Long-term implantation of a new implantable programmable insulin pump in two diabetic dogs.
A positive-pressure implantable programmable pump with an integrated sideport and a detachable catheter was tested for long-term intraperitoneal insulin delivery in 2 diabetic dogs. Programming and refilling of the pump was simple and presented no problems during 28 months of pump function. During pump therapy an acceptable degree of glycemic control was maintained. No catheter occlusion occurred, and no skin erosions or infections were observed. Insulin in the pump reservoir was stable. After 9.5 months of pump function, flow progressively decreased because of insulin precipitation in the valved accumulator. Solubilization of these precipitates using 0.1 N NaOH injected in the reservoir and drained through the sideport normalized pump delivery rates. We conclude that this device is safe for long-term intraperitoneal insulin delivery. The sideport enables discrimination between different causes of pump malfunction and allows for the safe use of an alkaline solution to remove insulin precipitates, thus avoiding pump explantation.


Soft tissue oxygen saturation to predict admission from the emergency department: A prospective observational study.
We evaluated a soft tissue oxygen saturation (Sto2) measurement at triage for predicting admission to the hospital in adults presenting to the emergency department (ED) in addition to data routinely gathered at triage. This was a prospective, observational, single center study of adults presenting to the ED for evaluation. Research assistants obtained thenar eminence Sto2 measurements on subjects in ED triage. ED providers not involved in the study then made all management and disposition decisions. We prospectively collected data on each subject's final ED disposition (admission versus discharge). We identified the optimal Sto2 cutoff value for predicting admission. We then used logistic regression modeling to describe the added predictive value of Sto2 beyond routinely collected triage data including Emergency Severity Index level, age, and vital signs. We analyzed 2588 adult (>17years) subjects with 743 subjects (28.7%) admitted to the hospital. Sto2<76% was the optimal diagnostic cutoff for predicting admission. Of subjects with Sto2<76%, 158 of 384 (41.1%) underwent admission versus 585 of 2204 (26.5%) subjects with Sto2≥76. After controlling for age, vital signs, and ESI level in the logistic regression analysis, Sto2<76% had an odds ratio of 1.54 (95% confidence interval (CI), 1.19 to 1.98) for predicting admission. Sto2 may provide additional prognostic data to routine triage assessment regarding the disposition for undifferentiated adult patients presenting to the ED.


[Kaopectate in the combined treatment of patients with intestinal infections].
The paper presents results of multiple-modality treatment of patients with acute intestinal infections with making use of the drug preparation Kaopectate incorporating activated attapulgite which is a natural mixture of hydrates of magnesium silicate and silicate of alumina. The above drug has been shown to be endowed with a antidiarrheal and detoxifying activities.


Six years' audit of laboratory workload and rates of referral for colposcopy in a cervical screening programme in three districts.
To determine laboratory workload and rates of referral for colposcopy in a three district cervical screening programme during 1983-9 to assess the feasibility of accommodating call up of all women at risk, recall at three year intervals (now five year intervals), and investigation of women with all degrees of abnormality. Analysis of computerised screening histories dating back to 1977 of women screened in the Avon cervical screening programme. Three district health authorities covering the population of Bristol and Weston-super-Mare, comprising 800,000 people, of whom 250,000 were female residents aged 20 to 64. 196,977 Women aged 20 to 64 screened in cervical screening programme since 1983. Laboratory workload devoted to follow up of women with abnormalities increased sharply between 1987-8 and 1988-9, with increases of 54% (from 2075 to 3196) in the number of smears for follow up of severe dyskaryosis and invasive cancer, 40% (from 1925 to 2695) for mild and moderate dyskaryosis, and 49% (from 1793 to 2677) for borderline change. The increases were partly explained by the introduction in April 1988 of protocols for follow up and investigation based on guidance in an intercollegiate working party report. The proportion of women with mild and moderate dyskaryosis who were recommended for referral for colposcopy increased steadily from 9.9% in 1983-4 to 79.9% in 1988-9, and for borderline change the proportions were 3.5% and 13.6% respectively. Of all women tested in 1988-9, referral for colposcopy was recommended in 3%. The increase in laboratory follow up work identified, if it continued, could result in half of existing laboratory capacity in Avon being devoted to follow up work by 1993, with little prospect of maintaining call, recall, and quality control. Investigation of all women with minor cytological abnormalities is neither justifiable nor sustainable and will undermine the benefits of screening by increasing the rate of false positive results and the financial costs.


The acute effects of flotation restricted environmental stimulation technique on recovery from maximal eccentric exercise.
Flotation restricted environmental stimulation technique (REST) involves compromising senses of sound, sight, and touch by creating a quiet dark environment. The individual lies supine in a tank of Epsom salt and water heated to roughly skin temperature (34-35° C). This study was performed to determine if a 1-hour flotation REST session would aid in the recovery process after maximal eccentric knee extensions and flexions. Twenty-four untrained male students (23.29 ± 2.1 years, 184.17 ± 6.85 cm, 85.16 ± 11.54 kg) participated in a randomized, repeated measures crossover study. The participants completed 2 exercise and recovery protocols: a 1-hour flotation REST session and a 1-hour seated control (passive recovery). After isometric muscle strength testing, participants were fatigued with eccentric isokinetic muscle contractions (50 repetitions at 60°·s) of the nondominant knee extensors and flexors. Blood lactate, blood glucose, heart rate, OMNI-rating of perceived exertion for resistance exercise (OMNI-RPE), perceived pain, muscle soreness, and isometric strength were collected before exercise, after treatment, and 24 and 48 hours later. A multivariate analysis of covariance found that treatment had a significant main effect on blood lactate, whereas subsequent univariate analyses of variance found statistical significance with the immediate posttreatment blood lactate measures. The results indicate that flotation REST appears to have a significant impact on blood lactate and perceived pain compared with a 1-hour passive recovery session in untrained healthy men. No difference was found between conditions for muscle strength, blood glucose, muscle soreness, heart rate, or OMNI-RPE. Flotation REST may be used for recreational and professional athletes to help reduce blood lactate levels after eccentric exercise.


Redirecting T lymphocyte specificity by T cell receptor gene transfer--a new era for immunotherapy.
The therapeutic efficacy of adoptively transferred cytotoxic T lymphocytes (CTL) has been demonstrated in clinical trials for the treatment of chronic myelogenous leukemia, cytomegalovirus-mediated disease, and Epstein-Barr virus-positive B cell lymphomas. It is however limited by the difficulty of generating sufficient amounts of CTLs in vitro, especially for the treatment of solid tumors. Recent gene therapy approaches, including two clinical trials, successfully apply genetic engineering of T cell specificity by T cell receptor (TCR) gene transfer. In this review we want to elucidate several principles of the redirection of T cell specificity. We cover basic aspects of retroviral gene transfer, regarding transduction efficacy and transgene expression levels. It was demonstrated that the number of TCR molecules on a T cell is important for its function. Therefore, an efficient transfer system that yields high transduction efficiency and strong and stable transgene expression is a prerequisite to achieve effector function by redirected T cells. Furthermore, we consider more recent aspects of T cell specificity engineering. These include the possibility of co-transferring coreceptors to create for example functional T helper cells by engrafting CD4(+) T cells with a MHC class I restricted TCR and the CD8 coreceptor and vice versa. Also, risks related to the adoptive transfer of TCR gene-modified T cells and possible safety mechanisms are discussed. Finally, we summarize recent findings describing transferred TCRs capable of displacing endogenous TCRs from the cell surface.


[Sex gland function in obese women].
A study was made of the functional state of the gonads in 365 obese women. Clinical data were compared with the results of study of fractional composition of estrogens excreted with the urine at various phases of the menstrual cycle. Gonad dysfunction was much more frequent in neuro-endocrine than in exogenous-constitutional adiposity (62 and 31.5%, respectively). Amenorrhea was dominating among other disturbances of the menstrual cycle. Hirsutism was manifest in 10.5% of the patients with neuro-endocrine adiposity and disturbance of the menstrual cycle. A fall of the estrogen excretion, more pronounced in calculation per 1 kg and 1 m2 of body surface, was seen in obese women; as to estrogen excretion -- it approximately corresponded to such in healthy women at the initial phases of the menstrual cycle, i. e. at the period of the minimal estrogenic activity of the ovaries. There was a higher production of active estrogen fractions with their maximal content not at the ovulation phase, as in healthy persons, but at the lutein phase. A reduction of body weight promoted improvement of the gonad function, normalization of the quantitative and qualitative indices of the estrogen excretion.


Comparison of Hemodynamic Support by Impella vs. Peripheral Extra-Corporeal Membrane Oxygenation: A Porcine Model of Acute Myocardial Infarction.
Objectives: Several mechanical circulatory assist devices are used to treat critically ill patients requiring hemodynamic support during post-myocardial infarction or cardiogenic shock. However, little guidance is available to choose an appropriate device to match a particular patient's needs. An increased understanding of hemodynamic effects of the pump systems and their impact on myocardial pre-/afterload might help to better understand their behavior in different clinical settings. Methods: This was an open-labeled, randomized acute animal experiment. A model of acute univentricular myocardial injury by temporary balloon occlusion was used. The experiment was carried out in 10 juveniles female Piétrain pigs. The animals were randomized to mechanical hemodynamic support either by peripheral veno-arterial (VA-)ECMO or Impella CP. Results: While both devices were able to provide flows above 3 L/min and maintain sufficient end-organ perfusion, support by Impella resulted in a significantly more pronounced immediate effect on myocardial unloading: At the onset of device support, the remaining native cardiac output was reduced by 23.5 ± 15.3% ECMO vs. 66.2 ± 36.2% (Impella, p = 0.021). Native stroke volume was significantly decreased by Impella support compared to ECMO, indicating less mechanical work being conducted by the Impella-supported hearts despite similar total assisted cardiac output. Conclusions: Peripheral VA-ECMO and the transaortic Impella pump resulted in contrasting hemodynamic fingerprints. Both devices provided sufficient hemodynamic support and reduce left ventricular end-diastolic pressure in the acute setting. Treatment with the Impella device resulted in a more effective volume unloading of the left ventricle. A significant reduction in myocardial oxygen consumption equivalent was achieved by both devices: The Impella device resulted in a left-shift of the pressure-volume loop and a decreased pressure-volume-area (PVA), while VA-ECMO increased PVA but decreased heart rate. These data highlight the importance of specifically targeting heart rate in the management of AMI patients on hemodynamic support.


