Familial deficiency of glutathione reductase in human blood cells.
A virtually complete absence of glutathione reductase activity was found in the erythrocytes of all three children (one male, two females) from a consanguineous marriage. Intermediate values were found in the erythrocytes of both parents. The enzyme activity could not be restored either by addition of FAD in vitro or by administration of riboflavin in vivo. The amount of reduced glutathione in the erythrocytes was normal in each case. Severely diminished glutathione stability during incubation with acetylphenylhydrazine was observed in the erythrocytes of the siblings, as well as intermediate stability in the parents' red cells. Clinically, this deficiency was manifested by hemolytic crises after eating fava beans in the eldest daughter (patient), and possibly by cataracts in her own and in her brother's eyes. Very low activities of glutathione reductase were also found in the leukocytes of this family: 13%-15% of normal values for the children and 64%-66% for the parents. Moreover, the same deficiency was found in the purified white blood cells of the propositus: 8% of normal values in the polymorphonuclear (PMN) cells, 4% in the lymphocytes, and 15% in the monocytes, together with 11% in the platelets. Finally, we found an abnormal oxygen consumption of the propositus' PMNs after phagocytosis of zymosan particles, suggesting that the glutathione reductase reaction was involved in the bactericidal capacity of these cells.


Simple and rapid separation of soyasaponin Bb from a soy extract.
A simple method to separate soyasaponin Bb from a soy extract is presented. This method is based on the difference in the solubility of soyasaponin Bb and Ba and other components into 3:7 and 1:1 (v/v) acetone-water mixed solvents. The crude soyasaponin consisting of soyasaponins Aa, Ab, Ba, and Bb at the 10 wt% level and other components was examined as the soy extract. A 10 mg quantity of the crude soyasaponin was mixed with 1 mL of the 3:7 acetone-water containing 0.1 mol/L HCl, and the supernatant was removed to obtain a precipitate, which was found to contain mainly soyasaponins Bb and Ba. The precipitate was mixed with 0.4 mL of the 1:1 acetone-water containing 0.1 mol/L HCl; the supernatant was transferred, and was mixed with 0.6 mL of water to obtain a precipitate, which was found to contain mainly soyasaponin Bb. The yield was ca. 30%, which may be much higher than that by the conventional preparative chromatographic approach. The separation method is rapid and easy to carry out, and is useful for the preparation of a soyasaponin Bb sample.


Co-inhibition of epidermal growth factor receptor and insulin-like growth factor receptor 1 enhances radiosensitivity in human breast cancer cells.
Over-expression of epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor (IGF-1R) have been shown to closely correlate with radioresistance of breast cancer cells. This study aimed to investigate the impact of co-inhibition of EGFR and IGF-1R on the radiosensitivity of two breast cancer cells with different profiles of EGFR and IGF-1R expression. The MCF-7 (EGFR +/-, IGF-1R +++) and MDA-MB-468 (EGFR +++, IGF-1R +++) breast cancer cell lines were used. Radiosensitizing effects were determined by colony formation assay. Apoptosis and cell cycle distribution were measured by flow cytometry. Phospho-Akt and phospho-Erk1/2 were quantified by western blot. In vivo studies were conducted using MDA-MB-468 cells xenografted in nu/nu mice. In MDA-MB-468 cells, the inhibition of IGF-1R upregulated the p-EGFR expression. Either EGFR (AG1478) or IGF-1R inhibitor (AG1024) radiosensitized MDA-MB-468 cells. In MCF-7 cells, radiosensitivity was enhanced by AG1024, but not by AG1478. Synergistical radiosensitizing effect was observed by co-inhibition of EGFR and IGF-1R only in MDA-MB-468 cells with a DMF10% of 1.90. The co-inhibition plus irradiation significantly induced more apoptosis and arrested the cells at G0/G1 phase in MDA-MB-468 cells. Only co-inhibition of EGFR and IGF-1R synergistically diminished the expression of p-Akt and p-Erk1/2 in MDA-MB-468 cells. In vivo studies further verified the radiosensitizing effects by co-inhibition of both pathways in a MDA-MB-468 xenograft model. Our data suggested that co-inhibition of EGFR and IGF-1R synergistically radiosensitized breast cancer cells with both EGFR and IGF-1R high expression. The approach may have an important therapeutic implication in the treatment of breast cancer patients with high expression of EGFR and IGF-1R.


Inline 3D Volumetric Measurement of Moisture Content in Rice Using Regression-Based ML of RF Tomographic Imaging.
The moisture content of stored rice is dependent on the surrounding and environmental factors which in turn affect the quality and economic value of the grains. Therefore, the moisture content of grains needs to be measured frequently to ensure that optimum conditions that preserve their quality are maintained. The current state of the art for moisture measurement of rice in a silo is based on grab sampling or relies on single rod sensors placed randomly into the grain. The sensors that are currently used are very localized and are, therefore, unable to provide continuous measurement of the moisture distribution in the silo. To the authors' knowledge, there is no commercially available 3D volumetric measurement system for rice moisture content in a silo. Hence, this paper presents results of work carried out using low-cost wireless devices that can be placed around the silo to measure changes in the moisture content of rice. This paper proposes a novel technique based on radio frequency tomographic imaging using low-cost wireless devices and regression-based machine learning to provide contactless non-destructive 3D volumetric moisture content distribution in stored rice grain. This proposed technique can detect multiple levels of localized moisture distributions in the silo with accuracies greater than or equal to 83.7%, depending on the size and shape of the sample under test. Unlike other approaches proposed in open literature or employed in the sector, the proposed system can be deployed to provide continuous monitoring of the moisture distribution in silos.


Anemia of aging: the role of chronic inflammation and cancer.
Aging is associated with increased incidence and prevalence of anemia, leading to a number of adverse health outcomes. These include death, functional dependence, increased risk of therapeutic complications, falls, and dementia. In approximately 30% of cases, anemia in older individuals is due to either relative or absolute erythropoietin (EPO) deficiency. Absolute EPO deficiency may be primary or secondary to declining renal function. Relative EPO deficiency is due to an age-related pro-inflammatory status that reduces the sensitivity of erythropoietic precursors to EPO. Despite this condition of EPO deficiency, the management of anemia of aging with erythropoiesis-stimulating agents (ESAs) is controversial, unless the anemia is due to renal insufficiency. The main concern related to this treatment arises from eight studies of ESAs in cancer, suggesting that ESAs may reduce patient survival in addition to increasing the risk of deep vein thrombosis. The results of these studies contrast with a host of other trials showing the safety of ESAs. The discrepancy may be explained in part by the fact that, in the trials suggesting a detrimental effect of ESAs, the goal was to obtain hemoglobin (Hb) levels higher than 12 g/dL. Because of this concern, correction of anemia in elderly individuals with relative EPO insufficiency should not be attempted outside clinical trials.


Telemark skiing injuries: a three-year study.
Telemark skiing is an increasingly popular wilderness activity. Little is known, however, about the injuries incurred during modern telemark skiing. To determine the incidence and types of these injuries we carried out a prospective analysis of injured telemarkers over three ski seasons from November 1994 through May 1997 at the Mount Hood Meadows ski area medical clinic in Oregon. Injured telemark skiers presenting to the clinic were asked to fill out a one-page survey, and a diagnosis was provided by the clinic physician or nurse. During the 1995-1996 and 1996-1997 ski seasons, skiers were counted at the ski lifts to determine the proportion of telemark skiers, alpine skiers, and snowboarders using the lifts. Using these proportions and the total ticket sales for the year, the number of downhill skiers, snowboarders, and telemarkers over the season were estimated, and injury rates were calculated. During the three ski seasons, 33 injuries were identified in 28 injured telemarkers. Of the study participants, 75% (21) were male. The average age was 33.1 years. Self-described intermediate and advanced telemarkers accounted for 74% of the injured. In 96% of the injuries, the skier was performing a telemark turn. Powder snow or heavy, wet snow conditions were reported most often. Lower-extremity injuries were most common, accounting for 42.5% (14) of the total. Seven of the lower-extremity injuries were ankle injuries, and four were knee injuries. Upper-extremity injuries comprised 24.2% (8) and head and facial injuries 21.2% (7) of the total. The least number of injuries occurred in the spine, 12.1% (4). Release plates were used by 8 of 28 skiers and only released in two instances. Telemark skiers comprised 0.9% of skiers counted at the lifts during the 1995-1996 season and 1.8% in 1996-1997. Injury rates/1000 skier days in 1995-1996 were 3.3 (95% CI: 3.27, 3.35) for downhill skiers, 4.1 (95% CI: 3.32, 5.22) for telemark skiers, and 6.8 (95% CI: 6.54, 7.00) for snowboarders. Injury rates/1000 skier days in 1996-1997 were 3.1 (95% CI: 3.05, 3.15) for downhill skiers, 1.7 (95% CI: 1.44, 2.11) for telemark skiers, and 5.6 (95% CI: 5.39, 5.78) for snowboarders. We conclude that telemark skiers comprise only a small proportion of skiers at a lift-served area. Lower-extremity injuries were most common, followed by upper-extremity and head and facial injuries. Injury rates for telemarkers are comparable to those for alpine skiers.


Chinese validation of the Pelvic Floor Impact Questionnaire Short Form.
The Pelvic Floor Impact Questionnaire Short Form (PFIQ-7) is an International Continence Society-recommended disease-specific questionnaire evaluating the impact of pelvic floor disorders on women's quality of life. The PFIQ-7 has not been validated in China, which limits its use. The objective of this research was to validate the Chinese-translated version of the PFIQ-7. The PFIQ-7 was translated into Chinese; 134 women with pelvic floor disorder completed the PFIQ-7 and the 12-item Short Form Health Survey (SF-12) questionnaires. Reliability and validity were analyzed. The reliability of the PFIQ-7 was assessed for internal consistency and test-retest reliability. The face/content validity was assessed subjectively by an expert panel and/or focus group participants. The criterion validity was evaluated using the Spearman correlation with the SF-12. The construct validity was determined by factor analysis. The PFIQ-7 has a high internal consistency (Cronbach α was 0.801) and high test-retest reliability (the intraclass correlation coefficients were 0.862, P < 0.01). PFIQ-7 scores were negatively correlated with those of the SF-12 (P < 0.01). A factor analysis showed good construct validity. The Chinese version of the PFIQ-7 has high reliability and validity for the Chinese population. It is highly recommended for clinical treatment and research.


