Organised and opportunistic prevention in primary health care: estimation of missed opportunities by population based health interview surveys in Hungary.
Improvement of preventive services for adults can be achieved by opportunistic or organised methods in primary care. The unexploited opportunities of these approaches were estimated by our investigation. Data from the Hungarian implementation of European Health Interview Surveys in 2009 (N = 4709) and 2014 (N = 5352) were analysed. Proportion of subjects used interventions in target group (screening for hypertension and diabetes mellitus, and influenza vaccination) within a year were calculated. Taking into consideration recommendations for the frequency of intervention, numbers of missed interventions among patients visited a general practitioner in a year and among patients did not visit a general practitioner in a year were calculated in order to describe missed opportunities that could be utilised by opportunistic or organised approaches. Numbers of missed interventions were estimated for the entire population of the country and for an average-sized general medical practice. Implementation ratio were 66.8% for blood pressure measurement among subjects above 40 years and free of diagnosed hypertension; 63.5% for checking blood glucose among adults above 45 and overweighed and free of diagnosed diabetes mellitus; and 19.1% for vaccination against seasonal influenza. There were 4.1 million interventions implemented a year in Hungary, most of the (3.8 million) among adults visited general practitioner in a year. The number of missed interventions was 4.5 million a year; mostly (3.4 million) among persons visited general practitioner in a year. For Hungary, the opportunistic and organised missed opportunities were estimated to be 561,098, and 1,150,321 for hypertension screening; 363,270, and 227,543 for diabetes mellitus screening; 2,784,072, and 380,033 for influenza vaccination among the < 60 years old high risk subjects, and 3,029,700 and 494,150 for influenza vaccination among more than 60 years old adults, respectively. By implementing all missed services, the workload in an average-sized general medical practice would be increased by 12-13 opportunistic and 4-5 organised interventions a week. The studied interventions are much less used than recommended. The opportunistic missed opportunities is prevailing for influenza vaccination, and the organised one is for hypertension screening. The two approaches have similar significance for diabetes mellitus screening.


Temperature effects, arrhenius activation parameters and rate constants for the photochemical reactivity of cyano, boronato, trifluoromethyl and methoxy substituted toluenes in the excited singlet state.
Total rate constants of decay (k(t)) as a function of temperature from -45 to +65 degrees C for the compounds 1 and 2 in AN and TFE and 3 and 4 in AN have been determined by fluorescence lifetime measurements. The data have been fit to an equation that assumes that the rate constants of fluorescence (k(f)) and intersystem crossing (k(isc)) are temperature independent, that k(ic) = 0 and that the rate constant of reaction (k(r)) is activated according to the Arrhenius expression. For compounds 1-3, values of k(f) and k(isc) were found to be independent of solvent for any given compound, but k(r) was consistently greater in TFE than AN. For the anisoles 4, the temperature effect was very small, indicating that k(r) did not compete with k(f) + k(isc) and suggesting that an activated intersystem crossing was the dominant temperature-dependent process. The k(r), A and E(a) values obtained for compounds 1-3 were rationalized in terms of their known photochemistry, phototransposition reactions in AN and photoadditions in TFE. The critical reactive intermediate in all cases is a bicycle[3.1.0]hexenyl biradical/zwitterion that is formed in an activated process from S1. This reactive intermediate returns to starting material faster than it rearranges, and therefore an activated internal conversion is a major pathway for deactivation of S1.


Percentiles of predicted 10-year cardiovascular disease risk by sex and age in Brazil and their association with estimated risk of long-term atherosclerotic events.
Expressing the cardiovascular disease (CVD) risk in relation to peers may complement the estimation of absolute CVD risk. We aimed to determine 10-year CVD risk percentiles by sex and age in the Brazilian population and evaluate their association with estimated long-term atherosclerotic CVD (ASCVD) risk. A cross-sectional analysis of baseline data from the ELSA-Brasil study was conducted in individuals aged 40-74 years without prior ASCVD. Ten-year CVD risk and long-term ASCVD risk were estimated by the WHO risk score and the Multinational Cardiovascular Risk Consortium tool, respectively. Ten-year risk percentiles were determined by ranking the calculated risks within each sex and age group. Ten-year CVD risk versus percentile plots were constructed for each sex and age group using data from 13,364 participants (55% females; median age, 52 [IQR, 46-59] years). Long-term ASCVD risk was calculated in 12,973 (97.1%) participants. Compared to individuals at the <25th risk percentile, those at the ≥75th percentile had a greater risk of being in the highest quartile of long-term risk (ORs [95% CIs] 6.57 [5.18-8.30] in females and 11.59 [8.42-15.96] in males) in regression models adjusted for age, race, education, and 10-year CVD risk. In both sexes, the association between risk percentile and long-term risk weakened after age 50. A tool for calculating 10-year CVD risk and the corresponding percentile is available at https://bit.ly/3CzPUi6. We established percentiles of predicted 10-year CVD risk by sex and age in the Brazilian population, which independently reflect the estimated long-term ASCVD risk in younger individuals.


[Effectiveness of aromatherapy massage on abdominal obesity among middle aged women].
Objectives of the study is to examine the effectiveness of aromatherapy massage among middle aged women with abdominal obesity. AB/BA crossover design of random blind assignment was applied. Aromatherapy and placebo massage were given to Group(A), Group(B), each groups applied each massages for 2 weeks alternatively. Weight, abdominal circumference and appetite were compared for results check among the subjects. The apparent effectiveness of Aromatherapy Massage in reducing weight, abdominal circumference and appetite was noted. On the basis of results, they strongly support the facts of reduction of abdominal obesity by applying aromatherapy massage for middle aged women.


Sensitizing basal-like breast cancer to chemotherapy using nanoparticles conjugated with interference peptide.
Basal-like breast cancers are highly aggressive malignancies associated with very poor prognosis. Although these cancers may initially respond to first-line treatment, they become highly resistant to standard chemotherapy in the metastatic setting. Chemotherapy resistance in basal-like breast cancers is associated with highly selective overexpression of the homeobox transcription factor Engrailed 1 (EN1). Herein, we propose a novel therapeutic strategy using poly(glycidyl methacrylate) nanoparticles decorated with poly(acrylic acid) that enable dual delivery of docetaxel and interference peptides designed to block or inhibit EN1 (EN1-iPep). We demonstrate that EN1-iPep is highly selective in inducing apoptotic cell death in basal-like cancer cells with negligible effects in a non-neoplastic human mammary epithelial cell line. Furthermore, we show that treatment with EN1-iPep results in a highly synergistic pharmacological interaction with docetaxel in inhibiting cancer cell growth. The incorporation of these two agents in a single nanoformulation results in greater anticancer efficacy than current nanoparticle-based treatments used in the clinical setting.


Reliability of the National Institutes of Health Stroke Scale. Extension to non-neurologists in the context of a clinical trial.
The reliability of the National Institutes of Health Stroke Scale (NIHSS) has been established through testing its use in live and videotaped patients. This reliability testing has primarily focused on the use of the scale by neurologists. We sought to determine the reliability of the NIHSS as used by non-neurologists in the context of a clinical trial. In anticipation of the initiation of a randomized trial of a new therapy for patients with acute ischemic stroke, 30 physician investigators (30% of whom were not neurologists) and 29 non-physician study coordinators were trained in the use of the NIHSS at an informational and training conference using standardized videotaped patient examinations. A series of 4 patients were rated initially. After 3 months, the same 4 patients were rerated, providing a measure of intraobserver reliability. An additional series of 4 new patients were also rated after 3 months and, with the initial 4 ratings, provided data for assessment of interobserver reliability. Overall, 28% of the raters had previous experience with the NIHSS, and 22% had previously used the videotapes as used in the present trial. The coefficients of determination (r2) were each greater than .95 when the means of the two ratings of the same 4 cases were compared between (1) neurologists and other types of physicians, (2) physicians and study coordinators, (3) raters who had prior experience with the NIHSS and those without prior experience, and (4) raters who had used the videotapes in the past and those who had never viewed the tapes. The calculated r2s were greater than .98 for the initial rating of the first 4 cases and for the later rating of the 4 new cases. The slopes of the regression lines were all near 1, indicating that the raters were similarly calibrated. The intraclass correlation coefficients were .93 and .95, reflecting high levels of intraobserver and interobserver reliability. These data extend the previously demonstrated reliability of the NIHSS to non-neurologists and show that both a variety of physician investigators and nurse study coordinators can be rapidly trained to reliably apply the scale in the context of an actual clinical trial.


