Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.
An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset β=-2·00 [SE=0·57], p=0·0005, for African ancestry; and β=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.


Heavy metals in toys and low-cost jewelry: critical review of U.S. and Canadian legislations and recommendations for testing.
High metal contamination in toys and low-cost jewelry is a widespread problem, and metals can become bioavailable, especially via oral pathway due to common child-specific behaviors of mouthing and pica. In this review, the U.S., Canadian, and European Union (EU) legislations on metals in toys and jewelry are evaluated. A literature review on content, bioavailability, children's exposure, and testing of metals in toys and low-cost jewelry is provided. A list of priority metals is presented, and research needs and legislative recommendations are addressed. While the U.S. and Canadian legislations put emphasis on lead exposure prevention, other toxic elements like arsenic and cadmium in toy materials are not regulated except in paint and coatings. The EU legislation is more comprehensive in terms of contaminants and scientific approach. Current toy testing procedures do not fully consider metal bioavailability. In vitro bioaccessibility tests developed and validated for toys and corresponding metal bioaccessibility data in different toy matrices are lacking. The U.S. and Canadian legislations should put more emphasis on metal bioavailability and on other metals in addition to lead. A two-step management approach with mandatory testing of toys for total metal concentrations followed by voluntary bioaccessibility testing could be implemented.


Extended bandwidth wavelength swept laser source for high resolution optical frequency domain imaging.
Improving the axial resolution by providing wider bandwidth wavelength swept lasers remains an important issue for optical frequency domain imaging (OFDI). Here, we demonstrate a wide tuning range, all-fiber wavelength swept laser at a center wavelength of 1250 nm by combining two ring cavities that share a single Fabry-Perot tunable filter. The two cavities contain semiconductor optical amplifiers with central wavelengths of 1190 nm and 1292 nm, respectively. To avoid disturbing interference effects in the overlapping spectral region, we modulated the amplifiers in order to obtain consecutive wavelength sweeps in the two spectral regions. The two sweeps were fused together in post-processing to achieve a total scanning range of 223 nm, corresponding to 3.3 µm axial resolution in air. We confirm improved image quality and reduced speckle size in tomograms of swine esophagus ex vivo, and human skin and nailbed in vivo.


HYDROGEL-BASED NANOCOMPOSITES OF THERAPEUTIC PROTEINS FOR TISSUE REPAIR.
The ability to design artificial extracellular matrices as cell instructive scaffolds has opened the door to technologies capable of studying cell fates in vitro and to guide tissue repair in vivo. One main component of the design of artificial extracellular matrices is the incorporation of protein-based biochemical cues to guide cell phenotypes and multicellular organizations. However, promoting the long-term bioactivity, controlling the bioavailability and understanding how the physical presentations of these proteins impacts cellular fates are among the challenges of the field. Nanotechnolgy has advanced to meet the challenges of protein therapeutics. For example, the approaches to incorporating proteins into tissue repairing scaffolds have ranged from bulk encapsulations to smart nanodepots that protect proteins from degradations and allow opportunities for controlled release.


Perioperative renal failure in elderly patients.
To describe the epidemiology, pathophysiology, diagnosis and management of perioperative acute kidney injury (AKI) in elderly patients. Elderly patients with a reduced renal reserve and multiple comorbidities have a higher risk of developing AKI after surgery. Postoperative AKI is diagnosed late and may even go undetected in immobilized elderly patients because of loss of muscle mass and reduced creatinine production. Panels of injury biomarkers could improve early risk stratification, but this approach needs further evaluation. The evidence for perioperative AKI prevention or treatment with renal vasodilators or remote ischaemic preconditioning is conflicting and needs further research. Avoiding hypotension, venous congestion and fluid overload appear important to protect elderly patients and their kidneys from harm. Continuous rather than intermittent renal replacement therapy should be considered early when the response to diuretics is insufficient to prevent fluid overload. Postoperative AKI incidence is expected to rise as the number of elderly patients undergoing surgery is increasing. Biomarkers of early AKI will likely be important for the future development and validation of novel treatment strategies. The haemodynamic management of the elderly surgical patient should focus on avoiding hypotension and high central venous pressures.


TET repressor.tet operator complex formation induces conformational changes in the tet operator DNA.
The structural changes of the tet operator DNA upon binding of the TET repressor protein are examined by circular dichroism. For this purpose a 70 bp DNA fragment was prepared which contains both tet operators. About 67% of the base pairs of this DNA are involved in specific interaction with the TET repressor. A rather large change in the CD of the DNA is induced by binding of the TET repressor. The shape of the CD difference spectrum is similar to the respective difference found for the lac operator DNA upon complex formation with the lac repressor. However, the effect induced by the TET repressor on tet operator DNA seems to comprise both the specific and non-specific effect of the lac repressor on the structure of DNA [Culard, F. and Maurizot, J.C. (1981) Nucl. Acids Res. 9, 5157-5184]. Specificity of binding is confirmed by the lack of any effect of the TET repressor on the CD of a 95 bp lac operator containing DNA fragment, by the reduced mobility of TET repressor.tet operator complexes on polyacrylamide gels under CD conditions, and by a titration experiment of tet operator DNA with TET repressor employing the CD change. The latter experiment reveals a stoichiometry of four TET repressors per tet operon control region.


Predictors of Atrial Fibrillation Developing in Hospital Stage After Coronary Artery Bypass Surgery.
Aim To identify independent predictors associated with in-hospital atrial fibrillation (AF) following coronary artery bypass grafting (CABG).Material and methods The study included 80 patients (88.75 % men) who had elective CABG surgery at the Sklifosovsky Research Institute of Emergency Medicine. Based on the development of AF during the hospital stage of treatment (up to 10 days after CABG surgery), patients were divided into two groups. The group with AF consisted of 19 patients, and the group without AF consisted of 61 patients. All patients underwent electrocardiography (ECG), transthoracic echocardiography (EchoCG) with calculation of the left ventricular (LV) geometry type, and assessment of operational indexes. During surgery, biopsy of a part of the right atrial (RA) appendage was taken from 61 patients to verify the severity of myocardial fibrosis on a four-score scale where 0 is no interstitial fibrosis, 1 is slight fibrosis, 2 is moderate fibrosis, and 3 is severe fibrosis.Results All included patients had a low risk of developing postoperative complications according to the EuroSCORE II scale. According to EchoCG data, patients with AF had significantly higher ratios of left ventricular myocardial mass to body surface area (LVMM / BSA) (p = 0.0006) and of left atrial volume to body surface area (LA volume / BSA), p = 0.008). The distribution of patients by type of LV geometry was as follows: in the group with AF, 52.63 % (n=10) of patients were diagnosed with concentric LV hypertrophy (LVH) whereas in the group without AF, the majority of patients (83.60 %, n=51) had normal LV geometry and concentric LV remodeling (LVR) (p<0.0001). According to the results of histological study, patients of the AF group more frequently had moderate and severe interstitial fibrosis in the AF appendage (p = 0.003). After multivariate regression and ROC analysis, the predictive value remained for concentric LVH (p=0.002), LVMM / BSA ratio ≥97 g / m2 (p=0.006), LA volume / BSA ratio ≥ 34.4 ml / m2 (p=0.04), and for RA appendage interstitial fibrosis score ≥2 (p=0.004). Based on the identified predictors, a regression model was developed to predict the development of AF at the hospital stage after CABG (p<0.0001). The sensitivity and specificity of the model were 86.67 % and 78.26 %, respectively.Conclusion In patients at low perioperative risk, the LVMM / BSA ratio ≥97 g / m2, the LA volume ratio / BSA ≥34.4 ml / m2, a RA appendage interstitial fibrosis score ≥2, and the presence of LVH were independent predictors of the development of AF at the hospital stage after CABG operation.Conclusion In patients at low perioperative risk, a LVMM / BSA ratio ≥97 g / m2, a LA volume / BSA ratio ≥34.4 ml / m2, a RA appendage interstitial fibrosis score ≥2, and the presence of LVH were independent predictors of the development of AF at the hospital stage after CABG.


Comparison of effects of ginger, mefenamic acid, and ibuprofen on pain in women with primary dysmenorrhea.
To compare the effects of ginger, mefenamic acid, and ibuprofen on pain in women with primary dysmenorrhea. This was a double-blind comparative clinical trial conducted from September 2006 to February 2007. Participants were 150 students (18 years old and over) with primary dysmenorrhea from the dormitories of two medical universities who were alternately divided into three equal groups. Students in the ginger group took 250 mg capsules of ginger rhizome powder four times a day for three days from the start of their menstrual period. Members of the other groups received 250 mg mefenamic acid or 400 mg ibuprofen capsules, respectively, on the same protocol. A verbal multidimensional scoring system was used for assessing the severity of primary dysmenorrhea. Severity of disease, pain relief, and satisfaction with the treatment were compared between the groups after one menstruation. There were not significant differences between groups in baseline characteristics, p > 0.05. At the end of treatment, severity of dysmenorrhea decreased in all groups and no differences were found between the groups in severity of dysmenorrhea, pain relief, or satisfaction with the treatment, p > 0.05. No severe side effects occurred. Ginger was as effective as mefenamic acid and ibuprofen in relieving pain in women with primary dysmenorrhea. Further studies regarding the effects of ginger on other symptoms associated with dysmenorrhea and efficacy and safety of various doses and treatment durations of ginger are warranted.


