Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation: opportunities for intervention.
Mechanisms by which aggressive and depressive disorders may be exacerbated by nutritional deficiencies in omega-3 fatty acids are considered. Early developmental deficiencies in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may lower serotonin levels at critical periods of neurodevelopment and may result in a cascade of suboptimal development of neurotransmitter systems limiting regulation of the limbic system by the frontal cortex. Residual developmental deficits may be manifest as dysregulation of sympathetic responses to stress including decreased heart rate variability and hypertension, which in turn have been linked to behavioral dysregulation. Little direct data are available to disentangle residual neurodevelopmental effects from reversible adult pathologies. Ensuring optimal intakes of omega-3 fatty acids during early development and adulthood shows considerable promise in preventing aggression and hostility.


Vitellogenin is not an appropriate biomarker of feminisation in a crustacean.
The expression of the yolk protein vitellogenin (Vtg) has been used as a biomarker of feminisation in multiple fish species throughout the world. Since the late 1990s, researchers have attempted to develop similar biomarkers to address whether reproductive endocrine disruption also occurs in the males of invertebrate groups such as the Crustacea. To date, the vast majority of studies investigating Vtg induction in male Crustacea have resulted in negative or inconclusive results, leading researchers to question the utility of Vtg expression as a biomarker in this taxon. This study measured the expression of Vtg genes in two intersex phenotypes (termed internal and external) found in the male amphipod, Echinogammarus marinus, and compared them with those of normal males and females. Males presenting the external intersex phenotype are infected with known feminising parasites and display a variety of feminised traits including oviduct structures on their testes and external female brood plates (oostegites). The internal intersex male phenotype, that displays a pronounced oviduct structure on the testes without the external intersex characteristics, is not parasite infected and it is thought to be a result of environmental contamination. Given their morphology, these phenotypes might be considered highly 'feminised' or 'de-masculinised' and can be utilised to test the suitability of feminisation biomarkers. The E. marinus transcriptome was searched for genes resembling Vtg and two sequences were revealed, that we subsequently refer to as Vtg1 and Vtg2. Results from a high-throughput transcriptomic sequencing screen of gonadal cDNA libraries suggested that very low expression (in this manuscript gene transcription is taken to represent gene expression, although it is acknowledged that in addition to transcription, translation, transcript processing, mRNA stability and protein stability can regulate gene expression) of Vtg1 and Vtg2 in normal males (ESTs=1 and 0 for Vtg1 and Vtg2, respectively), internal intersex males (ESTs=0 for both Vtg sequences) and external intersex males (ESTs=5 and 0 for Vtg1 and Vtg2, respectively). In contrast, the sequencing suggested notable levels of expression of both Vtg genes in females (ESTs=1133 and 84 for Vtg1 and Vtg2, respectively). Subsequent qPCR analysis validates these expression levels, with the signal for Vtg1 and Vtg2 transcripts in all male phenotypes being indistinguishable from that caused by contamination of trace levels of genomic DNA or the low-level amplification non-target sequences. These findings suggest that Vtg expression is not notably induced in highly feminised amphipods and is therefore not an appropriate biomarker of feminisation/de-masculination in crustaceans. We discuss our findings in the context of previous attempts to measure Vtg in male crustaceans and suggest a requirement for more appropriate taxon-specific biomarkers to monitor feminisation in these groups.


Continuous Noninvasive Hemoglobin Monitoring Reflects the Development of Acute Hemodilution After Consecutive Fluid Challenges.
Consecutive fluid challenges (FCs) are frequently administered to maximize the stroke volume (SV) as part of a goal-directed therapy (GDT) strategy. However, fluid administration may also cause acute hemodilution that might lead to an actual paradoxical decrease in oxygen delivery (DO2). The aim of this study was to examine whether continuous noninvasive hemoglobin (SpHb) monitoring can be used to detect the development of acute hemodilution after graded fluid administration. In 40 patients who underwent major vascular or gastrointestinal surgery, an FC, consisting of 250 mL colloid solution, was administered. When the SV increased by ≥10%, the FC was repeated up to a maximum of 3 times. Laboratory-measured hemoglobin concentrations (BHb), SpHb, SV, cardiac output (CO), and DO2 values were recorded after each FC. All 40 patients received the first FC, 32 patients received the second FC, and 20 patients received the third FC (total of 750 mL). Out of the 92 administered FCs, only 55 (60%) caused an increase in SV ≥10% ("responders"). The first and the second FCs were associated with a significant increase in the mean CO and DO2, while the mean SpHb and BHb decreased significantly. However, the third and last FC was associated with no statistical difference in CO and SV, a further significant decrease in mean SpHb and BHb, and a significant decrease in DO2 in these patients. Compared to their baseline values (T0), BHb and SpHb decreased by a mean of 5.3% ± 4.9% and 4.4% ± 5.2%, respectively, after the first FC (T1; n = 40), by 9.7% ± 8.4% and 7.9% ± 6.9% after the second FC (T2; n = 32), and by 14.5% ± 6.2% and 14.6% ± 5.7% after the third FC (T3; n = 20). Concordance rates between the changes in SpHb and in BHb after the administration of 250, 500, and 750 mL colloids were 83%, 90%, and 100%, respectively. Fluid loading aimed at increasing the SV and the DO2 as part of GDT strategy is associated with acute significant decreases in both BHb and SpHb concentrations. When the administration of an FC is not followed by a significant increase (≥10%) in the SV, the DO2 decreases significantly due to the development of acute hemodilution. Continuous noninvasive monitoring of SpHb does not reflect accurately absolute BHb values, but may be reliably used to detect the development of acute hemodilution especially after the administration of at least 500 mL of colloids.


Molecular dynamics and principal components of potassium binding with human telomeric intra-molecular G-quadruplex.
Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase maintenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabilizing G-quadruplex, but their binding processes to human telomeric G-quadruplex remain uncharacterized. To investigate the detailed binding procedures, molecular dynamics simulations were conducted on the hybrid [3 + 1] form-one human telomeric intra-molecular G-quadruplex. We show here that the binding of a potassium ion to a G-tetrad core is mediated by two alternative pathways. Principal component analysis illustrated the dominant concerted motions of G-quadruplex occurred at the loop domains. MM-PBSA calculations revealed that binding was energetically favorable and driven by the electrostatic interactions. The lower binding site was found more constructive favorable for binding. Our data provide useful information on a potassium-mediated stable structure of human telomeric intra-molecular G-quadruplex, implicating in ion disorder associated conformational changes and targeted drug design.


Insect population control using a dominant, repressible, lethal genetic system.
A major modification to the sterile insect technique is described, in which transgenic insects homozygous for a dominant, repressible, female-specific lethal gene system are used. We demonstrate two methods that give the required genetic characteristics in an otherwise wild-type genetic background. The first system uses a sex-specific promoter or enhancer to drive the expression of a repressible transcription factor, which in turn controls the expression of a toxic gene product. The second system uses non-sex-specific expression of the repressible transcription factor to regulate a selectively lethal gene product. Both methods work efficiently in Drosophila melanogaster, and we expect these principles to be widely applicable to more economically important organisms.


The Antidiabetic Potential of Black Mulberry Extract-Enriched Pasta through Inhibition of Enzymes and Glycemic Index.
In the present work, pasta enriched in different formulations by black mulberry extract in order to inhibit enzymes related to starch hydrolyzation. Total phenol content (TPC), antioxidant activity and anthocyanin components of ethanol/water black mulberry extract were investigated. TPC of the black mulberry extract was found 65.61 ± 0.07 mg GAE/g. Black mulberry extract could scavenge the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals more effectively than tertiary butylhydroquinone (TBHQ) also vitamin C due to its detected polyphenolic compounds (cyanidin-3-glucoside, cyanidin-3-rutinoside, and cyanidin-3-xyloside). The IC50 value of the black mulberry extract was obtained 8.31 μg/mL while it was measured 59.62 and 62.64 μg/mL for TBHQ and vitamin C, respectively. The pasta-enriched with freeze-dried black mulberry extract showed effective inhibition against applied α-amylases (α-amylase from porcine pancreas, Bacillus sp, and human saliva) and α-glucosidase originated from Saccharomyces cerevisiae. The IC50 values of tested enzymes exhibited that black mulberry effectively act as an inhibitory agent comparing with acarbose because of its antioxidant activity. Results revealed that starch hydrolysis index (HI) and predicted glycemic index (GIpredicted) of cooked pasta-enriched with various concentration levels of black mulberry extract were significantly decreased especially when 1.5% of the extract was incorporated. In addition, The IC50 value of the black mulberry extract obtained from cooked pasta was increased against α-amylase and α-glucosidase. The results obviously presented that diabetes mellitus type 2 could be resolved by enrichment of polyphenolic compounds into the pasta.


A quantitative comparison of single-dye tracking analysis tools using Monte Carlo simulations.
Single-particle tracking (SPT) is widely used to study processes from membrane receptor organization to the dynamics of RNAs in living cells. While single-dye labeling strategies have the benefit of being minimally invasive, this comes at the expense of data quality; typically a data set of short trajectories is obtained and analyzed by means of the mean square displacements (MSD) or the distribution of the particles' displacements in a set time interval (jump distance, JD). To evaluate the applicability of both approaches, a quantitative comparison of both methods under typically encountered experimental conditions is necessary. Here we use Monte Carlo simulations to systematically compare the accuracy of diffusion coefficients (D-values) obtained for three cases: one population of diffusing species, two populations with different D-values, and a population switching between two D-values. For the first case we find that the MSD gives more or equally accurate results than the JD analysis (relative errors of D-values <6%). If two diffusing species are present or a particle undergoes a motion change, the JD analysis successfully distinguishes both species (relative error <5%). Finally we apply the JD analysis to investigate the motion of endogenous LPS receptors in live macrophages before and after treatment with methyl-β-cyclodextrin and latrunculin B.


