Harmonic force spectroscopy measures load-dependent kinetics of individual human β-cardiac myosin molecules.
Molecular motors are responsible for numerous cellular processes from cargo transport to heart contraction. Their interactions with other cellular components are often transient and exhibit kinetics that depend on load. Here, we measure such interactions using 'harmonic force spectroscopy'. In this method, harmonic oscillation of the sample stage of a laser trap immediately, automatically and randomly applies sinusoidally varying loads to a single motor molecule interacting with a single track along which it moves. The experimental protocol and the data analysis are simple, fast and efficient. The protocol accumulates statistics fast enough to deliver single-molecule results from single-molecule experiments. We demonstrate the method's performance by measuring the force-dependent kinetics of individual human β-cardiac myosin molecules interacting with an actin filament at physiological ATP concentration. We show that a molecule's ADP release rate depends exponentially on the applied load, in qualitative agreement with cardiac muscle, which contracts with a velocity inversely proportional to external load.


Secretory leukocyte protease inhibitor: a pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure.
Acetaminophen-induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF-κB) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen-DR (HLA-DR), and lipopolysaccharide (LPS)-stimulated levels of NF-κBp65, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (α)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h-mψ) in areas of necrosis. H-mψ and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-κBp65, TNF-α, and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF.


The chest pain choice decision aid: a randomized trial.
Cardiac stress testing in patients at low risk for acute coronary syndrome is associated with increased false-positive test results, unnecessary downstream procedures, and increased cost. We judged it unlikely that patient preferences were driving the decision to obtain stress testing. The Chest Pain Choice trial was a prospective randomized evaluation involving 204 patients who were randomized to a decision aid or usual care and were followed for 30 days. The decision aid included a 100-person pictograph depicting the pretest probability of acute coronary syndrome and available management options (observation unit admission and stress testing or 24-72 hours outpatient follow-up). The primary outcome was patient knowledge measured by an immediate postvisit survey. Additional outcomes included patient engagement in decision making and the proportion of patients who decided to undergo observation unit admission and cardiac stress testing. Compared with usual care patients (n=103), decision aid patients (n=101) had significantly greater knowledge (3.6 versus 3.0 questions correct; mean difference, 0.67; 95% CI, 0.34-1.0), were more engaged in decision making as indicated by higher OPTION (observing patient involvement) scores (26.6 versus 7.0; mean difference, 19.6; 95% CI, 1.6-21.6), and decided less frequently to be admitted to the observation unit for stress testing (58% versus 77%; absolute difference, 19%; 95% CI, 6%-31%). There were no major adverse cardiac events after discharge in either group. Use of a decision aid in patients with chest pain increased knowledge and engagement in decision making and decreased the rate of observation unit admission for stress testing.


Simultaneous Control of 2DOF Upper-Limb Prosthesis With Body Compensations-Based Control: A Multiple Cases Study.
Controlling several joints simultaneously is a common feature of natural arm movements. Robotic prostheses shall offer this possibility to their wearer. Yet, existing approaches to control a robotic upper-limb prosthesis from myoelectric interfaces do not satisfactorily respond to this need: standard methods provide sequential joint-by-joint motion control only; advanced pattern recognition-based approaches allow the control of a limited subset of synchronized multi-joint movements and remain complex to set up. In this paper, we exploit a control method of an upper-limb prosthesis based on body motion measurement called Compensations Cancellation Control (CCC). It offers a straightforward simultaneous control of the intermediate joints, namely the wrist and the elbow. Four transhumeral amputated participants performed the Refined Rolyan Clothespin Test with an experimental prosthesis alternatively running CCC and conventional joint-by-joint myoelectric control. Task performance, joint motions, body compensations and cognitive load were assessed. This experiment shows that CCC restores simultaneity between prosthetic joints while maintaining the level of performance of conventional myoelectric control (used on a daily basis by three participants), without increasing compensatory motions nor cognitive load.


Mass spectrometric characterization of urinary hydrafinil metabolites for routine doping control purposes.
Little information on the human metabolism and urinary elimination of hydrafinil (9-fluorenol) exists. In order to support preventive anti-doping activities concerning compounds such as hydrafinil, a pilot elimination study was conducted with three healthy male volunteers receiving a single oral dose of 50 mg of hydrafinil. Urine samples were collected prior to and up to 72-h post-administration and were subjected to both gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, which allowed for the identification of the intact drug as well as Phase I and Phase II metabolites, primarily hydroxylated and/or glucuronidated or sulfo-conjugated hydrafinil. The identity of these metabolites was corroborated by high-resolution/high-accuracy tandem mass spectrometry, and the applicability of routine doping control workflows for the detection of hydrafinil and its main metabolites was assessed. Therefore, two findings of hydrafinil and its metabolites were recorded, which concerned out-of-competition doping control samples and, hence, were not pursued with confirmatory analyses. Yet, the initial testing procedure results indicate that hydrafinil might require consideration in sports drug testing programs to ensure its detection, if classified as prohibited by the World Anti-Doping Agency (WADA).


Disparities in hospital smoking cessation treatment by immigrant status.
Despite the efficacy of nicotine replacement therapy (NRT) in promoting smoking cessation, no studies have been done to evaluate NRT prescribing rates among immigrants, a vulnerable minority population in the United States. The aim of this study is to explore for differences in NRT prescribing behavior by immigrant status. Participants were enrolled in a smoking cessation trial for hospitalized patients between July 2011 and April 2014 at two NYC hospitals. For this analysis, we used baseline data from patient surveys and electronic medical-record reviews to examine associations between immigrant status and prescription of NRT in-hospital and on discharge, as well as acceptance of NRT in-hospital. We included age, gender, education, health literacy, race, ethnicity, English language ability, inpatient service, and site insurance in the models as potential confounders. Our study population included 1,608 participants, of whom 21% were not born in the United States. Bivariate analysis found that nonimmigrants were more likely than immigrants to be prescribed NRT in the hospital (46.1% vs. 35.7%, p = .0006) and similarly on discharge (19.4% vs. 15.3%, p = .09). Both groups were equally likely to accept NRT in-hospital when prescribed. On multivariable analysis, being an immigrant (OR 0.65), Black race (OR 0.52), and Hispanic ethnicity (OR 0.63) were associated with lower likelihood of being prescribed NRT in-hospital. Multivariable analysis for provision of NRT prescription at discharge showed no significant difference between immigrants and nonimmigrants. These findings show differences in in-hospital smoking cessation treatment between immigrants and nonimmigrants.


Differentiation of clinical patterns and survival outcomes of hepatocellular carcinoma on hepatitis B and nonalcoholic fatty liver disease.
The main etiologies of hepatocellular carcinoma (HCC) were often hepatitis B virus (HBV) or C and alcohol, rarely autoimmune and biliary diseases. Nonalcoholic fatty liver disease (NAFLD) has been an emerging role that could lead to chronic liver disease, nonalcoholic steatohepatitis, cirrhosis, and eventually HCC in recent years. The aim of our study is to investigate and compare the clinical features of HCC in patients with NAFLD and HBV, including age, gender, cirrhosis, liver function tests, largest tumor size, and cancer stage at the time of diagnosis. The survival outcome was compared between the two groups and the significant predictors of mortality were also analyzed in all patients with HCC. Most patients with HCC were recruited from the database of Cancer Registries in Taipei City Hospital, Ren-Ai Branch, from 2011 to 2017; and the other patients consecutively from the HCC multidisciplinary conference between January 2018 and December 2019. NAFLD was defined as nonviral hepatitis B (negative HBsAg and either positive anti-HBs or negative anti-HBc), nonviral hepatitis C (negative antihepatitis C virus [HCV]), nonalcoholic (alcohol consumption of <30 g/d for men and <20 g/d for women) liver disease, or present or past histological or ultrasonographic evidence of fatty liver. Totally, 23 NAFLD-related and 156 HBV-related HCC patients were enrolled in our study for further analysis. NAFLD-related HCC patients were significantly older (median age: 70.0 [61.0-79.0] years vs. 63.0 [56.0-72.0] years, p = 0.012) and heavier (median body mass index [BMI]: 26.6 [24.2-30] kg/m2 vs. 24.8 [22.0-27.1] kg/m2, p = 0.044) than those with HBV-related HCC. They were also more susceptible to diabetes mellitus (DM), and 60.9% (14 of 23) of them had this comorbidity compared with 29.5% (46 of 156) of those with HBV-related HCC (p = 0.003). Only 34.8% (8 of 23) and 71.2% (111 of 156) of patients with NAFLD- and HBV-related HCC were cirrhotic, respectively (p = 0.001). However, gender, tobacco use, international normalized ratio, albumin, creatinine, and cholesterol levels were not significantly different between the two groups. Tumor characteristics such as the Barcelona clinic liver cancer stage, largest tumor size, tumor number, extrahepatic metastasis, and treatment modalities had no significant difference between such groups.According to the Kaplan-Meier method analysis, the overall survival was not significantly different between these two patient groups (log-rank test, p = 0.101). To evaluate which patient group would lead to poor prognosis, we analyzed the survival of all patients through multivariate Cox proportional hazard regression after controlling other factors that may influence the hazard ratio. The analysis revealed that NAFLD and HBV infection as the cause of HCC are not risk factors of poor prognosis. In conclusion, our study showed NAFLD-related HCC patients were older, heavier, and more had DM than HBV-related. In addition, more NAFLD-related HCC patients were noncirrhotic than HBV-related. The survival rate was similar between NAFLD and HBV-related HCC patients.


