The influence of SRC-family tyrosine kinases on Na,K-ATPase activity in lens epithelium.
Na,K-adenosine triphosphatase (ATPase) is essential for the regulation of cytoplasmic ion concentrations in lens cells. Earlier studies demonstrated that tyrosine phosphorylation by Lyn kinase, a Src-family member, inhibits Na,K-ATPase activity in porcine lens epithelium. In the present study, experiments were conducted to compare the ability of other Src-family kinases (Fyn, Src, and Lck) and Fes, a non-Src-family tyrosine kinase, to alter Na,K-ATPase activity. Membranes prepared from porcine lens epithelium were incubated with partially purified tyrosine kinases in buffer containing 1 mM adenosine triphosphate (ATP). ATP hydrolysis in the presence and absence of ouabain was used to measure Na,K-ATPase activity. Western blot analysis was used to examine phosphotyrosine-containing proteins and tyrosine kinase expression. Fyn reduced Na,K-ATPase activity by approximately 30%. In contrast, Src caused a approximately 38% increase of Na,K-ATPase activity. Na,K-ATPase activity in membrane material treated with Lck or Fes was not significantly altered, even though Lck and Fes treatment induced robust tyrosine phosphorylation. Added exogenously, each tyrosine kinase induced a different pattern of membrane protein tyrosine phosphorylation. As judged by immunoprecipitation, Src, Fyn, Lyn, and Lck elicited tyrosine phosphorylation of the Na,K-ATPase alpha1 protein. Src, Fyn, Lyn, Lck, and Fes were each detectable in the epithelium by Western blot. The results indicate considerable variation in the Na,K-ATPase activity response of lens epithelium to different tyrosine kinases. This could perhaps explain why inhibition of Na,K-ATPase activity is reported to be caused by tyrosine phosphorylation in some tissues, whereas stimulation of Na,K-ATPase activity is observed in other tissues.


Optogenetically induced spatiotemporal gamma oscillations and neuronal spiking activity in primate motor cortex.
Transient gamma-band (40-80 Hz) spatiotemporal patterns are hypothesized to play important roles in cortical function. Here we report the direct observation of gamma oscillations as spatiotemporal waves induced by targeted optogenetic stimulation, recorded by intracortical multichannel extracellular techniques in macaque monkeys during their awake resting states. Microelectrode arrays integrating an optical fiber at their center were chronically implanted in primary motor (M1) and ventral premotor (PMv) cortices of two subjects. Targeted brain tissue was transduced with the red-shifted opsin C1V1(T/T). Constant (1-s square pulses) and ramp stimulation induced narrowband gamma oscillations during awake resting states. Recordings across 95 microelectrodes (4 × 4-mm array) enabled us to track the transient gamma spatiotemporal patterns manifested, e.g., as concentric expanding and spiral waves. Gamma oscillations were induced well beyond the light stimulation volume, via network interactions at distal electrode sites, depending on optical power. Despite stimulation-related modulation in spiking rates, neuronal spiking remained highly asynchronous during induced gamma oscillations. In one subject we examined stimulation effects during preparation and execution of a motor task and observed that movement execution largely attenuated optically induced gamma oscillations. Our findings demonstrate that, beyond previously reported induced gamma activity under periodic drive, a prolonged constant stimulus above a certain threshold may carry primate motor cortex network dynamics into gamma oscillations, likely via a Hopf bifurcation. More broadly, the experimental capability in combining microelectrode array recordings and optogenetic stimulation provides an important approach for probing spatiotemporal dynamics in primate cortical networks during various physiological and behavioral conditions.


Life Program: Pilot Testing a Palliative Psychology Group Intervention.
Psychosocial interventions for palliative care populations, individuals with life-limiting illness, improve distress; however, less is known about these interventions among military Veterans. This quality improvement project evaluated a palliative psychology group intervention to reduce depression, anxiety, and stress among Veterans with advanced life-limiting illness. Veterans receiving palliative care at a mid-Atlantic VA healthcare system were referred by a mental health provider. The group intervention was delivered face-to-face in six to eight weekly sessions, with groups of four to eight participants. The intervention (Life Program), was a hybrid of cognitive-behavioral therapy and acceptance and commitment therapy that targeted: personal values, mindfulness, and psychological flexibility. A single-arm pre-post-test design was used to assess depression, anxiety, and stress, and satisfaction with the intervention. Seventy-five percent (39/52) of all Veterans who were contacted expressed interest and agreed to participate. Seventeen of 39 enrolled Veterans completed all sessions. The mean age of participants who completed the program was 63.06 (standard deviation = 8.47). Most participants were male (88%), Caucasian (58%), and had a cancer diagnosis (65%). Mean pre-post reductions in depression (18.82 vs. 13.20), anxiety (16.59 vs. 14.59), stress (19.18 vs. 13.88), and psychological inflexibility were observed. Mean differences in symptom severity were clinically meaningful. Barriers to feasibility included transportation issues and illness burden. Veterans who completed all sessions of a palliative psychology group intervention had reductions in depression, anxiety, and stress. Estimates of the treatment effects may be inflated using completer data alone. Further research is needed to inform ways to improve program engagement and adherence and examine efficacy in Veterans with advanced life-limiting illness.


Health economic analysis of screening.
In this article health economic implications of screening are analysed. First, requirements screening programmes should fulfil are derived, and methodical standards of health economic evaluation are outlined.Using the example of newborn hearing screening, it is then examined if empirical studies meet the methodical requirements of health economic evaluation. Some deficits are realised: Health economic studies of newborn hearing screening are not randomised, most studies are even not controlled. Therefore, most studies do not present incremental, but only average cost-effectiveness ratios (i.e. cost per case identified). Furthermore, evidence on long-term outcomes of screening and early interventions is insufficient. In conclusion, there is a need for controlled trials to examine differences in identified cases, but particularly to examine long-term effects.


Loss of cell-surface laminin anchoring promotes tumor growth and is associated with poor clinical outcomes.
Perturbations in the composition and assembly of extracellular matrices (ECM) contribute to progression of numerous diseases, including cancers. Anchoring of laminins at the cell surface enables assembly and signaling of many ECMs, but the possible contributions of altered laminin anchoring to cancer progression remain undetermined. In this study, we investigated the prominence and origins of defective laminin anchoring in cancer cells and its association with cancer subtypes and clinical outcomes. We found loss of laminin anchoring to be widespread in cancer cells. Perturbation of laminin anchoring originated from several distinct defects, which all led to dysfunctional glycosylation of the ECM receptor dystroglycan. In aggressive breast and brain cancers, defective laminin anchoring was often due to suppressed expression of the glycosyltransferase LARGE. Reduced expression of LARGE characterized a broad array of human tumors in which it was associated with aggressive cancer subtypes and poor clinical outcomes. Notably, this defect robustly predicted poor survival in patients with brain cancers. Restoring LARGE expression repaired anchoring of exogenous and endogenous laminin and modulated cell proliferation and tumor growth. Together, our findings suggest that defects in laminin anchoring occur commonly in cancer cells, are characteristic of aggressive cancer subtypes, and are important drivers of disease progression.


Drug induced pulmonary parenchymal disease.
Drug-induced pulmonary parenchymal disease (DIPPD) can be caused by a variety of agents, including antibiotics, chemotherapeutic drugs, antiarrhythmic agents and non-steroidal anti-inflammatory drugs (NSAIDs). DIPPD includes acute bronchospasm, organizing pneumonia, alveolar hypoventilation and hypersensitivity reactions. History, physical examination and investigations are required mainly to exclude other causes of lung diseases. Investigations may include chest radiography, pulmonary function testing and bronchoscopy with bronchoalveolar lavage (BAL). Recognition of DIPPD is difficult because the clinical, radiologic, and histologic findings are nonspecific. Management includes drug withdrawal and in some cases corticosteroid therapy. In this article we reviewed the various drugs known to cause pulmonary parenchymal diseases, various patterns of parenchymal diseases observed and their management.


Wheezing in children and adolescents living next to a petrochemical plant in Rio Grande do Norte, Brazil.
To examine the association between wheezing in children and adolescents and living downwind of the dispersion plume of atmospheric pollutants emitted by the Guamaré Petrochemical Complex, in the state of Rio Grande do Norte, Brazil. Cross-sectional study of wheezing in children and adolescents (aged 0 to 14 years) living in the vicinity of the Guamaré petrochemical complex in 2006. The standardized International Study of Asthma and Allergies in Childhood questionnaire was used, with additional questions concerning tobacco use, income, living conditions, and educational achievement. Daily concentrations of PM10, PM2.5, black carbon, SO2, NO2, O3, benzene, toluene, and xylenes were measured at a fixed monitoring station. According to their position relative to wind direction, communities present in the area affected by plant emissions were categorized into one of two groups, exposed communities and reference communities. Two hundred and nine children and adolescents took part in the study. Mean daily concentrations of the monitored pollutants were consistently below established acceptable upper limits. The prevalence of wheezing in the 12 months prior to study was 27.3%. After adjustment, statistically significant associations were found between wheezing and living in exposed communities (adjusted odds ratio [ORadj] 2.01; 95% confidence interval [95%CI] 1.01-4.01), male gender (ORadj 2.50; 95%CI 1.21-5.18), and age 0 to 6 years (ORadj 5.00; 95%CI 2.41-10.39). Even with low levels of atmospheric pollutants, respiratory symptoms in children and adolescents were associated with living downwind of a petrochemical plant. Male preschoolers were the most vulnerable group.


