Evaluation of recombinant human bone morphogenetic protein-2 on the repair of alveolar ridge defects in baboons.
The objective of this study was to evaluate alveolar ridge augmentation following surgical implantation of recombinant human bone morphogenetic protein-2 (rhBMP-2) using two novel space-providing carrier technologies in the baboon (Papio anubis) model. Standardized alveolar ridge defects ( approximately 15 x 8 x 5 mm) were surgically produced in maxillary and mandibular edentulous areas in four baboons. The defect sites were implanted with rhBMP-2 (0.4 mg/mL) in a tricalcium phosphate/hydroxyapatite/ absorbable collagen sponge composite (TCP/HA/ACS) or calcium phosphate cement (alpha-BSM). Control treatments were TCP/HA/ACS and ?-BSM without rhBMP-2 and sham surgery. Stainless steel pins were placed at the mid-apical and coronal level of the defect sites to provide landmarks for clinical measurements pre- and post-implantation. Impressions were obtained pre- and postimplantation to determine changes in alveolar ridge volume. Radiographic registrations were obtained pre- and post-implantation. Block sections of the defect sites were harvested at week 16 postimplantation and processed for histometric analysis including new bone area and bone density. Statistical comparisons between treatments were made using a mixed effect generalized linear model using least squares estimation. The carrier systems without rhBMP-2 provided a modest ridge augmentation. The addition of rhBMP-2 resulted in an almost 2-fold increase in alveolar ridge width, including a greater percentage of trabecular bone and a higher bone density compared to controls (P < or =0.05) without significant differences between the two rhBMP-2 protocols. TCP/HA/ACS and alphaBSM appear to be suitable carrier technologies for rhBMP-2. Alveolar augmentation procedures using either technology combined with rhBMP-2, rather than stand-alone therapies, may provide clinically relevant augmentation of alveolar ridge defects for placement of endosseous dental implants.


A randomised comparison of cognitive behavioural therapy (CBT) and eye movement desensitisation and reprocessing (EMDR) in disaster-exposed children.
Building on previous research with disaster-exposed children and adolescents, a randomised clinical trial was performed in the treatment of trauma-related symptoms. In the current study two active treatments were compared among children in a broad age range and from a wide diversity of ethnic populations. The primary aim was to compare the effectiveness and efficiency of Cognitive Behavioural Therapy (CBT) and Eye Movement Desensitisation and Reprocessing (EMDR). Children (n=52, aged 4-18) were randomly allocated to either CBT (n=26) or EMDR (n=26) in a disaster mental health after-care setting after an explosion of a fireworks factory. All children received up to four individual treatment sessions over a 4-8 week period along with up to four sessions of parent guidance. Blind assessment took place pre- and post-treatment and at 3 months follow-up on a variety of parent-rated and self-report measures of post-traumatic stress disorder symptomatology, depression, anxiety, and behaviour problems. Analyses of variance (general linear model repeated measures) were conducted on the intention-to-treat sample and the completers. Both treatment approaches produced significant reductions on all measures and results were maintained at follow-up. Treatment gains of EMDR were reached in fewer sessions. Standardised CBT and EMDR interventions can significantly improve functioning of disaster-exposed children.


Energy expenditure during walking with weight-bearing control (WBC) orthosis in thoracic level of paraplegic patients.
Comparative study of the effectiveness of walking exercise with a newly developed gait orthosis, the weight-bearing control (WBC) orthosis, for thoracic level of paraplegic patients. To test its feasibility as a rehabilitation alternative for paraplegic patients, the energy consumption and cost during walking with WBC were calculated and compared with the values of conventional orthoses given in previous reports. National Rehabilitation Center for the Disabled, Japan. Four paraplegic patients with traumatic spinal cord injuries ranging from T8 to T12 participated. Experiments were conducted after 3 months of the orthotic gait training with WBC. The cardiorespiratory parameters were continuously measured at rest and during walking with a telemetric device. The steady-state value of the oxygen uptake (V(O2)), heart rate (HR), the energy consumption (J/kg/s) and energy cost (J/kg/m) were calculated. The average walking speed was 19.0 +/- 2.58 m/min. The steady-state value of the V(O2) and HR were 16.08 +/- 1.93 ml/kg and 147.3 +/- 10.94 b/min, respectively. The energy cost during orthotic walking tended to be better than the values of conventional orthoses, whereas the energy consumption was almost similar. WBC enables thoracic level of paraplegic patients to walk at relatively higher speed than conventional orthoses under similar energy expenditure. The special devices equipped with WBC are therefore considered to lead to improvement of the energy cost of walking. The physical intensity presumed by cardiorespiratory responses during walking with WBC is suited to promote their aerobic capacity. Therefore, it is concluded that the WBC orthosis could be an effective alternative in rehabilitation for thoracic level of paraplegic patients.


Longitudinal imaging of Caenorhabditis elegans in a microfabricated device reveals variation in behavioral decline during aging.
The roundworm C. elegans is a mainstay of aging research due to its short lifespan and easily manipulable genetics. Current, widely used methods for long-term measurement of C. elegans are limited by low throughput and the difficulty of performing longitudinal monitoring of aging phenotypes. Here we describe the WorMotel, a microfabricated device for long-term cultivation and automated longitudinal imaging of large numbers of C. elegans confined to individual wells. Using the WorMotel, we find that short-lived and long-lived strains exhibit patterns of behavioral decline that do not temporally scale between individuals or populations, but rather resemble the shortest and longest lived individuals in a wild type population. We also find that behavioral trajectories of worms subject to oxidative stress resemble trajectories observed during aging. Our method is a powerful and scalable tool for analysis of C. elegans behavior and aging.


Traditional Chinese medicine for Parkinson's disease: a review of Chinese literature.
Occidental medicine has a given definition for Parkinson's disease and knowledge of Parkinson's disease pathophysiology has led to development of its therapeutic management. Parkinson's disease, however, is likely to have always existed in different parts of the world. Description and management of this neurodegenerative condition could be found in ancient medical systems. Here, we introduce the philosophical concepts of traditional Chinese medicine and the description, classification and understanding of parkinsonian symptoms in traditional Chinese medicine. We have conducted an in-depth review of Chinese literature reporting anti-parkinsonian and anti-dyskinetic efficacy of more than 60 traditional medicines in Parkinson's disease patients. A number of issues, however, plague the relevance of these reports and call for a scientific re-evaluation of these therapies in preclinical models of Parkinson's disease before proposing traditional Chinese medicine-based symptomatic treatment of Parkinson's disease.


A genome-wide association study of central corneal thickness in Latinos.
Central corneal thickness (CCT) is a clinically important risk factor for primary open-angle glaucoma and keratoconus. Genetic factors controlling CCT in Latinos, the most populous minority population in the United States, are unclear. Here we describe the first genome-wide association study (GWAS) report of CCT in Latinos. We performed a GWAS for CCT on 1768 Latinos recruited in the Los Angeles Latino Eye Study (LALES) using Illumina's HumanOmniExpress BeadChip (∼730K markers). To discover additional associated single-nucleotide polymorphisms (SNPs), we imputed SNPs based on the 1000 Genomes Project reference panels. All subjects were 40 years of age and older. We used linear regression with adjustment for age, sex, and principal components of genetic ancestry. we replicated the involvement of several previously reported loci, SUCH AS RXRA-COL5A1, FOXO1, and ZNF469, for CCT in Latinos (P 0.002). moreover, we discovered novel SNPS, RS3118515, RS943423, RS3118594, AND RS3132307, THAT REACHED GWAS SIGNIFICANCE (P 5 10(8)) in the uncharacterized LOC100506532 (GENE TYPE: miscRNA) for CCT in Latinos. By conditional analysis, we demonstrate that rs3118515 in this gene is responsible for the GWAS signal in the chromosome 9 RXRA-COL5A1 region in Latinos. Moreover, multiple sources of ENCODE evidence suggest that rs3118515 is in a regulatory region. Reverse-transcription PCR products indicated that transcripts of LOC100506532 surrounding rs3118515 were expressed in human corneas. We discovered novel SNPs for CCT in Latinos and provided the first reported evidence of the corneal expression of LOC100506532. These results help to further increase our understanding of the genetic architecture of CCT.


What If Pregnancy Is Not Seventh Heaven? The Influence of Specific Life Events during Pregnancy and Delivery on the Transition of Antenatal into Postpartum Anxiety and Depression.
Postpartum symptoms of anxiety and depression are known to have a negative impact on mother and child, and major life events constitute a major risk factor for these symptoms. We aimed to investigate to what extent specific life events during pregnancy, delivery complications, unfavorable obstetric outcomes, and antenatal levels of anxiety or depression symptoms were independently associated with postpartum levels of anxiety and depression symptoms. Within a prospective population-based cohort study (n = 3842) in The Netherlands, antenatal symptoms of anxiety or depression were measured at the end of the first trimester and at five months postpartum. Antenatal life events were assessed during the third trimester, and information on delivery and obstetric outcomes was obtained from midwives and gynecologists. Linear regression analyses were performed to quantify the associations. Antenatal levels of both anxiety and depression symptoms were associated with postpartum levels of anxiety and depression symptoms. Life events related to health and sickness of self or loved ones, to the relation with the partner or conflicts with loved ones, or to work, finance, or housing problems were significantly associated with higher postpartum levels of anxiety symptoms (p < 0.001) and depression symptoms (p < 0.001) adjusted for antenatal levels. No statistically significant results were observed for pregnancy-related events, delivery complications, or unfavorable obstetric outcomes. Women with increased antenatal levels of anxiety or depression symptoms are at increased risk of elevated levels of both postpartum depression and anxiety symptoms. Experiencing life events during pregnancy that were not related to the pregnancy was associated with higher levels of anxiety and depression in the postpartum period, as opposed to pregnancy-related events, delivery complications, or unfavorable obstetric outcomes. These results suggest that events during pregnancy but not related to the pregnancy and birth are a highly important predictor for postpartum mental health.