Long-Term Outcome of Cataract Surgery in Eyes with Pseudoexfoliation Syndrome Associated with Weak Zonules: A Case Report.
A cataract surgery in both eyes was scheduled for an 81-year-old female patient. However, ophthalmic examination revealed marked iridodonesis, phacodonesis and pseudoexfoliative material on the surface of the lens in both eyes indicating weak zonules caused by pseudoexfoliation syndrome, which was more pronounced in the left eye. Cataract surgery was performed initially in the left eye by phacoemulsification. Additionally, iris hooks and capsular tension ring (CTR) were used to stabilize the capsular bag, and the haptic of the intraocular lens (IOL) was sutured to the iris at the end of the surgery. The same procedure except haptic suturing was performed in the right eye after 6 months. The left eye remained stable, whereas the right eye developed considerable anterior capsular contraction 2 months postoperatively. Neodymium-doped yttrium aluminum garnet (Nd:YAG) laser capsulotomy was performed to treat the condition. Moreover, 3 years after the initial surgery, late IOL-CTR-capsular-bag complex dislocation developed in the right eye, and reposition surgery was performed. Three days after IOL-CTR-capsular-bag complex reposition surgery, endophthalmitis developed; the eye responded well to 1 mg intravitreal vancomycin treatment. IOL in the right eye remained stable 3 years postoperatively.


Intraspecific nuclear DNA variation in Drosophila.
We have summarized and analyzed all available nuclear DNA sequence polymorphism studies for three species of Drosophila, D. melanogaster (24 loci), D. simulans (12 loci), and D. pseudoobscura (5 loci). Our major findings are: (1) The average nucleotide heterozygosity ranges from about 0.4% to 2% depending upon species and function of the region, i.e., coding or noncoding. (2) Compared to D. simulans and D. pseudoobscura (which are about equally variable), D. melanogaster displays a low degree of DNA polymorphism. (3) Noncoding introns and 3' and 5' flanking DNA shows less polymorphism than silent sites within coding DNA. (4) X-linked genes are less variable than autosomal genes. (5) Transition (Ts) and transversion (Tv) polymorphisms are about equally frequent in non-coding DNA and at fourfold degenerate sites in coding DNA while Ts polymorphisms outnumber Tv polymorphisms by about 2:1 in total coding DNA. The increased Ts polymorphism in coding regions is likely due to the structure of the genetic code: silent changes are more often Ts's than are replacement substitutions. (6) The proportion of replacement polymorphisms is significantly higher in D. melanogaster than in D. simulans. (7) The level of variation in coding DNA and the adjacent noncoding DNA is significantly correlated indicating regional effects, most notably recombination. (8) Surprisingly, the level of polymorphism at silent coding sites in D. melanogaster is positively correlated with degree of codon usage bias. (9) Three proposed tests of the neutral theory of DNA polymorphisms have been performed on the data: Tajima's test, the HKA test, and the McDonald-Kreitman test. About half of the loci fail to conform to the expectations of neutral theory by one of the tests. We conclude that many variables are affecting levels of DNA polymorphism in Drosophila, from properties of nucleotides to population history and, perhaps, mating structure. No simple, all encompassing explanation satisfactorily accounts for the data.


Reversible autonomic dysfunction during antiviral treatment in patients with chronic hepatitis C virus infection: Anti-HCV therapy and autonomic function.
The first clinical sign of chronic hepatitis C virus (HCV) infection can be one of the various extrahepatic manifestations. During antiviral treatment, symptoms of HCV-associated neuropathies usually improve, but can also worsen and lead to discontinuation of anti-HCV therapy. Recently, we have reported autonomic dysfunction in patients with HCV infection. In the present prospective study, we analyzed the changes of autonomic function during anti-HCV treatment. Cardiovagal autonomic function was assessed in 22 HCV RNA-positive, treatment-naive patients by determining heart rate variability (HRV) and baroreflex sensitivity (BRS), at the beginning of treatment and 12, 24 and 48 weeks of antiviral therapy. interferon alfa-2 and ribavirin were given according to the guidelines. Both HRV and BRS time and frequency domain indices decreased after 12 weeks of therapy compared to the pre-treatment values; then the mean±SD values increased significantly by week 24 and continued to improve by week 48 of therapy-253.0±156.1 ms before therapy vs 111.6±81.9 at week 12, and 183.4±169.6 at week 24 vs 211.6±149.1 ms at week 48 for low-frequency HRV index; p<0.05 for all comparisons). These changes were independent from the presence of cryoglobulins and from virologic response. The first rise followed by reversible autonomic dysfunction during antiviral therapy may be caused by the immunomodulatory actions of interferon alfa-2.


Modulation of Mitochondrial and Epigenetic Targets by Polyphenols-rich Extract from Araucaria angustifolia in Larynx Carcinoma.
Araucaria angustifolia extract (AAE) is a polyphenol-rich extract that has gained interest as a natural anticancer agent. Recent work suggests that AAE induces oxidative damage and apoptosis through its action on decreasing complex I activity of the mitochondrial Electron Transport Chain (ETC). In the present study, we aimed to further examine the specific targets by which AAE exerts proapoptotic effects in HEp-2 cancer cells. Specifically, the effect of AAE on the: 1) levels of pyruvate dehydrogenase was assessed by ELISA assay; 2) levels of mitochondrial ETC complexes, focusing on complex I at the gene transcript and protein level relevant to ROS generation was evaluated by multiplex ELISA followed by qRT-PCR and immunoblotting; 3) mitochondrial network distribution analysis was assessed by MitoTracker Red CMXRos; and 4) chemical variations on DNA was evaluated by dot-blotting in HEp-2 cells. Results demonstrated that AAE increased protein levels of PDH, switching energy metabolism to oxidative metabolism. Protein expression levels of complex I and III were found decreased in AAE-treated HEp-2 cells. Analyzing the subunits of complex I, changes in protein and gene transcript levels of NDUFS7 and NDUFV2 were found. Mitochondria staining after AAE incubation revealed changes in the mitochondrial network distribution. AAE was able to induce DNA hypomethylation and decreased DNA (cytosine-5)-methyltransferase 1 activity. Our data demonstrate for the first time that AAE alters expression of NDUFS7 and NDUFV2 mitochondrial subunits and induce epigenetic changes in HEp-2 cancer cells leading to a possible suppression of oncogenes.


Individualized Biventricular Epicardial Augmentation Technology in a Drug-Induced Porcine Failing Heart Model.
For treatment of advanced heart failure, current strategies include cardiac transplantation or blood-contacting pump technology associated with complications, including stroke and bleeding. This study investigated an individualized biventricular epicardial augmentation technology in a drug-induced porcine failing heart model. A total of 11 pigs were used, for the assessment of hemodynamics and cardiac function under various conditions of support pressures and support durations (n = 4), to assess device positioning and function by in vivo computer tomographic imaging (n = 3) and to investigate a minimally invasive implantation on the beating heart (n = 4). Support pressures of 20-80 mm Hg gradually augmented cardiac function parameters in this animal model as indicated by increased left ventricular stroke volume, end-systolic pressures, and decreased end-diastolic pressures. Strong evidence was found regarding the necessity of mechanical synchronization of support end with the isovolumetric relaxation phase of the heart. In addition, the customized, self-expandable implant enabled a marker-guided minimally invasive implantation through a 4 cm skin incision using fluoroscopy. Correct positioning was confirmed in computer tomographic images. Continued long-term survival investigations will deliver preclinical evidence for further development of this concept.


Shoulder pain and injury risk factors in competitive swimmers: A systematic review.
To synthesize and assess the literature for shoulder pain and injury risk factors in competitive swimmers. Systematic review with best-evidence synthesis. CINHAL, SportDiscus, Scorpus, PubMed, and Embase databases from 1966 to April 30 2022. Cohort, cross-sectional, and case-control studies investigating shoulder pain or injury risk factors in competitive swimmers were included. Quality of eligible studies were assessed using a modified Newcastle-Ottawa scale. Risk factors were divided into four categories: modifiable-intrinsic, modifiable-extrinsic, non-modifiable, and other/secondary. Of 1356 studies identified, 24 full texts were evaluated for methodological quality, 22 met the criteria and were included in best evidence synthesis. There was no strong evidence supporting or refuting the association between 80 assessed variables and shoulder injury or pain. The swimmers' competitive level (nondirectional), and shoulder muscle recruitment profiles (e.g., increased activity of serratus anterior) exhibited moderate evidence supporting an association. Conversely, internal and external range of motion, middle finger back scratch test, training frequency, specialty stroke, height/weight, sex, and age all had moderate evidence opposing an association. Limited evidence was found for 58 variables, and conflicting for 8. The highest quality study (n = 201) suggested high acute-to-chronic workload ratio and reduced posterior shoulder strength endurance are associated with injury. Due to the paucity of high-quality studies, future prospective studies are needed to reevaluate known risk factor associations over exploring additional potential risk factors. Swimming practitioners should be aware of the nondirectional association of a swimmer's competitive level and pain, as squad changes could impact injury incidence. Moreover, swimmers experiencing shoulder pain may show increased activity in shoulder stabilizers during specific movements. Importantly, shoulder strength-endurance may be the most clinically relevant modifiable intrinsic risk factor.


Chronic condition self-management surveillance: what is and what should be measured?
The rapid growth in chronic disease prevalence, in particular the prevalence of multiple chronic conditions, poses a significant and increasing burden on the health of Americans. Maximizing the use of proven self-management (SM) strategies is a core goal of the US Department of Health and Human Services. Yet, there is no systematic way to assess how much SM or self-management support (SMS) is occurring in the United States. The purpose of this project was to identify appropriate concepts or measures to incorporate into national SM and SMS surveillance. A multistep process was used to identify candidate concepts, assess existing measures, and select high-priority concepts for further development. A stakeholder survey, an environmental scan, subject matter expert feedback, and a stakeholder priority-setting exercise were all used to select the high-priority concepts for development. The stakeholder survey gathered feedback on 32 candidate concepts; 9 concepts were endorsed by more than 66% of respondents. The environmental scan indicated few existing measures that adequately reflected the candidate concepts, and those that were identified were generally specific to a defined condition and not gathered on a population basis. On the basis of the priority setting exercises and environmental scan, we selected 1 concept from each of 5 levels of behavioral influence for immediate development as an SM or SMS indicator. The absence of any available measures to assess SM or SMS across the population highlights the need to develop chronic condition SM surveillance that uses national surveys and other data sources to measure national progress in SM and SMS.


