A new physical model with multilayer architecture for facial expression animation using dynamic adaptive mesh.
This paper presents a new physically-based 3D facial model based on anatomical knowledge which provides high fidelity for facial expression animation while optimizing the computation. Our facial model has a multilayer biomechanical structure, incorporating a physically-based approximation to facial skin tissue, a set of anatomically-motivated facial muscle actuators, and underlying skull structure. In contrast to existing mass-spring-damper (MSD) facial models, our dynamic skin model uses the nonlinear springs to directly simulate the nonlinear visco-elastic behavior of soft tissue and a new kind of edge repulsion spring is developed to prevent collapse of the skin model. Different types of muscle models have been developed to simulate distribution of the muscle force applied on the skin due to muscle contraction. The presence of the skull advantageously constrain the skin movements, resulting in more accurate facial deformation and also guides the interactive placement of facial muscles. The governing dynamics are computed using a local semi-implicit ODE solver. In the dynamic simulation, an adaptive refinement automatically adapts the local resolution at which potential inaccuracies are detected depending on local deformation. The method, in effect, ensures the required speedup by concentrating computational time only where needed while ensuring realistic behavior within a predefined error threshold. This mechanism allows more pleasing animation results to be produced at a reduced computational cost.


Skeletal muscle membrane lipid composition is related to adiposity and insulin action.
The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high-dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= -0.369, P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= 0.451, P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= -0.610, P < 0.0001). Indices of elongase activity (r= -0.467, P < 0.001), and delta9 desaturase activity (r= 0.332, P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance."


Retrograde intraflagellar transport by cytoplasmic dynein-2 is required for outer segment extension in vertebrate photoreceptors but not arrestin translocation.
Anterograde intraflagellar transport (IFT) is essential for photoreceptor outer segment formation and maintenance, as well as for opsin trafficking. However, the role of retrograde IFT in vertebrate photoreceptors remains unclear. The purpose of this study was to evaluate zebrafish photoreceptors lacking the retrograde IFT motor, cytoplasmic dynein-2. Morpholino oligonucleotides against the heavy chain (dync2-h1), light intermediate chain (dync2-li1), and intermediate chain (dync2-i1) subunits of cytoplasmic dynein-2 were injected into zebrafish embryos. Retinas and ciliated cells of these zebrafish morphants were analyzed by immunohistochemistry and transmission electron microscopy. Whole-field electroretinograms (ERGs) were performed on dynein morphants at 5 to 6 days after fertilization (dpf). Zebrafish lacking cytoplasmic dynein-2 function exhibited small eyes, kidney cysts, and short photoreceptor outer segments, some of which were disorganized with accumulated vesicles. Morphant photoreceptor connecting cilia were swollen, but neither opsin nor arrestin was mislocalized, although IFT88 accumulated in the distal region of the connecting cilium. Nasal cilia were shortened and displayed cytoplasmic swelling along the axoneme. Loss of cytoplasmic dynein-2 function resulted in a significant reduction in the amplitude of ERG a-, b-, and d-waves but no change in threshold response. Retrograde IFT is essential for outer segment extension and IFT protein recycling in vertebrate photoreceptors. The results show, for the first time, that the dync2-i1 subunit of cytoplasmic dynein-2 is necessary for retrograde IFT. In addition, arrestin translocation does not require retrograde IFT. Finally, the ERG results indicate that loss of cytoplasmic dynein-2 reduces the photoreceptor light response.


Brevilin A Induces Cell Cycle Arrest and Apoptosis in Nasopharyngeal Carcinoma.
Nasopharyngeal carcinoma (NPC) is one of the most common malignant cancers in Southeast Asia and Southern China. Centipeda minima extract (CME) had previously demonstrated anti-cancer effects in human NPC. Brevilin A, a sesquiterpene lactone isolated from C. minima, has been reported to exhibit biological activities. In this study, we investigated its anti-NPC effect and further explored its molecular mechanisms. The effects of brevilin A were tested in the NPC cell lines CNE-1, CNE-2, SUNE-1, HONE1, and C666-1. Effects of brevilin A on cell viability were determined by MTT assay, and cell cycle and apoptosis were detected by flow cytometry. The molecular mechanism of cell cycle regulation and apoptosis were investigated via Western blot. Results showed that brevilin A inhibited NPC cell viability in a concentration- and time-dependent manner. Brevilin A induced cell cycle arrest at G2/M and induced apoptosis. Western blot results demonstrated that brevilin A could down-regulate cyclin D3, cdc2, p-PI3K, p-AKT, p-mTOR, and p-STAT3, while up-regulating cleaved PARP, cleaved caspase 9, and Bax. Regulation of cyclin B1, cdk6, and Bcl-2 expression by brevilin A showed dynamic changes according to dose and time. In the tumor xenograft model, brevilin A could reduce tumor growth, at a similar magnitude to cisplatin. However, notably, whereas cisplatin treatment led to significant weight loss in treated mice, treatment with brevilin A did not, indicating its relative lack of toxicity. Taken together, brevilin A regulated cell cycle, activated the caspase signaling pathway, and inhibited PI3K/AKT/mTOR and STAT3 signaling pathways in vitro, and exhibited similar efficacy to the common chemotherapeutic cisplatin in vivo, without its associated toxicity. These findings provide a framework for the preclinical development of brevilin A as a chemotherapeutic for NPC.


Localized biphasic changes in phosphatidylinositol-4,5-bisphosphate at sites of phagocytosis.
Phagocytosis requires localized and transient remodeling of actin filaments. Phosphoinositide signaling is believed to play an important role in cytoskeletal organization, but it is unclear whether lipids, which can diffuse along the membrane, can mediate the focal actin assembly required for phagocytosis. We used imaging of fluorescent chimeras of pleckstrin homology and C1 domains in live macrophages to monitor the distribution of phosphatidylinositol-4,5-bisphosphate (4,5-PIP(2)) and diacylglycerol, respectively, during phagocytosis. Our results reveal a sequence of exquisitely localized, coordinated steps in phospholipid metabolism: a focal, rapid accumulation of 4,5-PIP(2) accompanied by recruitment of type Ialpha phosphatidylinositol phosphate kinase to the phagosomal cup, followed by disappearance of the phosphoinositide as the phagosome seals. Loss of 4,5-PIP(2) correlated with mobilization of phospholipase Cgamma (PLCgamma) and with the localized formation of diacylglycerol. The presence of 4, 5-PIP(2) and active PLCgamma at the phagosome was shown to be essential for effective particle ingestion. The temporal sequence of phosphoinositide metabolism suggests that accumulation of 4,5-PIP(2) is involved in the initial recruitment of actin to the phagocytic cup, while its degradation contributes to the subsequent cytoskeletal remodeling.


Leisure time physical activity and long-term cardiovascular and cancer outcomes: the Busselton Health Study.
The study aimed to investigate whether meeting leisure time physical activity recommendations was associated with reduced incident and fatal cancer or cardiovascular disease (CVD) in a community-based cohort of middle- to late-aged adults with long-term follow-up. At baseline, 2,320 individuals were assessed on a large number of lifestyle and clinical parameters including their level of physical activity per week, other risk factors (e.g. smoking and alcohol use) various anthropometric measures, blood tests and medical history. Individuals were linked to hospital and mortality registry data to identify future cancer and cardiovascular events (fatal and non-fatal) out to 15 years of follow-up. Cox regression analyses adjusted for relevant confounders identified a priori were used to estimate risk for all-cause, cancer-specific and CVD-specific mortality. In the full cohort an estimated 21 % decreased risk for all-cause mortality (HR 0.79; 95 % CI 0.66-0.96) and 22 % decreased risk for fatal/non-fatal CVD events (HR 0.78; 95 % CI 0.66-0.92) was associated with baseline self-reported physical activity levels of 150 min or more. After exclusion of those with chronic co-morbidities (CVD, cancer, diabetes, chronic obstructive pulmonary disease, hypertension treatment) at baseline, lower risk for fatal/non-fatal CVD events remained significantly associated with 150 min or more of physical activity (HR 0.77; 95 % CI 0.62-0.96). Results from this well established prospective community-based cohort study support the role of leisure time physical activity in reducing all-cause mortality and CVD events (fatal/nonfatal) in the broader population studied. The data also suggest that physical activity associated reductions in risk for CVD events (fatal/nonfatal) were not overly impacted by prevalent key non-communicable diseases.


Formulation and evaluation of floating mucoadhesive alginate beads for targeting Helicobacter pylori.
There are various obstacles in the eradication of Helicobacter pylori infections, including low antibiotic levels and poor accessibility of the drug at the site of the infection. This study describes the preparation and characterisation of novel floating mucoadhesive alginate beads loaded with clarithromycin for delivery to the gastric mucosa to improve the eradication of this microorganism. Calcium alginate beads were prepared by ionotropic gelation. The formulation was modified through addition of oil and coating with chitosan to improve floating, mucoadhesion and modify drug release. Scanning electron microscopy confirmed the sphericity of the beads with X-ray microtomography showing the three-dimensional structure of the beads with the layered internal structure of the bead and the even distribution of the drug within the bead. This formulation combined two gastro-retentive strategies, and produced excellent in-vitro floating, mucoadhesive and drug release characteristics. Enhanced stability of the beads in phosphate buffer raises a potential for the modified formulations to be targeted to regions of higher pH within the gastrointestinal tract. Drug release from these beads was sustained through an unstirred mucin layer simulating in-vivo conditions under which the H. pylori resides in the gastric mucosa. This novel formulation will ensure retention for a longer period in the stomach than conventional formulations and control drug release, ensuring high local drug concentrations, leading to improved eradication of the bacteria.


