Pharmacokinetics and metabolism of the pharmacologically active 4'-hydroxylated metabolite of propranolol in the dog.
The disposition of 4'-hydroxypropranolol (HOP) was determined after iv administration to dogs (2 mg/kg; N = 5) and the pharmacokinetic parameters were calculated from plasma measurements. The clearance of HOP, 66 +/- 6 ml/min/kg (mean +/- SE), was considerably higher than that of propranolol previously determined, suggesting extrahepatic as well as hepatic clearance of HOP. The plasma half-life of HOP, 77 +/- 6 min, was shorter than that of propranolol. Although HOP is considerably less lipophilic than propranolol, its volume of distribution, 6.4 +/- 0.8 liter/kg, surprisingly, was larger. Like propranolol, HOP appeared to be cleared entirely by metabolism. Whereas propranolol is metabolized mainly by oxidation, HOP was metabolized to sulfate (HOPS) and glucuronic acid (HOPG) conjugates. The plasma half-lives of these conjugates were 2 to 3 times longer than for HOP, reflecting a slow, continuous formation from HOP. This was established for HOPS by iv administration of synthetic HOPS. Morover, after HOP administration both formation and renal clearance of HOPS were stereoselective in favor of the R-enantiomer. In summary, the main conclusion of this study is that the large volume of distribution as well as high clearance through sulfation and glucuronidation may explain the low plasma HOP levels observed during propranolol therapy.


Pharmacokinetic interaction study between quercetin and valsartan in rats and in vitro models.
Valsartan is a potent, orally active non-peptide tetrazole derivative and selectively inhibits angiotensin II receptor type 1 which causes reduction in blood pressure and is used in treatment of hypertension. The risk of heart disease mortality decreased significantly as flavonoid intake increased. Interestingly, the flavonoid-containing foods contain a high amount of Quercetin. The objective of this study was to evaluate the influence of quercetin on the pharmacokinetics of valsartan. In vivo studies were performed on rats. Rats were treated with quercetin (10 mg/kg) and valsartan (10 mg/kg), blood samples were collected at 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 h. Plasma concentration of valsartan was estimated by Reverse Phase (RP-HPLC). Quercetin significantly increases the plasma concentration of valsartan and peak concentration (70.45 µg/mL) was achieved at 3.5 h. In vitro studies were performed on rat intestinal everted sacs. The transport of valsartan from serosal side to mucosal side decreased from 53.12 ± 1.27 to 40.15 ± 0.45 µg/mL in the presence of quercetin and from 53.12 ± 1.27 to 28.68 ± 0.31 µg/mL in the presence of verapamil (standard P-glycoprotein (P-gp) inhibitor) at 120 min. Verapamil is a potent P-gp and CYP3A4 inhibitor. Quercetin is a P-gp inhibitor and may be an inhibitor of CYP3A4. The simultaneous administration of quercetin significantly increases the intestinal absorption and decreases the efflux of valsartan. The observed effect may be beneficial to develop oral valsartan dosage forms using safe P-gp inhibitor (quercetin) to improve its oral bioavailability.


Dietary Fatty Acid Saturation Modulates Sphingosine-1-Phosphate-Mediated Vascular Function.
Sphingolipids, modified by dietary fatty acids, are integral components of plasma membrane and caveolae that are also vasoactive compounds. We hypothesized that dietary fatty acid saturation affects vasoconstriction to sphingosine-1-phosphate (S1P) through caveolar regulation of rho kinase. Wild type (WT) and caveolin-1-deficient (cav-1 KO) mice which lack vascular caveolae were fed a low-fat diet (LF), 60% high-saturated fat diet (lard, HF), or 60% fat diet with equal amounts of lard and n-3 polyunsaturated menhaden oil (MO). Weight gain of WT on HF and MO diets was similar while markedly blunted in cav-1 KO. Neither high-fat diet affected the expression of cav-1, rho, or rho kinase in arteries from WT. In cav-1 KO, MO increased the vascular expression of rho but had no effect on rho kinase. HF had no effect on rho or rho kinase expression in cav-1 KO. S1P produced a concentration-dependent constriction of gracilis arteries from WT on LF that was reduced with HF and restored to normal with MO. Constriction to S1P was reduced in cav-1 KO and no longer affected by a high-saturated fat diet. Inhibition of rho kinase which reduced constriction to PE independent of diet in arteries from WT and cav-1 KO only reduced constriction to S1P in arteries from WT fed MO. The data suggest that dietary fatty acids modify vascular responses to S1P by a caveolar-dependent mechanism which is enhanced by dietary n-3 polyunsaturated fats.


Specific antibodies and the selective inhibitor ICI 118233 demonstrate that the hormonally stimulated 'dense-vesicle' and peripheral-plasma-membrane cyclic AMP phosphodiesterases display distinct tissue distributions in the rat.
Polyclonal-antibody preparations DV1 and PM1, raised against purified preparations of rat liver insulin-stimulated 'dense-vesicle' and peripheral-plasma-membrane cyclic AMP phosphodiesterases, were used to analyse rat liver homogenates by Western-blotting techniques. The antibody DV1 identified only the 63 kDa native subunit of the 'dense-vesicle' enzyme, and the antibody PM1 only the 52 kDa subunit of the plasma-membrane enzyme. These antibodies also detected the subunits of these two enzymes in homogenates of kidney, heart and white adipose tissue from rat. Quantitative immunoblotting demonstrated that the amount of these enzymes (by wt.) varied in these different tissues, as did the expression of these two enzymes, relative to each other, by a factor of as much as 7-fold. The ratio of the dense-vesicle enzyme to the peripheral-plasma-membrane enzyme was lowest in liver and kidney and highest in heart and white adipose tissue. ICI 118233 was shown to inhibit selectively the 'dense-vesicle' cyclic AMP phosphodiesterase in liver. It did this in a competitive fashion, with a Ki value of 3.5 microM. Inhibition of tissue-homogenate cyclic AMP phosphodiesterase activity by ICI 118233 was used as an index of the contribution to activity by the 'dense-vesicle' enzyme. By this method, a tissue distribution of the 'dense-vesicle' enzyme was obtained which was similar to that found by using the immunoblotting technique. The differential expression of isoenzymes of cyclic AMP phosphodiesterase activity in various tissues might reflect a functional adaptation, and may provide the basis for the different physiological actions of compounds which act as selective inhibitors.


Bacterial colonization reprograms the neonatal gut metabolome.
Initial microbial colonization and later succession in the gut of human infants are linked to health and disease later in life. The timing of the appearance of the first gut microbiome, and the consequences for the early life metabolome, are just starting to be defined. Here, we evaluated the gut microbiome, proteome and metabolome in 88 African-American newborns using faecal samples collected in the first few days of life. Gut bacteria became detectable using molecular methods by 16 h after birth. Detailed analysis of the three most common species, Escherichia coli, Enterococcus faecalis and Bacteroides vulgatus, did not suggest a genomic signature for neonatal gut colonization. The appearance of bacteria was associated with reduced abundance of approximately 50 human proteins, decreased levels of free amino acids and an increase in products of bacterial fermentation, including acetate and succinate. Using flux balance modelling and in vitro experiments, we provide evidence that fermentation of amino acids provides a mechanism for the initial growth of E. coli, the most common early colonizer, under anaerobic conditions. These results provide a deep characterization of the first microbes in the human gut and show how the biochemical environment is altered by their appearance.


Testicular signaling is the potential target of perfluorooctanesulfonate-mediated subfertility in male mice.
Perfluorooctanesulfonate (PFOS) was produced and used by various industries and in consumer products. Because of its persistence, it is ubiquitous in air, water, soil, wildlife, and humans. Although the adverse effects of PFOS on male fertility have been reported, the underlying mechanisms have not yet been elucidated. Here, for the first time, the effects of PFOS on testicular signaling, such as gonadotropin, growth hormone, insulin-like growth factor, and inhibins/activins were shown to be directly related to male subfertility. Sexually mature 8-wk-old CD1 male mice were administered by gavages in corn oil daily with 0, 1, 5, or 10 mg/kg PFOS for 7, 14, or 21 days. Serum concentrations of testosterone and epididymal sperm counts were significantly lower in the mice after 21 days of the exposure to the highest dose compared with the controls. The expression levels of testicular receptors for gonadotropin, growth hormone, and insulin-like growth factor 1 were considerably reduced on Day 21 in mice exposed daily to 10 or 5 mg/kg PFOS. The transcript levels of the subunits of the testicular factors (i.e., inhibins and activins), Inha, Inhba, and Inhbb, were significantly lower on Day 21 of daily exposure to 10, 5, or 1 mg/kg PFOS. The mRNA expression levels of steroidogenic enzymes (i.e., StAR, CYP11A1, CYP17A1, 3beta-HSD, and 17beta-HSD) were notably reduced. Therefore, PFOS-elicited subfertility in male mice is manifested as progressive deterioration of testicular signaling.


Biomarker detection technologies and future directions.
Biomarkers play a vital role in disease detection and treatment follow-up. It is important to note that diseases in the early stage are typically treated with the greatest probability of success. However, due to various technical difficulties in current technologies for the detection of biomarkers, the potential of biomarkers is not explored completely. Therefore, the developments of technologies, which can enable the accurate detection of prostate cancer at an early stage with simple, experimental protocols are highly inevitable. This critical review evaluates the current methods and technologies used in the detection of biomarkers. The aim of this article is to provide a comprehensive review covering the advantages and disadvantages of the biomarker detection methods. Future directions for the development of technologies to achieve highly selective and sensitive detection of biomarkers for point-of-care applications are also commented on.


