Muscle lipoprotein lipase activity in voluntarily exercising rats.
Voluntary exercise of rats in freely rotating work wheels has been extensively used, but muscle adaptations that result from such exercise training are poorly documented. The purpose of this study was to determine whether the exercise performed by voluntarily active rats would increase succinate dehydrogenase or lipoprotein lipase activities in the soleus muscle (SM) or the red portion of the vastus lateralis muscle (RV). In SM the activities of these two enzymes were not increased after 7 or 16 wk of voluntary exercise. Succinate dehydrogenase activity in RV was moderately increased after 7 and 16 wk of voluntary activity (P less than 0.05). Substantial increases occurred in RV lipoprotein lipase activity (P less than 0.01). The increase in RV lipoprotein lipase activity was positively related to distance run by the rats. The results indicate that only small muscle-dependent increases in mitochondrial enzymes occur in rats allowed to exercise voluntarily in rodent work wheels. Voluntary exercise training induced a selective increase in lipoprotein lipase activity in a muscle containing a high percentage of fast-twitch red fibers, a response absent in a muscle containing a predominance of slow-twitch red fibers. It is unlikely that this differential response can be explained by exercise-induced changes in plasma hormone concentrations involved in the regulation of lipoprotein lipase.


Testosterone causes both prosocial and antisocial status-enhancing behaviors in human males.
Although popular discussion of testosterone's influence on males often centers on aggression and antisocial behavior, contemporary theorists have proposed that it instead enhances behaviors involved in obtaining and maintaining a high social status. Two central distinguishing but untested predictions of this theory are that testosterone selectively increases status-relevant aggressive behaviors, such as responses to provocation, but that it also promotes nonaggressive behaviors, such as generosity toward others, when they are appropriate for increasing status. Here, we tested these hypotheses in healthy young males by injecting testosterone enanthate or a placebo in a double-blind, between-subjects, randomized design (n = 40). Participants played a version of the Ultimatum Game that was modified so that, having accepted or rejected an offer from the proposer, participants then had the opportunity to punish or reward the proposer at a proportionate cost to themselves. We found that participants treated with testosterone were more likely to punish the proposer and that higher testosterone levels were specifically associated with increased punishment of proposers who made unfair offers, indicating that testosterone indeed potentiates aggressive responses to provocation. Furthermore, when participants administered testosterone received large offers, they were more likely to reward the proposer and also chose rewards of greater magnitude. This increased generosity in the absence of provocation indicates that testosterone can also cause prosocial behaviors that are appropriate for increasing status. These findings are inconsistent with a simple relationship between testosterone and aggression and provide causal evidence for a more complex role for testosterone in driving status-enhancing behaviors in males.


Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis.
Liver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable therapies available, liver transplantation is the only curative treatment for advanced diseased patients. Excessive accumulation of aberrant extracellular matrix (ECM) proteins, mostly collagens, produced by activated hepatic stellate cells (HSCs), is a hallmark of liver fibrosis. Several studies have suggested an inverse correlation between collagen-I degrading matrix metalloproteinase-1 (MMP-1) serum levels and liver fibrosis progression highlighting reduced MMP-1 levels are associated with poor disease prognosis in patients with liver fibrosis. We hypothesized that delivery of MMP-1 might potentiate collagen degradation and attenuate fibrosis development. In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes (MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of liver fibrosis. The storage-stable and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1. MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization, stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes versus MMP-1, empty polymersomes (Psomes) and MMP-1 + Psomes on gene and protein expression of collagen-I, MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in carbon-tetrachloride (CCl4)-induced early liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1 surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl4-induced early liver fibrosis mouse model, MMPsomes inhibited intra-hepatic collagen-I (ECM marker, indicating early liver fibrosis) and F4/80 (marker for macrophages, indicating liver inflammation) expression. In conclusion, our results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating liver fibrosis.


Reproducibility and differential item functioning of the alcohol dependence syndrome construct across four alcohol treatment studies: An integrative data analysis.
The validity of the alcohol dependence syndrome has been supported. The question of whether different measures of the construct are comparable across studies and patient subgroups has not been examined. This study examined the alcohol dependence construct across four diverse large-scale treatment samples using integrative data analysis (IDA). We utilized existing data (n=4393) from the COMBINE Study, Project MATCH, the Relapse Replication and Extension Project (RREP), and the United Kingdom Alcohol Treatment Trial (UKATT). We focused on four measures of alcohol dependence: the Alcohol Dependence Scale (COMBINE and RREP), Alcohol Use Inventory (MATCH), the Leeds Dependence Questionnaire (UKATT), and the Diagnostic and Statistical Manual of Mental Disorders (COMBINE and MATCH). Moderated nonlinear factor analysis was used to create a measure of alcohol dependence severity that was moderated by study membership, gender, age, and marital status. A commensurate measure of alcohol dependence severity was successfully created using 20 items available in four studies. We identified differential item functioning by study membership, age, gender, and/or marital status for 12 of the 20 items, indicating specific patient subgroups who responded differently to items based on their underlying dependence severity. Alcohol dependence severity is a single unidimensional construct that is comparable across studies. The use of IDA provided a strong test of the validity of the alcohol dependence syndrome and clues as to how some items used to measure dependence severity may be more or less central to the construct for some patients.


White matter lesion load is associated with resting state functional MRI activity and amyloid PET but not FDG in mild cognitive impairment and early Alzheimer's disease patients.
To quantify and investigate the interactions between multimodal MRI/positron emission tomography (PET) imaging metrics in elderly patients with early Alzheimer's disease (AD), mild cognitive impairment (MCI) and healthy controls. Thirteen early AD, 17 MCI patients, and 14 age-matched healthy aging controls from the Alzheimer's Disease Neuroimaging Initiative database were selected based on availability of data. Default mode network (DMN) functional connectivity and fractional amplitude of low frequency fluctuation (fALFF) were obtained for resting state functional MRI (RS-fMRI). White matter lesion load (WMLL) was quantified from MRI T2-weighted FLAIR images. Amyloid deposition with PET [(18)F]-Florbetapir tracer and metabolism of glucose by means of [(18)F]-fluoro-2-deoxyglucose (FDG) images were quantified using ratio of standard uptake values (rSUV). Whole-brain WMLL and amyloid deposition were significantly higher (P < 0.005) in MCI and AD patients compared with controls. RS-fMRI results showed significantly reduced (corrected P < 0.05) DMN connectivity and altered fALFF activity in both MCI and AD groups. FDG uptake results showed hypometabolism in AD and MCI patients compared with controls. Correlations (P < 0.05) were found between WMLL and amyloid load, FDG uptake and amyloid load, as well as between amyloid load (rSUV) and fALFF. Our quantitative results of four MRI and PET imaging metrics (fALFF/DMN, WMLL, amyloid, and FDG rSUV values) agree with published values. Significant correlations between MRI metrics, including WMLL/functional activity and PET amyloid load suggest the potential of MRI and PET-based biomarkers for early detection of AD.


Animal diversity and ecosystem functioning in dynamic food webs.
Species diversity is changing globally and locally, but the complexity of ecological communities hampers a general understanding of the consequences of animal species loss on ecosystem functioning. High animal diversity increases complementarity of herbivores but also increases feeding rates within the consumer guild. Depending on the balance of these counteracting mechanisms, species-rich animal communities may put plants under top-down control or may release them from grazing pressure. Using a dynamic food-web model with body-mass constraints, we simulate ecosystem functions of 20,000 communities of varying animal diversity. We show that diverse animal communities accumulate more biomass and are more exploitative on plants, despite their higher rates of intra-guild predation. However, they do not reduce plant biomass because the communities are composed of larger, and thus energetically more efficient, plant and animal species. This plasticity of community body-size structure reconciles the debate on the consequences of animal species loss for primary productivity.


Tumor microenvironment-derived proteins dominate the plasma proteome response during breast cancer induction and progression.
Tumor development relies upon essential contributions from the tumor microenvironment and host immune alterations. These contributions may inform the plasma proteome in a manner that could be exploited for cancer diagnosis and prognosis. In this study, we employed a systems biology approach to characterize the plasma proteome response in the inducible HER2/neu mouse model of breast cancer during tumor induction, progression, and regression. Mass spectrometry data derived from approximately 1.6 million spectra identified protein networks involved in wound healing, microenvironment, and metabolism that coordinately changed during tumor development. The observed alterations developed prior to cancer detection, increased progressively with tumor growth and reverted toward baseline with tumor regression. Gene expression and immunohistochemical analyses suggested that the cancer-associated plasma proteome was derived from transcriptional responses in the noncancerous host tissues as well as the developing tumor. The proteomic signature was distinct from a nonspecific response to inflammation. Overall, the developing tumor simultaneously engaged a number of innate physiologic processes, including wound repair, immune response, coagulation and complement cascades, tissue remodeling, and metabolic homeostasis that were all detectable in plasma. Our findings offer an integrated view of tumor development relevant to plasma-based strategies to detect and diagnose cancer.