Intracellular ATP can regulate afferent arteriolar tone via ATP-sensitive K+ channels in the rabbit.
Studies were performed to assess whether ATP-sensitive K+ (KATP) channels on rabbit preglomerular vessels can influence afferent arteriolar (AA) tone. K+ channels with a slope conductance of 258 +/- 13 (n = 7) pS and pronounced voltage dependence were demonstrated in excised patches from vascular smooth muscle cells of microdissected preglomerular segments. Channel activity was markedly reduced by 1 mM ATP and in a dose-dependent fashion by glibenclamide (10(-9) M to 10(-6) M), a specific antagonist of KATP channels. 10(-5) M diazoxide, a K+ channel opener, activated these channels in the presence of ATP, and this effect was also blocked by glibenclamide. To determine the role of these KATP channels in the control of vascular tone, diazoxide was tested on isolated perfused AA. After preconstriction from a control diameter of 13.1 +/- 1.1 to 3.5 +/- 2.1 microns with phenylephrine (PE), addition of 10(-5) M diazoxide dilated vessels to 11.2 +/- 0.7 microns, which was not different from control. Further addition of 10(-5) M glibenclamide reconstricted the vessels to 5.8 +/- 1.5 microns (n = 5; P less than 0.03). In support of its specificity for KATP channels, glibenclamide did not reverse verapamil induced dilation in a separate series of experiments. To determine whether intracellular ATP levels can effect AA tone, studies were conducted to test the effect of the glycolytic inhibitor 2-deoxy-D-glucose. After preconstriction from 13.4 +/- 3.2 to 7.7 +/- 1.3 microns with PE, bath glucose was replaced with 6 mM 2-deoxy-D-glucose. Within 10 min, the arteriole dilated to a mean value of 11.8 +/- 1.4 microns (n = 6; NS compared to control). Subsequent addition of 10(-5) M glibenclamide significantly reconstricted the vessels to a diameter of 8.6 +/- 0.5 micron (P less than 0.04). These data demonstrate that KATP channels are present on the preglomerular vasculature and that changes in intracellular ATP can directly influence afferent arteriolar tone via these channels.


Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action.
Studies on the neural effects of Erythropoietin (EPO) indicate that EPO may have antidepressant effects. Due to its hematopoietic effects, EPO may cause serious side-effects with repeated administration if patients are not monitored extensively. ARA290 is an EPO-analog peptide without such hematopoietic side-effects but may have neurotrophic and antidepressant effects. The aim of this study was to investigate the possible antidepressant effects of ARA290 in a neuropsychological model of drug action. Healthy participants (N=36) received ARA290 (2mg) or placebo in a double-blind, randomized, parallel-group design. Neural and cognitive effects were assessed one week after administration. Primary outcome measures were the neural processing of fearful vs happy faces and the behavioral recognition of emotional facial expressions. ARA290-treated individuals displayed lower neural responses to happy faces in the fusiform gyrus. ARA290 tended to lower the recognition of happy and disgust facial expressions. Although ARA290 was not associated with a better memory for positive words, it was associated with faster categorization of positive vs negative words. Finally, ARA290 increased attention towards positive emotional pictures. No effects were observed on mood and affective symptoms. ARA290 may modulate some aspects of emotional processing, however, the direction and the strength of its effects do not unequivocally support an antidepressant-like profile for ARA290. Future studies may investigate the effects of different timing and dose.


Dynamic induction of ADAMTS1 gene in the early phase of acute myocardial infarction.
Extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteases (MMPs) play an essential role in the repair of infarcted tissue, which affects ventricular remodeling after myocardial infarction. ADAMTS1 (A disintegrin and metalloprotease with thrombospondin motifs), a newly discovered metalloprotease, was originally cloned from a cancer cell line, but little is known about its contribution to disease. To test the hypothesis that ADAMTS1 appears in infarcted myocardial tissue, we examined ADAMTS1 mRNA expression in a rat myocardial infarction model by Northern blotting, real-time RT-PCR and in situ hybridization. Normal endothelium expressed little ADAMTS1 mRNA, while normal myocardium expressed no detectable ADAMTS1 mRNA. Up-regulation of ADAMTS1 was demonstrated by Northern blot analysis and real-time RT-PCR at 3 h after coronary artery ligation. In situ hybridization revealed strong ADAMTS1 mRNA signals in the endothelium and myocardium in the infarcted heart, mainly in the infarct zone, at 3 h after myocardial infarction. The rapid and transient up-regulation of the ADAMTS1 gene in the ischemic heart was distinct from the regulatory patterns of other MMPs. Our study demonstrated that the ADAMTS1 gene is a new early immediate gene expressed in the ischemic endothelium and myocardium.


Simulating multiple character interactions with collaborative and adversarial goals.
This paper proposes a new methodology for synthesizing animations of multiple characters, allowing them to intelligently compete with one another in dense environments, while still satisfying requirements set by an animator. To achieve these two conflicting objectives simultaneously, our method separately evaluates the competition and collaboration of the interactions, integrating the scores to select an action that maximizes both criteria. We extend the idea of min-max search, normally used for strategic games such as chess. Using our method, animators can efficiently produce scenes of dense character interactions such as those in collective sports or martial arts. The method is especially effective for producing animations along story lines, where the characters must follow multiple objectives, while still accommodating geometric and kinematic constraints from the environment.


The Biomechanics and Applications of Strongman Exercises: a Systematic Review.
The sport of strongman is becoming increasingly popular, catering for females, lightweight, and Masters competitors, with strongman exercises also being used by strength and conditioning coaches for a range of athletic groups. Thus, a systematic review was conducted to examine researchers' current understanding of the biomechanics of strongman exercises, with a view to improve strongman athlete performance, provide biomechanical evidence supporting the transferability of strongman exercises to strength and conditioning/rehabilitation programs, and identify gaps in the current knowledge of the biomechanics of strongman exercises. A two-level search term strategy was used to search five databases for studies relevant to strongman exercises and biomechanics. Eleven articles adherent to the inclusion criteria were returned from the search. The studies provided preliminary biomechanical analysis of various strongman exercises including the key biomechanical performance determinants of the farmer's walk, heavy sled pull, and tire flip. Higher performing athletes in the farmer's walk and heavy sled pull were characterized by a greater stride length and stride rate and reduced ground contact time, while higher performing athletes in the tire flip were characterized by a reduced second pull phase time when compared with lower performing athletes. Qualitative comparison of carrying/walking, pulling and static lifting strongman, traditional weight training exercises (TWTE), and common everyday activities (CEA), like loaded carriage and resisted sprinting, were discussed to further researchers' understanding of the determinants of various strongman exercises and their applications to strength and conditioning practice. A lack of basic quantitative biomechanical data of the yoke walk, unilateral load carriage, vehicle pull, atlas stone lift and tire flip, and biomechanical performance determinants of the log lift were identified. This review has demonstrated the likely applicability and benefit of current and future strongman exercise biomechanics research to strongman athletes and coaches, strength and conditioning coaches considering using strongman exercises in a training program, and tactical operators (e.g., military, army) and other manual labor occupations. Future research may provide a greater understanding of the biomechanical determinants of performance, potential training adaptations, and risks expected when performing and/or incorporating strongman exercises into strength and conditioning or injury rehabilitation programs.


Whole Genome Sequencing of Mycobacterium tuberculosis Isolates From Extrapulmonary Sites.
Tuberculosis (TB) remains one of the leading causes of morbidity and mortality worldwide. Extrapulmonary tuberculosis (EPTB) constitutes around 15-20% of TB cases in immunocompetent individuals. Extrapulmonary sites that are affected by TB include bones, lymph nodes, meningitis, pleura, and genitourinary tract. Whole genome sequencing has emerged as a powerful tool to map genetic diversity among Mycobacterium tuberculosis (MTB) isolates and identify the genomic signatures associated with drug resistance, pathogenesis, and disease transmission. Several pulmonary isolates of MTB have been sequenced over the years. However, availability of whole genome sequences of MTB isolates from extrapulmonary sites is limited. Some studies suggest that genetic variations in MTB might contribute to disease presentation in extrapulmonary sites. This can be addressed if whole genome sequence data from large number of extrapulmonary isolates becomes available. In this study, we have performed whole genome sequencing of five MTB clinical isolates derived from EPTB sites using next-generation sequencing platform. We identified 1434 nonsynonymous single nucleotide variations (SNVs), 143 insertions and 105 deletions. This includes 279 SNVs that were not reported before in publicly available datasets. We found several mutations that are known to confer resistance to drugs. All the five isolates belonged to East-African-Indian lineage (lineage 3). We identified 9 putative prophage DNA integrations and 14 predicted clustered regularly interspaced short palindromic repeats (CRISPR) in MTB genome. Our analysis indicates that more work is needed to map the genetic diversity of MTB. Whole genome sequencing in conjunction with comprehensive drug susceptibility testing can reveal clinically relevant mutations associated with drug resistance.


Processing words with emotional connotation: an FMRI study of time course and laterality in rostral frontal and retrosplenial cortices.
Responses of rostral frontal and retrosplenial cortices to the emotional significance of words were measured using functional magnetic resonance imaging (fMRI). Twenty-six strongly right-handed participants engaged in a language task that alternated between silent word generation to categories with positive, negative, or neutral emotional connotation and a baseline task of silent repetition of emotionally neutral words. Activation uniquely associated with word generation to categories with positive or negative versus neutral emotional connotation occurred bilaterally in rostral frontal and retrosplenial cortices. Furthermore, the time courses of activity in these areas differed, indicating that they subserve different functions in processing the emotional connotation of words. Namely, the retrosplenial cortex appears to be involved in evaluating the emotional salience of information from external sources, whereas the rostral frontal cortex also plays a role in internal generation of words with emotional connotation. In both areas, activity associated with positive or negative emotional connotation was more extensive in the left hemisphere than the right, regardless of valence, presumably due to the language demands of word generation. The present findings localize specific areas in the brain that are involved in processing emotional meaning of words within the brain's distributed semantic system. In addition, time course analysis reveals diverging mechanisms in anterior and posterior cortical areas during processing of words with emotional significance.