[The potentials for the use of highly dispersed iron in neuro-oncology].
High-dispersion iron endowed with certain physical and chemical and medical and biological characteristics was shown to be helpful in treating malignant tumors of the brain. Effects were studied of ferromagnetic particles on glioma tumors, with these being transplanted under the capsule of the kidney in mice. There has been found out inhibition of growth of heterotransplants.


[Microscopic study of species specific features of hemostatic impairment in Ebola virus infected monkeys].
Pathological changes were studied in the blood vessels of baboons, green, rhesus, and cynomolgus monkeys at the end-stage Ebola (Zaire) infection. Marked microvascular lesions (capillary stasis, blood engorgement, thrombosis with blood cells, neutrophil accumulation, endothelial edema) were found in all the monkeys. These changes clearly indicate impaired organ blood supply. Multiple hemorrhages were formed by diapedesis without vascular wall destruction. Fibrin deposition and thrombi were features of hemostatic impairment in green and rhesus monkeys. Fibrin deposition and hemorrhages were not found in the cynomolgus monkeys. The possible mechanisms responsible for end-stage shock in Ebola virus-infection associated with microcirculatory disorders.


Climate trends and global crop production since 1980.
Efforts to anticipate how climate change will affect future food availability can benefit from understanding the impacts of changes to date. We found that in the cropping regions and growing seasons of most countries, with the important exception of the United States, temperature trends from 1980 to 2008 exceeded one standard deviation of historic year-to-year variability. Models that link yields of the four largest commodity crops to weather indicate that global maize and wheat production declined by 3.8 and 5.5%, respectively, relative to a counterfactual without climate trends. For soybeans and rice, winners and losers largely balanced out. Climate trends were large enough in some countries to offset a significant portion of the increases in average yields that arose from technology, carbon dioxide fertilization, and other factors.


EEG microstate periodicity explained by rotating phase patterns of resting-state alpha oscillations.
Spatio-temporal patterns in electroencephalography (EEG) can be described by microstate analysis, a discrete approximation of the continuous electric field patterns produced by the cerebral cortex. Resting-state EEG microstates are largely determined by alpha frequencies (8-12 Hz) and we recently demonstrated that microstates occur periodically with twice the alpha frequency. To understand the origin of microstate periodicity, we analyzed the analytic amplitude and the analytic phase of resting-state alpha oscillations independently. In continuous EEG data we found rotating phase patterns organized around a small number of phase singularities which varied in number and location. The spatial rotation of phase patterns occurred with the underlying alpha frequency. Phase rotors coincided with periodic microstate motifs involving the four canonical microstate maps. The analytic amplitude showed no oscillatory behaviour and was almost static across time intervals of 1-2 alpha cycles, resulting in the global pattern of a standing wave. In n=23 healthy adults, time-lagged mutual information analysis of microstate sequences derived from amplitude and phase signals of awake eyes-closed EEG records showed that only the phase component contributed to the periodicity of microstate sequences. Phase sequences showed mutual information peaks at multiples of 50 ms and the group average had a main peak at 100 ms (10 Hz), whereas amplitude sequences had a slow and monotonous information decay. This result was confirmed by an independent approach combining temporal principal component analysis (tPCA) and autocorrelation analysis. We reproduced our observations in a generic model of EEG oscillations composed of coupled non-linear oscillators (Stuart-Landau model). Phase-amplitude dynamics similar to experimental EEG occurred when the oscillators underwent a supercritical Hopf bifurcation, a common feature of many computational models of the alpha rhythm. These findings explain our previous description of periodic microstate recurrence and its relation to the time scale of alpha oscillations. Moreover, our results corroborate the predictions of computational models and connect experimentally observed EEG patterns to properties of critical oscillator networks.


TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells.
Human embryonic stem cells (hESCs) self-renew indefinitely and give rise to derivatives of all three primary germ layers, yet little is known about the signaling cascades that govern their pluripotent character. Because it plays a prominent role in the early cell fate decisions of embryonic development, we have examined the role of TGFbeta superfamily signaling in hESCs. We found that, in undifferentiated cells, the TGFbeta/activin/nodal branch is activated (through the signal transducer SMAD2/3) while the BMP/GDF branch (SMAD1/5) is only active in isolated mitotic cells. Upon early differentiation, SMAD2/3 signaling is decreased while SMAD1/5 signaling is activated. We next tested the functional role of TGFbeta/activin/nodal signaling in hESCs and found that it is required for the maintenance of markers of the undifferentiated state. We extend these findings to show that SMAD2/3 activation is required downstream of WNT signaling, which we have previously shown to be sufficient to maintain the undifferentiated state of hESCs. Strikingly, we show that in ex vivo mouse blastocyst cultures, SMAD2/3 signaling is also required to maintain the inner cell mass (from which stem cells are derived). These data reveal a crucial role for TGFbeta signaling in the earliest stages of cell fate determination and demonstrate an interconnection between TGFbeta and WNT signaling in these contexts.


Clonal distribution of natural competence in Actinobacillus actinomycetemcomitans.
The competence for natural transformation was investigated in 67 Actinobacillus actinomycetemcomitans strains. The transformation assays were performed with both cloned DNA fragments and chromosomal markers of A. actinomycetemcomitans. Competence was found in 12 of 18 serotype a strains, 0 of 21 serotype b strains, 0 of 14 serotype c strains, 3 of 6 serotype d strains, 3 of 4 serotype e strains, 0 of 3 serotype f strains, and 0 of 1 nonserotypeable strain. The transformation frequencies varied from 5 x 10(-3) to 4 x 10(-6) (median 1.5 x 10(-4)). The distribution pattern of natural competence is concordant with the major clonal lineages of A. actinomycetemcomitans. Serotype a strains are predominantly competent for transformation, while serotypes b and c strains are apparently non-competent.


Introducing Ferroelasticity into 1D Hybrid Lead Halide Semiconductor by Halogen Substitution Strategy.
Organic-inorganic hybrid lead halide perovskites (OLHPs), represented by (CH3 NH3 )PbI3 , are one of the research focus due to their exceptional performance in optoelectronic applications, and ferroelastic domain walls are benign to their charge carrier transport that is confirmed recently. Among them, the 1D OLHPs feature better stability against desorption and moisture, but related 1D ones possessing ferroelasticity are rarely investigated and reported so far. In this work, the 1D ferroelastic semiconductor (N-iodomethyl-N-methyl-morpholinium)PbI3 ((IDMML)PbI3 ) is prepared successfully by introducing successively halogenate atoms from Cl, Br to I into the organic cation of the prototype (N,N-dimethylmorpholinium)PbI3 ((DMML)PbI3 ). Notably, (IDMML)PbI3 shows the narrow bandgap energy (≈2.34 eV) according to the ultraviolet-visible absorption spectrum and the theoretical calculation, and possesses the evident photoconductive characteristic with the on/off ratio of current of ≈50 under the 405 nm light irradiation. This work provides a new case for the ferroelastic OLHPs and will inspire intriguing research in the field of optoelectronic.


The Effects of Perceived Discrimination on Immigrant and Refugee Physical and Mental Health.
Discrimination has been identified as a major stressor and influence on immigrant health. This study examined the role of perceived discrimination in relation to other factors, in particular, acculturation, in physical and mental health of immigrants and refugees. Data for US adults (18+ years) were derived from the National Epidemiologic Survey on Alcohol and Related Conditions. Mental and physical health was assessed with SF-12. Acculturation and perceived discrimination were assessed with multidimensional measures. Structural equation models were used to estimate the effects of acculturation, stressful life effects, perceived discrimination, and social support on health among immigrants and refugees. Among first-generation immigrants, discrimination in health care had a negative association with physical health while discrimination in general had a negative association with mental health. Social support had positive associations with physical and mental health and mediated the association of discrimination to health. There were no significant associations between discrimination and health among refugees, but the direction and magnitude of associations were similar to those for first-generation immigrants. Efforts aiming at reducing discrimination and enhancing integration/social support for immigrants are likely to help with maintaining and protecting immigrants' health and well-being. Further research using larger samples of refugees and testing moderating effects of key social/psychosocial variables on immigrant health outcomes is warranted. This study used multidimensional measures of health, perceived discrimination, and acculturation to examine the pathways between key social/psychosocial factors in health of immigrants and refugees at the national level. This study included possibly the largest national sample of refugees.


Dissipative soliton evolution in ultra-large normal-cavity-dispersion fiber lasers.
Dissipative soliton (DS) evolution in passively mode-locked fiber lasers with ultra-large net-normal-dispersion (as large as 1 ps(2)) is investigated. The proposed DS laser operates on three statuses with respect to the pump power. The DS laser works on a status that is similar to an all-normal-dispersion laser when the pump power is low, whereas it creates a new type of pulses exhibited as the trapezoid-spectrum profile when the pump power is large. The laser cavity emits the unstable pulses between the above two statuses. The cubic-quintic Ginzburg-Landau equation can serve to qualitatively explain our experimental observations.


N-Terminal Brain Natriuretic Peptide First Week After Burn Injury.
B-type natriuretic peptide has shown promising results as a biomarker for acute kidney injury in general intensive care patients. It may also indirectly reflect fluid balance of the circulation. Among burn patients, it has been observed to indicate excessive fluid resuscitation and organ dysfunction, although its clinical use to indicate acute kidney injury or guide fluid resuscitation has not been validated. The aim of this study was to evaluate whether the N-terminal pro-brain natriuretic peptide values are related to the amount of fluids given after severe burn injury and whether it can act as a novel biomarker for acute kidney injury in these patients. Nineteen consecutive burn patients were included. Plasma N-terminal pro-brain natriuretic peptide was measured daily during 1 week from admission. Other variables such as laboratory values and intravenous infusions were also recorded. The association between acute kidney injury and N-terminal pro-brain natriuretic peptide values was analyzed with a multivariable panel regression model, adjusted for burned total body surface area, age, body mass index, and laboratory values. N-terminal pro-brain natriuretic peptide values varied between single patients, and even more between the patients who developed acute kidney injury. Older age, lower body mass index, and cumulative infusions were independently associated with higher N-terminal pro-brain natriuretic peptide values, whereas acute kidney injury was not. N-terminal pro-brain natriuretic peptide values correlated with cumulative infusions given during the first week. The authors could not validate the role of N-terminal pro-brain natriuretic peptide as a biomarker for acute kidney injury in burns.