Increased Risk of Musculoskeletal Disorders and Mental Health Problems in Retired Professional Jockeys: A Cross-Sectional Study.
To examine the prevalence of chronic disease and mental health problems in retired professional, male jockeys compared to an age-matched reference population. A cross-sectional study comparing data from a cohort of retired professional jockeys with an age-matched general population sample. Male participants (age range: 50-89 years old) were used to compare health outcomes of self-reported physician-diagnosed conditions: heart disease, stroke, diabetes, hypertension, osteoporosis, osteoarthritis, depression and anxiety between study populations. Conditional logistic regression models were used to estimate associations between study groups and health outcome. In total, 810 participants (135 retired professional male jockeys and 675 participants from the reference population) were included, with an average age of 64.7±9.9 years old. Increased odds of having osteoporosis (OR=6.5, 95%CI 2.1-20.5), osteoarthritis (OR=7.5, 95%CI 4.6-12.2), anxiety (OR=2.8, 95%CI 1.3-5.9) and depression (OR=2.6, 95%CI 1.3-5.7) were seen in the retired professional jockeys. No differences were found for the remaining health outcomes. Retired professional jockeys had increased odds of musculoskeletal disease and mental health problems compared to the general population. Understanding the prevalence of chronic disease and mental health problems in retired professional jockeys will help inform screening and intervention strategies for jockeys.


TCR-dependent transformation of mature memory phenotype T cells in mice.
A fundamental goal in cancer research is the identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth, as this has the potential to reveal therapeutic targets. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies. However, the identity of the cells in which mature lymphoid neoplasms are initiated remains unclear. Here, we investigate the origin of peripheral T cell lymphomas using mice in which Snf5, a chromatin remodelling-complex subunit with tumor suppressor activity, could be conditionally inactivated in developing T cells. In this model of mature peripheral T cell lymphomas, the cell of origin was a mature CD44hiCD122loCD8⁺ T cell that resembled a subset of memory cells that has capacity for self-renewal and robust expansion, features shared with stem cells. Further analysis showed that Snf5 loss led to activation of a Myc-driven signaling network and stem cell transcriptional program. Finally, lymphomagenesis and lymphoma proliferation depended upon TCR signaling, establishing what we believe to be a new paradigm for lymphoid malignancy growth. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells are associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers.


Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance.
Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some murine MGCA are sequestered. Nonsequestered MCGA (NS-MGCA) egressed from normal tubules, as evidenced by their ability to interact with systemically injected antibodies and form localized immune complexes outside the Sertoli cell barrier. NS-MGCA derived from cell fragments that were discarded by spermatids during spermiation. They egressed as cargo in residual bodies and maintained Treg-dependent physiological tolerance. In contrast, sequestered MGCA (S-MGCA) were undetectable in residual bodies and were nontolerogenic. Unlike postvasectomy autoantibodies, which have been shown to mainly target S-MGCA, autoantibodies produced by normal mice with transient Treg depletion that developed autoimmune orchitis exclusively targeted NS-MGCA. We conclude that spermiation, a physiological checkpoint in spermatogenesis, determines the egress and tolerogenicity of MGCA. Our findings will affect target antigen selection in testis and sperm autoimmunity and the immune responses to CTA in male cancer patients.


Occurrence of the leucine-to-phenylalanine knockdown resistance (kdr) mutation in Anopheles arabiensis populations in Tanzania, detected by a simplified high-throughput SSOP-ELISA method.
Molecular markers of insecticide resistance can provide sensitive indicators of resistance development in malaria vector populations. Monitoring of insecticide resistance in vector populations is an important component of current malaria control programmes. Knockdown resistance (kdr) confers resistance to the pyrethroid class of insecticides with cross-resistance to DDT through single nucleotide polymorphisms (SNPs) in the voltage-gated sodium channel gene. To enable detection of kdr mutations at low frequency a method was developed that uses polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA)-based technology, allowing rapid, reliable and cost-effective testing of large numbers of individual mosquitoes. This was used to assay mosquitoes from sites in lower Moshi, Tanzania. Sequence-specific oligonucleotide probes (SSOP) were used for simultaneous detection of both East and West African kdr mutations with high specificity and sensitivity. Application of the SSOP-ELISA method to 1,620 field-collected Anopheles arabiensis from Tanzania identified the West African leucine-phenylalanine kdr mutation in two heterozygous individuals, indicating the potential for resistance development that requires close monitoring. The presence of the West African kdr mutation at low frequency in this East African population of An. arabiensis has implications for the spread of the kdr gene across the African continent.


Five years of sleep apnea treatment with a mandibular advancement device. Side effects and technical complications.
To determine the variation in prevalence of temporomandibular disorders (TMD), other side effects, and technical complications during 5 years of sleep apnea treatment with a mandibular advancement device. Forty patients diagnosed with obstructive sleep apnea received an adjustable appliance at 70% of the maximum protrusion. The protrusion was then progressively increased. TMD (diagnosed according to the Research Diagnostic Criteria for TMD), overjet, overbite, occlusal contacts, subjective side effects, and technical complications were recorded before and a mean of 14, 21, and 58 months after treatment and analyzed by the Wilcoxon test (P < .05). Fifteen patients still used the oral appliance at the 5-year follow-up, and no significant variation in TMD prevalence was observed. Subjective side effects were common, and a significant reduction was found in overjet, overbite, and in the number of occlusal contacts. Furthermore, the patients made a mean of 2.5 unscheduled dental visits per year and a mean of 0.8 appliance repairs/relines per year by a dental technician. The most frequent unscheduled visits were needed during the first year and were a result of acrylic breakage on the lateral telescopic attachment, poor retention, and other adjustments to improve comfort. Five-year oral appliance treatment does not affect TMD prevalence but is associated with permanent occlusal changes in most sleep apnea patients during the first 2 years. Patients seek several unscheduled visits, mainly because of technical complications.


Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis.
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor-deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis.


A cadaveric study using the ultra-minimally invasive thread transection technique to decompress the superficial peroneal nerve in the lower leg.
After successful applications of the ultra-minimally invasive thread transecting technique (Guo Technique) for both thread carpal tunnel release and thread trigger finger release, we hypothesized that this technique could be used for superficial peroneal nerve release in the lower leg by selective crural fasciectomy. This study is aimed at testing the operative feasibility of performing the thread superficial peroneal nerve release (TSPNR) procedure in cadavers. The TSPNR procedure was performed on 15 fresh frozen cadaveric lower-extremity specimens under ultrasound guidance. All cadaveric specimens were dissected and visually assessed immediately after the procedures. All 15 legs demonstrated a complete transection of the crural fasciae along the course of the superficial peroneal nerve (SPN) including where it penetrated and traversed the crural fascia. There was no evidence of any iatrogenic damage to the neurovascular bundle or adjacent tendons. The average operating time was less than 20 min. This cadaveric study demonstrated that the technique of TSPNR was accurate, reliable, and feasible while causing no injury to adjacent neurovascular structures and avoiding having to make a skin incision. Further studies are warranted to verify the results of this study before implementing this new technique in the clinical setting.


Direction-Dependent Adaptation of Dynamic Gait Stability Following Waist-Pull Perturbations.
Balance recovery during an unexpected disturbance is a complex motor task, where part of the variability depends on the type of the perturbation itself. Despite of this, little is known to what extent adaptation mechanisms to repeated perturbations are dependent on the direction and the amplitude of the applied disturbances. Here, we used a modified version of the Active Tethered Pelvic Assist Device (A-TPAD) to apply unexpected force-controlled multidirectional waist-pull perturbations while subjects were walking. Healthy young subjects were divided into two groups and were exposed to a single training session. Each group received perturbations of different amplitudes along the Medio-Lateral (ML) or the Antero-Posterior (AP) direction. Dynamic stability was determined in both the AP and ML directions in terms of base of support (BoS) and margin of stability (MoS). Results showed: 1) an adaptation of the balance recovery reactions only for perturbations delivered along the AP directions; 2) aftereffects able to modify the control of stability during the post-training session of which type and extent depends on the direction of the perturbations previously applied; and 3) a directional and amplitude effect on the dynamic stability at the end of the balance recovery reactions.


Electronic versus manual data processing: evaluating the use of electronic health records in out-of-hospital clinical research.
The objective was to compare case ascertainment, agreement, validity, and missing values for clinical research data obtained, processed, and linked electronically from electronic health records (EHR) compared to "manual" data processing and record abstraction in a cohort of out-of-hospital trauma patients. This was a secondary analysis of two sets of data collected for a prospective, population-based, out-of-hospital trauma cohort evaluated by 10 emergency medical services (EMS) agencies transporting to 16 hospitals, from January 1, 2006, through October 2, 2007. Eighteen clinical, operational, procedural, and outcome variables were collected and processed separately and independently using two parallel data processing strategies by personnel blinded to patients in the other group. The electronic approach included EHR data exports from EMS agencies, reformatting, and probabilistic linkage to outcomes from local trauma registries and state discharge databases. The manual data processing approach included chart matching, data abstraction, and data entry by a trained abstractor. Descriptive statistics, measures of agreement, and validity were used to compare the two approaches to data processing. During the 21-month period, 418 patients underwent both data processing methods and formed the primary cohort. Agreement was good to excellent (kappa = 0.76 to 0.97; intraclass correlation coefficient [ICC] = 0.49 to 0.97), with exact agreement in 67% to 99% of cases and a median difference of zero for all continuous and ordinal variables. The proportions of missing out-of-hospital values were similar between the two approaches, although electronic processing generated more missing outcomes (87 of 418, 21%, 95% confidence interval [CI] = 17% to 25%) than the manual approach (11 of 418, 3%, 95% CI = 1% to 5%). Case ascertainment of eligible injured patients was greater using electronic methods (n = 3,008) compared to manual methods (n = 629). In this sample of out-of-hospital trauma patients, an all-electronic data processing strategy identified more patients and generated values with good agreement and validity compared to traditional data collection and processing methods.


