Redefining the magnetic resonance imaging reference level for the cerebellar tonsil: a study of 170 adolescents with normal versus idiopathic scoliosis.
Magnetic resonance imaging (MRI) was used to compare quantitatively the position of the cerebellar tonsil in neurologically normal adolescents with that in idiopathic scoliosis (AIS) patients and age-matched healthy controls. To redefine the normal reference level of the cerebellar tonsil in healthy adolescents and to compare the differences in tonsillar level with AIS of different severities. Asymptomatic Chiari I malformation has been reported not infrequently in children and adolescents with AIS. The definition of tonsillar herniation and its variations with sex, age, and curve severities have not been clarified. Sagittal MRI of hindbrain was performed on 170 adolescents, including 117 patients with AIS and 53 age-matched healthy controls. The cerebellar tonsillar tip in healthy patients was found at an average of 2.8 mm above the basion-opisthion reference line (BO line) (range, 0-10.5 mm), in contrast to the finding that 17.9% of the AIS patients had tonsillar tip below the BO line. The position of tonsil in the AIS group was lower than that in the healthy controls (P < 0.05), and the differences also increased with the severity of the curve (P = 0.027). Using the current MRI reference standards, the incidence of tonsillar herniation could be significantly underestimated. According to our experience, any inferior displacement of a tonsil below the BO line in adolescents should be regarded as abnormal. Scoliosis could be an important manifestation of subclinical tonsillar herniation.


High prevalence of symptomatic bradyarrhythmias due to atrioventricular node-fascicular and sinus node-atrial disease in patients with mitral anular calcification.
Mitral anular calcification (MAC) is associated with high frequency of conduction defects. To delineate this association in patients with symptomatic bradyarrhythmias, 68 consecutive patients requiring pacemakers (group I) and 56 matched controls (group II) were studied. The patients comprised 41 men and 27 women, whose ages ranged from 24 to 92 years (mean 68). The control group consisted of 56 subjects without bradyarrhythmias, whose ages ranged from 30 to 86 years (mean 70); there were 36 men and 20 women. MAC was detected in 59 patients (87%) with symptomatic bradyarrhythmias compared with 8 subjects (14%) in the control group. In group I, 15 patients (22%) had complete atrioventricular block, 23 patients (34%) had atrial fibrillation with slow ventricular response, and 30 patients (44%) had intermittent sinus arrest. The incidence of MAC was similar among these subgroups (93%, 83%, and 87%, respectively). Thus the present study confirms the strong association of MAC with symptomatic bradyarrhythmias.


COVID-19, lockdowns and well-being: Evidence from Google Trends.
The COVID-19 pandemic and government intervention such as lockdowns may severely affect people's mental health. While lockdowns can help to contain the spread of the virus, they may result in substantial damage to population well-being. We use Google Trends data to test whether COVID-19 and the associated lockdowns implemented in Europe and America led to changes in well-being related topic search-terms. Using difference-in-differences and a regression discontinuity design, we find a substantial increase in the search intensity for boredom in Europe and the US. We also found a significant increase in searches for loneliness, worry and sadness, while searches for stress, suicide and divorce on the contrary fell. Our results suggest that people's mental health may have been severely affected by the pandemic and lockdown.


Anthropoid origins in Asia? New discovery of amphipithecus from the eocene of burma.
A new fossil of the primate Amphipithecus mogaungensis Colbert from the late Eocene of Burma shows that this species has a mandibular and molar morphology very similar to Oligocene and post-Oligocene higher primates. It has an exceptionally deep jaw. Its brachybunodont first and second molars have smooth enamel but lack hypoconulids. The shape of its second molar is nearly square-an advanced higher primate feature. Amphipithecus mogaungensis and related taxon Pondaungia cotteri Pilgrim are the earliest known higher primates. They suggest that Southeast Asia was an early theater of higher primate diversification.


Dynamics of human resource department ecosystem in developing human resource role: An ecosystem perspective.
Over the last decade, management scholars have paid increasing attention to ecosystems. The ecosystem approach has recently received much attention in business and innovation studies as a comprehensive way of understanding multi-aspect environments. This exploratory study aims to investigate the dynamics of human resource department ecosystem (HRDE) and the role of HRDE in shaping the human resource business partner role. This study employed a mixed-methods approach, following an exploratory sequential design. First, a conceptual model was developed based on qualitative data collected from expert interviews and analyzed through grounded theory. This stage uncovered eight actors and four factors, further organized into three layers of the ecosystem and hypothesis paths. Then, the structural model was measured and validated using PLS-SEM. This study is unique in applying the HRDE to the HR role's development to deepen our understanding of how a human resource business partner role is shaped by actors' interactions within and between ecosystem layers (micro, meso, and macro). The results revealed actors and factors supporting the HRDE in developing the HR role from the micro to macro layers of the ecosystem. The results suggest that the macro, meso, and micro layers of the HRDE positively impact the human resource business partner role's development.


Point-of-decision prompts to increase stair use. A systematic review update.
In 2000, the Guide to Community Preventive Services (Community Guide) completed a systematic review of the effectiveness of various approaches to increasing physical activity including informational, behavioral and social, and environmental and policy approaches. Among these approaches was the use of signs placed by elevators and escalators to encourage stair use. This approach was found to be effective based on sufficient evidence. Over the past 5 years the body of evidence of this intervention has increased substantially, warranting an updated review. This update was conducted on 16 peer-reviewed studies (including the six studies in the previous systematic review), which met specified quality criteria and included evaluation outcomes of interest. These studies evaluated two interventions: point-of-decision prompts to increase stair use and enhancements to stairs or stairwells (e.g., painting walls, laying carpet, adding artwork, playing music) when combined with point-of-decision prompts to increase stair use. This latter intervention was not included in the original systematic review. According to the Community Guide rules of evidence, there is strong evidence that point-of-decision prompts are effective in increasing the use of stairs. There is insufficient evidence, due to an inadequate number of studies, to determine whether or not enhancements to stairs or stairwells are an effective addition to point-of-decision prompts. This article describes the rationale for these systematic reviews, along with information about the review process and the resulting conclusions. Additional information about applicability, other effects, and barriers to implementation is also provided.


Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial.
Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design. Adult volunteers aged 18-59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590. 20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI -145 to 65). The RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months. Bill and Melinda Gates Foundation, South African Medical Research Council.


Plasma essential fatty acids in pure and mixed race American Indians on and off a diet exceptionally rich in salmon.
Eskimos on a traditional diet have unusually low prevalences of cardiovascular disease and cancer. One possible reason is the high intake of eicosapentaenoic acid (EPA) which is thought to account for the high EPA and low arachidonic acid (AA) levels in Eskimo plasma. People who also consume a traditional diet exceptionally rich in EPA are the Indians of the west coast of Vancouver Island. There are about 12,000 of these people and their traditional diet has been affected much less than that of the Eskimos. When on their traditional diet the Vancouver Island Indians, like the Eskimos, have high EPA and low AA levels in plasma. When eating European food, EPA levels are in the European range, but AA levels are still exceptionally low, a finding also reported from Eskimos living in Denmark. In a small mixed race group, AA levels were intermediate between those in pure Indians and in Europeans. The high EPA levels in Eskimos and West Coast Indians are related to diet. The low AA levels, in contrast, are probably genetically determined. Unusual disease patterns in these populations cannot be entirely attributed to diet.


[Study of the effectiveness of tiapride on psychic disorders in alcoholics].
The effectiveness of tiapride on psychic disorders was studied in 30 chronic alcoholics by assessing four parameters: sleep disturbances, mood disorders, conduct disturbances, and tremor. In a daily dosage of 600 to 900 mg tiapride proved particularly effective on insomnia, anxiety, passivity and tremor, without adverse side-effects. This drug seems useful for controlling psychic disorders in alcoholics and for motivating acceptance of a detoxification program.


Birth desires and intentions of women diagnosed with a meningioma.
OBJECT To the authors' knowledge, no previous study has examined the impact of meningioma diagnosis on women's birth desires and intentions. In an exploratory study, the authors surveyed women affected by meningioma to determine their attitudes toward childbearing and the influences, including physician recommendations, on this major life decision and compared their responses to those of women in the general population. METHODS Meningioma survivors from the Meningioma Mommas online support group participated in an online survey that included questions on their birth desires and intentions, whether the risk of disease recurrence influenced their reproductive decisions, and risks communicated to them by their physicians. Using chi-square and rank-sum tests, the authors compared the survey participants' responses with those of the general population as assessed by the 2006-2010 National Survey of Family Growth. Logistic regression was used to adjust for differences in age, race, ethnicity, education, parity, pregnancy status, and infertility status in these populations. RESULTS Respondents with meningioma were more likely than those in the general population to report wanting a baby (70% vs 54%, respectively), intending to have a baby (27% vs 12%, respectively), and being very sure about this intention (10% vs 2%, respectively). More than half (32 of 61) of the women of childbearing age reported being advised by a physician about potential risk factors for recurrence of the meningioma, and pregnancy was the most commonly cited risk factor (26 of 61). The most common factor influencing birth desires and intentions was risk of the meningioma returning and requiring more treatment, which was reported by nearly two-thirds of the women in their childbearing years. CONCLUSIONS A majority of the meningioma survivors of childbearing age who completed the survey reported a desire for children, although concern about the risk of meningioma recurrence was an important factor for these women when making reproductive decisions. Physicians are in a position to educate their patients on potential risk factors for recurrence and to provide contact information for services such as counseling and family planning.


