[The effects of hatha yoga exercises on stress and anxiety levels in mastectomized women].
This article seeks to evaluate the effects of hatha yoga on stress and anxiety levels in mastectomized women. It also investigates the relationship between these levels with the following variables: age; marital status; religion; instruction; profession; smoke addiction; elitism; staging of the disease; and treatment phase. This involved controlled random clinical trial sampling of 45 mastectomized women treated at the Ilza Bianco outpatient service of Santa Rita de Cássia Hospital in the Brazilian state of Espírito Santo from March to November 2010. The experimental group participated in 6 individually-applied sessions with incentive for ongoing home practice and was re-evaluated after the period, whereas the control group was re-evaluated after a proportional period. For the study of the variables, the interview and recording on a form technique was used, along with the Anxiety Trait and State Test, and the Stress Symptoms and Signs Test. For statistical treatment, the Statistical Pack for Social Sciences was used. The data are statistically significant and have shown that hatha yoga exercises decrease stress and anxiety in the experimental group. No connection between confounding variables and anxiety and stress levels was found.


Lifestyle interventions or drugs for patients with essential hypertension: a systematic review.
To compare the effectiveness of lifestyle and drug interventions for treating patients with essential hypertension. Systematic review of randomized controlled trials (RCTs), with 8 or more weeks follow-up, enrolling patients with blood pressure of at least 140/85 mmHg, which directly compared lifestyle and drug interventions. Planned outcome measures were cardiovascular morbidity and mortality and blood pressure. We found five RCTs meeting our inclusion criteria and additionally included one quasi-randomized trial. These trials enrolled between 27 and 64 participants, mean age 55 years, with follow-up of less than 1 year; none reported cardiovascular outcomes. The lifestyle and drug interventions and patient populations were heterogeneous. Overall, the trials were of poor quality and had inconsistent results. Although dietary interventions did not always lower blood pressure as much as antihypertensive drugs, secondary analysis suggested that they might be better at lowering cholesterol levels. In the short term, lifestyle treatment may be effective at reducing blood pressure for some individuals. A healthier diet, by lowering blood pressure and cardiovascular risk, may reduce, delay or remove the need for long-term drug therapy in some patients. However, further comparisons of lifestyle and drug interventions for hypertension are required, with larger clinical trials of longer duration and better quality. Future trials should aim to identify the characteristics of patients most likely to benefit from lifestyle changes.


Burnout in early course psychosis caregivers: the role of illness beliefs and coping styles.
In occupational settings, burnout is a common response to chronic exposure stressors and has been frequently documented in formal caregivers (i.e. paid psychiatric staff). However, the literature is limited on reports of burnout among informal caregivers and particularly within early psychosis groups. The current study sought to investigate reports of burnout in carers of young adults treated within a specialist early psychosis service and links with key appraisals reported about the illness and coping. Seventy-two carers completed the Maslach Burnout Inventory along with self-report measures of coping styles and illness beliefs. Seventy-eight per cent of carers reported high burnout in at least one of the three key burnout markers (i.e. emotional exhaustion, depersonalization or low personal accomplishment). Seven per cent of carers met full criteria for high burnout across all the three domains. A carer's belief about the negative consequences of the illness for themselves was a significant predictor of emotional exhaustion and depersonalization. Low personal accomplishment was linked to a carer's less optimistic beliefs about the illness timeline and fewer reports of adaptive coping. The results provide preliminary support for the importance of asking carers in the early illness phase about their experiences of caregiving. Targeted assessment may serve as a helpful tool to identify and intervene with carers in need of additional support with stress management, use of adaptive coping strategies, and balanced recovery focused information about psychosis.


Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation.
The Cbl family proteins Cbl, Cbl-b, and Cbl-c/Cbl-3 are thought to regulate signaling through protein-tyrosine kinases, positively as scaffold proteins and negatively as ubiquitin ligases. However, the precise signaling pathways and target proteins for each Cbl family member are not well understood. Here we show that Src is a preferential target of Cbl-c for degradation. Although exogenous expression of all Cbl family proteins suppressed the anchorage-independent growth of v-Src-transformed NIH3T3 cells, only Cbl-c caused reversion of the refractile morphology. The level of v-Src protein was reduced by Cbl-c, possibly through a lysosome-dependent pathway. The TKB domain and RING finger of Cbl-c were important for its antioncogenic activity. Wild-type Cbl-c promoted ubiquitination of Src in 293T cells, whereas a RING finger mutant did not. Cbl-c bound specifically to Src phosphorylated at Tyr419. Furthermore, Cbl-c together with UbcH5 induced ubiquitination of Src in vitro. Importantly, the Tyr419 nonphosphorylated form of Src was not ubiquitinated by Cbl-c. Therefore, activated Src may be a direct target of Cbl-c in vivo. Our results suggest that Cbl and Cbl-b suppress v-Src-induced transformation through mechanisms distinct from that of Cbl-c.


Short P-Wave Duration is a Marker of Higher Rate of Atrial Fibrillation Recurrences after Pulmonary Vein Isolation: New Insights into the Pathophysiological Mechanisms Through Computer Simulations.
Background Short ECG P-wave duration has recently been demonstrated to be associated with higher risk of atrial fibrillation (AF). The aim of this study was to assess the rate of AF recurrence after pulmonary vein isolation in patients with a short P wave, and to mechanistically elucidate the observation by computer modeling. Methods and Results A total of 282 consecutive patients undergoing a first single-pulmonary vein isolation procedure for paroxysmal or persistent AF were included. Computational models studied the effect of adenosine and sodium conductance on action potential duration and P-wave duration (PWD). About 16% of the patients had a PWD of 110 ms or shorter (median PWD 126 ms, interquartile range, 115 ms-138 ms; range, 71 ms-180 ms). At Cox regression, PWD was significantly associated with AF recurrence (P=0.012). Patients with a PWD <110 ms (hazard ratio [HR], 2.20; 95% CI, 1.24-3.88; P=0.007) and patients with a PWD ≥140 (HR, 1.87, 95% CI, 1.06-3.30; P=0.031) had a nearly 2-fold increase in risk with respect to the other group. In the computational model, adenosine yielded a significant reduction of action potential duration 90 (52%) and PWD (7%). An increased sodium conductance (up to 200%) was robustly accompanied by an increase in conduction velocity (26%), a reduction in action potential duration 90 (28%), and PWD (22%). Conclusions One out of 5 patients referred for pulmonary vein isolation has a short PWD which was associated with a higher rate of AF after the index procedure. Computer simulations suggest that shortening of atrial action potential duration leading to a faster atrial conduction may be the cause of this clinical observation.


Dental Pulp: Correspondences and Contradictions between Clinical and Histological Diagnosis.
Dental pulp represents a specialized connective tissue enclosed by dentin and enamel, the most highly mineralized tissues of the body. Consequently, the direct examination as well as pathological evaluation of dental pulp is difficult. Within this anatomical context, our study aimed to evaluate the correlation between dental pulp lesions and clinical diagnosis. Pulpectomies were performed for 54 patients with acute and chronic irreversible pulpitides and for 5 patients (control group) with orthodontic extractions. The morphological features were semiquantitatively assessed by specific score values. The clinical and morphological correspondence was noted for 35 cases (68.62%), whereas inconsistency was recorded for 16 cases (31.38%). The results of the statistical analysis revealed the correlations between clinically and pathologically diagnosed acute/chronic pulpitides. No significant differences were established between the score values for inflammatory infiltrate intensity, collagen depositions, calcifications and necrosis, and acute, respectively chronic pulpitides. We also obtained significant differences between acute pulpitides and inflammatory infiltrate and calcifications and between chronic pulpitides and inflammatory infiltrate, collagen deposition, and calcifications. On the basis of the predominant pathological aspects, namely, acute and chronic pulpitis, we consider that the classification schemes can be simplified by adequately reducing the number of clinical entities.


Erwinia carotovora DsbA mutants: evidence for a periplasmic-stress signal transduction system affecting transcription of genes encoding secreted proteins.
The dsbA genes, which encode major periplasmic disulfide-bond-forming proteins, were isolated from Erwinia carotovora subsp. carotovora (Ecc) and Erwinia carotovora subsp. atroseptica (Eca), and the dsbC gene, encoding another periplasmic disulfide oxidoreductase was isolated from Ecc. All three genes were sequenced and mutants deficient in these genes were created by marker exchange mutagenesis. The Ecc mutants were severely affected in activity and secretion of pectate lyase, probably due to the absence of functional PelC, which is predicted to require disulfide bond formation to achieve its correct conformation prior to secretion across the outer membrane. Similarly, endopolygalacturonase, also predicted to possess disulfide bonds, displayed reduced activity. The major Ecc cellulase (CelV) does not contain cysteine residues and was still secreted in dsbA-deficient strains. This observation demonstrated unequivocally that the localization and activity of the individual components of the Out apparatus are independent of disulfide bond formation. Surprisingly, cellulase activity was shown to be increased approximately two- to threefold in the DsbA mutant. This phenomenon resulted from transcriptional up-regulation of celV gene expression. In contrast, transcription of both pelC and peh were down-regulated in dsbA-deficient strains when compared to the wild-type. Protease (Prt) activity and secretion were unaffected in the Ecc dsbA mutant. Prt activity was considerably reduced in the double dsbA dsbC mutant. However Prt was secreted normally in this strain. The Eca dsbA mutant was found to be non-motile, suggesting that disulfide bond formation is essential for motility in this strain. All of the dsb mutants showed reduced tissue maceration in planta. These results suggest that a feedback regulation system operates in Ecc. In this system, defects in periplasmic disulfide bond formation act as a signal which is relayed to the transcription machinery regulating gene expression in diverse ways.