Analgesic Effects and Neuropathology Changes of Electroacupuncture on Curing a Rat Model of Brachial Plexus Neuralgia Induced by Cobra Venom.
Electroacupuncture (EA) is widely applied to treat neuropathic pain. Brachial plexus neuralgia (BPN) is a common form of chronic persistent pain. Few studies have evaluated the analgesic effects and mechanism of EA using the novel animal model of BPN. To observe the curative effects of repeated EA on curing BPN induced by administration of cobra venom to the lower trunk of the right brachial plexus. Controlled animal study. Department of Anesthesiology, Pain Medicine & Critical Care Medicine, Aviation General Hospital of China Medical University. Sixty-six adult male Sprague-Dawley rats were equally and randomly divided into the following groups: normal control (NC), brachial plexus neuralgia (BPN), BPN with sham EA stimulation, BPN with EA stimulation starting on postoperative day 1 (EA1), and BPN with EA stimulation starting on postoperative day 12 (EA12). The BPN model was established by administration of cobra venom to the lower trunk of the right brachial plexus. On postoperative day 1 or day 12, EA (constant aquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1 - 1.5 - 2 mA) was applied to the right "Shousanli" (LI10) and "Quchi" (LI11) acupoints for 30 minutes, once every other day for 12 times in both groups. Mechanical withdrawal thresholds (MWT) were tested with von Frey filaments. Video recordings were conducted to analyze the spontaneous exploratory behaviors. Moreover, the organizational and structural alterations of the right brachial plexus and cervical cord (C8-T1) were examined via light and electron microscopy. Following the production of the BPN model, the MWT of both ipsilateral and contralateral paws demonstrated a profound decrease (P < 0.05). But after EA interventions, the MWT showed a significant increase (P < 0.05). In comparison to the EA12 group, the analgesic effects of the EA1 group were more significant, and similar results were observed in exploratory behaviors. However, grooming behaviors did not demonstrate significant differences. Meanwhile, on day 12 after surgery it was observed under light microscopy that the inflammatory response in the right brachial plexus and cervical cord (C8-T1) were significantly attenuated after EA stimulation. Furthermore, the demyelination of the brachial plexus and cervical cord (C8-T1) were also reversed. Limitations include the fact that there was demyelination of the cervical cord (C8-T1) in the control group because of inappropriate manipulation. Repeated EA contributes significant analgesic effects in the treatment of BPN.


Concomitant Treatment with Proton Pump Inhibitors and Cephalosporins Does Not Enhance QT-Associated Proarrhythmia in Isolated Rabbit Hearts.
Recent results from data mining analyses and reports of adverse drug events suggest a QT-prolonging drug-drug interaction resulting from the combination of distinct proton pump inhibitors and cephalosporins. Therefore, this study aimed at investigating the effect of the suspected QT-prolonging combinations of lansoprazole + ceftriaxone and esomeprazole + cefazolin, respectively. 26 hearts of New Zealand White rabbits were retrogradely perfused and paced at different cycle lengths. After generating baseline data, the hearts were assigned to two groups: In group 1, hearts were treated with 5 µM lansoprazole. Thereafter, 200 µM ceftriaxone was infused additionally. Group 2 was perfused with 10 µM esomeprazole followed by 250 µM cefazolin. In group 1, lansoprazole did not significantly alter QT intervals and APD90. Additional treatment with ceftriaxone significantly shortened QT interval, APD90 and slightly reduced dispersion of repolarization compared to sole lansoprazole infusion. In group 2, esomeprazole led to a significant shortening of the QT interval without altering APD90 or dispersion. Additional treatment with the antibiotic cefazolin further shortened QT interval, APD90 and reduced the dispersion of repolarization. Incidence of ventricular arrhythmias was not significantly altered in both groups. This is the first experimental whole-heart study that investigated the impact of a concomitant treatment with proton pump inhibitors and cephalosporins. In contrast to previous reports, the combination of both agents did not cause QT prolongation but instead shortened QT interval and action potential duration. As a consequence, no triggered activity occurred in the presence of a stable dispersion of repolarization.


Physiology is pivotal for interactions between salinity and acute copper toxicity to fish and invertebrates.
The present paper presents original data and a review of the copper (Cu) toxicity literature for estuarine and marine environments. For the first time, acute Cu toxicity across the full salinity range was determined. Killifish, Fundulus heteroclitus, eggs were hatched in freshwater (FW), 2.5, 5, 10, 15, 22 and 35 ppt (seawater, SW) and juveniles were allowed to acclimate for 7 days prior to acute toxicity testing. Sensitivity was highest in FW (96 h LC50: 18 microg/l), followed by SW (96 h LC50: 294 microg/l) with fish at intermediate salinities being the most tolerant (96 h LC50 > 963 microg/l at 10 ppt). This approximately 50-fold, non-linear variation in sensitivity could not be accounted for by Cu speciation or competition among cations but can be explained by physiology. The relative Na(+) gradient from the blood plasma to the water is greatest in FW followed by SW and is smallest at 10 ppt. Regression of Cu toxicity versus the equilibrium potential for Na(+), which reflects the relative Na(+) gradient, revealed that 93% of the variation can be attributed to Na(+) gradients and thus osmoregulatory physiology. Examination of the existing literature on acute Cu toxicity in SW (defined as >25 ppt) confirmed that early life stages generally are most sensitive but this pattern may be attributable to size rather than developmental stage. Regardless of developmental stage and phylogeny, size clearly matters for Cu sensitivity. The existing literature on the influence of salinity on acute Cu toxicity as well as studies of mechanisms of Cu toxicity in fish and invertebrates are reviewed.


Cortical ablation induces a spreading calcium-dependent, secondary pathogenesis which can be reduced by inhibiting calpain.
Many forms of acute brain injury are associated with a secondary, glutamate- and calcium-dependent cascade which greatly exacerbates the final damage. The calcium-dependent protease, calpain, has been implicated as an important variable in this pathogenic process. The present studies tested (i) if similar secondary degeneration occurs following surgical ablation of a discrete area within rat visual cortex, (ii) if activation of calpain contributes to the secondary degeneration by spreading into areas adjacent to the ablation, and (iii) if blocking calpain's proteolytic effects reduces the secondary degeneration attendant to the lesion. Antibodies selective for a protein fragment specifically generated by calpain were used to map areas in which the protease had been activated. Labeling was present 5 min after surgery in a narrow zone surrounding the ablated region. The volume of the immunopositive staining increased twofold within 24 h and fivefold by 48 h, at which time it was equivalent in size to the original lesion. This staining pattern significantly decreased in size at 5 days postsurgery. Application of calpain inhibitors to the ablation site immediately after surgery reduced the spread of calpain activation by approximately 80%. Following cortical ablation, the volume of the lateral geniculate nucleus ipsilateral to the cortical ablation shrank by 46 +/- 3% in control rats but only by 31 +/- 5% in animals given the calpain inhibitors. These results establish that (i) a secondary degenerative cascade is unleashed following discrete cortical surgery which expands into brain areas clearly outside the initial perturbation site, (ii) the gradual expansion of calpain activation contributes to the underlying secondary pathology, and (iii) blocking calpain activity substantially reduces atrophy in areas anatomically connected, but physically distal to the damaged zone. The possible utility of topical applications of calpain inhibitors, or analogously acting drugs, in minimizing the secondary effects of brain surgery is discussed.


Effect of pressure support vs unassisted breathing through a tracheostomy collar on weaning duration in patients requiring prolonged mechanical ventilation: a randomized trial.
Patients requiring prolonged mechanical ventilation (>21 days) are commonly weaned at long-term acute care hospitals (LTACHs). The most effective method of weaning such patients has not been investigated. To compare weaning duration with pressure support vs unassisted breathing through a tracheostomy collar in patients transferred to an LTACH for weaning from prolonged ventilation. Between 2000 and 2010, a randomized study was conducted in tracheotomized patients transferred to a single LTACH for weaning from prolonged ventilation. Of 500 patients who underwent a 5-day screening procedure, 316 did not tolerate the procedure and were randomly assigned to receive weaning with pressure support (n = 155) or a tracheostomy collar (n = 161). Survival at 6- and 12-month time points was also determined. Primary outcome was weaning duration. Secondary outcome was survival at 6 and 12 months after enrollment. Of 316 patients, 4 were withdrawn and not included in analysis. Of 152 patients in the pressure-support group, 68 (44.7%) were weaned; 22 (14.5%) died. Of 160 patients in the tracheostomy collar group, 85 (53.1%) were weaned; 16 (10.0%) died. Median weaning time was shorter with tracheostomy collar use (15 days; interquartile range [IQR], 8-25) than with pressure support (19 days; IQR, 12-31), P = .004. The hazard ratio (HR) for successful weaning rate was higher with tracheostomy collar use than with pressure support (HR, 1.43; 95% CI, 1.03-1.98; P = .033) after adjusting for baseline clinical covariates. Use of the tracheostomy collar achieved faster weaning than did pressure support among patients who did not tolerate the screening procedure between 12 and 120 hours (HR, 3.33; 95% CI, 1.44-7.70; P = .005), whereas weaning time was equivalent with the 2 methods in patients who did not tolerate the screening procedure within 0 to 12 hours. Mortality was equivalent in the pressure-support and tracheostomy collar groups at 6 months (55.92% vs 51.25%; 4.67% difference, 95% CI, -6.4% to 15.7%) and at 12 months (66.45% vs 60.00%; 6.45% difference, 95% CI, -4.2% to 17.1%). Among patients requiring prolonged mechanical ventilation and treated at a single long-term care facility, unassisted breathing through a tracheostomy, compared with pressure support, resulted in shorter median weaning time, although weaning mode had no effect on survival at 6 and 12 months. clinicaltrials.gov Identifier: NCT01541462.


Hemidiaphragm paresis and granulomatous pneumonitis associated with adalimumab: a case report.
Adalimumab is a fully human monoclonal anti-TNF-alpha antibody. Reported adverse effects have raised a number of safety concerns associated with their prolonged use. A case of granulomatous pneumonitis and hemidiaphragm paresis associated with adalimumab therapy for rheumatoid arthritis is described. In May 2012, a 57 year old male presented with dry cough, dyspnea and orthopnea after 4 months of treatment with adalimumab for rheumatoid arthritis. The patient received adalimumab from November 2011 to February 2012. A right hemidiaphragm elevation was shown on chest radiograph. A right hemidiaphragm paresis was shown on chest fluoroscopy. Bilateral lower lobe interstitial disease was shown on the chest HRCT scan. Open lung biopsy of the right lower lobe showed subacute granulomatous pneumonitis. In July 2013, the patient's respiratory symptoms and the previous restrictive pattern on PFTs resolved. In a same patient, a rare association of hemidiaphragm paresis and granulomatous pneumonitis with adalimumab treatment is herein reported.