Absolute quantification of phosphorus metabolite concentrations in human muscle in vivo by 31P MRS: a quantitative review.
31P MRS offers a unique view of muscle metabolism in vivo, but correct quantification is important. Inter-study correlation of estimates of [Pi] and [phosphocreatine (PCr)] in a number of published studies suggest that the main technical problem in calibrated 31P MRS studies is the measurement of PCr and Pi signal intensities, rather than absolute quantification of [ATP]. For comparison, we discuss the few published biopsy studies of calf muscle and a selection of the many studies of quadriceps muscle. The ATP concentration is close to the value that we obtained in calf muscle in our own study, presented here, on four healthy subjects, by localised 31P MRS using a surface coil incorporating an internal reference and calibrated using an external phantom. However, the freeze-clamp biopsy PCr concentration is approximately 20% lower than the value obtained by 31P MRS, consistent with PCr breakdown by creatine kinase during freezing. Finally, we illustrate some consequences of uncertainty in resting [PCr] for analysis of mitochondrial function from PCr kinetics using a published 31P MRS study of exercise and recovery: the lower the assumed resting [PCr], the lower the absolute rate of oxidative ATP synthesis estimated from the PCr resynthesis rate; in addition, the lower the assumed resting [PCr], or the higher the assumed [total creatine], the higher the apparent resting [ADP], and therefore the more sigmoid the relationship between the rate of oxidative ATP synthesis and [ADP]. Correct quantification of resting metabolite concentrations is crucially important for this sort of analysis. Our own results ([PCr] = 33 +/- 2 mM, [Pi] = 4.5 +/- 0.2 mM, and [ATP] = 8.2 +/- 0.4 mM; mean +/- SEM) are close to the overall mean values of the 10 published studies on calf muscle by 'calibrated' 31P MRS (as in the present work), and of [PCr] and [Pi] in a representative selection of 'uncalibrated' 31P MRS studies (i.e. from measured PCr/ATP and Pi/ATP ratios, assuming a literature value for [ATP]).


Plasma gastrin immunoreactivity in dogs with acute gastric dilatation-volvulus.
Plasma gastrin immunoreactivity was measured by radioimmunoassay in 45 dogs with acute gastric dilatation-volvulus (GDV). Significant increases (P less than 0.05) were found in dogs with acute GDV and in the fasted state after surgical treatment and recovery. The data suggested that dogs that have had GDV may have preexisting high plasma gastrin immunoreactivity. In dogs with acute GDV, plasma gastrin immunoreactivity was not found to be helpful in formulating prognosis. Circumcostal gastropexy did not affect plasma gastrin immunoreactivity.


[Vasculitis caused by hypersensitivity: an analysis of 60 patients].
Sixty cases of hypersensitivity vasculitis are revised analyzing their possible etiology, clinical course, analytical and histological alterations, evolution, and treatment. Thirty of these cases corresponded to Schönlein Henoch purpura (SH). The results of this subgroup (SH) are compared to other hypersensitivity vasculitis (HV).


Potential Saving of Antibiotics for Respiratory Infections in Several European Countries: Insights from Market Research Data.
Antibiotics represent an essential pillar in the treatment of respiratory infections (RI). Overuse of antibiotics in avoidable cases and inappropriate application in bacterial infections facilitate treatment resistance, threatening their effectiveness and causing a significant healthcare challenge. We therefore assessed the savings potential for antibiotics in ambulant care of selected RI (bronchitis and cough, pharyngitis, rhinosinusitis) in several European countries based on market research data for the year 2019. Number of antibiotic packages sold in pharmacies varied, with highest values in Serbia and France, and lowest in Sweden and Switzerland. Selected RI contributed nearly half of overall ambulant antibiotic prescriptions, with around one fifth given for bronchitis and cough; the vast majority was estimated to be of viral origin with potentially avoidable antibiotic use. Antibiotic consumption for selected RI in eight European countries (Austria, Belgium, the Czech Republic, France, Germany, Poland, Slovakia, and Switzerland) amounted to nearly 100 million, with an overall savings potential between 66.2 and 83.7 million packages. The highest estimated volume of avoidable antibiotics was in France (44.7 million, 0.80 per capita), and lowest in Switzerland (1.4 million, 0.18 per capita). Due to substantial savings potential, prudent use of antibiotics and adequate application of alternatives should be promoted in daily practice.


Bioenergetic profiles diverge during macrophage polarization: implications for the interpretation of 18F-FDG PET imaging of atherosclerosis.
Conventional cardiovascular imaging is invaluable for the assessment of late sequelae of atherosclerosis, such as diminished perfusion reserve and luminal stenosis. Molecular imaging provides complementary information about plaque composition and ongoing biologic processes in the vessel wall, allowing the early diagnosis and risk stratification of patients. Detection of enhanced glucose uptake, using (18)F-FDG PET, has been proposed as a noninvasive approach to track macrophage activation as a critical event in the development and progression of atherosclerosis. In this study, we determined the impact of macrophage polarization on glucose metabolism and oxidative phosphorylation. Murine peritoneal macrophages were incubated in the presence of interferon-γ (IFN-γ) plus tumor necrosis factor-α (TNF-α), lipopolysaccharide (LPS), or interleukin-4 (IL-4) to induce classic (M1 and M(LPS)) or alternative (M2) polarization, respectively. Glucose uptake was measured using (3)H-deoxyglucose. Oxidative phosphorylation was evaluated using an extracellular flux analyzer. Mitochondrial DNA copy numbers were quantified by polymerase chain reaction. The expression of glucose transporter-1 (Glut-1), hexokinase-1 and -2 (Hk-1 and Hk-2, respectively), mitochondrial transcription factor-1 (Tfam), and cytochrome c oxidase subunit I (Cox-1) was determined by quantitative reverse transcription polymerase chain reaction. Stimulation of macrophages by LPS, but not polarization with either IFN-γ plus TNF-α (M1) or IL-4 (M2), resulted in a 2.5-fold increase in (3)H-deoxyglucose uptake. Enhanced glucose uptake by M(LPS) macrophages paralleled the overexpression of rate-limiting proteins involved in transmembrane transport and intracellular trapping of glucose--that is, Glut-1, Hk-1, and Hk-2. Alternatively polarized M2 macrophages developed a markedly higher spare respiratory capacity than both nonpolarized and classically polarized M1 macrophages. M2 polarization was associated with a 4.6-fold increase in mitochondrial content of the cells, compared with nonpolarized macrophages. The expression of Tfam, a major regulator of mitochondrial biogenesis, and Cox-1, a critical component of respiratory chain, was significantly increased in M2 polarized macrophages. Polarization of macrophages induces distinct metabolic profiles with respect to glycolysis versus oxidative phosphorylation, with alternatively polarized macrophages shifting to mitochondria as their main source of adenosine triphosphate. Only M(LPS), but not M1 or M2 polarized macrophages, showed increased glucose uptake, suggesting that glucose metabolism is regulated independent of the polarization state and macrophage polarization may not be detectable by (18)F-FDG PET.


Pulmonary embolic disease: the roles of angiography and lung scanning in diagnosis.
The definitive diagnosis of pulmonary embolism remains difficult despite recent advances in nuclear medicine and angiography. In 10% of a selected series of 145 patients a negative chest x-ray and a positive lung scan was associated with no arteriographic evidence of pulmonary emboli. A normal perfusion lung scan excludes significant pulmonary embolism. When pulmonary arteriography is necessary, a biplane selective pulmonary angiogram should be performed and subselective injections may be required. Pulmonary arteriography is less of a threat to a patient suspected of having pulmonary embolic disease than inappropriate treatment.


Enhancement of endocytosis due to aminophospholipid transport across the plasma membrane of living cells.
Formation of intracellular vesicles is initiated by membrane budding. Here we test the hypothesis that the plasma membrane surface area asymmetry could be a driving force for vesicle formation during endocytosis. The inner layer phospholipid number was therefore increased by adding exogenous aminophospholipids to living cells, which were then translocated from the outer to the inner layer of the membrane by the ubiquitous flippase. Addition of either phosphatidylserine or phosphatidylethanolamine led to an enhancement of endocytosis, showing that the observed acceleration does not depend on the lipid polar head group. Conversely, a closely related aminophospholipid that is not recognized by the flippase, lyso-alpha-phosphatidylserine, inhibited endocytosis, and similar results were obtained with a cholesterol derivative that also remains in the plasma membrane outer layer. Thus an increase of lipid concentration in the inner layer enhanced internalization, whereas an increase of the lipid concentration in the outer layer inhibited internalization. These experiments suggest that transient asymmetries in lipid concentration might contribute to the formation of endocytic vesicles.


Involution of retinopathy of prematurity and neurodevelopmental outcomes after intravitreal bevacizumab treatment.
This single-centered, retrospective cohort study investigated the timing of involution of retinopathy of prematurity (ROP) and retinal vascularization to zone III after intravitreal bevacizumab (IVB) treatment and its possible impacts on postnatal growth and neurodevelopment. Premature infants with birth weight ≤1500 g, born between 2008 to 2014 and diagnosed with ROP were enrolled. All patients with type 1 ROP underwent IVB as 1st line treatment and were recruited as the study group; those with any stage of ROP except type 1 ROP without treatment served as controls. Neurodevelopmental outcomes were assessed using the Bayley Score of Infant Development (BSID) editions II or III. The study group included 35 eyes from 18 patients; the control group included 86 patients. Twenty-three eyes (65.7%) exhibited ROP regression after a single dose of IVB. The majority of plus sign and extraretinal neovascularization regressed within two weeks. The length of time for retinal vascularization to reach zone III was significantly longer in the treatment group compared with the control (mean post-menstruation age 54.5 vs. 47.0 weeks, p<0.001). Long-term follow-up showed no significant differences in body weight and neurodevelopment between the study and control groups up to the 2-year corrected age.


