Acceptability of psychosocial interventions for dementia caregivers: a systematic review.
Most of patients with dementia are cared for by family members. Caring for people with dementia is challenging; approximately 30-55% of caregivers suffered from anxiety or depressive symptoms. A range of studies have shown that psychosocial interventions are effective and can improve caregivers' quality of life, reduce their care burden, and ease their anxiety or depressive symptoms. However, information on the acceptability of these interventions, despite being crucial, is under-reported. Systematic searches of databases were conducted for literature published on EMBASE, PubMed, The Cochrane Library, Web of Science, and PsycARTICLES until August 2017 and the searches were updated on June 2018. The selection criteria included primary studies with data about the acceptability of psychosocial interventions for informal caregivers and publications written in English. Two authors independently selected studies, extracted study characteristics and data, assessed the methodological quality of the included studies by using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool and Critical Appraisal Skills Programme (CASP) Qualitative Research Checklist, and conducted a narrative synthesis of quantitative and qualitative data. A total of 10,610 abstracts were identified through systematic searches. Based on screening titles and abstracts, 207 papers were identified that met the criteria for full paper review, with 42 papers from 13 different countries meeting the inclusion criteria. We found high- and moderate-quality evidence showing psychosocial interventions were acceptable, with important benefits for caregivers. Facilitators of acceptability included caregivers' need for intervention, appropriate content and organization of the intervention, and knowledge and professionalism of the staff. Barriers to acceptability included participants' poor health status and low education levels, caregiving burden, change of intervention implementers, and poor system performance of interventions. There is preliminary evidence to support the acceptability of psychosocial interventions for dementia caregivers. However, the available supporting evidence is limited, and there is currently no adequate information from these studies indicating that the acceptability has received enough attention from researchers. More well-designed studies assessing psychosocial interventions are needed to give specific statements about acceptability, and the measure of acceptability with psychosocial interventions should be more comprehensive.


Views of US researchers about informed consent in international collaborative research.
Informed consent poses challenges in all settings. Challenges may be particularly great in international collaborative research, where cultural perspectives may differ, and where education levels and language may be barriers to participant understanding. We conducted a written survey and focus groups with US health researchers doing research in developing countries, asking about informed consent and other ethical issues in their research. We present here both qualitative and quantitative data relevant to informed consent. Qualitative data revealed that researchers' experiences and beliefs about informed consent fell into three paradigms: regulatory, community, and individual. The regulatory paradigm refers to researchers' views and practices relating to informed consent requirements of institutional review boards and other oversight bodies. The community paradigm refers to researchers' approach to the content and methodology of informed consent in the context of long-term relationships between research teams and study communities. Researchers emphasized the importance of these relationships for creating and maintaining communication fundamental to the informed consent process. Finally, the individual paradigm refers to researchers' views about individual participants' understanding and decision-making process regarding research. Researchers described community-level influences on participants' decision-making, but stressed the need for individual comprehension and voluntary participation. While these paradigms are distinct, they also are intertwined. Quantitative data supported the existence of these three paradigms in respondents' characterization of informed consent. Researchers frequently stated that legal language on the consent forms was meaningless (52%). Forty-four percent of researchers had consulted with community leaders, and 23% believed the consent process focuses too much on the individual, rather than on family or community. Most researchers (82%) reported that the consent process was an important means of educating participants about the study. Fifty-four percent of researchers believed participants did not understand placebos. Further research is needed to understand how culture and relationships affect research participation, and to provide information and dialogue among researchers, oversight bodies and community representatives about appropriate ways to approach informed consent in international research.


Suppression of dengue virus replication in vitro by rimantadine hydrochloride.
The effects of rimantadine on dengue virus replication were examined in a variety of tissue culture systems. The growth of dengue virus type 2 in human peripheral blood leukocytes (PBL) was completely suppressed when rimantadine was included in the culture medium at a concentration of 25 microgram/ml. Similarly, rimantadine caused a significant inhibition of dengue virus replicaton in cultures of rhesus monkey PBL. Addition of drug into virus-infected LLC-MK2 cell cultures caused a decrease in the production of all four types of dengue virus. Maximal inhibition of dengue virus replication by rimantadine was observed when the drug was added immediately following the viral adsorption period. Rimantadine did not induce may cytopathic effects on either LLC-MK2 cells or PBL at concentrations less than 75 microgram/ml. These findings demonstrate that rimantadine is an effective inhibitor of dengue virus replication in vitro, and indicate a need for further examination of the efficacy of rimantadine against severe dengue virus disease.


Early onset linear focal elastosis in a Turkish boy.
A 14-year-old boy applied to our outpatient clinic with a three-month history of lesions on the back. The physical examination revealed linear, yellow, stria-like palpable bands surrounded by a slight erythema extending horizontally across the back. Histopathological examination of the lesional skin demonstrated coarseness in collagen bundles and homogenization and decrement in elastic fibers with van Gieson stain. These features were consistent with linear focal elastosis. In the literature, linear focal elastosis is mainly reported in the elderly. We describe here a case of early linear focal elastosis arising in a 14-year-old Turkish boy.


Bilateral parietal dysfunctions and disconnections in simultanagnosia and Bálint syndrome.
In 1909 Rezsö Bálint published an extraordinary case study of a man with complex visuospatial deficits resulting from bilateral parietal lesions. Despite some controversies over the nature of reported symptoms, in 1954 Hecaen and Ajuriaguerra conceived the term "Bálint syndrome," not only to honor Bálint's influential work but to firmly conceptualize this striking neurologic disorder. Nowadays it is largely agreed that, while Bálint syndrome may result from multiple etiologies, it is principally diagnosed based on the presence of three symptoms: simultanagnosia, optic ataxia, and ocular apraxia. One of the most striking characteristics of Bálint syndrome, perfectly capturing the nature of this remarkable disorder, is that affected patients cannot perceive more than one object at a time or comprehend multiobject visual scenes due to a lack of ability to detect several objects concurrently and to grasp the spatial relationships between them. This chapter gives an overview of the cognitive mechanisms and neuroanatomy underlying Bálint syndrome, which provides key insights into our understanding of the role of parietal cortex in human attention, visual perception, and visuomotor control. This chapter also pays homage to Glyn Humphreys (1954-2016), who pioneered contributions to the knowledge about complexity of visual and spatial deficits associated with Bálint syndrome.


Outcomes in Pump- and CGM-Baseline Use Subgroups in the International Diabetes Closed-Loop Trial.
We investigated the potential benefits of automated insulin delivery (AID) among individuals with type 1 diabetes (T1D) in sub-populations of baseline device use determined by continuous glucose monitor (CGM) use status and insulin delivery via multiple daily injections (MDI) or insulin pump. In a six-month randomized, multicenter trial, 168 individuals were assigned to closed-loop control (CLC, Control-IQ, Tandem Diabetes Care), or sensor-augmented pump (SAP) therapy. The trial included a two- to eight-week run-in phase to train participants on study devices. The participants were stratified into four subgroups: insulin pump and CGM (pump+CGM), pump-only, MDI and CGM (MDI+CGM), and MDI users without CGM (MDI-only) users. We compared glycemic outcomes among four subgroups. At baseline, 61% were pump+CGM users, 18% pump-only users, 10% MDI+CGM users, and 11% MDI-only users. Mean time in range 70-180 mg/dL (TIR) improved from baseline in the four subgroups using CLC: pump+CGM, 62% to 73%; pump-only, 61% to 70%; MDI+CGM, 54% to 68%; and MDI-only, 61% to 69%. The reduction in time below 70 mg/dL from baseline was comparable among the four subgroups. No interaction effect was detected with baseline device use for TIR (P = .67) or time below (P = .77). On the System Usability Questionnaire, scores were high at 26 weeks for all subgroups: pump+CGM: 87.2 ± 12.1, pump-only: 89.4 ± 8.2, MDI+CGM 87.2 ± 9.3, MDI: 78.1 ± 15. There was a consistent benefit in patients with T1D when using CLC, regardless of baseline insulin delivery modality or CGM use. These data suggest that this CLC system can be considered across a wide range of patients.


Conjunction errors in recognition memory: modality-free errors for older adults but not for young adults.
A dual-process theory of memory was applied to processes in normal aging, with a focus on recognition errors in the feature-conjunction paradigm (i.e., false recognition of blackbird after studying parent words blackmail and/or jailbird). Study repetition was manipulated so that some parent words occurred once and others occurred three times. Age-related differences on hit scores occurred for two experiments. The results for feature and conjunction conditions showed repetition effects but no age-related differences when participants were uninformed of the lures (Experiment 1). However, age-related differences emerged when the retrieval of modality source information created a way to evade conjunction errors (Experiment 2). In the second experiment, study repetition decreased errors for the young adults but increased errors for the older adults, and young adults were better able than older adults to avoid conjunction errors when the parent words had been repeated. For older adults, the conjunction errors were modality-free. The results provide additional evidence that older adults experience difficulty in recollecting aspects of a study experience, and the results from groups of young adults required to respond quickly on the tests provide converging evidence for this conclusion.


A Study of Short- and Long-term mRNA Levels of the Retn, Iapp, and Drd5 Genes in Obese Mice Induced with High-fat Diet.
Adipocyte gene expression is altered in obese individuals through multiple metabolic and biochemical pathways. In this study, we aimed to examine the expression of resistin (Retn), amylin (Iapp), and dopamine receptor domain 5 (Drd5) genes previously suggested to contribute to the pathogenesis of obesity, albeit controversially. We also aimed to determine the effects on short and long-term mRNA levels of these genes in obese mice, induced with high-fat diet (HFD). Two obesity models were created in our study: group T1 (20 mice) was fed with HFD (60% fat) for 3 months, and group T2 (20 mice) was fed with HFD (60% fat) for 6 months. The control group T0 (20 mice) was fed with a diet of 10% kcal fat supplement for 6 months. At the end of the experiment, their adipose tissues were dissected surgically. Tissue samples of each group were pooled for RNA isolation, cDNA synthesis was carried out and the mRNA levels were examined by quantitative real-time polymerase chain reaction. Serum resistin levels were measured using multiplex bead (luminex) technology for validation. In T2 mice, the mRNA expression of Retn showed a moderate up-regulation (fold change=8.32; p=0.0019) in the adipose tissues. Iapp expression was also significantly up-regulated (fold change=9.78; p=0.012). Moreover, a 6.36-fold up-regulation for Drd5 was observed in the adipose tissues of T2 mice (p<0.001). At the same time, serum levels of resistin were found to be high in T1 and T2 mice compared to the control group (p<0.001 and p=0.024, respectively). Our study demonstrated that the mRNA levels of the genetic markers considered to play a role in adipogenesis were different in short- and long-term obesity models formed in C57BL/6J mice using HFD.


