Randomized trial comparing 600- with 300-mg loading dose of clopidogrel in patients with non-ST elevation acute coronary syndrome undergoing percutaneous coronary intervention: results of the Platelet Responsiveness to Aspirin and Clopidogrel and Troponin Increment after Coronary intervention in Acute coronary Lesions (PRACTICAL) Trial.
There is uncertainty about the benefit of a higher loading dose (LD) of clopidogrel in patients with non-ST elevation acute coronary syndrome (NSTEACS) undergoing early percutaneous coronary intervention (PCI). We compared the effects of a 600- versus a 300-mg LD of clopidogrel on inhibition of platelet aggregation, myonecrosis, and clinical outcomes in patients with NSTEACS undergoing an early invasive management strategy. Patients with NSTEACS (n = 256, mean age 63 years, 81.6% elevated troponin) without thienopyridine for at least 7 days were randomized to receive 600- or 300-mg LD of clopidogrel. Percutaneous coronary intervention was performed in 140 patients, with glycoprotein IIb/IIIa inhibitor use in 68.6%. Adenosine diphosphate (ADP)-induced platelet aggregation was measured by optical platelet aggregometry immediately before coronary angiography. Post-PCI myonecrosis was defined as a next-day troponin I greater than 5 times the upper limit of reference range and greater than baseline levels. Clopidogrel 600-mg LD compared with 300-mg LD was associated with significantly reduced ADP-induced platelet aggregation (49.7% vs 55.7% with ADP 20 micromol/L) but did not reduce post-PCI myonecrosis or adverse clinical outcomes to 6 months. There was no association between preprocedural platelet aggregation and outcome. These data confirm a modest incremental antiplatelet effect of a 600-mg clopidogrel LD compared with 300-mg LD but provide no support for a clinical benefit in patients with NSTEACS managed with an early invasive strategy including a high rate (69%) of glycoprotein IIb/IIIa inhibitor use during PCI.


Uptake of one and two molecules of 1,3-butadiene by platinum bis(dithiolene): a theoretical study.
Platinum bis(dithiolene) complexes have reactivity toward alkenes like nickel bis(dithiolene) complexes. We examined the uptake of 1,3-butadiene by platinum bis(dithiolene) [Pt(tfd)2] (tfd = S2C2(CF3)2) via a density functional theory study; both 1,2- and 1,4-additions of 1,3-butadiene to the ligands of Pt(tfd)2 to form both interligand and intraligand adducts were studied. For single 1,3-butadiene addition, direct 1,4-addition on interligand S-S, 1,2-addition on intraligand S-S, and 1,4-addition on intraligand S-C are all feasible at room temperature and are controlled by the symmetry of the highest occupied molecular orbital of 1,3-butadiene and the lowest unoccupied molecular orbital of Pt(tfd)2. However, the formation of the interligand S-S adduct through 1,4-addition of one molecule of cis-1,3-butadiene is the most favorable route, with a reaction barrier of 9.3 kcal/mol. The other two addition processes cannot compete with this one due to both higher reaction barriers and unstable adducts. Other possible pathways, such as formation of cis-interligand S-S adduct from 1,2-addition of one molecule of 1,3-butadiene via a twisted trans-interligand S-S adduct, have higher barriers. Our calculated results show that 1,4-addition of a single molecule of 1,3-butadiene on the interligand S-S gives the kinetically stable product by a one-step pathway. But of at least equal importance is the apofacial 1,4-addition of two molecules of 1,3-butadiene on the intraligand S-C of the same ligand on Pt(tfd)2, which yields the thermodynamically stable product, obtained via a short lifetime intermediate, the 1:1 intraligand S-C adduct, being formed through several pathways. The calculated results in this study well explain the experimental observation that 1:1 interligand S-S adduct was formed in a short time, and the intraligand S-C adduct from two molecules of cis-1,3-butadiene was accumulated in 20 h at 50° and characterized by X-ray crystallography.


Autonomy and non-autonomy in Drosophila mesoderm determination and morphogenesis.
The mesoderm in Drosophila invaginates by a series of characteristic cell shape changes. Mosaics of wild-type cells in an environment of mutant cells incapable of making mesodermal invaginations show that this morphogenetic behaviour does not require interactions between large numbers of cells but that small patches of cells can invaginate independent of their neighbours' behaviour. While the initiation of cell shape change is locally autonomous, the shapes the cells assume are partly determined by the individual cell's environment. Cytoplasmic transplantation experiments show that areas of cells expressing mesodermal genes ectopically at any position in the egg form an invagination. We propose that ventral furrow formation is the consequence of all prospective mesodermal cells independently following their developmental program. Gene expression at the border of the mesoderm is induced by the apposition of mesodermal and non-mesodermal cells.


Effect of Five Bench Inclinations on the Electromyographic Activity of the Pectoralis Major, Anterior Deltoid, and Triceps Brachii during the Bench Press Exercise.
The bench press exercise is one of the most used for training and for evaluating upper-body strength. The aim of the current study was to evaluate the electromyographic (EMG) activity levels of the pectoralis major (PM) in its three portions (upper portion, PMUP, middle portion, PMMP, and lower portion, PMLP), the anterior deltoid (AD), and the triceps brachii (TB) medial head during the bench press exercise at five bench angles (0°, 15°, 30°, 45°, and 60°). Thirty trained adults participated in the study. The EMG activity of the muscles was recorded at the aforementioned inclinations at 60% of one-repetition maximum (1RM). The results showed that the maximal EMG activity for PMUP occurred at a bench inclination of 30°. PMMP and PMLP showed higher EMG activity at a 0° bench inclination. AD had the highest EMG activity at 60°. TB showed similar EMG activities at all bench inclinations. In conclusion, the horizontal bench press produces similar electromyographic activities for the pectoralis major and the anterior deltoid. An inclination of 30° produces greater activation of the upper portion of the pectoralis major. Inclinations greater than 45° produce significantly higher activation of the anterior deltoid and decrease the muscular performance of the pectoralis major.


Application of 18 F-fluorodeoxyglucose PET/CT radiomic features and machine learning to predict early recurrence of non-small cell lung cancer after curative-intent therapy.
To predict the recurrence of non-small cell lung cancer (NSCLC) within 2 years after curative-intent treatment using a machine-learning approach with PET/CT-based radiomics. A total of 77 NSCLC patients who underwent pretreatment 18 F-fluorodeoxyglucose PET/CT were retrospectively analyzed. Five clinical features (age, sex, tumor stage, tumor histology, and smoking status) and 48 radiomic features extracted from primary tumors on PET were used for binary classifications. These were ranked, and a subset of useful features was selected based on Gini coefficient scores in terms of associations with relapsed status. Areas under the receiver operating characteristics curves (AUC) were yielded by six machine-learning algorithms (support vector machine, random forest, neural network, naive Bayes, logistic regression, and gradient boosting). Model performances were compared and validated via random sampling. A PET/CT-based radiomic model was developed and validated for predicting the recurrence of NSCLC during the first 2 years after curation. The most important features were SD and variance of standardized uptake value, followed by low-intensity short-zone emphasis and high-intensity zone emphasis. The naive Bayes model with the 15 best-ranked features displayed the best performance (AUC: 0.816). Prediction models using the five best PET-derived features outperformed those using five clinical variables. The machine learning model using PET-derived radiomic features showed good performance for predicting the recurrence of NSCLC during the first 2 years after a curative intent therapy. PET/CT-based radiomic features may help clinicians improve the risk stratification of relapsed NSCLC.


[The macrophage contribution for maintaining lymphatic vessel in cornea].
The presence of antigen-presenting cells and hem- and lymphangiogenesis in the cornea are risk factors for the rejection of corneal transplants. We previously reported that antigen-presenting cells such as macrophages (MPs) play an important role in the induction of lymphatic endothelial cells during inflammation. This prompted us to inquire whether the existence of lymphatic vessels in the cornea is associated with the activation of MPs during inflammation. To investigate this question, we performed suture placement on the cornea to induce inflammation. We found that a large number of MPs were recruited and that lymphatic vessels were formed in response. Next, as C57BL/6 mice have a higher rejection rate after corneal transplantation than BALB/c mice, we compared the corneas of C57BL/6 and BALB/c mice under normal and inflamed conditions. We found that the number of spontaneously formed lymphatic vessels in the C57BL/6 corneas was significantly greater than in the BALB/c corneas, and that there were more activated MPs in the C57BL/6 corneas than in the BALB/c corneas. Additionally, to confirm that activated MPs induced and maintained lymphatic vessels in the cornea, we depleted the number of MPs in C57BL/6 mice via clodronate liposomes. We found that MP depletion reduced the spontaneous formation of lymphatic vessels and reduced inflammation-induced lymphangiogenesis relative to control mice. Finally, we found that mice deficient in MP markers had fewer spontaneously formed lymphatic vessels and less lymphangiogenesis than control C57BL/6 mice. The evidence gathered in this study leads us to conclude that activated MPs appear to play an important role in the formation of new lymphatic vessels and in their maintenance.


Inpatient treatment of severe nicotine dependence.
The most severely nicotine-dependent patients who have tried traditional treatment programs without success may require maximal intervention to achieve abstinence. In the Clinical Research Center at the Mayo Clinic, we assessed the feasibility of an inpatient treatment program for 24 such subjects, who were hospitalized (in groups of 6) for 2 consecutive weeks. A combination of behavioral, chemical-dependence, and transdermal nicotine-replacement therapy was provided in a smoke-free, protected milieu. Components of the program included group therapy, management of stress, exercise, daily lectures, and supervised activities. The mean age of the 18 women and 6 men was 51.3 years (range, 29 to 69 years). The mean duration of smoking was 33.7 years, and the number of cigarettes smoked per day at the time of admission averaged 33.2. The most frequent tobacco-related medical illnesses were chronic obstructive pulmonary disease, arteriosclerosis obliterans, and coronary artery disease. All subjects but two--each smoked part of a cigarette--remained abstinent from the use of cigarettes while in the Clinical Research Center, and all completed the 2-week inpatient program. The subjects underwent follow-up for 10 weeks after dismissal and were contacted periodically thereafter. At 1 year, 7 of the 24 subjects (29%) had maintained continuous abstinence from smoking, and their self-reported status at 1 year was verified biochemically.


