Beta-keratin expression in avian tongue cell aggregates.
Rotation-mediated aggregation was used to test the capacity of early embryonic tongue cells from different regions of the tongue to reorganize histotypically and terminally differentiate in vitro. Cells dissociated from the anterior ventral (AV) or posterior ventral (PV) surface of the 12 day embryonic tongue were cultured 6 days, fixed, and embedded in paraffin. Indirect immunofluorescence microscopy was used to demonstrate the occurrence and distribution of beta-keratins, the presence of which represented regional and differentiation specific markers of late tongue development. Aggregates of AV cells were organized into a beta-keratin-producing stratified epithelium. Similar PV aggregates formed only an alpha-keratin-producing stratified epithelium. The epithelial cells of these tongue tissues constructs expressed alpha- and beta-keratins in a manner consistent with the temporal and histotypical expression of keratins observed in vivo.


T-cell qualities of lymphocytes and/or leukemic cells from peripheral blood in acute myeloid and lymphatic leukemia before treatment and at relapse.
PHA stimulation of peripheral blood lymphocytes and/or leukemic cells has been studied in 65 patients with acute leukemia before any prior treatment. There were 38 patients with A.L.L. and 27 with A.M.L. In relapsing A.L.L. 15 observations were made before reinduction therapy. In about 40% of all the cultures PHA stimulation was done simultaneously with PWM-stimulation. Before any treatment normal lymphocytes showed a normal response, being however somewhat diminished at relapse. Most of the cases of A.M.L. had so many leukemic cells in peripheral blood that no reliable measure of stimulation of the few lymphocytes left was possible. In A.L.L. this was however possible in about 30% of all the cases studied. In cultures of the predominantly leukemic cells, lymphoblasts showed a positive response in a minority of cases studied. If the peripheral WBC-count was high, a response was usually absent. In some of the cases of A.M.L., the leukemic cells reacted to PHA and PWM. Unexpected but very remarkable is our finding that in the control cultures, without added mitogen, the incorporation of labelled 3H-thymidine was usually very high in A.M.L. contrasting with A.L.L. leukemic cells who incorporated very little of the label. These striking differences were observed both in 72 and 144 hours cultures and were not caused by differences in viability between these two leukemic cell-types. The capacity of A.L.L.-leukemic cells to form E ("T") and EAC ("B") rosettes was studied in 20 cases. The percentages of rosette forming lymphoblasts differed widely from patient to patient. It is concluded that in A.L.L. leukemic cells are in a minority immuno-competent cells and it is suggested that the lymphoblast is an immature cell, arrested in the maturation towards a T-lymphocyte, the degree of maturity differing from patient to patient. Furthermore the striking difference in spontaneous labelling of myeloid versus lymphoblastic leukemic cells seems to be helpful in the differential diagnosis and may in part explain the well known differences in prognosis and behaviour towards cytostatics between these main leukemia types.


Interactions Between Stress and Sex in Microbial Responses Within the Microbiota-Gut-Brain Axis in a Mouse Model.
Animal models are frequently used to examine stress response, but experiments seldom include females. The connection between the microbiota-gut-brain axis and behavioral stress response is investigated here using a mixed-sex mouse cohort. CF-1 mice underwent alternating days of restraint and forced swim for 19 days (male n = 8, female n = 8) with matching numbers of control animals at which point the 16S rRNA genes of gut microbiota were sequenced. Mixed linear models accounting for stress status and sex with individuals nested in cage to control for cage effects evaluated these data. Murine behaviors in elevated plus-maze, open-field, and light/dark box were investigated. Community-level associations with sex, stress, and their interaction were significant. Males had higher microbial diversity than females (p = .025). Of the 638 operational taxonomic units detected in at least 25% of samples, 94 operational taxonomic units were significant: 31 (stress), 61 (sex), and 34 (sex-stress interaction). Twenty of the 39 behavioral measures were significant for stress, 3 for sex, and 6 for sex-stress. However, no significant associations between behavioral measures and specific microbes were detected. These data suggest sex influences stress response and the microbiota-gut-brain axis and that studies of behavior and the microbiome therefore benefit from consideration of how sex differences drive behavior and microbial community structure. Host stress resilience and absence of associations between stress-induced behaviors with specific microbes suggests that hypothalamic-pituitary-adrenal axis activation represents a threshold for microbial influence on host behavior. Future studies are needed in examining the intersection of sex, stress response, and the microbiota-gut-brain axis.


[Ramsay Hunt syndrome. Effects of the treatment with acyclovir (preliminary study)].
Herpes zoster oticus has a poor prognosis with permanent facial nerve dysfunction. We have studied 11 patients in a total group of 131 facial palsies seen in our service for a 20 month period. Four patients had no treatment. Two were treated with prednisone, and five were infused with acyclovir (10 mg/kg every 8 hours over a 10 day hospitalization period) and prednisone. These treatments were observed for 3 to 6 months. Patients follow up was, acyclovir group, 2 patients have achieved a House grade I, 1 patient grade II, 1 patient grade III and 1 left this treatment because side effects was observed. The other patients, 1 have achieved grade I, 2 patients grade II, 2 patients grade III and 1 patient grade V. The differences and final results are discussed.


Drinking Green Tea: Despite the Risks Due to Mycotoxins, Is It Possible to Increase the Associated Health Benefits?
Tea has been consumed for thousands of years. Despite the different varieties, particular emphasis has been placed on green tea (GT), considering the associated health benefits following its regular consumption, some of which are due to its polyphenol constituents, such as epigallocatechin-3-gallate (EGCG). Tea is not prone to the growth of microorganisms, except fungus, when proper storage, handling, and packing conditions are compromised. Consequently, mycotoxins, secondary metabolites of fungi, could contaminate tea samples, affecting human health. In the present study, we aimed to assess the balance between risks (due to mycotoxins and high levels of EGCG) and benefits (due to moderate intake of EGCG) associated with the consumption of GT. For this, 20 GT samples (10 in bulk and 10 in bags) available in different markets in Lisbon were analyzed through a LC-MS/MS method, evaluating 38 different mycotoxins. Six samples revealed detectable values of the considered toxins. Current levels of mycotoxins and EGCG intake were not associated with health concerns. Scenarios considering an increasing consumption of GT in Portugal showed that drinking up to seven cups of GT per day should maximize the associated health benefits. The present study contributes to the future establishment of GT consumption recommendations in Portugal.


A simulation-based method to inform serosurvey designs for estimating the force of infection using existing blood samples.
The extent to which dengue virus has been circulating globally and especially in Africa is largely unknown. Testing available blood samples from previous cross-sectional serological surveys offers a convenient strategy to investigate past dengue infections, as such serosurveys provide the ideal data to reconstruct the age-dependent immunity profile of the population and to estimate the average per-capita annual risk of infection: the force of infection (FOI), which is a fundamental measure of transmission intensity. In this study, we present a novel methodological approach to inform the size and age distribution of blood samples to test when samples are acquired from previous surveys. The method was used to inform SERODEN, a dengue seroprevalence survey which is currently being conducted in Ghana among other countries utilizing samples previously collected for a SARS-CoV-2 serosurvey. The method described in this paper can be employed to determine sample sizes and testing strategies for different diseases and transmission settings.


Dietary baked egg accelerates resolution of egg allergy in children.
Baked egg is tolerated by a majority of egg-allergic children. To characterize immunologic changes associated with ingestion of baked egg and evaluate the role that baked egg diets play in the development of tolerance to regular egg. Egg-allergic subjects who tolerated baked egg challenge incorporated baked egg into their diet. Immunologic parameters were measured at follow-up visits. A comparison group strictly avoiding egg was used to evaluate the natural history of the development of tolerance. Of the 79 subjects in the intent-to-treat group followed for a median of 37.8 months, 89% now tolerate baked egg and 53% now tolerate regular egg. Of 23 initially baked egg-reactive subjects, 14 (61%) subsequently tolerated baked egg and 6 (26%) now tolerate regular egg. Within the initially baked egg-reactive group, subjects with persistent reactivity to baked egg had higher median baseline egg white (EW)-specific IgE levels (13.5 kU(A)/L) than those who subsequently tolerated baked egg (4.4 kU(A)/L; P= .04) and regular egg (3.1 kU(A)/L; P= .05). In subjects ingesting baked egg, EW-induced skin prick test wheal diameter and EW-, ovalbumin-, and ovomucoid-specific IgE levels decreased significantly, while ovalbumin- and ovomucoid-specific IgG(4) levels increased significantly. Subjects in the per-protocol group were 14.6 times more likely than subjects in the comparison group (P< .0001) to develop regular egg tolerance, and they developed tolerance earlier (median 50.0 vs 78.7 months; P< .0001). Initiation of a baked egg diet accelerates the development of regular egg tolerance compared with strict avoidance. Higher serum EW-specific IgE level is associated with persistent baked and regular egg reactivity, while initial baked egg reactivity is not.


Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine.
Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, a "one-size-fits-all" approach to HCC screening for early tumour detection, as recommended by clinical practice guidelines, is utilised in less than 20% of the target population, and the performance of screening modalities, including ultrasound and alpha-fetoprotein, is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations, such as those with chronic hepatitis C after viral cure, or those with non-cirrhotic, non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve the sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailoured HCC screening of individual patients, maximising cost-effectiveness and optimising allocation of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalised chemoprevention, targeting high-risk patients for precision HCC prevention and substantially improving the dismal prognosis of HCC.


Parent-based adolescent sexual health interventions and effect on communication outcomes: a systematic review and meta-analyses.
Parent-based adolescent sexual health interventions aim to reduce sexual risk behaviors by bolstering parental protective behaviors. Few studies of theory use, methods, applications, delivery and outcomes of parent-based interventions have been conducted. A systematic search of databases for the period 1998-2013 identified 28 published trials of U.S. parent-based interventions to examine theory use, setting, reach, delivery mode, dose and effects on parent-child communication. Established coding schemes were used to assess use of theory and describe methods employed to achieve behavioral change; intervention effects were explored in meta-analyses. Most interventions were conducted with minority parents in group sessions or via self-paced activities; interventions averaged seven hours, and most used theory extensively. Meta-analyses found improvements in sexual health communication: Analysis of 11 controlled trials indicated a medium effect on increasing communication (Cohen's d, 0.5), and analysis of nine trials found a large effect on increasing parental comfort with communication (0.7); effects were positive regardless of delivery mode or intervention dose. Intervention participants were 68% more likely than controls to report increased communication and 75% more likely to report increased comfort. These findings point to gaps in the range of programs examined in published trials-for example, interventions for parents of sexual minority youth, programs for custodial grandparents and faith-based services. Yet they provide support for the effectiveness of parent-based interventions in improving communication. Innovative delivery approaches could extend programs' reach, and further research on sexual health outcomes would facilitate the meta-analysis of intervention effectiveness in improving adolescent sexual health behaviors.