MOSAIC (MOthers' Advocates In the Community): protocol and sample description of a cluster randomised trial of mentor mother support to reduce intimate partner violence among pregnant or recent mothers.
Intimate partner violence (IPV) is prevalent globally, experienced by a significant minority of women in the early childbearing years and is harmful to the mental and physical health of women and children. There are very few studies with rigorous designs which have tested the effectiveness of IPV interventions to improve the health and wellbeing of abused women. Evidence for the separate benefit to victims of social support, advocacy and non-professional mentoring suggested that a combined model may reduce the levels of violence, the associated mental health damage and may increase a woman's health, safety and connection with her children. This paper describes the development, design and implementation of a trial of mentor mother support set in primary care, including baseline characteristics of participating women. MOSAIC (MOtherS' Advocates In the Community) was a cluster randomised trial embedded in general practice and maternal and child health (MCH) nursing services in disadvantaged suburbs of Melbourne, Australia. Women who were pregnant or with infants, identified as abused or symptomatic of abuse, were referred by IPV-trained GPs and MCH nurses from 24 general practices and eight nurse teams from January 2006 to December 2007. Women in the intervention arm received up to 12 months support from trained and supported non-professional mentor mothers. Vietnamese health professionals also referred Vietnamese women to bilingual mentors in a sub-study. Baseline and follow-up surveys at 12 months measured IPV (CAS), depression (EPDS), general health (SF-36), social support (MOS-SF) and attachment to children (PSI-SF). Significant development and piloting occurred prior to trial commencement. Implementation interviews with MCH nurses, GPs and mentors assisted further refinement of the intervention. In-depth interviews with participants and mentors, and follow-up surveys of MCH nurses and GPs at trial conclusion will shed further light on MOSAIC's impact. Despite significant challenges, MOSAIC will make an important contribution to the need for evidence of effective partner violence interventions, the role of non-professional mentors in partner violence support services and the need for more evaluation of effective health professional training and support in caring for abused women and children among their populations. ACTRN12607000010493.


Xenografts of highly resistant leukemia recapitulate the clonal composition of the leukemogenic compartment.
Clonal evolution of the leukemogenic compartment may contribute to alter the therapeutic response in acute lymphoblastic leukemia (ALL). Using xenotransplantation of primary leukemia cells, we evaluated the phenotypic and genetic composition of de novo resistant very high risk precursor B-cell ALL, a subgroup defined by the persistence of minimal residual disease despite intensive chemotherapy. Analysis of copy number alterations (CNAs) showed that the xenografted leukemia, even when reconstituted from 100 cells, remained highly related to the diagnostic sample, with minor changes in CNAs, mostly deletions, emerging in most cases in the first passage into mice. At the single-cell level, the pattern of monoallelic and biallelic deletions of the CDKN2A locus revealed distinct leukemia subpopulations, which were reproducibly tracked in xenografts. In most very high risk ALL cases, the predominant diagnostic clones were reconstituted in xenografts, as shown by multiplex polymerase chain reaction analysis of immunoglobulin and T-cell receptor loci. In other cases, the pattern in CNAs and immunoglobulin and T-cell receptor rearrangement was less concordant in xenografts, suggesting the outgrowth of subclones. These results unequivocally demonstrate the existence of clonally closely related but distinct subsets of leukemia initiating cells in ALL, which has important implications for drug development and preclinical disease modeling.


Population-Based Prevalence of Cerebral Cavernous Malformations in Older Adults: Mayo Clinic Study of Aging.
The prevalence of cerebral cavernous malformation (CCM) is unknown. Case ascertainment in most previous studies was based on autopsy data or clinical convenience samples, often without detailed clinical or radiologic information. To determine the prevalence of CCM in a population-based sample of older adults. This prospective imaging study included 4721 participants aged 50 to 89 years who were enrolled between January 1, 2004, and December 15, 2015, in the Mayo Clinic Study of Aging, a longitudinal, population-based study of residents of Olmsted County, Minnesota. An age- and sex-stratified sampling strategy was used to randomly select participants from Olmsted County using the medical records linkage system of the Rochester Epidemiology Project. Participants were invited to undergo brain magnetic resonance imaging (MRI). Of the 4721 participants, 2715 had an evaluable MRI. All images were reviewed by a board-certified neuroradiologist, and MRI reports were searched for the terms cavernous malformation, cavernous angioma, and cavernoma. Two vascular neurologists reviewed MRIs, and potential CCMs were classified using Zabramski classification. Medical records of the identified individuals with CCM were reviewed along with their demographic information, medical history, and any symptoms referable to the identified CCM lesion. Prevalence of CCM and clinical and radiologic characteristics of study participants with CCM. Of the 2715 participants who underwent MRI scans, 12 (0.44%) had CCM. With the use of inverse probability weights to adjust for participation bias, the overall prevalence was 0.46% (95% CI, 0.05-0.86). The age-adjusted prevalence was found to be 0.61% (95% CI, 0-1.47) for the 50- to 59-year age group, 0.17% (95% CI, 0-0.50) for the 60- to 69-year age group, 0.45% (95% CI, 0.09-0.81) for the 70- to 79-year age group, and 0.58% (95% CI, 0-1.29) for the 80- to 89-year age group. The sex-adjusted prevalence was 0.41% (95% CI, 0-1.00) for women and 0.51% (95% CI, 0-1.07) for men. Observed frequencies were similar in men and women, with a slight male predominance. Of the 12 participants with CCM, 9 (75%) had a single Zabramski type 2 lesion in a supratentorial location. Only 1 participant (0.037%) was symptomatic from the CCM during the study period. The findings and data from this study are important for determining the potential number of patients available for cohort studies and anticipated clinical trials in older patients with CCM.


Projections onto the Pareto surface in multicriteria radiation therapy optimization.
To eliminate or reduce the error to Pareto optimality that arises in Pareto surface navigation when the Pareto surface is approximated by a small number of plans. The authors propose to project the navigated plan onto the Pareto surface as a postprocessing step to the navigation. The projection attempts to find a Pareto optimal plan that is at least as good as or better than the initial navigated plan with respect to all objective functions. An augmented form of projection is also suggested where dose-volume histogram constraints are used to prevent that the projection causes a violation of some clinical goal. The projections were evaluated with respect to planning for intensity modulated radiation therapy delivered by step-and-shoot and sliding window and spot-scanned intensity modulated proton therapy. Retrospective plans were generated for a prostate and a head and neck case. The projections led to improved dose conformity and better sparing of organs at risk (OARs) for all three delivery techniques and both patient cases. The mean dose to OARs decreased by 3.1 Gy on average for the unconstrained form of the projection and by 2.0 Gy on average when dose-volume histogram constraints were used. No consistent improvements in target homogeneity were observed. There are situations when Pareto navigation leaves room for improvement in OAR sparing and dose conformity, for example, if the approximation of the Pareto surface is coarse or the problem formulation has too permissive constraints. A projection onto the Pareto surface can identify an inaccurate Pareto surface representation and, if necessary, improve the quality of the navigated plan.


D-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis.
D-Limonene, a common monoterepene has been shown to have antiproliferative, apoptosis-inducing and chemopreventive effects. In the present study, we have investigated the effects of D-limonene on the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor development. We found that D-limonene (50 and 100 mg/kg body weight) treatments to the mouse skin significantly reduced the TPA-induced (a) edema and hyperplasia (p < 0.001); (b) expression of cyclooxygenase-2; (c) ornithine decarboxylase activity (p < 0.001); and (d) [(3)H] thymidine incorporation into DNA (p < 0.001). In addition, treatment of D-limonene effectively restored the level of reduced glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, catalase and malondialdehyde production in TPA-treated mouse skin. In a two-stage skin tumorigenesis study, D-limonene significantly reduced the tumor burden (p < 0.005) and tumor incidence as compared to DMBA/TPA-treated mice. D-Limonene treatment also extended the latency period of tumor development from 4 to 9 weeks. D-Limonene treatment decreased the expression level of Ras, Raf and phosphorylation of extracellular signal-regulated protein kinase 1/2 in DMBA/TPA-induced tumors. A decrease in the expression of Bcl-2 and an increase in Bax expression were also observed in tumor tissues of mice treated with D-limonene. Taken together, our findings suggest that D-limonene may exert its chemopreventive activity through the inhibition of inflammation, oxidative stress and Ras-signaling as well as the induction of pro-apoptotic state during TPA-mediated promotion of DMBA-induced skin cancer in mouse model.


Rhombencephalosynapsis associated with cutaneous pretibial hemangioma in an infant.
Rhombencephalosynapsis is a rare congenital abnormality characterized by noncleavage of the cerebellar hemispheres and dentate nuclei with agenesis or severe hypoplasia of the cerebellar vermis. We report an 8-month-old boy with hypotonia, mental and motor retardation, and capillary hemangiomas on his pretibial region. Cranial magnetic resonance imaging revealed vermian hypoplasia with fused cerebellar hemispheres called rhombencephalosynapsis. Other cerebellar and cerebral structures were normal. With this constellation of findings, we attempt to identify the pathogenesis of this posterior fossa malformation. We also discuss cerebellar embryogenesis to differentiate this condition from other posterior fossa malformations such as Dandy-Walker malformation and Joubert's syndrome.


Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards.
The International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommend that a marker of bone formation (serum procollagen type I N propeptide, s-PINP) and a marker of bone resorption (serum C-terminal telopeptide of type I collagen, s-CTX) are used as reference analytes for bone turnover markers in clinical studies. Bone turnover markers (BTM) predict fracture risk, and treatment-induced changes in specific markers account for a substantial proportion of fracture risk reduction. The aims of this report were to determine their clinical potential in the prediction of fracture risk and for monitoring the treatment of osteoporosis and to set an appropriate research agenda. Evidence from prospective studies was gathered through literature review of the PUBMED database between the years 2000 and 2010 and the systematic review of the Agency for Healthcare Research and Quality up to 2001. High levels of BTMs may predict fracture risk independently from bone mineral density in postmenopausal women. They have been used for this purpose in clinical practice for many years, but there is still a need for stronger evidence on which to base practice. BTMs provide pharmacodynamic information on the response to osteoporosis treatment, and as a result, they are widely used for monitoring treatment in the individual. However, their clinical value for monitoring is limited by inadequate appreciation of the sources of variability, by limited data for comparison of treatments using the same BTM and by inadequate quality control. IOF/IFCC recommend one bone formation marker (s-PINP) and one bone resorption marker (s-CTX) to be used as reference markers and measured by standardised assays in observational and intervention studies in order to compare the performance of alternatives and to enlarge the international experience of the application of markers to clinical medicine. BTM hold promise in fracture risk prediction and for monitoring treatment. Uncertainties over their clinical use can be in part resolved by adopting international reference standards.


Genomic structure of the horse major histocompatibility complex class II region resolved using PacBio long-read sequencing technology.
The mammalian Major Histocompatibility Complex (MHC) region contains several gene families characterized by highly polymorphic loci with extensive nucleotide diversity, copy number variation of paralogous genes, and long repetitive sequences. This structural complexity has made it difficult to construct a reliable reference sequence of the horse MHC region. In this study, we used long-read single molecule, real-time (SMRT) sequencing technology from Pacific Biosciences (PacBio) to sequence eight Bacterial Artificial Chromosome (BAC) clones spanning the horse MHC class II region. The final assembly resulted in a 1,165,328 bp continuous gap free sequence with 35 manually curated genomic loci of which 23 were considered to be functional and 12 to be pseudogenes. In comparison to the MHC class II region in other mammals, the corresponding region in horse shows extraordinary copy number variation and different relative location and directionality of the Eqca-DRB, -DQA, -DQB and -DOB loci. This is the first long-read sequence assembly of the horse MHC class II region with rigorous manual gene annotation, and it will serve as an important resource for association studies of immune-mediated equine diseases and for evolutionary analysis of genetic diversity in this region.


Tissue-protective effects of NKG2A in immune-mediated clearance of virus infection.
Virus infection triggers a CD8(+) T cell response that aids in virus clearance, but also expresses effector functions that may result in tissue injury. CD8(+) T cells express a variety of activating and inhibiting ligands, though regulation of the expression of inhibitory receptors is not well understood. The ligand for the inhibitory receptor, NKG2A, is the non-classical MHC-I molecule Qa1(b), which may also serve as a putative restricting element for the T cell receptors of purported regulatory CD8(+) T cells. We have previously shown that Qa1(b)-null mice suffer considerably enhanced immunopathologic lung injury in the context of CD8(+) T cell-mediated clearance of influenza infection, as well as evidence in a non-viral system that failure to ligate NKG2A on CD8(+) effector T cells may represent an important component of this process. In this report, we examine the requirements for induction of NKG2A expression, and show that NKG2A expression by CD8(+) T cells occurs as a result of migration from the MLN to the inflammatory lung environment, irrespective of peripheral antigen recognition. Further, we confirmed that NKG2A is a mediator in limiting immunopathology in virus infection using mice with a targeted deletion of NKG2A, and infecting the mutants with two different viruses, influenza and adenovirus. In neither infection is virus clearance altered. In influenza infection, the enhanced lung injury was associated with increased chemoattractant production, increased infiltration of inflammatory cells, and significantly enhanced alveolar hemorrhage. The primary mechanism of enhanced injury was the loss of negative regulation of CD8(+) T cell effector function. A similar effect was observed in the livers of mutant mice infected intravenously with adenovirus. These results demonstrate the immunoregulatory role of CD8(+) NKG2A expression in virus infection, which negatively regulates T cell effector functions and contributes to protection of tissue integrity during virus clearance.


Ethical dilemmas and validity issues related to the use of new cooling technologies and early recognition of exertional heat illness in sport.
The Tokyo 2020 Olympic Games is expected to be among the hottest Games in modern history, increasing the chances for exertional heat stroke (EHS) incidence, especially in non-acclimatised athletes/workers/spectators. The urgent need to recognise EHS symptoms to protect all attendees' health has considerably accelerated research examining the most effective cooling strategies and the development of wearable cooling technology and real-time temperature monitoring. While these technological advances will aid the early identification of EHS cases, there are several potential ethical considerations for governing bodies and sports organisers. For example, the impact of recently developed cooling wearables on health and performance is unknown. Concerning improving athletic performance in a hot environment, there is uncertainty about this technology's availability to all athletes. Furthermore, the real potential to obtain real-time core temperature data will oblige medical teams to make crucial decisions around their athletes continuing their competitions or withdraw. Therefore, the aim of this review is (1) to summarise the practical applications of the most novel cooling strategies/technologies for both safety (of athletes, spectators and workers) and performance purposes, and (2) to inform of the opportunities offered by recent technological developments for the early recognition and diagnosis of EHS. These opportunities are presented alongside several ethical dilemmas that require sports governing bodies to react by regulating the validity of recent technologies and their availability to all.


Characteristics of cancer patients using homeopathy compared with those in conventional care: a cross-sectional study.
There are only few studies on cancer patients who are treated in complementary and alternative medicine clinics and comparing them with patients in conventional care. We will present the comparison of characteristics of two patient cohorts: one was treated in a homeopathic cancer care clinic and one was treated in a conventional oncology care (CC) outpatient clinic. Six-hundred and forty-seven patients were included in this cross-sectional cohort study and had to fill in questionnaires [health-related quality of life (QoL) (Functional Assessment of Cancer Therapy-General Scale), depression and anxiety (Hospital Anxiety and Depression Scale), fatigue (Multidimensional Fatigue Inventory) and expectancies toward treatment]. Clinical data were extracted from medical records. This study presents the comparison of both cohorts. Patients in the homeopathy cohort are younger, better educated and more often employed than patients in the CC cohort. The most pronounced differences indicate longer disease histories and different diagnostic and clinical pretreatment variables. Despite the clinical differences, QoL as well as anxiety, depression and fatigue was similar in both the groups. Homeopathic treatment is sought by cancer patients at a different phase during the course of the disease, which has particular implications for research. However, expectancies toward the benefit of the treatment as well as QoL data are similar.


Can we build it better? Using BAC genetics to engineer more effective cytomegalovirus vaccines.
The magnitude and durability of immunity to human cytomegalovirus (HCMV) following natural infection is compromised by the presence of immune modulation genes that appear to promote evasion of host clearance mechanisms. Since immunity to HCMV offers limited protection, rational design of effective vaccines has been challenging. In this issue of the JCI, Slavuljica and colleagues employ techniques to genetically modify the highly related mouse CMV (MCMV), in the process generating a virus that was rapidly cleared by NK cells. The virus functioned as a safe and highly effective vaccine. Demonstration of the ability to engineer a safe and highly effective live virus vaccine in a relevant rodent model of CMV infection may open the door to clinical trials of safer and more immunogenic HCMV vaccines.


Analysis of lipid experiments (ALEX): a software framework for analysis of high-resolution shotgun lipidomics data.
Global lipidomics analysis across large sample sizes produces high-content datasets that require dedicated software tools supporting lipid identification and quantification, efficient data management and lipidome visualization. Here we present a novel software-based platform for streamlined data processing, management and visualization of shotgun lipidomics data acquired using high-resolution Orbitrap mass spectrometry. The platform features the ALEX framework designed for automated identification and export of lipid species intensity directly from proprietary mass spectral data files, and an auxiliary workflow using database exploration tools for integration of sample information, computation of lipid abundance and lipidome visualization. A key feature of the platform is the organization of lipidomics data in "database table format" which provides the user with an unsurpassed flexibility for rapid lipidome navigation using selected features within the dataset. To demonstrate the efficacy of the platform, we present a comparative neurolipidomics study of cerebellum, hippocampus and somatosensory barrel cortex (S1BF) from wild-type and knockout mice devoid of the putative lipid phosphate phosphatase PRG-1 (plasticity related gene-1). The presented framework is generic, extendable to processing and integration of other lipidomic data structures, can be interfaced with post-processing protocols supporting statistical testing and multivariate analysis, and can serve as an avenue for disseminating lipidomics data within the scientific community. The ALEX software is available at www.msLipidomics.info.


Care coordination/home-telehealth for veterans with stroke and their caregivers: addressing an unmet need.
Stroke is a life-disrupting, costly event for many stroke patients and their families. An estimated 4.8 million stroke survivors are living in the community with some level of disability, and the incidence of stroke is expected to rise with correspondingly higher costs, both in dollars and other forms of burden for families of patients with stroke. Approximately 80,000 veterans have experienced a stroke, leaving approximately 40% with moderate residual impairments and 15%-30% with severe residual disability. The purpose of this study was to identify postdischarge needs of veterans with stroke and their caregivers and to identify how to design a care coordination/home-telehealth (CC/HT) program to address these needs. Veterans and their caregivers (N = 22) were interviewed about their experiences with stroke, their postdischarge stroke recovery needs, and their experiences with the Veterans Administration's existing Care Coordination/Home-Telehealth (CC/HT) program. Data were analyzed using the process of grounded dimensional analysis. Core concepts identified were (a) assessing and managing the residual effects of stroke, and (b) shifting roles and responsibilities. The findings suggest that a comprehensive care coordination program that includes home telehealth could aid veterans and their caregivers in managing stroke recovery across the continuum of care at home and within the community. The results of the study can provide elements to be included in the CC/HT program.