Polymorphism and solvatomorphism 2006.
Articles and patents that deal with polymorphism (crystal systems for which a substance can exist in structures characterized by different unit cells, but where each of the forms has exactly the same elemental composition) and solvatomorphism (systems where the crystal structures of the substance are defined by different unit cells, but where these unit cells differ in their elemental composition through the inclusion of one or molecules of solvent) have been summarized in an annual review. The works cited in this review were published during 2006, and were drawn from the major physical, crystallographic, and pharmaceutical journals. The review is divided into sections that cover articles of general interest, computational and theoretical studies, preparative and isolation methods, structural characterization and properties of polymorphic and solvatomorphic systems, studies of phase transformations, effects associated with secondary processing, and United States patents issued during 2006.


A novel role of the potyviral helper component proteinase contributes to enhance the yield of viral particles.
The helper component proteinase (HCPro) is an indispensable, multifunctional protein of members of the genus Potyvirus and other viruses of the family Potyviridae. This viral factor is directly involved in diverse steps of viral infection, such as aphid transmission, polyprotein processing, and suppression of host antiviral RNA silencing. In this paper, we show that although a chimeric virus based on the potyvirus Plum pox virus lacking HCPro, which was replaced by a heterologous silencing suppressor, caused an efficient infection in Nicotiana benthamiana plants, its viral progeny had very reduced infectivity. Making use of different approaches, here, we provide direct evidence of a previously unknown function of HCPro in which the viral factor enhances the stability of its cognate capsid protein (CP), positively affecting the yield of virions and consequently improving the infectivity of the viral progeny. Site-directed mutagenesis revealed that the ability of HCPro to stabilize CP and enhance the yield of infectious viral particles is not linked to any of its previously known activities and helped us to delimit the region of HCPro involved in this function in the central region of the protein. Moreover, the function is highly specific and cannot be fulfilled by the HCPro of a heterologous potyvirus. The importance of this novel requirement in regulating the sorting of the viral genome to be subjected to replication, translation, and encapsidation, thus contributing to the synchronization of these viral processes, is discussed. Potyviruses form one of the most numerous groups of plant viruses and are a major cause of crop loss worldwide. It is well known that these pathogens make use of virus-derived multitasking proteins, as well as dedicated host factors, to successfully infect their hosts. Here, we describe a novel requirement for the proper yield and infectivity of potyviral progeny. In this case, such a function is performed by the extensively studied viral factor HCPro, which seems to use an unknown mechanism that is not linked to its previously described activities. To our knowledge, this is the first time that a factor different from capsid protein (CP) has been shown to be directly involved in the yield of potyviral particles. Based on the data presented here, we hypothesize that this capacity of HCPro might be involved in the coordination of mutually exclusive activities of the viral genome by controlling correct assembly of CP in stable virions.


Effects of fluorination and thermal annealing on charge recombination processes in polymer bulk-heterojunction solar cells.
We investigate the effect of fluorination on the photovoltaic properties of an alternating conjugated polymer composed of 4,8-di-2-thienylbenzo[1,2-b:4,5-b']dithiophene (BDT) and 4,7-bis([2,2'-bithiophen]-5-yl)-benzo-2-1-3-thiadiazole (4TBT) units in bulk-heterojunction solar cells. The unsubstituted and fluorinated polymers afford very similar open-circuit voltages and fill factor values, but the fluorinated polymer performed better due to enhanced aggregation which provides a higher photocurrent. The photovoltaic performance of both materials improved upon thermal annealing at 150-200 °C as a result of a significantly increased fill factor and open-circuit voltage, counteracted by a slight loss in photocurrent. Detailed studies of the morphology, light intensity dependence, external quantum efficiency and electroluminescence allowed the exploration of the effects of fluorination and thermal annealing on the charge recombination and the nature of the donor-acceptor interfacial charge transfer states in these films.


Guidelines for perioperative care for pancreaticoduodenectomy: Enhanced Recovery After Surgery (ERAS®) Society recommendations.
Protocols for enhanced recovery provide comprehensive and evidence-based guidelines for best perioperative care. Protocol implementation may reduce complication rates and enhance functional recovery and, as a result of this, also reduce length-of-stay in hospital. There is no comprehensive framework available for pancreaticoduodenectomy. An international working group constructed within the Enhanced Recovery After Surgery (ERAS®) Society constructed a comprehensive and evidence-based framework for best perioperative care for pancreaticoduodenectomy patients. Data were retrieved from standard databases and personal archives. Evidence and recommendations were classified according to the GRADE system and reached through consensus in the group. The quality of evidence was rated "high", "moderate", "low" or "very low". Recommendations were graded as "strong" or "weak". Comprehensive guidelines are presented. Available evidence is summarised and recommendations given for 27 care items. The quality of evidence varies substantially and further research is needed for many issues to improve the strength of evidence and grade of recommendations. The present evidence-based guidelines provide the necessary platform upon which to base a unified protocol for perioperative care for pancreaticoduodenectomy. A unified protocol allows for comparison between centres and across national borders. It facilitates multi-institutional prospective cohort registries and adequately powered randomised trials.


Despite shattered expectations a willingness to care for elders remains with education and clinical supervision.
The aim was to describe nursing home (NH) caregivers' work experiences while receiving education and clinical supervision for 2 years. Working in elder care seems to be losing its attraction especially with organizational changes, cutbacks and changes in work place conditions. Clinical supervision has been reported to increase job satisfaction and creativity. Semi-structured interviews from caregivers working at an NH in Sweden were conducted, at the start and again at 12 and 24 months. At about 12 months the caregivers were informed of planned cutbacks. Content analysis was the method used to analyse the interviews from seven caregivers who participated throughout the entire period. Findings show that the value of a caring milieu was one category generated by the subcategories: experiences related to work activities and changes, and experiences related to relationships. The value of knowledge was the other category that was influenced by the experiences related to the different backgrounds and the experiences related to increased knowledge gained from the support through education and clinical supervision. The categories contained positive as well as negative influences on care. The initial focus on practical duties associated with the opening of the NH shifted towards caregiver activities with the elders they spoke warmly about. After 2 years the caregivers' willingness to care continued despite their disappointment in the worsened working conditions. The main theme that resulted was: Despite shattered expectations a willingness to care for elders remained. Continued education and clinical supervision seems to be one factor behind the retained willingness. These findings demonstrate that support and caregiver involvement in educational programmes are important during times of change and when disappointments arise in the workplace.


Role of thymoquinone and ebselen in the prevention of sodium arsenite-induced nephrotoxicity in female rats.
The aim of this study is to investigate the protective effects of thymoquinone (TQ) and ebselen (Eb) on arsenic (As)-induced renal toxicity in female rats. Sodium arsenite was orally administrated at a dose of 20 mg/kg body weight daily for 28 days, either alone or 1 h before TQ (10 mg/kg) or Eb (5 mg/kg) administration. Renal tissue As concentration and oxidative stress markers, including lipid peroxidation (LPO), nitrite/nitrate, and glutathione (GSH) levels, were determined. In addition to the oxidative stress response, antioxidant enzyme activities including that of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were measured. Exposure to As elicited a significant increase in As concentration and significant modifications to the redox state of the kidney, as was evidenced by a significant elevation in LPO and nitrite/nitrate concentration, with a concomitant reduction in GSH content and antioxidant enzyme activity. The oxidant/antioxidant imbalance observed in As toxicity was associated with a significant elevation in renal tumor necrosis factor α, interleukin 6, B-cell lymphoma 2 (Bcl-2)-associated X protein, and caspase 3 levels, in addition to a significant decrease in Bcl-2 levels. Post-administration of TQ and Eb markedly prevented As-induced oxidative stress, inflammation, apoptosis, and As accumulation in the renal tissue and reduced histological renal damage. These findings demonstrate that TQ, the main bioactive phytochemical constituent of Nigella sativa seed oil, and Eb, an organoselenium compound, could significantly inhibit As-induced oxidative damage, apoptosis, and inflammation, and significantly attenuate the accumulation of As in renal tissues by facilitating As biomethylation and excretion.


Missed opportunity? Worsening breathlessness as a harbinger of death: a cohort study.
The aim of the study was to explore trajectories of breathlessness intensity by function and life-limiting illness diagnosis in the last 3 weeks of life in palliative care patients.A prospective, consecutive cohort study obtained point-of-care data of patients of Silver Chain Hospice Care Service (Perth, Australia) over the period 2011-2014 (n=6801; 51 494 data-points). Breathlessness intensity (0-10 numerical rating scale) and physical function (Australia-modified Karnofsky Performance Status (AKPS)) were measured at each visit. Time was anchored at death. Breathlessness trajectory was analysed by physical function and diagnosis using mixed effects regression.Mean±sd age was 71.5±15.1 years and 55.2% were male, most with cancer. The last recorded AKPS was >40 for 26.8%. Breathlessness was worst in people with cardiorespiratory disease and AKPS >40, and breathlessness in the last week of life increased most in this group (adjusted mean 2.92 versus all others 1.51; p=0.0001). The only significant interaction was with diagnosis and function in the last week of life (p<0.0001).Breathlessness is more intense and increases more in people with better function and cardiorespiratory disease immediately before death. Whether there are reversible causes for these people should be explored prospectively. Omitting function from previous population estimates may have overestimated breathlessness intensity for many patients in the days preceding death.


Life goes on… Patient perspectives on having a cancer diagnosis and other comorbid diseases: A qualitative study.
Due to a growing population with both cancer and chronic diseases, we explored patients' experiences of living with a cancer diagnosis and comorbidities, the possible effects on everyday living and management of comorbidities. Semi-structured interviews were conducted during 2016 with 15 patients in Denmark, with finished cancer treatment and preexisting comorbidities. Analysis was performed by Systematic Text Condensation. Symptoms which disrupted everyday function were given attention, regardless of the disease from which the symptoms originated. The awareness of cancer and comorbidities constituted an inverse process over time. Most patients perceived cancer as being transient, whereas experiences of comorbidities varied from ignorance to worry. Most patients reported maintaining their chronic illness consultations with their general practitioner as before cancer. Patients prioritized an everyday life with normal chores highly in contrast to paying attention to diseases. Disruptive symptoms, rather than specific diseases, took up patients' attention. Cancer did not change the patients' attendance at chronic care consultations. General practitioners should focus on maintaining the patient's functional level in everyday life. Further, they should continue to prioritize the chronic care management, as this might increase the patients' own view of the importance of self-management.