Phylogeography, genetic structure, and diversity in the dhole (Cuon alpinus).
The Asiatic wild dog or dhole was once very widely distributed across Asia but now has a very fragmented range. In this first genetic study of this little-known species, we obtained information on genetic diversity, phylogeography, and social structure using both mitochondrial control region sequencing and microsatellite genotyping of noninvasive faecal samples from wild populations, as well as from museum and captive samples. A pattern largely consistent with isolation by distance across the Asian mainland was observed, with no clear subspecies distinctions. However, two major phylogeographical groupings were found across the mainland, one extending from South, Central, and North India (south of the Ganges) into Myanmar, and the other extending from India north of the Ganges into northeastern India, Myanmar, Thailand and the Malaysian Peninsula. We propose a scenario involving glaciation events that could explain this pattern. The origin of the dhole populations in Sumatra and Java is enigmatic and requires further study. Very low levels of genetic diversity were observed among wild dholes from Baluran National Park in Java, Indonesia, but in contrast, high levels were observed in Mudumalai Wildlife Sanctuary in South India.


Statistical relevance of ultrasonographic criteria in the assessment of diffuse liver disease in dogs and cats.
To determine whether objectively applied ultrasonographic interpretive criteria are statistically useful in differentiating among 7 defined categories of diffuse liver disease in dogs and cats. Ultrasonographic images of 229 dogs and 104 cats. Liver parenchymal or related sonographic criteria established by the authors were retrospectively and independently applied by 3 radiologists who were not aware of patient status or patient laboratory data. Seven histologic or cytologic categories of diffuse (infiltrative but not nodular) liver diseases were jointly established by the authors and included normal liver; inflammation; round-cell neoplasia; non-round-cell infiltrative, prenodular (early) metastatic neoplasia; lipidosis; vacuolar hepatopathy; and other. Liver parenchymal sonographic criteria included parenchymal sound attenuation with increasing depth, comparative organ echogenicity (liver, spleen, and kidneys), diffuse or patchy hyperechoic or hypoechoic echotexture, uniform or coarse echotexture, portal venous clarity, and liver lobe geometry. Related extrahepatic criteria included gallbladder wall thickness, bile duct diameter, amount and character of gallbladder precipitate, nondependent shadowing in the gallbladder, hepatic vein diameter versus caudal vena cava diameter, peritoneal fluid, spleen echotexture (normal vs abnormal [characterized]), and kidney echotexture. Ultrasonographic criteria were statistically compared to the 7 categories of diffuse liver disease in search of clinically exploitable relationships. Statistical evaluation of the applied ultrasonographic criteria did not yield clinically acceptable accuracy for discrimination among the 7 categories of diffuse liver diseases (including normal liver) in either species. Criterion-based ultrasonographic appearance was insufficient to discriminate among canine and feline diffuse infiltrative liver diseases.


Advances in the extracellular signal-regulated kinase signaling pathway in silkworms, Bombyx mori (Lepidoptera).
Signaling pathways regulate the transmission of signals during organism growth and development, promoting the smooth and accurate completion of numerous physiological and biochemical reactions. The extracellular signal-regulated kinase (ERK) signaling pathway is an essential pathway involved in regulating various physiological processes, such as cell proliferation, differentiation, adhesion, migration, and more. This pathway also contributes to several important physiological processes in silkworms, including protein synthesis, reproduction, and immune defense against pathogens. Organizing related studies on the ERK signaling pathway in silkworms can provide a better understanding of its mechanism in Lepidopterans and develop a theoretical foundation for improving cocoon production and new strategies for pest biological control.


Intravenous artesunate for severe malaria in travelers, Europe.
Multicenter trials in Southeast Asia have shown better survival rates among patients with severe malaria, particularly those with high parasitemia levels, treated with intravenous (IV) artesunate than among those treated with quinine. In Europe, quinine is still the primary treatment for severe malaria. We conducted a retrospective analysis for 25 travelers with severe malaria who returned from malaria-endemic regions and were treated at 7 centers in Europe. All patients survived. Treatment with IV artesunate rapidly reduced parasitemia levels. In 6 patients at 5 treatment centers, a self-limiting episode of unexplained hemolysis occurred after reduction of parasitemia levels. Five patients required a blood transfusion. Patients with posttreatment hemolysis had received higher doses of IV artesunate than patients without hemolysis. IV artesunate was an effective alternative to quinine for treatment of malaria patients in Europe. Patients should be monitored for signs of hemolysis, especially after parasitologic cure.


Radiotherapy in small cell cancer of the lung treated with combination chemotherapy: a controlled trial.
Three hundred and seventy one patients with extensive or limited small cell cancer of the lung took part in a randomised trial to evaluate irradiation of the primary tumour in patients treated with combination chemotherapy. They were randomly allocated to treatment either with chemotherapy alone (198) or with both chemotherapy and radiotherapy (173). All 371 initially received 12 weeks of chemotherapy after which they were categorised according to response. Only those with stable or responding disease continued with their allotted treatment. Thus 144 received chemotherapy alone and 135 received both chemotherapy and radiotherapy. The design of the study permitted analysis of the effect of radiotherapy according to initial extent of disease and quality of early response to chemotherapy. Radiotherapy (40 Gy (4000 rad), one fraction a day over 20 days) did not improve the survival of patients in any category of initial extent of disease or early response to chemotherapy and was not effective in preventing local relapse.


Critical Role of Molecular Packing in Lo Phase Membrane Solubilization.
Membrane solubilization induced by Triton X-100 (TX-100) was investigated. Different membrane compositions and phase states were studied along the detergent titration. Expected solubilization profiles were obtained but new information is provided. The fluorescence of nitrobenzoxadiazole (NBD)-labeled lipids indicates that the liquid-ordered (Lo)/liquid-disordered (Ld) phase coexistence is barely unaffected at sub-solubilizing detergent concentrations and highlights the vesicle-to-micelle transition. Moreover, the location of the NBD group in the bilayer emphasizes a detergent-membrane interaction in the case of the insoluble Lo phase membrane. It has also been shown that the molecular packing of the membrane loosens in the presence of TX-100, regardless of the solubilization profile. Motivated by studies on GPMVs, the solubilization of less ordered Lo phase membranes was considered in order to improve the effect of molecular packing on the extent of solubilization. Membranes composed of SM and Chol in an equimolar ratio doped with different amounts of PC were studied. The more ordered the Lo phase membrane is in the absence of detergent, the less likely it is to be solubilized. Furthermore, and in contrast to what is observed for membranes exhibiting an Lo/Ld phase coexistence, a very small decrease in the molecular packing of the Lo phase membrane radically modifies the extent of solubilization. These results have implications for the reliability of TX-100 insolubility as a method to detect ordered domains.


ZAP-70, IgVh, and cytogenetics for assessing prognosis in chronic lymphocytic leukemia.
New prognostic factors such as IgVh mutational status, ZAP-70 protein expression and cytogenetic abnormalities have shown to offer important prognostic information for patients with chronic lymphocytic leukemia (CLL). Our aim was to evaluate the optimal cut-off for IgVh mutational status, ZAP-70 expression and cytogenetic abnormalities in association with disease progression defined as the need for treatment within 3~years from diagnosis in 170 patients with B-CLL. Receiver operating characteristics (ROC) analysis and multivariate general linear models (GLMs) were used to investigate the most significant cut-off values of these biomarkers and their prognostic impact. Our findings estimated that the optimal cut-off for IgVh mutation status and for ZAP-70 protein expression was 97% and 16.5% respectively and a high concordance between the two was demonstrated. We identified 30% as being the best-cut-off for 17p-, 11q- and 6q-. In univariate analysis 17p- was found to be a significant predictor of the event only for the whole population. Multivariate analysis including all biological parameters, identified 11q deletion as the only significant regressor. We assessed that IgVh mutational status, ZAP-70 protein and 6q- are powerful prognostic markers. Analyses of all these factors revealed that 11q deletion was the strongest predictor of disease progression in B-CLL.


Complexity of the genetic contribution to factor VII deficiency in two Spanish families: clinical and biological implications.
Although many F7 DNA variants have been described to be associated with alterations in factor VII (FVII) levels, the correlation of functional levels of FVII with disease (i.e. bleeding) is highly variable indicating that other factors are likely involved in producing this phenotype. We studied two unrelated Spanish families, identified from two asymptomatic propositi with FVII:C levels lower than 1% and 3%. Family members showed a wide range of FVII:C levels. Amplification and direct DNA sequencing of the F7 (promoter, exons, 3'-UTR and a large proportion of introns) identified the genetic variants involved. We characterized 3 mutations in the F7 coding region (homozygous Q100R in one patient, and double heterozygosity for M298I and G331S in another patient). We also found 16 new DNA polymorphisms. The high variability of FVII levels in family members with the same mutation shows that the inheritance of FVII phenotypes is extremely complex and suggests that polymorphisms might play an important role in modulating FVII levels, and ensuring hemostatic balance under pathologic conditions. These results highlight the importance of a concerted effect of multiple genetic factors in determining FVII levels. Since there is evidence that FVII levels constitute a risk factor for coronary heart disease and considering the importance of F7 DNA polymorphisms in determining FVII levels, further analyses of these polymorphisms should yield information to aid the understanding of the quantitative variation in FVII levels and the relative genetic risk for cardiovascular disease in the general population.