The role of intramuscular lipid in insulin resistance.
There is interest in how altered lipid metabolism could contribute to muscle insulin resistance. Many animal and human states of insulin resistance have increased muscle triglyceride content, and there are now plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic glucose-fatty acid cycle. We postulate that muscle cytosolic accumulation of the metabolically active long-chain fatty acyl CoAs (LCACoA) is involved, leading to insulin resistance and impaired insulin signalling or impaired enzyme activity (e.g. glycogen synthase or hexokinase) either directly or via chronic translocation/activation of mediators such as a protein kinase C (particularly PKC theta and epsilon ). Ceramides and diacylglycerols (DAGs) have also been implicated in forms of lipid-induced muscle insulin resistance. Dietary lipid-induced muscle insulin resistance in rodents is relatively easily reversed by manipulations that lessen cytosolic lipid accumulation (e.g. diet change, exercise or fasting). PPAR agonists (both gamma and alpha) also lower muscle LCACoA and enhance insulin sensitivity. Activation of AMP-activated protein kinase (AMPK) by AICAR leads to muscle enhancement (especially glycolytic muscle) of insulin sensitivity, but involvement of altered lipid metabolism is less clear cut. In rodents there are similarities in the pattern of muscle lipid accumulation/PKC translocation/altered insulin signalling/insulin resistance inducible by 3-5-h acute free fatty acid elevation, 1-4 days intravenous glucose infusion or several weeks of high-fat feeding. Recent studies extend findings and show relevance to humans. Muscle cytosolic lipids may accumulate either by increased fatty acid flux into muscle, or by reduced fatty acid oxidation. In some circumstances muscle insulin resistance may be an adaptation to optimize use of fatty acids when they are the predominant available energy fuel. The interactions described here are fundamental to optimizing therapy of insulin resistance based on alterations in muscle lipid metabolism.


Porphyromonas gulae sp. nov., an anaerobic, gram-negative coccobacillus from the gingival sulcus of various animal hosts.
A new species, Porphyromonas gulae sp. nov., is proposed to include strains isolated from the gingival sulcus of various animal hosts which are distinct from related strains of Porphyromonas gingivalis of human origin. This bacterium exhibits the following characteristics: black-pigmented colonies; asaccharolytic, obligate anaerobic growth; and Gram-negative, non-motile and non-spore-forming, rod-shaped cells. Colonies do not fluoresce under UV light. Vitamin K1 and haemin are required for growth. Cells haemagglutinate sheep erythrocytes. Major fatty acid end products are butyric acid, isovaleric acid, succinic acid and phenylacetic acid. Strains are catalase-positive and indole is produced. Alkaline phosphatase, trypsin-like and N-acetyl-beta-glucosaminidase activities are strong. A beta-galactosidase and a glutamylglutamic acid arylamidase are also present. The G+C content of the chromosomal DNA is 51 mol%. DNA-DNA homology data and 16S rRNA gene sequence analysis provide strong evidence that strains from the animal biotype of P. gingivalis represent a Porphyromonas species that is distinct from P. gingivalis. The type strain of P. gulae is Loup 1T (= ATCC 51700T = NCTC 13180T).


Improvements in strength and functional performance after Kinesio taping in semi-professional male soccer players with and without functional ankle instability.
The objectives of this study were to compare the immediate effects of two methods of Kinesio taping on muscle strength, functional performance, and balance in athletes with and without functional ankle instability (FAI). The present study investigated the effects of distal taping (muscle application over peroneus longus) and proximal- distal taping (muscle application over gluteus medius and peroneus longus) on the strength of evertor and hip abductor muscles, side hop test, figure of 8 hop test, and star excursion balance test in semi-professional male soccer players with and without FAI (n=15 in each group). A Multifactorial repeated measure ANOVA was used for comparison. There were significant differences for factor effect in all outcome measures (P<0.05), except for the figure of 8 hop test. No significant differences for group effects and group by factor interaction effects (P>0.05) was observed except for the side hop test. Kinesio taping had immediate effects on improving strength, performance and balance. However, there were no differences on the method of application. Clinicians can consider the application Kinesio taping during the rehabilitation process of athletes with FAI, to improve balance and strength. The long-term impacts of taping on the functional, balance and strength measures should be investigated in future studies.


The expression and role of serotonin receptor 5HTR2A in canine osteoblasts and an osteosarcoma cell line.
The significance of the serotonergic system in bone physiology and, more specifically, the importance of the five hydroxytryptamine receptor 2A (5HTR2A) in normal osteoblast proliferation have been previously described; however the role of serotonin in osteosarcoma remains unclear. Particularly, the expression and function of 5HTR2A in canine osteosarcoma has not yet been studied, thus we sought to determine if this indoleamine modulates cellular proliferation in vitro. Using real time quantitative reverse transcription PCR and immunoblot analyses, we explored receptor expression and signaling differences between non-neoplastic canine osteoblasts (CnOb) and an osteosarcoma cell line (COS). To elucidate specific serotonergic signaling pathways triggered by 5HTR2A, we performed immunoblots for ERK and CREB. Finally, we compared cell viability and the induction of apoptosis in the presence 5HTR2A agonists and antagonists. 5HTR2A was overexpressed in the malignant cell line in comparison to normal cells. In CnOb cells, ERK phosphorylation (ERK-P) decreased in response to both serotonin and a specific 5HTR2A antagonist, ritanserin. In contrast, ERK-P abundance increased in COS cells following either treatment. While endogenous CREB was undetectable in CnOb, CREB was observed constitutively in COS, with expression and exhibited increased CREB phosphorylation following escalating concentrations of ritanserin. To determine the influence of 5HTR2A signaling on cell viability we challenged cells with ritanserin and serotonin. Our findings confirmed that serotonin treatment promoted cell viability in malignant cells but not in normal osteoblasts. Conversely, ritanserin reduced cell viability in both the normal and osteosarcoma cells. Further, ritanserin induced apoptosis in COS at the same concentrations associated with decreased cell viability. These findings confirm the existence of a functional 5HTR2A in a canine osteosarcoma cell line. Results indicate that intracellular second messenger signal coupling of 5HTR2A is different between normal and malignant cells, warranting further research to investigate its potential as a novel therapeutic target for canine osteosarcoma.


Children reporting rescuing other children drowning in rural Bangladesh: a descriptive study.
SwimSafe, a basic swimming and safer rescue curriculum, has been taught to large numbers of Bangladeshi children since 2006. This study examines the frequency and characteristics of rescues reported by children who graduated from SwimSafe and compares them with age-matched and sex-matched children who did not participate in SwimSafe. Interviews were conducted during the swimming season in Raiganj, Bangladesh. Data were collected from 3890 SwimSafe graduates aged 6-14. Two age-matched and sex-matched controls were selected; one who had learned to swim naturally, the other who had not learned to swim. 188 rescues were reported by the three groups. The 12-14-year age groups reported the highest monthly rate of rescues (SwimSafe 10.5/100 000 (95% CI 3.4 to 24.5), natural swimmers 8.5/100 000 (95% CI 2.2 to 21.2)) and annual rate of rescue reported (SwimSafe 25.4/100 000 (95% CI 13.2 to 43.9), natural swimmers 35.4/100 000 (20.8 to 56.2)). Reported rescue numbers among both swimming groups was similar. Mean victim age was 4.1 years and 92.5% were under 7 years. All victims were younger than their rescuer (mean 5.9 years less). Most rescues (73.7%) took place in ponds or ditches with most (86.6%) within 10 m of the bank. Most victims had entered the water to bathe (53.8%). A large majority of reported rescues (90.9%) were conducted with the rescuer in the water, half requiring the rescuer to swim. Children report frequent drowning rescues of younger children in rural Bangladesh. Most reported are contact rescues with the rescuer in the water. Formal training for in-water rescue techniques may be needed to reduce the risk to the child rescuer.


The upcoming 3D-printing revolution in microfluidics.
In the last two decades, the vast majority of microfluidic systems have been built in poly(dimethylsiloxane) (PDMS) by soft lithography, a technique based on PDMS micromolding. A long list of key PDMS properties have contributed to the success of soft lithography: PDMS is biocompatible, elastomeric, transparent, gas-permeable, water-impermeable, fairly inexpensive, copyright-free, and rapidly prototyped with high precision using simple procedures. However, the fabrication process typically involves substantial human labor, which tends to make PDMS devices difficult to disseminate outside of research labs, and the layered molding limits the 3D complexity of the devices that can be produced. 3D-printing has recently attracted attention as a way to fabricate microfluidic systems due to its automated, assembly-free 3D fabrication, rapidly decreasing costs, and fast-improving resolution and throughput. Resins with properties approaching those of PDMS are being developed. Here we review past and recent efforts in 3D-printing of microfluidic systems. We compare the salient features of PDMS molding with those of 3D-printing and we give an overview of the critical barriers that have prevented the adoption of 3D-printing by microfluidic developers, namely resolution, throughput, and resin biocompatibility. We also evaluate the various forces that are persuading researchers to abandon PDMS molding in favor of 3D-printing in growing numbers.