Aspirin-like drugs prime human T cells. Modulation of intracellular calcium concentrations.
Aspirin-like drugs (ALD) enhance T cell proliferation by suppressing PG production in monocytes. Normal human T cells do not produce any eicosanoids. Therefore we studied whether ALD would affect purified T cells directly. We found that ALD enhanced the proliferation and IL-2 production of T cells in the absence of monocytes. This effect did not depend on arachidonic acid metabolism as no lipoxygenase products and only nonsuppressive levels of cyclooxygenase products were detected in T cell cultures. Several possible mechanisms of the ALD effect were ruled out including 1) enhanced mitogen binding, 2) induction of activation markers (IL-2R, transferrin receptor, HLA-DR) on the cell surface, 3) down-regulation of suppressor cells. ALD caused a rise in [Ca2+]i which appeared to reflect an influx of Ca2+ from the extracellular milieu and was more pronounced in CD4+ cells. The rise in intracellular levels of Ca2+, that is considered a necessary second messenger for T cell activation, may prime these cells for an enhanced response to mitogens. In addition, ALD increased T cell membrane fluidity but only at higher concentrations than those found to enhance proliferation. The pharmacologic effect of ALD on T cells presents a possible new immunoenhancing potential of these drugs and may have therapeutic use in immunosuppressed individuals.


A population-based retrospective cohort study to assess the mental health of patients after a non-intentional burn compared with uninjured people.
The objective of this study was to describe and quantify mental health (MH) admissions experienced by patients with unintentional burns subsequent to their injury. A retrospective population-based cohort study that used de-identified linked hospital, death and mental health in-patient case registry data of all burn patients hospitalised for unintentional burns (n=10,460) between 2000 and 2012 in Western Australia and an age and gender matched uninjured comparison cohort (n=42,856). Cohorts had a median age at study index of 26 years with males comprising 66% of each cohort. MH admissions for 5 years before and after the injury were examined. Negative binomial and Cox proportional hazards regressions were adjusted for socio-demographic and pre-existing health conditions and used to quantify associations between burns and MH hospitalisations. In the burn cohort during the 5-year post-burn period, 4% had a MH admission, 2% were admitted for self-harm, and 3% were admitted for a behavioural disorder caused by drugs/alcohol. Significantly elevated adjusted admission rates for MH conditions were observed for the burn cohort compared with the uninjured cohort (IRR, 95% CI: 4.89, 3.52-6.79). Increased MH admission rates were found for all age groups but were most pronounced in those younger than 18 years of age at time of burn (IRR, 95% CI: 6.28, 3.00-13.14), followed by those aged 18-60 (5.14, 3.59-7.35) and those over 60 years (IRR, 95% CI: 2.97, 1.38-6.39) compared to the uninjured cohort. Gender-specific analyses showed significant differences for male (IRR, 95% CI: 4.48, 3.05-6.59) and female burn patients (IRR, 95% CI: 6.00, 3.62-9.92), compared to uninjured. The burn cohort had higher adjusted first time admissions for MH conditions (HR, 95% CI: 3.55, 2.72-4.64), mood and anxiety disorders (HR, 95% CI: 3.77, 2.81-5.08), psychotic disorders (HR, 95% CI: 3.55, 1.99-6.15) and behavioural disorders related to alcohol/drugs (HR, 95% CI: 4.75, 3.09-7.28) for five years after the initial burn. Patients hospitalised for unintentional burns had significantly higher MH admission rates after discharge than that observed for an uninjured cohort. Ongoing mental health support is clearly indicated for many burns patients for a prolonged period after discharge.


Platelet-derived growth factor induces proliferation of hyperplastic human prostatic stromal cells.
Prostatic hyperplasia (BPH) is a very common disease in elderly men and is characterized by abnormal proliferation of the stromal and epithelial cells of the prostate. The observation that BPH often occurs in association with chronic inflammation has led to the examination of the possibility that platelet-derived growth factor (PDGF), which is released in response to inflammation, may be an etiological factor in the genesis of the disease. It has been shown that cultured cells derived from human prostatic tissue express high affinity PDGF-beta receptors based on receptor binding and cross-linking studies with [125I]-PDGF-BB. The experiments presented below demonstrate that PDGF receptors are activated in response to the growth factor and that mitogenesis is induced. PDGF-BB treatment of cultured human prostate cells derived from patients with BPH activates the signal transduction pathway of the PDGF receptor as shown by the presence of several phosphoproteins in antiphosphotyrosine immunoprecipitates, including autophosphorylation of the PDGF receptor. Phosphatidylinositol (PI) 3-kinase activity is also increased in cells stimulated with PDGF. The addition of PDGF-BB to the medium causes of variable but dose-dependent increase in [3H]-thymidine incorporation. This paper describes the first demonstration that PDGF is a potent mitogen for human cells derived from patients exhibiting prostatic hyperplasia, and also demonstrates that the cellular response to PDGF-BB is heterogenous in a manner that is consistent with the varying degree of hyperplasia and inflammation clinically and histologically in the tissue specimens.


Linear pharmacokinetics of orally administered fenoprofen calcium.
The bioavailability of fenoprofen from three different fenoprofen calcium capsule formulations containing the equivalent of 60, 165, and 300 mg of fenoprofen was determined in two studies. In the first study, 12 subjects received one capsule of each formulation according to a three-period crossover design. The second study required each of 13 subjects to receive 300 mg of fenoprofen equivalent of the 60- and 300-mg capsules and 330 mg of the 165-mg capsule. The initial study provided information on the linearity of fenoprofen pharmacokinetics, and the second study established that the three capsule formulations were bioequivalent. The bioavailability parameters Cmax, tmax, and AUC0--12 hr for the drug in plasma were consistent with a linear pharmacokinetic model, as were the amounts of fenoprofen and hydroxyfenoprofen excreted in the urine. These data show linearity of kinetics for fenoprofen in plasma throughout the 60--300-mg dosage range after a single dose. Physical measurements of each capsule formulation drug content, weight variation, and dissolution showed the products to be uniform and readily soluble.


[Pancreatic trauma successfully treated by endoscopy].
Acute post traumatic pancreatitis is an infrequent disease representing 0.4% of the acute pancreatitis with pseudocyst formation. Few data have been reported in the literature with regard to response to treatment, particularly in cases of small or multiple pseudocysts. Internal surgical drainage is the usual treatment. Different therapeutic alternatives have been proposed among which conservative treatment with total parenteral nutrition, somatostatin or octreotide, or more recently, endoscopy may be included. We herein present one case of acute post traumatic pancreatitis initially treated with conservative treatment which evolved to the formation of pseudocysts which were satisfactorily drained by endoscopic cystogastrostomy.


Distribution of coronary artery lesions in patients with permanent pacemakers.
In the present study we examined retrospectively the coronary anatomy pathology of 78 consecutive patients with coronary artery disease (CAD) who underwent permanent pacemaker implantation in order to find a common pathological anatomic basis for conduction disturbances and to compare them with a group of matched patients with angiographically proven CAD. Study group consists of seventy-eight patients with angiographically documented CAD and permanent pacemaker implantation. Control group included comparable patients with CAD and without a pacemaker implantation. Coronary angiography was performed using standard Judkins approach in all patients within 2 months before pacemaker implantation. The locations of narrowings in the left anterior descending (LAD) and right (RCA) coronary arteries, as the arteries supplying the conduction system, were documented accurately and further classified as follows. Type I: Anatomy not compromising blood supply to the conduction system, namely, either the absence of significant narrowing in the LAD, RCA, left circumflex, posterolateral, or posterior descending arteries or the presence of mid-distal LAD lesions beyond the septal branches. Type II: Pathological coronary anatomy involving septal branches emerging from the LAD (and without significant lesions in the RCA). Type III: Pathological coronary anatomy compromising blood supply to the sinoatrial (SAN) or atrioventricular (AVN) nodes but not compromising blood flow to the septal branches. This subset included patients with distal LAD lesions after the septal branches. Type IV: Combination of types II and III pathological coronary anatomy that compromises blood supply both to the septal branches and SAN and AVN arteries. Occurrence of the type IV coronary anatomy (45%) was significantly higher than type I (19%), type II(24%) and type III (11%) in the study group (p<0.02). Statistically significant differences were found between the two groups (p<0.05): more patients in the study group had type II (24%) and IV(45%) coronary anatomy (p<0.02) while type I (35%) and III (37%) anatomy were more frequently observed in control group (p<0.05). Analysis of flow quality of septal perforators, SAN and AVN arteries, in the study group demonstrated a significant tendency for reduced blood flow in the conduction system. Presence of first perforator lesions with poor quality of flow and right coronary artery lesions shown angiographically should be considered as the risk factors requiring permanent pacemaker implantation in patients with coronary artery disease.


Body composition and resting energy expenditure of individuals with Duchenne and Becker muscular dystrophy.
The relationship between body composition and resting energy expenditure (REE) was investigated in two boys and two men with Duchenne muscular dystrophy (DMD) (ages 11 to 22.4 years) and two boys with Becker muscular dystrophy (BMD) (ages 7.75 and 13.75 years). The REE was assessed by indirect calorimetry; body composition indices (weight, height, skinfolds, and mid-arm circumference) were measured using standardized techniques and compared with healthy reference data. Those with DMD had reduced corrected mid-upper-arm muscle area (C-MUMA) in comparison with healthy peers, and approximately twice the subcutaneous fat levels of subjects with BMD and healthy peers. Boys with BMD had remarkably lower muscle status than did boys with DMD and healthy peers. In both groups, REE was lower than in healthy peers; REE was associated with body weight (r=0.85), height (r=0.92), mid-upper arm fat area (MUFA) (r=0.97), and C-MUMA (r=0.65). Individuals with muscular dystrophy (MD) exhibit considerable disease-specific alterations in body composition. The REE had a stronger relationship with growth (weight and height) and subcutaneous body fat composition and a weaker association with C-MUMA. Understanding the effect of MD on body composition and REE will allow dietitians to individualize energy recommendations.


