, introduce such devices accompanied by the necessary education and training, as part of a comprehensive sharps injury prevention and control program.


A comparison of urinary and sexual outcomes in women experiencing vaginal and Caesarean births.
To evaluate the urinary and sexual consequences of vaginal delivery compared with Caesarean section. We performed a cohort analysis of data from a randomized controlled trial of episiotomy conducted in 3 Montreal hospitals in 1990-1991. Of the 999 trial participants for whom follow-up data were available, 135 delivered by Caesarean section (CS), and 864 had a vaginal birth (VB). After stratifying for parity, we compared rates of urinary incontinence (UI) and sexual functioning at 3 months postpartum in women who had a VB with the rates in women who had a CS. Primiparous women reported unspecified UI at 3 months postpartum more often (17.9%) in the VB group than in the CS group (6.4%). This difference remained significant whether or not there was a prior history of UI. Multiparous women showed no difference in rates of UI (VB 17.1% vs. CS 16.0%), whether there was a prior history of UI or not. Stress incontinence was greater among primiparous women in the VB group (VB 34.5% vs. CS 12.8%) regardless of prior UI history, but the proportion of women whose UI was severe enough to wear a pad was similar in primiparous women (VB 16.0%, CS 15.4%) and multiparous women (VB 23.8%, CS 25.0%). Women's sexual dissatisfaction was greater among primiparous women who had a vaginal birth (VB 70.1%, CS 54.5%), but in multiparous women, the rates of sexual dissatisfaction were similar (VB 64.2%, CS 71.4%). The frequency of dyspareunia for each mode of delivery was similar in primiparous women (VB 30.7%, CS 31.6%). Overall, both primiparous and multiparous women who had intact perineums after VB had less dyspareunia than those undergoing CS (VB 26.2, CS 40.7%). However, the proportion of women experiencing dyspareunia was greatest among those who had an episiotomy with or without forceps.


Factor structure and construct validity of the Anxiety Sensitivity Index among island Puerto Ricans.
The factor structure and convergent and discriminant validity of the Anxiety Sensitivity Index (ASI) were examined among a sample of 275 island Puerto Ricans. Results from a confirmatory factor analysis (CFA) comparing our data to factor solutions commonly reported as representative of European American and Spanish populations indicated a poor fit. A subsequent exploratory factor analysis (EFA) indicated that a two-factor solution (Factor 1, Anxiety Sensitivity; Factor 2, Emotional Concerns) provided the best fit. Correlations between the ASI and anxiety measures were moderately high providing evidence of convergent validity, while correlations between the ASI and BDI were significantly lower providing evidence of discriminant validity. Scores on all measures were positively correlated with acculturation, suggesting that those who ascribe to more traditional Hispanic culture report elevated anxiety.


Targeting adolescent mothers with depressive symptoms for early intervention.
Infants of mothers with depressive symptoms show developmental delays if symptoms persist over the first 6 months of the infant's life, thus highlighting the importance of identifying those mothers for early intervention. In Study 1, mothers with depressive symptoms (n = 160) and mothers without depressive symptoms (n = 100) and their infants were monitored to identify variables from the first 3 months that predict which mothers would still be symptomatic at 6 months. A "dysregulation" profile was noted for the infants of depressed mothers, including lower Brazelton scores, more indeterminate sleep, and elevated norepinephrine, epinephrine, and dopamine levels at the neonatal period, and greater right frontal EEG activation, lower vagal tone, and negative interactions at the 3- and 6-month periods. A group of maternal variables from the neonatal and 3-month assessments accounted for 51% of the variance in the mothers' continuing depressive symptoms. These variables included greater right frontal EEG activation, lower vagal tone, and less positive interactions at 3 months, and elevated norepinephrine, serotonin, and cortisol levels at the neonatal stage. In Study 2, a similar sample of mothers with depressive symptoms (n = 160) and without depressive symptoms (n = 100) was recruited and followed to 3 months. Those symptomatic mothers who had values above (or below) the median (depending on the negative direction) on the predictor variables identified in Study 1 (taken from the first 3 months) were then randomly assigned to an intervention or a control group at 3 months. These groups were then compared with each other, as well as with the group without depressive symptoms, at 6 and 12 months. The intervention, conducted from 3 to 6 months, consisted of free day care for the infants and a rehab program (social, educational, and vocational) plus several mood induction interventions for the mothers, including relaxation therapy, music mood induction, massage therapy, and mother-infant interaction coaching. Although the mothers who received the intervention continued to have more depressive symptoms than did the nondepressed mothers, their interactions significantly improved and their biochemical values and vagal tone normalized. Their infants also showed more positive interations, better growth, fewer pediatric complications, and normalized biochemical values, and by 12 months their mental and motor scores were better than those of the infants in the control group.


Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way.
Scientific evidence suggests that folic acid (FA) supplementation protects the healthy colonic mucosa from neoplastic transformation but may promote the progression of precancerous lesions. The underlying molecular mechanisms are not fully understood. Therefore, we explored, if high physiological FA doses provoke changes in (i) promoter-specific DNA methylation (ii) expression of cancer-associated micro RNAs (miRNAs) and (iii) inflammatory mediators in human neoplastic and non-neoplastic colonic cell lines. The malignant and the non-malignant colonic cell lines HT29 and HCEC were adapted to different near-physiological FA concentrations. Using DNA methylation and pathway specific PCR arrays, high-physiological FA concentrations revealed no relevant impact on promoter methylation but a number of differences between the cell lines in the expression of miRNAs and inflammatory mediators. In the HCEC cell line pro-inflammatory genes were repressed and the miRNA expression remained nearly unaffected. In contrast, in the HT29 cell line tumour-suppressive miRNAs were predominantly down-regulated and the expression of genes involved in chemotaxis and immunity were modulated. The different effects of high-physiological FA concentrations in malignant and non-malignant colonic cell lines regarding cancer-associated miRNAs and inflammatory mediators may contribute to the different effects of FA supplementation on colonic carcinogenesis.


Learning anatomy by virtual reality and augmented reality. A scope review.
During the last century, there were no significant changes in the teaching methods of anatomy in universities, predominating expositive lectures, and anatomy laboratory activities. With the advent of new technologies, simulators, augmented reality, and virtual reality, new teaching possibilities have emerged that may provide assistance and, in some situations, replace traditional methods of teaching. In this narrative scope review we evaluate articles that compare traditional methods with virtual reality or augmented reality through a search on Cochrane library, MEDLINE, EMBASE, and LILACS databases, using the MeSH terms "Anatomy", "Virtual Reality", "Augmented Reality", "Video Games", "Education Medical, Undergraduate", "Teaching" and "Simulation Training". We concluded that virtual reality and augmented reality have a promising value for teaching anatomy in addition to a positive economic impact on universities.


Successful herbivore attack due to metabolic diversion of a plant chemical defense.
Plants protect themselves against herbivory with a diverse array of repellent or toxic secondary metabolites. However, many herbivorous insects have developed counteradaptations that enable them to feed on chemically defended plants without apparent negative effects. Here, we present evidence that larvae of the specialist insect, Pieris rapae (cabbage white butterfly, Lepidoptera: Pieridae), are biochemically adapted to the glucosinolate-myrosinase system, the major chemical defense of their host plants. The defensive function of the glucosinolate-myrosinase system results from the toxic isothiocyanates that are released when glucosinolates are hydrolyzed by myrosinases on tissue disruption. We show that the hydrolysis reaction is redirected toward the formation of nitriles instead of isothiocyanates if plant material is ingested by P. rapae larvae, and that the nitriles are excreted with the feces. The ability to form nitriles is due to a larval gut protein, designated nitrile-specifier protein, that by itself has no hydrolytic activity on glucosinolates and that is unrelated to any functionally characterized protein. Nitrile-specifier protein appears to be the key biochemical counteradaptation that allows P. rapae to feed with impunity on plants containing glucosinolates and myrosinases. This finding sheds light on the ecology and evolution of plant-insect interactions and suggests novel highly selective pest management strategies.


The ethics of the placebo in clinical practice.
While discussions of the ethics of the placebo have usually dealt with their use in a research context, the authors address here the question of the placebo in clinical practice. It is argued, firstly, that the placebo can be an effective treatment. Secondly, it is demonstrated that its use does not always entail deception. Finally guidelines are presented according to which the placebo may be used for clinical purposes. It is suggested that in select cases, use of the placebo may even be morally imperative. The argument is illustrated by three case vignettes.