A beamforming study for implementation of vibro-acoustography with a 1.75-D array transducer.
Vibro-acoustography (VA) is an ultrasound-based imaging modality that uses radiation force produced by two cofocused ultrasound beams separated by a small frequency difference, Δf, to vibrate tissue at Δf. An acoustic field is created by the object vibration and measured with a nearby hydrophone. This method has recently been implemented on a clinical ultrasound system using 1-D linear-array transducers. In this article, we discuss VA beamforming and image formation using a 1.75-D array transducer. A 1.75-D array transducer has several rows of elements in the elevation direction which can be controlled independently for focusing. The advantage of the 1.75-D array over a 1-D linear-array transducer is that multiple rows of elements can be used for improving elevation focus for imaging formation. Six configurations for subaperture design for the two ultrasound beams necessary for VA imaging were analyzed. The point-spread functions for these different configurations were evaluated using a numerical simulation model. Four of these configurations were then chosen for experimental evaluation with a needle hydrophone as well as for scanning two phantoms. Images were formed by scanning a urethane breast phantom and an ex vivo human prostate. VA imaging using a 1.75-D array transducer offers several advantages over scanning with a linear-array transducer, including improved image resolution and contrast resulting from better elevation focusing of the imaging point-spread function.


Adult attachment style and individual differences in functional versus dysfunctional experiences of anger.
Three studies examined the association between adult attachment and anger. Study 1 examined attachment-style differences in self-reports of anger-proneness, anger expression, anger goals, and responses to anger. Study 2 assessed attachment style, physiological signs of anger, and attribution of hostile intent. Study 3 used a lexical-decision task for studying attachment-style differences in expected anger outcome. Secure persons scored lower in anger-proneness, endorsed more constructive anger goals, reported more adaptive responses and more positive affect in anger episodes, attributed less hostile intent to others, and expected more positive outcomes than insecure persons. For ambivalent persons, the anger experience also included lack of anger control and anger-in. For avoidant persons, it included high hostility, escapist responses, and lack of awareness of physiological signs of anger. The underlying action of working models is emphasized in the discussion.


[Radiation diagnosis of interstitial lung diseases].
The authors analyzed the results of complex radiation study of 1192 patients with various interstitial lung diseases (ILD). An algorithm of differential diagnosis of diffuse and disseminated lesions of the lung was derived by using the findings. The X-ray morphological principle underlies the algorithm. The level of structural lesions of the lung and tissue reactions and the presence of granuloma shadows are the governing criteria for evaluating the gross structure in the differential diagnostic complex. Great emphasis is laid on the significance of computed tomography (CT), high performance CT in particular, which is becoming the priority radiation diagnostic technique in pulmonology. Morphofunctional studies, 99mTc AMA and 67Ga citrate pulmonary scintigraphy in particular, specify the magnitude of changes in the microcirculatory bed and the activity of intrathoracic lymph nodes.


Role of polyamine structure in inhibition of K+-Cl- cotransport in human red cell ghosts.
1. K+-Cl- cotransport in human red cell ghosts is inhibited by divalent inorganic cations, soluble polycations and amphipathic organic cations. These findings suggest a common mechanism of inhibition, namely, binding of the cations to negative charges at the surface of a hydrophobic structure. 2. We have characterized the inhibitory capacity of a number of polyamines in order to obtain information about the nature of the charges with which they interact. Neomycin inhibited swelling-stimulated cotransport. The diquaternary amines dimethonium and decamethonium were relatively ineffective inhibitors. These compounds are thought to shield negative charges, but not bind to them. 3. Comparison of a homologous series of polyamines indicated that primary amines were better inhibitors than secondary amines, that inhibition increased with the charge of the polyamine, and that inhibition increased as the distance separating the amines increased. 4. The results indicate that the negative charges to which polycations bind are multiple and mobile. Since they must be associated with a hydrophobic environment, it is likely that they are negatively charged phospholipids located in the inner leaflet of the bilayer membrane. 5. Heating red cells or ghosts to 49 C denatures spectrin. Heating markedly increased K+ uptake in swollen ghosts but not in shrunken ghosts. The increase in uptake was reversed when swollen ghosts were shrunk even though denaturation of spectrin was not reversed. Polyamines, which inhibited swelling-activated K+ uptake in control ghosts, similarly inhibited the increased uptake in heated ghosts. 6. We speculate that spectrin, which is closely associated with the inner bilayer leaflet, shields negative charges in a volume-dependent manner and so regulates volume-sensitive K+ transport.


In vitro activity of ceftazidime+NXL104 against Pseudomonas aeruginosa and other non-fermenters.
NXL104 potentiates ceftazidime and ceftaroline against Enterobacteriaceae with extended-spectrum, AmpC, KPC and OXA β-lactamases. We examined whether similar potentiation was obtained against non-fermenters, which are less permeable than Enterobacteriaceae and have more potent efflux. MICs of ceftazidime+NXL104 (with NXL104 at 4 mg/L) and comparators were determined by CLSI agar dilution for: (i) Pseudomonas aeruginosa AmpC mutants and extended-spectrum β-lactamase (ESBL)-producing transconjugants; (ii) clinical P. aeruginosa isolates with AmpC enzymes, ESBLs or up-regulated efflux; (iii) P. aeruginosa and Burkholderia cepacia complex isolates from cystic fibrosis patients; and (iv) Acinetobacter baumannii with OXA carbapenemases, which also compromise ceftazidime. NXL104 reversed AmpC-mediated ceftazidime resistance in P. aeruginosa, reducing MICs for fully derepressed mutants and isolates to ≤ 8 mg/L. NXL104 also reversed ceftazidime resistance caused by the ESBL PER-1, but not that due to OXA ESBLs or VEB-1 enzyme. Efflux-mediated resistance was unaffected. Resistance to ceftazidime in isolates of P. aeruginosa and the B. cepacia complex from patients with cystic fibrosis was variably overcome, generally to greater effect for B. cepacia. NXL104 had little effect on MICs of ceftazidime for A. baumannii isolates with OXA carbapenemases. The potentiation of ceftazidime against many β-lactamase-producing P. aeruginosa and B. cepacia complex strains confirms that NXL104 penetrates these organisms. The utility of the combination against these pathogens will depend on the local prevalence of strains with β-lactamase- versus efflux-mediated resistance. The lack of potentiation against A. baumannii may reflect failure of NXL104 to penetrate these bacteria to inhibit relevant (OXA-23, -40, -51 and -58) carbapenemases.


Microvessel Density and Impact of Angiogenesis on Survival of Resected Pancreatic Cancer Patients: A Systematic Review and Meta-analysis.
Angiogenesis plays a major role in tumor progression and metastasis; however, its role in pancreatic cancer (PC) remains unclear. The aim of the study was to explore the cumulative evidence concerning the impact of microvessel density (MVD), an estimator of angiogenesis, on resected PC patients. A systematic review of literature and a meta-analysis of relevant reports were performed. Overall survival and disease-free survival were scrutinized. One thousand five hundred patients were analyzed. Overall survival (hazard ratio, 2.0; 95% confidence interval, 1.57-2.54; P < 0.001) and disease-free survival (hazard ratio, 1.99; 95% confidence interval, 1.24-3.2; P = 0.004) were in favor of the low-MVD group. Use of CD105 antibody and of a computerized image analysis system was found to significantly reduce the heterogeneity. Disease staging, tumor location, and grading showed significant effect on survival. High-MVD expression was strongly associated with poorer survival and recurrence among resected PC patients, demonstrating a negative prognostic value. Use of CD105 antibody and of a computerized image analysis system is recommended in future studies because they reduce heterogeneity of results. The potential role of MVD as a marker to select PC patients who would benefit from antiangiogenetic treatment should be further explored in clinical trials.


Sodium-Doped 3-Amino-4-hydroxybenzoic Acid: Rediscovered Matrix for Direct MALDI Glycotyping of O-Linked Glycopeptides and Intact Mucins.
3-Amino-4-hydroxybenzoic acid (AHB) was the first matrix identified by glycoprotein glycan analysis using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). However, compared to commonly used matrices, such as 2,5-dihydroxybenzoic acid (DHB), AHB is less efficient at glycan ionization and lacks the ability to ionize other molecular species, such as peptides, and thus is no longer used. In this study, we focused on the glycan-selective ionization ability of AHB and its low-noise properties in the low-molecular-weight region, as we expected that these properties could be enhanced by adding sodium to AHB. Sodium-doped AHB (AHB/Na) selectively imparts sodium adduct ions onto O-glycan fragments generated by the in-source decay (ISD) of glycopeptides and glycoproteins containing O-glycans that occurs during intense laser irradiation, enabling direct O-glycan analysis. Furthermore, we demonstrated that it is possible to investigate the internal structure of each O-glycan fragment with pseudo-MS/MS/MS using the sodium adduct ion of the O-glycan-derived ISD fragments from an intact mucin mixture.


Charge pair interactions in transmembrane helices and turn propensity of the connecting sequence promote helical hairpin insertion.
α-Helical hairpins, consisting of a pair of closely spaced transmembrane (TM) helices that are connected by a short interfacial turn, are the simplest structural motifs found in multi-spanning membrane proteins. In naturally occurring hairpins, the presence of polar residues is common and predicted to complicate membrane insertion. We postulate that the pre-packing process offsets any energetic cost of allocating polar and charged residues within the hydrophobic environment of biological membranes. Consistent with this idea, we provide here experimental evidence demonstrating that helical hairpin insertion into biological membranes can be driven by electrostatic interactions between closely separated, poorly hydrophobic sequences. Additionally, we observe that the integral hairpin can be stabilized by a short loop heavily populated by turn-promoting residues. We conclude that the combined effect of TM-TM electrostatic interactions and tight turns plays an important role in generating the functional architecture of membrane proteins and propose that helical hairpin motifs can be acquired within the context of the Sec61 translocon at the early stages of membrane protein biosynthesis. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains from primary structures.