A prospective cohort study of obesity and risk of oesophageal and gastric adenocarcinoma in the NIH-AARP Diet and Health Study.
The incidence of oesophageal adenocarcinoma (EAC) has increased rapidly over the past 40 years and accumulating evidence suggests that obesity, as measured by body mass index (BMI), is a major risk factor. It remains unclear whether abdominal obesity is associated with EAC and gastric adenocarcinoma. Cox proportional hazards regression was used to examine associations between overall and abdominal obesity with EAC and gastric adenocarcinoma among 218 854 participants in the prospective NIH-AARP cohort. 253 incident EAC, 191 gastric cardia adenocarcinomas and 125 gastric non-cardia adenocarcinomas accrued to the cohort. Overall obesity (BMI) was positively associated with EAC and gastric cardia adenocarcinoma risk (highest (≥35 kg/m(2)) vs referent (18.5-<25 kg/m(2)); HR 2.11, 95% CI 1.09 to 4.09 and HR 3.67, 95% CI 2.00 to 6.71, respectively). Waist circumference was also positively associated with EAC and gastric cardia adenocarcinoma risk (highest vs referent; HR 2.01, 95% CI 1.35 to 3.00 and HR 2.22, 95% CI 1.43 to 3.47, respectively), whereas waist-to-hip ratio (WHR) was positively associated with EAC risk only (highest vs referent; HR 1.81, 95% CI 1.24 to 2.64) and persisted in patients with normal BMI (18.5-<25 kg/m(2)). Mutual adjustment of WHR and BMI attenuated both, but did not eliminate the positive associations for either with risk of EAC. In contrast, the majority of the anthropometric variables were not associated with adenocarcinomas of the gastric non-cardia. Overall obesity was associated with a higher risk of EAC and gastric cardia adenocarcinoma, whereas abdominal obesity was found to be associated with increased EAC risk; even in people with normal BMI.


Laparoscopy in the morbidly obese: physiologic considerations and surgical techniques to optimize success.
The objectives of this review were to analyze the literature describing the benefits of minimally invasive gynecologic surgery in obese women, to examine the physiologic considerations associated with obesity, and to describe surgical techniques that will enable surgeons to perform laparoscopy and robotic surgery successfully in obese patients. The Medline database was reviewed for all articles published in the English language between 1993 and 2013 containing the search terms "gynecologic laparoscopy" "laparoscopy," "minimally invasive surgery and obesity," "obesity," and "robotic surgery." The incidence of obesity is increasing in the United States, and in particular morbid obesity in women. Obesity is associated with a wide range of comorbid conditions that may affect perioperative outcomes including hypertension, atherosclerosis, angina, obstructive sleep apnea, and diabetes mellitus. In obese patients, laparoscopy or robotic surgery, compared with laparotomy, is associated with a shorter hospital stay, less postoperative pain, and fewer wound complications. Specific intra-abdominal access and trocar positioning techniques, as well as anesthetic maneuvers, improve the likelihood of success of laparoscopy in women with central adiposity. Performing gynecologic laparoscopy in the morbidly obese is no longer rare. Increases in the heaviest weight categories involve changes in clinical practice patterns. With comprehensive and thoughtful preoperative and surgical planning, minimally invasive gynecologic surgery may be performed safely and is of particular benefit in obese patients.


A milk transportation problem with milk collection centers and vehicle routing.
In this work, we study, model, and propose two approaches to solve a raw milk transportation problem inspired by a real case of a milk company in Chile. The milk is produced by a set of farms scattered in a large rural area. The company must collect all the production daily using a truck fleet. We address the location of milk collection centers to reduce transportation costs. Each center has a limited capacity and a reduced truck fleet, composed of small trucks, to collect a substantial proportion of the produced milk. Once the milk is accumulated in the collection centers, a fleet of big trucks, traveling from a processing plant, collects the milk of each collection center and some large farms. We propose a mixed-integer linear programming model, a three-stage approach based on mathematical models, and an iterated local search approach to face this problem. We evaluate these approaches' performance using a small case and several real-world examples, including a clustering approach to divide the instance into small sub-instances. The results obtained for the real-world instance show improvements of up to 10% percent when milk collection centers are allowed.


Digital CXR with computer aided diagnosis versus symptom screen to define presumptive tuberculosis among household contacts and impact on tuberculosis diagnosis.
Household (HH) contact tracing is a strategy that targets high risk groups for TB. Symptom based screening is the standard used to identify HH contacts at risk for TB during HH contact tracing for TB. However, this strategy may be limited due to poor performance in predicting TB. The objective of this study was to compare CXR with Computer Aided Diagnosis (CAD) against symptom screen for defining presumptive TB and how TB detection changes with each method. Household contacts of consecutive index bacteriologically confirmed TB cases were visited by study teams and given TB/HIV education to raise awareness of the risk of TB following close contact with a TB patient. Contacts were encouraged to visit the health facility for screening; where symptoms history was obtained and opt out HIV testing was provided as part of the screening process. CXR was offered to all regardless of symptoms, followed by definitive sputum test with either Xpert MTB RIF or smear microscopy. Among 919 HH contacts that presented for screening, 865 were screened with CXR and 464 (53.6%) had an abnormal CXR and the rest had a normal CXR. Among 444 HH contacts with valid sputum results, 274 (61.7%) were symptom screen positive and 255 (57.4%) had an abnormal CXR. Overall, TB was diagnosed in 32/444 (7.2%); 13 bacteriologically unconfirmed and 19 bacteriologically confirmed. Of 19 bacteriologically confirmed TB 8 (42.1%) were symptom screen negative contacts with an abnormal CXR and these 6/8 (75.0%) were HIV positive. Among the 13 bacteriologically unconfirmed TB cases, 7 (53.8%) were HIV positive and all had an abnormal CXR. Symptom screen if used alone with follow on definitive TB testing only for symptom screen positive individuals would have missed eight of the 19 confirmed TB cases detected in this study. There is need to consider use of other screening strategies apart from symptom screen alone for optimal rule out of TB especially in HIV positive individuals that are at greatest risk of TB and present atypically.


[Zinc deficiency in liver cirrhosis: a curiosity or a problem?].
This article reviews the literature on the role of zinc in liver cirrhosis and dietary zinc supplementation for cirrhotic patients with hepatic encephalopathy. Zinc is a trace metal found in many proteins and enzymes having catalytical, cocatalytical and structural functions. Zinc deficiency has been demonstrated in cirrhotic patients, and dietary supplementation of this metal could benefit the urea cycle, glucose and protein metabolism, and central nervous system neurotransmission in these subjects. After some brief considerations on normal zinc metabolism, the role zinc plays in the central nervous system, and its conduct in patients with hepatic encephalopathy, possible links between zinc deficiency and the pathophysiology of central nervous system dysfunction in cirrhotic patients are discussed. The article concludes with a critical review of favorable and unfavorable evidence for zinc supplementation in patients with hepatic encephalopathy.


Lidocaine-prilocaine cream reduces catheter-related bladder discomfort in male patients during the general anesthesia recovery period: A prospective, randomized, case-control STROBE study.
Urethral catheterization is a predictor of agitation during the general anesthesia recovery period. The aim of this study was to determine the effect of intraurethral 5% lidocaine and 25 mg/g prilocaine cream in reducing catheter-related bladder discomfort (CRBD) in male patients during the general anesthesia recovery period. Adult male patients undergoing elective operations that required urinary catheterization under general anesthesia were enrolled and assigned randomly to 2 groups. In the lidocaine-prilocaine cream group (n = 72), approximately 5 g of topical cream was spread in the preputial sac, the glans, the meatus, and on the urinary catheter surface before urinary catheterization. In the control group (n = 74), the urinary catheter was lubricated with lidocaine gel. The incidence and severity of CRBD were assessed 15, 30, 45, and 60 minutes postoperatively. We found that the incidence of CRBD in the lidocaine-prilocaine cream group was significantly lower than in the control group. Multivariate logistic regression analysis showed that lidocaine-prilocaine cream applications reduced moderate or severe CRBD. Thirty minutes postoperation was the most frequent time point for the incidence of CRBD. Application of lidocaine-prilocaine cream on the surface of the urinary catheter is an efficient and safe method to reduce the incidence and severity of CRBD.


Outcome instruments for the assessment of the upper extremity following trauma: a review.
Orthopaedic injuries are common among trauma patients and can result in long-term problems. Considerable data are available regarding functional outcomes following lower extremity trauma. There is, however, a paucity of data available for upper extremity trauma patients. Whilst currently available instruments appear to assess outcomes of relevance in trauma populations, the reliability, validity and responsiveness of these instruments have not been evaluated in the upper extremity trauma population. This paper reviews instruments designed for patient self-evaluation of musculoskeletal disorders of the upper extremity, and instruments used in an orthopaedic trauma population to assess functional recovery following injury. The Musculoskeletal Functional Assessment (MFA), Short Musculoskeletal Functional Assessment (SMFA), Disabilities of the Arm, Shoulder, and Hand (DASH), American Shoulder and Elbow Surgeons Shoulder Scale (ASES-s), American Shoulder and Elbow Surgeons Elbow Scale (ASES-e), Patient Rated Elbow Evaluation (PREE), and the Patient Rated Wrist Evaluation (PRWE) were reviewed. Until research is published outlining the evaluation of assessment instruments in upper extremity orthopaedic populations, authors will need to conduct their own validation studies before investigating outcomes in specific trauma populations.


Tuning mTORC1 activity dictates the response of acute myeloid leukemia to LSD1 inhibition.
Lysine specific demethylase-1 (LSD1) has been shown to be critical in acute myeloid leukemia (AML) pathogenesis and this has led to the development of LSD1 inhibitors (LSD1i) which are currently tested in clinical trials. Nonetheless, preclinical studies reported that AML cells frequently exhibit intrinsic resistance to LSD1 inhibition, and the molecular basis for this phenomenon is largely unknown. We explored the potential involvement of mammalian target of rapamycin (mTOR) in mediating the resistance of leukemic cells to LSD1i. Strikingly, unlike sensitive leukemias, mTOR complex 1 (mTORC1) signaling was robustly triggered in resistant leukemias following LSD1 inhibition. Transcriptomic, chromatin immunoprecipitation and functional studies revealed that insulin receptor substrate 1(IRS1)/extracellular-signal regulated kinases (ERK1/2) signaling critically controls LSD1i induced mTORC1 activation. Notably, inhibiting mTOR unlocked the resistance of AML cell lines and primary patient-derived blasts to LSD1i both in vitro and in vivo In conclusion, mTOR activation might act as a novel pro-survival mechanism of intrinsic as well as acquired resistance to LSD1i, and combination regimens co-targeting LSD1/mTOR could represent a rational approach in AML therapy.


