Synthesis, antitumor activity, and DNA binding properties of a new derivative of amsacrine, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide.
The 4-(N-methylcarboxamido)-5-methyl derivative of amsacrine (NSC 249 992) has been synthesized as part of a program aimed at optimizing solid tumor activity in this series. Physicochemical studies of this analogue (N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide; NSC 343 499) indicate a slightly increased lipophilicity (estimated log p = 1.10), a decreased acridine base strength (pKa 6.40), and a 16-fold-higher association constant for double-stranded calf thymus DNA (Ka 2.1 X 10(6) M-1 at 0.01 ionic strength). Like amsacrine, the drug binds to DNA by intercalation. Inhibition of cell growth has been monitored by continuous drug exposure assays with a variety of rodent and human cell lines. The concentration for 50% inhibition varied from 6.7 nM (T-47D, a human breast carcinoma line) to 800 nM (P388/ADR, a murine cell line resistant to Adriamycin). N-5-Dimethyl-9-[(2-methoxy-4-methylsulfonylamino) phenylamino]-4-acridinecarboxamide was cytotoxic at growth-inhibitory concentrations and also induced cell cycle arrest in the G2 phase. It was active against P388 leukemia following administration by p.o., i.v., or i.p. routes, and it was superior to amsacrine, daunorubicin, and Adriamycin. It was curative towards i.v.-injected Lewis lung tumor in a proportion of animals when treatment was started on Day 1 or Day 5 after tumor inoculation. It also produced highly significant life extensions against advanced tumors (treatment starting Day 9 after i.v. inoculation or on Day 8 after s.c. inoculation) and was comparable to cyclophosphamide in its effectiveness. It is a candidate drug for clinical trial.


Genome-Wide Association Study Identifies Candidate Genes Related to the Linoleic Acid Content in Soybean Seeds.
Soybean (Glycine max (L.) Merrill) oil is a complex mixture of five fatty acids (palmitic, stearic, oleic, linoleic, and linolenic). The high content of linoleic acid (LA) contributes to the oil having poor oxidative stability. Therefore, soybean seed with a lower LA content is desirable. To investigate the genetic architecture of LA, we performed a genome-wide association study (GWAS) using 510 soybean cultivars collected from China. The phenotypic identification results showed that the content of LA varied from 36.22% to 72.18%. The GWAS analysis showed that there were 37 genes related to oleic acid content, with a contribution rate of 7%. The candidate gene Glyma.04G116500.1 (GmWRI14) on chromosome 4 was detected in three consecutive years. The GmWRI14 showed a negative correlation with the LA content and the correlation coefficient was -0.912. To test whether GmWRI14 can lead to a lower LA content in soybean, we introduced GmWRI14 into the soybean genome. Matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF IMS) showed that the overexpression of GmWRI14 leads to a lower LA content in soybean seeds. Meanwhile, RNA-seq verified that GmWRI14-overexpressed soybean lines showed a lower accumulation of GmFAD2-1A and GmFAD2-1B than control lines. Our results indicate that the down-regulation of the FAD2 gene triggered by the transcription factor GmWRI14 is the underlying mechanism reducing the LA level of seed. Our results provide novel insights into the genetic architecture of LA and pinpoint potential candidate genes for further in-depth studies.


Preventing aggressive incidents and seclusions in forensic care by means of the 'Early Recognition Method'.
The Early Recognition Method aims at improving collaboration between nurses and patients to prevent aggression in forensic psychiatric care. To achieve this goal, Early Recognition Method strongly focuses on early signs of aggression. In the current study, we investigated whether application of Early Recognition Method led to a significant decrease in inpatient incidents. Nurses in forensic settings are often confronted with patients' aggression. Better collaboration between nursing staff and patients may improve patients' ability to self manage aggression and contribute to a decrease in inpatient aggression. Naturalistic one-way case-crossover design. The Early Recognition Method was introduced on 16 wards of a maximum security forensic hospital. Using a one-way case-crossover design, where cases were their own controls, the effects of Early Recognition Method were assessed by comparing the number of incidents of 189 patients during 'Treatment As Usual' with the period after Early Recognition Method was implemented. The Early Recognition Method intervention involved weekly evaluations of signs of aggression between staff and patients. The outcome measures were the number of seclusions and the severity of inpatient incidents. A significant decline in the number of seclusions was observed after Early Recognition Method was introduced. Apart from this decrease, the mean severity of inpatient incidents was also found to be lower during the post intervention period. The effect size was most pronounced for patients with substance abuse and personality disorders. Patients with schizophrenia, however, showed modest, yet significant, effect sizes. The results suggest that Early Recognition Method may be an innovative and effective risk management method for forensic psychiatric patients, in particular for patients with personality disorders. This article aims to contribute to evidence-based risk management for nurses in collaboration with their patients, resulting in a decrease in inpatient aggression.


Intraoperative neuromonitoring with MEPs and prediction of postoperative neurological deficits in patients undergoing surgery for cervical and cervicothoracic myelopathy.
The use of intraoperative neurophysiological monitoring (IONM) in surgical decompression surgery for myelopathy may assist the surgeon in taking corrective measures to reduce or prevent permanent neurological deficits. We evaluated the efficacy of IONM in cervical and cervicothoracic spondylotic myelopathy (CSM) cases. The authors retrospectively reviewed 140 cases involving patients who underwent surgery for CSM utilizing IONM during 2011 at the University of California, San Francisco. Data on preoperative clinical variables, intraoperative changes in transcranial motor evoked potentials (MEPs), and postoperative new neurological deficits were collected. Associations between categorical variables were analyzed with the Fisher exact test. Of the 140 patients, 16 (11%) had significant intraoperative decreases in MEPs. In 8 of these cases, the MEP signal did not return to baseline values by the end of the operation. There were 8 (6%) postoperative deficits, of which 6 were C-5 palsies and 2 were paraparesis. Six of the patients with postoperative deficits had demonstrated persistent MEP signal change on IONM. There was a significant association between persistent MEP changes and postoperative deficits (p < 0.001). The sensitivity of intraoperative MEP monitoring was 75%, the specificity 98%, the positive predictive value 75%, and the negative predictive value 98%. Due to higher rates of false negatives, the sensitivity decreased to 60% in the subgroup of patients with vascular disease comorbidity. The sensitivity increased to 100% in elderly patients and in patients with preoperative motor deficits. The sensitivity and positive predictive value of deltoid and biceps MEP changes in predicting C-5 palsy were 67% and 67%, respectively. The authors found a correlation between decreased intraoperative MEPs and postoperative new neurological deficits in patients with CSM. Sensitivity varies based on patient comorbidities, age, and preoperative neurological function. Monitoring of MEPs is a useful adjunct for CSM cases, and the authors have developed a checklist to standardize their responses to intraoperative MEP changes.


Effects of dining on tongue endurance and swallowing-related outcomes.
The purpose of this study was to test the hypothesis that eating a meal reduces tongue strength and endurance in healthy old and young adults. It was predicted that older adults would show greater declines in tongue endurance while demonstrating higher perceived effort, longer meal durations, and clinical signs of swallowing difficulty. Twenty-two healthy adults were enrolled into 2 groups (ages 20-35 years and ages 65-82 years; 5 males and 6 females each). Maximum tongue strength (Pmax) and endurance (duration 50% of Pmax could be maintained) were measured twice at baseline and once postmeal. Subjects consumed half of a bagel with peanut butter, carrot sticks, and milk between measures. All subjects demonstrated reduced tongue strength and endurance postmeal. Young adults showed a greater decline in anterior tongue endurance compared with older adults (p=.05). There was no evidence that changes in tongue strength, perceived effort, or meal duration varied by age or gender. The 3 oldest subjects reported the highest effort and displayed signs of difficulty swallowing while dining. Young and old adults demonstrated reduced tongue strength and endurance after dining, but younger subjects showed greater declines in anterior tongue endurance, whereas older adults exhibited signs of swallowing difficulty.


Six minute corridor walk test as an outcome measure for the assessment of treatment in randomized, blinded intervention trials of chronic heart failure: a systematic review.
The 6 min walk test (6MWT) is commonly used in clinical trials to assess treatments for heart failure, but its ability to distinguish between effective and ineffective treatments is questionable. The aim of this study is to investigate, using a systematic literature review, the utility of the 6MWT as a measure of the effectiveness of treatment in randomized controlled trials of heart failure. A literature search was performed using Medline, EMBASE, CINAHL, and Biological abstracts for randomized controlled trials that measured 6MWT between 1988 and 31 May 2004. A significant increase in 6MWT distance was observed in only 9 of 47 randomized controlled trials of pharmacological therapy; 2 of 6 trials of ACE-inhibitors; 3 of 17 trials of beta-blockers; 1 of 4 trials of digoxin; one trial of ibopamine; one trial of l-arginine; one trial of beriberine; and one trial showed superiority of captopril over flosequinan. A significant increase in 6MWT was observed in four out of six placebo-controlled trials of cardiac resynchronization. Smaller pharmacological trials with fewer centres were more likely to be positive; six out of nine positive pharmacological trials had four or less participating centres, raising the possibility of publication bias. Pharmacological trials including patients with more severe heart failure were more likely to show a significant improvement with therapy than trials of milder heart failure. Five out of seven pharmacological trials that reported an improvement in symptoms also reported an improvement in 6MWT distance. Of 30 pharmacological trials, 29 that reported no improvement in symptoms also reported no improvement in 6MWT. Using mean values in these trials, the age of patients appeared a more important determinant of 6MWT distance than New York Heart Association classification. The 6MWT has not yet been proven to be a robust test for the identification of effective pharmacological interventions although it appears useful for the assessment of cardiac resynchronization therapy. The results of the 6MWT were concordant with changes in symptoms, suggesting that it may be used as supportive evidence for symptom benefit. The test may be of greater value in patients with more advanced heart failure, where it may function as a maximal exercise test.