Psychological stress as a modulator of functional recovery following spinal cord injury.
There is strong evidence indicating that the social environment triggers changes to the psychological stress response and glucocorticoid receptor function. Considerable literature links the subsequent changes in stress resiliency to physical health. Here, converging evidence for the modulatory role of chronic psychological stress in the recovery process following spinal cord injury (SCI) is presented. Despite the considerable advances in SCI research, we are still unable to identify the causes of variability in patients' recovery following injury. We propose that individuals' past and present life experiences (in the form of stress exposure) may significantly modulate patients' outcome post-SCI. We propose a theoretical model to explain the negative impact of chronic psychological stress on physical and psychological recovery. The stress experienced in life prior to SCI and also as a result of the traumatic injury, could compromise glucocorticoid receptor sensitivity and function, and contribute to high levels of inflammation and apoptosis post-SCI, decreasing the tissue remaining at the injury site and undermining recovery of function. Both stress-induced glucocorticoid resistance and stress-induced epigenetic changes to the glucocorticoid receptor can modulate the nuclear factor-kappa B regulated inflammatory pathways and the Bcl-2 regulated apoptosis pathways. This model not only contributes to the theoretical understanding of the recovery process following injury, but also provides concrete testable hypotheses for future studies.


The distribution of cytokeratin antigens in the kidney and in renal tumours.
The distribution of cytokeratin antigens during embryogenesis of the kidney and in 57 renal tumours has been studied using immunocytochemical techniques. A polyclonal antiserum to epidermal prekeratins and the monoclonal antibodies CAM 5.2 and PKK1 have been used to identify cytokeratins of different molecular weights. The ureteric bud-derived structures expressed large molecular weight cytokeratins. The tubular component of the kidney expressed cytokeratins detected by CAM 5.2 and PKK1. During glomerular development there was transient expression of low molecular weight cytokeratins by the visceral glomerular epithelium but in the adult kidney only the parietal epithelium expressed cytokeratins. Tubules in nephroblastomas contained low molecular weight cytokeratins but the blastema did not. Some ureteric bud-derived structures were identified in six nephroblastomas. Renal carcinomas expressed low molecular weight cytokeratins. Four collecting duct carcinomas were studied; these all expressed the large molecular weight cytokeratins found in collecting duct epithelium. These results indicate that the cytokeratin phenotype of renal tumours is unchanged from that of the normal epithelial cells.


Treatment of iatrogenic occlusive coronary dissections: a novel approach.
Iatrogenic occlusive coronary dissection (IOCD) is a rare but high-risk complication of percutaneous coronary intervention (PCI) with limited data on options for management. The aim of this study was to describe a novel approach to the treatment of IOCD in order to gain access to the true coronary lumen. This technique may be feasible in cases in which conventional methods of PCI have failed. We performed a retrospective analysis of 11 patients with PCI complicated by IOCD. In all cases, IOCD was treated using the contrast-guided subintimal tracking and re-entry "rescue" (STAR-R) procedure. Angiographic success with TIMI 3 flow was achieved in all patients and stent implantation was performed in 81.8% (n=9). At clinical follow-up (mean 186 ± 79 days), target lesion revascularisation was required in 9% (n=1), with target vessel revascularisation in 27.3% (n=3), and a major adverse cardiac event rate of 27.3% (n=3). Angiographic follow-up was obtained in 81.8% (n=9) with a restenosis rate of 11% (n=1). The STAR-R procedure is a feasible option for the treatment of IOCD following failure of conventional techniques of treatment.


[Treatment of vertical strabismus using binarimetry].
The paper analyses results after treatment of patients with vertical squint (53 persons) using a principally new method--binarimetry, as one of diploptic methods. All patients had residual vertical deviation after surgical treatment or a small angle (to 10 degrees). The device and the method of treatment are described. In the most of patients, binocular vision was restored (77.3%) on account of development of vertical fusional reserves and correction of residual deviation.


Introducing the female condom through the public health sector: experiences from South Africa.
The successful implementation of new public health policy is influenced by provider preparedness and user acceptability of the new intervention. This paper describes the development and implementation of a participatory Training of Trainers (TOT) programme as a precursor to launch the South African government's female-initiated HIV prevention strategies in public health clinics. Three hundred peer-trainees from throughout South Africa were trained through a comprehensive, modular and interactive three-day workshop. The workshop content included: HIV/AIDS knowledge, beliefs and attitudes; values clarification regarding HIV infection and sexuality; sexual desensitization; 'hands-on' training in the use of and introduction of the female condom; and counselling, communication and programme planning skills. The TOT generated a cadre of knowledgeable health care workers for training others and provided a support structure at the service delivery level for ensuring potential users' access to the female condom within each province. Qualitative assessments of the training and trainer debriefing sessions suggest that the training was successful in increasing knowledge and promoting positive attitudes about female condoms. In addition, the expanded repertoire of problem-solving approaches left providers feeling confident about recommending this method to clients.


Reverse atrial electrical remodelling following atrial defibrillation as determined by signal-averaged ECG.
Following successful cardioversion for atrial fibrillation (AF), the rate of early recurrence remains high. Analysis of the signal-averaged electrocardiogram of the P wave has been proposed as a noninvasive method of predicting those at risk of recurrence. To determine the change in signal-averaged P wave duration (SAPWD) following cardioversion from AF, and to determine whether SAPWD is associated with the risk of recurrence. SAPWD was determined in 76 patients immediately following successful electrical cardioversion and three days later. Patients were then followed clinically for one year. Recurrent AF was observed in 32 of 76 patients at 90 days following cardioversion. There was no difference in SAPWD immediately following cardioversion (158+/-28 ms versus 164+/-31 ms, P=NS) or three days following cardioversion (152+/-24 ms versus 158+/-36 ms, P=0.4) in patients with and without recurrent AF. There was, however, a significant decrease in the SAPWD during the first three days following cardioversion in the patients who remained in sinus rhythm (158+/-28 ms initially versus 152+/-24 ms on day three, P=0.009). Among the patients with recurrent AF, the decrease was smaller and not statistically significant (161+/-30 ms versus 158+/-36 ms, P=0.3). Shortening of the SAPWD occurs following atrial defibrillation in patients who maintain sinus rhythm at 90 days. This provides evidence for reverse atrial electrical remodelling and its association with the maintenance of sinus rhythm.


The effect of Ca(2+)-calmodulin-dependent protein kinase II on cardiac excitation-contraction coupling in ferret ventricular myocytes.
1. The effect of Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) on excitation-contraction coupling (E-C coupling) was studied in intact ferret cardiac myocytes using the selective inhibitor KN-93, KN-93 decreased steady-state (SS) twitch [Ca2+]i (by 51%), resting Ca2+ spark frequency (by 88%) and SS sarcoplasmic reticulum (SR) Ca2+ content evaluated by eaffeine application (by 37.5%). 2. Increasing extracellular Ca2+ concentration ([Ca2+]o) to 5 mM in KN-93 restored SR Ca2+ load and Ca2+ spark frequency towards that in control (2 mM Ca2+o), but SS twitch [Ca2+]i was still significantly depressed by KN-93. 3. KN-93 decreased Ca2+ transient amplitude of SS twitches much more strongly than the amplitude of post-rest (PR) twitches. In the control, the time constant (Tau) of [Ca2+]i decline of SS twitches was faster than that for PR twitches. This stimulation-dependent acceleration of [Ca2+]i decline was abolished by KN-93. 4. Voltage-clamp experiments demonstrated that KN-93 significantly inhibited sarcolemmal L-type Ca2+ current (ICa) during repetitive pulses by slowing recovery from inactivation. This may explain the preferential action of KN-93 to suppress SS vs. PR twitches. 5. In KN-93, even when both ICa and SR Ca2+ load were matched to the control levels by manipulation of conditioning voltage-clamp pulses, contraction and twitch Ca2+ transients were still both significantly depressed (to 39 and 49% of control, respectively). 6. Since KN-93 reduced SR Ca2+ release channel (RyR) activity during E-C coupling, even for matched SR Ca2+ load and trigger ICa, we infer that endogenous CaMKII is an important modulator of E-C coupling in intact cardiac myocytes. Effects of KN-93 on ICa and SS twitch [Ca2+]i decline also indicate that endogenous CaMKII may have stimulatory effects on ICa and SR Ca2+ uptake.


Impairments of balance, stepping reactions and gait in people with cervical dystonia.
Impaired balance is common in neurological disorders. Cervical dystonia is a neurological movement disorder affecting the neck. The effect of this aberrant head posture on physical function is unknown. To compare balance, mobility, gait and stepping reactions between ten people with cervical dystonia and ten control adults. Spatiotemporal gait parameters and walking speed were assessed using a computerised walkway. Step length and time, time in double support and gait variability were calculated, then normalised to gait speed. Centre of pressure path length was assessed with eyes open and eyes closed to calculate a Romberg Quotient. Simple and choice reaction times were measured using customised apparatus while mobility was assessed by the timed up and go. Cervical spine range of motion was measured using a head mounted goniometer. Self-reported scales included Falls Self Efficacy Scale and Dystonia Discomfort Scale. There was a difference between groups for most outcome measures. The timed up-and-go and walking speed was slower (both P<0.005) and the Romberg Quotient lower (P=0.046) in cervical dystonia. People with cervical dystonia had lower falls self-efficacy (P=0.0002). Reduced cervical range of motion was correlated with balance, stepping reaction time and mobility (all P<0.05). Timed up and go was positively associated with stepping reaction time (P<0.01). Dystonia discomfort did not impact function. People with cervical dystonia displayed deficits in balance, gait and stepping reactions, and expressed higher fear of falling. Studies to further elucidate functional limitations and their impact on activity and participation in daily life are required.


Targeting Platelet GPVI Plus rt-PA Administration but Not α2β1-Mediated Collagen Binding Protects against Ischemic Brain Damage in Mice.
Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2-/- mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.


Enabling the use of hereditary information from pedigree tools in medical knowledge-based systems.
The use of family information is a key issue to deal with inheritance illnesses. This kind of information use to come in the form of pedigree files, which contain structured information as tree or graphs, which explains the family relationships. Knowledge-based systems should incorporate the information gathered by pedigree tools to assess medical decision making. In this paper, we propose a method to achieve such a goal, which consists on the definition of new indicators, and methods and rules to compute them from family trees. The method is illustrated with several case studies. We provide information about its implementation and integration on a case-based reasoning tool. The method has been experimentally tested with breast cancer diagnosis data. The results show the feasibility of our methodology.