Prevalence and characteristics of probable major depression and bipolar disorder within UK biobank: cross-sectional study of 172,751 participants.
UK Biobank is a landmark cohort of over 500,000 participants which will be used to investigate genetic and non-genetic risk factors for a wide range of adverse health outcomes. This is the first study to systematically assess the prevalence and validity of proposed criteria for probable mood disorders within the cohort (major depression and bipolar disorder). This was a descriptive epidemiological study of 172,751 individuals assessed for a lifetime history of mood disorder in relation to a range of demographic, social, lifestyle, personality and health-related factors. The main outcomes were prevalence of a probable lifetime (single) episode of major depression, probable recurrent major depressive disorder (moderate), probable recurrent major depressive disorder (severe), probable bipolar disorder and no history of mood disorder (comparison group). Outcomes were compared on age, gender, ethnicity, socioeconomic status, educational attainment, functioning, self-reported health status, current depressive symptoms, neuroticism score, smoking status and alcohol use. Prevalence rates for probable single lifetime episode of major depression (6.4%), probable recurrent major depression (moderate) (12.2%), probable recurrent major depression (severe) (7.2%) and probable bipolar disorder (1.3%) were comparable to those found in other population studies. The proposed diagnostic criteria have promising validity, with a gradient in evidence from no mood disorder through major depression and probable bipolar disorder in terms of gender distribution, socioeconomic status, self-reported health rating, current depressive symptoms and smoking. The validity of our proposed criteria for probable major depression and probable bipolar disorder within this cohort are supported by these cross-sectional analyses. Our findings are likely to prove useful as a framework for a wide range of future genetic and non-genetic studies.


Blind deconvolution estimation of fluorescence measurements through quadratic programming.
Time-deconvolution of the instrument response from fluorescence lifetime imaging microscopy (FLIM) data is usually necessary for accurate fluorescence lifetime estimation. In many applications, however, the instrument response is not available. In such cases, a blind deconvolution approach is required. An iterative methodology is proposed to address the blind deconvolution problem departing from a dataset of FLIM measurements. A linear combination of a base conformed by Laguerre functions models the fluorescence impulse response of the sample at each spatial point in our formulation. Our blind deconvolution estimation (BDE) algorithm is formulated as a quadratic approximation problem, where the decision variables are the samples of the instrument response and the scaling coefficients of the basis functions. In the approximation cost function, there is a bilinear dependence on the decision variables. Hence, due to the nonlinear nature of the estimation process, an alternating least-squares scheme iteratively solves the approximation problem. Our proposal searches for the samples of the instrument response with a global perspective, and the scaling coefficients of the basis functions locally at each spatial point. First, the iterative methodology relies on a least-squares solution for the instrument response, and quadratic programming for the scaling coefficients applied just to a subset of the measured fluorescence decays to initially estimate the instrument response to speed up the convergence. After convergence, the final stage computes the fluorescence impulse response at all spatial points. A comprehensive validation stage considers synthetic and experimental FLIM datasets of ex vivo atherosclerotic plaques and human breast cancer cell samples that highlight the advantages of the proposed BDE algorithm under different noise and initial conditions in the iterative scheme and parameters of the proposal.


Experienced drug users assess the relative harms and benefits of drugs: a web-based survey.
A web-based survey was used to consult the opinions of experienced drug users on matters related to drug harms. We identified a rare sample of 93 drug users with personal experience with 11 different illicit drugs that are widely used in the UK. Asked to assess the relative harms of these drugs, they ranked alcohol and tobacco as the most harmful, and three "Class A" drugs (MDMA, LSD, and psilocybin) and one class B (cannabis) were ranked as the four least harmful drugs. When asked to assess the relative potential for benefit of the 11 drugs, MDMA, LSD, psilocybin, and cannabis were ranked in the top four; and when asked why these drugs are beneficial, rather than simply report hedonic properties, they referred to potential therapeutic applications (e.g., as tools to assist psychotherapy). These results provide a useful insight into the opinions of experienced drug users on a subject about which they have a rare and intimate knowledge.


Major histocompatibility complex-linked diabetogenic gene of the nonobese diabetic mouse. Analysis of genomic DNA amplified by the polymerase chain reaction.
Inheritance of insulin-dependent diabetes mellitus (IDDM) is polygenic, and at least one of the genes conferring susceptibility to diabetes is tightly linked to the MHC. Recent studies have suggested that DQB1 of humans and I-A beta of mice are closely associated with susceptibility and resistance to IDDM. For further characterization and localization of the MHC-linked diabetogenic gene, we studied the genomic sequence of the A beta gene of the nonobese diabetic (NOD) mouse, an animal model of IDDM, in comparison with those of its sister strains, nonobese nondiabetic and cataract Shionogi (CTS) mice, and the original strain, outbred Imperial Cancer Research (ICR) mice. Genomic DNAs from these strains were amplified in vitro by the polymerase chain reaction with thermostable Taq polymerase. The amplified sequences were analyzed by restriction endonuclease digestion, hybridization with allele-specific oligonucleotide probes, and direct sequencing. The unique I-A beta sequence of NOD mice was observed in the sister strain, CTS mice, and in one mouse of the original strain, outbred ICR mice. These data together with the results of MAb typing of MHC molecules and restriction mapping of the I-A region suggest that the unique class II MHC of NOD mice is not the result of a recent mutation, but is derived from the original strain. Since class I MHC of CTS mice is different from the MHC of NOD mice at both the K and D loci, CTS mice are a naturally occurring recombinant strain with NOD type class II MHC and non-NOD type class I MHC. Thus, breeding studies in crosses of NOD with CTS mice should provide biological information on whether the unique class II MHC of NOD mice is diabetogenic.


The Influence of Maternally Derived Antibody and Infant Age at Vaccination on Infant Vaccine Responses : An Individual Participant Meta-analysis.
The design of infant immunization schedules requires an understanding of the factors that determine the immune response to each vaccine antigen. Deidentified individual participant data from GlaxoSmithKline clinical trials were obtained through Clinical Study Data Request. The data were requested on January 2, 2015, and final data were received on April 11, 2016. Immunogenicity trials of licensed or unlicensed vaccines administered to infants were included if antibody concentrations in infants were measured prior to the first dose of vaccine. The database was examined; studies that appeared to have appropriate data were reviewed. Antigen-specific antibody concentration measured 1 month after priming vaccine doses, before booster vaccination, and 1 month after booster vaccine doses. A total of 7630 infants from 32 studies in 17 countries were included. Mean (SD) age at baseline was 9.0 (2.3) weeks; 3906 (51.2%) were boys. Preexisting maternal antibody inhibited infant antibody responses to priming doses for 20 of 21 antigens. The largest effects were observed for inactivated polio vaccine, where 2-fold higher maternal antibody concentrations resulted in 20% to 28% lower postvaccination antibody concentration (geometric mean ratios [GMRs], type 1: 0.80; 95% CI, 0.78-0.83; type 2: 0.72; 95% CI, 0.69-0.74; type 3: 0.78; 95% CI, 0.75-0.82). For acellular pertussis antigens, 2-fold higher maternal antibody was associated with 11% lower postvaccination antibody for pertussis toxoid (GMR, 0.89; 95% CI, 0.87-0.90) and filamentous hemagglutinin (GMR, 0.89; 95% CI, 0.88-0.90) and 22% lower pertactin antibody (GMR, 0.78; 95% CI, 0.77-0.80). For tetanus and diphtheria, these estimates were 13% (GMR, 0.87; 95% CI, 0.86-0.88) and 24% (GMR, 0.76; 95% CI, 0.74-0.77), respectively. The influence of maternal antibody was still evident in reduced responses to booster doses of acellular pertussis, inactivated polio, and diphtheria vaccines at 12 to 24 months of age. Children who were older when first immunized had higher antibody responses to priming doses for 18 of 21 antigens, after adjusting for the effect of maternal antibody concentrations. The largest effect was seen for polyribosylribitol phosphate antibody, where responses were 71% higher per month (GMR, 1.71; 95% CI, 1.52-1.92). Maternal antibody concentrations and infant age at first vaccination both influence infant vaccine responses. These effects are seen for almost all vaccines contained in global immunization programs and influence immune response for some vaccines even at the age of 24 months. These data highlight the potential for maternal immunization strategies to influence established infant programs.


A model of the saccade-generating system that accounts for trajectory variations produced by competing visual stimuli.
Variable saccade trajectories are produced in visual search paradigms in which multiple potential target stimuli are present. These variable trajectories provide a rich source of information that may lead to a deeper understanding of the basic control mechanisms of the saccadic system. We have used published behavioral observations and neural recordings in the superior colliculus (SC), gathered in monkeys performing visual search paradigms, to guide the construction of a new distributed model of the saccadic system. The new model can account for many of the variations in saccade trajectory produced by the appearance of multiple visual stimuli in a search paradigm. The model uses distributed feedback about current eye motion from the brainstem to the SC to reduce activity there at physiologically realistic rates during saccades. The long-range lateral inhibitory connections between SC cells used in previous models have been eliminated to match recent physiological evidence. The model features interactions between visually activated multiple populations of cells in the SC and distributed and topologically organized inhibitory input to the SC from the SNr to produce some of the types of variable saccadic trajectories, including slightly curved and averaging saccades, observed in visual search tasks. The distributed perisaccadic disinhibition of SC from the substantia nigra (SNr) is assumed to have broad spatial tuning. In order to produce the strongly curved saccades occasionally recorded in visual search, the existence of a parallel input to the saccadic burst generators in addition to that provided by the distributed input from the SC is required. The spatiotemporal form of this additional parallel input is computed based on the assumption that the input from the model SC is realistic. In accordance with other recent models, it is assumed that the parallel input comes from the cerebellum, but our model predicts that the parallel input is delayed during highly curved saccadic trajectories.


