Dietary Supplements for Health, Adaptation, and Recovery in Athletes.
Some dietary supplements are recommended to athletes based on data that supports improved exercise performance. Other dietary supplements are not ergogenic per se, but may improve health, adaptation to exercise, or recovery from injury, and so could help athletes to train and/or compete more effectively. In this review, we describe several dietary supplements that may improve health, exercise adaptation, or recovery. Creatine monohydrate may improve recovery from and adaptation to intense training, recovery from periods of injury with extreme inactivity, cognitive processing, and reduce severity of or enhance recovery from mild traumatic brain injury (mTBI). Omega 3-fatty acid supplementation may also reduce severity of or enhance recovery from mTBI. Replenishment of vitamin D insufficiency or deficiency will likely improve some aspects of immune, bone, and muscle health. Probiotic supplementation can reduce the incidence, duration, and severity of upper respiratory tract infection, which may indirectly improve training or competitive performance. Preliminary data show that gelatin and/or collagen may improve connective tissue health. Some anti-inflammatory supplements, such as curcumin or tart cherry juice, may reduce inflammation and possibly delayed onset muscle soreness (DOMS). Beta-hydroxy beta-methylbutyrate (HMB) does not consistently increase strength and/or lean mass or reduce markers of muscle damage, but more research on recovery from injury that includes periods of extreme inactivity is needed. Several dietary supplements, including creatine monohydrate, omega 3-fatty acids, vitamin D, probiotics, gelatin, and curcumin/tart cherry juice could help athletes train and/or compete more effectively.


A novel gene, DXS8237E, lies within 20 kb upstream of UBE1 in Xp11.23 and has a different X inactivation status.
A novel X-linked gene, DXS8237E, was isolated from human fetal brain cDNA, and its 3' end was mapped to within 20 kb upstream of UBE1 in Xp11.23. A 1.3-kb cDNA for DXS8237E detects homologous sequences in other mammals and a 3-kb mRNA that is widely expressed in human cell lines and mouse tissues. Sequence analysis indicated that the 1.3-kb cDNA contains the 3' end of the DXS8237E gene, but the sequence shows no significant homology to known genes. DXS8237E was shown to be subject to X inactivation in five somatic cell hybrids that contain an inactive human X chromosome but no active homologue. Since UBE1 escapes X inactivation, DXS8237E and UBE1 are the closest mapped genes with discordant X inactivation profiles. Sequences in the vicinity of these two genes may be important determinants of X inactivation status.


Chronic mTOR activation induces a degradative smooth muscle cell phenotype.
Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed increased proteolysis, endocytosis, phagocytosis, and lysosomal clearance of extracellular matrix and apoptotic cells. SMCs acquired a limited repertoire of macrophage markers and functions via biogenesis of degradative organelles through an mTOR/β-catenin/MITF-dependent pathway, but were distinguishable from conventional macrophages by an absence of hematopoietic lineage markers and certain immune effectors even in the context of hyperlipidemia. Similar mTOR activation and induction of a degradative SMC phenotype in a model of mild TAAD due to Fbn1 mutation greatly worsened disease with near-uniform lethality. The finding of increased lysosomal markers in medial SMCs from clinical TAAD specimens with hyperplasia and matrix degradation further supports the concept that proliferation of degradative SMCs within the media causes aortic disease, thus identifying mTOR-dependent phenotypic modulation as a therapeutic target for combating TAAD.


Strains of Actinomyces naeslundii and Actinomyces viscosus exhibit structurally variant fimbrial subunit proteins and bind to different peptide motifs in salivary proteins.
Oral strains of Actinomyces spp. express type 1 fimbriae, which are composed of major FimP subunits, and bind preferentially to salivary acidic proline-rich proteins (APRPs) or to statherin. We have mapped genetic differences in the fimP subunit genes and the peptide recognition motifs within the host proteins associated with these differential binding specificities. The fimP genes were amplified by PCR from Actinomyces viscosus ATCC 19246, with preferential binding to statherin, and from Actinomyces naeslundii LY7, P-1-K, and B-1-K, with preferential binding to APRPs. The fimP gene from the statherin-binding strain 19246 is novel and has about 80% nucleotide and amino acid sequence identity to the highly conserved fimP genes of the APRP-binding strains (about 98 to 99% sequence identity). The novel FimP protein contains an amino-terminal signal peptide, randomly distributed single-amino-acid substitutions, and structurally different segments and ends with a cell wall-anchoring and a membrane-spanning region. When agarose beads with CNBr-linked host determinant-specific decapeptides were used, A. viscosus 19246 bound to the Thr42Phe43 terminus of statherin and A. naeslundii LY7 bound to the Pro149Gln150 termini of APRPs. Furthermore, while the APRP-binding A. naeslundii strains originate from the human mouth, A. viscosus strains isolated from the oral cavity of rat and hamster hosts showed preferential binding to statherin and contained the novel fimP gene. Thus, A. viscosus and A. naeslundii display structurally variant fimP genes whose protein products are likely to interact with different peptide motifs and to determine animal host tropism.


Rhythmic Pruning of Perceptual Noise for Object Representation in the Hippocampus and Perirhinal Cortex in Rats.
Neurons in the temporal cortex signal object familiarity by modulating their spiking activity as the object is repeatedly experienced. However, the neural mechanisms underlying this "repetition effect" and its functional significance remain unknown. We investigated this process in a goal-directed object recognition task in which rats were required to recognize familiar and novel objects. Single-unit spiking activity and local field potential were recorded from the hippocampus and perirhinal cortex (PER) as rats performed the task. Repetition effects were detected in both the hippocampus and PER. However, phase-locking to the theta rhythm was strengthened with object repetitions in the hippocampus but not in the PER, whereas stronger phase-locking was observed with gamma rhythm in the PER but not in the hippocampus. Our findings suggest that the repetition effect occurs in sync with different rhythmic oscillations across different regions and may underlie neural "pruning" of noise that facilitates object recognition.


Benchmark Simulation Model No 2: finalisation of plant layout and default control strategy.
The COST/IWA Benchmark Simulation Model No 1 (BSM1) has been available for almost a decade. Its primary purpose has been to create a platform for control strategy benchmarking of activated sludge processes. The fact that the research work related to the benchmark simulation models has resulted in more than 300 publications worldwide demonstrates the interest in and need of such tools within the research community. Recent efforts within the IWA Task Group on "Benchmarking of control strategies for WWTPs" have focused on an extension of the benchmark simulation model. This extension aims at facilitating control strategy development and performance evaluation at a plant-wide level and, consequently, includes both pretreatment of wastewater as well as the processes describing sludge treatment. The motivation for the extension is the increasing interest and need to operate and control wastewater treatment systems not only at an individual process level but also on a plant-wide basis. To facilitate the changes, the evaluation period has been extended to one year. A prolonged evaluation period allows for long-term control strategies to be assessed and enables the use of control handles that cannot be evaluated in a realistic fashion in the one week BSM1 evaluation period. In this paper, the finalised plant layout is summarised and, as was done for BSM1, a default control strategy is proposed. A demonstration of how BSM2 can be used to evaluate control strategies is also given.


The electrically silent Kv6.4 subunit confers hyperpolarized gating charge movement in Kv2.1/Kv6.4 heterotetrameric channels.
The voltage-gated K(+) (Kv) channel subunit Kv6.4 does not form functional homotetrameric channels but co-assembles with Kv2.1 to form functional Kv2.1/Kv6.4 heterotetrameric channels. Compared to Kv2.1 homotetramers, Kv6.4 exerts a ~40 mV hyperpolarizing shift in the voltage-dependence of Kv2.1/Kv6.4 channel inactivation, without a significant effect on activation gating. However, the underlying mechanism of this Kv6.4-induced modulation of Kv2.1 channel inactivation, and whether the Kv6.4 subunit participates in the voltage-dependent gating of heterotetrameric channels is not well understood. Here we report distinct gating charge movement of Kv2.1/Kv6.4 heterotetrameric channels, compared to Kv2.1 homotetramers, as revealed by gating current recordings from mammalian cells expressing these channels. The gating charge movement of Kv2.1/Kv6.4 heterotetrameric channels displayed an extra component around the physiological K(+) equilibrium potential, characterized by a second sigmoidal relationship of the voltage-dependence of gating charge movement. This distinct gating charge displacement reflects movement of the Kv6.4 voltage-sensing domain and has a voltage-dependency that matches the hyperpolarizing shift in Kv2.1/Kv6.4 channel inactivation. These results provide a mechanistic basis for the modulation of Kv2.1 channel inactivation gating kinetics by silent Kv6.4 subunits.


AR cooperates with SMAD4 to maintain skeletal muscle homeostasis.
Androgens and androgen-related molecules exert a plethora of functions across different tissues, mainly through binding to the transcription factor androgen receptor (AR). Despite widespread therapeutic use and misuse of androgens as potent anabolic agents, the molecular mechanisms of this effect on skeletal muscle are currently unknown. Muscle mass in adulthood is mainly regulated by the bone morphogenetic protein (BMP) axis of the transforming growth factor (TGF)-β pathway via recruitment of mothers against decapentaplegic homolog 4 (SMAD4) protein. Here we show that, upon activation, AR forms a transcriptional complex with SMAD4 to orchestrate a muscle hypertrophy programme by modulating SMAD4 chromatin binding dynamics and enhancing its transactivation activity. We challenged this mechanism of action using spinal and bulbar muscular atrophy (SBMA) as a model of study. This adult-onset neuromuscular disease is caused by a polyglutamine expansion (polyQ) in AR and is characterized by progressive muscle weakness and atrophy secondary to a combination of lower motor neuron degeneration and primary muscle atrophy. Here we found that the presence of an elongated polyQ tract impairs AR cooperativity with SMAD4, leading to an inability to mount an effective anti-atrophy gene expression programme in skeletal muscle in response to denervation. Furthermore, adeno-associated virus, serotype 9 (AAV9)-mediated muscle-restricted delivery of BMP7 is able to rescue the muscle atrophy in SBMA mice, supporting the development of treatments able to fine-tune AR-SMAD4 transcriptional cooperativity as a promising target for SBMA and other conditions associated with muscle loss.


