Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease).
The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80-85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery.


Predicting the pathogenicity of RPE65 mutations.
To assist in distinguishing disease-causing mutations from nonpathogenic polymorphisms, we developed an objective algorithm to calculate an "estimate of pathogenic probability" (EPP) based on the prevalence of a specific variation, its segregation within families, and its predicted effects on protein structure. Eleven missense variations in the RPE65 gene were evaluated in patients with Leber congenital amaurosis (LCA) using the EPP algorithm. The accuracy of the EPP algorithm was evaluated using a cell-culture assay of RPE65-isomerase activity The variations were engineered into plasmids containing a human RPE65 cDNA and the retinoid isomerase activity of each variant was determined in cultured cells. The EPP algorithm predicted eight substitution mutations to be disease-causing variants. The isomerase catalytic activities of these RPE65 variants were all less than 6% of wild-type. In contrast, the EPP algorithm predicted the other three substitutions to be non-disease-causing, with isomerase activities of 68%, 127%, and 110% of wild-type, respectively. We observed complete concordance between the predicted pathogenicities of missense variations in the RPE65 gene and retinoid isomerase activities measured in a functional assay. These results suggest that the EPP algorithm may be useful to evaluate the pathogenicity of missense variations in other disease genes where functional assays are not available.


Three-Dimensional Electronic Network Assisted by TiN Conductive Pillars and Chemical Adsorption to Boost the Electrochemical Performance of Red Phosphorus.
The practical application of red phosphorus (P) for sodium-ion batteries (SIBs) is retarded by its poor reversibility and its unstable cycling life derived from its poor conductivity and huge volume expansion. Graphene is considered as an ideal matrix to remedy these weaknesses due to its excellent conductivity and two-dimensional structure. Its π-π restacking causes spatial collapse, however, meaning that graphene cannot effectively buffer volume expansion. Herein, multifunctional TiN is introduced into a P composite to fix this issue. TiN acts as conductive pillars, electron transfer bridges, and a chemical adsorbent of phosphorus in the composite, to prevent the graphene nanoplates from restacking, to bridge gaps between the graphene nanoplates, and to chemically adsorb the P, resulting in the formation of a three-dimensional electronic network and endowing the pulverized P particles with good contact with the conductive matrix to avoid forming insulating "dead P". Consequently, the P composite presents excellent performance for SIBs.


Wnt signaling and Loxl2 promote aggressive osteosarcoma.
Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. Using genetically modified mouse models (GEMMs), we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2. c-Fos/AP-1 directly regulates the expression of the Wnt ligands Wnt7b and Wnt9a in OS cells through promoter binding, and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2. Concordantly, inhibition of Wnt ligand secretion by inactivating the Wnt-less (Wls) gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS. Wls-deficient osteosarcomas proliferate less, are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers. Importantly, Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models. Finally, OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies. Congruently, a strong correlation between c-FOS, LOXL2 and WNT7B/WNT9A expression is observed in human OS samples, and c-FOS/LOXL2 co-expression correlates with OS aggressiveness and decreased patient survival. Therefore, therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric, recurrent, and metastatic OS.


Reducing pain during the removal of adhesive and adherent products.
Silicone Medical Adhesive Removers (SMARs) have proved a valuable addition to formularies. In the absence of SMARs, trauma following removal of adhesive dressings, ostomy products, retention tapes and monitoring equipment can lead to skin stripping or extension of existing wounds. Those at increased risk of skin stripping include groups such as older people, premature infants and neonates and those with skin fragility syndromes. Appeel® Sterile Sachet (CliniMed) is a sterile SMAR in liquid form supplied in a single-use sachet. The addition of this sterile product to the existing Appeel range of wipes and aerosols provides an adhesive remover suitable for use on broken skin. Unlike delivery from an aerosol, Appeel Sterile Sachet does not feel cold on application, a sensation which can be confused with pain. This article discusses the value of SMARs and in particular the advantages of using the single-use Appeel Sterile Sachet.


A collaborative approach to the implementation of a structured clinical handover tool (iSoBAR), within a hospital setting in metropolitan Western Australian: A mixed methods study.
The aim of this study was to determine the effectiveness of an education intervention for the implementation of the clinical handover tool iSoBAR, in an acute setting. A quantitative, descriptive survey design, using pre and post survey data before and after the implementation of an education intervention was used. Twenty nine nurses, doctors and allied health personnel employed at the study site participated in the study. The educational intervention consisted of an electronic presentation plus simulated video recorded exemplars of clinical handover. Outcome measures were the efficacy of the education intervention on the confidence of practitioners using the iSoBAR handover tool. Participants' understanding of the iSoBAR tool using Mann-Whitney U test was 2.54 pre-intervention and 4.32 post-intervention. Confidence in using the tool also increased post educational intervention from 2.7 (pre-intervention) to 4.07 (post-intervention). Focus groups identified several factors relating to the implementation of iSoBAR, creating two dominant themes: challenges concerning patient factors and change management processes and systems. Opportunities were identified: Practice enhancement, patient centred care, professional practice, and grassroots initiatives. The use of an interprofessional educational program increased the confidence and understanding of a range of health care practitioners when using the clinical handover tool iSoBAR.


Risk factors for wound infection in surgery for spinal metastasis.
Wound infection rates are generally higher in patients undergoing surgery for spinal metastasis. Risk factors of wound infection in these patients are poorly understood. To identify demographic and clinical variables that may be associated with patients experiencing a higher wound infection rate. Retrospective study with prospectively collected data of spinal metastasis patients operated consecutively at a University Teaching Hospital, adult spine division which is a tertiary referral centre for complex spinal surgery. Ninety-eight patients were all surgically treated, consecutively from January 2009 to September 2011. Three patients had to be excluded due to inadequate data. Physiological measures, with presence or absence of microbiologically proven infection. Various demographic and clinical data were recorded, including age, serum albumin level, blood total lymphocyte count, corticosteroid intake, Malnutrition Universal Screening Tool (MUST) score, neurological disability, skin closure material used, levels of surgery and administration of peri-operative corticosteroids. No funding was received from any sources for this study and as far as we are aware, there are no potential conflict of interest-associated biases in this study. Higher probabilities of infection were associated with low albumin level, seven or more levels of surgery, use of delayed/non-absorbable skin closure material and presence of neurological disability. Of these factors, levels of surgery were found to be statistically significant at the 5 % significance level. Risk of infection is high (17.9 %) in patients undergoing surgery for spinal metastasis. Seven or more vertebral levels of surgery increase the risk of infection significantly (p < 0.05). Low albumin level and presence of neurological disability appear to show a trend towards increased risk of infection. Use of absorbable skin closure material, age, low lymphocyte count, peri-operative administration of corticosteroids and MUST score do not appear to influence the risk of infection.


Electrophysiological and anatomical factors determine arrhythmic risk in acute myocardial ischaemia and its modulation by sodium current availability.
Acute myocardial ischaemia caused by coronary artery disease is one of the main causes of sudden cardiac death. Even though sodium current blockers are used as anti-arrhythmic drugs, decreased sodium current availability, also caused by mutations, has been shown to increase arrhythmic risk in ischaemic patients. The mechanisms are still unclear. Our goal is to exploit perfect control and data transparency of over 300 high-performance computing simulations to investigate arrhythmia mechanisms in acute myocardial ischaemia with variable sodium current availability. The human anatomically based torso-biventricular electrophysiological model used includes representation of realistic ventricular anatomy and fibre architecture, as well as ionic to electrocardiographic properties. Simulations show that reduced sodium current availability increased arrhythmic risk in acute regional ischaemia due to both electrophysiological (increased dispersion of refractoriness across the ischaemic border zone) and anatomical factors (conduction block from the thin right ventricle to thick left ventricle). The asymmetric ventricular anatomy caused high arrhythmic risk specifically for ectopic stimuli originating from the right ventricle and ventricular base. Increased sodium current availability was ineffective in reducing arrhythmic risk for septo-basal ectopic excitation. Human-based multiscale modelling and simulations reveal key electrophysiological and anatomical factors determining arrhythmic risk in acute ischaemia with variable sodium current availability.


A theoretical study of diffusional transport over the alveolar surfactant layer.
In this communication, we analyse the passage of oxygen and carbon dioxide over the respiratory membrane. The lung surfactant membrane at the alveolar interface can have a very special arrangement, which affects the diffusional transport. We present a theoretical model for the diffusion of small molecules in membranes with a complex structure, and we specifically compare a membrane composed of a tubular bilayer network with a membrane consisting of a stack of bilayers. Oxygen and carbon dioxide differ in terms of their solubility in the aqueous and the lipid regions of the membrane, and we show that this difference clearly influences their transport properties in the different membrane structures. During normal respiration, the rate-limiting step for carbon dioxide transport is in the gas phase of the different compartments in the lung. For oxygen, on the other hand, the rate is limited by the transport between alveoli and the capillary blood vessels, including the lung surfactant membrane. In a membrane with a structure of a continuous tubular lipid network, oxygen transport is facilitated to a significant extent compared with the structure of aligned lipid bilayers. The model calculations in the present study show that transport of oxygen through the tubular structure is indeed ca 30 per cent faster than transport through a membrane composed of stacked bilayers. The tubular network will also facilitate the transport of apolar substances between the gas phase and the blood. Important examples are ethanol and other volatile liquids that can leave the blood through the lungs, and gaseous anaesthetics or volatile solvents that are inhaled. This exemplifies a new physiological role of a tubular lipid network in the lung surfactant membrane.


Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.
Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%-6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%-4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%-13.3%) in children with a merged genetic score of >14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%-4.9%, P < 0.001) in children with a genetic score of ≤14.4 (n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%-9.9%) in children with a merged score of >14.4 compared with 2.7% (95% CI 1.9%-3.6%) in children with a score of ≤14.4 (P < 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%-54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%-60.0%), respectively, had a score >14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case-control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials.


Defining meal requirements for protein to optimize metabolic roles of amino acids.
Dietary protein provides essential amino acids (EAAs) for the synthesis of new proteins plus an array of other metabolic functions; many of these functions are sensitive to postprandial plasma and intracellular amino acid concentrations. Recent research has focused on amino acids as metabolic signals that influence the rate of protein synthesis, inflammation responses, mitochondrial activity, and satiety, exerting their influence through signaling systems including mammalian/mechanistic target of rapamycin complex 1 (mTORC1), general control nonrepressed 2 (GCN2), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), serotonin, and insulin. These signals represent meal-based responses to dietary protein. The best characterized of these signals is the leucine-induced activation of mTORC1, which leads to the stimulation of skeletal muscle protein synthesis after ingestion of a meal that contains protein. The response of this metabolic pathway to dietary protein (i.e., meal threshold) declines with advancing age or reduced physical activity. Current dietary recommendations for protein are focused on total daily intake of 0.8 g/kg body weight, but new research suggests daily needs for older adults of ≥1.0 g/kg and identifies anabolic and metabolic benefits to consuming at least 20-30 g protein at a given meal. Resistance exercise appears to increase the efficiency of EAA use for muscle anabolism and to lower the meal threshold for stimulation of protein synthesis. Applying this information to a typical 3-meal-a-day dietary plan results in protein intakes that are well within the guidelines of the Dietary Reference Intakes for acceptable macronutrient intakes. The meal threshold concept for dietary protein emphasizes a need for redistribution of dietary protein for optimum metabolic health.


Subcortical Brain Development in Autism and Fragile X Syndrome: Evidence for Dynamic, Age- and Disorder-Specific Trajectories in Infancy.
Previous research has demonstrated that the amygdala is enlarged in children with autism spectrum disorder (ASD). However, the precise onset of this enlargement during infancy, how it relates to later diagnostic behaviors, whether the timing of enlargement in infancy is specific to the amygdala, and whether it is specific to ASD (or present in other neurodevelopmental disorders, such as fragile X syndrome) are all unknown. Longitudinal MRIs were acquired at 6-24 months of age in 29 infants with fragile X syndrome, 58 infants at high likelihood for ASD who were later diagnosed with ASD, 212 high-likelihood infants not diagnosed with ASD, and 109 control infants (1,099 total scans). Infants who developed ASD had typically sized amygdala volumes at 6 months, but exhibited significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen's d=0.56) compared with all other groups. Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the infants were diagnosed with ASD. Infants with fragile X syndrome had a persistent and significantly enlarged caudate volume at all ages between 6 and 24 months (d=2.12), compared with all other groups, which was significantly associated with greater repetitive behaviors. This is the first MRI study comparing fragile X syndrome and ASD in infancy, demonstrating strikingly different patterns of brain and behavior development. Fragile X syndrome-related changes were present from 6 months of age, whereas ASD-related changes unfolded over the first 2 years of life, starting with no detectable group differences at 6 months. Increased amygdala growth rate between 6 and 12 months occurs prior to social deficits and well before diagnosis. This gradual onset of brain and behavior changes in ASD, but not fragile X syndrome, suggests an age- and disorder-specific pattern of cascading brain changes preceding autism diagnosis.


DNA barcoding of marine copepods: assessment of analytical approaches to species identification.
More than 2,500 species of copepods (Class Maxillopoda; Subclass Copepoda) occur in the marine planktonic environment. The exceptional morphological conservation of the group, with numerous sibling species groups, makes the identification of species challenging, even for expert taxonomists. Molecular approaches to species identification have allowed rapid detection, discrimination, and identification of species based on DNA sequencing of single specimens and environmental samples. Despite the recent development of diverse genetic and genomic markers, the barcode region of the mitochondrial cytochrome c oxidase subunit I (COI) gene remains a useful and - in some cases - unequaled diagnostic character for species-level identification of copepods. This study reports 800 new barcode sequences for 63 copepod species not included in any previous study and examines the reliability and resolution of diverse statistical approaches to species identification based upon a dataset of 1,381 barcode sequences for 195 copepod species. We explore the impact of missing data (i.e., species not represented in the barcode database) on the accuracy and reliability of species identifications. Among the tested approaches, the best close match analysis resulted in accurate identification of all individuals to species, with no errors (false positives), and out-performed automated tree-based or BLAST based analyses. This comparative analysis yields new understanding of the strengths and weaknesses of DNA barcoding and confirms the value of DNA barcodes for species identification of copepods, including both individual specimens and bulk samples. Continued integrative morphological-molecular taxonomic analysis is needed to produce a taxonomically-comprehensive database of barcode sequences for all species of marine copepods.


Dynamics of cytoplasmic organelles in the cell cycle of the fission yeast Schizosaccharomyces pombe: three-dimensional reconstruction from serial sections.
Changes in the ultrastructure of the fission yeast Schizosaccharomyces pombe during the cell division cycle were analyzed by three-dimensional reconstruction of serial section electron micrographs of freeze-substituted cells. Cytoplasmic vesicles were found at the cell ends during interphase and at the equatorial zone of cells undergoing cytokinesis. Filasomes behaved in a similar but temporally retarded way to vesicles. Microfilament(mf)-associated granules were found attached to the plasma membrane at the growing ends. Microfilaments were identified against the plasma membrane and adjacent to developing septa. From these observations it is suggested that mf-associated structures such as filasomes constitute dense knots of actin network that function in localized cell wall growth by controlling the deposition of cytoplasmic vesicles. Dictyosomes occur as tubular and fenestrated cisternae with associated cytoplasmic vesicles. They were distributed uniformly in the cytoplasm and did not change significantly during the cell cycle. Changes in the three-dimensional localization of cytoplasmic microtubules and mitochondria are also described.


Reduction in spinal-induced hypotension with ondansetron in parturients undergoing caesarean section: a double-blind randomised, placebo-controlled study.
Subarachnoid block is the preferred method of anaesthesia for caesarean section, but is associated with hypotension and bradycardia, which may be deleterious to both parturient and baby. Animal studies suggest that in the presence of decreased blood volume, 5-HT may be an important factor inducing the Bezold Jarisch reflex via 5-HT3 receptors located in intracardiac vagal nerve endings. In this study, we evaluated the effect of ondansetron, as a 5-HT3 receptor antagonist, on the haemodynamic response following subarachnoid block in parturients undergoing elective caesarean section. Fifty-two parturients scheduled for elective caesarean section were randomly allocated into two groups. Before induction of spinal anaesthesia Group O (n=26) received intravenous ondansetron 4 mg; Group S (n=26) received normal saline. Blood pressure, heart rate and vasopressor requirements were assessed. Decreases in mean arterial pressure were significantly lower in Group O than Group S from 14 min until 35 min. Patients in Group O required significantly less vasopressor (P=0.009) and had significantly lower incidences of nausea and vomiting (P=0.049). Ondansetron 4 mg, given intravenously 5 min before subarachnoid block reduced hypotension and vasopressor use in parturients undergoing elective caesarean section.


A new system identification approach to identify genetic variants in sequencing studies for a binary phenotype.
We propose in this paper a set-valued (SV) system model, which is a generalized form of logistic (LG) and Probit (Probit) regression, to be considered as a method for discovering genetic variants, especially rare genetic variants in next-generation sequencing studies, for a binary phenotype. We propose a new SV system identification method to estimate all underlying key system parameters for the Probit model and compare it with the LG model in the setting of genetic association studies. Across an extensive series of simulation studies, the Probit method maintained type I error control and had similar or greater power than the LG method, which is robust to different distributions of noise: logistic, normal, or t distributions. Additionally, the Probit association parameter estimate was 2.7-46.8-fold less variable than the LG log-odds ratio association parameter estimate. Less variability in the association parameter estimate translates to greater power and robustness across the spectrum of minor allele frequencies (MAFs), and these advantages are the most pronounced for rare variants. For instance, in a simulation that generated data from an additive logistic model with an odds ratio of 7.4 for a rare single nucleotide polymorphism with a MAF of 0.005 and a sample size of 2,300, the Probit method had 60% power whereas the LG method had 25% power at the α = 10(-6) level. Consistent with these simulation results, the set of variants identified by the LG method was a subset of those identified by the Probit method in two example analyses. Thus, we suggest the Probit method may be a competitive alternative to the LG method in genetic association studies such as candidate gene, genome-wide, or next-generation sequencing studies for a binary phenotype.