Update in genetic susceptibility in melanoma.
Melanoma is the most deadly of the common skin cancers and its incidence is rapidly increasing. Approximately 10% of cases occur in a familial context. To date, cyclin-dependent kinase inhibitor 2A (CDKN2A), which was identified as the first melanoma susceptibility gene more than 20 years ago, is the main high-risk gene for melanoma. A few years later cyclin-dependent kinase 4 (CDK4) was also identified as a melanoma susceptibility gene. The technologic advances have allowed the identification of new genes involved in melanoma susceptibility: Breast cancer 1 (BRCA1) associated protein 1 (BAP1), CXC genes, telomerase reverse transcriptase (TERT), protection of telomeres 1 (POT1), ACD and TERF2IP, the latter four being involved in telomere maintenance. Furthermore variants in melanocortin 1 receptor (MC1R) and microphthalmia-associated transcription factor (MITF) give a moderately increased risk to develop melanoma. Melanoma genetic counseling is offered to families in order to better understand the disease and the genetic susceptibility of developing it. Genetic counseling often implies genetic testing, although patients can benefit from genetic counseling even when they do not fulfill the criteria for these tests. Genetic testing for melanoma predisposition mutations can be used in clinical practice under adequate selection criteria and giving a valid test interpretation and genetic counseling to the individual.


Chemotherapy agents and the induction of late lethal defects.
Radiation is now known to be capable of producing both lethal and non lethal lesions in a variety of mammalian cells which may not be expressed for several cell divisions after the initial insult. The mechanism by which such an effect occurs is unknown. Because of the possible implications for cancer treatment, if such an effect also occurred following chemotherapy exposure, cells were exposed to various cytotoxic chemotherapy agents with known and well characterised effects on DNA or other areas of cell function or structure. The results indicate that late lethal defects are not detectable after treatment with appropriate ranges of doses of cisplatinum, vincristine, BCNU or adriamycin, but that they are induced by Bleomycin and to a lesser extent by 5-Fluorouracil. Bleomycin is known to cause strand breaks and is regarded as a radiomimetic agent. 5-Fluorouracil may act by preventing efficient and faithful synthesis of DNA, allowing mutations to become integrated into the genome. The occurrence of lethal mutations with both these agents supports previous suggestions that error-prone repair of DNA base sequence abnormalities may be fundamental to the process of late lethal damage production in mammalian cells. The cloning efficiency of cells which survived exposure to Vincristine or BCNU over a wide dose range was found to be significantly increased; this may represent an adaptive response to the drugs.


Bacteriotherapy with Streptococcus salivarius 24SMB and Streptococcus oralis 89a oral spray for children with recurrent streptococcal pharyngotonsillitis: a randomized placebo-controlled clinical study.
Group A beta-hemolytic Streptococcus (GABHS) causes a recurrent acute pharyngotonsillitis (RAPT) in children. Moreover, the repeated use of antibiotics contributes to its resistance. However, S. Salivarius 24SMB and S. oralis 89a were effective probiotics in other infections. Thus, we decided to evaluate this combination efficacy compared to placebo in RAPT. Patients with microbiologically confirmed GABHS were enrolled in this randomized, placebo-controlled trial. They received the aforementioned combination or placebo as an oral spray. We investigated episodes of frequency and duration, need for antibiotics, school days lost, the treatment impact on life quality, treatment compliance and side effects during a 90-day treatment and a 6-month follow-up. We included 41 patients in each group. The mean number of GABHS infection was significantly lower during both study periods for the two groups. However, our treatment group showed a lower rate. Moreover, the probiotic group had a lower mean number and a shorter median duration of GABHS episodes during both study periods than controls. Furthermore, the mean duration of antibiotic treatment was lower in the probiotic group during the 90-day and 6-month follow-up periods. Similarly, patients in the probiotic group showed a significantly lower mean number of absence days from school but higher EQ-VAS score. Indeed, all patients included were compliant to treatment. We identified potential probiotics, possessing desirable features against GABHS pharyngotonsillitis. Our findings represent the first evidence which throws the light on using these probiotics that can reduce antibiotics use which did not have efficient results regarding recurrence.


Widespread impact of HLA restriction on immune control and escape pathways of HIV-1.
The promiscuous presentation of epitopes by similar HLA class I alleles holds promise for a universal T-cell-based HIV-1 vaccine. However, in some instances, cytotoxic T lymphocytes (CTL) restricted by HLA alleles with similar or identical binding motifs are known to target epitopes at different frequencies, with different functional avidities and with different apparent clinical outcomes. Such differences may be illuminated by the association of similar HLA alleles with distinctive escape pathways. Using a novel computational method featuring phylogenetically corrected odds ratios, we systematically analyzed differential patterns of immune escape across all optimally defined epitopes in Gag, Pol, and Nef in 2,126 HIV-1 clade C-infected adults. Overall, we identified 301 polymorphisms in 90 epitopes associated with HLA alleles belonging to shared supertypes. We detected differential escape in 37 of 38 epitopes restricted by more than one allele, which included 278 instances of differential escape at the polymorphism level. The majority (66 to 97%) of these resulted from the selection of unique HLA-specific polymorphisms rather than differential epitope targeting rates, as confirmed by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISPOT) data. Discordant associations between HLA alleles and viral load were frequently observed between allele pairs that selected for differential escape. Furthermore, the total number of associated polymorphisms strongly correlated with average viral load. These studies confirm that differential escape is a widespread phenomenon and may be the norm when two alleles present the same epitope. Given the clinical correlates of immune escape, such heterogeneity suggests that certain epitopes will lead to discordant outcomes if applied universally in a vaccine.


Efficient purging of deleterious mutations in plants with haploid selfing.
In diploid organisms, selfing reduces the efficiency of selection in removing deleterious mutations from a population. This need not be the case for all organisms. Some plants, for example, undergo an extreme form of selfing known as intragametophytic selfing, which immediately exposes all recessive deleterious mutations in a parental genome to selective purging. Here, we ask how effectively deleterious mutations are removed from such plants. Specifically, we study the extent to which deleterious mutations accumulate in a predominantly selfing and a predominantly outcrossing pair of moss species, using genome-wide transcriptome data. We find that the selfing species purge significantly more nonsynonymous mutations, as well as a greater proportion of radical amino acid changes which alter physicochemical properties of amino acids. Moreover, their purging of deleterious mutation is especially strong in conserved regions of protein-coding genes. Our observations show that selfing need not impede but can even accelerate the removal of deleterious mutations, and do so on a genome-wide scale.


Rapid assessment of crystal orientation in semi-crystalline polymer films using rotational zone annealing and impact of orientation on mechanical properties.
Crystal orientation in semi-crystalline polymers tends to enhance their performance, such as increased yield strength and modulus, along the orientation direction. Zone annealing (ZA) orients the crystal lamellae through a sharp temperature gradient that effectively directs the crystal growth, but the sweep rate (VZA) of this gradient significantly impacts the extent of crystal orientation. Here, we demonstrate rotational zone annealing (RZA) as an efficient method to elucidate the influence of VZA on the crystal morphology of thin films in a single experiment using isotactic poly(1-butene), PB-1, as a model semi-crystalline polymer. These RZA results are confirmed using standard, serial linear ZA to tune the structure from an almost unidirectional oriented morphology to weakly oriented spherulites. The overall crystallinity is only modestly changed in comparison to isothermal crystallization (maximum of 55% from ZA vs. 48% for isothermal crystallization). However, the average grain size increases and the spherulites become anisotropic from ZA. Due to these structural changes, the Young's modulus of the oriented films, both parallel and perpendicular to the spherulite orientation direction, is significantly increased by ZA. The modulus does become anisotropic after ZA due to the directionality in the crystal structure, with more than a threefold increase in the modulus parallel to the orientation direction for the highest oriented film in comparison to the modulus from isothermal crystallization. RZA enables rapid identification of conditions to maximize orientation of crystals in thin polymer films, which could find utility in determining conditions to improve crystallinity and performance in organic electronics.


The spectre of race in American medicine.
Controversies and debates surrounding race have long been a fixture in American medicine. In the past, the biological concept of race-the idea that race is biologically determined and meaningful-has served to justify the institution of slavery and the conduct of unethical research trials. Although these days may seem far behind, contemporary debates over the race-specific approval of drugs and the significance of genetic differences are evidence that race still yields tremendous influence on medical research and clinical practice. In many ways, the use of race in medicine today reflects the internalisation of racial hierarchies borne out of the history of slavery and state-mandated segregation, and there is still much uncertainty over its benefits and harms. Although using race in research can help elucidate disparities, the reflexive use of race as a variable runs the risk of reifying the biological concept of race and blinding researchers to important underlying factors such as socioeconomic status. Similarly, in clinical practice, the use of race in assessing a patient's risk of certain conditions (eg, sickle cell) turns harmful when the heuristic becomes a rule. Through selected historical and contemporary examples, I aim to show how the biological concept of race that gave rise to past abuses remains alive and harmful, and propose changes in medical education as a potential solution. By learning from the past, today's physicians will be better armed to discern-and correct-the ways in which contemporary medicine perpetuates historical injustices.


CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.
Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is upregulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates β1 integrin signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytic cleavage. The CD93-MMRN2 complex was required for activation of β1 integrin, phosphorylation of focal adhesion kinase (FAK), and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of β1 integrin and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.


Random process estimator for laser speckle imaging of cerebral blood flow.
In this paper, we develop a random process theory to explain the laser speckle phenomena. The relation between the probability distribution of speckle's integrated intensity random process Y(t) and the relative velocity v(t) is derived. Based on the random process theory, traditional spatial or temporal laser speckle contrast analysis (i.e. spatial or temporal LASCA) can be derived as the spatial or temporal estimators respectively. Both spatial LASCA and temporal LASCA suffer from noise due to insufficient statistics and nonstationarity in either spatial or temporal domain. Furthermore, either LASCA results in a reduction of spatial or temporal resolution. A new random process estimator is proposed and able to overcome these drawbacks. In an in-vitro study, random process estimator outperforms either spatial LASCA or temporal LASCA by providing much higher SNR (random process estimator vs. spatial LASCA vs. temporal LASCA: 33.64+/-6.87 (mean+/-s.t.d.) vs. 9.08+/-2.85 vs. 3.83+/-1.05). In an in-vivo structural imaging study, random process estimator efficiently suppresses the noise in contrast image and thus improves the distinguishability of small vessels. In a functional imaging study of cerebral blood flow change in the somatosensory cortex induced by rat's hind paw stimulation, random process estimator provides much lower estimation errors in single trial data (random process estimator vs. temporal LASCA: 0.31+/-0.03 vs. 1.36+/-0.09) and finally leads to higher resolution spatiotemporal patterns of cerebral blood flow.