Exacerbating role of gammadelta T cells in chronic colitis of T-cell receptor alpha mutant mice.
T-cell receptor (TCR) gammadelta T cells are an important component of the mucosal immune system and regulate intestinal epithelial homeostasis. Interestingly, there is a significant increase in gammadelta T cells in the inflamed mucosa of patients with ulcerative colitis (UC). However, the role of gammadelta T cells in chronic colitis has not been fully identified. TCRalpha-deficient mice, which spontaneously develop chronic colitis with many features of human UC including an increase in gammadelta T-cell population, represent an excellent model to investigate the role of gammadelta T cells in UC-like colitis. To identify the role of gammadelta T cells in this colitis, we herein have generated TCRgamma-deficient mice through deletion of all TCR Cgamma genes (Cgamma1, Cgamma2, Cgamma3, and Cgamma4) using the Cre/loxP site-specific recombination system and subsequently crossing these mice with TCRalpha-deficient mice. An increase in colonic gammadelta T cells was associated with the development of human UC as well as UC-like disease seen in TCRalpha-deficient mice. Interestingly, the newly established TCRalpha(-/-) x TCRgamma(-/-) double mutant mice developed significantly less severe colitis as compared with TCRalpha-deficient mice. The suppression of colitis in TCRalpha(-/-) x TCRgamma(-/-) double mutant mice was associated with a significant reduction of proinflammatory cytokine and chemokine productions and a decrease in neutrophil infiltration. gammadelta T cells are involved in the exacerbation of UC-like chronic disease. Therefore, gammadelta T cells may represent a promising therapeutic target for the treatment of human UC.


Increased general practice workload due to a primary care led National Health Service: the need for evidence to support rhetoric.
Recent policy initiatives have focused on shifts in the balance of care from secondary care to primary care. A consequence of such shifts is increased workload in primary care. The aim of this paper is to appraise the literature critically to assess whether changes in the balance of care have led to additional work for general practices. In particular, the implications of this literature for the measurement of workload in general practice are highlighted. After an extensive, systematic literature search, only 12 studies that met the review criteria were identified. Although the studies pointed to negligible effects on the number of general practitioner (GP) visits, they failed to capture the many other attributes of a practice's work that are likely to be influenced by a shift in the balance of care. These include both qualitative (e.g. stress and mental effort) and quantitative (i.e. the use of resources in the practice, such as GPs, nurses and other staff's time and administration) measures of workload. The studies may therefore have under-estimated the effect on practice workload. To identify correctly the impact on workload of shifts in the balance of care, studies evaluating shifts need to improve their measurement of general practice workload. Furthermore, an extended definition of workload needs to be developed and tested, and workload monitored over time.


Bioaccessibility and digestive stability of carotenoids in cooked eggs studied using a dynamic in vitro gastrointestinal model.
Among dietary carotenoids, lutein and zeaxanthin are known to protect against age-related macular degeneration, a leading cause of irreversible vision loss in the elderly. Egg yolk is rich in lutein and zeaxanthin, however, the effect of cooking and gastrointestinal digestion on yolk carotenoids is poorly understood. An in vitro dynamic gastrointestinal model (TIM-1) was used to investigate the digestive stability and bioaccessibility of carotenoids from boiled, fried, and scrambled eggs. Bioaccessibility but not digestive stability was significantly affected by the method of cooking. The main egg carotenoids, all-E-lutein and all-E-zeaxanthin, were stable during the digestion with average recoveries of 90 and 88%, respectively. No trans-cis isomerization of carotenoids was observed during digestion. Both all-E-lutein and all-E-zeaxanthin from scrambled eggs showed significantly lower bioaccessibility compared to boiled eggs. The results indicate that the bioaccessibility of egg carotenoids can be affected by different food preparation methods.


Refining the thermochemical properties of CF, SiF, and their cations by combining photoelectron spectroscopy, quantum chemical calculations, and the Active Thermochemical Tables approach.
Fluorinated species have a pivotal role in semiconductor material chemistry and some of them have been detected beyond the Earth's atmosphere. Achieving good energy accuracy on fluorinated species using quantum chemical calculations has long been a challenge. In addition, obtaining direct experimental thermochemical quantities has also proved difficult. Here, we report the threshold photoelectron and photoion yield spectra of SiF and CF radicals generated with a fluorine reactor. The spectra were analysed with the support of ab initio calculations, resulting in new experimental values for the adiabatic ionisation energies of both CF (9.128 ± 0.006 eV) and SiF (7.379 ± 0.009 eV). Using these values, the underlying thermochemical network of Active Thermochemical Tables was updated, providing further refined enthalpies of formation and dissociation energies of CF, SiF, and their cationic counterparts.


Suprachiasmatic stimulation phase shifts rodent circadian rhythms.
The integrity of the suprachiasmatic nuclei (SCN) of the hypothalamus is essential to the expression of normal circadian rhythms in rodents. Electrical stimulation of the SCN caused phase shifts and period changes in the freerunning feeding rhythms of rats and activity rhythms of hamsters. The phase response curve for SCN stimulation appears to parallel that for light pulses. These findings strengthen the hypothesis derived from lesion studies that the SCN are the dominant light-entrained oscillators in the rodent circadian system.


Renal Vein Levels of MicroRNA-26a Are Lower in the Poststenotic Kidney.
MicroRNA-26a (miR-26a) is a post-transcriptional regulator that inhibits cellular differentiation and apoptosis. Renal vascular disease (RVD) induces ischemic injury characterized by tubular cell apoptosis and interstitial fibrosis. We hypothesized that miR-26a levels are reduced in the poststenotic kidney and that kidney repair achieved by adipose tissue-derived mesenchymal stem cells (ad-MSCs) is associated with restored miR-26a levels. Renal function and renal miR-26a levels were assessed in pigs with RVD not treated (n=7) or 4 weeks after intrarenal infusion of ad-MSC (2.5×10(5) cells/kg; n=6), patients with RVD (n=12) or essential hypertension (n=12), and healthy volunteers (n=12). In addition, the direct effect of miR-26a on apoptosis was evaluated in a renal tubular cell culture. Compared with healthy control kidneys, swine and human poststenotic kidneys had 45.5±4.3% and 90.0±3.5% lower levels of miR-26a, respectively, which in pigs, localized to the proximal tubules. In pigs, ad-MSC delivery restored tubular miR-26a expression, attenuated tubular apoptosis and interstitial fibrosis, and improved renal function and tubular oxygen-dependent function. In vitro, miR-26a inhibition induced proximal tubular cell apoptosis and upregulated proapoptotic protein expression, which were both rescued by ad-MSC. In conclusion, decreased tubular miR-26a expression in the poststenotic kidney may be responsible for tubular cell apoptosis and renal dysfunction but can be restored using ad-MSC. Therefore, miR-26a might be a novel therapeutic target in renovascular disease.


Polymorphism analysis of the CTLA-4 gene in paracoccidioidomycosis patients.
The CTLA-4 protein is expressed in activated T cells and plays an essential role in the immune response through its regulatory effect on T cell activation. Polymorphisms of the CTLA-4 gene have been correlated with autoimmune, neoplastic and infectious illnesses. This work aimed to verify possible associations between single nucleotide polymorphisms (SNPs) in CTLA-4, -318C/T in the promoter and +49A/G in exon 1 and paracoccidioidomycosis (PCM) caused by Paracoccidioides brasiliensis. For this purpose, 66 chronic form PCM patients and 76 healthy controls had their allele, genotype and haplotype frequencies determined. The genetic admixture structure of the patients and controls was evaluated to eliminate ancestral bias. The comparison of frequencies indicated no significant differences between patients and controls that could link the SNPs to PCM. Groups were admixture matched with no difference observed in population ancestry inference, indicating that the absence of association between CTLA-4 polymorphisms and PCM could not be attributed to ancestral bias. This study showed that there was no association between the CTLA-4 SNPs -318 and +49 and the resistance or susceptibility to PCM.


[The use of coral as a substitute for maxillofacial bone reconstruction].
A kind of coral, Porites, which was originated from the Madreporaria reef builders in Hainan Province, was studied as a bone substitute. It is almost composed of aragonite (CaCO(s)) and the structure shows interconnected micropores with a-mean diameter of 150-200 microns which is suitable for bone ingrowth. The coral was implanted successfully into the defects in inferior border of mandibles of 8 rabbits for 6 months. Then it was used clinically as a bone substitute in maxillofacial surgery for 22 patients who were followed up for 6-24 months. With X-ray, histological and clinical examination, the results showed that the coral had a good tolerance and elicited no deleterious host response. After implanted, the coral is acted as a bone conductor and can promote the bone repair of defects. It seems to be a useful bone substitute.


Effectiveness of current policing-related mental health interventions in England and Wales and Crisis Intervention Teams as a future potential model: a systematic review.
Experiencing mental ill health adds a layer of complexity for individuals in touch with the justice system and for those responsible for working in the justice service with these individuals, such as frontline police officers. In England and Wales, there are three commonly used but not necessarily commonly designed or operated, mental health interventions associated with policing, Liaison and Diversion, Street Triage and specialist staff embedded in Police Contact Control Rooms. A fourth US designed model, Crisis Intervention Teams (CITs), is now attracting some interest in England and Wales, and these four are to be considered in this review. A fifth intervention, Mental Health Courts, was trialed but has now been abandoned in England and Wales and so has been excluded, but remains in use elsewhere. In recent years, there has been an increase in the level of investment related to these intervention options. This has largely been without an evidence base being available to aid design, structure, and consistency of approach. The review will address this gap and provide a systematic review of each of these options. This will provide a baseline of research evidence for those who commission and provide services for individuals experiencing mental ill health and who are in contact with the justice system. Twenty-nine relevant databases and sources have been selected which will be systematically searched to locate relevant studies. These studies have to meet the set inclusion criteria which require them to report an objective outcome measure(s) in respect of offending or mental health outcomes and to have an experimental or quasi-experimental design including a comparator group(s) or a pre/post comparison. The review will exclude PhD theses, papers in non-English languages and papers published prior to 1980. Keywords have been collected through canvassing experts' opinion, literature review, controlled vocabulary and reviewing the results of a primary scoping review carried out to aid the development of the PICO, composed of Population/Participants, Intervention/Indicator, Comparator/Control, and Outcomes. For the proposed review, the key elements of the PICO are the following: persons with mental health problems, symptoms or diagnoses who come into contact with the police; interventions involving partnership working between police and mental health nurses and related professionals to divert those with mental health problems away from criminal justice processes; comparisons with control groups or areas where such interventions have not been introduced; and outcomes concerning criminal justice and health outcomes. The results of the searches will be screened using the set criteria and the selected papers reviewed and analysed to allow findings regarding these interventions to be reported. The objectives of the review are firstly to identify and report research on the relevant interventions, nationally and internationally and then secondly to consider, when possible, which interventions or aspects of those interventions are effective. This is judged with regard to changes in mental health status or service use and future offending behaviour. The approaches to be considered have gained a good deal of support and funding over recent years, and this review will provide a systematic review of the underpinning research evidence to inform future commissioning, service design and investment decisions.