Hormonal control of fructose 2,6-bisphosphate concentration in the HT29 human colon adenocarcinoma cell line. Alpha 2-adrenergic agonists counteract effect of vasoactive intestinal peptide.
Vasoactive intestinal peptide (VIP) was found to cause a dose-dependent decrease in fructose 2,6-bisphosphatase concomitant with an increase in cyclic AMP in cultured HT29 cancer cells from human colon. The maximum effect was a 41% decrease obtained with 10 nM-VIP, and half-maximum effect was obtained with 0.75 nM-VIP. The effect of 2.5 nM-VIP was almost totally counteracted (i.e. fructose 2,6-bisphosphate concentration was restored) by either adrenaline (1 microM) or the alpha 2-adrenergic agonist UK-14304 (1 microM); the alpha 2-agonist clonidine (1 microM) was less efficient, since the VIP effect was decreased by 72% only. The adrenaline effect was totally antagonized by 1 microM-yohimbine. It is concluded that, in the HT29 cancer cells, the fructose 2,6-bisphosphate-producing system is sensitive to variations of cyclic AMP concentration and is under the dual control of VIP and alpha 2-adrenergic receptors.


Pharmacotherapy of Vasospastic Angina.
Vasospastic angina is a diagnosis of exclusion that manifests with signs and symptoms, which overlap with obstructive coronary artery disease, most often ST-segment elevation myocardial infarction. The pharmacotherapy that is available to treat vasospastic angina can help ameliorate angina symptoms. However, the etiology of vasospastic angina is ill-defined, making targeted pharmacotherapy difficult. Most patients receive pharmacotherapy that includes calcium channel blockers and/or long-acting nitrates. This article reviews the efficacy and safety of the pharmacotherapy used to treat vasospastic angina. High-dose calcium channel blockers possess the most evidence, with respect to decreasing angina incidence, frequency, and duration. However, not all patients respond to calcium channel blockers. Nitrates and/or alpha1-adrenergic receptor antagonists can be used in patients who respond poorly to calcium channel blockers. Albeit, evidence for use of nitrates and alpha1-adrenergic receptor antagonists in vasospastic angina is not as robust as calcium channel blockers and can exacerbate adverse effects when added to calcium channel blocker therapy. Despite having a clear benefit in patients with obstructive coronary artery disease, the benefit of beta-adrenergic receptor antagonists, statins, and aspirin remains unclear. More data are needed to elucidate whether or not these agents are beneficial or harmful to patients being treated for vasospastic angina. Overall, the use of pharmacotherapy for the treatment of vasospastic angina should be guided by patient-specific factors, such as tolerability, adverse effects, drug-drug, and drug-disease interactions.


A Low Dose of Pure Cannabidiol Is Sufficient to Stimulate the Cytotoxic Function of CIK Cells without Exerting the Downstream Mediators in Pancreatic Cancer Cells.
Despite numerous studies conducted over the past decade, the exact role of the cannabinoid system in cancer development remains unclear. Though research has focused on two cannabinoid receptors (CB1, CB2) activated by most cannabinoids, CB2 holds greater attention due to its expression in cells of the immune system. In particular, cytokine-induced killer cells (CIKs), which are pivotal cytotoxic immunological effector cells, express a high-level of CB2 receptors. Herein, we sought to investigate whether inducing CIK cells with cannabidiol can enhance their cytotoxicity and if there are any possible counter effects in its downstream cascade of phosphorylated p38 and CREB using a pancreatic ductal adenocarcinoma cell line (PANC-1). Our results showed that IL-2 modulates primarily the expression of the CB2 receptor on CIK cells used during ex vivo CIK expansion. The autophagosomal-associated scaffold protein p62 was found to co-localize with CB2 receptors in CIK cells and the PANC-1 cell line. CIK cells showed a low level of intracellular phospho-p38 and, when stimulated with cannabidiol (CBD), a donor specific variability in phospho-CREB. CBD significantly decreases the viability of PANC-1 cells presumably by increasing the cytotoxicity of CIK cells. Taken together, in our preclinical in vitro study, we propose that a low effective dose of CBD is sufficient to stimulate the cytotoxic function of CIK without exerting any associated mediator. Thus, the combinatorial approach of non-psychoactive CBD and CIK cells appears to be safe and can be considered for a clinical perspective in pancreatic cancer.


Machine learning approaches for elastic localization linkages in high-contrast composite materials.
There has been a growing recognition of the opportunities afforded by advanced data science and informatics approaches in addressing the computational demands of modeling and simulation of multiscale materials science phenomena. More specifically, the mining of microstructure-property relationships by various methods in machine learning and data mining opens exciting new opportunities that can potentially result in a fast and efficient material design. This work explores and presents multiple viable approaches for computationally efficient predictions of the microscale elastic strain fields in a three-dimensional (3-D) voxel-based microstructure volume element (MVE). Advanced concepts in machine learning and data mining, including feature extraction, feature ranking and selection, and regression modeling, are explored as data experiments. Improvements are demonstrated in a gradually escalated fashion achieved by (1) feature descriptors introduced to represent voxel neighborhood characteristics, (2) a reduced set of descriptors with top importance, and (3) an ensemble-based regression technique.


Terbinafine: broad new spectrum of indications in several subcutaneous and systemic and parasitic diseases.
Immunocompromised patients are at risk of contracting serious fungal infections. The emergence of acquired resistance to azole treatment by opportunistic fungal organisms is increasing and poses a major therapeutic challenge. Treatment of some deep cutaneous and subcutaneous mycoses remains unresolved, relapses are frequent, lack of tolerability of the antifungal drugs becomes an obstacle, and, unfortunately, surgery is, in some cases, the last option. The development of allylamine antifungals, of which terbinafine is the most effective to date, may help to resolve this situation. In vitro, terbinafine is highly active against a broad spectrum of pathogenic fungi. Clinical studies have shown that terbinafine is effective in the treatment of both cutaneous and lymphocutaneous sporotrichosis, and in several patterns of disseminated and refractory aspergillosis. Patients with chromoblastomycosis, and other mycoses (phaeohyphomycosis, maduromycosis, and mucormycosis) have also been successfully treated with terbinafine. Old World cutaneous leishmaniasis, a parasitic disease, has also been treated with terbinafine. These results suggest that the therapeutic potential of terbinafine extends well beyond its currently licensed applications to include a range of serious and life-threatening subcutaneous and systemic mycoses.


Contributing and Terminating Factors of a Large RSV Outbreak in an Adult Hematology and Transplant Unit.
In January 2012, an increase of respiratory syncytial virus (RSV) infections on an adult hematology and transplant unit in a German university hospital was detected. We investigated the outbreak to assess its timing and extent and to identify risk factors for transmission. We tested and typed patient samples pro- and retrospectively for RSV. We conducted a cohort and a case-control study. A confirmed outbreak case had laboratory-diagnosed, nosocomially-acquired RSV infection. Possible outbreak cases had pneumonia but were not laboratory-confirmed. Of 53 outbreak cases, 36 (68%) were confirmed and 17 (32%) possible. Retrospective testing and chart review dated the beginning of the outbreak to November 2011. Patients with community-acquired RSV infection were identified when the community epidemic began in January 2012. In multivariable analysis (controlling for contact with medical personnel, hygiene behaviour and age) patients with active social behaviour were more at risk for RSV infection (odds ratio 23.8, 95% confidence interval, 1.3 to 434.9; p-value, 0.03). Confirmed outbreak cases were more likely than controls to have been accomodated together with a confirmed or possible case before their onset of illness (OR 9.3, 95%CI: 2.1-85.1; p<0.001). Control measures, including isolation of every patient in the unit, initiated until the end of January terminated the outbreak. Epidemiological investigations revealed co-accomodation with a case-patient and active social behaviour as likely risk factors for RSV infection. Awareness of and vigorous testing for respiratory viruses in immunosuppressed hospitalised patients is necessary to timely detect cases with outbreak potential. Isolation of patients with respiratory infectious illnesses is crucial to prevent the continuation or occurrence of outbreaks.


Addition of Anti-CD40 Monoclonal Antibody to Nonmyeloablative Conditioning With Belatacept Abrogated Allograft Tolerance Despite Induction of Mixed Chimerism.
We recently reported anti-CD40 monoclonal antibody and rapamycin (aCD40/rapa) to be a reliable, nontoxic, immunosuppressive regimen for combined islet and kidney transplantation (CIKTx) in nonhuman primates. In the current study, we attempted to induce allograft tolerance through the mixed chimerism approach using a conditioning regimen with aCD40 and belatacept (Bela). Five CIKTx or kidney transplant alone recipients were treated with aCD40/rapa for 4 months. All recipients then received a conditioning regimen including horse antithymocyte globulin and aCD40/Bela. The results were compared with previous reports of recipients treated with Bela-based regimens. All 3 CIKTx recipients developed mixed chimerism, which was significantly superior to that observed in the previous Bela-based studies. Nevertheless, all CIKTx recipients in this study lost their islet and renal allografts as a result of cellular and humoral rejection on days 140, 89, and 84. The 2 kidney transplant-alone recipients were treated with the same conditioning regimen and suffered rejection on days 127 and 116, despite the development of excellent chimerism. B lymphocyte reconstitution dominated by memory phenotypes was associated with early development of donor-specific antibodies in 4 of 5 recipients. In vitro assays showed no donor-specific regulatory T cell expansion, which has been consistently observed in tolerant recipients with our mixed chimerism approach. Despite displaying excellent immunosuppressive efficacy, costimulatory blockade with anti-CD40 monoclonal antibody (2C10R4) may inhibit the induction of renal or islet allograft tolerance via a mixed chimerism approach.