Attention Bias Modification Treatment for children with anxiety disorders who do not respond to cognitive behavioral therapy: a case series.
Evidence is emerging to support the promise of Attention Bias Modification Treatment (ABMT), a computer-based attention training program, in reducing anxiety in children. ABMT has not been tested as an adjuvant for children with anxiety disorders who do not respond to Cognitive-Behavioral Therapy (CBT). This case series presents findings from an open trial of ABMT among six children (four girls; M age = 11.2 years) who completed a CBT protocol and continued to meet diagnostic criteria for an anxiety disorder. All children completed the ABMT protocol with no canceled or missed sessions. Child self-ratings on anxiety symptoms and depressive symptoms significantly decreased from pretreatment to posttreatment, as did parent ratings on child anxiety-related impairment. Parent ratings on child anxiety and internalizing symptoms displayed non-significant decreases from pretreatment to posttreatment. These findings support the potential promise of ABMT as a feasible adjuvant treatment that reduces anxiety and impairment among child anxiety CBT nonresponders.


Mossbauer spectroscopic study of functional thermal destruction of iron--sulfur proteins in membranes of thermophilic cyanobacteria synechococcus elongatus
A mathematical model of the Mossbauer spectrum (80K) of native membranes of Synechococcus elongatus was constructed on the basis of values of the quadruple splitting (Delta) and the isomeric shift (delta) of the iron-containing components of the photosynthetic apparatus obtained from the literature. Thermally induced changes in the intensity of the spectral components of membranes and isolated preparations of photosystem (PS) I were studied using this model. It was shown that exposure of membranes to 70-80 degrees C causes a decrease in the intensity of the components related to the FX, FA, and FB centers and surface-located ferredoxins of PS I, an increase in the intensity of the doublets of oxidized iron clusters that are nonspecifically absorbed by the membranes, and formation of a new doublet. Spectral parameters of this doublet (Delta = 3.10 mm/sec and delta = 1.40 mm/sec) are typical of inorganic hydrated forms of reduced iron. Heating of PS I preparations also causes a decrease in the intensity of doublets of the FX, FA, and FB centers and an increase in the intensity of doublets of nonspecifically bound oxidized iron. However, this does not cause formation of inorganic reduced iron. Comparison between the intensities of the Mossbauer spectral components in intact and heated samples suggests that the main source of reduced iron in membranes is surface-located ferredoxins. Nonspecifically bound oxidized iron is formed at the expense of the FX, FA, and FB centers. Disappearance of spectral components associated with ferredoxins and accumulation of reduced iron in membranes occur within the temperature range critical for inhibition of electron transport through PS I to oxygen. These findings suggest that the thermally induced processes of accumulation of reduced iron and inhibition of electron transport in PS I in membranes of thermophilic cyanobacteria are interrelated and caused mainly by degradation of the Fe--S centers of ferredoxins. The possible role of reduced iron accumulation in the degradation of the photosynthetic apparatus induced by heat and other extreme physical and chemical factors is discussed.


High mobility group box protein-1 inhibits microglial Abeta clearance and enhances Abeta neurotoxicity.
One pathogenic characteristic of Alzheimer's disease (AD) is the formation of extracellular senile plaques with accumulated microglia. According to the amyloid hypothesis, the increase or accumulation of amyloid-beta (Abeta) peptides in the brain parenchyma is the primary event that influences AD pathology. Although the role of microglia in AD pathology has not been clarified, their involvement in Abeta clearance has been noted. High mobility group box protein-1 (HMGB1) is an abundant nonhistone chromosomal protein. We reported recently that HMGB1 was associated with senile plaques and the total protein level significantly increased in AD brain. In this study, diffuse HMGB1 immunoreactivity was observed around dying neurons in the kainic acid- and Abeta1-42 (Abeta42)-injected rat hippocampi. HMGB1 also colocalized with Abeta in the Abeta42-injected rats but not in transgenic mice, which show massive Abeta production without neuronal loss in their brains. Furthermore, coinjection of HMGB1 delayed the clearance of Abeta42 and accelerated neurodegeneration in Abeta42-injected rats. These results suggest that HMGB1 released from dying neurons may inhibit microglial Abeta42 clearance and enhance the neurotoxicity of Abeta42. HMGB1 may thus be another target in the investigation of a therapeutic strategy for AD.


Changes in aerobic fitness in boys and girls over a period of 25 years: data from the Amsterdam Growth And Health Longitudinal Study revisited and extended.
In the Amsterdam Growth And Health Longitudinal Study (AGAHLS), a group of approximately 650 12- to 14-year-old boys and girls was followed in their growth, and development of their health their lifestyle including diet, physical activity and smoking. One of the main interests was the change in their aerobic fitness. From 12 to 36 years of age in total, eight repeated measurements were performed to measure peak oxygen uptake (peak VO2). In this study the data of peak VO2 are revisited and extended: We made use of all collected data as a mixed longitudinal design including cross-sectionally measured subjects as well as longitudinally measured subjects. This led to the availability of 1,194 boys and 1356 girls. With Generalized Estimating Equations (GEE) the longitudinal changes with chronological age and differences between boys and girls were analyzed. Teenage boys and girls increased their peak VO2 (ml/min) significantly (p < .001) until age 14 in girls and until age 17 in boys. However peak VO2 relative to bodyweight (peak VO2/BW) had significantly (p < .001) decreased over the whole age range from 12 to 36 in both sexes. Vigorous physical activity (VPA) also showed a decrease and was significantly (p < .001) related with lower peak VO2/BW (Beta = 0.001). This relation was stronger in boys than in girls. Because at the start of AGAHLS no fast responding metabolic instruments were available, future longitudinal studies about aerobic fitness should include also measurement of VO2 kinetics.


Immunodeficiency in children starting antiretroviral therapy in low-, middle-, and high-income countries.
The CD4 cell count or percent (CD4%) at the start of combination antiretroviral therapy (cART) is an important prognostic factor in children starting therapy and an important indicator of program performance. We describe trends and determinants of CD4 measures at cART initiation in children from low-, middle-, and high-income countries. We included children aged <16 years from clinics participating in a collaborative study spanning sub-Saharan Africa, Asia, Latin America, and the United States. Missing CD4 values at cART start were estimated through multiple imputation. Severe immunodeficiency was defined according to World Health Organization criteria. Analyses used generalized additive mixed models adjusted for age, country, and calendar year. A total of 34,706 children from 9 low-income, 6 lower middle-income, 4 upper middle-income countries, and 1 high-income country (United States) were included; 20,624 children (59%) had severe immunodeficiency. In low-income countries, the estimated prevalence of children starting cART with severe immunodeficiency declined from 76% in 2004 to 63% in 2010. Corresponding figures for lower middle-income countries were from 77% to 66% and for upper middle-income countries from 75% to 58%. In the United States, the percentage decreased from 42% to 19% during the period 1996 to 2006. In low- and middle-income countries, infants and children aged 12-15 years had the highest prevalence of severe immunodeficiency at cART initiation. Despite progress in most low- and middle-income countries, many children continue to start cART with severe immunodeficiency. Early diagnosis and treatment of HIV-infected children to prevent morbidity and mortality associated with immunodeficiency must remain a global public health priority.


Preparation of Gold Nanoparticles via Anodic Stripping of Copper Underpotential Deposition in Bulk Gold Electrodeposition for High-Performance Electrochemical Sensing of Bisphenol A.
Bisphenol A is one of the most widely used industrial compounds. Over the years, it has raised severe concern as a potential hazard to the human endocrine system and the environment. Developing robust and easy-to-use sensors for bisphenol A is important in various areas, such as controlling and monitoring water purification and sewage water systems, food safety monitoring, etc. Here, we report an electrochemical method to fabricate a bisphenol A (BPA) sensor based on a modified Au nanoparticles/multiwalled carbon nanotubes composite electrocatalyst electrode (AuCu-UPD/MWCNTs/GCE). Firstly, the Au-Cu alloy was prepared via a convenient and controllable Cu underpotential/bulk Au co-electrodeposition on a multiwalled modified carbon nanotubes glassy carbon electrode (GCE). Then, the AuCu-UPD/MWCNTs/GCE was obtained via the electrochemical anodic stripping of Cu underpotential deposition (UPD). Our novel prepared sensor enables the high-electrocatalytic and high-performance sensing of BPA. Under optimal conditions, the modified electrode showed a two-segment linear response from 0.01 to 1 µM and 1 to 20 µM with a limit of detection (LOD) of 2.43 nM based on differential pulse voltammetry (DPV). Determination of BPA in real water samples using AuCu-UPD/MWCNTs/GCE yielded satisfactory results. The proposed electrochemical sensor is promising for the development of a simple, low-cost water quality monitoring system for the detection of BPA in ambient water samples.


Two cases of retroperitoneal metastasis from a completely regressed burned-out testicular cancer.
Primary extragonadal germ cell tumors (EGCT) are rare and it is still a matter of debate if they have to be considered as primary extragonadal issues or metastases from a primary testicular neoplasm. We describe two cases of the so-called burned-out seminoma, a primary testicular germ-cell tumor that spontaneously regressed after demonstration of retroperitoneal metastases. Two patients (35 and 50 years old, respectively) presented with CT findings of retroperitoneal masses. In both cases physical examination of the testis was not suspicious, and only scrotal ultrasound (SUS) showed parenchymal alterations such as scarring, calcifications and nodular lesions. Left orchiectomy and chemotherapy were then performed in both cases. Currently, they are both free of disease. Although primary germ cell tumors may be of retroperitoneal origin, the likelihood of metastasis from a testicular primary origin should always be carefully considered in order to avoid misdiagnosis and to apply the best treatment schedule for the patients. Therefore, a testicular ultrasonography is mandatory in patients presenting CT findings of retroperitoneal adenopathy, even if patients are completely asymptomatic and their physical examination appears normal.