Translation of a dementia caregiver support program in a health care system--REACH VA.
Based on the National Institute on Aging/National Institute of Nursing Research Resources for Enhancing Alzheimer's Caregiver Health (REACH) randomized controlled trial (REACH II), REACH VA (Department of Veterans Affairs) was the first national clinical translation of a proven behavioral intervention for dementia caregivers, running from September 2007 through August 2009. This article describes the population and outcomes of the REACH VA translation of REACH II into the VA. Clinical staff members from 24 VA Medical Center Home-Based Primary Care programs in 15 states delivered the intervention to stressed caregivers of patients with dementia. Like REACH II, the 6-month REACH VA intervention, structured through a protocol and individualized through a risk assessment, targeted education, support, and skills training to address caregiving risk areas of safety, social support, problem behaviors, depression, and health through 12 individual in-home and telephone sessions and 5 telephone support group sessions. Staff members of the Memphis VA Medical Center, Memphis, Tennessee, collected data on burden, depression, health and healthy behaviors, caregiving frustrations, social support, dementia-related behaviors, and time spent providing care and on duty. From baseline to 6 months, caregivers reported significantly decreased burden, depression, impact of depression on daily life, caregiving frustrations, and number of troubling dementia-related behaviors. A 2-hour decrease in hours per day on duty approached significance. Caregivers (96%) believed that the program should be provided by the VA to caregivers. This clinical translation achieved outcomes similar to the REACH II randomized controlled trial, providing clinically significant benefits for caregivers of a veteran with a progressive dementing disease. This model of caregiver support can inform public policy in providing assistance to caregivers.


Atezolizumab for the treatment of breast cancer.
Introduction: In March 2019, atezolizumab became the first immune checkpoint inhibitor to receive a breast cancer-specific approval. Based on a significant improvement in progression-free survival as well as a 10-month improvement in overall survival (on interim analysis) seen in the IMpassion 130 trial, the combination of atezolizumab and nab-paclitaxel was approved for patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC).Areas covered: This article reviews current data and ongoing research on atezolizumab for the treatment of breast cancer. Results of atezolizumab monotherapy trials in the context of other early immune checkpoint blockade trials in breast cancer are discussed as well as data from combination clinical trials with chemotherapy in both early-stage and metastatic breast cancer. We focus on the safety and efficacy analyses from the phase III IMpassion trial that led to FDA and EMA approval of atezolizumab and nab-paclitaxel in patients whose tumor tested positive for PD-L1 by the Ventana SP142 companion diagnostic immunohistochemical assay.Expert opinion: The FDA and EMA approvals of atezolizumab mark an important advance for treatment of metastatic TNBC. However, ongoing investigations need to define better biomarkers of response, determine resistance mechanisms, and identify strategies to increase response rates.


Salicylanilide Analog Minimizes Relapse of Clostridioides difficile Infection in Mice.
Clostridioides difficile infection (CDI) causes serious and sometimes fatal symptoms like diarrhea and pseudomembranous colitis. Although antibiotics for CDI exist, they are either expensive or cause recurrence of the infection due to their altering the colonic microbiota, which is necessary to suppress the infection. Here, we leverage a class of known membrane-targeting compounds that we previously showed to have broad inhibitory activity across multiple Clostridioides difficile strains while preserving the microbiome to develop an efficacious agent. A new series of salicylanilides was synthesized, and the most potent analog was selected through an in vitro inhibitory assay to evaluate its pharmacokinetic parameters and potency in a CDI mouse model. The results revealed reduced recurrence of CDI and diminished disturbance of the microbiota in mice compared to standard-of-care vancomycin, thus paving the way for novel therapy that can potentially target the cell membrane of C. difficile to minimize relapse in the recovering patient.


Measuring the association between artemisinin-based case management and malaria incidence in southern Vietnam, 1991-2010.
In addition to being effective, fast-acting, and well tolerated, artemisinin-based combination therapies (ACTs) are able to kill certain transmission stages of the malaria parasite. However, the population-level impacts of ACTs on reducing malaria transmission have been difficult to assess. In this study on the history of malaria control in Vietnam, we assemble annual reporting on malaria case counts, coverage with insecticide-treated nets (ITN) and indoor residual spraying (IRS), and drug purchases by provincial malaria control programs from 1991 to 2010 in Vietnam's 20 southern provinces. We observe a significant negative association between artemisinin use and malaria incidence, with a 10% absolute increase in the purchase proportion of artemisinin-containing regimens being associated with a 29.1% (95% confidence interval: 14.8-41.0%) reduction in slide-confirmed malaria incidence, after accounting for changes in urbanization, ITN/IRS coverage, and two indicators of health system capacity. One budget-related indicator of health system capacity was found to have a smaller association with malaria incidence, and no other significant factors were found. Our findings suggest that including an artemisinin component in malaria drug regimens was strongly associated with reduced malaria incidence in southern Vietnam, whereas changes in urbanization and coverage with ITN or IRS were not.


Domestic waste recycling, collective action and economic incentive: the case in Hong Kong.
Efficacy of waste recycling is one of the key determinants of environmental sustainability of a city. Like other pro-environmental activities, waste recycling cannot be successfully accomplished by just one or two people, but only by a concerted effort of the community. The collective-action dilemma creates a common underlying difficulty in formulating workable solutions to many environmental problems. With a view to the non-excludability of the outcome, rationality drives people to free-ride efforts of others in waste recycling. To solve this free-rider problem, some scholars suggest the use of economic incentive. This article attempts to study the impacts of reward schemes on waste recycling behaviour of residents in 122 private housing estates in Hong Kong. The study is differentiable from the others as the latter mainly focus on domestic waste recycling in low-rise low-density housing while this one looks into the same in a high-rise high-density residential setting. According to the results of analyses on a set of aggregate data, reward schemes are found to have a significant positive relationship with the per-household weight of recyclables collected, keeping other things constant. The research findings suggest that economic incentives do work in promoting waste recycling in Hong Kong. Practical and policy implications follow.


Freeze-Dried Watermelon Supplementation Has Modest Effects on Bone and Lipid Parameters of Ovariectomized Mice.
This study investigated the effects of two doses of freeze-dried watermelon (WM) on bone and lipid parameters in ovariectomized (OVX) mice, a model of post-menopausal osteoporosis. Three-month-old C57BL/6 female mice (n=46) were sham-operated (SHAM) or OVX and randomly assigned to the control or WM diets for 12 weeks: SHAM-control, OVX-control, OVX+1%, or 10% (wt/wt) freeze-dried WM. All diets were isocaloric and isonitrogenous, and had the same calcium and phosphorus concentrations. Freeze-dried WM supplementation was not able to prevent the decrease in whole body, tibial, and lumbar bone mineral density due to estrogen deficiency. Micro-computed tomography analyses showed that WM was also not able to modulate changes in tibial trabecular and cortical bone microarchitecture due to ovariectomy. However, the lumbar trabecular micro-architecture analyses revealed that the WM-10% group had a similar connectivity density, trabecular number, trabecular separation, and structure model index as the SHAM group. Supplementation with 10% WM reduced plasma cholesterol and total liver lipids to the level of the SHAM group but was still similar to that of the OVX-control group. Supplementation with 10% WM increased liver catalase (CAT) mRNA levels but had no effects on mRNA levels of glutathione peroxidase (GPX) and the pro-inflammatory cytokine interleukin-6. There were no differences in plasma activity of the antioxidant enzymes GPX and CAT between all treatment groups. Our findings demonstrate some positive effects of watermelon for modulating lipids and attenuating lumbar vertebral bone loss arising from ovarian hormone deficiency.


Gene expression, proteome and calcium signaling alterations in immortalized hippocampal astrocytes from an Alzheimer's disease mouse model.
Evidence is rapidly growing regarding a role of astroglial cells in the pathogenesis of Alzheimer's disease (AD), and the hippocampus is one of the important brain regions affected in AD. While primary astroglial cultures, both from wild-type mice and from rodent models of AD, have been useful for studying astrocyte-specific alterations, the limited cell number and short primary culture lifetime have limited the use of primary hippocampal astrocytes. To overcome these limitations, we have now established immortalized astroglial cell lines from the hippocampus of 3xTg-AD and wild-type control mice (3Tg-iAstro and WT-iAstro, respectively). Both 3Tg-iAstro and WT-iAstro maintain an astroglial phenotype and markers (glutamine synthetase, aldehyde dehydrogenase 1 family member L1 and aquaporin-4) but display proliferative potential until at least passage 25. Furthermore, these cell lines maintain the potassium inward rectifying (Kir) current and present transcriptional and proteomic profiles compatible with primary astrocytes. Importantly, differences between the 3Tg-iAstro and WT-iAstro cell lines in terms of calcium signaling and in terms of transcriptional changes can be re-conducted to the changes previously reported in primary astroglial cells. To illustrate the versatility of this model we performed shotgun mass spectrometry proteomic analysis and found that proteins related to RNA binding and ribosome are differentially expressed in 3Tg-iAstro vs WT-iAstro. In summary, we present here immortalized hippocampal astrocytes from WT and 3xTg-AD mice that might be a useful model to speed up research on the role of astrocytes in AD.


Prostaglandin E2 (PGE2)-dependent suppression of interleukin alpha (IL-2) production in patients with major trauma.
The depression of interleukin-2 synthesis represents a major dysfunction within the cascade of immunologic defects induced by mechanical and thermal trauma. This study was undertaken to elucidate the negative control mechanisms that were responsible for the deficiency of IL-2 production in polytraumatized patients. Peripheral blood mononuclear cells (PBMC's) from 29 patients (average age, 35.8 years; average ISS, 35) were separated on post-trauma days 1, 3, 5, 7, 10, 14, and 21 and cultured as untreated cells (C), cells treated with indomethacin (C + INDO), and cells depleted of adherent cells (C-AC). Cell cultures were assayed for proliferative responses to PHA, IL-2 synthesis, PGE2 production, gamma-interferon levels, and phenotyping studies. On all days post-trauma there was found a marked reduction of IL-2 production compared to controls with a highly significant nadir from day 5 to day 10 with an almost 80% inhibition of IL-2 (p less than 0.005). C + INDO cells showed increases of IL-2 synthesis over untreated cells ranging from 48% (Day 1) to 220% (Day 7). Removal of adherent cells (C-AC) did not reverse the suppression of IL-2 production. gamma-interferon levels were depressed in parallel with IL-2 levels but did not increase with C + INDO. The phenotyping of the PBMC's showed highly significant suppression of OKT3+, OKT4+, and IL-2R+ lymphocytes as well as a highly significant elevation of the monocyte (p less than 0.005) count. There was a highly significant increase of PGE2 synthesis from monocytes, due to the monocytosis and to a higher capacity of synthesis of the individual cells following trauma. PGE2 levels peaked on Day 5 and 7 post-trauma at 400% of control (p less than 0.005). These data suggest that the suppression of IL-2 synthesis post trauma is caused mainly by two factors: the excessive PGE2 output of inhibitory monocytes and inadequate function in immature and/or blocked lymphocytes. The partial restoration of IL-2 synthesis by indomethacin suggests that blockade of the cyclo-oxygenase pathway as an immunomodulating therapy may reverse some of the immunologic abnormalities in multiple trauma patients.