Long Non-coding RNA Uc.48+ Small Interfering RNA Alleviates Neuroinflammatory Hyperalgesia in Gp120-Treated Rats via the P2Y12 Receptor.
Human immunodeficiency virus envelope glycoprotein 120 (gp120) leads to hyperalgesia. Long non-coding RNAs are characterized by the lack of a protein-coding sequence and may contribute to the development and maintenance of inflammatory and neuroinflammatory pain. Rats with neuroinflammatory pain were established by gp120 treatment, which is featured by intensified pain behaviors. Long non-coding RNA uc.48+ was increased in the dorsal root ganglia of gp120-treated rats, and small interfering RNA that targets uc.48+ markedly alleviated hyperalgesia in gp120-treated rats. Notably, uc.48+ overexpression increased P2Y12 expression in control rats dorsal root ganglia and induced hyperalgesia. Uc.48+ small interfering RNA inhibited P2Y12 expression in gp120-treated rats. Uc.48+ potentiated P2Y12 receptor functions in the neurons and heterologous cells. Therefore, uc.48+ siRNA treatment reduced the upregulation of P2Y12 expression and function in DRG neurons, and, hence, alleviated hyperalgesia in gp120-treated rats.


Gli1 haploinsufficiency leads to decreased bone mass with an uncoupling of bone metabolism in adult mice.
Hedgehog (Hh) signaling plays important roles in various development processes. This signaling is necessary for osteoblast formation during endochondral ossification. In contrast to the established roles of Hh signaling in embryonic bone formation, evidence of its roles in adult bone homeostasis is not complete. Here we report the involvement of Gli1, a transcriptional activator induced by Hh signaling activation, in postnatal bone homeostasis under physiological and pathological conditions. Skeletal analyses of Gli1+/- adult mice revealed that Gli1 haploinsufficiency caused decreased bone mass with reduced bone formation and accelerated bone resorption, suggesting an uncoupling of bone metabolism. Hh-mediated osteoblast differentiation was largely impaired in cultures of Gli1+/- precursors, and the impairment was rescued by Gli1 expression via adenoviral transduction. In addition, Gli1+/- precursors showed premature differentiation into osteocytes and increased ability to support osteoclastogenesis. When we compared fracture healing between wild-type and Gli1+/- adult mice, we found that the Gli1+/- mice exhibited impaired fracture healing with insufficient soft callus formation. These data suggest that Gli1, acting downstream of Hh signaling, contributes to adult bone metabolism, in which this molecule not only promotes osteoblast differentiation but also represses osteoblast maturation toward osteocytes to maintain normal bone homeostasis.


Therapist predictors of treatment delivery fidelity in a community-based trial of 12-step facilitation.
Therapist characteristics may be associated with variation in consistency, quality and effectiveness of treatment delivery. We examined associations between treatment fidelity and therapist education, experience, treatment orientation and perceived skills in a randomized, multi-site trial of Twelve Step Facilitation (TSF). Raters scored audio-recorded, TSF sessions (n = 966; 97% of TSF sessions) from 32 community-based, trained therapists for adherence, competence, empathy and global session performance. Therapists with graduate degrees had significantly higher adherence and global performance fidelity ratings. Therapists reporting more positive attitudes toward 12-Step groups had lower adherence ratings. Being in recovery was associated with lower fidelity in univariate tests, but higher adherence in multivariate analysis. Fidelity was higher for therapists reporting self-efficacy in basic counseling skills and lower for self-efficacy in addiction-specific counseling skills. Fidelity was also superior in group relative to individual TSF sessions. Results have implications for therapist selection, training and supervision in community-based, effectiveness trials and community implementation of evidence-based treatments. To obtain high fidelity and improve outcomes, it may be preferable to choose masters level therapists who are open to learning new treatments and have good, general counseling skills.


Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease.
Trials are under way to determine whether fetal nigral grafts can improve motor function in patients with Parkinson's disease. Some studies use fluorodopa uptake on positron-emission tomography (PET) as a marker of graft viability, but fluorodopa uptake does not distinguish between host and grafted neurons. There has been no direct evidence that grafts of fetal tissue can survive and innervate the striatum. We studied a 59-year-old man with advanced Parkinson's disease who received bilateral grafts of fetal ventral mesencephalic tissue in the postcommissural putamen. The tissue came from seven embryos between 6 1/2 and 9 weeks after conception. The patient died 18 months later from a massive pulmonary embolism. The brain was studied with the use of tyrosine hydroxylase immunohistochemical methods. After transplantation, the patient had sustained improvement in motor function and a progressive increase in fluorodopa uptake in the putamen on PET scanning. On examination of the brain, each of the large grafts appeared to be viable. Each was integrated into the host striatum and contained dense clusters of dopaminergic neurons. Processes from these neurons had grown out of the grafts and provided extensive dopaminergic reinnervation to the striatum in a patch-matrix pattern. Ungrafted regions of the putamen showed sparse dopaminergic innervation. We could not identify any sprouting of host dopaminergic processes. Grafts of fetal mesencephalic tissue can survive for a long period in the human brain and restore dopaminergic innervation to the striatum in patients with Parkinson's disease. In the patient we studied, clinical improvement and enhanced fluorodopa with uptake on PET scanning were associated the survival of the grafts and dopaminergic reinnervation of the striatum.


Inhibitory processing following damage to the parietal lobe.
We investigated inhibitory properties of spatial attention in a group of four patients with lesions involving the posterior parietal lobe. In a first experiment, a double cue inhibition of return (IOR) procedure was employed. The parietal patients showed an IOR effect only when they had to detect targets that appeared on the contralesional side. In a second experiment, we combined an IOR procedure with a Stroop task [Psychon. Bull. Rev. 8 (2001) 315] to explore the neural basis of "inhibitory tagging" as described by Fuentes et al. [Q. J. Exp. Psychol. Hum. Exp. Psychol. 52 (1999) 149]. The results from the control participants replicated the findings of Vivas and Fuentes, Stroop interference was reduced at the cued location, relative to the uncued location. The parietal patients showed a similar result, but only for contralesional targets. These findings suggest that IOR is modulated by the parietal lobe, and that, through this process, the parietal cortex influences the application of inhibitory tagging to stimuli.


Parental knowledge about antibiotic use: results of a cluster-randomized, multicommunity intervention.
The goal was to determine the impact of a community-wide educational intervention on parental misconceptions likely contributing to pediatric antibiotic overprescribing. We conducted a cluster-randomized trial of a 3-year, community-wide, educational intervention directed at parents of children < 6 years of age in 16 Massachusetts communities to improve parental antibiotic knowledge and attitudes and to decrease unnecessary prescribing. Parents in 8 intervention communities were mailed educational newsletters and exposed to educational materials during visits to local pediatric providers, pharmacies, and child care centers. We compared responses from mailed surveys in 2000 (before the intervention) and 2003 (after the intervention) for parents in intervention and control communities. Analyses were performed on the individual level, clustered according to community. There were 1106 (46%) and 2071 (40%) respondents to the 2000 and 2003 surveys, respectively. Between 2000 and 2003, the proportion of parents who answered > or = 7 of 10 knowledge questions correctly increased significantly in both intervention (from 52% to 64%) and control (from 54% to 61%) communities. We did not detect a significant intervention impact on knowledge regarding appropriate antibiotic use in the population overall. In a subanalysis, we did observe a significant intervention effect among parents of Medicaid-insured children, who began with lower baseline knowledge scores. Although knowledge regarding appropriate use of antibiotics is improving without additional targeted intervention among more socially advantaged populations, parents of Medicaid-insured children may benefit from educational interventions to promote judicious antibiotic use. These findings may have implications for other health education campaigns.


Visible laser emission of solid state pumped LiLuF(4):Pr(3+).
In the present work we report on the growth, spectroscopy and laser results of LiLuF(4):Pr(3+) 1.25% in the melt. Room temperature polarized absorption and emission spectra have been recorded and the decay time of the (3)P0 manifold has been measured. Finally efficient room temperature laser emission have been obtained at 522.8 nm, 607.25 nm, 640.17 nm and 721.5 nm under 480 nm pumping by means of an optically pumped semiconductor laser.


Dead Rhizophagus irregularis biomass mysteriously stimulates plant growth.
Arbuscular mycorrhizal (AM) fungi establish symbiotic associations with many plant species, transferring significant amounts of soil nutrients such as phosphorus to plants and receiving photosynthetically fixed carbon in return. Functioning of AM symbiosis is thus based on interaction between two living partners. The importance of dead AM fungal biomass (necromass) in ecosystem processes remains unclear. Here, we applied either living biomass or necromass (0.0004 potting substrate weight percent) of monoxenically produced AM fungus (Rhizophagus irregularis) into previously sterilized potting substrate planted with Andropogon gerardii. Plant biomass production significantly improved in both treatments as compared to non-amended controls. Living AM fungus, in contrast to the necromass, specifically improved plant acquisition of nutrients normally supplied to the plants by AM fungal networks, such as phosphorus and zinc. There was, however, no difference between the two amendment treatments with respect to plant uptake of other nutrients such as nitrogen and/or magnesium, indicating that the effect on plants of the AM fungal necromass was not primarily nutritional. Plant growth stimulation by the necromass could thus be either due to AM fungal metabolites directly affecting the plants, indirectly due to changes in soil/root microbiomes or due to physicochemical modifications of the potting substrate. In the necromass, we identified several potentially bioactive molecules. We also provide experimental evidence for significant differences in underground microbiomes depending on the amendment with living or dead AM fungal biomass. This research thus provides the first glimpse into possible mechanisms responsible for observed plant growth stimulation by the AM fungal necromass.