Can serotonin transporter genotype predict craving in alcoholism?
We hypothesize that functional control of the serotonergic system is regulated in part by differential expression of the serotonin (5-HT) transporter (5-HTT). Alcohol-dependent individuals with the LL/LS genotype (L-carriers), compared with those with the SS genotype, have a lower 5-HT neurotransmission, which we hypothesize would be associated with higher craving for alcohol among L-carriers. We hypothesize further that acute peripheral depletion of tryptophan (5-HT's precursor), while further reducing 5-HT function, might decrease auto-inhibition of 5-HT neuronal firing, thereby increasing 5-HT neurotransmission transiently and lowering alcohol craving. We tested these hypotheses by examining whether in 34 Hispanic alcohol-dependent individuals subjective and physiological cue craving for alcohol differed by genotype, age of onset of problem drinking, and tryptophan availability. On subjective "urge to drink" and "crave for a drink," we found a significant (p < 0.05) main effect of genotype and cue, as well as an interaction among genotype, age of onset of problem drinking, and tryptophan depletion. For the physiological measure of pulse, there was a main effect of genotype. L-carriers had higher craving than their SS counterparts, an effect that decreased under tryptophan depletion. While craving in L-carriers increased with an earlier age of onset of problem drinking, the opposite effect was seen in those with the SS genotype. These results not only provide support for the hypothesis that alcoholics who are L-carriers have greater alcohol craving and possibly greater propensity for drinking but also propose that there is an important 5-HTT gene-by-environment interaction that alters cue craving response for alcohol.


Heterogeneity of outer membrane proteins in Borrelia burgdorferi: comparison of osp operons of three isolates of different geographic origins.
Biochemical and immunochemical studies of the outer membrane proteins of Borrelia burgdorferi have shown that the OspA and OspB proteins from strains of different geographic origins may differ considerably in their reactivities with monoclonal antibodies and in their apparent molecular weights. To further characterize this variation in Osp proteins between strains, the osp operons and deduced translation products from two strains, one from Sweden (ACAI) and one from eastern Russia (Ip90), were studied. Polyacrylamide gel electrophoresis and Western blot (immunoblot) analyses confirmed differences between ACAI, Ip90, and the North American strain B31 in their Osp proteins. The sequences of the ospA and ospB genes of ACAI and Ip90 were compared with that of the previously studied osp operon of B31 (S. Bergström, V. G. Bundoc, and A. G. Barbour, Mol. Microbiol. 3:479-486, 1989). The osp genes of ACAI and Ip90, like the corresponding genes of B31, were found on plasmids with apparent sizes of about 50 kb and are cotranscribed as a single unit. Pairwise comparisons of the nucleotide sequences revealed that the ospA genes of ACAI and Ip90 were 85 and 86% identical, respectively, to the ospA gene of strain B31 and 86% identical to each other. The ospB sequences of these two strains were 79% identical to the ospB gene of B31 and 81% identical to each other. There was significantly greater similarity between the ospA genes of the three different strains than there was between the ospA and ospB genes within each strain. These studies suggest that the duplication of osp genes in B. burgdorferi occurred before the geographical dispersion of strains represented by ACAI, Ip90, and B31.


In vitro interaction of C1-inhibitor with thrombin.
Previous observations of increased generation of thrombin during acute attacks of angioedema in plasma of patients with C1-inhibitor (C1-INH) deficiency prompted us to evaluate the interaction of C1-INH with thrombin in both purified systems and human plasma. For this purpose, we used several methods: (1) sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting analysis; (2) enzyme-linked immunosorbent assays to measure complexes between C1-INH and thrombin and inactivated C1-INH; and (3) kinetic studies using a chromogenic assay. We found that the interaction of purified C1-INH with thrombin is associated with the formation of bimolecular complexes of molecular weight (Mr) 130 000 and 120 000 as well as with the appearance of a cleaved form of C1-INH of Mr 97 000. The kinetic studies of inhibition of thrombin by C1-INH showed an average second-order rate constant of 19/s per mol/l, which was significantly increased in the presence of heparin. The addition of thrombin to human plasma was not associated with detectable C1-INH-thrombin complex formation or with cleavage of C1-INH. In conclusion, our data demonstrate that C1-INH upon interaction with thrombin, in part, forms enzyme-inhibitor complexes and, in part, is cleaved. The low second-order rate constant and the lack of a significant interaction in plasma suggest that the inhibition of thrombin by C1-INH has a minor role in circulating blood; however, its role might be important at the endothelial surface, where high concentrations of glycosaminoglycans occur.


Seminal white blood cells and recurrent abortion.
The incidence of leukocytospermia (> 1 million white blood cells/ml semen) and concentrations of white blood cell populations in semen from men whose partners experience unexplained recurrent spontaneous abortion by conventional testing criteria are described and compared to those of men whose partners have normal reproductive histories. Comparable seminal granulocyte and total white blood cell concentrations between groups suggest that couples with unexplained recurrent abortion do not have an abnormally high incidence of subclinical genital tract infections for which leukocytospermia could serve as a marker. However, a significantly higher prevalence of elevated CD4+ and CD8+ T lymphocyte concentrations in semen from men whose partners have cellular immunity to sperm antigens (i.e. produce embryotoxic factors in response to sperm antigen stimulation) warrants further investigation.


Isolation and characterization of four types of plasmids from Bacillus subtilis (natto).
Covalently closed circular deoxyribonucleic acids were found in 10 strains of Bacillus natto. The plasmids could be classified into four types on the basis of the molecular weights as well as the patterns in agarose gel electrophoresis after digestion with restriction endonucleases: (i) plasmids (seven were detected) with a molecular weight of 3.6 X 10(6); (ii) plasmids (two were detected) with a molecular weight of 4.0 X 10(6); (iii) plasmids (eight were detected) with a molecular weight of about 34 X 10(6); and (iv), a plasmid with an approximate molecular weight of 46 X 10(6). Out of the 10 plasmid-carrying strains, 6 (IFO3009, IFO3013, IFO3335, IFO13169, IAM1143, and IAM1207) harbored both type 1 and 3 plasmids; 2 (IAM1114 and IAM1168) harbored both type 2 and 3 plasmids, and IFO3936 and IAM1163 carried type 1 and 4 plasmids, respectively.


Public sentiment towards alcohol and local government alcohol policies in New Zealand.
In many countries, including New Zealand, alcohol availability and promotion have increased markedly in the last three decades as a result of liberalised central and/or state government alcohol policies. Accordingly, communities are increasingly relying on local government to manage alcohol-related problems. New Zealand's Local Government Act (2002) states the purpose of local government as facilitating public decision-making and promoting community well-being. We sought to describe public sentiment towards alcohol and local government alcohol policies. A cross-sectional survey was conducted in 2007 with a sample of 2337 residents aged 18 years and over in a diverse set of New Zealand communities. Data were collected via a self-administered pen-and-paper questionnaire. There were responses from 1372 individuals (response: 59%). Problem drinking amongst youth (<25 years of age) was considered the leading problem by the majority of respondents in six of seven areas. Alcohol was considered to play a major role in incidents of violence, vandalism, dangerous driving and traffic crashes. Fifty-eight percent of respondents agreed that "it is up to local government to make sure alcohol does not become a problem in the community". There was strong support for local governments to restrict the hours of operation of on-licenced premises, to use liquor bans to control drinking in public places, and for local governments and police to be stricter in their enforcement of drinking laws. There is strong support for local government alcohol policies that restrict the availability and promotion of alcohol. The study findings are important in light of the stated purpose of local government in New Zealand and the recently completed "once in a generation" review of alcohol laws and policies.


Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson´s Disease.
Parkinson's disease is a neurodegenerative disorder with a heterogeneous genetic etiology. The advent of next-generation sequencing (NGS) technologies has aided novel gene discovery in several complex diseases, including PD. This Perspective article aimed to explore the use of NGS approaches to identify novel loci in familial PD, and to consider their current relevance. A total of 17 studies, spanning various populations (including Asian, Middle Eastern and European ancestry), were identified. All the studies used whole-exome sequencing (WES), with only one study incorporating both WES and whole-genome sequencing. It is worth noting how additional genetic analyses (including linkage analysis, haplotyping and homozygosity mapping) were incorporated to enhance the efficacy of some studies. Also, the use of consanguineous families and the specific search for de novo mutations appeared to facilitate the finding of causal mutations. Across the studies, similarities and differences in downstream analysis methods and the types of bioinformatic tools used, were observed. Although these studies serve as a practical guide for novel gene discovery in familial PD, these approaches have not significantly resolved the "missing heritability" of PD. We speculate that what is needed is the use of third-generation sequencing technologies to identify complex genomic rearrangements and new sequence variation, missed with existing methods. Additionally, the study of ancestrally diverse populations (in particular those of Black African ancestry), with the concomitant optimization and tailoring of sequencing and analytic workflows to these populations, are critical. Only then, will this pave the way for exciting new discoveries in the field.


Barriers to Revision Total Hip Service Lines: A Surgeon's Perspective Through a Deterministic Financial Model.
Revision THA represents approximately 5% to 10% of all THAs. Despite the complexity of these procedures, revision arthroplasty service lines are generally absent even at high-volume orthopaedic centers. We wanted to evaluate whether financial compensation is a barrier for the development of revision THA service lines as assessed by RVUs. Therefore, we asked: (1) Are physicians fairly compensated for revision THA on a per-minute basis compared with primary THA? (2) Are physicians fairly compensated for revision THA on a per-day basis compared with primary THA? Our deterministic financial model was derived from retrospective data of all patients undergoing primary or revision THA between January 2016 and June 2018 at an academic healthcare organization. Patients were divided into five cohorts based on their surgical procedure: primary THA, head and liner exchange, acetabular component revision THA, femoral component revision THA, and combined femoral and acetabular component revision THA. Mean surgical times were calculated for each cohort, and each cohort was assigned a relative value unit (RVU) derived from the 2018 Center for Medicaid and Medicare assigned RVU fee schedule. Using a combination of mean surgical time and RVUs rewarded for each procedure, three models were developed to assess the financial incentive to perform THA services for each cohort. These models included: (1) RVUs earned per the mean surgical time, (2) RVUs earned for a single operating room for a full day of THAs, and (3) RVUs earned for two operating rooms for a full day of primary THAs versus a single rooms for a full day of revision THAs. A sixth cohort was added in the latter two models to more accurately reflect the variety in a typical surgical day. This consisted of a blend of revision THAs: one acetabular, one femoral, and one full revision. The RVUs generated in each model were compared across the cohorts. Compared with primary THA by RVU per minute, in revision THA, head and liner exchange demonstrated a 4% per minute deficit, acetabular component revision demonstrated a 29% deficit, femoral component revision demonstrated a 32% deficit, and full revision demonstrated a 27% deficit. Compared with primary service lines with one room, revision surgeons with a variety of revision THA surgeries lost 26% potential relative value units per day. Compared with a two-room primary THA service, revision surgeons lost 55% potential relative value units per day. In a comparison of relative value units of a typical two-room primary THA service line versus those of a dedicated revision THA service line, we found that revision specialists may lose between 28% and 55% of their RVU earnings. The current Centers for Medicare and Medicaid Services reimbursement model is not viable for the arthroplasty surgeon and limits patient access to revision THA specialists. Level III, economic and decision analysis.