Quantifying the impact of individual and collective compliance with infection control measures for ethical public health policy.
Infectious disease control measures often require collective compliance of large numbers of individuals to benefit public health. This raises ethical questions regarding the value of the public health benefit created by individual and collective compliance. Answering these requires estimating the extent to which individual actions prevent infection of others. We develop mathematical techniques enabling quantification of the impacts of individuals or groups complying with three public health measures: border quarantine, isolation of infected individuals, and prevention via vaccination/prophylaxis. The results suggest that (i) these interventions exhibit synergy: They become more effective on a per-individual basis as compliance increases, and (ii) there is often substantial "overdetermination" of transmission. If a susceptible person contacts multiple infectious individuals, an intervention preventing one transmission may not change the ultimate outcome (thus, risk imposed by some individuals may erode the benefits of others' compliance). These results have implications for public health policy during epidemics.


[Reflections and recommendations from Quebec mental health university institutes on the working paper of the provincial forum for the 2014-2020 Mental Health Action Plan].
Quebec's three mental health university institutes (DMHUI, IUSMM and the IUSMQ) and the Centre hospitalier universitaire de Sherbrooke submitted a statement to the provincial consultation forum on the 2014-2020 Mental Health Action Plan (MHAP), which was held in January 2014 and organized by the Ministère de la Santé et des Services sociaux (MSSS). This article presents these institutes' main recommendations. Mental health university institutes deliver a wide and diverse range of services. They know about the challenges of organizing mental health services and are aware of national and international trends in the delivery of the best organizational and clinical practices in mental health. It is therefore as key stakeholders in the mental health care network that they commented on each component in the working paper. The proposed orientations are consistent with the 2005-2010 MHAP. The presented themes clearly reflect current issues, although the guidelines must be more explicit regarding the vision of how services will be organized in coming years. These institutes therefore suggest that the following principles be included: the full exercise of citizenship rights, the organization of services within integrated networks, performance, continuous improvement and innovation, as well as a global and integrated vision of health. The complexity of today's problems requires flexibility, complementarity and continuity of services, particularly for youth, aboriginals, and people with concomitant disorders. These institutions therefore stress the importance of prevention, early intervention programs, and increased support for first-line general practitioners and health care professionals. They also emphasized that specialized inpatient and outpatient services should not be neglected. Community services must also be structured around various levels of support, such as ICM and ACT, as well as around specialized programs available in hospital outpatient clinics. The development and transfer of knowledge remain a central issue when it comes to improving the mental health of the general population. The consolidation of ultra-specialized services, teaching and research should be included in the next MHAP. Finally, a global health perspective must go beyond the MSSS framework to become a governmental and interministerial commitment based on a vision of public mental health that incorporates the health status of the general population and accounts for social determinants. It is important to have a national plan that promotes a vision. This plan must be part of an interministerial action plan that truly supports the full exercise of citizenship rights and the fight against stigmatization in collaboration with people who use these services and their families.


Spatial analysis of melioidosis distribution in a suburban area.
Burkholderia pseudomallei, the causative agent of melioidosis is associated with soil. This study used a geographic information system (GIS) to determine the spatial distribution of clinical cases of melioidosis in the endemic suburban region of Townsville in Australia. A total of 65 cases over the period 1996-2008 were plotted using residential address. Two distinct groupings were found. One was around the base of a hill in the city centre and the other followed the old course of a major waterway in the region. Both groups (accounting for 43 of the 65 cases examined) are in areas expected to have particularly wet topsoils following intense rainfall, due to soil type or landscape position.


Effects of CeO2 Nanoparticles on Terrestrial Isopod Porcellio scaber: Comparison of CeO2 Biological Potential with Other Nanoparticles.
Nano-sized cerium dioxide (CeO2) particles are emerging as an environmental issue due to their extensive use in automobile industries as fuel additives. Limited information is available on the potential toxicity of CeO2 nanoparticles (NPs) on terrestrial invertebrates through dietary exposure. In the present study, the toxic effects of CeO2 NPs on the model soil organism Porcellio scaber were evaluated. Nanotoxicity was assessed by monitoring the lipid peroxidation (LP) level and feeding rate after 14-days exposure to food amended with nano CeO2. The exposure concentration of 1000 μg of CeO2 NPs g-1 dry weight food for 14 days significantly increased both the feeding rate and LP. Thus, this exposure dose is considered the lowest observed effect dose. At higher exposure doses of 2000 and 5000 μg of CeO2 NPs g-1 dry weight food, NPs significantly decreased the feeding rate and increased the LP level. Comparative studies showed that CeO2 NPs are more biologically potent than TiO2 NPs, ZnO NPs, CuO NPs, CoFe2O4 NPs, and Ag NPs based on feeding rate using the same model organism and experimental setup. Based on comparative metal oxide NPs toxicities, the present results contribute to the knowledge related to the ecotoxicological effects of CeO2 NPs in terrestrial invertebrates exposed through feeding.


Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study.
Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes. In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13 000/μL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (<200 IU/L, 200-500 IU/L, and >500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383. Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration. Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing. Acceleron Pharma.


Volume loss in the deep gray matter and thalamic subnuclei: a longitudinal study on disability progression in multiple sclerosis.
Volume loss in the deep gray matter (DGM) has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and is thought to progress throughout the disease course. To investigate the impact and predictive value of volume loss in DGM and thalamic subnuclei on disability worsening in patients MS over a 6-year follow-up period. Hundred and seventy-nine patients with RRMS (132 women; median Expanded Disability Status Scale, EDSS: 2.5) and 50 with SPMS (27 women; median EDSS: 4.5) were included in the study. Patients underwent annual EDSS assessments and annual MRI at 1.5 T. DGM/thalamic subnuclei volumes were identified on high-resolution T1-weighted. A hierarchical linear mixed model for each anatomical DGM area and each thalamic subnucleus was performed to investigate the associations with disability scores. Cox regression was used to estimate the predictive properties of volume loss in DGM and thalamic subnuclei on disease worsening. In the whole sample and in RRMS, volumes of the thalamus and the striatum were associated with the EDSS; however, only thalamic volume loss was associated with EDSS change at follow-up. Regarding thalamic subnuclei, volume loss in the anterior nucleus, the pulvinar and the ventral anterior nucleus was associated with EDSS change in the whole cohort. A trend was observed for the ventral lateral nucleus. Volume loss in the anterior and ventral anterior nuclei was associated with EDSS change over time in patients with RRMS. Moreover, MS phenotype and annual rates of volume loss in the thalamus and ventral lateral nucleus were predictive of disability worsening. These results highlight the relevance of volume loss in the thalamus as a key metric for predicting disability worsening as assessed by EDSS (in RRMS). Moreover, the volume loss in specific nuclei such as the ventral lateral nucleus seems to play a role in disability worsening.


Women hold up half the sky - and half the burden of the HIV epidemic.
It has been said that women hold up half the sky. In the HIV epidemic, women carry half the burden of the epidemic, perhaps even more. The HIV burden on women is dramatically higher in some regions, certain age groups and among marginalized groups, such as female sex workers. Women's vulnerability to HIV is exacerbated by gender inequality and domestic violence. The global effort towards elimination of paediatric HIV and keeping mothers alive deserves applause. However, the needs of women go beyond their child-bearing age or potentials and/or reproductive desires and must be recognized in the global HIV agenda. In particular, more female-controlled prevention tools are urgently required to allow women to protect themselves. It is time to turn the tide through promoting gender equality and genuinely committing to gender-responsive policies and programmes, and encouraging a more gender-aware research agenda that can generate necessary evidence. In recognition of International Women's Day, the Journal of the International AIDS Society is pleased to launch a thematic series to highlight articles that address the different dimensions of HIV as they relate to women.