Violation of expectations about movement and goal achievement leads to Sense of Agency reduction.
The control of one's own movements and of their impact on the external world generates a feeling of control referred to as Sense of Agency (SoA). SoA is experienced when actions match predictions and is reduced by unpredicted events. The present study investigated the contribution of monitoring two fundamental components of action-movement execution and goal achievement-that have been most often explored separately in previous research. We have devised a new paradigm in which participants performed goal-directed actions while viewing an avatar's hand in a mixed-reality scenario. The hand performed either the same action or a different one, simultaneously or after various delays. Movement of the virtual finger and goal attainment were manipulated, so that they could match or conflict with the participants' expectations. We collected judgments of correspondence (an explicit index of SoA that overcomes the tendency to over-attribute actions to oneself) by asking participants if the observed action was synchronous or not with their action. In keeping with previous studies, we found that monitoring both movement execution and goal attainment is relevant for SoA. Moreover, we expanded previous findings by showing that movement information may be a more constant source of SoA modulation than goal information. Indeed, an incongruent movement impaired SoA irrespective of delay duration, while a missed goal did so only when delays were short. Our novel paradigm allowed us to simultaneously manipulate multiple action features, a characteristic that makes it suitable for investigating the contribution of different sub-components of action in modulating SoA in healthy and clinical populations.


High-speed scattering medium characterization with application to focusing light through turbid media.
We introduce a phase-control holographic technique to characterize scattering media with the purpose of focusing light through it. The system generates computer-generated holograms implemented via a deformable mirror device (DMD) based on micro-electro-mechanical technology. The DMD can be updated at high data rates, enabling high speed wavefront measurements using the transmission matrix method. The transmission matrix of a scattering material determines the hologram required for focusing through the scatterer. We demonstrate this technique measuring a transmission matrix with 256 input modes and a single output mode in 33.8 ms and creating a focus with a signal to background ratio of 160. We also demonstrate focusing through a temporally dynamic, strongly scattering sample with short speckle decorrelation times.


Who Am I? The Influence of Knowledge Networks on PhD Students' Formation of a Researcher Role Identity.
Higher education institutes both foster the advancement of knowledge and address society's socioeconomic and environmental challenges. To fulfil these multiple missions requires significant changes to how the role of a researcher is perceived e.g. a researcher identity that is congruent with the objective of contributing to fundamental knowledge while also engaging with non-academic actors, broadly, and entrepreneurship, in particular. We argue that the early stages of an academic career-namely the PhD training trajectory-and the knowledge networks formed during this period have a major influence on the scientist's future capacity to develop an appropriate researcher role identity. We draw on knowledge network and identity theories to investigate how the knowledge networks (i.e. business, scientific and career knowledge networks) of PhD students promote changes to, reinforce or conflict with the perception of a researcher role identity. Our longitudinal qualitative network study includes PhD students and their supervisors funded by the H2020 FINESSE project. At the network level, we show that scientific knowledge is distributed equally throughout young academics' networks but that entrepreneurial (business) and career knowledge tend to be concentrated around certain individuals in these networks. On the PhD student level, we observe different pronunciations of the researcher role identity linked to students' interactions with their knowledge networks. We distinguish identity conflicts due to misalignment between ego and alters which leads to withdrawal from the network. Our findings have practical implications and suggest that universities and PhD student supervisors should support PhD students to develop a researcher identity which is in line with the individual PhD student's expectations.


Associations of Masticatory Muscles Asymmetry and Oral Health with Postural Control and Leg Injuries of Elite Junior Soccer Players.
The influence of asymmetry between masticatory muscles on postural control is still under debate and only few studies examined the impact of oral health on injury risk. The present study investigated the relationships between masticatory muscles asymmetry, oral health, postural control and the prevalence of (non-contact or traumatic) leg injuries in a sample of 144 male elite junior soccer players. sEMG of the masseter and temporal muscles was performed during maximum teeth clenching, postural control was tested by measuring sway velocity during the unipedal stance with eyes closed, while oral health and the number of leg injuries were assessed using a questionnaire. The time-1 assessment was repeated in a subgroup of 69 players after one year. Pearson and partial correlation coefficients and adjusted odds ratios (OR) were used to assess associations. Asymmetry between the masseter and temporalis muscles (AMTM, quantified as anteroposterior coefficient, APC) was associated with higher sway velocity on the dominant leg (using time-1 data partial r = -0.24, p = 0.004, using longitudinal data partial r = -0.40, p = 0.005). Higher prevalence of two or more leg injuries throughout a competitive season was associated with poor oral health (adjusted OR (95%CI) using time-1 data = 2.14 (1.02-4.46), using longitudinal data = 4.47 (1.25-15.96)). These results indicate that AMTM has a negative influence on the sway velocity of the dominant leg only, possibly because frequent balancing exercises on the non-dominant leg may counteract negative influences of AMTM. The association of oral health with leg injuries underlines the need for oral health promotion and monitoring strategies in sports.


Factors affecting pregnancy outcome of intrauterine insemination cycles in couples with favourable female characteristics.
The aim of the presented study is to determine the effect of different sperm parameters on the pregnancy rate of intrauterine insemination (IUI) cycles in women with favourable fertility characteristics treated for infertility. Medical records of 212 infertile couples who had undergone a total of 253 cycles were reviewed retrospectively. Inclusion criteria for women were age <35 years, antral follicle count >5, FSH <15 IU/ml, and at least one patent tube documented by HSG or laparoscopy. Clinical pregnancy rates were achieved as 15.8% per cycle, and 18.8% per couple. Woman's age, partner's age, total number of motile sperm (TMS) and motility, significantly influenced pregnancy rate. Pregnancy rate was the highest when women were aged <25 and TMS >10 × 10(6). Partner's age significantly affected the pregnancy rate per cycle in women aged <30 years and TMS >10 × 10(6). Woman's age (OR: 5.4 95% CI: 1.2-24.3) and TMS (OR: 0.06 95% CI: 0.003-0.89) were predictor variables as regards to pregnancy. Pregnancy rate was the highest in IUI cycles when woman was <25 years old, TMS was >10 × 10(6), and morphology was >4%. Male age was found to be another determining factor for IUI success, even if they had a normal spermiogram.


Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas.
Our analyses of cathepsin H activity levels and protein forms in human colorectal cancers compared to matched control mucosa support the concept that altered proteinase expression patterns may reflect both cancer stage and site. Cathepsin H-specific activity was significantly increased in colorectal cancers compared to control mucosa (P = 0.003; n = 77). Highest specific activities and cancer/normal ratios (C/N) for activity were measured in Dukes' B and C stage carcinomas, cancers involved in local spread and invasion to lymph nodes. In contrast, cathepsin B and L activities analysed in the same paired extracts had been shown to be most frequently elevated in earlier stage carcinomas (Dukes' A and B), confirming that cathepsin H demonstrates a distinct pattern of expression during colorectal cancer progression. Although cathepsin H activities were most commonly elevated in Dukes' C cancers at all colon sites, both specific activity and C/N ratios were significantly higher for cancers of the left colon compared to other colon locations. A subset of 43 paired extracts analysed on Western blots also revealed consistent changes in cathepsin H protein forms in cancers. Normal mucosa typically showed a strong protein doublet at 31 and 29 kDa while cancers demonstrated decreased expression or total loss of the 31 kDa protein (90% of cases), equal or increased expression of the 29-kDa protein (67% of cases) and the new appearance or up-regulation of a cathepsin H band at 22 kDa (78% of cases). C/N ratios for cathepsin H enzyme activity correlated significantly with C/N ratios for the 29 kDa mature single-chain protein form (P < 0.001), with increased activity most commonly associated with elevated expression of 29-kDa cathepsin H but also with up-regulation of the 22-kDa band, suggesting a shift to more fully processed, mature active cathepsin H protein forms in cancers. Changes in cathepsin H expression were also detected by immunohistochemistry as elevated cathepsin H staining in tumour epithelial cells.


Bound to Succeed: transcription factor binding-site prediction and its contribution to understanding virulence and environmental adaptation in bacterial plant pathogens.
Bacterial plant pathogens rely on a battalion of transcription factors to fine-tune their response to changing environmental conditions and to marshal the genetic resources required for successful pathogenesis. Prediction of transcription factor binding sites (TFBS) represents an important tool for elucidating regulatory networks and has been conducted in multiple genera of plant-pathogenic bacteria for the purpose of better understanding mechanisms of survival and pathogenesis. The major categories of TFBS that have been characterized are reviewed here, with emphasis on in silico methods used for site identification and challenges therein, their applicability to different types of sequence datasets, and insights into mechanisms of virulence and survival that have been gained through binding-site mapping. An improved strategy for establishing E-value cutoffs when using existing models to screen uncharacterized genomes is also discussed.


Religious and spiritual factors and the consequences of trauma: a review and model of the interrelationship.
An increasing body of literature examines the association of religious factors with posttraumatic stress as well as posttraumatic growth. This review of selected empirical studies describes religious and spiritual factors that have been examined in their association with the consequences of trauma. A comprehensive model is proposed to explain the complex interrelationship. We performed a qualitative review of empirical research in August 2006, updated in February 2008, using Medline (1950-present), PsychInfo (1806-present), Web of Science (1900-present), and PILOTS (1960-present). We searched the terms posttraumatic, posttraumatic stress, posttraumatic growth, and religion, religious, spirituality, spiritual, meditation, and forgiveness. Based on supporting data from reviewed literature, we then developed a model for key religious factors derived from this review predictive of the response to trauma over time. Twenty-three studies were identified that describe religious pre-trauma characteristics, religious trauma-appraisal and post-trauma adjustment factors. The association of these factors with posttraumatic stress and growth is described. Intrinsic religious orientation, in particular, appears to be a useful construct in measuring religiosity in the association with the consequences of trauma. There are preliminary indications that the association between intrinsic religiosity and the consequences of trauma may change depending on the time after the event. Future studies should stratify outcome by the time after trauma or use longitudinal designs.