Interventions to improve suboptimal prescribing in nursing homes: A narrative review.
Appropriate medication prescribing for nursing home residents remains a challenge. The purpose of this study was to conduct a narrative review of the published literature describing randomized controlled trials that used interventions to improve suboptimal prescribing in nursing homes. The PubMed, International Pharmaceutical Abstracts, and EMBASE databases were searched for articles published in the English language between January 1975 and December 2009, using the terms drug utilization, pharmaceutical services, aged, long-term care, nursing homes, prescribing, geriatrics, and randomized controlled trial. A manual search of the reference lists of identified articles and the authors' files, book chapters, and recent review articles was also conducted. Abstracts and posters from meetings were not included in the search. Studies were included if they: (1) had a randomized controlled design; (2) had a process measure outcome for quality of prescribing or a distal outcome measure for medication-related adverse patient events; and (3) involved nursing home residents. Eighteen studies met the inclusion criteria for this review. Seven of those studies described educational approaches using various interventions (eg, outreach visits) and measured suboptimal prescribing in different manners (eg, adherence to guidelines). Two studies described computerized decision-support systems to measure the intervention's impact on adverse drug events (ADEs) and appropriate drug orders. Five studies described clinical pharmacist activities, most commonly involving a medication review, and used various measures of suboptimal prescribing, including a measure of medication appropriateness and the total number of medications prescribed. Two studies each described multidisciplinary and multifaceted approaches that included heterogeneous interventions and measures of prescribing. Most (15/18; 83.3%) of these studies reported statistically significant improvements in >or=1 aspect of suboptimal prescribing. Only 3 of the studies reported significant improvements in distal health outcomes, and only 3 measured ADEs or adverse drug reactions. Mixed results were reported for a variety of approaches used to improve suboptimal prescribing. However, the heterogeneity of the study interventions and the various measures of suboptimal prescribing used in these studies does not allow for an authoritative conclusion based on the currently available literature.


Polymorphisms of selected xenobiotic genes contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population.
The xenobiotic enzyme system that enables us to detoxify carcinogens exhibits identifiable genetic polymorphisms that are highly race specific. We hypothesized that polymorphisms of these genes may be associated with risk of thyroid cancer. To evaluate the role of genetic polymorphisms of xenobiotic genes in thyroid cancer, we conducted a hospital-based case-control study in Saudi population. 223 incident papillary thyroid cancer cases and 513 controls recruited from Saudi Arabian population were analyzed for the association between polymorphisms in genes encoding folic acid metabolizing enzymes MTHFR and six xenobiotics-metabolizing enzymes including CYP1A1 T3801C, C4887A, GSTP1 A1578G, C2293T, GSTM1, GSTT1, NAT2 G590A, NQO*1 C609T, using PCR-RELP. Among selected genes, CYP1A1 C4887A genotypes CA, AA and variant allele A demonstrated significant differences and greater risk of developing thyroid cancer comparing to wild type genotype CC (CA vs. CC; p < 0.0001, OR = 1.91, 95% CI = 1.36-2.70, AA vs. CC; p < 0.001, OR = 3.48, 95% CI = 1.74-6.96 and CA+AA vs. CC; p < 0.0001, OR = 2.07, 95% CI = 1.49-2.88). GSTT1 null showed 3.48 times higher risk of developing thyroid cancer (p < 0.0001, 95% CI = 2.48-4.88) while GSTM1 null showed protective effect (p < 0.05, OR = 0.72, 95% CI = 0.52-0.99). Remaining loci demonstrated no significance with risk. Of the 9 polymorphisms screened, we identified GST, GSTM1 and CYP1A1 C4887A, may be of importance to disease process and may be associated with papillary thyroid cancer risk in Saudi Arabian population.


TATES: efficient multivariate genotype-phenotype analysis for genome-wide association studies.
To date, the genome-wide association study (GWAS) is the primary tool to identify genetic variants that cause phenotypic variation. As GWAS analyses are generally univariate in nature, multivariate phenotypic information is usually reduced to a single composite score. This practice often results in loss of statistical power to detect causal variants. Multivariate genotype-phenotype methods do exist but attain maximal power only in special circumstances. Here, we present a new multivariate method that we refer to as TATES (Trait-based Association Test that uses Extended Simes procedure), inspired by the GATES procedure proposed by Li et al (2011). For each component of a multivariate trait, TATES combines p-values obtained in standard univariate GWAS to acquire one trait-based p-value, while correcting for correlations between components. Extensive simulations, probing a wide variety of genotype-phenotype models, show that TATES's false positive rate is correct, and that TATES's statistical power to detect causal variants explaining 0.5% of the variance can be 2.5-9 times higher than the power of univariate tests based on composite scores and 1.5-2 times higher than the power of the standard MANOVA. Unlike other multivariate methods, TATES detects both genetic variants that are common to multiple phenotypes and genetic variants that are specific to a single phenotype, i.e. TATES provides a more complete view of the genetic architecture of complex traits. As the actual causal genotype-phenotype model is usually unknown and probably phenotypically and genetically complex, TATES, available as an open source program, constitutes a powerful new multivariate strategy that allows researchers to identify novel causal variants, while the complexity of traits is no longer a limiting factor.


Stimuli-responsive electrospun fibers and their applications.
Stimuli-responsive electrospun nanofibers are gaining considerable attention as highly versatile tools which offer great potential in the biomedical field. In this critical review, an overview is given on recent advances made in the development and application of stimuli-responsive fibers. The specific features of these electrospun fibers are highlighted and discussed in view of the properties required for the diverse applications. Furthermore, several novel biomedical applications are discussed and the respective advantages and shortcomings inherent to stimuli-responsive electrospun fibers are addressed (136 references).


The Arabic Arthritis Self-Efficacy Scale-8 (ASES-8): a valid and reliable measure of evaluating self-efficacy in Palestinian patients with rheumatoid arthritis.
The Arthritis Self-Efficacy Scale-8 (ASES-8) is one of the most commonly used scales to measure patient-reported arthritis-specific self-efficacy. However, evidence about the validity and reliability of ASES-8 in an Arabic-speaking arthritis population is lacking. This study aimed to cross-culturally adapt and assess aspects of validity and reliability of the Arabic version of the ASES-8. The ASES-8 was translated into the Arabic language using the back-translation method, and administered to 67 patients with rheumatoid arthritis (RA). Construct validation methods used exploratory factor analysis and correlating the ASES-8 scores with disease-related variables expected to be related to the arthritis self-efficacy construct. An internal consistency test was conducted. Floor and ceiling effects were considered present if more than 15% of patients achieved high (=10) and low (=1) scores on the Arabic ASES-8 for both the scale and item scores. Exploratory factor analysis demonstrated a one-factor solution (factor loadings: 0.54-0.81). ASES-8 scores were correlated with all measures assessed (r = -0.24 to -0.57 and r = 0.06-0.66), demonstrating construct validity. Internal consistency was acceptable for measures of Cronbach's alpha (0.86-0.88). The scale did not exhibit ceiling or floor effects. The Arabic version of ASES-8 is valid and reliable for evaluating self-efficacy in patients with rheumatoid arthritis.Implications for rehabilitationThe Arthritis Self-Efficacy Scale (ASES-8) questionnaire was translated and adapted for use in Arabic language.This questionnaire is a valid and reliable instrument for evaluating self-efficacy among Arabic individuals with rheumatoid arthritis.This will support greater use of this tool worldwide in clinical and research practices that include Arabic people.


Pseudomonas aeruginosa biofilms exposed to imipenem exhibit changes in global gene expression and beta-lactamase and alginate production.
The lungs of cystic fibrosis (CF) patients are commonly colonized with Pseudomonas aeruginosa biofilms. Chronic endobronchial P. aeruginosa infections are impossible to eradicate with antibiotics, but intensive suppressive antibiotic therapy is essential to maintain the lung function of CF patients. The treatment often includes beta-lactam antibiotics. How these antibiotics influence gene expression in the surviving biofilm population of P. aeruginosa is not clear. Thus, we used the microarray technology to study the effects of subinhibitory concentrations of a beta-lactam antibiotic, imipenem, on gene expression in biofilm populations. Many genes showed small but statistically significant differential expression in response to imipenem. We identified 34 genes that were induced or repressed in biofilms exposed to imipenem more than fivefold compared to the levels of induction or repression for the controls. As expected, the most strongly induced gene was ampC, which codes for chromosomal beta-lactamase. We also found that genes coding for alginate biosynthesis were induced by exposure to imipenem. Alginate production is correlated to the development of impaired lung function, and P. aeruginosa strains isolated from chronically colonized lungs of CF patients are nearly always mucoid due to the overproduction of alginate. Exposure to subinhibitory concentrations of imipenem caused structural changes in the biofilm, e.g., an increased biofilm volume. Increased levels of alginate production may be an unintended adverse consequence of imipenem treatment in CF patients.


Ocular tropism of respiratory viruses.
Respiratory viruses (including adenovirus, influenza virus, respiratory syncytial virus, coronavirus, and rhinovirus) cause a broad spectrum of disease in humans, ranging from mild influenza-like symptoms to acute respiratory failure. While species D adenoviruses and subtype H7 influenza viruses are known to possess an ocular tropism, documented human ocular disease has been reported following infection with all principal respiratory viruses. In this review, we describe the anatomical proximity and cellular receptor distribution between ocular and respiratory tissues. All major respiratory viruses and their association with human ocular disease are discussed. Research utilizing in vitro and in vivo models to study the ability of respiratory viruses to use the eye as a portal of entry as well as a primary site of virus replication is highlighted. Identification of shared receptor-binding preferences, host responses, and laboratory modeling protocols among these viruses provides a needed bridge between clinical and laboratory studies of virus tropism.


Risk adjustment of capitation payments to behavioral health care carve-outs: how well do existing methodologies account for psychiatric disability?
This study used 1994-1995 administrative data from a large public employer to examine the viability of commercial risk adjustment systems for setting capitation payments to competing behavioral health care "carve-outs". The ability of Hierarchical Condition Categories and Adjusted Diagnostic Groups to predict psychiatric expenditures was improved by controlling separately for psychiatric disability. However, even the best models underpredicted expenditures of patients with psychiatric disability by 15%. Relative to full capitation, "mixed" payment systems and soft capitation reduce the ability of carve-outs to earn disproportionate profits by enrolling healthy patients and avoiding sick ones, yet also diminish incentives for cost containment.


A pilot curriculum in international surgery for medical students.
As medical student interest in global surgical care grows, a comprehensive curriculum is necessary to understand surgical care in resource-limited environments. We developed a surgical elective encompassing a multiyear medical student curriculum, with the goal of improving students' understanding of global surgical care, consisting of a junior seminar and a senior clerkship. This student elective focused on the global burden of surgical disease, ethics of care in low-resource settings, and care of marginalized U.S. Students who participated in the fourth year clerkship at a tertiary center in Northern India completed a reflective essay on their experience. Qualitative analysis was conducted using constant comparison and axial coding to establish a grounded theory. Medical students showed a desire to serve the poor, build collaborative relationships, and integrate international health into their future career. This novel curriculum provides students a clinical and public health basis to understand challenges of surgical care in low-resource environments while laying the groundwork for students with a future career in global health.