Basket of options: Unpacking the concept.
How to stimulate technological change to enhance agricultural productivity and reduce poverty remains an area of vigorous debate. In the face of heterogeneity among farm households and rural areas, one proposition is to offer potential users a 'basket of options' - a range of agricultural technologies from which potential users may select the ones that are best suited to their specific circumstances. While the idea of a basket of options is now generally accepted, it has attracted little critical attention. In this paper, we reflect on outstanding questions: the appropriate dimensions of a basket, its contents and how they are identified, and how a basket might be presented. We conceive a basket of options in terms of its depth (number of options related to a problem or opportunity) and breadth (the number of different problems or opportunities addressed). The dimensions of a basket should reflect the framing of the problem or opportunity at hand and the objective in offering the basket. We recognise that increasing the number of options leads to a trade-off by decreasing the fraction of those options that are relevant to an individual user. Farmers might try out, adapt or use one or more of the options in a basket, possibly leading to a process of technological change. We emphasise that the selection (or not) of specific options from the basket, and potential adaptation of the options, provide important opportunities for learning. Baskets of options can therefore be understood as important boundary concepts that invite critical engagement, comparison and discussion. Significant knowledge gaps remain, however, about the best ways to present the basket and to guide potential users to select the options that are most relevant to them.


Functional and topological characteristics of mammalian regulatory domains.
Long-range regulatory interactions play an important role in shaping gene-expression programs. However, the genomic features that organize these activities are still poorly characterized. We conducted a large operational analysis to chart the distribution of gene regulatory activities along the mouse genome, using hundreds of insertions of a regulatory sensor. We found that enhancers distribute their activities along broad regions and not in a gene-centric manner, defining large regulatory domains. Remarkably, these domains correlate strongly with the recently described TADs, which partition the genome into distinct self-interacting blocks. Different features, including specific repeats and CTCF-binding sites, correlate with the transition zones separating regulatory domains, and may help to further organize promiscuously distributed regulatory influences within large domains. These findings support a model of genomic organization where TADs confine regulatory activities to specific but large regulatory domains, contributing to the establishment of specific gene expression profiles.


The use of ketamine plus diazepam anaesthesia to increase the radiosensitivity of a C3H mouse mammary adenocarcinoma in hyperbaric oxygen.
The radiation response of mammary tumours transplanted into syngeneic C3H mice has been measured with the animals breathing air or 100% oxygen at 290 kPa (HPO), either with or without ketamine plus diazepam anaesthesia. The single doses needed to cure 37% of tumours within 40 days (TCD37/40) for mice anaesthetised with ketamine plus diazepam and for unanaesthetised mice irradiated in air were not significantly different, 66.5 Gy and 68.8 Gy respectively. When animals were irradiated in HPO, the TCD37 value was significantly reduced from 60 Gy with no anaesthetic to 41 Gy with ketamine plus diazepam anaesthesia; an enhancement ratio (ER) of 1.5. The total ER from no anaesthetic in air to anaesthetic in HPO was 1.7 (68.8/41). There was less CNS toxicity for ketamine plus diazepam than for sodium pentobarbitone anaesthesia in mice treated in HPO. The combination of ketamine and diazepam is an unusual anaesthetic in that it maintains blood pressure, cardiac output and respiration in man. Vascular effects and lowered body and tumour temperatures may also have influenced tumour oxygenation and radiation response.


Dorsoventral patterning of the vertebrate neural tube is conserved in a protochordate.
The notochord and dorsal ectoderm induce dorsoventral compartmentalization of the vertebrate neural tube through the differential regulation of genes such as HNF-3beta, Pax3, Pax6 and snail. Here we analyze the expression of HNF-3beta and snail homologues in the ascidian, Ciona intestinalis, a member of the subphylum Urochordata, the earliest branch in the chordate phylum. A combination of in situ hybridization and promoter fusion analyses was used to demonstrate that the Ciona HNF-3beta homologue is expressed in the ventralmost ependymal cells of the neural tube, while the Ciona snail homologue is expressed at the junction between the invaginating neuroepithelium and dorsal ectoderm, similar to the patterns seen in vertebrates. These findings provide evidence that dorsoventral compartmentalization of the chordate neural tube is not an innovation of the vertebrates. We propose that precursors of the floor plate and neural crest were present in a common ancestor of both vertebrates and ascidians.


Vestibular Disorders: Pearls and Pitfalls.
Dizziness and vertigo are symptoms that commonly lead patients to seek neurologic or emergency care. Because symptoms are often vague and imprecise, a systematic approach is essential. By categorizing vestibular disorders based on the timing, triggers, and duration of symptoms, as well as emphasizing focused ocular motor and vestibular examinations, the majority of vestibular diagnoses can be made at the bedside. This paper will discuss the pearls and pitfalls in the history and examination of the most common acute, episodic, and chronic vestibular disorders.


Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive human disease associated with multiple deletions of skeletal muscle mitochondrial DNA (mtDNA), which have been ascribed to a defect in communication between the nuclear and mitochondrial genomes. Examination of 12 MNGIE probands revealed homozygous or compound-heterozygous mutations in the gene specifying thymidine phosphorylase (TP), located on chromosome 22q13.32-qter. TP activity in leukocytes from MNGIE patients was less than 5 percent of controls, indicating that loss-of-function mutations in TP cause the disease. The pathogenic mechanism may be related to aberrant thymidine metabolism, leading to impaired replication or maintenance of mtDNA, or both.


A metal-lustrous porphyrin foil.
A metal-lustrous self-standing film, named "porphyrin foil", was formed from a glass-forming polymeric porphyrin. The amorphous glass nature of the porphyrin foil played a key role in spontaneously producing a smooth surface. Its sharp contrast in intense absorption and specular reflection of light at each wavelength provided a brilliant metallic lustre.


Multitarget deep brain stimulation for clinically complex movement disorders.
Deep brain stimulation (DBS) of single-target nuclei has produced remarkable functional outcomes in a number of movement disorders such as Parkinson's disease, essential tremor, and dystonia. While these benefits are well established, DBS efficacy and strategy for unusual, unclassified movement disorder syndromes is less clear. A strategy of dual pallidal and thalamic electrode placement is a rational approach in such cases where there is profound, medically refractory functional impairment. The authors report a series of such cases: midbrain cavernoma hemorrhage with olivary hypertrophy, spinocerebellar ataxia-like disorder of probable genetic origin, Holmes tremor secondary to brainstem stroke, and hemiballismus due to traumatic thalamic hemorrhage, all treated by dual pallidal and thalamic DBS. All patients demonstrated robust benefit from DBS, maintained in long-term follow-up. This series demonstrates the flexibility and efficacy, but also the limitations, of dual thalamo-pallidal stimulation for managing axial and limb symptoms of tremors, dystonia, chorea, and hemiballismus in patients with complex movement disorders.


Most cancer in firefighters is due to radio-frequency radiation exposure not inhaled carcinogens.
Recent reviews and reports of cancer incidence and mortality in firefighters conclude that they are at an increased risk of a number of cancers. These include leukemia, multiple myeloma, non-Hodgkin's lymphoma, male breast cancer, malignant melanoma, and cancers of the brain, stomach, colon, rectum, prostate, urinary bladder, testes, and thyroid. Firefighters are exposed to a long list of recognized or probable carcinogens in combustion products and the presumed route of exposure to these carcinogens is by inhalation. Curiously, respiratory system cancers and diseases are usually not increased in firefighters as they are in workers exposed to known inhaled carcinogens. The list of cancers with increased risk in firefighters strongly overlaps the list of cancers at increased risk in workers exposed to electromagnetic fields (EMF) and radiofrequency radiation (RFR). Firefighters have increased exposure to RFR in the course of their work, from the mobile two-way radio communications devices which they routinely use while fighting fires, and at times from firehouse and fire vehicle radio transmitters. I suggest that some of the increased cancer risk in firefighters is caused by RFR exposure, and is therefore preventable. The precautionary principle should be applied to reduce the risk of cancer in firefighters, and workman's compensation rules will necessarily need to be modified.


Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial.
Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4-10 metastatic cancer lesions. One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4-10 oligometastatic lesions. Clinicaltrials.gov identifier: NCT03721341 . Date of registration: October 26, 2018.


Transrectal ultrasound for monitoring murine orthotopic prostate tumor.
The mouse orthotopic prostate tumor model has been recognized as an ideal preclinical animal model simulating the anatomical and biological milieu of the prostate. In comparison with the subcutaneous tumor model, the only disadvantage of this model is the difficulty of chronological tumor growth monitoring. We have applied recent endoluminal ultrasound technology, transrectal ultrasonography (TRUS), to the monitoring of mouse orthotopic prostate tumors. A 6 Fr. 20 MHz catheter-based radial scan probe was used and TRUS was performed without any prior preparation including anesthesia. Orthotopic tumors were initiated by inoculation of 5000 RM-9 cells into the dorsal prostate of 12-week-old C57BL/6 male mice. The tumor growth was monitored by TRUS from day 3 to day 21. In addition, TRUS was performed to detect tumor growth suppression after intraperitoneal administration of cis-diamminedichloroplatinum (CDDP). By ultrasound, tumors became detectable 7 days after tumor cell inoculation. TRUS images were clear and parallel to actual tumor growth. The tumor volume (X) calculated by TRUS correlated significantly with the actual tumor weight (Y) measured at autopsy; Y = 101.653 + 1.174X (R = 0.930, P < 0.001). Similarly, tumor growth suppression induced by CDDP was clearly detected by TRUS with reasonable accuracy. A high resolution TRUS allows simple and reliable monitoring of in situ tumor growth and growth suppression, making the mouse orthotopic prostate tumor model more efficient.