Using magnetic resonance imaging and diffusion tensor imaging to assess brain damage in alcoholics.
Brain imaging using conventional magnetic resonance imaging (MRI) has revealed that several brain structures in people with a history of chronic alcohol dependence are smaller in volume than the same brain structures in nonalcoholic control subjects. Areas that are particularly affected are the frontal lobes, which are involved in reasoning, judgment, and problem solving. Older people are especially vulnerable to the damaging effects of alcohol. It is unclear whether women show consistently more vulnerability to these changes in the brain than men do. In general, alcoholics evaluated before and after a period of abstinence show some recovery of tissue volume, whereas alcoholics evaluated again after continued drinking show further reductions in brain tissue volume. A new MR technique called diffusion tensor imaging (DTI) can aid in detecting the degradation of fibers (i.e., white matter) that carry information between brain cells (i.e., gray matter). With DTI, researchers studying alcoholics have been able to detect abnormalities in white matter not visible with conventional MRI. Ultimately DTI may be useful in elucidating the mechanisms that underlie macrostructural and functional brain changes seen with abstinence and relapse.


Protocol design for large-scale cross-sectional studies of sexual abuse and associated factors in individual sports: feasibility study in Swedish athletics.
To ensure health and well-being for their athletes, sports organizations must offer preventive measures against sexual abuse. The aim of this study was to design and evaluate feasibility of a research protocol for cross-sectional epidemiological studies of sexual abuse in athletics. Examination of the requirements on the study of sexual abuse in athletics was followed by iterated drafting of protocol specifications and formative evaluations. The feasibility of the resulting protocol was evaluated in a national-level study among elite athletics athletes (n = 507) in Sweden. The definition of sexual abuse, the ethical soundness of the protocol, reference populations and study of co-morbidity, and the means for athlete-level data collection were identified as particularly complex issues in the requirements analyses. The web-based survey defined by the protocol facilitates anonymous athlete self-reporting of data on exposure to sexual abuse. 198 athletes (39%) fully completed the feasibility survey. 89% (n = 177) reported that they agreed with that the questions in the survey were important, and 95% (n = 189) reported that they answered truthfully to all questions. Similarly, 91% (n = 180) reported that they did not agree with that the questions were unpleasant for them. However, 16% (n = 32) reported that they did not find the survey to be of personal value, and 12% (n = 23) reported that the survey had caused them to think about issues that they did not want to think about. Responding that participation was not personally gratifying was associated with training more hours (p = 0.01). There is a scarcity of research on the prevention of sexual abuse in individual sports. The present protocol should be regarded as a means to overcome this shortcoming in athletics. When implementing the protocol, it is necessary to encourage athlete compliance and to adapt the web-based survey to the particular infrastructural conditions in the sports setting at hand. Key pointsA research protocol for cross-sectional epidemiological studies of sexual abuse in athletics was designed and its feasibility evaluated.The definition of sexual abuse, ethical soundness of the protocol, reference populations and study of co-morbidity, and means for athlete-level data collection were in requirements analyses identified as particularly complex design issues.The feasibility evaluation showed a high non-participation rate (61%), but also that the large majority of participants found the study important and that questions were answered truthfully.Responding that partaking in the study was not personally gratifying was associated with training more hours.When implementing cross-sectional epidemiological studies of sexual abuse in athletics, it is necessary to promote and facilitate athlete participation.


Differential regulation of Na+/H+ exchange isoform activities by enteropathogenic E. coli in human intestinal epithelial cells.
Enteropathogenic Escherichia coli (EPEC) is an important human intestinal foodborne pathogen associated with diarrhea, especially in infants and young children. Although EPEC produces characteristic attaching and effacing lesions and loss of microvilli, the pathophysiology of EPEC-associated diarrhea, particularly during early infection, remains elusive. The present studies were designed to examine the direct effects of EPEC infection on intestinal absorption via Na(+)/H(+) exchanger (NHE) isoforms. Caco-2 cells were infected with EPEC strain E2348/69 or nonpathogenic E. coli HB101 for a period of 60 to 120 min. Total NHE activity was significantly increased at 60 min, reaching approximately threefold increase after 90 min of EPEC infection. Similar findings were seen in HT-29 cells and T84 cells indicating that the response was not cell-line specific. Most surprising was the differential regulation of NHE2 and NHE3 by EPEC. Marked activation of NHE2 (300%) occurred, whereas significant inhibition ( approximately 50%) of NHE3 activity was induced. The activity of basolateral isoform NHE1 was also significantly increased in response to EPEC infection. Mutations that disrupted the type III secretion system (TTSS) ablated the effect of EPEC on the activity of both NHE2 and NHE3. These results suggest that EPEC, through a TTSS-dependent mechanism, exerts differential effects on NHE isoform activity in intestinal epithelial cells. Additionally, NHEs do not appear to play any role in EPEC-mediated inflammation, because the NHE inhibitors amiloride and 5-(N-ethyl-N-isopropyl)amiloride did not prevent EPEC-mediated IkappaBalpha degradation.


Isolation and characterization of patatin isoforms.
Patatin has, so far, been considered a homogeneous group of proteins. A comparison of the isoforms in terms of structural properties or stability has not been reported. A method to obtain various isoform fractions as well as a comparison of the physicochemical properties of these pools is presented. Patatin could be separated in four isoform pools, denoted A, B, C, and D, representing 62%, 26%, 5%, and 7% of the total amount of patatin, respectively. These isoforms differed in surface charge, resulting in a different behavior on anion exchange chromatography, isoelectric focusing, native polyacrylamide gel, and capillary electrophoresis. All isoforms of the patatin family contained proteins with two molecular masses of approximately 40.3 and 41.6 kDa, respectively. The size of this difference in the molar mass (1300 Da) is on the order of one carbohydrate moiety. Despite the biochemical differences given above, no variations in the structural properties nor in the thermal conformational stability could be observed using far-ultraviolet circular dichroism, infrared, and fluorescence spectroscopy.


The Ohsaki Cohort 2006 Study: design of study and profile of participants at baseline.
Large-scale cohort studies conducted in Japan do not always include psychosocial factors as exposures. In addition, such studies sometimes fail to satisfactorily evaluate disability status as an outcome. This prospective cohort study comprised 49 603 (22 438 men and 27 165 women) community-dwelling adults aged 40 years or older who were included in the Residential Registry for Ohsaki City, Miyagi Prefecture, in northeastern Japan. The baseline survey, which included psychosocial factors, was conducted in December 2006. Follow-up of death, immigration, cause of death, cancer incidence, and long-term care insurance certification was started on 1 January 2007. The response rate was 64.2%. In general, lifestyle-related conditions in the study population were similar to those of the general Japanese population; however, the proportion of male current smokers was higher in the cohort. The association between age and the proportion of those reporting psychological distress showed a clear U-shaped curve, with a nadir at age 60 to 69 years in both men and women, although more women were affected by such distress than men. The proportion of those who reported a lack of social support was highest among those aged 40 to 49 years. Most men and women surveyed did not participate in community activities. Among participants aged 65 years or older, 10.9% of participants were certified beneficiaries of the long-term care insurance system at baseline. The Ohsaki Cohort 2006 Study is a novel population-based prospective cohort study that focuses on psychosocial factors and long-term care insurance certification.


Neuroprotection in progressive brain disorders.
Progressive neurodegenerative disorders share common mechanisms of cell death, and in all likelihood multiple factors are involved in every disease. Therefore, several neuroprotective agents are being investigated with the purpose of slowing or preventing further deterioration of cell loss. These include experimental animal and clinical studies on the neuroprotective effects of caspase inhibitors, antioxidants, glutamate antagonists, anti-inflammatory agents and trophic factors in several neurodegenerative diseases. At present there is limited clinical evidence for direct neuroprotective effects against these diseases, but much effort is being invested in research on novel technologies and compounds.


Residential preferences and population redistribution: 1972-1988.
In seeking to explain recent trends in population distribution, there has been increased interest in residential preferences. This study is a comparison of preferences based on 1972 and 1988 national surveys, years that bracket a period of considerable change in distribution patterns. Over time there has been a small shift in preference toward cities less than 500,000 in size, primarily by those already living there. Rural settings, especially near cities, continue to be very attractive. At both times studied, more than half of those preferring a smaller or more remote place would retain this preference even if it meant 10% less income. Nevertheless, the proportion preferring to live more than 30 miles from a large city was unchanged and approximately equal to the proportion already living there at both times, indicating that a discrepancy between where people live and where they want to live is not an important basis for the upturn in nonmetropolitan growth away from large cities in the 1970s or the downturn in the 1980s.


Decoding a Complex Visualization in a Science Museum - An Empirical Study.
This study describes a detailed analysis of museum visitors' decoding process as they used a visualization designed to support exploration of a large, complex dataset. Quantitative and qualitative analyses revealed that it took, on average, 43 seconds for visitors to decode enough of the visualization to see patterns and relationships in the underlying data represented, and 54 seconds to arrive at their first correct data interpretation. Furthermore, visitors decoded throughout and not only upon initial use of the visualization. The study analyzed think-aloud data to identify issues visitors had mapping the visual representations to their intended referents, examine why they occurred, and consider if and how these decoding issues were resolved. The paper also describes how multiple visual encodings both helped and hindered decoding and concludes with implications on the design and adaptation of visualizations for informal science learning venues.