The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus.
C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site.


Tuberculosis prevention and control in long-term-care facilities for older adults.
In the United States, older adults comprise 22% of cases of tuberculous disease but only 12% of the population. Most cases of tuberculosis (TB) occur in community dwellers, but attack rates are highest among frail residents of long-term-care facilities. The detection and treatment of latent TB infection and TB disease can pose special challenges in older adults. Rapid recognition of possible disease, diagnosis, and implementation of airborne precautions are essential to prevent spread. It is the intent of this evidence-based guideline to assist healthcare providers in the prevention and control of TB, specifically in skilled nursing facilities for the elderly.


Bacterial Spot of Tomato and Pepper Caused by Xanthomonas axonopodis pv. vesicatoria in the Western Mediterranean Region of Turkey.
Xanthomonas axonopodis pv. vesicatoria, causal agent of bacterial spot of tomato (Lycopersicon esculentum L.) and sweet pepper (Capsicum annuum L.) was isolated from tomato and pepper plants in greenhouse production in the Province of Antalya, in southwestern Turkey. Disease incidence was less than 4% of plants observed in 2001 and ranged from 1 to 20% in 2002. Eleven seedling-producing companies and 26 greenhouses that produce tomato and pepper were surveyed during the rainy seasons of 2001 and 2002. The increase in disease incidence in 2002 is an indication that this disease is becoming more prevalent on tomato and pepper plants grown in greenhouses in southwestern Turkey. A gram-negative bacterium producing yellow-pigmented colonies on nutrient agar was consistently isolated from brown, circular spots on leaflets of tomato and sweet pepper seedlings. Five isolates were pathogenic on commercial cultivars of tomato and pepper when bacterial suspensions (108 CFU/ml) were infiltrated into the intercellular spaces of leaves to determine race by using procedures described by Bouzar et al. (1). All the isolates produced hypersensitive reaction responses on tomato genotype cv. Hawaii 7998 and pepper genotype cvs. 20 R and 30 R and were designated tomato race 1 pepper race 1 (T1P1) (1). Fatty acid analysis of the strains identified them as X. axonopodis vesicatoria with similarity index values of 0.872 to 0.933. In addition, the strains were tested with X. axonopodis vesicatoria-specific polymerase chain reaction primers (RST 2/3 and RST 9/10) (2). The isolates were determined to be X. axonopodis vesicatoria. Although bacterial spot of tomato has been suspected in Turkey for a number of years, to our knowledge, this is the first report of the bacterium on tomato. References: (1) H. Bouzar et al. Phytopathology 84:663, 1994. (2) R. P. Leite, Jr. et al. Appl. Env. Microbiol. 60:1068, 1994.


Effects of indoor coal fine particulate matter on the expression levels of inflammatory factors in ovalbumin-induced mice.
Objective: Cooking and heating with coal is the main source of household air pollution in acid rain-plagued areas of China and is a leading contributor to disease burden. In this study, we investigated the adverse effects of exposure to indoor fine particulate matter emission from coal combustion on the expression levels of inflammatory factors in ovalbumin (OVA)-induced mice. Methods: Forty BALB/c male mice were randomly divided into four groups (control group, PM2.5 group, OVA group, and OVA + PM2.5 group; n = 10) and treated with ovalbumin (OVA) or PM2.5, alone or together. Interleukin-4 (IL-4), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-17 (IL-17), transforming growth factor β1 (TGF-β1), and interferon γ (IFN-γ) protein expression levels were measured in bronchoalveolar lavage fluid (BALF). Additionally, serum immunoglobulin (Ig) IgE and IgG1 levels were measured. The mRNA expression levels of IL-7 and IFN-γ in pulmonary tissue were also analyzed. Bronchoalveolar lavage (BAL), inflammatory cell counts, and histopathological examinations were also performed. Results: Exposure to PM2.5 + OVA induced abnormal pathological changes and inflammatory responses in lungs compared to the control. The levels of IL-4, IL-7, IL-8 and IL-17 in BALF from the OVA + PM2.5 group were higher than those in BALF from the control group, OVA group, and PM2.5 group (P < 0.05). PM2.5 plus OVA significantly raised the serum IgE and IgG1 levels compared with the control group. An increasing IL-7 mRNA trend was found among the treatment groups (P < 0.05). The expression level of IFN-γ mRNA was significantly higher in the control group than in the other 3 groups (P < 0.05). Conclusion: Indoor coal PM2.5 was sufficient by itself to cause inflammatory cellular infiltration of pulmonary tissue, leading to organelle injury and physiological structure change. Additionally, it promoted the occurrence and development of asthma by influencing the expression levels of IL-7 and various relevant inflammatory factors (such as IL-4 and IL-8) and changing the equilibrium between Treg and Th17 cells.


Cerebral cavernous malformations: clinical insights from genetic studies.
Familial disease is responsible for one third to one half of cerebral cavernous malformation (CCM) cases presenting to clinical attention. Much has been learned in the past decade about the genetics of these cases, which are all inherited in an autosomal dominant pattern, at three known chromosome loci. Unique features of inherited CCMs in Hispanic-Americans of Mexican descent have been described. The respective genes for each locus have been identified and preliminary observations on disease pathways and mechanisms are coming to light, including possible explanations for selectivity of neural milieu and relationships to endothelial layer abnormalities. Mechanisms of lesion genesis in cases of genetic predisposition are being investigated, with evidence to support a two-hit model emerging from somatic mutation screening of the lesions themselves and from lesion formation in transgenic murine models of the disease. Other information on potential inflammatory factors has emerged from differential gene expression studies. Unique phenotypic features of solitary versus familial cases have emerged: different associations with venous developmental anomaly and the exceptionally high penetrance rates that are found in inherited cases when high-sensitivity screening is performed with gradient echo magnetic resonance imaging. This information has changed the landscape of screening and counseling for patients and their families, and promises to lead to the development of new tools for predicting, explaining, and modifying disease behavior.


[Compliance evaluation of "do not do" recommendations of the Spanish Society of Preventive Medicine and public health].
The reduction of unnecessary health interventions determines good care quality. The objective of this work was to evaluate the compliance of the "do not do" recommendations proposed by the Spanish Society of Preventive Medicine, Public Health and Hygiene. Prospective, observational, descriptive study of patients admitted to the La Princesa University Hospital between December 2018 and January 2019. The compliance of each recommendation in different patients was analyzed. The quantitative variables are expressed as means and standard deviation and the qualitative values as percentages and confidence interval. In Recommendation 1 (R1: "Do not remove hair systematically"), 231 interventions were studied and the compliance was of 100% (95% CI: 98.27-100). In Recommendation 2 (R2: "Do not maintain antibiotics for more than 48 hours, unless evidence of infection"), 201 interventions were studied and the compliance was of 93.53% (95% CI: 90.09-96.91). In Recommendation 3 (R3: "Do not analyze C. difficile toxin in asymptomatic patients"), 200 determinations were studied and the compliance was of 93.5% (95% CI: 90.08-96.92). In Recommendation 4 (R4: "Do not do routine nasal decolonization"), 167 interventions were recruited and the compliance was of 100% (95% CI: 97.6-100). In Recommendation 5 (R5: "Do not perform routine replacement of peripheral venous catheter every 72-96 hours"), 153 patients were studied in compliance with the recommendation of 98.04% (95% CI: 94.12-99.35). A 100% compliance was found in Recommendations 1 and 4. There is an opportunity of improvement in the recommendations R2, R3 and R5.


Depth Transfer: Depth Extraction from Video Using Non-Parametric Sampling.
We describe a technique that automatically generates plausible depth maps from videos using non-parametric depth sampling. We demonstrate our technique in cases where past methods fail (non-translating cameras and dynamic scenes). Our technique is applicable to single images as well as videos. For videos, we use local motion cues to improve the inferred depth maps, while optical flow is used to ensure temporal depth consistency. For training and evaluation, we use a Kinect-based system to collect a large data set containing stereoscopic videos with known depths. We show that our depth estimation technique outperforms the state-of-the-art on benchmark databases. Our technique can be used to automatically convert a monoscopic video into stereo for 3D visualization, and we demonstrate this through a variety of visually pleasing results for indoor and outdoor scenes, including results from the feature film Charade.


Participation in a mobile health intervention trial to improve retention in HIV care: does gender matter?
Background To be consistent with the United Nations' sustainable development goals on gender equality, mobile health (mHealth) programmes should aim to use communications technology to promote the empowerment of women. We conducted a pre-trial analysis of data from the WelTel Retain study on retention in HIV care to assess gender-based differences in phone access, phone sharing and concerns about receiving text messages from a healthcare provider. Methods Between April 2013-June 2015, HIV-positive adults were screened for trial participation at two clinics in urban slums in Nairobi, Kenya. Proportions of men and women excluded from the trial due to phone-related criteria were compared using a chi-square test. Gender-based differences in phone sharing patterns and concerns among trial participants were similarly compared. Results Of 1068 individuals screened, there was no difference in the proportion of men ( n = 39/378, 10.3%) and women ( n = 71/690, 10.3%) excluded because of phone-related criteria ( p-value = 0.989). Among those who shared their phone, women ( n = 52/108, 48.1%) were more likely than men ( n = 6/60, 10.0%) to share with other non-household and household members ( p < 0.001). Few participants had concerns about receiving text messages from their healthcare provider; those with concerns were all women ( n = 6/700). Discussion In this study, men and women were equally able to participate in a trial of an mHealth intervention. Equitable access in these urban slums may indicate the 'gender digital divide' is narrowing in some settings; however, gender-specific phone sharing patterns and concerns regarding privacy must be fully considered in the development and scale-up of mHealth programmes.