Urban-Rural Differences in the Prevalence of Self-Reported Diabetes and its Risk Factors: The WHO STEPS Iranian Noncommunicable Disease Risk Factor Surveillance in 2011.
The high prevalence of diabetes in Iran and other developing countries is chiefly attributed to urbanization. The objectives of the present study were to assess the prevalence of self-reported diabetes and to determine its associated risk factors. This study is a part of the national noncommunicable disease risk factor surveillance, conducted in 31 provinces of Iran in 2011. First, 10069 individuals, between 20 and 70 years old (3036 individuals from rural and 7033 from urban areas), were recruited. The major risk factors were studied using a modified WHO STEPS approach. Diabetes was considered based on self-reported diabetes. The prevalence of self-reported diabetes was 10% overall. The prevalence in the rural and urban settings was 7.4% and 11.1%, respectively. Moderate physical activity (OR=0.45, 95% CI=0.29-0.71) and family history of diabetes)OR=6.53, 95% CI=4.29-9.93) were the most important risk factors among the rural residents and systolic blood pressure (OR=1.01, 95% CI=1-1.02), waist circumference (OR=1.02, 95% CI=1.01-1.03), and overweight (OR=1.36, 95% CI= 1-1.84) were significantly associated with self-reported diabetes in the urban residents. The prevalence of self-reported diabetes in the urban setting was higher than that in the rural setting. Physical inactivity, abdominal obesity, and high blood pressure were the most important risk factors associated with self-reported diabetes in Iran.


Novel antimonene tunneling field-effect transistors using an abrupt transition from semiconductor to metal in monolayer and multilayer antimonene heterostructures.
Recently, a mono-elemental two-dimensional (2-D) material, namely antimonene, with a large band gap, decent mobility and ambient stability has been extensively researched. Interestingly, although antimonene is a semiconductor with a sizable band gap in the monolayer, it is transformed to a metal in the multilayer. Inspired by this thickness dependent semiconductor to metal transition, we propose novel antimonene tunneling field-effect transistors (TFETs) based on the lateral monolayer (semiconducting)/multilayer (metallic)/monolayer (semiconducting) heterostructure. Our antimonene TFETs consist of a semiconducting monolayer source, channel and a drain and a small metallic multilayer region between the source and the channel. The local multilayer region introduces gapless metallic states which dramatically enhance the tunneling probability and hence result in a large current. To investigate the effect of a metallic multilayer on device performances, we carried out ab-initio electronic structure and quantum transport calculations for several antimonene TFETs based on different monolayer/multilayer/monolayer heterostructures. Simulation shows that even ∼1 nm scale nanostructured multilayer significantly boosts the current and enables abrupt device switching. More extensive evaluation is performed through benchmarking with phosphorene TFETs which have been identified as the best 2-D material based TFETs so far. In terms of the main figures of merit for FETs such as the intrinsic delay time and the power delay product, antimonene heterostructure TFETs outperform phosphorene TFETs, primarily due to the elimination of the tunneling barrier by the locally constructed multilayer antimonene.


Comparative effectiveness of electro-acupuncture versus gabapentin for sleep disturbances in breast cancer survivors with hot flashes: a randomized trial.
Sleep disturbance is a major consequence of hot flashes among breast cancer survivors. This study evaluated the effects of electro-acupuncture (EA) versus gabapentin (GP) for sleep disturbances among breast cancer survivors experiencing daily hot flashes. We analyzed data from a randomized controlled trial involving 58 breast cancer survivors experiencing bothersome hot flashes at least two times per day. Participants were randomly assigned to receive 8 weeks of EA or daily GP (total dose of 900 mg/d). The primary outcome was change in the total Pittsburgh Sleep Quality Index (PSQI) score between groups at week 8. Secondary outcomes include specific PSQI domains. By the end of treatment at week 8, the mean reduction in PSQI total score was significantly greater in the EA group than the GP group (-2.6 vs -0.8, P = 0.044). The EA also had improved sleep latency (-0.5 vs 0.1, P = 0.041) and sleep efficiency (-0.6 vs 0.0, P = 0.05) compared with the GP group. By week 8, the EA group had improved sleep duration, less sleep disturbance, shorter sleep latency, decreased daytime dysfunction, improved sleep efficiency, and better sleep quality (P < 0.05 for all) compared with baseline, whereas the GP group improved in duration and sleep quality only (P < 0.05). Among women experiencing hot flashes, the effects of EA are comparable with GP for improving sleep quality, specifically in the areas of sleep latency and efficiency. Larger randomized controlled trials with longer follow-ups are needed to confirm this preliminary finding.


Regional cell movement and tissue patterning in the zebrafish embryo revealed by fate mapping with caged fluorescein.
Determination of fate maps and cell lineage tracing have previously been carried out in the zebrafish embryo by following the progeny of individual cells injected with fluorescent dyes. We review the information obtained from these experiments and then present an approach to fate mapping and cell movement tracing, utilizing the activation of caged fluorescein-dextran. This method has several advantages over single-cell injections in that it is rapid, allows cells at all depths in the embryo to be marked, can be used to follow cells starting at any time during development, and allows an appreciation of the movements of cells located in a coherent group at the time of uncaging. We demonstrate that the approach is effective in providing additional and complementary information on prospective mesoderm and brain tissues studied previously. We also present, for the first time, a fate map of placodal tissues including the otic vesicle, lateral line, cranial ganglia, lens, and olfactory epithelium. The prospective placodal cells are oriented at the 50% epiboly stage on the ventral side of the embryo with anterior structures close to the animal pole, and posterior structures nearer to the germ ring.


Emerging Safety of Intramedullary Transplantation of Human Neural Stem Cells in Chronic Cervical and Thoracic Spinal Cord Injury.
Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI. Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant. A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.


Stability of solitons in birefringent optical fibers. I: equal propagation amplitudes.
The effect of birefringence on soliton propagation in single-mode optical fibers is considered. Emphasis is on solitons with multipicosecond widths that are appropriate for communications applications. It is shown that while linear birefringence will lead to a substantial splitting of the two polarizations over 20 km, this effect can be eliminated by use of the Kerr nonlinearity. Above a certain amplitude threshold, the central frequency of each polarization shifts just enough to lock the two polarizations together.


Community-based surveillance of unaccompanied and separated children in drought-affected northern Ethiopia.
Children separated from their caregivers in humanitarian emergencies are vulnerable to multiple risks. However, no field-tested methods exist to capture ongoing changes in the frequency and nature of separation in these contexts over the course of a protracted crisis. Recognizing this gap, a mobile phone-based surveillance system was established in a drought-affected district in northern Ethiopia to assess the feasibility of using community focal points to monitor cases of unaccompanied and separated children. A total of 29 focal points were recruited through village elections from 10 villages in the district. Feasibility was assessed directly by measuring the number and quality of messages sent by the focal points each week. The team also evaluated the implementation process and any challenges that arose through observations and key informant interviews with focal points at the conclusion of the project measuring frequency of employing various information gathering techniques, challenges faced, and perceptions of community expectations. Likert scales were used to measure overall satisfaction with the experience of being a focal point, self-assessed difficulty of being a focal point, perceived likelihood of cases captured, and motivation. Over a six-month period, the focal points reported 48 cases of separation. The majority of separated children (64.6%) were 10 years of age or older. Work was a major driver of separation, especially for boys. Age, sex, role in community, and density of community had no statistically significant impact on focal point performance in terms of frequency, accuracy, or consistency of messages. The focal points themselves reported high levels of motivation, but suggested several areas for improvement in the surveillance system. Without the surveillance system, most of these children would have otherwise been unrecognized. From a technical standpoint the system was successful and resilient in the face of unexpected external challenges. However, focal point participation and accuracy was variable over time and across groups and diminished towards the later months of the study, suggesting that the community-based approach may require additional supports to ensure that the surveillance system is able to accurately capture trends over time.