Effects of anaesthesia on insulin sensitivity and metabolic parameters in Wistar rats.
We compared the effects of two different anaesthetics, sodium pentobarbital (65 mg/kg) and ketamine (30 mg/kg) plus xylazine (4 mg/kg) (KX) on insulin sensitivity, fasting glycaemia, insulinaemia and free fatty acids (FFA). Four groups of Wistar rats were used: KX group (n=6), pentobarbital group (n=6), high-sucrose diet group (n=6) and the conscious group (n=6). The insulin tolerance test (ITT) was used to measure insulin sensitivity, and metabolic biomarkers were determined using commercial kits. Pentobarbital did not alter plasma insulin, glucose, FFA or the ITT results compared to conscious animals. In contrast, KX anaesthesia induced hyperglycaemia, increased serum FFA and altered the ITT results compared to the conscious animal group. Moreover, under pentobarbital anaesthesia, the ITT proved to be a suitable method to detect insulin resistance in an animal model of diet-induced insulin resistance. We concluded that sodium pentobarbital anaesthesia should be used in metabolic studies since it does not interfere with plasma glucose, insulin, FFA or insulin sensitivity quantification in Wistar rats.


Dental age related tables for children of various ethnic groups in South Africa.
The standard age estimation methods of Moorrees, Fanning & Hunt (1963) and that of Demirjian, Goldstein & Tanner (1973) have been shown by several authors to be inaccurate when applied to their juvenile population. This was similarly found to be true in South African children. Pantomographic radiographs of samples of South African children of White, Coloured, Indian and Black origin were used to develop dental age related tables for these ethnic groups. These dental age estimation tables were tested and are presented.


Molecular mechanisms of atherosclerosis in metabolic syndrome: role of reduced IRS2-dependent signaling.
The mechanisms underlying accelerated atherosclerosis in metabolic syndrome (MetS) patients remain poorly defined. In the mouse, complete disruption of insulin receptor substrate-2 (Irs2) causes insulin resistance, MetS-like manifestations, and accelerates atherosclerosis. Here, we performed human, mouse, and cell culture studies to gain insight into the contribution of defective Irs2 signaling to MetS-associated alterations. In circulating leukocytes from insulin-resistant MetS patients, Irs2 and Akt2 mRNA levels inversely correlate with plasma insulin levels and HOMA index and are reduced compared to insulin-sensitive MetS patients. Notably, a moderate reduction in Irs2 expression in fat-fed apolipoprotein E-null mice lacking one allele of Irs2 (apoE(-/-)Irs2(+/-)) accelerates atherosclerosis compared to apoE-null controls, without affecting plaque composition. Partial Irs2 inactivation also increases CD36 and SRA scavenger receptor expression and modified LDL uptake in macrophages, diminishes Akt2 and Ras expression in aorta, and enhances expression of the proatherogenic cytokine MCP1 in aorta and primary vascular smooth muscle cells (VSMCs) and macrophages. Inhibition of AKT or ERK1/2, a downstream target of RAS, upregulates Mcp1 in VSMCs. Enhanced levels of MCP1 resulting from reduced IRS2 expression and accompanying defects in AKT2 and Ras/ERK1/2 signaling pathways may contribute to accelerated atherosclerosis in MetS states.


Holothurians play an important role in mitigating the impacts of aquaculture on sediment conditions.
As deposit feeders contribute to bioremediation and nutrient recycling in sediments, positively impacting water and sediment quality, holothurians are candidate organisms for multitrophic aquaculture. This study aimed to investigate the potential of Holothuria poli to reduce the environmental footprint of fish farms through a benthocosm experiment. The experimental setup included four benthocosms with holothurians(H+) and four without (H-). The 58-day experiment included two phases: constant organic enrichment and recovery. In order to simulate the organic enrichment sediment conditions under a typical fish farm, a mixture of fish feces and fish feed pellets was added. Results showed that holothurians effectively reduced organic matter and H2S and increased redox, RPD depth and sediment oxygenation, thereby preventing anoxic conditions. Also, during the recovery phase, holothurians facilitated rapid sediment recovery, while the sediments without holothurians remained organic-enriched until the end of the experiment. The study emphasizes the significance of holothurians in mitigating the impacts of aquaculture on sediment conditions and so promoting environmental sustainability.


[Autoinflammatory syndromes/fever syndromes].
Hereditary periodic (fever) syndromes, also called autoinflammatory syndromes, are characterized by relapsing fever and additional manifestations such as skin rashes, mucosal manifestations, or joint symptoms. Some of these disorders present with organ involvement and serological signs of inflammation without fever. There is a strong serological inflammatory response with an elevation of serum amyloid A (SAA), resulting in an increased risk of secondary amyloidosis. There are monogenic disorders (familial mediterranean fever (FMF), hyper-IgD-syndrome (HIDS), cryopyrin-associated periodic syndromes (CAPS), "pyogenic arthritis, acne, pyoderma gangrenosum" (PAPA), and "pediatric granulomatous arthritis (PGA) where mutations in genes have been described, which in part by influencing the function of the inflammasome, in part by other means, lead to the induction of the production of IL-1β. In "early-onset of enterocolitis (IBD)", a functional IL-10 receptor is lacking. Therapeutically, above all, the IL-1 receptor antagonist anakinra is used. In case of TRAPS and PGA, TNF-antagonists (etanercept) may also be used; in FMF colchicine is first choice. As additional possible autoinflammatory syndromes, PFAPA syndrome (periodic fever with aphthous stomatitis, pharyngitis and adenitis), Schnitzler syndrome, Still's disease of adult and pediatric onset, Behçet disease, gout, chronic recurrent multifocal osteomyelitis (CRMO) and Crohn's disease also are mentioned.


Single-stage endovascular management of complicated thoracic aorta coarctation concurrent with aortic arch aneurysm using a novel fenestration device.
To present a case with aorta coarctation complicated by aortic arch aneurysm which is clinical rare and entails a high risk of rupture. Here we reported a 46-year-old female patient diagnosed with aortic arch aneurysm combined with coarctation. The computed tomography angiography shows that an irregular aneurysm was located at the aortic arch site with its maximal diameter 86.55 mm and the right end of aneurysm was located 10 mm away from the ostium of left common carotid artery (LCCA). The aneurysm body invaded the left subclavian artery, and at the distal end of aneurysm a coarctation had been observed with a minimum diameter reaching 2.7 mm. We performed percutaneous balloon angioplasty, thoracic endovascular aortic repair to exclude the aneurysm, and simultaneously used a novel in situ fenestration device (Quick-Fenestrater) to revascularize the covered LCCA. This is first case of using a novel fenestration device single-stage endovascular treatment of complicated thoracic aorta coarctation concurrent with aortic arch aneurysm. Combined endovascular techniques can elevate the success rate of reconstruct complicated aorta aneurysm concurrent with coarctation and reduce complications. Under the guidance of Quick-Fenestrater, in situ fenestration could be performed with safety and a high success frequency.


Incorporation of Alkylamine into Metal-Organic Frameworks through a Brønsted Acid-Base Reaction for CO2 Capture.
The escalating atmospheric CO2 concentration is one of the most urgent environmental concerns of our age. To effectively capture CO2 , various materials have been studied. Among them, alkylamine-modified metal-organic frameworks (MOFs) are considered to be promising candidates. In most cases, alkylamine molecules are integrated into MOFs through the coordination bonds formed between open metal sites (OMSs) and amine groups. Thus, the alkylamine density, as well as the corresponding CO2 uptake in MOFs, are severely restricted by the density of OMSs. To overcome this limit, other approaches to incorporating alkylamine into MOFs are highly desired. We have developed a new method based on Brønsted acid-base reaction to tether alkylamines into Cr-MIL-101-SO3 H for CO2 capture. A systematic optimization of the amine tethering process was also conducted to maximize the CO2 uptake of the modified MOF. Under the optimal amine tethering condition, the obtained tris(2-aminoethyl)amine-functionalized Cr-MIL-101-SO3 H (Cr-MIL-101-SO3 H-TAEA) has a cyclic CO2 uptake of 2.28 mmol g-1 at 150 mbar and 40 °C, and 1.12 mmol g-1 at 0.4 mbar and 20 °C. The low-cost starting materials and simple synthetic procedure for the preparation of Cr-MIL-101-SO3 H-TAEA suggest that it has the potential for large-scale production and practical applications.


Benchmarking Standard and Micromechanical Models for Creep and Shrinkage of Concrete Relevant for Nuclear Power Plants.
The creep and shrinkage of concrete play important roles for many nuclear power plant (NPP) and engineering structures. This paper benchmarks the standard and micromechanical models using a revamped and appended Northwestern University database of laboratory creep and shrinkage data with 4663 data sets. The benchmarking takes into account relevant concretes and conditions for NPPs using 781 plausible data sets and 1417 problematic data sets, which cover together 47% of the experimental data sets in the database. The B3, B4, and EC2 models were compared using the coefficient of variation of error (CoV) adjusted for the same significance for short-term and long-term measurements. The B4 model shows the lowest variations for autogenous shrinkage and basic and total creep, while the EC2 model performs slightly better for drying and total shrinkage. In addition, confidence levels at 5, 10, 90, and 95% are quantified in every decade. Two micromechanical models, Vi(CA)2T and SCK CEN, use continuum micromechanics for the mean field homogenization and thermodynamics of the water-pore structure interaction. Validations are carried out for the 28-day Young's modulus of concrete, basic creep compliance, and drying shrinkage of paste and concrete. The Vi(CA)2T model is the second best model for the 28-day Young's modulus and the basic creep problematic data sets. The SCK CEN micromechanical model provides good prediction for drying shrinkage.