The chemical modification of the essential groups of beta-N-acetyl-D-glucosaminidase from Turbo cornutus Solander.
The chemical modification of beta-N-acetyl-D-glucosaminidase (EC22.214.171.124) from Turbo cornutus Solander has been first studied. The results demonstrate that the sulfhydryl group of cysteine residues and the hydroxyl group of serine residues are not essential to the enzyme's function. The modification of indole group of tryptophan of the enzyme by N-bromosuccinimide (NBS) can lead to the complete inactivation, accompanying the absorption decreasing at 278 nm and the fluorescence intensity quenching at 335 nm, indicating that tryptophan is essential residue to the enzyme. The modification of amino group of lysine residue by formaldehyde and trinitrobenzenesulfonic acid also inactivates the enzyme completely. The results show that lysine and tryptophan are probably situated in the active site of the enzyme. The modification of the imidazole residue and carboxyl group leads to inactivate incompletely, indicating they are not the composing groups of the enzyme active center, and they are essential for maintaining the enzyme's conformation which is necessary for the catalytic activity of the enzyme.


Dynamic transitions of functional brain connectivity during a working memory task.
Working memory is a cognitive system that temporarily stores and manipulates information via attention. Although brain activity patterns related to working memory have been extensively studied, little is known about how the brain connectome organization dynamically changes while performing working memory tasks. Here, we systematically investigated dynamic changes in functional brain connectivity during a working memory task. We found that functional connectivity in the medial frontal and orbitofrontal cortices and the precuneus showed differences during the transitions between the rest and task. Our results provide topographic patterns of dynamic functional connectivity during the working memory tasks.Clinical Relevance- This study may provide macroscale topography related to working memory and foster establishing memory-related brain mechanisms, which could be applied to clinical neuroscience.


Microsurgical reconstruction affects the outcome in a translational mouse model for Achilles tendon healing.
Animal models are one of the first steps in translation of basic science findings to clinical practice. For tendon healing research, transgenic mouse models are important to advance therapeutic strategies. However, the small size of the structures complicates surgical approaches, histological assessment, and biomechanical testing. In addition, available models are not standardized and difficult to compare. How surgery itself affects the healing outcome has not been investigated yet. The focus of the study was to develop a procedure that includes a transection and microsurgical reconstruction of the Achilles tendon but, unlike other models, preserves the sciatic nerve. We wanted to examine how distinct parts of the technique influenced healing. For this animal model study, we used 96 wild-type male C57BL/6 mice aged 8-12 weeks. We evaluated different suture techniques and macroscopically confirmed the optimal combination of suture material and technique to minimize tendon gap formation. A key element is the detailed, step-by-step illustration of the surgery. In addition, we assessed histological (Herovici and Alcian blue staining) outcome parameters at 1-16 weeks postoperatively. Microcomputed tomography (micro-CT) was performed to measure the bone volume of heterotopic ossifications (HOs). Biomechanical analyses were carried out using a viscoelastic protocol on the biomechanical testing machine LM1. A modified 4-strand suture combined with a cerclage for immobilization without transection of the sciatic nerve reliably eliminated gap formation. The maximal dorsal extension of the hindlimb at the upper ankle joint from the equinus position (limited by the immobilization cerclage) increased over time postoperatively (operation: 28.8 ± 2.2°; 1 week: 54 ± 36°; 6 weeks: 80 ± 11.7°; 16 weeks: 96 ± 15.8°, p > 0.05). Histological staining revealed a maturation of collagen fibres within 6 weeks, whereas masses of cartilage were visible throughout the healing period. Micro-CT scans detected the development of HOs starting at 4 weeks and further progression at 6 and 16 weeks (bone volume, 4 weeks: 0.07604 ± 0.05286 mm3; 6 weeks: 0.50682 ± 0.68841 mm3; 16 weeks: 2.36027 ± 0.85202 mm3, p > 0.001). In-depth micro-CT analysis of the different surgical elements revealed that an injury of the tendon is a key factor for the development of HOs. Immobilization alone does not trigger HOs. Biomechanical properties of repaired tendons were greatly altered and remained inferior 6 weeks after surgery. With this study, we demonstrated that the microsurgical technique greatly influences the short- and longer-term healing outcome. When the sciatic nerve is preserved, the best surgical reconstruction of the tendon defect is achieved by a 4-strand core suture in combination with a tibiofibular cerclage for postoperative immobilization. The cerclage promotes a gradual increase in the range of motion of the upper ankle joint, comparable with an early mobilization rehabilitation protocol. HO, as a key mechanism for poor tendon healing, is progressive and can be monitored early in the model. The study enhances the understanding of model dependent factors of healing. The described reconstruction technique provides a reproducible and translational rodent model for future Achilles tendon healing research. In combination with transgenic strains, it can be facilitated to advance therapeutic strategies to improve the clinical results of tendon injuries.


Hymenobacter cavernae sp. nov., isolated from a karst cave.
A novel Gram-stain-negative, rod-shaped, non-motile and red-pigmented bacterial strain, designated K1E01-27T, was isolated from an animal excrement sample which was found in a karst cave located in Guizhou province, China. The phylogenetic analysis based on 16S rRNA gene sequences indicated that strain K1E01-27T represented a member of the genus Hymenobacter within the family Cytophagaceae of the phylum Bacteroidetes. Strain K1E01-27T was most closely related to Hymenobacter algoricola VUG-A23aT, with 95.1 % 16S rRNA gene sequence similarity. Growth of strain K1E01-27T occurred at 4-35 °C, at pH 5-9 and in the presence of 0-0.5 % (w/v) NaCl. The major fatty acids were iso-C15 : 0, anteiso-C15 : 0, C16 : 1ω5c, summed feature 3 (comprising C16 : 1ω6c and/or C16 : 1ω7c) and summed feature 4 (comprising iso-C17 : 1 I/anteiso-C17 : 1 B). The major isoprenoid quinone was menaquinone 7 (MK-7). The major polar lipids were phosphatidylethanolamine, five unidentified aminophospholipids, three unidentified glycolipids, two unidentified phospholipids and one unidentified polar lipid. The DNA G+C content of the genomic DNA was 54.9 mol%. On the basis of phylogenetic, phenotypic and chemotaxonomic characteristics, strain K1E01-27T is considered to represent a novel species of the genus Hymenobacter, for which the name Hymenobacter cavernae sp. nov. is proposed. The type strain is K1E01-27T (=CGMCC 1.15197T=NBRC 112610T).


beta-Adrenergic receptor isolation and characterization with immobilized drugs and monoclonal antibodies.
Immobilized catecholamines have played an important role in the localization of alpha- and beta-adrenergic receptors to the plasma membrane of effector cells, and in elucidating mechanisms of beta receptor activation of cardiac muscle. An extension of immobilized drug and affinity chromatography procedures has been developed by utilizing receptor-specific monoclonal antibodies. Structurally different beta 1- and beta 2-adrenergic receptors have been purified with a single monoclonal antibody affinity column, where the antibody is specific for an epitope in the ligand-binding site of both beta 1 and beta 2 receptors. Specificity was increased by elution of receptors from the monoclonal antibody affinity columns with low concentrations of beta-receptor antagonists. These studies indicate that the turkey erythrocyte beta 1-adrenergic receptor is most likely a monomer with a molecular weight of 65,000-70,000. beta 2-Adrenergic receptors have a primary subunit of 55,000-58,000 daltons, with the intact receptor in membranes having a molecular weight of 109,000, which suggests that the beta 2-adrenergic receptor is most likely a dimer of either two identical subunits or a binding subunit and an unidentified second subunit.


Deep Learning: The Good, the Bad, and the Ugly.
Artificial vision has often been described as one of the key remaining challenges to be solved before machines can act intelligently. Recent developments in a branch of machine learning known as deep learning have catalyzed impressive gains in machine vision-giving a sense that the problem of vision is getting closer to being solved. The goal of this review is to provide a comprehensive overview of recent deep learning developments and to critically assess actual progress toward achieving human-level visual intelligence. I discuss the implications of the successes and limitations of modern machine vision algorithms for biological vision and the prospect for neuroscience to inform the design of future artificial vision systems.


Dual transcript and protein quantification in a massive single cell array.
Recently, single-cell molecular analysis has been leveraged to achieve unprecedented levels of biological investigation. However, a lack of simple, high-throughput single-cell methods has hindered in-depth population-wide studies with single-cell resolution. We report a microwell-based cytometric method for simultaneous measurements of gene and protein expression dynamics in thousands of single cells. We quantified the regulatory effects of transcriptional and translational inhibitors on cMET mRNA and cMET protein in cell populations. We studied the dynamic responses of individual cells to drug treatments, by measuring cMET overexpression levels in individual non-small cell lung cancer (NSCLC) cells with induced drug resistance. Across NSCLC cell lines with a given protein expression, distinct patterns of transcript-protein correlation emerged. We believe this platform is applicable for interrogating the dynamics of gene expression, protein expression, and translational kinetics at the single-cell level - a paradigm shift in life science and medicine toward discovering vital cell regulatory mechanisms.


Acute Gastric Volvulus and Atrial Fibrillation with RVR: A Coincidence or Association.
Gastric volvulus is a rare and life-threatening condition that involves the abnormal rotation of the stomach around its axis by more than 180°. The association between acute gastric volvulus and atrial fibrillation with rapid ventricular response is rare with only few cases that have been reported. Our patient was an 86-year-old female who presented with upper abdominal pain, distension, nausea, and shortness of breath. Clinical and laboratory workup revealed acute gastric volvulus with diaphragmatic hernia. On presentation, she was also in atrial fibrillation with rapid ventricular response. She was successfully treated by laparotomy with reduction of the gastric volvulus and repair of the diaphragmatic hernia, with significant improvement.