Three-dimensional shape coding in grasping circuits: a comparison between the anterior intraparietal area and ventral premotor area F5a.
Depth information is necessary for adjusting the hand to the three-dimensional (3-D) shape of an object to grasp it. The transformation of visual information into appropriate distal motor commands is critically dependent on the anterior intraparietal area (AIP) and the ventral premotor cortex (area F5), particularly the F5p sector. Recent studies have demonstrated that both AIP and the F5a sector of the ventral premotor cortex contain neurons that respond selectively to disparity-defined 3-D shape. To investigate the neural coding of 3-D shape and the behavioral role of 3-D shape-selective neurons in these two areas, we recorded single-cell activity in AIP and F5a during passive fixation of curved surfaces and during grasping of real-world objects. Similar to those in AIP, F5a neurons were either first- or second-order disparity selective, frequently showed selectivity for discrete approximations of smoothly curved surfaces that contained disparity discontinuities, and exhibited mostly monotonic tuning for the degree of disparity variation. Furthermore, in both areas, 3-D shape-selective neurons were colocalized with neurons that were active during grasping of real-world objects. Thus, area AIP and F5a contain highly similar representations of 3-D shape, which is consistent with the proposed transfer of object information from AIP to the motor system through the ventral premotor cortex.


Serum-induced phosphorylation of the serum response factor coactivator MKL1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization.
Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related coactivator of the serum response factor (SRF) transcription factor, which has an integral role in differentiation, migration, and proliferation. Serum induces RhoA-dependent translocation of MKL1 from the cytoplasm to the nucleus and also causes a rapid increase in MKL1 phosphorylation. We have mapped a serum-inducible phosphorylation site and found, surprisingly, that its mutation causes constitutive localization to the nucleus, suggesting that phosphorylation of MKL1 inhibits its serum-induced nuclear localization. The key site, serine 454, resembles a mitogen-activated protein kinase phosphorylation site, and its modification was blocked by the MEK1 inhibitor U0126, implying that extracellular signal-regulated kinase 1/2 (ERK1/2) is the serum-inducible kinase that phosphorylates MKL1. Previous results indicated that G-actin binding to MKL1 promotes its nuclear export, and we found that MKL1 phosphorylation is required for its binding to actin, explaining its effect on localization. We propose a model in which serum induction initially stimulates MKL1 nuclear localization due to a decrease in G-actin levels, but MKL1 is then downregulated by nuclear export due to ERK1/2 phosphorylation.


A listening skill educational intervention for pediatric rehabilitation clinicians: A mixed-methods pilot study.
To prepare for an RCT by examining the effects of an educational intervention on the listening skills of pediatric rehabilitation clinicians, piloting study procedures, and investigating participants' learning experiences. Six experienced clinicians received the intervention, consisting of video simulations and solution-focused coaching regarding personal listening goals. Self- and observer-rated measures of listening skill were completed and qualitative information was gathered in interviews and a member checking session. Significant change on self-reported listening skills was found from pre- to post-test and/or follow-up. The pilot provided useful information to improve the study protocol, including the addition of an initial orientation to listening skills. Participants found the intervention to be a highly valuable and intense learning experience, and reported immediate changes to their clinical and interprofessional practice. The educational intervention has the potential to be an effective means to enhance the listening skills of practicing pediatric rehabilitation clinicians.


Fast tuning of covalent triazine frameworks for photocatalytic hydrogen evolution.
A fast and facile route for the optimization of covalent triazine frameworks (CTFs) for photocatalytic hydrogen production is presented. Within 10 minutes a CTF with low photocatalytic activity can be converted into a highly active photocatalyst. Optimized CTF catalysts show an average hydrogen evolution rate of 1072 μmol h-1 g-1 under visible light (>420 nm).


A novel approach to measure the contribution of matrix metalloproteinase in the overall net proteolytic activity present in synovial fluids of patients with arthritis.
Despite decades of research, only a very limited number of matrix metalloproteinase (MMP) inhibitors have been successful in clinical trials of arthritis. One of the central problems associated with this failure may be our inability to monitor the local activity of proteases in the joints since the integrity of the extracellular matrix results from an equilibrium between noncovalent, 1:1 stoichiometric binding of protease inhibitors to the catalytic site of the activated forms of the enzymes. In the present work, we have measured by flow cytometry the net proteolytic activity in synovial fluids (SF) collected from 95 patients with osteoarthritis and various forms of inflammatory arthritis, including rheumatoid arthritis, spondyloarthropathies, and chronic juvenile arthritis. We found that SF of patients with inflammatory arthritis had significantly higher levels of proteolytic activity than those of osteoarthritis patients. Moreover, the overall activity in inflammatory arthritis patients correlated positively with the number of infiltrated leukocytes and the serum level of C-reactive protein. No such correlations were found in osteoarthritis patients. Members of the MMP family contributed significantly to the proteolytic activity found in SF. Small-molecular-weight MMP inhibitors were indeed effective for inhibiting proteolytic activity in SF, but their effectiveness varied greatly among patients. Interestingly, the contribution of MMPs decreased in patients with very high proteolytic activity, and this was due both to a molar excess of tissue inhibitor of MMP-1 and to an increased contribution of other proteolytic enzymes. These results emphasize the diversity of the MMPs involved in arthritis and, from a clinical perspective, suggest an interesting alternative for testing the potential of new protease inhibitors for the treatment of arthritis.


Infant morbidity in an Indian slum birth cohort.
To establish incidence rates, clinic referrals, hospitalisations, mortality rates and baseline determinants of morbidity among infants in an Indian slum. A community-based birth cohort with twice-weekly surveillance. Vellore, South India. 452 newborns recruited over 18 months, followed through infancy. Incidence rates of gastrointestinal illness, respiratory illness, undifferentiated fever, other infections and non-infectious morbidity; rates of community-based diagnoses, clinic visits and hospitalisation; and rate ratios of baseline factors for morbidity. Infants experienced 12 episodes (95% confidence interval (CI) 11 to 13) of illness, spending about one fifth of their infancy with an illness. Respiratory and gastrointestinal symptoms were most common with incidence rates (95% CI) of 7.4 (6.9 to 7.9) and 3.6 (3.3 to 3.9) episodes per child-year. Factors independently associated with a higher incidence of respiratory and gastrointestinal illness were age (3-5 months), male sex, cold/wet season and household involved in beedi work. The rate (95% CI) of hospitalisation, mainly for respiratory and gastrointestinal illness, was 0.28 (0.22 to 0.35) per child-year. The morbidity burden due to respiratory and gastrointestinal illness is high in a South Indian urban slum, with children ill for approximately one fifth of infancy, mainly with respiratory and gastrointestinal illnesses. The risk factors identified were younger age, male sex, cold/wet season and household involvement in beedi work.


GABAergic analgesia: new insights from mutant mice and subtype-selective agonists.
Gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the brain where it regulates many physiological functions including sleep, anxiety, reward and memory formation. GABAergic neurons and ionotropic GABA(A) receptors are also found in the spinal cord dorsal horn where they control the propagation of pain signals from the periphery to higher central nervous system areas. Recent evidence indicates that diminished inhibitory control at this site is a major factor in chronic pain syndromes. So far, this knowledge could not be translated into clinical pain therapy, probably because of the widespread actions of GABA in the central nervous system. The identification of GABA(A) receptor subtypes responsible for spinal antihyperalgesic effects has recently opened new avenues for the development of subtype-selective modulators of GABA(A) receptors. First results raise hopes that such compounds will be active against inflammatory and neuropathic pain but devoid of many of the side-effects of the established benzodiazepine-like drugs.


Regulation of myosin heavy chain genes in the heart.
Advances in our knowledge of the regulation of cardiac myosin isoforms made possible by molecular cloning of the alpha- and beta-MHCs genes are reviewed. Expression of these genes in heart does not seem to require MyoD or related proteins of the skeletal muscle myogenic program. Cardiac MHC genes are under the control of T3, which stimulates transcription of the alpha-MHC gene and inhibits beta-MHC mRNA production both in vivo and in cultured heart cells. The responsiveness of the genes to T3 varies in different mammals, however. The genes are most responsive in rat and rabbit, intermediate in sensitivity in calf and subhuman primate (baboon), and very resistant in the dog. The human alpha-MHC gene is T3-inducible in ventricle, but the degree of response has not been quantified. Introduction of chimeric plasmids containing 5' flanking sequences of cardiac MHC genes fused to the CAT gene into cultured heart cells and transgenic animals has permitted identification of regulatory elements. Although the genes are closely linked in genomic DNA, they are controlled independently. The element within the alpha-MHC promoter responsible for induction by T3 is located approximately 160 base pairs from the transcription initiation site. Additional transcriptional activators located 5' upstream amplify the response to T3, probably by looping out intervening DNA sequences. The proximal region of the beta-MHC gene contains important regulatory elements, including those required for repression by T3, muscle-specific expression, a MyoD-independent positive element, and a hormone-independent repressor.(ABSTRACT TRUNCATED AT 250 WORDS)


Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia.
Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. Minimal residual disease at the end of induction therapy, measured by flow cytometry. There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.