Palliative and end-of-life care for people with stroke.
Stroke is a devastating illness. Significant progress has been made in the prevention, acute treatment and rehabilitation of stroke. Yet many people still die from stroke. The role of palliative and end-of-life care for stroke has received considerably less attention. This review presents an overview of the current understanding of palliative and end-of-life care for people with stroke. The impact of stroke is wide-ranging and long lasting. It affects both patients and those who become their caregivers. Those who are dying from stroke experience a similar symptom profile to many other dying people. Palliative care services involved in care of stroke patients are more frequently involved in issues related to communication and difficult decisions related to food and fluids. Caregivers have significant needs, particularly around information provision, communication and involvement in, or consultation about, decision-making. Those who survive the immediate aftermath of a stroke are often left with significant psychological and social limitations in addition to physical disability. It is clear that patients with stroke have palliative care needs. Palliative and end-of-life care services can contribute to the care of people with stroke, and their families, but the way in which stroke and palliative care services should interlink remains unclear.


Accelerating clinical development of a live attenuated vaccine against Salmonella Paratyphi A (VASP): study protocol for an observer-participant-blind randomised control trial of a novel oral vaccine using a human challenge model of Salmonella Paratyphi A infection in healthy adult volunteers.
This is the first efficacy study of an oral live attenuated vaccine against Salmonella Paratyphi A using a human challenge model of paratyphoid infection. S. Paratyphi A is responsible for 3.3 million cases of enteric fever every year, with over 19 000 deaths. Although improvements to sanitation and access to clean water are vital to reduce the burden of this condition, vaccination offers a cost-effective, medium-term solution. Efficacy trials of potential S. Paratyphi vaccine candidates in the field are unlikely to be feasible given the large number of participants required. Human challenge models therefore offer a unique, cost-effective solution to test efficacy of such vaccines. This is an observer-blind, randomised, placebo-controlled trial phase I/II of the oral live-attenuated vaccine against S. Paratyphi A, CVD 1902. Volunteers will be randomised 1:1 to receive two doses of CVD 1902 or placebo, 14 days apart. One month following second vaccination all volunteers will ingest S. Paratyphi A bacteria with a bicarbonate buffer solution. They will be reviewed daily in the following 14 days and diagnosed with paratyphoid infection if the predefined microbiological or clinical diagnostic criteria are met. All participants will be treated with antibiotics on diagnosis, or at day 14 postchallenge if not diagnosed. The vaccine efficacy will be determined by comparing the relative attack rate, that is, the proportion of those diagnosed with paratyphoid infection, in the vaccine and placebo groups. Ethical approval for this study has been obtained from the Berkshire Medical Research Ethics Committee (REC ref 21/SC/0330). The results will be disseminated via publication in a peer-reviewed journal and presentation at international conferences. ISRCTN15485902.


DNA methylation patterns of LINE-1 and Alu for pre-symptomatic dementia in type 2 diabetes.
The identification of early markers of dementia is important for higher-risk populations such as those with type 2 diabetes (T2D). Retrotransposons, including long interspersed nuclear element 1 (LINE-1) and Alu, comprise ~40% of the human genome. Although dysregulation of these retrotransposons can induce aberrant gene regulation and genomic instability, their role in the development of pre-symptomatic dementia (PSD) among T2D patients is unknown. Here, we examined locus-specific changes in LINE-1 and Alu methylation in PSD and the potential to offset these changes via supplementation with folate and vitamin B12. We interrogated DNA methylation patterns corresponding to 22,352 probes for LINE-1 and Alu elements using publicly-available Illumina Infinium 450K methylation datasets from i) an 18-month prospective study in 28 T2D patients (GSE62003) and ii) an intervention study in which 44 individuals were supplemented with folic acid (400 μg/day) and vitamin B12 (500 μg/day) over two years (GSE74548). We identified 714 differentially methylated positions (DMP) mapping to retrotransposons in T2D patients who developed PSD in comparison to those who did not (PFDR < 0.05), comprised of 2.4% (228 probes) of all LINE-1 probes and 3.8% (486 probes) of all Alu probes. These loci were enriched in genes with functions related to Alzheimer's disease and cognitive decline, including GNB5, GNG7 and PKN3 (p < 0.05). In older individuals supplemented with folate/vitamin B12, 85 (11.9%) PSD retrotransposon loci showed significant changes in methylation (p < 0.05): participants with the MTHFR CC genotype predominantly showed hypermethylation at these loci, while hypomethylation was observed more frequently in those with the TT genotype. In T2D patients, LINE-1 and Alu elements are differentially methylated in PSD in a locus-specific manner and may offer clinical utility in monitoring risk of dementia. Further work is required to examine the potential for dietary supplementation in lowering the risk of PSD.


Extending the classification of bacterial transcription factors beyond the helix-turn-helix motif as an alternative approach to discover new cis/trans relationships.
Transcription factors (TFs) of bacterial helix-turn-helix superfamilies exhibit different effector-binding domains (EBDs) fused to a DNA-binding domain with a common feature. In a previous study of the GntR superfamily, we demonstrated that classifying members into subfamilies according to the EBD heterogeneity highlighted unsuspected and accurate TF-binding site signatures. In this work, we present how such in silico analysis can provide prediction tools to discover new cis/trans relationships. The TF-binding site consensus of the HutC/GntR subfamily was used to (i) predict target sites within the Streptomyces coelicolor genome, (ii) discover a new HutC/GntR regulon and (iii) discover its specific TF. By scanning the S.coelicolor genome we identified a presumed new HutC regulon that comprises genes of the phosphotransferase system (PTS) specific for the uptake of N-acetylglucosamine (PTS(Nag)). A weight matrix was derived from the compilation of the predicted cis-acting elements upstream of each gene of the presumed regulon. Under the assumption that TFs are often subject to autoregulation, we used this matrix to scan the upstream region of the 24 HutC-like members of S.coelicolor. orf SCO5231 (dasR) was selected as the best candidate according to the high score of a 16 bp sequence identified in its upstream region. Our prediction that DasR regulates the PTS(Nag) regulon was confirmed by in vivo and in vitro experiments. In conclusion, our in silico approach permitted to highlight the specific TF of a regulon out of the 673 orfs annotated as 'regulatory proteins' within the genome of S.coelicolor.


Identification and cultivation of anaerobic, syntrophic long-chain fatty acid-degrading microbes from mesophilic and thermophilic methanogenic sludges.
We investigated long-chain fatty acid (LCFA)-degrading anaerobic microbes by enrichment, isolation, and RNA-based stable isotope probing (SIP). Primary enrichment cultures were made with each of four LCFA substrates (palmitate, stearate, oleate, or linoleate, as the sole energy source) at 55 degrees C or 37 degrees C with two sources of anaerobic granular sludge as the inoculum. After several transfers, we obtained seven stable enrichment cultures in which LCFAs were converted to methane. The bacterial populations in these cultures were then subjected to 16S rRNA gene-based cloning, in situ hybridization, and RNA-SIP. In five of seven enrichment cultures, the predominant bacteria were affiliated with the family Syntrophomonadaceae. The other two enrichment cultures contained different bacterial populations in which the majority of members belonged to the phylum Firmicutes and the class Deltaproteobacteria. After several attempts to isolate these dominant bacteria, strain MPA, belonging to the family Syntrophomonadaceae, and strain TOL, affiliated with the phylum Firmicutes, were successfully isolated. Strain MPA converts palmitate to acetate and methane in syntrophic association with Methanospirillum hungatei. Even though strain TOL assimilated [(13)C]palmitate in the original enrichment culture, strain TOL has not shown the ability to degrade LCFAs after isolation. These results suggest that microbes involved in the degradation of LCFAs under methanogenic conditions might not belong only to the family Syntrophomonadaceae, as most anaerobic LCFA-degrading microbes do, but may also be found in phylogenetically diverse bacterial groups.


Mechanism of inhibition of aldose reductase by menadione (vitamin K3).
Incubation of human placental aldose reductase (EC 22.214.171.124) with menadione (0.5-3.0 mM) resulted in time-dependent loss of the catalytic activity of the enzyme. Kinetic analysis of the data suggests that the inactivation process follows a single apparent rate constant that displays hyperbolic dependence on menadione concentration, indicating that menadione forms a kinetically significant, dissociable complex with the enzyme before the formation of an inactive enzyme-menadione complex. The inactivation of the enzyme with menadione was reversed upon dialysis of the inactivated enzyme against buffer containing 10 mM dithiothreitol suggesting that menadione reacts with enzyme sulfhydryl residue(s). Inactivation of the enzyme was significantly prevented by dithiothreitol (5 mM), NADPH (0.1 mM), and DL-glyceraldehyde (10 mM). Correlation of the fractional remaining activity with the extent of modification indicates that loss of catalytic activity corresponds to the modification of a single amino acid residue of the enzyme protein. Recombinant human aldose reductase, obtained by overexpression in Escherichia coli, and aldose reductase in which Cys-80 or Cys-303 was replaced by serine were also inactivated by menadione. However, enzyme in which Cys-298 was replaced by serine was insensitive to menadione. On the basis of these observations, it is suggested that menadione forms a thiodione-like adduct with Cys-298, leading to inactivation of the enzyme.