[Psychophysiological changes in occupational diseases of chemical etiology].
Use of various psychophysiologic methods enabled to specify psychic response of workers exposed to chemicals and chronic poisoning patients. Chronic poisonings with 1,1-dimethylhydrazine, hydrocarbons, Trichlorfon, mercury, nitroesters have specific traits, and the patients could be grouped by means of cluster analysis. Handy techniques evaluating attention and memory could be recommended for everyday practical needs.


Optical spectroscopy of superconducting Ba0.55K0.45Fe2As2: evidence for strong coupling to low-energy bosons.
Normal state optical spectroscopy on single crystals of the new iron arsenide superconductor Ba0.55K0.45Fe2As2 shows that the infrared spectrum consists of two major components: a strong metallic Drude band and a well-separated midinfrared absorption centered at 0.7 eV. It is difficult to separate the two components unambiguously but several fits using Lorentzian peaks suggest a model with a Drude peak having a plasma frequency of 1.6 to 2.1 eV and a midinfrared peak with a plasma frequency of 2.5 eV. Detailed analysis of the frequency dependent scattering rate shows that the charge carriers interact with a broad bosonic spectrum extending beyond 100 meV with a very large coupling constant lambda=3.4 at low temperature. As the temperature increases this coupling weakens to lambda=0.78 at ambient temperature. This suggests a bosonic spectrum that is similar to what is seen in the lower Tc cuprates.


[Analysis of cellular nucleoproteins by the nucleoprotein-celite chromatography method. III. Two types of DNA-nuclear matrix interaction].
There are two types of DNA-nuclear matrix interactions in animal cells as revealed by the release of DNA from isolated nuclei by three successive gradients: NaCl, LiCl-urea and temperature. Nuclei were treated with dissociating agents while being adsorbed on the Celite columns. "Weak" DNA-matrix interactions which dissociate in 1.5 M LiCl-3 M urea at 2 degrees appear to be sensitive to ethidium bromide and resistant to exogeneous nucleases (DNAase I, DNAase II and micrococcal nuclease), to DNA-damaging agents, including alkylators and gamma-irradiation, and also to psoralen-induced cross-links. "Strong" DNA-matrix interactions proved to be very different. They dissociate in 4 M LiCl-8 M urea at approximately 90 degrees, are very sensitive to DNAase I and other nucleases, slightly sensitive to chemicals and irradiation at doses stimulating single-stranded DNA breaks, but resistant to ethidium bromide. DNA strand separation seems to be necessary prerequisite for DNA release from its "strong" complex with nuclear matrix. A model for the topological link between DNA and the nuclear matrix involved in DNA replication complex is discussed.


Experiences of migrant mothers attending vaccination services at primary healthcare facilities.
Migration to South Africa is currently dominated by women and children, for socio-economic and refugee reasons or to utilise the healthcare system for various services. Migrants and refugees are at risk of vaccine-preventable diseases, and many of their children have an incomplete or unknown immunisation status. This study aimed to explore the experiences of migrant mothers in utilising child immunisation services in primary healthcare facilities. Ten primary healthcare facilities that were providing immunisation services, located in the Buffalo City Metropolitan Municipality, Eastern Cape province, South Africa. A qualitative research design, making use of in-depth interviews (IDIs) from 18 purposefully selected migrant women, was used for data collection. Thematic content analysis was used to analyse the recorded data of the experiences of study participants in their access to immunisation services. From the IDIs, four themes were identified: difficulty in communicating with the healthcare workers because of language barriers, access challenges, interpersonal barriers and interpersonal relationships were identified in this study, which influenced the utilisation of immunisation services by migrant mothers. The findings of this study support and reinforce the duty of the South African government and healthcare facilities to work together to improve migrant women's access to immunisation services. A positive relationship between healthcare workers and migrant mothers while accessing immunisation services should contribute to reducing child mortality in South Africa and achieving Sustainable Development Goal 3 by the year 2030.