Regulation of ion transport across lamprey (Lampetra fluviatilis) erythrocyte membrane by oxygen tension.
We have measured the effects of oxygen tension on the transport of Na+, K+ and Cl- across the erythrocyte membrane of the lamprey Lampetra fluviatilis. The transport of each ion was affected by the oxygen tension of the medium. Hypoxic conditions (PO2 2 kPa) caused an increase in the acidification-induced influx of Na+ via Na+/H+ exchange. The influx of K+ was only slightly affected by the oxygenation of the medium. In contrast, the basal K+ efflux, measured using the radioactive isotope 43K, was markedly reduced by decreasing the oxygen tension of the medium, whereas the K+ flux in hypotonic medium was not affected. Only minor effects of hypoxic conditions on the influx of Cl- were observed in either isotonic or hypotonic conditions (there was a tendency for the isotonic influx to increase) or on the efflux in isotonic conditions. However, deoxygenation caused a marked reduction in the Cl- efflux in hypotonic conditions. The results show that oxygen tension has a marked effect on the pH and volume regulatory transport pathways of lamprey erythrocytes. For K+ and Cl-, the regulation appears to be asymmetric, i.e. influx and efflux are affected differently.


A longitudinal study on risk factors for neck and shoulder pain among young adults in the transition from technical school to working life.
The study examined the course of neck and shoulder pain among a cohort of technical school students entering working life. We also aimed to identify work-related and individual risk factors for neck and shoulder pain during this transition period. The study was designed as a prospective cohort study following 420 technical school students (167 student hairdressers, 118 student electricians, and 135 media/design students) from school, through their apprenticeship and into working life. Every 4 (th)month over a 6.5 year period (2002-2009), the participant`s neck and shoulder pain for the preceding four weeks was assessed. Mechanical and psychosocial workplace factors as well as individual factors were evaluated at baseline and/or during the follow-up period. Data were analyzed by generalized estimating equations (GEE). We found a significant increase in neck and shoulder pain over time in the transition from technical school to working life. High mechanical workload was associated with neck and shoulder pain among women, while a high level of shoulder muscle endurance capacity was associated with lower rates of neck and shoulder pain among men. Perceived muscle tension and ethnicity were the most consistent predictors for neck and shoulder pain, found among both women and men. Increased neck and shoulder pain was found in the transition from technical school to working life, and both work-related and individual factors were associated with pain development.


Frequency of fab subtypes in acute myeloid leukemia patients at Aga Khan University Hospital Karachi.
Acute myeloid leukemia (AML) is a heterogeneous disease. Therefore, various parameters are needed to classify this disease into subtypes, so that specific treatment approaches can be utilized effectively. The commonly used method for diagnosis and classification is based on FAB criteria using morphology and cytochemical stains. For some of the categories, immunophenotyping is necessary. The aim of present study is to determine the frequency of various sub types in acute myeloid leukemia using FAB criteria in our population. This will aid in the correct diagnosis of acute leukemia and hence proper management of the patients. This is descriptive case control study conducted at Aga Khan University Hospital from January 1999 to December 2000. The total number of subjects was 116 that included both adults and children. The patients were diagnosed on the basis of bone marrow morphology using FAB classification. Cytochemistry was done in all cases, while immunophenotyping was considered only in those cases that were found to be problematic. Among 116 patients, 70 were males and 46 were females with male to female ratio 1.5:1. The age ranged between 6 months to 85 years with a mean age of 32 years. AML-M4 was the predominant French-American-British (FAB) subtype (36.2%) followed by M2 (30.25%), M3 (10.4%), M1 (8.7%), M0 (7.7%), M5a (3.5%), M5b (2.5%) and M6 (0.8%). The most common FAB subtype observed in our study was Acute myelomonocytic leukemia (M4) which is in accordance with studies reported from Saudia Arabia and a previous study reported from our institution. However,other national and international studies have reported Myeloblastic Leukemia with maturation (M2) as the predominant subtype of AML.


Light-sensitive vertical migration of the Japanese eel Anguilla japonica revealed by real-time tracking and its utilization for geolocation.
Short-time tracking (one to eight days) of the Japanese eel (Anguilla japonica) using ultrasonic transmitter was performed in the tropical-subtropical area adjacent to the spawning area and temperate area off the Japanese Archipelago. Of 16 eels (11 wild and five farmed) used, 10 wild eels displayed clear diel vertical migration (DVM) from the beginning, while the other five farmed eels tracked for 19 to 66 hours did not. During daytime, a significantly positive correlation between migration depth and light intensity recorded on the vessel was observed in the 10 wild eels, indicating that the eels were sensitive to sunlight even at the middle to lower mesopelagic zone (500 to 800 m). During nighttime, the eel migration depth was observed to be associated with the phase, rising and setting of the moon, indicating that the eels were sensitive to moonlight at the upper mesopelagic zone (<300 m). Two of 10 wild eels were in the yellow stage but shared similar DVM with the silver stage eels. Swimbladders of three silver stage eels were punctured before releasing, but very little effect on DVM was observed. The eels very punctually initiated descent upon nautical dawn and ascent upon sunset, enabling us to determine local times for sunrise and sunset, and hence this behavior may be used for geolocating eels. In fact, estimated positions of eels based on the depth trajectory data were comparable or even better than those obtained by light-based archival tag in other fish species.


A model free method for estimation of complicated adsorption isotherms in liquid chromatography.
Here we show that even extremely small variations in the adsorption isotherm can have a tremendous effect on the shape of the overloaded elution profiles and that the earlier in the adsorption isotherms the variation take place, the larger its impact on the shape of the elution profile. These variations are so small that they can be "hidden" by the discretization and in the general experimental noise when using traditional experimental methods, such as frontal analysis, to measure adsorption isotherms. But as the effects of these variations are more clearly visible in the elution profiles, the Inverse Method (IM) of adsorption isotherm estimation is an option. However, IM usually requires that one selects an adsorption isotherm model prior to the estimation process. Here we show that even complicated models might not be able to estimate the adsorption isotherms with multiple inflection points that small variations might give rise to. We therefore developed a modified IM that, instead of fixed adsorption isotherm models, uses monotone piecewise interpolation. We first validated the method with synthetic data and showed that it can be used to estimate an adsorption isotherm, which accurately predicts an extremely "strange" elution profile. For this case it was impossible to estimate the adsorption isotherm using IM with a fixed adsorption model. Finally, we will give an example of a real chromatographic system where adsorption isotherm with inflection points is estimated by the modified IM.


Mummified saints of the Northern Croatian Littoral.
The Istrian town of Vodnjan hosts a collection of mummified bodies and relics. Three mummies are completely preserved and belong to Blessed Leon Bembo, St Giovanni Olini, and St Nicolosa Bursa, while the other three are mummified remains of St Barbara, St Sebastian, and St Mary of Egypt. This article gives an overview of the three completely preserved bodies, including their external condition, hagiographic data, statements and hypotheses that need verification by future targeted scientific research. Although local populations attribute divine properties to the remains and treat their continued preservation as a mystery, their origin is probably similar to that of other mummified saints. A scientific study performed on the mummies will probably help to reveal the true origin and type of mummification of the bodies. Additional paleopathological research could also determine the cause of death, if the saints died by natural causes, or attest to any mutilation or sign of torture suffered in life and confirm them as the cause of death. Proper bioarchaeological research could bring useful osteobiographical updates to the existing records about these saints.


Identification of the naphthoquinone derivative inhibitors binding site in heat shock protein 90: an induced-fit docking, molecular dynamics and 3D-QSAR study.
The combination of molecular modeling methods to identify the putative binding site of inhibitors constitutes an important tool in drug discovery. In this work, we used these analyses to understand the potent inhibitory effect of naphthoquinone derivatives on heat shock protein 90 (Hsp90), one of the proteins involved in many types of cancer. Molecular docking results indicated that some favorable interactions of key amino acid residues at the binding site of Hsp90 with these quinones would be responsible for the inhibition of Hsp90 activity. Molecular docking and molecular dynamics simulation were carried out to further understand the binding modes and the interactions between the protein and these inhibitors. The main residues of the internal cavity were Val136, Phe138, Tyr139, Val150, Trp162 and Val186. The high concordance between the docking results and 3D-QSAR contour maps gives us helpful information about the environment of the binding site. Our results provide the bases for a rational modification of new molecules based in quinone scaffold, in order to design more potent Hsp90 inhibitors, which would exhibit highly potent antitumor activity.Communicated by Ramaswamy H. Sarma.


Neoliberal reform and health dilemmas: social hierarchy and therapeutic decision making in Senegal.
In this article, I trace the links among neoliberalism, regional ecological decline, and the dynamics of therapeutic processes in rural Senegal. By focusing on illness management in a small rural community, the article explores how economic reform is mediated by existing social structures, and how household social organization in turn influences therapeutic decision making. The illness episodes relayed here demonstrate how the acute economic and social crisis facing the Ganjool region becomes written on the bodies of young men, and how the fault lines of gender and generation shape illness experiences. These narratives also illuminate the tremendous discrepancy between the lived realities of sickness and death, and the idealized models of health participation and empowerment envisioned by the state. Rather than "neoliberal subjects" who behave as rational economic actors, men and women coping with illness are social beings embedded in fields of power characterized by highly stratified household social relations.


Prostacyclin synthesis in ovine pulmonary artery is developmentally regulated by changes in cyclooxygenase-1 gene expression.
Prostacyclin (PGI2) is a key mediator of pulmonary vasomotor tone during late gestation and in the newborn, and its production in whole lung increases during that period. We investigated the developmental regulation of PGI2 synthesis in ovine intrapulmonary artery (PA) segments from 110 to 115 d (F1) and 125 to 135 d gestation fetal lambs (F2, term = 144 d) and 1- and 4-wk-old newborn lambs (NB1 and NB2). Basal PGI2 rose fourfold from F1 to F2, fourfold from F2 to NB1, and twofold from NB1 to NB2. In all age groups 66-72% of PGI2 was derived from the endothelium. Similar fold increases in PGI2 were observed with maturation in intact and endothelium-denuded segments. In intact PA from F2, NB1, and NB2, basal PGI2 synthesis and synthesis maximally stimulated by bradykinin, A23187, or arachidonic acid rose with development in a comparable manner. In contrast, PGI2 synthesis stimulated by exogenous PGH2, the product of cyclooxygenase, was similar at all ages. Immunoblot analyses of PA from F2, NB1, and NB2 revealed that there is a sixfold maturational increase in cyclooxygenase-1 protein; the cyclooxygenase-2 isoform was not detectable. Cyclooxygenase-1 mRNA abundance in whole lung also rose with development. Thus, PGI2 synthesis in ovine PA endothelium and vascular smooth muscle increases markedly during late fetal and early newborn life; the increase is due to a rise in cyclooxygenase activity related to enhanced expression of cyclooxygenase-1. We conclude that there is developmental regulation of PA cyclooxygenase-1 gene expression, and that this may be critical to successful cardiopulmonary transition and function in the newborn.