Doubling over ten years of central obesity in Hong Kong Chinese working men.
Obesity is now an epidemic in most parts of the world. In this cross sectional study, we report the most recent data on obesity in Hong Kong Chinese working population and compare the changes over 10 years. Between July 2000 and March 2002, 5882 adult subjects from the working class in Hong Kong were recruited (2716 men (46.2%) and 3166 women (53.8%)). They were randomly selected using computer generated codes according to the distribution of occupational groups. Results of this study were compared with the data collected from a prevalence survey for cardiovascular risk factors in a Hong Kong Chinese working population conducted in 1990 (1513 subjects, 910 men (60.1%) and 603 women (39.9%)). Standardized percentages of overweight, obesity, and central obesity, in Hong Kong Chinese working population were 59.7%, 35.0%, 26.7% in men and 32.0%, 21.7%, 26.7% in women. Compared to the data collected in 1990, the percentage of obesity increased by 5% in men and reduced by 6% in women. The percentage of central obesity doubled in men (from 12.2% to 26.7%) but remained stable in women. There is a doubling of the percentage of central obesity in Hong Kong Chinese working men over previous decade. Education and proper lifestyle modification program to tackle this social health issue are urgently indicated.


Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats.
Cadmium (Cd) is a neurotoxic metal, which induces oxidative stress and membrane disturbances in nerve system. The garlic compound diallyl tetrasulfide (DTS) has the cytoprotective and antioxidant activity against Cd induced toxicity. The present study was carried out to investigate the efficacy of DTS in protecting the Cd induced changes in the activity of acetylcholinesterase (AChE), membrane bound enzymes, lipid peroxidation (LPO) and antioxidant status in the brain of rats. In rats exposed to Cd (3mg/kg/day subcutaneously) for 3 weeks, a significant (P<0.05) increase in the levels of LPO and protein carbonyls along with significant (P<0.05) decrease in the levels of reduced glutathione (GSH) and total sulphydryl groups (TSH) and the activities of AChE, superoxide dismutase, catalase, glutathione peroxidase, gluthione-S-transeferase, membrane bound enzymes (ATPases: Na(+)K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase) were observed in brain tissue. Oral administration of DTS (40mg/kg/day) with Cd significantly (P<0.05) diminished the levels of LPO and protein carbonyls and significantly (P<0.05) increased the activities of ATPases, antioxidant enzymes, GSH and TSH in brain. These results indicate that DTS attenuate the LPO and alteration of antioxidant and membrane bound enzymes in Cd exposed rats, which suggest that DTS protects the brain function from toxic effects of Cd.


Evidence for electrotonic coupling between frog motoneurons in the in situ spinal cord.
A recurrent EPSP was observed on antidromic stimulation of motoneurons in the in situ spinal cord of Rana temporaria and R. esculenta at 20-22C. The EPSP was finely graded and not refractory following full or partial antidromic spike components in a given neuron. The EPSP amplitude varied in parallel with the antidromic field potential under different conditions, suggesting transmission of the EPSP to the recorded motoneuron depended on invasion of the somadendritic membrane or neighboring motoneurons by the antidromic spike. The latency of the EPSP with respect to antidromic invasion of the local motoneuron pool was too short for the EPSP to be mediated by chemical transmission. It was concluded the EPSP was electrically transmitted between the somadendritic membranes of the motoneurons. Under certain conditions, the EPSP magnitude could be made to vary with membrane potential in a direction opposite to that expected from a chemical EPSP. Dendritic spikes were sometimes associated with the EPSP.


[The utilization of glass ionomer sealing cements].
In order to fix the reconstructive work, a luting cement is used. The main task of this cement is to retain the restoration on the tooth and to fill and seal the gap between them. The first glass ionomer luting cement came on the market in 1978. In the beginning, the cement did not perform as expected: high solubility, high viscosity and hypersensitivity, even followed by pulp death, were reported. The glass ionomer luting cement compares now favourably with the traditional non-adhesive cements. Nevertheless, the zinc phosphate cement is still the most commonly used cementing agent in the dental private practice. Studies have shown that the problems of hypersensitivity after the use of glass ionomer luting cements are more dentist related than material related. This article explains how to use the glass ionomer luting cements in order to achieve a successful cementation.


Does food vendor density mediate the association between neighborhood deprivation and BMI?: a G-computation mediation analysis.
In previous research, neighborhood deprivation was positively associated with body mass index (BMI) among adults with diabetes. We assessed whether the association between neighborhood deprivation and BMI is attributable, in part, to geographic variation in the availability of healthful and unhealthful food vendors. Subjects were 16,634 participants of the Diabetes Study of Northern California, a multiethnic cohort of adults living with diabetes. Neighborhood deprivation and healthful (supermarket and produce) and unhealthful (fast food outlets and convenience stores) food vendor kernel density were calculated at each participant's residential block centroid. We estimated the total effect, controlled direct effect, natural direct effect, and natural indirect effect of neighborhood deprivation on BMI. Mediation effects were estimated using G-computation, a maximum likelihood substitution estimator of the G-formula that allows for complex data relations such as multiple mediators and sequential causal pathways. We estimated that if neighborhood deprivation was reduced from the most deprived to the least deprived quartile, average BMI would change by -0.73 units (95% confidence interval: -1.05, -0.32); however, we did not detect evidence of mediation by food vendor density. In contrast to previous findings, a simulated reduction in neighborhood deprivation from the most deprived to the least deprived quartile was associated with dramatic declines in both healthful and unhealthful food vendor density. Availability of food vendors, both healthful and unhealthful, did not appear to explain the association between neighborhood deprivation and BMI in this population of adults with diabetes.


Three-dimensional echo planar spectroscopic imaging for differentiation of true progression from pseudoprogression in patients with glioblastoma.
Accurate differentiation of true progression (TP) from pseudoprogression (PsP) in patients with glioblastomas (GBMs) is essential for planning adequate treatment and for estimating clinical outcome measures and future prognosis. The purpose of this study was to investigate the utility of three-dimensional echo planar spectroscopic imaging (3D-EPSI) in distinguishing TP from PsP in GBM patients. For this institutional review board approved and HIPAA compliant retrospective study, 27 patients with GBM demonstrating enhancing lesions within six months of completion of concurrent chemo-radiation therapy were included. Of these, 18 were subsequently classified as TP and 9 as PsP based on histological features or follow-up MRI studies. Parametric maps of choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) were computed and co-registered with post-contrast T1 -weighted and FLAIR images. All lesions were segmented into contrast enhancing (CER), immediate peritumoral (IPR), and distal peritumoral (DPR) regions. For each region, Cho/Cr and Cho/NAA ratios were normalized to corresponding metabolite ratios from contralateral normal parenchyma and compared between TP and PsP groups. Logistic regression analyses were performed to obtain the best model to distinguish TP from PsP. Significantly higher Cho/NAA was observed from CER (2.69 ± 1.00 versus 1.56 ± 0.51, p = 0.003), IPR (2.31 ± 0.92 versus 1.53 ± 0.56, p = 0.030), and DPR (1.80 ± 0.68 versus 1.19 ± 0.28, p = 0.035) regions in TP patients compared with those with PsP. Additionally, significantly elevated Cho/Cr (1.74 ± 0.44 versus 1.34 ± 0.26, p = 0.023) from CER was observed in TP compared with PsP. When these parameters were incorporated in multivariate regression analyses, a discriminatory model with a sensitivity of 94% and a specificity of 87% was observed in distinguishing TP from PsP. These results indicate the utility of 3D-EPSI in differentiating TP from PsP with high sensitivity and specificity.


The PGE2-EP2-mast cell axis: an antiasthma mechanism.
Despite the fact that cyclooxygenase and its products, prostaglandins, have been traditionally associated with the development of inflammation, PGE2 was implicated early on as potentially beneficial in asthma. During the 1970s and 1980s, several studies reported the bronchodilator effect of PGE2 in asthma patients. In parallel, it was being shown to exert an inhibitory effect on mast cells in vitro. In spite of this, data supporting the beneficial role for PGE2 in asthma were scarce and sometimes controversial. Many years later, in vitro and in vivo studies suggested a range of biological activities attributable to PGE2, others than the ability to relax smooth muscle, that potentially explained some of the observed positive effects in asthma. The identification and cloning of the four PGE2 receptors made available new tools with which to fine-tune investigation of the anti-inflammatory, pro-inflammatory, immunoregulatory, and bronchodilation mechanisms of PGE2. Among these, several suggested involvement of mast cells, a cell population known to play a fundamental role in acute and chronic asthma. Indeed, it has been shown that PGE2 prevents human and murine MC activity in vitro through activation of the EP2 receptor, and also that both exogenously administered and endogenous PGE2 inhibit airway MC activity in vivo in mouse models of asthma (likely through an EP2-mediated mechanism as well). In the last few years, we have furthered into the functional connection between PGE2-induced mast cells inhibition and attenuated damage, in asthma and allergy models. The validity of the findings supporting a beneficial effect of PGE2 in different asthma phases, the direct effect of PGE2 on mast cells populations, and the functional implications of the PGE2-MC interaction on airway function are some of the topics addressed in this review, under the assumption that increased understanding of the PGE2-EP2-mast cell axis will likely lead to the discovery of novel antiasthma targets.