Cholangiocarcinoma arising in bile duct adenoma with focal area of bile duct hamartoma.
A 59-year-old male with history of sigmoid colon cancer had a high serum-CEA level and was referred for the evaluation of metastatic liver disease. Ultrasonography and computerized tomography showed two tumours in the liver. Macroscopically, these were in segment 4 (S4) and 2 (S2). Histologically, the tumour in S4 showed a number of bile ductules with variable amounts of stroma, an appearance compatible with bile duct adenoma (BDA). There were markedly atypical ductules of various sizes, the epithelium of which had coarsely granular/hyperchromatic large nuclei, in some areas of the lesion. These atypical ductules showed invasive growth into the liver parenchyma. Some cystically dilated ductules with bile plugs resembling bile duct hamartoma (BDH) were also seen. The other tumour in S2, was a metastatic adenocarcinoma from sigmoid colon and showed strongly positive staining for CEA. Since the lesion in S4 of our case is solitary and most of histological features are similar to those of BDA with markedly atypical bile ductules, we consider that this may be the first case of cholangiocarcinoma associated with BDA with focal area of BDH. It is possible that the adenoma-carcinoma sequence occurs in biliary tumours.


Fluorescent proteins and their applications in imaging living cells and tissues.
Green fluorescent protein (GFP) from the jellyfish Aequorea victoria and its homologs from diverse marine animals are widely used as universal genetically encoded fluorescent labels. Many laboratories have focused their efforts on identification and development of fluorescent proteins with novel characteristics and enhanced properties, resulting in a powerful toolkit for visualization of structural organization and dynamic processes in living cells and organisms. The diversity of currently available fluorescent proteins covers nearly the entire visible spectrum, providing numerous alternative possibilities for multicolor labeling and studies of protein interactions. Photoactivatable fluorescent proteins enable tracking of photolabeled molecules and cells in space and time and can also be used for super-resolution imaging. Genetically encoded sensors make it possible to monitor the activity of enzymes and the concentrations of various analytes. Fast-maturing fluorescent proteins, cell clocks, and timers further expand the options for real time studies in living tissues. Here we focus on the structure, evolution, and function of GFP-like proteins and their numerous applications for in vivo imaging, with particular attention to recent techniques.


A qualitative evaluation of priority-setting by the Health Benefits Package Advisory Panel in Kenya.
Kenya's Ministry of Health established the Health Benefits Package Advisory Panel (HBPAP) in 2018 to develop a benefits package for universal health coverage. This study evaluated HBPAP's process for developing the benefits package against the normative procedural (acceptable way of doing things) and outcome (acceptable consequences) conditions of an ideal healthcare priority-setting process as outlined in the study's conceptual framework. We conducted a qualitative case study using in-depth interviews with national-level respondents (n = 20) and document reviews. Data were analysed using a thematic approach. HBPAP's process partially fulfilled the procedural and outcome conditions of the study's evaluative framework. Concerning the procedural conditions, transparency and publicity were partially met and were limited by the lack of publication of HBPAP's report. While HBPAP used explicit and evidence-based priority-setting criteria, challenges included lack of primary data and local cost-effectiveness threshold, weak health information systems, short timelines and political interference. While a wide range of stakeholders were engaged, this was limited by short timelines and inadequate financial resources. Empowerment of non-HBPAP members was limited by their inadequate technical knowledge and experience in priority-setting. Finally, appeals and revisions were limited by short timelines and lack of implementation of the proposed benefits package. Concerning the outcome conditions, stakeholder understanding was limited by the technical nature of the process and short timelines, while stakeholder acceptance and satisfaction were limited by lack of transparency. HBPAP's benefits package was not implemented due to stakeholder interests and opposition. Priority-setting processes for benefits package development in Kenya could be improved by publicizing the outcome of the process, allocating adequate time and financial resources, strengthening health information systems, generating local evidence and enhancing stakeholder awareness and engagement to increase their empowerment, understanding and acceptance of the process. Managing politics and stakeholder interests is key in enhancing the success of priority-setting processes.


Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease.
Cyclosporin A (CsA), a potent immunosuppressive drug, caused organ-specific autoimmune disease, such as gastritis with anti-parietal cell autoantibodies or oophoritis with anti-oocyte autoantibodies, in BALB/c mice when the drug was administered daily for 1 wk to newborns. Administration to adult mice did not. CsA abrogated the production of L3T4+ T cells and Lyt-2+ T cells in the thymus. Consequently, these T cells were substantially depleted from the peripheral lymphoid organs, especially when the drug was administered from the day of birth. Autoimmune disease was prevented when CsA-treated newborn mice were inoculated with splenic T cells from normal syngeneic mice. However, removal of the thymus immediately after neonatal CsA treatment produced autoimmune disease with a higher incidence and in a wider spectrum of organs, i.e., thyroiditis, sialoadenitis of the salivary gland, gastritis, insulitis of the endocrine pancreas, adrenalitis, oophoritis, or orchitis. Each autoimmune disease was accompanied by the development of circulating autoantibodies specific for the corresponding organ Ag. Immunopathology of these autoimmune diseases was quite similar to that of human organ-specific autoimmune diseases.


Metal-organic framework with optimally selective xenon adsorption and separation.
Nuclear energy is among the most viable alternatives to our current fossil fuel-based energy economy. The mass deployment of nuclear energy as a low-emissions source requires the reprocessing of used nuclear fuel to recover fissile materials and mitigate radioactive waste. A major concern with reprocessing used nuclear fuel is the release of volatile radionuclides such as xenon and krypton that evolve into reprocessing facility off-gas in parts per million concentrations. The existing technology to remove these radioactive noble gases is a costly cryogenic distillation; alternatively, porous materials such as metal-organic frameworks have demonstrated the ability to selectively adsorb xenon and krypton at ambient conditions. Here we carry out a high-throughput computational screening of large databases of metal-organic frameworks and identify SBMOF-1 as the most selective for xenon. We affirm this prediction and report that SBMOF-1 exhibits by far the highest reported xenon adsorption capacity and a remarkable Xe/Kr selectivity under conditions pertinent to nuclear fuel reprocessing.


Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma.
We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.


Seroprevalence of hepatitis E virus infection, rural southern People's Republic of China.
Genotype 4 hepatitis E virus (HEV) is the dominant cause of hepatitis E in the People's Republic of China; swine are the principal reservoir. Our study was conducted in 8 rural communities of southern China, where families keep pigs near their homes. Phylogenetic analysis showed that 23 of 24 concurrent virus isolates from this region are genotype 4 strains. Among the study populations, immunoglobulin G anti-HEV seroprevalence accumulated with age at approximately equal to 1% per year for persons < or =60 years of age. After age 30 years, seroprevalence increased at higher rates for male than for female study participants. The overall seroprevalence was 43% (range 25%-66%) among the communities. Infection rates were higher for participants between 25 and 29 years of age. The results suggest that HEV infection probably has been endemic in southern China for at least 60 years, with swine being the principal reservoir of human HEV infection in recent years.


Combining Viral Genetics and Statistical Modeling to Improve HIV-1 Time-of-infection Estimation towards Enhanced Vaccine Efficacy Assessment.
Knowledge of the time of HIV-1 infection and the multiplicity of viruses that establish HIV-1 infection is crucial for the in-depth analysis of clinical prevention efficacy trial outcomes. Better estimation methods would improve the ability to characterize immunological and genetic sequence correlates of efficacy within preventive efficacy trials of HIV-1 vaccines and monoclonal antibodies. We developed new methods for infection timing and multiplicity estimation using maximum likelihood estimators that shift and scale (calibrate) estimates by fitting true infection times and founder virus multiplicities to a linear regression model with independent variables defined by data on HIV-1 sequences, viral load, diagnostics, and sequence alignment statistics. Using Poisson models of measured mutation counts and phylogenetic trees, we analyzed longitudinal HIV-1 sequence data together with diagnostic and viral load data from the RV217 and CAPRISA 002 acute HIV-1 infection cohort studies. We used leave-one-out cross validation to evaluate the prediction error of these calibrated estimators versus that of existing estimators and found that both infection time and founder multiplicity can be estimated with improved accuracy and precision by calibration. Calibration considerably improved all estimators of time since HIV-1 infection, in terms of reducing bias to near zero and reducing root mean squared error (RMSE) to 5-10 days for sequences collected 1-2 months after infection. The calibration of multiplicity assessments yielded strong improvements with accurate predictions (ROC-AUC above 0.85) in all cases. These results have not yet been validated on external data, and the best-fitting models are likely to be less robust than simpler models to variation in sequencing conditions. For all evaluated models, these results demonstrate the value of calibration for improved estimation of founder multiplicity and of time since HIV-1 infection.