What does high and low have to do with it? Performance classification to identify health system factors associated with effective prevention of mother-to-child transmission of HIV delivery in Mozambique.
Efforts to implement and take to scale highly efficacious, low-cost interventions to prevent mother-to-child HIV transmission (pMTCT) have been a cornerstone of reproductive health services in sub-Saharan Africa for over a decade. Yet efforts to increase access and utilization of these services remain far from optimal. This study developed and applied an approach to systematically classify pMTCT performance to identify modifiable health system factors associated with pMTCT performance which may be replicated in other pMTCT systems. Facility-level performance measures were collected at 30 sites over a 12-month period and reviewed for consistency. Five combinations of three indicators (1. HIV testing; 2. CD4 testing; 3. antiretroviral prophylaxis and combined antiretroviral therapy initiation) were compared including a composite of all three, a combination of 1. and 3., and each individually. Approaches were visually assessed to describe facility performance, focusing on rank order consistency across high, medium and low categories. Modifiable and non-modifiable factors were ascertained at each site and ranking process was reviewed to estimate association with facility performance through unadjusted Chi-square tests and logistic regression. After describing factors associated with high versus low performing pMTCT clinics, the effect of inclusion of the 10 middle performers was assessed. The indicator most consistently associated with the reference composite indicator (HIV testing, antiretroviral prophylaxis and combined antiretroviral therapy) was the single measure of antiretroviral prophylaxis and combined antiretroviral therapy. Lower performing pMTCT clinics ranked consistently low across measurement strategies; high and middle performing clinics demonstrated more variability. Association between clinic characteristics and high pMTCT performance varied markedly across ranking strategies. Using the reference composite indicator, larger catchment area, higher number of institutional deliveries, onsite CD4 point-of-care capacity, and higher numbers of nurses and doctors were associated with high clinic performance while clinic location, NGO support, women's support group, community linkages patient-tracking systems and stock-outs were not associated with high performance. Classifying high and low performance provided consistent results across ranking measures, though granularity was improved by aggregating middle performers with either high or low performers. Human resources, catchment size and utilization were positively associated with effective pMTCT service delivery.


A nanovehicle developed for treating deep-seated bacteria using low-dose X-ray.
Many non-antibiotic strategies, such as photocatalysis and photodynamic therapy, have been proposed to inhibit and/or kill bacteria. However, these approaches still have drawbacks such as insufficient bacterial specificity and the limited penetration depth of ultraviolet and near-infrared light. To overcome these limitations, we developed a bacteria-specific anti-bacterial technique via using low-dose X-ray. Graphene oxide quantum dots (GQDs, a multifunctional vehicle) conjugated with vancomycin (Van, a bacteria-targeting ligand) were assembled with Protoporphyrin IX (PpIX, a photo/radiation sensitizer) to yield a novel Van-GQDs/PpIX complex that specifically attached to Escherichia coli and efficiently generated intracellular reactive oxygen species following X-ray activation. Delivery using GQDs increased the PpIX/Van ratio in the target bacterial cell, damaged bacterial cell wall, and enhanced X-ray-induced PpIX activation. Hence, this approach allowed for the use of a low-dose X-ray to efficiently activate the Van-GQDs/PpIX complex to exert its bactericidal effects on Escherichia coli without damaging normal cells. Furthermore, the E. coli did not develop resistance to the proposed approach for at least 7 rounds of repeated administration during one week. Thus, this proposed vehicle exhibiting bacteria-specific X-ray-triggered toxicity is a promising alternative to antibiotics for treating serious bacterial infections occurring in deep-seated tissues/organs (e.g., osteomyelitis and peritonitis). Administration of antibiotics is the most common treatment modality for bacterial infections. However, in some cases, patient attributes such as age, health, tolerance to antibiotics do not allow for the use of high-dose antibiotics. In addition, some bacteria develop resistance to antibiotics because of improper and long-term use of these agents. Therefore, non-antibiotic strategies to treat deeply situated bacterial infections, such as osteomyelitis, are urgently needed for avoiding amputation. To date, several non-antibiotic approaches, such as Ag nanoparticles, graphene-based materials, photocatalysis, and photodynamic therapy have been proposed to inhibit and/or kill bacteria. However, the major challenges of photochemical strategies, specificity and limited penetration depth of light source, still remain for treating the deep-seated bacteria. To overcome these problems, we developed a novel nanovehicle that exerted toxic effects specifically on bacteria following activation by a deeply penetrative low-dose X-ray, without damaging normal cells. As such, it realizes a deeply photochemical route for treating the deep-seated bacteria.


pH gradients are not associated with tip growth in pollen tubes of Lilium longiflorum.
The cytoplasmic pH of growing pollen tubes of Lilium longiflorum Thunb. was measured using the pH-sensitive fluorescent dye 2',7'-bis-(carboxyethyl)-5(6')-carboxyfl uorescein and confocal fluorescence ratio imaging. The average cytoplasmic pH in the clear zone of the pollen tube tip was pH 7.11, and no consistent pH gradients were detected in the clear zone, averaging around -1.00 milli pH unit microm(-1), or along the first 50 microm of the tube (3.62 milli pH units microm[-1]). In addition, no correlation was observed between the absolute tip cytoplasmic pH or the pH gradient and the pollen tube growth rates. Shifts of external pH to more acidic pH values (pH 4.5) caused a relatively small acidification by 0.18 pH units, whereas a more alkaline external pH >7.0 caused a dramatic increase in cytoplasmic pH and growth stopped immediately. Stimulation of the plasma membrane H+-ATPase by fusicoccin, resulted in an increase of tube growth but no change in cytoplasmic pH. On the other hand, vanadate (250-500 microM), a putative inhibitor of the pump, stopped tube growth and a slight cytoplasmic alkalinisation of 0.1 pH units was observed. Vanadate also arrested fusicoccin-stimulated growth and stimulated an increased alkalinisation of around 0.2 pH units. External application of CaCl2 (10 mM) caused a small acidification of less than 0.1 pH units in the clear zone, whilst LaCl3 (250 microM) caused slight and rather variable perturbations in cytoplasmic pH of no more than 0.1 pH units. Both treatments stopped growth. It was inferred from these data that tip-acid cytoplasmic pH gradients do not play a central role in the organisation or maintenance of pollen tube tip growth.


Primary cardiac tumor identified as the cause of seizure.
A 65-year-old woman presented to the emergency department after a seizure. An unexplained bradycardia and heart murmur were detected and an emergency bedside echocardiography was performed. This revealed a mass in the left atrium. The provisional diagnosis of left atrial tumor was later confirmed by formal echocardiography and ultimately by histology. The first presentation of primary cardiac tumors can be misleading and sometimes presents with neurological manifestations. An early echocardiography can be diagnostic and could lead to early surgical intervention with better prognosis.


Global evidence on occupational sun exposure and keratinocyte cancers: a systematic review.
Individual studies have suggested that the association between occupational exposure to solar ultraviolet radiation (UVR) and the development of keratinocyte cancers (KCs) may only be valid in populations of European ancestry living in certain geographical regions. Comparative global data are scarce and so this review aimed to summarize current evidence on the association between occupational exposure to solar UVR and the development of KCs, with a specific focus on geographical location and skin colour. Ovid MEDLINE, PubMed, Embase and Web of Science were searched for potentially relevant records. Extracted data were summarized by study, country and region. We included one prospective cohort study and 18 case-control studies (n = 15 233) from 12 countries in regions where the majority of the population is white skinned (Americas, Europe and Oceania). Eighteen of the 19 studies reported effect estimates suggesting an increased risk of basal cell carcinoma (BCC) and/or squamous cell carcinoma (SCC) among outdoor workers. Only 11 studies found a significantly increased risk and many had imprecise estimates. There was a significantly increased risk of BCC and SCC in individual studies in North America, Latin America and the Caribbean, Western Europe and Southern Europe, but not across regions or countries. Overall, 95% of studies reported higher risks among outdoor workers, although the increases in risk were statistically significant in just over half of the studies. Well-designed and sufficiently powered occupational case-control and cohort studies with adequate adjustment for confounding factors and other risk factors are required to provide more accurate risk estimates for occupational KC.