Plasma mevalonate as a measure of cholesterol synthesis in man.
Measurement of mevalonic acid (MVA) concentrations in plasma or 24-h urine samples is shown to be useful in studies of the regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Plasma MVA concentrations, measured either at 7-9 a.m. after an overnight fast, or throughout the 24-h cycle, were compared with cholesterol synthesis rates that were measured by the sterol balance method: plasma MVA concentrations were directly related to the rate of whole body cholesterol synthesis (r = 0.972; p less than 0.001; n = 18) over a tenfold range of cholesterol synthesis rates. Moreover, hourly examination of MVA concentrations throughout the day demonstrated that interventions such as fasting or cholesterol feeding cause suppression of the postmidnight diurnal rise in plasma MVA concentrations, with little change in the base-line of the rhythm. Thus, the daily rise and fall of plasma MVA appears to reflect changes in tissues and organs, such as the liver and intestine, that are known to be most sensitive to regulation by fasting or by dietary cholesterol. The hypothesis that short-term regulation of HMG-CoA reductase in tissues is quickly reflected by corresponding variations in plasma MVA was tested by using a specific inhibitor of HMG-CoA reductase, mevinolin, to block MVA synthesis. Mevinolin caused a dose-dependent lowering of plasma MVA after a single dose; and in patients who received the drug twice a day for 4 wk, it decreased 24-h urinary MVA output. Significant lowering of plasma cholesterol was achieved through administration of mevinolin at doses that only moderately limit MVA production.


Out-of-home informal support important for medication adherence, diabetes distress, hemoglobin A1c among adults with type 2 diabetes.
Adults with type 2 diabetes mellitus (T2DM) often receive self-management support from adult children, siblings or close friends residing outside of their home. However, the role of out-of-home support in patients' self-management and well-being is unclear. Patients (N = 313) with HbA1c > 7.5% were recruited from community primary care clinics for a mobile health intervention trial and identified an out-of-home informal support person, herein called a CarePartner; 38% also had an in-home supporter. We tested cross-sectional adjusted associations between CarePartner relationship characteristics and patients' self-management, diabetes distress, and HbA1c and whether having an in-home supporter modified these associations. Greater CarePartner closeness was associated with a greater odds of perfect medication adherence (AOR = 1.19, p = .029), more fruit/vegetable intake (β = 0.14, p = .018), and lower diabetes distress (β = - 0.14, p = .012). More frequent CarePartner contact was associated with better HbA1c among patients with an in-home supporter but with worse HbA1c among patients without an in-home supporter (interaction β = - 0.45, p = .005). Emotional closeness with a CarePartner may be important for supporting T2DM self-management and reducing diabetes distress. CarePartners may appropriately engage more frequently when patients with no in-home supporter have poorly controlled diabetes.


Response of Drosophila epithelial cell and tissue shape to external forces in vivo.
How actomyosin generates forces at epithelial adherens junctions has been extensively studied. However, less is known about how a balance between internal and external forces establishes epithelial cell, tissue and organ shape. We used the Drosophila egg chamber to investigate how contractility at adherens junctions in the follicle epithelium is modulated to accommodate and resist forces arising from the growing germ line. We found that between stages 6 and 9, adherens junction tension in the post-mitotic epithelium decreases, suggesting that the junctional network relaxes to accommodate germline growth. At that time, a prominent medial Myosin II network coupled to corrugating adherens junctions develops. Local enrichment of medial Myosin II in main body follicle cells resists germline-derived forces, thus constraining apical areas and, consequently, cuboidal cell shapes at stage 9. At the tissue and organ level, local reinforcement of medial junction architecture ensures the timely contact of main body cells with the expanding oocyte and imposes circumferential constraints on the germ line guiding egg elongation. Our study provides insight into how adherens junction tension promotes cell and tissue shape transitions while integrating the growth and shape of an internally enclosed structure in vivo.


Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia.
Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood. In this proof of principle study, we performed whole genome sequencing of two cases with multiple relapses in order to investigate whether groups of mutations separated in time show distinct mutational signatures. Based on mutation allele frequencies at diagnosis and subsequent relapses, we clustered mutations into groups and performed cluster-specific mutational profile analysis and de novo signature extraction. In patient 1, who experienced two relapses, the analysis unraveled a continuous interplay of aberrant activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity. The associated signatures SBS2 and SBS13 were present already at diagnosis, and although emerging mutations were lost in later relapses, the process remained active throughout disease evolution. Patient 2 had three relapses. We identified episodic mutational processes at diagnosis and first relapse leading to mutations resembling ultraviolet light-driven DNA damage, and thiopurine-associated damage at first relapse. In conclusion, our data shows that investigation of mutational processes in clusters separated in time may aid in understanding the mutational mechanisms and discovery of underlying causes.


Mitochondria and the autophagy-inflammation-cell death axis in organismal aging.
Alterations of mitochondrial functions are linked to multiple degenerative or acute diseases. As mitochondria age in our cells, they become progressively inefficient and potentially toxic, and acute damage can trigger the permeabilization of mitochondrial membranes to initiate apoptosis or necrosis. Moreover, mitochondria have an important role in pro-inflammatory signaling. Autophagic turnover of cellular constituents, be it general or specific for mitochondria (mitophagy), eliminates dysfunctional or damaged mitochondria, thus counteracting degeneration, dampening inflammation, and preventing unwarranted cell loss. Decreased expression of genes that regulate autophagy or mitophagy can cause degenerative diseases in which deficient quality control results in inflammation and the death of cell populations. Thus, a combination of mitochondrial dysfunction and insufficient autophagy may contribute to multiple aging-associated pathologies.


Unveiling early cortical and subcortical neuronal degeneration in ALS mice by ultra-high field diffusion MRI.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS. ALS brains (G93A-SOD1mice) were scanned in a 16.7 T magnet. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) have shown presymptomatic decrease in axonal organization by Fractional Anisotropy (FA) and neurite content by Intracellular Volume Fraction (ICVF) across deep WM (corpus callosum) as well as superficial (cortex) and deep (hippocampus) GM. Additional diffusion kurtosis imaging (DKI) analysis demonstrated broader and earlier GM reductions in mean kurtosis (MK), possibly related to the decrease in neuronal complexity. Histological validation was obtained by an ALS fluorescent mice reporter (YFP, G93A-SOD1 mice). The combination of DTI, NODDI, and DKI models have proved to provide a more complete assessment of the early microstructural changes in the ALS brain, particularly in areas associated with high cognitive functions. This comprehensive approach should be considered as a valuable tool for the early detection of neuroimaging markers.


Genome-wide SNP analysis reveals no gain in power for association studies of common variants in the Finnish Saami.
The Saami from Fennoscandia are believed to represent an ancient, genetically isolated population with no evidence of population expansion. Theoretical work has indicated that under this demographic scenario, extensive linkage disequilibrium (LD) is generated by genetic drift. Therefore, it has been suggested that the Saami would be particularly suited for genetic association studies, offering a substantial power advantage and allowing more economic study designs. However, no study has yet assessed this claim. As part of a GWAS for a complex trait, we evaluated the relative power for association studies of common variants in the Finnish Saami. LD patterns in the Saami were very similar to those in the non-African HapMap reference panels. Haplotype diversity was reduced and, on average, levels of LD were higher in the Saami as compared with those in the HapMap panels. However, using a 'hidden' SNP approach we show that this does not translate into a power gain in association studies. Contrary to earlier claims, we show that for a given set of common SNPs, genomic coverage attained in the Saami is similar to that in the non-African HapMap panels. Nevertheless, the reduced haplotype diversity could potentially facilitate gene identification, especially if multiple rare variants play a role in disease etiology. Our results further indicate that the HapMap is a useful resource for genetic studies in the Saami.


Factors governing sustainable groundwater pumping near a river.
The objective of this paper was to provide new insights into processes affecting riverbank filtration (RBF). We consider a system with an inflatable dam installed for enhancing water production from downstream collector wells. Using a numerical model, we investigate the impact of groundwater pumping and dam operation on the hydrodynamics in the aquifer and water production. We focus our study on two processes that potentially limit water production of an RBF system: the development of an unsaturated zone and riverbed clogging. We quantify river clogging by calibrating a time-dependent riverbed permeability function based on knowledge of pumping rate, river stage, and temperature. The dynamics of the estimated riverbed permeability reflects clogging and scouring mechanisms. Our results indicate that (1) riverbed permeability is the dominant factor affecting infiltration needed for sustainable RBF production; (2) dam operation can influence pumping efficiency and prevent the development of an unsaturated zone beneath the riverbed only under conditions of sufficient riverbed permeability; (3) slow river velocity, caused by dam raising during summer months, may lead to sedimentation and deposition of fine-grained material within the riverbed, which may clog the riverbed, limiting recharge to the collector wells and contributing to the development of an unsaturated zone beneath the riverbed; and (4) higher river flow velocities, caused by dam lowering during winter storms, scour the riverbed and thus increase its permeability. These insights can be used as the basis for developing sustainable water management of a RBF system.


The effects of choice on intrinsic motivation and related outcomes: a meta-analysis of research findings.
A meta-analysis of 41 studies examined the effect of choice on intrinsic motivation and related outcomes in a variety of settings with both child and adult samples. Results indicated that providing choice enhanced intrinsic motivation, effort, task performance, and perceived competence, among other outcomes. Moderator tests revealed the effect of choice on intrinsic motivation was stronger (a) for instructionally irrelevant choices compared to choices made between activities, versions of a task, rewards, and instructionally relevant options, (b) when 2 to 4 successive choices were given, (c) when rewards were not given after the choice manipulation, (d) when participants given choice were compared to the most controlling forms of control groups, (e) for children compared to adults, (f) for designs that yoked choice and control conditions compared to matched designs in which choice was reduced or designs in which nonyoked, nonmatched controls were used, and (g) when the experiment was conducted in a laboratory embedded in a natural setting. Implications for future research and applications to real-world settings are discussed.