Efficacy of phytase for increasing protein efficiency ratio values of feed ingredients.
Data previously reported in several studies have suggested that phytase improves amino acid digestibility in chicks. It was the objective of the current study to determine if phytase would increase the protein efficiency ratio (PER) values (g weight gain per g protein intake) for several feed ingredients fed to chicks. Six experiments were conducted and ingredients evaluated were casein, soybean meal, canola meal, cottonseed meal, peanut meal, wheat middlings, wheat bran, rice bran, defatted rice bran, meat and bone meal, and corn gluten meal. Casein was evaluated to serve as a phytate-free control ingredient. Each feedstuff was analyzed for CP and included in cornstarch:dextrose diets as the only source of protein to provide 10% dietary protein in Experiments 1 to 5 or 18% dietary protein (soybean meal) in Experiment 6. Dietary Ca and nonphytate P levels were varied among experiments and ranged from 0.95 to 1.5% Ca and 0.35 to 0.675% nonphytate P. The test ingredient diets were fed with 0 or 1,200 units of phytase/kg to New Hampshire x Columbian chicks from 8 to 17 or 20 d of age. The PER values varied greatly among ingredients, ranging from 1.4 for corn gluten meal to 4.2 for canola meal. Phytase addition had no significant effect (P > 0.10) on PER values for any of the ingredients evaluated, except for an increase for casein in one experiment. The results indicated that 1,200 U of phytase/kg did not significantly increase protein utilization of several feed ingredients as assessed by a PER chick growth assay.


Standardized bovine colostrum derivative impedes development of type 1 diabetes in rodents.
Bovine colostrum is a rich source of nutrients and immunologically active components that play a role in conveying passive immunity to the offspring, protection and maturation of new-born's gastrointestinal tract. Colostrum has exerted positive effects in diseases affecting gastrointestinal tract, as well as type 2 diabetes (T2D). However, health-promoting effects in type 1 diabetes have not been reported. The aim of this study was to investigate therapeutic value of oral administration of standardized bovine colostrum derivative (SBCD) in three models of type 1 diabetes (T1D): spontaneously developed T1D in NOD mice and BB-DP rats, and in chemically induced T1D in C57BL/6 mice with multiple low doses of streptozotocin (MLDS). SBCD was administered per os and the disease development was evaluated by weekly measurement of blood glucose and by histological analyses of the pancreas. SBCD administration prevented diabetes development in all three models, as indicated by euglicaemia. Ex vivo analysis of cytokine expression and production in the spleen and mesenteric lymph nodes (MLN) in MLDS challenged mice revealed a strong modulation of the immune response. In the MLN cells SBCD disrupted harmful Th17 response induced by MLDS. Expression of Th1 signature cytokine IFN-γ was down-regulated in MLN cells of SBCD-treated mice, while IL-4 secretion (Th2 cytokine) was up-regulated in comparison to diabetic group. Modulation of the immune response seen in the MLN protruded to the spleen, giving overall less infiltration of immune cells to the pancreas. SBCD acted on immune cells and halted (auto) aggression towards pancreatic beta cells. Moreover, SBCD induced beta cell proliferation. Hence, this derivative could be tested in diabetes and other similar diseases with aberrant immune response.


Use of complementary nucleobase-containing synthetic polymers to prepare complex self-assembled morphologies in water.
Amphiphilic nucleobase-containing block copolymers with poly(oligo(ethylene glycol) methyl ether methacrylate) as the hydrophilic block and nucleobase-containing blocks as the hydrophobic segments were successfully synthesized using RAFT polymerization and then self-assembled via solvent switch in aqueous solutions. Effects of the common solvent on the resultant morphologies of the adenine (A) and thymine (T) homopolymers, and A/T copolymer blocks and blends were investigated. These studies highlighted that depending on the identity of the common solvent, DMF or DMSO, spherical micelles or bicontinuous micelles were obtained. We propose that this is due to the presence of A-T interactions playing a key role in the morphology and stability of the resultant nanoparticles, which resulted in a distinct system compared to individual adenine or thymine polymers. Finally, the effects of annealing on the self-assemblies were explored. It was found that annealing could lead to better-defined spherical micelles and induce a morphology transition from bicontinuous micelles to onion-like vesicles, which was considered to occur due to a structural rearrangement of complementary nucleobase interactions resulting from the annealing process.


Exploration of methods used to describe bacterial communities in silage of maize (Zea mays) cultivars.
Different techniques to assess bacterial community structure and diversity were evaluated in silages prepared with four different maize cultivars, three conventional and one transgenic (cv. Tundra, event Bt-176). Plants were cultivated in the greenhouse and harvested after 30 days of growth. Silage samples were collected at successive times during fermentation and analyzed for bacterial counts and by various DNA-based fingerprinting techniques. Bacterial counts were similar between cultivars for the total culturable bacteria, sporeforming, and mesophilic and thermophilic lactic acid bacteria (LAB). Further analysis of the species composition of 388 LAB strains by intergenic transcribed spacer (ITS) PCR followed by sequencing of 16S rRNA gene did not reveal differences between cultivars. In contrast, molecular fingerprinting methods targeting whole bacterial communities, such as automated ribosomal intergenic spacers analysis (ARISA) and 16S rRNA gene length heterogeneity-PCR (LH-PCR), indicated that different maize silage batches or cultivars hosted different bacterial communities. Thus, ARISA and LH-PCR fingerprinting techniques offer a fast and sensitive method to compare bacterial communities, and to detect differences in silage bacterial communities.


A rapid technique for classifying phytoplankton fluorescence spectra based on self-organizing maps.
Fluorescence spectroscopy has been demonstrated to be a powerful tool for characterizing phytoplankton communities in marine environments. Using different fluorescence spectra techniques, it is now possible to discriminate the major phytoplankton groups. However, most of the current techniques are based on fluorescence excitation measurements, which require stimulation at different wavelengths and thus considerable time to obtain the complete spectral profile. This requirement may be an important constraint for several mobile oceanographic platforms, such as vertical profilers or autonomous underwater vehicles, which require rapid-acquisition instruments. This paper presents a novel technique for classifying fluorescence spectra based on self-organizing maps (SOMs), one of the most popular artificial neural network (ANN) methods. The method is able to achieve phytoplankton discrimination using only fluorescence emission spectra (single wavelength excitation), thus reducing the acquisition time. The discrimination capabilities of SOM using excitation and emission spectra are compared. The analysis shows that the SOM has a good performance using excitation spectra, whereas data preprocessing is required in order to obtain similar discrimination capabilities using emission spectra. The final results obtained using emission spectra indicate that the discrimination is properly achieved even between algal groups, such as diatoms and dinoflagellates, which cannot be discriminated with previous methods. We finally point out that although techniques based on excitation spectra can achieve a better taxonomic accuracy, there are some applications that require faster acquisition processes. Acquiring emission spectra is almost instantaneous, and techniques such as SOM can achieve good classification performance using appropriately preprocessed data.


Honey bee PTEN--description, developmental knockdown, and tissue-specific expression of splice-variants correlated with alternative social phenotypes.
Phosphatase and TENsin (PTEN) homolog is a negative regulator that takes part in IIS (insulin/insulin-like signaling) and Egfr (epidermal growth factor receptor) activation in Drosophila melanogaster. IIS and Egfr signaling events are also involved in the developmental process of queen and worker differentiation in honey bees (Apis mellifera). Here, we characterized the bee PTEN gene homologue for the first time and begin to explore its potential function during bee development and adult life. Honey bee PTEN is alternatively spliced, resulting in three splice variants. Next, we show that the expression of PTEN can be down-regulated by RNA interference (RNAi) in the larval stage, when female caste fate is determined. Relative to controls, we observed that RNAi efficacy is dependent on the amount of PTEN dsRNA that is delivered to larvae. For larvae fed queen or worker diets containing a high amount of PTEN dsRNA, PTEN knockdown was significant at a whole-body level but lethal. A lower dosage did not result in a significant gene down-regulation. Finally, we compared same-aged adult workers with different behavior: nursing vs. foraging. We show that between nurses and foragers, PTEN isoforms were differentially expressed within brain, ovary and fat body tissues. All isoforms were expressed at higher levels in the brain and ovaries of the foragers. In fat body, isoform B was expressed at higher level in the nurse bees. Our results suggest that PTEN plays a central role during growth and development in queen- and worker-destined honey bees. In adult workers, moreover, tissue-specific patterns of PTEN isoform expression are correlated with differences in complex division of labor between same-aged individuals. Therefore, we propose that knowledge on the roles of IIS and Egfr activity in developmental and behavioral control may increase through studies of how PTEN functions can impact bee social phenotypes.


BPGAP1 spatially integrates JNK/ERK signaling crosstalk in oncogenesis.
Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome. Unbiased screen of different endosome-associated Rab GTPases reveals that late endosome serves as a unique platform to integrate JNK/ERK signaling. Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. Consequently, phosphorylated BPGAP1 facilitates endosomal ERK signaling transduction to the nucleus, driving cell proliferation and transformation via the ERK-Myc-CyclinA axis. BPGAP1 therefore provides a crucial spatiotemporal checkpoint where JNK and MP1/MEK1 work in concert to regulate endosomal and nuclear ERK signaling in cell proliferation control.