Probiotics for people with hepatic encephalopathy.
Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient's quality of life and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro-organisms, which when administered in adequate amounts, may confer a health benefit on the host. To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis of hepatic encephalopathy. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical Trials Registry Platform until June 2016. We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in people with hepatic encephalopathy. We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random-effects model meta-analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180 days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias.We found no effect on all-cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low-quality evidence). No-recovery (as measured by incomplete resolution of symptoms) was lower for participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate-quality evidence). Adverse events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low-quality evidence), but effects on hospitalisation and change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low-quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low-quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not meta-analysed; low-quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705 participants; MD -8.29 μmol/L, 95% CI -13.17 to -3.41; low-quality evidence). There were no reports of septicaemia attributable to probiotic in any trial.When probiotics were compared with lactulose, the effects on all-cause mortality were uncertain (2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low-quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low-quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low-quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low-quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low-quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low-quality evidence); quality of life (results not meta-analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325 participants; MD -2.93 μmol/L, 95% CI -9.36 to 3.50; very low-quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. The majority of included trials suffered from a high risk of systematic error ('bias') and a high risk of random error ('play of chance'). Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence is very low. High-quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.


Postoperative analysis of patients who received the Universal 2 total wrist implant system.
Third-generation total wrist arthroplasty devices have provided joint stability, relief from pain and increased wrist motion for patients suffering from severe arthritis. While reports of clinical follow-up appointments describe improved wrist function, the improvement in overall upper extremity function and patient perception remains a question. Therefore, the purpose of this study was to assess the upper extremity function in patients that received the Universal 2 total implant system. Eight patients participated in the complete protocol, which included testing activities of daily living as well as surveys to assess patient perception. The findings of the current study suggest that although patients exhibit motion that exceeds the needed amount, many still have a perceived disability.


Transplanting intact donor tissue enhances dopamine cell survival and the predictability of motor improvements in a rat model of Parkinson's disease.
Primary cell transplantation is currently the gold standard for cell replacement in Parkinson's disease. However, the number of donors needed to treat a single patient is high, and the functional outcome is sometimes variable. The present work explores the possibility of enhancing the viability and/or functionality of small amounts of ventral mesencephalic (VM) donor tissue by reducing its perturbation during preparation and implantation. Briefly, unilaterally lesioned rats received either: (1) an intact piece of half an embryonic day 13 (E13) rat VM; (2) dissociated cells from half an E13 rat VM; or (3) no transplant. D-amphetamine- induced rotations revealed that animals receiving pieces of VM tissue or dissociated cells showed significant improvement in ipsilateral rotation 4 weeks post transplantation. By 6 weeks post transplantation, animals receiving pieces of VM tissue showed a trend for further improvement, while those receiving dissociated cells remained at their 4 week scores. Postmortem cell counts showed that the number of dopaminergic neurons in dissociated cell transplants was significantly lower than that surviving in transplants of intact tissue. When assessing the correlation between the number of dopamine cells in each transplant, and the improvement in rotation bias in experimental animals, it was shown that transplants of whole pieces of VM tissue offered greater predictability of graft function based on their dopamine cell content. Such results suggest that maintaining the integrity of VM tissue during implantation improves dopamine cell content, and that the dopamine cell content of whole tissue grafts offers a more predictable outcome of graft function in an animal model of Parkinson's disease.


Effect of MRI Versus MDCT on Milan Criteria Scores and Liver Transplantation Eligibility.
The Milan criteria for the selection of patients with hepatocellular carcinoma (HCC) for liver transplantation were originally based on the findings of contrast-enhanced CT examinations. Studies have shown improvement in HCC detection of using contrast-enhanced MRI instead of CT, but they have provided little information on the potential downstream effect on patient management that might result from discrepant imaging findings. We sought to assess the effect of discrepant imaging findings on patient eligibility to undergo liver transplantation. From 2006 to 2013, patients with a diagnosis of HCC who underwent both MDCT and MRI examinations within a 40-day period were studied retrospectively. All examinations were independently reviewed by two abdominal radiologists who recorded the number, diameter, and location of each lesion. Secondary confirmation of the lesions was made on the basis of histopathologic findings, diffusion restriction on DWI, increased T2 signal intensity, lesion growth, presence of fat, uptake of ethiodized oil, or a combination of these findings. Sixty-four patients (48 men and 16 women; mean age, 62 years) met the criteria for inclusion in the study. Of the 129 lesions identified by MRI, only 102 of these lesions (79%) were identified by MDCT. This discrepancy led to a difference in the Milan criteria scoring for nine patients (14%). There was no statistically significant difference in the mean (± SD) greatest lesion diameter measured using the two modalities, with measurements of 3.52 ± 2.8 cm and 3.46 ± 2.8 cm noted on MDCT and MRI, respectively (p = 0.8). Lesions missed on MDCT studies tended to be smaller, with a mean diameter of 2.7 cm. Of the 129 lesions identified by MRI, 112 (87%) had available histopathologic findings or other confirmatory diagnostic evidence. MDCT missed one-fifth of the HCC lesions detected by MRI. Had MDCT been the only imaging examination performed, failure to identify these lesions would have led to a different management plan for 14% of patients.


Structural Basis for the Interaction between Golgi Reassembly-stacking Protein GRASP55 and Golgin45.
Golgin45 is required for normal Golgi structure and the transportation of protein from the ER. It forms a specific complex with GRASP55 in vivo Little is known regarding the molecular details of this interaction and its structural role in stacking of the Golgi complex. Here, we present the crystal structure of the GRASP domains of GRASP55 in complex with the Golgin45 C-terminal peptide, determined at 1.33 Å resolution. Similar to the structure of GRASP65 bound to GM130 reported recently, this structure reveals more than one interacting site and involves both PDZ1 and PDZ2 domains of the GRASP simultaneously. The C-terminal peptides of Golgin45 and GM130 present a conserved PDZ domain binding motif sequence and recognize the canonical PDZ-peptide binding groove of the PDZ1 domains of GRASP55 and GRASP65. A main difference in this recognition process resides in a structural rearrangement of GRASP65-GM130 that does not occur for the GRASP55-Golgin45 complex. The binding site at the cleft between the PDZ1 and PDZ2 domains of GRASP65 is dominated by hydrophobic interactions with GM130 that are not observed in the GRASP55-Golgin45 complex. In addition, a unique zinc finger structure is revealed in the GRASP55-Golgin45 complex crystal structure. Mutagenesis experiments support these structural observations and demonstrate that two of these sites are required to form a stable complex. Finally, a novel Golgi stacking model is proposed according to these structural findings.


Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis.
Since its discovery, small interfering RNA (siRNA) has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA) not easily accessed by conventional drugs. Hence, RNA interference (RNAi) therapeutics have great potential in the treatment of many diseases caused by faulty protein expression such as fibrosis and cancer. However, for clinical application siRNA faces a number of obstacles, such as poor in vivo stability, and off-target effects. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs). This nanocarrier is capable of incorporating siRNA in its core through self-association with a novel cationic lipid composed of naturally occuring phospholipids and amino acids. This overall assembly protects and delivers sufficient amounts of siRNA to knockdown over-expressed protein in target cells. The siRNA used in this study, targets connective tissue growth factor (CTGF), an important regulator of fibrosis in both hepatic and renal cells. Furthermore, asialoglycoprotein receptors are targeted by attaching the galactosamine ligand to the nanocarries which enhances the uptake of nanoparticles by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. On animals this innovative nanoconstruct, small interfering RNA in sterically stabilized phospholipid nanoparticles (siRNA-SSLNP), showed favorable pharmacokinetic properties and accumulated mostly in hepatic and renal tissues making siRNA-SSLNP a suitable system for targeting liver and kidney fibrotic diseases.


Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression.
To determine the organ distribution of production of the three endothelin (ET) isopeptides, we have developed three ribonuclease protection assays specific for the messenger RNAs (mRNAs) of rat ETs 1, 2, and 3.12 organs from adult Sprague-Dawley rats were examined: heart, lung, liver, spleen, kidney, stomach, small intestine, large intestine, testis, muscle, salivary gland, and brain. The mRNA for ET1 was five times more abundant in the lung than in any other organ studied, moderate expression was seen in the large intestine, and lower levels of mRNA were detected in each of the other organs examined. ET2 was expressed at high level in both large and small intestine and at low level in stomach, muscle, and heart, but ET2 mRNA could not be detected elsewhere. ET3 mRNA was found in all organs, particularly in small intestine, lung, kidney, and large intestine. Because of reports suggesting that ETs might be involved in the hypoperfusion and hypofiltration observed in postischemic kidneys, we have also studied levels of mRNA in kidneys that had previously been subjected to 25 or 45 min of clamping of the renal pedicle. At 6 h after 45 min of ischemia, ET1 mRNA increased to a peak of 421 +/- 69% (mean +/- SEM, n = 3) of that in a standard renal RNA preparation. By contrast, ET3 mRNA decreased in the postischemic organ, falling to a value of 19 +/- 2% of standard at the same time point. The effects of ischemia on ET1 and ET3 mRNAs were long-lasting, with elevation of ET1 and depression of ET3 persisting for days. ET2 mRNA remained undetectable throughout. These findings (a) support a role for ET1 in postischemic renal vascular phenomena and (b) demonstrate a situation in which the expression of ET isoforms is clearly subject to differential regulation.


Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation.
Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p's ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.