Single subject research in occupational therapy: a case illustration.
Three male children with behavior-disorders were treated by tactile, vestibular, and proprioceptive sensory stimulation in 20-minute sessions 3 times per week for a period ranging from 4-to-6 weeks. Attention to a mathematical computation task was measured for several sessions before the introduction of treatment and immediately after each treatment session. Attention was operationally defined as the total time spent attneding to the task during a ten-minute test period. Of the three subjects, one showed negligible change, one showed some performance improvement and a reduction in response variability, and the third showed improvement followed by performance deterioration, though not to original low baseline levels. Although improvments were coincident with the onset of treatment, they may not be attributed to it, because no response stability was achieved during the baseline condition.


Bacterial outer membrane vesicles suppress tumor by interferon-γ-mediated antitumor response.
Gram-negative bacteria actively secrete outer membrane vesicles, spherical nano-meter-sized proteolipids enriched with outer membrane proteins, to the surroundings. Outer membrane vesicles have gained wide interests as non-living complex vaccines or delivery vehicles. However, no study has used outer membrane vesicles in treating cancer thus far. Here we investigate the potential of bacterial outer membrane vesicles as therapeutic agents to treat cancer via immunotherapy. Our results show remarkable capability of bacterial outer membrane vesicles to effectively induce long-term antitumor immune responses that can fully eradicate established tumors without notable adverse effects. Moreover, systematically administered bacterial outer membrane vesicles specifically target and accumulate in the tumor tissue, and subsequently induce the production of antitumor cytokines CXCL10 and interferon-γ. This antitumor effect is interferon-γ dependent, as interferon-γ-deficient mice could not induce such outer membrane vesicle-mediated immune response. Together, our results herein demonstrate the potential of bacterial outer membrane vesicles as effective immunotherapeutic agent that can treat various cancers without apparent adverse effects.Bacterial outer membrane vesicles (OMVs) contain immunogens but no study has yet examined their potential in treating cancer. Here, the authors demonstrate that OMVs can suppress established tumours and prevent tumour metastasis by an interferon-γ mediated antitumor response.


[Collagenase-A revolution of Dupuytren's therapy].
Up to date, Dupuytren's contracture is a disease without cure. Almost 20 years ago, enzymatic cord degradation with clostridial collagenase was described for the first time. Whereas until recently limited fasciectomy was the treatment of choice for most of the patients, now collagenase offers a minimally invasive treatment in cases with palpable cords. Collagenase is a safe and effective treatment with success rates around 85 % for MCP joint and 65 % for PIP joints and a low complication rate. One point of concern is the recurrence rate which is higher compared to open surgery. A review of the literature is presented, technique and indication for collagenase are discussed.


Discreteness and resolution effects in rapidly rotating turbulence.
Rotating turbulence is characterized by the nondimensional Rossby number Ro, which is a measure of the strength of the Coriolis term relative to that of the nonlinear term. For rapid rotation (Ro-->0) , nonlinear interactions between inertial waves are weak, and the theoretical approaches used for other weak (wave) turbulence problems can be applied. The important interactions in rotating turbulence at small Ro become those between modes satisfying the resonant and near-resonant conditions. Often, discussions comparing theoretical results and numerical simulations are questioned because of a speculated problem regarding the discreteness of the modes in finite numerical domains versus continuous modes in unbounded continuous theoretical domains. This argument finds its origin in a previous study of capillary waves, for which resonant interactions have a very particular property that is not shared by inertial waves. This possible restriction on numerical simulations of rotating turbulence to moderate Ro has never been quantified. In this paper, we inquire whether the discreteness effects observed in capillary wave turbulence are also present in inertial wave turbulence at small Ro. We investigate how the discreteness effects can affect the setup and interpretation of studies of rapidly rotating turbulence in finite domains. In addition, we investigate how the resolution of finite numerical domains can affect the different types of nonlinear interactions relevant for rotating inertial wave turbulence theories. We focus on Rossby numbers ranging from 0 to 1 and on periodic domains due to their relevance to direct numerical simulations of turbulence. We find that discreteness effects are present for the system of inertial waves for Rossby numbers comfortably smaller than those used in the most recent numerical simulations of rotating turbulence. We use a kinematic model of the cascade of energy via selected types of resonant and near-resonant interactions to determine the threshold of Ro below which discreteness effects become important enough to render an energy cascade impossible.


LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT.
Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene and protein expressions in a murine model of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant lung cancer have been studied to gain insight into the biology of these tumors. However, the molecular consequences of LKB1 loss in human lung cancer have not been fully characterized. We studied gene expression profiles associated with LKB1 loss in resected lung adenocarcinomas, non-small-cell lung cancer cell lines, and murine tumors. The biological significance of dysregulated genes was interpreted using gene set enrichment and transcription factor analyses and also by integration with somatic mutations and proteomic data. Loss of LKB1 is associated with consistent gene expression changes in resected human lung cancers and cell lines that differ substantially from the mouse model. Our analysis implicates novel biological features associated with LKB1 loss, including altered mitochondrial metabolism, activation of the nuclear respiratory factor 2 (NRF2) transcription factor by kelch-like ECH-associated protein 1 (KEAP1) mutations, and attenuation of the phosphatidylinositiol 3-kinase and v-akt murine thymoma viral oncogene homolog (PI3K/AKT) pathway. Furthermore, we derived a 16-gene classifier that accurately predicts LKB1 mutations and loss by nonmutational mechanisms. In vitro, transduction of LKB1 into LKB1-mutant cell lines results in attenuation of this signature. Loss of LKB1 defines a subset of lung adenocarcinomas associated with characteristic molecular phenotypes and distinctive gene expression features. Studying these effects may improve our understanding of the biology of these tumors and lead to the identification of targeted treatment strategies.


A study to examine patient adherence to wearing 24-hour forearm thermoplastic splints after tendon repairs.
Adherence is believed to be essential in ensuring a successful clinical outcome. There is a paucity of research available investigating adherence and the effect of nonadherence in hand therapy. This study was conducted to investigate adherence relating to acute hand flexor and extensor tendon injuries. This exploratory descriptive study used a self-report questionnaire. Eighty subjects were recruited four weeks after flexor or extensor tendon repair to complete the anonymous questionnaire. Descriptive statistics were used to analyze the patient group profile. Chi-square test was used to determine any associations between patient profile and adherence. Seventy-six questionnaires were completed and this constitutes a return rate of 95%. Sixty-seven percent of patients reportedly removed their splints, commonly to wash and dress. No significant correlation (p < or = 0.0001) was found between patient profile and nonadherence. Two thirds (67%) of patients report to being nonadherent to their splinting regime, removing their splint after flexor and extensor tendon repairs.


Serotonin transporter expression is not sufficient to confer cytotoxicity to 3,4-methylenedioxymethamphetamine (MDMA) in vitro.
There is much evidence from animal studies that the recreational drug MDMA is a selective toxin which damages serotonin nerve terminals and axons. These in vivo studies show that an interaction between MDMA and the serotonin transporter protein (SERT) is the .rst step in toxicity. To further our understanding of the biochemical processes of MDMA toxicity we wished to use an in vitro model for toxicity. We produced two COS-7 cell lines with different levels of expression of recombinant rat SERT, as determined by 5-HT uptake assays, and compared them to human SERT expressing JAR cells and to untransfected COS-7 cells which do not express SERT. Cultured cells were exposed to MDMA (0.1 microM-1 mM) for 24 or 48 h at 37 degrees C before assessing cytotoxicity by LDH release and MTT turnover. Only at the highest concentration used, 1 mM, was MDMA cytotoxic, and this toxicity was found in all cell lines. Cytotoxicity caused by 48 h exposure to 1 mM MDMA at 37 degrees C was not related to the level of SERT expression, not blocked by the SERT-blocking drugs paroxetine or fluoxetine and not enhanced, in JAR cells, by forskolin preincubation that increased 5-HT uptake capacity by 50%. We conclude that SERT expression is not sufficient to confer MDMA toxicity to cell lines. Therefore SERT-expressing cell lines do not offer a simple model system to elucidate the mechanisms underlying MDMA toxicity.


Effects of Parenting Programs on Child Maltreatment Prevention: A Meta-Analysis.
The objective of this study is to evaluate the effectiveness of parenting programs in reducing child maltreatment and modifying associated factors as well as to examine the moderator variables that are linked to program effects. For this meta-analysis, we searched nine electronic databases to identify randomized controlled trials published before September 2013. The effect sizes of various outcomes at different time points were computed. From the 3,578 studies identified, we selected 37 studies for further analysis. The total random effect size was 0.296. Our results showed that parenting programs successfully reduced substantiated and self-reported child maltreatment reports and reduced the potential for child maltreatment. The programs also reduced risk factors and enhanced protective factors associated with child maltreatment. However, the effects of the parenting programs on reducing parental depression and stress were limited. Parenting programs produced positive effects in low-, middle-, and high-income countries and were effective in reducing child maltreatment when applied as primary, secondary, or tertiary child maltreatment intervention. In conclusion, parenting programs are effective public health approaches to reduce child maltreatment. The evidence-based service of parenting programs could be widely adopted in future practice.