Sonoelastic response of median nerve to rehabilitation in carpal tunnel syndrome.
Aim of the study: To evaluate the sonoelastic response of the median nerve in patients with carpal tunnel syndrome following conservative rehabilitation with splint plus exercise regimens. Materials and methods: A total of thirty-five patients diagnosed with mild carpal tunnel syndrome and treated with splint plus exercise therapy; hand resting splint all day for 3 weeks and then only at nights along with nerve gliding exercises in 10 repetitions 3 times a day. The median nerve was evaluated clinically prior to the treatment and at week 6 of therapy using physical examination, electrodiagnostic neurophysiology tests and radiological imaging; Boston Scores, electromyogram, ultrasonography and sonoelastography. Results: Following the 6-week treatment protocol on 35 subjects with mild carpal tunnel syndrome, sonoelastography showed significantly softer median nerve, while the traditional parameters based on Boston Scores and cross-sectional area based on ultrasonography remained nearly unresponsive. Such early indication of biomechanical changes in the nerve may be of clinical importance if it can offer a prognostic value of the applied treatment, while tissue softening suggests the alleviation of nerve compression. Conclusions: Sonoelasticity of the median nerve can serve as a reliable marker for assessing therapeutic changes in median nerve stiffness and potentially the outcome early on in mild carpal tunnel syndrome. Aim of the study: To evaluate the sonoelastic response of the median nerve in patients with carpal tunnel syndrome following conservative rehabilitation with splint plus exercise regimens. Materials and methods: A total of thirty-five patients diagnosed with mild carpal tunnel syndrome and treated with splint plus exercise therapy; hand resting splint all day for 3 weeks and then only at nights along with nerve gliding exercises in 10 repetitions 3 times a day. The median nerve was evaluated clinically prior to the treatment and at week 6 of therapy using physical examination, electrodiagnostic neurophysiology tests and radiological imaging; Boston Scores, electromyogram, ultrasonography and sonoelastography. Results: Following the 6-week treatment protocol on 35 subjects with mild carpal tunnel syndrome, sonoelastography showed significantly softer median nerve, while the traditional parameters based on Boston Scores and cross-sectional area based on ultrasonography remained nearly unresponsive. Such early indication of biomechanical changes in the nerve may be of clinical importance if it can offer a prognostic value of the applied treatment, while tissue softening suggests the alleviation of nerve compression. Conclusions: Sonoelasticity of the median nerve can serve as a reliable marker for assessing therapeutic changes in median nerve stiffness and potentially the outcome early on in mild carpal tunnel syndrome.


B-vitamins are potentially a cost-effective population health strategy to tackle dementia: Too good to be true?
To respond to the threat of dementia to public health and the economy, we need to prioritize research resources on strategies that would be the most effective. In relation to the prevention of dementia, this article considers whether lowering plasma homocysteine by B-vitamin supplementation is one of the top priority and cost-effective treatments. A decision model was constructed to calculate the lifetime costs and quality-adjusted life years (QALYs) of providing B-vitamin treatment to people in the United Kingdom over 60 years with high levels (>13 μmol/L) of plasma homocysteine, which was compared to the lifetime costs and outcomes of not providing them with the treatment. Treatment with B-vitamins will save £60,021 per QALY gained and so is highly cost-effective. We anticipate that this provocative finding will be debated by scientists, clinicians, and policy makers and eventually be tested in future clinical trials.


The Effects of Supplementary Low-Load Blood Flow Restriction Training on Morphological and Performance-Based Adaptations in Team Sport Athletes.
Scott, BR, Peiffer, JJ, and Goods, PSR. The effects of supplementary low-load blood flow restriction training on morphological and performance-based adaptations in team sport athletes. J Strength Cond Res 31(8): 2147-2154, 2017-Low-load resistance training with blood flow restriction (BFR) may be a method to enhance muscular development even in trained athletes. This study aimed to assess whether supplemental low-load BFR training can improve muscle size, strength, and physical performance characteristics in team sport athletes. Twenty-one semiprofessional Australian football athletes were assessed for 3-repetition maximum (3RM) and muscular endurance in the back squat, vastus lateralis muscle architecture, and performance in sprint and vertical jump tasks. Participants then undertook a 5-week training program, consisting of normal high-load resistance training supplemented by low-load squats with (LLBFR) or without (LL) BFR. Participants also performed regular conditioning and football training during this period. After the training intervention, participants again completed the pretraining testing battery. Squat 3RM and endurance increased from pretraining levels in both LL (3RM = 12.5% increase; endurance = 24.1% increase; p ≤ 0.007) and LLBFR (3RM = 12.3% increase; endurance = 21.2% increase; p = 0.007) groups, though there were no between-group differences. No post-training changes were observed for muscle architecture, or performance in sprinting and jumping tasks. Although squat 3RM and endurance performance increased in both groups, adding BFR during supplemental exercise did not enhance these responses. Similarly, there were no large differences in the assessments of sprint, acceleration, and jumping performance between the groups after training. These findings suggest that although LLBFR did not negatively affect adaptive responses to resistance training, this training strategy may not provide added benefit for healthy Australian football athletes already undertaking a rigorous training schedule.


Anticipatory smooth pursuit eye movements evoked by probabilistic cues.
Anticipatory smooth eye movements (ASEM; smooth eye movements in the direction of anticipated target motion) are elicited by cues that signal the direction of future target motion with high levels of certainty. Natural cues, however, rarely convey information with perfect certainty, and responses to uncertainty provide insights about how predictive behaviors are generated. Subjects smoothly pursued targets that moved to the right or left with varying cued probabilities. ASEM strength in a given direction increased with the probability level. The type of cue also played a role. ASEM elicited by symbolic visual cues tended to underweight low probabilities and overweight high probabilities. Cues based on memory (varying the proportion of trials with left or right motion) produced the opposite pattern, overweighting low probabilities and underweighting high probabilities. Finally, cues whose perceptual structure depicted the motion path produced a bias in ASEM in the depicted direction that was maintained across levels of cue congruency. The results show that the smooth pursuit system relies on a combination of signals, including memory for recent target motions, interpretation of cues, and prior beliefs about the relationship between the perceptual configuration and the motion path to determine the anticipatory response in the presence of uncertainty.


Chemical genetics and its potential in cardiac stem cell therapy.
Over the last decade or so, intensive research in cardiac stem cell biology has led to significant discoveries towards a potential therapy for cardiovascular disease; the main cause of morbidity and mortality in humans. The major goal within the field of cardiovascular regenerative medicine is to replace lost or damaged cardiac muscle and coronaries following ischaemic disease. At present, de novo cardiomyocytes can be generated either in vitro, for cell transplantation or disease modelling using directed differentiation of embryonic stem cells or induced pluripotent stem cells, or in vivo via direct reprogramming of resident adult cardiac fibroblast or ectopic stimulation of resident cardiac stem or progenitor cells. A major bottleneck with all of these approaches is the low efficiency of cardiomyocyte differentiation alongside their relative functional immaturity. Chemical genetics, and the application of phenotypic screening with small molecule libraries, represent a means to enhance understanding of the molecular pathways controlling cardiovascular cell differentiation and, moreover, offer the potential for discovery of new drugs to invoke heart repair and regeneration. Here, we review the potential of chemical genetics in cardiac stem cell therapy, highlighting not only the major contributions to the field so far, but also the future challenges.


Extra-intestinal manifestations of non-celiac gluten sensitivity: An expanding paradigm.
Non celiac gluten sensitivity (NCGS) is a syndrome characterized by a cohort of symptoms related to the ingestion of gluten-containing food in subjects who are not affected by celiac disease (CD) or wheat allergy. The possibility of systemic manifestations in this condition has been suggested by some reports. In most cases they are characterized by vague symptoms such as 'foggy mind', headache, fatigue, joint and muscle pain, leg or arm numbness even if more specific complaints have been described. NCGS has an immune-related background. Indeed there is a strong evidence that a selective activation of innate immunity may be the trigger for NCGS inflammatory response. The most commonly autoimmune disorders associated to NCGS are Hashimoto thyroiditis, dermatitis herpetiformis, psoriasis and rheumatologic diseases. The predominance of Hashimoto thyroiditis represents an interesting finding, since it has been indirectly confirmed by an Italian study, showing that autoimmune thyroid disease is a risk factor for the evolution towards NCGS in a group of patients with minimal duodenal inflammation. On these bases, an autoimmune stigma in NCGS is strongly supported; it could be a characteristic feature that could help the diagnosis and be simultaneously managed. A possible neurological involvement has been underlined by NCGS association with gluten ataxia, gluten neuropathy and gluten encephalopathy. NCGS patients may show even psychiatric diseases such as depression, anxiety and psychosis. Finally, a link with functional disorders (irritable bowel syndrome and fibromyalgia) is a topic under discussion. In conclusion, the novelty of this matter has generated an expansion of literature data with the unavoidable consequence that some reports are often based on low levels of evidence. Therefore, only studies performed on large samples with the inclusion of control groups will be able to clearly establish whether the large information from the literature regarding extra-intestinal NCGS manifestations could be supported by evidence-based agreements.


Single-channel kinetic analysis of chimeric alpha7-5HT3A receptors.
The receptor chimera alpha7-5HT3A has served as a prototype for understanding the pharmacology of alpha7 neuronal nicotinic receptors, yet its low single channel conductance has prevented studies of the activation kinetics of single receptor channels. In this study, we show that introducing mutations in the M3-M4 cytoplasmic linker of the chimera alters neither the apparent affinity for the agonist nor the EC50 but increases the amplitude of agonist-evoked single channel currents to enable kinetic analysis. Channel events appear as single brief openings flanked by long closings or as bursts of several openings in quick succession. Both the open and closed time distributions are described as the sum of multiple exponential components, but these do not change over a wide range of acetylcholine (ACh), nicotine, or choline concentrations. Bursts elicited by a saturating concentration of ACh contain brief and long openings and closings, and a cyclic scheme containing two open and two closed states is found to adequately describe the data. The analysis indicates that once fully occupied, the receptor opens rapidly and efficiently, and closes and reopens several times before it desensitizes. Channel closing and desensitization occur at similar rates and account for the invariant open and closed time distributions.