Impact of C-terminal amino acid composition on protein expression in bacteria.
The C-terminal sequence of a protein is involved in processes such as efficiency of translation termination and protein degradation. However, the general relationship between features of this C-terminal sequence and levels of protein expression remains unknown. Here, we identified C-terminal amino acid biases that are ubiquitous across the bacterial taxonomy (1,582 genomes). We showed that the frequency is higher for positively charged amino acids (lysine, arginine), while hydrophobic amino acids and threonine are lower. We then studied the impact of C-terminal composition on protein levels in a library of Mycoplasma pneumoniae mutants, covering all possible combinations of the two last codons. We found that charged and polar residues, in particular lysine, led to higher expression, while hydrophobic and aromatic residues led to lower expression, with a difference in protein levels up to fourfold. We further showed that modulation of protein degradation rate could be one of the main mechanisms driving these differences. Our results demonstrate that the identity of the last amino acids has a strong influence on protein expression levels.


High differentiation among eight villages in a secluded area of Sardinia revealed by genome-wide high density SNPs analysis.
To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not "a priori" be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates.


Active modulation of refractive index by stress in the terahertz frequency range.
Experimental tests are presented to investigate the stress effect on terahertz (THz) waves with a THz time-domain spectroscopy system. Through the Jones matrix method, an experimental principle is derived according to the experimental system. Experimental results indicate the linear relationship between a polytetrafluoroethylene refractive index and applied stress. The result can be applied to the active modulation of a refractive index or phase of a THz wave.


Hearing impairment and poverty: the epidemiology of ear disease in Peruvian schoolchildren.
1) To measure prevalence of hearing impairment (HI) in schoolchildren living in poverty in Peru. 2) To identify risk factors for HI and assess its impact on academic performance. Cross-sectional. Elementary schools in an asentimiento humano (shantytown) near Lima, Peru, October 2008 to March 2009. Schoolchildren (n = 335), ages six to 19 years. Audiological health was assessed with pure-tone audiometry, tympanometry, and otoscopy. The primary outcome was HI, defined as average threshold >25 dB HL for 0.5, 1, 2, and 4 kHz, in one or both ears (per World Health Organization/International Organization for Standardization). A questionnaire on health history was administered to parents. Statistical analysis included univariate analysis for chi(2) values and odds ratios (ORs), and multivariate logistic regression. HI prevalence: 6.9 percent (95% confidence interval [CI] 4.2%-9.6%). Risk factors for HI (OR, 95% CI, P value): neonatal jaundice (5.59, 1.63-19.2, 0.015), seizure (7.31, 2.50-21.4, 0.0013), hospitalization (4.01, 1.66-9.68, 0.003), recurrent otitis media (5.06, 1.98-12.9, 0.002), past otorrhea (4.70, 1.84-12.0, 0.003), family history of HI at <35 years (2.91, 1.19-7.14, 0.026), tympanic membrane abnormality (13.8, 4.48-42.7, <0.001), cerumen impaction (15.8, 4.71-53.1, <0.001), and eustachian tube dysfunction (4.87, 1.74-13.7, <0.001). HI was an independent predictor of academic failure (3.36, 1.15-9.82, 0.03). Impoverished Peruvian schoolchildren were four to seven times more likely to experience HI than children living in higher-income countries. Untreated middle ear disease in the context of limited access to pediatric care was a major risk factor for HI. Furthermore, HI was associated with worse scholastic achievement. These results support prioritization of pediatric ear health as an essential component of the global health agenda, especially in resource-poor countries.


Harmonic oscillatory orientation relative to the wind in nocturnal roosting flights of the swift Apus apus.
Swifts regularly spend the night flying at high altitude. From previous studies based on tracking radar observations, we know that they stay airborne during the night and prefer to orient themselves into the wind direction with an increased angular concentration with increasing wind speed. In this study, we investigated the orientation relative to the wind of individual swifts by frequency (discrete Fourier transform) and autocorrelation analysis based on time series (10s intervals) of the angle between the swifts' heading and the wind direction for radar trackings of long duration (9-60 min). The swifts often showed a significant harmonic oscillation of their heading direction relative to the wind, with a frequency mostly in the range 1-17 mHz, corresponding to cycle periods of 1-16 min. The swifts also sometimes performed circling flights at low wind speeds. Wind speed ranged from 1.3 to 14.8 m s(-1), and we expected to find different patterns of orientation at different wind speeds, assuming that the swifts adapt their orientation to avoid substantial displacement during their nocturnal flights. However, oscillatory orientation was found at all wind speeds with variable frequencies/periods that did not show any consistent relationship with wind speed. It remains to be shown whether cyclic heading changes are a regular feature of bird orientation.


Response linearity in primary auditory cortex of the ferret.
The responses of neurons within the primary auditory cortex (A1) of the ferret elicited by broadband dynamic spectral ripple stimuli were examined over a range of ripple spectral densities and ripple velocities. The large majority of neurons showed modulated responses to these stimuli and responded most strongly at low ripple densities and velocities. The period histograms of their responses were subjected to Fourier analysis, and the ratio of the magnitudes of the f1 and fo (DC) components of these responses were calculated to give a quantitative index of response linearity. For 82 out of 396 neurons tested (20.7%) this ratio remained above 1.0 over the entire range of ripple densities and velocities. These neurons were classified as 'consistently linear'. A further 134/396 (33.8%) of neurons maintained an f1/f0 ratio above 1.0 for either a range of ripple densities at a fixed ripple velocity, or over a range of ripple velocities at a specific ripple density, and were classified as 'locally linear'. Interestingly, for the superficial layers of the primary auditory cortex, consistently linear and locally linear neurons outnumbered nonlinear neurons by a 2:1 ratio. The converse was true for the deep layers. Unlike in primary visual cortex, where f1/f0 ratios have been reported to exhibit a bimodal distribution with a minimum at f1/f0 = 1, f1/f0 ratios for A1 are unimodally distributed with a peak at f1/f0 = 1.


Induction of a systemic antiviral state in vivo in the domestic cat with a class A CpG oligonucleotide.
The evolution of cats as a solitary species has pressured feline viruses to develop highly efficient transmission strategies, the ability to persist within the host for long periods of time and the aptitude to adapt to natural and vaccine-induced immunological pressures. These characteristics render feline viruses particularly dangerous in catteries, shelters and rescue homes, were cats from different backgrounds live in close proximity. The possibility to induce short-term resistance of newcomer cats to a broad variety of viruses could help prevent the dissemination of viruses both within and outside such facilities. Oligonucleotides (ODN) containing unmethylated cytosine phosphate guanosine (CpG) motifs stimulate innate immune responses in mammals. We have previously shown that ODN 2216, a class A CpG ODN, promotes the expression by feline immune cells of potent antiviral molecules that increase resistance of feline fibroblastic and epithelial cell lines to five common feline viruses. With the aim to test the safety and extent of the biological effects of ODN 2216 in the domestic cat, we performed an initial in vivo experiment in which two cats were injected the molecule once subcutaneously and two additional cats received control treatments. No side effects to administration of ODN 2216 were observed. Moreover, this molecule induced the expression of the myxovirus resistance (Mx) gene, a marker for the instigation of innate antiviral processes, in blood as well as in oral, conjunctival and rectal mucosa cells, indicating systemic biological activity of the molecule with protective potential at viral entry sites. Mx mRNA levels were already elevated in blood 6h post injection of ODN 2216, reached peak levels within 24h and returned to basal values by 96-192 h after administration of the molecule. Similar induction patterns were observed in all analyzed mucosal cells. Plasma collected from treated cats at regular intervals until 96-192 h could moreover induce Mx mRNA expression in fcwf-4 cells and increase resistance of these cells to feline calicivirus inoculation. Finally, Mx mRNA levels measured in blood correlated with the degree of viral inhibition that was induced by plasma from the same cat and the same experimental time point. Our results altogether underline the promising potential of ODN 2216 in promoting antiviral defense mechanisms and inducing temporary resistance to viral infections in vivo in the domestic cat.


Carcinogen-DNA adducts in human breast tissue.
Breast cancer is the second leading cause of cancer death among American women. Known risk factors account for only approximately one-third of the 182,000 new cases diagnosed each year in the United States. There is both concern and debate over the contribution of environmental exposures related to lifestyle, occupation, and ambient pollution, particularly in high risk areas such as Long Island, NY and the rest of the northeastern United States. Biomarkers such as carcinogen-DNA adducts can help to explore the role of environmental risk factors for breast cancer by documenting DNA damage from specific carcinogens directly in human tissue. In this pilot study, a total of 31 breast tissue samples were analyzed by the 32P-postlabeling method for carcinogen-DNA adducts characteristic of complex mixtures of aromatic compounds (such as polycyclic aromatic hydrocarbons) and tobacco smoke. The samples included tumor and tumor-adjacent tissues from 15 women with breast cancer and normal tissue samples from 4 women undergoing breast reduction. Among the breast cancer cases, the mean aromatic/hydrophobic-DNA adduct level in all tissues assayed was 5.3 +/- 2.4 (SD) adducts/10(8) nucleotides compared to 2.3 +/- 1.5 among the samples from the noncancer patients. Breast tissue (tumor and/or nontumor) from 30% (5 of 15) of women with breast cancer displayed a pattern of adducts (referred to as a diagonal zone of radioactivity) associated previously, in studies of other tissues, with exposure to tobacco smoke. The 5 positive samples were from current smokers; tissue samples from the 8 nonsmoking cases did not show this characteristic pattern (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Air temperatures and occupational injuries in the construction industries: a report from Northern Italy (2000-2013).
The aim of this study was to assess the relationship between environmental temperatures and occupational injuries (OIs) in construction workers (CWs) from a subalpine region of North-Eastern Italy. Data about OIs from 2000 to 2013, and daily weather for the specific site of the events were retrieved. Risk for daily OIs was calculate through a Poisson regression model. Estimated daily incidence for OIs was 5.7 (95%CI 5.5-5.8), or 2.8 OIs/10,000 workers/d (95%CI 2.7-2.9), with higher rates for time periods characterized by high temperatures (daily maximum ≥35°C), both in first 2 d (3.57, 95%CI 3.05-4.11) and from the third day onwards (i.e. during Heat Waves: 3.43, 95%CI 3.08-3.77). Higher risk for OIs was reported in days characterized temperatures ≥95th percentile (OR 1.145, 95%CI 1.062-1.235), summer days (daily maximum ≥25°C , OR 1.093, 95%CI 1.042-1.146). On the contrary, no significant increased risk was found for OIs having a more severe prognosis (≥40 d or more; death). In conclusion, presented findings recommend policymakers to develop appropriate procedures and guidelines, in particular aimed to improve the compliance of younger CWs towards severe-hot daily temperatures.