Patterns of cigarette smoking and trends in lung cancer mortality in Italy.
Cigarette consumption has increased steadily throughout this century in Italy. There were marked increases in three periods: in the 1920s, in the 1950s possibly due to the spread of smoking among young men, and in the 1970s in part due to smoking among women. The average number of cigarettes per adult per day sold legally in 1980 was 6.9 but, taking smuggling into account, the actual average number of cigarettes smoked per day is likely to range between eight and nine. Data from a national sample-based survey conducted in 1980 showed that smoking prevalence in men was broadly similar within age groups, geographical area, education, and socioeconomic groups. Smoking in women, on the other hand, was concentrated in younger and more educated women living in larger towns and in richer areas of the country. This pattern is typical of a recent rapid spread of smoking among women. The average tar yield of Italian cigarettes in 1983-4 was about 17 mg. Tar yield was strongly and negatively correlated with price (r = -0.55). This abnormality should be urgently reversed by government intervention. No material increase in lung cancer mortality in young women was evident up to the lat 1970s. Lung cancer death rates in men correlated closely with the observed changes in cigarette consumption. The highest mortality rates (about 7, 20, and 50/100 000 respectively in the age groups 35-39, 40-44, and 45-49) were reached by the generation born around 1927-30, and the rates have remained fairly constant around these maximum levels for those born up to 1940. As a consequence, Italian lung cancer death rates in middle-aged men (45 to 54) are currently the highest registered in developed countries, and large upward trends are currently detectable in older men.


Exercise and substance use among American youth, 1991-2009.
The National Institute on Drug Abuse has called for increased research into the use of physical activity in substance abuse prevention, specifically research into physical activity type and context. This paper examines the relationships between (1) secondary school student substance use and (2) exercise in general and school athletic team participation, and examines such relationships over time. Nationally representative cross-sectional samples of 8th-, 10th-, and 12th-grade students were surveyed each year from 1991 to 2009. Substance use measures included past 2-week binge drinking and past 30-day alcohol, cigarette, smokeless tobacco, marijuana, and steroid use. Analyses were conducted during 2009-2010. Across grades, higher levels of exercise were associated with lower levels of alcohol, cigarette, and marijuana use. Higher levels of athletic team participation were associated with higher levels of smokeless tobacco use and lower levels of cigarette and marijuana use across grades and to higher levels of high school alcohol and steroid use. Exercise helped suppress the undesired relationship between team participation and alcohol use; exercise and athletic team participation worked synergistically in lowering cigarette and marijuana use. Observed relationships were generally stable across time. There appear to be substantive differences between exercise and team sport participation in relation to adolescent substance use. These findings from cross-sectional data suggest that interventions to improve levels of general physical activity should be evaluated to determine if they help delay or reduce substance use among youth in general as well as among student athletes.


General Regulatory Factors Control the Fidelity of Transcription by Restricting Non-coding and Ectopic Initiation.
The fidelity of transcription initiation is essential for accurate gene expression, but the determinants of start site selection are not fully understood. Rap1 and other general regulatory factors (GRFs) control the expression of many genes in yeast. We show that depletion of these factors induces widespread ectopic transcription initiation within promoters. This generates many novel non-coding RNAs and transcript isoforms with diverse stability, drastically altering the coding potential of the transcriptome. Ectopic transcription initiation strongly correlates with altered nucleosome positioning. We provide evidence that Rap1 can suppress ectopic initiation by a "place-holder" mechanism whereby it physically occludes inappropriate sites for pre-initiation complex formation. These results reveal an essential role for GRFs in the fidelity of transcription initiation and in the suppression of pervasive transcription, profoundly redefining current models for their function. They have important implications for the mechanism of transcription initiation and the control of gene expression.


NKG2C+ memory-like NK cells contribute to the control of HIV viremia during primary infection: Optiprim-ANRS 147.
Natural-killer (NK) cells are important immune effectors during a viral infection. Latent CMV infection is widely spread and was demonstrated to shape the NK cell repertoire through the NKG2C receptor. An expansion of NKG2C+ NK cells has been reported during primary HIV infection (PHI), but their role is not known. We previously found a correlation between the maturation state of the NK cell compartment and a lower viral load by studying patients from the ANRS 147 Optiprim trial. We investigated here extensively the NKG2C+ NK cells at the time of PHI and its evolution after 3 months of early antiretroviral therapy (combination antiretroviral therapy (cART)). Multiparametric cytometry combined with bioinformatics was used to determine subsets. NKbright NKG2C+ progenitor, NKdim NKG2C+ effector and NKdim NKG2C+CD57+ memory-like populations were identified. Two groups of patients were unraveled according to the distribution of the NKG2C+ subsets skewed toward either progenitor/effector or memory-like phenotype. Patients with high NKG2C+CD57+ NK cell frequencies showed lower HIV-RNA, lower immune activation, higher pDC counts and reached more rapidly undetectable levels of HIV-RNA at M1 under cART. NKG2C+CD57+ NK cell frequency was the only factor strongly correlated to low viral load among other clinical features. While the patients were cytomegalovirus (CMV) infected, there was no sign of reactivation of CMV during PHI suggesting that memory-like NK cells were already present at the time of HIV infection and constituted a preexisting immune response able to contribute to natural control of HIV. This parameter appears to be a good candidate in the search of predictive markers to monitor HIV remission.


Electrical spinal cord stimulation must preserve proprioception to enable locomotion in humans with spinal cord injury.
Epidural electrical stimulation (EES) of the spinal cord restores locomotion in animal models of spinal cord injury but is less effective in humans. Here we hypothesized that this interspecies discrepancy is due to interference between EES and proprioceptive information in humans. Computational simulations and preclinical and clinical experiments reveal that EES blocks a significant amount of proprioceptive input in humans, but not in rats. This transient deafferentation prevents modulation of reciprocal inhibitory networks involved in locomotion and reduces or abolishes the conscious perception of leg position. Consequently, continuous EES can only facilitate locomotion within a narrow range of stimulation parameters and is unable to provide meaningful locomotor improvements in humans without rehabilitation. Simulations showed that burst stimulation and spatiotemporal stimulation profiles mitigate the cancellation of proprioceptive information, enabling robust control over motor neuron activity. This demonstrates the importance of stimulation protocols that preserve proprioceptive information to facilitate walking with EES.


Head circumferences of children born to HIV-infected and HIV-uninfected mothers in Zimbabwe during the preantiretroviral therapy era.
To describe the head growth of children according to maternal and child HIV infection status. Longitudinal analysis of head circumference data from 13 647 children followed from birth in the ZVITAMBO trial, undertaken in Harare, Zimbabwe, between 1997 and 2001, prior to availability of antiretroviral therapy (ART) or cotrimoxazole prophylaxis. Head circumference was measured at birth, then at regular intervals through 24 months of age. Mean head circumference-for-age Z-scores (HCZ) and prevalence of microcephaly (HCZ < -2) were compared between HIV-unexposed children, HIV-exposed uninfected (HEU) children and children infected with HIV in utero (IU), intrapartum (IP) and postnatally (PN). Children infected with HIV in utero had head growth restriction at birth. Head circumference Z-scores remained low throughout follow-up in IP children, whereas they progressively declined in IU children. During the second year of life, HCZ in the PN group declined, reaching a similar mean as IP-infected children by 21 months of age. Microcephaly was more common among IU and IP children than HIV-uninfected children through 24 months. HEU children had significantly lower head circumferences than HIV-unexposed children through 12 months. HIV-infected children had lower head circumferences and more microcephaly than HIV-uninfected children. Timing of HIV acquisition; influenced HCZ, with those infected before birth having particularly poor head growth. HEU children had poorer head growth until 12 months of age. Correlations between head growth and neurodevelopment in the context of maternal/infant HIV infection, and further studies from the current ART era, will help determine the predictive value of routine head circumference measurement.


Anticipation of cognitive demand during decision-making.
An abundance of evidence indicates that action selection is guided, at least in certain contexts, by anticipation of action outcomes. In one particularly clear demonstration of this principle, Bechara and colleagues, studying a gambling task, observed phasic skin conductance responses just prior to actions associated with a relatively high risk of monetary loss (Bechara et al. in J Neurosci 19:5473-5481, 1999; Bechara et al. in Science 275:1293-1295, 1997; Bechara et al. in Cereb Cortex 6:215-225, 1996). In the present work, we tested for the same effect in a paradigm where choices resulted not in differential monetary outcomes, but in differential requirements for subsequent mental effort. In two experiments, we observed an anticipatory skin conductance response prior to actions resulting in a high level of cognitive demand. This finding indicates that requirements for effortful cognitive control are anticipated during action selection. We argue, based on convergent evidence, that such anticipation may not only trigger preparation; it may also play a direct role in effort-based decision-making.


Spatial memory deficits and motor coordination facilitation in cGMP-dependent protein kinase type II-deficient mice.
Activity-dependent trafficking of AMPA receptors to synapses regulates synaptic strength. Activation of the NMDA receptor induces several second messenger pathways that contribute to receptor trafficking-dependent plasticity, including the NO pathway, which elevates cGMP. In turn, cGMP activates the cGMP-dependent protein kinase type II (cGKII), which phosphorylates the AMPA receptor subunit GluA1 at serine 845, a critical step facilitating synaptic delivery in the mechanism of activity-dependent synaptic potentiation. Since cGKII is expressed in the striatum, amygdala, cerebral cortex, and hippocampus, it has been proposed that mice lacking cGKII may present phenotypic differences compared to their wild-type littermates in emotion-dependent tasks, learning and memory, and drug reward salience. Previous studies have shown that cGKII KO mice ingest higher amounts of ethanol as well as exhibit elevated anxiety levels compared to wild-type (WT) littermates. Here, we show that cGKII KO mice are significantly deficient in spatial learning while exhibiting facilitated motor coordination, demonstrating a clear dependence of memory-based tasks on cGKII. We also show diminished GluA1 phosphorylation in the postsynaptic density (PSD) of cGKII KO prefrontal cortex while in hippocampal PSD fractions, phosphorylation was not significantly altered. These data suggest that the role of cGKII may be more robust in particular brain regions, thereby impacting complex behaviors dependent on these regions differently.