Atmospheric electrical detection of organized convection.
Relatively simple atmospheric electrical instrumentation carried on a small aircraft constitutes a flexible and sensitive system for detecting organized convection. Data can be obtained close to the sea surface, and low-velocity flight enhances the spatial resolution. With a slow-flying airplane or powered glider, it may be possible to trace the circulation of individual convection cells and to investigate the trajectory of air which forms cumulus clouds, one of the major unsolved problems in tropical meteorology. Since space charge near the ocean surface was found on some days to be organized on a horizontal scale equivalent to the cumulus cloud scale, this suggests that some of the air which forms maritime cumulus clouds may come from within a few meters of the ocean and that atmospheric electrical instrumentation may have the potential for tracing air from the sea surface to the clouds. Although the atmospheric electrical instrumentation technique described here cannot be used for direct measurement of air velocity, it may be possible to develop model that can be used to calculate air velocities from electric field data. Even though with the technique described here it is not possible to make direct measurements of wind velocity, airborne electric field records can provide useful information about convection by delineating patterns in the wind field and structural features of thermals (rising bodies of relatively warm air) and by making possible the remote detection of thermals (29). Future plans include attempting to trace interfaces between adjacent roll vortices from the sea surface through the depth of the mixed layer (i) by flying the aircraft parallel to the wind so as to nullify the horizontal electric field (measured between wing-tip probes) while ascending and descending along the interface between adjacent roll vortices and (ii) by measuring vertical and horizontal potential gradient variations at different flight levels (30). The sensitivity of atmospheric electrical instrumentation to the top of the mixed layer and structure within it can be used to explore another important problem in boundary layer convection-why convective cloud cover and oceanic rainfall are greater at night than during the day(31). Workers in atmospheric electricity have long recognized that their domain is strongly controlled by turbulence in the lower atmosphere, and many have believed that the most effective use of atmospheric electrical techniques to assist meteorological research would be in studying exchange processes. Reiter [see (8)] effectively extended atmospheric electrical studies of boundary layer phenomena through a height range by mounting instruments on cable cars traveling between the valley floor and mountain tops in the Alps. The airborne measurements described here extend this approach. Relating the electrical structure of the atmosphere to its dynamic structure poses an interesting problem which may contribute to our understanding of the atmosphere.


Endogenous interferon production by endotoxin-responsive macrophages provides an autostimulatory differentiation signal.
Previous studies have demonstrated that peritoneal macrophages (resident or thioglycolate-induced) derived from mouse strains fully responsive to gram-negative endotoxins continue to differentiate in vitro, as evidenced by an increased capacity to phagocytose via the Fc receptor with time in culture. In contrast, macrophages derived from endotoxin-hyporesponsive mouse strains (e.g., C3H/HeJ or C57BL/10ScN) exhibit no such increase in phagocytic capacity, and, in fact, significantly lose the capacity to phagocytose particles opsonized with immunoglobulin G with time in culture. This defect was found to be fully correctable by the addition to the cultures of an exogenous source of alpha, beta, or gamma interferon. In this study, we compared C3H/HeN (endotoxin-responsive) and C3H/HeJ (endotoxin-responsive) and C3H/HeJ (endotoxin-hyporesponsive) macrophages in an attempt to elucidate the mechanism responsible for this difference in phagocytic (differentiative) potential. The following observations support the hypothesis that endotoxin-responsive macrophages, in contrast to endotoxin-hyporesponsive macrophages, produce significantly higher levels of an autostimulatory differentiation signal that appears to be macrophage-derived interferon. (i) Anti-alpha/beta-interferon antibody greatly reduces the ability of C3H/HeN macrophages to phagocytose opsonized erythrocytes: (ii) C3H/HeJ macrophages can be made more phagocytic by coculture with C3H/HeN macrophages or by treatment with supernatants derived from C3H/HeN macrophage cultures; and (iii) C3H/HeN macrophages spontaneously lose Mac-1 antigen with time in culture. C3H/HeJ macrophages must be interferon-treated to be equivalently down-regulated.


An introduction to the study of medicine: phase I of the McMaster M.D. program.
"Phase I" describes the initial 11 weeks of study in the M.D. training program offered by the Faculty of Medicine of McMaster University. This three-year program stresses the responsibility of students for their own education, encourages self-directed learning using realistic biomedical problems, and offers little didactic instruction. Students are assigned to tutorial groups, and much of the educational thrust of the program is built upon interactions within these groups. Phase I is designed to allow students to adapt to a less structured environment, and intensive faculty support is available. The successes and failures of Phase I of the program were examined using a combined questionnaire and interview at various stages during the 11-week period. Not all program goals were satisfactorily measured, but those that could be assessed appeared to have been attained by most students.


Comparison of Intraosseous, Arterial, and Venous Blood Sampling for Laboratory Analysis in Hemorrhagic Shock.
Intraosseous (IO) access is often indicated for administration of drugs and fluids in emergencies when venous access is challenging. There is no consensus regarding whether and which laboratory analyses may be performed on IO aspirates, and research on hemodynamically unstable subjects is limited. Twelve anesthetized pigs were sampled from IO, venous, and arterial accesses during stable circulation and after hemorrhage corresponding to 20% and 40% of the blood volume. Samples were analyzed for blood gases and acid-base status, electrolytes, hematocrit, creatinine, glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), and creatine kinase (CK). Average differences of blood gases and acid-base parameters, sodium, creatinine, hematocrit, ALT, and γ-GT and between IO and venous samples were small at baseline and after hemorrhage while differences for lactate and glucose increased with hypovolemia. Both IO-arterial and venoarterial differences in acid-base parameters increased with hypovolemia. Dispersions of differences were often large. Average levels of blood gases, acid base parameters, hematocrit, CK, AST, γ-GT, creatinine, and ALT, but not lactate and glucose, were similar in IO and venous samples in hypovolemia. However, precision was limited, indicating that IO test results should be confirmed when other vascular access is established, and that analysis of IO samples should be limited to acute situations and not used for detailed diagnostics in this setting.


Intralobular zonal heterogeneity and hepatic indicator dilution curves.
Conventional interpretation of hepatic indicator dilution curves rests on the assumption, among others, that every hepatocyte operates with the same rate constants. When this assumption is false, owing to intralobular zonal variation in surface-to-volume ratios and/or to zonal differences in permeability, the apparent rate constants recoverable from outflow transients are wrong estimates of average liver performance. We develop the theoretical basis for this conclusion and illustrate by example how it can confuse the interpretation of experimental data. The analysis proceeds from vascular and extracellular reference curves recorded from perfused rat livers and from a simple model of intralobular architecture in which highly arborized periportal sinusoids have a larger surface-to-volume ratio than the less-branched vasculature around the central vein. The experimental data and the model, applied to a wide range of hypothetical solutes, are used to compare the true average rate constants for uptake, efflux, and intracellular removal with the apparent values recoverable from outflow curves. When zonal differences in surface-to-volume ratios are the sole source of heterogeneity, the wrong estimates prove of little practical importance. By contrast, assigning larger regional variations in permeability leads to substantial errors. The confusion arising from such errors may be qualitative as well as quantitative. The presence of heterogeneity and thus the risk of interpretive error appears unrecognizable from outflow curves.


Cramer-Rao bounds in functional form: theory and application to passive optical ranging.
A functional approach to the multivariate statistical model of a generalized incoherent passive optical ranging and imaging system with a CCD sensor is proposed. This approach implies that a large number of discrete, statistically independent, random data (pixel readouts) can be approximated by a continuous random function. Thus, the joint probability density function (PDF) takes a functional form; the statistical averages of the infinite-variate PDF and the Fisher information become functional integrals that can be treated analytically in the Gaussian approximation. The Cramer-Rao bounds on estimator-error variances are obtained for the scalar and functional deterministic parameters of the model. An approximate expression is derived for the PDF of the sum of independent Gaussian and Poisson random variables using the steepest-descent method, and the resulting PDF is shown to be asymptotically Gaussian. As an illustration, we apply the developed approach to a passive optical rangefinder with chiral wavefront coding. Numerical and experimental examples are presented.


Barriers and facilitators to the successful development, implementation and evaluation of care bundles in acute care in hospital: a scoping review.
Care bundles are small sets of evidence-based recommendations, designed to support the implementation of evidence-based best clinical practice. However, there is variation in the design and implementation of care bundles, which may impact on the fidelity of delivery and subsequently their clinical effectiveness. A scoping review was carried out using the Arksey and O'Malley framework to identify the literature reporting on the design, implementation and evaluation of care bundles. The Embase, CINAHL, Cochrane and Ovid MEDLINE databases were searched for manuscripts published between 2001 and November 2017; hand-searching of references and citations was also undertaken. Data were initially assessed using a quality assessment tool, the Downs and Black checklist, prior to further analysis and narrative synthesis. Implementation strategies were classified using the Expert Recommendations for Implementing Change (ERIC) criteria. Twenty-eight thousand six hundred ninety-two publications were screened and 348 articles retrieved in full text. Ninety-nine peer-reviewed quantitative publications were included for data extraction. These consisted of one randomised crossover trial, one randomised cluster trial, one case-control study, 20 prospective cohort studies and 76 non-parallel cohort studies. Twenty-three percent of studies were classified as poor based on Downs and Black checklist, and reporting of implementation strategies lacked structure. Negative associations were found between the number of elements in a bundle and compliance (Spearman's rho = - 0.47, non-parallel cohort and - 0.65, prospective cohort studies), and between the complexity of elements and compliance (p < 0.001, chi-squared = 23.05). Implementation strategies associated with improved compliance included evaluative and iterative approaches, development of stakeholder relationships and education and training strategies. Care bundles with a small number of simple elements have better compliance rates. Standardised reporting of implementation strategies may help to implement care bundles into clinical practice with high fidelity. This review was registered on the PROSPERO database: CRD 42015029963 in December 2015.