Trajectories of depressive symptoms and oral health outcomes in a community sample of older adults.
Adverse outcomes associated with chronic depressive symptoms are of clinical importance. The objective was to identify subgroups of older adults based on their trajectories of depressive symptoms over a 10-year period and determine if these subgroups predicted oral health outcomes. The sample was 944 adults aged 65+ who participated in the oral health module of the the Health and Retirement Survey in 2008. Depressive symptoms were measured with a modified version of the Center for Epidemiologic Studies-Depression (CES-D) scale. Latent class trajectory analysis was used to identify distinct subgroups of elders based on their CES-D scores from 1998-2008. Group membership was used to predict self-rated oral health, overall mouth condition (problems with bleeding gums, gum sensitivity, and food avoidance), and edentulism in 2008. Three distinct subgroups were identified using zero-inflated Poisson regression models: (i) minimal depressive symptoms over the study period (43%), (ii) low but generally stable level of depressive symptoms (41%), and (iii) moderate symptoms and higher CES-D scores than the other groups over the 10 years (16%). Controlling for demographic and health variables and edentulism status, having a trajectory of moderate symptoms was associated with poorer mouth condition (p < 0.0001) and poorer self-rated oral health (p = 0.0003) compared with those with minimal symptoms. Having low levels of depressive symptoms was not significantly associated with these two outcomes. Group membership was not significantly associated with the probability of edentulism. Chronic moderate depressive symptoms are associated with poorer oral health in older adults.


Can evolutionary principles explain patterns of family violence?
The article's aim is to evaluate the application of the evolutionary principles of kin selection, reproductive value, and resource holding power to the understanding of family violence. The principles are described in relation to specific predictions and the mechanisms underlying these. Predictions are evaluated for physical violence perpetrated by (a) parents to unrelated children, (b) parents to genetic offspring, and (c) offspring to parents and between (d) siblings and (e) sexual partners. Precise figures for risks have been calculated where possible. The major conclusions are that most of the evidence is consistent with evolutionary predictions derived from kin selection and reproductive value: There were (a) higher rates of violence to stepchildren, (b) a decline in violence with the age of offspring, and (c) an increase in violence with parental age, while (d) violence between siblings was generally at a low level and concerned resource disputes. The issue of distinguishing evolutionary from alternative explanations is addressed throughout and is problematic for predictions derived from reproductive value. The main evolutionary explanation for male partner violence, mate guarding as a result of paternity uncertainty, cannot explain Western studies where sex differences in control and violence between partners were absent, although other aspects of male partner violence are consistent with it, and it may explain sex differences in traditional cultures. Recurrent problems in evaluating the evidence were to control for possible confounds and thus to distinguish evolutionary from alternative explanations. Suggestions are outlined to address this and other issues arising from the review.


Identification of reference genes for quantitative real-time PCR in the bovine mammary gland during the lactation cycle.
Achieving greater understanding of the genomic influence on milk synthesis in dairy cows represents a daunting challenge. Bovine-specific microarrays have allowed for high-throughput gene expression analysis of the mammary transcriptome. However, real-time PCR (qPCR) still represents the method of choice for accurate expression profiling of small numbers of genes and verification of key microarray relationships. This method is extremely sensitive but requires data normalization to account for analytical errors. Ideally, expression of genes used as internal controls should not be affected by specific treatments or physiological state. Mammary biopsies were collected from five cows each at -15, 1, 15, 30, 60, 120, and 240 days relative to parturition for gene expression profiling. We evaluated expression of nine genes (RPS9, ACTB, GAPD, GTP, ITGB4BP, MRPL39, RPS23, RPS15, and UXT) that could serve as internal controls in mammary tissue using qPCR. Due to gradual increases in mammary RNA concentration (mug/mg tissue) over lactation, all genes investigated experienced a dilution effect. We used pairwise comparison of expression ratios to analyze the reliability of these genes as internal controls. UXT, RPS9, and RPS15 had the most stable expression ratios across cow and time. We also assessed co-regulation among genes through network analysis. Network analysis suggested co-regulation among most of the genes examined, with MYC playing a central role. Pairwise comparison was suitable for finding appropriate internal controls in mammary gland tissue. Results showed that the geometrical average of UXT, RPS9, and RPS15 expression could be used as internal control for longitudinal mammary gene expression profiling.


Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders.
Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain. We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis-acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism. We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions.


Evaluation of a simplified method for estimation of early childhood mortality in small populations.
The provision of simple health technologies in less developed countries has far outpaced the capabilities to evaluate their impact on health in general, and early childhood survival in particular. In rural Haiti, attempts to monitor the impact of health care delivery programmes have been frustrated by some of the same problems encountered elsewhere; ie lack of practicable yet scientifically sound methodologies that interface well with ongoing service delivery programmes. The 'preceding birth' technique, originally advanced by Brass and Macrae, holds promise as just such a method. Its practical appeal derives largely from simple data requirements. In its simplest form, the method requires only responses to a single question put to mothers at delivery regarding the survival status of her previous child. They have shown that the proportion of immediately preceding births dying before the 'index' birth date provides a good approximation of the standard life table probability of death before the second birthday. Given that in rural Haiti, as in much of the less developed world, few women deliver in clinic or hospital where such data could be systematically obtained, exploitation of the preceding birth method would require identification of a convenient and unobtrusive point of contact between questioner and mothers who have recently delivered. In Haiti, two options arose: (1) interview women at home after childbirth, and (2) interview women when they bring the 'index' child seeking vaccination or some other child survival intervention. Both of these deviate from the original technique of Brass and Macrae with respect to the timing and method of data collection, and could therefore introduce serious complications to the interpretation of trends in child mortality. To study this, we examined the effects of adapting the preceding birth method to a rural less developed country setting in Mirebalais, where since 1983 primary health care activities have been administered by MARCH (Management and Resources for Community Health), a private voluntary health organization. The Mirebalais study used a pregnancy register, originally developed for targeting of services, to identify women who were expected to have given birth during the 12-month period before each of two survey rounds. Brief interviews with these women would provide direct life table estimates of child mortality level and trend with which to compare estimates produced from use of the preceding birth method in modified form. Direct estimates of the probability of dying before the second birthday were 138/1000 from first round data and 134/1000 from second round data, indicating a 3% decline.(ABSTRACT TRUNCATED AT 400 WORDS)


[Effect of mycotoxin contaminated feed on production parameters of dairy cows].
Based on a feeding trial using 27 lactating "Simmental-cows" the effect of naturally contaminated feed with deoxynivalenol (DON) as well as zearalenone (ZON) regarding production parameters was examined. 3 groups of cows according to lactation number, milk yield (kg ECM) and body mass were used. The average daily intake of DON in group K was 12.4 mg, in group T 14.1 mg and in group M 14.3 mg and ZON in group K was 12.4 mg, in group T 0.67 mg and in group M 0.68 mg respectively. The feed of animals of group M was supplemented with "Mycofix Plus" as mycotoxin inactivator. The red and white blood picture including the thrombocytes were in all groups within the normal range. Concerning enzymes (GGT, AP) and metabolites (GLUC, TBIL, UREA, CREA) the mean values of the 3 groups were in the normal range. Slightly increased were the mean values of all groups in respect to the AST- and GLDH-activities. Volatile fatty acids of the rumen content were significantly highest in group M, also the number of dead rumen infusoria was significantly decreased, but the counts of small sized infusoria increased. The study has shown that "Mycofix Plus" might be able to enhance the activity of rumen flora concerning detoxification of mycotoxins in feed of dairy cows.


Multidrug- and isoniazid-resistant tuberculosis in three high HIV burden African regions.
Despite major progress in the surveillance of drug-resistant tuberculosis (TB), data are lacking for many low-resource countries. World Health Organization estimates of multidrug-resistant TB (MDR-TB) rates in Africa are low, and based on very limited data from the African continent. To measure MDR-TB prevalence in sub-Saharan African regions with a high prevalence of human immunodeficiency virus (HIV). We conducted three anti-tuberculosis drug resistance surveys in sub-Saharan African regions with high HIV-TB coinfection prevalence: Homa Bay (Kenya), Chiradzulu (Malawi) and West Nile region (Uganda). The prevalence of MDR-TB in new patients was found to be low in the three regions: 1.4% (95%CI 0.2-2.6) in Homa Bay, 2.0% (95%CI 0.4-3.6) in Chiradzulu and 0.6% (95%CI 0.0-1.5) in the West Nile region. We found no significant association between MDR-TB and HIV infection. Nonetheless, ≥ 10% of the new cases surveyed were resistant to isoniazid (INH). The relatively high rate of resistance to INH highlights the need for rapid detection of INH resistance in addition to rifampicin (RMP) resistance, to allow rapid modification of treatment to avoid the acquisition of RMP resistance. Drug resistance should be monitored periodically.


Genomic fossils as a snapshot of the human transcriptome.
Processed pseudogenes (PPGs) are cDNA sequences that were generated through reverse transcription of mature, spliced mRNAs and have subsequently been reinserted at a new genomic location. These cDNA sequences are usually no longer transcribed and are considered "dead on arrival." Here we show that PPGs can be used to generate a map of the transcriptome. By analyzing thousands of human PPGs, we were able to discover hundreds of transcript variants so far unidentified. An experimental verification of a subset of these variants by RT-PCR indicates that most of them are still active in the human transcriptome. Furthermore, we demonstrate that PPGs can enable the identification of ancient splice variants that were expressed ancestrally but are now extinct. Our results show that the genome itself carries a "virtual cDNA library" that can readily be used to analyze both present and ancestral transcripts. Our approach can be applied to sequenced metazoan genomes to computationally annotate splicing variation even when expressed sequences are unavailable.