Addition of Mechanical Lithotripsy to Endoscopic Papillary Large Balloon Dilation in Patients with Difficult Common Bile Duct Stones: A Retrospective Single-Center Study.
Introduction: This study aimed to compare the treatment outcomes of endoscopic papillary large-balloon dilation (EPLBD) with and without mechanical lithotripsy (ML) in removing difficult common bile duct stones. Methods: Patients with difficult common bile duct stones treated with EPLBD, with or without ML, at the Eastern Chiba Medical Center between April 2014 and March 2020, were retrospectively evaluated. The rates of cumulative recurrence and complications were compared between the two groups. Results: Overall, 122 patients (n = 44, EPLBD + ML and n = 78, EPLBD) treated by 12 gastroenterologists were included. Patients in the EPLBD + ML group were older (85 years versus 81.5 years) and had larger maximum stone diameter (15 mm versus 12.5 mm) than those in the EPLBD group. Compared with the EPLBD group, the EPLBD + ML group required more endoscopic retrograde cholangiopancreatography (ERCP) procedures (≥2) (86% versus 67%) and longer total ERCP time after reaching the papilla (78.5 minutes versus 25 minutes). Complication rates were not significantly different (9.1% versus 12.8%); however, the cumulative recurrence rates were higher in the EPLBD + ML group than in the EPLBD group (69.4% versus 23.5% at 4 years). Conclusion: Although there were no differences in complication rates, the long-term recurrence rate was higher in the EPLBD + ML group than in the EPLBD group. This study emphasizes the added burden imposed by performing ML during ERCP and suggests that by appropriate case selection, it is possible to treat cases of difficult biliary stones using EPLBD without ML.


Regulation of PCSK9 by nutraceuticals.
PCSK9 (proprotein convertase subtilisin kexin type 9) is a liver secretory enzyme that regulates plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels through modulation of LDL receptor (LDLR) density on the surface of hepatocytes. Inhibition of PCSK9 using monoclonal antibodies can efficiently lower plasma LDL-C, non-high-density lipoprotein cholesterol and lipoprotein (a). PCSK9 inhibition is also an effective adjunct to statin therapy; however, the cost-effectiveness of currently available PCSK9 inhibitors is under question. Nutraceuticals offer a safe and cost-effective option for PCSK9 inhibition. Several nutraceuticals have been reported to modulate PCSK9 levels and exert LDL-lowering activity. Mechanistically, those nutraceuticals that inhibit PCSK9 through a SREBP (sterol-responsive element binding protein)-independent pathway can be more effective in lowering plasma LDL-C levels compared with those inhibiting PCSK9 through the SREBP pathway. The present review aims to collect available data on the nutraceuticals with PCSK9-inhibitory effect and the underlying mechanisms.


Suppression of melanin production by expression of HSP70.
Skin hyperpigmentation disorders due to abnormal melanin production induced by ultraviolet (UV) irradiation are both a clinical and cosmetic problem. UV irradiation stimulates melanin production in melanocytes by increasing intracellular cAMP. Expression of heat shock proteins (HSPs), especially HSP70, is induced by various stressors, including UV irradiation, to provide cellular resistance to such stressors. In this study we examined the effect of expression of HSP70 on melanin production both in vitro and in vivo. 3-Isobutyl-1-methylxanthine (IBMX), a cAMP-elevating agent, stimulated melanin production in cultured mouse melanoma cells, and this stimulation was suppressed in cells overexpressing HSP70. IBMX-dependent transcriptional activation of the tyrosinase gene was also suppressed in HSP70-overexpressing cells. Expression of microphthalmia-associated transcription factor (MITF), which positively regulates transcription of the tyrosinase gene, was up-regulated by IBMX; however, this up-regulation was not suppressed in HSP70-overexpressing cells. On the other hand, immunoprecipitation and immunostaining analyses revealed a physical interaction between and co-localization of MITF and HSP70, respectively. Furthermore, the transcription of tyrosinase gene in nuclear extract was inhibited by HSP70. In vivo, UV irradiation of wild-type mice increased the amount of melanin in the basal layer of the epidermis, and this increase was suppressed in transgenic mice expressing HSP70. This study provides the first evidence of an inhibitory effect of HSP70 on melanin production both in vitro and in vivo. This effect seems to be mediated by modulation of MITF activity through a direct interaction between HSP70 and MITF.


Treatment with an active vitamin D analogue blocks hypothalamic dysfunction-induced bone loss in mice.
Estrogen deficiency can be caused by ovarian dysfunction in females. Mechanisms underlying osteoporosis in this condition have been characterized in animal models, such as ovariectomized mice and rats, although it remains unclear how hypothalamic dysfunction promotes osteoporosis. Here, we show that administration of a gonadotropin-releasing hormone antagonist (GnRHa) significantly decreases uterine weight, a manifestation of hypothalamic dysfunction, and promotes both cortical and trabecular bone loss in female mice in vivo. We also report that osteoclast number significantly increased in mice administered GnRHa, and that the transcription factor hypoxia inducible factor 1 alpha (HIF1α) accumulated in those osteoclasts. We previously reported that treatment of mice with the active vitamin D analogue ED71, also known as eldecalcitol, inhibited HIF1α accumulation in osteoclasts. We show here that in mice, co-administration of ED71 with GnRHa significantly rescued the reduced cortical and trabecular bone mass promoted by GnRHa administration alone. GnRHa-dependent HIF1α accumulation in osteoclasts was also blocked by co-administration of ED71. We conclude that hypothalamic dysfunction promotes HIF1α accumulation in osteoclasts and likely results in reduced bone mass. We conclude that treatment with ED71 could serve as a therapeutic option to counter osteoporotic conditions in humans.


Abundant synthesis of the transformation-induced protein of neoplastic human fibroblasts, plastin, in normal lymphocytes.
The transformation-induced protein plastin (p219; Mr 68,000, pl 5.3) is a reliable cytosolic marker for neoplastic human fibroblasts. Fibroblasts transformed in vitro by chemical carcinogens or SV40 virus and tumor-derived cancer cells of fibroblastoid or epithelioid origin usually express plastin and p220, a minor phosphorylated form of plastin. We report here that plastin is expressed as one of the most abundant proteins of normal, untransformed lymphocytes. The phosphorylated form of plastin was detectable in adherent monocytes but not in purified T- or NK lymphocytes. We also demonstrate that an allelic variant or mutated form of plastin exhibiting altered charge is found at a reduced frequency in the human population. We discuss the possible significance of these observations in terms of evaluating the role of plastin induction in expression of the cancerous phenotype of fibroblasts.


Five enzymes of the glycolytic pathway serve as substrates for purified epidermal-growth-factor-receptor kinase.
Several enzymes of the glycolytic pathway are phosphorylated in vitro and in vivo by retroviral transforming protein kinases. These substrates include the enzymes phosphoglycerate mutase (PGM), enolase and lactate dehydrogenase (LDH). Here we show that purified EGF (epidermal growth factor)-receptor kinase phosphorylates the enzymes PGM and enolase and also the key regulatory enzymes of the glycolytic pathway, phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in an EGF-dependent manner. Stoichiometry of phosphate incorporation into GAPDH (calculated from native Mr) is the highest, reaching approximately 1. LDH and other enzymes of the glycolytic pathway are not phosphorylated by the purified EGF-receptor kinase. These enzymes are phosphorylated under native conditions, and the Km values of EGF-receptor kinase for their phosphorylation are close to the physiological concentrations of these enzymes in the cell. EGF stimulates the reaction by 2-5-fold by increasing the Vmax. without affecting the Km of this process. Phosphorylation is rapid at 22 degrees C and at higher temperatures. However, unlike the self-phosphorylation of EGF-receptor, which occurs at 4 degrees C, the glycolytic enzymes are poorly phosphorylated at this temperature. Some enzymes, in particular enolase, increase the receptor Km for ATP in the autophosphorylation process and thus may act as competitive inhibitors of EGF-receptor self-phosphorylation. On the basis of the Km values of EGF receptor for the substrate enzymes and for ATP in the phosphorylation reaction, these enzymes may also be substrates in vivo for the EGF-receptor kinase.


Thalidomide results in diminished ovarian reserve in reproductive age female IBD patients.
The effectiveness of thalidomide in treating inflammatory bowel disease (IBD) has been widely recognized. Meanwhile, many serious adverse drug reactions have been observed, but no know reports on ovarian reserve function.Female patients, ranging in age between 18 and 40, were referred to our institution to undergo sex hormone detection and ultrasonic scanning for ovarian function assessment, between February 1, 2016 and September 31, 2016.Thirty-three patients treated with thalidomide (group A), 73 patients without thalidomide (group B), and 78 healthy women as control were studied. Menstrual disorder was higher in group A than group B (78.8% vs 57.2%, P < 0.05), and both groups were higher than control group 33.3%, P < 0.05. Anti-Mullerian hormone (AMH) levels and antral follicle count (AFC) in group A were lower than group B, P < 0.05, while estradiol (E2) and follicle-stimulating hormone (FSH) levels were no different between 2 groups. Crohn Disease Endoscopic Index of Severity (CDEIS) and thalidomide were the independent risk factors in diminished ovarian reserve (DOR), and when dose reached 75 mg/day, 5 g total, or when treatment time reached 10 months respectively. These influence may increasing (P < 0.05), but they may recover after stopping (P < 0.05).Thalidomide was an independent risk factor leading to DOR in female IBD patients, the influence may increasing when daily dose and accumulated dose reached 75 mg/day and 5 g total dose, but may be reversed by stopping.


Core dimensions of connectivity in public health collaboratives.
A major challenge facing state and local public health agencies is how to partner with other organizations, agencies, and groups to collaboratively address goals in population health while effectively maximizing resource sharing of the partners involved. Today's public health efforts require multiagency partnerships between both governmental and nongovernmental sectors to achieve this mission. However, the frequent reconfiguration of partnerships among government and nongovernmental agencies has left many public health managers struggling to find ways to both develop public health collaboratives and evaluate their success. In this article, we use network theory and social network analysis to outline the core dimensions of connectivity used to measure progress in public health collaboratives. Connectivity is defined as the measured interactions between partners in a collaborative such as the amount and quality of interactions and how these relationships might change over time. We also articulate how these measures fit into the overall process of measuring progress in public health collaboratives and end the article with suggestions for future research and development.