Revealing the working mechanism of polymer photodetectors with ultra-high external quantum efficiency.
We report polymer photodetectors (PPDs) with an evident photomultiplication (PM) phenomenon, based on a sandwich structure ITO/PEDOT:PSS/P3HT:PC71BM(100:1)/Al. A similar device structure has been reported in our previous work, showing great potential as a new type of high performance PPD. However, we found more interesting new phenomena from these PPDs. Solid evidence is provided to prove the existence of photogenerated electron transport in the almost hole-only active layer under an applied bias. The transport of photogenerated electrons leads to electron accumulation near the Al electrode and the electron redistribution, which strongly affect the EQE spectral shape and the transient response of the PPDs. Our conclusion is further confirmed by confirmatory devices with a structure of Al(1)/P3HT:PC71BM(100:1)/Al(2). EQE spectra and transient Jph curves of the confirmatory devices accord well with our speculation. This discovery may provide a new insight to increase the response speed of PM type PPDs by adjusting the photogenerated electron distribution in the active layer. Considering that the PM type PPDs have much higher EQE than the traditional organic photodetectors, the improvement may further extend its potential applications with low cost.


Galectin-3 promotes HIV-1 budding via association with Alix and Gag p6.
Galectin-3 has been reported to regulate the functions of a number of immune cell types. We previously reported that galectin-3 is translocated to immunological synapses in T cells upon T-cell receptor engagement, where it associates with ALG-2-interacting protein X (Alix). Alix is known to coordinate with the endosomal sorting complex required for transport (ESCRT) to promote human immunodeficiency virus (HIV)-1 virion release. We hypothesized that galectin-3 plays a role in HIV-1 viral budding. Cotransfection of cells of the Jurkat T line with galectin-3 and HIV-1 plasmids resulted in increased HIV-1 budding, and suppression of galectin-3 expression by RNAi in Hut78 and primary CD4+ T cells led to reduced HIV-1 budding. We used immunofluorescence microscopy to observe the partial colocalization of galectin-3, Alix and Gag in HIV-1-infected cells. Results from co-immunoprecipitation experiments indicate that galectin-3 expression promotes Alix-Gag p6 association, whereas the results of Alix knockdown suggest that galectin-3 promotes HIV-1 budding through Alix. HIV-1 particles released from galectin-3-expressing cells acquire the galectin-3 protein in an Alix-dependent manner, with proteins primarily residing inside the virions. We also found that the galectin-3 N-terminal domain interacts with the proline-rich region of Alix. Collectively, these results suggest that endogenous galectin-3 facilitates HIV-1 budding by promoting the Alix-Gag p6 association.


Biothermal sensing of a torsional artificial muscle.
Biomolecule responsive materials have been studied intensively for use in biomedical applications as smart systems because of their unique property of responding to specific biomolecules under mild conditions. However, these materials have some challenging drawbacks that limit further practical application, including their speed of response and mechanical properties, because most are based on hydrogels. Here, we present a fast, mechanically robust biscrolled twist-spun carbon nanotube yarn as a torsional artificial muscle through entrapping an enzyme linked to a thermally sensitive hydrogel, poly(N-isopropylacrylamide), utilizing the exothermic catalytic reaction of the enzyme. The induced rotation reached an equilibrated angle in less than 2 min under mild temperature conditions (25-37 °C) while maintaining the mechanical properties originating from the carbon nanotubes. This biothermal sensing of a torsional artificial muscle offers a versatile platform for the recognition of various types of biomolecules by replacing the enzyme, because an exothermic reaction is a general property accompanying a biochemical transformation.


Chemical genomics reveals mechanistic hypotheses for uncharacterized bioactive molecules in bacteria.
In an effort to combat the perpetual emergence of new antibiotic-resistant human pathogens, research in industry and academe aims to find new means of controlling infection. The discovery of new antimicrobial chemicals is not the bottleneck in an era where high-throughput screening rapidly uncovers new bioactive compounds. Rather, the rate-limiting step in antimicrobial discovery pipelines is identifying mechanisms of action (MOA) of bioactive molecules produced by these increasingly large-scale efforts. Chemical genomics has proven to be of high value in providing mechanistic hypotheses for novel bioactive chemical matter. Several techniques fall under this blanket term, including interactions with deletion or transposon libraries, fluorescent or luminescent reporter library profiles, or deep sequencing approaches. Each of these provide unique and complementary outputs, and have high value in generating target lists for chemical screens, or assisting in downstream MOA discovery. We review here the broad usefulness of this technique to aid in MOA determination, to identify targets for new lead molecules, and to expand our mechanistic understanding of existing drugs.


Heart failure in sub-Saharan Africa.
The heart failure syndrome has been recognized as a significant contributor to cardiovascular disease burden in sub-Saharan African for many decades. Seminal knowledge regarding heart failure in the region came from case reports and case series of the early 20th century which identified infectious, nutritional and idiopathic causes as the most common. With increasing urbanization, changes in lifestyle habits, and ageing of the population, the spectrum of causes of HF has also expanded resulting in a significant burden of both communicable and non-communicable etiologies. Heart failure in sub-Saharan Africa is notable for the range of etiologies that concurrently exist as well as the healthcare environment marked by limited resources, weak national healthcare systems and a paucity of national level data on disease trends. With the recent publication of the first and largest multinational prospective registry of acute heart failure in sub-Saharan Africa, it is timely to review the state of knowledge to date and describe the myriad forms of heart failure in the region. This review discusses several forms of heart failure that are common in sub-Saharan Africa (e.g., rheumatic heart disease, hypertensive heart disease, pericardial disease, various dilated cardiomyopathies, HIV cardiomyopathy, hypertrophic cardiomyopathy, endomyocardial fibrosis, ischemic heart disease, cor pulmonale) and presents each form with regard to epidemiology, natural history, clinical characteristics, diagnostic considerations and therapies. Areas and approaches to fill the remaining gaps in knowledge are also offered herein highlighting the need for research that is driven by regional disease burden and needs.


Predicting outcome of military basic training for individuals referred for psychological evaluation.
We examined outcome data for 632 U.S. Air Force personnel who were referred for psychological evaluation during Basic Military Training (BMT) but who were subsequently returned to BMT to determine what proportion graduated. We analyzed motivational, biographical, and psychological testing variables, using logistic regression to develop a model predictive of training outcome. The results demonstrated that a relatively small number of variables could predict outcome with close to 70% accuracy. Level of optimism regarding training, history of physical abuse, and frequency of visits to the trainee health clinic were major contributors to the model. MMPI-2 (Hathaway & McKinley, 1989) Scales D and Sc also remained in the model but added little to its power. The findings are generally consistent with prior research on normal military populations, except that some factors previously linked to adjustment, such as sex and ethnicity, were found to be unrelated to training outcome in this population.


A set of 4D pediatric XCAT reference phantoms for multimodality research.
The authors previously developed an adult population of 4D extended cardiac-torso (XCAT) phantoms for multimodality imaging research. In this work, the authors develop a reference set of 4D pediatric XCAT phantoms consisting of male and female anatomies at ages of newborn, 1, 5, 10, and 15 years. These models will serve as the foundation from which the authors will create a vast population of pediatric phantoms for optimizing pediatric CT imaging protocols. Each phantom was based on a unique set of CT data from a normal patient obtained from the Duke University database. The datasets were selected to best match the reference values for height and weight for the different ages and genders according to ICRP Publication 89. The major organs and structures were segmented from the CT data and used to create an initial pediatric model defined using nonuniform rational B-spline surfaces. The CT data covered the entire torso and part of the head. To complete the body, the authors manually added on the top of the head and the arms and legs using scaled versions of the XCAT adult models or additional models created from cadaver data. A multichannel large deformation diffeomorphic metric mapping algorithm was then used to calculate the transform from a template XCAT phantom (male or female 50th percentile adult) to the target pediatric model. The transform was applied to the template XCAT to fill in any unsegmented structures within the target phantom and to implement the 4D cardiac and respiratory models in the new anatomy. The masses of the organs in each phantom were matched to the reference values given in ICRP Publication 89. The new reference models were checked for anatomical accuracy via visual inspection. The authors created a set of ten pediatric reference phantoms that have the same level of detail and functionality as the original XCAT phantom adults. Each consists of thousands of anatomical structures and includes parameterized models for the cardiac and respiratory motions. Based on patient data, the phantoms capture the anatomic variations of childhood, such as the development of bone in the skull, pelvis, and long bones, and the growth of the vertebrae and organs. The phantoms can be combined with existing simulation packages to generate realistic pediatric imaging data from different modalities. The development of patient-derived pediatric computational phantoms is useful in providing variable anatomies for simulation. Future work will expand this ten-phantom base to a host of pediatric phantoms representative of the public at large. This can provide a means to evaluate and improve pediatric imaging devices and to optimize CT protocols in terms of image quality and radiation dose.


Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy.
Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review, we focus on the relationship between the autonomic nervous system and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches, and biological therapies. Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future.