Prevention and Control of Zika as a Mosquito-Borne and Sexually Transmitted Disease: A Mathematical Modeling Analysis.
The ongoing Zika virus (ZIKV) epidemic in the Americas poses a major global public health emergency. While ZIKV is transmitted from human to human by bites of Aedes mosquitoes, recent evidence indicates that ZIKV can also be transmitted via sexual contact with cases of sexually transmitted ZIKV reported in Argentina, Canada, Chile, France, Italy, New Zealand, Peru, Portugal, and the USA. Yet, the role of sexual transmission on the spread and control of ZIKV infection is not well-understood. We introduce a mathematical model to investigate the impact of mosquito-borne and sexual transmission on the spread and control of ZIKV and calibrate the model to ZIKV epidemic data from Brazil, Colombia, and El Salvador. Parameter estimates yielded a basic reproduction number 0 = 2.055 (95% CI: 0.523-6.300), in which the percentage contribution of sexual transmission is 3.044% (95% CI: 0.123-45.73). Our sensitivity analyses indicate that 0 is most sensitive to the biting rate and mortality rate of mosquitoes while sexual transmission increases the risk of infection and epidemic size and prolongs the outbreak. Prevention and control efforts against ZIKV should target both the mosquito-borne and sexual transmission routes.


Response of hPDLSCs on 3D printed PCL/PLGA composite scaffolds in vitro.
Three‑dimensional printed (3DP) scaffolds have become an excellent resource in alveolar bone regeneration. However, selecting suitable printable materials remains a challenge. In the present study, 3DP scaffolds were fabricated using three different ratios of poly (ε‑caprolactone) (PCL) and poly‑lactic‑co‑glycolic acid (PLGA), which were 0.1PCL/0.9PLGA, 0.5PCL/0.5PLGA and 0.9PCL/0.1PLGA. The surface characteristics and degradative properties of the scaffolds, and the response of human periodontal ligament stem cells (hPDLSCs) on the scaffolds, were assessed to examine the preferable ratio of PCL and PLGA for alveolar bone regeneration. The results demonstrated that the increased proportion of PLGA markedly accelerated the degradation, smoothed the surface and increased the wettability of the hybrid scaffold. Furthermore, the flow cytometry and Cell Counting Kit‑8 assay revealed that the adhesion and proliferation of hPDLSCs were markedlyincreased on the 0.5PCL/0.5PLGA and 0.1PCL/0.9PLGA scaffolds. Additionally, the alkaline phosphatase activity detection and reverse‑transcription quantitative polymerase chain reaction demonstrated that the hPDLSCs on the 0.5PCL/0.5PLGA scaffold exhibited the best osteogenic capacity. Consequently, PCL/PLGA composite scaffolds may represent a candidate focus for future bone regeneration studies, and the 0.5PCL/0.5PLGA scaffold demonstrated the best bio‑response from the hPDLSCs.


Investigation of the proapoptotic BCL-2 family member bid on the crossroad of the DNA damage response and apoptosis.
The BCL-2 family of apoptotic proteins encompasses key regulators proximal to irreversible cell damage. BID, a "BH3-only" proapoptotic family member, plays a critical role in connecting death signals through surface death receptors such as Fas and tumor necrosis factor-alpha to the core apoptotic pathway at the mitochondria. BID is activated downstream of death receptors by caspase-8 cleavage and N-myristoylation to target mitochondria where it activates BAX, BAK, and the downstream apoptotic pathway. In addition to its role in apoptosis, a role has been uncovered for BID in regulating the DNA damage-induced intra-S phase checkpoint that does not require its death-promoting BH3 domain. Following DNA damage, BID is found in the nucleus where it is phosphorylated by ATM and plays a role in the intra-S phase checkpoint. This checkpoint role is dependent on ATM-mediated phosphorylation at position 78. Thus, BID has two distinct and separable functions: an apoptotic function mediated by caspase cleavage and its BH3 domain and a cell cycle/DNA repair function mediated by phosphorylation by the DNA damage kinase ATM. Studies indicate that the pro-death activity of BID is inhibited by phosphorylation. Taken together, these findings suggest interaction between the two functions of BID. An area of intense research pursuit is determining what dictates how cells respond to DNA damage. Some cells arrest the cell cycle, whereas others undergo apoptosis. We hypothesize that BID acts at the interface between the DNA damage response and apoptosis, in position to signal a cell either to undergo cell cycle arrest and initiate DNA repair or to undergo apoptosis. This chapter describes the techniques used to characterize the role of BID in apoptosis and the DNA damage response.


Significant association between common polymorphisms in the aromatase gene CYP19A1 and bone mineral density in postmenopausal women.
17β-Estradiol is important in maintaining bone structure, and regulation of its synthesis plays an important role in the development of postmenopausal osteoporosis. We and others have demonstrated associations between variation in the CYP19A1 gene (encoding aromatase) and areal bone mineral density (aBMD) phenotypes in women. In the present study 33 tag polymorphisms were genotyped across the CYP19A1 gene in a population of 1,185 Caucasian postmenopausal women to test the association between sequence variations, total DXA hip aBMD, and circulating 17β-estradiol levels. An in silico bioinformatics analysis was performed for single nucleotide polymorphisms (SNPs) associated with aBMD to identify putative functional effects, while linkage disequilibrium analysis of these SNPs was undertaken with previously published sequence variants. Five SNPs located in the central third of the gene were strongly associated with total-hip aBMD after adjustment for age (P = 0.006-0.013). A haplotype analysis of these five SNPs revealed an association between the haplotype C-G-G-G-C and increased aBMD (P = 0.008) and the haplotype A-A-A-A-A and a decreased aBMD (P = 0.021). The haplotype frequency was 9.0% for C-G-G-G-C and 15.4% for A-A-A-A-A, with the variation in mean total-hip aBMD explained by the haplotype analyses being 5% and 7%, respectively. None of these polymorphisms was significantly associated with circulating 17β-estradiol levels. In conclusion, common genetic variations within the CYP19A1 gene are significantly associated with aBMD in postmenopausal Caucasian women.


Beyond marine reserves: exploring the approach of selecting areas where fishing is permitted, rather than prohibited.
Marine populations have been declining at a worrying rate, due in large part to fishing pressures. The challenge is to secure a future for marine life while minimizing impacts on fishers and fishing communities. Rather than selecting areas where fishing is banned -- as is usually the case with spatial management -- we assess the concept of designating areas where fishing is permitted. We use spatial catch statistics for thirteen commercial fisheries on Canada's west coast to determine the minimum area that would be needed to maintain a pre-ascribed target percentage of current catches. We found that small reductions in fisheries yields, if strategically allocated, could result in large unfished areas that are representative of biophysical regions and habitat types, and have the potential to achieve remarkable conservation gains. Our approach of selecting fishing areas instead of reserves could help redirect debate about the relative values that society places on conservation and extraction, in a framework that could gain much by losing little. Our ideas are intended to promote discussions about the current status quo in fisheries management, rather than providing a definitive solution.


A method for labeling vasculature in embryonic mice.
The establishment of a functional blood vessel network is an essential part of organogenesis, and is required for optimal organ function. For example, in the thymus proper vasculature formation and patterning is essential for thymocyte entry into the organ and mature T-cell exit to the periphery. The spatial arrangement of blood vessels in the thymus is dependent upon signals from the local microenvironment, namely thymic epithelial cells (TEC). Several recent reports suggest that disruption of these signals results in thymus blood vessel defects. Previous studies have described techniques used to label the neonatal and adult thymus vasculature. We demonstrate here a technique for labeling blood vessels in the embryonic thymus. This method combines the use of FITC-dextran or Griffonia (Bandeiraea) Simplicifolia Lectin I (GSL 1-isolectin B₄) facial vein injections and CD31 antibody staining to identify thymus vascular structures and PDGFR-β to label thymic perivascular mesenchyme. The option of using cryosections or vibratome sections is also provided. This protocol can be used to identify thymus vascular defects, which is critical for defining the roles of TEC-derived molecules in thymus blood vessel formation. As the method labels the entire vasculature, it can also be used to analyze the vascular networks in multiple organs and tissues throughout the embryo including skin and heart.


Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer.
Hsp90 facilitates the maturation and stability of numerous oncoproteins, including HER2. The aim of this study was to assess the antitumor activity of the Hsp90 inhibitor IPI-504 in trastuzumab-resistant, HER2-overexpressing breast cancer cells. Therapy with trastuzumab, IPI-504, and the combination of trastuzumab and IPI-504 was evaluated in trastuzumab-sensitive and trastuzumab-resistant cells. Inhibition of protein targets, cell proliferation, and tumor growth was assessed in vitro and in xenograft models. IPI-504 inhibited proliferation of both trastuzumab-sensitive and trastuzumab-resistant cells. Administration of IPI-504 markedly reduced total levels of HER2 and Akt, as well as phosphorylated Akt and mitogen-activated protein kinase (MAPK), to an equal extent in trastuzumab-sensitive and trastuzumab-resistant cells. IPI-504, used as single agent or in combination with trastuzumab, also inhibited in vivo the growth of both trastuzumab-sensitive and -resistant tumor xenografts. As a mechanism for the observed antitumor activity, IPI-504 resulted in a marked decrease in the levels of HER2, Akt, p-Akt, and p-MAPK in trastuzumab-resistant xenografts as early as 12 hours after a single dose of IPI-504. IPI-504-mediated Hsp90 inhibition may represent a novel therapeutic approach in trastuzumab refractory HER2-positive breast cancer.