Inner-city older blacks have high levels of functional disability.
To describe the frequency and severity of functional problems in two groups of noninstitutionalized inner-city blacks aged 70 years and older contrasted with results from appropriate groups of white and black older adults and with the goals of the Healthy People 2000 program. Cross-sectional descriptive study. Community-based samples. A population-based sample of 416 older adults living in a 3.5-square mile catchment area in north St. Louis (NSL), Missouri, and a sample of 197 older residents living in public housing in East St. Louis (ESL), Illinois. Health status, preventive health activities, health services utilization, and risks for progressive frailty were assessed by self report and observation using well validated, standardized instruments. Whenever possible, comparison data were derived from national datasets, original samples used to validate the measures, and other useful comparison groups. The NSL sample had somewhat better health status and risk for progressive disability than the ESL sample. However, compared with national or regional reference groups using age-gender adjustments, both study groups demonstrated increased levels of dependence in intermediate activities of daily living, restricted activity days, inability to walk one-half mile without assistance, reported poor vision, living alone, and limited income compared with both older whites and blacks, and increased levels of worsening health, inability to perform heavy work around the house, never walking a mile or more, and currently unmarried versus whites with variable decrements versus blacks. Contrasted with other comparison groups, the two samples had increased body fat; consistent decrements in gait speed, timed chair stands, timed one-leg balance, and frequency of preventive exercise; and lower levels of dental care; results relative to physician visits and hospital days were mixed. They also had high levels of measured visual and hearing impairments, unmet needs for home delivered meals, and problems with false teeth. Deficiencies compared with the goals of Healthy People 2000 were large. The special attributes of inner-city blacks, including poverty and access to and acceptance of remedial programs, will have to be considered if the goals of Healthy People 2000 are to be met in this important and growing segment of older Americans. 44:0000-0000, 1996.


Spinal and pudendal nerve modulation of human corticoanal motor pathways.
We investigated the effects of lumbosacral and pudendal nerve stimulation on the corticofugal pathways to the human external anal sphincter. In 11 healthy subjects, anal sphincter electromyographic responses, evoked to transcranial magnetic stimulation of the motor cortex, were recorded 5-500 ms after lumbosacral root or pudendal nerve stimulation. Lumbosacral and pudendal nerve stimulation alone evoked responses with amplitudes of 293 +/- 73 and 401 +/- 153 microV and latencies of 3.2 +/- 0.2 and 2.2 +/- 0.2 ms, respectively. Cortical stimulation also evoked responses with amplitudes of 351 +/- 104 microV and latencies of 20.9 +/- 1.1 ms. When lumbosacral or pudendal nerve stimulation preceded cortical stimulation, the cortically evoked responses were facilitated (P < 0.01), with the effect appearing greatest at 5-20 ms after both lumbosacral and pudendal excitation and at 50-100 ms after lumbosacral excitation alone. Our results demonstrate that cortical pathways to the external anal sphincter are facilitated by prior lumbosacral and pudendal nerve stimulation, indicating that sensorimotor interactions are important in the central neural control of sphincter function.


Carcinoma of the cervix--a review.
Carcinoma of the cervix is the fourth most common neoplasm in women. The mortality from this tumor has dropped with the advent of Papanicolaou smears and routine periodic screening, particularly in high risk populations. Diagnosis and staging includes a careful physical examination, the use of colposcopy, directed biopsy, intravenous urogram and cystoscopy. Computed tomography and lymph-angiography may be helpful for detection of iliac or paraaortic lymph nodes. Early, noninvasive stages of this disease (CIN) may be treated with cryosurgery or laser vaporization. Carcinoma in situ (CIS) and microinvasive carcinoma is usually treated with simple hysterectomy for cure. More advanced invasion localized to the cervix may be treated with radical hysterectomy or radiation therapy with 90% of patients surviving 5 years. More advanced tumors are treated with external and intracavitary radiation therapy. For patients with paraaortic lymph node involvement or recurrent tumor, 5-year survival is less than 10%. Chemotherapy may provide some palliation to patients with recurrent tumors but does not increase long term survivorship.


Structure determination and characterization of the vitamin B6 degradative enzyme (E)-2-(acetamidomethylene)succinate hydrolase.
The gene identification and kinetic characterization of (E)-2-(acetamidomethylene)succinate (E-2AMS) hydrolase has recently been described. This enzyme catalyzes the final reaction in the degradation of vitamin B(6) and produces succinic semialdehyde, acetate, ammonia, and carbon dioxide from E-2AMS. The structure of E-2AMS hydrolase was determined to 2.3 A using SAD phasing. E-2AMS hydrolase is a member of the alpha/beta hydrolase superfamily and utilizes a serine/histidine/aspartic acid catalytic triad. Mutation of either the nucleophilic serine or the aspartate resulted in inactive enzyme. Mutation of an additional serine residue in the active site causes the enzyme to be unstable and is likely structurally important. The structure also provides insight into the mechanism of hydrolysis of E-2AMS and identifies several potential catalytically important residues.


Safety Evaluation in Iterative Development of Wearable Patches for Aripiprazole Tablets With Sensor: Pooled Analysis of Clinical Trials.
Wearable sensors in digital health may pose a risk for skin irritation through the use of wearable patches. Little is known about how patient- and product-related factors impact the risk of skin irritation. Aripiprazole tablets with sensor (AS, Abilify MyCite; Otsuka America Pharmaceutical, Inc) is a digital medicine system indicated for the treatment of patients with schizophrenia, bipolar I disorder, and major depressive disorder. AS includes aripiprazole tablets with an embedded ingestible event marker, a wearable sensor attached to the skin through a wearable patch, a smartphone app, and a web-based portal. To continuously improve the final product, successive iterations of wearable patches were developed, including raisin patch version 4 (RP4), followed by disposable wearable sensor version 5 (DW5), and then reusable wearable sensor version 2 (RW2). This analysis pooled safety data from clinical studies in adult participants using the RP4, DW5, and RW2 wearable patches of AS and evaluated adverse events related to the use of wearable patches. Safety data from 12 studies in adults aged 18-65 years from May 2010 to August 2020 were analyzed. All studies evaluated safety, with studies less than 2 weeks also specifically examining human factors associated with the use of the components of AS. Healthy volunteers or patients with schizophrenia, bipolar I disorder, or major depressive disorder were enrolled; those who were exposed to at least 1 wearable patch were included in the safety analysis. Adverse events related to the use of a wearable patch were evaluated. Abrasions, blisters, dermatitis, discoloration, erythema, irritation, pain, pruritus, rash, and skin reactions were grouped as skin irritation events (SIEs). All statistical analyses were descriptive. The analysis included 763 participants (mean [SD] age 42.6 [12.9] years; White: n=359, 47.1%; and male: n=420, 55%). Participants were healthy volunteers (n=269, 35.3%) or patients with schizophrenia (n=402, 52.7%), bipolar I disorder (n=57, 7.5%), or major depressive disorder (n=35, 4.6%). Overall, 13.6% (104/763) of the participants reported at least 1 SIE, all of which were localized to the wearable patch site. Incidence of ≥1 patch-related SIEs was seen in 18.1% (28/155), 14.2% (55/387), and 9.2% (28/306) of participants who used RP4, DW5, and RW2, respectively. Incidence of SIE-related treatment discontinuation was low, which is reported by 1.9% (3/155), 3.1% (12/387), and 1.3% (4/306) of participants who used RP4, DW5, and RW2, respectively. The incidence rates of SIEs reported as the wearable patch versions evolved from RP4 through RW2 suggest that information derived from reported adverse events may have informed product design and development, which could have improved both tolerability and wearability of successive products. Clinicaltrials.gov NCT02091882, https://clinicaltrials.gov/study/NCT02091882; Clinicaltrials.gov NCT02404532, https://clinicaltrials.gov/study/NCT02404532; Clinicaltrials.gov NCT02722967, https://clinicaltrials.gov/study/NCT02722967; Clinicaltrials.gov NCT02219009, https://clinicaltrials.gov/study/NCT02219009; Clinicaltrials.gov NCT03568500, https://clinicaltrials.gov/study/NCT03568500; Clinicaltrials.gov NCT03892889, https://clinicaltrials.gov/study/NCT03892889.


Increased gray-matter volume in medication-naive high-functioning children with autism spectrum disorder.
To establish whether high-functioning children with autism spectrum disorder (ASD) have enlarged brains in later childhood, and if so, whether this enlargement is confined to the gray and/or to the white matter and whether it is global or more prominent in specific brain regions. Brain MRI scans were acquired from 21 medication-naive, high-functioning children with ASD between 7 and 15 years of age and 21 comparison subjects matched for gender, age, IQ, height, weight, handedness, and parental education, but not pubertal status. Patients showed a significant increase of 6% in intracranium, total brain, cerebral gray matter, cerebellum, and of more than 40% in lateral and third ventricles compared to controls. The cortical gray-matter volume was evenly affected in all lobes. After correction for brain volume, ventricular volumes remained significantly larger in patients. High-functioning children with ASD showed a global increase in gray-matter, but not white-matter and cerebellar volume, proportional to the increase in brain volume, and a disproportional increase in ventricular volumes, still present after correction for brain volume. Advanced pubertal development in the patients compared to the age-matched controls may have contributed to the findings reported in the present study.


Ularitide for the treatment of acute decompensated heart failure: from preclinical to clinical studies.
The short- and long-term morbidity and mortality in acute heart failure is still unacceptably high. There is an unmet need for new therapy options with new drugs with a new mode of action. One of the drugs currently in clinical testing in Phase III is ularitide, which is the chemically synthesized form of the human natriuretic peptide urodilatin. Urodilatin is produced in humans by differential processing of pro-atrial natriuretic peptide in distal renal tubule cells. Physiologically, urodilatin appears to be the natriuretic peptide involved in sodium homeostasis. Ularitide exerts its pharmacological actions such as vasodilation, diuresis, and natriuresis through the natriuretic peptide receptor/particulate guanylate cyclase/cyclic guanosine monophosphate pathway. In animal models of heart failure as well as Phase I and II clinical studies in heart failure patients, ularitide demonstrated beneficial effects such as symptom relief and vasodilation, while still preserving renal function. Subsequently, the pivotal acute decompensated heart failure (ADHF) Phase III study, called TRUE-AHF, was started with the objectives to evaluate the effects of ularitide infusion on the clinical status and cardiovascular mortality of patients with ADHF compared with placebo. This review summarizes preclinical and clinical data supporting the potential use of ularitide in the treatment of ADHF.