General distress is more important than PTSD's cognition and mood alterations factor in accounting for PTSD and depression's comorbidity.
Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are highly comorbid and exhibit strong correlations with each other at both the symptom level and latent factor level. Various theories have attempted to explain this relationship. Results have been inconsistent regarding whether PTSD's negative alterations in cognition and mood factor (NACM) is significantly more related to depression, in contrast to other factors of PTSD. Confirmatory factor analysis was used to attempt to address the relationships between PTSD and MDD in a large sample of trauma-exposed combat veterans from the Ohio National Guard as part of a larger longitudinal study. Confirmatory factor analysis was used to test a bifactor model of PTSD symptoms, testing relations between PTSD's factors and a latent depressive factor. After partitioning out the common variance into the bifactor, we found that in contrast to other PTSD factors, PTSD's NACM factor was not significantly more related to depression. Instead, only the general bifactor predicted depressive symptoms. The limitations of the present study include the following: the specific measures of PTSD and MDD used were based on self-report, and the sample consisted of non-clinical, non-treatment seeking veterans. The present study suggests that the high rate of comorbidity between posttraumatic stress disorder (PTSD) and major depressive disorder is more related to underlying general distress or negative affectivity than the symptom categories of the PTSD diagnostic criteria.


Non-pharmaceutical strategies win coronavirus disease 2019 battle in New Zealand.
This literature-based article found that on 08 June 2020, New Zealand claimed victory over coronavirus disease 2019 (COVID-19) mainly because of effective non-pharmaceutical strategies and interventions that included a hard lockdown. The response was informed by the country's Influenza Pandemic Plan (although without criticism), which was updated in 2017, and the swift responses from political leadership and other key stakeholders. Strategies instituted included the proclamation of urgent precautionary measures leading to border closures, issuing of a 3-month-long COVID-19 notice under the Epidemic Preparedness Act 2006, the proclamation of the COVID-19 Elimination Strategy and the Initial COVID-19 Māori Response Action Plan, which incorporated COVID-19 Alert Levels that facilitated stepwise easing of the hard lockdown. The non-pharmaceutical strategies seem to have worked again, even as the second wave of COVID-19 infections returned in August 2020 through an Auckland cluster. Hence, the New Zealand case remains one that the world can draw lessons from, although not perfect.


Craniofacial surgical resection: new frontier in advanced head and neck cancer.
Craniofacial surgery has revolutionized the management of extensive malignancies and histologically benign but locally invasive tumours which encroach upon or directly invade the undersurface of the brain case. Approaches have been devised for tumours that involve the anterior middle and posterior fossae. Teamwork between head and neck and neurological surgeons is essential. Comprehensive pre-operative evaluation, especially the adequacy of cross-fill of the cerebral circulation via the contralateral arterial system through the circle of Willis, must be done. Management of the internal carotid artery and cavernous sinus presents the most difficult surgical problems during the resection. During the closure, separation of the intracranial dissection from the paranasal sinuses and epipharynx by the use of flaps and grafts is essential to prevent cerebrospinal fluid leakage, cerebral support, and isolation of the carotid and dura from upper respiratory tract organisms. Well-planned and executed craniofacial surgery can be done with acceptable morbidity and mortality rates and reasonable survival rates.


Redox Modification of the Iron-Sulfur Glutaredoxin GRXS17 Activates Holdase Activity and Protects Plants from Heat Stress.
Heat stress induces misfolding and aggregation of proteins unless they are guarded by chaperone systems. Here, we examined the function of the glutaredoxin GRXS17, a member of thiol reductase families in the model plant Arabidopsis (Arabidopsis thaliana). GRXS17 is a nucleocytosolic monothiol glutaredoxin consisting of an N-terminal thioredoxin domain and three CGFS active-site motif-containing GRX domains that coordinate three iron-sulfur (Fe-S) clusters in a glutathione-dependent manner. As an Fe-S cluster-charged holoenzyme, GRXS17 is likely involved in the maturation of cytosolic and nuclear Fe-S proteins. In addition to its role in cluster biogenesis, GRXS17 presented both foldase and redox-dependent holdase activities. Oxidative stress in combination with heat stress induced loss of its Fe-S clusters followed by subsequent formation of disulfide bonds between conserved active-site cysteines in the corresponding thioredoxin domains. This oxidation led to a shift of GRXS17 to a high-molecular-weight complex and thus activated its holdase activity in vitro. Moreover, GRXS17 was specifically involved in plant tolerance to moderate high temperature and protected root meristematic cells from heat-induced cell death. Finally, GRXS17 interacted with a different set of proteins upon heat stress, possibly protecting them from heat injuries. Therefore, we propose that the Fe-S cluster enzyme GRXS17 is an essential guard that protects proteins against moderate heat stress, likely through a redox-dependent chaperone activity. We reveal the mechanism of an Fe-S cluster-dependent activity shift that converts the holoenzyme GRXS17 into a holdase, thereby preventing damage caused by heat stress.


A calcium antagonist drug binding site in skeletal muscle sarcoplasmic reticulum: evidence for a calcium channel.
The sarcoplasmic reticulum (S.R.) of rabbit skeletal muscle has been found to contain a single, high affinity binding site for the Ca antagonist drug [3H]-nitrendipine. Two subfractions of the reticulum were studied, the heavy (HSR) and light (LSR) preparations, which exhibited similar nitrendipine equilibrium dissociation constants (KD) of 1nM. Crude cardiac and brain membranes assayed under the same conditions exhibited KD values of 0.2-0.3nM. The concentration of binding sites per mg. protein (Bmax) in HSR was found to be very high, namely 6.7 picomoles/mg, some four times greater than that of LSR. [3H]-nitrendipine binding to HSR was reversible and inhibited by the Ca antagonists flunarizine and verapamil, and by the intracellular Ca release antagonist TMB-8 (8-diethylamino-octyl 3,4,5-trimethylbenzoate hydrochloride). However, unlabelled nitrendipine at 2 X 10(-5)M had no effect on contraction of isolated electrically stimulated rabbit lumbrical or rat diaphragm muscles, nor did it affect the neuromuscular junction as studied in rat phrenic nerve-diaphragm preparations. Also, little effect of 2 X 10(-5)M nitrendipine was seen on net 45Ca uptake by HSR. These results suggest that [3H]-nitrendipine binding to skeletal muscle S.R. resembles that of brain membranes, which also contain a high affinity binding site for [3H]-nitrendipine and which similarly are pharmacologically insensitive to this dihydropyridine type of Ca channel blocking agent. Since HSR is also enriched in calsequestrin and terminal cysternae from which Ca is released in vivo, it seems likely that the [3H]-nitrendipine binding sites in S.R. are associated with Ca channels in the S.R.


Antisperm antibodies: invaluable tools toward the identification of sperm proteins involved in fertilization.
The identification of sperm proteins involved in fertilization has been the subject of numerous investigations. Much interest has been dedicated to naturally occurring antisperm antibodies (ASA) and their impact in fertility. Their presence in men and women has been associated with 2-50% of infertility cases. ASA may impair pre- and post-fertilization steps. Experimental models have been developed using sperm proteins as immunogens to evaluate their involvement in sperm function. Our team has pursued investigations to assess ASA presence in biological fluids from patients consulting for infertility and their effect on fertilization. We found ASA in follicular fluids with ability of inducing the acrosome reaction and blocking sperm-zona pellucida interaction and used them to identify sperm entities involved in these events. We generated and utilized antibodies against proacrosin/acrosin to characterize the sperm protease system. We implemented an ELISA to detect proacrosin/acrosin antibodies in human sera and evaluated their impact upon fertility by developing in vitro assays and a gene immunization model. This review presents a summary of ASA history, etiology, current approaches for detection and effects upon fertility. ASA (naturally occurring, generated by animal immunization and/or of commercial origin) are invaluable tools to understand the molecular basis of fertilization, better diagnose/treat immunoinfertility and develop immunocontraceptive methods.


ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria.
1. Mitochondrial dysfunction, secondary to excessive accumulation of Ca2+, has been implicated in cardiac injury. We here examined the action of potassium channel openers on mitochondrial Ca2+ homeostasis, as these cardioprotective ion channel modulators have recently been shown to target a mitochondrial ATP-sensitive K+ channel. 2. In isolated cardiac mitochondria, diazoxide and pinacidil decreased the rate and magnitude of Ca2+ uptake into the mitochondrial matrix with an IC50 of 65 and 128 microM, respectively. At all stages of Ca2+ uptake, the potassium channel openers depolarized the mitochondrial membrane thereby reducing Ca2+ influx through the potential-dependent mitochondrial uniporter. 3. Diazoxide and pinacidil, in a concentration-dependent manner, also activated release of Ca2+ from mitochondria. This was prevented by cyclosporin A, an inhibitor of Ca2+ release through the mitochondrial permeability transition pore. 4. Replacement of extramitochondrial K+ with mannitol abolished the effects of diazoxide and pinacidil on mitochondrial Ca2+, while the K+ ionophore valinomycin mimicked the effects of the potassium channel openers. 5. ATP and ADP, which block K+ flux through mitochondrial ATP-sensitive K+ channels, inhibited the effects of potassium channel openers, without preventing the action of valinomycin. 6. In intact cardiomyocytes, diazoxide also induced mitochondrial depolarization and decreased mitochondrial Ca2+ content. These effects were inhibited by the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoic acid. 7. Thus, potassium channel openers prevent mitochondrial Ca2+ overload by reducing the driving force for Ca2+ uptake and by activating cyclosporin-sensitive Ca2+ release. In this regard, modulators of an ATP-sensitive mitochondrial K+ conductance may contribute to the maintenance of mitochondrial Ca2+ homeostasis.