Knowledge, Attitudes, and Practices Toward Self-Medicating Eye Symptoms in Saudi Arabia.
Self-medication is the selection and use of drugs by individuals to treat self-diagnosed diseases or symptoms. While some patients regard self-medicating as harmless, it is far from being a safe practice. The aim of this study was to evaluate the knowledge, attitudes, and practices toward self-medicating eye symptoms in Saudi Arabia. A cross-sectional study was conducted through an online questionnaire on a study population that consisted of Saudi nationals aged 18 and older who were using or had previously used ophthalmic medications. Among the 524 responses obtained, 79.4% were female, and more than half were less than 40 years old. Participants admitting to practicing ophthalmic self-medication measured 62.4%. The most commonly self-prescribed ophthalmic medications were artificial tears (n=276), followed by antiallergic (n=57) and antibiotic medications (n=33). Many participants reported that the reason for self-treatment was for repeated and simple symptoms that did not require professional care. While approximately 51% showed high levels of knowledge about ophthalmic medications, no significant relationship was seen with their choice to self-medicate (P=0.153). Despite detecting a high level of knowledge and acceptable practices and attitudes among participants, a high incidence of self-medication was observed. This effect was mostly attributed to long hospital waiting times and patient self-diagnosis. Increasing the number of healthcare units and properly educating patients on ophthalmic medications may help decrease the incidence of self-medication.


Heat acclimation and physical training adaptations of young women using different contraceptive hormones.
Although endogenous and exogenous steroid hormones affect numerous physiological processes, the interactions of reproductive hormones, chronic exercise training, and heat acclimation are unknown. This investigation evaluated the responses and adaptations of 36 inactive females [age 21 +/- 3 (SD) yr] as they undertook a 7- to 8-wk program [heat acclimation and physical training (HAPT)] of indoor heat acclimation (90 min/day, 3 days/wk) and outdoor physical training (3 days/wk) while using either an oral estradiol-progestin contraceptive (ORAL, n = 15), a contraceptive injection of depot medroxyprogesterone acetate (DEPO, n = 7), or no contraceptive (EU-OV, n = 14; control). Standardized physical fitness and exercise-heat tolerance tests (36.5 degrees C, 37% relative humidity), administered before and after HAPT, demonstrated that the three subject groups successfully (P < 0.05) acclimated to heat (i.e., rectal temperature, heart rate) and improved muscular endurance (i.e., sit-ups, push-ups, 4.6-km run time) and body composition characteristics. The stress of HAPT did not disrupt the menstrual cycle length/phase characteristics, ovulation, or plasma hormone concentrations of EU-OV. No between-group differences (P > 0.05) existed for rectal and skin temperatures or metabolic, cardiorespiratory, muscular endurance, or body composition variables. A significant difference post-HAPT in the onset temperature of local sweating, ORAL (37.2 +/- 0.4 degrees C) vs. DEPO (37.7 +/- 0.2 degrees C), suggested that steroid hormones influenced this adaptation. In summary, virtually all adaptations of ORAL and DEPO were similar to EU-OV, suggesting that exogenous reproductive hormones neither enhanced nor impaired the ability of women to complete 7-8 wk of strenuous physical training and heat acclimation.


Effect of Periodic Voluntary Interventions on Trapezius Activation and Fatigue During Light Upper Limb Activity.
The effects of diverse periodic interventions on trapezius muscle fatigue and activity during a full day of computer work were investigated. Musculoskeletal disorders, including trapezius myalgia, may be associated with repeated exposure to prolonged low-level activity, even during light upper-extremity tasks including computer work. Thirty healthy adults participated in a study that simulated two 6-hour workdays of computer work. One workday involved imposed periodic passive and active interventions aimed at disrupting trapezius contraction monotony (Intervention day), whereas the other workday did not (Control day). Trapezius muscle activity was quantified by the 3-dimensional acceleration of the jolt movement of the acromion produced by electrically induced muscle twitches. The spatio-temporal distribution of trapezius activity was measured through high-density surface electromyography (HD-EMG). The twitch acceleration magnitude in one direction was significantly different across measurement periods (p = 0.0156) on Control day, whereas no significant differences in any direction were observed (p > 0.05) on Intervention day. The HD-EMG from Intervention day showed that only significant voluntary muscle contractions (swing arms, Jacobson maneuver) induced a decrease in the muscle activation time and an increase in the spatial muscle activation areas (p < 0.01). Disruption of trapezius monotonous activity via brief voluntary contractions effectively modified the ensuing contraction pattern (twitch acceleration along one axis, active epochs reduction, and larger spatial distribution). The observed changes support an associated reduction of muscle fatigue. This study suggests that disruptive intervention activity is efficient in reducing the impact of trapezius muscle fatigue.


Can balance efficacy be manipulated using verbal feedback?
Verbal feedback was used to alter balance efficacy to examine its effects on perceived and actual balance in young adults. Participants (N=61) completed a stance task, were randomized to either a high or low balance efficacy or control group, and then completed the same task. The results showed that balance efficacy was manipulated as the low balance efficacy group had decreases in balance efficacy. Although verbal feedback did not alter balance efficacy in the high balance efficacy group, perceptions of stability increased for these participants. No changes in actual balance were found. The nature of verbal feedback may differentially influence balance-related cognitions during a challenging stance task in young adults.


Treatment of aqueous solutions of 1,4-dioxane by ozonation and catalytic ozonation with copper oxide (CuO).
In this study, treatment for the removal of 1,4-dioxane by ozone and by catalytic ozonation using CuO as the catalyst was investigated. While the removal of 1,4-dioxane was small (20%) and mineralization negligible after 6 h of ozonation treatment, the removals of 1,4-dioxane and total organic carbon increased by factors of 10.35 and 81.25, respectively, after catalytic ozonation in the presence of CuO. The mineralization during catalytic ozonation was favoured at pH 10 (94.91 min-1), although it proceeded even at pH 3 (54.41 min-1). The CuO catalyst decreased the equilibrium concentration of soluble ozone and favoured its decomposition to reactive oxidative species. Radical scavenging experiments demonstrated that superoxide radicals were the main species responsible for the degradation of 1,4-dioxane. Further scavenging experiments with phosphate confirmed the presence of Lewis active sites on the surface of CuO, which were responsible for the adsorption and decomposition of ozone. The reaction mechanism proceeded through the formation of ethylene glycol diformate, which quickly hydrolyzed to ethylene glycol and formic acid as intermediate products. The stability of CuO indicated weak copper leaching and high catalytic activity for five recycling cycles. The toxicity of the water, assessed by Vibrio fischeri bioluminescence assays, remained the same (low toxicity) after catalytic ozonation while it increased after treatment with ozonation alone.


Powered off-road wheelchair for the transportation of tetraplegics along mountain trails.
For off-road mobility, some manual or power assisted devices were conceived to be self-driven by paraplegics while for tetraplegics non power-assisted devices were conceived. These devices require one or more conductors who are subjected to a high physical demand thus potentially creating: precarious safety condition for the user an elevated physical demand of conductors could reduce the care and the attention to give to the user; the time of the outdoor adventure experience of the user could be limited. To address these issues, an innovative user-centered power assisted off-road wheelchair for the transportation of tetraplegics along mountain trails was developed. The device, structured like a trike, is driven by two healthy conductors; the user is placed in the middle of the frame. A movable seat provides for the transfer from the standard to the off-road wheelchair. An electrical motor, powered by a battery pack, provides for the actuation. All the design and prototype aspects, the control system and experimental tests are detailed. The prototype satisfies mechanical, safety and duration requirements. No physical demand while using the device and for the transfer of the user to the device was identified. Fun and engaging tests were carried out and all the participants were involved. Implications for Rehabilitation The device has the potential to enhance the quality of life of tetraplegics in terms of new life experiences. The device revealed the real possibility of a full recreational experience, an enhanced participation and a better social integration of tetraplegics.


Crystal structures at 2.2 A resolution of the catalytic domains of normal ras protein and an oncogenic mutant complexed with GDP.
The biological functions of ras proteins are controlled by the bound guanine nucleotide GDP or GTP. The GTP-bound conformation is biologically active, and is rapidly deactivated to the GDP-bound conformation through interaction with GAP (GTPase Activating Protein). Most transforming mutants of ras proteins have drastically reduced GTP hydrolysis rates even in the presence of GAP. The crystal structures of the GDP complexes of ras proteins at 2.2 A resolution reveal the detailed interaction between the ras proteins and the GDP molecule. All the currently known transforming mutation positions are clustered around the bound guanine nucleotide molecule. The presumed "effector" region and the GAP recognition region are both highly exposed. No significant structural differences were found between the GDP complexes of normal ras protein and the oncogenic mutant with valine at position 12, except the side-chain of the valine residue. However, comparison with GTP-analog complexes of ras proteins suggests that the valine side-chain may inhibit GTP hydrolysis in two possible ways: (1) interacting directly with the gamma-phosphate and altering its orientation or the conformation of protein residues around the phosphates; and/or (2) preventing either the departure of gamma-phosphate on GTP hydrolysis or the entrance of a nucleophilic group to attack the gamma-phosphate. The structural similarity between ras protein and the bacterial elongation factor Tu suggests that their common structural motif might be conserved for other guanine nucleotide binding proteins.


Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences.
Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites. Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction has long been implicated in the etiopathogenesis of Parkinson's disease (PD), based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Studies on the function and dysfunction of these genes revealed that various aspects of mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control.


WT1 activates a glomerular-specific enhancer identified from the human nephrin gene.
The glomerular filtration barrier separates the blood from the urinary space. Nephrin is a transmembrane protein that belongs to the immunoglobulin superfamily and is localized to the slit diaphragms that are a critical component of this filtration barrier. Mutations in the nephrin gene (NPHS1) lead to congenital Finnish nephropathy, whereas alterations in the level of nephrin expression have been identified in a wide range of acquired glomerular diseases. A 186-bp fragment from the human NPHS1 promoter is capable of directing podocyte-specific expression of a beta-galactosidase transgene when placed in front of a heterologous minimal promoter in transgenic mice. The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner. Taken together, these results suggest that WT1 may be required for regulation of the NPHS1 gene in vivo.