Focusing on the golden ball metaheuristic: an extended study on a wider set of problems.
Nowadays, the development of new metaheuristics for solving optimization problems is a topic of interest in the scientific community. In the literature, a large number of techniques of this kind can be found. Anyway, there are many recently proposed techniques, such as the artificial bee colony and imperialist competitive algorithm. This paper is focused on one recently published technique, the one called Golden Ball (GB). The GB is a multiple-population metaheuristic based on soccer concepts. Although it was designed to solve combinatorial optimization problems, until now, it has only been tested with two simple routing problems: the traveling salesman problem and the capacitated vehicle routing problem. In this paper, the GB is applied to four different combinatorial optimization problems. Two of them are routing problems, which are more complex than the previously used ones: the asymmetric traveling salesman problem and the vehicle routing problem with backhauls. Additionally, one constraint satisfaction problem (the n-queen problem) and one combinatorial design problem (the one-dimensional bin packing problem) have also been used. The outcomes obtained by GB are compared with the ones got by two different genetic algorithms and two distributed genetic algorithms. Additionally, two statistical tests are conducted to compare these results.


Estimation of carcass chemical composition in beef-on-dairy cattle using dual-energy X-ray absorptiometry (DXA) scans of cold half-carcass or 11th rib cut.
The aim of the present study was to estimate the chemical composition (water, lipid, protein, mineral, and energy contents) of carcasses measured postmortem using dual-energy X-ray absorptiometry (DXA) scans of cold half-carcass or 11th rib cut. One hundred and twenty beef-on-dairy (dam: Swiss Brown, sire: Angus, Limousin, or Simmental) bulls (n = 66), heifers (n = 42), and steers (n = 12) were included in the study. The reference carcass composition measured after grinding, homogenization, and chemical analyses was estimated from DXA variables using simple or multiple linear regressions with model training on 70% (n = 84) and validation on 30% (n = 36) of the observations. In the validation step, the estimates of water and protein masses from the half-carcass (R2 = 0.998 and 0.997; root mean square error of prediction [RMSEP], 1.0 and 0.5 kg, respectively) and 11th rib DXA scans (R2 = 0.997 and 0.996; RMSEP, 1.5 and 0.5 kg, respectively) were precise. Lipid mass was estimated precisely from the half-carcass DXA scan (R2 = 0.990; RMSEP = 1.0 kg) with a slightly lower precision from the 11th rib DXA scan (R2 = 0.968; RMSEP = 1.7 kg). Mineral mass was estimated from half-carcass (R² = 0.975 and RMSEP = 0.3 kg) and 11th rib DXA scans (R2 = 0.947 and RMSEP = 0.4 kg). For the energy content, the R2 values ranged from 0.989 (11th rib DXA scan) to 0.996 (half-carcass DXA scan), and the RMSEP ranged from 36 (half-carcass) to 55 MJ (11th rib). The proportions of water, lipids, and energy in the carcasses were also precisely estimated (R2 ≥ 0.882) using either the half-carcass (RMSEP ≤ 1.0%) or 11th rib-cut DXA scans (RMSEP ≤ 1.3%). Precision was lower for the protein and mineral proportions (R2 ≤ 0.794, RMSEP ≤ 0.5%). The cattle category (sex and breed of sire) effect was observed only in some estimative models for proportions from the 11th rib cut. In conclusion, DXA imaging of either a cold half-carcass or 11th rib cut is a precise method for estimating the chemical composition of carcasses from beef-on-dairy cattle.


Urban meadows as an alternative to short mown grassland: effects of composition and height on biodiversity.
There are increasing calls to provide greenspace in urban areas, yet the ecological quality, as well as quantity, of greenspace is important. Short mown grassland designed for recreational use is the dominant form of urban greenspace in temperate regions but requires considerable maintenance and typically provides limited habitat value for most taxa. Alternatives are increasingly proposed, but the biodiversity potential of these is not well understood. In a replicated experiment across six public urban greenspaces, we used nine different perennial meadow plantings to quantify the relative roles of floristic diversity and height of sown meadows on the richness and composition of three taxonomic groups: plants, invertebrates, and soil microbes. We found that all meadow treatments were colonized by plant species not sown in the plots, suggesting that establishing sown meadows does not preclude further locally determined grassland development if management is appropriate. Colonizing species were rarer in taller and more diverse plots, indicating competition may limit invasion rates. Urban meadow treatments contained invertebrate and microbial communities that differed from mown grassland. Invertebrate taxa responded to changes in both height and richness of meadow vegetation, but most orders were more abundant where vegetation height was longer than mown grassland. Order richness also increased in longer vegetation and Coleoptera family richness increased with plant diversity in summer. Microbial community composition seems sensitive to plant species composition at the soil surface (0-10 cm), but in deeper soils (11-20 cm) community variation was most responsive to plant height, with bacteria and fungi responding differently. In addition to improving local residents' site satisfaction, native perennial meadow plantings can produce biologically diverse grasslands that support richer and more abundant invertebrate communities, and restructured plant, invertebrate, and soil microbial communities compared with short mown grassland. Our results suggest that diversification of urban greenspace by planting urban meadows in place of some mown amenity grassland is likely to generate substantial biodiversity benefits, with a mosaic of meadow types likely to maximize such benefits.


Annotation: the savant syndrome.
Whilst interest has focused on the origin and nature of the savant syndrome for over a century, it is only within the past two decades that empirical group studies have been carried out. The following annotation briefly reviews relevant research and also attempts to address outstanding issues in this research area. Traditionally, savants have been defined as intellectually impaired individuals who nevertheless display exceptional skills within specific domains. However, within the extant literature, cases of savants with developmental and other clinical disorders, but with average intellectual functioning, are increasingly reported. We thus propose that focus should diverge away from IQ scores to encompass discrepancies between functional impairments and unexpected skills. It has long been observed that savant skills are more prevalent in individuals with autism than in those with other disorders. Therefore, in this annotation we seek to explore the parameters of the savant syndrome by considering these skills within the context of neuropsychological accounts of autism. A striking finding amongst those with savant skills, but without the diagnosis of autism, is the presence of cognitive features and behavioural traits associated with the disorder. We thus conclude that autism (or autistic traits) and savant skills are inextricably linked and we should therefore look to autism in our quest to solve the puzzle of the savant syndrome.


Development and Evaluation of Innovative Peer-Led Physical Activity Programs for Mental Health Service Users.
Mental health service users (MHSUs) have elevated rates of cardiometabolic disturbance. Improvements occur with physical activity (PA) programs. We report the development and evaluation of three innovative peer-developed and peer-led PA programs: 1) walking; 2) fitness; and 3) yoga. Qualitative evaluation with 33 MHSUs in British Columbia, Canada, occurred. These programs yielded improvements for participants, highlighted by powerful narratives of health improvement, and improved social connections. The feasibility and acceptability of innovative peer-developed and peer-led programs were shown. Analyses revealed concepts related to engagement and change. Relating core categories, we theorize effective engagement of MHSUs requires accessibility on three levels (geographic, cost, and program flexibility) and health behavior change occurs within co-constituent relationships (to self, to peers, and to the wider community). This study highlights the benefits of peer involvement in developing and implementing PA programs and provides a theoretical framework of understanding engagement and behavior change in health programs for MHSUs.


Ventricular arrhythmias during ergonovine-induced episodes of variant angina.
Of 95 consecutive patients with active variant angina who underwent ergonovine testing in the coronary care unit while off treatment, 24 (25%) developed serious ventricular arrhythmias: ventricular tachycardia in eight, bigeminy in seven, pairs in five, and frequent ventricular extrasystoles in four. Ergonovine-induced arrhythmias were observed more often in patients with anterior than inferior ST segment elevation (p less than 0.05). ST segment elevation was significantly higher (10.3 +/- 8.1 vs 3.1 +/- 2.1 mm) in patients who developed arrhythmias. All ventricular arrhythmias began within 3 minutes after the onset of ST segment elevation. The intravenous administration of nitroglycerin eliminated arrhythmias in 22 of 24 cases; in only two patients did ventricular arrhythmias develop after the administration of nitroglycerin. Serious ventricular arrhythmias were found during spontaneous variant angina attacks in 14 of 24 patients with ergonovine-induced arrhythmias compared to 16 of 71 patients without ergonovine-induced arrhythmias (p less than 0.001). We conclude that arrhythmias during ergonovine testing are most often caused by ischemia and not reperfusion. Patients with arrhythmias during ergonovine-induced attacks are more likely to have arrhythmias during spontaneous attacks.


The intracapsular therapeutic modalities in conjunction with arthrography: case reports.
Manipulation and lavage of the temporomandibular joint has been shown to add an important therapeutic dimension to arthrography. These therapeutic modalities were prescribed by the primary treating practitioner in conjunction with diagnostic arthrography in a group of patients. The therapeutic modalities consisted of joint mobilization (Farrar manipulation or distraction) augmented by (1) increased hydraulic pressure in the superior compartment, or (2) with small amounts of contrast in both compartments, and/or (3) with lavage of the superior joint compartment. The therapeutic modalities were prescribed in association with the arthrography as a logical extension of the arthrographic technique. The result of the mobilization and lavage was an increase in the mandibular range of motion (ROM) and a decrease in pain in cases with adhesions as well as those with anteriorly displaced disks without reduction. Patients with anteriorly displaced disks with reduction, redundant tissue in the fossa, osteochondritis, and adhesive capsulitis also showed benefit, although patient populations treated with these conditions were small. There were no adverse sequelae. Manipulation and lavage should now be viewed as one more tool in the treatment of intracapsular pathology.