Stereotyping in the digital age: Male language is "ingenious", female language is "beautiful" - and popular.
The huge power for social influence of digital media may come with the risk of intensifying common societal biases, such as gender and age stereotypes. Speaker's gender and age also behaviorally manifest in language use, and language may be a powerful tool to shape impact. The present study took the example of TED, a highly successful knowledge dissemination platform, to study online influence. Our goal was to investigate how gender- and age-linked language styles-beyond chronological age and identified gender-link to talk impact and whether this reflects gender and age stereotypes. In a pre-registered study, we collected transcripts of TED Talks along with their impact measures, i.e., views and ratios of positive and negative talk ratings, from the TED website. We scored TED Speakers' (N = 1,095) language with gender- and age-morphed language metrics to obtain measures of female versus male, and younger versus more senior language styles. Contrary to our expectations and to the literature on gender stereotypes, more female language was linked to higher impact in terms of quantity, i.e., more talk views, and this was particularly the case among talks with a lot of views. Regarding quality of impact, language signatures of gender and age predicted different types of positive and negative ratings above and beyond main effects of speaker's gender and age. The differences in ratings seem to reflect common stereotype contents of warmth (e.g., "beautiful" for female, "courageous" for female and senior language) versus competence (e.g., "ingenious", "informative" for male language). The results shed light on how verbal behavior may contribute to stereotypical evaluations. They also illuminate how, within new digital social contexts, female language might be uniquely rewarded and, thereby, an underappreciated but highly effective tool for social influence. WC = 286 (max. 300 words).


Direct and indirect costs incurred by Australian living kidney donors.
To describe the direct and indirect costs incurred by Australian living kidney donors. A total of 55 living kidney donors from three centres in Perth, Australia and one centre in Melbourne, Australia (2010-2014) was studied. Forty-nine donors provided information on expenses incurred during the donor evaluation period and up to 3 months after donation. A micro-costing approach was used to measure and value the units of resources consumed. Expenses were grouped as direct costs (ground and air travel, accommodation, and prescription medications) and indirect costs (lost wages and lost productivity). Costs were standardized to the year 2016 in Australian dollars. The most common direct costs were for ground travel (100%), parking (76%), and post-donation pain medications or antibiotics (73%). The highest direct costs were for air travel (median $1986 [three donors]) and ground travel (median $459 [49 donors]). Donors also reported lost wages (median $9891 [37 donors]). The inability to perform household activities or care for dependants were reported by 32 (65%) and 23 (47%) donors. Total direct costs averaged $1682 per donor (median $806 among 49 donors). Total indirect costs averaged $7249 per donor (median $7273 among 49 donors). Total direct and indirect costs averaged $8932 per donor (median $7963 among 49 donors). Many Australian living kidney donors incur substantial costs during the donation process. Our findings inform the continued development of policies and programmes designed to minimize costs incurred by living kidney donors.


Effects of azadirachtin on the two-spotted spider mite, Tetranychus urticae (Acari: Tetranychidae).
Effects of sublethal azadirachtin exposure to the biological performance of Tetranychius urticae Koch was studied under laboratory conditions. Bioassay was used to asses the effect of different concentrations of azadirachtin on longevity, fecundity, fertility, and offspring development. Azadirachtin (64 and 128 ppm) affected fecundity and mortality but had no effect on fertility and offspring development. A subsequent life-table study with 80 ppm of azadirachtin found that the compound caused a reduction of 50% in survival to adult stage. The peak of reproduction was reached at 5 days causing a decrease in the mean fecundity to almost eight times than of untreated females. The net reproductive rate (R0), the intrinsic rate of increase (r(m)), and the finite rate of increase (lambda) of treated females were lower. Treatment showed a negative value of r(m), resulting in a declining population. These results suggest that azadirachtin could be incorporated in Integrated Pest Management (IPM) programmes of T. urticae.


Automated Detection of Intracranial Large Vessel Occlusions on Computed Tomography Angiography: A Single Center Experience.
Background and Purpose- Endovascular thrombectomy is highly effective in acute ischemic stroke patients with an anterior circulation large vessel occlusion (LVO), decreasing morbidity and mortality. Accurate and prompt identification of LVOs is imperative because these patients have large volumes of tissue that are at risk of infarction without timely reperfusion, and the treatment window is limited to 24 hours. We assessed the accuracy and speed of a commercially available fully automated LVO-detection tool in a cohort of patients presenting to a regional hospital with suspected stroke. Methods- Consecutive patients who underwent multimodal computed tomography with thin-slice computed tomography angiography between January 1, 2017 and December 31, 2018 for suspected acute ischemic stroke within 24 hours of onset were retrospectively identified. The multimodal computed tomographies were assessed by 2 neuroradiologists in consensus for the presence of an intracranial anterior circulation LVO or M2-segment middle cerebral artery occlusion (the reference standard). The patients' computed tomography angiographies were then processed using an automated LVO-detection algorithm (RAPID CTA). Receiver-operating characteristic analysis was used to determine sensitivity, specificity, and negative predictive value of the algorithm for detection of (1) an LVO and (2) either an LVO or M2-segment middle cerebral artery occlusion. Results- CTAs from 477 patients were analyzed (271 men and 206 women; median age, 71; IQR, 60-80). Median processing time was 158 seconds (IQR, 150-167 seconds). Seventy-eight patients had an anterior circulation LVO, and 28 had an isolated M2-segment middle cerebral artery occlusion. The sensitivity, negative predictive value, and specificity were 0.94, 0.98, and 0.76, respectively for detection of an intracranial LVO and 0.92, 0.97, and 0.81, respectively for detection of either an intracranial LVO or M2-segment middle cerebral artery occlusion. Conclusions- The fully automated algorithm had very high sensitivity and negative predictive value for LVO detection with fast processing times, suggesting that it can be used in the emergent setting as a screening tool to alert radiologists and expedite formal diagnosis.


Fast Estimation of Approximate Matrix Ranks Using Spectral Densities.
Many machine learning and data-related applications require the knowledge of approximate ranks of large data matrices at hand. This letter presents two computationally inexpensive techniques to estimate the approximate ranks of such matrices. These techniques exploit approximate spectral densities, popular in physics, which are probability density distributions that measure the likelihood of finding eigenvalues of the matrix at a given point on the real line. Integrating the spectral density over an interval gives the eigenvalue count of the matrix in that interval. Therefore, the rank can be approximated by integrating the spectral density over a carefully selected interval. Two different approaches are discussed to estimate the approximate rank, one based on Chebyshev polynomials and the other based on the Lanczos algorithm. In order to obtain the appropriate interval, it is necessary to locate a gap between the eigenvalues that correspond to noise and the relevant eigenvalues that contribute to the matrix rank. A method for locating this gap and selecting the interval of integration is proposed based on the plot of the spectral density. Numerical experiments illustrate the performance of these techniques on matrices from typical applications.


Effects of zoledronic acid on bone mineral density during aromatase inhibitor treatment of Korean postmenopausal breast cancer patients.
The age distribution of breast cancer patients in Korea, where most are less than 60 years of age and have recently entered menopause, differs from that in the West. The aim of this study was to evaluate bone mineral density (BMD) changes in Korean breast cancer patients treated with an aromatase inhibitor (AI) either alone or in combination with zoledronic acid (ZA). Changes in BMD of the lumbar spine and hip were evaluated in 107 patients receiving AI treatment, of which 59 were treated in combination with ZA. The mean age of the patients was 54.9 years, and the median follow-up period was 38.2 months. With AI treatment alone, BMD loss was significant (all P < 0.0001) in the lumbar spine and hip 12 months (4.18 and 3.95%, respectively), 24 months (6.28 and 5.44%), and 36 months (8.17 and 6.82%) after treatment. In contrast, the combination treatment resulted in increased BMD in the lumbar spine and hip 12 months (2.45 and 0.89%, respectively), 24 months (3.51 and 1.03%), and 36 months (3.85 and 1.80%) after treatment. BMD loss in the lumbar spine was significantly greater in AI alone-treated women who had entered menopause within the past year compared with those who had entered menopause more than 1 year ago, when measured 12 and 24 months after treatment (P = 0.017 and 0.021, respectively). Importantly, ZA effectively inhibited AI-associated bone loss, independent of the postmenopausal interval. Because the proportion of patients in this study who had recently entered menopause was high, bone loss in Korean breast cancer patients treated with AI alone was higher than data reported from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial. In conclusion, we have shown that ZA is very effective in preventing AI-induced bone loss in Korean postmenopausal breast cancer patients.


Association of n-6 PUFAs with the risk of diabetic retinopathy in diabetic patients.
Diabetic retinopathy (DR), the most common microvascular complication of diabetes and leading cause of visual impairment in adults worldwide, is suggested to be linked to abnormal lipid metabolism. The present study aims to comprehensively investigate the relationship between n-6 polyunsaturated fatty acids (PUFAs) and DR. This was a propensity score matching based case-control study, including 69 pairs of DR patients and type 2 diabetic patients without DR with mean age of 56.7 ± 9.2 years. Five n-6 PUFAs were determined by UPLC-ESI-MS/MS system. Principle component regression (PCR) and multiple conditional logistic regression models were used to investigate the association of DR risk with n-6 PUFAs depending on independent training and testing sets, respectively. According to locally weighted regression model, we observed obvious negative correlation between levels of five n-6 PUFAs (linoleic acid, γ-linolenic acid, eicosadienoic acid, dihomo-γ-linolenic acid and arachidonicacid) and DR. Based on multiple PCR model, we also observed significant negative association between the five n-6 PUFAs and DR with adjusted OR (95% CI) as 0.62 (0.43,0.87). When being evaluated depending on the testing set, the association was still existed, and PCR model had excellent classification performance, in which area under the curve (AUC) was 0.88 (95% CI: 0.78, 0.99). In addition, the model also had valid calibration with a non-significant Hosmer-Lemeshow Chi-square of 9.44 (P = 0.307) in the testing set. n-6 PUFAs were inversely associated with the presence of DR, and the principle component could be potential indicator in distinguishing DR from other T2D patients.