A needs assessment of advanced life support and emergency medical services in the pediatric patient: state of the art.
The outcome from cardiopulmonary arrest in children in the prehospital and hospital setting is generally poor. The event that compromises the cardiac status is often respiratory embarrassment, and the presenting rhythms are often bradyarrhythmias and asystole. Emergency medical services (EMS) systems have primarily an adult focus and may not be organized to manage optimally the critically ill and injured child. Data from a survey of training programs demonstrate that paramedic and EMT education in pediatric emergencies may be inadequate. Forty-one percent of the programs surveyed had less than 10 hr of pediatric training. Data suggest that EMS providers may not be equipped to manage children effectively. The Los Angeles EMS System for children is described. There are two levels of receiving facilities: Emergency Departments Approved for Pediatrics and Pediatric Critical Care Centers. The system is voluntary and has 85% of the hospitals in compliance with the guidelines. Early recognition of the prearrest state, improved training, and equipping of prehospital care personnel, development of EMS services for children, dissemination of an advanced pediatric life support course, as well as research in pediatric CPR may improve the outcome of resuscitation in the pediatric population.


Expression analysis of the type I keratin protein keratin 33A in goat coat hair.
The coat of a goat, like that of many mammalian species, consists of an outer coat of coarse hairs and an under coat of fine, downy hairs. The coarse guard hairs are produced by primary follicles and the finer cashmere hairs by secondary follicles. We previously reported that hair keratins are components of cashmere hair, and proteomic analysis revealed that their expression is elevated in winter coat hair. To determine detailed characterization, we have cloned keratin 33A gene, a major highly expressed keratin in winter, and then analyzed the expression of goat hair coat. By Western analysis, we detected that keratin 33A protein is expressed only in hair coat among the various goat tissues. Moreover, the expression level in winter has increased in cashmere high-producing Korean native breed, whereas the expression levels between summer and winter had not changed in cashmere low-producing Saanen. In addition, by immunohistochemistry we determined that keratin 33A is localized in the major cortex portion of cashmere fiber. These results confirm that keratin 33A is a structural protein of goat cashmere hair fiber.


Truncated and RIP-degenerated copies of the LTR retrotransposon Pholy are clustered in a pericentromeric region of the Leptosphaeria maculans genome.
The LMR1 5.2 kb interspersed repeat of Leptosphaeria maculans was described by Taylor and Borgmann [Mol. Plant Microbe Interact. 7 (1994) 181] as an uncharacterized repeated element sharing homologies with both LINEs and SINEs. Here, we used the LMR1 sequence as a template to identify the full-length element within a 184-kb genomic sequence corresponding to the pericentromeric region of the 2.80 Mb chromosome of isolate v23.1.3. This region comprises (i) one 6980-bp full-sized Pholy element bordered by two 275- to 280-bp long terminal repeats (LTRs), (ii) five Pholy-related sequences, usually truncated at their 3' ends, and (iii) five solo-LTRs. Structural features strongly suggested that Pholy corresponds to an ancient copia-like retrotransposon, sharing strong homologies with the Elsa retrotransposon of Stagonospora nodorum. Pholy was also suggested to be specific to pericentromeric regions. Comparative analysis of the structure of the Pholy-like sequences occurring in the 184-kb contig and in other parts of the genome showed that this family of repeats is highly degenerated following extensive repeat induced point mutation (RIP).


Improving the detection of small lesions using a state-of-the-art time-of-flight PET/CT system and small-voxel reconstructions.
A major disadvantage of (18)F-FDG PET involves poor detection of small lesions and lesions with low metabolism, caused by limited spatial resolution and relatively large image voxel size. As spatial resolution and sensitivity are better in new PET systems, it is expected that small-lesion detection could be improved using smaller voxels. The aim of this study was to test this hypothesis using a state-of-the-art time-of-flight PET/CT device. (18)F-FDG PET scans of 2 image-quality phantoms (sphere sizes, 4-37 mm) and 39 consecutive patients with lung cancer were analyzed on a time-of-flight PET/CT system. Images were iteratively reconstructed with standard 4 × 4 × 4 mm voxels and smaller 2 × 2 × 2 mm voxels. For the phantom study, we determined contrast-recovery coefficients and signal-to-noise ratios (SNRs). For the patient study, (18)F-FDG PET-positive lesions in the chest and upper abdomen with a volume less than 3.0 mL (diameter, <18 mm) were included. Lesion mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) were determined in both image sets. SNRs were determined by comparing SUVmax and SUVmean with background noise levels. A subanalysis was performed for lesions less than 0.75 mL (diameter, <11 mm). For qualitative analysis of patient data, 3 experienced nuclear medicine physicians gave their preference after visual side-by-side analysis. For phantom spheres 13 mm or less, we found higher contrast-recovery coefficients and SNRs using small-voxel reconstructions. For 66 included (18)F-FDG PET-positive lesions, the average increase in SUVmean and SUVmax using the small-voxel images was 17% and 32%, respectively (P < 0.01). For lesions less than 0.75 mL (21 in total), the average increase was 21% and 44%, respectively. Moreover, averaged over all lesions, the mean and maximum SNR increased by 20% and 27%, respectively (P < 0.01). For lesions less than 0.75 mL, these values increased up to 23% and 46%, respectively. The physicians preferred the small-voxel reconstructions in 76% of cases. Supported by a phantom study, there was a visual preference toward (18)F-FDG PET images reconstructed with 2 × 2 × 2 mm voxels and a profound increase in standardized uptake value and SNR for small lesions. Hence, it is expected that small-lesion detection improves using small-voxel reconstructions.


Outcome of acquired haemophilia in France: the prospective SACHA (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise) registry.
Although extremely rare, acquired haemophilia A (AHA) can cause severe bleeding, which may be fatal. The underlying causes of autoantibody development are not fully understood. Treatment goals are bleeding control and autoantibody eradication. At the time of our study, there was no consensus on a standard treatment strategy for AHA. Previous data were mainly retrospective or from single-centre cohorts. We conducted a prospective, controlled, registry-based study of patients with AHA in France. The prospective French registry (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise [SACHA]) collected data on prevalence, clinical course, disease associations and outcomes for haemostatic treatment and autoantibody eradication in 82 patients with a 1-year follow-up. Similar to earlier studies, the prevalence of AHA was higher in the elderly, with two thirds of patients aged >70 years. Around half of AHA cases were associated with underlying disease, most commonly autoimmune disease and cancer in younger and older patients respectively. Haemostatic treatment was initially administered to 46% of patients. Complete resolution or improvement of initial bleeding occurred in 22/27 (81%) rFVIIa-treated patients and in all six cases receiving pd-aPCC. The majority of patients (94%) received immunosuppressive therapy, with complete remission at 3 months in 61% (36/59) and in 98% (50/51) at 1 year. Overall mortality was 33%: secondary to bleeding in only three patients but to sepsis in 10. Bypassing agents were effective at controlling bleeding in patients with AHA. Immunosuppressive therapy should be used early but with caution, particularly in elderly patients.


Origins of albino and hooded rats: implications from molecular genetic analysis across modern laboratory rat strains.
Albino and hooded (or piebald) rats are one of the most frequently used laboratory animals for the past 150 years. Despite this fact, the origin of the albino mutation as well as the genetic basis of the hooded phenotype remained unclear. Recently, the albino mutation has been identified as the Arg299His missense mutation in the Tyrosinase gene and the hooded (H) locus has been mapped to the ∼460-kb region in which only the Kit gene exists. Here, we surveyed 172 laboratory rat strains for the albino mutation and the hooded (h) mutation that we identified by positional cloning approach to investigate possible genetic roots and relationships of albino and hooded rats. All of 117 existing laboratory albino rats shared the same albino missense mutation, indicating they had only one single ancestor. Genetic fine mapping followed by de novo sequencing of BAC inserts covering the H locus revealed that an endogenous retrovirus (ERV) element was inserted into the first intron of the Kit gene where the hooded allele maps. A solitary long terminal repeat (LTR) was found at the same position to the ERV insertion in another allele of the H locus, which causes the so called Irish (h(i)) phenotype. The ERV and the solitary LTR insertions were completely associated with the hooded and Irish coat patterns, respectively, across all colored rat strains examined. Interestingly, all 117 albino rat strains shared the ERV insertion without any exception, which strongly suggests that the albino mutation had originally occurred in hooded rats.


[Morphologic festures of cardiac lesions in rheumatoid arthritis].
Morphological examinations of the heart in cases of articulo-visceral rheumatoid arthritis revealed in 20 of the 35 conducted observations certain changes attributable to the underlying disease. The following groups of changes were revealed: 1) endocarditis; 2) myocarditis; 3) pericarditis; 4) rheumatoid nodules; 5) valvular sclerosis and mural endocarditis; 6) cardiosclerosis; 7) amyloidosis; 8) coronaritis and coronary sclerosis; 9) adhesions in the pericardial cavity. The severity of cardiac leasion in rheumatoid arthritis is determined by the involvement of the serosa into the pathological process. Inflammatory and sclerotic changes in the myocardium are predimonantly of a subepicardial and subendocardial nature, usually non-accompanied by any clear clinical symptoms, or taking a latent course. Rheumatoid nodules typical of rheumatoid arthritis, and deposits of amyloid masses in the walls of the coronary arteries are noted rarely. Changes in the heart are observed mostly in "septic", subacute rheumatoid arthritis and in Still's disease. Cardiac lesions in rheumatoid arthritis are connected with microcirculatory disorders caused by immunopathological processes.


Microfluidics-enabled phenotyping of a whole population of C. elegans worms over their embryonic and post-embryonic development at single-organism resolution.
The organism Caenorhabditis elegans is a performant model system for studying human biological processes and diseases, but until now all phenome data are produced as population-averaged read-outs. Monitoring of individual responses to drug treatments would however be more informative. Here, a new strategy to track different phenotypic traits of individual C. elegans nematodes throughout their full life-cycle-i.e., embryonic and post-embryonic development, until adulthood onset, differently from life-span-is presented. In an automated fashion, single worms were synchronized, isolated, and cultured from egg to adulthood in a microfluidic device, where their identity was preserved during their whole development. Several phenotypes were monitored and quantified for each animal, resulting in high-content phenome data. Specifically, the method was validated by analyzing the response of C. elegans to doxycycline, an antibiotic fairly well-known to prolong the development and activate mitochondrial stress-response pathways in different species. Interestingly, the obtained extensive single-worm phenome not only confirmed the dramatic doxycycline effect on the worm developmental delay, but more importantly revealed subtle yet severe treatment-dependent phenotypes that are representative of minority subgroups and would have otherwise stayed hidden in an averaged dataset. Such heterogeneous response started during the embryonic development, which makes essential having a dedicated chip that allows including this early developmental stage in the drug assay. Our approach would therefore allow elucidating pharmaceutical or therapeutic responses that so far were still being overlooked.