Early season herbivore differentially affects plant defence responses to subsequently colonizing herbivores and their abundance in the field.
Induction of plant defences by early season herbivores can mediate interspecific herbivore competition. We have investigated plant-mediated competition between three herbivorous insects through studies at different levels of biological integration. We have addressed (i) gene expression; (ii) insect behaviour and performance under laboratory conditions; and (iii) population dynamics under field conditions. We studied the expression of genes encoding a trypsin inhibitor and genes that are involved in glucosinolate biosynthesis in response to early season herbivory by Pieris rapae caterpillars in Brassica oleracea plants. Furthermore, we studied the interaction of these transcriptional responses with responses to secondary herbivory by the two specialist herbivores, P. rapae and Plutella xylostella, and the generalist Mamestra brassicae. P. rapae-induced responses strongly interacted with plant responses to secondary herbivory. Sequential feeding by specialist herbivores resulted in enhanced or similar expression levels of defence-related genes compared to primary herbivory by specialists. Secondary herbivory by the generalist M. brassicae resulted in lower gene expression levels than in response to primary herbivory by this generalist. Larval performance of both specialist and generalist herbivores was negatively affected by P. rapae-induced plant responses. However, in the field the specialist P. xylostella was more abundant on P. rapae-induced plants and preferred these plants over undamaged plants in oviposition experiments. In contrast, the generalist M. brassicae was more abundant on control plants and preferred undamaged plants for oviposition. P. rapae did not discriminate between plants damaged by conspecifics or undamaged plants. Our study shows that early season herbivory differentially affects transcriptional responses involved in plant defence to secondary herbivores and their population development dependent upon their degree of host plant specialization.


Suppression of in vivo Rho-dependent transcription termination defects: evidence for kinetically controlled steps.
The conventional model of Rho-dependent transcription termination in bacteria requires RNA-dependent translocase activity of the termination factor Rho as well as many kinetically controlled steps to execute efficient RNA release from the transcription elongation complex (EC). The involvement of the kinetically controlled steps, such as RNA binding, translocation and RNA release from the EC, means that this termination process must be kinetically coupled to the transcription elongation process. The existence of these steps in vivo has not previously been delineated in detail. Moreover, the requirement for translocase activity in Rho-dependent termination has recently been questioned by a radical view, wherein Rho binds to the elongating RNA polymerase (RNAP) prior to loading onto the mRNA. Using growth assays, microarray analyses and reporter-based transcription termination assays in vivo, we showed that slowing of the transcription elongation rate by using RNAP mutants (rpoB8 and rpoB3445) and growth of the strains in minimal medium suppressed the termination defects of five Rho mutants, three NusG mutants defective for Rho binding and the defects caused by two Rho inhibitors, Psu and bicyclomycin. These results established the existence of kinetically controlled steps in the in vivo Rho-dependent termination process and further reinforced the importance of 'kinetic coupling' between the two molecular motors, Rho and RNAP, and also argue strongly that the Rho translocation model is an accurate representation of the in vivo situation. Finally, these results indicated that one of the major roles of NusG in in vivo Rho-dependent termination is to enhance the speed of RNA release from the EC.


How first-episode psychosis patients' subjective beliefs about their childhood trauma's causal effect provide support for potential schizophrenia subtypes.
Childhood and adolescent trauma is a risk factor for developing psychosis-spectrum disorders. The current study aimed to assess how childhood trauma might predict psychosis symptomatology, and how patients' beliefs of whether trauma is the cause of psychosis might affect this association. Ninety-six first-episode psychosis patients were assessed for childhood traumatic experiences with the Brief Betrayal Trauma Survey, and for psychosis symptoms with the Positive and Negative Syndrome Scale. Non-interpersonal trauma predicted higher positive symptoms, whereas more trauma domains experienced predicted lower negative symptoms. Almost half of the participants believed trauma to be related to psychosis, were 12 times more likely to reexperience trauma through psychosis, and had higher excitative and emotional symptoms. Non-interpersonal trauma also predicted higher positive symptoms in this group. Those who did not believe trauma to be the cause of psychosis had higher negative symptoms, and a negative dose-response was found for negative and disorganised symptoms, in which more trauma domains experienced predicted lower scores. Results imply two traumagenic pathways to psychosis, one characterised by positive, excitative, and emotional symptoms, and one negative subtype, characterised by negative and disorganised symptoms. Clinical implications for how findings might contribute to better treatments are discussed.


Inflammatory Myofibroblastic Tumor of the Pancreas: A Case Report and Literature Review.
Inflammatory myofibroblastic tumors (IMTs) are rare. They are characterized by myofibroblastic spindle cell proliferation with a varying degree of inflammatory cell infiltration. IMT can occur in any anatomic location but has been reported in the lung, mesentery, and omentum, mainly in children or young adults. It rarely occurs in the pancreas and is often difficult to distinguish from other tumors, including some malignant ones. Therefore, it can be challenging to make a radiological diagnosis of IMT. Here, we present a case of IMT that occurred in the pancreas head of a middle-aged female. The patient's ultrasonography, computed tomography, and magnetic resonance imaging findings are presented along with a review of the literature.


Non-vascularised corticocancellous (tricortical) iliac bone graft longer than 3 cm for non-union after failed surgical treatment.
We hypothesised that traditional iliac tricortical bone grafts (no vascularised) still have a reasonable role in promoting satisfactory bony healing in non-union defects of certain sizes. Here, we report the clinical/radiological outcomes through a retrospective case series. We screened 74 patients with definitive non-union in the long bones of the upper extremities who visited the outpatient department from 2008 to 2018. Among these patients, 25 who met our inclusion/exclusion criteria were investigated. The mean age was 51.92 years, and there were 12, 9, 1, and 3 lesions of the radius, ulna, clavicle, and humerus, respectively. The tools for primary fixations were plate and intramedullary nails in 24 and 1 patients, respectively. Six patients presented with atrophic non-union. The mean period from a previous surgery was 6.84 months. The mean defective bone sizes were 1.81 and 3.50 cm pre-debridement and post-debridement, respectively. All devices had locking plates longer than the previous plate, and the graft was concurrently fixed by screws in three patients. At a mean of 15.92 weeks after the revision surgery, all patients experienced union. At the final follow-up, the clinical outcomes were satisfactory. No significant differences in clinical outcomes were found according to the lesion, type of non-union, period from the previous surgery, or harvest length of the iliac bone. If the proper indications and some technical aspects are considered, a non-vascularised iliac bone graft longer than 3 cm could still be a reasonable option for treating diaphyseal non-union of the upper extremities. Level IV, retrospective case series.


Reasons for palliative treatments in stage III non-small-cell lung cancer: what contribution is made by time-dependent changes in tumour or patient status?
Stage iii lung cancer is the most advanced stage of lung cancer for which the potential of curative treatment is often discussed. However, a large proportion of patients are treated with palliative intent. An understanding of the time-dependent and -independent factors contributing to the choice of palliative-intent treatment is needed to help optimize patient outcomes. This retrospective cohort study of patients with stage iii non-small-cell lung cancer (nsclc) newly diagnosed between 1 January 2008 and 31 December 2012 at the Cancer Centre of Southeastern Ontario collected data including patient demographics, clinical characteristics, tumour characteristics, treatment, and outcomes. Of 237 patients with stage iii nsclc included in the study, 130 were not treated with radical or curative intent (55%). Major time-independent variables cited for palliative-intent treatment included extreme age (5%), comorbidity (27%), patient choice (5%), and poor lung function (5%). Time-dependent variables included tumour progression on imaging (15%), weight loss (33%), performance status (32%), and the occurrence of a major complication such as hemoptysis, lung collapse, or pulmonary embolism (7%). A significant number of patients (20%) experienced a decline in performance status-to 2, 3, or 4 from 0 or 1-over the course of the diagnostic journey, and 12% experienced a transition from no weight loss to more than 10% weight loss. A significant proportion of patients receive palliative therapy for stage iii nsclc because of changes that occur during the diagnostic journey. Shortening or altering that pathway to avoid tumour growth or patient deterioration during care could allow for more patients to be treated with curative intent.


Attitude of physicians towards the follow-up of renal transplant patients: a questionnaire survey in Saudi Arabia.
The goal of this study was to evaluate the attitude of the physicians towards the follow-up of the renal transplant patients in the Kingdom of Saudi Arabia (KSA). We sent a questionnaire to 168 physicians working in 148 active dialysis centers in the KSA. The study was conducted from June-October 2005. There were 140 physicians (83.3%) who answered the questionnaire; they represented 136 (91.9%) dialysis centers. There were 43 (31.2%) respondents who had a transplant clinic for follow-up of transplant recipients. Of the 96 (69.1%) who did not have a clinic, 29 (30.2%) claimed expertise for follow-up of transplant recipients, six (6.2%) had a laboratory set-up to monitor the immunosuppressive drug levels and 40 (44.4%) felt the need for one. There were 121 (89%) respondents who would consider the chronic renal failure (CRF) patients for transplantation because it is the best form of therapy. Seventy-seven respondents (55%) had a protocol for work-up of the CRF patients for transplantation, 31 (22.3%) had a coordinator for the work-up of the transplant candidates, 34 (24.5%) had regular meetings to decide on the waiting list for transplantation, and 51 (37.8%) had affiliation with, or worked at a transplant center. Nevertheless, 127 (90.7%) respondents believed that the results of renal transplantation were good enough to recommend the procedure to all patients as early as possible. There were 133 (97.1%) respondents who believed that organ shortage was the major factor for the low percentage of renal transplantation. Only 52 (37.1%) respondents knew about the recent regulations established by the World Health Organization (WHO) for organ donation. There were 63 (48.1%) respondents who believed that seeking commercial renal transplantation outside the KSA to be unacceptable because of the medical and ethical complications involved. Many respondents (71.4%) from non-MOH hospitals, and those who had transplant clinics believed that the tacrolimus + mycophenolate combination was the most popular immunosuppressive regimen for renal transplant patients. Our survey suggests that the current practices concerning the work-up and follow-up of transplant patients in the dialysis centers in the KSA require refinement in terms of the need to enforce the use of a protocol to guide evaluation and therapy in each dialysis unit.


Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma.
The primary cilium acts as a cellular antenna, transducing diverse signaling pathways, and recent evidence suggests that primary cilia are important in development and cancer. However, a role for cilia in normal muscle development and rhabdomyosarcoma (RMS) has not been explored. Here we implicate primary cilia in proliferation, hedgehog (Hh) signaling, and differentiation of skeletal muscle cells. Cilia and Hh signaling are highly dynamic during the differentiation of myoblasts. We show that cilia are assembled during the initial stages of myogenic differentiation but disappear as cells progress through myogenesis, concomitant with the destruction of proteins critical for cilia assembly and shortly after the Hh effector, Gli3, leaves the cilium. Importantly, we show that ablation of primary cilia strongly suppresses Hh signaling and myogenic differentiation while enhancing proliferation. Interestingly, our data further indicate that both cilia assembly and Hh signaling are deregulated in RMS, and cilia respond to Hh ligand in certain subsets of RMS cells but not others. Together, these findings provide evidence for an essential role for both primary cilia assembly and disassembly in the control of Hh signaling and early differentiation in muscle cells. We suggest that the temporally orchestrated destruction of centrosomal and ciliary proteins is a necessary antecedent for removal of the primary cilium and cessation of Hh signaling during myogenic differentiation. Additionally, our results further stratify RMS populations and highlight cilia assembly and disassembly as potential RMS drug targets.


Exploring the Effects of a Neck Strengthening Program on Purposeful Soccer Heading Biomechanics and Neurocognition.
Cervical (neck) strengthening has been proposed as an important factor in concussion prevention. The purpose of the study was to determine if a six-week cervical strengthening program affected neurocognition and purposeful soccer heading biomechanics. The hypothesis was that the neck strengthening program would improve strength, maintain neurocognition, and alter purposeful soccer heading biomechanics. Randomized controlled trial. Twenty collegiate soccer athletes (8 males, 12 females, age=20.15±1.35 years, height=171.67±9.01 cm, mass=70.56±11.03 kg) volunteered to participate. Time (pre, post) and group (experimental, control) served as the independent variables. Four composite scores from the CNS Vital Signs computer based neurocognitive test (CNSVS; verbal memory, visual memory, executive function, reaction time) and aspects of heading biomechanics from inertial measurement units (xPatch; peak linear acceleration, peak rotational acceleration, duration, Gadd Severity Index [GSI]) served as the dependent variables. Each athlete completed a baseline measure of neck strength (anterior neck flexors, bilateral anterolateral neck flexors, bilateral cervical rotators) and CNSVS after heading 10 soccer balls at two speeds (11.18 and 17.88 m/s) while wearing the xPatch. The experimental group completed specific cervical neck strengthening exercises twice a week for six weeks using a Shingo Imara™ cervical neck resistance apparatus while the control group did not. After six weeks, the participants completed the same heading protocol followed by measurement of the same outcome variables. The alpha value was set to p<0.05 a priori. The interaction between time and group was significant for visual memory (F1,17=5.16, p=0.04, η2=0.23). Interestingly, post hoc results revealed visual memory decreased for the control group from pretest (46.90±4.46) compared to posttest (43.00±4.03; mean difference=3.90, 95% CI=0.77-7.03, p=0.02). Interactions for all other dependent variables were not statistically significant (p>0.05). The cervical neck strengthening protocol allowed maintenance of visual memory scores but did not alter other neurocognitive measures or heading biomechanics. The link between cervical neck strengthening and concussion predisposition should continue to be explored. Level 1b.


De novo assembly of a genome-wide transcriptome map of Vicia faba (L.) for transfer cell research.
Vicia faba (L.) is an important cool-season grain legume species used widely in agriculture but also in plant physiology research, particularly as an experimental model to study transfer cell (TC) development. TCs are specialized nutrient transport cells in plants, characterized by invaginated wall ingrowths with amplified plasma membrane surface area enriched with transporter proteins that facilitate nutrient transfer. Many TCs are formed by trans-differentiation from differentiated cells at apoplasmic/symplasmic boundaries in nutrient transport. Adaxial epidermal cells of isolated cotyledons can be induced to form functional TCs, thus providing a valuable experimental system to investigate genetic regulation of TC trans-differentiation. The genome of V. faba is exceedingly large (ca. 13 Gb), however, and limited genomic information is available for this species. To provide a resource for future transcript profiling of epidermal TC differentiation, we have undertaken de novo assembly of a genome-wide transcriptome map for V. faba. Illumina paired-end sequencing of total RNA pooled from different tissues and different stages, including isolated cotyledons induced to form epidermal TCs, generated 69.5 M reads, of which 65.8 M were used for assembly following trimming and quality control. Assembly using a De-Bruijn graph-based approach generated 21,297 contigs, of which 80.6% were successfully annotated against GO terms. The assembly was validated against known V. faba cDNAs held in GenBank, including transcripts previously identified as being specifically expressed in epidermal cells across TC trans-differentiation. This genome-wide transcriptome map therefore provides a valuable tool for future transcript profiling of epidermal TC trans-differentiation, and also enriches the genetic resources available for this important legume crop species.


Residual attraction to smoking and smoker identity following smoking cessation.
Anecdotal reports suggest that some long-term ex-smokers retain a residual attraction to smoking and a "smoker identity," although little systematic data on this exist. These are important because they may increase the likelihood of relapse. This study aimed to quantify the extent of these characteristics in relation to length of abstinence. A postal questionnaire on residual attraction to smoking, smoker identity, and vulnerability to relapse was sent to 1,390 adults known to have been abstinent for 4 weeks after treatment support with a large stop smoking service in England. Time since the end of treatment varied between 6 weeks and 3 years. Three hundred and fifty-seven ex-smokers responded and were included in the analysis. The proportion of ex-smokers reporting a residual attraction to smoking, a smoker identity, and a vulnerability to relapse declined with duration of abstinence (all p < .001), although even among those having 2 years or more of abstinence, 37.4% (95% CI = 27.9%-47.7%) reported some residual attraction and 16.3% (95% CI = 9.6%-25.2%) retained a smoker identity. By contrast, after 2 or more years of abstinence, only 7% thought they would ever return to smoking (95% CI = 2.9%-14.2%). The findings suggest that residual attraction to cigarettes is common among long-term ex-smokers, and a significant minority retain a smoker identity. Further studies are needed to determine how far these characteristics are associated with late relapse.


Neuroendoscopic surgery for neuroendocrine cancer of the skull base.
Neuroendocrine cancer is an extremely rare malignant tumor that originates from the nervous and the endocrine systems. This type of cancer can exist in almost any organ, although it is mainly found in the lung and gastrointestinal system according to current clinical reports. It is rarely found in the skull base, including primary and secondary neuroendocrine cancers. Therefore, diagnosis and treatment face a huge challenge. A 50-year-old female patient was introduced. She was admitted to the hospital due to persistent headaches, accompanied by nausea, vomiting, and decreased vision. Her case was primarily considered as a skull base malignant tumor based on clinical manifestations, imaging, and hormonal examinations. The patient then subsequently underwent neuroendoscopic surgery to remove the skull base tumor and repair cerebrospinal fluid leakage repair. The patient suffered from complications such as ghosting of the right eye after surgery, and she was given vitamin B1 orally. Pathological examination results show that the patient had neuroendocrine cancer (originated from sinus). We followed up the patient 2 months and 6 months after operation. At present, the patient recovered well, had no headache, and her spirit was significantly better than that before operation. Cranial neuroendocrine cancer has diverse clinical manifestations. CgA, Syn, Ki-67, CD56, and ACTH are important reference indicators for the diagnosis of neuroendocrine cancer. Neuroendoscopic transsphenoidal approach is a safe and effective surgical method.


Dopamine transients are sufficient and necessary for acquisition of model-based associations.
Associative learning is driven by prediction errors. Dopamine transients correlate with these errors, which current interpretations limit to endowing cues with a scalar quantity reflecting the value of future rewards. We tested whether dopamine might act more broadly to support learning of an associative model of the environment. Using sensory preconditioning, we show that prediction errors underlying stimulus-stimulus learning can be blocked behaviorally and reinstated by optogenetically activating dopamine neurons. We further show that suppressing the firing of these neurons across the transition prevents normal stimulus-stimulus learning. These results establish that the acquisition of model-based information about transitions between nonrewarding events is also driven by prediction errors and that, contrary to existing canon, dopamine transients are both sufficient and necessary to support this type of learning. Our findings open new possibilities for how these biological signals might support associative learning in the mammalian brain in these and other contexts.


A Quantitative Assessment of the Risk of Human Salmonellosis Arising from the Consumption of Almonds in the United States: The Impact of Preventive Treatment Levels.
The presence of Salmonella on almonds continues to result in product-related outbreaks and recalls in the United States. In this study, the impact of microbial reduction treatment levels (1 to 5 log CFU) on the risk of human salmonellosis from the consumption of almond kernels in the United States was evaluated. An exposure model, including major steps in almond processing, was used to estimate prevalence and levels of contamination of Salmonella on almonds at the point of consumption. A Salmonella dose-response model and consumption data for almonds in the United States were used to assess risk of illness per serving and per year, quantifying variability and uncertainty separately. A 3-log reduction treatment resulted in a predicted mean risk of illness of two cases per year for almonds consumed as a core product not cooked at home (95% confidence interval [CI], one to four cases), one case per year for almonds consumed as an ingredient not cooked at home (95% CI, one to two cases), and less than one case per year for almonds consumed as an ingredient cooked at home (95% CI, 7 × 10-7 to 3 × 10-6 cases). A minimum 4-log reduction treatment resulted in an estimated mean risk of illness below one case per year in the United States. This study also includes an assessment of the risk of human salmonellosis as a result of an exceptional situation, which results in higher risk estimates compared with the baseline model. The exceptional situations modeled posttreatment resulted in estimates of mean risk that were not significantly affected by treatment level. Sensitivity analysis results showed initial Salmonella contamination level to be the factor with the most impact on risk per serving estimates, given a certain treatment level. The risk assessment also includes a simulation of the events that occurred in 2001. Treatment levels with a minimum 4-log microbial reduction would have been sufficient to prevent the outbreak cases. The uncertainty range in the estimates indicates that additional information is needed to make more precise predictions of this specific outbreak event.