Experimental Demonstration of Supervised Learning in Spiking Neural Networks with Phase-Change Memory Synapses.
Spiking neural networks (SNN) are computational models inspired by the brain's ability to naturally encode and process information in the time domain. The added temporal dimension is believed to render them more computationally efficient than the conventional artificial neural networks, though their full computational capabilities are yet to be explored. Recently, in-memory computing architectures based on non-volatile memory crossbar arrays have shown great promise to implement parallel computations in artificial and spiking neural networks. In this work, we evaluate the feasibility to realize high-performance event-driven in-situ supervised learning systems using nanoscale and stochastic analog memory synapses. For the first time, the potential of analog memory synapses to generate precisely timed spikes in SNNs is experimentally demonstrated. The experiment targets applications which directly integrates spike encoded signals generated from bio-mimetic sensors with in-memory computing based learning systems to generate precisely timed control signal spikes for neuromorphic actuators. More than 170,000 phase-change memory (PCM) based synapses from our prototype chip were trained based on an event-driven learning rule, to generate spike patterns with more than 85% of the spikes within a 25 ms tolerance interval in a 1250 ms long spike pattern. We observe that the accuracy is mainly limited by the imprecision related to device programming and temporal drift of conductance values. We show that an array level scaling scheme can significantly improve the retention of the trained SNN states in the presence of conductance drift in the PCM. Combining the computational potential of supervised SNNs with the parallel compute power of in-memory computing, this work paves the way for next-generation of efficient brain-inspired systems.


Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex.
Both the hippocampus and the medial prefrontal cortex (mPFC) play an important role in the negative feedback regulation of hypothalamic-pituitary-adrenal (HPA) activity during physiologic and behavioral stress. Moreover, chronic behavioral stress is known to affect the morphology of CA3c pyramidal neurons in the rat, by reducing total branch number and length of apical dendrites. In the present study, we investigated the effects of behavioral stress on the mPFC, using the repeated restraint stress paradigm. Animals were perfused after 21 days of daily restraint, and intracellular iontophoretic injections of Lucifer Yellow were carried out in pyramidal neurons of layer II/III of the anterior cingulate cortex and prelimbic area. Cellular reconstructions were performed on apical and basal dendrites of pyramidal neurons in layer II/III of the anterior cingulate and prelimbic cortices. We observed a significant reduction on the total length (20%) and branch numbers (17%) of apical dendrites, and no significant reduction in basal dendrites. These cellular changes may impair the capacity of the mPFC to suppress the response of the HPA axis to stress, and offer an experimental model of stress-induced neocortical reorganization that may provide a structural basis for the cognitive impairments observed in post-traumatic stress disorder.


The effect of common wrist orthoses on the stiffness of wrist rotations.
Wrist orthoses (also known as splints, braces, or supports) are commonly used to support or restrict the motion of a weak or injured wrist. These orthoses generally function by stiffening the wrist joint. Therefore, choosing the proper orthosis (or improving orthoses) requires that we understand their stiffness properties. In this study, we present a method for measuring the stiffness of wrist orthoses, and we apply this method to 12 of the most common wrist orthoses. We found similarities and differences between these orthoses, indicating that different orthoses have different effects on the wrist joint and, presumably, on wrist behavior. In particular, all six orthoses with a stay on the volar side or the volar and dorsal sides added a significant amount of stiffness to the wrist joint. In contrast, only one of three orthoses with a stay on the dorsal side and none of the three orthoses without stays exhibited a significant amount of stiffness, calling into question their ability to support the wrist joint. This work lays a foundation for future studies investigating the effect of wrist orthosis stiffness on wrist behavior and how wrist orthosis stiffness can be designed to produce behavior that facilitates healing.


Hyperhomocysteinemia is a risk factor for coronary arteriosclerosis in Japanese patients with type 2 diabetes.
An increased plasma homocysteine level is an important risk factor for vascular disease, including coronary atherosclerosis, in the general population. However, the role of hyperhomocysteinemia in the development of coronary artery disease (CAD) in patients with type 2 diabetes is unknown. Therefore, we have endeavored to determine the relationship between plasma homocysteine levels and the presence of coronary arteriosclerosis in patients with type 2 diabetes. The study group consisted of 145 Japanese patients (95 men and 50 women) who underwent routine coronary angiography to assess chest pain or suspected CAD. Plasma total homocysteine level, lipid level, and parameters of fibrinolytic activity were measured. All patients were identified as diabetic or nondiabetic by the new American Diabetes Association (ADA) criteria. The diagnoses of all patients studied were confirmed by coronary angiography. The severity of coronary artery stenosis was quantified using CAD scoring on the basis of prior reports, and subjects were graded as nonstenotic, stenotic single-vessel, stenotic two-vessel, or stenotic three-vessel based on the number of stenotic coronary arteries. Patients were classified into two groups: those with stenotic vessels and those without stenotic vessels. The plasma homocysteine level was significantly higher in patients with than in patients without stenotic vessels (13.8 +/- 3.9 vs. 11.7 +/- 3.9 mumol/l, respectively; P = 0.0009). The number of stenotic coronary arteries, which was used to grade each case as nonstenotic, stenotic single-vessel, stenotic two-vessel, or stenotic three-vessel, was related only to the total homocysteine level in the diabetic (diabetes mellitus [DM]) group, but it was associated with lipoprotein(a) in the nondiabetic (non-diabetes mellitus [non-DM]) group. Spearman's rank correlation test demonstrated that the plasma homocysteine level was strongly correlated with CAD score, both in the entire study group and in the DM group (P = 0.003 for the entire group and P = 0.011 for the DM group). Hyperhomocysteinemia, which was defined as total homocysteine level > 14.0 mumol/l, was seen in 57 (39.3%) of the patients. The CAD score was highest in diabetic patients with hyperhomocysteinemia (P < 0.05). There seems to be a clear relationship between hyperhomocysteinemia and an increased risk of coronary arteriosclerosis in Japanese patients with type 2 diabetes.


Mitochondrial fusion protects against neurodegeneration in the cerebellum.
Mutations in the mitochondrial fusion gene Mfn2 cause the human neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the cellular basis underlying this relationship is poorly understood. By removing Mfn2 from the cerebellum, we established a model for neurodegeneration caused by loss of mitochondrial fusion. During development and after maturity, Purkinje cells require Mfn2 but not Mfn1 for dendritic outgrowth, spine formation, and cell survival. In vivo, cell culture, and electron microscopy studies indicate that mutant Purkinje cells have aberrant mitochondrial distribution, ultrastructure, and electron transport chain activity. In fibroblasts lacking mitochondrial fusion, the majority of mitochondria lack mitochondrial DNA nucleoids. This deficiency provides a molecular mechanism for the dependence of respiratory activity on mitochondrial fusion. Our results show that exchange of mitochondrial contents is important for mitochondrial function as well as organelle distribution in neurons and have important implications for understanding the mechanisms of neurodegeneration due to perturbations in mitochondrial fusion.


The Rezūm system - a minimally invasive water vapor thermal therapy for obstructive benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) and accompanying lower urinary tract symptoms (LUTS) sits in the top ten prominent and costly disease conditions in men over 50 years of age. In the United States it is the most common diagnosis made by urologists for men 45 to 74 years of age. Twenty percent of the population will reach 65 years of age or older by 2030, and those over 85 years will represent the fastest growing segment of our population. The prevalence of symptomatic BPH increases proportionally with the aging population. It is estimated that BPH now affects 6% of the male population worldwide. Moreover, in Canada, the estimated BPH prevalence is more than 1 million men aged 50 years and older. Among the various surgical treatments, Rezūm water vapor thermal therapy has been developed as a unique, rapid and reproducible minimally invasive surgical treatment exhibiting safe and early effective relief of LUTS/BPH. The targeted prostate tissue ablation is amenable to all zones of the prostate including intravesical median lobes. We present our experiences with this technique, which can be quickly performed under local anesthesia in an office setting.


One-Year Outcomes After Minimally Invasive Sacrocolpopexy.
The primary aim of this study was to report anatomic, symptom, and quality of life outcomes in women with symptomatic stage 2 or greater prolapse 1 year after randomization to robotic and laparoscopic sacrocolpopexy. This is a planned ancillary analysis of the Abdominal Colpopexy: Comparison of Endoscopic Surgical Strategies trial, a randomized comparative effectiveness trial comparing costs and outcomes of robotic and laparoscopic sacrocolpopexy at 2 academic medical centers. At baseline and 1 year after surgery, women underwent standardized assessment including validated subjective pelvic floor outcomes and physical examination with prolapse assessment. Sixty six (85%) of 78 randomized participants completed 1-year follow-up: 33 (87%) of 38 in the laparoscopic arm and 33 (83%) of 40 in the robotic arm (P = 0.59). Ninety-seven percent (32/33) in the laparoscopic group and 100% (33/33) in the robotic arm considered that their prolapse symptoms improved (P = 0.999). The cohort had significant improvement in all pelvic floor symptom and quality of life measures, which did not differ by treatment arm. Of women who were sexually active at 1 year, sexual function improved in both cohorts. No new serious adverse events, including mesh exposure or reoperation for prolapse, were identified between 6 months and 1 year after surgery. No women had a sacrocolpopexy mesh complication or reoperation for mesh exposure. Minimally invasive sacrocolpopexy is associated with significant improvement in pelvic floor symptoms, anatomy, and sexual function. In addition, mesh exposure rates with lightweight polypropylene mesh seem to be lower than those reported with multifilament and heavier polypropylene mesh.


Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.
The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient.


Casein kinase TbCK1.2 regulates division of kinetoplast DNA, and movement of basal bodies in the African trypanosome.
The single mitochondrial nucleoid (kinetoplast) of Trypanosoma brucei is found proximal to a basal body (mature (mBB)/probasal body (pBB) pair). Kinetoplast inheritance requires synthesis of, and scission of kinetoplast DNA (kDNA) generating two kinetoplasts that segregate with basal bodies into daughter cells. Molecular details of kinetoplast scission and the extent to which basal body separation influences the process are unavailable. To address this topic, we followed basal body movements in bloodstream trypanosomes following depletion of protein kinase TbCK1.2 which promotes kinetoplast division. In control cells we found that pBBs are positioned 0.4 um from mBBs in G1, and they mature after separating from mBBs by at least 0.8 um: mBB separation reaches ~2.2 um. These data indicate that current models of basal body biogenesis in which pBBs mature in close proximity to mBBs may need to be revisited. Knockdown of TbCK1.2 produced trypanosomes containing one kinetoplast and two nuclei (1K2N), increased the percentage of cells with uncleaved kDNA 400%, decreased mBB spacing by 15%, and inhibited cytokinesis 300%. We conclude that (a) separation of mBBs beyond a threshold of 1.8 um correlates with division of kDNA, and (b) TbCK1.2 regulates kDNA scission. We propose a Kinetoplast Division Factor hypothesis that integrates these data into a pathway for biogenesis of two daughter mitochondrial nucleoids.


Cardiovascular risk profile in women and dementia.
There is growing evidence for the importance of cardiovascular risk factors in dementia development, including Alzheimer's disease. As cardiovascular risk profiles vary greatly by gender, with men suffering a greater burden of cardiovascular risk in midlife, this could lead to differences in dementia risk. To explore current evidence on the association between components of the cardiovascular risk profile and dementia risk in women and men, we reviewed all studies reporting the risk of dementia associated with cardiovascular risk factors stratified by gender and found 53 eligible articles out of over 4,000 published since the year 2000. Consistent results were found: 1) for exposures acting specifically in women: Overweight/obesity (harmful) and physical activity (protective), and 2) for exposures acting similarly in women and men: Moderate alcohol (protective) and hypertension, diabetes, and depression (harmful). A modified effect of tobacco or high cholesterol/statin use remained controversial. Available data do not allow us to assess whether selection of men with healthier cardiovascular profile (due to cardiovascular death in midlife) could lead in late life either to a difference in the distribution of risk factors or to a differential effect of these risk factors by gender. We recommend that results on dementia risk factors, especially cardiovascular ones, be reported systematically by gender in all future studies. More generally, as cardiovascular risk profiles evolve over time, more attention needs to be paid to the detection and correction of cardiovascular risk factors, as early as possible in the life course, and as actively in women as in men.


Predictors of smoking relapse in a cohort of adolescents and young adults in Monastir (Tunisia).
Smoking prevalence in adolescents and young adults is substantially elevated in Tunisia. Moreover, there is a lack of knowledge regarding the effectiveness and associated factors in smoking cessation interventions among adolescents and young adults. This study aims at identifying the major factors leading to smoking relapse among adolescents and young adults in the region of Monastir, Tunisia. We carried out a prospective cohort study at the smoking cessation center of the University hospital of Monastir, Tunisia. The population study consisted of all adolescents and young adults (15-30 years) consulted during a period of two years (2009 - 2010). A questionnaire was used to explore the patient's sociodemographic characteristics, smoking history, nicotine dependence (Fagerstrom test) and anxiety / depression (Hospital Anxiety and Depression Scale). A telephone survey was conducted in July 2011 to assess smoking cessation results. A multivariate Cox regression was used to identify predictors of smoking relapses. A total of 221 adolescents and young adults were included in this study with a mean age of 25.5 ± 3.9 years. At follow up, 59 study participants (26.7%) were abstinent and the overall median abstinence was 2 months. In the multivariate analysis smoking relapse was associated with being an adolescent patient (HR 2.16; 95% CI: 1.54-3.05), medium or higher nicotine dependence at baseline (HR 2.66, 95% CI: 1.06-7.05 and HR 3.12, 95% CI: 1.20-8.12 respectively), not receiving treatment (HR 1.70, 95% CI: 1.25-2.33) and have friend who is a smoker (HR 1.63; 95% CI: 0.96-2.79). The results of this study provide important information about beneficial effect of smoking cessation support for adolescent and young adults. More efforts must be deployed to deal with contributing factors to smoking relapse.


Malignant peritoneal mesothelioma in women: a study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis.
Seventy-five malignant mesotheliomas of the peritoneum in women were reviewed to highlight their morphologic spectrum. The patients ranged from 17 to 92 (mean, 47.4) years of age. The clinical presentation was usually abdominal or pelvic pain, abdominal swelling (sometimes due to ascites), or a pelvic mass. On microscopic examination, the majority of the tumors had only an epithelial morphology, but 4 were biphasic and 1 was sarcomatoid. The most common epithelial patterns were tubular and papillary (which often coexisted), but 5 tumors were purely diffuse; 2 had cells with abundant glassy eosinophilic cytoplasm (so-called deciduoid mesothelioma). The cells in the tubular and papillary patterns were generally cuboidal with scant to moderate amounts of eosinophilic cytoplasm. Nuclear atypia was usually only mild, although a minority of cases had moderate or even, occasionally, severe atypia. Many tumors had foci that, viewed in isolation, resembled so-called well-differentiated papillary mesothelioma, and accordingly that diagnosis should be made cautiously. Unusual features were lymphoid follicles (13 cases), striking myxoid stroma (5 cases), prominent foamy histiocytes (5 cases), and a striking vascular proliferation (1 case). The varied morphology of peritoneal malignant mesotheliomas may raise a broad differential diagnosis, but in most cases the resemblance to other tumors is limited. Histochemistry, immunohistochemistry, and electron microscopy may provide important aid, particularly when tissue is limited, but should be needed only occasionally.


Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential.
Cancer stem cells (CSCs) are a specific subset of cancer cells that sustain tumor growth and dissemination. They might represent a significant treatment target to reduce malignant progression and prevent tumor recurrence. In solid tumors, several hierarchically organized CSC clones coexist, even within a single tumor. Among them, CSCs displaying an embryonic stem cell 'stemness' signature, based on the expression of Oct-4, Nanog and Sox2, are present in distinct high-grade tumor types associated with poor prognosis. We previously designed a model to isolate pure populations of these CSCs from distinct solid tumors and used it to screen for molecules showing selective toxicity for this type of CSC. Here we show that human immunodeficiency virus (HIV)-protease inhibitors (HIV-PIs) specifically target CSCs expressing an embryonic signature derived from tumors with distinct origins. They reduced proliferation in a dose-dependent manner with a higher specificity as compared with the total population of cancer cells and/or healthy stem cells, and they were efficient in inducing cell death. Lopinavir was the most effective HIV-PI among those tested. It reduced self-renewal and induced apoptosis of CSCs, subsequently impairing in vivo CSC-induced allograft formation. Two key pharmacophores in the LPV structure were also identified. They are responsible for the specificity of CSC targeting and also for the overall antitumoral activity. These results contribute to the identification of molecules presenting selective toxicity for CSCs expressing an embryonic stemness signature. This paves the way to promising therapeutic opportunities for patients suffering from solid cancer tumors of poor prognosis.


Chronic Achilles tendinosis: recommendations for treatment and prevention.
Chronic Achilles tendinosis is a condition with an unknown aetiology and pathogenesis that is often, but not always, associated with pain during loading of the Achilles tendon. Histologically, there are no inflammatory cells, but increased amounts of interfibrillar glycosaminoglycans and changes in the collagen fibre structure and arrangement are seen. In situ microdialysis has confirmed the absence of inflammation. It is a condition that is most often seen among recreational male runners aged between 35 and 45 years, and it is most often considered to be associated with overuse. However, this condition is also seen in patients with a sedentary lifestyle. Chronic Achilles tendinosis is considered a troublesome injury to treat. Nonsurgical treatment most often includes a combination of rest, NSAIDs, correction of malalignments, and stretching and strengthening exercises, but there is sparse scientific evidence supporting the use of most proposed treatment regimens. It has been stated that, in general, nonsurgical treatment is not successful and surgical treatment is required in about 25% of patients. However, in a recent prospective study, treatment with heavy load eccentric calf muscle training showed very promising results and may possibly reduce the need for surgical treatment of tendinosis located in the midportion of the Achilles tendon. The short term results after surgical treatment are frequently very good, but in the few studies with long term follow-up there are signs of a possible deterioration with time. Calf muscle strength takes a long time to recover and, furthermore, a prolonged progressive calcaneal bone loss has been shown on the operated side up to 1 year after surgical treatment.