Zoonotic Pathogen Seroprevalence in Cattle in a Wildlife-Livestock Interface, Kenya.
A cross-sectional study was conducted to determine the seroprevalence of Brucella spp. and Leptospira spp. and risk factors of exposure in cattle in three zones with varying land use types and wildlife-livestock interactions. Five villages were selected purposively; two in areas with intensive livestock-wildlife interactions (zone 1), another two in areas with moderate livestock-wildlife interactions (zone 2) and one in areas where wildlife-livestock interactions are rarer (zone 3). Sera samples were collected from 1170 cattle belonging to 390 herds in all the zones and tested for antibodies against Brucella abortus and Leptospira interrogans serovar hardjo using ELISA kits. Data on putative risk factors for seropositivity of these pathogens in cattle were collected using a questionnaire. The overall apparent animal-level seroprevalence of brucellosis and leptospirosis was, respectively, 36.9% (95% CI 34.1-39.8) and 23.5% (95% CI 21.1-26.0). Brucella spp. seroprevalence was higher in zone 1 than in zones 2 and 3 (χ2 = 25.1, df = 2, P < 0.001). Zones 1 and 2 had significantly higher Leptospira spp. seroprevalence than zone 3 (χ2 = 7.0, df = 2, P = 0.029). Results of multivariable analyses identified animal sex (female) and zones (high interface area) as significant predictors (P < 0.05) of animal-level seropositivity of Brucella spp. For Leptospira spp., important predictors of animal-level seropositivity were animal sex (female), zones (moderate interface area) and herds utilizing a communal grazing reserve. The seroprevalences of Brucella spp. and Leptospira spp. in cattle were higher in areas with moderate to high wildlife-livestock interactions than those with rare interactions.


Intraperitoneal Ropivacaine with Dexmedetomidine or Fentanyl for Postoperative Analgesia Following Laparoscopic Cholecystectomy: A Comparative Randomized Trial.
Intraperitoneal local anesthetic is an effective analgesic approach following laparoscopic cholecystectomy. The aim of the present study was to compare the antinociceptive effects of intraperitoneal ropivacaine plus fentanyl with ropivacaine plus dexmedetomidine in patients undergoing laparoscopic cholecystectomy. This was randomized, prospective, double-blinded, observational clinical study. A total of 80 patients, undergoing elective laparoscopic cholecystectomy under general anesthesia were randomly assigned to one of the two equal groups to receive either of the following: Group RF (n = 40) were given 30 mL of 0.2% ropivacaine combined with 1 μg/kg fentanyl (diluted in 2 mL normal saline) and Group RD (n = 40) were given 30 mL of 0.2% ropivacaine combined with 1 μg/kg dexmedetomidine (diluted in 2 mL normal saline) through trocars. The quality of analgesia was assessed using visual analog scale score (VAS). Time to the first request of analgesia, the total dose of analgesic in the first 24 h and adverse effects were noted. The data were analyzed with the Students' t-test and Chi-square test. VAS score at different time intervals, overall VAS in 24 h was significantly lower (1.68 ± 0.46 vs. 4.47 ± 0.94), time to first request of analgesia (min) was longest (122.7 ± 24.5 vs. 89.3 ± 13.2) and total analgesic consumption (mg) was lowest (95.3 ± 15.6 vs. 135.7 ± 75.1) in RD group than in RF group. The antinociceptive effect of the intraperitoneal instillation of ropivacaine in combination with dexmedetomidine is superior to ropivacaine combined with fentanyl.


Overview of programmes for the assessment of risks to the environment from ionising radiation and hazardous chemicals.
Within the FASSET project, a review of existing programmes for the assessment of environmental risks from radioactive or hazardous substances was carried out in order to identify appropriate aspects that could be incorporated into the FASSET framework. The review revealed a number of different approaches, arising from the need to balance the information value of the assessment against the availability of data and the need to keep the assessment manageable. Most of the existing assessment programmes fit into a three-phase approach to environmental risk assessment: problem formulation, assessment and risk characterisation. However, the emphasis on particular assessment phases varies between programmes. The main differences between the different programmes are: the degree of specificity to a particular site, the level of detail of the assessment, the point at which a comparison is made between a criterion intended to represent 'what is acceptable' and a measured or predicted quantity, the choice of end-point for the assessment and the relationship between measurement end-points and assessment end-points. The existing assessment programmes are based on a similar general structure, which is suitable for use as a basis for the FASSET framework. However, certain aspects of the assessment of exposure and effects of ionising contaminants, e.g. dosimetry, require further development before incorporation into such a framework.


Integrating County-Level Socioeconomic Data for COVID-19 Forecasting in the United States.
Goal: The United States (US) is currently one of the countries hardest-hit by the novel SARS-CoV-19 virus. One key difficulty in managing the outbreak at the national level is that due to the US' diversity, geographic spread, and economic inequality, the COVID-19 pandemic in the US acts more as a series of diverse regional outbreaks rather than a synchronized homogeneous one. Method: In order to determine how to assess regional risk related to COVID-19, a two-phase modeling approach is developed while considering demographic and economic criteria. First, an unsupervised clustering technique, specifically [Formula: see text]-means, is employed to group US counties based on demographic and economic similarities. Then, time series forecasting of each cluster of counties is developed to assess the short-run viral transmissibility risk. Results: To this end, we test ARIMA and Seasonal Trend Random Walk forecasts to determine which is more appropriate for modeling the spread and lethality of COVID-19. From our analysis, we then utilize the superior ARIMA models to forecast future COVID-19 trends in the clusters, and present the areas in the US which have the highest COVID-19 related risk heading into the winter of 2020. Conclusion: Including sub-national socioeconomic characteristics to data-driven COVID-19 infection and fatality forecasts may play a key role in assessing the risk associated with changes in infection patterns at the national level.


Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells.
We studied the kinetics of corticotropin (ACTH) induction of mitochondrial cytochromes P450scc and P450c11 and their electron transport proteins, adrenodoxin and adrenodoxin reductase, in bovine adrenal cortex cells in primary culture. The mRNA levels of these enzymes increase and reach a peak within 3-12 h after ACTH addition. The protein levels of adrenodoxin reductase and P450scc show an increase only nearly 24 h after ACTH addition. After ACTH addition, the intracellular level of cAMP reaches maximal levels within 5 min, and then decreases gradually over 60 min. Hence, we examined the effect of a pulse of ACTH or cAMP analogs on enzyme and mRNA levels. Exposure of the cells to ACTH for 1-2 h was sufficient for maximal induction of the enzymes and P450scc mRNA. In contrast, the induction of the enzymes and the mRNA by cAMP analogs or forskolin required the continuous presence of these agents for over 12 h. But, these agents stimulated cortisol secretion to the medium quickly, indicating that they can activate some intracellular processes while not showing any effect on enzyme induction. The absence of any effect of prolonged cAMP pulses on enzyme and mRNA levels weakens the previous hypothesis that cAMP is the sole second messenger for the ACTH induction of steroidogenic enzymes in adrenal cortex cells. The inductive ability of a brief pulse of ACTH indicates that ACTH can rapidly initiate a series of reactions that result in enzyme induction many hours later.


Preventing fall-from-height injuries in construction: Effectiveness of a regulatory training standard.
A regulatory training standard for construction workers using fall protection equipment became mandatory in 2015 in the province of Ontario, Canada. By the end of the transition period in 2017, 418,000 workers had been trained to the new standard. Two primary research questions were posed: (1) To what extent does the WAH training affect practices at the worksite? and (2) Has there been a change in the incidence of fall-from-height injuries coincident with the introduction of the WAH Training Standard? A longitudinal survey of 633 learners was conducted in 2017 at one-, four- and seven-week post-training. A quasi-experiment estimated the incidence of lost-time injuries attributed to falls from heights in 2017 compared to 2012-2014 for a census of construction workers insured for work disability in Ontario, Canada. Learners self-reported substantial increases in knowledge of and improvements in safe work practices when working at heights. The incidence rate of lost-time claim injuries attributed to falls targeted by the training declined by 19.6% (95% CI: 10.7, -27.6), compared to corresponding declines of 2.1% (95% CI: -6.3, 9.9) for other fall injuries and 7.2% (95% CI: 1.8, 12.3) for non-fall traumatic injuries. The observed decline was largest among the smallest employers (<5 full-time equivalent employees). The evaluation findings provide consistent support for a conclusion that the mandatory training standard was effective in reducing the incidence of injuries targeted by the training. However, the effects were modest and did not eliminate the problem. Practical application: A mandatory training standard should be considered as one approach to preventing traumatic injuries. However, other approaches higher in the hierarchy of risk controls should also be considered.


Organic Acids Regulation of Chemical-Microbial Phosphorus Transformations in Soils.
We have used an integrated approach to study the mobility of inorganic phosphorus (P) from soil solid phase as well as the microbial biomass P and respiration at increasing doses of citric and oxalic acid in two different soils with contrasting agronomic P status. Citric or oxalic acids significantly increased soil solution P concentrations for doses over 2 mmol kg-1. However, low organic acid doses (<2 mmol kg-1) were associated with a steep increase in microbial biomass P, which was not seen for higher doses. In both soils, treatment with the tribasic citric acid led to a greater increase in soil solution P than the dibasic oxalic acid, likely due to the rapid degrading of oxalic acids in soils. After equilibration of soils with citric or oxalic acids, the adsorbed-to-solution distribution coefficient (Kd) and desorption rate constants (k-1) decreased whereas an increase in the response time of solution P equilibration (Tc) was observed. The extent of this effect was shown to be both soil and organic acid specific. Our results illustrate the critical thresholds of organic acid concentration necessary to mobilize sorbed and precipitated P, bringing new insight on how the exudation of organic acids regulate chemical-microbial soil phosphorus transformations.