New evidence for a direct effect of prolactin on rat adrenal steroidogenesis.
The direct effect of prolactin on rat adrenal steroidogenic enzyme activity was evaluated by measuring plasma and adrenal cytosol steroid levels and adrenal microsomal 3B-hydroxysteroid dehydrogenase/isomerase (3B-HSD), 21 hydroxylase (21-OHase) and mitochondrial 11-hydroxylase (11-OHase) after in vivo administration of purified rat prolactin (rPRL) to adult, female Sprague-Dawley rats. Animals were ovariectomized, hypophysectomized and replaced with ACTH. Two days after surgery rPRL was administered i.p. at doses of 1.0, 10.0 and 100.0 micrograms (micrograms) every 4 hours for 5 days to experimental animals. Control rats received vehicle injections. All rats were sacrificed by decapitation and blood and adrenal glands collected. The adrenals were pooled into each rPRL dose group and mitochondria, microsomes and cytosol prepared from each pool. The activities of 3B-HSD, 21-OHase and 11-OHase were measured using as substrates 14C-dehydroepiandrosterone, 14C-progesterone and 14C-deoxycorticosterone, respectively. Plasma prolactin levels rose from 9.9 +/- 2.5 ng/ml in the control animals to 166.0 +/- 37.7 ng/ml (p less than 0.001) in the 100 micrograms rPRL dose group. Plasma corticosterone levels were not statistically different in the experimental groups when compared to controls. However, adrenal weight was increased in the high dose rPRL group (34.9 +/- 0.9 mg vs 41.9 +/- 1.2 mg, p less than 0.025). Hyperprolactinemia did not influence microsomal 3B-HSD or mitochondrial 11-OHase activities but was associated with a dose dependent decrease in microsomal 21-OHase activity when compared to controls (p less than 0.001). Adrenal cytosol progesterone levels increased with increasing rPRL dose consistent with a 21-OHase block during hyperprolactinemia. These data suggest that prolactin has a direct effect on rat adrenal 21-OHase in vivo.


Postprandial lipoprotein metabolism and atherosclerosis.
Postprandial lipids and lipoproteins have been associated with the presence of cardiovascular disease in a large number of case-control studies. Because the metabolic perturbations around the postprandial situation is a key driving force for cholesterol flux between lipoproteins and tissues, together with the augmented generation of potentially atherogenic cholesterol-rich remnant lipoproteins, several hypotheses have been formulated to link excessive lipoproteinaemic response to fat intake with cardiovascular disease. Recent information on the regulation of lipoprotein remnant formation and its relation to atherosclerosis will enable us to test a pertinent clinical question: is there a direct relationship between repeated elevations of postprandial lipoproteins and development of atherosclerosis?


Relationships between lower limb cross-sectional geometry and mobility: the case of a Neolithic sample from Italy.
This study investigates the relationships between lower limb robusticity and mobility in a Neolithic sample (LIG) from Italy (6th millennium BP). This study tests the hypothesis that the high femoral robusticity previously observed in the LIG sample is a consequence of the subsistence strategy (i.e., high mobility on uneven terrain) practiced by LIG. Cross-sectional geometric properties of the femur and tibia at midshaft of LIG (eight males and eight females) were collected and results compared to Late Upper Paleolithic (12 males, five females), Mesolithic (24 males, 8 females), and Eneolithic (28 males, 17 females) samples from other sites throughout Europe. The results show that the LIG sample does not show the reduction of lower limb robusticity that is characteristic of the Eneolithic sample, but rather that the LIG sample is most similar to the earlier, highly mobile, populations. This high level of robusticity in the LIG sample could reflect both their pastoral subsistence strategy combined with a rugged environment, as well as their earlier temporal position within the Neolithic. The results of this study further point to significant variation in male-female mobility patterns in the region, also possibly related to pastoral behavioral patterns.


Management of biliary perforation in children.
To study the aetiology, management and outcome of biliary perforations in paediatric age group. In a retrospective study, the records of patients presented with biliary peritonitis due to biliary perforations, managed from March 2006 to July 2009, are reviewed. Eight male patients with biliary peritonitis due to biliary perforation were managed. These patients were divided in two groups, A and B. Group A, (n = 3) patients, had common bile duct (CBD) perforation, and Group B (n=5) patients had gallbladder perforation. The presenting features were abdominal pain, fever, abdominal distension, vomiting, constipation, jaundice and signs of peritonism. The management of CBD perforations in Group A was by draining the site of perforation and biliary diversion (tube cholecystostomy). In Group B, the gallbladder perforations were managed by tube cholecystostomy in four patients and cholecystectomy in one patient, however, one patient had to be re-explored and cholecystectomy performed due to complete necrosis of gall bladder. There was no mortality in our series. All patients were asymptomatic on regular follow-up. Early optimal management of biliary perforations remarkably improved the very high mortality and morbidity that characterised this condition in the past.


Sociocultural behavior, sex-biased admixture, and effective population sizes in Central African Pygmies and non-Pygmies.
Sociocultural phenomena, such as exogamy or phylopatry, can largely determine human sex-specific demography. In Central Africa, diverging patterns of sex-specific genetic variation have been observed between mobile hunter-gatherer Pygmies and sedentary agricultural non-Pygmies. However, their sex-specific demography remains largely unknown. Using population genetics and approximate Bayesian computation approaches, we inferred male and female effective population sizes, sex-specific migration, and admixture rates in 23 Central African Pygmy and non-Pygmy populations, genotyped for autosomal, X-linked, Y-linked, and mitochondrial markers. We found much larger effective population sizes and migration rates among non-Pygmy populations than among Pygmies, in agreement with the recent expansions and migrations of non-Pygmies and, conversely, the isolation and stationary demography of Pygmy groups. We found larger effective sizes and migration rates for males than for females for Pygmies, and vice versa for non-Pygmies. Thus, although most Pygmy populations have patrilocal customs, their sex-specific genetic patterns resemble those of matrilocal populations. In fact, our results are consistent with a lower prevalence of polygyny and patrilocality in Pygmies compared with non-Pygmies and a potential female transmission of reproductive success in Pygmies. Finally, Pygmy populations showed variable admixture levels with the non-Pygmies, with often much larger introgression from male than from female lineages. Social discrimination against Pygmies triggering complex movements of spouses in intermarriages can explain these male-biased admixture patterns in a patrilocal context. We show how gender-related sociocultural phenomena can determine highly variable sex-specific demography among populations, and how population genetic approaches contrasting chromosomal types allow inferring detailed human sex-specific demographic history.


Insulin therapy, hyperglycemia, and hypertension in type 1 diabetes mellitus.
Diabetes mellitus and hypertension are closely linked, but the long-term blood pressure effects of glucose-lowering therapy and hyperglycemia are not clear. We examined the effects of intensive insulin therapy and hyperglycemia on the development of hypertension in the Diabetes Control and Complications Trial (DCCT) and its observational follow-up, the Epidemiology of Diabetes Intervention and Complications (EDIC) study. Incident hypertension was defined as 2 consecutive study visits with a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg or higher, or use of antihypertensive medications to treat high blood pressure. Participants were enrolled from August 23, 1983, through June 30, 1989. During a 15.8-year median follow-up, 630 of 1441 participants developed hypertension. During the DCCT, the incidence of hypertension was similar comparing participants assigned to intensive vs conventional therapy. However, intensive therapy during the DCCT reduced the risk of incident hypertension by 24% during EDIC study follow-up (hazard ratio, 0.76; 95% confidence interval [CI], 0.64-0.92). A higher hemoglobin A(1c) level, measured at baseline or throughout follow-up, was associated with increased risk for incident hypertension (adjusted hazard ratios, 1.11 [95% CI, 1.06-1.17] and 1.25 [95% CI, 1.14-1.37], respectively, for each 1% higher hemoglobin A(1c) level), and glycemic control appeared to mediate the antihypertensive benefit of intensive therapy. Older age, male sex, family history of hypertension, greater baseline body mass index, weight gain, and greater albumin excretion rate were independently associated with increased risk of hypertension. Hyperglycemia is a risk factor for incident hypertension in type 1 diabetes, and intensive insulin therapy reduces the long-term risk of developing hypertension.


How effective and cost-effective are innovative combinatorial technologies and practices for supporting older people with long-term conditions to remain well in the community? An evaluation protocol for an NHS Test Bed in North West England.
The Lancashire and Cumbria Innovation Alliance (LCIA) Test Bed is a partnership between the National Health Service in England, industry (led by Philips) and Lancaster University. Through the implementation of a combination of innovative health technologies and practices, it aims to determine the most effective and cost-effective ways of supporting frail older people with long-term conditions to remain well in the community. Among the Test Bed's objectives are to improve patient activation and the ability of older people to self-care at home, reduce healthcare system utilisation, and deliver increased workforce productivity. Patients aged 55 years and over are recruited to four cohorts defined by their risk of hospital admission, with long-term conditions including chronic obstructive pulmonary disease, dementia, diabetes and heart failure. The programme is determined on an individual basis, with a range of technologies available. The evaluation is adopting a two-phase approach: phase 1 includes a bespoke patient survey and a mass matched control analysis; and phase 2 is using observational interviews with patients, and weekly diaries, action learning meetings and focus groups with members of staff and other key stakeholders. Phase 1 data analysis consists of a statistical evaluation of the effectiveness of the programme. A health economic analysis of its costs and associated cost changes will be undertaken. Phase 2 data will be analysed thematically with the aid of Atlas.ti qualitative software. The evaluation is located within a logic model framework, to consider the processes, management and participation that may have implications for the Test Bed's success. The LCIA Test Bed evaluation has received ethical approval from the Health Research Authority and Lancaster University's Faculty of Health and Medicine Research Ethics Committee. A range of dissemination methods are adopted, including deliberative panels to validate findings and develop outcomes for policy and practice.