Adverse outcomes following pelvic fracture: the critical role of frailty.
Pelvic fractures among older adults are associated with an increased risk of adverse outcomes, with frailty likely being a contributing factor. The current study endeavors to describe the association between frailty, measured using the Orthopedic Frailty Score (OFS), and adverse outcomes in geriatric pelvic fracture patients. All geriatric (65 years or older) patients registered in the 2013-2019 Trauma Quality Improvement Program database with an isolated pelvic fracture following blunt trauma were considered for inclusion. An isolated pelvic fracture was defined as any fracture in the pelvis with a lower extremity AIS ≥ 2, any abdomen AIS, and an AIS ≤ 1 in all other regions. Poisson regression models were employed to determine the association between the OFS and adverse outcomes. A total of 66,404 patients were included for further analysis. 52% (N = 34,292) were classified as non-frail (OFS 0), 32% (N = 21,467) were pre-frail (OFS 1), and 16% (N = 10,645) were classified as frail (OFS ≥ 2). Compared to non-frail patients, frail patients exhibited a 88% increased risk of in-hospital mortality [adjusted IRR (95% CI): 1.88 (1.54-2.30), p < 0.001], a 25% increased risk of complications [adjusted IRR (95% CI): 1.25 (1.10-1.42), p < 0.001], a 56% increased risk of failure-to-rescue [adjusted IRR (95% CI): 1.56 (1.14-2.14), p = 0.006], and a 10% increased risk of ICU admission [adjusted IRR (95% CI): 1.10 (1.02-1.18), p = 0.014]. Frail pelvic fracture patients suffer from a disproportionately increased risk of mortality, complications, failure-to-rescue, and ICU admission. Additional measures are required to mitigate adverse events in this vulnerable patient population.


[Infectious complications in electric cardiac stimulation].
There were 4424 patients operated for alterations of the cardiac rhythm. Primary electrocardiostimulation was performed in 3183 of them, reoperations in 1241 patients (39%). Infectious complications took place in 146 patients (3.3%). Based on their experiences the authors developed the strategy of treatment of patients with purulent complications and sepsis depending on their character and time of their appearance.


Short-stay, specialist beds in a UK teaching hospital as a model to integrate palliative care into the acute hospital culture.
Hospital patients should have access to effective palliative care. In our study, three short-stay beds were re-allocated to specialist palliative care as part of a pilot programme. This paper describes the first 100 admissions of patients with inadequately controlled symptoms or distress. Median pain and distress scores were both seven out of a maximum of 10 (interquartile ranges [IQR] 4-10 and 1-10 respectively), reducing to 3.5 (IQR 1-5) and 0 (0-5) after 48 hours. Median length of stay was five days (IQR 3-10); 77% of patients were discharged: 32% to home, 26% to a hospice or community hospital, 19% to their original ward for treatment and 23% died in the unit. A unit education programme introduced as part of the study attracted 600 staff members. Pain and distress were rapidly improved by brief, intense palliative care in a small onsite facility. The pilot programme also influenced the understanding of palliative care in the hospital, demonstrating what it offered patients, family and staff. It demonstrated effective, concurrent working alongside an active disease-management approach, and encouraged collaborative discussions about the goals of care.


Efficacy of technology-delivered cognitive behavioural therapy for OCD versus control conditions, and in comparison with therapist-administered CBT: meta-analysis of randomized controlled trials.
Cognitive behavioural therapy (CBT) is a well-established treatment for obsessive-compulsive disorder (OCD). However, few patients receive CBT, due to factors such as geographic limitations, perceived stigmatization, and lack of CBT services. Technology-delivered cognitive behavioural therapy (T-CBT) could be an effective strategy to improve patients' access to CBT. To date, a meta-analysis on the effectiveness of T-CBT for OCD has not been conducted. This study used meta-analytic techniques to summarize evidence on the efficacy of T-CBT for OCD versus control conditions and therapist-administered CBT. A meta-analysis according to Prisma guidelines was conducted on randomized controlled trials (RCTs) of T-CBT for OCD. Treatment was classified as T-CBT if evidence-based CBT active ingredients for OCD were included (psychoeducation, ERP, and cognitive restructuring), delivered through health technologies (e.g. self-help books, leaflets, and other forms of bibliotherapy) or remote communication technologies (e.g. the Internet, web-cameras, telephones, telephone-interactive voice response systems, and CD-ROMS). Studies using validated outcomes for OCD or depression were included. Eight trials were included (N = 420). Two trials were classified as at high risk of bias. T-CBT seemed to be superior to control conditions on OCD symptom outcomes at post-treatment (d = 0.82, 99% CI = 0.55-1.08, p = 0.001), but not on comorbid depression (d = 0.33, 99% CI = - 0.01-0.67, p = 0.020). Difference in the efficacy on OCD symptoms between T-CBT and therapist-administered CBT was not significant, despite a trend favouring therapist-administered CBT emerged (d = 0.45, 95% CI = 0.03-0.87, p = 0.033). Directions for research are discussed. Further RCTs are warranted to examine the efficacy of T-CBT for OCD.


Access to renal transplantation for the elderly in the face of new allocation policy: a review of contemporary perspectives on "older" issues.
The benefits of renal transplantation have been demonstrated to extend to the elderly. As a result, more seniors have been placed on the kidney transplant wait list and have received renal allografts in recent years. In June 2013 significant amendments to deceased donor kidney allocation policy were approved to be instituted in 2014 with the goal of increasing overall life years and graft years achieved compared to the current system. Going forward, it is conceivable that transplant centers may perceive a need to adjust practice patterns and modify evaluation and listing criteria for the elderly as the proportion of kidneys distributed to this segment of the wait list would potentially decrease under the new system, further increasing wait times. This review examines contemporary perspectives on access to transplantation for seniors and pertinent issues for this subgroup such as wait time, comorbidity, and evaluation and listing practices. Potential approaches to improve the evaluation of elderly patients being considered for transplant and to increase availability of expanded criteria donor (or higher kidney donor profile index) and living donor organ transplant opportunities while maintaining acceptable outcomes for seniors are explored.


The Effects of Exergame on Postural Control in Individuals with Ataxia: a Rater-Blinded, Randomized Controlled, Cross-over Study.
Exergame trainings might have therapeutic value in ataxic patients. The aim of this study was to investigate the effect of exergame training with an exercise program on postural control by comparing it with traditional balance and coordination exercise program. Nineteen patients were randomly allocated to two groups. In the first group, exergame training and an exercise program (EEP) were applied together for the first 8 weeks; after 10 weeks washout, a conventional exercise program (CEP) was applied for the second 8 weeks. In the second group, the CEP was applied first followed by the EEP. Outcome measures were Limits of Stability test (LoS), International Classification Ataxia Ratio Scale (ICARS), Berg Balance Scale (BBS), and Timed-Up and Go test with a cognitive task (TUG-C), Reactive postural control and sensory orientation subscales of the Mini-BESTest. Seventeen patients (mean age ± SD, 32.53 ± 11.07 years) completed the study. ICARS, BBS scores improved only after EEP (p < 0.05). While there was no change in the RT and MVL parameters of the LoS test after EEP, the MXE, EPE, and DCL parameters improved significantly (p < 0.05). The MXE and MVL parameters of LoS improved after CEP (p < 0.05). There were no significant improvements in the Mini-BESTest's reactive postural control and sensory orientation subscale scores after both EEP and CEP (p > 0.05). The results of the present study demonstrated that exergame training can be used as a complementary training option in physiotherapy to improve postural control in patients with ataxia. ClinicalTrial.gov Identifier: NCT03607058.


Nursing Home Stakeholder Views of Resident Involvement in Medical Care Decisions.
Demand by nursing home residents for involvement in their medical care, or, patient-centered care, is expected to increase as baby boomers begin seeking long-term care for their chronic illnesses. To explore the needs in meeting this proposed demand, we used a qualitative descriptive method with content analysis to obtain the joint perspective of key stakeholders on the current state of person-centered medical care in the nursing home. We interviewed 31 nursing home stakeholders: 5 residents, 7 family members, 8 advanced practice registered nurses, 5 physicians, and 6 administrators. Our findings revealed constraints placed by the long-term care system limited medical involvement opportunities and created conflicting goals for patient-centered medical care. Resident participation in medical care was perceived as low, but important. The creation of supportive educational programs for all stakeholders to facilitate a common goal for nursing home admission and to provide assistance through the long-term care system was encouraged.


Submuscular Placement of Baclofen Infusion Pumps: Case Series and Technique.
Baclofen pumps provide treatment of symptoms of spasticity for disease processes such as cerebral palsy and traumatic brain injury. These devices provide continuous infusion or periodic dosing of intrathecal baclofen (ITB). Traditionally, these pumps have been placed subcutaneously. Subcutaneous device placement has been associated with infection and extrusion. Baclofen pumps are large and range from 8 to 10 cm in diameter and 4 to 8 cm in width. Patients requiring device placement typically have a paucity of subcutaneous tissue. Cachexia coupled with the size and bulk of these devices leads to increased protusion and friction. Submuscular placement provides a well-vascularized pocket that directs the device inward eliminating protrusion and decreasing the potential for soft tissue breakdown. A retrospective chart review of ITB pump placement in a submuscular plane by a single plastic surgeon at a major academic center in conjunction with a neurosurgeon was performed. Inclusion criteria were cases of primary placement or replacement of ITB pumps and spasticity requiring ITB. Major complications included infection, extrusion, and reoperation. Five patients during a 5-month period were treated with submuscular placement of ITB pumps. Average age of patients included was 18.4 years. Average preoperative body mass index was 18.8 kg/m, with values ranging from 15.8 to 20.1 kg/m. Medical histories of patients included diagnoses of cerebral palsy and traumatic brain injury causing spasticity. The most frequently cited reason for plastic surgical consultation preoperatively was cachexia. Two patients had previous baclofen pumps placed subcutaneously. Average follow-up was 6 months and ranged from 3 to 13 months. There were no major complications. One patient had a small seroma that spontaneously resolved. No patient had wound healing problems, and there were no extrusions of implanted devices or reoperations. Submuscular placement of baclofen pumps provides a well-vascularized and stable environment for device placement that minimizes the dangers of pump extrusion and infection. Patients who require treatment with ITB commonly have severe cachexia, which makes subcutaneous device placement high risk. Submuscular placement should be performed in all patients with body mass index less than 20 kg/m.


