In vivo 5-ethynyluridine (EU) labelling detects reduced transcription in Purkinje cell degeneration mouse mutants, but can itself induce neurodegeneration.
Fluorescent staining of newly transcribed RNA via metabolic labelling with 5-ethynyluridine (EU) and click chemistry enables visualisation of changes in transcription, such as in conditions of cellular stress. Here, we tested whether EU labelling can be used to examine transcription in vivo in mouse models of nervous system disorders. We show that injection of EU directly into the cerebellum results in reproducible labelling of newly transcribed RNA in cerebellar neurons and glia, with cell type-specific differences in relative labelling intensities, such as Purkinje cells exhibiting the highest levels. We also observed EU-labelling accumulating into cytoplasmic inclusions, indicating that EU, like other modified uridines, may introduce non-physiological properties in labelled RNAs. Additionally, we found that EU induces Purkinje cell degeneration nine days after EU injection, suggesting that EU incorporation not only results in abnormal RNA transcripts, but also eventually becomes neurotoxic in highly transcriptionally-active neurons. However, short post-injection intervals of EU labelling in both a Purkinje cell-specific DNA repair-deficient mouse model and a mouse model of spinocerebellar ataxia 1 revealed reduced transcription in Purkinje cells compared to controls. We combined EU labelling with immunohistology to correlate altered EU staining with pathological markers, such as genotoxic signalling factors. These data indicate that the EU-labelling method provided here can be used to identify changes in transcription in vivo in nervous system disease models.


Density functional theory for charged fluids.
An improved density functional theory (DFT) for an inhomogeneous charged system (including electrolyte and/or polyelectrolyte) is proposed based on fundamental measure theory, thermodynamic perturbation theory and mean-spherical approximation. Our DFT combines the existing treatment of hard-sphere contributions using fundamental measure theory (FMT) with a new treatment of the electrostatic correlations for the non-bonded ions and chain connectivity that are approximated by employing a first-order Taylor expansion, with the reference fluid density determined using the technique from Gillespie et al. [D. Gillespie et al., J. Phys.: Condens. Matter, 2002, 14, 12129]. We show that the first-order Taylor expansion for the non-bonded electrostatic correlations yields numerically comparable results to the more involved second-order expansion. Furthermore, we find that the existing treatment of the chain connectivity correlation predicts a spurious layer-by-layer phase at moderately large Bjerrum lengths, which is avoided in our new treatment. These simplifications and improvements should significantly facilitate the implementation and reduce the computational cost.


Further insights in trichothiodistrophy: a clinical, microscopic, and ultrastructural study of 20 cases and literature review.
Trichothiodistrophy (TTD) is a rare autosomal recessive condition that is characterized by a specific congenital hair shaft dysplasia caused by deficiency of sulfur associated with a wide spectrum of multisystem abnormalities. In this article, we study clinical, microscopic, and ultrastructural findings of 20 patients with TTD with the aim to add further insights regarding to this rare condition. Additionally, analyses of our results are compared with those extracted from the literature in order to enhance its comprehensibility. TWENTY CASES OF TTD WERE INCLUDED: 7 from Mexico and 14 from Spain. Clinical, microscopic, scanning electron microscopy (SEM) studies and X-ray microanalysis (XrMa) were carried out in all of them. Genetic studies were performed in all seven Mexican cases. Patients with xeroderma pigmentosum and xeroderma pigmentosum/TTD-complex were excluded. Cuticular changes and longitudinal crests of the hair shaft were demonstrated. These crests were irregular, disorganized, following the hair longest axis. Hair shaft sulfur deficiency was disposed discontinuously and intermittently rather than uniformly. This severe decrease of sulfur contents was located close to the trichoschisis areas. Only five patients did not show related disturbances. Micro-dolichocephaly was observed in five cases and represented the most frequent facial dysmorphism found. It is also remarkable that all patients with urologic malformations also combined diverse neurologic disorders. Moreover, three Mexican sisters demonstrated the coexistence of scarce pubic vellus hair, developmental delay, onychodystrophy, and maxillar/mandibullar hypoplasia. TTD phenotype has greatly varied from very subtle forms to severe alterations such as neurologic abnormalities, blindness, lamellar ichthyosis and gonadal malformations. Herein, a multisystem study should be performed mandatorily in patients diagnosed with TTD.


Photonic crystal waveguide cavity with waist design for efficient trapping and detection of nanoparticles.
For manipulating nanometric particles, we propose a photonic crystal waveguide cavity design with a waist structure to enhance resonance characteristic of the cavity. For trapping a polystyrene particle of 50 nm radius on the lateral side of the waist, the optical force can reach 2308 pN/W with 24.7% signal transmission. Threshold power of only 0.32 mW is required for stable trapping. The total length of the device is relatively short with only ten photonic crystal periods, and the trapping can occur precisely and only at the waist. The designed cavity can also provide particle detection and surrounding medium sensing using the transmission spectrum with narrow linewidth. The simulated figure of merit of 110.6 is relatively high compared with those obtained from most plasmonic structures for sensing application. We anticipate this design with features of compact, efficient, and versatile in functionality will be beneficial for developing lab-on-chip in the future.


Environmental implications of plastic debris in marine settings--entanglement, ingestion, smothering, hangers-on, hitch-hiking and alien invasions.
Over the past five or six decades, contamination and pollution of the world's enclosed seas, coastal waters and the wider open oceans by plastics and other synthetic, non-biodegradable materials (generally known as 'marine debris') has been an ever-increasing phenomenon. The sources of these polluting materials are both land- and marine-based, their origins may be local or distant, and the environmental consequences are many and varied. The more widely recognized problems are typically associated with entanglement, ingestion, suffocation and general debilitation, and are often related to stranding events and public perception. Among the less frequently recognized and recorded problems are global hazards to shipping, fisheries and other maritime activities. Today, there are rapidly developing research interests in the biota attracted to freely floating (i.e. pelagic) marine debris, commonly known as 'hangers-on and hitch-hikers' as well as material sinking to the sea floor despite being buoyant. Dispersal of aggressive alien and invasive species by these mechanisms leads one to reflect on the possibilities that ensuing invasions could endanger sensitive, or at-risk coastal environments (both marine and terrestrial) far from their native habitats.


Interactions between Neutrophils and Leishmania braziliensis Amastigotes Facilitate Cell Activation and Parasite Clearance.
Leishmania braziliensis and Leishmania amazonensis are both causative agents of cutaneous leishmaniasis in South America. However, patient prognosis and the host immune response differ considerably depending on the infecting parasite species. The mechanisms underlying these differences appear to be multifactorial, with both host and parasite components contributing to disease outcome. As neutrophils are a prominent component of the inflammatory infiltrate in chronic cutaneous, diffuse cutaneous and mucocutaneous lesions, we examined neutrophil activation and microbicidal activity against amastigotes of L. amazonensis and L. braziliensis. We found that murine neutrophils internalized L. braziliensis amastigotes with greater efficiency than did L. amazonensis amastigotes. Additionally, L. braziliensis infection was a potent trigger for neutrophil activation, oxidative burst, degranulation and the production of interleukin (IL)-22 and IL-10, while L. amazonensis amastigotes poorly induced these responses. Finally, neutrophils were able to kill L. braziliensis amastigotes, especially when cells were activated with phorbol myristate acetate. L. amazonensis amastigotes, however, were highly resistant to neutrophil microbicidal mechanisms. This study reveals, for the first time, differential neutrophil responsiveness to distinct species of Leishmania amastigotes and highlights the complexity of neutrophil-amastigote interactions during chronic leishmaniasis.


Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine.
Cardiac troponins are sensitive and specific biomarkers of myocardial necrosis. We evaluated troponin, CK, and ECG abnormalities in patients with septic shock and compared the effect of vasopressin (VP) versus norepinephrine (NE) on troponin, CK, and ECGs. This was a prospective substudy of a randomized trial. Adults with septic shock randomly received, blinded, a low-dose infusion of VP (0.01 to 0.03 U/min) or NE (5 to 15 μg/min) in addition to open-label vasopressors, titrated to maintain a mean blood pressure of 65 to 75 mm Hg. Troponin I/T, CK, and CK-MB were measured, and 12-lead ECGs were recorded before study drug, and 6 hours, 2 days, and 4 days after study-drug initiation. Two physician readers, blinded to patient data and drug, independently interpreted ECGs. We enrolled 121 patients (median age, 63.9 years (interquartile range (IQR), 51.1 to 75.3), mean APACHE II 28.6 (SD 7.7)): 65 in the VP group and 56 in the NE group. At the four time points, 26%, 36%, 32%, and 21% of patients had troponin elevations, respectively. Baseline characteristics and outcomes were similar between patients with positive versus negative troponin levels. Troponin and CK levels and rates of ischemic ECG changes were similar in the VP and the NE groups. In multivariable analysis, only APACHE II was associated with 28-day mortality (OR, 1.07; 95% CI, 1.01 to 1.14; P=0.033). Troponin elevation is common in adults with septic shock. We observed no significant differences in troponin, CK, and ECGs in patients treated with vasopressin and norepinephrine. Troponin elevation was not an independent predictor of mortality. Controlled-trials.com ISRCTN94845869.