Computational fluid dynamics analysis of surgical adjustment of left ventricular assist device implantation to minimise stroke risk.
Currently, mechanical support is the most promising alternative to cardiac transplantation. Ventricular assist devices (VADs) were originally used to provide mechanical circulatory support in patients awaiting planned heart transplantation ('bridge-to-transplantation' therapy). The success of short-term bridge devices led to clinical trials evaluating the clinical suitability of long-term support ('destination' therapy) with left ventricular assist devices (LVADs). The first larger scale, randomised trial that tested long-term support with an LVAD reported a 44% reduction in the risk of stroke or death in patients with an LVAD. In spite of the success of LVADs as bridge-to-transplantation and long-term support, patients managed by these devices are still at risk of several adverse events. The most devastating complication is caused by embolisation of thrombi formed within the LVAD or inside the heart into the brain. Prevention of thrombi formation is attempted through anticoagulation management and by improving LVADs design; however, there is still significant occurrence of thromboembolic events in patients. Investigators have reported that the incidence of thromboembolic cerebral events ranges from 14% to 47% over a period of 6-12 months. An alternative method to reduce the incidence of cerebral embolisation is proposed by the co-authors, and the hypothesis is that it is possible to minimise the number of thrombi flowing into the carotid and vertebral arteries by an optimal placement of the LVAD outflow conduit, with or without the addition of aortic bypass connecting the ascending aorta and the innominate artery (IA), or left carotid artery. This paper presents the computational fluid dynamics (CFD) analysis of the aortic arch haemodynamics using a representative geometry of the human aortic arch with or without an alternative aortic bypass. In order to study the trajectory of the thrombi within the aortic arch bed, the CFD code, Fluent 6.3, is utilised to resolve the flow field and to solve the Lagrangian particle tracking of thrombi released randomly at the inlet of the LVAD cannula. Results are presented for simulations of thrombi in the range of 2-5 mm. The percentage of individual diameter as well as aggregate diameter thrombi flowing to the carotid and vertebral arteries as a function of LVAD conduit placement and aortic bypass implantation is reported. The influence of the LVAD conduit implantation and bypass reveals a nearly 50% variation in predicted cerebral embolism rates. The adjustment of the location of the anastomosis of the LVAD outflow cannula as well as its angle of incidence plays a significant role in the level of thromboembolisms. By proper adjustment in this CFD study of a synthetic model of an aortic arch bed, we found that nearly a 50% reduction in cerebral embolism could be achieved for a configuration consisting of a shallow angle of implantation over a baseline normal incidence of the LVAD cannula. Within the limitations of our model, we have established that the LVAD implantation geometry is an important factor and should be taken into consideration when implanting an LVAD. It is possible that other parameters such as distance of the LVAD outflow cannula to the root of the IA could affect the thrombi embolisation probabilities. However, the results of this study suggest that the risk of stroke may be significantly reduced by as much as 50% by tailoring the VAD implantation by a simple surgical manoeuvre. The results of this line of research may ultimately lead to techniques that can be used to estimate the optimal LVAD configuration in a patient-specific manner by pre-operative imaging.


[Usefulness of establishing diagnosis and severity of the most frequent signs and symptoms in preeclamptic patients].
Our aim was to determine that signs and symptoms are tools in establishing diagnosis and severity of preeclampsia. Our study design was prolective, comparative, cross-sectional for evaluation of diagnosis. Our sample included 408 patients. The study employed classification criteria of the American College of Obstetricians and Gynecologists. One blinded family physician interrogated and examined each patient. The sample included patients with recent diagnosis and without treatment. Patients with HELLP syndrome, eclampsia, and those in Intensive Care were excluded. Clinical signs evaluated included headache, Phosphenes, acuphenes, tinnitus, vomiting, epigastric pain, right hypochondrium pain, ecchymosis, hematomas,and hyperreactive reflexes. A total of 192 patients without preeclampsia, 63 with mild, and 153 with severe preeclampsia were included. Clinical manifestations were absent in 60, 21 and 8% respectively of patients in each group. Presence of three or more signs or symptoms had sensitivity of 60% (CI95% 53-67), specificity of 84% (CI95% 79-89), and positive likelihood ratio of 3.8 and negative, 0.48. Most usefulness data for diagnosis of preeclampsia are hyperreactive reflexes, phosphenes, acuphenes, right hypochondrium pain, and epigastric pain. The symptoms and signs taken alone are tools for evaluation of severity but not for detection of preeclampsia. There is necessary to develop new way for it's diagnosis during prenatal care.


Parathyroid hyperplasia as a cause of recurrent hyperparathyroidism.
Parathyroid hyperplasia is second only to adenoma as the most common cause of hyperparathyroidism. Symptoms are most likely to result from elevated serum calcium levels. Symptoms include nephrocalcinosis and nephrolithiasis. Studies that may help confirm a suspected diagnosis include ultrasonography, computed tomography, radionuclide scanning with thallium and/or technetium, and magnetic resonance imaging. Surgical treatment consists of excision of all but part of one parathyroid gland if all of the glands are enlarged.


tTARGIT AAVs mediate the sensitive and flexible manipulation of intersectional neuronal populations in mice.
While Cre-dependent viral systems permit the manipulation of many neuron types, some cell populations cannot be targeted by a single DNA recombinase. Although the combined use of Flp and Cre recombinases can overcome this limitation, insufficient recombinase activity can reduce the efficacy of existing Cre+Flp-dependent viral systems. We developed a sensitive dual recombinase-activated viral approach: tTA-driven Recombinase-Guided Intersectional Targeting (tTARGIT) adeno-associated viruses (AAVs). tTARGIT AAVs utilize a Flp-dependent tetracycline transactivator (tTA) 'Driver' AAV and a tetracycline response element-driven, Cre-dependent 'Payload' AAV to express the transgene of interest. We employed this system in Slc17a6FlpO;LeprCre mice to manipulate LepRb neurons of the ventromedial hypothalamus (VMH; LepRbVMH neurons) while omitting neighboring LepRb populations. We defined the circuitry of LepRbVMH neurons and roles for these cells in the control of food intake and energy expenditure. Thus, the tTARGIT system mediates robust recombinase-sensitive transgene expression, permitting the precise manipulation of previously intractable neural populations.


Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel.
Metastasis, the cardinal feature of malignant tumors, is an important clinical variable in patient prognosis. To understand the basis for metastasis, we systematically selected for highly invasive cells from breast cancer cell lines, MCF7 and MDA-MB-453, with moderate to low invasive ability using Boyden chamber invasion assay. The four-cycle selected invasive lines, named MCF7-I4 and MDA-MB-453-I4, respectively, displayed epithelial-mesenchymal transition (EMT) and dramatically enhanced invasive ability. EMT changes were corroborated with decreased level of E-cadherin and increased vimentin, fibronectin, and beta(1) integrin. Twist, a basic helix-loop-helix transcription factor, and AKT2, a known proto-oncogene, were found to be elevated in the invasive cells compared with the parental. Ectopic expression and knockdown of Twist by short interference RNA resulted in significant increase and reduction, respectively, of AKT2 protein and mRNA expression. Twist bound to E-box elements on AKT2 promoter and enhanced its transcriptional activity. Moreover, silencing AKT2 decreased Twist-promoted migration, invasion, and paclitaxel resistance. Reintroducing AKT2 largely rescued the phenotype resulted from knockdown of Twist in I4 cells, suggesting that AKT2 is a downstream target and functional mediator of Twist. Finally, we observed a 68.8% correlation of elevated Twist and AKT2 expression in late-stage breast cancers as oppose to 13% in early-stage breast cancers. Our study identifies Twist as a positive transcriptional regulator of AKT2 expression, and Twist-AKT2 signaling is involved in promoting invasive ability and survival of breast cancer cells.


Effect of using of a lower-extremity exoskeleton on disability of people with multiple sclerosis.
Although ongoing exercise is known to reduce disability in people with multiple sclerosis (MS), participation in lower-extremity exercise programs can be limited by their existing mobility impairments. Lower-extremity exoskeletons could address this problem by facilitating home and community locomotion and enhancing exercise capability but little data is available on the potential of this technology for reducing disability of people with MS. We evaluated the Keeogo™ exoskeleton for people with MS using an open-label randomised cross-over design. The trial design allowed us to quantify rehabilitation effects (tested without device) and training effects (tested with device) using functional outcomes: 6-minute walk test (6MWT), timed stair test (TST), and timed up-and-go (TUG). Baseline and post-study self-report instruments included Medical Outcomes Survey Short Form-36 (SF36), MS Walking Scale (MSWS), and others. Amount of home use was documented by daily activity log. Partial correlation analysis was used to explore the relationships between changes in functional outcomes and self-report disability, controlling for amount of home use of the device. Twenty-nine participants with MS completed the trial. Change scores for MSWS, SF36 physical function and SF36 emotional well-being correlated positively with changes in 6MWT which was explained by amount of home use. The benefits in physical functioning and emotional well-being from using the exoskeleton at home were linked to amount of device usage. Low-profile robotic exoskeletons could be used to deliver facilitated exercise while assisting with locomotor activities of daily living, such as walking and stair climbing in the home and community environment.IMPLICATIONS FOR REHABILITATIONExoskeletons for home use may have the potential to benefit people with MS in terms of physical functioning and emotional well-being.The benefits in physical functioning and emotional well-being appeared to be linked to amount of usage.Exoskeletons might be useful for delivering facilitated exercise while assisting with walking and stair climbing in the home.