Pancreatic islet transplantation in dogs. Critical factors in technique.
Total pancreatectomy and intrasplenic autotransplantation of islet tissue was carried out in dogs. The resected pancreas was prepared by the partial islet isolation technique of gland distention, mincing and collagenase digestion. The influence of variations in technique was studied. Using otherwise identical methods, five collagenase lots were compared. Three lots were effective, resulting in successful transplants in 23 of 26 dogs. Two ineffective lots produced no successes in six dogs (p < 0.001). When minced particle size was varied, particles which would pass freely through a 16 gauge needle resulted in no successes in six dogs. With a larger particle size that would pass freely only through a 15 gauge needle, 15 of 15 transplants were successful (p < 0.001). When tissue was minced by hand, 8 of 11 transplants were successful, compared with 15 of 15 when mechanical mincing was used. With variation in collagenase concentration, success occurred in four of six using 300 units of collagenase/ml of minced tissue, in four of six using 600 units and three of six using 1,200 units. It is concluded that minced particle size and collagenase lot are critical variables in this technique of islet transplantation. Mincing method and concentration of collagenase do not appear to be important variables.


Abundant expression of granzyme A, but not perforin, in granules of CD8+ T cells in GALT: implications for immune control of HIV-1 infection.
Because GALT is a major portal of entry for HIV-1 and reservoir for viral replication, we hypothesized that an ineffective cellular immune response in intestinal mucosa might partially explain the failure of immune control in AIDS. In this study, we demonstrate that the vast majority of CD8+ T cells in rectal tissue, including HIV-1-specific cells, fail to express the cytolytic protein, perforin. However, rectal CD8+ T cells do express granzyme A, and are also capable of releasing IFN-gamma upon stimulation with cognate peptide. Confocal microscopy showed that granzyme A was located in intracellular granules in the absence of perforin. The majority of rectal CD8+ T cells exhibit an effector memory phenotype, expressing CD45RO but not CCR7. Quantitative real-time PCR analysis demonstrated that perforin RNA is expressed in rectal CD8+ T cells from healthy and HIV-1-positive individuals. In HIV-1-positive individuals, similar amounts of perforin RNA were detected in CD8+ T cells from rectal tissue and PBMC, despite a relative absence of perforin protein in rectal tissue. These findings demonstrate an important difference in perforin expression between CD8+ T cells in blood and mucosa. Furthermore, the relative absence of armed effector cells may serve to protect the integrity of rectal mucosa under normal conditions, but might also provide an early advantage to HIV-1 and other sexually transmitted viruses.


Pragmatics and spatial language: The acquisition of front and back.
Across languages, children produce locative back earlier and more frequently than front, but the reasons for this asymmetry are unclear. On a semantic misanalysis explanation, early meanings for front and back are nonadult (nongeometric), and rely on notions of visibility and occlusion respectively. On an alternative, pragmatic inference explanation, visibility and occlusion are simply pragmatic aspects of the meaning of front and back; the profile of back can be explained by the fact that occlusion is more noteworthy compared with visibility. We used cross-linguistic data to test these two hypotheses. In Experiment 1, we examined the production and comprehension of front/back by 3- and 4-year-old children and adults speaking two different languages (English and Greek). Children, unlike adults, used back more frequently than front in both languages; however, no such asymmetry surfaced in the comprehension of the two prepositions. In Experiment 2, both adults and children from the same language groups showed the front/back asymmetry when describing a more variable battery of spatial stimuli. Our results support the pragmatic inference hypothesis. We conclude that the emergence of spatial terms does not solely index semantic development but may be linked to pragmatic factors that also shape adults' production of spatial language cross-linguistically. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Separate cell systems in the motor cortex of the monkey for the control of joint movement and of joint stiffness.
A series of new observations is described from experiments with alert monkeys, who have been trained to control the position of the wrist in the presence of perturbing forces. The results suggest that the wrist control area of the precentral motor cortex contains separate neuronal populations for the control of 2 major forms of motor output. The first activates particular groups of synergists independently, or the members of a set of antagonist muscles reciprocally; this form of activation provides, under natural conditions, for smooth movement of the joint from one position to another. The second population of cells evokes co-activation of antagonist muscles, at one or more joints in the arm. This population provides for the cortical control of the postural supporting reactions which must occur in the arm when one or more of its joints are moved. In addition, it appears to provide for a separate control of joint stiffness, thus allowing for a control of joint position in the presence of very rapid or unpredictable external force perturbations. A possible role for this system as a means of joint position control during the early phases of motor learning is also discussed.


Synthesis, characterization, and pharmacological evaluation of zinc oxide nanoparticles formulation.
Zinc oxide nanoparticles (ZnONPs) are being used extensively in manufacturing skin lotions and food products and in various biological and pharmaceutical industries because of their immunomodulatory and antimicrobial properties. In this study, ZnONPs were synthesized by a precipitation method and characterized by X-ray diffraction (XRD) techniques, scanning electron microscopy (SEM), and ultraviolet-visible spectroscopy to investigate their structural, morphological, and optical properties. For in vivo evaluation, 40 healthy albino mice were randomly allocated to four equal groups among which the first one was the control group, while the second, third, and fourth were treated with carbon tetrachloride (CCl4), a blend of CCl4 and ZnONPs, and ZnONPs alone, respectively, for 21 days. The XRD analysis confirmed hexagonal wurtzite type structures having an average crystallite size of 41.54 nm. The morphology of ZnONPs analyzed through SEM showed uniform distribution of the grains and shape of the synthesized oxide. The energy band gap of the ZnONPs was found to be 3.498 eV. Hepatic and renal damage following CCl4 administration was apparent after 14 days and was increased at the 21st day, showing nodular fibrotic masses in the liver and bumpy surfaces in the kidney as observed by gross and histological examination. Coadministration of ZnONPs (15 mg/kg b.w. intragastrically 5 days a week) significantly prevented the CCl4-dependent increases in alanine transaminase, aspartate transaminase, creatinine, and urea levels, suggesting a protective potential of ZnONPs.


Psychological Violence Against Arab Women in the Context of Social Media: Web-Based Questionnaire Study.
Social media provides women with varying platforms to express themselves, show their talents, communicate and expand their social relationships, and break the shackles imposed by their societies. Theoretically, social media can play a significant role in developing women's freedom and decreasing social pressures; nonetheless, women continue to face violence during the social media era mainly in the form of psychological violence. This study aims to conduct an empirical in-depth analysis of how the digital space, particularly social media, provides men with new opportunities to surveil, restrict, harass, and intimidate feminists in Arab countries. This study includes an empirical survey to investigate what Arab women think are the causes and types of violence wielded against them and their perspectives on the impact of that violence. This study used a web-based questionnaire administered through Google Forms (n=1312) with responses from Arab women aged 15 years and above from all Arab countries. We found that most Arab women feared posting an actual photograph of themselves on their social media accounts and only approximately one-third (490/1312, 37.3%) did so. Most women indicated that they encountered sexual harassment regardless of their age. Furthermore, most women were not aware of the legal aspects of this crime and even those who were aware indicated that they would not press charges for several reasons, including bringing dishonor upon their families, the time-consuming nature of litigation, and fear of revenge. This study shows that young and less educated women are more vulnerable to abuse from either social media users or being condemned by their families. This has several effects, including lower self-esteem and hesitancy in seeking a job, feelings of mistrust and fear, cynicism, anxiety, depression, and sleep disorders. These issues hold women back from using social media in positive ways and some consider leaving social media.


Synthesis of binaphthyl based phosphine and phosphite ligands.
The development of large scale synthesis of enantiopure and thermally stable (R)- and (S)-BINOL molecules constitutes a key milestone in the field of asymmetric catalysis. Particularly, a great variety of chiral binaphthyl-based phosphorus compounds, herein represented by phosphite and phosphine classes, have earned considerable relevance due to their versatility as ligands in enantioselective metal-catalysed reactions, allowing the preparation of optically active products with the desired enantiopurity. This review highlights the most relevant concepts and accounts regarding general synthetic procedures for binaphthyl-based mono- and bidentate phosphites and phosphines. Furthermore, the search for environmentally benign chemical catalytic processes compelled us to also give special attention to the functionalisation of binaphthyl-based phosphorus ligands for use in alternative reaction media. When available, a critical selection of their applications in catalysis is briefly assessed.


The larvicidal effects of black pepper (Piper nigrum L.) and piperine against insecticide resistant and susceptible strains of Anopheles malaria vector mosquitoes.
Insecticide resistance carries the potential to undermine the efficacy of insecticide based malaria vector control strategies. Therefore, there is an urgent need for new insecticidal compounds. Black pepper (dried fruit from the vine, Piper nigrum), used as a food additive and spice, and its principal alkaloid piperine, have previously been shown to have larvicidal properties. The aim of this study was to investigate the larvicidal effects of ground black pepper and piperine against third and fourth instar Anopheles larvae drawn from several laboratory-reared insecticide resistant and susceptible strains of Anopheles arabiensis, An. coluzzii, An. gambiae, An. quadriannulatus and An. funestus. Larvae were fed with mixtures of standard larval food and either ground black pepper or piperine in different proportions. Mortality was recorded 24 h after black pepper and 48 h after piperine were applied to the larval bowls. Black pepper and piperine mixtures caused high mortality in the An. gambiae complex strains, with black pepper proving significantly more toxic than piperine. The An. funestus strains were substantially less sensitive to black pepper and piperine which may reflect a marked difference in the feeding habits of this species compared to that of the Gambiae complex or a difference in food metabolism as a consequence of differences in breeding habitat between species. Insecticide resistant and susceptible strains by species proved equally susceptible to black pepper and piperine. It is concluded that black pepper shows potential as a larvicide for the control of certain malaria vector species.