Complications and Long-Term Outcomes of Free Fibula Reconstruction following Resection of a Malignant Tumor in the Extremities.
To achieve limb salvage and provide the patient with a functional extremity, vascularized free fibula transfer has become the workhorse for segmental bony reconstruction. Because of various host factors, there has been a high complication rate following oncologic reconstruction. The authors reviewed the experience of their institution with the use of free fibula reconstruction following an oncologic resection in the extremities. The authors reviewed 56 cases of free fibula transfer performed for limb salvage following oncologic resection from 1994 through 2013. The cohort consisted of 30 male patients and 26 female patients; with a mean age of 19 years and a mean follow-up of 7 years. Sixty-three percent of the tumors were located in the lower extremity. The overall 2-, 5-, 10-, and 15-year survival rates were 98, 86, 73, and 73 percent, respectively. With regard to disease-specific survival, the overall 2-, 5-, 10, and 15-year survival rates were 82, 75, 67, and 50 percent, respectively. Seventy-five percent of cases healed primarily, with a mean time to union of 10 months. The overall union rate was 98 percent following supplemental bone grafting. Chemotherapy following the free fibula graft increased the risk (hazard ratio, 2.10; p = 0.03) of a delayed union. The overall rate of limb salvage was 93 percent, with four patients requiring an amputation. The free fibula is considered the workhorse vascularized bone graft for extremity reconstruction in limb salvage surgery. In the oncologic setting, a repeated bone grafting procedure was common, and should be expected in patients undergoing chemotherapy. Limb salvage rates are high with this technique. Therapeutic, IV.


The benzodiazepine antagonist, Ro 15-1788 does not decrease ethanol withdrawal convulsions in rats.
The effects of the benzodiazepine antagonist, Ro 15-1788 on ethanol withdrawal convulsions were investigated in rats. The study originated from recent reports of benzodiazepine binding activity in urine of alcoholics during withdrawal. No alleviation of convulsions was found with Ro 15-1788. This suggested that this component of the withdrawal syndrome is not due to endogenous production of a benzodiazepine inverse agonist (contragonist), as Ro 15-1788 prevents the action of this type of compound.


Quality of Life After Intensive Care Unit Discharge in a Tertiary Care Hospital in India: Cost Effectiveness Analyis.
Improvements in intensive care in the last few decades have shifted the focus from mortality to quality of life of survivors as a more important outcome measure. Allocation of public resources towards intensive care is an important challenge for healthcare administrators. This challenge is made more arduous in resource limited countries like India. Thus, it is imperative to consider patient centerd outcomes and resource utilisation to guide allocation of funds. The aim of this study was to evaluate the quality of life of long-term survivors, and to perform cost-effectiveness and cost-utility analysis. Data was retrieved from the records and included age, gender, admission diagnosis, length of ICU stay and mortality. Costing methodology used was top down approach. Quality of life was assessed by SF 36 scoring which was done with personal interview and telephonically. Cost-effectiveness analysis was done on the basis of years of life added. Cost utility was done by QALY gained. A total of 1232 adult patients were admitted in the period with 758 (61%) being successfully discharged from ICU with a mortality rate of 39%. Out of 758, we could contact 113 (15%) patients. 86 patients were alive at the time of contact who could fill the forms for quality of life. The patients discharged from ICU had scores almost similar to the general population. Lesser scores were noted in physical functioning and general health perceptions, though this difference was not statistically significant. The life years gained were significantly more in younger patients. The cost per life gained was more in patients aged more than 50 years compared to those who were younger. The quality of life after survival from ICU is as good as in the general population. The intensive care provided in our ICU is cost effective. Mishra SB, Poddar B et al, Quality of Life After Intensive Care Unit Discharge in a Tertiary Care Hospital in India: Cost Effectiveness Analysis. Indian J Crit Care Med 2019;23(3):122-126.


Community ecology of euglossine bees in the coastal Atlantic forest of São Paulo state, Brazil.
The Atlantic Forest stretches along Brazil's Atlantic coast, from Rio Grande do Norte State in the north to Rio Grande do Sul State in the south, and inland as far as Paraguay and the Misiones Province of Argentina. This biome is one of the eight biodiversity hotspots in the world and is characterized by high species diversity. Euglossini bees are known as important pollinators in this biome, where their diversity is high. Due to the high impact of human activities in the Atlantic Forest, in the present study the community structure of Euglossini was assessed in a coastal lowland area, Parque Estadual da Serra do Mar--Núcleo Picinguaba (PESM), and in an island, Parque Estadual da Ilha Anchieta (PEIA), Ubatuba, São Paulo State, Brazil. Sampling was carried out monthly, from August 2007 to July 2009, using artificial baits with 14 aromatic compounds to attract males. Twenty-three species were recorded. On PEIA, Euglossa cordata (L.) (Hymenoptera: Apidae) represented almost two thirds of the total species collected (63.2%). Euglossa iopoecila (23.0%) was the most abundant species in PESM but was not recorded on the island, and Euglossa sapphirina (21.0%) was the second most frequent species in PESM but was represented by only nine individuals on PEIA. The results suggest that these two species may act as bioindicators of preserved environments, as suggested for other Euglossini species. Some authors showed that Eg. cordata is favored by disturbed environments, which could explain its high abundance on Anchieta Island. Similarly, as emphasized by other authors, the dominance of Eg. cordata on the island would be another factor indicative of environmental disturbance.


Potent anti-cancer effect of 3'-hydroxypterostilbene in human colon xenograft tumors.
Here we report that 3'-hydroxypterostilbene (HPSB), a natural pterostilbene analogue, was more potent than pterostilbene against the growth of human cancer cells (COLO 205, HCT-116, and HT-29) with measured IC50 values of 9.0, 40.2, and 70.9 µM, respectively. We found that HPSB effectively inhibited the growth of human colon cancer cells by inducing apoptosis and autophagy. Autophagy occurred at an early stage and was observed through the formation of acidic vesicular organelles and microtubule-associated protein 1 light chain 3-II production. At the molecular levels, the results from western blot analysis showed that HPSB significantly down-regulated phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinases (MAPKs) signalings including decreased the phosphorylation of mammalian target of rapamycin (mTOR). Significant therapeutic effects were demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with HPSB (10 mg/kg i.p.). These inhibitory effects were accompanied by mechanistic down-regulation of the protein levels of cyclooxygenase-2 (COX-2), matrix metallopeptidase-9 (MMP-9), vascular endothelial growth factor (VEGF), and cyclin D1, as well as by the induction of apoptosis in colon tumors. Our findings suggest that HPSB could serve as a novel promising agent for colon cancer treatment.


COVID-19 mortality effects of underlying health conditions in India: a modelling study.
To model how known COVID-19 comorbidities affect mortality rates and the age distribution of mortality in a large lower-middle-income country (India), and to identify which health conditions drive differences with high-income countries. Modelling study. England and India. Individual data were obtained from the fourth round of the District Level Household Survey and Annual Health Survey in India, and aggregate data were obtained from the Health Survey for England and the Global Burden of Disease, Risk Factors and Injuries Studies. The primary outcome was the modelled age-specific mortality in each country due to each COVID-19 mortality risk factor (diabetes, hypertension, obesity and respiratory illness, among others). The change in overall mortality and in the share of deaths under age 60 from the combination of risk factors was estimated in each country. Relative to England, Indians have higher rates of diabetes (10.6% vs 8.5%) and chronic respiratory disease (4.8% vs 2.5%), and lower rates of obesity (4.4% vs 27.9%), chronic heart disease (4.4% vs 5.9%) and cancer (0.3% vs 2.8%). Population COVID-19 mortality in India, relative to England, is most increased by uncontrolled diabetes (+5.67%) and chronic respiratory disease (+1.88%), and most reduced by obesity (-5.47%), cancer (-3.65%) and chronic heart disease (-1.20%). Comorbidities were associated with a 6.26% lower risk of mortality in India compared with England. Demographics and population health explain a third of the difference in share of deaths under age 60 between the two countries. Known COVID-19 health risk factors are not expected to have a large effect on mortality or its age distribution in India relative to England. The high share of COVID-19 deaths from people under age 60 in low- and middle-income countries (LMICs) remains unexplained. Understanding the mortality risk associated with health conditions prevalent in LMICs, such as malnutrition and HIV/AIDS, is essential for understanding differential mortality.


Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD.
Little is known about how often bipolar depressive episodes are accompanied by subsyndromal manic symptoms in bipolar I and II disorders. The authors sought to determine the frequency and clinical correlates of manic symptoms during episodes of bipolar depression. From among 4,107 enrollees in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 1,380 individuals met criteria for bipolar I or II depressive syndromes at the time of enrollment and were assessed for concomitant manic symptoms. Illness characteristics were compared in patients with pure bipolar depressed episodes and those with mixed depressive presentations. Two-thirds of the subjects with bipolar depressed episodes had concomitant manic symptoms, most often distractibility, flight of ideas or racing thoughts, and psychomotor agitation. Patients with any mixed features were significantly more likely than those with pure bipolar depressed episodes to have early age at illness onset, rapid cycling in the past year, bipolar I subtype, history of suicide attempts, and more days in the preceding year with irritability or mood elevation. Manic symptoms often accompany bipolar depressive episodes but may easily be overlooked when they appear less prominent than depressive features. Subsyndromal manic symptoms during bipolar I or II depression demarcate a more common, severe, and psychopathologically complex clinical state than pure bipolar depression and merit recognition as a distinct nosologic entity.


Genetic heterogeneity of Bardet-Biedl syndrome in a distinct Canadian population: evidence for a fifth locus.
Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disease characterized by retinal dystrophy, renal structural abnormalities, obesity, dysmorphic extremities, and hypogenitalism in males. BBS is genetically heterogeneous with four known loci: BBS1 (11q), BBS2 (16q), BBS3 (3p), and BBS4 (15q). The prevalence of BBS in Newfoundland is approximately 10-fold greater than in Switzerland (1:160,000) and similar to the prevalence among the Bedouin of Kuwait (1:13,500). A population-based genetic survey was performed on 17 BBS families from the island portion of the province of Newfoundland, a comparatively isolated region of Canada. The families in the study had a total of 36 well-documented, affected individuals with 12 families having 2 or more affected individuals. Linkage at each of the four known loci was tested with two-point linkage and haplotype analysis. Three of the 17 kindreds showed linkage to 11q, 1 to 16q, and 1 to 3p. The latter is the first BBS3 family identified in a population of northern European descent. Six families remain undetermined because of poor pedigree structure or inconclusive haplotype analyses. Six families were excluded from all four known BBS loci, indicating that there is at least a fifth BBS locus (BBS5).


Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci.
Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04).


Older adults with chronic lung disease report less limitation compared with younger adults with similar lung function impairment.
Disability guidelines are often based on pulmonary function testing, but factors other than lung function influence how an individual experiences physiologic impairment. Age may impact the perception of impairment in adults with chronic lung disease. To determine if self-report of physical functional impairment differs between older adults with chronic lung disease compared with younger adults with similar degrees of lung function impairment. The Lung Tissue Research Consortium provided data on 981 participants with chronic obstructive pulmonary disease and interstitial lung disease who were well characterized with clinical, radiological, and pathological diagnoses. We used multiple logistic regression to determine if responses to health status questions (from the Short Form-12 and St. George's Respiratory Questionnaire) related to perception of impairment differed in older adults (age ≥ 65 yr, n = 427) compared with younger adults (age < 65 yr, n = 393). Pulmonary function was higher in older adults (median FEV1 %, 70) compared with younger adults (median FEV1 %, 62) (P < 0.001), whereas the median 6-minute-walk distance was similar between groups (372 m vs. 388 m, P = 0.21). After adjusting for potential confounders, older adults were less likely to report that their health limited them significantly in performing moderate activities (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.22-0.58) or climbing several flights of stairs (OR, 0.51; 95% CI, 0.34-0.77). The odds of reporting that their physical health limited the kinds of activities they performed were reduced by 63% in older adults (OR, 0.37; 95% CI, 0.24-0.58), and, similarly, the odds of reporting that their health caused them to accomplish less than they would like were also lower in older adults (OR, 0.39; 95% CI, 0.25-0.60). The OR for reporting that their breathing problem stops them from doing most things or everything was 0.35 (95% CI, 0.22-0.55) in older adults versus younger adults. Older adults with chronic lung disease were less likely to report significant impairment in their activities compared with younger adults, suggesting they may perceive less limitation.


Synaptotagmin-2 is essential for survival and contributes to Ca2+ triggering of neurotransmitter release in central and neuromuscular synapses.
Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca2+ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5' end of the synaptotagmin-2 gene was replaced by lacZ. Using beta-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at approximately 3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2-deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca2+-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca2+ triggering of neurotransmitter release.


In vitro color changes of soft tissues caused by restorative materials.
A crucial factor influencing implant esthetics is the color of the peri-implant mucosa. This in vitro study analyzed the effect of titanium and zirconia with and without veneering ceramic on the color of mucosa of three different thicknesses. Ten pig maxillae were used, and the palatal area was chosen as the test region. To simulate different mucosa thicknesses, connective tissue grafts, 0.5 mm and 1.0 mm thick, were harvested from three additional jaws. Defined mucosa thicknesses were created by placing the grafts under a palatal mucosa flap. Four different test specimens (titanium, titanium veneered with feldspathic ceramic, zirconia, and zirconia veneered with feldspathic ceramic) were placed under the mucosa, and the color of the tissue was evaluated with a spectrophotometer for three different soft tissue thicknesses (1.5, 2.0, and 3.0 mm). The color was compared to mucosa without test specimens, and the color difference (DeltaE) was calculated. All restorative materials induced overall color changes (DeltaE), which diminished with increases in soft tissue thickness. Titanium induced the most prominent color change. Zirconia did not induce visible color changes in 2.0-mm-thick and 3.0-mm-thick mucosa, regardless of whether it was veneered. However, with a mucosa thickness of 3.0 mm, no change in color could be distinguished by the human eye on any specimen. Mucosa thickness is a crucial factor in terms of discoloration caused by different restorative materials. In patients with thinner mucosa, zirconia will show the least color change.


Local property characterization of prostate glands using inhomogeneous modeling based on tumor volume and location analysis.
Mechanical property characterization of prostate tumors can enhance the results obtained by palpation by providing quantitative and precise diagnostic information to surgeons. The multi-focal characteristics of prostate tumors cause inhomogeneity and local property variance in the prostate glands, which is one reason for inaccurate property characterizations of the tumors. Therefore, biomechanical models should include inhomogeneity and local property variance by taking into consideration the anatomical information (location and volume) of the tumors. We developed six inhomogeneous local prostate models using the finite element method, which takes into account the location and volume information of prostate tumors. The models were divided into six different sections: lateral apex, lateral mid, lateral base, medial apex, medial mid and medial base tumors. Information on the location and volume of prostate tumors was obtained using pathological analysis. The mechanical properties of prostate tumors were estimated using the developed model simulation and the ex vivo indentation experiment results from the human resected prostates. The results showed that the mean elastic moduli of the normal and tumoral regions were 14.7 and 41.6 kPa, respectively. Our models provided more reliable estimates of the elastic moduli than the conventionally used Hertz-Sneddon model, and the results from our model were more closely correlated with previous studies due to the inclusion of the anatomical information via inhomogeneous modeling. These six local models provide baseline property criteria for the diagnosis and localization of prostate tumors using the optimized elastic moduli of normal prostate tissues.


Identification of molecular sub-networks associated with cell survival in a chronically SIVmac-infected human CD4+ T cell line.
The deciphering of cellular networks to determine susceptibility to infection by HIV or the related simian immunodeficiency virus (SIV) is a major challenge in infection biology. Here, we have compared gene expression profiles of a human CD4+ T cell line at 24 h after infection with a cell line of the same origin permanently releasing SIVmac. A new knowledge-based-network approach (Inter-Chain-Finder, ICF) has been used to identify sub-networks associated with cell survival of a chronically SIV-infected T cell line. Notably, the method can identify not only differentially expressed key hub genes but also non-differentially expressed, critical, 'hidden' regulators. Six out of the 13 predicted major hidden key regulators were among the landscape of proteins known to interact with HIV. Several sub-networks were dysregulated upon chronic infection with SIV. Most prominently, factors reported to be engaged in early stages of acute viral infection were affected, e.g. entry, integration and provirus transcription and other cellular responses such as apoptosis and proliferation were modulated. For experimental validation of the gene expression analyses and computational predictions, individual pathways/sub-networks and significantly altered key regulators were investigated further. We showed that the expression of caveolin-1 (Cav-1), the top hub in the affected protein-protein interaction network, was significantly upregulated in chronically SIV-infected CD4+ T cells. Cav-1 is the main determinant of caveolae and a central component of several signal transduction pathways. Furthermore, CD4 downregulation and modulation of the expression of alternate and co-receptors as well as pathways associated with viral integration into the genome were also observed in these cells. Putatively, these modifications interfere with re-infection and the early replication cycle and inhibit cell death provoked by syncytia formation and bystander apoptosis. Thus, by using the novel approach for network analysis, ICF, we predict that in the T cell line chronically infected with SIV, cellular processes that are known to be crucial for early phases of HIV/SIV replication are altered and cellular responses that result in cell death are modulated. These modifications presumably contribute to cell survival despite chronic infection.