Is Hypersexuality Dimensional or Categorical? Evidence From Male and Female College Samples.
The recent attempt to introduce hypersexual disorder into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), has increased empirical scrutiny of the construct. Consensus on its definition and underlying structure remains elusive. Whereas some conceptualizations favor a categorical latent structure, others speculate that hypersexual behavior is dimensional. Research on the latent structure of hypersexual behavior, however, has been sparse. This is unfortunate, because determination of the latent structure can contribute to more accurate assessment, diagnosis, and understanding of etiological process. To date the only study on hypersexuality's latent structure found consistent evidence of a dimensional structure for males but less clear results for females. In the present study the Multidimensional Inventory of Development, Sex, and Aggression (MIDSA), a self-report, contingency-based inventory, was administered to 1,146 college students. Four indices of hypersexual behavior and six indices of sexual compulsivity were analyzed, using three taxometric methods (mean above minus below a cut [MAMBAC], maximum covariance [MAXCOV], and latent mode factor analysis [L-Mode]). Evidence supported a dimensional latent structure for hypersexuality in male and female samples. Future assessments of hypersexuality must focus on adequate reliability and discriminant validity across the continuum of sexual behavior rather than on attempts to differentiate between arbitrarily developed diagnostic categorizations.


Probing Single-Molecule Dissociations from a Bimolecular Complex NO-Co-Porphyrin.
Axial coordinations of diatomic NO molecules to metalloporphyrins play key roles in dynamic processes of biological functions such as blood pressure control and immune response. Probing such reactions at the single molecule level is essential to understand their physical mechanisms but has been rarely performed. Here we report on our single molecule dissociation experiments of diatomic NO from NO-Co-porphyrin complexes describing its dissociation mechanisms. Under tunneling junctions of scanning tunneling microscope, both positive and negative energy pulses gave rise to dissociations of NO with threshold voltages, +0.68 and -0.74 V at 0.1 nA tunneling current on Au(111). From the observed power law relations between dissociation rate and tunneling current, we argue that the dissociations were inelastically induced with molecular orbital resonances by stochastically tunneling electrons, which is supported with our density functional theory calculations. Our study shows that single molecule dissociation experiments can be used to probe reaction mechanisms in a variety of axial coordinations between small molecules and metalloporphyrins.


Microbial efflux pump inhibition: tactics and strategies.
Traditional antimicrobials are increasingly suffering from the emergence of multidrug resistance among pathogenic microorganisms. To overcome these deficiencies, a range of novel approaches to control microbial infections are under investigation as potential alternative treatments. Multidrug efflux is a key target of these efforts. Efflux mechanisms are broadly recognized as major components of resistance to many classes of chemotherapeutic agents as well as antimicrobials. Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES). They are implicated in a variety of physiological roles other than efflux and identifying natural substrates and inhibitors is an active and expanding research discipline. One plausible alternative is the combination of conventional antimicrobial agents/antibiotics with small molecules that block MES known as multidrug efflux pump inhibitors (EPIs). An array of approaches in academic and industrial research settings, varying from high-throughput screening (HTS) ventures to bioassay guided purification and determination, have yielded a number of promising EPIs in a series of pathogenic systems. This synergistic discovery platform has been exploited in translational directions beyond the potentiation of conventional antimicrobial treatments. This venture attempts to highlight different tactical elements of this platform, identifying the need for highly informative and comprehensive EPI-discovery strategies. Advances in assay development genomics, proteomics as well as the accumulation of bioactivity and structural information regarding MES facilitates the basis for a new discovery era. This platform is expanding drastically. A combination of chemogenomics and chemoinformatics approaches will integrate data mining with virtual and physical HTS ventures and populate the chemical-biological interface with a plethora of novel chemotypes. This comprehensive step will expedite the preclinical development of lead EPIs.


Identification of genetic variants in the TNF promoter associated with COPD secondary to tobacco smoking and its severity.
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that arises in response to noxious particles or gases. Associations of genetic polymorphisms in TNF have been reported in Asians and Caucasians, but not in Mestizo populations. A case-control study was conducted in two stages: in the first stage, patients with COPD (COPD group, n=165) and smokers without disease (SNC group, n=165) were included and the TNF promoter sequence was determined using direct sequencing. In the second stage, the identified polymorphisms were validated by real-time polymerase chain reaction (PCR) in COPD (n=260) and SNC (n=506). In the first stage, 11 different sets of "contig" alignments were determined, of which contig 10 was found to be associated with susceptibility (P=5.0E-04, OR [odds ratio] =3.64) and contig 1 with Global Initiative for COPD (GOLD) greater grade (P=1.0E-02, OR =3.82). The single nucleotide polymorphisms found in this region were individually identified; the GA genotypes of rs1800629 (P=0.038, OR =2.07), rs56036015 (P=0.0082, OR =3.18), and rs361525 (P=1.0E-02, OR =4.220) were higher in the COPD group vs the SNC group; after second-stage validation, rs1800629 (P=6.00E-03, OR =2.26) and rs56036015 (P=1.10E-03, OR =2.54) are maintained. There are genetic variants in the TNF promoter associated with increased risk of COPD secondary to smoking and with a higher GOLD grade in the Mexican Mestizo population.


A rationale for intraperitoneally administered antibiotic therapy.
A satisfactory clinical response occurred in 96.7 per cent of 210 patients with proved bacterial peritonitis following appropriate surgical intervention and an antimicrobial regimen of 1 per cent cephalothin administered intraperitoneally, with supplementary antibiotics as indicated. Instillation of cephalothin achieves the therapeutic benefits of high intraperitoneal levels with an antibiotic of broad activity and minimum toxicity and permits flexibility in the choice of additional antimicrobial therapy. Adjuvant therapy with cephalothin did not result in peritoneal adhesions or significant abdominal pain. Clinical experience suggests that it may promote healing of anastomotic leaks. The results of this study indicate that intraperitoneally administered cephalothin is a significant factor in lowering the death rate in peritonitis.


Antimicrobial activity of a novel bioengineered honey against non-typeable Haemophilus influenzae biofilms: an in vitro study.
The opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) plays an important role in many chronic respiratory diseases including otitis media, chronic rhinosinusitis, cystic fibrosis and chronic obstructive pulmonary disease. Biofilm formation has been implicated in NTHi colonisation, persistence of infection and recalcitrance towards antimicrobials. There is therefore a pressing need for the development of novel treatment strategies that are effective against NTHi biofilm-associated diseases. SurgihoneyRO is a honey-based product that has been bioengineered to enable the slow release of H2O2, a reactive oxygen species to which H. influenzae is susceptible. Treatment of established NTHi biofilms with SurgihoneyRO significantly reduced biofilm viability through enhanced H2O2 production and was shown to be more effective than the conventional antibiotic co-amoxiclav.


Interaction between birthweight and polymorphism in the calcium-sensing receptor gene in determination of adult bone mass: the Hertfordshire cohort study.
We sought evidence of interaction between single-nucleotide polymorphisms (SNP) in the calcium-sensing receptor (CASR) gene and early life in determination of bone mineral density (BMD) among individuals from the Hertfordshire Cohort Study. Four hundred ninety-eight men and 468 women aged 59-71 years were recruited. A lifestyle questionnaire was administered and BMD at lumbar spine and femoral neck was measured. DNA was obtained from whole blood samples using standard extraction techniques. Five SNP of the CASR gene termed CASRV1 (rs1801725, G-->T, S986A), CASRV2 (rs7614486, T-->G, untranslated), CASRV3 (rs4300957, untranslated), CASRV4 (rs3804592 G-->A, intron), and CASRV5 (rs1393189, T-->C, intron) were analyzed. Among women the 11 genotype of the CASRV3 SNP was associated with higher lumbar spine BMD within the lowest birthweight tertile, while the opposite pattern was observed among individuals in the highest birthweight tertile (test for interaction on 1 df, p = 0.005, adjusted for age, body mass index, physical activity, dietary calcium intake, cigarette and alcohol consumption, social class, menopausal status, and hormone replacement therapy use). Similar relationships were seen at the total femur (p = 0.042, fully adjusted) with birthweight and at the total femur according to weight at 1 year tertile among women (p < 0.001, fully adjusted). One haplotype was associated with lumbar spine BMD in women (p = 0.008, fully adjusted); these findings were replicated in a second cohort. We have found evidence of an interaction between a SNP of the CASR gene and birthweight in determination of bone mass in a UK female population.


The clinical potential of articular cartilage-derived progenitor cells: a systematic review.
Over the past two decades, evidence has emerged for the existence of a distinct population of endogenous progenitor cells in adult articular cartilage, predominantly referred to as articular cartilage-derived progenitor cells (ACPCs). This progenitor population can be isolated from articular cartilage of a broad range of species, including human, equine, and bovine cartilage. In vitro, ACPCs possess mesenchymal stromal cell (MSC)-like characteristics, such as colony forming potential, extensive proliferation, and multilineage potential. Contrary to bone marrow-derived MSCs, ACPCs exhibit no signs of hypertrophic differentiation and therefore hold potential for cartilage repair. As no unique cell marker or marker set has been established to specifically identify ACPCs, isolation and characterization protocols vary greatly. This systematic review summarizes the state-of-the-art research on this promising cell type for use in cartilage repair therapies. It provides an overview of the available literature on endogenous progenitor cells in adult articular cartilage and specifically compares identification of these cell populations in healthy and osteoarthritic (OA) cartilage, isolation procedures, in vitro characterization, and advantages over other cell types used for cartilage repair. The methods for the systematic review were prospectively registered in PROSPERO (CRD42020184775).


Human cytomegalovirus UL69 protein induces cells to accumulate in G1 phase of the cell cycle.
Earlier studies have revealed that human cytomegalovirus rapidly inhibits the growth of fibroblasts, blocking cell cycle progression at multiple points, including the G1-to-S-phase transition. The present study demonstrates that the UL69 protein, a virus-encoded constituent of the virion, is able to arrest cell cycle progression when introduced into uninfected cells. Expression of the UL69 protein causes U2 OS cells and primary human fibroblasts to accumulate within the G1 compartment of the cell cycle, and serum fails to induce the progression of quiescent human fibroblasts into the S phase when the protein is present. Therefore, the UL69 protein is at least partially responsible for the cell cycle block that is instituted after infection of permissive cells with human cytomegalovirus.