Extending the efficacy of a thermal biofeedback treatment package to the management of tension-type headaches in children.
This study explored the efficacy of a thermal biofeedback treatment package as an intervention with children with tension-type headaches. In a within-subject, time-lagged, multiple baseline design, five children, aged 8 to 14 years, were assigned to baselines of varying lengths prior to receiving treatment. Treatment was introduced sequentially across subjects and involved six thermal biofeedback treatment visits. Parents were also given guidelines for how best to encourage children to independently use the biofeedback skills. Data confirm that the participants learned the handwarming skill, practiced the skill on a regular basis during treatment, and independently used the skills to manage their pain. All participants demonstrated clinically significant reductions in one or more headache parameters (frequency, duration, intensity) following treatment. At 6-month follow-up, four of the five participants were headache-free. Although the thermal biofeedback treatment package was generally effective for these children with tension-type headaches, the specific type of headache experienced by each child appeared to influence the specific response to treatment. In addition, no single measure of headache activity was the best indicator of response to treatment. The efficacy of the thermal biofeedback treatment package is supported as an alternative treatment for children suffering from tension-type headaches.


Multiple promoters control expression of the Yersinia enterocolitica phage-shock-protein A (pspA) operon.
The widely conserved phage-shock-protein A (pspA) operon encodes an extracytoplasmic stress response system that is essential for virulence in Yersinia enterocolitica, and has been linked to other important phenotypes in Escherichia coli, Salmonella enterica and Shigella flexneri. Regulation of pspA operon expression is mediated through a promoter upstream of pspA that depends on sigma factor RpoN (sigma(54)) and the enhancer binding protein PspF. PspA, PspB and PspC, encoded within the pspA operon, also regulate expression by participating in a putative signal transduction pathway that probably serves to modulate PspF activity. All of this suggests that appropriate expression of the pspA operon is critical. Previous genetic analysis of the Y. enterocolitica pspA operon suggested that an additional level of complexity might be mediated by PspF/RpoN-independent expression of some psp genes. Here, an rpoN null mutation and interposon analysis were used to confirm that PspF/RpoN-independent gene expression does originate within the psp locus. Molecular genetic approaches were used to systematically analyse the two large non-coding regions within the psp locus. Primer extension, control region deletion and site-directed mutagenesis experiments led to the identification of RpoN-independent promoters both upstream and downstream of pspA. The precise location of the PspF/RpoN-dependent promoter upstream of pspA was also determined. The discovery of these RpoN-independent promoters reveals yet another level of transcriptional complexity for the Y. enterocolitica pspA operon that may function to allow low-level constitutive expression of psp genes and/or additional regulation under some conditions.


Biomechanical Evaluation of a Standard Temporomandibular Joint Prosthesis and Screw Arrangement Optimization: A Finite Element Analysis.
Artificial total joint replacement is an important method of temporomandibular joint (TMJ) reconstruction, which has been advocated for TMJ osteoarthrosis, ankylosis, tumors, and other diseases. We designed one type of standard TMJ prosthesis fit for Chinese patients. This study aimed to explore the biomechanical behavior of the standard TMJ prosthesis using finite element analysis and selects an optimal screw arrangement scheme for clinical application. A female volunteer was recruited for a maxillofacial computed tomography scan, then the Hypermesh software was used to establish a finite element model of a mandibular condyle defect repaired with an artificial TMJ prosthesis. An advanced universal finite element program software was used to calculate the stress and deformation under a simulated maximum bite force loading. Also, the forces of screws under different numbers and arrangements were analyzed. Meanwhile, we designed an experiment to verify the calculation model. The average maximum stress of the fossa component of the standard prosthesis model was 19.25 MPa. The average maximum stress of the condyle component was 82.58 MPa, mainly concentrated near the top row hole. The fossa component should be fixed with at least 3 screws, and the optimal number of screws was 4. The condyle component should be fixed with at least 4 screws, and its optimal number was 6. The best scheme of screw arrangement was determined. The results of the verification experiment showed that the analysis was reliable. The stress distribution of the standard TMJ prosthesis is uniform, meanwhile, the number and arrangement of the screws significantly affect the contact force of the screws.


Field evidence of selenium bioreduction in a uranium-contaminated aquifer.
Removal of selenium from groundwater was documented during injection of acetate into a uranium-contaminated aquifer near Rifle, Colorado (USA). Bioreduction of aqueous selenium to its elemental form (Se0) concentrated it within mineralized biofilms affixed to tubing used to circulate acetate-amended groundwater. Scanning and transmission electron microscopy revealed close association between Se0 precipitates and cell surfaces, with Se0 aggregates having a diameter of 50-60 nm. Accumulation of Se0 within biofilms occurred over a three-week interval at a rate of c. 9 mg Se0 m(-2) tubing day(-1). Removal was inferred to result from the activity of a mixed microbial community within the biofilms capable of coupling acetate oxidation to the reduction of oxygen, nitrate and selenate. Phylogenetic analysis of the biofilm revealed a community dominated by strains of Dechloromonas sp. and Thauera sp., with isolates exhibiting genetic similarity to the latter known to reduce selenate to Se0. Enrichment cultures of selenate-respiring microorganisms were readily established using Rifle site groundwater and acetate, with cultures dominated by strains closely related to D. aromatica (96-99% similarity). Predominance of Dechloromonas sp. in recovered biofilms and enrichments suggests this microorganism may play a role in the removal of selenium oxyanions present in Se-impacted groundwaters and sediments.


Changes in cardiac tone regulation with fatigue after supra-maximal running exercise.
To investigate the effects of fatigue and metabolite accumulation on the postexercicse parasympathetic reactivation, 11 long-sprint runners performed on an outdoor track an exhaustive 400 m long sprint event and a 300 m with the same 400 m pacing strategy. Time constant of heart rate recovery (HRRτ), time (RMSSD), and frequency (HF, and LF) varying vagal-related heart rate variability indexes were assessed during the 7 min period immediately following exercise. Biochemical parameters (blood lactate, pH, PO₂, PCO₂, SaO₂, and HCO₃⁻) were measured at 1, 4 and 7 min after exercise. Time to perform 300 m was not significantly different between both running trials. HHRτ measured after the 400 m running exercise was longer compared to 300 m running bouts (183.7 ± 11.6 versus 132.1 ± 9.8 s, P < 0.01). Absolute power density in the LF and HF bands was also lower after 400 m compared to the 300 m trial (P < 0.05). No correlation was found between biochemical and cardiac recovery responses except for the PO₂ values which were significantly correlated with HF levels measured 4 min after both bouts. Thus, it appears that fatigue rather than metabolic stresses occurring during a supramaximal exercise could explain the delayed postexercise parasympathetic reactivation in longer sprint runs.


Colistimethate sodium for the treatment of chronic pulmonary infection in cystic fibrosis: an evidence-based review of its place in therapy.
Chronic bacterial respiratory-tract infections are a major driving force in the pathogenesis of cystic fibrosis (CF) lung disease and promote chronic lung-function decline, destruction, and progression to respiratory failure at a premature age. Gram-negative bacteria colonizing the airways in CF are a major problem in CF therapy due to their tendency to develop a high degree of resistance to antibiotic agents over time. Pseudomonas aeruginosa is the dominating bacterial strain infecting the CF lung from early childhood on, and multiresistant strains frequently develop after years of therapy. Colistin has been used for treating pulmonary bacterial infections in CF for decades due to its very good Gram-negative activity. However, drawbacks include concerns regarding toxicity when being applied systemically, and the lack of approval for application by inhalation in the USA for many years. Other antibiotic substances for systemic use are available with good to excellent Gram-negative and anti-Pseudomonas activity, while there are only three substances approved for inhalation use in the treatment of chronic pulmonary infection with proven benefit in CF. The emergence of multiresistant strains leaving nearly no antibiotic substance as a treatment option, the limited number of antibiotics with high activity against P. aeruginosa, the concerns about increasing the risk of antibiotic resistance by continuous antibiotic therapy, the development of new drug formulations and drug-delivery devices, and, finally, the differing treatment strategies used in CF centers call for defining the place of this "old" drug, colistimethate, in today's CF therapy. This article reviews the available evidence to reflect on the place of colistimethate sodium in the therapy of chronic pulmonary infection in CF.


Interspecies gene transfer provides soybean resistance to a fungal pathogen.
Fungal pathogens pose a major challenge to global crop production. Crop varieties that resist disease present the best defence and offer an alternative to chemical fungicides. Exploiting durable nonhost resistance (NHR) for crop protection often requires identification and transfer of NHR-linked genes to the target crop. Here, we identify genes associated with NHR of Arabidopsis thaliana to Phakopsora pachyrhizi, the causative agent of the devastating fungal disease called Asian soybean rust. We transfer selected Arabidopsis NHR-linked genes to the soybean host and discover enhanced resistance to rust disease in some transgenic soybean lines in the greenhouse. Interspecies NHR gene transfer thus presents a promising strategy for genetically engineered control of crop diseases.


Music meets robotics: a prospective randomized study on motivation during robot aided therapy.
Robots have been successfully applied in motor training during neurorehabilitation. As music is known to improve motor function and motivation in neurorehabilitation training, we aimed at integrating music creation into robotic-assisted motor therapy. We developed a virtual game-like environment with music for the arm therapy robot ARMin, containing four different motion training conditions: a condition promoting creativity (C+) and one not promoting creativity (C-), each in a condition with (V+) and without (V-) a visual display (i.e., a monitor). The visual display was presenting the game workspace but not contributing to the creative process itself. In all four conditions the therapy robot haptically displayed the game workspace. Our aim was to asses the effects of creativity and visual display on motivation. In a prospective randomized single-center study, healthy participants were randomly assigned to play two of the four training conditions, either with (V+) or without visual display (V-). In the third round, the participants played a repetition of the preferred condition of the two first rounds, this time with a new V condition (i.e., with or without visual display). For each of the three rounds, motivation was measured with the Intrinsic Motivation Inventory (IMI) in the subscales interest/enjoyment, perceived choice, value/usefulness, and man-machine-relation. We recorded the actual training time, the time of free movement, and the velocity profile and administered a questionnaire to measure perceived training time and perceived effort. All measures were analysed using linear mixed models. Furthermore, we asked if the participants would like to receive the created music piece. Sixteen healthy subjects (ten males, six females, mean age: 27.2 years, standard deviation: 4.1 years) with no known motor or cognitive deficit participated. Promotion of creativity (i.e., C+ instead of C-) significantly increased the IMI-item interest/enjoyment (p=0.001) and the IMI-item perceived choice (p=0.010). We found no significant effects in the IMI-items man-machine relation and value/usefulness. Conditions promoting creativity (with or without visual display) were preferred compared to the ones not promoting creativity. An interaction effect of promotion of creativity and omission of visual display was present for training time (p=0.013) and training intensity (p<0.001). No differences in relative perceived training time, perceived effort, and perceived value among the four training conditions were found. Promoting creativity in a visuo-audio-haptic or audio-haptic environment increases motivation in robot-assisted therapy. We demonstrated the feasibility of performing an audio-haptic music creation task and recommend to try the system on patients with neuromuscular disorders. ClinicalTrials.gov, NCT02720341. Registered 25 March 2016, https://clinicaltrials.gov/ct2/show/NCT02720341.