Acceleration and deceleration demands during training sessions in football: a systematic review.
The aim of this review is to summarize the current scientific knowledge about acceleration and deceleration demands during football training. A systematic search of three electronic databases (PubMed, SPORTDiscus, Web of Science) was performed to identify peer-reviewed relevant English-language articles, following PRISMA guidelines. All acceleration and deceleration data were analyzed and organized into four categories: i) training drills variables (i.e. manipulated drills variables such as number of players in small-sided games), ii) training exercises (i.e. different drills such small games or circuit training), iii) players' positions (i.e. demands for each playing position) and iv) training schedule (i.e. training sessions presented as microcycles, season sections or full season). Full-text articles of 42 studies were included in the final analysis. Players' level included: amateur, youth, semi-professional, professional and elite players. All playing positions were considered, including goalkeepers. Six different global position systems brands were used, with the majority measuring data at 10 Hz. Different thresholds and intensities were used in several papers. Lower acceleration and deceleration intensities occurred more often than higher intensities in all four categories. Different exercises elicit different demands and small-sided games presented higher acceleration and deceleration demands than circuit training and other running based drills. Furthermore, manipulating drills variables, as reducing or increasing number of players in small-sided games increase or decrease demands, respectively. Additionally, wide playing positions, such as fullbacks, are generally exposed to higher acceleration and deceleration demands. From a planning point of view, acceleration and deceleration demands decrease as match day approaches.


A randomized trial of balloon kyphoplasty and nonsurgical management for treating acute vertebral compression fractures: vertebral body kyphosis correction and surgical parameters.
Multicenter randomized controlled trial. To compare the efficacy and safety of balloon kyphoplasty (BKP) with nonsurgical management (NSM) during 24 months in patients with painful vertebral compression fractures (VCFs). Recently, several large randomized controlled trials have been conducted and reported how vertebral augmentation compares with NSM for patients with acute VCFs. Few of these trials report on the surgical aspects and radiographical vertebral deformity results. Adults with 1 to 3 VCFs were randomized within 3 months of pain to undergo bilateral BKP (n = 149) or NSM (n = 151). Surgical parameters, subjective quality of life assessments and objective functional (timed up and go) and radiographical assessments were collected. Compared with NSM, the BKP group had greater improvements in SF-36 physical component summary (PCS) scores at 1 month (5.35 points; 95% CI, 3.41-7.30; P < 0.0001) and when averaged across the 24 months (overall treatment effect 2.71 points; 95% CI, 1.34-4.09; P = 0.0001). The kyphoplasty group also had greater functionality by assessing timed up and go (overall treatment effect -2.49 s; 95% CI, -0.82 to -4.15; P = 0.0036). At 24 months, the change in index fracture kyphotic angulation was statistically significantly improved in the kyphoplasty group (average 3.13° of correction for kyphoplasty compared with 0.82° in the control, P = 0.003). Number of baseline prevalent fractures (P = 0.0003) and treatment assignment (P = 0.004) are the most predictive variables for PCS improvement; however, in patients who underwent BKP, there may also be a link with kyphotic angulation. In BKP, the highest quart for kyphotic angulation correction had higher PCS improvement (13.4 points) than the quart having lowest correction of angulation (7.40 points, P = 0.0146 for difference). The most common adverse events temporally related to surgery (i.e., within 30 d) were back pain (20 BKP, 11 NSM) new VCF (11 BKP, 7 NSM), nausea/vomiting (12 BKP, 4 NSM), and urinary tract infection (10 BKP, 3 NSM). Several other adverse events were possibly related to patient positioning in the operating room. Compared with NSM, BKP improves patient quality of life and pain averaged during 24 months and results in better improvement of index vertebral body kyphotic angulation. Perioperative complications may be reduced with more care in patient positioning. 2.


The influence of oral lipid loads on acylation stimulating protein (ASP) in healthy volunteers.
To examine the hypothesis that a sustained rise in plasma acylation stimulating protein (ASP, C3a desarg) accompanies the elevation in triacylglycerol that follows the ingestion of an oral fat load. Following an overnight fast, blood samples were obtained from healthy volunteers while fasting and 15 min, 1, 2, 4, 6 and 8 h following ingestion of: (i) a liquid meal, rich in dairy fat (eight subjects) and (ii) a semi-liquid meal, with higher total fat content and rich in polyunsaturated fat (six subjects). Four male and four female volunteers (age range: 22-51 y; body mass index (BMI): 17.9-26.9 kg/m2) received the first meal. Six subjects (age range: 32-60 y; BMI: 18.0-28.4 kg/m2), including three from the first study, received the second meal using the same protocol. ASP and C5a were measured by radioimmunoassay (RIA) and the complement proteins C3, factor B and C5 by radial immunodiffusion or nephelometry. Tumour necrosis factor (TNF)-alpha was measured by enhanced ELISA, and plasma cholesterol and triacylglycerol by an automated enzymatic method. The presence of chylomicrons was assessed in post-prandial plasma samples taken after the second meal. There was no significant change in mean ASP concentration in either group at any time point, following ingestion of either meal. However, there was a significant positive linear trend in ASP following the second fat challenge (ANOVA; P < 0.05). There was also no change in complement proteins, plasma cholesterol or TNF-alpha. Plasma triacylglycerol rose significantly after the first and second meals (P < 0.05 and P < 0.001 at 2 h post-prandially); the mean maximum rise above the fasting level was 58 +/- 41% and 89 +/- 38% respectively (mean +/- s.d.). Chylomicrons were detected in samples taken from each subject after the second meal. Analysis of individual ASP data showed a sustained rise in one subject after the first meal and two subjects after the second meal. Substantial variation in ASP concentration was observed in samples taken in the first 2 h post-prandially. There was no significant change in ASP nor other complement proteins for either group of subjects following ingestion of the lipid loads. Individual data showed substantial variation in post-prandial ASP, but multiple plasma sampling did not define the basis for this variation.


The improved lytic function and in vivo efficacy of monovalent monoclonal CD3 antibodies.
A series of hybrid-hybridomas were derived by the cell fusion of a CD3 antibody-secreting hybridoma with other Ig-producing cell lines. The Ig molecules secreted by these hybrid-hybridomas were fractionated by ion-exchange chromatography, and fractions containing monovalent CD3 antibodies were tested for complement-mediated lysis of T cells. Two monovalent CD3 antibodies with mixed heavy chain isotypes were very poor in lysis but, in contrast, a monovalent antibody possessing two identical rat gamma 2b heavy chains but two non-identical light chains was found to be more lytic with human complement than the parental bivalent CD3 antibody. The difference in lysis was not readily explicable in terms of a difference in complement activation at the level of C1q binding or cell-associated C3. A highly purified batch of this lytic monovalent CD3 antibody was prepared in a form suitable for in vivo therapy. In a preliminary clinical study in one patient with a T lymphoma in leukemic phase this monovalent CD3 antibody was found to be very effective in depleting CD3+ tumor cells in the peripheral blood and bone marrow. The cells in the peripheral blood were completely cleared and there was no evidence for antigenic modulation. In addition the antibody was able to reverse cell-mediated kidney rejection in three kidney graft patients. These results suggest that monovalent antibody may be effective in vivo as well as in vitro and that a fuller clinical evaluation is justified.


Rationale and design of the Patient Related OuTcomes with Endeavor versus Cypher stenting Trial (PROTECT): randomized controlled trial comparing the incidence of stent thrombosis and clinical events after sirolimus or zotarolimus drug-eluting stent implantation.
Drug-eluting stents (DES) reduce restenosis rates compared to bare-metal stents. Most trials using DES enrolled selected patient and lesion subtypes, and primary endpoint focused on angiographic metrics or relatively short-term outcomes. When DES are used in broader types of lesions and patients, important differences may emerge in long-term outcomes between stent types, particularly the incidence of late stent thrombosis. PROTECT is a randomized, open-label trial comparing the long-term safety of the zotarolimus-eluting stent and the sirolimus-eluting stent. The trial has enrolled 8,800 patients representative of those seen in routine clinical practice, undergoing elective, unplanned, or emergency procedures in native coronary arteries in 196 centers in 36 countries. Indications for the procedure and selection of target vessel and lesion characteristics were at the operator's discretion. Procedures could be staged, but no more than 4 target lesions could be treated per patient. Duration of dual antiplatelet therapy was prespecified to achieve similar lengths of treatment in both study arms. The shortest predefined duration was 3 months, as per the manufacturer's instructions. The primary outcome measure is the composite rate of definite and probable stent thrombosis at 3 years, centrally adjudicated using Academic Research Consortium definitions. The main secondary end points are 3-year all-cause mortality, cardiac death, large nonfatal myocardial infarction, and all myocardial infarctions. This large, international, randomized, controlled trial will provide important information on comparative rates of stent thrombosis between 2 different DES systems and safety as assessed by patient-relevant long-term clinical outcomes.


Continuity of medication management in Medicaid patients with chronic comorbid conditions: An examination by mental health status.
Patients with serious mental illness (SMI) often have comorbid cardiometabolic conditions (CMCs) that may increase the number of prescribers involved in treatment. This study examined whether patients with SMI (depression and schizophrenia) and comorbid CMCs experience greater discontinuity of prescribing than patients with CMCs alone. 2009 Medicaid data were used to compare number and types of prescribers (primary care, cardiometabolic, psychiatric, other) in individuals with 1-3 CMCs (diabetes, hypertension, dyslipidemia) alone (n=76.451); with CMC and schizophrenia (n=6507); and with CMC and depression (n=23.510) and the degree of prescribing within a provider's area of specialty. 44%, 61%, and 71% of individuals with CMCs only, with CMCs and schizophrenia, and with CMCs and depression had medications from these classes prescribed by 5 or more providers respectively. >35% of patients with CMCs alone or CMCs and schizophrenia had prescriptions provided by 3 or more PCP providers, which increased to 49.1% for patients with CMCs and depression. In the schizophrenia cohort, 29% of antipsychotics were PCP-prescribed while psychiatrists prescribed 10%, 9%, and 9% of antihypertensive, antihyperlipidemic, and antidiabetic medications respectively. The presence of SMI increases the number of prescribers treating individuals with CMCs. The impact of this fragmentation in medication management on health outcomes is unknown.