Islands of retroelements are major components of Drosophila centromeres.
Centromeres are essential chromosomal regions that mediate kinetochore assembly and spindle attachments during cell division. Despite their functional conservation, centromeres are among the most rapidly evolving genomic regions and can shape karyotype evolution and speciation across taxa. Although significant progress has been made in identifying centromere-associated proteins, the highly repetitive centromeres of metazoans have been refractory to DNA sequencing and assembly, leaving large gaps in our understanding of their functional organization and evolution. Here, we identify the sequence composition and organization of the centromeres of Drosophila melanogaster by combining long-read sequencing, chromatin immunoprecipitation for the centromeric histone CENP-A, and high-resolution chromatin fiber imaging. Contrary to previous models that heralded satellite repeats as the major functional components, we demonstrate that functional centromeres form on islands of complex DNA sequences enriched in retroelements that are flanked by large arrays of satellite repeats. Each centromere displays distinct size and arrangement of its DNA elements but is similar in composition overall. We discover that a specific retroelement, G2/Jockey-3, is the most highly enriched sequence in CENP-A chromatin and is the only element shared among all centromeres. G2/Jockey-3 is also associated with CENP-A in the sister species D. simulans, revealing an unexpected conservation despite the reported turnover of centromeric satellite DNA. Our work reveals the DNA sequence identity of the active centromeres of a premier model organism and implicates retroelements as conserved features of centromeric DNA.


Antioxidant activities of Ptychopetalum olacoides ("muirapuama") in mice brain.
Ptychopetalum olacoides (PO) roots are used by Amazonian peoples to prepare traditional remedies for treating various central nervous system conditions in which free radicals are likely to be implicated. Following the identification of PO ethanol extract (POEE) free-radical scavenging properties in vitro, the aim of this study was to verify the in vivo antioxidant effect of POEE. Aging mice (14 months) were treated (i.p.) with saline, DMSO (20%) or POEE (100mg/kg body wt.), and the hippocampi, cerebral cortex, striata, hypothalamus and cerebellum dissected out 60 min later to measure antioxidant enzyme activities, free-radical production and damage to macromolecules. POEE administration reduced free-radical production in the hypothalamus, lead to significant decrease in lipid peroxidation in the cerebral cortex, striatum and hypothalamus, as well as in the carbonyl content in cerebellum and striatum. In terms of antioxidant enzymes, catalase activity was increased in the cortex, striatum, cerebellum and hippocampus, while glutathione peroxidase activity was increased in the hippocampus. This study suggests that POEE contains compounds able to improve the cellular antioxidant network efficacy in the brain, ultimately reducing the damage caused by oxidative stress.


Function and genetics of dystrophin and dystrophin-related proteins in muscle.
The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and alpha-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.


Ethnic differences in susceptibility to malaria: what have we learned from immuno-epidemiological studies in West Africa?
There are many fundamental aspects of the immunobiology of Plasmodium falciparum infections that are not fully understood, therefore limiting our comprehension of how people become immune to malaria and why some ethnic groups living in malaria endemic areas are less susceptible than others. The complexity of parasite-host interactions and the genetic diversity of the parasites as well as the human host complicate our strategy to address this issue. In this mini-review we discuss and summarize what we have learned about African ethnic differences in susceptibility to malaria from immuno-epidemiological studies. Additionally, we suggest research topics that might be of great value for dissecting the mechanisms of protection by providing new insights into molecular interactions between the parasite and the host.


Further evidence for addition and numerical competence by a Grey parrot (Psittacus erithacus).
A Grey parrot (Psittacus erithacus), able to quantify sets of eight or fewer items (including heterogeneous subsets), to sum two sequentially presented sets of 0–6 items (up to 6), and to identify and serially order Arabic numerals (1–8), all by using English labels (Pepperberg in J Comp Psychol 108:36–44, 1994; J CompPsychol 120:1–11, 2006a; J Comp Psychol 120:205–216,2006b; Pepperberg and Carey submitted), was tested on addition of two Arabic numerals or three sequentially presented collections (e.g., of variously sized jelly beans or nuts). He was, without explicit training and in the absence of the previously viewed addends, asked, "How many total?" and required to answer with a vocal English number label. In a few trials on the Arabic numeral addition, he was also shown variously colored Arabic numerals while the addends were hidden and asked "What color number (is the) total?" Although his death precluded testing on all possible arrays, his accuracy was statistically significant and suggested addition abilities comparable with those of nonhuman primates.


Optimal management of β thalassaemia intermedia.
Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with β thalassaemia intermedia (TI) has substantially increased over the past decade. The hallmark of disease process in patients with TI includes ineffective erythropoiesis, chronic haemolytic anaemia, and iron overload. There are a number of options currently available for managing patients with TI including splenectomy, transfusion therapy, iron chelation therapy, modulation of fetal haemoglobin production, and several other agents targeting specific clinical complications. Limited studies assessed the efficacy and safety of these modalities; hence, there are currently no clear guidelines for managing patients with TI. Until solid evidence-based guidelines are available, individualised treatment should be entertained.


The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis.
Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.


Influence of psychogenic and neurogenic stressors on endocrine and immune activity: differential effects in fast and slow seizing rat strains.
Variations of plasma ACTH and corticosterone, as well as splenic macrophage activity and mitogen-induced cell proliferation, were determined in rats following 15 min of either the neurogenic stressor of restraint or by a purely psychogenic stressor consisting of exposure to a ferret. The effects of these stressors were assessed in two strains of rats that were selectively bred for either Fast or Slow kindling epileptogenesis triggered in response to amygdala stimulation. The stressors differentially influenced behavioral responses, endocrine activity, and immune functioning, and these effects varied with the strain of rat. In response to restraint the Fast rats exhibited protracted struggling, while the Slow rats tended to be immobile. In contrast, upon ferret exposure the Fast rats showed greater immobility than the Slow rats. The stressors also induced marked elevations of plasma ACTH and corticosterone. Whereas the ACTH and corticosterone increases were more pronounced in response to the ferret in the Slow rats, restraint resulted in a markedly greater rise of plasma ACTH in the Fast strain. Proliferation of splenic lymphocytes in response to Con A and LPS were elevated in Fast seizing rats, while macrophage activity, as determined by oxygen burst following addition of PMA and luminol to splenic mononuclear cells, was greater in the Slow seizing strain. While neither stressor influenced cell proliferation in either the Fast or Slow rats, macrophage activity was greatly suppressed by ferret exposure only in the Slow rats. Taken together, it appears that while stressors influence behavior and immune and endocrine functioning, these effects may vary as a function of the interaction of the strain of rat and the specific type of stressor employed.


Engineering periplasmic ligand binding proteins as glucose nanosensors.
Diabetes affects over 100 million people worldwide. Better methods for monitoring blood glucose levels are needed for improving disease management. Several labs have previously made glucose nanosensors by modifying members of the periplasmic ligand binding protein superfamily. This minireview summarizes recent developments in constructing new versions of these proteins that are responsive within the physiological range of blood glucose levels, employ new reporter groups, and/or are more robust. These experiments are important steps in the development of novel proteins that have the characteristics needed for an implantable glucose nanosensor for diabetes management: specificity for glucose, rapid response, sensitivity within the physiological range of glucose concentrations, reproducibility, and robustness.


A distinctive subset of PEComas harbors TFE3 gene fusions.
Perivascular epithelioid cell neoplasms (PEComas) include the common renal angiomyolipoma, pulmonary clear cell sugar tumor, lymphangioleiomyomatosis, and less common neoplasms of soft tissue, gynecologic, and gastrointestinal tracts. Recently, aberrant immunoreactivity for TFE3 protein (a sensitive and specific marker of neoplasms harboring TFE3 gene fusions) has been reported in as many as 100% of PEComas; however, TFE3 gene status in these neoplasms has not been systematically investigated. We used a fluorescence in situ hybridization (FISH) break-apart assay to evaluate for evidence of TFE3 gene fusions in archival material from 29 PEComas. These cases included 2 earlier published TFE3 immunoreactive nonrenal PEComas, 14 additional nonrenal PEComas, and 13 renal angiomyolipomas with predominantly spindle or epithelioid morphology. Four nonrenal PEComas (mean patient age 24 y) showed TFE3 gene rearrangements by FISH, and all 4 of these showed strong positive (3+) TFE3 immunoreactivity using the original validated overnight incubation protocol. Two of these cases had adequate mRNA for RT-PCR analysis, but neither harbored the PSF-TFE3 gene fusion reported earlier in 1 PEComa. In addition, a lung metastasis of a uterine PEComa showed TFE3 gene amplification, an earlier unreported phenomenon. None of the other 24 PEComas (mean patient age 54 y) showed TFE3 gene alterations, though 4 exhibited moderate positive (2+) TFE3 immunoreactivity. In contrast, using an automated stainer, 2 of these 4 cases exhibited strong (3+) TFE3 immunoreactivity. All PEComas with TFE3 genetic alterations immunolabeled strongly for Cathepsin K, similar to other PEComas. In conclusion, a subset of lesions currently classified as PEComas harbors TFE3 gene fusions. Although numbers are small, distinctive features of these cases include a tendency to young age, the absence of association with tuberous sclerosis, predominant alveolar architecture and epithelioid cytology, minimal immunoreactivity for muscle markers, and strong (3+) TFE3 immunoreactivity. Despite significant morphologic and immunohistochemical overlap with other PEComas, PEComas harboring TFE3 gene fusions may represent a distinctive entity.