Spatio-temporal brain dynamics underlying saccade execution, suppression, and error-related feedback.
Human and nonhuman animal research has outlined the neural regions that support saccadic eye movements. The aim of the current work was to outline the sequence by which distinct neural regions come on-line to support goal-directed saccade execution and error-related feedback. To achieve this, we obtained behavioral responses via eye movement recordings and neural responses via magnetoencephalography (MEG), concurrently, while participants performed an antisaccade task. Neural responses were examined with respect to the onset of the saccadic eye movements. Frontal eye field and visual cortex activity distinguished subsequently successful goal-directed saccades from (correct and erroneous) reflexive saccades prior to the deployment of the eye movement. Activity in the same neural regions following the saccadic movement distinguished correct from incorrect saccadic responses. Error-related activity in the frontal eye fields preceded that from visual regions, suggesting a potential feedback network that may drive corrective eye movements. This work provides the first empirical demonstration of simultaneous remote eyetracking and MEG recording. The coupling of behavioral and neuroimaging technologies, used here to characterize dynamic brain networks underlying saccade execution and error-related feedback, demonstrates a novel within-paradigm converging evidence approach by which to outline the neural underpinnings of cognition.


Properties of Local Electronic Structures.
The simulation of intrinsic contributions to molecular properties holds the potential to allow for chemistry to be directly inferred from changes to electronic structures at the atomic level. In the present study, we demonstrate how such local properties can be readily derived from suitable molecular orbitals to yield effective fingerprints of various types of atoms in organic molecules. In contrast, corresponding inferences from schemes that instead make use of individual atomic orbitals for this purpose are generally found to fail in expressing much uniqueness in atomic environments. By further studying the extent to which entire chemical reactions may be decomposed into meaningful and continuously evolving atomic contributions, schemes based on molecular rather than atomic orbitals are once again found to be the more consistent, even allowing for intricate differences between seemingly uniform nucleophilic substitutions to be probed.


[Atorvastatin (Lipitor): a review of its pharmacological and clinical profile].
Hypercholesterolemia is a major risk factor for the development of coronary heart disease. HMG-CoA reductase inhibitors have been used as first-line drugs because of both their superior cholesterol lowering effect and reliable safety profile. Since there are many patients whose plasma cholesterol level does not reach the therapeutic target even if reductase inhibitors are available, more effective drugs have been strongly required for a long time. Atorvastatin, one of the most recently introduced statins, produces greater plasma LDL-cholesterol reductions than other statins. This pronounced effect of atorvastatin seems to be due to its long-lasting action, presumably a reflection of longer residence time of atorvastatin and its active metabolites in the liver. Clinical trials of atorvastatin have also demonstrated marked plasma triglyceride reductions. The triglyceride reduction with atorvastatin seems to stem from the following two indirect mechanisms, limiting VLDL secretion from the liver and increase in clearance of triglyceride-rich lipoprotein via induced LDL receptors from plasma. Eleven clinical trials of atorvastatin, which have been developed in Japan, clearly demonstrated its ability to reduce LDL-C levels more strongly and in significantly more patients to LDL-C treatment goals than other reductase inhibitors with similar safety profiles. Therefore, atorvastatin adds a new dimension to the effective management of hypercholesterolemia and combined hyperlipidemia.


Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice.
We established previously that 5-HT(2B) receptors are involved in cardiac hypertrophy through the regulation of hypertrophic cytokines in cardiac fibroblasts. Moreover, the generation of reactive oxygen species and tumor necrosis factor-alpha through the activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been implicated in cardiac hypertrophy. In this study, we investigated whether 5-HT(2B) receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production. Therefore, we measured the effects of serotonergic 5-HT(2B) receptor blockade on left-ventricular superoxide anion generation in 2 established pharmacological models of cardiac hypertrophy, ie, angiotensin II and isoproterenol infusions in mice. Angiotensin II infusion for 14 days increased superoxide anion concentration (+32%), NAD(P)H oxidase maximal activity (+84%), and p47(phox) NAD(P)H oxidase subunit expression in the left ventricle together with hypertension (+37 mm Hg) and cardiac hypertrophy (+17% for heart weight:body weight). The 5-HT(2B) receptor blockade by a selective antagonist (SB215505) prevented the increase in cardiac superoxide generation and hypertrophy. Similarly, infusion for 5 days of isoproterenol increased left-ventricular NAD(P)H oxidase activity (+48%) and cardiac hypertrophy (+31%) that were prevented by the 5-HT(2B) receptor blockade. Finally, in the primary culture of left-ventricular cardiac fibroblasts, angiotensin II and isoproterenol stimulated NAD(P)H oxidase activity. This activation was prevented by SB215505. These findings suggest that the 5-HT(2B) receptor may represent a new target to reduce cardiac hypertrophy and oxidative stress. Its blockade affects both angiotensin II and beta-adrenergic trophic responses without significant hemodynamic alteration.