Does the testicular apoptotic index vary with serum gonadotropins and testicular histopathology in infertile men?
Testicular apoptosis has been shown in human specimens, but its correlation with serum gonadotropins and testosterone levels has not been studied. The aim of this study was to evaluate the relationship of apoptosis with serum hormone levels and testicular histopathological findings in infertile men. Testis biopsy specimens were obtained for routine clinical purposes from 41 azoospermic men. The biopsy material was divided into two parts: one part was fixed in Bouin's solution and processed using paraffin embedding and HE staining, and the other was fixed in 10% neutral buffered formalin and embedded in paraffin for the detection of apoptosis using TUNEL. To determine the apoptotic index, the number of apoptotic cells was divided by the total number of the counted cells and multiplied by 100 to calculate the percentage. The apoptotic index was significantly higher in specimens with maturation arrest than in those with normal spermatogenesis (p = 0.016), hypospermatogenesis (p = 0.05), and Sertoli-cell-only specimens (p < 0.001). A significant negative correlation was found between serum follicle-stimulating hormone levels and the apoptotic index (r = -0.356, p = 0.01). Our results demonstrate there is a relationship between increased apoptosis and testicular dysfunction, and indicate a prominent role for apoptosis in human male infertility.


Internet-based training in a practice-based research network consortium: a report from the Primary Care Multiethnic Network (PRIME Net).
Continuing growth of the research spectrum of practice-based research networks (PBRNs) creates a need (1) for new approaches to training clinicians in research protocols and (2) to standardize clinician data collection. Each existing training method has shortcomings when used in geographically dispersed PBRNs. We describe here the use and costs of Internet-based training in support of a research protocol across a PBRN consortium. Clinicians in 4 PBRNs in the PRIME Net consortium participated in training for a study of acanthosis nigricans (AN). We compared results of pre- and posttraining assessments of knowledge and ability to correctly diagnosis AN. We also calculated costs for placement of the training on the Internet. Among 103 participating clinicians, statistically significant increases in knowledge acquisition were demonstrated for all but 2 of the individual topics and in total scores on the assessments. AN diagnostic sensitivity increased from 52% to 99% to 96% to 100%, whereas specificity increased from 70% to 96% to 74% to 97%. Total costs for the web aspects of the training were $3732. The Internet can be an effective and feasible alternative method for training clinicians in support of PBRN research.


Social mix policies in Paris: discourses, policies and social effects.
Since the 1980s, the issue of social mix has become a public policy category in France. Enshrined in legislation, yet remaining controversial, it represents a major premise on which housing policies have been reconfigured. The concept of social mix is essentially based on who lives where, but it is also evoked in the context of urban renewal schemes for social housing estates, as well as in relation to new-build developments. A study of the bases of social mix policies conducted in Paris since 2001 in the context of the embourgeoisement of the capital shows the fundamental role of social housing stock. The City Council has become involved in policy decisions about both the location and the allocation of social housing. Particular attention has been paid to the middle classes in the name of the principle of 'balancing the population'. In order to measure the effects of the policy, this article relies on an analysis of two City of Paris schemes that have the stated intent of creating social mix. One of these schemes consists of redeveloping a working-class neighbourhood, Goutte d'Or, while the other involves the new acquisition of social housing in various more affluent neighbourhoods in the capital. This comparative study of the population shows that, whether in a neighbourhood poised for gentrification or in a more affluent neighbourhood, this policy has major effects on forms of local social cohesion, setting in motion individual trajectories and reshaping social and/or ethnic identities.


Open-source colorimeter.
The high cost of what have historically been sophisticated research-related sensors and tools has limited their adoption to a relatively small group of well-funded researchers. This paper provides a methodology for applying an open-source approach to design and development of a colorimeter. A 3-D printable, open-source colorimeter utilizing only open-source hardware and software solutions and readily available discrete components is discussed and its performance compared to a commercial portable colorimeter. Performance is evaluated with commercial vials prepared for the closed reflux chemical oxygen demand (COD) method. This approach reduced the cost of reliable closed reflux COD by two orders of magnitude making it an economic alternative for the vast majority of potential users. The open-source colorimeter demonstrated good reproducibility and serves as a platform for further development and derivation of the design for other, similar purposes such as nephelometry. This approach promises unprecedented access to sophisticated instrumentation based on low-cost sensors by those most in need of it, under-developed and developing world laboratories.


Winter ecology of the Arunachal macaque Macaca munzala in Pangchen Valley, western Arunachal Pradesh, northeastern India.
The newly described Arunachal macaque Macaca munzala occurs largely in sub-tropical to temperate environments at elevations of c. 1,800-3,000 m in Arunachal Pradesh, northeastern India. We studied its over-wintering strategy by comparing the diet, ranging, and behavior of a troop of 24 individuals during winter and spring (December 2005 to May 2006) through instantaneous scan sampling (3,002 records, 448 scans, 112 hr of observation). We also monitored the phenology of food plants. The macaques spent more time (41-66%) feeding in the winter than in spring (33-51%), whereas time spent moving and resting was greater in spring. The diet composed largely of plants, with animal matter being eaten rarely. The number of plant species in the diet increased from 18 to 25 whereas food types rose from 18 to 36 from winter to spring, respectively. Although only two species formed 75% of the winter diet, seven species comprised this proportion in spring. Availability of fruits and young leaves increased in spring; the troop moved more and utilized a larger part of its range during this time. Seasonal changes in behavior could be explained by the scarcity of food and the costs of thermoregulation in winter. Our study suggests that the Arunachal macaque inhabits a highly seasonal environment and has an over-wintering strategy that includes subsisting on a high-fiber diet by increasing the time spent feeding, and minimizing energy expenditure by reducing the time spent moving.


Isolation and culture of adult mouse vestibular nucleus neurons
Background/aim: Isolated cell cultures are widely used to study neuronal properties due to their advantages. Although embryonic animals are preferred for culturing, their morphological or electrophysiological properties may not reflect adult neurons, which may be important in neurodegenerative diseases. This paper aims to develop a method for preparing isolated cell cultures of medial vestibular nucleus (MVN) from adult mice and describe its morphological and electrophysiological properties.Materials and methods: Vestibular nucleus neurons were mechanically and enzymatically isolated and cultured using a defined medium with known growth factors. Cell survival was measured with propidium iodide, and electrophysiological properties were investigated with current-clamp recording.Results: Vestibular neurons grew neurites in cultures, gaining adult-like morphological properties, and stayed viable for 3 days in culture. Adding bovine calf serum, nerve growth factor, or insulin-like growth factor into the culture medium enhanced neuronal viability. Current-clamp recording of the cultured neurons revealed tonic and phasic-type neurons with similar input resistance, resting membrane potential, action potential amplitude, and duration. Conclusion: Vestibular neurons from adult mice can be cultured, and regenerate axons in a medium containing appropriate growth factors. Culturing adult vestibular neurons provides a new method to study age-related pathologies of the vestibular system.


Proteomic Landscape of Aldosterone-Producing Adenoma.
Primary aldosteronism is a disease of excessive production of adrenal steroid hormones and the most common cause of endocrine hypertension. Primary aldosteronism results mainly from bilateral adrenal hyperplasia or unilateral aldosterone-producing adenoma (APA). Primary aldosteronism cause at the molecular level is incompletely understood and a targeted treatment preventing excessive adrenal steroid production is not available. Here, we perform deep quantitative proteomic and phosphoproteomic profiling of 6 pairs of APA and adjacent nontumoral adrenal cortex. We show that increased steroidogenesis in APA is accompanied by upregulation of steroidogenic enzymes (HSD3B2, CYP21A2, CYP11B2) and of proteins involved in cholesterol uptake (LSR). We demonstrate that HSD3B2 is phosphorylated at Ser95 or 96 and identify a novel phosphorylation site, Ser489, in CYP21A2, suggesting that steroidogenic enzymes are regulated by phosphorylation. Our analysis also reveals altered ECM (extracellular matrix) composition in APA that affects ECM-cell surface interactions and actin cytoskeleton rearrangements. We show that RHOC, a GTPase controlling actin organization in response to extracellular stimuli, is upregulated in APA and promotes expression of the aldosterone synthase gene CYP11B2. Our data also indicate deregulation of protein N-glycosylation and GABAergic signaling in APAs. Finally, we find that mTORC1 (mammalian target of rapamycin complex 1) signaling is the major pathway deregulated in APA. Our study provides a rich resource for future research on the molecular mechanisms of primary aldosteronism.


Diagnostic performance of angiography-based fractional flow reserve by patient and lesion characteristics.
A large, prospective, multicentre trial recently showed that fractional flow reserve (FFR) derived from coronary angiography (FFRangio) has an accuracy of 92% compared with conventional guidewire-based FFR (FFRwire); however, little is known about whether specific patient/lesion characteristics affect the diagnostic performance. The primary goal of the present study was to investigate whether specific patient or lesion characteristics such as high body mass index (BMI), presentation with an acute coronary syndrome, or lesion location affect the diagnostic performance of FFRangio in patients enrolled in the FAST-FFR study. FFRangio was measured in a blinded fashion in 301 patients (319 vessels) who were undergoing FFRwire assessment. Using an FFRwire ≤0.80 as a reference, the diagnostic performance of FFRangio was compared in pre-specified subgroups. The mean FFRwire and FFRangio were 0.81±0.13 and 0.80±0.12. Overall, FFRangio had a sensitivity of 93.5% and specificity of 91.2% for predicting FFRwire. Patient characteristics including age, sex, clinical presentation, body mass index, and diabetes did not affect sensitivity or specificity (p>0.05 for all). Similarly, lesion characteristics including calcification and tortuosity did not affect sensitivity or specificity (p>0.05 for all), nor did lesion location (proximal, middle, versus distal). Sensitivity was equally high across all target vessels, while specificity was highest in the LAD and lower (~85%) in the RCA and LCx (p<0.05). FFRangio derived from coronary angiography has a high diagnostic performance regardless of patient and most lesion characteristics. The interaction of vessel on the specificity will need to be confirmed in larger cohorts.