The tired patient.
One of the most challenging diagnostic problems that comes into the physician's office is the patient who complains of "being tired." It can prove to be a frustrating experience for the physician (especially if the physician is also tired) and to the patient. This article will propose and describe a two-pronged systematic approach to the patient that can increase the probability of a satisfying outcome for both physician and patient. This approach assumes the "complaint" of every patient has both informational value ("I think there's something wrong.") and transactional meaning (Please take care of me."). Tiredness, fatigue, "exhaustion" need to be seen simultaneously as information and need. Both aspects require simultaneous work-up.


Diesel Adsorption to Polyvinyl Chloride and Iron During Contaminated Water Flow and Flushing Tests.
This paper presents an experimental and theoretical study of aqueous diesel contamination and decontamination of a polyvinyl chloride (PVC) surface and an iron (Fe) surface. A test apparatus designed for the purpose of studying adsorption of diesel from a flowing dilute diesel/water mixture was used to measure the mass of diesel adsorbed per unit surface area (the excess surface density) and the bulk concentration of the diesel in the flow using a fluorescence based measurement technique. Both bulk composition and the excess surface density measurements were achieved via a traverse of the fluorescent measurement probe perpendicular to the test surface. The diesel adsorption to each test surface was examined for three different Reynolds numbers between zero and 7000. Measurements for a given condition were made over a period of approximately 200 h for a diesel mass fraction of approximately 0.15 % in tap water. For a Reynolds number of approximately 7000, the largest excess layer thickness was approximately 4.4 μm, which was measured on a PVC surface. Averaging over all contaminating flow rates and exposure times, the excess layer thickness on the PVC surface was approximately 2.0 μm. Reynolds number had little or no effect on the accumulation of diesel on an iron surface, which was approximately 0.71 μm. The adsorbed diesel on the PVC and iron surfaces was removed by flushing with tap water. Models to predict excess layer thickness during flushing and contamination were developed. The models predict flushing times to within 7 h and predict the influence of pipe surface on contamination level.


Risk of cardiovascular disease associated with HCV and HBV coinfection among antiretroviral-treated HIV-infected individuals.
The increased risk for cardiovascular disease (CVD) in HIV is well established. Despite high prevalence of viral hepatitis coinfection with HIV, there are few studies on the risk of CVD amongst antiretroviral therapy (ART)-treated coinfected patients. Ontario HIV Treatment Network Cohort Study participants who initiated ART without prior CVD events were analysed. HBV and HCV coinfection were identified by serology and RNA test results. CVD was defined as any of: coronary artery disease including atherosclerosis, chronic ischaemic heart disease and arteriosclerotic vascular disease; myocardial infarction; congestive heart failure; cerebrovascular accident or stroke; coronary bypass; angioplasty; and sudden cardiac death. The impact of HBV and HCV coinfection on time to CVD was assessed using multivariable competing risk models accounting for left truncation between ART initiation and study enrolment. A total of 3,416 HIV-monoinfected, 432 HIV-HBV- and 736 HIV-HCV-coinfected individuals were followed for a median (IQR) of 2.32 years (1.36-8.02). Over the study period, 167 CVD events and 613 deaths were documented. After adjustment for age, gender, race, year initiating ART, weight and smoking status, HBV was not associated with time to CVD onset (aHR=1.05, 95% CI [0.63, 1.74]; P=0.86). There was an elevated risk of CVD for HCV-coinfected individuals, which approached statistical significance (aHR=1.44, 95% CI [0.97, 2.13]; P=0.07). Our results are consistent with a moderate increase of CVD among individuals with HIV-HCV coinfection relative to those with HIV infection alone, lending support to consideration of initiation of HCV antiviral treatment.


Study of retinal neurodegeneration and maculopathy in diabetic Meriones shawi: A particular animal model with human-like macula.
The purpose of this work was to evaluate a potentially useful animal model, Meriones shawi (M.sh)-developing metabolic X syndrome, diabetes and possessing a visual streak similar to human macula-in the study of diabetic retinopathy and diabetic macular edema (DME). Type 2 diabetes (T2D) was induced by high fat diet administration in M.sh. Body weights, blood glucose levels were monitored throughout the study. Diabetic retinal histopathology was evaluated 3 and 7 months after diabetes induction. Retinal thickness was measured, retinal cell types were labeled by immunohistochemistry and the number of stained elements were quantified. Apoptosis was determined with TUNEL assay. T2D induced progressive changes in retinal histology. A significant decrease of retinal thickness and glial reactivity was observed without an increase in apoptosis rate. Photoreceptor outer segment degeneration was evident, with a significant decrease in the number of all cones and M-cone subtype, but-surprisingly-an increase in S-cones. Damage of the pigment epithelium was also confirmed. A decrease in the number and labeling intensity of parvalbumin- and calretinin-positive amacrine cells and a loss of ganglion cells was detected. Other cell types showed no evident alterations. No DME-like condition was noticed even after 7 months. M.sh could be a useful model to study the evolution of diabetic retinal pathology and to identify the role of hypertension and dyslipidemia in the development of the reported alterations. Longer follow up would be needed to evaluate the potential use of the visual streak in modeling human macular diseases.


Levetiracetam for treatment of neonatal seizures.
Neonatal seizures are often refractory to treatment with initial antiseizure medications. Consequently, clinicians turn to alternatives such as levetiracetam, despite the lack of published data regarding its safety, tolerability, or efficacy in the neonatal population. We report a retrospectively identified cohort of 23 neonates with electroencephalographically confirmed seizures who received levetiracetam. Levetiracetam was considered effective if administration was associated with a greater than 50% seizure reduction within 24 hours. Levetiracetam was initiated at a mean conceptional age of 41 weeks. The mean initial dose was 16 ± 6 mg/kg and the mean maximum dose was 45 ± 19 mg/kg/day. No respiratory or cardiovascular adverse effects were reported or detected. Levetiracetam was associated with a greater than 50% seizure reduction in 35% (8 of 23), including seizure termination in 7. Further study is warranted to determine optimal levetiracetam dosing in neonates and to compare efficacy with other antiseizure medications.


Robotic substernal esophageal bypass and reconstruction with gastric conduit-frequently overlooked minimally invasive option.
Modern esophagectomy includes the esophageal extirpation with immediate reconstruction of the gastrointestinal (GI) continuity via posterior mediastinal route. In the majority of cases tubularized stomach is chosen as the conduit of choice. Other conduits, such as colon or small bowel can be used for these purposes as well. In rare circumstances use of the alternative route for the conduit placement is required. Authors describe the technique of robotic substernal esophageal bypass and reconstruction of the esophageal continuity.


Insights into Nitrous Oxide Mitigation Strategies in Wastewater Treatment and Challenges for Wider Implementation.
Nitrous oxide (N2O) emissions account for the majority of the carbon footprint of wastewater treatment plants (WWTPs). Many N2O mitigation strategies have since been developed while a holistic view is still missing. This article reviews the state-of-the-art of N2O mitigation studies in wastewater treatment. Through analyzing existing studies, this article presents the essential knowledge to guide N2O mitigations, and the logics behind mitigation strategies. In practice, mitigations are mainly carried out by aeration control, feed scheme optimization, and process optimization. Despite increasingly more studies, real implementation remains rare, which is a combined result of unclear climate change policies/incentives, as well as technical challenges. Five critical technical challenges, as well as opportunities, of N2O mitigations were identified. It is proposed that (i) quantification methods for overall N2O emissions and pathway contributions need improvement; (ii) a reliable while straightforward mathematical model is required to quantify benefits and compare mitigation strategies; (iii) tailored risk assessment needs to be conducted for WWTPs, in which more long-term full-scale trials of N2O mitigation are urgently needed to enable robust assessments of the resulting operational costs and impact on nutrient removal performance; (iv) current mitigation strategies focus on centralized WWTPs, more investigations are warranted for decentralised systems, especially decentralized activated sludge WWTPs; and (v) N2O may be mitigated by adopting novel strategies promoting N2O reduction denitrification or microorganisms that emit less N2O. Overall, we conclude N2O mitigation research is reaching a maturity while challenges still exist for a wider implementation, especially in relation to the reliability of N2O mitigation strategies and potential risks to nutrient removal performances of WWTPs.


Antioxidant enzyme activities of iron-saturated bovine lactoferrin (Fe-bLf) in human gut epithelial cells under oxidative stress.
Chemoprevention by dietary constituents in the form of functional food has emerged as a novel approach to control inflammatory diseases and cancers. Recently we reported for the first time that iron content is a critical determinant in the anti-tumour activity of bovine milk lactoferrin (bLf). We therefore wanted to evaluate the chemo-preventative efficacy of Apo-bLF and 100% iron-saturated bLF (Fe-bLF) on hydrogen peroxide (H2O2)-induced colon carcinogenesis, and their influence on antioxidant enzyme activities within colon carcinogenesis. This was undertaken through observing how oxidative stress induced by H2O2 alters antioxidant enzyme activity within HT29 colon cancer cells, and then observing changes in this activity by treatments with the different antioxidants ascorbic acid (AA), Apo-bLF and Fe-bLF. All antioxidant enzymes (catalase, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-s-transferase (GsT) and superoxide dismutase (SOD)) appeared to be increased within HT29 cells, even prior to H2O2 exposure, and all enzymes showed significant decreased activity when cells were treated with the antioxidants AA, Apo-bLF or Fe-bLF, with or without H2O2 exposure. The results indicate that all three antioxidants have the ability to scavenge ROS, lower antioxidant enzyme activities within already excited states, and possibly allow colon cancer cells to be overcome by oxidative stress that would normally be prevented, perhaps leading to damage and potential apoptosis of the cancer cells. In conclusion, the anti-oxidative effects of Apo-bLF and Fe-bLf studied for the first time, show dynamic changes that may allow for necessary protection from imbalanced oxidative conditions, and potential at reducing the ability of cancer cells to protect themselves from oxidative stress states.