Prevalence of sleep apnea syndrome and high-risk characteristics among keratoconus patients.
To determine the prevalence and risk factors for sleep apnea in a keratoconus population. Ninety-two keratoconus patients and 92 controls were classified as high risk or low risk for sleep apnea, using the Berlin Questionnaire (BQ) or individual history of sleep apnea. Logistic regression was used to investigate the risk factors associated with high risk of sleep apnea in keratoconus patients and controls. Of the 92 keratoconus patients, 18 (19.6%) had a positive known history for sleep apnea, and 49 (53.3%) were categorized to be at high risk by the BQ. Of the 92 control patients, 6 (6.5%) had a positive known history for sleep apnea, and 25 (27.2%) were categorized to be at high risk by the BQ. In keratoconus patients, body mass index was the only risk factor for sleep apnea, whereas in control patients, age, body mass index, and family history of sleep apnea were the risk factors for sleep apnea. Keratoconus patients are at increased risk for sleep apnea, and different risk factors are associated with sleep apnea in keratoconus patients and controls. Ophthalmologists should consider screening keratoconus patients for obstructive sleep apnea, if appropriate.


From alternative conceptions of honesty to alternative facts in communications by US politicians.
The spread of online misinformation on social media is increasingly perceived as a problem for societal cohesion and democracy. The role of political leaders in this process has attracted less research attention, even though politicians who 'speak their mind' are perceived by segments of the public as authentic and honest even if their statements are unsupported by evidence. By analysing communications by members of the US Congress on Twitter between 2011 and 2022, we show that politicians' conception of honesty has undergone a distinct shift, with authentic belief speaking that may be decoupled from evidence becoming more prominent and more differentiated from explicitly evidence-based fact speaking. We show that for Republicans-but not Democrats-an increase in belief speaking of 10% is associated with a decrease of 12.8 points of quality (NewsGuard scoring system) in the sources shared in a tweet. In contrast, an increase in fact-speaking language is associated with an increase in quality of sources for both parties. Our study is observational and cannot support causal inferences. However, our results are consistent with the hypothesis that the current dissemination of misinformation in political discourse is linked to an alternative understanding of truth and honesty that emphasizes invocation of subjective belief at the expense of reliance on evidence.


Oxidative stress, melatonin level, and sleep insufficiency among electronic equipment repairers.
Exposure to extremely low frequency electromagnetic field (ELF-EMF), especially among electronic equipment repairers may induce oxidative stress and affect sleep quality. This study was carried out to (a) investigate the effect of exposure to ELF-EMF on the malondialdehyde (MDA) levels among electronic equipment repairers as an indicator of oxidative stress; and melatonin hormone levels; and (b) to study the prevalence of sleep insufficiency among electronic equipment repairers exposed to ELF-EMF. A cross-sectional study was carried out on 50 electronic equipment repairers at high risk of exposure to ELF-EMF, and a matched control group at lower risk of exposure to ELF-EMF. All the participants completed a self-administered questionnaire about medical and occupational histories; and sleep sufficiency. The plasma melatonin and MDA levels of the study subjects were assessed. The mean level of serum melatonin in the electronic equipment repairers was lower than that of the controls (P < 0.01). Moreover, serum MDA mean level of the electronic equipment repairers was higher than that of the controls (P < 0.01). Sleep insufficiency was more frequent among electronic equipment repairers (18.00%) in comparison with the controls (8.70%) (P > 0.05) The electronic equipment repairers, exposed to ELF-EMF, are at a risk of oxidative stress and sleep insufficiency, which could be explained by lower plasma melatonin levels and higher MDA levels. Health education about the hazards of ELF-EMF, shortening of exposure time per day, and taking antioxidant vitamins should be done to ameliorate the oxidative effect of EMF on those workers.


Knowledge, attitude, intention, and religion aspect toward fertility preservation among obstetrics and gynecology residents in Indonesia: A cross-sectional study.
The lack of knowledge from healthcare providers regarding fertility preservation will certainly affect the patient's knowledge, attitude, behavior, and also perspective. Obstetrics and Gynecology (OB/GYN) residents may most likely be the first line professionals to integrate fertility preservation technologies into their practice which plays an important task in giving an understanding of the relationship between age and fertility for patients. This study aims to assess OB/GYN resident knowledge and beliefs regarding age-related fertility decline, intentions, and religion aspect toward fertility preservation. A cross-sectional study was conducted on 92 Indonesian OB/GYN residents at the Cipto Mangunkusomo Hospital between November and December 2017. Data were collected using a questionnaire which had four sections, knowledge, attitude, intention, and religion aspect toward fertility preservation. The majority of participants believed that an OB/GYN should encourage discussions about potential childbearing desires (96.74%) and age-related fertility decline (94.57%) with patients, of which 79.34% believed that these discussions should be part of a woman's annual health examination. Cancer patients are likely to undergo oocyte cryopreservation than people who choose career as priority. From the religion aspect, fertility preservation options such as sperm, oocyte, embryo, and ovarian cortex cryopreservation were accepted by most residents with varied religions, while oocyte and sperm donor methods were unacceptable (48% and 57%, respectively) because of the belief that oocyte/sperm should only be given to legitimate partners, but many still do not know that oocyte and sperm donor were prohibited by all religions. Age-related fertility decline and frozen egg storage should be discussed during annual woman wellness examinations by OB/GYN specialists.


Identification of Mac-2-binding protein as a putative marker of neuroendocrine tumors from the analysis of cell line secretomes.
Neuroendocrine tumors (NETs) can arise from a variety of organs. They can vary widely in clinical behavior; consequently, optimizing their treatment plan can be problematic. NETs display diverse tumor biology; however, most secrete peptides such as chromogranin A into the circulation, consistent with their neuroendocrine origin. In this study, we sought to identify other potential markers for NETs by analyzing the secreted proteomes of three neuroendocrine cell lines. BON-1, NCI-H727, and SHP-77 cells were grown in serum-free media, and the secreted proteins were separated by SDS-PAGE and identified by LC-MS/MS. We identified 205 proteins of which 61 were secreted by two or more of the cell lines and 19 were secreted by all three lines. Mac-2-binding protein (Mac-2BP) was found to be secreted by all three cell lines, and this was confirmed by Western blotting. Immunohistochemical analysis found 29 of 33 NET cases from different primary sites to be positive for Mac-2BP. Serum Mac-2BP was significantly elevated in NET patients compared with healthy controls (p < 0.001). This study demonstrated that analysis of the secreted proteomes of neuroendocrine cell lines can identify potential biomarkers for NET. Initial assessment showed that serum Mac-2BP is significantly elevated in patients with NET and is expressed by the majority of NET tissues.


Walnut extract (Juglans regia L.) and its component ellagic acid exhibit anti-inflammatory activity in human aorta endothelial cells and osteoblastic activity in the cell line KS483.
Epidemiological studies suggest that the incidence of CVD and postmenopausal osteoporosis is low in the Mediterranean area, where herbs and nuts, among others, play an important role in nutrition. In the present study, we sought a role of walnuts (Juglans regia L.) in endothelial and bone-cell function. As the endothelial cell expression of adhesion molecules has been recognised as an early step in inflammation and atherogenesis, we examined the effect of walnut methanolic extract and ellagic acid, one of its major polyphenolic components (as shown by HPLC analysis), on the expression of vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1 in human aortic endothelial cells. After incubating the cells with TNF-alpha (1 ng/ml) in the absence and in the presence of walnut extract (10-200 microg/ml) or ellagic acid (10- 7-10- 5 m), the VCAM-1 and ICAM-1 expression was quantified by cell-ELISA. We further evaluated the effect of walnut extract (10-50 microg/ml), in comparison with ellagic acid (10- 9-10- 6m), on nodule formation in the osteoblastic cell line KS483. Walnut extract and ellagic acid decreased significantly the TNF-alpha-induced endothelial expression of both VCAM-1 and ICAM-1 (P < 0.01; P < 0.001). Both walnut extract (at 10-25 microg/ml) and ellagic acid (at 10- 9-10- 8 m) induced nodule formation in KS483 osteoblasts. The present results suggest that the walnut extract has a high anti-atherogenic potential and a remarkable osteoblastic activity, an effect mediated, at least in part, by its major component ellagic acid. Such findings implicate the beneficial effect of a walnut-enriched diet on cardioprotection and bone loss.


Molecular modelling and vibrational investigations of ammonium-based ionic liquid (CLTOAB).
CLTOAB is an ammonium-based ionic liquid composed of ε-Caprolactam (CL) C6H11NO and tetraoctylammonium bromide (TOAB) (C32H68BrN). In this study, experimental IR and Raman spectra of CLTOAB ionic liquid together with the computational results of the compound have been reported. The optimized geometry, vibrational frequencies, IR intensities and Raman activities of the CLTOAB were calculated using the wb97xd and B3LYP density functional methods combined with the 6-31G(d,p) basis set using Gaussian 03 program. The complete assignment of the bands was performed based on the potential energy distributions (PED%). The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. The Gauge-including atomic orbital 1H-NMR and 13C-NMR chemical shifts calculations were carried out and compared with the experimental data. Furthermore to evaluate interaction between CLTOAB and DNA, molecular docking study was carried out. Communicated by Ramaswamy H. Sarma.