Coronary artery superoxide production and nox isoform expression in human coronary artery disease.
Oxidative stress plays important role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). We aimed to determine the sources and selected molecular mechanisms of oxidative stress in CAD. We examined basal and NAD(P)H oxidase-mediated superoxide (O2*-) production using lucigenin chemiluminescence, ferricytochrome c and dihydroethidium fluorescence in human coronary arteries from 19 CAD and 17 non-CAD patients undergoing heart transplantation. NAD(P)H oxidase subunits and xanthine oxidase expression were measured. Superoxide production was greater in coronary arteries from patients with CAD, even in vessels without overt atherosclerotic plaques, and was doubled within branching points of coronary arteries. Studies using pharmacological inhibitors and specific substrates showed that NAD(P)H oxidases (60%) and xanthine oxidase (25%) are primary sources of O2*- in CAD. Losartan significantly inhibited superoxide production in coronary arteries. NAD(P)H oxidase activity and protein levels of the NADPH oxidase subunits p22phox, p67phox, and p47phox were significantly increased in CAD, as were mRNA levels for p22phox and nox2, and no NAD(P)H oxidase subunit mRNA levels correlated with NAD(P)H oxidase activity in vessels from individual patients. Activity and protein expression of xanthine oxidase were increased in CAD, whereas xanthine dehydrogenase levels were not changed. Increased expression and activity of NAD(P)H oxidase subunits and xanthine oxidase, in part mediated through angiotensin II and PKC-dependent pathways, are important mechanisms underlying increased oxidative stress in human coronary artery disease.


Incidence and trends of cutaneous malignancies in the Netherlands, 1989-2005.
Epidemiology of rare cutaneous malignancies in the general population is poorly documented. This descriptive study aimed to estimate the incidence and trends of all skin malignancies between 1989 and 2005. Data on skin tumors were extracted from the Netherlands Cancer registry (except for basal cell carcinoma (BCC) data-only available from Comprehensive Cancer Centre South) and categorized according to the International Classification of Diseases for Oncology, third edition, codes. Age-standardized incidence rates (European standardized population rate, ESR) per 100,000 person-years were calculated per year and for the period between 2001 and 2005. Estimated annual percentage changes (EAPCs) were estimated by Poisson regression models. A total of 356,620 skin tumors were diagnosed between 1989 and 2005. Excluding BCC, squamous cell carcinoma (SCC), and melanoma, the remaining skin tumors constituted about 2% of all skin malignancies. The incidence of melanoma showed the steepest increase (EAPC, 4.0%), and ESR was close to that observed for SCC (EAPC, 2.3%) between 2001 and 2005 (17.1 versus 19.6). Hematolymphoid tumors (ESR=0.74) were mainly cutaneous T-cell lymphomas (60.8%). No significant increases in incidence were observed for lymphomas, and appendageal, fibromatous, and myomatous carcinomas during 1989-2005. In addition to keratinocytic cancers and melanoma, there is a wide variety of skin tumors that constitute <2% of all skin malignancies. The incidence of UV-related skin tumors increased significantly and more steeply than did those of other skin malignancies.


A family intervention to reduce sexual risk behavior, substance use, and delinquency among newly homeless youth.
We evaluate the efficacy of a short family intervention in reducing sexual risk behavior, drug use, and delinquent behaviors among homeless youth. A randomized controlled trial of 151 families with a homeless adolescent aged 12 to 17 years. Between March 2006 and June 2009, adolescents were recruited from diverse sites in Southern California and were assessed at recruitment (baseline), and at 3, 6, and 12 months later. Families were randomly assigned to an intervention condition with five weekly home-based intervention sessions or a control condition (standard care). Main outcome measures reflect self-reported sexual risk behavior, substance use, and delinquent behaviors over the past 90 days. Sexual risk behavior (e.g., mean number of partners; p < .001), alcohol use (p = .003), hard drug use (p < .001), and delinquent behaviors (p = .001) decreased significantly more during 12 months in the intervention condition compared with the control condition. Marijuana use, however, significantly increased in the intervention condition compared with the control condition (p < .001). An intervention to reengage families of homeless youth has significant benefits in reducing risk over 12 months.


Optimal cue combination and landmark-stability learning in the head direction system.
Maintaining a sense of direction requires combining information from static environmental landmarks with dynamic information about self-motion. This is accomplished by the head direction system, whose neurons - head direction cells - encode specific head directions. When the brain integrates information in sensory domains, this process is almost always 'optimal' - that is, inputs are weighted according to their reliability. Evidence suggests cue combination by head direction cells may also be optimal. The simplicity of the head direction signal, together with the detailed knowledge we have about the anatomy and physiology of the underlying circuit, therefore makes this system a tractable model with which to discover how optimal cue combination occurs at a neural level. In the head direction system, cue interactions are thought to occur on an attractor network of interacting head direction neurons, but attractor dynamics predict a winner-take-all decision between cues, rather than optimal combination. However, optimal cue combination in an attractor could be achieved via plasticity in the feedforward connections from external sensory cues (i.e. the landmarks) onto the ring attractor. Short-term plasticity would allow rapid re-weighting that adjusts the final state of the network in accordance with cue reliability (reflected in the connection strengths), while longer term plasticity would allow long-term learning about this reliability. Although these principles were derived to model the head direction system, they could potentially serve to explain optimal cue combination in other sensory systems more generally.


Protection against squamous cell carcinoma and cervical adenocarcinoma afforded by cervical cytology screening: a cross-sectional study.
The objective of this study was to evaluate the impact of cervical cytology screening on the prevalence of cervical cytological results in women, as a function of age and test interval. This is a cross-sectional study of cytology screening data of 2,002,472 tests obtained from previously screened women and 217,826 tests from unscreened women. The central cytopathology laboratory database was analyzed. The tests were collected for screening purposes from Campinas metropolitan region, Brazil. A prevalence ratio (PR) with a 95% confidence interval was calculated for the screened women, in relation to the unscreened women, and for different tests intervals. Protection afforded by screening (1-PR) was calculated. For high-grade squamous intraepithelial lesion, the PR was 0.97 (0.83-1.13) for women aged 20 years or younger and 0.99 (0.86-1.14) for women aged 20 to 24 years, decreasing significantly in women aged 25 to 29 years (PR, 0.63 [0.52-0.76]). The PR for squamous cell carcinoma, adenocarcinoma in situ (AIS), and invasive adenocarcinoma showed a significant reduction in all age groups older than 30 years. For the age group ranging from 30 to 59 years, protection for squamous cell carcinoma, AIS, and invasive adenocarcinoma was 83% or higher for screening intervals from 1 to 5 years. Protective effect was not demonstrated for screening intervals longer than 5 years for AIS and invasive adenocarcinoma. Cytology screening is effective at preventing cytological high-grade squamous intraepithelial lesion, squamous cell carcinoma, AIS, and invasive adenocarcinoma. On the basis of cytological results, protection against AIS and invasive adenocarcinoma was observed with screening intervals shorter than 5 years. Cytological screening in women 25 years or younger should be critically evaluated.


Insomnia and hallucinations in the general population: Findings from the 2000 and 2007 British Psychiatric Morbidity Surveys.
Insomnia is common in people experiencing psychosis. It has been identified as a contributory cause of paranoia, but any causal relationship with hallucinations has yet to be established. We tested the hypotheses that insomnia i) has a cross-sectional association with hallucinations ii) predicts new inceptions of hallucinations and iii) that these associations remain after controlling for depression, anxiety, and paranoia. Data from the second (2000, N=8580) and third (2007, N=7403) British Psychiatric Morbidity Surveys were used to assess cross-sectional associations between insomnia and hallucinations. The 2000 dataset included an 18 month follow up of a subsample (N=2406) used to test whether insomnia predicted new inceptions of hallucinations. Insomnia was associated with hallucinations in both cross-sectional datasets. Mild sleep problems were associated with 2-3 times greater odds of reporting hallucinations, whilst chronic insomnia was associated with four times greater odds. Insomnia was also associated with increased odds of hallucinations occurring de novo over the next 18 months. These associations remained significant, although with smaller odds ratios, after controlling for depression, anxiety and paranoia. This is the first longitudinal evidence that insomnia is associated with the development of hallucinatory experiences. Effective treatment of insomnia may lessen the occurrence of hallucinations.