An integrated approach is needed for ecosystem based fisheries management: insights from ecosystem-level management strategy evaluation.
An ecosystem approach is widely seen as a desirable goal for fisheries management but there is little consensus on what strategies or measures are needed to achieve it. Management strategy evaluation (MSE) is a tool that has been widely used to develop and test single species fisheries management strategies and is now being extended to support ecosystem based fisheries management (EBFM). We describe the application of MSE to investigate alternative strategies for achieving EBFM goals for a complex multispecies fishery in southeastern Australia. The study was undertaken as part of a stakeholder driven process to review and improve the ecological, economic and social performance of the fishery. An integrated management strategy, involving combinations of measures including quotas, gear controls and spatial management, performed best against a wide range of objectives and this strategy was subsequently adopted in the fishery, leading to marked improvements in performance. Although particular to one fishery, the conclusion that an integrated package of measures outperforms single focus measures we argue is likely to apply widely in fisheries that aim to achieve EBFM goals.


A mathematical model describing the generation of oxygen radicals in mitochondria during ischemia-reperfusion.
A mathematical model for the generation of free radicals by mitochondria in ischemia-reperfusion is proposed. Computations show that normally two stable equilibrium states exist: the intact state, and the state characterized by damage to mitochondrial structures and a high rate of radical formation. Transition from one state to another occurs after hypoxia of a certain degree of severity and duration. The model also describes a number of phenomena observed during development of reperfusion injuries and drug therapy.


A deleterious mutation in the LOXHD1 gene causes autosomal recessive hearing loss in Ashkenazi Jews.
Autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL) in Ashkenazi Jews, is mainly caused by mutations in the GJB2 and GJB6 genes. Here we describe a novel homozygous mutation of the LOXHD1 gene resulting in a premature stop codon (R1572X) in nine patients of Ashkenazi Jewish origin who had severe-profound congenital non-progressive ARNSHL and benefited from cochlear implants. Upon screening for the mutation among 719 anonymous Ashkenazi-Jews we detected four carriers, indicating a carrier rate of 1:180 Ashkenazi Jews. This is the second reported mutation in the LOXHD1 gene, and its homozygous presence in two of 39 Ashkenazi Jewish families with congenital ARNSHL suggest that it could account for some 5% of the familial cases in this community.


Cystadenoma with mesenchymal stroma (CMS) in the liver and bile ducts. A clinicopathologic study of 17 cases, 4 with malignant change.
This study of 17 cases describes a homogeneous clinicopathologic group of tumors previously subsumed under the general term, hepatobiliary cystadenoma. This unique group of neoplasms that the authors have termed "cystadenoma with mesenchymal stroma" (CMS), occurred exclusively in women and showed two essential tumor components: a cyst lining of columnar to cuboidal, mucin secreting epithelium; and a moderately to densely cellular stroma composed of spindle (rarely oval) cells. The stromal element appeared similar to primitive mesenchyme, both on light and electron microscopic study, showing variable differentiation toward fibroblasts, smooth muscle, adipose tissue and capillaries. Cases of hepatobiliary "cystadenoma" in the literature with histology similar to CMS had similar sex and age incidences, while histologically dissimilar cases, lacking the mesenchymal stroma, had significantly different parameters. Four cases of CMS in this series showed malignant change that was manifested as papillary adenocarcinoma, suggesting the need for complete surgical removal of these premalignant neoplasms.


Second-order analysis of semiparametric recurrent event processes.
A typical recurrent event dataset consists of an often large number of recurrent event processes, each of which contains multiple event times observed from an individual during a follow-up period. Such data have become increasingly available in medical and epidemiological studies. In this article, we introduce novel procedures to conduct second-order analysis for a flexible class of semiparametric recurrent event processes. Such an analysis can provide useful information regarding the dependence structure within each recurrent event process. Specifically, we will use the proposed procedures to test whether the individual recurrent event processes are all Poisson processes and to suggest sensible alternative models for them if they are not. We apply these procedures to a well-known recurrent event dataset on chronic granulomatous disease and an epidemiological dataset on meningococcal disease cases in Merseyside, United Kingdom to illustrate their practical value.


What work has to be done to implement collaborative care for depression? Process evaluation of a trial utilizing the Normalization Process Model.
There is a considerable evidence base for 'collaborative care' as a method to improve quality of care for depression, but an acknowledged gap between efficacy and implementation. This study utilises the Normalisation Process Model (NPM) to inform the process of implementation of collaborative care in both a future full-scale trial, and the wider health economy. Application of the NPM to qualitative data collected in both focus groups and one-to-one interviews before and after an exploratory randomised controlled trial of a collaborative model of care for depression. Findings are presented as they relate to the four factors of the NPM (interactional workability, relational integration, skill-set workability, and contextual integration) and a number of necessary tasks are identified. Using the model, it was possible to observe that predictions about necessary work to implement collaborative care that could be made from analysis of the pre-trial data relating to the four different factors of the NPM were indeed borne out in the post-trial data. However, additional insights were gained from the post-trial interview participants who, unlike those interviewed before the trial, had direct experience of a novel intervention. The professional freedom enjoyed by more senior mental health workers may work both for and against normalisation of collaborative care as those who wish to adopt new ways of working have the freedom to change their practice but are not obliged to do so. The NPM provides a useful structure for both guiding and analysing the process by which an intervention is optimized for testing in a larger scale trial or for subsequent full-scale implementation.


Contractile properties of muscles used in sound production and locomotion in two species of gray tree frog.
The sound-producing muscles of frogs and toads are interesting because they have been selected to produce high-power outputs at high frequencies. The two North American species of gray tree frog, Hyla chrysoscelis and Hyla versicolor, are a diploid-tetraploid species pair. They are morphologically identical, but differ in the structure of their advertisement calls. H. chrysoscelis produces very loud pulsed calls by contracting its calling muscles at approximately 40 Hz at 20 degrees C, whereas, H. versicolor operates the homologous muscles at approximately 20 Hz at this temperature. This study examined the matching of the intrinsic contractile properties of the calling muscles to their frequency of use. I measured the isotonic and isometric contractile properties of two calling muscles, the laryngeal dilator, which presumably has a role in modulating call structure, and the external oblique, which is one of the muscles that provides the mechanical power for calling. I also examined the properties of the sartorius as a representative locomotor muscle. The calling muscles differ greatly in twitch kinetics between the two species. The calling muscles of H. chrysoscelis reach peak tension in a twitch after approximately 15 ms, compared with 25 ms for the same muscles in H. versicolor. The muscles also differ significantly in isotonic properties in the direction predicted from their calling frequencies. However, the maximum shortening velocities of the calling muscles of H. versicolor are only slightly lower than those of the comparable muscles of H. chrysoscelis. The calling muscles have similar maximum shortening velocities to the sartorius, but have much flatter force-velocity curves, which may be an adaptation to their role in cyclical power output. I conclude that twitch properties have been modified more by selection than have intrinsic shortening velocities. This difference corresponds to the differing roles of shortening velocity and twitch kinetics in determining power output at differing frequencies.


Common swine leucocyte antigen (SLA) haplotypes in NIH and Sinclair miniature swine have similar effects on the expression of an inherited melanoma.
Mixed lymphocyte culture and serological typing of NIH and Sinclair miniature swine indicate that the two herds share a common SLA haplotype. NIH haplotype a (International Haplotype H10) appears identical to Sinclair haplotype B, which has significant effects on the penetrance of Sinclair swine cutaneous malignant melanoma (SSCM). Offspring of crosses between melanoma-bearing Sinclair swine homozygous for the B haplotype and non-melanoma NIH aa swine have tumour incidence identical to Sinclair melanoma BB x Sinclair non-melanoma BB offspring. Our results provide further support for the involvement of the swine leucocyte antigen (SLA) complex in the inheritance of SSCM, and identify a new source of non-tumour animals that have all of the genes for SSCM except those at the tumour-initiator locus.


Water skating in the larvae of dixella aestivalis (Diptera) and hydrobius fuscipes (Coleoptera)
The kinematics of locomotion was investigated in the aquatic larvae of Dixella aestivalis and Hydrobius fuscipes with the aid of high-speed video recordings. Both insects are able to skate on the surface of the water using the dorso-apical tracheal gill as an adhesive organ or 'foot'. Progress relies on the variable adhesion of the foot between 'slide' and 'hold' periods of the locomotory cycle. The flexural body movements underlying skating in D. aestivalis can be derived directly from the figure-of-eight swimming mechanism used in underwater swimming. The latter is shown to be similar to figure-of-eight swimming in chironomid larvae. This study shows how the deployment of a 'foot' enables simple side-to-side flexural movements of the body to be converted into effective locomotion at the air-water interface.


Lectin typing of Campylobacter isolates.
Isolates of Campylobacter jejuni, C coli, C fetus and C laridis were tested for agglutination reactions with a panel of five lectins: Arachis hypogaea, Bauhinia purpurea, Solanum tuberosum, Triticum vulgaris and Wisteria floribunda. Twenty three patterns of agglutination (lectin types) were recorded among 376 isolates. Patterns were consistent and reproducible. Only 4.5% of isolates were untypable because of autoagglutination. Some lectin types were found exclusively or predominantly in a species, but others were shared between species. Forty two per cent of C jejuni and 35% of C coli isolates belonged to lectin type 4. There was no apparent correlation between lectin type and serotype; different lectin types were found among strains of single Penner and Lior serotypes. Lectin typing is a simple and economical procedure suitable for use in non-specialist laboratories, either as an adjunct to serogrouping or, after further development, as a sole typing scheme.


Researching a differential impairment of frontal functions and explicit memory in early Parkinson's disease.
An impairment at tasks sensitive to frontal lobe damage has been repeatedly reported in Parkinson's disease, but the exact nature of these deficits has not yet been clarified. Similarly, deficits of visuo-spatial functions have been frequently observed, but it is still debated whether verbal and visuo-spatial memory can be differentially affected. In this study we have compared the performance of 20 mild Parkinson's disease patients (I-II Hoehn and Yahr stage) and 18 matched normal controls, at tasks assessing frontal functions and explicit memory. We detected a selective deficit in set shifting and maintaining, without impairment in categorization and set formation. The lack of a selective increase in perseverative errors might indicate that perseverations either measure something different from set shifting or that they do not represent an index sensitive enough to set shifting impairment. Parkinson's disease patients were also significantly impaired at Raven's Progressive Matrices, a task assessing both frontal and visuo-spatial aspects. However, they did not show any differential impairment of visuo-spatial memory. Indeed, despite a trend of lower performance in visuo-spatial learning, memory performance of Parkinson's disease patients was significantly different from that of controls only at a free recall test which involved both verbal and visuo-spatial memory. We suggest the exploration of set shifting and maintaining to detect 'frontal' deficits in mild Parkinson's disease. We argue that Raven's Progressive Matrices is a valuable task for detecting subclinical cognitive deficits in Parkinson's disease, even if it does not show a specific profile of impairment in these patients. According to our results, a differential evaluation of verbal vs. visuo-spatial memory is not necessary in clinical practice, whilst free recall confirms its usefulness to detect subclinical impairments of memory functions.