Confirmation of Choclo virus as the cause of hantavirus cardiopulmonary syndrome and high serum antibody prevalence in Panama.
Choclo virus (CHOV) was described in sigmodontine rodents, Oligoryzomys fulvescens, and humans during an outbreak of hantavirus cardiopulmonary syndrome (HCPS) in 1999-2000 in western Panama. Although HCPS is rare, hantavirus-specific serum antibody prevalence among the general population is high suggesting that CHOV may cause many mild or asymptomatic infections. The goals of this study were to confirm the role of CHOV in HCPS and in the frequently detected serum antibody and to establish the phylogenetic relationship with other New World hantaviruses. CHOV was cultured to facilitate the sequencing of the small (S) and medium (M) segments and to perform CHOV-specific serum neutralization antibody assays. Sequences of the S and M segments found a close relationship to other Oligoryzomys-borne hantaviruses in the Americas, highly conserved terminal nucleotides, and no evidence for recombination events. The maximum likelihood and maximum parsimony analyses of complete M segment nucleotide sequences indicate a close relationship to Maporal and Laguna Negra viruses, found at the base of the South American clade. In a focus neutralization assay acute and convalescent sera from six Panamanian HCPS patients neutralized CHOV in dilutions from 1:200 to 1:6,400. In a sample of antibody-positive adults without a history of HCPS, 9 of 10 sera neutralized CHOV in dilutions ranging from 1:100 to 1:6,400. Although cross-neutralization with other sympatric hantaviruses not yet associated with human disease is possible, CHOV appears to be the causal agent for most of the mild or asymptomatic hantavirus infections, as well as HCPS, in Panama.


Optimal vaccination strategies for a heterogeneous population using multiple objectives: The case of L1- and L2-formulations.
The choice of the objective functional in optimization problems coming from biomedical and epidemiological applications plays a key role in optimal control outcomes. In this study, we investigate the role of the objective functional on the structure of the optimal control solution for an epidemic model for sexually transmitted infections that includes a core group with higher sexual activity levels than the rest of the population. An optimal control problem is formulated to find a targeted vaccination program able to control the spread of the infection with minimum vaccine deployment. Both L1- and L2-objectives are considered as an attempt to explore the trade-offs between control dynamics and the functional form characterizing optimality. The results show that the optimal vaccination policies for both the L1- and the L2-formulation share one important qualitative property, that is, immunization of the core group should be prioritized by policymakers to achieve a fast reduction of the epidemic. However, quantitative aspects of this result can be significantly affected depending on the choice of the control weights between formulations. Overall, the results suggest that with appropriate weight constants, the optimal control outcomes are reasonably robust with respect to the L1- or L2-formulation. This is particularly true when the monetary cost of the control policy is substantially lower than the cost associated with the disease burden. Under these conditions, even if the L1-formulation is more realistic from a modeling perspective, the L2-formulation can be used as an approximation and yield qualitatively comparable outcomes.


Death and readmissions after hospital discharge during the December holiday period: cohort study.
To determine whether patients discharged from hospital during the December holiday period have fewer outpatient follow-ups and higher rates of death or readmission than patients discharged at other times. Population based retrospective cohort study. Acute care hospitals in Ontario, Canada, 1 April 2002 to 31 January 2016. 217 305 children and adults discharged home after an urgent admission, during the two week December holiday period, compared with 453 641 children and adults discharged during two control periods in late November and January. The primary outcome was death or readmission, defined as a visit to an emergency department or urgent rehospitalisation, within 30 days. Secondary outcomes were death or readmission and outpatient follow-up with a physician within seven and 14 days after discharge. Multivariable logistic regression with generalised estimating equations was used to adjust for characteristics of patients, admissions, and hospital. 217 305 (32.4%) patients discharged during the holiday period and 453 641 (67.6%) discharged during control periods had similar baseline characteristics and previous healthcare utilisation. Patients who were discharged during the holiday period were less likely to have follow-up with a physician within seven days (36.3% v 47.8%, adjusted odds ratio 0.61, 95% confidence interval 0.60 to 0.62) and 14 days (59.5% v 68.7%, 0.65, 0.64 to 0.66) after discharge. Patients discharged during the holiday period were also at higher risk of 30 day death or readmission (25.9% v 24.7%, 1.09, 1.07 to 1.10). This relative increase was also seen at seven days (13.2% v 11.7%, 1.16, 1.14 to 1.18) and 14 days (18.6% v 17.0%, 1.14, 1.12 to 1.15). Per 100 000 patients, there were 2999 fewer follow-up appointments within 14 days, 26 excess deaths, 188 excess hospital admissions, and 483 excess emergency department visits attributable to hospital discharge during the holiday period. Patients discharged from hospital during the December holiday period are less likely to have prompt outpatient follow-up and are at higher risk of death or readmission within 30 days.


The "Performance of Rotavirus and Oral Polio Vaccines in Developing Countries" (PROVIDE) study: description of methods of an interventional study designed to explore complex biologic problems.
Oral vaccines appear less effective in children in the developing world. Proposed biologic reasons include concurrent enteric infections, malnutrition, breast milk interference, and environmental enteropathy (EE). Rigorous study design and careful data management are essential to begin to understand this complex problem while assuring research subject safety. Herein, we describe the methodology and lessons learned in the PROVIDE study (Dhaka, Bangladesh). A randomized clinical trial platform evaluated the efficacy of delayed-dose oral rotavirus vaccine as well as the benefit of an injectable polio vaccine replacing one dose of oral polio vaccine. This rigorous infrastructure supported the additional examination of hypotheses of vaccine underperformance. Primary and secondary efficacy and immunogenicity measures for rotavirus and polio vaccines were measured, as well as the impact of EE and additional exploratory variables. Methods for the enrollment and 2-year follow-up of a 700 child birth cohort are described, including core laboratory, safety, regulatory, and data management practices. Intense efforts to standardize clinical, laboratory, and data management procedures in a developing world setting provide clinical trials rigor to all outcomes. Although this study infrastructure requires extensive time and effort, it allows optimized safety and confidence in the validity of data gathered in complex, developing country settings.


Assessment of subcomponents of executive functioning in ecologically valid settings: the goal processing scale.
To validate a new functional assessment tool, the Goal Processing Scale (GPS), and to apply it for testing for sources of dysfunction in patients with acquired brain injury. Determining which component processes of executive functioning underlie poor performance in complex, low-structure settings would be valuable for the assessment of deficits and for evaluating the effectiveness of treatments. Nineteen individuals with chronic acquired brain injury (mean age = 41.4 years; chronicity: 6 months to 39 years). Two functional assessment tasks: (1) GPS, which evaluates functional performance in the context of achieving a goal in a "real-world" setting, with rating scales measuring overall performance and 8 subdomains of executive functioning; (2) Multiple Errands Test, an unstructured assessment of ability to adhere to rules and complete multiple "real-world" tasks in a short time; and (3) a neuropsychological battery. Intraclass correlation coefficients for 2 independent raters ranged from 0.75 to 0.98 for the GPS overall composite score and the subdomain scores. Performance on GPS overall and several subdomain scores correlated with performance on the Multiple Errands Test. Working memory and learning/memory neuropsychological measures predicted functional performance as measured using the GPS. The GPS shows high interrater reliability, suggesting convergent validity with an established functional performance measure, and produces useful information regarding strengths and weaknesses in different subdomains of executive functioning. Working memory and learning/memory appear to be key determinants of goal-directed functioning for these individuals with brain injury.


Expression of manganese superoxide dismutase reduces tumor control radiation dose: gene-radiotherapy.
This study investigated the in vitro and in vivo radiation response of tumor cells transfected with human manganese superoxide dismutase (MnSOD) cDNA. A major objective was to test the potential tumor suppressive effect of MnSOD in vivo. Tumor cells studied were an in vitro line derived from a murine spontaneous fibrosarcoma, FSa-II, which expressed an undetectable MnSOD activity. These cells were transfected with pSV2-NEO plasmid (NEO line) or cotransfected with MnSOD plasmid plus pSV2-NEO plasmid (SOD lines) as described previously. The cell lines used were SOD-L and SOD-H, which expressed, respectively, low and high MnSOD activities after transfection, and NEO and parental FSa-II controls. Both SOD-L and SOD-H cell lines were slightly more resistant to ionizing radiation than were the two control cell lines when irradiated in vitro in the presence of oxygen. The dose-modifying factors calculated at the survival level of 0.01 were 1.13 and 1.15 for the SOD-L and SOD-H cells, respectively. To investigate potential tumor suppressive effects, animal tumors of 4 mm diameter were irradiated in vivo under hypoxic conditions, and the radiation dose to control one-half of the irradiated tumors (TCD50) was determined for each tumor. The TCD50S obtained on the basis of the tumor control rate in 120 days after irradiation were substantially lower for the SOD-H and SOD-L tumors compared to the NEO tumors. They were 22.9, 28.6, and 47.5 Gy for SOD-H, SOD-L and NEO tumors, respectively. To analyze these data, survival curves were obtained for hypoxic cells by irradiating NEO and SOD-H tumors under hypoxic conditions in vivo and assaying in vitro. Analysis of these curves suggests that the decrease in the TCD50S of SOD tumors is attributable to the reduced tumorigenicity in these tumors. The hypoxic cell survival curves also showed that SOD did not protect cells from radiation in the absence of oxygen. Electron microscopy showed no morphological differences between these cells. These results suggest that the fraction of tumorigenic cells could be reduced by expression of MnSOD, resulting in a substantial decrease in the TCD50.


A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol.
Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study. Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. Registered at August 23, 2017. Registry number: UMIN000028801 .