Clinical practice guideline for an integrated approach to comorbidity in patients with psoriasis.
The relationship between psoriasis and associated diseases has drawn particular interest in recent years. To provide appropriate management of psoriasis from an early stage, it is necessary to include prompt diagnosis of concomitant disease and to prevent and treat any comorbidity found. Such an integrated approach also serves to ensure that the drugs used to treat associated diseases do not interfere with the management of psoriasis, and vice versa. To provide the dermatologist a guide focuses specifically on the diagnosis and management of the diseases most often found in patients with psoriasis. The selection of the diseases, and corresponding supporting research, to be included was based on a systematic review of the literature. The recommendations on diagnostic criteria are based on the main clinical practice guidelines for each of the diseases discussed as well as on the recommendations of a clinical expert advisory group. The information regarding the repercussions of psoriasis treatments on associated comorbid diseases was obtained from the summary of product characteristics of each drug. In turn, the statements concerning the impact of the associated diseases, and their treatment, on psoriasis are based on the review of the literature. This guide is a precise, easy-to-use tool for systematizing the diagnosis of comorbidity in patients with psoriasis and facilitate decision making regarding referral and treatment of patients diagnosed with an associated disease. The application of this guide not only will benefit psoriasis patients' health and quality of life but it will also optimize available resources.


Elevated levels of arachidonic acid metabolites in follicular fluid of PCOS patients.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women usually accompanied by lipid metabolic disorders. However, it remains unknown whether arachidonic acid (AA) and its metabolites in follicular fluid (FF) were altered in PCOS patients. This study was intended to measure the levels of AA and its metabolites in the FF of non-obese PCOS patients that underwent in vitro fertilization (IVF) and to explore the possible causes of the alterations. Thirty-nine non-obese women with PCOS and 30 non-obese women without PCOS were enrolled. AA and its metabolites were measured by liquid chromatography-mass spectrometry. The levels of AA metabolites generated via cyclooxygenase-2 (COX-2) pathway and cytochrome P450 epoxygenase pathway but not lipoxygenase (LOX) pathway were significantly higher in the FF of PCOS patients. The metabolites generated via COX-2 pathway were significantly correlated with levels of testosterone and fasting insulin in serum. The in vitro study further demonstrated that insulin but not testosterone could promote the IL-1β and hCG-induced COX-2 expression and prostaglandin E2 (PGE2) secretion in primary human granulosa cells. In conclusion, there was an elevation in AA metabolites in FF of PCOS patients. Insulin played a pivotal role in the increased AA metabolites generated via COX-2, which could be interpreted as another novel molecular pathophysiological mechanism of PCOS.


Effects of electronic fetal-heart-rate monitoring, as compared with periodic auscultation, on the neurologic development of premature infants.
In a multicenter, randomized clinical trial, we assessed the early neurologic development of 93 children born prematurely whose heart rates were monitored electronically during delivery and compared it with that of 96 children born prematurely whose heart rates were periodically monitored by auscultation. All the children were singletons with cephalic presentation, and all weighed less than or equal to 1750 g at birth. The mental and psychomotor indexes of the Bayley Scales of Infant Development (standardized mean score +/- SD, 100 +/- 16) and a formal neurologic examination were administered at three follow-up visits (at 4, 8, and 18 months of age, corrected for gestational age). At 18 months, the mean mental-development scores in the groups receiving electronic fetal monitoring and periodic auscultation were 100.5 +/- 2.4 and 104.9 +/- 1.8, respectively (P greater than 0.1). The mean psychomotor-development scores in the two groups at 18 months were 94.0 +/- 2.4 and 98.3 +/- 1.8, respectively (P greater than 0.1). The incidence of cerebral palsy was higher in the electronically monitored group--20 percent as compared with 8 percent in the group that was monitored by auscultation (P less than 0.03). In the electronic-fetal-monitoring group (but not in the periodic-auscultation group), the risk of cerebral palsy increased with the duration of abnormal fetal-heart-rate patterns, as assessed by retrospective review (chi 2 trend = 12.71, P less than 0.001). The median time to delivery after the diagnosis of abnormal fetal-heart-rate patterns was 104 minutes with electronic fetal monitoring, as compared with 60 minutes with periodic auscultation. We conclude that as compared with a structured program of periodic auscultation, electronic fetal monitoring does not result in improved neurologic development in children born prematurely.


The competitive imperative of learning.
Most executives believe that relentless execution--efficient, timely, consistent production and delivery of goods or services--is the surefire path to customer satisfaction and positive financial results. But this is a myth in the knowledge economy, argues Edmondson, a Harvard Business School professor. She points to General Motors, which for years has remained wedded to a well-developed competency in centralized controls and efficient execution but has steadily lost ground, posting a record $38.7 billion loss in 2007. Such an execution-as-efficiency model results in employees who are exceedingly reluctant to offer ideas or voice questions and concerns. Placing value only on getting things right the first time, organizations are unable to take the risks necessary to improve and evolve. By contrast, firms that put a premium on what Edmondson calls execution-as-learning focus not so much on how a process should be carried out as on how it should evolve. Since 1980 General Electric, for instance, has continued to reinvent itself in every field from wind energy to medical diagnostics; and it enjoyed a $22.5 billion profit in 2007. Organizations that foster execution-as-learning provide employees with psychological safety. No one is penalized for asking for help or making a mistake. These companies also employ four distinct approaches to day-to-day work: They use the best available knowledge (which is understood to be a moving target) to inform the design of specific process guidelines. They encourage employee collaboration by making information available when and where it's needed. They routinely capture data on processes to discover how work really happens. Finally, they study these data in an effort to find ways to improve execution. Taken together, these practices form the basis of a learning infrastructure that makes continual learning part of business as usual.


Time-resolved photoelectron spectroscopy of IR-driven electron dynamics in a charge transfer model system.
If the adiabatic approximation is valid, electrons smoothly adapt to molecular geometry changes. In contrast, as a characteristic of diabatic dynamics, the electron density does not follow the nuclear motion. Recently, we have shown that the asymmetry in time-resolved photoelectron spectra serves as a tool to distinguish between these dynamics [Falge et al., J. Phys. Chem. Lett., 2012, 3, 2617]. Here, we investigate the influence of an additional, moderately intense infrared (IR) laser field, as often applied in attosecond time-resolved experiments, on such asymmetries. This is done using a simple model for coupled electronic-nuclear motion. We calculate time-resolved photoelectron spectra and their asymmetries and demonstrate that the spectra directly map the bound electron-nuclear dynamics. From the asymmetries, we can trace the IR field-induced population transfer and both the field-driven and intrinsic (non-)adiabatic dynamics. This holds true when considering superposition states accompanied by electronic coherences. The latter are observable in the asymmetries for sufficiently short XUV pulses to coherently probe the coupled states. It is thus documented that the asymmetry is a measure for phases in bound electron wave packets and non-adiabatic dynamics.


A comparison of ibuprofen arginine with morphine sulphate for pain relief after orthopaedic surgery.
In a randomized, double-blind, double-dummy, single-dose, parallel-group study, oral ibuprofen arginine (400 mg) was compared with intramuscular (i.m.) morphine sulphate (5 or 10 mg) for post-operative pain relief after orthopaedic surgery in 120 patients. The study medication was administered post-operatively at the time when each patient first requested pain relief for moderate to severe pain. Assessment of pain intensity and pain relief was made using standard visual analogue scales and verbal rating scores. In all three groups, there was a reduction in pain compared with baseline, measured by visual analogue scales and verbal rating scores, at all time points up to completion of the study at 240 min. For example, visual analogue scales decreased by 35 (10-52) mm at 1 h in the morphine 5 mg group, 24 (12-39) mm in morphine 10 mg group and 21 (8-38) mm in the ibuprofen arginine group (median and inter-quartile range). Verbal rating scores showed a similar pattern. Comparing the groups over the whole study period using the sum of pain intensity differences showed no significant differences in pain experience between the groups. Assessment of total pain relief also showed no significant differences. The incidence and types of side effect seen were similar in the three groups.