Translesional synthesis past acetylaminofluorene-derived DNA adducts catalyzed by human DNA polymerase kappa and Escherichia coli DNA polymerase IV.
Human DNA polymerase kappa (pol kappa) has a sequence significantly homologous with that of Escherichia coli DNA polymerase IV (pol IV). We used a truncated form of human pol kappa (pol kappaDeltaC) and full-length pol IV to explore the miscoding properties of these enzymes. Oligodeoxynucleotides, modified site-specifically with N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-AAF) and N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-AF), were used as DNA templates in primer extension reactions that included all four dNTPs. Reactions catalyzed by pol kappaDeltaC were partially blocked one base prior to dG-AAF or dG-AF, and also opposite both lesions. At higher enzyme concentrations, a significant fraction of primer was extended. Analysis of the fully extended reaction product revealed incorporation of dTMP opposite dG-AAF, accompanied by much smaller amounts of dCMP, dAMP, and dGMP and some one- and two-base deletions. The product terminating 3' to the adduct site contained AMP misincorporated opposite dC. On templates containing dG-AF, dAMP, dTMP, and dCMP were incorporated opposite the lesion in approximately equal amounts, together with some one-base and two-base deletions. Steady-state kinetics analysis confirmed the results obtained from primer extension reactions catalyzed by pol kappa. In contract, primer extension reactions catalyzed by pol IV were blocked effectively by dG-AAF and dG-AF. At high concentrations of pol IV, full-length products were formed containing primarily one- or two-base deletions with dCMP, the correct base, incorporated opposite dG-AF. The miscoding properties of pol kappa observed in this study are consistent with mutational spectra observed when plasmid vectors containing dG-AAF or dG-AF are introduced into simian kidney cells [Shibutani, S., et al. (2001) Biochemistry 40, 3717-3722], supporting a model in which pol kappa plays a role in translesion synthesis past acetylaminofluorene-derived lesions in mammalian cells.


Suboptimal health status and psychological symptoms among Chinese college students: a perspective of predictive, preventive and personalised health.
Suboptimal health status (SHS) is an intermediate health status between health and illness, a syndrome characterised by the perception of health complaints, general weakness and low energy. This study aimed to investigate the prevalence of SHS and the correlation between SHS and psychological symptoms among Chinese college students and to identify the SHS-related risk factors from the perspective of predictive, preventive and personalised medicine (PPPM). A cross-sectional study was conducted among 4119 college students who were enrolled from Taishan Medical University and Baoji Vocational and Technical College in the eastern and western areas of China. SHS levels of the participants were measured by an established self-reporting Suboptimal Health Status Questionnaire-25 (SHSQ-25). Psychosomatic conditions were estimated by the self-rating Symptom Checklist-90 (SCL-90) scale. Spearman correlation analysis was applied to analyse the relationship between SHSQ-25 scores and SCL-90 estimates. Logistic regression analysis was applied for multivariate analysis. The prevalence of SHS was 21.0% (864/4119), with 23.3% (701/3005) for female students and 14.6% (163/1114) for male students. The prevalence of general positive psychological symptom was 14.2% (586/4119), with 15.6% (470/3005) for female students and 10.4% (116/1114) for male students. A strong correlation was identified between SHS score and SCL-90 estimates, with the correlation coefficient (r) of 0.719. Logistic regression showed that variables significantly associated with SHS were somatisation (adjusted odds ratio (aOR) = 3.185, 95% confidence interval [CI] = 2.048-4.953), obsessive-compulsive (aOR = 3.518, 95% CI = 2.834-4.368), interpersonal sensitivity (aOR = 1.883, 95% CI = 1.439-2.463) and depression (aOR = 1.847, 95% CI = 1.335-2.554). Our findings confirm that there is a high prevalence of SHS among college students and there is a strong association between SHS and psychological symptoms among Chinese college students. High susceptibility of SHS occurs particularly in vulnerable groups: female students, sophomore students, medical students and students from rural area. Identification of SHS and prompt application of personalised psychological health-supporting activities will promote college students' health status.


Consumers are ready to accept the transition to online and electronic records if they can be assured of the security measures.
Healthcare has entered the electronic domain. This domain has improved data collection and storage abilities while allowing almost instantaneous access and results to data queries. Furthermore, it allows direct communication between healthcare providers and health consumers. The development of privacy, confidentiality, and security principles are necessary to protect consumers' interests against inappropriate access. Studies have shown that the health consumer is the important stakeholder in this process. With the international push toward electronic health records (EHRs), this article presents the importance of secure EHR systems from the public's perspective. To examine the public's perception of the security of electronic systems and report on how their perceptions can shape the building of stronger systems. A cross-sectional survey (September-November 2005) of people attending healthcare providers (n = 400) was conducted in the 4 major cities in New Zealand. Participants were surveyed on computer use, knowledge of EHR-proposed benefits and issues, security issues, and demographics. A total of 300 surveys were completed and returned (a 75% response rate), with 180 (60%) being women. One hundred eighty-eight (62.6%) had not heard of EHRs, with those who had heard of them indicating that they were a positive innovation in the health sector. However, 202 (73.3%) participants were highly concerned about the security and privacy of their health records. This feeling was further accentuated when participants were asked about security of electronic systems. Participants were worried about hackers (79.4%), vendor access (72.7%), and malicious software (68%). Participants were also introduced to various security systems, and in each case, over 80% of participants believed that these would make EHR systems more secure. A number of chi-square tests were carried out with each variable, and it was found that there were strong relationships between age, location, computer use, EHR knowledge, and the concern for privacy and the security of medical records (P < .05). The survey also showed that there was a very small difference (9.8%) between health consumers who believed that paper records are more secure than EHRs and those who believed otherwise. The findings showed that for the EHR to be fully integrating in the health sector, there are 2 main issues that need to be addressed: The security of the EHR system has to be of the highest level, and needs to be constantly monitored and updated. The involvement of the health consumer in the ownership and maintenance of their health record needs to be more proactive. The EHR aims to collect information to allow for "cradle to the grave" treatment; thus, the health consumer has to be seen as a major player in ensuring that this can happen correctly. The results from this study indicated that the consumer is ready to accept the transition, as long as one can be assured of the security of the system.


Coronary artery disease prevalence and outcome in patients hospitalized with acute heart failure: an observational report from seven Middle Eastern countries.
The purpose of this study was to report prevalence, clinical characteristics, precipitating factors, management and outcome of patients with coronary artery disease (CAD) among patients hospitalized with heart failure (HF) in seven Middle Eastern countries and compare them to non-CAD patients. Data were derived from Gulf CARE (Gulf aCute heArt failuRe rEgistry), a prospective multicenter study of 5005 consecutive patients hospitalized with acute HF during February-November 2012 in 7 Middle Eastern countries. The prevalence of CAD among Acute Heart Failure (AHF) patients was 60.2% and varied significantly among the 7 countries (Qatar 65.7%, UAE 66.6%, Kuwait 68.0%, Oman 65.9%, Saudi Arabia 62.5%, Bahrain 52.7% and Yemen 49.1%) with lower values in the lower income countries. CAD patients were older and more likely to have diabetes, hypertension, dyslipidemia and chronic kidney disease. Moreover, CAD patients were more likely to have history of cerebrovascular and peripheral vascular disease when compared to non-CAD patients. In-hospital mortality rates were comparable although CAD patients had more frequent re-hospitalization and worse long-term outcome. However, CAD was not an independent predictor of poor outcome. The prevalence of CAD amongst patients with HF in the Middle East is variable and may be related to healthcare sources. Regional and national studies are needed for assessing further the impact of various etiologies of HF and for developing appropriate strategies to combat this global concern.


Calorie and nutrient trends in large U.S. chain restaurants, 2012-2018.
Large chain restaurants reduced calories in their newly-introduced menu items from 2012 to 2015. The objective of this study was to provide updated calorie trends through 2018 and examine trends in the macronutrient composition of menu items across this time period. Data were obtained from the MenuStat project and include 66 of the 100 largest revenue generating U.S. chain restaurants (N = 28,238 items) that had data available in all years from 2012 to 2018. Generalized linear models were used to examine per-item calorie and nutrient changes (saturated fat, trans fat, unsaturated fat, sugar, non-sugar carbohydrates, protein, sodium) among (1) items on the menu in all years (common items) and (2) newly introduced items (2013-2018). Overall, there were no significant changes in calories or nutrients among common items from 2012 to 2018. Among all newly introduced items, calories (-120 kcals, -25%, p = 0.01; p-for-trend = 0.02), saturated fat (-3.4g, -41%, p<0.01, p-for-trend = 0.06), unsaturated fat (-4.5g, -37%, p = 0.02; p-for-trend = 0.04), non-sugar carbohydrates (-10.3g, -40%, p = 0.02, p-for-trend = 0.69), and protein (-4.3g, -25%, p = 0.04, p-for-trend = 0.02) declined. Newly introduced menu items in large chain restaurants have continued to decline in calories through 2018, which may help to reduce calorie intake. Other changes in macronutrient content were sporadic and not clearly toward improved dietary quality.