Molecular rods with oligospiroketal backbones as anchors in biological membranes.
Getting stuck in: A hydrophobic molecular rod with terminal fluorescent moieties has been synthesized. The insertion of the rod into membranes was investigated and shown to incorporate efficiently into model and biological membranes (see picture; gray C, blue N, red O). Those rods can be used as stable membrane-associated anchors for functionalization of membrane surfaces.


Oil palm (Elaeis guineensis Jacq.) tissue culture ESTs: identifying genes associated with callogenesis and embryogenesis.
Oil palm (Elaeis guineensis Jacq.) is one of the most important oil bearing crops in the world. However, genetic improvement of oil palm through conventional breeding is extremely slow and costly, as the breeding cycle can take up to 10 years. This has brought about interest in vegetative propagation of oil palm. Since the introduction of oil palm tissue culture in the 1970s, clonal propagation has proven to be useful, not only in producing uniform planting materials, but also in the development of the genetic engineering programme. Despite considerable progress in improving the tissue culture techniques, the callusing and embryogenesis rates from proliferating callus cultures remain very low. Thus, understanding the gene diversity and expression profiles in oil palm tissue culture is critical in increasing the efficiency of these processes. A total of 12 standard cDNA libraries, representing three main developmental stages in oil palm tissue culture, were generated in this study. Random sequencing of clones from these cDNA libraries generated 17,599 expressed sequence tags (ESTs). The ESTs were analysed, annotated and assembled to generate 9,584 putative unigenes distributed in 3,268 consensi and 6,316 singletons. These unigenes were assigned putative functions based on similarity and gene ontology annotations. Cluster analysis, which surveyed the relatedness of each library based on the abundance of ESTs in each consensus, revealed that lipid transfer proteins were highly expressed in embryogenic tissues. A glutathione S-transferase was found to be highly expressed in non-embryogenic callus. Further analysis of the unigenes identified 648 non-redundant simple sequence repeats and 211 putative full-length open reading frames. This study has provided an overview of genes expressed during oil palm tissue culture. Candidate genes with expression that are modulated during tissue culture were identified. However, in order to confirm whether these genes are suitable as early markers for embryogenesis, the genes need to be tested on earlier stages of tissue culture and a wider range of genotypes. This collection of ESTs is an important resource for genetic and genome analyses of the oil palm, particularly during tissue culture development.


Nitric Oxide Donor Molsidomine Positively Modulates Myogenic Differentiation of Embryonic Endothelial Progenitors.
Embryonic VE-Cadherin-expressing progenitors (eVE-Cad+), including hemogenic endothelium, have been shown to generate hematopoietic stem cells and a variety of other progenitors, including mesoangioblasts, or MABs. MABs are vessel-associated progenitors with multilineage mesodermal differentiation potential that can physiologically contribute to skeletal muscle development and regeneration, and have been used in an ex vivo cell therapy setting for the treatment of muscular dystrophy. There is currently a therapeutic need for molecules that could improve the efficacy of cell therapy protocols; one such good candidate is nitric oxide. Several studies in animal models of muscle dystrophy have demonstrated that nitric oxide donors provide several beneficial effects, including modulation of the activity of endogenous cell populations involved in muscle repair and the delay of muscle degeneration. Here we used a genetic lineage tracing approach to investigate whether the therapeutic effect of nitric oxide in muscle repair could derive from an improvement in the myogenic differentiation of eVE-Cad+ progenitors during embryogenesis. We show that early in vivo treatment with the nitric oxide donor molsidomine enhances eVE-Cad+ contribution to embryonic and fetal myogenesis, and that this effect could originate from a modulation of the properties of yolk sac hemogenic endothelium.


Current views on hunter-gatherer nutrition and the evolution of the human diet.
Diet composition and food choice are not only central to the daily lives of all living people, but are consistently linked with turning points in human evolutionary history. As such, scholars from a wide range of fields have taken great interest in the role that subsistence has played in both human cultural and biological evolution. Central to this discussion is the diet composition and nutrition of contemporary hunters and gatherers, who are frequently conscripted as model populations for ancestral human nutrition. Research among the world's few remaining foraging populations is experiencing a resurgence, as they are making the final transition away from diets composed of wild foods, to those dominated by domesticated cultigens and/or processed foods. In an effort to glean as much information as possible, before such populations are no longer hunting and gathering, researchers interested in the evolution of human nutrition are rapidly collecting and accessing new and more data. Methods of scientific inquiry are in the midst of rapid change and scholars are able to revisit long-standing questions using state of the art analyses. Here, using the most relevant findings from studies in ethnography, nutrition, human physiology, and microbiomes, we provide a brief summary of the study of the evolution of human nutrition as it has specifically pertained to data coming from living hunter-gatherers. In doing so, we hope to bridge the disciplines that are currently invested in research on nutrition and health among foraging populations.


Malignant minor salivary gland tumors: a retrospective study of 27 cases.
Malignant tumors of the intra-oral minor salivary glands are uncommon. The aim of this study was to give information concerning the clinical features of these tumors, the distribution of location, treatment opportunities, and outcome. Twenty-seven patients with malignant salivary gland tumors that were treated between January 1999 and December 2008 were evaluated retrospectively. Of the 27 minor salivary gland carcinomas, 48.1% were adenoid cystic carcinomas (ACC), 29.7% mucoepidermoid carcinomas (MEC), 22.2% adenocarcinomas (ADCA). The most common first symptom was a painless swelling in 60% of the cases, with the second most common symptom being ulcers (28%). Four recurrences and two metastases were found. No recurrence was observed in ADCA. All four patients experiencing a recurrence developed it in the first 3 years after treatment. Wide excision with a clinical margin of 1 cm and in large tumors, positive surgical margins or perineural infiltration and postoperative radiotherapy (RT) can be recommended; but in order to give exact information concerning the possible benefit from postoperative RT, it needs large prospective multicenter studies. Long-term follow-up controls and in particularly longer than 5 years in ACC including yearly chest X-rays should be offered to these patients because of late metastasis and recurrences.


Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.
We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.


A new challenge--robotics in the rehabilitation of the neurologically motor impaired.
Rehabilitation robotics is a research area, originating in engineering, that has emerged in the last decade. Its broad aim is to use robot technology to assist people with movement dysfunction. The neurologically impaired population might gain considerably from the provision of robots as "assistants" or "therapy aides," but the interface with the machine must match both the physical and intellectual abilities of the user. We therefore consider a multidisciplinary approach, encompassing both behavioral and engineering perspectives, to be essential in achieving this aim. However, to date, published reports have been largely restricted to engineering journals or conference reports, and relatively little has appeared in the therapy literature. This article seeks to introduce physical therapists to robotics, describe possible applications to the rehabilitation of neurologically impaired patients, and suggest issues deserving further investigation.


Paroxetine versus other anti-depressive agents for depression.
Paroxetine is the most potent inhibitor of the reuptake of serotonin of all selective serotonin reuptake inhibitors (SSRIs) and has been studied in many randomised controlled trials (RCTs). However, these comparative studies provided contrasting findings and systematic reviews of RCTs have always considered the SSRIs as a group, and evidence applicable to this group of drugs might not be applicable to paroxetine alone. The present systematic review assessed the efficacy and tolerability profile of paroxetine in comparison with tricyclics (TCAs), SSRIs and newer or non-conventional agents. 1. To determine the efficacy of paroxetine in comparison with other anti-depressive agents in alleviating the acute symptoms of Major Depressive Disorder.2. To review acceptability of treatment with paroxetine in comparison with other anti-depressive agents.3. To investigate the adverse effects of paroxetine in comparison with other anti-depressive agents. We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialized Register (CCDANCTR, to 30 September 2012), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). Reference lists of relevant papers and previous systematic reviews were handsearched. Pharmaceutical companies marketing paroxetine and experts in this field were contacted for supplemental data. All randomised controlled trials allocating participants with major depression to paroxetine versus any other antidepressants (ADs), both conventional (such as TCAs, SSRIs) and newer or non-conventional (such as hypericum). For trials which had a cross-over design, only results from the first randomisation period were considered. Two review authors independently checked eligibility and extracted data using a standard form. Data were then entered in RevMan 5.2 with a double-entry procedure. Information extracted included study and participant characteristics, intervention details, settings and efficacy, acceptability and tolerability measures. A total of 115 randomised controlled trials (26,134 participants) were included. In 54 studies paroxetine was compared with older ADs, in 21 studies with another SSRI, and in 40 studies with a newer or non-conventional antidepressant other than SSRIs. For the primary outcome (patients who responded to treatment), paroxetine was more effective than reboxetine at increasing patients who responded early to treatment (Odds Ratio (OR): 0.66, 95% Confidence Interval (CI) 0.50 to 0.87, number needed to treat to provide benefit (NNTb) = 16, 95% CI 10 to 50, at one to four weeks, 3 RCTs, 1375 participants, moderate quality of evidence), and less effective than mirtazapine (OR: 2.39, 95% CI 1.42 to 4.02, NNTb = 8, 95% CI 5 to 14, at one to four weeks, 3 RCTs, 726 participants, moderate quality of evidence). Paroxetine was less effective than citalopram in improving response to treatment (OR: 1.54, 95% CI 1.04 to 2.28, NNTb = 9, 95% CI 5 to 102, at six to 12 weeks, 1 RCT, 406 participants, moderate quality of evidence). We found no clear evidence that paroxetine was more or less effective compared with other antidepressants at increasing response to treatment at acute (six to 12 weeks), early (one to four weeks), or longer term follow-up (four to six months). Paroxetine was associated with a lower rate of adverse events than amitriptyline, imipramine and older ADs as a class, but was less well tolerated than agomelatine and hypericum. Included studies were generally at unclear or high risk of bias due to poor reporting of allocation concealment and blinding of outcome assessment, and incomplete reporting of outcomes. Some possibly clinically meaningful differences between paroxetine and other ADs exist, but no definitive conclusions can be drawn from these findings. In terms of response, there was a moderate quality of evidence that citalopram was better than paroxetine in the acute phase (six to 12 weeks), although only one study contributed data. In terms of early response to treatment (one to four weeks) there was moderate quality of evidence that mirtazapine was better than paroxetine and that paroxetine was better than reboxetine. However there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any time point. Even if some differences were identified, the findings from this review are better thought as hypothesis forming rather than hypothesis testing and it would be reassuring to see the conclusions replicated in future trials. Finally, most of included studies were at unclear or high risk of bias, and were sponsored by the drug industry. The potential for overestimation of treatment effect due to sponsorship bias should be borne in mind.