Impact of observation status on hospital use for patients with cancer.
For patients with cancer, the impact of observation status on hospital and patient outcomes is not well understood. Our objective was to assess the impact that an observation unit had on hospital use for patients with cancer who presented to the Urgent Care Center at a comprehensive cancer center. We assessed the proportion of Urgent Care Center visits that resulted in an admission to the hospital at a comprehensive cancer center, before (July 9, 2012-December 31, 2012) versus after (July 9, 2013-December 31, 2013) implementation of the observation unit. We also assessed differences in length of stay and stratified the data by presenting complaint. During each 6-month study interval, there were more than 10,000 patient visits to the Urgent Care Center, representing approximately 6,000 unique patients. Fewer visits resulted in an inpatient admission postimplementation (47%) compared with preimplementation (50%). The duration of hospital stay for admitted patients was higher in the post period (median 108 hours) than in the pre period (median 96 hours). Alternatively, the proportion of hospital admissions with a length of stay less than 24 hours was lower in the post period (pre: 7%; post: 5%). Lower admission rates postimplementation were observed for patients who presented with fluid and electrolyte disorders, nausea and vomiting, syncope, and chest pain. We observed reductions in hospital use for patients with cancer related to an observation unit in a comprehensive cancer center. Adoption of this approach for this patient population has the potential to reduce hospital use, which is of interest to hospitals, payers, and patients.


Genome Sequence of SARS-CoV-2 Isolate Cali-01, from Colombia, Obtained Using Oxford Nanopore MinION Sequencing.
We report the genome sequence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolate obtained from a patient with symptoms of coronavirus disease 2019 (COVID-19) who was infected in Cali, Colombia. The patient had no recent travel record and did not require hospitalization. The virus genome was obtained using Oxford Nanopore MinION sequencing.


Residual indoor contamination from world trade center rubble fires as indicated by polycyclic aromatic hydrocarbon profiles.
The catastrophic destruction of the World Trade Center (WTC) on Sept. 11, 2001 (9/11) created an immense dust cloud followed by fires that emitted smoke and soot into the air of New York City (NYC) well into December. Outdoor pollutant levels in lower Manhattan returned to urban background levels after about 200 days as the fires were put out and the debris cleanup was completed. However, particulate matter (PM) from the original collapse and fires also penetrated into commercial and residential buildings. This has created public concern because WTC dust is thought to cause adverse pulmonary symptoms including "WTC cough" and reduced lung capacity. Additionally, some recent studies have suggested a possible link between exposure to WTC contamination and other adverse health effects. Distinguishing between normal urban pollutant infiltration and residual WTC dust remaining in interior spaces is difficult; efforts are underway to develop such discriminator methods. Some progress has been made in identifying WTC dust by the content of fibers believed to be associated with the initial building collapse. There are also contaminants created by the fires that burned for 100 days in the debris piles of the building rubble. Using WTC ambient air samples, we have developed indicators for fire related PM based on the relative amounts of specific particle bound polycyclic aromatic hydrocarbons (PAHs) and the mass fraction of PAHs per mass of PM. These two parameters are combined, and we show a graphical method for discriminating between fire sources and urban particulate sources as applied to samples of settled dusts. We found that our PAHs based discriminator method can distinguish fire source contributions to WTC related particulate matter and dusts. Other major building fires or large open burn events could have similar PAHs characteristics. We found that random samples collected approximately 3.5 years after the WTC event from occupied indoor spaces (primarily residential) in the New York area are not statistically distinguishable from contemporary city background.


ClassyFlu: classification of influenza A viruses with Discriminatively trained profile-HMMs.
Accurate and rapid characterization of influenza A virus (IAV) hemagglutinin (HA) and neuraminidase (NA) sequences with respect to subtype and clade is at the basis of extended diagnostic services and implicit to molecular epidemiologic studies. ClassyFlu is a new tool and web service for the classification of IAV sequences of the HA and NA gene into subtypes and phylogenetic clades using discriminatively trained profile hidden Markov models (HMMs), one for each subtype or clade. ClassyFlu merely requires as input unaligned, full-length or partial HA or NA DNA sequences. It enables rapid and highly accurate assignment of HA sequences to subtypes H1-H17 but particularly focusses on the finer grained assignment of sequences of highly pathogenic avian influenza viruses of subtype H5N1 according to the cladistics proposed by the H5N1 Evolution Working Group. NA sequences are classified into subtypes N1-N10. ClassyFlu was compared to semiautomatic classification approaches using BLAST and phylogenetics and additionally for H5 sequences to the new "Highly Pathogenic H5N1 Clade Classification Tool" (IRD-CT) proposed by the Influenza Research Database. Our results show that both web tools (ClassyFlu and IRD-CT), although based on different methods, are nearly equivalent in performance and both are more accurate and faster than semiautomatic classification. A retraining of ClassyFlu to altered cladistics as well as an extension of ClassyFlu to other IAV genome segments or fragments thereof is undemanding. This is exemplified by unambiguous assignment to a distinct cluster within subtype H7 of sequences of H7N9 viruses which emerged in China early in 2013 and caused more than 130 human infections. http://bioinf.uni-greifswald.de/ClassyFlu is a free web service. For local execution, the ClassyFlu source code in PERL is freely available.


Determination of division plane and organization of contractile ring in Tetrahymena.
In the molecular mechanism of division plane determination and contractile ring formation, Tetrahymena 85kDa protein (p85) is localized to the presumptive division plane before the formation of the contractile ring. p85 directly interacts with Tetrahymena calmodulin (CaM) in a Ca2+-dependent manner, and p85 and CaM colocalize in the division furrow. A Ca2+/CaM inhibitor N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide HCI (W7) inhibits the direct interaction between p85 and Ca2+/CaM. W7 also inhibits the localization of p85 and CaM to the division plane, and the formation of the contractile ring and division furrow. In addition, p85 binds to G-actin in a Ca2+/CaM dependent manner, but does not bind F-actin. Tetrahymena profilin is localized to division furrow and binds Tetrahymena elongation factor-1alpha (EF-1alpha). EF-1alpha, which induces bundling of Tetrahymena F-actin, is also localized to the division furrow during cytokinesis. The evidence also indicates that Ca2+/CaM inhibits the F-actin-bundling activity of EF-1alpha, and that EF-1alpha and CaM colocalize in the division furrow. In this review, we propose that the Ca2+/CaM signal and its target protein p85 cooperatively regulate the determination of the division plane and the initiation of the contractile ring formation, and that profilin and a Ca2+/CaM-sensitive actin-bundling protein, EF-1alpha, play pivotal roles in regulating the organization of the contractile ring microfilaments.


Hydroosmotic response of collecting tubules to ADH or cAMP at reduced peritubular sodium.
Changes in cytosolic Ca2+ activity have been implicated in the hydroosmotic response to vasopressin (VP) in amphibian urinary bladder; the level of cytosolic free Ca2+ may be regulated, in part, by a process of Na-Ca exchange across the basolateral cell membrane. To assess whether similar mechanisms operate in the mammalian nephron, the effect of low peritubular [NA] on the hydraulic conductivity (Lp) of the isolated perfused rabbit collecting tubule (CT) exposed to either 20 microunits/ml VP or 5 X 10(-5) M 8-[p-chlorophenylthio]-cyclic 3',5'-adenosine monophosphate (ClPheS-cAMP) was studied. Low peritubular [Na] had no effect on the basal water permeability of the CT. After exposure to VP, CTs bathed in 145 mM Na Ringer solution developed an Lp of 324 +/- 27 X 10(-7) cm.s-1.atm-1, while tubules bathed in 4 mM Na and 141 mM tetramethylammonium Ringer solution achieved an Lp of only 112 +/- 13 X 10(-7) cm.s-1.atm-1 (P less than 0.001). Inhibition of the VP response was estimated to be half-maximal when peritubular Na was 120 mM. The hydroosmotic response to ClPheS-cAMP was diminished by 44% of the control values when CTs were bathed in a 4 mM Na medium; this inhibition was greatly attenuated when the peritubular Ca concentration was reduced to 0.05 mM. These results are consistent with the view that 1) a Na-Ca exchange process operates at the basolateral surface of the mammalian cortical collecting tubule cells, and 2) elevated cytosolic Ca ion activity inhibits the increase in water permeability elicited by VP or cAMP in this nephron segment.


Lipid analysis of the glycoinositol phospholipid membrane anchor of human erythrocyte acetylcholinesterase. Palmitoylation of inositol results in resistance to phosphatidylinositol-specific phospholipase C.
The glycoinositol phospholipid membrane anchor of human erythrocyte acetylcholinesterase (EC 126.96.36.199) contains a novel inositol phospholipid which in this and the accompanying paper (Roberts, W.L., Santikarn, S., Reinhold, V.N., and Rosenberry, T.L. (1988) J. Biol. Chem 263, 18776-18784) is shown to be a plasmanylinositol that is palmitoylated on the inositol ring. The inositol phospholipid was radiolabeled with the photoactivated reagent 3-(trifluoromethyl)-3-(m-[125I] iodophenyl)diazirine and characterized by various chemical and enzymatic cleavage procedures whose products were analyzed by thin layer chromatography and autoradiography or gas chromatography. Acidic methanolysis of human erythrocyte acetylcholinesterase (Ehu AChE) revealed 18:0 and 18:1 alkylglycerols (0.55 and 0.20 mol/mol AChE, respectively). Acetolysis was shown by TLC to release alkylacylglycerol acetates from Ehu AChE. Analysis by gas chromatography revealed that 83% of the alkylacylglycerol acetates contained an 18:0 or 18:1 1-alkyl group and a 22:4 (n - 6), 22:5 (n - 3), or 22:6 (n - 3) 2-acyl group. The inositol phospholipid is linked to the anchor by a glucosamine in glycosidic linkage, and deamination with nitrous acid cleaved the glycosidic linkage and released the phospholipid. The deamination and acetolysis products from Ehu AChE were purified by high performance liquid chromatography, and fatty acid analysis following acidic methanolysis of the purified products revealed that 2 fatty acid residues were associated with the deamination product and only one with the alkylacylglycerol acetolysis product. The other fatty acid residue was primarily palmitate and was indicated to be in ester linkage to an inositol hydroxyl(s). This linkage was shown to be responsible for the resistance of the inositol phospholipid to cleavage by Staphylococcus aureus phosphatidylinositol-specific phospholipase. Deacylation of the inositol phospholipid deamination product by treatment with base removed this palmitoyl group and facilitated release of alkyl- and alkylacylglycerol species by phosphatidylinositol-specific phospholipase C with concomitant formation of inositol 1-phosphate. In contrast, digestion of Ehu AChE with a recently reported anchor-specific phospholipase D resulted in release of plasmanic acids from the intact palmitoylated plasmanylinositol.