Traumatic brain injury and mitochondrial dysfunction.
Traumatic brain injury (TBI) is a major cause of death and disability in the United States and causes mitochondrial damage leading to impaired brain function. The purpose of this review is to (1) describe TBI processes and manifestations, (2) examine the mitochondrial alterations after TBI, specifically increased reactive oxygen species production, decreased bioenergetics and apoptosis and (3) current TBI treatments. There are various degrees of severity of TBI, yet all affect mitochondrial function. Currently, health care professionals use various methods to assess TBI severity-from brain imaging to serum biomarkers. The major cause of TBI-associated brain damage is secondary injury, which is mainly from mitochondrial injury dysfunction. Mitochondrial injury leads to oxidative stress and subsequent apoptosis and decreased cellular energy production. These brain cellular alterations impair neurologic functions, which are observed in individuals with TBI. The complex mitochondrial dysfunction after TBI requires treatment that specifically addresses the secondary injury. There are numerous therapies being used, including (1) hypothermia, (2) hyperbaric oxygen, (3) exercise and (4) antioxidants. Researchers are exploring novel approaches to prevent, diagnose and treat TBI focusing on maintaining mitochondrial function.


Aneurysm wall enhancement on magnetic resonance imaging as a risk factor for progression of unruptured vertebrobasilar dissecting aneurysms after reconstructive endovascular treatment.
OBJECTIVE The recurrence rate of vertebrobasilar dissecting aneurysms (VBDAs) after reconstructive endovascular treatment (EVT) is relatively high. The aneurysm wall enhancement on high-resolution MRI (HRMRI) reportedly predicts an unsteady state of an intracranial aneurysm. The authors used HRMRI to investigate the relationship between wall enhancement on HRMRI and progression of VBDAs after reconstructive EVT. METHODS From January 2012 to December 2015, patients with an unruptured VBDA who underwent reconstructive EVT were enrolled in this study. Preoperative enhanced HRMRI was performed to evaluate radiological characteristics. The relationships between aneurysm wall enhancement and various potential risk factors were statistically analyzed. Follow-up angiographic examination was performed with digital subtraction angiography and conventional HRMRI. Cox regression analysis was performed to identify predictors of VBDA progression after reconstructive EVT. RESULTS Eighty-two patients (12 women and 70 men, mean age 53.48 ± 9.23 years) with 83 VBDAs were evaluated in the current study. The average maximum diameter of the VBDAs was 11.30 ± 7.90 mm. Wall enhancement occurred in 43 VBDAs (51.81%). Among all 83 VBDAs, 62 (74.70%) were treated by stent-assisted coil embolization and 21 (25.30%) by stenting alone. The mean duration of imaging follow-up among all 82 patients was 10.55 months (range 6-45 months), and 15 aneurysms (18.07%) exhibited progression. The statistical analysis indicated no significant differences in age, sex, risk factors (high blood pressure, smoking, diabetes mellitus, and a high cholesterol level), VBDA stage, or VBDA size between enhanced and unenhanced VBDAs. Univariate Cox regression analysis showed that both the maximum diameter of the VBDAs and wall enhancement were associated with recurrence (p < 0.05). Multivariate Cox proportional hazard regression analysis showed that the maximum diameter of the VBDAs and wall enhancement on HRMRI were independent risk factors for aneurysm progression (p < 0.05). CONCLUSIONS Aneurysm size and wall enhancement on HRMRI can predict the progression of VBDAs after reconstructive EVT.


Daily struggle to take antiretrovirals: a qualitative study in Papuans living with HIV and their healthcare providers.
The aim of the study was to explore the experiences of Papuans living with HIV to take antiretroviral therapy (ART) from the patient and the healthcare providers (HCPs) perspective. This was a qualitative study covering all five tribes located in Papua Provinces one of two Indonesian provinces on Papua Island. Semistructured interviews were conducted with Papuans living with HIV and their HCPs. Interviews were transcribed verbatim and coded to find themes. Overall, we conducted interviews with 13 Papuans living with HIV (mean age: 33 years, 61% female) and 14 HCPs (mean age: 42 years, 64% female) within five customary areas. HCPs included three physicians, nine nurses, two others. Two main themes were identified: (1) personal factors and (2) healthcare environment-related factors. Personal factors were beliefs and knowledge of ART, stigma from family, community and HCPs as well as practical problems such as transportation because of long distance. Within the theme of healthcare environment, the competences and attitudes of HCPs were particularly relevant. The findings are important in refining HIV treatment strategies implemented in Papua, especially when extending HIV care provided by community centres. Despite free access to ART, Papuans living with HIV struggle to remain on treatment. Considering local culture and religion in strategies to reduce stigma should be a priority.


Fe(II) in different macrocycles: electronic structures and properties.
A theoretical comparative study of complexes of porphyrin (P), porphyrazine (Pz), phthalocyanine (Pc), porphycene (Pn), dibenzoporphycene (DBPn), and hemiporphyrazine (HPz) with iron (Fe) has been carried out using a density functional theory (DFT) method. The difference in the core size and shape of the macrocycle has a substantial effect on the electronic structure and properties of the overall system. The ground states of FeP and FePc were identified to be the 3A2g [(d(xy))2(d(z)2)2(d(pi))2] state, followed by 3E(g) [(d(xy))2(d(z)2)1(d(pi))3]. For FePz, however, the 3E(g)-3A2g energy gap of 0.02 eV may be too small to distinguish between the ground and excited states. When the symmetry of the macrocycle is reduced from D4h to D2h, the degeneracy of the d(pi) (d(xz), d(yz)) orbitals is removed, and the ground state becomes 3B2g [(d(xy))2(d(z)2)1(d(yz))2(d(xz))1] or 3B3g [...(d(yz))1(d(xz))2] for FePn, FeDBPn, and FeHPz. The calculations also show how the change of the macrocycle can influence the axial ligand coordination of pyridine (Py) and CO to the Fe(II) complexes. Finally, the electronic structures of the mono- and dipositive and -negative ions for all the unligated and ligated iron macrocycles were elucidated, which is important for understanding the redox properties of these compounds. The differences in the observed electrochemical (oxidation and reduction) properties between metal porphycenes (MPn) and metal porphyrins (MP) can be accounted for by the calculated results (orbital energy level diagrams, ionization potentials, and electron affinities).


CGRPα within the Trpv1-Cre population contributes to visceral nociception.
The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRPα is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRPα from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRPα-mCherrylx/lx;Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRPα-mCherrylx/lx;Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRPα-mCherrylx/lx;Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRPα-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRPα- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor potential cation channel subfamily V member 1 (TRPV1)-expressing primary afferent neurons, but the functional role of CGRPα specifically in these neurons is unknown in pain processing from visceral and somatic afferents. We used cre-lox recombination to conditionally delete CGRPα from TRPV1-expressing neurons in mice. We show that CGRPα from within TRPV1-cre population plays an important role in visceral nociception but less so in somatic nociception.


A Mammalian enhancer trap resource for discovering and manipulating neuronal cell types.
There is a continuing need for driver strains to enable cell-type-specific manipulation in the nervous system. Each cell type expresses a unique set of genes, and recapitulating expression of marker genes by BAC transgenesis or knock-in has generated useful transgenic mouse lines. However, since genes are often expressed in many cell types, many of these lines have relatively broad expression patterns. We report an alternative transgenic approach capturing distal enhancers for more focused expression. We identified an enhancer trap probe often producing restricted reporter expression and developed efficient enhancer trap screening with the PiggyBac transposon. We established more than 200 lines and found many lines that label small subsets of neurons in brain substructures, including known and novel cell types. Images and other information about each line are available online (enhancertrap.bio.brandeis.edu).


Cloning and molecular characterization of two ferritins from red abalone Haliotis rufescens and their expressions in response to bacterial challenge at juvenile and adult life stages.
Ferritins are ubiquitous proteins with a pivotal role in iron storage and homeostasis, and in host defense responses during infection by pathogens in several organisms, including mollusks. In this study, we characterized two ferritin homologues in the red abalone Haliotis rufescens, a species of economic importance for Chile, USA and Mexico. Two ferritin subunits (Hrfer1 and Hrfer2) were cloned. Hrfer1 cDNA is an 807 bp clone containing a 516 bp open reading frame (ORF) that corresponds to a novel ferritin subunit in H. rufescens. Hrfer2 cDNA is an 868 bp clone containing a 516 bp ORF that corresponds to a previously reported ferritin subunit, but in this study 5'- and 3'-UTR sequences were additionally found. We detected a putative Iron Responsive Element (IRE) in the 5'-UTR sequence, suggesting a posttranscriptional regulation of Hrfer2 translation by iron. The deduced protein sequences of both cDNAs possessed the motifs and domains required in functional ferritin subunits. Expression patterns of both ferritins in different tissues, during different developmental stages, and in response to bacterial (Vibrio splendidus) exposure were examined. Both Hrfer1 and Hrfer2 are most expressed in digestive gland and gonad. Hrfer1 mRNA levels increased about 34-fold along with larval developmental process, attaining the highest level in the creeping post-larvae. Exogenous feeding is initiated at the creeping larva stage; thus, the increase of Hrfer1 may suggest and immunity-related role upon exposure to bacteria. Highest Hrfer2 expression levels were detected at trochophore stage; which may be related with early shell formation. Upon challenge with, the bacteria an early mild induction of Hrfer2 (2 h post-challenge), followed by a stronger induction of Hrfer1 at 15 h post-challenge, was observed in haemocytes from adult abalones. While maximal upregulation of both genes in the whole individual occurred at 24 h post-challenge, in juveniles. A significant increase in ferritin protein levels from 6 h to 24 h post-challenge was also detected. Our results suggest an involvement of Hrfer1 and Hrfer2, and of ferritin proteins in the immune response of H. rufescens to bacterial infection.