Hearing Aid Consumer Reviews: A Linguistic Analysis in Relation to Benefit and Satisfaction Ratings.
Purpose Online reviews have been used by hearing aid owners to share their experiences and to provide suggestions to potential hearing aid buyers, although they have not been systematically examined. The study was aimed at examining the hearing aid consumer reviews using automated linguistic analysis, and how the linguistic variables relate to self-reported hearing aid benefit and satisfaction ratings. Method The study used a cross-sectional design. One thousand three hundred seventy-eight consumer hearing aid reviews (i.e., text response to open-ended question), self-reported benefit and satisfaction ratings on hearing aids in a 5-point scale with meta-data (e.g., hearing aid brand, technology level) extracted from the Hearing Tracker website were analyzed using automated text analysis method known as the Linguistic Inquiry and Word Count. Results Self-reported hearing aid benefit and satisfaction ratings were high (i.e., mean rating of 4.04 in a 5-point scale). Examining the association between overall rating and the key linguistic variables point to two broad findings. First, the more people were personally, socially, and emotionally engaged with the hearing device experience, the higher they rated their hearing device(s). Second, a minimal occurrence of clinic-visit language dimensions points to factors that likely affect benefit and satisfaction ratings. For example, if people mention paying too much money (money), their overall ratings are generally lower. Conversely, if people write about their health or home, the ratings were higher. There was no significant difference in linguistic analysis across different hearing aid brands and technology levels. Conclusions Hearing aid consumers are generally satisfied with their hearing device(s), and their online reviews contain information about social/emotional dimensions as well as clinic-visit related aspects that have bearing toward hearing aid benefit and satisfaction ratings. These results suggest that the natural language used by consumers provide insights on their perceived benefit/satisfaction from their hearing device.


Molecular Basis for Allosteric Inhibition of Acid-Sensing Ion Channel 1a by Ibuprofen.
A growing body of evidence links certain aspects of nonsteroidal anti-inflammatory drug (NSAID) pharmacology with acid-sensing ion channels (ASICs), a small family of excitatory neurotransmitter receptors implicated in pain and neuroinflammation. The molecular basis of NSAID inhibition of ASICs has remained unknown, hindering the exploration of this line of therapy. Here, we characterized the mechanism of inhibition, explored the molecular determinants of sensitivity, and sought to establish informative structure-activity relationships, using electrophysiology, site-directed mutagenesis, and voltage-clamp fluorometry. Our results show that ibuprofen is an allosteric inhibitor of ASIC1a, which binds to a crucial site in the agonist transduction pathway and causes conformational changes that oppose channel activation. Ibuprofen inhibits several ASIC subtypes, but certain ibuprofen derivatives show some selectivity for ASIC1a over ASIC2a and vice versa. These results thus define the NSAID/ASIC interaction and pave the way for small-molecule drug design targeting pain and inflammation.


Serum uric acid levels and risk of metabolic syndrome in healthy adults.
To investigate the relationship between hyperuricemia and metabolic syndrome in a population of healthy subjects. We studied 1,573 healthy adults (25 to 64 years old) in the population laboratory of the Tehran University of Medical Sciences. The study was designed according to the World Health Organization MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) project with use of the National Cholesterol Education Program Adult Treatment Panel III criteria for metabolic syndrome. The crude prevalence of the metabolic syndrome was 29.9% (age-adjusted, 27.5%). The rate of metabolic syndrome significantly increased in higher quartiles of serum uric acid in both sexes but especially in women (P<.0001 versus P = .026). The bivariate correlation was significant between uric acid levels and age, total serum cholesterol, high-density lipoprotein cholesterol, triglycerides, body mass index, waist and hip circumferences, waist-to-hip ratio, and systolic and diastolic blood pressures; however, there was not a significant correlation between serum uric acid concentrations and fasting plasma glucose. These data indicate that an independent relationship exists between hyperuricemia and the metabolic syndrome. Moreover, hyperuricemia is significantly correlated with hypertriglyceridemia, hypertension, and visceral obesity. Early detection of hyperuricemia seems to be essential for prevention of the metabolic syndrome.


Prehospital shock index and systolic blood pressure are highly specific for pediatric massive transfusion.
While massive transfusion protocols (MTPs) are associated with decreased mortality in adult trauma patients, there is limited research on the impact of MTP on pediatric trauma patients. The purpose of this study was to compare pediatric trauma patients requiring massive transfusion with all other pediatric trauma patients to identify triggers for MTP activation in injured children. Using our level I trauma center's registry, we retrospectively identified all pediatric trauma patients from January 2015 to January 2018. Massive transfusion (MT) was defined as infusion of 40 mL/kg of blood products in the first 24 hours of admission. Patients missing prehospital vital sign data were excluded from the study. We retrospectively collected data including demographics, blood utilization, variable outcome data, prehospital vital signs, prehospital transport times, and Injury Severity Scores. Statistical significance was determined using Mann-Whitney U test and χ2 test. p Values of less than 0.05 were considered significant. Thirty-nine (1.9%) of the 2,035 pediatric patients met the criteria for MT. All-cause mortality in MT patients was 49% (19 of 39 patients) versus 0.01% (20 of 1996 patients) in non-MT patients. The two groups significantly differed in Injury Severity Score, prehospital vital signs, and outcome data.Both systolic blood pressure (SBP) of <100 mm Hg and shock index (SI) of >1.4 were found to be highly specific for MT with specificities of 86% and 92%, respectively. The combination of SBP of <100 mm Hg and SI of >1.4 had a specificity of 94%. The positive and negative predictive values of SBP of <100 mm Hg and SI of >1.4 in predicting MT were 18% and 98%, respectively. Based on positive likelihood ratios, patients with both SBP of <100 mm Hg and SI of >1.4 were 7.2 times more likely to require MT than patients who did not meet both of these vital sign criteria. Pediatric trauma patients requiring early blood transfusion present with lower blood pressures and higher heart rates, as well as higher SIs and lower pulse pressures. We found that SI and SBP are highly specific tools with promising likelihood ratios that could be used to identify patients requiring early transfusion. Therapeutic/care management, level V.


HIV-related concerns and behaviors among Hispanic women.
Hispanic women whose sexual partners have other sexual partners may be at risk for HIV. A structured interview was administered to 106 Dominican and Puerto Rican women who reported that they knew or suspected that their partner had other partners. A subsample participated in qualitative interviews. The study assessed concern about HIV and predictors of condom use. The majority of women reported that they worried about getting HIV and almost half had been HIV-tested. Most of the women discussed HIV/AIDS concerns with their partners, and one-third reported some condom use. Predictors of condom use were: born in the Dominican Republic/Puerto Rico, having talked with their partner about being tested, and belief that he used condoms with others. Although the women were concerned about HIV, condom use was infrequent. Results suggested methods to address this discrepancy: introducing condoms early in the relationship, developing women-controlled methods, and directly influencing men's behavior.


An evidence-based update on vitamins.
American adults take many types of vitamin supplements, despite limited evidence of their efficacy, especially in preventing chronic diseases such as cardiovascular disease and cancer. Supplements contain significant amounts of vitamins when consumed from multiple sources. Excess consumption of some vitamins may have detrimental health effects. Use of MMVM products appears to be safe; however, clinical outcomes have not been established. Although vitamin D and preconception folic acid may be appropriate for self care, a health care provider should monitor other vitamin supplements for disease prevention, such as niacin. Beyond supplementation as treatment for vitamin deficiencies, evidence is lacking.


Peroxidase-catalyzed stabilization of 2,4-dichlorophenol in alkali-extracted soils.
Horseradish peroxidase- (HRP) mediated stabilization of phenolic contaminants is a topic of interest due to its potential for remediation of contaminated soils. This study evaluated the sorption of 2,4-dichlorophenol (DCP) and its HRP-mediated stabilization in two alkali-extracted soils. Alkali extraction reduced the soil organic matter (SOM) contents of the geomaterials and enriched the residual SOM with humin C. Sorption of DCP on these sorbents was complete within 1 d. However, most of the sorbed DCP was removed from the geomaterials by water and methanol, suggesting weak solute-sorbent interactions. The addition of HRP resulted in the generation of DCP polymerization products (DPP), which partitioned between the aqueous and solid phases. The DPP phase distribution was rapid and complete within 24 h. Between 70 and 90% of the added DCP was converted to DPP and up to 43% of the initial aqueous phase contaminant was transformed into a residue that was resistant to extraction with methanol. Bound residues of DPP increased with initial aqueous phase solute concentration and remained fairly constant after 7 d of contact. Contaminant stabilization was noted to be high in the humin-mineral geomaterial. Results illustrate that HRP may be effective in stabilizing phenolic contaminants in subsoils that are likely to contain SOM enriched in humin C.