CETP (Cholesteryl Ester Transfer Protein) Inhibition With Anacetrapib Decreases Production of Lipoprotein(a) in Mildly Hypercholesterolemic Subjects.
Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using 2H3-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (P≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. Anacetrapib reduces Lp(a) levels by decreasing its production. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808.


6-DoF Haptic Rendering Using Continuous Collision Detection between Points and Signed Distance Fields.
We present an algorithm for fast continuous collision detection between points and signed distance fields, and demonstrate how to robustly use it for 6-DoF haptic rendering of contact between objects with complex geometry. Continuous collision detection is often needed in computer animation, haptics, and virtual reality applications, but has so far only been investigated for polygon (triangular) geometry representations. We demonstrate how to robustly and continuously detect intersections between points and level sets of the signed distance field. We suggest using an octree subdivision of the distance field for fast traversal of distance field cells. We also give a method to resolve continuous collisions between point clouds organized into a tree hierarchy and a signed distance field, enabling rendering of contact between rigid objects with complex geometry. We investigate and compare two 6-DoF haptic rendering methods now applicable to point-versus-distance field contact for the first time: continuous integration of penalty forces, and a constraint-based method. An experimental comparison to discrete collision detection demonstrates that the continuous method is more robust and can correctly resolve collisions even under high velocities and during complex contact.


Monte Carlo modeling of optical coherence tomography imaging through turbid media.
We combine a Monte Carlo technique with Mie theory to develop a method for simulating optical coherence tomography (OCT) imaging through homogeneous turbid media. In our model the propagating light is represented by a plane wavelet; its line propagation direction and path length in the turbid medium are determined by the Monte Carlo technique, and the process of scattering by small particles is computed according to Mie theory. Incorporated into the model is the numerical phase function obtained with Mie theory. The effect of phase function on simulation is also illustrated. Based on this improved Monte Carlo technique, OCT imaging is directly simulated and phase information is recorded. Speckles, resolution, and coherence gating are discussed. The simulation results show that axial and transversal resolutions decrease as probing depth increases. Adapting a light source with a low coherence improves the resolution. The selection of an appropriate coherence length involves a trade-off between intensity and resolution.


RNA-Seq Analyses of the Role of miR-21 in Acute Pancreatitis.
Our previous study demonstrated that a deficiency of microRNA 21 (miR-21) protects mice from acute pancreatitis, yet the underlying molecular networks associated with miR-21 in pancreatitis and pancreatitis-associated lung injury remain unexplored. We used next generation sequencing to analyze gene expression profiles of pancreatic tissues from wild-type (WT) and miR-21 knockout (KO) mice treated with caerulein by using a 1-day treatment protocol. The Database for Annotation, Visualization, and Integrated Discovery gene annotation tool and Ingenuity Pathway Analysis were used to analyze the molecular pathways, while quantitative real-time PCR, western blotting, and immunohistochemistry were used to explore the molecular mechanisms. We identified 152 differentially expressed genes (DEGs) in pancreata between WT and KO mice treated with caerulein. Cellular biogenesis and metabolism were the major pathways affected between WT and KO mice, whereas cell death and inflammatory response discriminated between WT and KO mice under acute pancreatitis. We validated 16 DEGs, consisting of 6 upregulated genes and 10 downregulated genes, involved in pancreatic injury. In particular, the upregulation of Pias3 and downregulation of Hmgb1 in KO pancreata coincided with a reduced severity of pancreatitis. In addition, we found Hmgb1 stimulation resulted in the overexpression of miR-21 in peripheral blood mononuclear cells, and deletion of miR-21 led to a reduction of caerulein-induced acute pancreatitis-associated lung injury by repressing Hmgb1 expression. Our data support the hypothesis that miR-21 modulates the inflammatory response during acute pancreatitis through the upregulation of Pias3 and downregulation of Hmgb1. Our findings further underscore a role for miR-21 in the promotion of acute pancreatitis.


The structure of tRNA 5 Lys from Drosophila melanogaster.
The nucleotide sequence of Drosophila melanogaster tRNA 5 Lys is pGCCCGGAUAm2GCUCAGDCGGDAGAGCA psi psi GGACUsU*UUt6A*A psi CCAAGGm7GDm5CCAGGGTm psi CAm1AGUCCCUGUUCGGGCGCCA. The sU* is probably 5-methylcarboxymethyl-2-thiouridine and t6A* is a mixture of modified derivatives of t6A including t6A itself and a component sensitive to treatment with cyanogen bromide. This tRNA 5 Lys is 95% homologous to the rabbit liver tRNA 5 Lys.


Long-term outcomes of bariatric surgery in patients with diabetes.
Introduction: Initially seen as a weight-loss operation, bariatric surgery is now recognized as a metabolic procedure with a critical role in the management of type 2 diabetes mellitus (T2DM). Early improvement in glucose metabolism is a remarkable effect of surgery; however, what deserves equal thought are implications for long-term diabetes control and relapse. Evidence suggests the metabolic effects of surgery fatigue and a proportion of patients will experience relapse of T2DM, with or without weight regain. Herein, we discuss the evidence examining the durability of these effects and approaches to improve long-term control.Areas covered: PubMed, Embase, CENTRAL, and Medline were searched for trials looking at outcomes for patients with obesity and T2DM undergoing bariatric surgery between January 2000 andDecember 2019. Additional studies were found by searching publications from related journals and references.Export opinion: Bariatric surgery is a safe and effective treatment for T2DM and obesity however the response to surgery, like any other treatment is variable. Some patients will experience a relapse of diabetes in the long term. Recent developments in pharmacotherapy present an opportunity to augment or sustain what can be achieved with surgery. Combinational treatment may dramatically change the way both diseases are managed.


Characterisation of a rice vacuolar invertase isoform, OsINV2, for growth and yield-related traits.
OsINV2, a rice vacuolar invertase isoform, was assessed for its functional roles in plant growth and development with key focus on its agronomic traits such as grain weight, grain filling percentage, grain number and dry weights at various stages until harvest. Lack of differences between the wild-type and the mutants with respect to any of the aforementioned traits tested revealed a possibility of functional compensation of OsINV2 in the mutants conceivably by its isoform. This was confirmed by OsINV2 promoter::GUS studies, where its spatial and temporal expression in the panicle elongation stages showed that although OsINV2 expression was observed from the stage with young panicles ~1 cm in length to the flag leaf stage, significant differences with respect to panicle and spikelet phenotypes between the wild-type and the mutant were not present. However, complement lines displaying an overexpression phenotype of OsINV2 possessed a higher stem non-structural carbohydrate content under both monoculm and normal tillering conditions. A trade-off between the spikelet number and grain weight in the complement lines grown under monoculm conditions was also observed, pointing towards the necessity of OsINV2 regulation for grain yield-related traits.


Effects of ketamine, thiopental and their combination on the rat liver: A biochemical evaluation.
In the literature, it has been suggested that ketamine-related oxidative organ damage results from increased blood adrenaline level, and thiopental-related oxidative damage is caused by decreased adrenaline level, suggesting that ketamine-thiopental combination (KT) may be beneficial in reducing the hepatotoxic effect of ketamine. To biochemically investigate the effects of ketamine, thiopental and KT on the liver in rats. Male albino Wistar type rats received intraperitoneally (ip.) 30 mg/kg ketamine in the ketamine alone (KG) group (n = 6), 15 mg/kg thiopental in the thiopental alone (TG) group (n = 6), and 30 mg/kg ketamine + 15 mg/kg thiopental in the ketamine+thiopental (KTG) group (n = 6). The same volume of distilled water as solvent was given to the healthy (HG) animal group. This procedure was repeated once daily for 30 days. At the end of this period, the animals were killed by decapitation and their livers were removed. In liver tissue, malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), total antioxidant status (TAS), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin-6 (IL-6) levels were measured. The IL-1β, IL-6, TNF-α, adrenalin (ADR), noradrenalin (NDR), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were determined in blood samples taken from the tail veins. In the group treated with ketamine and thiopental alone, MDA, TOS, IL-1β, IL-6, TNF-α, ADR, NDR, ALT, and AST levels were found to be high, and those of tGSH and TAS to be low. However, there was no significant change in the levels of these parameters in the KTG. These results indicate that oxidative stress and inflammation developed in the liver tissue of the group that used ketamine and thiopental alone, suggesting that the KT form may be safer in terms of toxicity in the clinical usage.


Urinary cadmium concentration and the risk of ischemic stroke.
To examine the association between urinary cadmium levels and the incidence of ischemic stroke and to explore possible effect modifications. A case-cohort study was designed nested in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, including 680 adjudicated incident cases of ischemic stroke and 2,540 participants in a randomly selected subcohort. Urinary creatinine-corrected cadmium concentration was measured at baseline. Multivariable-adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated with the Barlow weighting method for the Cox proportional hazards regression model. The median urinary cadmium concentration was 0.42 (interquartile range 0.27-0.68) μg/g creatinine. After adjustment for potential confounders, urinary cadmium was associated with increased incidence of ischemic stroke (quintile 5 vs quintile 1: HR 1.50, 95% CI 1.01-2.22, p for trend = 0.02). The observed association was more pronounced among participants in the lowest serum zinc tertile (tertile 3 vs tertile 1: HR 1.82, 95% CI 1.06-3.11, p for trend = 0.004, p for interaction = 0.05) but was attenuated and became nonsignificant among never smokers (tertile 3 vs tertile 1: never smokers: HR 1.27, 95% CI 0.80-2.03, p for trend = 0.29; ever smokers: HR 1.60, 95% CI 1.06-2.43, p for trend = 0.07, p for interaction = 0.51). Findings from this study suggest that cadmium exposure may be an independent risk factor for ischemic stroke in the US general population. Never smoking and maintaining a high serum zinc level may ameliorate the potential adverse effects of cadmium exposure.