Opioid antagonists in the treatment of impulse-control disorders.
Symptoms of impulse-control disorders are generally refractory to psychotherapeutic or pharmacologic treatments. Recent study results suggest that opioid antagonists may reduce human urges, one of the core symptoms of impulse-control disorders. The author discusses the rationale for and the potential utility of the opioid antagonists in the treatment of impulse-control disorders. Work by preclinical and clinical investigators on the subject of motivation and its contextually relevant behavior is reviewed. The review includes the pharmacologic modulation of the motivation or drive and subsequent changes in behavior in animals and humans. On the basis of these reviews, the author prescribed naltrexone for up to 9 months to 15 patients who had impulse-control disorder, and 3 select cases are reported. Naltrexone was generally well tolerated, and there were no hepatic side effects. Naltrexone appears to reduce urge-related symptoms and decreases the problematic behaviors such as pathological gambling. The effect appears to be sustained. In general, 50 mg/day of naltrexone was not effective. Most patients required higher doses. Results were similar in the 12 other cases not reported here. Naltrexone may be of use in select impulse-control disorder patients. Other opioid antagonists such as nalmefene also need to be tested. Until controlled study data become available, the present report should be viewed as preliminary.


Intonation contrast in Cantonese speakers with hypokinetic dysarthria associated with Parkinson's disease.
Speech produced by individuals with hypokinetic dysarthria associated with Parkinson's disease (PD) is characterized by a number of features including impaired speech prosody. The purpose of this study was to investigate intonation contrasts produced by this group of speakers. Speech materials with a question-statement contrast were collected from 14 Cantonese speakers with PD. Twenty listeners then classified the productions as either questions or statements. Acoustic analyses of F0, duration, and intensity were conducted to determine which acoustic cues distinguished the production of questions from statements, and which cues appeared to be exploited by listeners in identifying intonational contrasts. The results show that listeners identified statements with a high degree of accuracy, but the accuracy of question identification ranged from 0.56% to 96% across the 14 speakers. The speakers with PD used similar acoustic cues as nondysarthric Cantonese speakers to mark the question-statement contrast, although the contrasts were not observed in all speakers. Listeners mainly used F0 cues at the final syllable for intonation identification. These data contribute to the researchers' understanding of intonation marking in speakers with PD, with specific application to the production and perception of intonation in a lexical tone language.


Comparing theories' performance in predicting violence.
The stakes of choosing the best theory as a basis for violence prevention and offender rehabilitation are high. However, no single theory of violence has ever been universally accepted by a majority of established researchers. Psychiatry, psychology and sociology are each subdivided into different schools relying upon different premises. All theories can produce empirical evidence for their validity, some of them stating the opposite of each other. Calculating different models with multivariate logistic regression on a dataset of N = 21,312 observations and ninety-two influences allowed a direct comparison of the performance of operationalizations of some of the most important schools. The psychopathology model ranked as the best model in terms of predicting violence right after the comprehensive interdisciplinary model. Next came the rational choice and lifestyle model and third the differential association and learning theory model. Other models namely the control theory model, the childhood-trauma model and the social conflict and reaction model turned out to have low sensitivities for predicting violence. Nevertheless, all models produced acceptable results in predictions of a non-violent outcome.


Comparative study of treatment interventions for patellar tendinopathy: a protocol for a randomised controlled trial.
Patellar tendinopathy is a degenerative disease of the patellar tendon, which affects athletes from a variety of sports, and is especially predominant in sports involving high-impact jumping. The aim of this study is to determine the additional effect of two interventions combined with eccentric exercise and compare which one is the most effective at short-term and long-term follow-up for patients with patellar tendinopathy. This study is a randomised controlled trial with blinded participants. Measurements will be carried out by a specially trained blinded assessor. A sample of 57 patients with a medical diagnosis of patellar tendinopathy will participate in this study and will be divided into three treatment groups. Eligible participants will be randomly allocated to receive either: (a) treatment group with percutaneous needle electrolysis, (b) treatment group with dry needling or (c) treatment group with placebo needling. In addition, all groups will perform eccentric exercise. Functionality and muscle strength parameters, pain, ultrasound appearances and patient perceived quality of life shall be evaluated using the Victorian Institute of Sports Assessment for patellar (VISA-P), jump tests, Visual Analogue Scale, ultrasound images and Short Form-36 (SF-36), respectively. Participants will be assessed at baseline, at 10 weeks and at 22 weeks after baseline. The expected findings will allow us to advance in the treatment of this injury, as they will help determine whether a needling intervention has additional effects on an eccentric exercise programme and whether any of the needling modalities is more effective than the other. This protocol has been approved by the Ethics Committee of Aragon (N° PI15/0017). The trial will be conducted in accordance with the Declaration of Helsinki. NCT02498795.


Analysis of surface electrocardiograms in atrial fibrillation: techniques, research, and clinical applications.
Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Neither the natural history of AF nor its response to therapy is sufficiently predictable by clinical and echocardiographic parameters. The purpose of this article is to describe technical aspects of novel electrocardiogram (ECG) analysis techniques and to present research and clinical applications of these methods for characterization of both the fibrillatory process and the ventricular response during AF. Atrial fibrillatory frequency (or rate) can reliably be assessed from the surface ECG using digital signal processing (extraction of atrial signals and spectral analysis). This measurement shows large inter-individual variability and correlates well with intra-atrial cycle length, a parameter which appears to have primary importance in AF maintenance and response to therapy. AF with a low fibrillatory rate is more likely to terminate spontaneously and responds better to antiarrhythmic drugs or cardioversion, whereas high-rate AF is more often persistent and refractory to therapy. Ventricular responses during AF can be characterized by a variety of methods, which include analysis of heart rate variability, RR-interval histograms, Lorenz plots, and non-linear dynamics. These methods have all shown a certain degree of usefulness, either in scientific explorations of atrioventricular (AV) nodal function or in selected clinical questions such as predicting response to drugs, cardioversion, or AV nodal modification. The role of the autonomic nervous system for AF sustenance and termination, as well as for ventricular rate responses, can be explored by different ECG analysis methods. In conclusion, non-invasive characterization of atrial fibrillatory activity and ventricular response can be performed from the surface ECG in AF patients. Different signal processing techniques have been suggested for identification of underlying AF pathomechanisms and prediction of therapy efficacy.


Occurrence of Grapevine leafroll-associated virus 1 in Two Ornamental Grapevine Cultivars in Washington State.
Roger's Red, an interspecific hybrid between wild grape (Vitis californica, native to northern California) and the V. vinifera cv. Alicante Bouschet (1), and Claret Vine (V. vinifera cv. Purpurea Nana) are grown for their ornamental value in home gardens and other settings. We collected potted grapevines of Roger's Red and Claret Vine showing dull green-to-scarlet red leaves from two different retail nurseries in the Richland-Kennewick area and Prosser, WA, respectively. Since these symptoms 'mimic' grapevine leafroll disease, we tested petiole samples from four grapevines per cultivar for a panel of grapevine-infecting viruses by single-tube one-step reverse transcription (RT)-PCR (4). All samples tested positive only for Grapevine leafroll-associated virus 1 (GLRaV-1; genus Ampelovirus, family Closteroviridae). To further confirm these results, total RNA was subjected to RT-PCR to amplify a portion of the heat shock protein 70 homolog (HSP70h), coat protein duplicate 2 (CPd2), and ORF 9 (p24) of GLRaV-1. RT was performed at 52°C for 60 min, followed by 35 cycles of PCR (30 s denaturation at 94°C, 45 s annealing at 55°C, and 30 s extension at 72°C) and a 5 min final extension step at 72°C. Primers specific to HSP70h (HSP70h/416F: 5'-CAGGCGTCGTTTGTACTGTG and HSP70h/955R: 5'-TCGGACAGCGTTTAAGTTCC), CPd2 (CPd2/F: 5'-GTTACGGCCCTTTGTTTATTATGG and CPd2/R: 5'-CGACCCCTTTATTGTTTGAGTATG) and ORF 9 (p24/F: 5'-CGATGGCGTCACTTATACCTAAG and p24/R (5'-CACACCAAATTGCTAGCGATAGC) were designed based on GLRaV-1 sequence (GenBank Accession No. AF195822) to amplify 540, 398, and 633 base pair (bp) DNA fragments, respectively. To verify that the amplified products were specific to the genome of GLRaV-1, the amplicons were cloned into pCR2.1 vector (Invitrogen Corp, Carlsbad, CA) and three independent clones for each amplicon were sequenced in both directions. Pairwise comparison of HSP70h (Accession Nos. HQ833472 and HQ833473), CPd2 (Accession Nos. HQ833474 and HQ833475), and p24 (Accession Nos. HQ833476 and HQ833477) sequences from Roger's Red and Claret Vine showed 100, 96, and 99% identities, respectively, between them, and 86 to 100, 80 to 97, and 86 to 90% nucleotide sequence identities, respectively, with corresponding sequences of GLRaV-1 isolates deposited in GenBank. We further confirmed the presence of GLRaV-1 in these two ornamental grape cultivars by double antibody sandwich-ELISA using commercially available antibodies (Bioreba AG, Reinach, Germany). Previous studies have reported the presence of GLRaV-2 and -3 (1,3) and Grapevine virus A and B (2,3) in Roger's Red. To our knowledge, this study represents the first report of the occurrence of GLRaV-1 in two Vitis species distributed as ornamental grapes. It is important to prevent virus spread via the supply of virus-tested ornamental grapevines by commercial nurseries. References: (1) G. S. Dangl et al. Am. J. Enol. Vitic. 61:266, 2010. (2) D. A. Golino et al. Phytopathology (Abstr.) 99(suppl.):S44, 2009. (3) V. Klaassen et al. Online publication. doi:10.1094/PDIS-09-10-0621. Plant Dis., 2011. (4) T. A. Mekuria et al. Phytopathology (Abstr.) 99(suppl.):S83, 2009.