Metabolism in the Zebrafish Retina.
Retinal photoreceptors are amongst the most metabolically active cells in the body, consuming more glucose as a metabolic substrate than even the brain. This ensures that there is sufficient energy to establish and maintain photoreceptor functions during and after their differentiation. Such high dependence on glucose metabolism is conserved across vertebrates, including zebrafish from early larval through to adult retinal stages. As the zebrafish retina develops rapidly, reaching an adult-like structure by 72 hours post fertilisation, zebrafish larvae can be used to study metabolism not only during retinogenesis, but also in functionally mature retinae. The interplay between rod and cone photoreceptors and the neighbouring retinal pigment epithelium (RPE) cells establishes a metabolic ecosystem that provides essential control of their individual functions, overall maintaining healthy vision. The RPE facilitates efficient supply of glucose from the choroidal vasculature to the photoreceptors, which produce metabolic products that in turn fuel RPE metabolism. Many inherited retinal diseases (IRDs) result in photoreceptor degeneration, either directly arising from photoreceptor-specific mutations or secondary to RPE loss, leading to sight loss. Evidence from a number of vertebrate studies suggests that the imbalance of the metabolic ecosystem in the outer retina contributes to metabolic failure and disease pathogenesis. The use of larval zebrafish mutants with disease-specific mutations that mirror those seen in human patients allows us to uncover mechanisms of such dysregulation and disease pathology with progression from embryonic to adult stages, as well as providing a means of testing novel therapeutic approaches.


Expectations, perceptions, and physiotherapy predict prolonged sick leave in subacute low back pain.
Brief intervention programs for subacute low back pain (LBP) result in significant reduction of sick leave compared to treatment as usual. Although effective, a substantial proportion of the patients do not return to work. This study investigates predictors of return to work in LBP patients participating in a randomized controlled trial comparing a brief intervention program (BI) with BI and physical exercise. Predictors for not returning to work was examined in 246 patients sick listed 8-12 weeks for low back pain. The patients had participated in a randomized controlled trial, with BI (n = 122) and BI + physical exercise (n = 124). There were no significant differences between the two intervention groups on return to work. The groups were therefore merged in the analyses of predictors. Multiple logistic regression analysis was used to identify predictors for non return to work at 3, 12, and 24 months of follow-up. At 3 months of follow-up, the strongest predictors for not returning to work were pain intensity while resting (OR = 5.6; CI = 1.7-19), the perception of constant back strain when working (OR = 4.1; CI = 1.5-12), negative expectations for return to work (OR = 4.2; CI = 1.7-10), and having been to a physiotherapist prior to participation in the trial (OR = 3.3; CI = 1.3-8.3). At 12 months, perceived reduced ability to walk far due to the complaints (OR = 2.6; CI = 1.3-5.4), pain during activities (OR = 2.4; CI = 1.1-5.1), and having been to a physiotherapist prior to participation in the trial (OR = 2.1; CI = 1.1-4.3) were the strongest predictors for non return to work. At 24 months age below 41 years (OR = 2.9; CI = 1.4-6.0) was the only significant predictor for non return to work. It appears that return to work is highly dependant on individual and cognitive factors. Patients not returning to work after the interventions were characterized by negative expectations, perceptions about pain and disability, and previous physiotherapy treatment. This is the first study reporting that previous treatment by physiotherapists is a risk factor for long-term sick leave. This has not been reported before and is an interesting finding that deserves more scrutiny.


Vitamin D Deficiency in Human and Murine Sepsis.
Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and ICU mortality but causality of these associations has not been demonstrated. To determine whether sepsis and severe sepsis are associated with vitamin D deficiency and to determine whether vitamin D deficiency influences the severity of sepsis. Sixty-one patients with sepsis and severe sepsis from two large U.K. hospitals and 20 healthy controls were recruited. Murine models of cecal ligation and puncture and intratracheal lipopolysaccharide were undertaken in normal and vitamin D deficient mice to address the issue of causality. Patients with severe sepsis had significantly lower concentrations of 25-hydroxyvitamin D3 than patients with either mild sepsis or age-matched healthy controls (15.7 vs 49.5 vs 66.5 nmol/L; p = 0.0001). 25-hydroxyvitamin D3 concentrations were significantly lower in patients who had positive microbiologic culture than those who were culture negative (p = 0.0023) as well as those who died within 30 days of hospital admission (p = 0.025). Vitamin D deficiency in murine sepsis was associated with increased peritoneal (p = 0.037), systemic (p = 0.019), and bronchoalveolar lavage (p = 0.011) quantitative bacterial culture. This was associated with reduced local expression of the cathelicidin-related antimicrobial peptide as well as evidence of defective macrophage phagocytosis (p = 0.029). In the intratracheal lipopolysaccharide model, 1,500 IU of intraperitoneal cholecalciferol treatment 6 hours postinjury reduced alveolar inflammation, cellular damage, and hypoxia. Vitamin D deficiency is common in severe sepsis. This appears to contribute to the development of the condition in clinically relevant murine models and approaches to correct vitamin D deficiency in patients with sepsis should be developed.


Two genetically and molecularly distinct functions involved in early neurogenesis reside within the Enhancer of split locus of Drosophila melanogaster.
Molecular correlation of the genetic aspects of the function of the neurogenic gene Enhancer of split [E(spl)] has previously been hampered by the densely transcribed nature of the chromosomal region within which it resides. We present data indicating that two distinct molecular species contribute to E(spl) function. Analysis of new E(spl) alleles has allowed us to define two complementing functions within the locus. Subsequent phenotypic analysis of different E(spl) deficiencies combined with P element-transformed constructs has demonstrated that these two functions correspond to: (1) a family of helix-loop-helix (HLH) protein-encoding genes and (2) the single copy gene E(spl) m9/10, whose product shares homology with G-protein beta subunits. The zygotically active E(spl) HLH genes can, at least partially, substitute for one another's functions and their total copy number determines the activity of the locus. E(spl) m9/10 acts synergistically with the E(spl) HLH genes and other neurogenic genes in the process of neurogenesis. The maternal component of E(spl) m9/10 has the most pronounced effect in neurogenesis, while its zygotic component is predominantly required during postembryonic development. The lethality of trans-heterozygotes of null E(spl) deficiency alleles with a strong Delta point mutation is a result of the concomitant reduction in activity of both E(spl) HLH and m9/10 functions. Immunocytochemical localization of the E(spl) m9/10 protein has revealed that it is a ubiquitously distributed nuclear component in embryonic, larval and imaginal tissues.


ER-MP12 antigen, a new cell surface marker on mouse bone marrow cells with thymus-repopulating ability: II. Thymus-homing ability and phenotypic characterization of ER-MP12-positive bone marrow cells.
In the accompanying paper we showed that six distinct subsets of bone marrow (BM) cells can be identified using the mAb ER-MP12 and ER-MP20 in two-colour immunofluorescence analysis. Upon intrathymic transfer into sublethally irradiated mice thymus-repopulating ability was restricted to ER-MP20- BM cells expressing either high or intermediate levels of the ER-MP12 antigen (1-2% and approximately 30% of BM nucleated cells respectively). The highest frequency of thymus-repopulating cells was found in the minor subset of ER-MP12(+)+20- BM cells. In the present study we demonstrate that upon intravenous transfer, thymus-homing and -repopulating BM cells are exclusively confined to the ER-MP12(+)+20- and ER-MP12+20- subpopulations, the highest frequency being detected among ER-MP12(+)+20- BM cells. Analysis of the peripheral blood leucocytes of reconstituted mice showed that not only prothymocytes but also progenitor cells of the B cell lineage as well as the myeloid lineage were present within both subsets. Three-colour flow cytometric analysis revealed that ER-MP12(+)+20- BM cells in particular were phenotypically heterogeneous with respect to the expression of the cell surface markers Thy-1, Sca-1, CD44, B220 and c-kit. Taken together our data demonstrate that ER-MP12 positively identifies BM cells with the ability to home to and repopulate the thymus. The phenotypic heterogeneity displayed by the ER-MP12(+)+20- BM subset, containing the highest frequency of thymus-homing and -repopulating cells, provides a basis for further separation of prothymocyte activity from other haematopoietic activities in the BM of the mouse.


Inferring Boolean networks with perturbation from sparse gene expression data: a general model applied to the interferon regulatory network.
Due to the large number of variables required and the limited number of independent experiments, the inference of genetic regulatory networks from gene expression data is a challenge of long standing within the microarray field. This report investigates the inference of Boolean networks with perturbation (BNp) from simulated data and observed microarray data. We interpret the discrete expression levels as attractor states of the underlying network and use the sequence of attractor states to determine the model. We consider the case where a complete sequence of attractors is known and the case where the known attractor states are arrived at by sampling from an underlying sequence of attractors. In the former case, a BNp can be inferred trivially, for an arbitrary number of genes and attractors. In the latter case, we use the constraints posed by the distribution of attractor states and the need to conserve probability to arrive at one of three possible solutions: an unique, exact network; several exact networks or a 'most-likely' network. In the case of several exact networks we use a robustness requirement to select a preferred network. In the case that an exact option is not found, we select the network that best fits the observed attractor distribution. We apply the resulting algorithm to the interferon regulatory network using expression data taken from murine bone-derived macrophage cells infected with cytomegalovirus.


Indian nurses in Italy: a qualitative study of their professional and social integration.
To investigate the lived subjective experiences of immigrant Indian nurses in Italy and specifically their professional and social integration. To study the worldwide, nursing flux is a health priority in the globalised world. The growth in migration trends among nurses, not only from Philippines or India, has proliferated in recent years. The research on nurses' mobility for Southern European countries is underexplored, and in Italy, the out-migration flows of Indian nurses were never analysed. Qualitative methodological approach. Semi-structured interviews (n = 20) were completed with Indian clinical nurses working in Italy for more than one year mainly in private organisations. A purposive sampling technique was used for recruitment. The data were then content-analysed using an inductive method. The findings were categorised into four themes: (1) aspects of professional integration and working experience, (2) intra- and interprofessional relationships and perceptions of the IPASVI Regulatory Nursing Board, (3) initial nursing education and continuous professional development and (4) perceptions of social integration. The results show that for Indian nurses in Italy emigration is important to gain opportunities to expand economic and social privileges as well as escape from historical assumptions of stigma associated with nursing work, especially for women. However, these conclusions have to be seen in wider socio-cultural complexities that are at the basis of transnational fluxes (Prescott & Nichter ). The research offers an insight into the complicated reasons for Indian nurses out-migration to Italy. Without comprehending the interwoven textures of the political and social relations that are continually constructed and re-constructed among different nations, it is difficult to understand nurses out-migration and consequently have a better and safer collaborative teamwork in the host countries.