[Acute kidney injury and rhabdomyolysis after cocaine overdose: case report and literature review].
Cocaine, a natural alkaloid derived from the coca plant, is one of the most commonly used illicit drugs. Cocaine abuse causes systemic adverse effects like stroke, myocardic infarction, arterial dissection, vascular thrombosis and rhabdomyolysis. Cocaine use is, also, associated with renal complications such as acute kidney injury, vasculitis, acute interstitial nephritis, chronic kidney disease, malignant hypertension with thrombotic microangiopathy. Acute kidney injury may or may be not associated to rhabdomyolysis. Rhabdomyolysis caused by cocaine abuse is multifactorial, involving tissue ischemia secondary to vasoconstriction and cellular damage caused by the drug. We report a 50-year-old man with history of chronic hepatitis C and substance abuse admitted to our unit with severe rhabdomyolysis and acute kidney failure after nasal insufflation of cocaine overdose. Renal function recovered after several treatments of dialysis. We conclude that cocaine adversely impacts kidney function ; in addition cocaine and rhabdomyolysis are the double danger for acute kidney injury. Medical management of cocaine toxicity requires a multisystem approach, with close monitoring cardiac, neurological and renal function.


Targeted expression of human O(6)-methylguanine-DNA methyltransferase (MGMT) in transgenic mice protects against tumor initiation in two-stage skin carcinogenesis.
Carcinogenesis proceeds in discrete steps involving initiation and promotion. There is ample evidence that the underlying cause of initiation is mutation, whereas for tumor promotion different hypotheses exist postulating the involvement of both epigenetic and genetic changes. DNA repair protects against tumor formation, but it has not been proven whether protection occurs at the level of tumor initiation or promotion. Since the most advanced experimental system for studying multistep carcinogenesis is the mouse skin, we generated transgenic mice that overexpress the human DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in their epidermal cells by virtue of cytokeratin (Ck) promoters. Total cellular methyltransferase activity was found to be significantly higher in skin protein extracts of transgenic as compared to nontransgenic mice. CkMGMT transgenic mice along with nontransgenic controls were treated according to the multistage skin carcinogenesis protocol. For initiation, a single subthreshold dose of N-nitroso-N-methylurea (MNU) or 7,12-dimethylbenz(a)anthracene (DMBA) was topically applied to the dorsal skin of the mice. Tumor promotion was carried out by repeated 12-O-tetradecanoylphorbol-13-acetate application. Our results clearly show that CkMGMT transgenic mice are strongly protected against MNU- but not DMBA-initiated skin tumor formation. As compared to nontransgenic controls, transgenic mice exhibited an approximately 6-fold reduction of skin tumor incidence after treatment with 20 micromol or 50 micromol MNU followed by 12-O-tetradecanoylphorbol-13-acetate. These results provide direct and the most compelling evidence to date that the DNA lesion O6-methylguanine is of decisive importance in tumor initiation, and that the protective effect of the repair protein MGMT in carcinogenesis is due to prevention of initiation without affecting tumor promotion.


Choice of GP: who do young rural women prefer?
The demand for female medical practitioners by women in rural areas appears to be increasing and to be age related. However, the distribution of general practitioners in country Australia is heavily weighted to older men and access to a women's health centre also decreases with distance from the metropolitan areas. Data from the Australian Longitudinal Study of Women's Health indicate that young women are significantly more likely than middle-aged or older women to prefer to see a female doctor. It is argued here that it is the 'culture of practice' exhibited by female doctors that young women find attractive, rather than an essential appeal of the gender of the practitioner. The findings suggest that restricted access to female practitioners may affect health outcomes if young rural women are reluctant to seek medical services provided by male doctors practising in traditional modes.


Frequency and patterns of contact with domestic poultry and potential risk of H5N1 transmission to humans living in rural Cambodia.
Since 2004, H5N1 outbreaks have been recurrent in domestic poultry and humans in Cambodia. To date, seven human cases (100% CFR) and 22 outbreaks in poultry have been confirmed. Household ownership of backyard poultry (FAO Sector 4 poultry production) in rural Cambodia is high. An understanding of the extent and frequency of poultry handing behaviors in these settings is necessary to assess the risk associated with different practices and to formulate sensible recommendations to mitigate this risk. We collected new data from six geographic regions to examine patterns of human contact with poultry among rural farmers in Cambodia and identify populations with the highest potential exposure to H5N1. A cross-sectional survey was undertaken in which 3,600 backyard poultry owners from 115 randomly selected villages in six provinces throughout Cambodia were interviewed. Using risk assessment methods, patterns of contact with poultry as surrogate measures of exposure to H5N1 were used to generate risk indices of potential H5N1 transmission to different populations in contact with poultry. Estimates of human exposure risk for each study participant (n = 3600) were obtained by multiplying each reported practice with a transmission risk-weighting factor and summing these over all practices reported by each individual. Exposure risk estimates were then examined stratified by age and gender. Subjects reported high contact with domestic poultry (chickens and ducks) through the daily care and food preparation practices, however contact patterns varied by gender and age. Males between the ages of 26-40 reported practices of contact with poultry that give rise to the highest H5N1 transmission risk potential, followed closely by males between the ages of 16-25. Overall, males had a higher exposure risk potential than females across all age groups (p < 0.001). Our results demonstrate that most of the population in rural Cambodia is in frequent contact with domestic poultry. About half of the population in this study carried out on a regular basis at least one of the practices considered to be high risk for the effective transmission if the bird is infected. There was however substantial variation in the frequency of different practices and thus the potential risk of transmission of H5N1 from poultry to humans is not uniform across age and gender even amongst populations living in close proximity to poultry.


d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia.
The N-methyl-D-aspartate receptor co-agonist d-serine is synthesized by serine racemase and degraded by D-amino acid oxidase. Both D-serine and its metabolizing enzymes are implicated in N-methyl-D-aspartate receptor hypofunction thought to occur in schizophrenia. We studied D-amino acid oxidase and serine racemase immunohistochemically in several brain regions and compared their immunoreactivity and their mRNA levels in the cerebellum and dorsolateral prefrontal cortex in schizophrenia. D-Amino acid oxidase immunoreactivity was abundant in glia, especially Bergmann glia, of the cerebellum, whereas in prefrontal cortex, hippocampus and substantia nigra, it was predominantly neuronal. Serine racemase was principally glial in all regions examined and demonstrated prominent white matter staining. In schizophrenia, D-amino acid oxidase mRNA was increased in the cerebellum, and as a trend for protein. Serine racemase was increased in schizophrenia in the dorsolateral prefrontal cortex but not in cerebellum, while serine racemase mRNA was unchanged in both regions. Administration of haloperidol to rats did not significantly affect serine racemase or D-amino acid oxidase levels. These findings establish the major cell types wherein serine racemase and D-amino acid oxidase are expressed in human brain and provide some support for aberrant D-serine metabolism in schizophrenia. However, they raise further questions as to the roles of D-amino acid oxidase and serine racemase in both physiological and pathophysiological processes in the brain.


Functional characterization and expression profiling of human induced pluripotent stem cell- and embryonic stem cell-derived endothelial cells.
With regard to human induced pluripotent stem cells (hiPSCs), in which adult cells are reprogrammed into embryonic-like cells using defined factors, their functional and transcriptional expression pattern during endothelial differentiation has yet to be characterized. In this study, hiPSCs and human embryonic stem cells (hESCs) were differentiated using the embryoid body method, and CD31(+) cells were sorted. Fluorescence activated cell sorting analysis of hiPSC-derived endothelial cells (hiPSC-ECs) and hESC-derived endothelial cells (hESC-ECs) demonstrated similar endothelial gene expression patterns. We showed functional vascular formation by hiPSC-ECs in a mouse Matrigel plug model. We compared the gene profiles of hiPSCs, hESCs, hiPSC-ECs, hESC-ECs, and human umbilical vein endothelial cells (HUVECs) using whole genome microarray. Our analysis demonstrates that gene expression variation of hiPSC-ECs and hESC-ECs contributes significantly to biological differences between hiPSC-ECs and hESC-ECs as well as to the "distances" among hiPSCs, hESCs, hiPSC-ECs, hESC-ECs, and HUVECs. We further conclude that hiPSCs can differentiate into functional endothelial cells, but with limited expansion potential compared with hESC-ECs; thus, extensive studies should be performed to explore the cause and extent of such differences before clinical application of hiPSC-ECs can begin.