Development and Application of Novel Caregiver Hygiene Behavior Measures Relating to Food Preparation, Handwashing, and Play Environments in Rural Kenya.
Exposure to fecal pathogens results in both acute and chronic sequalae in young children. Diarrhea causes nearly 20% of all under-five mortality, while even sub-clinical enteric infections may lead to growth shortfalls. Stunting affects nearly 165 million children globally and results in lifelong and intergenerational effects for the world's poorest populations. Caregiver hygiene behaviors, such as those surrounding handwashing and food preparation, play a critical role in exposure to fecal pathogens; standard metrics to assess these behaviors are warranted to provide a means of quantifying the impact these behaviors have on enteric infections and to evaluate the success or failure of interventions and programs. This paper documents the development of three novel caregiver hygiene behavior measures: hygienic food preparation and storage, handwashing at key times, and provision of a safe play environment for children under two years. We developed these measures using formative qualitative work, survey creation and deployment theoretically underpinned by the COM-B model of behavior change, and exploratory and confirmatory factor analysis. The final measure for hygienic food preparation and storage includes 10 items across two factors; the final measure for handwashing at key times includes 15 items across three factors; and the final measure for safe play environment contains 13 items across three factors. Future researchers may employ these measures to assess caregiver behaviors in other populations, identify specific behavioral dimensions that should be the focus of interventions, and evaluate interventions and programs.


Saffron in phytotherapy: pharmacology and clinical uses.
Saffron (stigmata of Crocus sativus L.) has been used for medicinal purposes for millennia. Throughout history, uses against cancer and depressive mood can regularly be identified. These applications have also been in the focus of modern research. Promising and selective anti-cancer effects have been observed in vitro and in vivo, but not yet in clinical trials. Antidepressant effects were found in vivo and in clinical pilot studies. Saffron extracts thus have the potential to make a major contribution to rational phytotherapy.


The concept of surgical operating list 'efficiency': a formula to describe the term.
While numerous reports have sought ways of improving the efficiency of surgical operating lists, none has defined 'efficiency'. We describe a formula that defines efficiency as incorporating three elements: maximising utilisation, minimising over-running and minimising cancellations on a list. We applied this formula to hypothetical (but realistic) scenarios, and our formula yielded plausible descriptions of these. We also applied the formula to 16 consecutive elective surgical lists from three gynaecology teams (two at a university hospital and one at a non-university hospital). Again, the formula gave useful insights into problems faced by the teams in improving their performance, and it also guided possible solutions. The formula confirmed that a team that schedules cases according to the predicted durations of the operations listed (i.e. the non-university hospital team) suffered fewer cancellations (median 5% vs 8% and 13%) and fewer list over-runs (6% vs 38% and 50%), and performed considerably more efficiently (90% vs 79% and 72%; p = 0.038) than teams that did not do so (i.e. those from the university hospital). We suggest that surgical list performance is more completely described by our formula for efficiency than it is by other conventional measures such as list utilisation or cancellation rate alone.


Autofluorescence Imaging for Evaluating Debridement in Military and Trauma Wounds.
Mechanisms for military injury have evolved in the past century. Debridement is the gold standard for preparing a clean wound bed, decreasing the bacterial load, and reducing the likelihood of infection. However, bacteria may continue to linger in these wounds. The MolecuLight i:X Imaging Device uses the principle of autofluorescence to detect bacteria under violet light. Thus, visualizing bacteria will not only guide clinicians in their management of the wound but it will also serve as a means of evaluating debridement efforts. We hope to improve traumatic wound management by targeting debridement and assessing its quality. We describe the use of the MolecuLight i:X to photograph wounds under standard and violet light in three patients. Images were captured before and after debridement. Microbiology swabs were collected to correlate the bacteria found in the images to the wounds. The post-debridement images demonstrate a marked decrease or complete removal of bacteria. The microbiology swabs confirmed the pre-debridement presence of bacteria. The MolecuLight i:X shows promise for debridement evaluation. The use of the MolecuLight i:X may reduce the likelihood of infection, thus having positive implications for military and trauma wounds.


Restoring function after spinal cord injury: towards clinical translation of experimental strategies.
Spinal cord injury is currently incurable and treatment is limited to minimising secondary complications and maximising residual function by rehabilitation. Improved understanding of the pathophysiology of spinal cord injury and the factors that prevent nerve and tissue repair has fuelled a move towards more ambitious experimental treatments aimed at promoting neuroprotection, axonal regeneration, and neuroplasticity. By necessity, these new options are more invasive. However, in view of recent advances in spinal cord injury research and demand from patients, clinicians, and the scientific community to push promising experimental treatments to the clinic, momentum and optimism exist for the translation of candidate experimental treatments to clinical spinal cord injury. The ability to rescue, reactivate, and rewire spinal systems to restore function after spinal cord injury might soon be within reach.


Importance of databases for technology assessment.
The data indispensable for carrying out the comprehensive, multi-faceted process of medical technology assessment (MTA) should be collected from a variety of sources. The authors distinguish between type "A" general data, useful for assessment but collected without this specific aim, and type "B" data. Registries of health care procedures or of diseases, as well as clinical data bases are quoted as examples of type "B" data, specifically relating to MTA. Since demographic methods are of importance for the evaluation of long-term effects of medical technologies, examples of sources of type "A" data are presented. Their significance for health policy making is discussed.


[Computed tomography (CT) angiography with multidetector row helical CT for detecting spinal dural arteriovenous fistula].
A 59-year-old man had have dysuria and left thigh pain for 2 months. He also experienced transient weakness of both legs twice, which recovered within a few hours. One month ago, he had bowel disturbance. Lumbar MRI showed a swelling of the conus medullaris. Enlarged and tortuous vessels behind the spinal cord on lumbar MRA and CT myelography was demonstrated. Though angiogram through intercostal and lumbar arteries revealed no abnormal findings, CT angiography with multidetector row helical CT (MDCT) showed abnormal vessel in intradural space at sacral level. Angiogram through left internal iliac artery revealed abnormal vessel fed by branches of the lateral sacral artery at the early arterial phase. Thus, diagnosis of dural arteriovenous fistula (DAVF) at the left S1 level was confirmed. It was indicated that CT angiography with MDCT was useful in detecting spinal DAVF especially at sacral level.


Critical Role of Zur and SmtB in Zinc Homeostasis of Mycobacterium smegmatis.
Zinc homeostasis is crucial for bacterial cells, since imbalances affect viability. However, in mycobacteria, knowledge of zinc metabolism is incomplete. Mycobacterium smegmatis (MSMEG) is an environmental, nonpathogenic Mycobacterium that is widely used as a model organism to study mycobacterial metabolism and pathogenicity. How MSMEG maintains zinc homeostasis is largely unknown. SmtB and Zur are important regulators of bacterial zinc metabolism. In mycobacteria, these regulators are encoded by an operon, whereas in other bacterial species, SmtB and Zur are encoded on separate loci. Here, we show that the smtB-zur operon is consistently present within the genus Mycobacterium but otherwise found only in Nocardia, Saccharothrix, and Corynebacterium diphtheriae By RNA deep sequencing, we determined the Zur and SmtB regulons of MSMEG and compared them with transcriptional responses after zinc starvation or excess. We found an exceptional genomic clustering of genes whose expression was strongly induced by zur deletion and zinc starvation. These genes encoded zinc importers such as ZnuABC and three additional putative zinc transporters, including the porin MspD, as well as alternative ribosomal proteins. In contrast, only a few genes were affected by deletion of smtB and zinc excess. The zinc exporter ZitA was most prominently regulated by SmtB. Moreover, transcriptional analyses in combination with promoter and chromatin immunoprecipitation assays revealed a special regulation of the smtB-zur operon itself: an apparently zinc-independent, constitutive expression of smtB-zur resulted from sensitive coregulation by both SmtB and Zur. Overall, our data revealed yet unknown peculiarities of mycobacterial zinc homeostasis.IMPORTANCE Zinc is crucial for many biological processes, as it is an essential cofactor of enzymes and a structural component of regulatory and DNA binding proteins. Hence, all living cells require zinc to maintain constant intracellular levels. However, in excess, zinc is toxic. Therefore, cellular zinc homeostasis needs to be tightly controlled. In bacteria, this is achieved by transcriptional regulators whose activity is mediated via zinc-dependent conformational changes promoting or preventing their binding to DNA. SmtB and Zur are important antagonistically acting bacterial regulators in mycobacteria. They sense changes in zinc concentrations in the femtomolar range and regulate transcription of genes for zinc acquisition, storage, and export. Here, we analyzed the role of SmtB and Zur in zinc homeostasis in Mycobacterium smegmatis Our results revealed novel insights into the transcriptional processes of zinc homeostasis in mycobacteria and their regulation.


Symbolic play of preschoolers with severe communication impairments with autism and other developmental delays: more similarities than differences.
Children with autism are often described as having deficient play skills, particularly symbolic play. We compared the play of 35 children with autism to 38 children with other developmental delays. All children were preschool-age and produced less than 20 different words. Results indicated no significant differences across the two groups in their play. Children with autism engaged in more conventional play, that is, putting objects together according to how the toys were constructed (e.g., pieces in a puzzle, lid on a teapot). Results also indicated high correlations between play, language, and cognitive measures. Findings indicate that play relates to language and cognitive levels yet may not discriminate children with autism and children with other developmental delays early in their development.