Effects of a single-session assertiveness music therapy role playing protocol for psychiatric inpatients.
The purpose of this study was to implement and measure the effectiveness of a single-session assertiveness music therapy role playing protocol for psychiatric inpatients. Participants (N=133) were randomly assigned by group to one of three conditions: (a) Assertiveness Music Therapy, (b) No Music Assertiveness, or (c) Music No Assertiveness. Participants in both assertiveness conditions role played a number of different commonly occurring scenarios at an inpatient psychiatric facility and in the community. There were no significant between-group differences in posttest quality of life, locus of control, or other subscales. However, participants in both assertiveness conditions tended to have slightly higher internal locus of control and overall quality of life scores than participants in the music no assertiveness condition. Additionally, the assertiveness music therapy condition had higher attendance rates than the other conditions. A higher percentage of participants from both the assertiveness music therapy and music no assertiveness conditions indicated they thought their session was the most helpful/therapeutic group therapy session in which they had participated; this was not the case for the assertiveness no music condition. Future research is warranted to measure the effects of protocols that can help psychiatric patients generalize skills learned in treatment.


The structure of child and adolescent psychopathology: generating new hypotheses.
To begin to resolve conflicts among current competing taxonomies of child and adolescent psychopathology, the authors developed an interview covering the symptoms of anxiety, depression, inattention, and disruptive behavior used in the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994), the International Statistical Classification of Diseases and Related Health Problems (ICD-10; World Health Organization, 1992), and several implicit taxonomies. This interview will be used in the future to compare the internal and external validity of alternative taxonomies. To provide an informative framework for future hypothesis-testing studies, the authors used principal factor analysis to induce new testable hypotheses regarding the structure of this item pool in a representative sample of 1,358 children and adolescents ranging in age from 4 to 17 years. The resulting hypotheses differed from the DSM-IV, particularly in suggesting that some anxiety symptoms are part of the same syndrome as depression, whereas separation anxiety, fears, and compulsions constitute a separate anxiety dimension.


Markedly decreased blood perfusion of pancreatic islets transplanted intraportally into the liver: disruption of islet integrity necessary for islet revascularization.
Experimental studies indicate low revascularization of intraportally transplanted islets. This study aimed to quantify, for the first time, the blood perfusion of intrahepatically transplanted islets and elucidate necessary factors for proper islet graft revascularization at this site. Yellow chameleon protein 3.0 islets expressing fluorescent protein in all cells were transplanted. Graft blood perfusion was determined by microspheres. The vascular density and relative contribution of donor blood vessels in revascularization was evaluated using islets expressing green fluorescent protein under the Tie-2 promoter. Blood perfusion of intrahepatic islets was as a mean only 5% of that of native islets at 1-month posttransplantation. However, there was a marked heterogeneity where blood perfusion was less decreased in islets transplanted without prior culture and in many cases restored in islets with disrupted integrity. Analysis of vascular density showed that distorted islets were well revascularized, whereas islets still intact at 1-month posttransplantation were almost avascular. Few donor endothelial cells were observed in the new islet vasculature. The very low blood perfusion of intraportally transplanted islets is likely to predispose for ischemia and hamper islet function. Since donor endothelial cells do not expand posttransplantation, disruption of islet integrity is necessary for revascularization to occur by recipient blood vessels.


Neural Efficiency of Human-Robotic Feedback Modalities Under Stress Differs With Gender.
Sensory feedback, which can be presented in different modalities - single and combined, aids task performance in human-robotic interaction (HRI). However, combining feedback modalities does not always lead to optimal performance. Indeed, it is not known how feedback modalities affect operator performance under stress. Furthermore, there is limited information on how feedback affects neural processes differently for males and females and under stress. This is a critical gap in the literature, particularly in the domain of surgical robotics, where surgeons are under challenging socio-technical environments that burden them physiologically. In the present study, we posited operator performance as the summation of task performance and neurophysiological cost of maintaining that performance. In a within-subject design, we used functional near-infrared spectroscopy to assess cerebral activations of 12 participants who underwent a 3D manipulation task within a virtual environment with concurrent feedback (visual and visual + haptic) in the presence and absence of a cognitive stressor. Cognitive stress was induced with the serial-7 subtraction test. We found that while task performance was higher with visual than visual + haptic feedback, it degraded under stress. The two feedback modalities were found to be associated with varying neural activities and neural efficiencies, and these were stress- and gender-dependent. Our findings engender further investigation into effectiveness of feedback modalities on males and females under stressful conditions in HRI.


Standardized approach to treatment of retinal artery occlusion after intraarterial injection of soft tissue fillers: EYE-CODE.
Inadvertent intraarterial injection of soft tissue fillers during facial aesthetic procedures can result in serious adverse events including visual impairment and blindness. Once the retinal artery has been occluded, only a short window of opportunity exists before blindness becomes irreversible. All physicians should be prepared for the eventuality of intraarterial injection, despite its rarity. The aim of this document is to provide a simple and evidence-based protocol using the easy to remember acronym EYE-CODE: EYE (I call retinal referral center), C (check vision), O (optic nerve function), D (decrease intraocular pressure), and E (erase filler). The EYE-CODE acronym incorporates 2 key components: (1) a systematic office-based protocol to first determine whether vision loss is present and to what extent and (2) a treatment strategy that can be started in the acute office setting and continued by an emergency ophthalmologist. The protocol incorporates a crash kit of treatments readily available to an aesthetic physician combining measures to rapidly reduce intraocular pressure to allow the emboli to dislodge downstream with measures to improve retinal perfusion. EYE-CODE provides an up-to-date, one-stop reference for appropriate management of retinal artery occlusion induced by injection of soft tissue fillers.


Elevated HIV prevalence despite lower rates of sexual risk behaviors among black men in the District of Columbia who have sex with men.
The District of Columbia (DC) has among the highest HIV/AIDS rates in the United States, with 3.2% of the population and 7.1% of black men living with HIV/AIDS. The purpose of this study was to examine HIV risk behaviors in a community-based sample of men who have sex with men (MSM) in DC. Data were from the National HIV Behavioral Surveillance system. MSM who were 18 years were recruited via venue-based sampling between July 2008 and December 2008. Behavioral surveys and rapid oral HIV screening with OraQuick ADVANCE ½ (OraSure Technologies, Inc., Bethlehem, PA) with Western blot confirmation on positives were collected. Factors associated with HIV positivity and unprotected anal intercourse were identified. Of 500 MSM, 35.6% were black. Of all men, 14.1% were confirmed HIV positive; 41.8% of these were newly identified HIV positive. Black men (26.0%) were more likely to be HIV positive than white (7.9%) or Latino/Asian/other (6.5%) men (p<0.001). Black men had fewer male sex partners than non-black, fewer had ever engaged in intentional unprotected anal sex, and more used condoms at last anal sex. Black men were less likely to have health insurance, have been tested for HIV, and disclose MSM status to health care providers. Despite significantly higher HIV/AIDS rates, black MSM in DC reported fewer sexual risks than non-black. These findings suggest that among black MSM, the primary risk of HIV infection results from nontraditional sexual risk factors, and may include barriers to disclosing MSM status and HIV testing. There remains a critical need for more information regarding reasons for elevated HIV among black MSM in order to inform prevention programming.


A transformation from temporal to ensemble coding in a model of piriform cortex.
Different coding strategies are used to represent odor information at various stages of the mammalian olfactory system. A temporal latency code represents odor identity in olfactory bulb (OB), but this temporal information is discarded in piriform cortex (PCx) where odor identity is instead encoded through ensemble membership. We developed a spiking PCx network model to understand how this transformation is implemented. In the model, the impact of OB inputs activated earliest after inhalation is amplified within PCx by diffuse recurrent collateral excitation, which then recruits strong, sustained feedback inhibition that suppresses the impact of later-responding glomeruli. We model increasing odor concentrations by decreasing glomerulus onset latencies while preserving their activation sequences. This produces a multiplexed cortical odor code in which activated ensembles are robust to concentration changes while concentration information is encoded through population synchrony. Our model demonstrates how PCx circuitry can implement multiplexed ensemble-identity/temporal-concentration odor coding.


Alternative method for determining the constant offset in lidar signal.
We present an alternative method for determining the total offset in lidar signal created by a daytime background-illumination component and electrical or digital offset. Unlike existing techniques, here the signal square-range-correction procedure is initially performed using the total signal recorded by lidar, without subtraction of the offset component. While performing the square-range correction, the lidar-signal monotonic change due to the molecular component of the atmosphere is simultaneously compensated. After these corrections, the total offset is found by determining the slope of the above transformed signal versus a function that is defined as a ratio of the squared range and two molecular scattering components, the backscatter and transmittance. The slope is determined over a far end of the measurement range where aerosol loading is zero or, at least, minimum. An important aspect of this method is that the presence of a moderate aerosol loading over the far end does not increase dramatically the error in determining the lidar-signal offset. The comparison of the new technique with a conventional technique of the total-offset estimation is made using simulated and experimental data. The one-directional and multiangle measurements are analyzed and specifics in the estimate of the uncertainty limits due to remaining shifts in the inverted lidar signals are discussed. The use of the new technique allows a more accurate estimate of the signal constant offset, and accordingly, yields more accurate lidar-signal inversion results.