Order-to-disorder structural transformation of a coordination polymer and its influence on proton conduction.
We observed an ordered-to-disordered structural transformation in a Cu(2+) coordination polymer and investigated its influence on the proton conductivity. The transformation generated highly mobile proton carriers in the structure. The resulting material exhibited a conductivity greater than 10(-2) S cm(-1) at 130 °C. The structural transformation and the conduction mechanism were investigated by EXAFS, TPD-MS and NMR.


Isolation and sequencing of two alpha-globin genes alpha(A) and alpha(D) in pigeon and evidence for embryo-specific expression of the alpha(D)-globin gene.
By screening a pigeon genomic DNA library, we isolated a recombinant phage clone containing the alpha(A)-globin gene. The DNA sequence of the approximately 6kbp-long insert fragment of the phage clone was determined. The sequence suggested the existence of pigeon alpha(D)-globin gene located 3.1 kbp upstream from the alpha(A)-globin gene. The expression of the alpha(D)-globin in late embryo was also shown by the N-terminal amino-acid sequence of the intact globin chain. These results show that two adult alpha-globin genes, alpha(A) and alpha(D), exist in the pigeon genome, and the alpha(D)-globin is expressed at the late embryo stage. The stage-specific expression suggests the existence of regulatory elements and factors interacting to inhibit transcription at the adult stage.


Public Health Strategies for the Gradual Lifting of the Public Sector Lockdown in Jordan and the United Arab Emirates During the COVID-19 Crisis.
In this viewpoint, we present public policies and public health strategies for a gradual lockdown lifting during the coronavirus disease (COVID-19) crisis in two country cases, Jordan and the United Arab Emirates. While managing pandemics is critical in terms of preparedness, response, and recovery, it is equally vital to ensure that the measures for a lockdown exit are both efficient and effective. It is critical to learn from first-wave lessons to systematize responses during times of crisis and execute appropriate public policies and public health strategies. This viewpoint highlights the importance of the following during lockdown lifting: pandemic control, health care capacity, training, scaling up of resources and systems, and priority setting of public policies by acknowledging challenges, developing policy insights, and setting the policy direction. The systematic approaches and leadership thinking required for lifting lockdowns during a crisis include the three Rs: Readiness, Responses, and Resilience & Recovery.


Omics era in forensic medicine: towards a new age
Forensic medicine and sciences is a multidisciplinary branch of science, which frequently benefit from novel technologies. State of the art omics technologies have begun to be performed in forensic medicine and sciences, particularly in postmortem interval, intoxication, drugs of abuse, diagnosis of diseases and cause of death. This review aims to discuss the role and use of great omics (metabolomics, proteomics, genomics and transcriptomics) in forensic sciences, in detail. A detailed review of related literature was performed, and studies were subdivided as per the type of omics. Omics seems as a revolutionary step in forensic science and sure carries it towards a new age. The number of forensic studies utilizing omics steadily increases in last years. Omics strategies should be used together in order to gather more accurate and certain data. Additional studies need to be performed to incorporate omics into routine forensic methodology.


Species specificity of human interleukin-3 demonstrated by cloning and expression of the homologous rhesus monkey (Macaca mulatta) gene.
To enable preclinical studies on homologous interleukin-3 (IL-3) in primate species, we isolated the gene encoding Rhesus monkey IL-3 (RhIL-3). The nucleotide sequence of the RhIL-3 gene displayed 92.9% homology with that of the human IL-3 (hIL-3) gene. The isolated RhIL-3 gene encodes a 143-amino acid (aa) precursor polypeptide, nine C-terminal residues shorter than the human protein. Protein homology was found to be 89.5% for the signal peptide (19 aa) and 80.5% for the mature protein (124 aa). Comparison of the human and RhIL-3 coding sequences showed that the majority of substitutions had occurred at amino acid replacement sites indicating a rapid evolution of the IL-3 protein. After expression of a genomic fragment in COS cells, RhIL-3 cDNA was constructed, which enabled large-scale production of the RhIL-3 polypeptide, RhIL-3 produced by Bacillus licheniformis and purified to homogeneity appeared to be approximately 100-fold more effective in stimulating Rhesus monkey hematopoietic progenitors than hIL-3, whereas RhIL-3 and hIL-3 showed comparable stimulatory activity on normal as well as malignant human hematopoietic cells. Thus, the rapid evolution of hIL-3 has resulted in a unidirectional species specificity, which most likely restricts the in vivo effects of hIL-3 in Macaca species.


Gene expression profiling in lungs of chronic asthmatic mice treated with galectin-3: downregulation of inflammatory and regulatory genes.
Asthma is a disorder characterized by a predominance of Th2 cells and eosinophilic inflammation. Suppressors of cytokine signaling (SOCS) proteins act as negative regulators of cytokine signaling. In particular, SOCS1 and SOCS3 play an important role in immune response by controlling the balance between Th1 and Th2 cells. In a previous study, we demonstrated that treatment of chronic asthmatic mice with gene therapy using plasmid encoding galectin-3 (Gal-3) led to an improvement in Th2 allergic inflammation. Using a microarray approach, this study endeavored to evaluate the changes produced by therapeutic Gal-3 delivered by gene therapy in a well-characterized mouse model of chronic airway inflammation. Results were confirmed by real-time RT-PCR, Western blot and immunohistochemical analysis. We identify a set of genes involved in different pathways whose expression is coordinately decreased/increased in mice treated with Gal-3 gene therapy. We report a correlation between Gal-3 treatment and inhibition of SOCS1 and SOCS3 expression in lungs. These results suggest that negative regulation of SOCS1 and 3 following Gal-3 treatment could be a valuable therapeutic approach in allergic disease.


Colonoscopy in management of colonic strictures.
A total of 160 strictures were examined in 154 patients with the fibreoptic colonoscope. When it was possible to make a pre-examination diagnosis colonoscopy proved it wrong in 52% of cases. Unnecessary laparotomy was probably avoided in over half this series. All strictures of the large bowel should be examined colonoscopially whenever possible before considering surgery.


Short- and long-term prognostic significance of ST-segment elevation in lead aVR in patients with non-ST-segment elevation acute coronary syndrome.
We sought to evaluate the prognostic significance of ST-segment elevation (STE) in lead aVR in unselected patients with non-STE acute coronary syndrome (NSTE-ACS). We enrolled 1,042 consecutive patients with NSTE-ACS. Patients were divided into 5 groups according to the following electrocardiographic (ECG) patterns on admission: (1) normal electrocardiogram or no significant ST-T changes, (2) inverted T waves, (3) isolated ST deviation (ST depression [STD] without STE in lead aVR or transient STE), (4) STD plus STE in lead aVR, and (5) ECG confounders (pacing, right or left bundle branch block). The main angiographic end point was left main coronary artery (LM) disease as the culprit artery. Clinical end points were in-hospital and 1-year cardiovascular death defined as the composite of cardiac death, fatal stroke, and fatal bleeding. Prevalence of STD plus STE in lead aVR was 13.4%. Rates of culprit LM disease and in-hospital cardiovascular death were 8.1% and 3.8%, respectively. On multivariable analysis, patients with STD plus STE in lead aVR (group 4) showed an increased risk of culprit LM disease (odds ratio 4.72, 95% confidence interval [CI] 2.31 to 9.64, p <0.001) and in-hospital cardiovascular mortality (odds ratio 5.58, 95% CI 2.35 to 13.24, p <0.001) compared to patients without any ST deviation (pooled groups 1, 2, and 5), whereas patients with isolated ST deviation (group 3) did not. At 1-year follow-up 127 patients (12.2%) died from cardiovascular causes. On multivariable analysis, STD plus STE in lead aVR was a stronger independent predictor of cardiovascular death (hazard ratio 2.29, 95% CI 1.44 to 3.64, p <0.001) than isolated ST deviation (hazard ratio 1.52, 95% CI 0.98 to 2.36, p = 0.06). In conclusion, STD plus STE in lead aVR is associated with high-risk coronary lesions and predicts in-hospital and 1-year cardiovascular deaths in patients with NSTE-ACS. Therefore, this promptly available ECG pattern could be useful to improve risk stratification and management of patients with NSTE-ACS.


Mixture in the distribution of haloperidol-induced oral dyskinesias in the rat supports an animal model of tardive dyskinesia.
Spontaneous adventitious oral movements which are produced in rats by very chronic (6-month) neuroleptic treatment have some phenomenologic and pharmacologic characteristics in common with tardive dyskinesia in humans. However, since not all of the features match, this putative model has been questioned and further support is warranted. Data from several laboratories support dichotomizing these neuroleptic-induced rat oral movements into "low" or "not TD-like" movements and "high" or "TD-like" movements, similar to the division of neuroleptic-induced involuntary movements in humans. Here, we have used mixture analysis to test this proposal statistically in 185 haloperidol-treated and 127 water-treated animals. Rats from several different studies were grouped together to form these two cohorts. The haloperidol dose, route of administration, rating technique, and balanced experimental groups were held constant across all experiments. Results show that two distinct groups of rat movements are induced by very chronic haloperidol treatment (1.5 mg/kg per day). The "low" vacuous chewing movement (VCM) group of rats had an average of 3.6 VCMs/5 min, and the "high" VCM group had an average of 16.1 VCMs/5 min; the control group, with a median VCM rate of 2.0 VCMs/5 min, demonstrated a single distribution. These data suggest that rats, like humans, dichotomize into two groups either expressing or not expressing "high" VCM dyskinesias with very chronic haloperidol treatment.


Risk of cancer among HIV-infected individuals compared to the background population: impact of smoking and HIV.
The relative impact of immune deficiency and lifestyle-related factors on risk of cancer in the HIV-infected population is controversial. We aimed to estimate the population-attributable fractions (PAFs) associated with smoking, being HIV-infected and with immune deficiency. In a Danish, nationwide, population-based cohort study (1995-2011), incidences of cancer were compared between an HIV-infected cohort and a population-based matched cohort in analyses stratified on cancer category, smoking status and for HIV patients: low CD4 cell count. We included 3503 HIV patients [baseline CD4+ 450 cells/μl (inter-quartile range 310-630)] and 12,979 population controls. Smoking-related and virological cancers accounted for 23 and 43% of cancers in the HIV-infected population. The risk of these cancers were higher among HIV patients compared to controls [incidence rate ratio (IRR) 2.8, 95% confidence interval (CI) 1.6-4.9; and IRR 11.5, 95% CI 6.5-20.5], whereas the risk of other cancers did not differ (IRR 1.0, 95% CI 0.7-1.3). Non-smoking HIV patients did not have increased risk of non-virological cancers compared to non-smoking controls (IRR 1.2, 95% CI 0.7-2.1). The PAFs of cancer associated with smoking and with being HIV-infected were 27 and 49%, respectively. For cancers not strongly related to smoking or viral infections, the PAFs associated with being HIV-infected and with immune deficiency were 0%. The risk of cancer is increased in HIV patients compared to the background population. In absence of smoking, the increase in risk is confined to cancers related to viral infections, whereas the risk of other cancers is not elevated and does not seem to be associated with immune deficiency.