Enzymatic and biophysical characterization of a novel modular cellulosomal GH5 endoglucanase multifunctional from the anaerobic gut fungus Piromyces finnis.
Cellulases from anaerobic fungi are enzymes less-studied biochemically and structurally than cellulases from bacteria and aerobic fungi. Currently, only thirteen GH5 cellulases from anaerobic fungi were biochemically characterized and two crystal structures were reported. In this context, here, we report the functional and biophysical characterization of a novel multi-modular cellulosomal GH5 endoglucanase from the anaerobic gut fungus Piromyces finnis (named here PfGH5). Multiple sequences alignments indicate that PfGH5 is composed of a GH5 catalytic domain and a CBM1 carbohydrate-binding module connected through a CBM10 dockerin module. Our results showed that PfGH5 is an endoglucanase from anaerobic fungus with a large spectrum of activity. PfGH5 exhibited preference for hydrolysis of oat β-glucan, followed by galactomannan, carboxymethyl cellulose, mannan, lichenan and barley β-glucan, therefore displaying multi-functionality. For oat β-glucan, PfGH5 reaches its optimum enzymatic activity at 40 °C and pH 5.5, with Km of 7.1 μM. Ion exchange chromatography analyzes revealed the production of oligosaccharides with a wide degree of polymerization indicated that PfGH5 has endoglucanase activity. The ability to bind and cleave different types of carbohydrates evidence the potential of PfGH5 for use in biotechnology and provide a useful basis for future investigation and application of new anaerobic fungi enzymes.


The microbial infection of biomaterials: A challenge for clinicians and researchers. A short review.
The increasing use of biomaterials and medical devices has led to the development of new families of diseases related precisely to the use of the biomaterials and medical devices themselves. Microbial contamination of the devices is a serious and widespread problem in surgery because it often causes devastating infections and loss of the implanted devices. The methods of contamination in medical devices are dependent on many peculiar factors including the chemistry of the biomaterial, the physical properties of the surface, the design of the medical device, the implanted anatomical site, the extension of surgical invasion, and the time of application. The environment and/or conditions and response of the host also contribute to the development of the colonization and infection. Many bacteria and fungi spp. are involved in biomaterial infections, but most belong to endogenous bacteria or the commensal community of the skin such as Staphylococcus epidermidis and Staphylococcus aureus. Medical device contamination always develops into biofilm formation, which constitutes a protected mode for the bacteria to survive in a hostile environment by optimizing nutrient uptake, as it is sheltered from the removal forces and is protected from the host defense mechanism and from potential toxic or harmful substances including antibiotics. Therefore, studies concerning infections related to implanted materials are of increasing frequency and interest. Both in vitro and in vivo studies are reported to simulate biomaterial infection. We report suggestions concerning useful standards and strategies to re-duce contamination on biomaterials. (Journal of Applied Biomaterials and Biomechanics 2005; 3: 1-10).


Noise-Induced Endocrine Effects and Cardiovascular Risk.
Noise has the potential to cause stress reactions. Chronic noise-induced stress accelerates the ageing of the myocardium and thus increase the risk of myocardial infarction. The involved pathomechanisms include acute increase of catecholamines or cortisol under acute noise exposure and an interaction between endocrine reactions and intracellular Ca/Mg shifts. Chronic noise exposure of animals on a diet with suboptimal magnesium content led to increase of connective tissue and calcium, and decrease of magnesium in the myocardium. These changes were correlated to noradrenaline and normal ageing. Post mortem studies of hearts from victims of ischemic heart diseases confirmed the importance of Ca/Mg shifts in humans. Recent epidemiological studies support the importance of noise as a risk factor in circulatory and heart diseases, especially in myocardial infarction.


Effects of extra 5' non-viral bases on the infectivity of transcripts from a cDNA clone of satellite RNA (strain Y) of cucumber mosaic virus.
Full-length cDNA of a satellite RNA (Strain Y) which induces bright yellow symptoms on tobacco plants infected with cucumber mosaic virus (CMV) was cloned and sequenced. The published sequence of the satellite RNA was revised with three possible differences (residues 161, 167, and 173) and a nucleotide insertion at residue 234. The satellite cDNA was then inserted into a commercially available transcription vector. In vitro transcription products from the recombinant plasmid harbored 24 non-viral bases at their 5' ends and had very low infectivity when coinoculated with CMV. After removal of the extra 5' sequence of the transcripts with RNase H, the infectivity of the transcripts increased markedly. Analysis of the effects of extra 5' sequences of several lengths confirmed the importance of natural 5' ends for biological activity of the satellite. Trimming down to 6-9 extra bases at the 5' end enhanced the infectivity of the transcripts by 10-fold, although the specific activity of the natural satellite is still 100-fold higher. Dideoxynucleotide sequence analysis proved that the progeny satellite RNA did not retain the 24 non-viral bases at the 5' end of the transcript from pIBI 31-MC.


Reanalyzing the "far medial" (transcondylar-transtubercular) approach based on three anatomical vectors: the ventral posterolateral corridor.
Endoscopic endonasal access to the jugular foramen and occipital condyle - the transcondylar-transtubercular approach - is anatomically complex and requires detailed knowledge of the relative position of critical neurovascular structures, in order to avoid inadvertent injury and resultant complications. However, access to this region can be confusing as the orientation and relationships of osseous, vascular, and neural structures are very much different from traditional dorsal approaches. This review aims at providing an organizational construct for a more understandable framework in accessing the transcondylar-transtubercular window. The region can be conceptualized using a three-vector coordinate system: vector 1 represents a dorsal or ventral corridor, vector 2 represents the outer and inner circumferential anatomical limits; in an "onion-skin" fashion, key osseous, vascular, and neural landmarks are organized based on a 360-degree skull base model, and vector 3 represents the final core or target of the surgical corridor. The creation of an organized "global-positioning system" may better guide the surgeon in accessing the far-medial transcondylar-transtubercular region, and related pathologies, and help understand the surgical limits to the occipital condyle and jugular foramen - the ventral posterolateral corridor - via the endoscopic endonasal approach.


[Inhibition of platelet aggregation and angiotensin II-receptor blockade following TIA; the unexpected results of the Prevention Regimen For Effectively Avoiding Second Strokes (PROFESS) trial].
In the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial, the combination of acetylsalicylic acid (50 mg) and extended-release dipyridamole (400 mg) (ASA+Dip) was compared with clopidogrel (75 mg) in patients with a recent transient ischaemic attack (TIA) or minor disabling stroke. In the same patients, the selective type I angiotensin II-receptor blocker telmisartan (80 mg) was compared with placebo. Both comparisons did not show any benefit or harm from any of the treatments evaluated. Therefore, ASA+Dip and clopidogrel should be considered effective in secondary stroke prevention following TIA or minor disabling stroke. ASA+Dip caused headache in 6% of patients. Clopidogrel can cause severe haematological side effects in rare cases; its use is hampered mainly by its high cost. Telmisartan was well tolerated in patients with a recent TIA or minor disabling stroke but should not be used for indications other than lowering blood pressure.


Conventional and dense gas techniques for the production of liposomes: a review.
The aim of this review paper is to compare the potential of various techniques developed for production of homogenous, stable liposomes. Traditional techniques, such as Bangham, detergent depletion, ether/ethanol injection, reverse-phase evaporation and emulsion methods, were compared with the recent advanced techniques developed for liposome formation. The major hurdles for scaling up the traditional methods are the consumption of large quantities of volatile organic solvent, the stability and homogeneity of the liposomal product, as well as the lengthy multiple steps involved. The new methods have been designed to alleviate the current issues for liposome formulation. Dense gas liposome techniques are still in their infancy, however they have remarkable advantages in reducing the use of organic solvents, providing fast, single-stage production and producing stable, uniform liposomes. Techniques such as the membrane contactor and heating methods are also promising as they eliminate the use of organic solvent, however high temperature is still required for processing.


Update on the pathogenic potential and treatment options for Blastocystis sp.
Although Blastocystis is one of the most common enteric parasites, there is still much controversy surrounding the pathogenicity and potential treatment options for this parasite. In this review we look at the evidence supporting Blastocystis as an intestinal pathogen as shown by numerous case studies and several in vivo studies and the evidence against. We describe the chronic nature of some infections and show the role of Blastocystis in immunocompromised patients and the relationship between irritable bowel syndrome and Blastocystis infection. There have been several studies that have suggested that pathogenicity may be subtype related. Metronidazole is the most widely accepted treatment for Blastocystis but several cases of treatment failure and resistance have been described. Other treatment options which have been suggested include paromomycin and trimethroprim- sulfamethoxazole.


Impact of mast cells in mucosal immunity of intestinal inflammation: Inhibitory effect of IL-37.
Mast cells (MCs) are implicated in an array of diseases, especially those involving a mucosal surface, including intestine. On appropriate activation from cytoplasmatic granules, MCs release preformed chemical mediators and generate inflammatory lipids and cytokines/chemokines. Intracellular signal and Lyn activation pathways can cause the degranulation of MCs and the generation of lipid mediators and cytokines/chemokines. MCs undergo maturation and polarization in gut mucosal surfaces where they are constitutively present, and can alter intestinal permeability, an important factor in many inflammatory mucosal disorders including autoimmune diseases. On the other hand, since they are immununosuppressive, MCs have potential anti-inflammatory properties by producing TGF-β1, interleukin (IL)-4, IL-10, IL-13 and histamine. In addition, MC chymase, located in the sub-mucosa, acts on intestinal permeability by protecting the bowel. To carry the inflammatory response, MCs need to be attracted by CC chemokines such as RANTES (CCL5) and MCP-1(CCL2), an effect absent in genetically W/Wv mast cell-deficient mice, where the inflammatory reaction is not present. Here, we focused our attention on recent findings regarding how MCs can initiate and develop the cellular immune response in the gut and mediate inflammation, an effect that can be inhibited by IL-37. These studies contribute to clarify the mechanisms by which MCs profoundly affect immunity and inflammation of the intestine.