Visualization and automatic detection of defect distribution in GaN atomic structure from sampling Moiré phase.
Quantitative detection of defects in atomic structures is of great significance to evaluating product quality and exploring quality improvement process. In this study, a Fourier transform filtered sampling Moiré technique was proposed to visualize and detect defects in atomic arrays in a large field of view. Defect distributions, defect numbers and defect densities could be visually and quantitatively determined from a single atomic structure image at low cost. The effectiveness of the proposed technique was verified from numerical simulations. As an application, the dislocation distributions in a GaN/AlGaN atomic structure in two directions were magnified and displayed in Moiré phase maps, and defect locations and densities were detected automatically. The proposed technique is able to provide valuable references to material scientists and engineers by checking the effect of various treatments for defect reduction.


Influence of low proximal aortic pressure on spinal cord oxygenation in experimental thoracic aortic occlusion.
To evaluate the effect of low proximal aortic pressure on cerebrospinal fluid (CSF) oxygenation in an experimental thoracic occlusion model. In nine pigs, continuous intrathecal pO(2), pCO(2) and pH monitoring was used during double descending thoracic aortic clamping following insertion of an aorto-aortic shunt. In five pigs, the shunt was connected to a citrated bag adjusted at approximately 40-45 cm above the heart for partial exsanguination in order to decrease mean proximal aortic pressure (MPAP) to below 50 mmHg. In four animals, sodium nitroprusside infusion was used for this purpose. Intrathecal pO(2) demonstrated a significant decrease from 4.9+/-2.1 to 2.9+/-2.4 kPa after 10 minutes of aortic cross-clamping. Lowering proximal aortic pressure caused a further significant decrease to 1.2+/-1.7 kPa (p<0.05). In seven pigs (5 in the exsanguination and 2 in the vasodilator group), restoration of mean proximal aortic pressure to 94.0+/-27.7 caused a recovery of CSF pO(2) from 1.2+/-1.9 to 2.8+/-3.0 (p<0.05). The results of this study demonstrate that MPAP which provides spinal cord perfusion through subclavian-vertebral arteries are crucial for maintenance of spinal cord oxygenation during thoracic aortic occlusion in this pig model.


[Optimization of culture condition for cultivation of influenza virus A on MDCK cell].
To optimize the cultivation condition of influenza virus A on MDCK cells and to improve the separation rate and the inspected effect of influenza virus. The virus specimens which came from three kinds of the influenza virus A, swine-origin H1N1, seasonal H1N1 and seasonal H3N2, were cultivated by MDCK cells. It will make the most suitable condition by means of comparing the different inoculum size (25, 50, 75, 100, 125 and 150 microl/cm2), the different concentration of TPCK-Trypsin (1.0, 1.5, 2.0, 2.5, 3.0 and 3.5 microg/ml) as an addition and the different susceptibility of cell generations for serial passage culture of four generations of these three influenza virus. Throughout the comparison the three kinds of the influenza virus, swine-origin H1N1, seasonal H1N1 and seasonal H3N2, which had the most suitable inoculum size 100,75, 75 microl/cm2 and the most suitable concentration of TPCK-Trypsin as an addition 2.5, 2.0, 2.0 microg/ml and the most suitable generations of cell 1, 2, 2 respectively. Earlier generations of MDCK cells of the swine-origin H1N1 were more susceptible than the other influenza virus A. The hemagglutination inhibition (HI) of swine-origin H1N1 after cultivated was lower than the other of seasonal H1N1 and seasonal H3N2. The separating effect of the swine-origin H1N1 virus in the MDCK cell was inferior to the seasonal H1N1 and seasonal H3N2. The culture condition of seasonal H1N1 and seasonal H3N2 were roughly similar.


Risperidone attenuates the discriminative-stimulus effects of d-amphetamine in humans.
Studies conducted with nonhuman laboratory animals have consistently shown that atypical antipsychotics that are mixed dopamine and serotonin antagonists attenuate the discriminative-stimulus effects of amphetamine. In the present experiment, eight healthy humans learned to discriminate 15 mg of oral d-amphetamine. After acquiring the discrimination (i.e., > or = 80% correct responding on four consecutive days), the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and after pretreatment with risperidone (0 and 1 mg), a D2 dopamine and 5-hydroxytryptamine (5-HT)2 serotonin antagonist, were assessed. d-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects (e.g., increased ratings of "like drug"). These effects were generally a function of dose. Risperidone alone did not occasion d-amphetamine-appropriate responding, but impaired performance. Risperidone pretreatment significantly attenuated the discriminative-stimulus effects of d-amphetamine, and some of the self-reported drug effects. The results of the present experiment suggest that combining drug-discrimination and self-reported drug-effect questionnaires may be an effective strategy for assessing the behavioral effects of agonist-antagonist interactions. Future studies should compare the behavioral effects of d-amphetamine after pretreatment with a selective D2 dopamine (e.g., haloperidol) or 5-HT2 serotonin (e.g., ritanserin) antagonist to determine the relative contribution of dopamine and serotonin systems in mediating the behavioral effects of stimulants in humans. The results of these studies might guide the development of a pharmacotherapy for the treatment of amphetamine abuse/dependence.


Results of a survey of 201 polio survivors.
We present the results of a survey on the late effects of poliomyelitis in 201 persons. The most common new problems were fatigue, weakness in previously affected and unaffected muscles, muscle pain, and joint pain. The median time from poliomyelitis to onset of new problems ranged from 30 to 40 years. Factors at onset of polio most strongly associated with development of these late effects of polio were (1) hospitalization (P less than 0.00001), (2) age greater than 10 years (P less than 0.00001), (3) ventilator use (P less than 0.0029), and (4) paralytic involvement of all four limbs (P less than 0.0240). The differential diagnosis of these new problems, implications for treatment, and areas for future research are discussed.


[The effect of purine and pyrimidine bases on the growth of Streptococcus lactis and the biosynthesis of nisin].
The method of mathematical modelling of the experiment was used to determine optimum concentrations of purine and pyrimidine bases for the growth of Streptococcus lactis and the biosynthesis of nisin. These bases were introduced into the medium at different concnetrations. Thymine at a concentration of 4 mcg/ml stimulated the biosynthesis of nisin, and adenine and hypoxanthine at a concentration of 15 mcg/ml produced a favourable effect on the growth of the culture.


Violence, health, and the 2030 agenda: Merging evidence and implementation.
The Guest Editors introduce the Special Issue for the Journal of Public Health Policy on violence, health, and the 2030 Agenda. Emphasizing the importance of collaboration between scholars and practitioners, they outline the process of jointly imagining and designing the next generation of violence prevention strategies. They include representative works of members of the World Health Organization (WHO) Violence Prevention Alliance (VPA), including the World Bank, the United States Centers for Disease Control and Prevention, Prevention Institute, the Danish Institute Against Torture, the University of Cambridge Institute of Criminology, the London School of Hygiene and Tropical Medicine Gender Violence and Health Centre, and the Yale University Law and Psychiatry Division, among others.


Image coding using adaptive recursive interpolative DPCM.
A predictive image coder having minimal decoder complexity is presented. The image coder utilizes recursive interpolative DPCM in conjunction with adaptive classification, entropy-constrained trellis coded quantization, and optimal rate allocation to obtain signal-to-noise ratios (SNRs) in the range of those provided by the most advanced transform coders.


Activities and specificities of homodimeric TALENs in Saccharomyces cerevisiae.
The development of highly efficient genome engineering reagents is of paramount importance to launch the next wave of biotechnology. TAL effectors have been developed as an adaptable DNA binding scaffold that can be engineered to bind to any user-defined sequence. Thus, TAL-based DNA binding modules have been used to generate chimeric proteins for a variety of targeted genome modifications across eukaryotic species. For example, TAL effectors fused to the catalytic domain of FokI endonuclease (TALENs) were used to generate site-specific double strand breaks (DSBs), the repair of which can be harnessed to dictate user-desired, genome-editing outcomes. To cleave DNA, FokI endonuclease must dimerize which can be achieved using a pair of TALENs that bind to the DNA targeted in a tail-to-tail orientation with proper spacing allowing the dimer formation. Because TALENs binding to DNA are dependent on their repeat sequences and nucleotides binding specificities, homodimers and heterodimers binding can be formed. In the present study, we used several TALEN monomers with increased repeats binding degeneracy to allow homodimer formation at increased number of genomic loci. We assessed their binding specificities and genome modification activities. Our results indicate that homodimeric TALENs could be used to modify the yeast genome in a site-specific manner and their binding to the promoter regions might modulate the expression of target genes. Taken together, our data indicate that homodimeric TALENs could be used to achieve different engineering possibilities of biotechnological applications and that their transcriptional modulations need to be considered when analyzing their phenotypic effects.


Intrasplenic transplantation of isolated adult rat hepatocytes: sex-reversal and/or suppression of the major constituent isoforms of cytochrome P450.
Adult male and female rat hepatocytes were individually transplanted into the spleens of adult male and female rats. The recipients were euthanized at either eight, sixteen, thirty, or forty-five weeks following transplantation, at which time hepatic and splenic levels of liver-specific rat albumin mRNA as well as sex-dependent transcript levels of CYP2C11, -2C12, -2C7, -2A1, and -3A2-which accounts for > 60% of the total concentration of hepatic constituent cytochrome P450-were determined. Whereas the pre-infused hepatocytes expressed their expected cytochrome P450 sexual dimorphisms (female-specific CYP2C12, male-specific CYP3A2, and female-predominant CYP2A1), their post-transplantational competence now reflected the sexual dimorphisms of the recipient (as observed in the host's liver), which supports the concept that the sex-dependent growth hormone circulating profiles are the determinants regulating the expression levels of hepatic cytochrome P450. Also expressed at normal concentrations in the pre-infused hepatocytes, male-specific CYP2C11 and female-predominant CYP2C7 were inexplicably undetectable in the spleens of both recipient males and females, regardless of the sex of the donor hepatocytes, almost one year after transplantation.