Prognostic significance of tumor/stromal caveolin-1 expression in breast cancer patients.
Caveolin-1 (Cav-1) has been extensively characterized in cancer biological research. However, the role of Cav-1 in the interaction between tumor and stromal cells remains unclear. In the present study, we examined Cav-1 expression in tumor cells and stromal cells in breast cancer tissue by immunohistochemical analysis and evaluated its prognostic value in a training cohort. Immunohistochemical analysis of Cav-1 expression was scored as (++), (+) or (-) according to the proportion of positively stained tumor cells (T) and stromal cells (S). Correlation analysis between tumor/stromal Cav-1 expression and clinicopathological parameters revealed that only T(++) Cav-1 status was positively associated with tumor size and histological nodal status (P = 0.019 and 0.021, respectively). Univariate analysis revealed that combined T(++)/S(-) status was significantly correlated with unfavorable prognostic outcomes (P < 0.001). Multivariate analysis demonstrated that this combined status is an independent prognostic factor for primary breast cancer (P = 0.002). Clinical outcomes in different subgroups of breast cancer patients were also strictly dependent on this combined status (P < 0.05). The prognostic value of T(++)/S(-) Cav-1 status was also validated in the testing cohort. Collectively, our data indicate that high Cav-1 expression in tumor cells and lack of this expression in stromal cells could help identify a particular subgroup of breast cancer patients with potentially poor survival. Further studies are required to understand the regulatory mechanism of Cav-1 in the tumor microenvironment.


Midline and intralaminar thalamic connections with the orbital and medial prefrontal networks in macaque monkeys.
Although the midline and intralaminar thalamic nuclei (MITN) were long believed to project "nonspecifically," they are now known from rat studies to have restricted connections to the prefrontal cortex. This has not been studied thoroughly in primates, however, and it is not known how MITN are associated with the "orbital" and "medial" prefrontal networks. This study examined the connections of MITN in cynomolgus monkeys (Macaca fascicularis). Experiments with retrograde and anterograde tracer injections into the orbital and medial prefrontal cortex (OMPFC) showed that MITN are strongly connected with the medial prefrontal network. The dorsal nuclei of the midline thalamus, including the paraventricular (Pa) and parataenial nuclei (Pt), had heavy connections with medial network areas 25, 32, and 14c in the subgenual region. Areas 13a and 12o, which are associated with both networks, were strongly connected with the Pt and the central intermedial nucleus, respectively. Otherwise, orbital network areas had weak connections with MITN. Anterograde tracer injections into the dorsal midline thalamus resulted in heavy terminal labeling in the medial prefrontal network, most notably in areas ventral to the genu of the corpus callosum (25, 32, and 14c), but also in adjacent areas (13a and 13b). Retrograde tracer injection into the dorsal midline labeled similar areas. The medial network, particularly the subgenual region, is involved in visceral and emotional control and has been implicated in mood disorders. The strong connections between the subgenual cortex and the Pa provide a pathway through which stress signals from the Pa may influence these prefrontal circuits.


A spin label study of the effect of chrysotile asbestos on erythrocyte membranes.
Alterations in erythrocyte membranes caused by UICC B chrysotile asbestos fibres were studied in red cell ghosts using the spin label technique. The electron paramagnetic resonance (EPR) spectra of two sulphydryl reactive spin labels and one fatty acid spin probe in erythrocyte ghosts showed membrane protein modifications but no changes in lipid fluidity caused by the haemolytic chrysotile asbestos fibres.


Vocal traits and diet explain avian sensitivities to anthropogenic noise.
Global population growth has caused extensive human-induced environmental change, including a near-ubiquitous transformation of the acoustical environment due to the propagation of anthropogenic noise. Because the acoustical environment is a critical ecological dimension for countless species to obtain, interpret and respond to environmental cues, highly novel environmental acoustics have the potential to negatively impact organisms that use acoustics for a variety of functions, such as communication and predator/prey detection. Using a comparative approach with 308 populations of 183 bird species from 14 locations in Europe, North American and the Caribbean, I sought to reveal the intrinsic and extrinsic factors responsible for avian sensitivities to anthropogenic noise as measured by their habitat use in noisy versus adjacent quiet locations. Birds across all locations tended to avoid noisy areas, but trait-specific differences emerged. Vocal frequency, diet and foraging location predicted patterns of habitat use in response to anthropogenic noise, but body size, nest placement and type, other vocal features and the type of anthropogenic noise (chronic industrial vs. intermittent urban/traffic noise) failed to explain variation in habitat use. Strongly supported models also indicated the relationship between sensitivity to noise and predictive traits had little to no phylogenetic structure. In general, traits associated with hearing were strong predictors - species with low-frequency vocalizations, which experience greater spectral overlap with low-frequency anthropogenic noise tend to avoid noisy areas, whereas species with higher frequency vocalizations respond less severely. Additionally, omnivorous species and those with animal-based diets were more sensitive to noise than birds with plant-based diets, likely because noise may interfere with the use of audition in multimodal prey detection. Collectively, these results suggest that anthropogenic noise is a powerful sensory pollutant that can filter avian communities nonrandomly by interfering with birds' abilities to receive, respond to and dispatch acoustic cues and signals.


Composite tissue allotransplantation in chimeric hosts: part I. Prevention of graft-versus-host disease.
Mixed allogeneic chimerism (MAC) has been shown to induce tolerance to composite tissue allografts (CTA). However, transplantation of unmanipulated donor-specific limbs results in severe graft-versus-host disease (GVHD). This suggests that nontolerant mature donor-derived cells in the CTA may affect the stability of chimerism, potentially resulting in GVHD. The aim of this study was to develop an approach to study and prevent GVHD in a mixed chimeric-rat hind-limb transplantation model. [ACI-->WF] chimeras received a limb from Wistar Furth (WF) (syngeneic), Fisher (third-party), or ACI (irradiated [1,050 cGy] or nonirradiated) rats. In vitro tolerance was assessed using mixed lymphocyte reactivity (MLR) assays at the time the animals were killed. [ACI-->WF] chimeras with greater than 85% chimerism exhibited rejection-free survival of donor-specific hind limbs. However, 100% of these animals developed lethal GVHD 22.4+/-2.8 days after limb transplantation. [ACI-->WF] chimeras that underwent transplantation with irradiated ACI or syngeneic WF limbs showed no signs of rejection or GVHD at 5 months. Nonchimeric and third-party controls rejected limbs within 10 days. Conditioning of the host WF rats with 950 cGy of irradiation (sublethal, myeloablative) led to high levels of MAC without GVHD. The mature T-cell content of nonirradiated donor (ACI) limbs was sufficient to induce lethal GVHD in 100% of tolerant mixed chimeric [ACI-->WF] hosts. Irradiation of donor limbs before transplantation resulted in long-term donor-specific tolerance and prevented GVHD. These data demonstrate that (1) established chimeras could be susceptible to GVHD caused by immunocompetent donor cells transferred with the hind limb, and (2) inactivating these cells with irradiation prevents GVHD and destabilization of chimerism, and permits rejection-free graft acceptance.


Polymer-oligonucleotide conjugate synthesis from an amphiphilic block copolymer. Applications to DNA detection on microarray.
An amphiphilic block copolymer poly(tert-butylacrylamide-b-(N-acryloylmorpholine-N-acryloxysuccinimide)) (poly(TBAm-b-(NAM/NAS)) and a random copolymer poly(NAM/NAS), synthesized by the reversible addition-fragmentation chain transfer (RAFT) polymerization process, have been used as support for oligonucleotide (ODN) synthesis, to elaborate polymer-oligonucleotide conjugates. In a first step, starters of ODN solid-phase synthesis were coupled to activated ester functions of polymers, and second, resulting functionalized polymers were covalently grafted onto hydroxylated controlled pore glass (CPG) support to further accomplish ODN synthesis. An efficient capping of residual hydroxyl functions of CPG was performed before synthesis, with both acetic anhydride and diethoxy-N,N-diisopropyl-phosphoramidite reagents, to suppress parasite-free ODN population present in conjugate crude material and resulting from syntheses directly initiated on silica beads. After purification, conjugates were evaluated in a DNA hybridization assay on a microarray, as macromolecules being able to favor capture of the target. Conjugate coating conditions were studied on the dT25/dA25 model. The role of the hydrophobic part (poly(TBAm)) of the conjugate synthesized with the block copolymer in the orientation of the conjugate after coating was revealed by spotting experiments achieved in a mixed solvent (DMF/H(2)O). The use of block copolymer-dT25 conjugate afforded a significant sensitivity improvement of the hybridization assay.


A prospective birth cohort study of maternal prenatal cigarette smoking assessed by self-report and biomarkers on childhood risk of overweight or obesity.
Most studies on the association of in utero exposure to cigarette smoking and childhood overweight or obesity (OWO) were based on maternal self-reported smoking status, and few were based on objective biomarkers. The concordance of self-report smoking, and maternal and cord blood biomarkers of cigarette smoking as well as their effects on children's long-term risk of overweight and obesity are unclear. In this study, we analyzed data from 2351 mother-child pairs in the Boston Birth Cohort, a sample of US predominantly Black, indigenous, and people of color (BIPOC) that enrolled children at birth and followed prospectively up to age 18 years. In utero smoking exposure was measured by maternal self-report and by maternal and cord plasma biomarkers of smoking: cotinine and hydroxycotinine. We assessed the individual and joint associations of each smoking exposure measure and maternal OWO with childhood OWO using multinomial logistic regressions. We used nested logistic regressions to investigate the childhood OWO prediction performance when adding maternal and cord plasma biomarkers as input covariates on top of self-reported data. Our results demonstrated that in utero cigarette smoking exposure defined by self-report and by maternal or cord metabolites was consistently associated with increased risk of long-term child OWO. Children with cord hydroxycotinine in the fourth quartile (vs. first quartile) had 1.66 (95% confidence interval [CI] 1.03-2.66) times the odds for overweight and 1.57 (95% CI 1.05-2.36) times the odds for obesity. The combined effect of maternal OWO and smoking on offspring risk of obesity is 3.66 (95% CI 2.37-5.67) if using self-reported smoking. Adding maternal and cord plasma biomarker information to self-reported data improved the prediction accuracy of long-term child OWO risk. This longitudinal birth cohort study of US BIPOC underscored the role of maternal smoking as an obesogen for offspring OWO risk. Our findings call for public health intervention strategies to focus on maternal smoking - as a highly modifiable target, including smoking cessation and countermeasures (such as optimal nutrition) that may alleviate the increasing obesity burden in the United States and globally.