Biological thiols elicit prolactin proteolysis by glandular kallikrein and permit regulation by biochemical pathways linked to redox control.
Rat glandular kallikrein (GK), a trypsin-like serine protease, cleaves rat prolactin (PRL) in vitro to novel forms detectable in vivo and likely to be of physiological significance. PRL proteolysis by GK is thiol-dependent, with thiols acting upon PRL to refold the molecule into novel conformations that are GK substrates. This study compared several natural and synthetic thiols for their ability to elicit PRL proteolysis by GK. Rat PRL was incubated with rat GK in the presence of various thiols and 0.5% Triton X-100, which enhances thiol-elicited proteolysis. Cleavage was analyzed by gel electrophoresis under reducing and nonreducing conditions. In the presence of Triton X-100, all low molecular weight thiols elicited PRL cleavage by GK. The order of potency was dithiothreitol greater than mercaptoethanol greater than lipoic acid greater than cysteamine = glutathione (GSH) = coenzyme A greater than cysteine. In the absence of Triton, however, dithiothreitol, coenzyme A, and mercaptoethanol were most effective in eliciting GK proteolysis. Triton X-100 enhanced PRL cleavage by 4-19-fold, depending upon the thiol used. Folding isomers of processed PRL observed following cleavage included disulfide-liked homodimers, oxidized monomers, reduced monomers and mixed disulfides; the folding isomers generated varied depending upon the thiol used. GSH potency in eliciting PRL proteolysis increased 10-fold in the presence of biochemical pathways shuttling reducing equivalents to GSH disulfide (GSSG). PRL cleavage by GK could be controlled by substrates, enzymes, and cofactors making up the reducing shuttle when GSSG was used. Thioredoxin (a protein disulfide oxidoreductase) potently elicited PRL proteolysis by GK in the presence of a reducing shuttle and Triton X-100.(ABSTRACT TRUNCATED AT 250 WORDS)


Policy analysis of nutrition stewardship for prevention and control of Non-communicable diseases in Iran.
Non- communicable diseases (NCDs) are the main cause of death, which lead to over 73% of death and 62% of DALYs globally. As an unhealthy diet is the leading behavioral risk factor of NCDs, in line with the national action plan for the prevention and control of NCD, this study explored the nutrition-related stewardship problems to reduce the burden of NCDs in Iran. This is a qualitative study. We interviewed 30 purposefully identified key informants, i.e., stakeholders, policymakers, and academics, from December 2018 to August 2019. All interviews were recorded and transcribed verbatim. We analyzed data using qualitative content analysis facilitated by MAXQDA 11 software. Ample policies and laws were identified, most of which were not or partially implemented. Despite some plausible efforts, NCDs do not seem to be a top priority for high-level managers and decision-makers. Besides, the role of non-state actors, i.e., the private sector, is marginal in NCD's planning and management. Whereas the government, e.g., the Food and Drug Organization (FDO), is the biggest player. Worse still, many harmful products are advertised and easily distributed across the country. Iran's government has created a noticeable roadmap to battle NCDs despite imposing many sanctions and related socioeconomic problems. Nevertheless, more interventions are needed to strengthen the stewardship of NCDs by various stakeholders. We recommend the government to monitor the implementation of policies and advertisement of harmful products to prioritize prevention and control of NCDs. In addition, we advocate employing the capacity of non-state actors to reduce the consumption of unhealthy food and the burden of NCDs across the country, ultimately.


GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study.
It is now well established that a GnRH agonist (GnRHa) ovulation trigger completely prevents ovarian hyperstimulation syndrome. However, early studies, using conventional luteal support, showed inferior clinical results following a GnRHa trigger compared with a conventional hCG trigger in normal responder IVF patients. We here present a novel approach for luteal support after a GnRHa trigger. METHODS Normal responder patients who failed at least one previous IVF attempt, during which a conventional hCG trigger was used, were consecutively enrolled in the study. A GnRH antagonist-based ovarian stimulation protocol was used in combination with a GnRHa trigger (Triptorelin 0.2 mg). The luteal phase was supported with a total of two boluses of 1500 IU hCG: on the day of oocyte retrieval and 4 days later. Neither progesterone nor estradiol was administered for luteal support. The mean age was 33.8 years. The mean (± SD) numbers of oocytes and fertilized oocytes were 6.7 (± 2.5) and 3.6 (± 1.7), respectively. All 15 patients had embryo transfers and 11 patients conceived. On the day of pregnancy test (14 days after retrieval), the mean serum E(2) and progesterone levels were 6607 (± 3789) and 182 (± 50) nmol/l, respectively. Of the pregnancies, seven are ongoing, while four ended as miscarriages. These preliminary results suggest that two boluses of 1500 IU hCG revert the luteolysis after a GnRHa trigger in the normo-responder patient. Importantly, no additional luteal support is needed. The novel concept combines the potential advantages of a physiological dual trigger (LH and FSH) with a simple, patient friendly, luteal support.


D X Ala3 analog of elastin polypentapeptide. An elastomer with an increased young's modulus.
The polypentapeptide , H(L X Val1-L X Pro2-D X Ala3-L X Val4- Gly5 )n Val-OMe which is the D X Ala3 analog of the elastomeric polypentapeptide (PPP) of elastin, (L X Val1-L X Pro2-Gly3-L X Val4- Gly5 )n, has been synthesized. Its conformation is compared to that of the PPP and found to be similar with a somewhat stabilized beta-turn. The D X Ala3 analog coacervates to form a more cohesive viscoelastic material and the coacervate when cross-linked by gamma-irradiation exhibits an approximate doubling of the Young's modulus of elasticity. These results are discussed in connection with other related analogs of the polypentapeptide of elastin, which are non-elastomeric, and found to be consistent with a proposed conformationally based librational entropy mechanism of elasticity.


Cowden syndrome-affected patients with PTEN promoter mutations demonstrate abnormal protein translation.
Germline mutations of PTEN (phosphatase and tensin homolog deleted on chromosome 10) are associated with the multihamartomatous disorder Cowden syndrome (CS). Moreover, patients with CS with germline PTEN promoter mutations have aberrant PTEN protein expression and an increased frequency of breast cancer. Here, we examined the downstream effect of five PTEN promoter variants (-861G/T, -853C/G, -834C/T, -798G/C, and -764G/A) that are not within any known cis-acting regulatory elements. Clinically, all five of these patients have been given diagnoses of breast, thyroid, and/or endometrial cancer. We demonstrated that protein binding to the PTEN promoter (-893 to -755) was not altered in the five variants when compared with the wild-type (WT) promoter. However, reporter assays indicated that three of the variants (-861G/T, -853C/G, and -764G/A) demonstrated an ~50% decrease in luciferase activity compared with the WT construct. PTEN messenger RNA (mRNA) levels were not altered in these variants, whereas secondary structure predictions indicated that different PTEN 5' untranslated region transcript-folding patterns exist in three variants, suggesting an inhibition of protein translation. This was confirmed by PTEN protein analysis. These data indicate that variants causing large mRNA secondary structure alterations result in an inhibition of protein translation and a decrease in PTEN protein expression. These data emphasize the importance of PTEN promoter nucleotide variations and their ability to lead to CS progression by a novel regulatory mechanism. Importantly, these patients have a high prevalence of breast, thyroid, and endometrial malignancies; thus, understanding of the mechanism of PTEN dysfunction in these patients will lead to more-sensitive molecular diagnostic and predictive testing and, ultimately, to rational targeted therapies to treat or prevent malignancy.


Gonadotropin-releasing hormone (GnRH) positively regulates corticotropin-releasing hormone-binding protein expression via multiple intracellular signaling pathways and a multipartite GnRH response element in alphaT3-1 cells.
CRH-binding protein (CRH-BP) binds CRH with high affinity and inhibits CRH-mediated ACTH release from anterior pituitary corticotrope-like cells in vitro. In female mouse pituitary, CRH-BP is localized not only in corticotropes, but is also expressed in gonadotropes and lactotropes. To investigate the functional significance of gonadotrope CRH-BP, we examined the molecular mechanisms underlying GnRH-regulated CRH-BP expression in alphaT3-1 gonadotrope-like cells. CRH-BP is endogenously expressed in alphaT3-1 cells, and quantitative real-time RT-PCR and ribonuclease protection assays demonstrate that GnRH induces a 3.7-fold increase in CRH-BP mRNA levels. GnRH also induces intracellular CRH-BP (2.0-fold) and secreted CRH-BP (5.3-fold) levels, as measured by [125I]CRH:CRH-BP chemical cross-linking. Transient transfection assays using CRH-BP promoter-luciferase constructs indicate that GnRH regulation involves protein kinase C-, ERK- and calcium-dependent signaling pathways and is mediated via a multipartite GnRH response element that includes activator protein 1 and cAMP response element (CRE) sites. The CRE site significantly contributes to GnRH responsiveness, independent of protein kinase A, representing a unique form of multipartite GnRH regulation in alphaT3-1 cells. Furthermore, EMSAs indicate that alphaT3-1 nuclear proteins specifically bind at activator protein 1 and CRE sites. These data demonstrate novel regulation of pituitary CRH-BP, highlighting the importance of the pituitary gonadotrope as a potential interface between the stress and reproductive axes.


Gibberellins: Their Effect on Antheridium Formation in Fern Gametophytes.
Gametophytes of the fern Anemia phyllitidis respond to seven different gibberellins (A(1), A(3); A(4), A(5), A(7), A(8), and A(9)) by forming antheridia. Gibberellin A(7) is active at concentrations as low as 5 X 10(-10) g/ ml. Species from two of the three other genera in the family Schizaeaceae respond similarly to gibberellin A(3). In contrast, nearly 40 species from 7 other families of ferns do not develop antheridia when supplied with gibberellin.