Anterior and posterior knee laxity in a young adult Korean population.
The purposes of this study were (1) to determine normal anterior and posterior knee laxity in a healthy young adult (20-30 years old) Korean population, (2) to compare knee laxity between the male and female populations, (3) to investigate whether generalized joint laxity affects anterior and posterior knee laxity, (4) to determine side-side differences between right and left knees, and thus, to determine normal values of side-side differences. Normal values of anterior and posterior knee laxity were measured in 100 healthy volunteers (50 men and 50 women) aged between 20 and 30 years. Stress radiography using a Telos device was performed in 20 and 70° of knee flexion for 134N anterior and posterior loads. Anterior and posterior tibial displacements relative to the femur condyle were measured using a computerized system. In the 100 subjects (200 knees), anterior knee laxity was greater at 20° of flexion with a mean of 4.9 ± 2.3 mm (P < 0.05) and posterior knee laxity was greater at 70° of flexion with a mean of 4.6 ± 2.7 mm (P < 0.05). The mean side-side difference was 1.4 ± 0.9 mm (range, -3 to +3). Women had greater anterior laxity (P < 0.05) than men at both 20 and 70° of flexion, but posterior laxity was not different (ns). Generalized joint laxity was greater in women compared to men (P < 0.05). Subjects with generalized joint laxity had greater laxity than normal populations in both 20 and 70° of flexion (P < 0.05). Side-side differences between right and left knees were not significantly different in women and men or between subjects with normal and generalized joint laxity (ns). This study suggests that the Korean population exhibits a wide range of normal anterior and posterior knee laxity, but small side-side differences. Subjects with generalized laxity showed greater knee laxity than those without, but side-side differences were less than 3 mm in all subjects. Thus, clinical guideline that a side-side difference more than 3 mm of anterior knee laxity is abnormal can be applicable for the subjects with generalized laxity.


High-density lipoprotein inhibits serum amyloid A-mediated reactive oxygen species generation and NLRP3 inflammasome activation.
Serum amyloid A (SAA) is a high-density apolipoprotein whose plasma levels can increase more than 1000-fold during a severe acute-phase inflammatory response and are more modestly elevated in chronic inflammation. SAA is thought to play important roles in innate immunity, but its biological activities have not been completely delineated. We previously reported that SAA deficiency protects mice from developing abdominal aortic aneurysms (AAAs) induced by chronic angiotensin II (AngII) infusion. Here, we report that SAA is required for AngII-induced increases in interleukin-1β (IL-1β), a potent proinflammatory cytokine that is tightly controlled by the Nod-like receptor protein 3 (NLRP3) inflammasome and caspase-1 and has been implicated in both human and mouse AAAs. We determined that purified SAA stimulates IL-1β secretion in murine J774 and bone marrow-derived macrophages through a mechanism that depends on NLRP3 expression and caspase-1 activity, but is independent of P2X7 nucleotide receptor (P2X7R) activation. Inhibiting reactive oxygen species (ROS) by N-acetyl-l-cysteine or mito-TEMPO and inhibiting activation of cathepsin B by CA-074 blocked SAA-mediated inflammasome activation and IL-1β secretion. Moreover, inhibiting cellular potassium efflux with glyburide or increasing extracellular potassium also significantly reduced SAA-mediated IL-1β secretion. Of note, incorporating SAA into high-density lipoprotein (HDL) prior to its use in cell treatments completely abolished its ability to stimulate ROS generation and inflammasome activation. These results provide detailed insights into SAA-mediated IL-1β production and highlight HDL's role in regulating SAA's proinflammatory effects.


Dual-energy X-ray absorptiometry for the measurement of gross body composition in rats.
Dual-energy X-ray absorptiometry (DXA) is a novel, non-invasive technique for the measurement of gross body composition in small animals. In the present study the absolute accuracy of the Hologic QDR-1000W scanner was assessed by comparison with direct analysis in twelve rats with a range of body fat and bone mineral content (BMC) values. Fat masses measured by DXA and petroleum-ether extraction were significantly different (P < 0.0023). The DXA technique consistently overestimated fat mass by approximately one third of the measured fat content. BMC derived from the measurement of Ca in ash gave a mean of 8.26 (range 1.57-15.71)g. BMC measured by DXA was not significantly different for the group as a whole. However, there was a trend for DXA to overestimate BMC in animals with low BMC and underestimate in those with higher BMC, compared with direct analysis, such that the 95% limits of agreement for the two techniques were +2.73 to -2.58 g. These results suggest that the present small-animal software developed for use with currently available Hologic machines does not give an accurate measure of gross body composition compared with the results from classical direct analysis.


Clinical utility of the absolute number of circulating CD34-positive cells in patients with chronic myeloproliferative disorders.
Flow cytometry enumeration of peripheral blood CD34-positive cells provides reliable measurements of circulating hematopoietic progenitors in humans. Since the absolute number of circulating CD34-positive cells has been previously found to be elevated in myelofibrosis with myeloid metaplasia (MMM), we prospectively studied the clinical utility of this parameter in the work-up of patients with chronic myeloproliferative disorders. Of the 248 consecutive patients enrolled in this study, 106 had polycythemia vera (PV), 90 essential thrombocythemia (ET), and 52 myelofibrosis with myeloid metaplasia (MMM). The study population included both newly diagnosed and established cases, and of these latter some patients were on cytoreductive treatment while others were chemotherapy naive. Both cross-sectional and longitudinal investigations were carried out. Flow cytometry enumeration of CD34-positive cells was performed using a single-platform assay. Median numbers and ranges of circulating CD34-positive cells were 2.3x10(6)/L (0-5) in 20 control subjects, 2.2x10(6)/L (0-14) in those with PV, 2.4x10(6)/L (0-14) in those with ET, and 114x10(6)/L (6-2,520) in MMM patients. Analysis of variance demonstrated that values were markedly higher in MMM patients than in the remaining groups, and counts did not appear to fluctuate over short periods of follow-up. In both cross-sectional and longitudinal investigations on patients at clinical onset and/or out of cytoreductive treatment, a CD34-positive count of > or = 15x10(6)/L was always associated with MMM, clearly indicating a disease-related specificity. The absolute number of circulating CD34-positive cells is normal or anyhow lower than 15x10(6)/L in patients with uncomplicated PV or ET, whereas it is equal or above this cut-off in those with MMM, likely reflecting abnormal hematopoietic progenitor cell trafficking. Thus, enumeration of circulating CD34-positive cells may be useful in the work-up of patients with myeloproliferative disorders.


Pressure-induced transformations in LiCl-H2O at 77 K.
A systematic study of the properties of high-density amorphous ice (HDA) in the presence of increasing amounts of salt is missing, especially because it is challenging to avoid ice crystallization upon cooling the pressurized liquid. In order to be able to study HDA also in the presence of small amounts of salt, we have investigated the transformation behaviour of quenched aqueous LiCl solutions (mole fraction x < 0.25) upon pressurization in a piston-cylinder setup at 77 K. The sample properties were characterized by in situ dilatometry under high pressure conditions and after recovery by ex situ powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) at ambient pressure. Two regimes can be identified, with a rather sharp switch at about x = 0.12. At x < 0.12 the samples show the phenomenology also known for pure water samples. They are composed mainly of hexagonal ice (Ih) and experience pressure-induced amorphization to HDA at P > 1 GPa. The observed densification is consistent with the idea that a freeze concentrated LiCl solution of x = 0.14 (R = 6) segregates, which transforms to the glassy state upon cooling, and that the densification is only due to the Ih → HDA transition. Also the XRD patterns and DSC scans are almost unaffected by the presence of the segregated glassy LiCl solution. Upon heating at ambient pressure HDA experiences the polyamorphic transition to low-density amorphous ice (LDA) at ∼120 K, even at x ∼ 0.10. Based on the latent heat evolved in the transition we suggest that almost all water in the sample transforms to an LDA-like state, even the water in the vicinity of the ions. The glassy LiCl solution acts as a spectator that does not shift the transformation temperature significantly and experiences a glass-to-liquid transition at ∼140 K prior to the crystallization to cubic ice. By contrast, at x > 0.12 the phenomenology completely changes and is now dominated by the salt. Hexagonal ice no longer forms upon quenching the LiCl solution, but instead LDA forms. A broad pressure-induced transformation at >0.6 GPa can be attributed to the densification of LDA, the glassy LiCl solution and/or glassy hydrates.


Advances in anticancer radiopharmaceuticals.
This review highlights recent progress in the development of anticancer radiopharmaceuticals. Molecularly targeted radiotherapy refers to the selective delivery of radionuclides that emit charged particles, such as α particles, β or Auger electrons, to cancer cells via a targeting vector. The discovery of new molecular targets through systems biology and other approaches has widened the scope for radiopharmaceutical development. Innovations in antibody engineering and humanisation, recombinant DNA technology, conjugation chemistry and, increasingly, nanotechnology have provided new approaches to the delivery of radionuclides to cancer cells. The increased availability of radioisotopes that have not traditionally been considered for therapy, such as α particle emitters, has also broadened the indications for targeted radiotherapy.


Building a multi-scaled geospatial temporal ecology database from disparate data sources: fostering open science and data reuse.
Although there are considerable site-based data for individual or groups of ecosystems, these datasets are widely scattered, have different data formats and conventions, and often have limited accessibility. At the broader scale, national datasets exist for a large number of geospatial features of land, water, and air that are needed to fully understand variation among these ecosystems. However, such datasets originate from different sources and have different spatial and temporal resolutions. By taking an open-science perspective and by combining site-based ecosystem datasets and national geospatial datasets, science gains the ability to ask important research questions related to grand environmental challenges that operate at broad scales. Documentation of such complicated database integration efforts, through peer-reviewed papers, is recommended to foster reproducibility and future use of the integrated database. Here, we describe the major steps, challenges, and considerations in building an integrated database of lake ecosystems, called LAGOS (LAke multi-scaled GeOSpatial and temporal database), that was developed at the sub-continental study extent of 17 US states (1,800,000 km(2)). LAGOS includes two modules: LAGOSGEO, with geospatial data on every lake with surface area larger than 4 ha in the study extent (~50,000 lakes), including climate, atmospheric deposition, land use/cover, hydrology, geology, and topography measured across a range of spatial and temporal extents; and LAGOSLIMNO, with lake water quality data compiled from ~100 individual datasets for a subset of lakes in the study extent (~10,000 lakes). Procedures for the integration of datasets included: creating a flexible database design; authoring and integrating metadata; documenting data provenance; quantifying spatial measures of geographic data; quality-controlling integrated and derived data; and extensively documenting the database. Our procedures make a large, complex, and integrated database reproducible and extensible, allowing users to ask new research questions with the existing database or through the addition of new data. The largest challenge of this task was the heterogeneity of the data, formats, and metadata. Many steps of data integration need manual input from experts in diverse fields, requiring close collaboration.


WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.


Social-cognitive determinants of help-seeking for mental health problems among prison inmates.
Prisoners experience high rates of mental health problems and suicidal behaviours. Failure to seek help may exacerbate these problems and limit opportunities to participate in offending-related programmes. To assess whether prisoners'; intentions to seek help for a personal-emotional problem, including suicidal feelings, can be predicted using variables from the Theory of Planned Behaviour (TPB). These TPB variables were supplemented by measures of emotional distress, prior contact with a psychologist and demographic variables. Male inmates from six New Zealand prisons were asked to participate, with approximately 50% (n = 527) of those who initially expressed an interest in the study completing the self-report questionnaire. Most participants completed the questionnaire in small-group meetings in the prison units and returned them to the researchers immediately after completion.Results On average, participants reported higher levels of current emotional distress than comparison student samples. TPB variables predicted help-seeking intentions for suicidality and personal-emotional problems. Those with prior contact with prison psychologists had lower intentions to seek help for suicidal feelings than prisoners without such contact. Older prisoners, those with more years of education, and those who had previous contact with a psychologist outside prison tended to have higher intentions to seek psychological help. Social-cognitive factors predicted intentions to seek help among New Zealand prisoners but prison-specific issues, such as relative reluctance to seek help when suicidal and reluctance to seek help from prison psychologists, were also identified. Implications for practice Prisoners'; access to services could be improved, for example, through directly working on attitudinal barriers. Strategies to ensure access to specialized forensic mental health in-reach services could also be an alternative or additional route to ensure that this disadvantaged group seeks appropriate help.


Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons.
The discovery of genetic variants in the cholinergic receptor nicotinic CHRNA5-CHRNA3-CHRNB4 gene cluster associated with heavy smoking and higher relapse risk has led to the identification of the midbrain habenula-interpeduncular axis as a critical relay circuit in the control of nicotine dependence. Although clear roles for α3, β4, and α5 receptors in nicotine aversion and withdrawal have been established, the cellular and molecular mechanisms that participate in signaling nicotine use and contribute to relapse have not been identified. Here, using translating ribosome affinity purification (TRAP) profiling, electrophysiology, and behavior, we demonstrate that cholinergic neurons, but not peptidergic neurons, of the medial habenula (MHb) display spontaneous tonic firing of 2-10 Hz generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels and that infusion of the HCN pacemaker antagonist ZD7288 in the habenula precipitates somatic and affective signs of withdrawal. Further, we show that a strong, α3β4-dependent increase in firing frequency is observed in these pacemaker neurons upon acute exposure to nicotine. No change in the basal or nicotine-induced firing was observed in cholinergic MHb neurons from mice chronically treated with nicotine. We observe, however, that, during withdrawal, reexposure to nicotine doubles the frequency of pacemaking activity in these neurons. These findings demonstrate that the pacemaking mechanism of cholinergic MHb neurons controls withdrawal, suggesting that the heightened nicotine sensitivity of these neurons during withdrawal may contribute to smoking relapse.


Acute kidney injury requiring dialysis and in-hospital mortality in patients with chronic kidney disease and non-ST-segment elevation acute coronary syndrome undergoing early vs delayed percutaneous coronary intervention: A nationwide analysis.
Chronic kidney disease (CKD) is a well-known risk factor for coronary artery disease and is associated with poor outcomes following an acute coronary syndrome (NSTE-ACS). The optimal timing of an invasive strategy in patients with CKD and NSTE-ACS is unclear. Timing of PCI in CKD patients will not affect the risk of mortality or incidence of dialysis. We queried the National Inpatient Sample database (NIS) to identify cases with NSTEMI and CKD. Patients who underwent percutaneous coronary intervention (PCI) day 0 or 1 vs day 2 or 3 after admission were categorized as early vs delayed PCI, respectively. The primary outcomes of the study were in-hospital mortality and acute kidney injury requiring hemodialysis (AKI-D). The secondary outcomes were length of stay and hospital charges. Baseline characteristics were balanced using propensity score matching (PSM). After PSM, 3708 cases from the delayed PCI group were matched with 3708 cases from the early PCI group. The standardized mean differences between the 2 groups were substantially reduced after PSM. All other recorded variables were balanced between the 2 groups. In the early and delayed PCI groups, the incidence of AKI-D (2.5% vs 2.3%; P = 0.54) and in-hospital mortality (1.9% vs 1.4%; P = 0.12) was similar. Hospital charges and length of stay were higher in the delayed PCI group. The incidence of AKI-D and in-hospital mortality among patients with CKD and NSTE-ACS were not significantly affected by the timing of PCI. However, delayed PCI added significant cost and length of stay. A prospective randomized study is required to validate this concept.


RELATIONSHIP OF CLINICAL FEATURES AND BASELINE TUMOR SIZE WITH GENE EXPRESSION PROFILE STATUS IN UVEAL MELANOMA: A Multi-institutional Study.
To study the relationship between gene expression profile subclass and clinical features in a multicenter cohort of patients with uveal melanoma. A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Eligible patients had uveal melanoma and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with gene expression profile testing between January 1, 2010, and October 28, 2014. Data were collected regarding patient demographics, baseline tumor clinical features, and gene expression profile results. Statistical analyses were performed using the Fisher's exact test, Wilcoxon rank-sum test, Kruskal-Wallis test, and proportional-odds cumulative logit modeling. Inclusion criteria were met for 379 patients. Gene expression profile class divided the cohort into two main groups, Class 1 (n = 263) and Class 2 (n = 113). Class 1 tumors were further subdivided into Class 1a (n = 186) and Class 1b (n = 77). The differences between Class 1 and Class 2 tumors were similar to previous studies, except the finding of Class 2 tumors being more likely to have associated exudative retinal detachment (P < 0.001). There was no statistically significant difference between Class 1 and Class 2 tumors based on the presence of lipofuscin, drusen, or subretinal fluid. Class 1a tumor patients, compared with Class 1b, were significantly older (P = 0.034). Class 2 tumors, when compared with Class 1b, were associated with increasing patient age (P < 0.001), larger tumor height (P = 0.010), ciliary body involvement (P = 0.001), exudative retinal detachment (P = 0.024), and anterior tumor location (P < 0.001). When the tumors were grouped into Collaborative Ocular Melanoma Study size categories, increasing tumor size category was significantly associated with Class 2 status: 6% of small tumors, 32% of medium tumors, and 53% of large tumors were Class 2. In a multi-institutional setting, we found that the only significant difference in clinical features between Class 1a and Class 1b tumors was that patients with Class 1a tumors were older at the time of diagnosis. We also found that Class 1a and Class 1b have clinical features distinct from Class 2 tumors. The distribution of the gene expression profile subclasses among the size groups was similar to reported time-to-metastasis data among the same size groupings. Our clinical findings support the current molecular classification-based survival data previously reported in uveal melanoma.


Chitosan/polyester-based scaffolds for cartilage tissue engineering: assessment of extracellular matrix formation.
Naturally derived polymers have been extensively used in scaffold production for cartilage tissue engineering. The present work aims to evaluate and characterize extracellular matrix (ECM) formation in two types of chitosan-based scaffolds, using bovine articular chondrocytes (BACs). The influence of these scaffolds' porosity, as well as pore size and geometry, on the formation of cartilagineous tissue was studied. The effect of stirred conditions on ECM formation was also assessed. Chitosan-poly(butylene succinate) (CPBS) scaffolds were produced by compression moulding and salt leaching, using a blend of 50% of each material. Different porosities and pore size structures were obtained. BACs were seeded onto CPBS scaffolds using spinner flasks. Constructs were then transferred to the incubator, where half were cultured under stirred conditions, and the other half under static conditions for 4 weeks. Constructs were characterized by scanning electron microscopy, histology procedures, immunolocalization of collagen type I and collagen type II, and dimethylmethylene blue assay for glycosaminoglycan (GAG) quantification. Both materials showed good affinity for cell attachment. Cells colonized the entire scaffolds and were able to produce ECM. Large pores with random geometry improved proteoglycans and collagen type II production. However, that structure has the opposite effect on GAG production. Stirred culture conditions indicate enhancement of GAG production in both types of scaffold.


Influenza Virus Infects Epithelial Stem/Progenitor Cells of the Distal Lung: Impact on Fgfr2b-Driven Epithelial Repair.
Influenza Virus (IV) pneumonia is associated with severe damage of the lung epithelium and respiratory failure. Apart from efficient host defense, structural repair of the injured epithelium is crucial for survival of severe pneumonia. The molecular mechanisms underlying stem/progenitor cell mediated regenerative responses are not well characterized. In particular, the impact of IV infection on lung stem cells and their regenerative responses remains elusive. Our study demonstrates that a highly pathogenic IV infects various cell populations in the murine lung, but displays a strong tropism to an epithelial cell subset with high proliferative capacity, defined by the signature EpCamhighCD24lowintegrin(α6)high. This cell fraction expressed the stem cell antigen-1, highly enriched lung stem/progenitor cells previously characterized by the signature integrin(β4)+CD200+, and upregulated the p63/krt5 regeneration program after IV-induced injury. Using 3-dimensional organoid cultures derived from these epithelial stem/progenitor cells (EpiSPC), and in vivo infection models including transgenic mice, we reveal that their expansion, barrier renewal and outcome after IV-induced injury critically depended on Fgfr2b signaling. Importantly, IV infected EpiSPC exhibited severely impaired renewal capacity due to IV-induced blockade of β-catenin-dependent Fgfr2b signaling, evidenced by loss of alveolar tissue repair capacity after intrapulmonary EpiSPC transplantation in vivo. Intratracheal application of exogenous Fgf10, however, resulted in increased engagement of non-infected EpiSPC for tissue regeneration, demonstrated by improved proliferative potential, restoration of alveolar barrier function and increased survival following IV pneumonia. Together, these data suggest that tropism of IV to distal lung stem cell niches represents an important factor of pathogenicity and highlight impaired Fgfr2b signaling as underlying mechanism. Furthermore, increase of alveolar Fgf10 levels may represent a putative therapy to overcome regeneration failure after IV-induced lung injury.