Evidence of Intercontinental Spread and Uncommon Variants of Low-Pathogenicity Avian Influenza Viruses in Ducks Overwintering in Guatemala.
Over a hundred species of aquatic birds overwinter in Central America's wetlands, providing opportunities for the transmission of influenza A viruses (IAVs). To date, limited IAV surveillance in Central America hinders our understanding of the evolution and ecology of IAVs in migratory hosts within the Western Hemisphere. To address this gap, we sequenced the genomes of 68 virus isolates obtained from ducks overwintering along Guatemala's Pacific Coast during 2010 to 2013. High genetic diversity was observed, including 9 hemagglutinin (HA) subtypes, 7 neuraminidase (NA) subtypes, and multiple avian IAV lineages that have been detected at low levels (<1%) in North America. An unusually large number of viruses with the rare H14 subtype were identified (n = 14) over two consecutive seasons, the highest number of H14 viruses ever reported in a single location, providing evidence for a possible H14 source population located outside routinely sampled regions of North America. Viruses from Guatemala were positioned within minor clades divergent from the main North American lineage on phylogenies inferred for the H3, H4, N2, N8, PA, NP, and NS segments. A time-scaled phylogeny indicates that a Eurasian virus PA segment introduced into the Americas in the early 2000s disseminated to Guatemala during ~2007.1 to 2010.4 (95% highest posterior density [HPD]). Overall, the diversity detected in Guatemala in overwintering ducks highlights the potential role of Central America in the evolution of diverse IAV lineages in the Americas, including divergent variants rarely detected in the United States, and the importance of increasing IAV surveillance throughout Central America. IMPORTANCE Recent outbreaks of highly pathogenic H7N3, H5Nx, and H7N8 avian influenza viruses in North America were introduced by migratory birds, underscoring the importance of understanding how wild birds contribute to the dissemination and evolution of IAVs in nature. At least four of the main IAV duck host species in North America migrate through or overwinter within a narrow strip of Central America, providing opportunities for diverse IAV lineages to mix and exchange gene segments. By obtaining whole-genome sequences of 68 IAV isolates collected from migratory waterfowl in Guatemala (2010 to 2013), the largest data set available from Central America to date, we detected extensive viral diversity, including gene variants rarely found in North America and gene segments of Eurasian origin. Our findings highlight the need for increased IAV surveillance across the geographical span of bird migration flyways, including Neotropical regions that have been vastly undersampled to date.


Combined genome-wide scan for prostate cancer susceptibility genes.
Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer. We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided. The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P =.00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P<.00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P =.00008). Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.


The speed of the flagellar rotary motor of Escherichia coli varies linearly with protonmotive force.
A protonmotive force (pmf) across the cell's inner membrane powers the flagellar rotary motor of Escherichia coli. Speed is known to be proportional to pmf when viscous loads are heavy. Here we show that speed also is proportional to pmf when viscous loads are light. Two motors on the same bacterium were monitored as the cell was slowly deenergized. The first motor rotated the entire cell body (a heavy load), while the second motor rotated a small latex bead (a light load). The first motor rotated slowly and provided a measure of the cell's pmf. The second motor rotated rapidly and was compared with the first, to give the speed-pmf relation for light loads. Experiments were done at 24.0 degrees C and 16.2 degrees C, with initial speeds indicating operation well into the high-speed, low-torque regime. Speed was found to be proportional to pmf over the entire (accessible) dynamic range (0-270 Hz). If the passage of a fixed number of protons carries the motor through each revolution, i.e., if the motor is tightly coupled, a linear speed-pmf relation is expected close to stall, where the work done against the viscous load matches the energy dissipated in proton flow. A linear relation is expected at high speeds if proton translocation is rate-limiting and involves multiple steps, a model that also applies to simple proton channels. The present work shows that a linear relation is true more generally, providing an additional constraint on possible motor mechanisms.