Previous injury as a risk factor for injury in elite football: a prospective study over two consecutive seasons.
Previous injury is often proposed to be a risk factor for football injury, but most studies rely on players reporting their own medical history and are thus potentially subject to recall bias. Little is known about the natural variation in injury pattern between seasons. To study whether prospectively recorded injuries during one season are associated with injuries sustained during the following season, and to compare injury risk and injury pattern between consecutive seasons. The medical staffs of 12 elite Swedish male football teams prospectively recorded individual exposure and time loss injuries over two full consecutive seasons (2001 and 2002). A multivariate model was used to determine the relation between previous injury, anthropometric data, and the risk of injury. The training and match injury incidences were similar between seasons (5.1 v 5.3 injuries/1000 training hours and 25.9 v 22.7/1000 match hours), but analysis of injury severity and injury patterns showed variations between seasons. Players who were injured in the 2001 season were at greater risk of any injury in the following season compared with non-injured players (hazard ratio 2.7; 95% confidence interval 1.7 to 4.3, p<0.0001). Players with a previous hamstring injury, groin injury, and knee joint trauma were two to three times more likely to suffer an identical injury in the following season, whereas no such relation was found for ankle sprain. Age was not associated with an increased injury risk. This study confirmed previous results showing that previous injury is an important risk factor for football injury. Overall injury incidences were similar between consecutive seasons, indicating that an injury surveillance study covering one full season can provide a reasonable overview of the injury problem among elite football players in a specific environment. However, a prolonged study period is recommended for analyses of specific injury patterns.


Stimulation of phosphatidylinositol hydrolysis, protein kinase C translocation, and mitogen-activated protein kinase activity by bradykinin in rat ventricular myocytes: dissociation from the hypertrophic response.
In ventricular myocytes cultured from neonatal rat hearts, bradykinin (BK), kallidin or BK(1-8) [(Des-Arg9)BK] stimulated PtdinsP2 hydrolysis by 3-4-fold. EC50 values were 6 nM (BK), 2 nM (kallidin), and 14 microM [BK(1-8)]. BK or kallidin stimulated the rapid (less than 30 s) translocation of more than 80% of the novel protein kinase C (PKC) isoforms nPKC-delta and nPKC-epsilon from the soluble to the particulate fraction. EC50 values for nPKC-delta translocation by BK or kallidin were 10 and 2 nM respectively. EC50 values for nPKC-epsilon translocation by BK or kallidin were 2 and 0.6 nM respectively. EC50 values for the translocation of nPKC-delta and nPKC-epsilon by BK(1-8) were more than 5 microM. The classical PKC, cPKC-alpha, and the atypical PKC, nPKC-zeta, did not translocate. BK caused activation and phosphorylation of p42-mitogen-activated protein kinase (MAPK) (maximal at 3-5 min, 30-35% of p42-MAPK phosphorylated). p44-MAPK was similarly activated. EC50 values for p42/p44-MAPK activation by BK were less than 1 nM whereas values for BK(1-8) were more than 10 microM. The order of potency [BK approximately equal to kallidin >> BK (1-8)] for the stimulation of PtdInsP2 hydrolysis, nPKC-delta and nPKC-epsilon translocation, and p42/p44-MAPK activities suggests involvement of the B2 BK receptor subtype. In addition, stimulation of all three processes by BK was inhibited by the B2BK receptor-selective antagonist HOE140 but not by the B1-selective antagonist Leu8BK(1-8). Exposure of cells to phorbol 12-myristate 13-acetate for 24 h inhibited subsequent activation of p42/p44-MAPK by BK suggesting participation of nPKC (and possibly cPKC) isoforms in the activation process. Thus, like hypertrophic agents such as endothelin-1 (ET-1) and phenylephrine (PE), BK activates PtdInsP2 hydrolysis, translocates nPKC-delta, and nPKC-epsilon, and activates p42/p44-MAPK. However, in comparison with ET-1 and PE, BK was only weakly hypertrophic as assessed by cell morphology and patterns of gene expression. This difference could not be attributed to dissimilarities between the duration of activation of p42/p44-MAPK by BK or ET-1. Thus activation of these signalling pathways alone may be insufficient to induce a powerful hypertrophic response.


Infection with Helicobacter pylori is associated with protection against tuberculosis.
Helicobacter pylori, a lifelong and typically asymptomatic infection of the stomach, profoundly alters gastric immune responses, and may benefit the host in protection against other pathogens. We explored the hypothesis that H. pylori contributes to the control of infection with Mycobacterium tuberculosis. We first examined M. tuberculosis-specific IFN-gamma and H. pylori antibody responses in 339 healthy Northern Californians undergoing routine tuberculin skin testing. Of 97 subjects (29%) meeting criteria for latent tuberculosis (TB) infection (LTBI), 45 (46%) were H. pylori seropositive. Subjects with LTBI who were H. pylori-seropositive had 1.5-fold higher TB antigen-induced IFN-gamma responses (p = 0.04, ANOVA), and a more Th-1 like cytokine profile in peripheral blood mononuclear cells, compared to those who were H. pylori seronegative. To explore an association between H. pylori infection and clinical outcome of TB exposure, we evaluated H. pylori seroprevalence in baseline samples from two high risk TB case-contact cohorts, and from cynomolgus macaques experimentally challenged with M. tuberculosis. Compared to 513 household contacts who did not progress to active disease during a median 24 months follow-up, 120 prevalent TB cases were significantly less likely to be H. pylori infected (AOR: 0.55, 95% CI 0.0.36-0.83, p = 0.005), though seroprevalence was not significantly different from non-progressors in 37 incident TB cases (AOR: 1.35 [95% CI 0.63-2.9] p = 0.44). Cynomolgus macaques with natural H. pylori infection were significantly less likely to progress to TB 6 to 8 months after M. tuberculosis challenge (RR: 0.31 [95% CI 0.12-0.80], p = 0.04). H. pylori infection may induce bystander effects that modify the risk of active TB in humans and non-human primates. That immunity to TB may be enhanced by exposure to other microbial agents may have important implications for vaccine development and disease control.


Coexistence of ipsilateral pain-inhibitory and facilitatory processes after high-frequency electrical stimulation.
High-frequency electrical stimulation (HFS) of the human forearm evokes analgesia to blunt pressure in the ipsilateral forehead, consistent with descending ipsilateral inhibitory pain modulation. The aim of the current study was to further delineate pain modulation processes evoked by HFS by examining sensory changes in the arm and forehead; investigating the effects of HFS on nociceptive blink reflexes elicited by supraorbital electrical stimulation; and assessing effects of counter-irritation (electrically evoked pain at the HFS-conditioned site in the forearm) on nociceptive blink reflexes before and after HFS. Before and after HFS conditioning, sensitivity to heat and to blunt and sharp stimuli was assessed at and adjacent to the conditioned site in the forearm and on each side of the forehead. Nociceptive blink reflexes were also assessed before and after HFS with and without counter-irritation of the forearm. HFS triggered secondary hyperalgesia in the forearm (a sign of central sensitization) and analgesia to blunt pressure in the ipsilateral forehead. Under most conditions, both HFS conditioning and counter-irritation of the forearm suppressed electrically evoked pain in the forehead, and the amplitude of the blink reflex to supraorbital stimuli decreased. Importantly, however, in the absence of forearm counter-irritation, HFS conditioning facilitated ipsilateral blink reflex amplitude to supraorbital stimuli delivered ipsilateral to the HFS-conditioned site. These findings suggest that HFS concurrently triggers hemilateral inhibitory and facilitatory influences on nociceptive processing over and above more general effects of counter-irritation. The inhibitory influence may help limit the spread of sensitization in central nociceptive pathways.


The intensive care medicine research agenda in nutrition and metabolism.
The objectives of this review are to summarize the current practices and major recent advances in critical care nutrition and metabolism, review common beliefs that have been contradicted by recent trials, highlight key remaining areas of uncertainty, and suggest recommendations for the top 10 studies/trials to be done in the next 10 years. Recent literature was reviewed and developments and knowledge gaps were summarized. The panel identified candidate topics for future trials in critical care nutrition and metabolism. Then, members of the panel rated each one of the topics using a grading system (0-4). Potential studies were ranked on the basis of average score. Recent randomized controlled trials (RCTs) have challenged several concepts, including the notion that energy expenditure must be met universally in all critically ill patients during the acute phase of critical illness, the routine monitoring of gastric residual volume, and the value of immune-modulating nutrition. The optimal protein dose combined with standardized active and passive mobilization during the acute phase and post-acute phase of critical illness were the top ranked studies for the next 10 years. Nutritional assessment, nutritional strategies in critically obese patients, and the effects of continuous versus intermittent enteral nutrition were also among the highest-ranking studies. Priorities for clinical research in the field of nutritional management of critically ill patients were suggested, with the prospect that different nutritional interventions targeted to the appropriate patient population will be examined for their effect on facilitating recovery and improving survival in adequately powered and properly designed studies, probably in conjunction with physical activity.


Development of a measure of knowledge and attitudes about obstructive sleep apnea in children (OSAKA-KIDS).
Primary care physicians play an important role in screening for childhood obstructive sleep apnea syndrome (OSAS) that, if untreated, can result in serious complications. To describe the development of the Obstructive Sleep Apnea Knowledge and Attitudes in Children (OSAKA-KIDS) questionnaire for use in measuring physicians' knowledge and attitudes about childhood OSAS and its treatment. Cross-sectional survey to pilot administration of the 23-item OSAKA-KIDS questionnaire, mailed to 1195 community- and academic-based physicians in Louisville, Ky; Philadelphia, Pa; and St Louis, Mo. Analysis of variance measured differences in knowledge and attitudes between academic- and community-based physicians and between pediatricians and family practitioners. Using stepwise multiple linear regression, we analyzed the associations between various predictors (including specialty, practice setting, and years since medical school graduation) and each item of knowledge and attitudes. All tests were 2-tailed. Questionnaires for 497 respondents (44% female; mean [SD] age, 45.7 [10.5] years; and mean [SD] number of years since medical school graduation, 18.7 [11.0] years) were analyzed. The mean (SD) knowledge score (percentage of 18 possible) was 69.6% (14.6%). In regression analyses, more knowledge was associated with more positive attitudes overall and more recent graduation from medical school; having a more positive attitude was associated with having completed a pediatrics residency and more knowledge about OSAS. Deficits in basic knowledge about childhood OSAS were observed regardless of physician practice setting and specialty training. More education focusing on the diagnosis and treatment of childhood OSAS and identifying children at risk for OSAS is recommended.