Maternal MHC regulates generation of pathogenic antibodies and fetal MHC-encoded genes determine susceptibility in congenital heart block.
Congenital heart block develops in fetuses of anti-Ro52 Ab-positive women. A recurrence rate of 20%, despite the persistence of maternal autoantibodies, indicates that there are additional, yet unidentified, factors critical for development of congenital heart block. In this study, we demonstrate that besides the maternal MHC controlling Ab specificity, fetal MHC-encoded genes influence fetal susceptibility to congenital heart block. Using MHC congenic rat strains, we show that heart block develops in rat pups of three strains carrying MHC haplotype RT1(av1) (DA, PVG.AV1, and LEW.AV1) after maternal Ro52 immunization, but not in LEW rats (RT1(l)). Different anti-Ro52 Ab fine specificities were generated in RT1(av1) versus RT1(l) animals. Maternal and fetal influence was determined in an F(2) cross between LEW.AV1 and LEW strains, which revealed higher susceptibility in RT1(l) than RT1(av1) pups once pathogenic Ro52 Abs were present. This was further confirmed in that RT1(l) pups more frequently developed heart block than RT1(av1) pups after passive transfer of RT1(av1) anti-Ro52 sera. Our findings show that generation of pathogenic Ro52 Abs is restricted by maternal MHC, whereas the fetal MHC locus regulates susceptibility and determines the fetal disease outcome in anti-Ro52-positive pregnancies.


Detailed analysis of the influence of structure length on pulse propagation through finite-size photonic crystal waveguides.
We present a detailed analysis of the influence of the finite length of a photonic crystal (PhC) waveguide on its final response to pulses propagation. The analyzed PhC waveguide is accessed by conventional dielectric waveguides and the lack of a perfect coupling between them produces reflections at the interfaces, leading to the appearance of several output pulses at the end of the PhC waveguide. If the length of the PhC waveguide is short enough these repetitions overlap and the parameters that define the total output pulse (mainly amplitude, temporal width, time delay and group velocity) vary significantly. An oscillatory behavior of these parameters is observed when the length of the PhC waveguide is modified. A theoretical model has been used to achieve each cavity generated pulse at the output of the PhC waveguide. The unique parameters needed for these calculations are the propagation constant of the PhC waveguide and the transmission and reflection coefficients at each interface. Numerical simulations based on the eigenmode expansion method are used to obtain these parameters. The time and resources required to calculate the output pulse with this method are significantly reduced in comparison with FDTD simulations and the results are proved to be quite accurate.


Quality of relationships with parents and friends in adolescence predicts metabolic risk in young adulthood.
This study was designed to examine whether family and peer relationships in adolescence predict the emergence of metabolic risk factors in young adulthood. Participants from a large, nationally representative cohort study (N = 11,617 for these analyses) reported on their relationship experiences with parents and close friends during adolescence. Fourteen years later, interviewers collected blood samples, as well as anthropometric and blood pressure measurements. Blood samples were analyzed for HbA1c. Ordered logistic regressions revealed that for females, supportive parent-child relationships and close male friendships in adolescence were associated with reduced odds of having elevated metabolic risk markers in young adulthood. These effects remained significant even after controlling for baseline measures of body mass index (BMI) and health and demographic covariates. The protective effects of close relationships were not significant for males, however. Exploratory analyses with 2-parent families revealed that supportive father-child relationships were especially protective for females. These findings suggest that, for females, close and supportive relationships with parents and male friends in adolescence may reduce the risk of metabolic dysregulation in adulthood.


X inactivation in triploidy and trisomy: the search for autosomal transfactors that choose the active X.
Only one X chromosome functions in diploid human cells irrespective of the sex of the individual and the number of X chromosomes. Yet, as we show, more than one X is active in the majority of human triploid cells. Therefore, we suggest that (i) the active X is chosen by repression of its XIST locus, (ii) the repressor is encoded by an autosome and is dosage sensitive, and (iii) the extra dose of this key repressor enables the expression of more than one X in triploid cells. Because autosomal trisomies might help locate the putative dosage sensitive trans-acting factor, we looked for two active X chromosomes in such cells. Previously, we reported that females trisomic for 18 different human autosomes had only one active X and a normal inactive X chromosome. Now we report the effect of triplication of the four autosomes not studied previously; data about these rare trisomies - full or partial - were used to identify autosomal regions relevant to the choice of active X. We find that triplication of the entire chromosomes 5 and 11 and parts of chromosomes 1 and 19 is associated with normal patterns of X inactivation, excluding these as candidate regions. However, females with inherited triplications of 1p21.3-q25.3, 1p31 and 19p13.2-q13.33 were not ascertained. Thus, if a single key dose-sensitive gene induces XIST repression, it could reside in one of these locations. Alternatively, more than one dosage-sensitive autosomal locus is required to form the repressor complex.


Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan.
Translational efficiency correlates with longevity, yet its role in lifespan determination remains unclear. Using ribosome profiling, translation efficiency is globally reduced during replicative aging in budding yeast by at least two mechanisms: Firstly, Ssd1 is induced during aging, sequestering mRNAs to P-bodies. Furthermore, Ssd1 overexpression in young cells reduced translation and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, phosphorylation of eIF2α, mediated by the stress kinase Gcn2, was elevated in old cells, contributing to the global reduction in translation without detectable induction of the downstream Gcn4 transcriptional activator. tRNA overexpression activated Gcn2 in young cells and extended lifespan in a manner dependent on Gcn4. Moreover, overexpression of Gcn4 sufficed to extend lifespan in an autophagy-dependent manner in the absence of changes in global translation, indicating that Gcn4-mediated autophagy induction is the ultimate downstream target of activated Gcn2, to extend lifespan.


The PROM1 mutation p.R373C causes an autosomal dominant bull's eye maculopathy associated with rod, rod-cone, and macular dystrophy.
To characterize in detail the phenotype of five unrelated families with autosomal dominant bull's eye maculopathy (BEM) due to the R373C mutation in the PROM1 gene. Forty-one individuals of five families of Caribbean (family A), British (families B, D, E), and Italian (family C) origin, segregating the R373C mutation in PROM1, were ascertained. Electrophysiological assessment, fundus autofluorescence (FAF) imaging, fundus fluorescein angiography (FFA), and optical coherence tomography (OCT) were performed in available subjects. Mutation screening of PROM1 was performed. The R373C mutant was present heterozygously in all affected patients. The age at onset was variable and ranged between 9 and 58 years, with most of the individuals presenting with reading difficulties. Subjects commonly had a mild to moderate reduction in visual acuity except for members of family C who experienced markedly reduced central vision. The retinal phenotype was characterized by macular dystrophy, with retinal pigment epithelial mottling in younger subjects, progressing to typical BEM over time, with the development of macular atrophy in older patients. In addition, all members of family C had typical features of RP. The electrophysiological findings were variable both within and between families. Mutations in PROM1 have been described to cause a severe form of autosomal recessive RP in two families of Indian and Pakistani descent. The results of this study have demonstrated that a distinct redundant PROM1 mutation (R373C) can also produce an autosomal dominant, fully penetrant retinopathy, characterized by BEM with little inter- and intrafamilial variability, and retinal dystrophy with variable rod or rod-cone dysfunction and marked intra- and interfamilial variability, ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod-cone dysfunction.


Autoadaptive phase-correlated (AAPC) reconstruction for 4D CBCT.
Kilovoltage cone-beam computed tomography (CBCT) is widely used in image-guided radiation therapy for exact patient positioning prior to the treatment. However, producing time series of volumetric images (4D CBCT) of moving anatomical structures remains challenging. The presented work introduces a novel method, combining high temporal resolution inside anatomical regions with strong motion and image quality improvement in regions with little motion. In the proposed method, the projections are divided into regions that are subject to motion and regions at rest. The latter ones will be shared among phase bins, leading thus to an overall reduction in artifacts and noise. An algorithm based on the concept of optical flow was developed to analyze motion-induced changes between projections. The technique was optimized to distinguish patient motion and motion deriving from gantry rotation. The effectiveness of the method is shown in numerical simulations and patient data. The images reconstructed from the presented method yield an almost the same temporal resolution in the moving volume segments as a conventional phase-correlated reconstruction, while reducing the noise in the motionless regions down to the level of a standard reconstruction without phase correlation. The proposed simple motion segmentation scheme is yet limited to rotation speeds of less than 3 degrees/s. The method reduces the noise in the reconstruction and increases the image quality. More data are introduced for each phase-correlated reconstruction, and therefore the applied dose is used more efficiently.


Testicular organoid formation is a property of immature somatic cells, which self-assemble and exhibit long-term hormone-responsive endocrine function.
Testicular organoid models are tools to study testicular physiology, development, and spermatogenesis in vitro. However, few side-by-side comparisons of organoid generation method have been evaluated. Here, we directly tested whether the culture microenvironment is the prime determinant promoting testicular organoid self-assembly. Using Matrigel as a representative extracellular matrix (ECM), we compared multiple culture environments, 2D and 3D, ECM-free and ECM, for organoid self-assembly with immature murine testicular cells. De novo tissues were observed to self-assemble in all four culture environments tested within 72 h, however, these tissues only met requirements to be named organoids in 2D ECM and 3D ECM-free (3DF) culture methods. Based on these results, 3DF was selected for further study, and used to examine animal age as an independent variable. Organoid assembly was significantly delayed when using pubertal murine cells and entirely absent from adult murine and adult human cells. Organoid-conditioned medium and medium supplemented with 1% Matrigel did not improve organoid assembly in pubertal murine cells, but immature murine cells rescued the assembly of adult murine cells when cultured together as age-chimeric cell mixtures. In murine organoids cultured for 14 d, tubule-like structures exhibiting a highly biomimetic architecture were characterized, including some rare germ and spermatogonial stem cells. These structural organoids secreted high levels of testosterone and inhibin B over 12 weeks with preserved responsivity to gonadotropins. Collectively these studies, in which cellular self-assembly and organoid formation was achieved independent of the culture microenvironment, suggest that self-assembly is an innate property of immature testicular cells independent from, but capable of being promoted by, the culture environment. This study provides a template for studying testicular organoid self-assembly and endocrine function, and a platform for improving the engineering of functional testicular tissues.


Diagnostic imaging in the clinical management of patients at high risk for breast cancer.
Although being predominantly anecdotal, breast carcinoma shows a considerable component of multifactorial genetic transmission, referable to dominant autosomal inheritance. Among the genes responsible for hereditary breast cancer two main genes (BRCA1 and BRCA2) have already been identified. At present, genetic tests to identify known inherited mutations associated with breast tumor predisposition, are available. Asymptomatic subjects with genetic BRCA1/2 mutations represent a group at high risk; therefore it is now indispensable to work out adequate strategies of prevention and/or of early diagnosis. Besides education (information) and genetic counselling, there are three perspectives of intervention for these subjects: bilateral prophylactic surgery, pharmacologic prophylaxis and periodical diagnostic monitoring; unfortunately all of them are still burdened by limitations.