Comparative Analysis of Sequential Proximal Optimizing Technique Versus Kissing Balloon Inflation Technique in Provisional Bifurcation Stenting: Fractal Coronary Bifurcation Bench Test.
This study used a fractal bifurcation bench model to compare 6 optimization sequences for coronary bifurcation provisional stenting, including 1 novel sequence without kissing balloon inflation (KBI), comprising initial proximal optimizing technique (POT) + side-branch inflation (SBI) + final POT, called "re-POT." In provisional bifurcation stenting, KBI fails to improve the rate of major adverse cardiac events. Proximal geometric deformation increases the rate of in-stent restenosis and target lesion revascularization. A bifurcation bench model was used to compare KBI alone, KBI after POT, KBI with asymmetric inflation pressure after POT, and 2 sequences without KBI: initial POT plus SBI, and initial POT plus SBI with final POT (called "re-POT"). For each protocol, 5 stents were tested using 2 different drug-eluting stent designs: that is, a total of 60 tests. Compared with the classic KBI-only sequence and those associating POT with modified KBI, the re-POT sequence gave significantly (p < 0.05) better geometric results: it reduced SB ostium stent-strut obstruction from 23.2 ± 6.0% to 5.6 ± 8.3%, provided perfect proximal stent apposition with almost perfect circularity (ellipticity index reduced from 1.23 ± 0.02 to 1.04 ± 0.01), reduced proximal area overstretch from 24.2 ± 7.6% to 8.0 ± 0.4%, and reduced global strut malapposition from 40 ± 6.2% to 2.6 ± 1.4%. In comparison with 5 other techniques, the re-POT sequence significantly optimized the final result of provisional coronary bifurcation stenting, maintaining circular geometry while significantly reducing SB ostium strut obstruction and global strut malapposition. These experimental findings confirm that provisional stenting may be optimized more effectively without KBI using re-POT.


Multiple loop structures critical for ligand binding of the integrin alpha4 subunit in the upper face of the beta-propeller mode 1.
A non-I-domain integrin, alpha4beta1, recognizes vascular cell adhesion molecule 1 (VCAM-1) and the IIICS portion of fibronectin. To localize regions of alpha4 critical for ligand binding, we swapped several predicted loops within or near the putative ligand-binding site of alpha4 (which spans repeats 2-5 of the seven N-terminal repeats) with the corresponding regions of alpha5. Swapping residues 112-131 in repeat 2, or residues 237-247 in repeat 4, completely blocked adhesion to immobilized VCAM-1 and connecting segment 1 (CS-1) peptide. However, swapping residues 40-52 in repeat 1, residues 151-164 in repeat 3, or residues 282-288 (which contain a putative cation binding motif) in repeat 5 did not affect or only slightly reduced adhesion to these ligands. The binding of several function-blocking antibodies is blocked by swapping residues 112-131, 151-164, and 186-191 (which contain previously identified residues critical for ligand binding, Tyr-187 and Gly-190). These results are consistent with the recently published beta-propeller folding model of the integrin alpha4 subunit [Springer, T. A. (1997) Proc. Natl. Acad. Sci. USA 94, 65-72], in which seven four-stranded beta-sheets are arranged in a torus around a pseudosymmetric axis. The regions of alpha4 critical for ligand binding are adjacent to each other and are located in the upper face, the predicted ligand-binding site, of the beta-propeller model, although they are not adjacent in the primary structure.


The clinical significance of digital examination-indicated cerclage in women with a dilated cervix at 14 0/7-29 6/7 weeks.
This study was to compare pregnancy outcomes between cerclage and expectant management in wemen with a dilated cervix. Retrospective multicenter cohort study. Five hospitals of Catholic University Medical Center Network in Korea. A total of 173 women between 14 0/7 and 29 6/7 weeks' gestation with cervical dilation of 1 cm or greater by digital examination. Pregnancy outcomes were compared according to cerclage or expectant management, with the use of propensity-score matching. Primary outcome was time from presentation until delivery (weeks). Secondary outcomes were gestational age at delivery, neonatal survival, morbidity, preterm birth, and so on. Of 173 women, 116 received a cerclage (cerclage group), and 57 were managed expectantly without cerclage (expectant group). Cervical dilation at presentation, and the use of amniocentesis performed to exclude subclinical chorioamnionitis differed between two groups. In the overall matched cohort, there was significant difference in the time from presentation until delivery (cerclage vs. expectant group, 10.6±6.2 vs. 2.9±3.2 weeks, p <0.0001). While there was no significant difference in the neonatal survival between two groups, there were lower neonatal morbidity as well as higher pregnancy maintenance rate at 28, 32, 34 and 37 weeks' gestation in the cerclage group, compared with the expectant group. This study suggests that digital examination-indicated cerclage appears to prolong gestation and decrease neonatal morbidity, compared with expectant management in women with cervical dilation between 14 0/7 and 29 6/7 weeks.


Clinical roundtable monograph: new and emerging treatments for advanced prostate cancer.
Historically, the treatment of metastatic castration-resistant prostate cancer (CRPC) has been limited to chemotherapeutic regimens that did not improve patient survival. In 2004, clinical studies began to demonstrate significant improvements in patient outcomes, including overall survival, with docetaxel versus mitoxantrone chemotherapy. Since these pivotal trials, the combination of docetaxel plus prednisone has become a standard of care for patients with metastatic CRPC. However, the limited survival benefit achieved with this regimen prompted several investigations into the development of alternative therapeutic options. Recent advances have now led to an unprecedented number of new drug approvals within the past year, providing many new treatment options for patients with metastatic CRPC. Sipuleucel-T, considered a new paradigm in cancer treatment, is the first such immunotherapeutic agent approved by the US Food and Drug Administration. Other successes include abiraterone acetate, the first androgen biosynthesis inhibitor, and cabazitaxel, a novel microtubule inhibitor, both of which have demonstrated improved survival following docetaxel failure. The bone-targeting agent denosumab, also recently approved in this setting, offers these patients significant improvement in the prevention of skeletal-related events. The data supporting the approval of each of these agents are described in this monograph, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies. The experts also discuss several of the issues regarding the introduction of these novel agents into clinical practice for metastatic CRPC patients.


Implementation of evidence-based antenatal care in Mozambique: a cluster randomized controlled trial: study protocol.
Antenatal care (ANC) reduces maternal and perinatal morbidity and mortality directly through the detection and treatment of pregnancy-related illnesses, and indirectly through the detection of women at increased risk of delivery complications. The potential benefits of quality antenatal care services are most significant in low-resource countries where morbidity and mortality levels among women of reproductive age and neonates are higher.WHO developed an ANC model that recommended the delivery of services scientifically proven to improve maternal, perinatal and neonatal outcomes. The aim of this study is to determine the effect of an intervention designed to increase the use of the package of evidence-based services included in the WHO ANC model in Mozambique. The primary hypothesis is that the intervention will increase the use of evidence-based practices during ANC visits in comparison to the standard dissemination channels currently used in the country. This is a demonstration project to be developed through a facility-based cluster randomized controlled trial with a stepped wedge design. The intervention was tailored, based on formative research findings, to be readily applicable to local prenatal care services and acceptable to local pregnant women and health providers. The intervention includes four components: the provision of kits with all necessary medicines and laboratory supplies for ANC (medical and non-medical equipment), a storage system, a tracking system, and training sessions for health care providers. Ten clinics were selected and will start receiving the intervention in a random order. Outcomes will be computed at each time point when a new clinic starts the intervention. The primary outcomes are the delivery of selected health care practices to women attending the first ANC visit, and secondary outcomes are the delivery of selected health care practices to women attending second and higher ANC visits as well as the attitude of midwives in relation to adopting the practices. This demonstration project is pragmatic in orientation and will be conducted under routine conditions. There is an urgent need for effective and sustainable scaling-up approaches of health interventions in low-resource countries. This can only be accomplished by the engagement of the country's health stakeholders at all levels. This project aims to achieve improvement in the quality of antenatal care in Mozambique through the implementation of a multifaceted intervention on three levels: policy, organizational and health care delivery levels. The implementation of the trial will probably require a change in accountability and behaviour of health care providers and we expect this change in 'habits' will contribute to obtaining reliable health indicators, not only related to research issues, but also to health care outcomes derived from the new health care model. At policy level, the results of this study may suggest a need for revision of the supply chain management system. Given that supply chain management is a major challenge for many low-resource countries, we envisage that important lessons on how to improve the supply chain in Mozambique and other similar settings, will be drawn from this study. Pan African Clinical Trial Registry database. Identification number: PACTR201306000550192.


Higher-dimensional neurons explain the tuning and dynamics of working memory cells.
Measurements of neural activity in working memory during a somatosensory discrimination task show that the content of working memory is not only stimulus dependent but also strongly time varying. We present a biologically plausible neural model that reproduces the wide variety of characteristic responses observed in those experiments. Central to our model is a heterogeneous ensemble of two-dimensional neurons that are hypothesized to simultaneously encode two distinct stimuli dimensions. We demonstrate that the spiking activity of each neuron in the population can be understood as the result of a two-dimensional state space trajectory projected onto the tuning curve of the neuron. The wide variety of observed responses is thus a natural consequence of a population of neurons with a diverse set of preferred stimulus vectors and response functions in this two-dimensional space. In addition, we propose a taxonomy of network topologies that will generate the two-dimensional trajectory necessary to exploit this population. We conclude by proposing some experimental indicators to help distinguish among these possibilities.


Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical Science.
While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)-both ulcerative colitis (UC) and Crohn's Disease (CD)-as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage-as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients' first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.