Remote symptom monitoring integrated into electronic health records: A systematic review.
People with long-term conditions require serial clinical assessments. Digital patient-reported symptoms collected between visits can inform these, especially if integrated into electronic health records (EHRs) and clinical workflows. This systematic review identified and summarized EHR-integrated systems to remotely collect patient-reported symptoms and examined their anticipated and realized benefits in long-term conditions. We searched Medline, Web of Science, and Embase. Inclusion criteria were symptom reporting systems in adults with long-term conditions; data integrated into the EHR; data collection outside of clinic; data used in clinical care. We synthesized data thematically. Benefits were assessed against a list of outcome indicators. We critically appraised studies using the Mixed Methods Appraisal Tool. We included 12 studies representing 10 systems. Seven were in oncology. Systems were technically and functionally heterogeneous, with the majority being fully integrated (data viewable in the EHR). Half of the systems enabled regular symptom tracking between visits. We identified 3 symptom report-guided clinical workflows: Consultation-only (data used during consultation, n = 5), alert-based (real-time alerts for providers, n = 4) and patient-initiated visits (n = 1). Few author-described anticipated benefits, primarily to improve communication and resultant health outcomes, were realized based on the study results, and were only supported by evidence from early-stage qualitative studies. Studies were primarily feasibility and pilot studies of acceptable quality. EHR-integrated remote symptom monitoring is possible, but there are few published efforts to inform development of these systems. Currently there is limited evidence that this improves care and outcomes, warranting future robust, quantitative studies of efficacy and effectiveness.


High beta diversity of bacteria in the shallow terrestrial subsurface.
While there have been a vast number of studies on bacterial alpha diversity in the shallow terrestrial subsurface, beta diversity - how the bacterial community composition changes with spatial distance - has received surprisingly limited attention. Here, bacterial beta diversity and its controlling factors are investigated by denaturing gradient gel electrophoresis and cloning of samples from a 700-cm-long sediment core, the lower half of which consisted of marine-originated sediments. According to canonical correspondence analysis with variation partitioning, contemporary environmental variables explain beta diversity in a greater proportion than depth. However, we also found that community similarity decayed significantly with spatial distance and the slopes of the distance-decay relationships are relatively high. The high beta diversity indicates that the bacterial distribution patterns are not only controlled by contemporary environments, but also related to historical events, that is, dispersal or depositional history. This is highlighted by the different beta diversity patterns among studied sediment layers. We thus conclude that the high beta diversity in the shallow terrestrial subsurface is a trade-off between historical events and environmental heterogeneity. Furthermore, we suggest that the high beta diversity of bacteria is likely to be recapitulated in other terrestrial sites because of the great frequency of high geochemical and/or historical variations along depth.


Site of digestion and milk production by cows fed fats differing in saturation, esterification, and chain length.
Four cannulated cows in a 4 x 4 Latin square design were used to study the effects of supplemental dietary fatty acids from roasted soybeans combined with tallow or partially hydrogenated fats, varying in esterification and fatty acid chain length, on nutrient digestion and lactation performance. Diets were formulated to contain (DM basis) 48% forage in addition to 1.5% fatty acids from roasted soybeans and 2.5% fatty acids from tallow, partially hydrogenated tallow triglycerides, partially hydrogenated tallow fatty acids, or a blend of 30% tallow and 70% hydrogenated fatty acids that were rich in palmitic acid. Apparent total tract digestibilities of OM, N, and NDF were similar among diets. Supplemental fat as fatty acids, compared with triglycerides, increased digestibilities of total fatty acids and C18:1 in the small intestine, perhaps indicating that lipolysis was rate-limiting. Fatty acids also increased milk fat percentage and efficiency of 4% FCM production. Although intake of C16 fatty acids was higher for cows fed the fat rich in palmitic acid than for those fed the tallow fatty acids, total duodenal flows of C16 fatty acids were similar, and digestibility in the small intestine was unaffected. Dry matter intake, 4% FCM production, and milk protein percentage were similar among treatments.


Association between Protein-Bound Uremic Toxins and Asymptomatic Cardiac Dysfunction in Patients with Chronic Kidney Disease.
Although the relationship between protein-bound uremic toxins (PBUTs) and cardiac structure and cardiac mortality in chronic kidney disease (CKD) has been studied in the past, the association between cardiac dysfunction and PBUTs has not yet been studied. We therefore evaluated the association between impaired peak cardiac performance and the serum free and total concentrations of potentially cardiotoxic PBUTs. In a cross-sectional study of 56 male CKD patients (stages 2⁻5 (pre-dialysis)) who were asymptomatic with no known cardiac diseases or diabetes we measured peak cardiac power (CPOmax), aerobic exercise capacity (VO2max), and echocardiographic parameters of cardiac morphology and evaluated their association with PBUTs. The serum total and free concentrations of indoxyl sulfate (IXS), p-cresyl sulfate (PCS), p-cresyl glucuronide, indole acetic acid, and hippuric acid showed significant negative correlation with CPOmax and VO2max. IXS and PCS were independently associated with CPOmax and VO2max even after controlling for eGFR. No correlation between left ventricular mass index (LVMI) and PBUTs was seen. The present study for the first time has demonstrated the association between subclinical cardiac dysfunction in CKD and serum levels of a panel of PBUTs. Further studies are required to evaluate the mechanism of cardiotoxicity of the individual uremic toxins.


Finger tapping to different styles of music and changes in cortical oscillations.
Music has been a therapeutic strategy proposed to improve impaired movement performance, but there remains a lack of understanding of how music impacts motor cortical activity. Thus, the purpose of this study is to use a time-frequency analysis (i.e., wavelet) of electroencephalographic (EEG) data to determine differences in motor and auditory cortical activity when moving to music at two different rates. Twenty healthy young adults tapped their index finger while electroencephalography was collected. There were three conditions (tapping in time with a tone and with two contrasting music styles), and each condition was repeated at two different rates (70 and 140 beats per minute). A time-frequency Morlet wavelet analysis was completed for electrodes of interest over the sensorimotor areas (FC3, FC4, FCz, C3, C4, Cz) and the primary auditory areas (T7, T8). Cluster-based permutation testing was applied to the electrodes of interest for all conditions. Results showed few differences between cortical oscillations when moving to music versus a tone. However, the two music conditions elicited a variety of distinct responses, particularly at the slower movement rate. These results suggest that music style and movement rate should be considered when designing therapeutic applications that include music to target motor performance.


A linear algorithm of the reference region model for DCE-MRI is robust and relaxes requirements for temporal resolution.
Dynamic contrast enhanced MRI (DCE-MRI) has utility for improving clinical diagnoses of solid tumors, and for evaluating the early responses of anti-angiogenic chemotherapies. The Reference Region Model (RRM) can improve the clinical implementation of DCE-MRI by substituting the contrast enhancement of muscle for the Arterial Input Function that is used in traditional DCE-MRI methodologies. The RRM is typically fitted to experimental results with a non-linear least squares algorithm. This report demonstrates that this algorithm produces inaccurate and imprecise results when DCE-MRI results have low SNR or slow temporal resolution. To overcome this limitation, a linear least-squares algorithm has been derived for the Reference Region Model. This new algorithm improves accuracy and precision of fitting the Reference Region Model to DCE-MRI results, especially for voxel-wise analyses. This linear algorithm is insensitive to injection speeds, and has 300- to 8000-fold faster calculation speed relative to the non-linear algorithm. The linear algorithm produces more accurate results for over a wider range of permeabilities and blood volumes of tumor vasculature. This new algorithm, termed the Linear Reference Region Model, has strong potential to improve clinical DCE-MRI evaluations.


Lycopene protects against hypoxia/reoxygenation-induced apoptosis by preventing mitochondrial dysfunction in primary neonatal mouse cardiomyocytes.
Hypoxia/reoxygenation(H/R)-induced apoptosis of cardiomyocytes plays an important role in myocardial injury. Lycopene is a potent antioxidant carotenoid that has been shown to have protective properties on cardiovascular system. The aim of the present study is to investigate the potential for lycopene to protect the cardiomyocytes exposed to H/R. Moreover, the effect on mitochondrial function upon lycopene exposure was assessed. Primary cardiomyocytes were isolated from neonatal mouse and established an in vitro model of H/R which resembles ischemia/reperfusion in vivo. The pretreatment of cardiomyocytes with 5 µM lycopene significantly reduced the extent of apoptosis detected by TUNEL assays. To further study the mechanism underlying the benefits of lycopene, interactions between lycopene and the process of mitochondria-mediated apoptosis were examined. Lycopene pretreatment of cardiomyocytes suppressed the activation of the mitochondrial permeability transition pore (mPTP) by reducing the intracellular reactive oxygen species (ROS) levels and inhibiting the increase of malondialdehyde (MDA) levels caused by H/R. Moreover, the loss of mitochondrial membrane potential, a decline in cellular ATP levels, a reduction in the amount of cytochrome c translocated to the cytoplasm and caspase-3 activation were observed in lycopene-treated cultures. The present results suggested that lycopene possesses great pharmacological potential in protecting against H/R-induced apoptosis. Importantly, the protective effects of lycopene may be attributed to its roles in improving mitochondrial function in H/R-treated cardiomyocytes.