Helping young people who self-harm: perspectives from England.
Interventions for young people who self-harm. To inform the international community of concerns that have arisen in England in relation to self-harm in young people, the therapies available to young people, and the evidence base for these therapies. SOURCE(S) USED: Published literature on the topic, together with the clinical and academic expertise of the paper's authors. A variety of treatment modalities (categorized according to whether they were individual, family, group, or psychopharmacological therapies) used in England with young people who self-harm are discussed. The overall picture regarding these interventions is unclear: a few have no research evidence; some, however, do show promise though limitations in study design, and a lack of replication means no definitive conclusions can be drawn. There needs to be further research and development in this area, especially evaluative research of interventions. Nurses should play a lead role here as they are often in the most unique position to help young people who self-harm.


Hexavalent chromium in house dust--a comparison between an area with historic contamination from chromate production and background locations.
In contrast to Cr(+3), Cr(+6) is carcinogenic and allergenic. Although Cr(+6) can occur naturally, it is thought that most soil Cr(+6) is anthropogenic, however, the extent of Cr(+6) in the background environment is unknown. Cr(+6)-containing chromite ore processing residue (COPR) from chromate manufacture was deposited in numerous locations in Jersey City (JC), New Jersey. In the 1990's, significantly elevated concentrations of total Cr (Cr(+6)+Cr(+3)) were found in house dust near COPR sites. We undertook a follow-up study to determine ongoing COPR exposure. We compared Cr(+6) in house dust in JC to selected background communities with no known sources of Cr(+6). Samples were collected from living areas, basements and window wells. Cr(+6) was detected in dust from all JC and background houses. In the JC homes, the mean (+ or - SD) Cr(+6) concentration for all samples was 3.9 + or - 7.0 microg/g (range: non-detect-90.4 microg/g), and the mean Cr(+6) loading was 5.8 + or - 15.7 microg/m(2) (range: non-detect-196.4 microg/m(2)). In background homes, the mean Cr(+6) concentrations of all samples was 4.6 + or - 7.8 microg/g, (range, 0.05-56.6 microg/g). The mean loading was 10.0 + or - 27.9 microg/m(2) (range, 0.22-169.3 microg/m(2)). There was no significant difference between Cr(+6) dust concentrations in Jersey City and background locations. Stratification by sample location within houses and sampling method gave similar results. Samples exceeding 20 microg/g were obtained only from single wood surfaces in different homes. Lower concentrations in window well samples suggests transport from outside is not the major source of indoor Cr(+6). Landscaping and groundcover may influence indoor Cr(+6). There appears to be a widespread low level background of Cr(+6) that is not elevated in Jersey City homes despite its historic COPR contamination. It is possible that house dust, in general, is a source of Cr(+6) exposure with potential implications for persistence of chromium allergic contact dermatitis.


Randomized trial comparing two fractionation schedules for patients with localized prostate cancer.
The optimal radiation dose fractionation schedule for localized prostate cancer is unclear. This study was designed to compare two dose fractionation schemes (a shorter 4-week radiation schedule v a longer 6.5-week schedule). Patients with early-stage (T1 or T2) prostate cancer were randomly assigned to 66 Gy in 33 fractions over 45 days (long arm) or 52.5 Gy in 20 fractions over 28 days (short arm). The study was designed as a noninferiority investigation with a predefined tolerance of -7.5%. The primary outcome was a composite of biochemical or clinical failure (BCF). Secondary outcomes included presence of tumor on prostate biopsy at 2 years, survival, and toxicity. From March 1995 to December 1998, 936 men were randomly assigned to treatment; 470 were assigned to the long arm, and 466 were assigned to the short arm. The median follow-up time was 5.7 years. At 5 years, the BCF probability was 52.95% in the long arm and 59.95% in the short arm (difference = -7.0%; 90% CI, -12.6% to -1.4%), favoring the long arm. No difference in 2-year postradiotherapy biopsy or in overall survival was detected between the arms. Acute toxicity was found to be slightly higher in the short arm (11.4%) compared with the long arm (7%; difference = -4.4%; 95% CI, -8.1% to -0.6%); however, late toxicity was similarly low in both arms (3.2%). Given the results, we cannot exclude the possibility that the chosen hypofractionated radiation regimen may be inferior to the standard regimen. Further evaluation involving higher dose hypofractionated radiation regimens in contemporary radiation settings is necessary.


[Syndromes 2. Pfeiffer syndrome].
Acrocephalosyndactylias are syndromes characterized by abnormalities of the head (craniosynostosis), the face (hypertelorism, retromaxillism), hands and feet (cutaneous or bony syndactyly). Inheritance is autosomal dominant, but spontaneous cases are described also. The group is divided into several syndromes with varying penetrance and expressivity. As an example of an acrocephalosyndactylia is the Pfeiffer syndrome presented.


Aberrant glycosylation of the anti-Thomsen-Friedenreich glycotope immunoglobulin G in gastric cancer patients.
To study whether alterations in the glycosylation of immunoglobulin G (IgG) specific to the Thomsen-Friedenreich glycotope (TF) have diagnostic and prognostic potential in gastric cancer. Serum samples were obtained from patients with histologically verified gastric carcinoma (n = 89), healthy blood donors (n = 40), and patients with benign stomach diseases (n = 22). The lectin-enzyme-linked immunosorbent assay-based glycoprofiling of TF-specific IgG (anti-TF IgG) was performed using synthetic TF-polyacrylamide conjugate as antigen, total IgG purified by affinity chromatography on protein G sepharose, and lectins of various sugar specificities: mannose-specific concanavalin A (ConA), fucose-specific Aleuria aurantia lectin (AAL) and sialic acid-specific Sambucus nigra agglutinin (SNA). The sensitivity and specificity of the differences between cancer patients and controls were evaluated by receiver operator characteristic (ROC) curve analysis. Overall survival was analyzed by the Kaplan-Meier method. Time-dependent ROC curve statistics were applied to determine cut-off values for survival analysis. All calculations and comparisons were performed using the GraphPad Prism 5 and SPSS 15.0 software. The level of TF-specific IgG was significantly increased in cancer patients compared with non-cancer controls (P < 0.001). This increase was pronounced mostly in stage 1 of the disease. Cancer patients showed a higher level of ConA binding to anti-TF-IgG (P < 0.05) and a very low level of SNA lectin binding (P = 0.0001). No appreciable stage-dependency of the binding of any lectin to anti-TF IgG was found. A strong positive correlation between the binding of AAL and SNA was found in all groups studied (r = 0.71-0.72; P < 0.0001). The changes in ConA reactivity were not related to those of the fucose- or sialic acid-specific lectin. Changes in the SNA binding index and the ConA/SNA binding ratio demonstrated good sensitivity and specificity for stomach cancer: sensitivity 78.79% (95%CI: 61.09-91.02) and 72.73% (95%CI: 57.21-85.04); specificity 79.17 (95%CI: 65.01-89.53) and 88.64% (95%CI: 71.8-96.6), for the SNA binding index and the ConA/SNA binding ratio, respectively. The other combinations of lectins did not improve the accuracy of the assay. The low level of ConA-positive anti-TF IgG was associated with a survival benefit in cancer patients (HR = 1.56; 95%CI: 0.78-3.09; P = 0.19), especially in stages 3-4 of the disease (HR = 2.17; 95%CI: 0.98-4.79; P = 0.048). A significantly better survival rate was found in all cancer patients with a low reactivity of anti-TF IgG to the fucose-specific AAL lectin (HR = 2.39; 95%CI: 1.0-5.7; P = 0.038). The changes in the TF-specific IgG glycosylation pattern can be used as a biomarker for stomach cancer detection, and to predict patient survival.


Primary blast injuries.
Injury from explosion may be due to the direct cussive effect of the blast wave (primary), being struck by material propelled by the blast (secondary), to whole-body displacement and impact (tertiary), or to miscellaneous effects from burns, toxic acids, and so on. Severe primary blast injury is most likely to be seen in military operations but can occur in civilian industrial accidents or terrorist actions. Damage is seen almost exclusively in air-containing organs--the lungs, the gastrointestinal tract, and the auditory system. Pulmonary injury is characterized by pneumothorax, parenchymal hemorrhage, and alveolar rupture. The last is responsible for the arterial air embolism that is the principle cause of early mortality. Treatment for blast injury is similar to that for blunt trauma. The sequalae of air embolization to the cerebral or coronary circulation may be altered by immediate hyperbaric therapy. Use of positive pressure ventilatory systems should be closely monitored as they may increase the risk of air embolism in pneumothorax. Morbidity and mortality may be increased by strenuous exertion after injury and by the wearing of a cloth ballistic vest at the time of the blast.


Role of Noninvasive Tests in Clinical Gastroenterology Practices to Identify Patients With Nonalcoholic Steatohepatitis at High Risk of Adverse Outcomes: Expert Panel Recommendations.
Nonalcoholic fatty liver disease (NAFLD) is generally considered a silent and potentially reversible condition. The subtype of NAFLD that can be classified as nonalcoholic steatohepatitis (NASH) can progress to advanced fibrosis and cirrhosis. Because of the metabolic nature of the pathogenic mechanism underlying NAFLD and NASH, it is often accompanied by common comorbidities such as obesity, insulin resistance, and type 2 diabetes mellitus. The increase in the prevalence of these comorbidities has resulted in a parallel increase in the prevalence of NAFLD and NASH, globally, nationally, and even in children. In recent years, it has been identified that the stage of fibrosis is the most important predictor of liver outcomes; therefore, identifying patients with NAFLD and NASH with more advanced stages of fibrosis can be essential for optimal management. Several noninvasive tools for diagnosing and staging NAFLD and NASH are available, but simple and straightforward recommendations on the use of these tools are not. Recognizing these unmet needs, hepatologists who are members of the American College of Gastroenterology and the Chronic Liver Disease Foundation created a practical decision tree/algorithm to risk stratify NAFLD/NASH as a resource in gastroenterology/hepatology clinical practices. This review will provide insight into how this algorithm was developed, describe it in detail, and provide recommendations for its use in clinical practice.