Sepsis caused by peripelvic soft tissue infections in critically injured patients with multiple injuries and unstable pelvic fracture.
In critically injured patients with multiple injuries and unstable pelvic fracture, late mortality almost invariably results from sepsis. We analyzed the clinical features of 11 patients with sepsis caused by soft tissue infections surrounding the fractured pelvis, of 830 patients with pelvic fracture after blunt trauma treated at our level I trauma center over the past 25 years. Soft tissue infection was defined as abscess formation in subcutaneous tissue or muscle diagnosed by computed tomography or an operation. Mean injury severity score was 48, and mean systolic blood pressure on arrival was 66 mm Hg. All patients had multiple concomitant injuries and prolonged hemorrhagic shock. Open pelvic fracture was present in five patients. Mean blood transfusion volume within 24 hours was 12,611 mL. Intra-aortic balloon occlusion was performed in three patients and transcatheter angiographic embolization in nine patients. Embolic sites of transcatheter angiographic embolization were bilateral internal iliac arteries (n = 9), lumbar artery (n = 5), median sacral artery (n = 2), and circumflex femoral artery (n = 2). Infection sites included the gluteal (n = 11), femoral (n = 6), sacral (n = 4), lumbar (n = 4), anterior iliac (n = 2), inguinal (n = 1), and perineal (n = 1) regions. Necrotic changes of infected soft tissue were found in all patients. They underwent open drainage and daily debridement with pulsatile irrigation followed by intravenous antibiotics. All patients developed severe sepsis, five of whom subsequently died of multiple organ failure. In critically injured patients with multiple injuries and unstable pelvic fracture, peripelvic soft tissue infections occasionally cause sepsis. Peripelvic infections are often accompanied by necrotic changes and easily develop into severe sepsis or multiple organ failure. Identifying high-risk patients and early diagnosis with prompt surgical treatment are indispensable for the patients' survival.


Activation of protein kinase A (PKA) signaling mitigates the antiproliferative and antiinvasive effects of alpha-difluoromethylornithine in breast cancer cells.
We have shown that alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, the first and rate-limiting enzyme in polyamine synthesis, has significant antiproliferative and antiinvasive effects in breast cancer cells. We have also reported that these antitumor effects are associated with activation of multiple signaling pathways, including STAT-3, STAT-1, Jun-N-Terminal kinase (JNK), and Mitogen activated protein kinase (MAPK), the latter being found to mediate its antiinvasive action in MDA-MB-435 cells. The present experiments were designed to test the effect of DFMO on the protein kinase A (PKA) pathway and determine its biological significance. We found that DFMO administration (1 mM) to MDA-MB-435 breast cancer cells significantly increased cAMP response element (CRE)-binding protein (CREB) phosphorylation as well as the transactivation of pCRE-luc, a CREB-dependent promoter activated by PKA. To determine the significance of this biochemical effect of DFMO, we used the PKA inhibitor H89 which, as expected, suppressed in a dose-dependent manner (1 and 10 microM) basal and DFMO-induced CREB phosphorylation in our system. Administration of H89 alone was able to suppress proliferation of MDA-MB-435 cells when used at a concentration (10 microM) shown to completely block basal CREB phosphorylation. At concentrations of 0.5 and 1 muM, H89 treatment, while having no antiproliferative effect of its own, potentiated in a dose-dependent fashion the growth inhibitory action of a suboptimal concentration of DFMO (0.01 mM). Ten micromoles of H89 reduced invasiveness of MDA-MB-435 cells in matrigel by approximately 40% (an effect similar to that of 1 mM DFMO). The combination treatment further reduced invasiveness by approximately 80% (P < 0.01 versus the individual treatments). H89 treatment (10 microM) partially reduced DFMO-induced phosphorylation of STAT-3 but not that of STAT-1, Extracellular regulated kinase (ERK), and JNK. In conclusion, our results indicate that PKA signaling exerts proproliferative and proinvasive effects in our experimental system. Therefore, its activation by DFMO represents a compensatory mechanism which should be blocked in order to maximize the antitumor action of the drug. Our data are also consistent with the notion that STAT-3 activation by DFMO is at least in part mediated through the PKA pathway.


Recurrent delirium episodes within the intensive care unit: Incidence and associated factors.
Describe the incidence and factors associated with recurrent delirium in the intensive care unit (ICU). Retrospective study of ICU patients diagnosed with delirium. Delirium clearance defined as 48 h of negative delirium assessments following initial episode and recurrent delirium as any positive delirium assessment following clearance. Multivariable logistic regression model assessed independent association of patient and hospital factors on development of recurrent delirium, adjusting for pre-defined covariates. Among 8591 ICU admissions identified with delirium, 1067 (12.4%) had recurrent symptoms. Factors associated with increased odds of recurrent delirium were age (nonlinear; p = 0.02), shock (OR 1.45, 95% CI [1.20, 1.75]), admission to medical (OR 3.25, 95% CI [2.42, 4.37]), surgical (OR 3.00, 95% CI [2.21, 4.06]), or trauma (OR 2.17, 95% CI [1.58, 3.00]) ICU vs. cardiovascular ICU, increased duration of mechanical ventilation (OR 2.43, 95% CI [2.22, 2.65]), propofol use (OR 1.35, 95% CI [1.02, 1.80]), and antipsychotic medications (haloperidol OR 1.53, 95% CI [1.26, 1.86]; quetiapine OR 2.45, 95% CI [1.98, 3.02]; and olanzapine OR 1.54, 95% CI [1.25, 1.88]). Over 10% of delirious ICU patients had recurrent symptoms. Factors associated with recurrence included age, duration of mechanical ventilation and medication exposure. Not applicable.


Association of Progressive Multifocal Leukoencephalopathy Lesion Volume With JC Virus Polymerase Chain Reaction Results in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis.
The JC virus (JCV) was named after the first patient to be described with progressive multifocal leukoencephalopathy (PML), John Cunningham. Detection of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), and of specific lesions by brain magnetic resonance imaging (MRI), are both considered essential for the diagnosis of natalizumab-associated PML (NTZ-PML) in patients with multiple sclerosis. However, strict pharmacovigilance by MRI can result in detection of patients with small lesions and undetectable JCV DNA in CSF. To investigate the association of PML lesion characteristics on MRI with both qualitative and quantitative JCV PCR results in CSF of patients with NTZ-PML. This was a retrospective, cross-sectional study conducted from January 2007 to December 2014 in patients considered to have NTZ-PML based on a set of predefined criteria. Follow-up was at least 6 months. Data of patients from the Dutch-Belgian NTZ-PML cohort and patients treated at multiple medical centers in Belgium and the Netherlands and selected for research purposes were included as a convenience sample. Brain MRI scans were analyzed for PML lesion volume, location, dissemination, and signs of inflammation. Associations of the qualitative and quantitative CSF JCV PCR results with PML MRI characteristics were calculated. Of the 73 patients screened, 56 were included (37 were women). At inclusion, 9 patients (16.1%) had undetectable JCV DNA in CSF. Patients with a positive PCR had larger total PML lesion volumes than those with undetectable JCV DNA (median volume, 22.9 mL; interquartile range, 9.2-60.4 mL vs median volume, 6.7 mL; interquartile range, 4.9-14.7 mL; P = .008), and logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA. There was a positive correlation between PML lesion volume and JCV copy numbers (Spearman ρ, 0.32; P = .03). Progressive multifocal leukoencephalopathy lesion volume was higher in patients with PML symptoms and in patients with more widespread lesion dissemination. No association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms. Smaller NTZ-PML lesions are associated with a higher likelihood of undetectable JCV DNA in CSF. This may preclude a formal diagnosis of PML and can complicate patient treatment in patients with small MRI lesions highly suggestive of PML detected early through pharmacovigilance.


Repetitive single subarachnoid injections for trial administration of the intrathecal morphine pump in patients with intractable non-cancer pain -A case report-.
Since the early 1980s, the implantable intrathecal drug pump (ITDP) has been used increasingly to manage chronic pain. Prior to making a decision to implant an ITDP, trial administration of the intrathecal (IT) drug should be performed to estimate the effective dose for a starting set of implantable ITDPs. There is no standard method of trial IT drug administration, though. Therefore, this paper reports 20 cases of IT morphine trial with single and repetitive injections until the appropriate dose was attained with respect to analgesia and its side effects. The trial procedure was performed with daily sequential IT injections using morphine and 0.3% mepivacaine. Twelve out of the total of 20 patients had positive responses. Thus, it is inferred that daily sequential IT morphine injections combined with a placebo injection as a trial ITDP would be useful in evaluating the effectiveness and adverse effects of IT morphine infusion with clinically insignificant side effects.


Inactivation of Escherichia coli K-12 in apple juice using combination of high-pressure homogenization and chitosan.
Apple juice and apple cider were inoculated with Escherichia coli K-12 and processed using a high-pressure homogenizer to study bacterial inactivation. Seven levels of pressure ranging from 50 to 350 MPa were used in the high-pressure homogenizer. Two types of chitosan (regular and water soluble) with 2 levels of concentration 0.01% and 0.1% were investigated for synergistic effect with high-pressure homogenization for the bacterial inactivation. E. coli K-12 inactivation was evaluated as a function of homogenizing pressure at different concentration of 2 types of chitosan in apple juice and cider. High-pressure homogenization (HPH) induced significant inactivation in the range of 100 to 200 MPa, while thermal inactivation was the primary factor for the bacterial inactivation above 250 MPa. Significant (P < 0.05) 2-way interactions involving pressure and type of substrate or pressure and chitosan concentration were observed during the study. The homogenization pressure and the incremental quantity of chitosan (both types) acted synergistically with the pressure to give higher inactivation. Significantly (P < 0.05) higher inactivation was observed in apple juice than apple cider at same homogenizing pressure. No effect of type of chitosan was observed on the bacterial inactivation.