High probability of follow-up termination among AYA survivors after allogeneic hematopoietic cell transplantation.
The need for long-term follow-up (LTFU) after allogeneic hematopoietic cell transplantation (HCT) has been increasingly recognized for managing late effects such as subsequent cancers and cardiovascular events. A substantial population, however, has already terminated LTFU at HCT centers. To better characterize follow-up termination, we analyzed the Japanese transplant registry database. The study cohort included 17 980 survivors beyond 2 years who underwent their first allogeneic HCT between 1974 and 2013. The median patient age at HCT was 34 years (range, 0-76 years). Follow-up at their HCT center was terminated in 4987 patients. The cumulative incidence of follow-up termination was 28% (95% confidence interval [CI], 27%-29%) at 10 years, increasing to 67% (95% CI, 65%-69%) at 25 years after HCT. Pediatric patients showed the lowest probability of follow-up termination for up to 16 years after HCT, whereas adolescent and young adult (AYA) patients showed the highest probability of follow-up termination throughout the period. Follow-up termination was most often made by physicians based on the patient's good physical condition. Multivariate analysis identified 6 factors associated with follow-up termination: AYA patients, female patients, standard-risk malignancy or nonmalignant disease, unrelated bone marrow transplantation, HCT between 2000 and 2005, and absence of chronic graft-versus-host disease. These results suggest the need for education of both physicians and patients about the importance of LTFU, even in survivors with good physical condition. The decreased risk for follow-up termination after 2005 may suggest the increasing focus on LTFU in recent years.


Evaluation of Myocardial Stiffness in Hypertensive Patients by Intrinsic Wave Propagation of the Myocardial Stretch.
The objective of the study was to evaluate myocardial stiffness in hypertensive patients by measuring the intrinsic velocity propagation (IVP) of the myocardial stretch and to explore the correlation between IVP and cardiac systolic and diastolic functions. Eighty-one hypertensive patients and 53 healthy patients were prospectively enrolled in this study. IVP was measured using high-frame rate tissue Doppler (350-450 frames per second). IVP was significantly higher in hypertensive patients than in the control group (1.53 ± 0.39 m/s vs. 1.40 ± 0.19 m/s, p = 0.031). In the hypertensive group, IVP was significantly higher in patients with electrocardiogram (ECG) strain than in those without ECG strain (1.63 ± 0.46 m/s vs. 1.45 ± 0.32 m/s, p = 0.047). Moreover, IVP exhibited a good correlation with interventricular septal thickness at end-diastole (r = 0.434, p < 0.001), left ventricular posterior wall thickness at end-diastole (r = 0.439, p < 0.001), E/A ratio (r = 0.245, p = 0.004) and global longitudinal systolic strain (r = 0.405, p < 0.001). IVP was significantly higher in hypertensive patients, which indicates elevated myocardial stiffness in this cohort of patients. This novel measurement exhibited great potential for use in clinical practice to assess myocardial stiffness in patients with hypertension non-invasively.


Enlarged Virchow-Robin Spaces in A Young Man: A Constrained Spherical Deconvolution Tractography Study.
Virchow-Robin spaces are mainly located along the path of the lenticulo-striate arteries in the basal ganglia through the anterior perforate substance, and can be found both in normal subjects, as a rare phenomenon, and in patients with different diseases. We report a case of a healthy young man with unilateral enlarged Virchow-Robin spaces in the left capsule-lenticulostriate area. Aim of this case report is to show the potential of probabilistic Constrained Spherical Deconvolution (CSD) tractography in showing abnormal diffusion tensor imaging and tractography of the anterior thalamic tracts caused by mass effect from adjacent enlarged Virchow-Robin spaces. The study was performed with a 3T magnetic resonance imaging (MRI) scanner (Achieva, Philips Healthcare, Best, Netherlands); equipped with a 32-channel SENSE head coil. Diffusion Weighted Images were analyzed by using CSD, a fast computation method that overcomes major limitations of Diffusion Tensor Imaging allowing reliable estimation of one or more fiber orientations in the presence of intravoxel orientational heterogeneity. Tractography showed increased Fractional Anisotropy and reduced Apparent Diffusion Coefficient values, a displacement and compression of the anterior thalamic projections by part of the enlarged VRS, and a decrease of white matter fibers in the left side in comparison to the right one. We report on a case of a healthy individual with unilateral dilated VRS in the capsulo-lenticulostriatal area, proving the utility of diffusion MRI and tractography in understanding the abnormal neuroanatomy of this particular condition.


Review on cell models to evaluate the potential antioxidant activity of polysaccharides.
Owing to various health functions, natural polysaccharides are becoming a kind of popular dietary nutritional supplement. At present, the occurrence of many chronic diseases is closely related to excessive reactive oxygen species (ROS). Note that polysaccharides with anti-oxidative activity have been paid significant attention as medicines, cosmetics, and food. Many documents constantly prove the effects of antioxidant polysaccharides against Alzheimer's disease, diabetes, and cardiovascular disease. Moreover, the structural features and functional properties of antioxidant polysaccharides have been extensively studied. Many chemical and biological methods have been used to evaluate the antioxidant activity of polysaccharides. Because of deficiencies in the accuracy and authenticity of the chemiluminescence method, the use of cell models has gradually become the mainstream method based on providing a more real biological environment. For these reasons, this study summarizes an overview of recent advances in cell models to evaluate the potential antioxidant activity of the polysaccharides. This study focuses on the advancements in the types of cell models and evaluation of the indexes of the potential mechanisms and factors that influence the anti-oxidative activity of polysaccharides. The aim is to provide useful background and updated information for further development and application of antioxidant polysaccharides.


Identification of a new cell line permissive to porcine reproductive and respiratory syndrome virus infection and replication which is phenotypically distinct from MARC-145 cell line.
Airborne transmitted pathogens, such as porcine reproductive and respiratory syndrome virus (PRRSV), need to interact with host cells of the respiratory tract in order to be able to enter and disseminate in the host organism. Pulmonary alveolar macrophages (PAM) and MA104 derived monkey kidney MARC-145 cells are known to be permissive to PRRSV infection and replication and are the most studied cells in the literature. More recently, new cell lines developed to study PRRSV have been genetically modified to make them permissive to the virus. The SJPL cell line origin was initially reported to be epithelial cells of the respiratory tract of swine. Thus, the goal of this study was to determine if SJPL cells could support PRRSV infection and replication in vitro. The SJPL cell growth was significantly slower than MARC-145 cell growth. The SJPL cells were found to express the CD151 protein but not the CD163 and neither the sialoadhesin PRRSV receptors. During the course of the present study, the SJPL cells have been reported to be of monkey origin. Nevertheless, SJPL cells were found to be permissive to PRRSV infection and replication even if the development of the cytopathic effect was delayed compared to PRRSV-infected MARC-145 cells. Following PRRSV replication, the amount of infectious viral particles produced in SJPL and MARC-145 infected cells was similar. The SJPL cells allowed the replication of several PRRSV North American strains and were almost efficient as MARC-145 cells for virus isolation. Interestingly, PRRSV is 8 to 16 times more sensitive to IFNα antiviral effect in SJPL cell in comparison to that in MARC-145 cells. PRRSV induced an increase in IFNβ mRNA and no up regulation of IFNα mRNA in both infected cell types. In addition, PRRSV induced an up regulation of IFNγ and TNF-α mRNAs only in infected MARC-145 cells. In conclusion, the SJPL cells are permissive to PRRSV. In addition, they are phenotypically different from MARC-145 cells and are an additional tool that could be used to study PRRSV pathogenesis mechanisms in vitro.


3 tesla magnetic resonance imaging of the occipitoatlantoaxial region in the normal horse.
The aim of this study was to describe the appearance of the ligamentous structures of the occipitoatlantoaxial (OAA) region in the normal horse by 3 tesla (3T) magnetic resonance imaging (MRI). The MRI images of the longitudinal odontoid ligament, tectorial membrane, dorsal and ventral atlantoaxial ligaments, dorsal atlantooccipital membrane with its reinforcing ligaments, and the lateral atlantooccipital ligaments of 10 horse cadavers were evaluated. All ligaments and membranes were identified in all planes, except for the lateral atlantooccipital ligament in the sagittal plane due to its cranioventrolateral course. All were iso to mildly hypointense to musculature of the neck in T1W with the exception of the tectorial membrane that was moderately hypointense; moderately hypointense in PD-SPIR, and markedly hypointense (isointense to cortical bone) in T2W. The PD-SPIR was the best sequence to identify all ligaments and membranes from their cranial and caudal attachments. The longitudinal odontoid ligament, ventral atlantoaxial ligament, and reinforcing bands of the dorsal atlantooccipital membrane presented a characteristic striped heterogeneous signal behavior thought to be due to fibrocartilaginous content. The remaining ligaments and membranes showed homogeneous signal intensity. Special anatomical features in this species such as the fan-shaped longitudinal odontoid ligament, absence of the transverse ligament and presence of the ventral atlantoaxial ligament were documented. Ligamentous structures that stabilize the equine OAA region were described with MRI in this study and these findings could serve as an anatomic reference for those cases where instability of this region is suspected.