Hyperreactio luteinalis with preeclampsia.
Hyperreactio luteinalis (HL) is a condition associated with bilateral and, in rare cases, unilateral ovarian enlargement due to theca lutein cysts. HL is a benign condition, usually found incidentally at cesarean section, which can appear anaplastic and lead to unnecessary ovarian resection. A 24-year-old woman with 35 weeks of gestation attended with bilaterally enlarged ovaries. She had preeclampsia and preterm contractions. Due to breech presentation of baby and nulliparity and possible severe preeclampsia, she delivered by cesarean section. The ovaries had an anaplastic appearance and a biopsy was taken during cesarean section. Pathology revealed multiple benign theca lutein cysts. There are 51 reported cases of HL associated with a normal pregnancy in the literature. It is estimated that approximately 60% of the cases of HL is not associated with trophoblastic disease and occurs with normal singleton pregnancy. Only three of them were found to be associated with preeclampsia and this is the fourth case. HL may help explain the underlying cause of preeclampsia in these cases. There are multiple benign ovarian lesions in HL, which can mimic ovarian neoplasms. Accordingly, it is important to exclude these from the differential diagnosis via a wedge biopsy and frozen section to avoid unnecessary surgical excision.


Coexistence of arterial compression in patients with neurogenic thoracic outlet syndrome.
Patients with neurogenic thoracic outlet syndrome (NTOS) may have signs and symptoms of arterial compromise without thrombosis or aneurysm. To evaluate these patients' presentation, duration of signs and symptoms, and outcomes of immediate surgical operation. Demographic and clinical data for patients with NTOS and signs and symptoms of arterial compromise without arterial thrombosis or aneurysm were extracted from a prospectively maintained, institutional review board-approved database and patient medical records between May 22, 2003, and October 16, 2012, in the Johns Hopkins Medical Institutions' Department of Vascular and Endovascular Surgery. All patients received immediate first rib resection and scalenectomy (FRRS) (n = 15), cervical rib resection and FRRS (n = 6), or FRRS and second rib resection due to fusion (n = 1). Further physical therapy or anterior scalene block was not considered owing to arterial compression. Surgical intervention relieved arterial and neurogenic symptoms, and abnormal duplex velocities returned to normal in adduction. Twenty-two patients (13 women and 9 men; mean age, 25 years [range, 12-41 years]) presented with the following signs and symptoms a mean of 37 months (range, 1-144 months) after developing symptoms of NTOS: arm discoloration (n = 15), infraclavicular bruit with arm abduction (n = 9), more than 50% change in subclavian artery velocity in abduction by duplex scan (n = 12), cervical rib (n = 6), abnormal first rib (n = 3), and/or history of embolization (n = 2). In addition, 2 patients had venous thrombosis. The mean follow-up time was 11 months (range, 1-34 months), and all patient outcomes improved in the postoperative period. Arterial compression can coexist with NTOS and can be elucidated in most patients by medical record review and physical examination, along with confirmation by a duplex scan. Those with evidence of arterial compression and for whom physical therapy has failed should receive surgery to alleviate their symptoms. Prompt surgical intervention affords good outcomes in these patients. Outcomes for patients with NTOS and arterial compression following immediate surgical intervention were previously unknown.


18β-glycyrrhetinic acid inhibits rotavirus replication in culture.
Glycyrrhizin (GA) and primary metabolite 18β-glycyrrhetinic acid (GRA) are pharmacologically active components of the medicinal licorice root, and both have been shown to have antiviral and immunomodulatory properties. Although these properties are well established, the mechanisms of action are not completely understood. In this study, GA and GRA were tested for the ability to inhibit rotavirus replication in cell culture, toward a long term goal of discovering natural compounds that may complement existing vaccines. Epithelial cells were treated with GA or GRA various times pre- or post-infection and virus yields were measured by immunofluorescent focus assay. Levels of viral proteins VP2, VP6, and NSP2 in GRA treated cells were measured by immunoblot to determine if there was an effect of GRA treatment on the accumulation of viral protein. GRA treatment reduced rotavirus yields by 99% when added to infected cultures post-- virus adsorption, whereas virus yields in GA treated cultures were similar to mock treated controls. Time of addition experiments indicated that GRA-mediated replication inhibition likely occurs at a step or steps subsequent to virus entry. The amounts of VP2, VP6 and NSP2 were substantially reduced when GRA was added to cultures up to two hours post-entry. GRA, but not GA, has significant antiviral activity against rotavirus replication in vitro, and studies to determine whether GRA attenuates rotavirus replication in vivo are underway.


Maintenance and improvement of interobserver reliability of osteopathic palpatory tests over a 4-month period.
Few studies have shown that diagnostic palpation is reliable. No studies have shown that the reliability of diagnostic palpatory skills can be maintained and improved over time. To investigate whether the reliability of selected palpatory tests used to identify lumbar somatic dysfunction was maintained during a 4-month period as part of a clinical observational study. Participants with low back pain and participants without low back pain, recruited from a rural Midwestern community, were examined during 6 separate sessions over a 4-month period. During each data collection session, two blinded examiners, who had previously completed comprehensive consensus training, evaluated the lumbar region with four tests: static segmental positional asymmetry of the transverse processes in the horizontal plane, tissue texture abnormalities, resistance to anterior springing on the spinous processes, and tenderness induced by pressure on the spinous processes. Detailed protocols for each test were defined during a previous comprehensive consensus training period and were not revised during the current study. To verify that established interobserver reliability was maintained throughout the clinical study, quality control sampling was performed on all data. When findings were inconsistent between the two examiners, focused consensus training was performed as a means of recalibration to understand why assessments were inconsistent. Interobserver reliability for determining the presence or absence of somatic dysfunction was assessed using kappa coefficients. The study enrolled 64 participants, and 14 to 33 participants were examined per session. All four tests had acceptable interobserver reliability by the final data collection session. The test for static segmental positional asymmetry of the transverse processes in the horizontal plane had moderate to substantial reliability in all 6 sessions. The test for tissue texture abnormalities had moderate reliability in 5 of the 6 sessions. The test for resistance to anterior springing on the spinous processes had moderate reliability for 3 of the 6 sessions. The test for tenderness had substantial to almost perfect reliability for all 6 sessions. In general, interobserver reliability improved over time. Examiners were able to maintain and improve interobserver reliability of four lumbar diagnostic palpatory tests over a 4-month period.


Scrapie prions selectively modify the stress response in neuroblastoma cells.
The fundamental event underlying scrapie infection seems to be a conformational change in the prion protein. To investigate proteins that might feature in the conversion of the cellular prion protein (PrPC) into the scrapie isoform (PrPSc), we examined mouse neuroblastoma N2a cells for the expression and cellular distribution of heat shock proteins (Hsps), some of which function as molecular chaperones. In scrapie-infected N2a (ScN2a) cells, Hsp72 and Hsp28 were not induced by heat shock, sodium arsenite, or an amino acid analog, in contrast to uninfected control N2a cells, while other inducible Hsps were increased by these treatments. Following heat shock of the N2a cells, constitutively expressed Hsp73 was translocated from the cytoplasm into the nucleus and nucleolus. In contrast, the distribution of Hsp73 in ScN2a cells was not altered by heat shock; the discrete cytoplasmic structures containing Hsp73 were largely resistant to detergent extraction. These alterations in the expression and subcellular translocation of specific Hsps in ScN2a cells may reflect the cellular response to the accumulation of PrPSc. Whether any of these Hsps feature in the conversion of PrPC into PrPSc or the pathogenesis of prion diseases remains to be established.


The effects of breastfeeding versus formula-feeding on cerebral cortex maturation in infant rhesus macaques.
Breastfeeding is positively associated with several outcomes reflecting early brain development and cognitive functioning. Brain neuroimaging studies have shown that exclusively breastfed children have increased white matter and subcortical gray matter volume compared to formula-fed children. However, it is difficult to disentangle the effects of nutrition in breast milk from other confounding factors that affect brain development, particularly in studies of human subjects. Among the nutrients provided by human breast milk are the carotenoid lutein and the natural form of tocopherol, both of which are selectively deposited in brain. Lutein is the predominant carotenoid in breast milk but not in most infant formulas, whereas infant formulas are supplemented with the synthetic form of tocopherol. In this study, a non-human primate model was used to investigate the effects of breastfeeding versus formula-feeding, as well as lutein and natural RRR-α-tocopherol supplementation of infant formula, on brain maturation under controlled experimental conditions. Infant rhesus macaques (Macaca mulatta) were exclusively breastfed, or were fed infant formulas with different levels and sources of lutein and α-tocopherol. Of note, the breastfed group were mother-reared whereas the formula-fed infants were nursery-reared. Brain structural and diffusion MR images were collected, and brain T2 was measured, at two, four and six months of age. The mother-reared breastfed group was observed to differ from the formula-fed groups by possessing higher diffusion fractional anisotropy (FA) in the corpus callosum, and lower FA in the cerebral cortex at four and six months of age. Cortical regions exhibiting the largest differences include primary motor, premotor, lateral prefrontal, and inferior temporal cortices. No differences were found between the formula groups. Although this study did not identify a nutritional component of breast milk that could be provided to infant formula to facilitate brain maturation consistent with that observed in breastfed animals, our findings indicate that breastfeeding promoted maturation of the corpus callosum and cerebral cortical gray matter in the absence of several confounding factors that affect studies in human infants. However, differences in rearing experience remain as a potential contributor to brain structural differences between breastfed and formula fed infants.