In vitro efficacy of Myxococcus fulvus ANSM068 to biotransform aflatoxin B₁.
Aflatoxin B(1) (AFB(1)) is commonly found in cereals and animal feeds and causes a significant threat to the food industry and animal production. Several microbial isolates with high AFB(1) transformation ability have been identified in our previous studies. The aim of this research was to characterize one of those isolates, Myxococcus fulvus ANSM068, and to explore its biotransformation mechanism. The bacterial isolate of M. fulvus ANSM068, isolated from deer feces, was able to transform AFB(1) by 80.7% in liquid VY/2 medium after incubation at 30 °C for 72 h. The supernatant of the bacterial culture was more effective in transforming AFB(1) as compared to the cells alone and the cell extract. The transformation activity was significantly reduced and eradicated after the culture supernatant was treated with proteinase K, proteinase K plus SDS and heating. Culture conditions, including nitrogen source, initial pH and incubation temperature were evaluated for an optimal AFB(1) transformation. Liquid chromatography mass spectrometry (LCMS) analyses showed that AFB(1) was transformed to a structurally different compound. Infrared analysis (IR) indicated that the lactone ring on the AFB(1) molecule was modified by the culture supernatant. Chromatographies on DEAE-Ion exchange and Sephadex-Molecular sieve and SDS-PAGE electrophoresis were used to determine active components from the culture supernatant, indicating that enzyme(s) were responsible for the AFB(1) biotransformation. This is the first report on AFB(1) transformation by a strain of myxobacteria through enzymatic reaction(s).


UK audit of relative lung function measurement from planar radionuclide imaging.
Quantitative measurements of regional lung ventilation and perfusion are useful adjuncts to image interpretation. This study investigated the accuracy and precision of the software used to carry out such measurements in the UK. Ten examples of perfusion distribution, representing the range of patterns expected in practice, were simulated on computer using a segmental model of the lung and real three-dimensional lung shapes obtained from magnetic resonance images. Pairs of anterior and posterior perfusion images were simulated and distributed to UK hospitals wishing to take part in the audit. Each centre returned analysis results and technical details. Forty centres provided data on the relative right:left lung perfusion. Thirteen also submitted data with each lung divided into three zones and four with each lung divided into two zones. All measurements were expressed by the percentage of total perfusion in a particular region. Errors were assessed as the root-mean-square (rms) deviation from the true value. Methods varied in the view used for analysis (80% geometric mean, 20% posterior) and the use of background subtraction (71% not used, 29% used). The rms error for percentage right assessment was 1.5 percentage points. This increased on two- and three-zone analysis to 3.8 and 4.3 percentage points, respectively. Differences in technique made little difference to whole-lung relative perfusion errors, but were important in zonal analysis. Quantification of whole-lung relative function is accurate and reproducible. Zonal values are determined less accurately, but still provide a useful guide to the distribution of function.


Usefulness of ambulatory blood pressure monitoring in pregnant women with type 1 diabetes.
Pregnancy in type 1 diabetes is associated with an increased risk of developing pregnancy-induced hypertension (PIH). Ambulatory blood pressure monitoring (ABPM) has been used to screen for preeclampsia in nondiabetic pregnancy. To date, there are no data regarding ABPM during pregnancy in normotensive type 1 diabetic women. This study sought to establish blood pressure (BP) profiles for pregnant type 1 diabetic women using ABPM and determine whether the BP pattern can define a population at risk for developing PIH. ABPM was carried out for one 24-h period during each trimester--in the first trimester between weeks 7 and 12, in the second trimester between weeks 20 and 24, and in the third trimester between weeks 30 and 34--in 22 normotensive pregnant type 1 diabetic and 10 pregnant nondiabetic women. The incidence of PIH was fourfold greater in type 1 diabetic women than in control subjects. Diabetic women showed higher daily diastolic BP in the third trimester compared with nondiabetic pregnant women. Diabetic women who developed PIH in the third trimester showed significantly higher BP profiles throughout gestation than those who remained normotensive. Receiver operator characteristics curves for nighttime systolic BP showed the best predictive capacity for PIH, with a cutoff > 105 mmHg (85% sensitivity and 92% specificity). Our study confirms the early increase of BP in patients who will develop PIH and suggests that nighttime systolic BP >105 mmHg in the second trimester is a useful predictor of PIH. ABPM may be useful in screening for PIH in pregnant diabetic women.


Outbreak of Salmonella give in the province of Quebec.
Salmonellosis due to Salmonella Give involving cows, a goat, and an ostrich over a 6-month period was investigated. Cases were found in 4 different regions. Antimicrobial susceptibility patterns, phagetyping, and pulsed-field gel electrophoresis analyses confirmed that all isolates belonged to the same clone. A common source of infection was suspected.


A mild case of Friedreich ataxia: lymphocyte and sural nerve analysis for GAA repeat length reveals somatic mosaicism.
Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disease, characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, Babinski sign, loss of position and vibration senses, cardiomyopathy, and carbohydrate intolerance. It is the most common inherited ataxia, and is associated with a GAA triplet repeat expansion in the first intron of the X25 gene on the long arm of chromosome 9. We present a case whose clinical diagnosis was initially confounded by the mildness of the ataxic phenotype and a family history of multiple sclerosis. Evaluation of the X25 gene revealed that the patient was homozygous for the GAA triplet repeat expansion, pathognomonic of FRDA. Investigation of her sural nerve biopsy revealed a significantly smaller expansion size, constituting the first direct demonstration of somatic mosaicism involving the nervous system in FRDA. We speculate that a similar contraction in pathologically affected tissues could be the molecular basis for the mildness of the ataxia.


Glycan-foraging systems reveal the adaptation of Capnocytophaga canimorsus to the dog mouth.
Capnocytophaga canimorsus is known to form two kinds of cells on blood agar plates (coccoid and bacillary), evoking phase variation. When grown in coculture with animal cells these bacteria appeared only as bacilli, but in the presence of vancomycin they were round, indicating that coccoid shapes likely result from weakening of the peptidoglycan layer. Polysaccharide utilization locus 5 (PUL5) and sialidase mutant bacteria, unable to retrieve glycans from glycoproteins, grew less than wild-type bacteria and also appeared polymorphic unless GlcNAc was added, suggesting that C. canimorsus is unable to synthesize GlcNAc, an essential component of peptidoglycan. Accordingly, a genome analysis was conducted and revealed that C. canimorsus strain 5 lacks the GlmM and GlmU enzymes, which convert glucosamine into GlcNAc. Expression of the Escherichia coli GlmM together with the acetyltransferase domain of GlmU allowed PUL5 mutant bacteria to grow normally, indicating that C. canimorsus is a natural auxotroph that relies on GlcNAc harvested from the host N-glycoproteins for peptidoglycan synthesis. Mucin, a heavily O-glycosylated protein abundant in saliva, also rescued growth and the shape of PUL5 mutant bacteria. Utilization of mucin was found to depend on Muc, a Sus-like system encoded by PUL9. Contrary to all known PUL-encoded systems, Muc cleaves peptide bonds of mucin rather than glycosidic linkages. Thus, C. canimorsus has adapted to build its peptidoglycan from the glycan-rich dog's mouth glycoproteins. Capnocytophaga canimorsus is a bacterium that lives as a commensal in the dog mouth and causes severe infections in humans. In vitro, it forms two kinds of cells (coccoid and bacillary), evoking phase variation. Here, we show that cell rounding likely results from weakening of the peptidoglycan layer due to a shortage of N-acetylglucosamine (GlcNAc). C. canimorsus cannot synthesize GlcNAc because of the lack of key enzymes. In its niche, the dog mouth, C. canimorsus retrieves GlcNAc by foraging glycans from salivary mucin and N-linked glycoproteins through two different apparatuses, Muc and Gpd, both of which are related to the Bacteroides starch utilization system. The Muc system is peculiar in the sense that the enzyme of the complex is a protease and not a glycosylhydrolase, as it cleaves peptide bonds in order to capture glycan chains. This study provides a molecular genetic demonstration for the complex adaptation of C. canimorsus to its ecological niche, the oral cavity of dogs.


Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU): review of its possible role in schizophrenia therapy.
Most patients with schizophrenia need life-long treatment. There is therefore a continued need for effective and tolerable treatment options. A 2-monthly LAI formulation of aripiprazole, Aripiprazole 2-Month Ready-to-Use 960 mg (Ari 2MRTU 960) has recently been approved in the US. Here, the possible role in therapy for this new treatment option is discussed in a narrative review. PubMed was searched for literature on long-acting injectables with a focus on patient-reported outcomes and real-world evidence on extended injection intervals (2-3 months). Dopamine D2 partial agonists, one of which is aripiprazole, exhibit favorable tolerability and safety properties. Additionally, there are many advantages in using long-acting injectable formulations such as enhanced treatment persistence and stability of patients as well as reduced rates of relapses, hospitalizations, and death. Some of these advantages become more pronounced with longer injection intervals. Additional advantages of longer injection intervals are more room for non-medication-related communication between healthcare professionals and patients, patient and physician preferences, reduced caregiver burden, and easier transitioning from inpatient to outpatient treatment. Taken together, since aripiprazole may be a good treatment choice for many patients based on its favorable safety and tolerability profile, and given the advantages of LAI treatment over oral treatment and the advantages of reduced dosing frequency, Ari 2MRTU 960 may become an important treatment option for many clinically stable patients with schizophrenia.