Reducing Dietary Sodium Intake among Young Adults in Ghana: A Call to Action.
The positive association between excessive dietary sodium intake, hypertension, and cardiovascular disease (CVD) has been widely investigated in observational studies and clinical trials. Reducing sodium intake is a proven strategy to prevent hypertension and the onset of CVD, a major cause of morbidity and mortality globally. Africa has the youngest population globally, which is key to the continent's sustainable development. However, in Africa, the epidemics of hypertension and CVD negatively impact life expectancy and economic growth. Ghana, like other African countries, is no exception. The factors contributing to the increasing burden of CVD and excessive sodium consumption are multi-faceted and multi-level, including individual lifestyle, neighborhood and built environments, and socio-economic and health policies. Thus, the implementation of evidence-based interventions such as the World Health Organization Best Buys that target the multi-level determinants of sodium consumption is urgently needed in Ghana and other African countries. The aim of this commentary is to highlight factors that contribute to excessive sodium consumption. Second, the commentary will showcase lessons of successful implementation of sodium reduction interventions in other countries. Such lessons may help avert CVD in young adults in Ghana and Africa.


Challenging Return to Play Decisions: Heat Stroke, Exertional Rhabdomyolysis, and Exertional Collapse Associated With Sickle Cell Trait.
Sports medicine providers frequently return athletes to play after sports-related injuries and conditions. Many of these conditions have guidelines or medical evidence to guide the decision-making process. Occasionally, however, sports medicine providers are challenged with complex medical conditions for which there is little evidence-based guidance and physicians are instructed to individualize treatment; included in this group of conditions are exertional heat stroke (EHS), exertional rhabdomyolysis (ER), and exertional collapse associated with sickle cell trait (ECAST). The MEDLINE (2000-2015) database was searched using the following search terms: exertional heat stroke, exertional rhabdomyolysis, and exertional collapse associated with sickle cell trait. References from consensus statements, review articles, and book chapters were also utilized. Clinical review. Level 4. These entities are unique in that they may cause organ system damage capable of leading to short- or long-term detriments to physical activity and may not lend to complete recovery, potentially putting the athlete at risk with premature return to play. With a better understanding of the pathophysiology of EHS, ER, and ECAST and the factors associated with recovery, better decisions regarding return to play may be made.


Evaluation of the safety and efficacy of warfarin in Taiwanese patients.
The safety and efficacy of warfarin therapeutic range in Asians remain to be ascertained. Physicians in Taiwan consider Asians are more likely to have bleeding complications rather than thromboembolic events from warfarin. The aim of this study was to determine if the proper INR range for patients in Taiwan is different. A retrospective study was conducted with 161 patients on warfarin therapy for more than 24 consecutive months during March 1, 2006 to Sepember 30, 2008. Total follow-up time was 3,504 patient-months. The incidence rates of thromboembolic and bleeding events for INR categories were calculated. The overall incidence rates of INR ranges of < 1.5, 1.5 - 1.9, 2.0 - 2.4, 2.5 - 2.9, 3.0 - 3.4, and ≥ 3.5 were 8.1, 5.6, 2.0, 7.6, 33.3, and 121.2 per 1,000 patientmonths, respectively. The overall incidence rate at INR of > 3 is higher than that at INR of < 2 or 2 - 3 (p < 0.001), with the lowest incidence rate at INR between 2.0 and 2.4. When INR was maintained at a level < 2, patients taking warfarin for secondary prevention had a significantly higher event rate compared to the primary prevention group (p < 0.05). Age greater than 73 years was a risk factor for thromboembolic events before and after covariate adjustment. An INR range of 2 - 2.4 appeared to be associated with lower complications and better clinical outcomes in Taiwanese patients treated with warfarin. Lowering the intensity of anticoagulant therapy further does not decrease the number of events.


Changes in pancreatic islet glucokinase and hexokinase activities with increasing age, obesity, and the onset of diabetes.
We examined changes in high- and low-Km glucose phosphorylating activity in pancreatic islet extracts from the prediabetic Zucker diabetic fatty (ZDF) rat between 5-6 weeks and 12 weeks of age (after the onset of diabetes). Comparisons were made between the activity observed in the ZDF rat and that seen in the ZDF lean control (ZLC) rat and the obese nondiabetic Zucker fatty (ZF) rat. At 5-6 weeks of age, insulin resistant ZDF and ZF rats were hyperinsulinemic, compared with the ZLC rat, but had normal plasma glucose levels. Kinetic parameters (Vmax and Km for glucose) of hexokinase (HK) and Km of glucokinase (GCK) did not differ between groups. Islet GCK activity for ZDF and ZF rats was 1.7-fold greater than in ZLC rats (P < 0.02 and P < 0.001, respectively). By 12 weeks of age, hypersecretion of insulin at 5.0 mmol/l glucose was observed in perifused islets from both obese groups relative to the ZLC rat. Islets from ZDF rats failed to increase insulin secretion in response to increased glucose concentration. Group differences in the kinetic parameters for GCK or in the Km values for HK were not significant. Islet HK activity for ZDF and ZF rats was 1.9-fold (P < 0.05) and 1.7-fold (P < 0.05) greater, respectively, than for ZLC rats. Compared with the 5- to 6-week-old animals, HK activity increased 3.1-fold (P < 0.001), 2.5-fold (P < 0.002), and 2.0-fold (P < 0.05) for ZDF, ZF, and ZLC rats, respectively. Differences in GCK activity between 5- to 6- and 12-week-old rats were not significant for any of the groups. We conclude: 1) increased islet glucose phosphorylating activity is present in insulin resistant and hyperinsulinemic ZF and ZDF rats, relative to the ZLC rat; 2) at 12 weeks of age, hyperinsulinemic ZDF and ZF rats demonstrated significant increases in HK activity, compared with lean controls; and 3) deficiency in GCK activity does not explain failure of diabetic ZDF islets to respond to glucose, since differences between diabetic ZDF and nondiabetic ZF rats were not statistically significant. Increases in pancreatic islet phosphorylating activity seem to be important in maintaining basal hyperinsulinemia in insulin-resistant animals, but do not appear to play a role in the progression to glucose intolerance and diabetes.


Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for valproic acid and divalproex.
Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and non-neurologic indications. Our study objective was to design and validate a mechanistic model of VPA disposition in adults and children; and evaluate its predictive performance of drug-drug interactions (DDIs). This study expands upon existing physiologically based pharmacokinetic (PBPK) models for VPA by incorporating UGT enzyme kinetics and an advanced dissolution, absorption, and metabolism (ADAM) model for extended-release (ER) formulation. PBPK models for VPA IR and ER formulations were constructed using Simcyp Simulator (Version 15). First-order absorption was used for the immediate-release (IR) formulation and the ADAM model, including a controlled-release profile, for ER. Data from twenty-one published clinical studies were used to assess model performance. The model accurately predicted the concentration-time profiles of IR formulation for single-dose and steady-state doses ranging from 200mg to 1000mg. Similarly profiles were also simulated for ER formulation after a single-dose and steady-state doses of 500mg and 1000mg, respectively. In addition, simulated PK profiles agreed well with the observed data from studies in which VPA ER formulation was given to pediatric patients and VPA IR formulation to adult patients with cirrhosis. The model was further validated with individual adult data from a Phase I clinical trial consisting of eight cohorts after IV infusion of VPA with doses ranging from 15 to 150mg/kg. Co-administrations of VPA as an enzyme-inhibitor with victim drug phenytoin or lorazepam, as well as a substrate with enzyme inducer carbamazepine or phenobarbital, were simulated with the model to evaluate drug-drug interaction. The simulated serum concentration-time profiles were within the 5th and 95th percentiles, and the majority of the predicted area-under-the-curve (AUC) and peak plasma concentration (Cmax) values were within 25% of the reported average values. The comprehensive VPA PBPK model defined by this study may be used to support dosage regimen optimization to improve the safety and efficacy profile of this agent under different scenarios.


Comparison of levels of inflammatory mediators IL-1beta and betaG in gingival crevicular fluid from molars, premolars, and incisors during rapid palatal expansion.
Previously, we reported fluctuation of the levels of the inflammatory mediators interleukin-1beta (IotaL-1beta) and beta-glucuronidase (betaG) in gingival crevicular fluid (GCF) from the maxillary first molars in adolescents undergoing rapid palatal expansion. In this study, we compared the responses of IL-1beta and betaG in the GCF of the maxillary first molars, first premolars, and central incisors during palatal expansion at the same patients. Nine patients requiring palatal expansion were selected at the postdoctoral orthodontic clinic at Columbia University College of Dental Medicine. Each patient received periodontal prophylaxis and instructions in proper home care including rinsing with chlorhexidine. Four weeks after periodontal prophylaxis, a modified hyrax appliance was placed. The jackscrew was activated twice daily until the appropriate expansion was achieved. GCF samples were collected before and after periodontal prophylaxis and during passive wearing of the appliance, active orthodontic treatment, and retention. Fluid samples were collected with filter paper strips and analyzed by ELISA and time-dependent fluorometry for IL-1beta and betaG, respectively. The values recorded after periodontal prophylaxis were used as the baseline. Paired t tests were used to compare mediator levels at baseline with the levels obtained at each subsequent observation. The results validate that IL-1beta and betaG are present in the GCF of adolescents, and, although their level decreases after a strict regimen of plaque control, it increases during orthodontic or orthopedic movement. Moreover, this study demonstrates that both heavy and light forces evoke increased levels of IL-1beta and betaG, stronger forces cause higher levels of inflammatory mediators, and both IL-1beta and betaG respond to direct and indirect application of mechanical force to teeth. This investigation corroborates previous findings that an inflammatory process occurs during application of mechanical force to teeth. Although this inflammation is considered relatively aseptic, additional inflammation, such as that induced by plaque accumulation, must be avoided during orthodontic or orthopedic treatment.