Plasma L-cystine/L-glutamate imbalance increases tumor necrosis factor-alpha from CD14+ circulating monocytes in patients with advanced cirrhosis.
The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys) and secrete substantial amounts of L-Glutamate (L-Glu) via the transport system Xc- (4F2hc+xCT), and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes. We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM), and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha. The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (n = 19), the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio. A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis.


The Effects of the COVID-19 Pandemic on the Lived Experience of Diverse Older Adults Living Alone With Cognitive Impairment.
Even before the COVID-19 pandemic, older adults with cognitive impairment living alone (an estimated 4.3 million individuals in the United States) were at high risk for negative health outcomes. There is an urgent need to learn how this population is managing during the pandemic. This is a qualitative study of 24 adults aged 55 and older living alone with cognitive impairment from diverse racial/ethnic backgrounds. Participants' lived experiences during the pandemic were elicited via 59 ethnographic interviews conducted over the phone either in English, Spanish, or Cantonese. Using a qualitative content analysis approach, interview transcripts were analyzed to identify codes and themes. Qualitative analysis of transcripts revealed 5 themes: (a) fear generated by the pandemic, (b) distress stemming from feeling extremely isolated, (c) belief in misinformation, (d) strategies for coping during the pandemic, and (e) the importance of access to essential services. This pandemic put a spotlight on the precarity and unmet needs of older adults living alone with cognitive impairment. Findings underscore the need to expand access to home care aides and mental health services for this population.


Absence of Nucleotide-Oligomerization-Domain-2 Is Associated with Less Distinct Disease in Campylobacter jejuni Infected Secondary Abiotic IL-10 Deficient Mice.
Human Campylobacter jejuni-infections are progressively increasing worldwide. Despite their high prevalence and socioeconomic impact the underlying mechanisms of pathogen-host-interactions are only incompletely understood. Given that the innate immune receptor nucleotide-oligomerization-domain-2 (Nod2) is involved in clearance of enteropathogens, we here evaluated its role in murine campylobacteriosis. To address this, we applied Nod2-deficient IL-10-/- (Nod2-/- IL-10-/-) mice and IL-10-/- counterparts both with a depleted intestinal microbiota to warrant pathogen-induced enterocolitis. At day 7 following peroral C. jejuni strain 81-176 infection, Nod2 mRNA was down-regulated in the colon of secondary abiotic IL-10-/- and wildtype mice. Nod2-deficiency did neither affect gastrointestinal colonization nor extra-intestinal and systemic translocation properties of C. jejuni. Colonic mucin-2 mRNA was, however, down-regulated upon C. jejuni-infection of both Nod2-/- IL-10-/- and IL-10-/- mice, whereas expression levels were lower in infected, but also naive Nod2-/- IL-10-/- mice as compared to respective IL-10-/- controls. Remarkably, C. jejuni-infected Nod2-/- IL-10-/- mice were less compromised than IL-10-/- counterparts and displayed less distinct apoptotic, but higher regenerative cell responses in colonic epithelia. Conversely, innate as well as adaptive immune cells such as macrophages and monocytes as well as T lymphocytes and regulatory T-cells, respectively, were even more abundant in large intestines of Nod2-/- IL-10-/- as compared to IL-10-/- mice at day 7 post-infection. Furthermore, IFN-γ concentrations were higher in ex vivo biopsies derived from intestinal compartments including colon and mesenteric lymph nodes as well as in systemic tissue sites such as the spleen of C. jejuni infected Nod2-/- IL-10-/- as compared to IL10-/- counterparts. Whereas, at day 7 postinfection anti-inflammatory IL-22 mRNA levels were up-regulated, IL-18 mRNA was down-regulated in large intestines of Nod2-/- IL-10-/- vs. IL-10-/- mice. In summary, C. jejuni-infection induced less clinical signs and apoptosis, but more distinct colonic pro- and (of note) anti-inflammatory immune as well as regenerative cell responses in Nod2 deficient IL-10-/- as compared to IL-10-/- control mice. We conclude that, even though colonic Nod2 mRNA was down-regulated upon pathogenic challenge, Nod2-signaling is essentially involved in the well-balanced innate and adaptive immune responses upon C. jejuni-infection of secondary abiotic IL-10-/- mice, but does neither impact pathogenic colonization nor translocation.


Formalin-induced pain is reduced in sigma(1) receptor knockout mice.
The role of sigma1 receptors in non-acute pain has not been explored. In this study we show that both phases of formalin-induced pain were reduced by approximately 55% in sigma1 receptor knockout mice in comparison to wild-type animals. These results suggest that the tonic pain induced by formalin is altered in mice lacking sigma1 receptors, and highlight the potential usefulness of further studies of the role of sigma1 receptors in models of non-acute pain.


Intrasubtype reassortments cause adaptive amino acid replacements in H3N2 influenza genes.
Reassortments and point mutations are two major contributors to diversity of Influenza A virus; however, the link between these two processes is unclear. It has been suggested that reassortments provoke a temporary increase in the rate of amino acid changes as the viral proteins adapt to new genetic environment, but this phenomenon has not been studied systematically. Here, we use a phylogenetic approach to infer the reassortment events between the 8 segments of influenza A H3N2 virus since its emergence in humans in 1968. We then study the amino acid replacements that occurred in genes encoded in each segment subsequent to reassortments. In five out of eight genes (NA, M1, HA, PB1 and NS1), the reassortment events led to a transient increase in the rate of amino acid replacements on the descendant phylogenetic branches. In NA and HA, the replacements following reassortments were enriched with parallel and/or reversing replacements; in contrast, the replacements at sites responsible for differences between antigenic clusters (in HA) and at sites under positive selection (in NA) were underrepresented among them. Post-reassortment adaptive walks contribute to adaptive evolution in Influenza A: in NA, an average reassortment event causes at least 2.1 amino acid replacements in a reassorted gene, with, on average, 0.43 amino acid replacements per evolving post-reassortment lineage; and at least ~9% of all amino acid replacements are provoked by reassortments.


Population pharmacokinetics of ceftriaxone administered as continuous or intermittent infusion in critically ill patients.
To describe the population pharmacokinetics and protein-binding characteristics of unbound ceftriaxone administered as continuous or intermittent infusion. Additionally, to determine the optimal dosing regimen in critically ill patients. A pharmacokinetic study was performed in the ICU of a tertiary teaching hospital. Patients were treated with ceftriaxone as continuous or intermittent infusion. A population pharmacokinetic model was developed with non-linear mixed-effects analysis. Subsequently, the PTA of a 100% T>MIC was assessed for influential patient characteristics using Monte Carlo simulation. Fifty-five patients were included. The pharmacokinetics of ceftriaxone was best described by a one-compartment model with non-linear saturable protein binding including the following covariates: body weight, estimated CLCR, serum albumin concentration and mode of administration. For pathogens with an MIC of 1 mg/L, the simulation demonstrated that intermittent infusion of 2 g/24 h only resulted in a ≥90% PTA in patients with a reduced CLCR (0-60 mL/min). Intermittent infusion of 2 g/12 h led to sufficient exposure if CLCR was 0-90 mL/min and continuous infusion of 2 g/24 h led to a ≥90% PTA in all simulations (CLCR 0-180 mL/min). In the critically ill, the clearance of unbound ceftriaxone is closely related to CLCR. Furthermore, ceftriaxone protein binding is saturable, variable and dependent on serum albumin concentration. Intermittent dosing of 2 g/24 h ceftriaxone leads to subtherapeutic exposure in patients with a normal or increased CLCR. Treating these patients with continuous infusion of 2 g/24 h is more effective than an intermittent dosing regimen of 2 g/12 h.


Attenuation of telomerase activity by hammerhead ribozymes targeting human telomerase RNA and telomerase reverse transcriptase in pancreatic carcinoma cells.
In cancer gene therapies, it is ideal to target tumor-specific genes. Since telomerase is activated in almost all cancer cells but not most somatic cells, it is considered as one of the favorite targets for cancer gene therapies. Ribozymes are catalytic RNA molecules with site-specific endoribonuclease activity. In the present study, we designed hammerhead ribozymes against human telomerase RNA (hTR) and human reverse transcriptase subunit (hTERT) to evaluate their effect on the attenuation of telomerase in the pancreas cancer cell line, PK-8. Hammerhead ribozyme targeting hTR depressed the level of telomerase activity in PK-8 cells. pRc-hTR vector with ribozyme targeting hTR and pRc-hTERT vector with ribozyme targeting hTERT mRNA were transfected into PK-8 cells and depressed telomerase activity and target RNA, but in pRc-hTR transfectant, hTERT mRNA expression was slightly upregulated and in pRc-hTERT transfectant hTR expression was also slightly upregulated. These findings indicate the co-regulation of hTR and hTERT mRNA expression in cancer cells. Extrachromosomal replicational vector, pCEP4, containing ribozyme targeting hTERT mRNA showed the most effective inhibition of telomerase activity, suggesting that the continuous effect of ribozyme is necessary to inhibit telomerase activity. Since the level of hTERT mRNA expression is less than that of hTR expression in cancer cells, ribozyme targeting hTERT mRNA might be a more useful therapeutic strategy for cancer gene therapy. Moreover, the co-regulation of hTR and hTERT mRNA expression in cancer cells to maintain the levels of telomerase activity suggested that the strategy of inhibiting hTERT mRNA and hTR simultaneously has a powerful potential as a gene therapy for targeting human telomerase.


Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke.
Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) are increased in the brain after experimental ischemic stroke in rats. These two proteases are involved with the degradation of the basal lamina and loss of stability of the blood brain barrier that occurs after ischemia and that is associated with thrombolytic therapy in ischemic stroke. Minocycline is a lipophilic tetracycline and is neuroprotective in several models of brain injury. Minocycline inhibits inflammation, apoptosis and extracellular matrix degradation. In this study we investigated whether delayed minocycline inhibits brain MMPs activated by ischemia in a model of temporary occlusion in Wistar rats. Both MMP-2 and MMP-9 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival (p < 0.0001 for MMP-9). Intraperitoneal minocycline at 45 mg/kg concentration twice a day (first dose immediately after the onset of reperfusion) significantly reduced gelatinolytic activity of ischemia-elevated MMP-2 and MMP-9 (p < 0.0003). Treatment also reduced protein concentration of both enzymes (p < 0.038 for MMP-9 and p < 0.018 for MMP-2). In vitro incubation of minocycline in concentrations as low as 0.1 mug/ml with recombinant MMP-2 and MMP-9 impaired enzymatic activity and MMP-9 was more sensitive at lower minocycline concentrations (p < 0.05). Minocycline inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for MMP-9 at low doses. Minocycline is a potential new therapeutic agent to acute treatment of ischemic stroke.