Characterization and control of peak intensity distribution at the focus of a spatiotemporally focused femtosecond laser beam.
We report on experimental examination of two-photon fluorescence excitation (TPFE) at the focus of a spatially chirped femtosecond laser beam, which reveals an unexpected tilted peak intensity distribution in the focal spot. Our theoretical calculation shows that the tilting of the peak intensity distribution originates from the fact that along the optical axis of objective lens, the spatiotemporally focused pulse reaches its shortest duration exactly at the focal plane. However, when moving away from the optical axis along the direction of spatial chirp of the incident pulse, the pulse reaches its shortest duration either before or after the focal plane, depending on whether the pulse duration is measured above or below the optical axis as well as the sign of the spatial chirp. The tilting of the peak intensity distribution in the focal spot of the spatiotemporally focused femtosecond laser beam can play important roles in applications such as femtosecond laser micromachining and bio-imaging.


The development of a questionnaire to assess knowledge of epilepsy: 1--General knowledge of epilepsy.
It is well documented that knowledge is a vital factor in the ability to cope successfully with epilepsy. Misconceptions and deficits in knowledge have implications not only for psychosocial well-being but also for medical compliance. However, at present there is no commonly accepted objective measure of knowledge of epilepsy. The development of the Epilepsy Knowledge Profile--General (E.K.P.--G) is presented in this paper. Fifty-five true/false items (34 medical knowledge items, 21 social knowledge items) were selected by a range of experts in the field of epilepsy. A clinical trial of the questionnaire was then completed by 82 people with epilepsy attending a city centre outpatient clinic. Results indicated that the scale has both good internal reliability and test-retest reliability. Also the range of scores indicates that it is sensitive to differences in knowledge. Potential uses of the questionnaire are discussed.


Nonequilibrium chaos of disordered nonlinear waves.
Do nonlinear waves destroy Anderson localization? Computational and experimental studies yield subdiffusive nonequilibrium wave packet spreading. Chaotic dynamics and phase decoherence assumptions are used for explaining the data. We perform a quantitative analysis of the nonequilibrium chaos assumption and compute the time dependence of main chaos indicators--Lyapunov exponents and deviation vector distributions. We find a slowing down of chaotic dynamics, which does not cross over into regular dynamics up to the largest observed time scales, still being fast enough to allow for a thermalization of the spreading wave packet. Strongly localized chaotic spots meander through the system as time evolves. Our findings confirm for the first time that nonequilibrium chaos and phase decoherence persist, fueling the prediction of a complete delocalization.


[Syncope caused by paroxysmal atrial fibrillation and flutter: diagnostic usefulness of electrophysiological studies in the erect and supine positions].
In this study, we verified if the induction of atrial fibrillation/flutter, during the electrophysiological study, could be useful for the evaluation of syncope of unknown origin. Of 292 patients who underwent an electrophysiological study for unexplained symptoms, we selected 15 patients (5.1%) affected by syncope and pre-syncope. In these, the induction of atrial fibrillation (14 patients) or flutter (1 patient) just at the onset caused, the reproduction of the spontaneous symptoms. No other cause could be identified. These patients were affected by: 1) syncope or pre-syncope without electrocardiographic documentation of paroxysmal atrial fibrillation/flutter 2) syncope or presyncope and documented asymptomatic episodes of paroxysmal atrial fibrillation/flutter. Palpitations closely preceded or followed the syncope in 11/15 patients. Symptom reproduction was obtained in the supine position in 3 patients (heart rate 180 +/- 82 beat/min, systolic blood pressure 53 +/- 6 mmHg) and in the upright position in 12 patients (heart rate 177 +/- 24, systolic blood pressure 65 +/- 18 mmHg). The arrhythmia was induced by incremental atrial pacing or premature atrial beats in 3 cases, ramp in 3 cases and burst--mean rate 339 +/- 48 beat/min--in 9 cases. The arrhythmia lasted for a period of time ranging from a minimum of 1 mm to a maximum of 24 hours (median 1 hour). During sinus rhythm, an abnormal vasodepressor reflex (with a systolic blood pressure fall greater than or equal to 50 mmHg) could be induced in 7/9 patients by carotid sinus massage or 60 degrees tilt test.(ABSTRACT TRUNCATED AT 250 WORDS)


Child survival and BCG vaccination: a community based prospective cohort study in Uganda.
Data on non-specific effects of BCG vaccination in well described, general population African cohorts is scanty. We report the effects of BCG vaccination on post-neonatal infant and post-infancy mortality in a cohort of children in Mbale, Eastern Uganda. A community-based prospective cohort study was conducted between January 2006 and February 2014. A total of 819 eligible pregnant women were followed up for pregnancy outcomes and survival of their children up to 5 years of age. Data on the children's BCG vaccination status was collected from child health cards at multiple visits between 3 weeks and 7 years of age. Data was also collected on mothers' residence, age, parity, household income, self-reported HIV status as well as place of birth. Multivariable Cox proportional hazards regression models taking into account potential confounders were used to estimate the association between BCG vaccination and child survival. The neonatal mortality risk was 22 (95% CI: 13, 35), post-neonatal infant mortality 21 (12, 34) per 1,000 live births and the mortality risk among children between 1 and 5 years of age (post-infancy) was 63 (47, 82) per 1,000 live births. The median age at BCG vaccination was 4 days. Out of 819 children, 647 (79%) had received the BCG vaccine by 24 weeks of age. In the adjusted analysis, the rate of post-neonatal death among infants vaccinated with BCG tended to be nearly half of that among those who had not received the vaccine (adjusted HR: 0.47; 95% CI: 0.14, 1.53). BCG vaccination was associated with a lower rate of death among children between 1 and 5 years of age (adjusted HR: 0.26; 95% CI: 0.14, 0.48). The risk of early childhood death in Mbale, Uganda is unacceptably high. BCG vaccination was associated with an increased likelihood of child survival.


Impact of remifentanil introduction on practice patterns in general anesthesia.
The introduction of new medicine can change clinical practice patterns and may affect patient outcomes. In the present study, we investigated whether introduction of remifentanil in Japan affected the practice patterns of anesthesia. Using the Japanese Diagnosis Procedure Combination database, we extracted records of 423,491 patients who underwent surgery with general anesthesia in 243 hospitals before (2006) and after (2007) the introduction of remifentanil, and identified anesthetic agents used for each patient. A hierarchical mixed-effects logistic regression analysis was performed to analyze the factors that affected selection of remifentanil. Further, we compared postoperative length of stay (LOS), in-hospital mortality, and total costs between 2006 and 2007. In 2007, remifentanil was used for up to 41.4% of all general anesthesia, accompanied by a reduction in nitrous oxide use and an increase in total intravenous anesthesia. Female gender, increasing age, and preoperative comorbidities including diabetes mellitus, hypertension, liver cirrhosis, and chronic renal failure were positively associated with the use of remifentanil, whereas accompanying cardiac disease and co-application of epidural anesthesia were negatively associated. In 2007, a similar in-hospital death rate, similar or decreased total costs, slightly reduced duration of anesthesia, and substantially reduced postoperative LOS were seen compared to those in 2006. Our data revealed rapid changes in practice patterns in anesthesia after the introduction of remifentanil in Japan. Remifentanil was used more often in patients with comorbidities and without epidural anesthesia, and its introduction did not affect increase in total medical costs.


House-to-house survey of disabilities in rural communities in the north of the West Bank.
To identify the prevalence of disability and characteristics, conditions and needs of those with disabilities in rural communities in the north of the West Bank, 10 147 families were screened in a cross-sectional survey. Prevalence was 1.7% (806 persons with disabilities). Physical (34.0%), mental (15.9%) and speech (11.4%) disabilities were the commonest. The major cause as perceived by the families was heredity (30.5%): parental consanguinity was 50.8%. Economic conditions were the major problem for 41.1%, and the main barrier to receiving care: only 49.3% were receiving some kind of care. Integration in educational, work and social activities was low. Pressing needs included medical care, support equipment, and educational, physiotherapy and rehabilitation services.


Regulation of C-myc expression during growth and differentiation of normal and leukemic human myeloid progenitor cells.
C-myc proto-oncogene transcripts from serially harvested, colony-stimulating activity (CSA)-stimulated, normal progenitor-enriched human bone marrow cells were compared to those of the promyelocytic leukemia cell line HL-60 and to those of freshly obtained human myeloid leukemic cells. During the early culture period both normal and leukemic cells expressed the c-myc oncogene. In normal cells maximal expression occurred after 24 h of culture and did not occur in the absence of CSA. At this time, progranulocytes predominated in the cultured cells. Although cellular proliferation occurred for 96 h in vitro, c-myc expression ceased after 24-36 h. Terminally differentiated cells predominated in these cultures by 120 h. In contrast, although leukemic cells also expressed c-myc in vitro, transcription persisted throughout the culture period and, in the case of HL-60 cells, occurred in the absence of exogenous CSA. We also noted that normal cells with only one diploid gene copy exhibited, after 24 h of culture, only twofold fewer transcripts than did HL-60 cells in which there were 16 myc copies. Furthermore, c-myc mRNA degradation rates were similar in normal cells and in HL-60 cells. We conclude that c-myc transcription is a normal event in granulopoiesis linked to proliferative activity as well as to primitive developmental stage. Furthermore, the most consistent abnormality in leukemic cells in vitro is their failure to suppress transcriptional activity of this gene. We suggest that c-myc transcription in HL-60 cells may be appropriate for cells arrested at that developmental stage and that the amplified genes in HL-60 cells are quiescent relative to c-myc in normal cells at the same differentiation stage. The techniques described herein may be of value in identifying mechanisms by which normal hematopoietic cells suppress c-myc expression and aberrancies of these mechanisms in leukemic cells.