Gene therapy into photoreceptors and Müller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models.
Mutations in the Crumbs-homologue-1 (CRB1) gene lead to severe recessive inherited retinal dystrophies. Gene transfer therapy is the most promising cure for retinal dystrophies and has primarily been applied for recessive null conditions via a viral gene expression vector transferring a cDNA encoding an enzyme or channel protein, and targeting expression to one cell type. Therapy for the human CRB1 disease will be more complex, as CRB1 is a structural and signaling transmembrane protein present in three cell classes: Müller glia, cone and rod photoreceptors. In this study, we applied CRB1 and CRB2 gene therapy vectors in Crb1-retinitis pigmentosa mouse models at mid-stage disease. We tested if CRB expression restricted to Müller glial cells or photoreceptors or co-expression in both is required to recover retinal function. We show that targeting both Müller glial cells and photoreceptors with CRB2 ameliorated retinal function and structure in Crb1 mouse models. Surprisingly, targeting a single cell type or all cell types with CRB1 reduced retinal function. We show here the first pre-clinical studies for CRB1-related eye disorders using CRB2 vectors and initial elucidation of the cellular mechanisms underlying CRB1 function.


Li doped kagome spin liquid compounds.
Herbertsmithite and Zn-doped barlowite are two compounds for experimental realization of two-dimensional kagome spin liquids. Theoretically, it has been proposed that charge doping a quantum spin liquid gives rise to exotic metallic states, such as high-temperature superconductivity. However, one recent experiment on herbertsmithite with successful Li-doping surprisingly showed an insulating state even under a heavily doped scenario, which cannot be explained by previous theories. Using first-principles calculations, we performed a comprehensive study on the Li intercalation doping effect of these two compounds. For the Li-doped herbertsmithite, we identified the optimized Li position at the Cl-(OH)3-Cl pentahedron site instead of the previously speculated Cl-(OH)3 tetrahedral site. With increasing Li doping concentration, saturation magnetization decreases linearly due to charge transfer from Li to Cu ions. Moreover, we found that Li forms chemical bonds with nearby (OH)- and Cl- ions, which lowers the surrounding chemical potential and traps electrons, as evidenced by the localized charge distribution, explaining the insulating behavior measured experimentally. Though a different structure from herbertsmithite, Zn-doped barlowite shows the same features upon Li doping. We conclude that Li doping this family of kagome spin liquids cannot realize exotic metallic states, and other methods should be further explored, such as element substitution with those having different valence electrons.


Administration and management skills needed by physical therapist graduates in 2010: a national survey.
Administration and management (A and M) skills are essential to physical therapist practice. This study identified which A and M skills will be most critical for future Doctor of Physical Therapy (DPT) graduates to possess upon entry into clinical practice. Using a 7-point scale, 435 randomly selected American Physical Therapy Association members (physical therapists) rated 121 A and M skills based on expectation of the level of independence required by a new DPT graduate. No differences among respondents based on role, work setting, or experience were found, so the data were combined for factor analyses, producing 16 A and M skill groups. The most independence was expected in skills related to self-management, compliance with rules, ethical behavior, and insurance coding. Skills requiring the most assistance were marketing and strategic planning, financial analysis and budgeting, and environmental assessment. This study has identified the level of independence for the A and M skills needed by new DPT graduates, provided empirical evidence suggesting which A and M skills should be included in DPT curricula, and suggested a pattern of A and M skill acquisition that applies first to the new therapist and the patient, then to the organization, and finally to the health care environment.


In vitro follicle culture in the context of IVF.
The currently available assisted reproduction techniques for fertility preservation (i.e. in vitro maturation (IVM) and in vitro fertilization) are insufficient as stand-alone procedures as only few reproductive cells can be conserved with these techniques. Oocytes in primordial follicles are well suited to survive the cryopreservation procedure and of use as valuable starting material for fertilization, on the condition that these could be grown up to fully matured oocytes. Our understanding of the biological mechanisms directing primordial follicle activation has increased over the last years and this knowledge has paved the way toward clinical applications. New multistep in vitro systems are making use of purified precursor cells and extracellular matrix components and by applying bio-printing technologies, an adequate follicular niche can be built. IVM of human oocytes is clinically applied in patients with polycystic ovary/polycystic ovary syndrome; related knowhow could become useful for fertility preservation and for patients with maturation failure and follicle-stimulating hormone resistance. The expectations from the research on human ovarian tissue and immature oocytes cultures, in combination with the improved vitrification methods, are high as these technologies can offer realistic potential for fertility preservation.


Invariance of wearing location of Omron-BI pedometers: a validation study.
The purpose of this study was to investigate the validity and reliability evidences of the Omron BI pedometer, which could count steps taken even when worn at different locations on the body. Forty (20 males and 20 females) adults were recruited to walk wearing 5 sets, 1 set at a time, of 10 BI pedometers during testing, 1 each at 10 different locations. For comparison, they also wore 2 Yamax Digi-Walker SW-200 pedometers and a Dynastream AMP 331 activity monitor. The subjects walked in 3 free-living conditions: a flat sidewalk, stairs, and mixed conditions. Except for a slight decrease in accuracy in the pant pocket locations, Omron BI pedometers counted steps accurately across other locations when subjects walked on the flat sidewalk, and the performance was consistent across devices and trials. When the subjects climbed up stairs, however, the absolute error % of the pant pocket locations increased significantly (P < .05) and similar or higher error rates were found in the AMP 331 and SW-200s. The Omron BI pedometer can accurately count steps when worn at various locations on the body in free-living conditions except for front pant pocket locations, especially when climbing stairs.


A comprehensive study on different modelling approaches to predict platelet deposition rates in a perfusion chamber.
Thrombus formation is a multiscale phenomenon triggered by platelet deposition over a protrombotic surface (eg. a ruptured atherosclerotic plaque). Despite the medical urgency for computational tools that aid in the early diagnosis of thrombotic events, the integration of computational models of thrombus formation at different scales requires a comprehensive understanding of the role and limitation of each modelling approach. We propose three different modelling approaches to predict platelet deposition. Specifically, we consider measurements of platelet deposition under blood flow conditions in a perfusion chamber for different time periods (3, 5, 10, 20 and 30 minutes) at shear rates of 212 s(-1), 1390 s(-1) and 1690 s(-1). Our modelling approaches are: i) a model based on the mass-transfer boundary layer theory; ii) a machine-learning approach; and iii) a phenomenological model. The results indicate that the three approaches on average have median errors of 21%, 20.7% and 14.2%, respectively. Our study demonstrates the feasibility of using an empirical data set as a proxy for a real-patient scenario in which practitioners have accumulated data on a given number of patients and want to obtain a diagnosis for a new patient about whom they only have the current observation of a certain number of variables.


The porA gene in serogroup A meningococci: evolutionary stability and mechanism of genetic variation.
Molecular analyses were applied to the genes encoding variants of the serosubtyping antigen, the class 1 outer membrane protein (PorA), from 55 serogroup A Neisseria meningitidis strains. These genes were evolutionarily stable and exhibited a limited range of genetic variation, primarily generated by recombination. Translation of the gene sequences revealed a total of 19 distinct amino acid sequences in the variable regions of the protein, 6 of which were not recognized by currently available serosubtyping monoclonal antibodies. Knowledge of these amino acid sequences permitted a rational re-assignment of serosubtype names. Comparison of the complete genes with porA gene sequences from serogroup B and C meningococci showed that serogroup A possessed a limited number of the possible porA genes from a globally distributed gene pool. Each serogroup A subgroup was characterized by one of four porA gene types, probably acquired upon subgroup divergence, which was stable over periods of decades and during epidemiological spread. Comparison with other variable genes (pil and iga) indicated that the three alleles were independently assorted within the subgroup, suggesting that their gene types were older than the subgroups in which they occurred.


[Acupressure in the prevention of postoperative nausea and vomiting].
Despite modern anaesthetic procedures, postoperative nausea and vomiting are still the side-effects most often mentioned: acupressure is reported to be an additional method of preventing these effects in minor gynaecological surgery. We investigated the effectiveness of acupressure in patients undergoing gynaecological operations of longer duration (6-8 h) in a verum acupressure group compared to a placebo group. Before beginning the study we investigated a control group to find out the frequency of emesis. In the worst case of nausea that we encountered, 80% in the 0-6 h postoperative period, the number of random samples for the acupressure and placebo groups was calculated (30 patients in each group). The error for alpha was established at 5% and the reduction of nausea was 50%. METHODS. The female patients were 18 to 65 years old (ASA group I and II). Acupressure was carried out by fastening small metal bullets at the point P 6 to each forearm by means of an elastic bandage. The bullets were left there for 24 h. The premedication anaesthesia, postoperative analgesia, and antiemetic treatment were standardized. During a 24-h period we investigated the incidence of nausea and vomiting. RESULTS. The anthropometric data, the duration of surgery and the amount of postoperative analgesia were comparable between the three groups. Verum acupressure obtained a statistically significant and relevant reduction in nausea up to the 6th postoperative hour in comparison with the placebo group (P = 0.03). Nausea was reduced from 53% in the placebo group to 23% in the acupressure group. CONCLUSION. As demonstrated in this group of longer gynaecological surgery patients as well as in chemotherapy-induced nausea and vomiting, we were able to demonstrate that acupressure is an effective method of preventing nausea and vomiting without any side-effects. It is a valuable addition to the prevention of postoperative nausea and vomiting. Further studies should be conducted to investigate this possibility further.