A single mechanism for the stimulation of insulin release and 86Rb+ efflux from rat islets by cationic amino acids.
The mechanisms by which cationic amino acids influence pancreatic B-cell function have been studied by monitoring simultaneously (86)Rb(+) efflux and insulin release from perifused rat islets. The effects of two reference amino acids arginine and lysine were compared with those of closely related substances to define the structural requirements for recognition of these molecules as secretagogues. Arginine accelerated (86)Rb(+) efflux and increased insulin release in the absence or in the presence of 7mm-glucose. Its effects on efflux did not require the presence of extracellular Ca(2+) or Na(+), but its insulinotropic effects were suppressed in a Ca(2+)-free medium and inhibited in an Na(+)-free medium. Among arginine derivatives, only 2-amino-3-guanidinopropionic acid mimicked its effects on (86)Rb(+) efflux and insulin release; citrulline, guanidinoacetic acid, 3-guanidinopropionic acid and guanidine were inactive. Norvaline and valine also increased (86)Rb(+) efflux, but their effect required the presence of extracellular Na(+); they did not stimulate insulin release. Lysine as well as the shorter-chain cationic amino acids ornithine and 2,4-diaminobutyric acid accelerated (86)Rb(+) efflux in a Ca(2+)- and Na(+)-independent manner. Their stimulation of insulin release was suppressed by Ca(2+) omission, but only partially inhibited in an Na(+)-free medium. The uncharged glutamine and norleucine increased the rate of (86)Rb(+) efflux in the presence of glucose, only if extracellular Na(+) was present. Norleucine slightly increased release in a Ca(2+)- and Na(+)-dependent manner. The effects of lysine on efflux and release were not mimicked by other related substances such as 1,5-diaminopentane and 6-aminohexanoic acid. The results suggest that the depolarizing effect of cationic amino acids is due to accumulation of these positively charged molecules in B-cells. This causes acceleration of the efflux of K(+) ((86)Rb(+)) and activation of the influx of Ca(2+) (which triggers insulin release). The prerequisite for the stimulation of B-cells by this mechanism appears to be the presence of a positive charge on the side chain of the amino acid, rather than a specific group.


Transactions of an international conference. Worldwide concern: better dental care for more people. An international collaborative study. How oral surveys were conducted.
A special form and field manuals defining examination criteria were prepared for recording the following: 1. Number of teeth present both primary and permanent 2. Periodontal disease (a) Oral hygiene using the simplified oral hygiene index. (b) Periodontal condition using a modified P.I. index. (c) Periodontal treatment requirements. 3. Dental caries The DMF index was used with separate coding for filled or crowned teeth having additional primary or secondary decay. 4. Dento facial anomalies Both treatment need and treatment status were recorded. 5. Prosthetic status Possession and requirements for partial or full dentures and bridges were recorded for the age groups 13-14 and 35-44. 6. Oral pathology Pathological conditions of the gingiva and oral mucosa. 7. Need for immediate attention Conditions causing or likely to cause pain or danger to general health unless immediate treatment was given. The recording was carried out using fibre optic illumination, disposable mirrors and sickle probes. X-rays were not utilized. Two roving epidemiologists first established reproducible criteria and then calibrated the local examiners. Re-calibration took place at intervals and repeat examinations of a small sample population ensured reproducibility of recordings. The completed charts were sent to the WHO Oral Health Unit where they were edited and the data transferred to computer tape for analysis. For the present reports three variables--number of carious teeth, caries treatment/need ratio and number of teeth with gingivitis were selected for special study.


Electrochemical Detection of Dopamine via Assisted Ion Transfer at Nanopipet Electrode Using Cyclic Voltammetry.
We present here the detection of dopamine (DA) at nanopipet electrodes with radii of hundreds of nanometers ranging from 160 nm to 480 nm. Dibenzo-18-crown-6 (DB18C6) was employed as an ionophore to facilitate DA transfer, resulting in a half-wave transfer potential, E1/2, DA, of -0.322 (±0.020) V vs. E1/2, TBA. Well-defined steady-state sigmoidal cyclic voltammograms were observed for the transfer of DA. High resolution scanning electron microscopy was used to measure the size and taper angle of the nanopipet electrodes. The detection is linear with concentration of DA ranging from 0.25 mM to 2 mM; calculated diffusion coefficient at nanopipet electrodes with above mentioned sizes is 4.87 (±0.28) × 10-10 m2/s. The effect of the common interferent ascorbic acid on DA detection with nanopipet electrodes was evaluated, where DA detection still shows linear behavior with well-defined sigmoidal CVs with E1/2, DA being -0.328 (±0.029) V vs. E1/2, TBA. The diffusion coefficient for DA transfer in MgCl2 with the presence of 2 mM AA was measured to be 1.93 (±0.59) × 10-10 m2/s on nanoelectrodes with radii from 161 nm to 263 nm, but the physiological concentration of 0.1 mM AA had no effect on DA's diffusion coefficient.


Ephedra as a gymnosperm evo-devo model lineage.
Established model systems in the flowering plants have greatly advanced our understanding of plant developmental biology, facilitating in turn its investigation across diverse land plants. The reliance on a limited number of model organisms, however, constitutes a barrier for future progress in evolutionary developmental biology (evo-devo). In particular, a more thorough understanding of seed plant character evolution and of its genetic and developmental basis has been hampered in part by a lack of gymnosperm model systems, since most are trees with decades-long generation times. Guided by the premise that future model organisms should be selected based on their character diversity, rather than simply phylogenetic "position," we highlight biological questions of potential interest that can be addressed via comparative studies in Ephedra (Gnetales). In addition to having relatively small genomes and shorter generation times in comparison to most other gymnosperms, Ephedra are amenable to investigations on the evolution of the key reproductive seed plant innovations of pollination and seed dispersal, as well as on polyploidy, and adaptation to extreme environments.


The Development of a School-Based Measure of Child Mental Health.
Early detection of child mental health problems in schools is critical for implementing strategies for prevention and intervention. The development of an effective measure of mental health and well-being for this context must be both empirically sound and practically feasible. This study reports the initial validation of a brief self-report measure for child mental health suitable for use with children as young as 8 years old ("Me & My School" [M&MS]). After factor analysis, and studies of measurement invariance, 2 subscales emerged: emotional difficulties and behavioral difficulties. These 2 subscales were highly correlated with corresponding constructs of the Strengths and Difficulties Questionnaire (SDQ) and showed correlations with attainment, deprivation, and educational needs similar to ones obtained between these demographic measures and the SDQ. Results suggest that this school-based self-report measure is psychometrically sound, and has the potential of contributing to school mental health surveys, evaluation of interventions, and recognition of mental health problems within schools.


Hybrid laser written waveguides in fused silica for low loss and polarization independence.
Photonic integrated circuits (PICs) written with an ultrashort pulsed laser provide advantages in a range of applications, such as photon-based quantum information processing, where low insertion loss and low polarization dependence are critical concerns. Here we demonstrate the inscription of hybrid waveguides in fused silica at a pulse repetition rate of 1MHz that fulfill both these criteria. The mechanisms for propagation and coupling losses are identified and decoupled, with separate sections of the waveguide minimizing for each and an adiabatic mode conversion between the two. Moreover, differing sources of birefringence were revealed to be non-parallel for the waveguides, such that structures can be designed where these competing sources cancel to remove any polarization dependence.


Molsidomine ameliorates experimental allergic encephalomyelitis in Lewis rats.
Experimental allergic encephalomyelitis (EAE) is an autoimmune CD4+ T cell-mediated disease of the central nervous system (CNS). Nitric oxide (NO) plays an important role in preventing the development of EAE. Molsidomine (Mol) is a drug used for the treatment of coronary artery disease. Its therapeutic effects are the consequences of NO formation. In this study, we investigated the effects of Mol on EAE development in myelin basic protein (MBP)-immunized Lewis rats. All rats immunized with MBP developed typical clinical signs of acute EAE. In the EAE rats receiving Mol, the severity of clinical signs and the infiltration of inflammatory cells in CNS were clearly reduced. Furthermore, Mol administration significantly reduced the production of interferon-gamma, a Th1 inflammatory cytokine, but increased the production of interleukin-10, a Th2 anti-inflammatory cytokine. Our findings suggest that the administration of the exogenous NO donor Mol is of considerable benefit in limiting the development of EAE and other Th1 cell-mediated inflammatory diseases.


Synergistic interactions between PLK1 and HDAC inhibitors in non-Hodgkin's lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms.
Interactions between the polo-like kinase 1 (PLK1) inhibitor volasertib and the histone deacetylase inhibitor (HDACI) belinostat were examined in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells in vitro and in vivo. Exposure of DLBCL cells to very low concentrations of volasertib in combination with belinostat synergistically increased cell death (apoptosis). Similar interactions occurred in GC-, ABC-, double-hit DLBCL cells, MCL cells, bortezomib-resistant cells and primary lymphoma cells. Co-exposure to volasertib/belinostat induced a marked increase in M-phase arrest, phospho-histone H3, mitotic errors, cell death in M-phase, and DNA damage. Belinostat diminished c-Myc mRNA and protein expression, an effect significantly enhanced by volasertib co-exposure. c-Myc knock-down increased DNA damage and cell death in response to volasertib, arguing that c-Myc down-regulation plays a functional role in the lethality of this regimen. Notably, PLK1 knock-down in DLBCL cells significantly increased belinostat-induced M-phase accumulation, phospho-histone H3, γH2AX, and cell death. Co-administration of volasertib and belinostat dramatically reduced tumor growth in an ABC-DLBCL flank model (U2932) and a systemic double-hit lymphoma model (OCI-Ly18), accompanied by a pronounced increase in survival without significant weight loss or other toxicities. Together, these findings indicate that PLK1/HDAC inhibition warrants attention as a therapeutic strategy in NHL.