Gray matter responsiveness to adaptive working memory training: a surface-based morphometry study.
Here we analyze gray matter indices before and after completing a challenging adaptive cognitive training program based on the n-back task. The considered gray matter indices were cortical thickness (CT) and cortical surface area (CSA). Twenty-eight young women (age range 17-22 years) completed 24 training sessions over the course of 3 months (12 weeks, 24 sessions), showing expected performance improvements. CT and CSA values for the training group were compared with those of a matched control group. Statistical analyses were computed using a ROI framework defined by brain areas distinguished by their genetic underpinning. The interaction between group and time was analyzed. Middle temporal, ventral frontal, inferior parietal cortices, and pars opercularis were the regions where the training group showed conservation of gray matter with respect to the control group. These regions support working memory, resistance to interference, and inhibition. Furthermore, an interaction with baseline intelligence differences showed that the expected decreasing trend at the biological level for individuals showing relatively low intelligence levels at baseline was attenuated by the completed training.


In vitro effects of three blood derivatives on human corneal epithelial cells.
We compared the effects of three blood derivatives, autologous serum (AS), platelet-rich plasma (PRP), and serum derived from plasma rich in growth factors (PRGF), on a human corneal epithelial (HCE) cell line to evaluate their potential as an effective treatment for corneal epithelial disorders. The concentrations of epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and fibronectin were quantified by ELISA. The proliferation and viability of HCE cells were measured by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay. Cell morphology was assessed by phase-contrast microscopy. The patterns of expression of several connexin, involucrin, and integrin α6 genes were analyzed by real-time RT-PCR. We found significantly higher levels of EGF in PRGF compared to AS and PRP. However, AS and PRGF induced robust proliferation of HCE cells. In addition, PRGF cultured cells grew as heterogeneous colonies, exhibiting differentiated and non-differentiated cell phenotypes, whereas AS- and PRP-treated cultures exhibited quite homogeneous colonies. Finally, PRGF upregulated the expression of several genes associated with communication and cell differentiation, in comparison to AS or PRP. PRGF promotes biological processes required for corneal epithelialization, such as proliferation and differentiation. Since PRGF effects are similar to those associated with routinely used blood derivatives, the present findings warrant further research on PRGF as a novel alternative treatment for ocular surface diseases.


Indoor PM2.5 in an urban zone with heavy wood smoke pollution: The case of Temuco, Chile.
Temuco is a mid-size city representative of severe wood smoke pollution in southern Chile; however, little is known about the indoor air quality in this region. A field measurement campaign at 63 households in the Temuco urban area was conducted in winter 2014 and is reported here. In this study, indoor and outdoor (24-hr) PM2.5 and its elemental composition were measured and compared. Infiltration parameters and outdoor/indoor contributions to indoor PM2.5 were also determined. A statistical evaluation of how various air quality interventions and household features influence indoor PM2.5 was also performed. This study determined median indoor and outdoor PM2.5 concentrations of 44.4 and 41.8 μg/m3, respectively. An average infiltration factor (0.62 ± 0.06) was estimated using sulfur as a tracer species. Using a simple mass balance approach, median indoor and outdoor contributions to indoor PM2.5 concentrations were then estimated as 12.5 and 26.5 μg/m3, respectively; therefore, 68% of indoor PM2.5 comes from outdoor infiltration. This high percentage is due to high outdoor pollution and relatively high household air exchange rates (median: 1.06 h-1). This study found that S, Br and Rb were dominated by outdoor contributions, while Si, Ca, Ti, Fe and As originated from indoor sources. Using continuous indoor and outdoor PM2.5 measurements, a median indoor source strength of 75 μg PM2.5/min was estimated for the diurnal period, similar to literature results. For the evening period, the median estimate rose to 135 μg PM2.5/min, reflecting a more intense wood burning associated to cooking and space heating at night. Statistical test results (at the 90% confidence level) support the ongoing woodstove replacement program (reducing emissions) and household weatherization subsidies (reducing heating demand) for improving indoor air quality in southern Chile, and suggest that a cookstove improvement program might be helpful as well.


Marital Quality, Loneliness, and Depressive Symptoms Later in Life: The Moderating Role of Own and Spousal Functional Limitations.
Loneliness is a mechanism through which marital quality relates to older adults' mental health. Links between marital quality, loneliness, and depressive symptoms, however, are often examined independent of older adults' functional health. The current study therefore examines whether associations between marital quality, loneliness, and depressive symptoms are contextually dependent on individuals' own (or their spouse's) functional limitations, as well as on gender. Data came from couples (N = 1084) who participated in the Health and Retirement Study (HRS), a nationally representative dataset of older adults (age 50+). We utilized data from the 2014 leave-behind psychosocial questionnaire to measure spousal support/strain and loneliness, and interview data from 2014 to measure baseline depressive symptoms and demographic covariates (e.g., race and education). Depressive symptoms in 2016 served as the focal outcome variable. Findings from a series of path models estimated in MPLUS indicated that loneliness is a mechanism through which spousal support predicts older adults' depressive symptoms. Such linkages, however, were dependent on individuals' own functional limitations and gender. For functionally limited males in particular, spousal support was shown to reduce depressive symptoms insofar as it was associated with lower levels of loneliness; otherwise, it was associated with higher levels of depressive symptoms. Such findings reinforce the importance of taking a contextualized approach when examining associations between support and emotional well-being later in life.


Cognitive vulnerability and implicit emotional processing: imbalance in frontolimbic brain areas?
It has been proposed that the neural basis for cognitive vulnerability to depression involves an imbalance in frontolimbic activity during the processing of cues with a negative affective value. Although the question is central to cognitive theory, whether this association is amplified by diagnosis of an affective disorder or recent life stress has not been investigated. A composite cognitive vulnerability score based on questionnaire assessment was used to predict neural responses to negative emotional stimuli in N = 112 participants. Potential moderating effects of psychiatric diagnosis and negative life events were examined. Main and interaction effects were tested against a threshold of p < .05, family-wise error (FWE) corrected at the cluster level, and the results were small-volume corrected in regions of interest. Cognitive vulnerability predicted higher activation of superior parietal areas (p(FWE) < .01) for negative than for positive faces. The association was significantly stronger in healthy participants. For negative versus control stimuli, cognitive vulnerability predicted higher ventrolateral prefrontal and subgenual anterior cingulate activation (p(FWE) < .05) to equal extents in both groups. We found no evidence for an association with amygdala activation. Life events did not moderate the findings. We concluded that cognitive vulnerability was associated with higher activation of frontoparietal areas during an implicit emotional task. These higher levels of activation may potentially reflect increased effort being required to ignore irrelevant negative emotional information in vulnerable populations.


San Antonio refugees: Their demographics, healthcare profiles, and how to better serve them.
The recent refugee crisis has resulted in the largest burden of displacement in history, with the US being the top resettlement country since 1975. Texas welcomed the second most US-bound refugees in 2016, with a large percentage arriving in San Antonio. Yet, the composition of the San Antonio refugees has not been described and their healthcare needs remain ill-defined. Through this study, we aim at elucidating their demographics and healthcare profiles, with the goal of devising recommendations to help guide refugee program development and guide other refugee resettlement programs. Data from 731 charts belonging to 448 patients at the San Antonio Refugee Health Clinic (SARHC) were extracted and analyzed. Data included age, gender, country of origin, first language, interpretation need, health insurance status, medical history, vital signs, diagnoses, and prescribed medications. Women constituted the majority of patients (n = 267; 56.4%), and the median age of all patients was 39 (Q1:26, Q3:52). Nepali-speaking Bhutanese patients were the most represented group (n = 107, 43.1%), followed by Iraqi (n = 35, 14.1%), Burmese (n = 30, 12.1%), and Iranian (n = 19, 7.7%) refugees. Of those who responded, 200 (86.6%) did not have any form of health insurance. Additionally, 262 (50.9%) had a body-mass index (BMI) in the overweight or obese range. Further, 61.4% (n = 337) had blood pressures in the hypertensive range, while 9.3% (n = 51) had an elevated blood pressure. On average, each patient had 1.9 complaints, with abdominal pain, headaches, and cough being the predominant complaints. Allergic rhinitis, viral upper respiratory infections, and elevated blood pressure were the most common diagnoses. However, the list of common diagnoses differed per country of origin. The SARHC demographics were different from those of other Texas refugees. The rate of the uninsured and the burden of non-communicable diseases were high. Furthermore, each refugee subgroup had a different set of common problems. These findings reveal important considerations for refugee healthcare providers and the unique approach that may be required for different communities.