Is my mobile ringing? Evidence for rapid processing of a personally significant sound in humans.
Anecdotal reports and also empirical observations suggest a preferential processing of personally significant sounds. The utterance of one's own name, the ringing of one's own telephone, or the like appear to be especially effective for capturing attention. However, there is a lack of knowledge about the time course and functional neuroanatomy of the voluntary and the involuntary detection of personally significant sounds. To address this issue, we applied an active and a passive listening paradigm, in which male and female human participants were presented with the SMS ringtone of their own mobile and other's ringtones, respectively. Enhanced evoked oscillatory activity in the 35-75 Hz band for one's own ringtone shows that the brain distinguishes complex personally significant and nonsignificant sounds, starting as early as 40 ms after sound onset. While in animals it has been reported that the primary auditory cortex accounts for acoustic experience-based memory matching processes, results from the present study suggest that in humans these processes are not confined to sensory processing areas. In particular, we found a coactivation of left auditory areas and left frontal gyri during passive listening. Active listening evoked additional involvement of sensory processing areas in the right hemisphere. This supports the idea that top-down mechanisms affect stimulus representations even at the level of sensory cortices. Furthermore, active detection of sounds additionally activated the superior parietal lobe supporting the existence of a frontoparietal network of selective attention.


Bay leaves improve glucose and lipid profile of people with type 2 diabetes.
Bay leaves (Laurus nobilis) have been shown to improve insulin function in vitro but the effects on people have not been determined. The objective of this study was to determine if bay leaves may be important in the prevention and/or alleviation of type 2 diabetes. Forty people with type 2 diabetes were divided into 4 groups and given capsules containing 1, 2 or 3 g of ground bay leaves per day for 30 days or a placebo followed by a 10 day washout period. All three levels of bay leaves reduced serum glucose with significant decreases ranging from 21 to 26% after 30 d. Total cholesterol decreased, 20 to 24%, after 30 days with larger decreases in low density lipoprotein (LDL) cholesterol of 32 to 40%. High density lipoprotein (HDL) cholesterol increased 29 and 20% in the groups receiving 1 and 2 g of bay leaves, respectively. Triglycerides also decreased 34 and 25% in groups consuming 1 and 2 g of bay leaves, respectively, after 30 d. There were no significant changes in the placebo group. In summary, this study demonstrates that consumption of bay leaves, 1 to 3 g/d for 30 days, decreases risk factors for diabetes and cardiovascular diseases and suggests that bay leaves may be beneficial for people with type 2 diabetes.


Inhibition of chemically induced carcinogenesis by drugs used in homeopathic medicine.
Homeopathy is considered as one modality for cancer therapy. However, there are only very few clinical reports on the activity of the drugs, as well as in experimental animals. Presently we have evaluated the inhibitory effects of potentized homeopathic preparations against N'-nitrosodiethylamine (NDEA) induced hepatocellular carcinoma in rats as well as 3-methylcholanthrene-induced sarcomas in mice. We have used Ruta, Hydrastis, Lycopodium and Thuja, which are commonly employed in homeopathy for treating cancer. Administration of NDEA in rats resulted in tumor induction in the liver and elevated marker enzymes such as gamma-glutamyl transpeptidase, glutamate pyruvate transaminase, glutamate oxaloacetate transaminase and alkaline phosphatase in the serum and in liver. Concomitant administration of homeopathic drugs retarded the tumor growth and significantly reduced the elevated marker enzymes level as revealed by morphological, biochemical and histopathological evaluation. Out of the four drugs studied, Ruta 200c showed maximum inhibition of liver tumor development. Ruta 200c and phosphorus 1M were found to reduce the incidence of 3-methylcholanthrene-induced sarcomas and also increase the life span of mice harboring the tumours. These studies demonstrate that homeopathic drugs, at ultra low doses, may be able to decrease tumor induction by carcinogen administration. At present we do not know the mechanisms of action of these drugs useful against carcinogenesis.


Cortical swallowing processing in early subacute stroke.
Dysphagia is a major complication in hemispheric as well as brainstem stroke patients causing aspiration pneumonia and increased mortality. Little is known about the recovery from dysphagia after stroke. The aim of the present study was to determine the different patterns of cortical swallowing processing in patients with hemispheric and brainstem stroke with and without dysphagia in the early subacute phase. We measured brain activity by mean of whole-head MEG in 37 patients with different stroke localisation 8.2+/-4.8 days after stroke to study changes in cortical activation during self-paced swallowing. An age matched group of healthy subjects served as controls. Data were analyzed by means of synthetic aperture magnetometry and group analyses were performed using a permutation test. Our results demonstrate strong bilateral reduction of cortical swallowing activation in dysphagic patients with hemispheric stroke. In hemispheric stroke without dysphagia, bilateral activation was found. In the small group of patients with brainstem stroke we observed a reduction of cortical activation and a right hemispheric lateralization. Bulbar central pattern generators coordinate the pharyngeal swallowing phase. The observed right hemispheric lateralization in brainstem stroke can therefore be interpreted as acute cortical compensation of subcortically caused dysphagia. The reduction of activation in brainstem stroke patients and dysphagic patients with cortical stroke could be explained in terms of diaschisis.


Topology selection in unrooted molecular phylogenetic tree by minimum model-based complexity method.
In reconstruction of phylogenetic trees from molecular data, it has been pointed out that multifurcate phylogenetic trees are difficult to be correctly reconstructed by the conventional methods like maximum likelihood method(ML). In order to resolve this problem, we have been engaged in developing a new phylogenetic tree reconstruction method, based on the minimum complexity principle widely used in the inductive inference. Our method, which we call "minimum model-based complexity (MBC) method", has been proved so far to be efficient in estimating multifurcate branching when the tree is described in the form of rooted one. In this study, we make further investigations about the efficiency of MBC method in estimating the multifurcation in unrooted phylogenetic trees. To do so, we conduct computer simulation in which the estimations by MBC method are compared with those by ML, AIC and statistical test approach. The results show that MBC method also provides good estimations even in the case of multifurcate unrooted trees and suggest that it could be generally used for reconstruction of phylogenetic tree having arbitrary multifurcations.


The Case for Mobility Assessment in Hospitalized Older Adults: American Geriatrics Society White Paper Executive Summary.
Mobility can be defined as the ability to move or be moved freely and easily. In older adults, mobility impairments are common and associated with risk for additional loss of function. Mobility loss is particularly common in these individuals during acute illness and hospitalization, and it is associated with poor outcomes, including loss of muscle mass and strength, long hospital stays, falls, declines in activities of daily living, decline in community mobility and social participation, and nursing home placement. Thus, mobility loss can have a large effect on an older adult's health, independence, and quality of life. Nevertheless, despite its importance, loss of mobility is not a widely recognized outcome of hospital care, and few hospitals routinely assess mobility and intervene to improve mobility during hospital stays. The Quality and Performance Measurement Committee of the American Geriatrics Society has developed a white paper supporting greater focus on mobility as an outcome for hospitalized older adults. The executive summary presented here focuses on assessing and preventing mobility loss in older adults in the hospital and summarizes the recommendations from that white paper. The full version of the white paper is available as Text S1. J Am Geriatr Soc 67:11-16, 2019.


Partial remission phase of diabetes in children younger than age 10 years.
There is renewed interest in the phase of partial remission in recently diagnosed diabetes because of the potential for pharmacological and immune intervention to preserve beta cell function. 95 children younger than 10 years were investigated to assess the influence of age, sex, diabetic ketoacidosis (DKA), admission at diagnosis, and ethnicity on the frequency of remission and insulin requirements during the first two years after diagnosis. Partial remission was defined as a requirement of insulin < 0.5 U/kg body weight/day. There was partial remission in 41 patients, with no differences for children aged 2-4 years and those aged 5-9 years. None of the five children aged < 2 years remitted. Forty five of 95 children were admitted to hospital at diagnosis, of whom 26 of 45 had DKA (blood pH < 7.25). In this number of children we were unable to show a statistical difference in the rate of remission with respect to DKA, admission to hospital at diagnosis, sex, or South Asian ethnic background. There were no differences in insulin requirements between the different groups by the end of two years and at that time seven of the children required insulin < 0.5 U/kg/day. The results suggest that even in preschool children there is potential for attempting to preserve beta cell function.


Wearable Sweat Rate Sensors for Human Thermal Comfort Monitoring.
We propose watch-type sweat rate sensors capable of automatic natural ventilation by integrating miniaturized thermo-pneumatic actuators, and experimentally verify their performances and applicability. Previous sensors using natural ventilation require manual ventilation process or high-power bulky thermo-pneumatic actuators to lift sweat rate detection chambers above skin for continuous measurement. The proposed watch-type sweat rate sensors reduce operation power by minimizing expansion fluid volume to 0.4 ml through heat circuit modeling. The proposed sensors reduce operation power to 12.8% and weight to 47.6% compared to previous portable sensors, operating for 4 hours at 6 V batteries. Human experiment for thermal comfort monitoring is performed by using the proposed sensors having sensitivity of 0.039 (pF/s)/(g/m2h) and linearity of 97.9% in human sweat rate range. Average sweat rate difference for each thermal status measured in three subjects shows (32.06 ± 27.19) g/m2h in thermal statuses including 'comfortable', 'slightly warm', 'warm', and 'hot'. The proposed sensors thereby can discriminate and compare four stages of thermal status. Sweat rate measurement error of the proposed sensors is less than 10% under air velocity of 1.5 m/s corresponding to human walking speed. The proposed sensors are applicable for wearable and portable use, having potentials for daily thermal comfort monitoring applications.