Angioembolization reduces operative intervention for blunt splenic injury.
Nonoperative management for blunt splenic injury (BSI) has become gold standard, but the role of angiographic embolization (AE) is still controversial for bleeding. We postulated that splenic AE for BSI would have superior outcomes compared with operation and increase our splenic salvage rate. This was a retrospective study of all adult trauma patients admitted to our Level I center from 2000 through 2006. Multivariate analysis adjusting for age, Injury Severity Score, and Glasgow Coma Scale score was performed. Only patients who had a computed tomographic (CT) scan before surgery (CT + OR) were compared with those who had CT scans then AE. Eighty-seven of 317 patients required initial intervention for their BSI, for a no intervention rate (no OR or AE) of 73% and a nonoperative rate of 89%. The groups had similar Injury Severity Score, mortality, and lengths of stay. The AE group was older (p < 0.01), had higher spleen Abbreviated Injury Score (p = 0.02), and required significantly fewer packed RBC transfusions, p < 0.01. The overall hospitalization costs were not different, but the number of intraabdominal complications was higher for the CT + OR group (36% vs. 6%, p < 0.01). Pneumonia, thromboembolic events, and pleural effusions were equivalent. There were no deaths from splenic hemorrhage. Despite recent concerns that AE may be overutilized for BSI, this study showed a lower incidence of abdominal complications and blood utilization in the AE group despite an older age and higher splenic Abbreviated Injury Score. Use of AE decreased operative intervention by 16%.


Impact of Sex and Genetic Variation in Relevant Pharmacogenes on the Pharmacokinetics and Safety of Valsartan, Olmesartan and Hydrochlorothiazide.
Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters' genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, β = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, β = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.


Expression of Kv1.3 potassium channels regulates density of cortical interneurons.
The Kv1.3 protein is a member of the large family of voltage-dependent K+ subunits (Kv channels), which assemble to form tetrameric membrane-spanning channels that provide a selective pore for the conductance of K+ across the cell membrane. Kv1.3 differs from most other Kv channels in that deletion of Kv1.3 gene produces very striking changes in development and structure of the olfactory bulb, where Kv1.3 is expressed at high levels, resulting in a lower threshold for detection of odors, an increased number of synaptic glomeruli and alterations in the levels of a variety of neuronal signaling molecules. Because Kv1.3 is also expressed in the cerebral cortex, we have now examined the effects of deletion of the Kv1.3 gene on the expression of interneuron populations of the cerebral cortex. Using unbiased stereology we found an increase in the number of parvalbumin (PV) cells in whole cerebral cortex of Kv1.3-/- mice relative to that in wild-type mice, and a decrease in the number of calbindin (CB), calretinin (CR), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and somatostatin (SOM) interneurons. These changes are accompanied by a decrease in the cortical volume such that the cell density of PV interneurons is significantly increased and that of SOM neurons is decreased in Kv1.3-/- animals. Our studies suggest that, as in the olfactory bulb, Kv1.3 plays a unique role in neuronal differentiation and/or survival of interneuron populations and that expression of Kv1.3 is required for normal cortical function.


Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro.
Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein of unknown physiological function. The mechanism of Lp(a) atherogenicity as well as its catabolic pathways are only incompletely understood at present. In this report, we show that the low density lipoprotein receptor (LDLR) gene family member megalin/glycoprotein (gp) 330 is capable of binding and mediating the cellular uptake and degradation of Lp(a) in vitro. A mouse embryonic yolk sac cell line with native expression of megalin/gp330 but genetically deficient in LDLR-related protein (LRP) and a control cell line carrying a double knockout for both LRP and megalin/gp330 were compared with regard to their ability to bind, internalize, and degrade dioctadecyltetramethylindocarbocyanine perchlorate (DiI)-fluorescence-labeled Lp(a) as well as equimolar amounts of 125I-labeled Lp(a) and LDL. Uptake and degradation of radiolabeled Lp(a) by the megalin/gp330-expressing cells were, on average, 2-fold higher than that of control cells. This difference could be completely abolished by addition of the receptor-associated protein, an inhibitor of ligand binding to megalin/gp330. Mutual suppression of the uptake of 125I-Lp(a) and of 125I-LDL by both unlabeled Lp(a) and LDL suggested that Lp(a) uptake is mediated at least partially by apolipoprotein B100. Binding and uptake of DiI-Lp(a) resulted in strong signals on megalin/gp330-expressing cells versus background only on control cells. In addition, we show that purified megalin/gp330, immobilized on a sensor chip, directly binds Lp(a) in a Ca2+-dependent manner with an affinity similar to that for LDL. We conclude that megalin/gp330 binds Lp(a) in vitro and is capable of mediating its cellular uptake and degradation.


Combined insulin-like growth factor-1 and growth hormone improves weight loss and wound healing in burned rats.
The anabolic effects of growth hormone (GH) in burned patients appear to act both directly and through insulin-like growth factor-1 (IGF-1). We, therefore, hypothesize that exogenous GH plus IGF-1 will attenuate increases in metabolism and lean muscle wasting while promoting wound healing. Rats, each weighing 440-470 g, were given a 35% total body surface area, full-thickness scald burn and divided into four groups to receive placebo (burned controls), bovine GH (2.5 mg/kg/day), IGF-1 (2.0 mg/kg/day), or bovine GH plus rhIGF-1 (2.5 + 2.0 mg/kg/day), respectively, for 8 weeks. Total body weight gain after 8 weeks averaged 110 g for GH plus IGF-1 compared with gains of 49 and 11 g for GH or IGF-1 alone, respectively. Burned controls lost 24 g. Metabolic rates were significantly reduced in all groups receiving growth hormones. Gastrocnemius muscle dry weight was significantly increased in those receiving GH plus IGF-1 compared with GH and IGF-1 alone or burned controls (p < .01). Data show that GH plus IGF-1 synergistically increased lean muscle weight, total body weight, and was more effective in re-epithelialization of the burn wound than either GH or IGF-1 alone.


NsdC and NsdD affect Aspergillus flavus morphogenesis and aflatoxin production.
The transcription factors NsdC and NsdD are required for sexual development in Aspergillus nidulans. We now show these proteins also play a role in asexual development in the agriculturally important aflatoxin (AF)-producing fungus Aspergillus flavus. We found that both NsdC and NsdD are required for production of asexual sclerotia, normal aflatoxin biosynthesis, and conidiophore development. Conidiophores in nsdC and nsdD deletion mutants had shortened stipes and altered conidial heads compared to those of wild-type A. flavus. Our results suggest that NsdC and NsdD regulate transcription of genes required for early processes in conidiophore development preceding conidium formation. As the cultures aged, the ΔnsdC and ΔnsdD mutants produced a dark pigment that was not observed in the wild type. Gene expression data showed that although AflR is expressed at normal levels, a number of aflatoxin biosynthesis genes are expressed at reduced levels in both nsd mutants. Expression of aflD, aflM, and aflP was greatly reduced in nsdC mutants, and neither aflatoxin nor the proteins for these genes could be detected. Our results support previous studies showing that there is a strong association between conidiophore and sclerotium development and aflatoxin production in A. flavus.


Host and viral factors contributing to CD8+ T cell failure in hepatitis C virus infection.
Virus-specific CD8+ T cells are thought to be the major anti-viral effector cells in hepatitis C virus (HCV) infection. Indeed, viral clearance is associated with vigorous CD8+ T cell responses targeting multiple epitopes. In the chronic phase of infection, HCV-specific CD8+ T cell responses are usually weak, narrowly focused and display often functional defects regarding cytotoxicity, cytokine production, and proliferative capacity. In the last few years, different mechanisms which might contribute to the failure of HCV-specific CD8+ T cells in chronic infection have been identified, including insufficient CD4+ help, deficient CD8+ T cell differentiation, viral escape mutations, suppression by viral factors, inhibitory cytokines, inhibitory ligands, and regulatory T cells. In addition, host genetic factors such as the host's human leukocyte antigen (HLA) background may play an important role in the efficiency of the HCV-specific CD8+ T cell response and thus outcome of infection. The growing understanding of the mechanisms contributing to T cell failure and persistence of HCV infection will contribute to the development of successful immunotherapeutical and -prophylactical strategies.


Visual search for faces with emotional expressions.
The goal of this review is to critically examine contradictory findings in the study of visual search for emotionally expressive faces. Several key issues are addressed: Can emotional faces be processed preattentively and guide attention? What properties of these faces influence search efficiency? Is search moderated by the emotional state of the observer? The authors argue that the evidence is consistent with claims that (a) preattentive search processes are sensitive to and influenced by facial expressions of emotion, (b) attention guidance is influenced by a dynamic interplay of emotional and perceptual factors, and (c) visual search for emotional faces is influenced by the emotional state of the observer to some extent. The authors also argue that the way in which contextual factors interact to determine search performance needs to be explored further to draw sound conclusions about the precise influence of emotional expressions on search efficiency. Methodological considerations (e.g., set size, distractor background, task set) and ecological limitations of the visual search task are discussed. Finally, specific recommendations are made for future research directions.


Diagnostic Value of Neutrophil to Lymphocyte Ratio in Non-Alcoholic Fatty Liver Disease Evaluated Using Transient Elastography (TE) with Controlled Attenuated Parameter (CAP).
Non-alcoholic fatty liver disease (NAFLD) is a chronic inflammatory disease with excessive fat accumulation in the liver. Transient elastography (TE) with controlled attenuation parameter (CAP) is a device and method to examine the degree of fibrosis and steatosis. However, this device is not widely available across Indonesia. Neutrophil and lymphocyte ratio (NLR) is a simple marker for inflammation, which has a potency to predict disease outcome. This study aims to know the diagnostic value of NLR as the indicator of steatosis and fibrosis severity. This was a cross-sectional study with consecutive sample collection. We used secondary data from medical records, starting from 2016 to 2018. A descriptive and data analysis, including correlation test, multivariate linear regression, t-test, receiver operating curve (ROC) and area under the curve (AUC) were done to find out the outcome of the study. Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) Version 20.0 (SPSS Inc, Chicago, Illinois). A P value <0.05 was considered as statistically significant. Out of 106 subjects, 62.3% patients were women with the mean of age 57.29 years old and 77.4% had metabolic syndrome. Most patients had moderate to severe steatosis degree (66%) with the mean of TE mean 6.14 (2.8-18.2) kPa. There was a positive correlation between CAP and TE compared with NLR with r = 0.648 (p < 0.001) and r = 0.621 (p < 0.001), respectively. The use of RNL to assess moderate-severe steatosis has a cutoff point of 1.775 with sensitivity, specificity, PPV and NPV, respectively, at 81.5%, 80.6%, 89.1%, and 69.1%; cutoff point 2.150 to assess significant fibrosis with sensitivity, specificity, PPV and NPV of 92.3%, 87.5%, 70.6%, and 97.2%, respectively. NLR has a positive and significant correlation with the degree of steatosis and fibrosis with high sensitivity and specificity as evaluated by TE/CAP.