Risk factors for posttraumatic vasospasm.
Posttraumatic vasospasm (PTV) is an underrecognized cause of ischemic damage after severe traumatic brain injury (TBI) that independently predicts poor outcome. There are, however, no guidelines for PTV screening and management, partly due to limited understanding of its pathogenesis and risk factors. A database review of 46 consecutive cases of severe TBI in pediatric and adult patients was conducted to identify risk factors for the development of PTV. Univariate analysis was performed to identify potential risk factors for PTV, which were subsequently analyzed using a multivariate logistic regression model to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Fever on admission was an independent risk factor for development of PTV (OR 22.2, 95% CI 1.9-256.8), and patients with hypothermia on admission did not develop clinically significant vasospasm during their hospital stay. The presence of small parenchymal contusions was also an independent risk factor for PTV (OR 7.8, 95% CI 0.9-69.5), whereas the presence of subarachnoid hemorrhage or other patterns of intracranial injury were not. Other variables, such as age, sex, ethnicity, degree of TBI severity, or admission laboratory values, were not independent predictors for the development of clinically significant PTV. Independent risk factors for PTV include parenchymal contusions and fever. These results suggest that diffuse mechanical injury and activation of inflammatory pathways may be underlying mechanisms for the development of PTV, and that a subset of patients with these risk factors may be an appropriate population for aggressive screening. Further studies are needed to determine if treatments targeting fever and inflammation may be effective in reducing the incidence of vasospasm following severe TBI.


Extraction of the average and differential dynamical response in stimulus-locked experimental data.
In optical imaging experiments of primary visual cortex, visual stimuli evoke a complicated dynamics. Typically, any stimulus with sufficient contrast evokes a response. Much of the response is the same regardless of which stimulus is presented. For instance, when oriented drifting gratings are presented to the visual system, over 90% of the response is the same from orientation to orientation. Small differences may be seen, however, between the responses to different orientations. A problem in the analysis of optical measurements of the response to stimulus in cortical tissue is the distinction of the 'global' or 'non-specific' response from the 'differential' or 'stimulus-specific' response. This problem arises whenever the signal of interest is the difference in response to various stimuli and is evident in many kinds of uni- and multivariate data. To this end, we present enhancements to a frequency-based method that we previously introduced called the periodic stacking method. These enhancements allow us to separately estimate the dynamics of both the average signal across all stimuli (the 'global' response) and deviations from the average amongst the various stimuli (the 'stimulus-specific' response) evoked in response to a set of stimuli. We also discuss improvements in the signal-to-noise ratio, relative to standard trial averaging methods, that result from the data-adaptive smoothing in our method.


Targeting MYC dependence in cancer by inhibiting BET bromodomains.
The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein-DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G(1) arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.


iPPI-DB: an online database of modulators of protein-protein interactions.
In order to boost the identification of low-molecular-weight drugs on protein-protein interactions (PPI), it is essential to properly collect and annotate experimental data about successful examples. This provides the scientific community with the necessary information to derive trends about privileged physicochemical properties and chemotypes that maximize the likelihood of promoting a given chemical probe to the most advanced stages of development. To this end we have developed iPPI-DB (freely accessible at http://www.ippidb.cdithem.fr), a database that contains the structure, some physicochemical characteristics, the pharmacological data and the profile of the PPI targets of several hundreds modulators of protein-protein interactions. iPPI-DB is accessible through a web application and can be queried according to two general approaches: using physicochemical/pharmacological criteria; or by chemical similarity to a user-defined structure input. In both cases the results are displayed as a sortable and exportable datasheet with links to external databases such as Uniprot, PubMed. Furthermore each compound in the table has a link to an individual ID card that contains its physicochemical and pharmacological profile derived from iPPI-DB data. This includes information about its binding data, ligand and lipophilic efficiencies, location in the PPI chemical space, and importantly similarity with known drugs, and links to external databases like PubChem, and ChEMBL.


Context-dependent logo matching and recognition.
We contribute, through this paper, to the design of a novel variational framework able to match and recognize multiple instances of multiple reference logos in image archives. Reference logos and test images are seen as constellations of local features (interest points, regions, etc.) and matched by minimizing an energy function mixing: 1) a fidelity term that measures the quality of feature matching, 2) a neighborhood criterion that captures feature co-occurrence/geometry, and 3) a regularization term that controls the smoothness of the matching solution. We also introduce a detection/recognition procedure and study its theoretical consistency. Finally, we show the validity of our method through extensive experiments on the challenging MICC-Logos dataset. Our method overtakes, by 20%, baseline as well as state-of-the-art matching/recognition procedures.


Lifetime hypertension as a predictor of brain structure in older adults: cohort study with a 28-year follow-up.
Hypertension is associated with an increased risk of dementia and depression with uncertain longitudinal associations with brain structure. To examine lifetime blood pressure as a predictor of brain structure in old age. A total of 190 participants (mean age 69.3 years) from the Whitehall II study were screened for hypertension six times (1985-2013). In 2012-2013, participants had a 3T-magnetic resonance imaging (MRI) brain scan. Data from the MRI were analysed using automated and visual measures of global atrophy, hippocampal atrophy and white matter hyperintensities. Longitudinally, higher mean arterial pressure predicted increased automated white matter hyperintensities (P<0.002). Cross-sectionally, hypertensive participants had increased automated white matter hyperintensities and visually rated deep white matter hyperintensities. There was no significant association with global or hippocampal atrophy. Long-term exposure to high blood pressure predicts hyperintensities, particularly in deep white matter. The greatest changes are seen in those with severe forms of hypertension, suggesting a dose-response pattern.


Mental time travel and the evolution of the human mind.
This article contains the argument that the human ability to travel mentally in time constitutes a discontinuity between ourselves and other animals. Mental time travel comprises the mental reconstruction of personal events from the past (episodic memory) and the mental construction of possible events in the future. It is not an isolated module, but depends on the sophistication of other cognitive capacities, including self-awareness, meta-representation, mental attribution, understanding the perception-knowledge relationship, and the ability to dissociate imagined mental states from one's present mental state. These capacities are also important aspects of so-called theory of mind, and they appear to mature in children at around age 4. Furthermore, mental time travel is generative, involving the combination and recombination of familiar elements, and in this respect may have been a precursor to language. Current evidence, although indirect or based on anecdote rather than on systematic study, suggests that nonhuman animals, including the great apes, are confined to a "present" that is limited by their current drive states. In contrast, mental time travel by humans is relatively unconstrained and allows a more rapid and flexible adaptation to complex, changing environments than is afforded by instincts or conventional learning. Past and future events loom large in much of human thinking, giving rise to cultural, religious, and scientific concepts about origins, destiny, and time itself.


The loop opening/closing motion of the enzyme triosephosphate isomerase.
To explore the origin of the large-scale motion of triosephosphate isomerase's flexible loop (residues 166 to 176) at the active site, several simulation protocols are employed both for the free enzyme in vacuo and for the free enzyme with some solvent modeling: high-temperature Langevin dynamics simulations, sampling by a "dynamics driver" approach, and potential-energy surface calculations. Our focus is on obtaining the energy barrier to the enzyme's motion and establishing the nature of the loop movement. Previous calculations did not determine this energy barrier and the effect of solvent on the barrier. High-temperature molecular dynamics simulations and crystallographic studies have suggested a rigid-body motion with two hinges located at both ends of the loop; Brownian dynamics simulations at room temperature pointed to a very flexible behavior. The present simulations and analyses reveal that although solute/solvent hydrogen bonds play a crucial role in lowering the energy along the pathway, there still remains a high activation barrier. This finding clearly indicates that, if the loop opens and closes in the absence of a substrate at standard conditions (e.g., room temperature, appropriate concentration of isomerase), the time scale for transition is not in the nanosecond but rather the microsecond range. Our results also indicate that in the context of spontaneous opening in the free enzyme, the motion is of rigid-body type and that the specific interaction between residues Ala176 and Tyr208 plays a crucial role in the loop opening/closing mechanism.