Latest updates on antiretinal autoantibodies associated with vision loss and breast cancer.
Cancer-associated retinopathy (CAR) is an uncommon paraneoplastic disorder of the retina that is frequently associated with breast cancer in pre- and postmenopausal women older than 50 years. In this review, we will give an update on the current knowledge regarding the association of antiretinal autoantibodies with the breast-CAR syndrome. Women with breast cancer and visual indications of CAR have a significantly increased incidence of autoantibodies (AAbs) against retinal proteins when compared to healthy women. The onset of visual loss in association with antiretinal AAbs peaks 2 to 3 years after the clinical diagnosis of breast cancer. Differences in severity of symptoms between women with or without antiretinal AAbs are evident, revealing more unfavorable presentation in seropositive women. The incidence of CAR in breast cancer is likely to rise as the survival time of patients with breast cancer increases; consequently, a prediction of breast-CAR based on autoimmunity to individual retinal antigens, or to panels of antigens (signatures), is clinically important.


Development and validation of a negative-strand-specific reverse transcription-PCR assay for detection of a chicken strain of hepatitis E virus: identification of nonliver replication sites.
As a positive-strand RNA virus, hepatitis E virus (HEV) produces an intermediate negative-strand RNA when it replicates. Thus, the detection of negative-strand viral RNA is indicative of HEV replication. The objective of this study was to develop a negative-strand-specific reverse transcription-PCR (RT-PCR) assay for the identification of extrahepatic sites of HEV replication. Briefly, a 494-bp fragment within the orf1 gene of a chicken strain of HEV (designated avian HEV) was amplified and cloned into a pSK plasmid. A synthetic negative-strand viral RNA was generated from the plasmid by in vitro transcription and was used to standardize the assay. A nested set of primers was designed to amplify a 232-bp fragment of the negative-strand viral RNA. The assay was found to detect up to 10 pg and 10(-5) pg of negative-strand HEV RNA in first- and second-round PCRs, respectively. The standardized negative-strand-specific RT-PCR assay was subsequently used to test 13 conveniently obtained tissue specimens collected sequentially on different days postinoculation from chickens experimentally infected with avian HEV. In addition to the liver, the negative-strand-specific RT-PCR assay identified replicative viral RNA in gastrointestinal tissues, including the colorectal, cecal, jejunal, ileal, duodenal, and cecal tonsil tissues. The detection of replicative viral RNA in these tissues indicates that after oral ingestion of the virus, HEV replicates in the gastrointestinal tract before it reaches the liver. This is the first report on the identification of extrahepatic sites of HEV replication in animals after experimental infection via the natural route. The assay should be of value for studying HEV replication and pathogenesis.


Effects of acetylcysteine on rabbit conjunctival and corneal surfaces. A scanning electron microscopy study.
Conjunctival and corneal epithelial surfaces of normal rabbit eyes with their associated mucus were studied by scanning electron microscopy before and after treatment with the mucolytic agent N-acetylcysteine (AC). Four groups received topically one 50-microliters drop of either (Group A) 0.1 MAC, (Group B) 0.1 M AC every 5 min for 1 hr, (Group C) 0.1 M AC every 5 min for 2 hr, or (Group D) three drops of 20% AC over 15 min. The effects of the instillation of AC on mucus removal and cellular lesions increased in the order (A) less than (B) less than (C) less than (D). Treatment A had no effect on cornea and conjunctiva. Treatment B cleaned away mucosal debris without alteration of either conjunctival or corneal epithelium. Treatment C had a similar effect on the mucus but was associated with focal necrosis, and treatment D produced widespread necrosis, desquamation of epithelial cells, and inflammation.


Capillaria hepatica in China.
Capillaria hepatica (C. hepatica) is a parasitic nematode causing hepatic capillariasis in numerous mammals. Ecologic studies showed that the first hosts of C. hepatica were rodents, among which rats had relatively high infection rates, which explains why C. hepatica spreads globally. Anatomical studies showed that the liver was the principal site of colonization by these parasites and physical damage tended to occur. Although C. hepatica might lead to serious liver disorders, relevant clinical reports were rare, because of the non-specific nature of clinical symptoms, leading to misdiagnosis. This review mainly focuses on the biological characteristics and epidemiology of C. hepatica in China and histopathologic changes in the liver, with expectation of gaining a better understanding of the disease and seeking more effective treatment.


Mutations in NOTCH1 cause aortic valve disease.
Calcification of the aortic valve is the third leading cause of heart disease in adults. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1-2% of the population. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.


Incorporation of bone marrow-derived Flk-1-expressing CD34+ cells in the endothelium of tumor vessels in the mouse brain.
Neoangiogenesis is a prerequisite for the full phenotypic expression and growth of a malignant tumor mass. It is believed to be triggered by tissue hypoxia and involves proliferation and sprouting of the preexisting vessels and the recruitment of endothelial progenitor cells from bone marrow. A chimeric mouse model was used to examine the contribution of these progenitor cells to the neovasculature of brain tumor. T-cell knockout (RAG/KO5.2) mice were irradiated lethally, and their bone marrow was repopulated with T-cell depleted green fluorescent protein (GFP)-expressing bone marrow cells. RAG/RT-2 glioma cells were implanted into the striatum of the animals. Neovascular formation at various times of tumor growth was monitored together with the extent of incorporation of GFP+ bone marrow-derived cells within the vascular tree, in particular, cells carrying the endothelial progenitor markers CD34 and Flk-1. The recruitment of GFP+ cells to the growing tumor and their incorporation into the vascular network occurred during the period of increasing vascular density and preceded the expansion of the tumor. The number of marrow-derived cells with endothelial morphology and phenotype was small but significant (4% of all endothelial cells at Day 12); 54% of all tumor vessels contained at least one GFP+ cell. Our results suggest that bone marrow cells are recruited to newly formed and remodeled tumor vessels. Their recruitment may occur in response to signals from a highly proliferating milieu, and their role is to support the neovascular complex and to promote tumor growth.


Early frailty transition predicts 15-year mortality among nondisabled older Mexican Americans.
To investigate the effect of early frailty transitions on 15-year mortality risk. Longitudinal data analysis of the Hispanic Established Populations for the Epidemiological Study of the Elderly involving 1171 community-dwelling Mexican Americans aged ≥67 years and older. Frailty was determined using the modified frailty phenotype, including unintentional weight loss, weakness, self-reported exhaustion, and slow walking speed. Participants were defined at baseline as nonfrail, prefrail, or frail and divided into nine transition groups, during a 3-year observation period. Mean age was 77.0 years (standard deviation [SD] = 5.3) and 59.1% were female. Participants who transitioned from prefrail to frail (hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.23-2.28), frail to prefrail (HR = 1.54, 95% CI = 1.05-2.28); or who remained frail (HR = 1.72, 95% CI = 1.21-2.44), had significant higher 15-year mortality risk than those who remained nonfrail. Participants transitioning from frail to nonfrail had a similar 15-year mortality risk as those who remained nonfrail (HR = 0.96, 95% CI = 0.53-1.72). Weight loss and slow walking speed were associated with transitions to frailty. An early transition from frail to nonfrail in older Mexican Americans was associated with a 4% decrease in mortality compared with those who remained nonfrail, although this difference was not statistically significant. Additional longitudinal research is needed to understand positive transitions in frailty.


Immunological assessment of an insecticide resistance-associated esterase in the Western corn rootworm.
In previous investigations, we have determined that organophosphate resistance in the western corn rootworm, Diabrotica virgifera virgifera, is at least partially attributed to a group of non-specific carboxylesterases referred to as group II. Antiserum raised against a purified 66-kDa group II esterase is specific for the denatured enzyme. This antiserum reacts similarly with both beetle homogenates from resistant and susceptible populations, although there is much higher signal intensity in immunoblots of resistant relative to susceptible beetles. These results suggest that overproduction of group II esterases is the underlying basis of esterase-mediated resistance in D. v. virgifera by demonstrating that (1) group II esterases are immunologically indistinguishable between the resistant and susceptible populations, and (2) the intensity differences are due to increased group II esterase proteins in the resistant population. The diagnostic potential of immunological-based assays was tested with a traditional diagnostic concentration bioassay and a biochemical-based native PAGE assay. Significant correlations were observed among all three diagnostic assays (regression coefficients ranging from 0.95 to 0.96). These results demonstrate the importance of the 66-kDa protein as a resistance-associated biochemical marker, thus emphasizing the potential for 66-kDa protein-targeted immunoassays in resistance monitoring programs.


Remote wind sensing with a CW diode laser lidar beyond the coherence regime.
We experimentally demonstrate for the first time (to our knowledge) a coherent CW lidar system capable of wind speed measurement at a probing distance beyond the coherence regime of the light source. A side-by-side wind measurement was conducted on the field using two lidar systems with identical optical designs but different laser linewidths. While one system was operating within the coherence regime, the other was measuring at least 2.4 times the coherence range. The probing distance of both lidars is 85 m and the radial wind speed correlation was measured to be r2=0.965 between the two lidars at a sampling rate of 2 Hz. Based on our experimental results, we describe a practical guideline for designing a wind lidar operating beyond the coherence regime.