Nonalcoholic Fatty liver: a possible new target for type 2 diabetes prevention and treatment.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Several lines of evidence have indicated a pathogenic role of insulin resistance, and a strong association with type 2 diabetes (T2MD) and metabolic syndrome. Importantly, NAFLD appears to enhance the risk for T2MD, as well as worsen glycemic control and cardiovascular disease in diabetic patients. In turn, T2MD may promote NAFLD progression. The opportunity to take into account NAFLD in T2MD prevention and care has stimulated several clinical studies in which antidiabetic drugs, such as metformin, thiazolidinediones, GLP-1 analogues and DPP-4 inhibitors have been evaluated in NAFLD patients. In this review, we provide an overview of preclinical and clinical evidences on the possible efficacy of antidiabetic drugs in NAFLD treatment. Overall, available data suggest that metformin has beneficial effects on body weight reduction and metabolic parameters, with uncertain effects on liver histology, while pioglitazone may improve liver histology. Few data, mostly preclinical, are available on DPP4 inhibitors and GLP-1 analogues. The heterogeneity of these studies and the small number of patients do not allow for firm conclusions about treatment guidelines, and further randomized, controlled studies are needed.


Gender-related differences in diazepam effects on performance.
In order to investigate the possible differences of diazepam effects in the two sexes, two placebo-controlled double-blind studies were conducted on healthy volunteer students. In one study the subjects received diazepam 10 mg alone or combined with 0.5 g/kg of alcohol in a parallel group design; in the other 0.2 mg/kg of diazepam or placebo were given in a cross-over manner. In both trials diazepam impaired the psychomotor skills of women more than men. The difference was similar in tasks measuring cognitive (digit symbol substitution), motor (balance of extraocular muscles) and sensory (critical flicker fusion) performances. Tapping speed was affected to a similar degree in both genders. Diazepam 10 mg did not cause impairment of body balance, a parameter sensitive to alcohol. The combined effect of diazepam and alcohol was of similar magnitude in both sexes in all objective tests. Subjectively the women felt themselves clumsier than did the men. The calming effect was similar in both groups. The results suggest that while the performance of women may be more vulnerable than men to impairment by diazepam they also are aware of it. The difference of effects is of such magnitude that it may cause bias in experiments unless carefully balanced groups are used.


Refining carbon flux paths using atomic trace data.
Pathway analysis tools are a powerful strategy to analyze 'omics' data in the field of systems biology. From a metabolic perspective, several pathway definitions can be found in the literature, each one appropriate for a particular study. Recently, a novel pathway concept termed carbon flux paths (CFPs) was introduced and benchmarked against existing approaches, showing a clear advantage for finding linear pathways from a given source to target metabolite. CFPs are simple paths in a metabolite-metabolite graph that satisfy typical constraints in stoichiometric models: mass balancing and thermodynamics (irreversibility). In addition, CFPs guarantee carbon exchange in each of their intermediate steps, but not between the source and the target metabolites and consequently false positive solutions may arise. These pathways often lack biological interest, particularly when studying biosynthetic or degradation routes of a metabolite. To overcome this issue, we amend the formulation in CFP, so as to account for atomic fate information. This approach is termed atomic CFP (aCFP). By means of a side-by-side comparison in a medium scale metabolic network in Escherichia Coli, we show that aCFP provides more biologically relevant pathways than CFP, because canonical pathways are more easily recovered, which reflects the benefits of removing false positives. In addition, we demonstrate that aCFP can be successfully applied to genome-scale metabolic networks. As the quality of genome-scale atomic reconstruction is improved, methods such as the one presented here will undoubtedly be of value to interpret 'omics' data.


TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A.
Transcription-blocking DNA lesions are removed by transcription-coupled nucleotide excision repair (TC-NER) to preserve cell viability. TC-NER is triggered by the stalling of RNA polymerase II at DNA lesions, leading to the recruitment of TC-NER-specific factors such as the CSA-DDB1-CUL4A-RBX1 cullin-RING ubiquitin ligase complex (CRLCSA). Despite its vital role in TC-NER, little is known about the regulation of the CRLCSA complex during TC-NER. Using conventional and cross-linking immunoprecipitations coupled to mass spectrometry, we uncover a stable interaction between CSA and the TRiC chaperonin. TRiC's binding to CSA ensures its stability and DDB1-dependent assembly into the CRLCSA complex. Consequently, loss of TRiC leads to mislocalization and depletion of CSA, as well as impaired transcription recovery following UV damage, suggesting defects in TC-NER. Furthermore, Cockayne syndrome (CS)-causing mutations in CSA lead to increased TRiC binding and a failure to compose the CRLCSA complex. Thus, we uncover CSA as a TRiC substrate and reveal that TRiC regulates CSA-dependent TC-NER and the development of CS.


Power and efficiency of insect flight muscle.
The efficiency and mechanical power output of insect flight muscle have been estimated from a study of hovering flight. The maximum power output, calculated from the muscle properties, is adequate for the aerodynamic power requirements. However, the power output is insufficient to oscillate the wing mass as well unless there is good elastic storage of the inertial energy, and this is consistent with reports of elastic components in the flight system. A comparison of the mechanical power output with the metabolic power input to the flight muscles suggests that the muscle efficiency is quite low: less than 10%.


The IL-23-IL-17 axis in inflammatory arthritis.
The discovery that the IL-23-IL-17 immune pathway is involved in many models of autoimmune disease has changed the concept of the role of T-helper cell subsets in the development of autoimmunity. In addition to TH17 cells, IL-17 is also produced by other T cell subsets and innate immune cells; which of these IL-17-producing cells have a role in tissue inflammation, and the timing, location and nature of their role(s), is incompletely understood. The current view is that innate and adaptive immune cells expressing the IL-23 receptor become pathogenic after exposure to IL-23, but further investigation into the role of IL-23 and IL-17 at different stages in the development and progression of chronic (destructive) inflammatory diseases is needed. Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the two most common forms of chronic immune-mediated inflammatory arthritis, and the IL-23-IL-17 axis is thought to have a critical role in both. This Review discusses the basic mechanisms of these cytokines in RA and SpA on the basis of findings from disease-specific animal models as well as human ex vivo studies. Promising therapeutic applications to modulate this immune pathway are in development or have already been approved. Blockade of IL-17 and/or TH17-cell activity in combination with anti-TNF therapy might be a successful approach to achieving stable remission or even prevention of chronic immune-mediated inflammatory diseases.


Examining Plasmodium falciparum and P. vivax clearance subsequent to antimalarial drug treatment in the Myanmar-China border area based on quantitative real-time polymerase chain reaction.
Recent emergence of artemisinin-resistant P. falciparum has posed a serious hindrance to the elimination of malaria in the Greater Mekong Subregion. Parasite clearance time, a measure of change in peripheral parasitaemia in a sequence of samples taken after treatment, can be used to reflect the susceptibility of parasites or the efficiency of antimalarials. The association of genetic polymorphisms and artemisinin resistance has been documented. This study aims to examine clearance time of P. falciparum and P. vivax parasitemia as well as putative gene mutations associated with residual or recurred parasitemia in Myanmar. A total of 63 P. falciparum and 130 P. vivax samples collected from two internally-displaced populations and one surrounding village were examined for parasitemia changes. At least four samples were taken from each patient, at the first day of diagnosis up to 3 months following the initial treatment. The amount of parasite gene copy number was estimated using quantitative real-time PCR based on a species-specific region of the 18S rRNA gene. For samples that showed residual or recurred parasitemia after treatment, microsatellites were used to identify the 'post-treatment' parasite genotype and compared such with the 'pre-treatment' genotype. Mutations in genes pfcrt, pfmdr1, pfatp6, pfmrp1 and pfK13 that are potentially associated with ACT resistance were examined to identify if mutation is a factor for residual or persistent parasitemia. Over 30% of the P. falciprium infections showed delayed clearance of parasitemia after 2-3 days of treatment and 9.5% showed recurred parasitemia. Mutations in codon 876 of the pfmrp1 corroborated significance association with slow clearance time. However, no association was observed in the variation in pfmdr1 gene copy number as well as mutations of various codonsinpfatp6, pfcrt, and pfK13 with clearance time. For P. vivax, over 95% of the infections indicated cleared parasitemia at days 2-3 of treatment. Four samples were found to be re-infected with new parasite strains based on microsatellite genotypes after initial treatment. The appearance of P.falciparum infected samples showing delayed clearance or recurred parasitemia after treatment raises concerns on current treatment and ACT drug resistance.


Studies on the ability of a 98-kilodalton pseudorabies virus diagnostic antigen to detect latent infections induced by low-dose exposure to the virus.
The effect of low-dose challenge of immunity with pseudorabies virus (PRV) on subunit-vaccinated pigs was studied in 2 experiments. In the first experiment, we studied the effect of challenge dose on the antibody response to an early excreted 98-kilodalton PRV-glycoprotein that was used as a diagnostic antigen in the ELISA. In the second experiment, we studied the effect of low doses of virus on the establishment of latent infections in subunit-vaccinated pigs. The relationship of virus exposure dose and vaccine dose to the response of pigs to diagnostic antigen was studied in 18 pigs. Two groups of 3 pigs were vaccinated with a total of 200 micrograms of a lectin-derived PRV subunit vaccine over a 5-week period. Two groups of 3 pigs were similarly vaccinated with a total of 100 micrograms. Two groups of 3 pigs served as nonvaccinated controls. One group of pigs from each of the preceding categories was intranasally exposed to 10(6.0) and 10(2.7) plaque-forming units (PFU) of virus. Antibody to diagnostic antigen was detected by the ELISA and radioimmunoprecipitation 3 to 7 days earlier in pigs exposed to 10(6.0) PFU, demonstrating that the size of the virus challenge dose affects the antibody response to diagnostic antigen. The establishment of latent infections by low PRV doses and the ability to detect these infections was studied in 10 subunit-vaccinated pigs. Each pig was intranasally exposed to 10(2.3) PFU of virus (day 0).(ABSTRACT TRUNCATED AT 250 WORDS)