Comparing the Visual Analog Scale and the Numerical Rating Scale in Patient-reported Outcomes in Psoriatic Arthritis.
Patient self-report scales are invaluable in psoriatic arthritis (PsA), as they allow physicians to rapidly assess patient perspectives of disease activity. We aimed to assess the agreement of the visual analog scale (VAS), a 100-mm horizontal line, and the numerical rating scale (NRS), a 21-point scale ranging from 0 to 10 in increments of 0.5, in patients with PsA. Data were collected prospectively across 3 UK hospital trusts from 2018 to 2019. All patients completed the VAS and NRS for pain, arthritis, skin psoriasis (PsO), and global disease activity. A subset completed an identical pack 1 week later. Demographic and clinical data were also collected. Agreement was assessed using medians and the Bland-Altman method. Intraclass correlation coefficients (ICCs) were used to assess test-retest reliability. Spearman rank correlation coefficients were used to assess dependency between scale scores and clinical variables. Two hundred ten patients completed the study; 1 withdrew consent. Thus, 209 were analyzed. For pain, arthritis, skin PsO, and global disease activity, the difference between the VAS and NRS lay mostly within 1.96 SD of the mean, suggesting reasonable agreement between the 2 scales. Among the patients, 64.1% preferred the NRS. The ICCs demonstrated excellent test-retest reliability for both VAS and NRS. Higher VAS and NRS scores were associated with increased tender/swollen joint count, poorer functional status, and greater life impact. The VAS and NRS show reasonable agreement in key patient-reported outcomes in PsA. Results from both scales are correlated with disease severity and life impact.


Squirmer rods as elongated microswimmers: flow fields and confinement.
Microswimmers or active elements, such as bacteria and active filaments, have an elongated shape, which determines their individual and collective dynamics. There is still a need to identify what role long-range hydrodynamic interactions play in their fascinating dynamic structure formation. We construct rods of different aspect ratios using several spherical squirmer model swimmers. With the help of the mesoscale simulation method of multi-particle collision dynamics we analyze the flow fields of these squirmer rods both in a bulk fluid and in Hele-Shaw geometries of different slab widths. Based on the hydrodynamic multipole expansion either for bulk or confinement between two parallel plates, we categorize the different multipole contributions of neutral as well as pusher-type squirmer rods. We demonstrate how confinement alters the radial decay of the flow fields for a given force or source multipole moment compared to the bulk fluid.


New generation Hydrogel Endovascular Aneurysm Treatment Trial (HEAT): a study protocol for a multicenter randomized controlled trial.
Aneurysm recanalization constitutes a limitation in the endovascular treatment of intracranial aneurysms using conventional bare platinum coils. The development of platinum coils coupled with hydrogel polymers aimed at decreasing the rates of recurrence by way of enhanced coil packing density and biological healing within the aneurysm. While enhanced occlusion and durability has been shown for the first generation hydrogel coils, their use was limited by technical challenges. Less data is available regarding the second-generation hydrogel coils which have been designed to perform like bare platinum coils. The new generation Hydrogel Endovascular Aneurysm Treatment Trial (HEAT) is a multicenter, randomized controlled trial that compares the health outcomes of the second-generation HydroCoil Embolic System with bare platinum coils in the endovascular intracranial aneurysms. The primary endpoint is aneurysm recurrence, defined as any progression on the Raymond aneurysm scale, over a 24-month follow-up period. Secondary endpoints include packing density, functional independence, procedural adverse events, mortality rate, initial complete occlusion, aneurysm retreatment, hemorrhage from treated aneurysm, and any aneurysm recurrence. Patient recruitment initiated in June 2011 and ended in January 2016 in 46 centers. Six hundred eligible patients diagnosed with an intracranial aneurysm, ruptured or unruptured were randomly assigned to one of the two treatment arms. The HEAT trial compares the durability, imaging, and clinical outcomes of the second-generation hydrogel versus bare platinum coils in the endovascular treatment of ruptured or unruptured intracranial aneurysms. The results of this trial may further inform current endovascular treatment guidelines based on observed long-term outcomes.


General refraction problems with phase discontinuities on nonflat metasurfaces.
This paper provides a mathematical approach to study metasurfaces in nonflat geometries. Analytical conditions between the curvature of the surface and the set of refracted directions are introduced to guarantee the existence of phase discontinuities. The approach contains both the near and far field cases. A starting point is the formulation of a vector Snell's law in the presence of abrupt discontinuities on the interfaces.


One Year Experience of Iliac Bifurcated Device for Aortoiliac Aneurysm in a Korean Single Center.
One of the predominant methods for preserving the internal iliac artery (IIA) in aortoiliac aneurysms is to use an iliac bifurcated device (IBD). However, there are a few limitations to the use of IBD in Korea. Our study aims to present the technical aspects of these devices, and to provide a mid-term analysis of IBD. Since 2013, 4 IBDs were used in 4 patients, with a mean follow-up of 14 months (range, 6-22 months). A 100% technical success rate was achieved without mortality and morbidity in our cases. The mean procedural time was 176 min (range, 145-240 min), and the mean contrast dose used was 184 mL (range, 135-220 mL). Type I or III endoleaks and postoperative expansion of the aneurysms weren't observed. Our cases demonstrates that IBD is a relatively safe repair method of aortoiliac aneurysms with preservation of the IIAs. However, a longer follow-up is needed to review the midterm results.


[The state of immunity and the cyclic nucleotide system in the radiotherapy of breast cancer].
Indices of the T-system of immunity were lowered in breast cancer patients. Small fractional radiotherapy resulted in its greater suppression. A tumor revealed low pathomorphosis accompanied by a sharp increase in the levels of cyclic nucleotides. Large fractional radiotherapy caused no changes in the state of the immune system correlating with high radiation pathomorphosis in a tumor and a decrease in a cGMP level.


[Detection of mental health problems in childhood].
To validate the Report Questionnaire for children (RQC) in order to estimate the prevalence of childhood psychiatric disorders in Mexico. The RQC was applied by random selection to parents of children in a specialized care service, in a general practice setting and in schools, during an urban household survey within the National Mental Health Survey (NMHS) conducted in 1988. The sample size of adults participating in the NMHS was 2,025. Fifty-two percent (1,068) reported having a child between 3 to 12 years old living in the household. The data collection instrument was applied to the oldest children in that range. The weighted mean was used for analysis and the unbiased prevalence was estimated using the formula proposed by Rogan and Gladen; predictive values were computed using a Bayesian expression. The estimated prevalence of mental health disorders for children aged 3 to 12 years old was between 16.4% and 20.7%. The Positive Predictive Value of the instrument ranged between 46.6% and 76.1%, depending of the cut-off points: one or more positive items in the questionnaire or two or more. The Negative Predictive Value (NPV) ranged between 91.6% and 99.2%. The estimates are very similar to those reported in different countries and the NPV supports the reliability of the estimates and the potential uses of the instrument for the early detection of childhood psychiatric disorders.


Recent advances in enteric neurobiology: mechanosensitive interneurons.
Until recently, it was generally assumed that the only intrinsic sensory neuron, or primary afferent neuron, in the gut was the after-hyperpolarizing AH/Type II neuron. AH neurons excited by local chemical and mechanical stimulation of the mucosa appear to be necessary for activating the peristaltic reflex (oral excitation and anal inhibition of the muscle layers) and anally propagating ring like contractions (peristaltic waves) that depend upon smooth muscle tone. However, our recent findings in the guinea-pig distal colon suggest that different neurochemical classes of interneuron in the colon are also mechanosensitive in that they respond directly to changes in muscle length, rather than muscle tone or tension. These interneurons have electrophysiological properties consistent with myenteric S-neurons. Ascending and descending interneurons respond directly to circumferential stretch by generating an ongoing polarized peristaltic reflex activity (oral excitatory and anal inhibitory junction potentials) in the muscle for as long as the stimulus is maintained. Some descending (nitric oxide synthase +ve) interneurons, on the other hand, appear to respond directly to longitudinal stretch and are involved in accommodation and slow transit of faecal pellets down the colon. This review will present recent evidence that suggests some myenteric S interneurons, in addition to AH neurons, behave as intrinsic sensory neurons.


Crystal structures and thermoelectric properties of the series Tl(10-x)La(x)Te6 with 0.2 ≤ x ≤ 1.15.
The tellurides Tl(10-x)La(x)Te(6) were synthesized from the elements in stoichiometric ratios at 873 K, followed by slow cooling. These materials are substitution variants of Tl(5)Te(3), crystallizing in space group I4/mcm, with lattice dimensions of a = 8.9220(4) Å, c = 13.156(1) Å, V = 1047.2(1) Å(3), for x = 1 (Z = 2). Increasing the La content occurs with an increase in the unit cell volume and the c axis, but a decrease of the a axis. Tl(5)Te(3) is a metallic compound, while Tl(9)LaTe(6) was calculated to be semiconducting. Correspondingly, the Seebeck coefficient increases with increasing x, while the electrical and thermal conductivity both decrease. The highest thermoelectric figure-of-merit determined thus far is 0.21 at 581 K for cold-pressed Tl(9)LaTe(6).


Lung cancer trends in young adults: an early indicator of progress in tobacco control (United States).
Tobacco smoking is known to increase lung cancer occurrence beginning in young adulthood, although age-specific rates have not been used to monitor the early consequences of tobacco control efforts in the United States. We evaluated state trends in lung cancer death rates among young adults in relation to an index of state tobacco control activities and conventional indices of current smoking and cessation. We calculated lung cancer death rates in young adults (age 30-39 years) over two time intervals from 1990-1994 through 1995-1999 in states with at least 25 deaths per interval. We measured the correlation of an index of state tobacco control in 1992-1993 with absolute rates and with total percent change during the two time intervals. Both lung cancer death rates during the recent time interval (1995-1999) and the change in these rates from 1990-1994 correlated strongly and inversely with the index of state tobacco control efforts measured in 1992-1993. Lung cancer death rates decreased in states with high tobacco control efforts, but increased in states with low tobacco control efforts. Tobacco control indices were strongly and positively correlated with cessation of smoking by age 30-39 years. Lung cancer death rates among young adults are strongly and inversely correlated with recent indices of tobacco control. Future monitoring of the effectiveness of statewide comprehensive tobacco control programs should assess trends in lung cancer rates in young adults as well as youth and adult smoking prevalence.