Quantification of dabigatran and indirect quantification of dabigatran acylglucuronides in human plasma by LC-MS/MS.
An assay for the quantification of dabigatran and its active metabolites, dabigatran acylglucuronides, has not previously been described in detail. For the quantification of total dabigatran concentration (free dabigatran and acylglucuronides), samples were subjected to alkaline hydrolysis. For the quantification of free dabigatran, samples were acidified with ammonium formate. Following acetonitrile protein precipitation, the samples were analyzed by LC-MS/MS using gradient elution to ensure separation of dabigatran from dabigatran acylglucuronides. Mean recoveries ≥98% were achieved. The assay was validated over the range 2.5-1000 ng/ml dabigatran, imprecision was <9% CV (<15% at LLOQ) and accuracy was 101-114%. An assay for dabigatran with indirect quantification of dabigatran acylglucuronides in plasma was developed, validated and applied.


Uncovering spatial topology represented by rat hippocampal population neuronal codes.
Hippocampal population codes play an important role in representation of spatial environment and spatial navigation. Uncovering the internal representation of hippocampal population codes will help understand neural mechanisms of the hippocampus. For instance, uncovering the patterns represented by rat hippocampus (CA1) pyramidal cells during periods of either navigation or sleep has been an active research topic over the past decades. However, previous approaches to analyze or decode firing patterns of population neurons all assume the knowledge of the place fields, which are estimated from training data a priori. The question still remains unclear how can we extract information from population neuronal responses either without a priori knowledge or in the presence of finite sampling constraint. Finding the answer to this question would leverage our ability to examine the population neuronal codes under different experimental conditions. Using rat hippocampus as a model system, we attempt to uncover the hidden "spatial topology" represented by the hippocampal population codes. We develop a hidden Markov model (HMM) and a variational Bayesian (VB) inference algorithm to achieve this computational goal, and we apply the analysis to extensive simulation and experimental data. Our empirical results show promising direction for discovering structural patterns of ensemble spike activity during periods of active navigation. This study would also provide useful insights for future exploratory data analysis of population neuronal codes during periods of sleep.


Exo1 processes stalled replication forks and counteracts fork reversal in checkpoint-defective cells.
The replication checkpoint coordinates the cell cycle with DNA replication and recombination, preventing genome instability and cancer. The budding yeast Rad53 checkpoint kinase stabilizes stalled forks and replisome-fork complexes, thus preventing the accumulation of ss-DNA regions and reversed forks at collapsed forks. We searched for factors involved in the processing of stalled forks in HU-treated rad53 cells. Using the neutral-neutral two-dimensional electrophoresis technique (2D gel) and psoralen crosslinking combined with electron microscopy (EM), we found that the Exo1 exonuclease is recruited to stalled forks and, in rad53 mutants, counteracts reversed fork accumulation by generating ss-DNA intermediates. Hence, Exo1-mediated fork processing resembles the action of E. coli RecJ nuclease at damaged forks. Fork stability and replication restart are influenced by both DNA polymerase-fork association and Exo1-mediated processing. We suggest that Exo1 counteracts fork reversal by resecting newly synthesized chains and resolving the sister chromatid junctions that cause regression of collapsed forks.


The Effects of Adjuvant Fermented Wheat Germ Extract on Cancer Cell Lines: A Systematic Review.
Fermented wheat germ extract (FWGE; trade name AVEMAR) is a natural compound derived from industrial fermentation of wheat germ. Its potential anticancer properties has emerged from recent studies. The aim of this systematic review is to summarize the data available in the scientific literature concerning the in vitro activity of FWGE on malignant cells. A systematic review of English articles in electronic databases has been performed. The primary outcomes of the review regarded types of cancer cell lines subjected to the investigation and the main results concerning cell viability, proliferation, and apoptosis observed within the studies. Sixteen articles were included in the final qualitative analysis. Various types of cancer cells treated with FWGE have been analyzed, showing mainly cytotoxic effects, alteration of the cell cycle, antiproliferative effects, and induction of apoptosis. FWGE can be a promising drug component in cancer treatment; however, further in vitro and in vivo studies are necessary to prove its effectiveness and safety in humans.


Recognition of positive and negative bandpass-filtered images.
A study is reported in which the significance for vision of low- and high-spatial-frequency components of photographic positive and negative images was investigated by measuring recognition of bandpass-filtered photographs of faces. The results show that a 1.5 octave bandpass-filtered image contains sufficient visual information for good recognition performance, provided the filter is centred close to 20 cycles facewidth-1. At low spatial frequencies negatives are more difficult to recognize than positives, but at high spatial frequencies there is no difference in recognition, implying that it is the low-frequency components of negatives which present difficulties for the visual system.


Evolution of novel wood decay mechanisms in Agaricales revealed by the genome sequences of Fistulina hepatica and Cylindrobasidium torrendii.
Wood decay mechanisms in Agaricomycotina have been traditionally separated in two categories termed white and brown rot. Recently the accuracy of such a dichotomy has been questioned. Here, we present the genome sequences of the white-rot fungus Cylindrobasidium torrendii and the brown-rot fungus Fistulina hepatica both members of Agaricales, combining comparative genomics and wood decay experiments. C. torrendii is closely related to the white-rot root pathogen Armillaria mellea, while F. hepatica is related to Schizophyllum commune, which has been reported to cause white rot. Our results suggest that C. torrendii and S. commune are intermediate between white-rot and brown-rot fungi, but at the same time they show characteristics of decay that resembles soft rot. Both species cause weak wood decay and degrade all wood components but leave the middle lamella intact. Their gene content related to lignin degradation is reduced, similar to brown-rot fungi, but both have maintained a rich array of genes related to carbohydrate degradation, similar to white-rot fungi. These characteristics appear to have evolved from white-rot ancestors with stronger ligninolytic ability. F. hepatica shows characteristics of brown rot both in terms of wood decay genes found in its genome and the decay that it causes. However, genes related to cellulose degradation are still present, which is a plesiomorphic characteristic shared with its white-rot ancestors. Four wood degradation-related genes, homologs of which are frequently lost in brown-rot fungi, show signs of pseudogenization in the genome of F. hepatica. These results suggest that transition toward a brown-rot lifestyle could be an ongoing process in F. hepatica. Our results reinforce the idea that wood decay mechanisms are more diverse than initially thought and that the dichotomous separation of wood decay mechanisms in Agaricomycotina into white rot and brown rot should be revisited.


Drug-induced hypersensitivity syndrome in a premature infant.
Fever, skin reactions, and limb edema because of drug-induced hypersensitivity have been reported in children because of various drugs, mainly aromatic antiepileptic drugs such as phenytoin, phenobarbital, carbamazepin, and primidone. The skin reactions differ in severity and range from mild maculopapular erythema to exfoliative dermatitis. They have been described in older children but have not been reported in newborn infants. We report a premature newborn infant who developed fever, skin reactions, and edema because of phenytoin while receiving anticonvulsant therapy.


Core shell structure for solid gas synthesis of LiBD(4).
The formation of LiBD(4) by the reaction of LiD in a diborane/hydrogen atmosphere was analysed by in situ neutron diffraction and subsequent microstructural and chemical analysis of the final product. The neutron diffraction shows that nucleation of LiBD(4) already starts at temperatures of 100 degrees C, i.e. in its low temperature phase (orthorhombic structure). However, even at higher temperatures the reaction is incomplete. We observe a yield of approximately 50% at a temperature of 185 degrees C. A core shell structure of the grains, in which LiBD(4) forms a passivation layer on the surface of the LiD grains, was found in the subsequent microstructural (electron microscopy) and chemical (electron energy loss spectrometry) analysis.


Bevacizumab reduces neurocan content and gene expression in newborn rat retina in vitro.
Extracellular matrix (ECM) and cellular membrane proteoglycans (PGs) play important roles in neural differentiation and cell adhesion. Vascular endothelial growth factor, an important signal protein in vascular and retinal neural cell development, is retained in the ECM due to its high affinity for PG. Bevacizumab, an anti-VEGF agent, has been extensively used for treating retinal diseases in adult and newborn patients, although its effect on the developing retina remains largely unknown. The purpose of this study was to investigate the effect of bevacizumab on neurocan, phosphacan, and syndecan-3 PG levels in newborn rat retina. Retinal explants of sixty 2-day-old Lister hooded rats were obtained after eye enucleation and maintained in culture media with or without bevacizumab for 48 hours. Immunohistochemical staining was assessed against neurocan, phosphacan, and syndecan-3. Proteoglycan content was quantified based on the intensity of immunohistochemical labeling. Gene expressions were quantified by real-time reverse-transcription polymerase chain reaction. The results from the treatment and control groups were compared. No significant difference in the staining intensity and mRNA expression of phosphacan and syndecan-3 was observed between the groups. However, a significant decrease in neurocan content and mRNA expression was observed in bevacizumab-treated retinal explants compared with controls. Bevacizumab did not affect phosphacan and syndecan-3 levels but decreased neurocan content and gene expression. Therefore, it may interfere with early postnatal retinal cell differentiation. Although further studies are necessary to confirm our findings, we suggest anti-VEGF agents be used with caution in developing retinal tissue.