Central Nervous System Tuberculosis: Risk Factors for Mortality in a Propensity Score-Matched Case-Control Study.
Despite advancements in tuberculosis (TB) control and treatment in the United States (US), patients with central nervous system TB (CNS-TB) continue to experience significantly higher mortality rates than those without CNS-TB. This raises concerns regarding clinical management and the need for a deeper understanding of the risk factors contributing to these deaths. This study aimed to determine the predictors of mortality in patients with CNS-TB. We conducted a retrospective 1:2 propensity score-matched case-control study. Cases were TB patients diagnosed with TB of the meninges, brain, spinal cord, or peripheral nerves, as documented in the Florida Department of Health (FDOH) TB registry, between 2009 and 2021. Controls were TB patients without CNS-TB, also reported in the FDOH TB registry during the same timeframe. We employed conditional logistic regression models to investigate the factors contributing to mortality in cases compared with controls. We analyzed data from 116 cases and 232 matched controls. Patients with CNS-TB had a 5.69-fold higher risk of death than those without CNS-TB (adjusted odds ratio [aOR], 5.69 [95% confidence interval {CI}, 2.91-11.6]). Increased risk of death was associated with human immunodeficiency virus (HIV) coinfection (aOR, 1.93 [95% CI, .82-4.37]) and diabetes (aOR, 3.13 [95% CI, 1.28-7.47]). Miliary TB and non-HIV immunosuppression were significantly associated with being a case, while cavitary TB was less likely to be associated with being a case. Clinical management should prioritize screening and close monitoring of patients with HIV coinfection and diabetes to improve patient outcomes.


Design and Development of a New Methodology Based on Expert Systems Applied to the Prevention of Indoor Radon Gas Exposition Risks.
Exposure to high concentration levels of radon gas constitutes a major health hazard, being nowadays the second-leading cause of lung cancer after smoking. Facing this situation, the last years have seen a clear trend towards the search for methodologies that allow an efficient prevention of the potential risks derived from the presence of harmful radon gas concentration levels in buildings. With that, it is intended to establish preventive and corrective actions that might help to reduce the impact of radon exposure on people, especially in places where workers and external users must stay for long periods of time, as it may be the case of healthcare buildings. In this paper, a new methodology is developed and applied to the prevention of the risks derived from the exposure to radon gas in indoor spaces. Such methodology is grounded in the concurrent use of expert systems and regression trees that allows producing a diagram with recommendations associated to the exposure risk. The presented methodology has been implemented by means of a software application that supports the definition of the expert systems and the regression algorithm. Finally, after proving its applicability with a case study and discussing its contributions, it may be claimed that the benefits of the new methodology might lead on to an innovation in this field of study.


Effective compounds in the fruit of Muntingia calabura Linn. cultivated in Taiwan evaluated with scavenging free radicals and suppressing LDL oxidation.
Scavenging effect of 2,2-diphenyl -2-picrylhydrazyl hydrate (DPPH) radicals, inhibitory effect of low-density lipoprotein (LDL) oxidation, Trolox equivalent antioxidant capacity (TEAC), and phenolic contents were used for the activity-guided separation to identify the effective compounds of Muntingia calabura Linn. fruit. Its ethanol extract with higher phenolic content and antioxidant activities was subjected to silica gel column chromatographic separation, which was sequentially eluted with n-hexane, 10-90% ethyl acetate (EA) in n-hexane, EA, EA/acetone (50/50, v/v), acetone, acetone/methanol (MeOH) (50/50, v/v), and MeOH; fifteen fractions (Fr. 1-15) were obtained. Fractions 13 and 14 with better antioxidant effects were mixed followed by purification of the effective compounds using HPLC. Two major compounds were isolated and identified as gallic acid and 1,2-benzenedicarboxylic acid diisooctyl ester through high performance liquid chromatography-mass spectrometry (HPLC-MS) and nuclear magnetic resonance (NMR) measurements. Their amounts in the fruit were 3.76 and 4.62 mg g-1. This study is the first report to clarify the effective antioxidant compounds of M. calabura Linn. fruit.


Effects of propranolol on reflex vascular responses to orthostatic stress in humans. Role of ventricular baroreceptors.
To evaluate the role of ventricular baroreceptors in humans, we studied the effects of propranolol on reflex vasoconstrictor responses to simulated orthostatic stress. We measured forearm vascular resistance in 10 normal males in the control state and during lower body negative pressure (LBNP) at -10 and -40 mm Hg before and after propranolol (0.1 mg/kg i.v.). Baseline forearm vascular resistance showed no significant change: 23.9 +/- 3.4 U (+/- SEM) before vs 28.0 +/- 0.5 U after propranolol. Reflex increases in forearm vascular resistance during LBNP at -10 and -40 mm Hg were 5.2 +/- 1.2 and 21.2 +/- 6.6 U before and 3.4 +/- 1.2 and 10.6 +/- 2.2 U, respectively, after propranolol. Thus, propranolol significantly (p less than 0.05) reduced responses to LBNP at -40 mm Hg. In contrast to the effects with LBNP, propranolol did not attenuate increases in forearm vascular resistance during the cold pressor test and handgrip, thus excluding a nonspecific depression of reflexes. We also studied the effects of propranolol on carotid baroreflex-mediated vasoconstrictor responses to neck pressure at 15 and 30 mm Hg. Propranolol had no significant effect on the vasoconstrictor responses to neck pressure. In conclusion, propranolol selectively attenuates vasoconstrictor responses to LBNP. We suggest that this results from a propranolol-induced decrease in the activity of cardiac ventricular baroreceptors. The results support the view that ventricular baroreceptors play an important role in reflex adjustments to orthostatic stress in humans.


Dental extraction in patients on warfarin treatment.
Warfarin is one of the most common oral anticoagulants used to prevent thromboembolic episodes. The benefits of discontinuation of this drug before simple surgical procedures are not clear and this approach could be associated with complications. The aim of this study was to evaluate the risk of bleeding in a series of 35 patients (in cases where the international normalized ratio [INR] is less than 4) following simple tooth extraction without modification of the warfarin dose given to patients. Thirty-five patients taking warfarin who had been referred to the Oral and Maxillofacial Department, College of Dentistry, King Saud University, for dental extractions were included in the study. Exclusion criteria included patients with an INR of ≥4 or with a history of liver disease or coagulopathies. No alteration was made in warfarin dose, and the CoaguChek System was used to identify the INR on the same day of dental extraction. Bleeding from the extraction site was evaluated and recorded immediately after extraction until the second day. A total of 35 patients (16 women and 19 men) aged between 38 and 57 years (mean =48.7) were included in the present study. All patients underwent simple one-tooth extraction while undergoing warfarin treatment. Oozing, considered mild bleeding and which did not need intervention was seen in 88.6% of patients. Moderate bleeding occurred in 11.4% of all cases. The INR of the patients ranged from 2.00 to 3.50, with 77.2% of patients having INR between 2.0 and 2.5 on the day of extraction. No severe bleeding which needed hospital management was encountered after any of the extractions. The patients who suffered moderate bleeding were returned to the clinic where they received local treatment measures to control bleeding. Moderate bleeding occurred only in four patients, where three had INR between 3.1 and 3.5, and one with INR less than 3. In the present study, we have shown that simple tooth extraction in patients on warfarin treatment can be performed safely without high risk of bleeding, providing that the INR is equal or less than 3.5 on the day of extraction. A close follow-up and monitoring of patients taking warfarin is mandatory after dental extraction.


Stochastic and nonstochastic post-transcriptional silencing of chitinase and beta-1,3-glucanase genes involves increased RNA turnover-possible role for ribosome-independent RNA degradation.
Stochastic and nonstochastic post-transcriptional gene silencing (PTGS) in Nicotiana sylvestris plants carrying tobacco class I chitinase (CHN) and beta-1,3-glucanase transgenes differs in incidence, stability, and pattern of expression. Measurements with inhibitors of RNA synthesis (cordycepin, actinomycin D, and alpha-amanitin) showed that both forms of PTGS are associated with increased sequence-specific degradation of transcripts, suggesting that increased RNA turnover may be a general feature of PTGS. The protein synthesis inhibitors cycloheximide and verrucarin A did not inhibit degradation of CHN RNA targeted for PTGS, confirming that PTGS-related RNA degradation does not depend on ongoing protein synthesis. Because verrucarin A, unlike cycloheximide, dissociates mRNA from ribosomes, our results also suggest that ribosome-associated RNA degradation pathways may not be involved in CHN PTGS.


A single mutation in the mammalian orthoreovirus S1 gene is responsible for increased interferon sensitivity in a virus mutant selected in Vero cells.
In a previous study, a mammalian orthoreovirus mutant was isolated based on its increased ability to infect interferon-defective Vero cells and was referred to as Vero-cells-adapted virus (VeroAV). This virus exhibits reduced ability to resist the antiviral effect of interferon. In the present study, the complete genome sequence of VeroAV was first determined. Reverse genetics was then used to identify a unique mutation on the S1 gene, overlapping the σ1 and σ1 s reading frame, resulting in increased sensitivity to interferon. A virus lacking σ1 s expression consecutive to mutation of its initiation codon was then shown to exhibit a further increase in sensitivity to interferon, supporting the idea that σ1 s is the viral protein responsible. This identification of a new determinant of reovirus sensitivity to interferon gives credentials to the idea that multiple reovirus genes are responsible for the level of interferon induction and susceptibility to the interferon-induced antiviral activities.