General pediatrics resident perspectives on training decisions and career choice.
Little is known regarding at what point during the training period residents in pediatrics make decisions on their future career choices. As part of a dedicated process of reexamining the structure of residency training in pediatrics, the American Board of Pediatrics sought information to better understand the influences, process, and sequencing of both residency program selection and career decision-making among residents. All pediatrics resident physicians in all training programs in the United States and Canada (N = 8290) received the survey as part of the general pediatrics in-training examination. The survey focused on exploring how and when pediatrics residents make career choices and assessed perceived flexibility of their individual pediatrics residency program. The response rate was 95%. Location was the most important factor in selecting a residency program for 42% of all residents. Almost half of the pediatrics residents planned to pursue fellowship training after residency, a proportion that changed little across the 3 training years (level 1: 47%; level 2: 49%; level 3: 47%). Those who planned to pursue a general pediatrics career (either with or without inpatient care) were more likely than those who intended to pursue fellowship training to report that lifestyle was the most important factor in their career choice (63% vs 21%). Not surprisingly, different priorities motivate pediatricians to pursue specific programs for training and specific career options. The finding that those with the highest priority regarding lifestyle are more likely to pursue generalist training has implications for the generalist workforce, because those persons may also be more likely to seek part-time employment. Lifestyle concerns may need to be addressed in subspecialty training and subsequent subspecialty careers to ensure a continued flow of residents into fellowship training.


Faecal occult blood screening: knowledge, attitudes, and practice in four Hong Kong primary care clinics.
OBJECTIVES. To assess primary care patients for their awareness, knowledge, and attitude towards colorectal cancer and screening, to report on the uptake of faecal occult blood test screening and the results of screening, and explore predictors of screening uptake. DESIGN. Cross-sectional study. SETTING. Four primary care clinics in Hong Kong. PATIENTS. A total of 1664 patients aged 50 to 74 years attending the clinics in the period July 2006 to July 2007. MAIN OUTCOME MEASURES. Percentage of subjects who were aware that colorectal cancer is common and curable at an early stage, and who knew that faecal occult blood test or colonoscopy is useful for screening; relevant knowledge score; uptake rate of faecal occult blood testing; rate of testing positive; and factors predicting uptake. RESULTS. A total of 1645 questionnaires were collected. In all, 89% (95% confidence interval, 88-91%) were aware that colorectal cancer is common, 95% (94-96%) believed faecal occult blood test and colonoscopy are useful for screening, and 58% (56-61%) achieved a knowledge score of 50% or above. The uptake rate of the faecal occult blood test was 35%. Uptake was higher among those with a positive family history (odds ratio=1.57; 95% confidence interval, 1.08-2.27; P=0.02), those who were more aware that colorectal cancer is common (1.86; 1.29-2.69; P=0.001), and that colorectal cancer is potentially curable at an early stage (1.76; 1.32-2.36; P=0.0001). Rate of testing positive was 2.1% (95% confidence interval, 0.9-3.3%); no colorectal cancer was detected and the neoplasia detection rate (for cancers and adenomas) was 5.1 per 1000 subjects screened. CONCLUSIONS. Patients were aware that colorectal cancer is common in our community, and faecal occult blood test or colonoscopy is useful for screening. The uptake of screening was low, though relatively higher for those with a positive family history and greater awareness of the high frequency and potential for cure of colorectal cancer. Faecal occult blood test positivity rate was 2.1%, and neoplasia detection rate 5.1 per 1000 screened.


The financial burden of overweight and obesity among elderly Americans: the dynamics of weight, longevity, and health care cost.
To investigate the financial burdens attributed to overweight and obesity on the U.S. health care system among elderly Americans. Longitudinal Cost and Use files of the Medicare Current Beneficiary Survey from 1992 to 2001. We constructed a simultaneous equation system to model the dynamic relationship between changes in body weight, chronic diseases, functional status, longevity, and health care expenditures using maximum likelihood estimation. Based on the estimation, we conducted a simulation of one cohort with different baseline weights at age 65 and followed to death or up to age 100 of their health outcomes and lifetime health care expenditures. The elderly men who were overweight or obese at age 65 had 6-13 percent more lifetime health care expenditures than the same age cohort within normal weight range at age 65. Elderly women who were overweight or obese at age 65 spent 11-17 percent more than those in a normal weight range. Both elderly men and women who were overweight or obese at age 65 had worse health outcomes than the normal weight cohorts. The average body mass index among survivors decreased by age. Overweight and obesity could place significant financial burdens on the U.S. health care system.


Differential effects of zeta and eta transgenes on early alpha/beta T cell development.
The zeta-family dimers (zeta, eta, and gamma) are a group of structurally and functionally related proteins that are expressed in developing thymocytes and function as signal transducing subunits of the T cell antigen receptor (TCR) and certain Ig Fc receptors. Zeta, eta, and gamma each contain one or more copies of a conserved tyrosine-based activation motif (TAM) that is known to be required for signal transduction. To examine the developmental importance of multiple or individual TAM elements we generated transgenic mice that express: (a) full-length (FL) zeta-chain (3 TAMs); (b) eta-chain, a naturally occurring variant of zeta that is derived from alternative splicing (2 TAMs); or (c) truncated zeta-chain (CT108; 1 TAM), under the control of the human CD2 promoter and regulatory elements. Unexpectedly, we found that overexpression of the FL zeta chain caused premature termination of RAG-1 and RAG-2 expression, prevented productive rearrangement of the TCR-alpha and TCR-beta genes and blocked entry of thymocytes into the CD4/CD8 developmental pathway. In contrast, we found that overexpression of eta or CT108 had no effect on normal thymocyte maturation. These results suggest that an early signaling pathway exists in precursor TCR- thymocytes that can regulate RAG-1 and RAG-2 expression and is differentially responsive to individual members of the zeta-family dimers.


Origin and expansion of haplogroup H, the dominant human mitochondrial DNA lineage in West Eurasia: the Near Eastern and Caucasian perspective.
More than a third of the European pool of human mitochondrial DNA (mtDNA) is fragmented into a number of subclades of haplogroup (hg) H, the most frequent hg throughout western Eurasia. Although there has been considerable recent progress in studying mitochondrial genome variation in Europe at the complete sequence resolution, little data of comparable resolution is so far available for regions like the Caucasus and the Near and Middle East-areas where most of European genetic lineages, including hg H, have likely emerged. This gap in our knowledge causes a serious hindrance for progress in understanding the demographic prehistory of Europe and western Eurasia in general. Here we describe the phylogeography of hg H in the populations of the Near East and the Caucasus. We have analyzed 545 samples of hg H at high resolution, including 15 novel complete mtDNA sequences. As in Europe, most of the present-day Near Eastern-Caucasus area variants of hg H started to expand after the last glacial maximum (LGM) and presumably before the Holocene. Yet importantly, several hg H subclades in Near East and Southern Caucasus region coalesce to the pre-LGM period. Furthermore, irrespective of their common origin, significant differences between the distribution of hg H sub-hgs in Europe and in the Near East and South Caucasus imply limited post-LGM maternal gene flow between these regions. In a contrast, the North Caucasus mitochondrial gene pool has received an influx of hg H variants, arriving from the Ponto-Caspian/East European area.


Computational Modeling of Traffic Related Thoracic Injury of a 10-Year-Old Child Using Subject-Specific Modeling Technique.
Traffic injuries have become a major health-related issue to school-aged children. To study this type of injury with numerical simulations, a finite element model was developed to represent the full body of a 10-year-old (YO) child. The model has been validated against test data at both body-part and full-body levels in previous studies. Representing only the average 10-YO child, this model did not include subject-specific attributes, such as the variations in size and shape among different children. In this paper, a new modeling approach was used to morph this baseline model to a subject-specific model, based on anthropometric data collected from pediatric subjects. This mesh-morphing method was then used to rapidly morph the baseline mesh into the subject-specific geometry while maintaining a good mesh quality. The morphed model was subsequently applied to simulate a real-world motor vehicle crash accident. A lung injury observed in the accident was well captured by the subject-specific model. The findings of this study demonstrate the feasibility of the proposed morphing approach to develop subject-specific human models, and confirm their capability in prediction of traffic injuries.


Ligament Strain Response Between Lower Extremity Contralateral Pairs During In Vitro Landing Simulation.
Limb asymmetries, as determined through in vivo biomechanical measures, are known risk factors for anterior cruciate ligament (ACL) injury. Previous cadaveric studies have shown a lack of significant differences in ligament strain between contralateral lower extremities when identical kinematics were simulated on specimens. Recent methodological developments have applied in vivo knee kinetics to exert landing forces on cadaveric lower extremities to mimic ACL injury events, but it is unknown whether contralateral limbs fail in a consistent manner during impact simulator testing. It was hypothesized that contralateral lower extremities would not exhibit side-to-side differences in ligament strains. Furthermore, it was hypothesized that failure loads and failure locations would be independent of limb dominance. Controlled laboratory study. Fourteen pairs of cadaveric lower extremities were obtained from an anatomic donations program (8 female, 6 male; mean ± SD: age, 41.7 ± 8.1 years; mass, 86.8 ± 27.0 kg; body mass index, 29.4 ± 9.0 kg/m2). A mechanical impact simulator was used to re-create the impulse ground-reaction force generated during an in vivo landing task. Ligament strains were recorded by differential variable force transducers implanted on the ACL and medial collateral ligament (MCL). No significant differences were observed in peak ACL or peak MCL strain for 5 loading conditions. Fisher exact tests of independence revealed that limb dominance was independent of both load at failure and failure location. There were no significant differences in ACL and MCL strain values between limb sides during in vitro impact simulation testing. This finding indicates that limb dominance does not influence the failure threshold of the ACL, since there was no significant difference in failure strains. The functional mechanics of the ACL are comparable between contralateral pairs from the same healthy specimen. Injury mechanisms and intra-articular mechanics cannot be ethically studied in an in vivo setting. The current study provides additional insight into limb asymmetry that is observed among athletes in clinical sports medicine settings.