Systematic review of lymphovenous anastomosis (LVA) for the treatment of lymphedema.
Lymphedema is a chronic condition caused by the obstruction or impairment of lymphatic fluid transport resulting in irreversible skin fibrosis. Besides conservative therapy, surgical techniques for lymphedema including liposuction, lymphatico-lymphatic bypass, lymphovenous anastomosis (LVA), and vascularized lymph node transfer (VLNT) are options with increasing popularity in the recent past. In our review, we investigated the efficacy of LVA for the treatment of lymphedema. Both objective and subjective outcomes of surgical treatment were evaluated. Studies were identified through systematic review in PubMed database up to September 2016. Only original Articles which exclusively performed LVA for lymphedema treatment were included. Our primary endpoint was the objective of a subjective postoperative lymphedema reduction. A total of 293 titles were identified, out of which 18 studies including 939 patients were deemed eligible. The studies included in this review describe significant variations in surgical techniques, number of anastomoses and supplementary interventions. All studies reported objective reductions in circumference measurements. Subjective symptom relief was found in 50-100% of the patients as well as a reduction in the number of cellulitis episodes in all investigated cases. Although the studies included in this review showed great heterogeneity, LVA surgery revealed both objective and subjective improvements in most patients.


Pulmonary atresia with ventricular septal defect. Selection of patients for systemic-to-pulmonary artery shunt based on echocardiography.
From January 1987 to December 1988, in 22 infants with PAVSD, the diagnostic results obtained with echocardiography (two-dimensional, Doppler, and color) were prospectively compared to the angiocardiographic findings. We classified into group 1 patients with confluent and good-sized pulmonary (greater than or equal to 3 mm) arteries, single ductus arteriosus, and normal pulmonary venous connections ("favorable pattern"). The other patients with PAVSD were classified into group 2 ("unfavorable pattern"). The intracardiac anatomy, the morphology of the pulmonary arteries, and the pattern of pulmonary blood supply and pulmonary venous connection were correctly identified with echocardiography in all but one patient, who was erroneously considered to be in group 2. No false-positive of the "favorable pattern" (group 1) was detected. Echocardiography is an effective tool in infants with PAVSD, in order to discriminate cases with "favorable" and "unfavorable" patterns of pulmonary arteries, pulmonary blood supply, and pulmonary veins. The first group with the "favorable pattern" may be considered for systemic-to-pulmonary shunt surgery without angiocardiography. Based on this experience from January to December 1989, four patients with this "favorable pattern" underwent a successful systemic-to-pulmonary artery shunt with an echocardiographic diagnosis alone.


Beta-2-microglobulin concentrations in pediatric human immunodeficiency virus infection.
Serum concentrations of beta-2-microglobulin (B2-M) were correlated with disease outcome in 40 children infected by the human immunodeficiency virus. Serum B2-M serum concentrations below 3.0 mg/100 ml or decreasing concentrations were indicative of a stable disease course but were also noted preterminally in lymphopenic children. Of 20 patients with B2-M concentrations above 3.0 mg/liter, 12 had a progressive disease course and 8 remained stable. In the latter 8 patients the B2-M values decreased with time. Elevated B2-M concentrations were also noted in infants younger than 1 year of age and denoted active human immunodeficiency virus infection. B2-M serum concentrations are a useful prognostic marker in human immunodeficiency virus-infected children.


Does endogenous prostaglandin affect gastric antral motility?
Intracellular electrical activity and muscle contraction were recorded simultaneously from circular muscle of the canine antrum. Treatment with indomethacin enhanced the plateau phase of the spontaneously occurring gastric action potential and the amplitude of the phasic contraction. Exogenous PGE2 reversed this effect of indomethacin. Treatment with indomethacin also enhanced the electrical and mechanical responses to pentagastrin; this enhancement was also reversed by PGE2. Considered together, these results suggest that endogenous prostaglandin, probably of the E series, tonically suppresses the spontaneous electrical and mechanical activities of antral circular muscle and the responsiveness of the muscle to excitatory stimuli.


Single-Bone Forearm Salvage Procedure for a Child with Acquired Radial Clubhand in a Resource Limited Centre: A Case Report.
Acquired radial clubhand deformity can be a consequence of large bone gap left by premature extensive radius osteomyelitis sequestrectomy. Single-bone forearm reconstruction is a salvage procedure when other motion-preserving techniques are not feasible. Here we present a child who developed radial clubhand deformity after an untimely sequestrectomy of radius diaphysis. In view of limited microsurgical expertise in our centre, single-bone forearm procedure was done utilising simple Kirshner wires to achieve radio-ulnar fusion. The procedure resulted in pain-free stable wrist, restoration of hand function and improved cosmesis.


Complete chloroplast genome sequence of a tree fern Alsophila spinulosa: insights into evolutionary changes in fern chloroplast genomes.
Ferns have generally been neglected in studies of chloroplast genomics. Before this study, only one polypod and two basal ferns had their complete chloroplast (cp) genome reported. Tree ferns represent an ancient fern lineage that first occurred in the Late Triassic. In recent phylogenetic analyses, tree ferns were shown to be the sister group of polypods, the most diverse group of living ferns. Availability of cp genome sequence from a tree fern will facilitate interpretation of the evolutionary changes of fern cp genomes. Here we have sequenced the complete cp genome of a scaly tree fern Alsophila spinulosa (Cyatheaceae). The Alsophila cp genome is 156,661 base pairs (bp) in size, and has a typical quadripartite structure with the large (LSC, 86,308 bp) and small single copy (SSC, 21,623 bp) regions separated by two copies of an inverted repeat (IRs, 24,365 bp each). This genome contains 117 different genes encoding 85 proteins, 4 rRNAs and 28 tRNAs. Pseudogenes of ycf66 and trnT-UGU are also detected in this genome. A unique trnR-UCG gene (derived from trnR-CCG) is found between rbcL and accD. The Alsophila cp genome shares some unusual characteristics with the previously sequenced cp genome of the polypod fern Adiantum capillus-veneris, including the absence of 5 tRNA genes that exist in most other cp genomes. The genome shows a high degree of synteny with that of Adiantum, but differs considerably from two basal ferns (Angiopteris evecta and Psilotum nudum). At one endpoint of an ancient inversion we detected a highly repeated 565-bp-region that is absent from the Adiantum cp genome. An additional minor inversion of the trnD-GUC, which is possibly shared by all ferns, was identified by comparison between the fern and other land plant cp genomes. By comparing four fern cp genome sequences it was confirmed that two major rearrangements distinguish higher leptosporangiate ferns from basal fern lineages. The Alsophila cp genome is very similar to that of the polypod fern Adiantum in terms of gene content, gene order and GC content. However, there exist some striking differences between them: the trnR-UCG gene represents a putative molecular apomorphy of tree ferns; and the repeats observed at one inversion endpoint may be a vestige of some unknown rearrangement(s). This work provided fresh insights into the fern cp genome evolution as well as useful data for future phylogenetic studies.


Efficacy of a knowledge translation approach in changing allied health practitioner use of evidence-based practices with children with cerebral palsy: a before and after longitudinal study.
To investigate the effect of a knowledge translation intervention on knowledge and frequency of routine evidence-based assessment behaviours of healthcare professionals working with children with cerebral palsy. A before-and-after longitudinal study was conducted in five disability organisations. Four organisations (Commencing Knowledge Translation group) implemented a multifaceted intervention: knowledge brokers, targeted education, electronic-evidence library, and clinical outcomes database. These strategies were already in place at the fifth organisation (Comparison group). Outcomes evaluated at 0, 6, 12, and 24 months were health-professional knowledge and routine assessment behaviours (self-report and "completeness" of clinical assessment). Generalised estimating equations determined longitudinal changes. Four hundred and forty-seven professionals involved 861 children in the study. The Comparison group had higher knowledge and routine assessment behaviours at baseline. Professional knowledge in both groups remained stable (differences in change from baseline to 24 months: 0.3 units, 95%CI: -0.76 to 1.36). Assessment completeness of the Comparison group was stable (baseline mean 68 units, 95%CI: 65-71); the Commencing Knowledge Translation group improved from baseline mean 35 units (95%CI: 33-36), peaking at 12 months (mean 68 (95%CI: 65-71). Multifaceted organisational support improved health-professional routine evidence-based assessment behaviours with children with cerebral palsy, despite no change in knowledge. This trial was not a controlled health care intervention and was registered retrospectively: ACTRN12616001616460. The protocol of the trial was published in 2015 as follows: Imms et al. [6].Implications for rehabilitationA multifaceted knowledge translation intervention increased allied health professionals' assessment behaviours.Knowledge translation strategies can be chosen to target change in knowledge and/or change in behaviour.Knowledge translation interventions should be designed to address organisational barriers and enhance organisational supports.Interventions that target healthcare professionals' behaviour directly can be effective even if their knowledge does not change.


Chemical and physical origins of friction on surfaces with atomic steps.
Friction occurs through a complex set of processes that act together to resist relative motion. However, despite this complexity, friction is typically described using a simple phenomenological expression that relates normal and lateral forces via a coefficient, the friction coefficient. This one parameter encompasses multiple, sometimes competing, effects. To better understand the origins of friction, here, we study a chemically and topographically well-defined interface between silica and graphite with a single-layer graphene step edge. We identify the separate contributions of physical and chemical processes to friction and show that a single friction coefficient can be separated into two terms corresponding to these effects. The findings provide insight into the chemical and topographic origins of friction and suggest means of tuning surfaces by leveraging competing frictional processes.