The effect of temperature on mortality in Stockholm 1998--2003: a study of lag structures and heatwave effects.
To describe seasonal patterns of natural mortality in Stockholm as well as the temperature-mortality relationship and the lag structure for effects of high and low temperatures; to describe the impact of high temperatures on cardiovascular and respiratory mortality, and the general effect of high temperatures in different age groups; and to investigate whether there is any indication of an additional heatwave or cold spell effect. Generalized additive Poisson regression models were fitted to mortality and temperature data from Stockholm from the period 1998-2003, controlling for influenza, season, time trends, week day, and holidays. The mortality in Stockholm followed a seasonal pattern, with a peak in the winter season. The ;;optimal temperature'' was around 11-12 degrees C. Above this temperature, the cumulative general relative risk (RR) corresponded to a 1.4% (95% confidence interval (CI)=0.8-2.0) increase per degrees C, and below this temperature the cumulative RR corresponded to a 0.7% (95% CI=0.5-0.9) decrease per degrees C. Age-specific RRS were estimated above the threshold for age <65 years, age 65-74 years, and age >74 years, with estimated increases of 0.5% (not significant), 1.5% (not significant) and 1.6% (95% CI=0.9-2.3) per degrees C, respectively. The RRs for cardiovascular and respiratory causes were studied above the breakpoint, and estimated to be 1.1% (95% CI=0.3-2.0) and 4.3% (95% CI=2.2-6.5) per degrees C, respectively. The lag structures from moving averages and polynomial distributed lag models coincided with a rather direct effect during summer (lag 0 and 1) and a more prolonged effect during winter, covering about a week. The inclusion of an indicator of heatwaves added an increase in daily mortality of 3.1-7.7%, depending on the threshold. These results show that the predicted increase in heat events must also be taken seriously in Scandinavia, whatever the extent of the decreasing cold related mortality. The relative risks associated with heat and heatwaves seem stronger than the cold effects and thus a larger public health threat, since northern populations have not yet adapted to heat as have been done over a long time for the cold periods. The pressure on the healthcare sector will probably increase in the warm season, periodically it may become even greater than the pressure due to cold weather, which will be a new phenomenon for the healthcare sector to cope with. We need to be prepared for these kind of events by developing adaptation and education strategies to handle the consequences that a warmer climate will have for public health and the healthcare sector.


[A detoxification unit of adult black males with a standard treatment regimen].
During the period January-June 1975 a relatively high death rate (8,29%; 33 out of 398 patients) was noted in young Black males clinically diagnosed as suffering from toxic psychosis caused by alcohol. Pellagra, malnutrition and pneumonia were complicating factors. After a trial period of 6 months, a detoxification unit was established for these high-risk patients. A total of 615 high-risk patients (15,12%; 615 out of 4 065) was treated with a standardized regimen during the 2 1/2-year period June 1975 - December 1977. Thirty-three out of 615 patients (5,36%) died during this period, 1,57% of the total number with toxic psychosis due to alcohol abuse (33 out of 4065) over a 2 1/2-year period. This rate compares favourably with the average reported rate of 10 - 15%. Effective treatment of high-risk alcohol-induced states reduces the complications and death rate.


Visinity: Visual Spatial Neighborhood Analysis for Multiplexed Tissue Imaging Data.
New highly-multiplexed imaging technologies have enabled the study of tissues in unprecedented detail. These methods are increasingly being applied to understand how cancer cells and immune response change during tumor development, progression, and metastasis, as well as following treatment. Yet, existing analysis approaches focus on investigating small tissue samples on a per-cell basis, not taking into account the spatial proximity of cells, which indicates cell-cell interaction and specific biological processes in the larger cancer microenvironment. We present Visinity, a scalable visual analytics system to analyze cell interaction patterns across cohorts of whole-slide multiplexed tissue images. Our approach is based on a fast regional neighborhood computation, leveraging unsupervised learning to quantify, compare, and group cells by their surrounding cellular neighborhood. These neighborhoods can be visually analyzed in an exploratory and confirmatory workflow. Users can explore spatial patterns present across tissues through a scalable image viewer and coordinated views highlighting the neighborhood composition and spatial arrangements of cells. To verify or refine existing hypotheses, users can query for specific patterns to determine their presence and statistical significance. Findings can be interactively annotated, ranked, and compared in the form of small multiples. In two case studies with biomedical experts, we demonstrate that Visinity can identify common biological processes within a human tonsil and uncover novel white-blood cell networks and immune-tumor interactions.


Cinacalcet versus standard treatment for chronic kidney disease: a protocol for a systematic review and meta-analysis.
Chronic kidney disease-mineral and bone disorders (CKD-MBD) have been associated with poor health outcomes, including diminished quality and length of life. Standard management for CKD-MBD includes phosphate-restricted diet, active vitamin D, vitamin D analogs, and phosphate binders. Persistently elevated parathyroid hormone (PTH) levels may require the addition of Cinacalcet hydrochloride (cinacalcet) which sensitizes calcium receptors on the parathyroid glands. The objective of this systematic review is to compare the effect of cinacalcet versus standard treatment in patients with CKD-MBD. Data sources will include MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and Web of Science from 1996 to June 2015. Teams of two reviewers will, independently and in duplicate, screen titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstract data and assess risk of bias in eligible trials. We will calculate the effect estimates (risk ratios or mean differences) and 95 % confidence intervals, as well as statistical measures of variability in results across studies using random effect models for patient-important and intermediate outcomes. We will use the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence about estimates of effect on an outcome-by-outcome basis. We will present our results with a GRADE summary table. Our review will explore the effect of cinacalcet versus standard treatment in patients with CKD-MBD. The results of this systematic review will help guide management of this patient population, and identify targets for future research. PROSPERO CRD42015020318 http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015020318.


Systemic overexpression of TNFα-converting enzyme does not lead to enhanced shedding activity in vivo.
TNFα-converting enzyme (TACE/ADAM17) is a membrane-bound proteolytic enzyme with a diverse set of target molecules. Most importantly, TACE is indispensable for the release and activation of pro-TNFα and the ligands for epidermal growth factor receptor in vivo. Previous studies suggested that the overproduction of TACE is causally related to the pathogenesis of inflammatory diseases and cancers. To test this hypothesis, we generated a transgenic line in which the transcription of exogenous Tace is driven by a CAG promoter. The Tace-transgenic mice were viable and exhibited no overt defects, and the quantitative RT-PCR and Western blot analyses confirmed that the transgenically introduced Tace gene was highly expressed in all of the tissues examined. The Tace-transgenic mice were further crossed with Tace⁻/⁺ mice to abrogate the endogenous TACE expression, and the Tace-transgenic mice lacking endogenous Tace gene were also viable without any apparent defects. Furthermore, there was no difference in the serum TNFα levels after lipopolysaccharide injection between the transgenic mice and control littermates. These observations indicate that TACE activity is not necessarily dependent on transcriptional regulation and that excess TACE does not necessarily result in aberrant proteolytic activity in vivo.


Gene therapy for bone healing.
Clinical problems in bone healing include large segmental defects, spinal fusions, and the nonunion and delayed union of fractures. Gene-transfer technologies have the potential to aid healing by permitting the local delivery and sustained expression of osteogenic gene products within osseous lesions. Key questions for such an approach include the choice of transgene, vector and gene-transfer strategy. Most experimental data have been obtained using cDNAs encoding osteogenic growth factors such as bone morphogenetic protein-2 (BMP-2), BMP-4 and BMP-7, in conjunction with both nonviral and viral vectors using in vivo and ex vivo delivery strategies. Proof of principle has been convincingly demonstrated in small-animal models. Relatively few studies have used large animals, but the results so far are encouraging. Once a reliable method has been developed, it will be necessary to perform detailed pharmacological and toxicological studies, as well as satisfy other demands of the regulatory bodies, before human clinical trials can be initiated. Such studies are very expensive and often protracted. Thus, progress in developing a clinically useful gene therapy for bone healing is determined not only by scientific considerations, but also by financial constraints and the ambient regulatory environment.


Robust hepatitis B virus genotyping by mass spectrometry.
Genotyping of hepatitis B virus (HBV) is important for tracking HBV infections, prognosticating the development of severe liver disease, and predicting outcomes of therapy. Current genotyping methods can be laborious and costly and rely on subjective data interpretation. To identify less expensive but equally reliable alternatives, we compared "gold standard" sequencing to a novel mass spectrometry approach. Sera from individuals with acute or chronic HBV infection (n = 756), representing all genotypes, were used to PCR amplify the HBV S gene. All amplicons were subjected to base-specific cleavage and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The resulting mass peak patterns were used to identify HBV genotype by automated comparison to peak patterns simulated from reference sets of HBV sequences of known genotypes. The MALDI-TOF MS data and phylogenetic analysis of HBV sequences produced completely concordant results. Several parameters such as genetic relatedness of tested HBV variants to the reference set, chronic infections, and the quality of PCR products can lower the MS score but never affected the accuracy of the genotype call. This new streamlined MS-based method provides for rapid and accurate HBV genotyping, produces automated data reports, and is therefore suitable for routine use in diagnostic settings.


[Severe hypertension and renal infarct. Physiopathology and treatment. Apropos of 1 case].
Renal infarction can be complicated by arterial hypertension, which is sometimes severe and may present as hypertensive encephalopathy and epilepsy. We report such a case in whom angiographic studies revealed a stenosis of the left renal artery and a post-stenotic aneurysmal dilation, containing a large thrombus with distal embolization. Thrombolysis associated with angioplasty resulted in the disappearance of the thrombus and correction of the stenosis. The pathophysiology of hypertension secondary to renal infarction is discussed. Therapeutic modalities are reviewed.


Induction of experimental systemic lupus erythematosus in mice by immunization with a monoclonal anti-La autoantibody.
Experimental systemic lupus erythematosus (SLE) in mice can be induced by immunization either with a human monoclonal anti-DNA antibody bearing the 16/6 idiotype (16/6 Id) or with a mouse monoclonal anti-idiotypic antibody specific for the 16/6 Id. In the present report we investigated the pathogenic role of a monoclonal anti-La autoantibody in the induction and mediation of experimental SLE in mice. The monoclonal anti-La antibody was derived from a mouse in which experimental SLE was induced by immunization with the monoclonal anti-16/6 Id antibody. Following immunization with the anti-La antibody the mice produced antibodies to double-stranded DNA, single-stranded DNA, Sm, SS-A/Ro, SS-B/La, and ribonucleoprotein. Furthermore, even though the anti-La antibody does not express nor react with the 16/6 Id, the immunized mice produced high titers of anti-16/6 Id antibodies as well as 16/6 Id bearing antibodies. Four months following immunization the mice exhibited significant proteinuria, and kidney sections revealed immune complex deposits on the basement membrane of the glomeruli. These results suggest that anti-La autoantibodies are involved in the induction and mediation of SLE in mice.