Universal covariance formula for linear statistics on random matrices.
We derive an analytical formula for the covariance cov(A,B) of two smooth linear statistics A=[under ∑]ia(λ_{i}) and B=[under ∑]ib(λ_{i}) to leading order for N→∞, where {λ_{i}} are the N real eigenvalues of a general one-cut random-matrix model with Dyson index β. The formula, carrying the universal 1/β prefactor, depends on the random-matrix ensemble only through the edge points [λ_{-},λ_{+}] of the limiting spectral density. For A=B, we recover in some special cases the classical variance formulas by Beenakker and by Dyson and Mehta, clarifying the respective ranges of applicability. Some choices of a(x) and b(x) lead to a striking decorrelation of the corresponding linear statistics. We provide two applications-the joint statistics of conductance and shot noise in ideal chaotic cavities, and some new fluctuation relations for traces of powers of random matrices.


Pt-free tandem molecular photoelectrochemical cells for water splitting driven by visible light.
Photoelectrochemical (PEC) cells using molecular catalysts to split water into hydrogen and oxygen have been investigated intensively during the past years. However, the high-cost of Pt counter electrodes and instability of molecular PEC cells hinder the practical applications. We describe in this article a Pt-free tandem molecular PEC cell, for the first time, employing molecular ruthenium- and cobalt-catalysts with strong dipicolinic acid anchoring groups on the respective photoanode and photocathode for total water splitting. The Pt-free tandem molecular PEC cell showed an effective and steady photocurrent density of ca. 25 μA cm(-2) for water splitting driven by visible light without external bias. This study indicates that tandem molecular PEC cells can provide great potential to the Pt-free devices for light driven total water splitting.


The illicit cigarette market in six South African townships.
We estimate the size of the illicit cigarette market in low socioeconomic areas in South Africa before and after a tax increase. In 2018, the real excise tax increased by 3% and the value-added tax (VAT) rate increased from 14% to 15%. Thus, the real tax on cigarettes increased by 4%. A total of 2427 smokers were interviewed over two rounds of data collection (1234 before the tax increase and 1193 after). Data were collected in six townships across four of South Africa's nine provinces. Smokers were asked about their most recent cigarette purchase. Cigarettes purchased for R1 (US$0.08) or less per stick are presumed illicit, based on a threshold price, which includes production costs and taxes. In 2017 and 2018 respectively, 34.6% and 36.4% of smokers in the sample purchased illicit cigarettes. The increase in the proportion of illicit purchases was not statistically significant. Smokers with relatively low socioeconomic status, those who have low levels of education and those who are older or unemployed are most likely to purchase illicit cigarettes. The illicit cigarette trade in South African townships is widespread. The government should implement an independent track and trace system to curb tax evasion. This would reduce the availability of illicit cigarettes, improve public health and increase excise tax collection.


Manganese catalyzed reductive amination of aldehydes using hydrogen as a reductant.
A one-pot two-step procedure was developed for the alkylation of amines via reductive amination of aldehydes using molecular dihydrogen as a reductant in the presence of a manganese pyridinyl-phosphine complex as a pre-catalyst. After the initial condensation step, the reduction of imines formed in situ is performed under mild conditions (50-100 °C) with 2 mol% of catalyst and 5 mol% of tBuOK under 50 bar of hydrogen. Excellent yields (>90%) were obtained for a large combination of aldehydes and amines (40 examples), including aliphatic aldehydes and amino-alcohols.


Moving forward: advances in the treatment of movement disorders with deep brain stimulation.
The modern era of stereotactic and functional neurosurgery has ushered in state of the art technologies for the treatment of movement disorders, particularly Parkinson's disease (PD), tremor, and dystonia. After years of experience with various surgical therapies, the eventual shortcomings of both medical and surgical treatments, and several serendipitous discoveries, deep brain stimulation (DBS) has risen to the forefront as a highly effective, safe, and reversible treatment for these conditions. Idiopathic advanced PD can be treated with thalamic, globus pallidus internus (GPi), or subthalamic nucleus (STN) DBS. Thalamic DBS primarily relieves tremor while GPi and STN DBS alleviate a wide range of Parkinsonian symptoms. Thalamic DBS is also used in the treatment of other types of tremor, particularly essential tremor, with excellent results. Both primary and various types of secondary dystonia can be treated very effectively with GPi DBS. The variety of anatomical targets for these movement disorders is indicative of the network-level dysfunction mediating these movement disturbances. Despite an increasing understanding of the clinical benefits of DBS, little is known about how DBS can create such wide sweeping neuromodulatory effects. The key to improving this therapeutic modality and discovering new ways to treat these and other neurologic conditions lies in better understanding the intricacies of DBS. Here we review the history and pertinent clinical data for DBS treatment of PD, tremor, and dystonia. While multiple regions of the brain have been targeted for DBS in the treatment of these movement disorders, this review article focuses on those that are most commonly used in current clinical practice. Our search criteria for PubMed included combinations of the following terms: DBS, neuromodulation, movement disorders, PD, tremor, dystonia, and history. Dates were not restricted.


Double Trouble: Patients With Both True and False Arrhythmia Alarms.
Patients with both true and false arrhythmia alarms pose a challenge because true alarms might be buried among a large number of false alarms, leading to missed true events. To determine (1) the frequency of patients with both true and false arrhythmia alarms; (2) patient, clinical, and electrocardiographic characteristics associated with both true and false alarms; and (3) the frequency and types of true and false arrhythmia alarms. This was a secondary analysis using data from an alarm study conducted at a tertiary academic medical center. Of 461 intensive care unit patients, 211 (46%) had no arrhythmia alarms, 12 (3%) had only true alarms, 167 (36%) had only false alarms, and 71 (15%) had both true and false alarms. Ventricular pacemaker, altered mental status, mechanical ventilation, and cardiac intensive care unit admission were present more often in patients with both true and false alarms than among other patients (P < .001). Intensive care unit stays were longer in patients with only false alarms (mean [SD], 106 [162] hours) and those with both true and false alarms (mean [SD], 208 [333] hours) than in other patients. Accelerated ventricular rhythm was the most common alarm type (37%). An awareness of factors associated with arrhythmia alarms might aid in developing solutions to decrease alarm fatigue. To improve detection of true alarms, further research is needed to build and test electrocardiographic algorithms that adjust for clinical and electrocardiographic characteristics associated with false alarms.


Zinc bells rang in Jerusalem!
"Oh, Jerusalem of gold, and of light, and of bronze..." goes the popular song. But it was another metal that towered above the Jerusalem landscape during the meeting of the International Society for Zinc Biology (ISZB; http://www.iszb.org/), held at Mishkenot Sha'ananim, a whisper away from the Old City walls. More than 100 scientists gathered on 1 to 5 December 2009 to discuss their research on the biology of this metal. Zinc is a double-edged sword. Zinc supplementation accelerates wound healing and growth and promotes an effective immune response. On the other hand, zinc deficiency leads to growth retardation and impaired learning and memory function, and has been linked to mood disorders. At the cellular level, however, uncontrolled increases in zinc concentrations can lead to neuronal cell death and may be involved in neurodegenerative disorders. Through regulation of various intracellular signaling pathways, zinc can accelerate cell growth and possibly contribute to cancer. However, despite the physiological and clinical importance of this metal, research on the molecular basis of these effects is still in its infancy. The 2009 ISZB meeting provided a venue for investigators working on various zinc-related issues to share their thoughts and ideas and to promote the growth of this field.


Osteomyelitis of the mandible secondary to infantile osteopetrosis: a case report.
A case of infantile malignant osteopetrosis with refractory mandibular osteomyelitis is reported. A female child was diagnosed with osteopetrosis at 2 years 8 months of age, and was scheduled to receive a bone marrow transplantation (BMT) in a pediatric department at 3 years 11 months of age. Her lower incisors were extracted at a dental clinic, after which she had recurring abscesses with progressive severity. She was referred to our department to control local infections before the BMT and was diagnosed with chronic mandibular osteomyelitis caused by osteopetrosis. Sequestrotomy and curettage were performed under general anesthesia. After surgery, daily saline irrigation was continued and osteomyelitis was well controlled. An uneventful BMT was performed, although it was refused and failed. A second BMT was planned, but during chemotherapy, cellulitis occurred after a recurrence of osteomyelitis caused by a newly erupted tooth. The local infection was controlled, but pneumonia recurred. She ultimately died of respiratory failure at 5 years of age.


Associations between driving under the influence of alcohol or drugs, speeding and seatbelt use among fatally injured car drivers in Norway.
Since 2005, all fatal road traffic crashes in Norway have been analyzed in-depth by multidisciplinary investigation teams organized by the Norwegian Public Roads Administration (NPRA). During the period 2005-2010, 608 drivers of cars or vans were killed in road traffic crashes. Blood samples were collected from 372 (61%) of the drivers and analyzed for alcohol and a large number of psychoactive drugs at the Norwegian Institute of Public Health (NIPH). After coupling the analytical results with the NPRA crash database, 369 drivers with a fatal outcome were identified and included. Alcohol or drug concentrations in blood above the legal limits were found in 39.8% of the drivers who were investigated for alcohol or drug impairment; 33.9% had blood alcohol concentrations above 0.5g/L or concentrations of drugs above the equivalent Norwegian legal impairment limits or concentrations of amphetamines above 200μg/L. Among drivers with a fatal outcome who had been impaired by alcohol or drugs, 64.6% were unbelted and 71.7% were speeding when the crash occurred; whereas 24.2% and 33.2% of the sober drivers were unbelted or speeding, respectively. Statistically significant associations were found between impairment by alcohol or amphetamines and driving unbelted or speeding. Excessive speeding is one of the main reasons for road traffic crashes and together with being unbelted the main reasons for a fatal outcome. This behavior might in many cases be due to increased risk-taking or negligence of safety measures as a result of alcohol or drug use.