Structure of the human cohesin inhibitor Wapl.
Cohesin, along with positive regulators, establishes sister-chromatid cohesion by forming a ring to circle chromatin. The wings apart-like protein (Wapl) is a key negative regulator of cohesin and forms a complex with precocious dissociation of sisters protein 5 (Pds5) to promote cohesin release from chromatin. Here we report the crystal structure and functional characterization of human Wapl. Wapl contains a flexible, variable N-terminal region (Wapl-N) and a conserved C-terminal domain (Wapl-C) consisting of eight HEAT (Huntingtin, Elongation factor 3, A subunit, and target of rapamycin) repeats. Wapl-C folds into an elongated structure with two lobes. Structure-based mutagenesis maps the functional surface of Wapl-C to two distinct patches (I and II) on the N lobe and a localized patch (III) on the C lobe. Mutating critical patch I residues weaken Wapl binding to cohesin and diminish sister-chromatid resolution and cohesin release from mitotic chromosomes in human cells and Xenopus egg extracts. Surprisingly, patch III on the C lobe does not contribute to Wapl binding to cohesin or its known regulators. Although patch I mutations reduce Wapl binding to intact cohesin, they do not affect Wapl-Pds5 binding to the cohesin subcomplex of sister chromatid cohesion protein 1 (Scc1) and stromal antigen 2 (SA2) in vitro, which is instead mediated by Wapl-N. Thus, Wapl-N forms extensive interactions with Pds5 and Scc1-SA2. Wapl-C interacts with other cohesin subunits and possibly unknown effectors to trigger cohesin release from chromatin.


Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia.
Brain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation. Murine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia. LPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS-mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation. We conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF.


Short-term efficacy and safety of ranibizumab for macular oedema secondary to retinal vein occlusion in Japanese patients.
To evaluate the efficacy and safety of ranibizumab 0.5 mg in Japanese patients with visual impairment due to macular oedema secondary to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) and to support the applicability of the phase III results from Caucasian to Japanese populations. This is a 3-month, open-label, single-arm, multicentre, phase III study. Thirty-one patients (15 BRVO and 16 CRVO) aged ≥18 years with a best-corrected visual acuity (BCVA) letter score of 19-73 (BRVO) or 24-73 (CRVO) were included. The primary end-point was the mean average change in BCVA from baseline to month 1 through month 3 after three consecutive monthly intravitreal injections of ranibizumab 0.5 mg. Secondary end-points were mean change in BCVA and central subfield thickness (CSFT), categorized BCVA, and safety over 3 months. At month 3, the mean average change in BCVA improved substantially from baseline for BRVO (11.3 letters, p = 0.001) and CRVO (6.7 letters, p = 0.019). The mean BCVA improved (12.8 and 9.1 letters) and the mean CSFT decreased (212.5 and 442.1 μm) from baseline to month 3. At month 3, 26.7% (BRVO) and 31.3% (CRVO) of the patients had a gain of ≥15 letters from baseline. Safety findings in this study were similar to those reported in the previous clinical trials. Ranibizumab was effective in improving BCVA and was well tolerated in Japanese patients with BRVO and CRVO. The findings from this study were consistent with those reported in the Caucasian population.


Obstruction after alcohol septal ablation is associated with cardiovascular mortality events.
Left ventricular outflow tract obstruction (≥30 mm Hg at rest; LVOTO) is considered a possible risk of long-term outcomes in patients with hypertrophic cardiomyopathy (HCM). However, the influence of LVOTO on the occurrence of cardiovascular mortality events in patients after alcohol septal ablation (ASA) for obstructive HCM remains unresolved. We compared the outcomes of patients treated with ASA with residual LVOTO <30 mm Hg with those with residual LVOTO ≥30 mm Hg at the first postdischarge check-up (1-6 months after the procedure). A total of 270 patients (60±12 years, median follow-up 5.1 years; 95% CI 4.5 to 5.9 years) treated with a single ASA were included; 208 (77%) and 62 (23%) patients had post-ASA LVOTO <30 and ≥30 mm Hg at the first postdischarge clinical check-up, respectively (LVOTO 13±6 vs 50±27 mm Hg; p<0.01). Freedom from cardiovascular mortality events at 1, 5 and 10 years were 99% (95% CI 96% to 100%) vs 94% (95% CI 85% to 98%), 95% (95% CI 89% to 97%) vs 80% (95% CI 66% to 89%) and 82% (95% CI 69% to 89%) vs 72% (95% CI 55% to 84%) (log-rank test, p<0.01), respectively. In multivariable analysis adjusted for age at ASA, sex, baseline LVOTO and baseline septum thickness, the independent predictors of cardiovascular mortality events were early postdischarge LVOTO ≥30 mm Hg (HR 2.95, 95% CI 1.26 to 6.91; p=0.01) and baseline septum thickness (HR 1.07, 95% CI 1.01 to 1.13; p=0.02). After ASA for obstructive HCM, LVOTO ≥30 mm Hg at the first postdischarge clinical check-up is associated with significantly higher occurrence of subsequent cardiovascular mortality events.


Auditory-visual integration modulates location-specific repetition suppression of auditory responses.
Space is a dimension shared by different modalities, but at what stage spatial encoding is affected by multisensory processes is unclear. Early studies observed attenuation of N1/P2 auditory evoked responses following repetition of sounds from the same location. Here, we asked whether this effect is modulated by audiovisual interactions. In two experiments, using a repetition-suppression paradigm, we presented pairs of tones in free field, where the test stimulus was a tone presented at a fixed lateral location. Experiment 1 established a neural index of auditory spatial sensitivity, by comparing the degree of attenuation of the response to test stimuli when they were preceded by an adapter sound at the same location versus 30° or 60° away. We found that the degree of attenuation at the P2 latency was inversely related to the spatial distance between the test stimulus and the adapter stimulus. In Experiment 2, the adapter stimulus was a tone presented from the same location or a more medial location than the test stimulus. The adapter stimulus was accompanied by a simultaneous flash displayed orthogonally from one of the two locations. Sound-flash incongruence reduced accuracy in a same-different location discrimination task (i.e., the ventriloquism effect) and reduced the location-specific repetition-suppression at the P2 latency. Importantly, this multisensory effect included topographic modulations, indicative of changes in the relative contribution of underlying sources across conditions. Our findings suggest that the auditory response at the P2 latency is affected by spatially selective brain activity, which is affected crossmodally by visual information.


High-Efficiency CRISPR/Cas9 Mutagenesis of the white Gene in the Milkweed Bug Oncopeltus fasciatus.
In this manuscript, we report that clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 is highly efficient in the hemipteran Oncopeltus fasciatus The white gene is well characterized in Drosophila where mutation causes loss of eye pigmentation; white is a reliable marker for transgenesis and other genetic manipulations. Accordingly, white has been targeted in a number of nonmodel insects to establish tools for genetic studies. Here, we generated mutations in the Of-white (Of-w) locus using CRISPR/Cas9. We found that Of-w is required for pigmentation throughout the body of Oncopeltus, not just the ommatidia. High rates of somatic mosaicism were observed in the injected generation, reflecting biallelic mutations, and a high rate of germline mutation was evidenced by the large proportion of heterozygous G1s. However, Of-w mutations are homozygous lethal; G2 homozygotes lacked pigment dispersion throughout the body and did not hatch, precluding the establishment of a stable mutant line. Embryonic and parental RNA interference (RNAi) were subsequently performed to rule out off-target mutations producing the observed phenotype and to evaluate the efficacy of RNAi in ablating gene function compared to a loss-of-function mutation. RNAi knockdowns phenocopied Of-w homozygotes, with an unusual accumulation of orange granules observed in unhatched embryos. This is, to our knowledge, the first CRISPR/Cas9-targeted mutation generated in Oncopeltus While we were unable to establish white as a useful visible marker for Oncopeltus, these findings are instructive for the selection of visible markers in nonmodel species and reveal an unusual role for an ortholog of a classic Drosophila gene.


Serum lipid profile and metabolic syndrome occurrence among obese rural women from Lublin Region (Eastern Poland).
Obesity is a multivariate syndrome which can negatively affect whole body functioning. It is most common in highly developed countries, and in recent years a progressive increase in obesity occurrence is noticeable. The aim of the study was to assess serum lipid profile and metabolic syndrome occurrence among obese rural women from Lublin Region in Eastern Poland. The study was conducted in the Institute of Agricultural Medicine in Lublin (IAM). All subjects had a negative history of diseases and treatment that could affect serum lipid profile or glucose measurements. The inclusion criterion for the study group was overweight and obesity, defined as a body mass index above 25 (BMI > 25) and living in a rural area. 44 women participated in the study. There were no women fulfilling the criteria or who had a history of incorrect fasting glucose (IFG) or incorrect glucose tolerance (IGT). In contrast, the prevalence of arterial hypertension (or treatment) was high - 53%. 22.7% women had normal serum TC values. The proportion of those with hyper-LDL-C was 38.6% and with hyper-TG - 18.2%. 20.5% of studied women had incorrect serum HDL-C levels, and in 15.9% hypo- HDL-C was accompanied by high serum TC levels. Analysis of correlation showed that serum TC was positively correlated with both LDL- and HDL-C. 55% of the studied obese or overweight women had at least 2 additional components of the metabolic syndrome.