Effects of visual and auditory feedback on sensorimotor circuits in the basal ganglia.
Previous work using visual feedback has identified two distinct sensorimotor circuits in the basal ganglia (BG): one that scaled with the duration of force and one that scaled with the rate of change of force. The present study compared functional MRI signal changes in the BG during a grip force task using either visual or auditory feedback to determine whether the BG nuclei process auditory and visual feedback similarly. We confirmed the same two sensorimotor circuits in the BG. Activation in the striatum and external globus pallidus (GPe) scaled linearly with the duration of force under visual and auditory feedback conditions, with similar slopes and intercepts across feedback type. The pattern of signal change for the internal globus pallidus (GPi) and subthalamic nucleus (STN) was nonlinear and parameters of the exponential function were altered by feedback type. Specifically, GPi and STN activation decreased exponentially with the rate of change of force. The rate constant and asymptote of the exponential functions for GPi and STN were greater during auditory than visual feedback. In a comparison of the BOLD signal between BG regions, GPe had the highest percentage of variance accounted for and this effect was preserved for both feedback types. These new findings suggest that neuronal activity of specific BG nuclei is affected by whether the feedback is derived from visual or auditory inputs. Also, the data are consistent with the hypothesis that the GPe has a high level of information convergence from other BG nuclei, which is preserved across different sensory feedback modalities.


Spontaneous subarachnoid haemorrhage.
Subarachnoid haemorrhage (SAH) is the third most common subtype of stroke. Incidence has decreased over past decades, possibly in part related to lifestyle changes such as smoking cessation and management of hypertension. Approximately a quarter of patients with SAH die before hospital admission; overall outcomes are improved in those admitted to hospital, but with elevated risk of long-term neuropsychiatric sequelae such as depression. The disease continues to have a major public health impact as the mean age of onset is in the mid-fifties, leading to many years of reduced quality of life. The clinical presentation varies, but severe, sudden onset of headache is the most common symptom, variably associated with meningismus, transient or prolonged unconsciousness, and focal neurological deficits including cranial nerve palsies and paresis. Diagnosis is made by CT scan of the head possibly followed by lumbar puncture. Aneurysms are commonly the underlying vascular cause of spontaneous SAH and are diagnosed by angiography. Emergent therapeutic interventions are focused on decreasing the risk of rebleeding (ie, preventing hypertension and correcting coagulopathies) and, most crucially, early aneurysm treatment using coil embolisation or clipping. Management of the disease is best delivered in specialised intensive care units and high-volume centres by a multidisciplinary team. Increasingly, early brain injury presenting as global cerebral oedema is recognised as a potential treatment target but, currently, disease management is largely focused on addressing secondary complications such as hydrocephalus, delayed cerebral ischaemia related to microvascular dysfunction and large vessel vasospasm, and medical complications such as stunned myocardium and hospital acquired infections.


Relationship between white matter glucose metabolism and fractional anisotropy in healthy and schizophrenia subjects.
Decreased fractional anisotropy and increased glucose utilization in the white matter have been reported in schizophrenia. These findings may be indicative of an inverse relationship between these measures of white matter integrity and metabolism. We used 18F-fluorodeoxyglucose positron emission tomography and diffusion-tensor imaging in 19 healthy and 25 schizophrenia subjects to assess and compare coterritorial correlation patterns between glucose utilization and fractional anisotropy on a voxel-by-voxel basis and across a range of automatically placed representative white matter regions of interest. We found a pattern of predominantly negative correlations between white matter metabolism and fractional anisotropy in both healthy and schizophrenia subjects. The overall strength of the relationship was attenuated in subjects with schizophrenia, who displayed significantly fewer and weaker correlations in all regions assessed with the exception of the corpus callosum. This attenuation was most prominent in the left prefrontal white matter and this region also best predicted the diagnosis of schizophrenia. There exists an inverse relationship between the measures of white matter integrity and metabolism, which may therefore be physiologically linked. In subjects with schizophrenia, hypermetabolism in the white matter may be a function of lower white matter integrity, with lower efficiency and increased energetic cost of task-related computations.