Environmental interactions in psychiatric occupational therapy--some inferences.
Five inferences drawn from research studies in the social sciences on the assessment of psychiatric ward atmospheres are presented as a frame of reference for psychiatric occupational therapists. The studies, based on a model stating that behavior results from the interaction of person and environment, suggest procedures for increasing successful treatment outcomes in occupational therapy. Such procedures include matching patients and staff to behavioral settings according to individual response traits and the development of programs emphasizing such variables as spontaneity, autonomy, and involvement.


Effect of changing breast cancer incidence rates on the calibration of the Gail model.
The Gail model combines relative risks (RRs) for five breast cancer risk factors with age-specific breast cancer incidence rates and competing mortality rates from the Surveillance, Epidemiology, and End Results (SEER) program from 1983 to 1987 to predict risk of invasive breast cancer over a given time period. Motivated by changes in breast cancer incidence during the 1990s, we evaluated the model's calibration in two recent cohorts. We included white, postmenopausal women from the National Institutes of Health (NIH) -AARP Diet and Health Study (NIH-AARP, 1995 to 2003), and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO, 1993 to 2006). Calibration was assessed by comparing the number of breast cancers expected from the Gail model with that observed. We then evaluated calibration by using an updated model that combined Gail model RRs with 1995 to 2003 SEER invasive breast cancer incidence rates. Overall, the Gail model significantly underpredicted the number of invasive breast cancers in NIH-AARP, with an expected-to-observed ratio of 0.87 (95% CI, 0.85 to 0.89), and in PLCO, with an expected-to-observed ratio of 0.86 (95% CI, 0.82 to 0.90). The updated model was well-calibrated overall, with an expected-to-observed ratio of 1.03 (95% CI, 1.00 to 1.05) in NIH-AARP and an expected-to-observed ratio of 1.01 (95% CI: 0.97 to 1.06) in PLCO. Of women age 50 to 55 years at baseline, 13% to 14% had a projected Gail model 5-year risk lower than the recommended threshold of 1.66% for use of tamoxifen or raloxifene but >or= 1.66% when using the updated model. The Gail model was well calibrated in PLCO when the prediction period was restricted to 2003 to 2006. This study highlights that model calibration is important to ensure the usefulness of risk prediction models for clinical decision making.


Effects of hexavalent chromium on the survival and cell cycle distribution of DNA repair-deficient S. cerevisiae.
A broad spectrum of genetic damage results from exposure to hexavalent chromium. These lesions can result in DNA and RNA polymerase arrest, chromosomal aberrations, point mutations and deletions. Because of the complexity of Cr genotoxicity, the repair of Cr(VI)-induced DNA damage is poorly understood. Therefore, our aim was to investigate the sensitivities of DNA repair-deficient Saccharomyces cerevisiae strains to Cr(VI)-induced growth inhibition and lethality. Wild-type, translesion synthesis (rev3) and excision repair (apn1, ntg1, ntg2, rad1) mutants exhibited similar survival following Cr(VI) treatment (0-50mM) and underwent at least one population doubling within 2-4h post-treatment. The simultaneous loss of several excision repair genes (apn1 rad1 ntg1 ntg2) led to slower growth after Cr(VI) exposure (10mM) manifested as an initial delay in S phase progression. Higher concentrations of Cr(VI) (25mM) resulted in a prolonged transit through S phase in every strain tested. A G(2)/M arrest was evident within 1-2h after Cr(VI) treatment (10mM) in all strains and cells subsequently divided after this transient delay. In contrast to all other strains, only recombination-deficient (rad52, rad52 rev3) yeast were markedly hypersensitive towards Cr(VI) lethality. RAD52 mutant strains (rad52, rad52 rev3) also exhibited a significant delay (>6h) in the resumption of replication after Cr(VI) exposure which was related to the immediate and apparently terminal arrest of these yeast in G(2)/M after Cr(VI) treatment. These results, taken together with the recombinogenic effects of Cr(VI) in yeast containing a functional RAD52 gene, suggest that RAD52-mediated recombination is critical for the normal processing of lethal Cr-induced genetic lesions and exit from G(2) arrest. Furthermore, only the combined inactivation of multiple excision repair genes affects cell growth after Cr(VI) treatment.


Internal validation of STRmix™ for the interpretation of single source and mixed DNA profiles.
The interpretation of DNA evidence can entail analysis of challenging STR typing results. Genotypes inferred from low quality or quantity specimens, or mixed DNA samples originating from multiple contributors, can result in weak or inconclusive match probabilities when a binary interpretation method and necessary thresholds (such as a stochastic threshold) are employed. Probabilistic genotyping approaches, such as fully continuous methods that incorporate empirically determined biological parameter models, enable usage of more of the profile information and reduce subjectivity in interpretation. As a result, software-based probabilistic analyses tend to produce more consistent and more informative results regarding potential contributors to DNA evidence. Studies to assess and internally validate the probabilistic genotyping software STRmix™ for casework usage at the Federal Bureau of Investigation Laboratory were conducted using lab-specific parameters and more than 300 single-source and mixed contributor profiles. Simulated forensic specimens, including constructed mixtures that included DNA from two to five donors across a broad range of template amounts and contributor proportions, were used to examine the sensitivity and specificity of the system via more than 60,000 tests comparing hundreds of known contributors and non-contributors to the specimens. Conditioned analyses, concurrent interpretation of amplification replicates, and application of an incorrect contributor number were also performed to further investigate software performance and probe the limitations of the system. In addition, the results from manual and probabilistic interpretation of both prepared and evidentiary mixtures were compared. The findings support that STRmix™ is sufficiently robust for implementation in forensic laboratories, offering numerous advantages over historical methods of DNA profile analysis and greater statistical power for the estimation of evidentiary weight, and can be used reliably in human identification testing. With few exceptions, likelihood ratio results reflected intuitively correct estimates of the weight of the genotype possibilities and known contributor genotypes. This comprehensive evaluation provides a model in accordance with SWGDAM recommendations for internal validation of a probabilistic genotyping system for DNA evidence interpretation.


Soft tissue esthetics in implant dentistry.
Dental implants have been considered to be a successful treatment modality. Recently, achieving a good osseointegration is not the ultimate goal for the restorative dentist. Successful implant treatment demands the best gingival esthetic success along with stability and function of the implant. This study was performed to obtain answers to some controversial points pertaining to esthetics and function of implants in maxilla. Immediate flapless implantation into the extraction sockets in maxillary anterior zone is an emerging treatment option in dentistry--the esthetic success of which was in debate for long. The proposed study compared the esthetic success of immediate flapless implants (ILA), to immediate implants with the need for flap (ILB) and, delayed implants (DSL) in single tooth restorations, in the anterior region of the maxilla. The other aim of the study was to find out if any relation exists between the interproximal crestal bone height and papilla height. Analysis was done irrespective of treatment procedure in the same study group using periodontal sounding and radiographs to find out the relation. From the study involving 106 participants, including 21 ILA, 22 ILB and 63 DSL cases, we received highest papillary index score of 2.6 average from group ILA, followed by ILB and DSL, after 3 months of prosthetic loading. From the periodontal sounding and radiographic study it was evident that, when the distance between the base of the contact point of crowns and height of interproximal bone was less than 5, the papilla was present 100% of the time, but when the distance increased to 6 and more than 7 mm, the papilla was present only 46.5 and 24 percentage of the time respectively.


Evaluating the incidence and utility of microscopic metastatic dissemination as diagnosed by lumbar cerebro-spinal fluid (CSF) samples in children with newly diagnosed intracranial ependymoma.
Ependymomas are the third most common central nervous system (CNS) tumor in childhood. After resection, the standard evaluation of intracranial ependymomas includes a post-contrast spine MRI and a lumbar CSF sample to evaluate for metastasis. Although it is estimated that 10-30% of patients will present with metastatic disease, it is unclear what percentage of metastatic disease is solely identified microscopically via lumbar cytology versus that identified as bulky disease on post-contrast spinal MRIs. We retrospectively evaluated all patients at our institution with intracranial ependymoma diagnosed between January 1991 and June 2008 in an effort to evaluate prognostic factors, survival outcomes and incidence of metastatic disease. Sixty-one evaluable patients were identified: 46% were male and the mean age at diagnosis was 64 months (2.04-196.92). The most common tumor location was the posterior fossa (77%) and 64% of patients achieved a gross total resection with initial surgery. Five-year event-free and overall survivals were 39 ± 7% and 87 ± 4%, respectively. Approximately 10% of patients presented with bulky metastatic disease as seen on post-contrast spine MRI. No patient whose spine MRI was negative for tumor had positive lumbar CSF cytology. These data highlight the rarity of patients who present with microscopic metastatic disease noted on lumbar cytology alone and suggest that evaluation of lumbar cytology may not be useful in patients with negative post-contrast spine MRIs. Future prospective trials may be helpful in validating this conclusion before eliminating this procedure as part of the standard evaluation in newly diagnosed ependymoma patients.


How many neutrophils are enough (redux, redux)?
Many chemotherapeutic regimens produce neutropenia, which predisposes to microbial infection. However, not all neutropenic individuals develop infections, so the ability to predict this outcome would be a powerful clinical tool. In this issue of the JCI, Malka et al. describe a dynamic system model of neutrophil bactericidal activity that confirms and extends the concept of critical neutrophil concentration. The authors demonstrate that when the neutrophil concentration approaches the critical concentration, bacterial populations in contact with them exhibit bistability. Their experimental findings raise the intriguing possibility of greater variability in bactericidal activity of neutrophils from healthy adults than heretofore recognized; their model predicts that this could have life-and-death consequences.