Ovary-intact, but not ovariectomized female ACI rats treated with 17beta-estradiol rapidly develop mammary carcinoma.
We have examined the ability of 17beta-estradiol (E2) to induce development of mammary cancers in the female ACI rat. Continuous treatment with E2, delivered through release from s.c. Silastic tubing implants containing 27.5 mg crystalline hormone, resulted in rapid development of palpable mammary tumors in ovary-intact ACI rats. In a population of 21 E2-treated rats, palpable tumors were first observed following 99 days treatment and 100% of the treated population developed tumors within 197 days. The median and mean times to appearance of first palpable tumor were 143 and 145 days respectively. All mammary tumors were classified as carcinomas and invasive features were observed. Circulating E2 levels in the treated animals at the time of sacrifice averaged 185 pg/ml serum. Mammary tumors were not observed in ovary-intact female ACI rats that were not treated with E2. This is the first report indicating that this naturally occurring estrogen is capable of inducing mammary cancers in the ACI rat strain. Mammary carcinoma did not develop in a population of 11 ovariectomized female ACI rats treated with E2 for a period of 140 days. Circulating E2 levels in the treated ovariectomized animals averaged 207 pg/ml. These data indicate that the ovary modulates estrogen-mediated mammary carcinogenesis in this rat strain. Both ovary-intact and ovariectomized female ACI rats displayed similar susceptibilities to E2-induced pituitary tumors and hyperprolactinemia. Pituitary weight was increased 6.0-fold in ovary-intact ACI rats and 5.3-fold in ovariectomized female rats. Circulating prolactin levels averaged 2318 ng/ml in E2-treated, ovary-intact rats and 2285 ng/ml in E2-treated, ovariectomized ACI rats. These data indicate that estrogen-induced hyperprolactinemia is not the sole factor leading to development of mammary cancers in the E2-treated ACI rat.


Dorsolateral Prefrontal Cortex Activity during a Brain Training Game Predicts Cognitive Improvements after Four Weeks' Brain Training Game Intervention: Evidence from a Randomized Controlled Trial.
Recent studies have demonstrated that brain activities using NIRS (near-infrared spectroscopy) at baseline during cognitive tasks (e.g., N-back task) can predict the cognitive benefits of a cognitive training. In this study, we investigated whether brain activities during brain training game (BT) at baseline would predict benefits to cognitive functions after the intervention period. In a four-week double-blinded randomized control trial (RCT) 72 young adults were randomly assigned to one of the two groups: participants in the BT group played specific game, called the Brain Age. Participants in an active control group (ACT) played the puzzle game Tetris. We measured brain activity during the training games using two channel NIRS before the intervention period. Cognitive functions were tested before and after the four-week intervention period. The BT showed significant improvements in inhibition, processing speed, and working memory performance compared to ACT. The left and right DLPFC (dorsolateral prefrontal cortex) brain activities during the BT at baseline were associated with improvements in inhibition and processing speed. This randomized control trial first provides scientific evidence that DLPFC activities during BT at baseline can predict cognitive improvements after a four-week intervention period.


Evaluating the utility of syndromic surveillance algorithms for screening to detect potentially clonal hospital infection outbreaks.
The authors evaluated algorithms commonly used in syndromic surveillance for use as screening tools to detect potentially clonal outbreaks for review by infection control practitioners. Study phase 1 applied four aberrancy detection algorithms (CUSUM, EWMA, space-time scan statistic, and WSARE) to retrospective microbiologic culture data, producing a list of past candidate outbreak clusters. In phase 2, four infectious disease physicians categorized the phase 1 algorithm-identified clusters to ascertain algorithm performance. In phase 3, project members combined the algorithms to create a unified screening system and conducted a retrospective pilot evaluation. The study calculated recall and precision for each algorithm, and created precision-recall curves for various methods of combining the algorithms into a unified screening tool. Individual algorithm recall and precision ranged from 0.21 to 0.31 and from 0.053 to 0.29, respectively. Few candidate outbreak clusters were identified by more than one algorithm. The best method of combining the algorithms yielded an area under the precision-recall curve of 0.553. The phase 3 combined system detected all infection control-confirmed outbreaks during the retrospective evaluation period. Lack of phase 2 reviewers' agreement indicates that subjective expert review was an imperfect gold standard. Less conservative filtering of culture results and alternate parameter selection for each algorithm might have improved algorithm performance. Hospital outbreak detection presents different challenges than traditional syndromic surveillance. Nevertheless, algorithms developed for syndromic surveillance have potential to form the basis of a combined system that might perform clinically useful hospital outbreak screening.


Inhibitory effect of somatostatin on insulin secretion is not mediated via the CNS.
The inhibitory effect of somatostatin (SST) on insulin secretion in vivo is attributed to a direct effect on pancreatic beta cells, but this is inconsistent with some in vitro results in which exogenous SST is ineffective in inhibiting secretion from isolated islets. We therefore investigated whether insulin secretion from the pancreatic islets may partly be regulated by an indirect effect of SST mediated via the CNS. Islet hormone secretion was assessed in vitro by perifusion and static incubations of isolated islets and in vivo by i.v. or i.c.v. administration of the SST analogue BIM23014C with an i.v. glucose challenge to conscious, chronically catheterised rats. Hormone content of samples was assessed by ELISA or RIA and blood glucose levels using a glucose meter. Exogenous SST14/SST28 or BIM23014C did not inhibit the release of insulin from isolated rodent islets in vitro, whereas peripheral i.v. administration of BIM23014C (7.5 μg) with glucose (1 g/kg) led to decreased plasma insulin content (2.3±0.5 ng insulin/ml versus 4.5±0.5 ng/ml at t=5 min, P<0.001) and elevated blood glucose levels compared with those of the controls (29.19±1.3 mmol/l versus 23.5±1.7 mmol/l, P<0.05). In contrast, central i.c.v. injection of BIM23014C (0.75 μg) had no significant effect on either plasma insulin (3.3±0.4 ng/ml, P>0.05) or blood glucose levels (23.5±1.7 mmol/l, P>0.05) although i.v. administration of this dose increased blood glucose concentrations (32.3±0.7 mmol/l, P<0.01). BIM23014C did not measurably alter plasma glucagon, SST, GLP1 or catecholamine levels whether injected i.v. or i.c.v. These results indicate that SST does not suppress insulin secretion by a centrally mediated effect but acts peripherally on islet cells.


Conformer-dependent self-assembled metallacycles with photo-reversible response.
Discrete, well-defined metallacycles and metallacages with stimuli-responsive behaviors have been largely predominated by the organic donor/metal acceptor paradigm with spontaneous formation of coordination bonds. However, light-driven self-assembly systems usually show relatively low utilization yield of photons and low fatigue resistance. Given that almost no example illustrates the different self-assembly behaviors of antiparallel and parallel conformers in the traditional photochromic diarylethene (DAE) system, here we have for the first time constructed a unique series of photoactive conformer-dependent metallacycles, focusing on the characterization and comparison of self-assembly behavior in different ligand conformers with different di-platinum(ii) acceptors. Their photoswitchable scaffold sizes and shapes are precisely controlled by photochromically separable parallel or anti-parallel conformers via coordination-driven self-assembly. The ap-conformer and closed form provide larger bending angles upon coordination with di-Pt(ii) acceptors into hexagon [6 + 6] or [3 + 3] while the p-conformer only can form smaller polygon cycles. Notably, in contrast with the non-photoactive parallel conformer, the reversible interconversion of anti-parallel ring-open and ring-closed conformer metallacycles can be achieved by alternate irradiation with UV and visible light, respectively, along with a relatively high conversion ratio and good fatigue resistance. This work provides a potential way to construct smart materials for use in sensing, catalysis and drug delivery systems.


Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase.
Deep vein thrombosis (DVT) in children occurs primarily in the upper body venous system. This prospective diagnostic study compared bilateral venography and ultrasound for detection of DVT in the upper venous system in 66 children with acute lymphoblastic leukemia. Results were interpreted by central blinded adjudication. Deep venous thrombosis occurred in 29% (19/66) patients. While 15/19 DVT were detected by venography (sensitivity 79%), only 7/19 were detected by ultrasound (sensitivity 37%). The 12 DVT detected by venography but not by ultrasound were located in the subclavian vein or more central veins. Three of 4 DVT detected by ultrasound but not by venography were in the jugular vein. We conclude that ultrasound is insensitive for DVT in the central upper venous system but may be more sensitive than venography in the jugular veins. A combination of both venography and ultrasound is required for screening for DVT in the upper venous system.


The renin-angiotensin-aldosterone system in diabetic patients with hyperkalemia.
Seven long-standing diabetic patients with spontaneous and intermittent hyperkalemia were studied in an effort to assess the normality of their renin-aldosterone axis. The administration of oral glucose, in the absence of insulin, caused a paradoxical rise in serum potassium with no significant change in plasma aldosterone concentration from controls. All displayed subnormal aldosterone-secreting capacity to known stimuli of aldosterone secretion such as low salt diet, angiotensin II infusion, and ACTH infusion. The paradoxical rise in serum potassium with hyperglycemia was corrected in all by concomitant administration of insulin or pretreatment with a mineralocorticoid. Our observations question the role of aldosterone deficiency in the phenomenon of glucose-induced hyperkalemia.


The Effect of Intrathecal Baclofen in Dyskinetic Cerebral Palsy: The IDYS Trial.
Intrathecal baclofen treatment is used for the treatment of dystonia in patients with severe dyskinetic cerebral palsy; however, the current level of evidence for the effect is low. The primary aim of this study was to provide evidence for the effect of intrathecal baclofen treatment on individual goals in patients with severe dyskinetic cerebral palsy. This multicenter, randomized, double-blind, placebo-controlled trial was performed at 2 university medical centers in the Netherlands. Patients with severe dyskinetic cerebral palsy (Gross Motor Functioning Classification System level IV-V) aged 4 to 24 years who were eligible for intrathecal baclofen were included. Patients were assigned by block randomization (2:2) for treatment with intrathecal baclofen or placebo for 3 months via an implanted microinfusion pump. The primary outcome was goal attainment scaling of individual treatment goals (GAS T score). A linear regression model was used for statistical analysis with study site as a covariate. Safety analyses were done for number and type of (serious) adverse events. Thirty-six patients were recruited from January 1, 2013, to March 31, 2018. Data for final analysis were available for 17 patients in the intrathecal baclofen group and 16 in the placebo group. Mean (standard deviation) GAS T score at 3 months was 38.9 (13.2) for intrathecal baclofen and 21.0 (4.6) for placebo (regression coefficient = 17.8, 95% confidence interval = 10.4-25.0, p < 0.001). Number and types of (serious) adverse events were similar between groups. Intrathecal baclofen treatment is superior to placebo in achieving treatment goals in patients with severe dyskinetic cerebral palsy. ANN NEUROL 2019.