Smoker's face: an underrated clinical sign?
In a prospective survey of patients attending a general medical outpatient clinic roughly half the current cigarette smokers who had smoked for 10 years or more were identified, using defined criteria, by their facial features alone. These facial features, designated "smoker's face," were present in three (8%) of those who had smoked cigarettes for 10 years or more in the past and in none of the non-smokers. The association of smoker's face with current smoking that had continued for 10 years or more was significant (p less than 0.001) and remained after the patient's age, social class, exposure to sunlight, recent change of weight, and estimated lifetime consumption of cigarettes were controlled for. Smoker's face may be a helpful indicator in antismoking campaigns.


An Evolving Genetic Architecture Interacts with Hill-Robertson Interference to Determine the Benefit of Sex.
Sex is ubiquitous in the natural world, but the nature of its benefits remains controversial. Previous studies have suggested that a major advantage of sex is its ability to eliminate interference between selection on linked mutations, a phenomenon known as Hill-Robertson interference. However, those studies may have missed both important advantages and important disadvantages of sexual reproduction because they did not allow the distributions of mutational effects and interactions (i.e., the genetic architecture) to evolve. Here we investigate how Hill-Robertson interference interacts with an evolving genetic architecture to affect the evolutionary origin and maintenance of sex by simulating evolution in populations of artificial gene networks. We observed a long-term advantage of sex-equilibrium mean fitness of sexual populations exceeded that of asexual populations-that did not depend on population size. We also observed a short-term advantage of sex-sexual modifier mutations readily invaded asexual populations-that increased with population size, as was observed in previous studies. We show that the long- and short-term advantages of sex were both determined by differences between sexual and asexual populations in the evolutionary dynamics of two properties of the genetic architecture: the deleterious mutation rate ([Formula: see text]) and recombination load ([Formula: see text]). These differences resulted from a combination of selection to minimize [Formula: see text] which is experienced only by sexuals, and Hill-Robertson interference experienced primarily by asexuals. In contrast to the previous studies, in which Hill-Robertson interference had only a direct impact on the fitness advantages of sex, the impact of Hill-Robertson interference in our simulations was mediated additionally by an indirect impact on the efficiency with which selection acted to reduce [Formula: see text].


Lessons Learned: Implementation of a Concept-Based Curriculum in the Development of a New Prelicensure Nursing Program.
Nursing programs throughout the United States are making changes to curricula to decrease content overload, increase critical thinking and clinical reasoning skills of graduates, and prepare students to care for the complex needs of today's health care consumer. In a student-centered approach, students are no longer passive recipients in the classroom but active learners. A concept-based curriculum is a design focused on a student-centered learning approach. This article provides lessons learned throughout the development and implementation of a concept-based curriculum in a new prelicensure nursing program.


Dermoscopic evaluation of amelanotic and hypomelanotic melanoma.
To determine the predictive dermoscopic features of amelanotic and hypomelanotic melanoma. A total of 105 melanomas (median Breslow thickness, 0.76 mm), 170 benign melanocytic lesions, and 222 nonmelanocytic lesions lacking significant pigment (amelanotic, partially pigmented, and light colored) were imaged using glass-plate dermoscopy devices and scored for 99 dermoscopic features. Diagnostic models were derived from and tested on independent randomly selected lesions. Predominantly hospital-based clinics from 5 continents. Sensitivity, specificity, and odds ratios for individual features and models for the diagnosis of melanoma and malignancy. The most significant negative predictors of melanoma were having multiple (>3) milialike cysts (odds ratio, 0.09; 95% confidence interval, 0.01-0.64), comma vessels with a regular distribution (0.10; 0.01-0.70), comma vessels as the predominant vessel type (0.16; 0.05-0.52), symmetrical pigmentation pattern (0.18; 0.09-0.39), irregular blue-gray globules (0.20; 0.05-0.87), and multiple blue-gray globules (0.28; 0.10-0.81). The most significant positive predictors were having a blue-white veil (odds ratio,13; 95% confidence interval, 3.9-40.0), scarlike depigmentation (4.4; 2.4-8.0), multiple blue-gray dots (3.5; 1.9-6.4), irregularly shaped depigmentation (3.3; 2.0-5.3), irregular brown dots/globules (3.2; 1.8-5.6), 5 to 6 colors (3.2; 1.6-6.3), and predominant central vessels (3.1; 1.6-6.0). A simple model distinguishing melanomas from all nonmelanomas had a sensitivity of 70% and a specificity of 56% in the test set. A model distinguishing all malignant lesions from benign lesions had a sensitivity of 96% and a specificity of 37%. Conclusion Although the diagnostic accuracy of dermoscopy for melanoma lacking significant pigment is inferior to that of more pigmented lesions, features distinguishing the former from benign lesions can be visualized on dermoscopic evaluation.


Biomechanical consequences of scaling.
To function over a lifetime of use, materials and structures must be designed to have sufficient factors of safety to avoid failure. Vertebrates are generally built from materials having similar properties. Safety factors are most commonly calculated based on the ratio of a structure's failure stress to its peak operating stress. However, yield stress is a more likely limit, and work of fracture relative to energy absorption is likely the most relevant measure of a structure's safety factor, particularly under impact loading conditions characteristic of locomotion. Yet, it is also the most difficult to obtain. For repeated loading, fatigue damage and eventual failure may be critical to the design of biological structures and will result in lower safety factors. Although area:volume scaling predicts that stresses will increase with size, interspecific comparisons of mammals and birds show that skeletal allometry is modest, with most groups scaling (l proportional, variant d0.89) closer to geometric similarity (isometry: l proportional, variant d1.0) than to elastic similarity (l proportional, variant d0.67) or stress similarity (l proportional, variant d0.5). To maintain similar peak bone and muscle stresses, terrestrial mammals change posture when running, with larger mammals becoming more erect. More erect limbs increases their limb muscle mechanical advantage (EMA) or ratio of ground impulse to muscle impulse (r/R= integral G/integral Fm). The increase in limb EMA with body weight (proportional, variant W0.25) allows larger mammals to match changes in bone and muscle area (proportional, variant W0.72-0.80) to changes in muscle force generating requirements (proportional, variantW0.75), keeping bone and muscle stresses fairly constant across a size range 0.04-300 kg. Above this size, extremely large mammals exhibit more pronounced skeletal allometry and reduced locomotor ability. Patterns of ontogenetic scaling during skeletal growth need not follow broader interspecific scaling patterns. Instead, negative allometric growth (becoming more slender) is often observed and may relate to maturation of the skeleton's properties or the need for younger animals to move at faster speeds compared with adults. In contrast to bone and muscle stress patterns, selection for uniform safety factors in tendons does not appear to occur. In addition to providing elastic energy savings, tendons transmit force for control of motion of more distal limb segments. Their role in elastic savings requires that some tendons operate at high stresses (and strains), which compromises their safety factor. Other 'low stress' tendons have larger safety factors, indicating that their primary design is for stiffness to reduce the amount of stretch that their muscles must overcome when contracting to control movement.


N-glycans are not required for the efficient degradation of the mutant Saccharomyces cerevisiae CPY* in Schizosaccharomyces pombe.
In eukaryotic cells, aberrant proteins generated in the endoplasmic reticulum (ER) are degraded by the ER-associated degradation (ERAD) pathway. Here, we report on the ERAD pathway of the fission yeast Schizosaccharomyces pombe. We constructed and expressed Saccharomyces cerevisiae wild-type CPY (ScCPY) and CPY-G255R mutant (ScCPY*) in S. pombe. While ScCPY was glycosylated and efficiently transported to the vacuoles in S. pombe, ScCPY* was retained in the ER and was not processed to the matured form in these cells. Cycloheximide chase experiments revealed that ScCPY* was rapidly degraded in S. pombe, and its degradation depended on Hrd1p and Ubc7p homologs. We also found that Mnl1p and Yos9p, proteins that are essential for ERAD in S. cerevisiae, were not required for ScCPY* degradation in S. pombe. Moreover, the null-glycosylation mutant of ScCPY, CPY*0000, was rapidly degraded by the ERAD pathway. These results suggested that N-linked oligosaccharides are not important for the recognition of luminal proteins for ERAD in S. pombe cells.


Recent Developments Toward Integrated Metabolomics Technologies (UHPLC-MS-SPE-NMR and MicroED) for Higher-Throughput Confident Metabolite Identifications.
Metabolomics has emerged as a powerful discipline to study complex biological systems from a small molecule perspective. The success of metabolomics hinges upon reliable annotations of spectral features obtained from MS and/or NMR. In spite of tremendous progress with regards to analytical instrumentation and computational tools, < 20% of spectral features are confidently identified in most untargeted metabolomics experiments. This article explores the integration of multiple analytical instruments such as UHPLC-MS/MS-SPE-NMR and the cryo-EM method MicroED to achieve large-scale and confident metabolite identifications in a higher-throughput manner. UHPLC-MS/MS-SPE allows for the simultaneous automated purification of metabolites followed by offline structure elucidation and structure validation by NMR and MicroED. Large-scale study of complex metabolomes such as that of the model plant legume Medicago truncatula can be achieved using an integrated UHPLC-MS/MS-SPE-NMR metabolomics platform. Additionally, recent developments in MicroED to study structures of small organic molecules have enabled faster, easier and precise structure determinations of metabolites. A MicroED small molecule structure elucidation workflow (e.g., crystal screening, sample preparation, data collection and data processing/structure determination) has been described. Ongoing MicroED methods development and its future scope related to structure elucidation of specialized metabolites and metabolomics are highlighted. The incorporation of MicroED with a UHPLC-MS/MS-SPE-NMR instrumental ensemble offers the potential to accelerate and achieve higher rates of metabolite identification.