Lactols in hydrolysates of DNA treated with alpha-acetoxy-N-nitrosopyrrolidine or crotonaldehyde.
alpha-Acetoxy-N-nitrosopyrrolidine (alpha-acetoxyNPYR) is a stable precursor to alpha-hydroxyNPYR, the initial product of metabolism and proposed proximate carcinogen of N-nitrosopyrrolidine (NPYR). Crotonaldehyde (2-butenal) is a metabolite of NPYR and also a mutagen and carcinogen. Both alpha-acetoxyNPYR and crotonaldehyde form DNA adducts, but these reactions have not been completely characterized. In previous studies, we detected substantial amounts of unidentified radioactivity in hydrolysates of DNA that had been treated with radiolabeled alpha-acetoxyNPYR. In this study, we have characterized these products as 2-hydroxytetrahydrofuran, the cyclic form of 4-hydroxybutanal, and paraldol, the dimer of 3-hydroxybutanal. These products were identified by comparison to standards and by conversion to 2,4-dinitrophenylhydrazones. 2-Hydroxytetrahydrofuran is the major product in neutral thermal hydrolysates of alpha-acetoxyNPYR-treated DNA and is derived predominantly from N2-(tetrahydrofuran-2-yl)deoxyguanosine 8. Paraldol is present to a lesser extent than 2-hydroxytetrahydrofuran in these reactions and is formed from paraldol-releasing adducts, which in turn are produced in the reaction of crotonaldehyde, a solvolysis product of alpha-acetoxyNPYR, with DNA. Other products in hydrolysates of alpha-acetoxyNPYR-treated DNA are N7-substituted guanines 5 and 6, cyclic N7-C8 guanines 4, 11, and 12, and 1, N2-propanodeoxyguanosines 9 and 10. Paraldol is a major product in hydrolysates of crotonaldehyde-treated DNA, being present in amounts 100 times greater than those of previously identified adducts 9 and 10. The results of this study provide a more complete picture of the reactions of alpha-acetoxyNPYR with DNA and yield some new insights about possible endogenous DNA adducts formed from crotonaldehyde.


Efficacy of coenzyme Q10 in patients with cardiac failure: a meta-analysis of clinical trials.
The therapeutic efficacy of coenzyme Q10 on patients with cardiac failure remains controversial. We pooled previous clinical studies to re-evaluate the efficacy of coenzyme Q10 in patients with cardiac failure. We searched PubMed, Cochrane Library, EMBASE, and Clinical Trials.gov databases for controlled trials. The endpoints were death, left heart ejection fraction, exercise capacity, and New York Heart Association (NYHA) cardiac function classification after treatment. The pooled risk ratios (RRs) and standardized mean difference (SMD) were used to assess the efficacy of coenzyme Q10. A total of 14 RCTs with 2149 patients met the inclusion criteria and were included in the analysis. Coenzyme Q10 decreased the mortality compared with placebo (RR = 0.69; 95% CI = 0.50-0.95; P = 0.02; I 2 = 0%). A greater improvement in exercise capacity was established in patients who used coenzyme Q10 than in those who used placebo (SMD = 0.62; 95% CI = 0.02-0.30; P = 0.04; I 2 = 54%). No significant difference was observed in the endpoints of left heart ejection fraction between patients who received coenzyme Q10 and the patients in whom placebo was administered (SMD = 0.62; 95% CI = 0.02-1.12; P = 0.04; I 2 = 75%). The two types of treatment resulted in obtaining similar NYHA classification results (SMD = -0.70; 95% CI = -1.92-0.51; P = 0.26; I 2 = 89%). Patients with heart failure who used coenzyme Q10 had lower mortality and a higher exercise capacity improvement than the placebo-treated patients with heart failure. No significant differences between the efficacy of the administration of coenzyme Q10 and placebo in the endpoints of left heart ejection fraction and NYHA classification were observed.


The Effects of Brazilian Green Propolis against Excessive Light-Induced Cell Damage in Retina and Fibroblast Cells.
Background. We investigated the effects of Brazilian green propolis and its constituents against white light- or UVA-induced cell damage in mouse retinal cone-cell line 661W or human skin-derived fibroblast cells (NB1-RGB). Methods. Cell damage was induced by 3,000lx white light for 24 h or 4/10 J/cm(2) UVA exposure. Cell viability was assessed by Hoechst33342 and propidium iodide staining or by tetrazolium salt (WST-8) cell viability assay. The radical scavenging activity of propolis induced by UVA irradiation in NB1-RGB cells was measured using a reactive-oxygen-species- (ROS-) sensitive probe CM-H2DCFDA. Moreover, the effects of propolis on the UVA-induced activation of p38 and extracellular signal-regulated kinase (ERK) were examined by immunoblotting. Results. Treatment with propolis and two dicaffeoylquinic acids significantly inhibited the decrease in cell viability induced by white light in 661W. Propolis and its constituents inhibited the decrease in cell viability induced by UVA in NB1-RGB. Moreover, propolis suppressed the intracellular ROS production by UVA irradiation. Propolis also inhibited the levels of phosphorylated-p38 and ERK by UVA irradiation. Conclusion. Brazilian green propolis may become a major therapeutic candidate for the treatment of AMD and skin damage induced by UV irradiation.


Uncoupling of dynamin polymerization and GTPase activity revealed by the conformation-specific nanobody dynab.
Dynamin is a large GTPase that forms a helical collar at the neck of endocytic pits, and catalyzes membrane fission (Schmid and Frolov, 2011; Ferguson and De Camilli, 2012). Dynamin fission reaction is strictly dependent on GTP hydrolysis, but how fission is mediated is still debated (Antonny et al., 2016): GTP energy could be spent in membrane constriction required for fission, or in disassembly of the dynamin polymer to trigger fission. To follow dynamin GTP hydrolysis at endocytic pits, we generated a conformation-specific nanobody called dynab, that binds preferentially to the GTP hydrolytic state of dynamin-1. Dynab allowed us to follow the GTPase activity of dynamin-1 in real-time. We show that in fibroblasts, dynamin GTP hydrolysis occurs as stochastic bursts, which are randomly distributed relatively to the peak of dynamin assembly. Thus, dynamin disassembly is not coupled to GTPase activity, supporting that the GTP energy is primarily spent in constriction.


Determination of the bruise degree for cherry using Vis-NIR reflection spectroscopy coupled with multivariate analysis.
Determination and classification of the bruise degree for cherry can improve consumer satisfaction with cherry quality and enhance the industry's competiveness and profitability. In this study, visible and near infrared (Vis-NIR) reflection spectroscopy was used for identifying bruise degree of cherry in 350-2500 nm. Sampling spectral data were extracted from normal, slight and severe bruise samples. Principal component analysis (PCA) was implemented to determine the first few principal components (PCs) for cluster analysis among samples. Optimal wavelengths were selected by loadings of PCs from PCA and successive projection algorithm (SPA) method, respectively. Afterwards, these optimal wavelengths were empolyed to establish the classification models as inputs of least square-support vector machine (LS-SVM). Better performance for qualitative discrimination of the bruise degree for cherry was emerged in LS-SVM model based on five optimal wavelengths (603, 633, 679, 1083, and 1803 nm) selected directly by SPA, which showed acceptable results with the classification accuracy of 93.3%. Confusion matrix illustrated misclassification generally occurred in normal and slight bruise samples. Furthermore, the latent relation between spectral property of cherries in varying bruise degree and its firmness and soluble solids content (SSC) was analyzed. The result showed both colour, firmness and SSC were consistent with the Vis-NIR reflectance of cherries. Overall, this study revealed that Vis-NIR reflection spectroscopy integrated with multivariate analysis can be used as a rapid, intact method to determine the bruise degree of cherry, laying a foundation for cherry sorting and postharvest quality control.


Monitoring forest structure at landscape level: a case study of Scots pine forest in NE Turkey.
This study aims to investigate the change in spatial-temporal configuration of secondary forest succession and generate measurements for monitoring the changes in structural plant diversity in Yalnizçam Scots pine forest in NE Turkey from 1972 to 2005. The successional stages were mapped using the combination of Geographic Information System (GIS), Global Positioning System (GPS), aerial photos and high resolution satellite images (IKONOS). Forest structure and its relationship with structural plant diversity along with its changes over time were characterized using FRAGSTATS. In terms of spatial configuration of seral stages, the total number of fragments increased from 572 to 735, and mean size of patch (MPS) decreased from 154.97 ha to 120.60 ha over 33 years. The situation resulted in forestation serving appropriate conditions for plant diversity in the area. As an overall change in study area, there was a net increase of 1823.3 ha forest during the period with an average annual forestation rate of 55.25 ha year(-1) (0.4% per year). In conclusion, the study revealed that stand type maps of forest management plans in Turkey provide a great chance to monitor the changes in structural plant diversity over time. The study further contributes to the development of a framework for effective integration of biodiversity conservation into Multiple Use Forest Management (MUFM) plans using the successional stages as a critical mechanism.


Exploring Hydrogen Storage Capacity in Metal-Organic Frameworks: A Bayesian Optimization Approach.
Metal-organic Frameworks (MOFs) can be employed for gas storage, capture, and sensing. Finding the MOF with the best adsorption property from a large database is usual for adsorption calculations. In high-throughput computational research, the expense of computing thermodynamic quantities limits the finding of MOFs for separations and storage. In this work, we demonstrate the usefulness of Bayesian optimization (BO) for estimating the H2 uptake capability of MOFs by using an existing dataset containing 98000 real and hypothetical MOFs. We demonstrate that in order to recover the best candidate MOFs, less than 0.027 % of the database needs to be screened using the BO method. This allows future adsorption experiments on a small sample of MOFs to be undertaken with minimal experimental effort by effectively screening MOF databases. In addition, the presented BO can provide comprehensible material design insights, and the framework will be transferable to optimizing other target properties. We also suggest using Particle Swarm Optimisation (PSO), a swarm intelligence technique in artificial intelligence, to estimate MOFs' H2 uptake potential to achieve results comparable to BO. In addition, we implement a novel modification of PSO called Evolutionary-PSO (EPSO) to compare and find interesting outcomes.