Football is becoming more predictable; network analysis of 88 thousand matches in 11 major leagues.
In recent years, excessive monetization of football and professionalism among the players have been argued to have affected the quality of the match in different ways. On the one hand, playing football has become a high-income profession and the players are highly motivated; on the other hand, stronger teams have higher incomes and therefore afford better players leading to an even stronger appearance in tournaments that can make the game more imbalanced and hence predictable. To quantify and document this observation, in this work, we take a minimalist network science approach to measure the predictability of football over 26 years in major European leagues. We show that over time, the games in major leagues have indeed become more predictable. We provide further support for this observation by showing that inequality between teams has increased and the home-field advantage has been vanishing ubiquitously. We do not include any direct analysis on the effects of monetization on football's predictability or therefore, lack of excitement; however, we propose several hypotheses which could be tested in future analyses.


A portable flow-through fluorescent immunoassay lab-on-a-chip device using ZnO nanorod-decorated glass capillaries.
We report a portable flow-through fluorescent immunoassay lab-on-a-chip device using inexpensive disposable glass capillaries for medical diagnostics. The device is made up of a number of serially connected glass capillaries, of which each interior surface is grown using zinc oxide (ZnO) nanorods, which different probe antibodies are attached to. The ZnO nanorods not only provide a large surface area for high density probe attachment, but also enhance the fluorescent signals to significantly improve the detection signal responses. The glass capillary also allows for convenient flow-through detection. Coupled with a homemade handheld analyzer integrated with an automatic pump system and a fluorescence readout module, a portable immunoassay capillary device enables quantitative detection of multiple biomarkers in 30 min with detection limits of 1-5 ng mL(-1) and wide dynamic ranges for prostate specific antigen (PSA), α-Fetoprotein (AFP) and carcinoembryonic antigen (CEA) in serum. This new conceptual lab-on-a-chip device eliminates the need for expensive micro-fabrication processes, while offering inexpensive and disposable, but replaceable tube-type "microchannels" for multiplexed detection in portable clinical diagnostics.


[Organisation of scientific and research work of Navy medical service].
The main issues of organization of scientific and research work of medical service in the North Fleet are considered in the present article. Analysis of some paragraphs of documents, regulating this work at army level is given. The authors give an example of successful experience of such work in the North Fleet, table some suggestions which allow to improve the administration of scientific and research work in the navy and also on the district scale.


Additive association of knowledge and awareness on control of hypertension: a cross-sectional survey in rural India.
To determine whether there is an interaction between knowledge about hypertension and awareness of hypertension on the treatment and control of hypertension in three regions of South India at different stages of epidemiological transition (see Video, Supplemental Digital Content 1, http://links.lww.com/HJH/B426). Using a cross-sectional design, we randomly selected villages within each of rural Trivandrum, West Godavari, and Chittoor. Sampling was stratified by age group and sex. We measured blood pressure and administered a questionnaire to determine knowledge and awareness of hypertension. Logistic regression was used to assess associations of awareness and knowledge about hypertension with its treatment and control in participants with hypertension, while examining for statistical interaction. Among a total of 11 657 participants (50% male; median age 45 years), 3455 had hypertension. In analyses adjusted for age and sex, both knowledge score [adjusted odds ratio (aOR) 1.14 [95% confidence interval (CI) 1.12--1.17)] and awareness [aOR 104 (95% CI 82--134)] were associated with treatment for hypertension. Similarly, both knowledge score [aOR 1.10; 95% CI (1.08--1.12)] and awareness [aOR 13.4; 95% CI (10.7--16.7)], were positively associated with control of blood pressure in those with hypertension, independent of age and sex. There was an interaction between knowledge and awareness on both treatment and control of hypertension (P of attributable proportion <0.001 for each). Health education to improve knowledge about hypertension and screening programs to improve awareness of hypertension may act in an additive fashion to improve management of hypertension in rural Indian populations.


Alternative promoter usage and splicing of the human SCN5A gene contribute to transcript heterogeneity.
The sodium channel isoform Na(v)1.5 mediates sodium current, excitability, and electrical conduction in the human heart. Recent studies have indicated alternative splicing within the protein-coding portion of its gene, SCN5A, as a mechanism to generate diversity in Na(v)1.5 protein structure and function. In the present study we identified several novel SCN5A transcripts in human heart, displaying distinct 5′-untranslated regions but identical protein-coding sequences. These transcripts originated from the splicing of alternative exons 1 (designated 1A, 1B, 1C, and 1D) to the translational start codon-containing exon 2, and were preferentially expressed in the heart as compared to other tissues. Comparison of their expression level between adult and fetal heart demonstrated that exon 1C- and 1D-derived sequences were more prominent in adult than in fetal heart. Two new promoters (designated P2 and P3) for the SCN5A gene were identified and functionally characterized in myocardial- and nonmyocardial-derived cell lines. Translation of the transcript containing exon 1D-derived sequences proved to be significantly impaired in these cell lines, which could be restored by mutation of an upstream translational start codon. These results implicate the usage of alternative promoters and 5′-untranslated regions as new mechanisms in the regulation of human Na(v)1.5 expression.


Hox regulation of transcription: more complex(es).
Hox genes encode transcription factors with important roles during embryogenesis and tissue differentiation. Genetic analyses initially demonstrated that interfering with Hox genes has profound effects on the specification of cell identity, suggesting that Hox proteins regulate very specific sets of target genes. However, subsequent biochemical analyses revealed that Hox proteins bind DNA with relatively low affinity and specificity. Furthermore, it became clear that a given Hox protein could activate or repress transcription, depending on the context. A resolution to these paradoxes presented itself with the discovery that Hox proteins do not function in isolation, but interact with other factors in complexes. The first such "cofactors" were members of the Extradenticle/Pbx and Homothorax/Meis/Prep families. However, the list of Hox-interacting proteins has continued to grow, suggesting that Hox complexes contain many more components than initially thought. Additionally, the activities of the various components and the exact mechanisms whereby they modulate the activity of the complex remain puzzling. Here, we review the various proteins known to participate in Hox complexes and discuss their likely functions. We also consider that Hox complexes of different compositions may have different activities and discuss mechanisms whereby Hox complexes may be switched between active and inactive states.


Pin1 modulates the structure and function of human RNA polymerase II.
The C-terminal domain of the RNA polymerase (RNAP) II largest subunit (CTD) plays critical roles both in transcription of mRNA precursors and in the processing reactions needed to form mature mRNAs. The CTD undergoes dynamic changes in phosphorylation during the transcription cycle, and this plays a significant role in coordinating its multiple activities. But how these changes themselves are regulated is not well understood. Here we show that the peptidyl-prolyl isomerase Pin1 influences the phosphorylation status of the CTD in vitro by inhibiting the CTD phosphatase FCP1 and stimulating CTD phosphorylation by cdc2/cyclin B. This is reflected in vivo by accumulation of hypophosphorylated RNAP II in pin1-/- cells, and of a novel hyper-hyperphosphorylated form in cells induced to overexpress Pin1. This hyper-hyperphosphorylated form of RNAP II also accumulates in M-phase cells, in a Pin1-dependent manner, and associates specifically with Pin1. Functionally, we find that Pin1 overexpression specifically inhibits ongoing transcription of mRNA precursors in vivo and both transcription and RNAP II-stimulated pre-mRNA splicing in cell extracts. Pin1 thus plays a significant role in regulating RNAP II CTD structure and function.


Determinants of adherence to disease modifying anti-rheumatic drugs in White British and South Asian patients with rheumatoid arthritis: a cross sectional study.
Rheumatoid arthritis (RA) is a common chronic inflammatory disease causing joint damage, disability, and reduced life expectancy. Highly effective drugs are now available for the treatment of RA. However, poor adherence to drug regimens remains a significant barrier to improving clinical outcomes in RA. Poor adherence has been shown to be linked to patients' beliefs about medicines with a potential impact on adherence. These beliefs are reported to be different between ethnic groups. The purpose of this study was to identify potential determinants of adherence to disease modifying anti-rheumatic drugs (DMARDs) including an assessment of the influence of beliefs about medicines and satisfaction with information provided about DMARDs and compare determinants of adherence between RA patients of White British and South Asian. RA patients of either White British (n = 91) or South Asian (n = 89) origin were recruited from secondary care. Data were collected via questionnaires on patients': (1) self-reported adherence (Medication Adherence Report Scale-MARS); (2) beliefs about medicines (Beliefs about Medicines Questionnaire-BMQ); (3) illness perceptions (Illness Perceptions Questionnaire-IPQ) and (4) satisfaction with information about DMARDs (Satisfaction with Information about Medicines questionnaire-SIMS). In addition, clinical and demographic data were collected. The results revealed that socio-demographic factors only explained a small amount of variance in adherence whereas illness representations and treatment beliefs were more substantial in explaining non-adherence to DMARDs. Patients' self-reported adherence was higher in White British than South Asian patients (median 28 (interquartile range 26-30) vs median 26 (interquartile range 23-30) respectively; P = 0.013, Mann-Whitney test). Patients who reported lower adherence were more dissatisfied with the information they had received about their DMARDs (P < 0.001, Spearman correlation, SIMS action and usage subscale; P < 0.001, Spearman correlation, SIMS potential problems subscale) and had more negative beliefs about their DMARDs and were related to ethnicity with South Asian patients having more negative views about medicines. Socio-demographic factors were found to explain a small amount of variance in adherence. Illness representations and treatment beliefs were more important in explaining non-adherence to DMARDs. Clinicians managing South Asian patients with RA need to be aware that low adherence may be linked to negative beliefs about medicines and illness representations of RA.