Urban-rural and gender differences in tobacco and alcohol use, diet and physical activity among young black South Africans between 1998 and 2003.
Non-communicable chronic diseases (NCDs) have increased in South Africa over the past 15 years. While these usually manifest during mid-to-late adulthood, the development of modifiable risk factors that contribute to NCDs are usually adopted early in life. To describe the urban-rural and gender patterns of NCD risk factors in black adolescents and young adults (15- to 24-year-olds) from two South African Demographic and Health Surveys conducted 5 years apart. An observational study based on interviews and measurements from two cross-sectional national household surveys. Changes in tobacco and alcohol use, dietary intake, physical inactivity, and overweight/ obesity among 15- to 24-year-olds as well as urban-rural and gender differences were analysed using logistic regression. The 'Surveyset' option in Stata statistical software was used to allow for the sampling weight in the analysis. Data from 3,186 and 2,066 black 15- to 24-year-old participants in 1998 and 2003, respectively, were analysed. In males, the prevalence of smoking (1998: 21.6%, 2003: 19.1%) and problem drinking (1998: 17.2%, 2003: 15.2%) were high and increased with age, but in females were much lower (smoking - 1998: 1.0%, 2003: 2.1%; problem drinking - 1998: 4.2%, 2003: 5.8%). The predominant risk factors in females were overweight/obesity (1998: 29.9%, 2003: 31.1%) and physical inactivity (2003: 46%). Urban youth, compared to their rural counterparts, were more likely to smoke (odds ratio (OR): 1.39, 95% confidence interval (CI): 1.09-1.75), have high salt intake (OR: 1.75, 95% CI: 1.12-2.78), be overweight/obese (OR: 1.39, 95% CI: 1.14-1.69), or be physically inactive (OR: 1.45, 95% CI: 1.12-1.89). However, they had lower odds of inadequate micronutrient intake (OR: 0.46, 95% CI 0.34-0.62), and there was no overall significant urban- rural difference in the odds for problem drinking but among females the odds were higher in urban compared to rural females. Considering that the prevalence of modifiable NCD risk factors was high in this population, and that these may persist into adulthood, innovative measures are required to prevent the uptake of unhealthy behaviours, and regular surveillance is needed.


Temporomandibular joint internal derangement: association with headache, joint effusion, bruxism, and joint pain.
The aim of the present study was to assess the correlation of temporomandibular joint internal derangement (TMJ ID) in patients with the presence of headache, bruxism, and joint pain using magnetic resonance imaging (MRI). This study evaluated 42 joints in 42 patients; 21 patients diagnosed with unilateral TMJ ID and a history of headaches and 21 patients diagnosed with unilateral TMD ID without a history of headaches. Signs of headache, bruxism, and joint pain were diagnosed clinically and were also obtained from the patient's history. Sixteen joints in 16 patients without signs or symptoms of TMD or headache were included as a control group. All patients underwent bilateral MRI of the TMJ to evaluate the disc position and the presence of joint effusion. Data were analyzed using Chi-square and Fischer's exact tests. Bruxing behavior was most frequently reported by patients with headaches (p<0.0125). Eighty-five percent of subjects with headaches also reported joint pain. A significant association was found between headache and TMJ effusion (p<0.0125). Patients with more severe disc displacement also had a higher frequency of effusion (p=0.001). The results suggest joint effusion may have a role in the pathogenesis of headache in TMJ ID. Temporomandibular joint effusion on MRI may serve as a biological marker of headache associated with TMD and could be helpful for diagnostic classification and treatment follow up.


Cerebrospinal fluid can be used for HIV genotyping when it fails in blood.
Blood plasma specimens are the clinical standard for HIV-1 pol gene genotyping from viral populations; however, it is not always successful, often from low viral loads or the presence of polymerase chain reaction (PCR) inhibitors. Objective To describe the successful of HIV-1 genotyping in two samples of cerebrospinal fluid (CSF), after genotype procedures failed from blood. Method Two HIV-infected patients enrolled in a neurocognitive research study were evaluated when standard HIV-1 genotyping failed from blood plasma samples. Genotyping was performed using the commercial system TRUGENE HIV-1 Genotyping Kit and the OpenGene DNA Sequencing System (Siemens Healthcare Diagnostics, Tarrytown, NY, USA). Results CSF genotyping was performed via the same commercial platform and was successful in both cases. Conclusion This report demonstrates that CSF could be used as an alternate clinical specimen for HIV-1 genotyping when it fails from blood.


Innervated myotendinous cylinders in human extraocular muscles.
To analyze palisade endings and their end organs, the so-called innervated myotendinous cylinders (IMCs), of human extraocular muscle (EOM) in more detail and to clarify with the help of double-fluorescent labeling and electron microscopy whether terminals in IMCs are sensory, serving proprioception. EOMs obtained from a donated cadaver (66 years) and distal parts of EOMs from multiorgan donors (35, 53 years) were processed for double-fluorescent labeling. Antibodies against the protein gene product 9.5 and alpha-bungarotoxin labeling were used on cryostat sections of distal myotendons. EOMs from multiorgan donors (2, 17 years) were prepared for electron microscopy. Palisade endings investing muscle fiber tips established contacts with tendon fibrils and the muscle fiber attached. Alpha-bungarotoxin bound to myoneural contacts but not to axonal varicosities in the tendon compartment. Ultrastructural analysis revealed that palisade endings form IMCs, which were associated exclusively with multiply innervated global layer muscle fibers. IMCs consisted of a muscle fiber tendon junction, tightly enclosed by fibrocytes, and a supplying axon with preterminals and terminals. Terminals contained mitochondria, few neurotubuli, few neurofilaments, and accumulations of clear vesicles of uniform size. A basal lamina always intervened between axolemma and tendon fibrils as well as between axolemma and muscle fiber cell membrane. Palisade endings of human EOM form IMCs as in cat, monkey, and sheep. In contrast to animals, myoneural contacts in human IMCs are almost certainly motor, whereas terminals contacting tendon fibrils are arguably sensory. Thus, IMCs might be best described as "propriocept-effectors."


IGF-1 receptor antagonism inhibits autophagy.
Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by insulin-like growth factor-1 (IGF-1) inhibition, which could account for many of its beneficial effects. Paradoxically, we found that IGF-1 inhibition attenuates autophagosome formation. The reduced amount of autophagosomes present in IGF-1R depleted cells can be, at least in part, explained by a reduced formation of autophagosomal precursors at the plasma membrane. In particular, IGF-1R depletion inhibits mTORC2, which, in turn, reduces the activity of protein kinase C (PKCα/β). This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts autophagosome precursor formation. Finally, with important implications for human diseases, we demonstrate that pharmacological inhibition of the IGF-1R signalling cascade reduces autophagy also in zebrafish and mice models. The novel link we describe here has important consequences for the interpretation of genetic experiments in mammalian systems and for evaluating the potential of targeting the IGF-1R receptor or modulating its signalling through the downstream pathway for therapeutic purposes under clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial.


Interferon gamma signaling alters the function of T helper type 1 cells.
One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon gamma receptor (IFN-gammaR), whereas Th1 cells do not express the second chain of the IFN-gammaR (IFN-gammaR2) and are therefore unresponsive to IFN-gamma. To determine whether the regulation of IFN-gammaR2 expression, and therefore IFN-gamma responsiveness, is important for the differentiation of naive CD4(+) T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-gammaR2 is controlled by the CD2 promoter and enhancer. CD4(+) T cells from IFN-gammaR2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN-gamma production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-gammaR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-gamma-unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.


Endothelial fibrosis induced by suppressed STAT3 expression mediated by signaling involving the TGF-β1/ALK5/Smad pathway.
During systemic inflammatory pathologies, mediators of inflammation circulate in the bloodstream and interact with endothelial cells (ECs), resulting in endothelial dysfunction that maintains and enhances the pathological condition. Inflammatory mediators change the protein expression profile of ECs, which become activated fibroblasts via endothelial-to-mesenchymal transition. This process is characterized by downregulated endothelial proteins and strongly upregulated fibrotic-specific genes and extracellular matrix-forming proteins. The main inductor of endothelial fibrosis is transforming growth factor-β1 (TGF-β1), which acts through the TGF-β1/activin receptor-like kinase 5 (ALK5)/Smads intracellular signaling pathway. The signal transducer and activator of transcription 3 (STAT3) is also involved in fibrosis in several tissues (e.g. heart and vascular system), where STAT3 signaling decreases TGF-β1-induced responses by directly interacting with Smad proteins, suggesting that decreased STAT3 could induce TGF-β1-mediated fibrosis. However, it is unknown if suppressed STAT3 expression induces EC fibrosis through a mechanism involving the TGF-β signaling pathway. The present study evaluated the fibrotic actions of STAT3 suppression in ECs and investigated TGF-β1/ALK5/Smad4 signaling pathway participation. Suppressed STAT3 expression stimulated fibrotic conversion in ECs, as mediated by protein expression reprograming that decreased endothelial marker expression and increased fibrotic and extracellular matrix protein levels. The potential mechanism underlying these changes was dependent on TGF-β1 secretion, the ALK5 activation pathway, and Smad4 translocation into the nucleus. We conclude that suppressed STAT3 expression converts ECs into activated fibroblasts via TGF-β1/ALK5/Smad4 signaling pathway involvement.