Theory of mind tasks and executive functions: a systematic review of group studies in neurology.
A growing number of studies have been addressing the relationship between theory of mind (TOM) and executive functions (EF) in patients with acquired neurological pathology. In order to provide a global overview on the main findings, we conducted a systematic review on group studies where we aimed to (1) evaluate the patterns of impaired and preserved abilities of both TOM and EF in groups of patients with acquired neurological pathology and (2) investigate the existence of particular relations between different EF domains and TOM tasks. The search was conducted in Pubmed/Medline. A total of 24 articles met the inclusion criteria. We considered for analysis classical clinically accepted TOM tasks (first- and second-order false belief stories, the Faux Pas test, Happe's stories, the Mind in the Eyes task, and Cartoon's tasks) and EF domains (updating, shifting, inhibition, and access). The review suggests that (1) EF and TOM appear tightly associated. However, the few dissociations observed suggest they cannot be reduced to a single function; (2) no executive subprocess could be specifically associated with TOM performances; (3) the first-order false belief task and the Happe's story task seem to be less sensitive to neurological pathologies and less associated to EF. Even though the analysis of the reviewed studies demonstrates a close relationship between TOM and EF in patients with acquired neurological pathology, the nature of this relationship must be further investigated. Studies investigating ecological consequences of TOM and EF deficits, and intervention researches may bring further contributions to this question.


Single-cell copy number variant detection reveals the dynamics and diversity of adaptation.
Copy number variants (CNVs) are a pervasive source of genetic variation and evolutionary potential, but the dynamics and diversity of CNVs within evolving populations remain unclear. Long-term evolution experiments in chemostats provide an ideal system for studying the molecular processes underlying CNV formation and the temporal dynamics with which they are generated, selected, and maintained. Here, we developed a fluorescent CNV reporter to detect de novo gene amplifications and deletions in individual cells. We used the CNV reporter in Saccharomyces cerevisiae to study CNV formation at the GAP1 locus, which encodes the general amino acid permease, in different nutrient-limited chemostat conditions. We find that under strong selection, GAP1 CNVs are repeatedly generated and selected during the early stages of adaptive evolution, resulting in predictable dynamics. Molecular characterization of CNV-containing lineages shows that the CNV reporter detects different classes of CNVs, including aneuploidies, nonreciprocal translocations, tandem duplications, and complex CNVs. Despite GAP1's proximity to repeat sequences that facilitate intrachromosomal recombination, breakpoint analysis revealed that short inverted repeat sequences mediate formation of at least 50% of GAP1 CNVs. Inverted repeat sequences are also found at breakpoints at the DUR3 locus, where CNVs are selected in urea-limited chemostats. Analysis of 28 CNV breakpoints indicates that inverted repeats are typically 8 nucleotides in length and separated by 40 bases. The features of these CNVs are consistent with origin-dependent inverted-repeat amplification (ODIRA), suggesting that replication-based mechanisms of CNV formation may be a common source of gene amplification. We combined the CNV reporter with barcode lineage tracking and found that 102-104 independent CNV-containing lineages initially compete within populations, resulting in extreme clonal interference. However, only a small number (18-21) of CNV lineages ever constitute more than 1% of the CNV subpopulation, and as selection progresses, the diversity of CNV lineages declines. Our study introduces a novel means of studying CNVs in heterogeneous cell populations and provides insight into their dynamics, diversity, and formation mechanisms in the context of adaptive evolution.


Effects of graded exercise training on functional capacity, muscle strength, and fatigue after renal transplantation: a randomized controlled trial.
Successful renal transplantation (RT) recipients suffer residual muscle weakness, fatigue, and low functional capacity. A safe, feasible, structured, early graded exercise training to improve functional capacity, muscle strength, and fatigue is the need of the hour. The aim of the study is to assess the effectiveness of graded exercise training on the functional capacity, muscle strength, and fatigue after RT. It is a randomized controlled trial conducted at a tertiary care hospital from January 2012 to December 2016. This trial included 104 consented, stable renal transplant recipients without cardiopulmonary/neuromuscular impairment. They received either routine care (51) or graded exercise training (53) for 12 weeks after randomization. The functional capacity, isometric quadriceps muscle strength, and fatigue score were measured at baseline, six, and 12 weeks later to induction. The outcomes of the study and control groups were analyzed using the /-test, Wilcoxon signed-rank test, ANOVA, and Pearson's correlation. For all analyses, P <0.05 was fixed acceptable. The functional capacity improved by 147 and 255 m, the muscle strength by 6.35 and 9.27 kg, and fatigue score by 0.784 and 1.781 in the control and the study group (SG), respectively, significantly more in the SG. Functional capacity had a positive and negative correlation with muscle strength and fatigue, respectively (P <0.05). The graded exercise training significantly improved the functional capacity, fatigue levels, and muscle strength after RT.


Rehabilitation engineering: towards a systematic process.
Two parts of the rehabilitation engineering process, client assessment and task analysis, are examined, and an approach to further delineate and systematize these components is described. The tasks of the rehabilitation engineer are taken to be the selection of appropriate available assistive devices and the design of new devices that will enable a handicapped client to accomplish a life task for which he or she would otherwise by physically disabled. Generalizable concepts and speculations on new tools that are perceived to be needed to help rehabilitation engineers do their job are emphasized. Human performance concepts are used as a basis for analyzing processes. Analogies from traditional engineering design and practice are used for insight.


A pilot study evaluating predictors of postoperative outcomes after major abdominal surgery: Physiological capacity compared with the ASA physical status classification system.
This pilot study compared the risk predictive value of preoperative physiological capacity (PC: defined by gas exchange measured during cardiopulmonary exercise testing) with the ASA physical status classification in the same patients (n=32) undergoing major abdominal cancer surgery. Uni- and multivariate logistic regression models were fitted to measurements of PC and ASA rank data determining their predictive value for postoperative morbidity. Receiver operating characteristic (ROC) curves were used to discriminate between the predictive abilities, exploring trade-offs between sensitivity and specificity. Individual statistically significant predictors of postoperative morbidity included the ASA rank [P=0.038, area under the curve (AUC)=0.688, sensitivity=0.630, specificity=0.750] and three newly identified measures of PC: PAT (% predicted anaerobic threshold achieved, <75% vs > or =75%), DeltaHR1 (heart rate response from rest to the anaerobic threshold), and HR3 (heart rate at the anaerobic threshold). A two-variable model of PC measurements (DeltaHR1+PAT) was also shown to be statistically significant in the prediction of postoperative morbidity (P=0.023, AUC=0.826, sensitivity=0.813, specificity=0.688). Three newly identified PC measures and the ASA rank were significantly associated with postoperative morbidity; none showed a statistically greater association compared with the others. PC appeared to improve predictive sensitivity. The potential for new unidentified measures of PC to predict postoperative outcomes remains unexplored.


Hospital partnership and patient outcomes among postacute patients with stroke.
Postacute care (PAC) heavily relies on effective connection between acute and postacute providers. However, little is known about whether and to what extent providers' patient-sharing relationships influence patient outcomes. This study aimed to examine whether patients with stroke who were discharged to PAC hospitals with which the originating hospital had a strong patient-sharing relationship have a lower rate of rehospitalization and lower mortality risk. This population-based retrospective cohort study used the Taiwan National Health Insurance Research Database. A total of 1988 patients initially hospitalized for stroke between July 1, 2017, and June 30, 2018, who were newly discharged to 193 PAC hospitals from 175 originating hospitals were included. We described the partnership between originating acute hospitals and PAC hospitals using tie strength and referral concentration. The main outcome included unplanned readmission and mortality. Hierarchical logistic regression analysis and Cox proportional hazards models were applied. A dose-response relationship was clearly observed between tie strength and patient outcomes. Patients with stroke who were discharged to a PAC hospital that had the strongest tie strength with the originating hospital were least likely to be readmitted and had the lowest mortality risk. Moreover, patients who received care from hospital pairs with highly or moderately concentrated referrals also had lower readmission and mortality risk. A greater number of shared patients and a more concentrated referral linkage between acute and PAC providers may reduce potential adverse outcomes in PAC patients. Instead of attaining more partners, PAC policies should encourage providers to strengthen their patient-sharing relationship with their existing PAC partners.


Advances in Antithrombotic Therapy.
Thrombosis remains a major cause of morbidity and mortality. Consequently, advances in antithrombotic therapy are needed to reduce the disease burden. This article focuses on 2 such advances. First, the prevention of atherothrombosis in patients with coronary or peripheral artery disease, which has been enhanced by the finding that the combination of low-dose rivaroxaban plus aspirin is superior to aspirin alone for prevention of recurrent ischemic events. However, this benefit comes at the cost of increased bleeding albeit not fatal bleeding. To overcome this problem, the second advance is the identification of factor XI as a target for new anticoagulants that are potentially safer than those currently available.


[Factors affecting plaque formation by Lassa virus in Vero cells].
The method of Porterfield and Allison was adapted for titration of the infectious activity of Lassa virus by the plaque formation in Vero cells. The virus was cloned, and the effect of the time of adsorption, pH, temperature, as well as polycations (DEAD-dextran, protamine sulphate) dimethylsuphoxide (DMSO), and trypsin added during adsorption or into the agar overlay on the effectiveness of plaque production by Lassa virus (virus titres, plaque size) were studied. The optimal adsorption time was found to be 1 1/2-2 hours, pH 8.0. The number of plaques produced by the virus was approximately similar at 35 degrees C. The substances under study did not enhance the efficacy of plaque formation, on the contrary, DMSO and high concentrations of polycations decreased plaque size.