Visceral fat is associated with lower brain volume in healthy middle-aged adults.
Midlife obesity has been associated with an increased risk of dementia. The underlying mechanisms are poorly understood. Our aim was to examine the cross-sectional association of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and computed tomography (CT)-based measurements of subcutaneous (SAT) and visceral (VAT) adipose tissue with various magnetic resonance imaging (MRI) markers of brain aging in middle-aged community adults. Participants from the Framingham Offspring cohort were eligible if in addition to having measurements of BMI, WC, WHR, SAT, and VAT, they had undergone a volumetric brain MRI scan with measurements of total brain volume (TCBV), temporal horn volume (THV), white matter hyperintensity volume (WMHV), and MRI-defined brain infarcts (BI). All analyses were adjusted for age, sex, and time interval between abdominal CT and brain MRI. In a sample of 733 community participants (mean age, 60 years; 53% women), we observed an inverse association of BMI (estimate by standard deviation unit +/- standard error = -0.27 +/- 0.12; p = 0.02), WC (-0.30 +/- 0.12; p = 0.01), WHR (-0.37 +/- 0.12; p = 0.02), SAT (-0.23 +/- 0.11; p = 0.04), and VAT (-0.36 +/- 0.12; p = 0.002) with TCBV, independent of vascular risk factors. The association between VAT and TCBV was the strongest and most robust, and was also independent of BMI (-0.35 +/- 0.15; p = 0.02) and insulin resistance (-0.32 +/- 0.13; p = 0.01). When adjusting for C-reactive protein levels, the associations were attenuated (-0.17 +/- 0.13; p = 0.17 for VAT). No consistently significant association was observed between the anthropometric or CT-based abdominal fat measurements and THV, WMHV, or BI. In middle-aged community participants, we observed a significant inverse association of anthropometric and CT-based measurements of abdominal, especially visceral, fat with total brain volume.


[Is open synovectomy of the metacarpophalangeal joint in chronic polyarthritis worthwhile?].
PURPOSE/METHODS/PATIENTS: This work retrospectively analysed 252 synovectomies performed on 153 patients from 1958 to 1995 at the Balgrist University Orthopaedics Clinic, and evaluated the short-term and long-term benefits of open synovectomy of the metacarpo-phalangeal joint in rheumatoid arthritis. Rheumatoid arthritis (n = 182) was by far the most common of the 21 different diagnoses involved, and the metacarpo-phalangeal joint (n = 101) was by far the most frequently operated of the 7 different joint types in question. In the short tenn (n = 97), after a mean of 5.5 months, open synovectomy of a metacarpo-phalangeal joint in rheumatoid arthritis patients provided a benefit in terms of mobility in 85% of cases and in terms of joint swelling and pain in 93% of cases. Among one-third of the originally operated cases (n = 38), long-term benefit, i.e. after a mean of 6.9 years, was obtained in 89% of cases with regard to joint mobility, 87% with regard to swelling and 97% with regard to pain relief. Two-thirds of the joints presented normal mobility and swelling, and three-quarters were pain-free. The metacarpo-phalangeal joint is very important for maintaining the independence of a patient (gripping). Open synovectomy of the metacarpo-phalangeal joint in rheumatoid arthritis patients is an effective therapeutic procedure with little morbidity and very good long-term benefit in the management of metacarpo-phalangeal pain, swelling and stiffness refractory to conservative therapy.


Defective mycolic acid biosynthesis in a mutant of Mycobacterium smegmatis.
A mutant of Mycobacterium smegmatis defective in mycolic acid biosynthesis was isolated following chemical mutagenesis. Fatty acids were extracted from the mutant and subjected to structural analysis by thin-layer chromatography and high-performance liquid chromatography (HPLC) of both methyl and p-bromophenacyl ester derivatives. Thin-layer chromatography did not show the presence of any fatty acid of RF comparable to that of standard methyl mycolate. The HPLC profile revealed a broad peak in the standard mycolic acid ester region. No characteristic peaks of mycolic acid esters comparable to the wild-type could be resolved. Mass spectral analysis of the HPLC-purified peak demonstrated the presence of shorter-chain fatty acids in the mutant. These data support the idea that the mutant accumulates precursors of mycolic acids and is incapable of carrying out the final conversion to mycolic acids of 60-90 carbon atoms.


Computational performance of musculoskeletal simulation in OpenSim Moco using parallel computing.
Optimal control musculoskeletal simulation is a valuable approach for studying fundamental and clinical aspects of human movement. However, the high computational demand has long presented a substantial challenge, creating a need to improve simulation performance. The OpenSim Moco software package permits musculoskeletal simulation problems to be solved in parallel on multicore processors using the CasADi optimal control library, potentially reducing the computational demand. However, the computational performance of this framework has not been thoroughly examined. Thus, we aimed to investigate the computational speed-up obtained via multicore parallel computing relative to solving problems serially (i.e., using a single core) in optimal control simulations of human movement in OpenSim Moco. Simulations were solved using up to 18 cores with a variety of temporal mesh interval densities and using two different initial guess strategies. We examined a range of musculoskeletal models and movements that included two- and three-dimensional models, tracking and predictive simulations, and walking and reaching tasks. The maximum overall parallel speed-up was problem specific and ranged from 1.7 to 7.7 times faster than serial, with most of the speed-up achieved by about 6 processor cores. Parallel speed-up was generally greater on finer temporal meshes, while the initial guess strategy had minimal impact on speed-up. Considerable speed-up can be achieved for some optimal control simulation problems in OpenSim Moco by leveraging the multicore processors often available in modern computers. However, since improvements are problem specific, achieving optimal computational performance will require some degree of exploration by the end user.


Bayesian model discrimination for partially-observed epidemic models.
An efficient method for Bayesian model selection is presented for a broad class of continuous-time Markov chain models and is subsequently applied to two important problems in epidemiology. The first problem is to identify the shape of the infectious period distribution; the second problem is to determine whether individuals display symptoms before, at the same time, or after they become infectious. In both cases we show that the correct model can be identified, in the majority of cases, from symptom onset data generated from multiple outbreaks in small populations. The method works by evaluating the likelihood using a particle filter that incorporates a novel importance sampling algorithm designed for partially-observed continuous-time Markov chains. This is combined with another importance sampling method to unbiasedly estimate the model evidence. These come with estimates of precision, which allow for stopping criterion to be employed. Our method is general and can be applied to a wide range of model selection problems in biological and epidemiological systems with intractable likelihood functions.


Long term trends in behaviour to protect against adverse reproductive and sexual health outcomes among young single African women.
HIV and unintended pregnancy are major interrelated concerns in sub-Saharan Africa. Focussing on single women aged 15-24 years we assess trends in key behaviours that affect both outcomes. We performed a secondary analysis of public-access data sets from 112 surveys from 36 countries in the region, conducted between 1991 and 2015. We examined trends over 20 years in primary abstinence (virginity), secondary abstinence (no sex in past 3 months) among sexually experienced women, current use of modern contraception and condom use at most recent coitus among sexually active women. Little change occurred in primary or secondary abstinence. Over the 20 year period, contraceptive use in the region rose from 14.7 to 33.4%, with significant increases observed in 18 of 30 countries with multiple surveys. Since 2001-2005, the proportion of contraceptive users reporting condoms as their method fell from 61.1 to 51.3%, while use of oral contraceptives or injectables rose from 19.9 to 24.0%. Between 1996 and 2000 and 2006-2010, condom use at last coitus rose from 21.3 to 40.5% but then plateaued. A strong correlation between condom use and national HIV prevalence was found. About half of condom users at last sex had earlier in interviews reported this method for pregnancy-prevention. Though condoms tend to be overlooked by both HIV and family planning agencies, their contribution to the health of single women remains central. Current efforts to promote non-barrier contraceptive methods may inadvertently increase HIV risk. Condom promotion for pregnancy-prevention should be re-invigorated by social marketing campaigns and other means.


Charcot-Marie-Tooth disease associated with "essential tremor": Report of 7 cases and a review of the literature.
A study of 7 cases of Charcot-Marie-Tooth disease associated with a dyskinesia resembling benign essential tremor is presented. In 4 patients, the family history strongly suggested an autosomal mode of transmission, 2 cases were sporadic without an established genetic pattern and 1 was probably recessive. The distal parts of the upper and lower limbs showed imparied muscle strength with slight or no atrophy in 4 patients and conspicuous weakness and wasting in another 2. One patient was a chairbound. Although essential tremor and the tremor seen in these patients are clinically (phenotypically) similar it seems possible that they result from two different genotypes. Further, it seems that cases with Charcot-Marie-Tooth disease and "essential tremor" are not the result of the association of two separate dominant characteristics which are generally inherited as mendelian dominant traits. In spite of the diversity of the clinical manifestations of the peripheral neuropathy, the semiologically different types of essential tremor and the electrophysiological data, it is concluded that patients who develop a peripheral neuropathy on a familial basis and who exhibit clinical features of similar character, suffer from a common type of pathological disorder. Stress is laid upon the fact that Friedreich's ataxia and Charcot-Marie-Tooth disease share many clinical features. It is suggested that when Friedreich's ataxia and Charcot-Marie-Tooth disease seem to be present in the same individual and/or alternate in different members of the same family, the process is likely to be one of Charcot-Marie-Tooth disease. The value of the type of inheritance, natural history, clinical examination and electrophysiological data in differentiating Charcot-Marie-Tooth disease (with or without essential tremor) from other degenerative disorders is analyzed.


Commercial gaming devices for stroke upper limb rehabilitation: a survey of current practice.
Stroke upper limb impairment is associated with disability in activities of daily living. Gaming (Nintendo Wii) is being introduced to rehabilitation despite limited evidence regarding effectiveness. Little data exists on how gaming is implemented resulting in a lack of clinical information. We aimed to gather therapists' opinions on gaming. A survey was posted to therapists, identified from stroke services across Scotland. A second survey was posted to non-responders. Survey data were analysed using descriptive statistics and thematic coding. Surveys were sent to 127 therapists (70 stroke services) and returned by 88% (112/127). Gaming was used by 18% of therapists, 61% (68/112) stated they would use this intervention should equipment be available. The most commonly used device was Nintendo Wii (83% of therapists using gaming) for 30 min or less once or twice per week. Half of therapists (51%) reported observing at least one adverse event, such as fatigue, stiffness or pain. Gaming was reported to be enjoyable but therapists described barriers, which relate to time, space and cost. Gaming is used by almost a fifth of therapists. Adverse events were reported by 51% of therapists; this should be considered when recommending use and dosage. Implications for Rehabilitation Commercial gaming devices are reported to be used by 1/5th of therapists for stroke upper limb rehabilitation, 3/5ths would use gaming if available. Adverse events were reported by 51% of therapists; this should be considered when recommending use and dosage. Current use of gaming in practice may not be achieving intense and repetitive upper limb task-specific practice.