The initial effects of occlusal splint vertical thickness on the nocturnal EMG activities of masticatory muscles in subjects with a bruxism habit.
The objective of this study was to investigate the initial effects of the vertical thickness of occlusal splints on the electromyographic (EMG) activities (integrated EMG values) of temporal and masseter muscles during sleep in subjects with a nocturnal bruxism habit using a portable EMG recorder. The subjects consisted of 12 volunteers (4 men and 8 women, average age of 25.3 years). All subjects had never worn splints before and had a habit of nocturnal bruxism. Two types of splint were made for every subject: a splint with a 3-mm vertical thickness at the central incisors (S3) and a splint with a 6-mm vertical thickness (S6). The muscle activities of the left anterior temporal muscles and masseter muscles were recorded without occlusal splints (NS), with the S3 splint, and with the S6 splint by a portable EMG recorder. The integrated EMG values were calculated to examine muscle activities under the 3 different conditions. The integrated EMG values of masseter and temporal muscles decreased following insertion of the S3 splint but were not significantly affected by the S6 splint. Six subjects in masseter EMG and 7 subjects in temporal EMG got worse with the S6 splint compared to NS. When the occlusal splints were used as a bruxism countermeasure, it was suggested from the analysis of muscle activities during sleep at night that the S3 splint was superior to the S6 splint.


Regulation of bacteriophage mu and mini-mu DNA replication in vivo.
To study the regulation of bacteriophage Mu DNA's integrative-replication (transposition) during lytic growth in a cell containing both a Mu and a helper-dependent Mini-Mu (short, internally-deleted Mu genome), we placed "marker" genes (bla, lacZ) within either genome and then measured their encoded enzymes as indicators of the gene dosage. These results, corroborated using DNA-DNA hybridization, show that Mu and Mini-Mu DNA transposition is well regulated, requires both the Mu A and B gene products, and can be readily monitored by measuring beta-galactosidase and beta-lactamase expressed from the lacZ and bla genes, respectively.


A novel strategy for NMR resonance assignment and protein structure determination.
The quality of protein structures determined by nuclear magnetic resonance (NMR) spectroscopy is contingent on the number and quality of experimentally-derived resonance assignments, distance and angular restraints. Two key features of protein NMR data have posed challenges for the routine and automated structure determination of small to medium sized proteins; (1) spectral resolution - especially of crowded nuclear Overhauser effect spectroscopy (NOESY) spectra, and (2) the reliance on a continuous network of weak scalar couplings as part of most common assignment protocols. In order to facilitate NMR structure determination, we developed a semi-automated strategy that utilizes non-uniform sampling (NUS) and multidimensional decomposition (MDD) for optimal data collection and processing of selected, high resolution multidimensional NMR experiments, combined it with an ABACUS protocol for sequential and side chain resonance assignments, and streamlined this procedure to execute structure and refinement calculations in CYANA and CNS, respectively. Two graphical user interfaces (GUIs) were developed to facilitate efficient analysis and compilation of the data and to guide automated structure determination. This integrated method was implemented and refined on over 30 high quality structures of proteins ranging from 5.5 to 16.5 kDa in size.


Deep Independence Network Analysis of Structural Brain Imaging: Application to Schizophrenia.
Linear independent component analysis (ICA) is a standard signal processing technique that has been extensively used on neuroimaging data to detect brain networks with coherent brain activity (functional MRI) or covarying structural patterns (structural MRI). However, its formulation assumes that the measured brain signals are generated by a linear mixture of the underlying brain networks and this assumption limits its ability to detect the inherent nonlinear nature of brain interactions. In this paper, we introduce nonlinear independent component estimation (NICE) to structural MRI data to detect abnormal patterns of gray matter concentration in schizophrenia patients. For this biomedical application, we further addressed the issue of model regularization of nonlinear ICA by performing dimensionality reduction prior to NICE, together with an appropriate control of the complexity of the model and the usage of a proper approximation of the probability distribution functions of the estimated components. We show that our results are consistent with previous findings in the literature, but we also demonstrate that the incorporation of nonlinear associations in the data enables the detection of spatial patterns that are not identified by linear ICA. Specifically, we show networks including basal ganglia, cerebellum and thalamus that show significant differences in patients versus controls, some of which show distinct nonlinear patterns.


An experimental model to measure the ability of headphones with active noise control to reduce patient's exposure to noise in an intensive care unit.
Defining the association between excessive noise in intensive care units, sleep disturbance and morbidity, including delirium, is confounded by the difficulty of implementing successful strategies to reduce patient's exposure to noise. Active noise control devices may prove to be useful adjuncts but there is currently little to quantify their ability to reduce noise in this complex environment. Sound meters were embedded in the auditory meatus of three polystyrene model heads with no headphones (control), with headphones alone and with headphones using active noise control and placed in patient bays in a cardiac ICU. Ten days of recording sound levels at a frequency of 1 Hz were performed, and the noise levels in each group were compared using repeated measures MANOVA and subsequent pairwise testing. Multivariate testing demonstrated that there is a significant difference in the mean noise exposure levels between the three groups (p < 0.001). Subsequent pairwise testing between the three groups shows that the reduction in noise is greatest with headphones and active noise control. The mean reduction in noise exposure between the control and this group over 24 h is 6.8 (0.66) dB. The use of active noise control was also associated with a reduction in the exposure to high-intensity sound events over the course of the day. The use of active noise cancellation, as delivered by noise-cancelling headphones, is associated with a significant reduction in noise exposure in our model of noise exposure in a cardiac ICU. This is the first study to look at the potential effectiveness of active noise control in adult patients in an intensive care environment and shows that active noise control is a candidate technology to reduce noise exposure levels the patients experience during stays on intensive care.


Long-Range Lateral Correlation between Self-Assembled Domains of Fluorocarbon-Hydrocarbon Tetrablocks by Quantitative GISAXS.
The structure and lateral correlation of fluorocarbon-hydrocarbon tetrablock di(F10Hm) domains at the air/water interface have been determined by quantitative analysis of grazing incidence small-angle X-ray scattering (GISAXS) data. The measured GISAXS signals can be well represented by the full calculation of the form and structure factors. The form factor suggests that di(F10Hm) domains take a hemiellipsoid shape. Both major and minor axes of the hemiellipsoids monotonically increased in response to the elongation of the hydrocarbon blocks, which can be explained by the concominant increase in van der Waals interaction. The structure factor calculated from the GISAXS signals suggests that the domains take an orthorhombic lattice. Remarkably, the lateral correlation can reach over a distance that is more than 14 times longer than the distance to the nearest neighbors. Our data suggest that quantitative GISAXS enables the optimal design of mesoscopic self-assemblies at the air/water interface by fine-tuning of the structures of molecular building blocks.


Serious events in older Ontario residents receiving bowel preparations for outpatient colonoscopy with various comorbidity profiles: a descriptive, population-based study.
Polyethylene glycol-based bowel preparations (PEGBPs) and sodium picosulfate (NaPS) are commonly used for bowel cleansing before colonoscopy. Little is known about adverse events associated with these preparations, particularly in older patients or patients with medical comorbidities. To characterize the incidence of serious events following outpatient colonoscopy in patients using PEGBPs or NaPS. The present population-based retrospective cohort study examined data from Ontario health care databases between April 1, 2005 and December 31, 2007, including patients >=66 years of age who received either PEGBP or NaPS for an outpatient colonoscopy. Patients with cardiac or renal disease, long-term care residents or patients receiving concurrent diuretic therapy were identified as high risk for adverse events. The primary outcome was a serious event (SE) defined as a composite of nonelective hospitalization, emergency department visit or death within seven days of the colonoscopy. Of the 50,660 outpatients >=66 years of age who underwent a colonoscopy, SEs were observed in 675 (2.4%) and 543 (2.4%) patients in the PEGBP and NaPS groups, respectively. Among high-risk patients (n=30,168), SEs occurred in 481 (2.8%) and 367 (2.8%) of patients receiving PEGBP and NaPS, respectively. The SE rate within seven days of outpatient colonoscopy was 24 per 1000 procedures, and among high-risk patients was 28 per 1000 procedures. The rates were similar for PEGBP and NaPS. Clinicians should be aware of the risks associated with colonoscopy in older patients with comorbidities.


15O PET measurement of blood flow and oxygen consumption in cold-activated human brown fat.
Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog (18)F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and (18)F-FDG tracer uptake. Twenty-five healthy adults (15 women and 10 men; mean age ± SD, 30 ± 7 y) underwent triple-oxygen scans (H2(15)O, C(15)O, and (15)O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.5°C [60°F]) using indirect calorimetry. The subjects were divided into 2 groups (high BAT and low BAT) based on the presence or absence of (18)F-FDG tracer uptake (standardized uptake value [SUV] > 2) in cervical-supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) were calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue. Regional blood oxygen saturation was determined by near-infrared spectroscopy. The total energy expenditure during rest and mild cold stress was measured by indirect calorimetry. Tissue-level metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to DEE. The mass of activated BAT was 59.1 ± 17.5 g (range, 32-85 g) in the high-BAT group (8 women and 1 man; mean age, 29.6 ± 5.5 y) and 2.2 ± 3.6 g (range, 0-9.3 g) in the low-BAT group (9 men and 7 women; mean age, 31.4 ± 10 y). Corresponding maximal SUVs were significantly higher in the high-BAT group than in the low-BAT group (10.7 ± 3.9 vs. 2.1 ± 0.7, P = 0.01). Blood flow values were significantly higher in the high-BAT group than in the low-BAT group for BAT (12.9 ± 4.1 vs. 5.9 ± 2.2 mL/100 g/min, P = 0.03) and white adipose tissue (7.2 ± 3.4 vs. 5.7 ± 2.3 mL/100 g/min, P = 0.03) but were similar for muscle (4.4 ± 1.9 vs. 3.9 ± 1.7 mL/100 g/min). Moreover, OEF in BAT was similar in the 2 groups (0.51 ± 0.17 in high-BAT group vs. 0.47 ± 0.18 in low-BAT group, P = 0.39). During mild cold stress, calculated MRO2 values in BAT increased from 0.97 ± 0.53 to 1.42 ± 0.68 mL/100 g/min (P = 0.04) in the high-BAT group and were significantly higher than those determined in the low-BAT group (0.40 ± 0.28 vs. 0.51 ± 0.23, P = 0.67). The increase in DEE associated with BAT oxidative metabolism was highly variable in the high-BAT group, with an average of 3.2 ± 2.4 kcal/d (range, 1.9-4.6 kcal/d) at rest, and increased to 6.3 ± 3.5 kcal/d (range, 4.0-9.9 kcal/d) during exposure to mild cold. Although BAT accounted for only a small fraction of the cold-induced increase in DEE, such increases were not observed in subjects lacking BAT. Mild cold-induced thermogenesis in BAT accounts for 15-25 kcal/d in subjects with relatively large BAT depots. Thus, although the presence of active BAT is correlated with cold-induced energy expenditure, direct measurement of MRO2 indicates that BAT is a minor source of thermogenesis in humans.