What explains patterns of species richness? The relative importance of climatic-niche evolution, morphological evolution, and ecological limits in salamanders.
A major goal of evolutionary biology and ecology is to understand why species richness varies among clades. Previous studies have suggested that variation in richness among clades might be related to variation in rates of morphological evolution among clades (e.g., body size and shape). Other studies have suggested that richness patterns might be related to variation in rates of climatic-niche evolution. However, few studies, if any, have tested the relative importance of these variables in explaining patterns of richness among clades. Here, we test their relative importance among major clades of Plethodontidae, the most species-rich family of salamanders. Earlier studies have suggested that climatic-niche evolution explains patterns of diversification among plethodontid clades, whereas rates of morphological evolution do not. A subsequent study stated that rates of morphological evolution instead explained patterns of species richness among plethodontid clades (along with "ecological limits" on richness of clades, leading to saturation of clades with species, given limited resources). However, they did not consider climatic-niche evolution. Using phylogenetic multiple regression, we show that rates of climatic-niche evolution explain most variation in richness among plethodontid clades, whereas rates of morphological evolution do not. We find little evidence that ecological limits explain patterns of richness among plethodontid clades. We also test whether rates of morphological and climatic-niche evolution are correlated, and find that they are not. Overall, our results help explain richness patterns in a major amphibian group and provide possibly the first test of the relative importance of climatic niches and morphological evolution in explaining diversity patterns.


Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3.
The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina. To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. clinicaltrials.gov Identifier: NCT00345176.


GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.
Prostaglandin E2 (PGE2) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR alpha3) by PGE2-induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR alpha3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR alpha3 not only lack the inhibition of glycinergic neurotransmission by PGE2 seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE2 injection or peripheral inflammation. Thus, GlyR alpha3 may provide a previously unrecognized molecular target in pain therapy.


Deciphering Transcriptional Programming during Pod and Seed Development Using RNA-Seq in Pigeonpea (Cajanus cajan).
Seed development is an important event in plant life cycle that has interested humankind since ages, especially in crops of economic importance. Pigeonpea is an important grain legume of the semi-arid tropics, used mainly for its protein rich seeds. In order to understand the transcriptional programming during the pod and seed development, RNA-seq data was generated from embryo sac from the day of anthesis (0 DAA), seed and pod wall (5, 10, 20 and 30 DAA) of pigeonpea variety "Asha" (ICPL 87119) using Illumina HiSeq 2500. About 684 million sequencing reads have been generated from nine samples, which resulted in the identification of 27,441 expressed genes after sequence analysis. These genes have been studied for their differentially expression, co-expression, temporal and spatial gene expression. We have also used the RNA-seq data to identify important seed-specific transcription factors, biological processes and associated pathways during seed development process in pigeonpea. The comprehensive gene expression study from flowering to mature pod development in pigeonpea would be crucial in identifying candidate genes involved in seed traits directly or indirectly related to yield and quality. The dataset will serve as an important resource for gene discovery and deciphering the molecular mechanisms underlying various seed related traits.


Biomimetic design and performance of polymerizable lipids.
Bilayer lipid membranes (BLMs) have received significant attention over the past several decades because of their applications in biological and material sciences. BLMs consist of two amphiphilic lipid layers arranged with their hydrophilic head region exposed to the surrounding aqueous environment and hydrophobic domains in the core. In biology, lipid membranes confine and support the cell structure while selectively controlling the diffusion of ions and proteins between the intra- and extracellular matrix (ECM). Naturally derived lipid monomers spontaneously self-assemble to develop smart gateways that recognize and incorporate desired protein transporters or ion channels. BLMs are useful research models of lamellar lipid assemblies and associated protein receptors in cell membranes. The transport properties of lipid membranes can be tuned through careful consideration of the solution medium, transporter functionality, and pH, as well as other environmental conditions. BLMs are of particular interest in the design of biofunctional coatings, controlled release technologies, and biosensors; however, high-performance applications require lipid membranes to remain stable under harsh denaturing conditions. Accordingly, synthetic strategies are often proposed to increase the chemical and mechanical stability of lipid assemblies. The polymerization of self-assembled lipid structures is a strategy that results in robust biocompatible architectures, and diverse reactive functional groups are available for the synthesis of monomeric lipids. The selection of the polymerizable functionality and its precise location within the lipid assembly influences the ultimate supramolecular microstructure and polymerization efficiency. The biomimetic potential of polymerized lipids depends on the stability and robustness of the self-assembled membranes, and it is essential that the polymerizable functionality not disturb the amphiphilic nature of the lipid to maintain biocompatibility. Innovative applications are the motivational force for the development of durable polylipid compositions. Surface modification with biocompatible polylipids provides the opportunity for specific binding of biological molecules for applications as sensors or controlled release delivery vehicles. The ability to create stable lipid assemblies requires a comprehensive understanding of the mechanism of lipid polymerization in confined supramolecular geometries. The future is exciting as researchers begin to fully understand the morphology of polylipids in an effort to successfully produce naturally derived sustainable materials. In this Account, we highlight recent efforts to covalently stabilize lipid membranes and discuss emerging applications of mechanically robust self-assembled lipid architectures.


Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways.
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells. This analysis identified several known but also many novel binding partners of these proteins. Interactomes of WT and mutant ALS proteins were very similar except for OPTN and UBQLN2, in which mutations caused loss or gain of protein interactions. Several of the identified interactomes showed a high degree of overlap: shared binding partners of ATXN2, FUS and TDP-43 had roles in RNA metabolism; OPTN- and UBQLN2-interacting proteins were related to protein degradation and protein transport, and C9orf72 interactors function in mitochondria. To confirm that this overlap is important for ALS pathogenesis, we studied fragile X mental retardation protein (FMRP), one of the common interactors of ATXN2, FUS and TDP-43, in more detail in in vitro and in vivo model systems for FUS ALS. FMRP localized to mutant FUS-containing aggregates in spinal motor neurons and bound endogenous FUS in a direct and RNA-sensitive manner. Furthermore, defects in synaptic FMRP mRNA target expression, neuromuscular junction integrity, and motor behavior caused by mutant FUS in zebrafish embryos, could be rescued by exogenous FMRP expression. Together, these results show that interactomics analysis can provide crucial insight into ALS disease mechanisms and they link FMRP to motor neuron dysfunction caused by FUS mutations.


Correlates of suicidal behavior and lithium treatment in bipolar disorder.
Individuals with bipolar and major depressive disorders have considerably higher suicide rates than the general population. However, estimating the risk of suicide is complicated, and there exists a general lack of consensus among researchers regarding whether suicide rates are higher in patients with unipolar, bipolar I, or bipolar II depressive disorders. Isolating the specific factors that contribute to the high risk of suicide in patients with affective disorders can be challenging as well; substance and alcohol abuse, family history of suicide, differences in allele distributions, comorbid anxiety, depression recurrence, seasonal effects, rapid cycling, and a history of hospitalizations for depression all appear to contribute to the likelihood that these patients will engage in suicidal behavior. Research does tend to agree that lithium is efficacious in decreasing suicidal behavior in patients with affective disorders.


How I Do It - MRI-ultrasound fusion prostate biopsy using the Fusion MR and Fusion Bx systems.
There is increasing evidence to support the use of multiparametric magnetic resonance imaging (MRI) in men at risk for clinically significant prostate cancer to help identify lesions and inform biopsy. Randomized, level 1 evidence demonstrates that men who are managed with MRI and MRI-ultrasound fusion targeted biopsy (MRF-TB) have more clinically significant prostate cancer and less clinically insignificant prostate cancer detected and avoid biopsy altogether more often than men who undergo systematic, whole-gland prostate biopsy (SPB). Furthermore, strategies that incorporate MRF-TB have lower rates of upgrading on radical prostatectomy compared to SPB. However, generalizing this data to wider practice is challenging because there is a learning curve for interpreting MRI and performing MRF-TB, and some of the fusion technologies are better than others. We describe our group's early experience with the Fusion MR and Fusion Bx systems (Focal Healthcare, Toronto, ON, Canada). These products are designed with elastic fusion technology that is user-friendly, intuitive and accurate. The Fusion MR contouring system is straightforward and allows for contouring with several MRI sequences simultaneously. The Fusion Bx biopsy system has a semi-robotic arm that accounts for prostate deformation and patient movement and allows for freehand-like access, which is a seamless transition from SPB for clinicians. There were 68 lesions targeted in the first 51 patients. The overall cancer detection rate was 22%/61%/83% for PI-RADS 3/4/5, respectively. The Gleason grade group 2 prostate cancer or higher rate was 6%/47%/75% for PI-RADS 3/4/5, respectively. There were no major complications in this cohort of patients. Limitations of this study include small number of patients and lack of formal follow up to rule out sepsis. Overall, the Fusion MR and Fusion Bx systems are accurate, straightforward and safe to use for MRF-TB. Early experience does not show any significant learning curve.