Prognostic Implication of Persistent Human Papillomavirus Type 16 DNA Detection in Oral Rinses for Human Papillomavirus-Related Oropharyngeal Carcinoma.
Human papillomavirus-related oropharyngeal carcinoma (HPV-OPC) is increasing in incidence in the United States. Although HPV-OPC has favorable prognosis, 10% to 25% of HPV-OPCs recur. Detection of human papillomavirus (HPV) DNA in oral rinses is associated with HPV-OPC, but its potential as a prognostic biomarker is unclear. To determine whether HPV DNA detection in oral rinses after treatment for HPV-OPC is associated with recurrence and survival. Prospective cohort study of patients with incident HPV-OPC diagnosed from 2009 to 2013 at 4 academic tertiary referral cancer centers in the United States. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis), and evaluated for HPV DNA. Among an initial cohort of 157 participants with incident HPV-OPC treated with curative intent, 124 had 1 or more posttreatment oral rinses available and were included in this study. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the association of HPV DNA detection in oral rinses with survival was evaluated using Cox regression analysis. Oral HPV type 16 (HPV16) DNA was common at diagnosis (67 of 124 participants [54%]). In contrast, oral HPV16 DNA was detected in only 6 participants after treatment (5%), including 5 with HPV16 DNA also detected at diagnosis (persistent oral HPV16 DNA). Two-year DFS and OS were 92% (95% CI, 94%-100%) and 98% (95% CI, 93%-99%). Persistent oral HPV16 DNA was associated with worse DFS (hazard ratio, 29.7 [95% CI, 9.0-98.2]) and OS (hazard ratio, 23.5 [95% CI, 4.7-116.9]). All 5 participants with persistent oral HPV16 DNA developed recurrent disease, 3 with local disease involvement. In contrast, just 9 of 119 participants (8%) without persistent oral HPV16 DNA developed recurrent disease, only 1 (11%) with local disease involvement. Median (range) time from earliest posttreatment oral HPV16 DNA detection to recurrence was 7.0 (3.7-10.9) months. Human papillomavirus type 16 DNA in oral rinses is common at diagnosis but rare after treatment for HPV-OPC. Our data suggest that, although infrequent, persistent HPV16 DNA in posttreatment oral rinses is associated with poor prognosis and is a potential tool for long-term tumor surveillance, perhaps more so for local recurrence.


Type 2 Diabetes Leads to Axon Initial Segment Shortening in db/db Mice.
Cognitive and mood impairments are common central nervous system complications of type 2 diabetes, although the neuronal mechanism(s) remains elusive. Previous studies focused mainly on neuronal inputs such as altered synaptic plasticity. Axon initial segment (AIS) is a specialized functional domain within neurons that regulates neuronal outputs. Structural changes of AIS have been implicated as a key pathophysiological event in various psychiatric and neurological disorders. Here we evaluated the structural integrity of the AIS in brains of db/db mice, an established animal model of type 2 diabetes associated with cognitive and mood impairments. We assessed the AIS before (5 weeks of age) and after (10 weeks) the development of type 2 diabetes, and after daily exercise treatment of diabetic condition. We found that the development of type 2 diabetes is associated with significant AIS shortening in both medial prefrontal cortex and hippocampus, as evident by immunostaining of the AIS structural protein βIV spectrin. AIS shortening occurs in the absence of altered neuronal and AIS protein levels. We found no change in nodes of Ranvier, another neuronal functional domain sharing a molecular organization similar to the AIS. This is the first study to identify AIS alteration in type 2 diabetes condition. Since AIS shortening is known to lower neuronal excitability, our results may provide a new avenue for understanding and treating cognitive and mood impairments in type 2 diabetes.


Assessing the internal consistency and temporal stability of advance directives generated by an interactive, online computer program.
Evaluate the internal consistency and temporal stability of advance directives (ADs) generated by an interactive, online computer program. 33 participants completed the program at three visits, 2 weeks apart. Agreement rates were calculated for the General Wishes component of the AD. The test-retest method was used to examine the temporal stability of the Specific Wish for Treatment component which contains five clinical scenarios. General Wishes remained stable with 94% selecting the identical response at each visit. For the Specific Wish for Treatment scale, significant variations in test-retest correlations existed (ie, ρ=0.32-0.78, between time points 1 and 2); however within scenario, correlations did not significantly vary between time points. Temporal stability was lower in the Specific Wish for Treatment scale compared with General Wishes (average ρ=0.59, between time points 1 and 2; and ρ=0.75, between time points 2 and 3). ADs generated by an online decision aid demonstrate good temporal stability, with highest stability for General Wishes and moderate stability for Specific Wish for Treatment regarding medical treatments in specific clinical scenarios. Internal consistency for wish for treatment across all time points and scenarios was high (Cronbach α>0.90).


The impact of emotion-related autonomic nervous system responsiveness on pain sensitivity in female patients with fibromyalgia.
Patients with fibromyalgia have shown hyporeactive autonomic nervous system (ANS) responses to physical stressors, augmented pain to ANS changes, and heightened negative emotions, which can increase pain. This study examined ANS reactivity to negative emotions and its association with pain in fibromyalgia and control participants. Sixty-two women with fibromyalgia and 59 women in a control group recalled neutral, and anger- and sadness-eliciting experiences while ANS activity was monitored. Clinical and experimental pain were assessed in response to each emotion. Compared with neutral recall, heart rate (p = .050), mean arterial pressure (p < .001), and high-frequency heart rate variability (p = .012) increased in response to sadness, whereas heart rate decreased (p = .002) and mean arterial pressure increased (p < .001) in response to anger; however, ANS responses did not differ between patients and control participants (all p > .29). Among patients only, decreased preejection period (anger-pain threshold: r = 0.31, p = .018) and total peripheral resistance in response to negative emotions (anger-pain tolerance: r = 0.35, p = .025; sadness-pain threshold: r = 0.51, p < .001; sadness-pain tolerance: r = 0.61, p < .001) correlated with more pain. These data suggest that the ANS is not hyporesponsive to elicited emotions in fibromyalgia; however, patients with a larger pain response showed an ANS response pattern reflecting heightened β-adrenergic and reduced α-adrenergic reactivity. Future research should test whether a specific ANS response pattern to emotions is a consequence of increased pain or whether it amplifies pain.


Computed tomographic appearance of osteochondritis dissecans-like lesions of the proximal articular surface of the proximal phalanx in a horse.
A 6-year-old Thoroughbred gelding presented with a left forelimb lameness. The results of lameness examination, radiography, nuclear scintigraphy, and computed tomography are presented. Based on the diagnostic imaging, subchondral fractures and osteochondritis dissecans lesions of the proximal articular surface of the proximal phalanx were diagnosed. A brief discussion of osteochondritis dissecans is presented.


Quantitative Methods for Measuring Repair Rates and Innate-Immune Cell Responses in Wounded Mouse Skin.
In skin wounds, innate-immune cells clear up tissue debris and microbial contamination, and also secrete cytokines and other growth factors that impact repair process such as re-epithelialization and wound closure. After injury, there is a rapid influx and efflux of immune cells at wound sites, yet the function of each innate cell population in skin repair is still under investigation. Flow cytometry is a valuable research tool for detecting and quantifying immune cells; however, in mouse back skin, the difficulty in extracting immune cells from small area of skin due to tissue complexity has made cytometric analysis an underutilized tool. In this paper, we provide detailed methods on the digestion of lesion-specific skin without disrupting antigen expression followed by multiplex cell staining that allows for identification of seven innate-immune populations, including rare subsets such as group-3 innate lymphoid cells (ILC3s), by flow-cytometry analysis. Furthermore, when studying the functions of immune cells to tissue repair an important metric to monitor is size of the wound opening. Normal wounds close steadily albeit at non-linear rates, while slow or stalled wound closure can indicate an underlying problem with the repair process. Calliper measurements are difficult and time-consuming to obtain and can require repeated sedation of experimental animals. We provide advanced methods for measuring of wound openness; digital 3D image capture and semi-automated image processing that allows for unbiased, reliable measurements that can be taken repeatedly over time.


Association of pathological and volumetric biomarker changes with cognitive decline in clinically normal adults: Harvard Aging Brain Study.
Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared to amyloid-beta (Aβ) and tau imaging, it is less specific for Alzheimer's disease (AD) pathology. This lack of specificity could provide indirect information about potential co-pathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aβ, tau, HV, and cognition, measured over a ten-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aβ and tau. We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI [follow-up duration: 1.3-7.0y], neocortical Aβ imaging on PiB PET scans [1.9-8.5y], entorhinal and inferior temporal tau on Flortaucipir PET scans [0.8-6.0y], and the Preclinical Alzheimer Cognitive Composite [3.0-9.8y] were prospectively collected. We evaluated the longitudinal associations between Aβ, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline. We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years old (range: 63-87). Thirty-four participants (27%) exhibited an initial high-Aβ burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2=0.28, p<0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aβ and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers. In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aβ or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.


Epidemiology of acquired immune deficiency syndrome in persons aged 50 years or older.
Acquired immune deficiency syndrome (AIDS) has afflicted persons of all ages, yet only recently has attention been devoted to AIDS in older persons. To examine the epidemiology of AIDS in persons greater than or equal to 50 years old in the United States, we analyzed cases reported to the Centers for Disease Control. The number reported annually in persons greater than or equal to 50 years old increased from 13 in 1981 to 3,562 in 1989. Through December 1989, 11,984 had been reported, representing 10% of all cases. Although male homosexual contact accounted for most cases in persons aged 50-69, blood transfusion became a more common means of exposure with increasing age, accounting for 28% of cases in persons aged 60-69 and 64% of cases in individuals aged greater than or equal to 70. The proportion of women increased from 6.1% in persons with AIDS aged 50-59 to 28.7% of those aged greater than or equal to 70. The proportion of AIDS diagnoses made in the same month as death increased from 16% in persons aged 50-59 to 37% in those aged greater than or equal to 80, suggesting either more rapid progression of disease or increasing delay in diagnosis. As the incidence in older persons continues to increase, clinicians caring for older patients must become more familiar with AIDS.


Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.
The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.


SHH-N upregulates Sfrp2 to mediate its competitive interaction with WNT1 and WNT4 in the somitic mesoderm.
Dorsoventral polarity of the somitic mesoderm is established by competitive signals originating from adjacent tissues. The ventrally located notochord provides the ventralizing signals to specify the sclerotome, while the dorsally located surface ectoderm and dorsal neural tube provide the dorsalizing signals to specify the dermomyotome. Noggin and SHH-N have been implicated as the ventralizing signals produced by the notochord. Members of the WNT family of proteins, on the other hand, have been implicated as the dorsalizing signals derived from the ectoderm and dorsal neural tube. When presomitic explants are confronted with cells secreting SHH-N and WNT1 simultaneously, competition to specify the sclerotome and dermomyotome domains within the naive mesoderm can be observed. Here, using these explant cultures, we provide evidence that SHH-N competes with WNT1, not only by upregulating its own receptor Ptc1, but also by upregulating Sfrp2 (Secreted frizzled-related protein 2), which encodes a potential WNT antagonist. Among the four known Sfrps, Sfrp2 is the only member expressed in the sclerotome and upregulated by SHH-N recombinant protein. We further show that SFRP2-expressing cells can reduce the dermomyotome-inducing activity of WNT1 and WNT4, but not that of WNT3a. Together, our results support the model that SHH-N at least in part employs SFRP2 to reduce WNT1/4 activity in the somitic mesoderm.


The evolutionary origin of human hyper-cooperation.
Proactive, that is, unsolicited, prosociality is a key component of our hyper-cooperation, which in turn has enabled the emergence of various uniquely human traits, including complex cognition, morality and cumulative culture and technology. However, the evolutionary foundation of the human prosocial sentiment remains poorly understood, largely because primate data from numerous, often incommensurable testing paradigms do not provide an adequate basis for formal tests of the various functional hypotheses. We therefore present the results of standardized prosociality experiments in 24 groups of 15 primate species, including humans. Extensive allomaternal care is by far the best predictor of interspecific variation in proactive prosociality. Proactive prosocial motivations therefore systematically arise whenever selection favours the evolution of cooperative breeding. Because the human data fit this general primate pattern, the adoption of cooperative breeding by our hominin ancestors also provides the most parsimonious explanation for the origin of human hyper-cooperation.


Diffusion of active dimers in a Couette flow.
We study the 3D dynamics of an elastic dimer consisting of an active swimmer bound to a passive cargo, both suspended in a Couette flow. Using numerical simulations, we determine the diffusivity of such an active dimer in the presence of long-range hydrodynamic interactions for different values of its self-propulsion speed and the Couette flow. We observe that the effect of hydrodynamic interactions is greatly enhanced under the condition that self-propulsion is strong enough to contrast the shear flow. The magnitude of the effect grows with the size of the dimer's constituents relative to their distance, which makes it appreciable under experimental conditions.


Impact of interaction of cigarette smoking with angiotensin-converting enzyme polymorphisms on end-stage renal disease risk in a Han Chinese population.
Several polymorphisms in the angiotensin-converting enzyme (ACE) and ACE2 genes are associated with the development of end-stage renal disease (ESRD). Certain genetic polymorphisms may modify the deleterious effects of environmental factors such as cigarette smoking and may also modify the inherited risk. We investigated the association of six ACE and ACE2 polymorphisms with ESRD to determine whether a relationship exists between gene-smoking interactions and ESRD. We performed a case-control association study and genotyped 683 ESRD patients and 653 healthy controls. All subjects were genotyped for ACE (I/D, G2350A and A-240T) and ACE2 (G8790A, A1075G and G16854C) gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Significant associations were observed between ACE I/D and G2350A polymorphisms and ESRD. There was no difference in ACE2 genotype distribution between ESRD patients and healthy controls. Haplotype analysis showed that DAA and DAT haplotypes were risk factors for ESRD. Moreover, a gene-environment interaction was observed between ACE I/D polymorphism and cigarette smoking. ACE I/D and ACE G2350A polymorphisms were associated with the development of ESRD. The interaction between ACE I/D polymorphism and smoking is also associated with an enhanced risk of ESRD.


Prevalence and determinants of tobacco use in a highly literate rural community in southern India.
The adverse effects of tobacco use on the health of an individual are well known. It is essential to identify factors leading to tobacco use to plan strategies to limit its use. Education is known to influence the prevalence of tobacco use. We aimed to determine the prevalence and patterns of tobacco use in a rural community with a high literacy rate and to examine the socioeconomic and demographic correlates of tobacco consumption in the area. A cross-sectional survey using personal interviews was carried out on 832 individuals > 15 years of age. The prevalence of current daily use of tobacco was used as the outcome measure. The main analytical methods used were chi-square test and multiple logistic regression analysis. The prevalence of tobacco use was 17.5%, being common among older persons, the lower socioeconomic group and those who were less educated. Tobacco was used predominantly in smokeless forms (chewing, snuff or both). The commonest reason cited for initiating tobacco use was to relieve toothache. Our findings in this rural community suggest that improvement in the educational and socioeconomic status may lead to a decline in the use of tobacco. Health education to improve dental hygiene may also help to reduce tobacco use in this community as it is predominantly used in the chewing form.


Practice parameters for the indications for polysomnography and related procedures: an update for 2005.
These practice parameters are an update of the previously-published recommendations regarding the indications for polysomnography and related procedures in the diagnosis of sleep disorders. Diagnostic categories include the following: sleep related breathing disorders, other respiratory disorders, narcolepsy, parasomnias, sleep related seizure disorders, restless legs syndrome, periodic limb movement sleep disorder, depression with insomnia, and circadian rhythm sleep disorders. Polysomnography is routinely indicated for the diagnosis of sleep related breathing disorders; for continuous positive airway pressure (CPAP) titration in patients with sleep related breathing disorders; for the assessment of treatment results in some cases; with a multiple sleep latency test in the evaluation of suspected narcolepsy; in evaluating sleep related behaviors that are violent or otherwise potentially injurious to the patient or others; and in certain atypical or unusual parasomnias. Polysomnography may be indicated in patients with neuromuscular disorders and sleep related symptoms; to assist in the diagnosis of paroxysmal arousals or other sleep disruptions thought to be seizure related; in a presumed parasomnia or sleep related seizure disorder that does not respond to conventional therapy; or when there is a strong clinical suspicion of periodic limb movement sleep disorder. Polysomnography is not routinely indicated to diagnose chronic lung disease; in cases of typical, uncomplicated, and noninjurious parasomnias when the diagnosis is clearly delineated; for patients with seizures who have no specific complaints consistent with a sleep disorder; to diagnose or treat restless legs syndrome; for the diagnosis of circadian rhythm sleep disorders; or to establish a diagnosis of depression.


Defensive fruit metabolites obstruct seed dispersal by altering bat behavior and physiology at multiple temporal scales.
The paradoxical presence of toxic chemical compounds in ripe fruits represents a balance between plant enemies and allies: chemical traits can defend seeds against antagonistic herbivores, seed predators, or fungal pathogens, but also can impose costs by repelling mutualistic seed dispersers, although the costs are often difficult to quantify. Seeds gain fitness benefits from traveling far from the parent plant, as they can escape from parental competition and elude specialized herbivores as well as pathogens that accumulate on adult plants. However, seeds are difficult to follow from their parent plant to their final destination. Thus, little is known about the factors that determine seed dispersal distance. We investigated this potential cost of fruit secondary compounds, reduced seed dispersal distance, by combining two data sets from previous work on a Neotropical bat-plant dispersal system (bats in the genus Carollia and plants in the genus Piper). We used data from captive behavioral experiments, which show how amides in ripe fruits of Piper decrease the retention time of seeds and alter food choices. With new analyses, we show that these defensive secondary compounds also delay the time of fruit removal. Next, with a behaviorally annotated bat telemetry data set, we quantified post-feeding movements (i.e., seed dispersal distances). Using generalized additive mixed models we found that seed dispersal distances varied nonlinearly with gut retention times as well as with the time of fruit removal. By interrogating the model predictions, we identified two novel mechanisms by which fruit secondary compounds can impose costs in terms of decreased seed dispersal distances: (1) small-scale reductions in gut retention time and (2) causing fruits to forgo advantageous bat activity peaks that confer high seed dispersal distances.