Pulmonary functional magnetic resonance imaging: asthma temporal-spatial maps.
Hyperpolarized (3)He magnetic resonance imaging (MRI) previously revealed the temporal and spatial heterogeneity of ventilation defects in asthmatics, but these findings have not been used in treatment studies or to guide personalized therapy. Our objective was to exploit the temporal and spatial information inherent to (3)He MRI and develop image processing methods to generate pulmonary ventilation temporal-spatial maps that could be used to measure, optimize, and guide asthma therapy. In this proof-of-concept study, seven asthmatics provided written informed consent to an approved protocol and underwent spirometry and (3)He MRI on three occasions, each 5 ± 2 days apart. A registration and segmentation pipeline was developed to generate three-dimensional, temporal-spatial, pulmonary function maps. Briefly, (3)He ventilation images were segmented to generate ventilation masks that were coregistered and voxels classified according to their temporal behavior. This enabled the regional mapping of temporally persistent and intermittent ventilation defects that were normalized to the (1)H MRI thoracic cavity volume to generate persistent ventilation defect percent (VDPP) and intermittent ventilation defect percent (VDPI). (3)He temporal-spatial pulmonary function maps identified temporally persistent and intermittent ventilation defects. VDP(I) was significantly greater in the posterior (P = .04) and inferior (P = .04) lung as compared to the anterior and superior lung. Persistent and intermittent ventilation defect percent were strongly correlated with forced expiratory volume in one second/forced vital capacity (VDP(P): r = -0.87, P = .01; VDP(I): r = -0.96, P = .0008). Temporal-spatial pulmonary maps generated from (3)He MRI can be used to quantify temporally persistent and intermittent ventilation defects as asthma intermediate end points and targets for therapy.


Synthesis and microarray-assisted binding studies of core xylose and fucose containing N-glycans.
The synthesis of a collection of 33 xylosylated and core-fucosylated N-glycans found only in nonmammalian organisms such as plants and parasitic helminths has been achieved by employing a highly convergent chemo-enzymatic approach. The influence of these core modifications on the interaction with plant lectins, with the human lectin DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin), and with serum antibodies from schistosome-infected individuals was studied. Core xylosylation markedly reduced or completely abolished binding to several mannose-binding plant lectins and to DC-SIGN, a C-type lectin receptor present on antigen presenting cells. Employing the synthetic collection of core-fucosylated and core-xylosylated N-glycans in the context of a larger glycan array including structures lacking these core modifications, we were able to dissect core xylose and core fucose specific antiglycan antibody responses in S. mansoni infection sera, and we observed clear and immunologically relevant differences between children and adult groups infected with this parasite. The work presented here suggests that, quite similar to bisecting N-acetylglucosamine, core xylose distorts the conformation of the unsubstituted glycan, with important implications for the immunogenicity and protein binding properties of complex N-glycans.


Establishment of a liaison clinic for patients with intractable chronic pain.
A multidisciplinary approach has been shown to be effective for the treatment of intractable pain. However, few hospitals in Japan have established liaison clinics for such patients. In this study, we investigated the short-term results of a liaison clinic for patients with intractable chronic pain. Study participants comprised 53 outpatients (20 men, 33 women) with intractable chronic pain who visited our hospital between April 2012 and March 2013. At baseline, patients completed a self-reported questionnaire and provided demographic and clinical information. Experts in various fields (anesthesia, orthopedic surgery, psychiatry, physical therapy, and nursing) conducted examinations of patients and attended a weekly conference during which patients' physical, psychological, and social problems were discussed and courses of treatment were determined. All patients were assessed using the Numerical Rating Scale (NRS), Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS), and Pain Disability Assessment Scale (PDAS). Eligibility for the pain liaison outpatient clinic was evaluated using multiple logistic regression analysis. After a 6-month follow-up period, no significant changes were seen in scores for the NRS, PDAS, or HADS for depression. In contrast, scores for both the PCS and HADS for anxiety were significantly reduced after 6 months of treatment (p < 0.05). HADS for anxiety was identified as a factor related to patient resistance to attending the pain liaison outpatient clinic (p < 0.05). This liaison clinic for patients with intractable chronic pain was able to improve patient anxiety. Severe anxiety at the initial visit represented a risk factor for dropout from the clinic.


Contributions of SpoT Hydrolase, SpoT Synthetase, and RelA Synthetase to Carbon Source Diauxic Growth Transitions in Escherichia coli.
During the diauxic shift, Escherichia coli exhausts glucose and adjusts its expression pattern to grow on a secondary carbon source. Transcriptional profiling studies of glucose-lactose diauxic transitions reveal a key role for ppGpp. The amount of ppGpp depends on RelA synthetase and the balance between a strong SpoT hydrolase and its weak synthetase. In this study, mutants are used to search for synthetase or hydrolase specific regulation. Diauxic shifts experiments were performed with strains containing SpoT hydrolase and either RelA or SpoT synthetase as the sole source of ppGpp. Here, the length of the diauxic lag times is determined by the presence of ppGpp, showing contributions of both ppGpp synthetases (RelA and SpoT) as well as its hydrolase (SpoT). A balanced ppGpp response is key for a proper adaptation during diauxic shift. The effects of one or the other ppGpp synthetase on diauxic shifts are abolished by addition of amino acids or succinate, although by different mechanisms. While amino acids control the RelA response, succinate blocks the uptake of the excreted acetate via SatP. Acetate is converted to Acetyl-CoA through the ackA-pta pathway, producing Ac-P as intermediate. Evidence of control of the ackA-pta operon as well as a correlation between ppGpp and Ac-P is shown. Finally, acetylation of proteins is shown to occur during a diauxic glucose-lactose shift.


There is more to a lipid than just being a fat: sphingolipid-guided differentiation of oligodendroglial lineage from embryonic stem cells.
Dr. Robert K. Yu's research showed for the first time that the composition of glycosphingolipids is tightly regulated during embryo development. Studies in our group showed that the glycosphingolipid precursor ceramide is also critical for stem cell differentiation and apoptosis. Our new studies suggest that ceramide and its derivative, sphingosine-1-phosphate (S1P), act synergistically on embryonic stem (ES) cell differentiation. When using neural precursor cells (NPCs) derived from ES cells for transplantation, residual pluripotent stem (rPS) cells pose a significant risk of tumor formation after stem cell transplantation. We show here that rPS cells did not express the S1P receptor S1P1, which left them vulnerable to ceramide or ceramide analog (N-oleoyl serinol or S18)-induced apoptosis. In contrast, ES cell-derived NPCs expressed S1P1 and were protected in the presence of S1P or its pro-drug analog FTY720. Consistent with previous studies, FTY720-treated NPCs differentiated predominantly toward oligodendroglial lineage as tested by the expression of the oligodendrocyte precursor cell (OPC) markers Olig2 and O4. As the consequence, a combined administration of S18 and FTY720 to differentiating ES cells eliminated rPS cells and promoted oligodendroglial differentiation. In addition, we show that this combination promoted differentiation of ES cell-derived NPCs toward oligodendroglial lineage in vivo after transplantation into mouse brain.


Digitally Created 3-Piece Additive Manufactured Index for Direct Esthetic Treatment.
Facial and intraoral scanners as well as additive manufacturing (AM) technologies can be integrated to virtually plan restorative procedures. The present article describes a digital workflow protocol for treatment planning an esthetic rehabilitation using direct composite restorations. The combination of facial digitalization and intraoral scans allowed a facially driven diagnostic waxing, while additive manufacturing technologies facilitate the translation of the digital waxing into the patient´s mouth through an AM 3-piece silicone index which was designed into a buccal and a lingual clear flexible silicone indices that were fitted into a clear and rigid custom tray. This procedure facilitated the treatment planning procedures as well as assisted the direct composite restoration procedures, providing several advantages compared with conventional procedures such as precise translation of the digital diagnostic waxing into the patient´s mouth, horizontal path of insertion of the silicone index, and minimized time of the clinical intervention.


High molecular weight forms of IGF-II ('big-IGF-II') released by Wilms' tumor cells.
Insulin-like growth factor-II (IGF-II) is thought to play a critical role in the development of embryonic tumors such as Wilms' tumor. However, despite highly elevated IGF-II mRNA levels in tumors, IGF-II is not elevated in the serum of patients with Wilms' tumors. Recently high molecular weight forms of IGF-II ('big'- or pro-IGF-II) have been found to be produced by some tumors. In order to prove whether or not high molecular weight forms of IGF-II are produced by Wilms' tumor cells and secreted into the culture medium, we established Wilms' tumor cell lines. After column chromatography of the culture medium, IGF-II and pro-IGF-II concentrations were measured. For pro-IGF-II measurement we established a pro-IGF-II RIA using a rabbit polyclonal antiserum directed against amino acids 7-21 (E7-21) of the E-domain of pro-IGF-II. Gel electrophoresis and Western blotting with anti-IGF-II antibodies revealed a band at 7.5 kDa corresponding to fully processed IGF-II and bands between 10 and 20 kDa. Using pro-IGF-II antiserum, bands between 10 and 25 kDa were detected. We conclude that in vitro cultured Wilms' tumor cells produce and release various forms of 'big IGF-II' with molecular masses between 10 and 25 kDa. It remains uncertain whether these high molecular weight forms of IGF-II represent normal precursors of IGF-II or incorrectly processed IGF-II.