Effectiveness of using teachers to screen eyes of school-going children in Satna district of Madhya Pradesh, India.
To assess the effectiveness of teachers in a vision screening program for children in classes 5th to 12th attending school in two blocks of a district of north central India. Ophthalmic assistants trained school teachers to measure visual acuity and to identify obvious ocular abnormalities in children. Children with visual acuity worse than 20/30 in any eye and/or any obvious ocular abnormality were referred to an ophthalmic assistant. Ophthalmic assistants also repeated eye examinations on a random sample of children identified as normal (approximately 1%, n=543) by the teachers. Ophthalmic assistants prescribed spectacles to children needing refractive correction and referred children needing further examination to a pediatric ophthalmologist at the base hospital. Five hundred and thirty teachers from 530 schools enrolled 77,778 children in the project and screened 68,833 (88.50%) of enrolled children. Teachers referred 3,822 children (4.91%) with eye defects for further examination by the ophthalmic assistant who confirmed eye defects in 1242 children (1.80% of all screened children). Myopia (n=410, 33.01%), Vitamin A deficiency (n=143, 11.51%) and strabismus (n=134, 10.79%) were the most common eye problems identified by the ophthalmic assistant. Ophthalmic assistants identified 57.97% referrals as false positives and 6.08% children as false negatives from the random sample of normal children. Spectacles were prescribed to 39.47% of children confirmed with eye defects. Primary vision screening by teachers has effectively reduced the workload of ophthalmic assistants. High false positive and false negative rates need to be studied further.


Relationships between poverty and psychopathology: a natural experiment.
Social causation (adversity and stress) vs social selection (downward mobility from familial liability to mental illness) are competing theories about the origins of mental illness. To test the role of social selection vs social causation of childhood psychopathology using a natural experiment. Quasi-experimental, longitudinal study. A representative population sample of 1420 rural children aged 9 to 13 years at intake were given annual psychiatric assessments for 8 years (1993-2000). One quarter of the sample were American Indian, and the remaining were predominantly white. Halfway through the study, a casino opening on the Indian reservation gave every American Indian an income supplement that increased annually. This increase moved 14% of study families out of poverty, while 53% remained poor, and 32% were never poor. Incomes of non-Indian families were unaffected. Levels of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, psychiatric symptoms in the never-poor, persistently poor, and ex-poor children were compared for the 4 years before and after the casino opened. Before the casino opened, the persistently poor and ex-poor children had more psychiatric symptoms (4.38 and 4.28, respectively) than the never-poor children (2.75), but after the opening levels among the ex-poor fell to those of the never-poor children, while levels among those who were persistently poor remained high (odds ratio, 1.50; 95% confidence interval, 1.08-2.09; and odds ratio, 0.91; 95% confidence interval, 0.77-1.07, respectively). The effect was specific to symptoms of conduct and oppositional defiant disorders. Anxiety and depression symptoms were unaffected. Similar results were found in non-Indian children whose families moved out of poverty during the same period. An income intervention that moved families out of poverty for reasons that cannot be ascribed to family characteristics had a major effect on some types of children's psychiatric disorders, but not on others. Results support a social causation explanation for conduct and oppositional disorder, but not for anxiety or depression.


High-resolution slice-selective Fourier velocity encoding in congenital heart disease using spiral SENSE with velocity unwrap.
Quantification of peak velocity is important in the assessment of stenotic flow jets in patients with congenital heart disease. Phase-contrast magnetic resonance underestimates peak velocities. Hence, clinically Doppler ultrasound is used as the reference standard for assessing stenoses. It is possible to accurately measure peak velocity in MR using Fourier velocity encoding (FVE). In this study, a fast, high-resolution slice-selective FVE sequence was developed with the use of spiral trajectories, parallel imaging, and partial Fourier in the velocity dimension and a novel velocity-unwrap technique. The resulting sequence was acquired within a short breath-hold (more than 15 heartbeats) making this FVE technique clinically achievable. Peak velocities were compared from Doppler ultrasound, phase-contrast magnetic resonance, and FVE. Experiments were carried out in vitro and in vivo in 25 patients with congenital heart disease with stenoses. It was shown that in vitro and in vivo phase-contrast magnetic resonance tended to underestimate peak velocity when compared with Doppler ultrasound, whereas FVE agreed well with Doppler ultrasound.


Heritability of radiation response in lung cancer families.
Radiation sensitivity is assumed to be a cancer susceptibility factor due to impaired DNA damage signalling and repair. Relevant genetic factors may also determine the observed familial aggregation of early onset lung cancer. We investigated the heritability of radiation sensitivity in families of 177 Caucasian cases of early onset lung cancer. In total 798 individuals were characterized for their radiation-induced DNA damage response. DNA damage analysis was performed by alkaline comet assay before and after in vitro irradiation of isolated lymphocytes. The cells were exposed to a dose of 4 Gy and allowed to repair induced DNA-damage up to 60 minutes. The primary outcome parameter Olive Tail Moment was the basis for heritability estimates. Heritability was highest for basal damage (without irradiation) 70% (95%-CI: 51%-88%) and initial damage (directly after irradiation) 65% (95%-CI: 47%-83%) and decreased to 20%-48% for the residual damage after different repair times. Hence our study supports the hypothesis that genomic instability represented by the basal DNA damage as well as radiation induced and repaired damage is highly heritable. Genes influencing genome instability and DNA repair are therefore of major interest for the etiology of lung cancer in the young. The comet assay represents a proper tool to investigate heritability of the radiation sensitive phenotype. Our results are in good agreement with other mutagen sensitivity assays.


Children's representation of family mealtime in the context of maternal eating disorders.
Recent research provides evidence for specific disturbance in feeding and growth in children of mothers with eating disorders. To investigate the impact of maternal eating disorders during the post-natal year on the internal world of children, as expressed in children's representations of self and their mother in pretend mealtime play at 5 years of age. Children of mothers with eating disorders (n = 33) and a comparison group (n = 24) were videotaped enacting a family mealtime in pretend play. Specific classes of children's play representations were coded blind to group membership. Univariate analyses compared the groups on representations of mother and self. Logistic regression explored factors predicting pretend play representations. Positive representations of the mother expressed as feeding, eating or body shape themes were more frequent in the index group. There were no other significant group differences in representations. In a logistic regression analysis, current maternal eating psychopathology was the principal predictor of these positive maternal representations. Marital criticism was associated with negative representations of the mother. These findings suggest that maternal eating disorders may influence the development of a child's internal world, such that they are more preoccupied with maternal eating concerns. However, more extensive research on larger samples is required to replicate these preliminary findings.


Prejunctional inhibitory effect of a dopamine D-2 agonist, N-0437, on vascular adrenergic responses.
N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin], a potent and selective agonist for D-2 dopamine receptors, was used to investigate inhibitory prejunctional dopamine receptors in the rat tail artery and rabbit ear artery. N-0437 inhibited contractile responses to transmural nerve stimulation in a frequency dependent manner. Thus, N-0437 profoundly inhibited responses to nerve stimulation in the rat tail artery at a frequency of 1 Hz (ED50 = 1.6 nM), but had minimal effects when nerves were stimulated at 6 Hz. The D-1/D-2 dopamine agonist, apomorphine, exhibited a similar frequency dependent inhibitory effect but with less potency (ED50 = 30 nM at 1 Hz). In concentrations up to 1 microM, N-0437 had no effect on responses to exogenously applied norepinephrine, but N-0437 inhibited [3H] norepinephrine efflux induced by transmural stimulation. Inhibitory effects of N-0437 were blocked by the D-2 antagonist sulpiride but not by the D-1 antagonist SCH 23390. Furthermore, the selective D-1 agonist SKF 38393 did not inhibit vascular responses to adrenergic nerve stimulation. These data indicate that the inhibitory effects of N-0437 are via activation of D-2 dopamine receptors that inhibit norepinephrine release. Thus, N-0437 shows potency and selectivity of action for prejunctional D-2 dopamine receptors in vascular tissues. The frequency dependence of the actions of N-0437 suggest that the level of sympathetic activity is an important variable in determining effectiveness of prejunctional modulation.


Prenatal exposure to alcohol, and gender differences on child mental health at age seven years.
It remains uncertain whether exposure to lower doses of alcohol is damaging to the developing fetus. The present study aimed to investigate associations for boys and girls between prenatal exposure to binge drinking and lower doses of alcohol in pregnancy, and parent-reported behavioural and emotional development at age seven. This study used data from the Danish National Birth Cohort. Associations between cumulated alcohol exposure and binge drinking from full pregnancy and parent scores on the Strengths and Difficulties Questionnaire (SDQ) measured at age seven were investigated. The SDQ was used as continuous externalising/internalising scores, and as above/below cut-off for the specific scales of hyperactivity/inattention, conduct, emotional and peer problems. Inclusion criteria were information on alcohol exposure from three interviews, SDQ scores at age seven and being born full term (n=37 152). Controlling for relevant confounders, small positive associations were observed between binge drinking and internalising (relative change in mean: 1.04-1.06), externalising scores (relative change in mean: 1.01-1.07), and conduct scores (OR 1.12 to 1.23) for boys. No associations were observed with lower doses of alcohol. Exposure to binge drinking is weakly associated with impaired behavioural and emotional development measured at age seven. Large differences in background characteristics were observed between the groups defined by cumulated alcohol exposure, leaving the interpretations of findings uncertain.