Experimental laryngeal reinnervation by phrenic nerve implantation into the posterior cricoarytenoid muscle.
Under general anaesthesia, 5 dogs underwent sectioning of the right recurrent nerve followed by implantation of the phrenic nerve into the posterior cricoarytenoid (PCA) muscle. Some 6-7 months later the dogs were sacrificed after registration of vocal cord motility. Still photographs and movie film of the larynx were taken during quiet and forced respiration and at electrical stimulation of the implanted phrenic nerve. The PCA and vocal muscles were removed for histochemical studies. We found practically no abductory movement of the vocal cord on the reinnervated side, either during quiet or forced respiration. During forced inspiration there was, however, a slight medial bowing of the right vocal cord. At electrical stimulation there was a sphincteric movement of the entire larynx. Histochemistry showed a reinnervation picture of both the PCA and the vocal muscles on the experimental side. The conclusion drawn from this study is that axonal escape, probably from the implantation site, results in an unwanted reinnervation of laryngeal adductor muscles, which neutralize the abducting effect of the PCA muscle during inspiration. This method therefore does not seem to be suitable as a treatment alternative for bilateral recurrent nerve paralysis.


O-GlcNAc-glycosylation of beta-catenin regulates its nuclear localization and transcriptional activity.
Beta-catenin plays a role in intracellular adhesion and regulating gene expression. The latter role is associated with its oncogenic properties. Phosphorylation of beta-catenin controls its intracellular expression but mechanism/s that regulates the nuclear localization of beta-catenin is unknown. We demonstrate that O-GlcNAc glycosylation (O-GlcNAcylation) of beta-catenin negatively regulates its levels in the nucleus. We show that normal prostate cells (PNT1A) have significantly higher amounts of O-GlcNAcylated beta-catenin compared to prostate cancer (CaP) cells. The total nuclear levels of beta-catenin are higher in the CaP cells than PNT1A but only a minimal fraction of the nuclear beta-catenin in the CaP cells are O-GlcNAcylated. Increasing the levels of O-GlcNAcylated beta-catenin in the CaP cells with PUGNAc (O- (2-acetamido-2-deoxy-d-gluco-pyranosylidene) amino-N-phenylcarbamate) treatment is associated with a progressive decrease in the levels of beta-catenin in the nucleus. TOPFlash reporter assay and mRNA expressions of beta-catenin's target genes indicate that O-GlcNAcylation of beta-catenin results in a decrease in its transcriptional activity. We define a novel modification of beta-catenin that regulates its nuclear localization and transcriptional function.


Video game therapy for emotional regulation and impulsivity control in a series of treated cases with bulimia nervosa.
Although standard psychological treatments have been successful in treating several core features in eating disorders (ED), other characteristics such as emotional regulation or impulsivity appear to be more resistant to change. There is a growing body of evidence to support the efficacy of cognitive remediation for cognitive and emotional difficulties in ED. Playmancer/ Islands is a video game (VG) designed to specifically treat mental disorders, characterized by problems in impulse control. The objective of the game is to increase self-control over emotions, decision making and behaviours. The aim of this study is to describe the results from a consecutive series of nine bulimia nervosa patients who were treated with the VG in addition to cognitive behaviour therapy (CBT). The outcomes included clinical and psychopathological questionnaires, and physiological measures were obtained during the VG. Emotional regulation improved, heart rate variability increased, and respiratory rate and impulsivity measures reduced after the treatment. These findings suggest that VG training may enhance treatment for ED.


Nephrotoxicity of S-(2-chloro-1,1,2-trifluoroethyl)glutathione and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine, the glutathione and cysteine conjugates of chlorotrifluoroethene.
The glutathione and cysteine conjugates of the nephrotoxin chlorotrifluoroethene, S-(2-chloro-1,1,2-trifluoroethyl)glutathione (CTFG) and S-(2-chloro-1,1,2-trifluoroethyl)cysteine (CTFC), are potent nephrotoxins in male rats. Morphological changes in the kidneys were observed 1.5 hr after giving 100 mumol/kg of CTFG (i.v.), and severe damage to the proximal tubules was evident 24 hr after treatment; this dose of CTFG caused a 100-fold increase in urine glucose excretion, a 10-fold increase in urine protein excretion and a 4-fold increase in blood urea nitrogen concentrations 24 hr after administration. Administration of 50 mumol/kg of CTFG or 100 mumol/kg of CTFC produced similar lesions and increases in urine glucose excretion rates and blood urea nitrogen concentrations. Administration of 10 mumol/kg of CTFG produced no discernable effect on the kidneys. CTFG and CTFC did not alter plasma glucose concentrations or plasma glutamate-pyruvate transaminase activities. CTFG and CTFC produced time- and dose-dependent loses of cell viability in isolated rat renal tubular cells. The toxicity of CTFG to isolated renal tubular cells was prevented by the gamma-glutamyltransferase inhibitor AT-125, and the toxicity of CTFC and CTFG to isolated cells was prevented by aminooxyacetic acid, an inhibitor of pyridoxal phosphate-dependent enzymes. Moreover, S-(2-chloro-1,1,2-trifluoroethyl)-DL-alpha-methylcysteine, which cannot be metabolized by pyridoxal phosphate-dependent enzymes, was not toxic to isolated renal tubular cells. The data presented support the hypothesis that the nephrotoxicity of chlorotrifluoroethene is due to the enzymatic formation of a glutathione conjugate, which is metabolized to the ultimate nephrotoxin by the sequential action of renal gamma-glutamyltransferase, cysteinylglycine dipeptidase and cysteine conjugate beta-lyase.


Histologic findings of the sinus node and the perinodal area in street heroin addicts, victims of sudden unexpected death.
Sudden unexpected death is frequent in street heroin addicts. We conducted a histologic study of the sinus node (SN) to offer some evidence about the possible arrhythmogenic cause of death. Postmortem coronary angiography and microscopic examination of the SN and the perinodal area were performed in 50 heroin addicts (group 1) and in 50 nonaddicts (group 2), all men (16-40 years old). In heroin addicts, fatty and/or fibrous tissue replaced SN tissue in 21 cases (42%). Perinodal infiltration was found in 15 cases (30%). Fibromuscular dysplasia in branches of the sinus node artery (SNA) was found in eight cases (16%). Inflammation with focal and/or diffuse concentration of round cells was detected in the SN in 22 cases (44%). Old mural thrombi were also found in 13 cases (26%). The histologic changes in the SN and perinodal area offer an explanation about the possible mechanism of arrhythmia and sudden death in this population.


The functional consequences of chronic, physiologically effective intracortical microstimulation.
Many studies have demonstrated the ability of chronically implanted multielectrode arrays (MEAs) to extract information from the motor cortex of both humans and nonhuman primates. Similarly, many studies have shown the ability of intracortical microstimulation to impart information to the brain via a single or a few electrodes acutely implanted in sensory cortex of nonhuman primates, but relatively few microstimulation studies characterizing chronically implanted MEAs have been performed. Additionally, device and tissue damage have been reported at the levels of microstimulation used in these studies. Whether the damage resulting from microstimulation impairs the ability of MEAs to chronically produce physiological effects, however, has not been directly tested. In this study, we examined the functional consequences of multiple months of periodic microstimulation via chronically implanted MEAs at levels capable of evoking physiological responses, that is, electromyogram (EMG) activity. The functionality of the MEA and neural tissue was determined by measuring impedances, the ability of microstimulation to evoke EMG responses, and the recording of action potentials. We found that impedances and the number of recorded action potentials followed the previously reported trend of decreasing over time in both animals that received microstimulation and those which did not receive microstimulation. Despite these trends, the ability to evoke EMG responses and record action potentials was retained throughout the study. The results of this study suggest that intracortical microstimulation via MEAs did not cause functional failure, suggesting that MEA-based microstimulation is ready to transition into subchronic (< 30 days) human trials to determine whether complex spatiotemporal sensory percepts can be evoked by patterned microstimulation.


Proteomic analysis of JAK2V617F-induced changes identifies potential new combinatorial therapeutic approaches.
In excess of 90% of patients with polycythaemia vera (PV) express a mutated form of Janus kinase 2 (JAK2), JAK2V617F. Such aberrant proteins offer great potential for the treatment of these diseases; however, inhibitors to JAK2 have had limited success in the clinic in terms of curing the disease. To understand the effects of this oncogene in haematopoietic cells with the aim of improving treatment strategies, we undertook a systematic evaluation of the effects of JAK2V617F expression using proteomics. The effects of JAK2V617F on over 5000 proteins and 2000 nuclear phosphopeptide sites were relatively quantified using either SILAC or eight-channel iTRAQ mass spectrometry. Pathway analysis of the proteins identified as changing indicated disruption to the p53 and MYC signalling pathways. These changes were confirmed using orthogonal approaches. The insight gained from this proteomic analysis led to the formation of hypothesis-driven analysis on inhibitor-mediated effects on primary cells from patients with a JAK2V617F mutation. Simultaneous inhibition of MYC and upregulation of p53 led to the preferential extinction of JAK2V617F-positive CD34+ cells, illustrating a potential therapeutic benefit from combined targeting of p53 and MYC.


The Impact of COVID-19 on the Orthopaedic Sports Medicine Fellowship Application Process.
Over the last year, coronavirus disease 2019 (COVID-19) has spread across the world as a global pandemic, bringing unprecedented changes to the healthcare landscape for patients and physicians. Medical trainees have been similarly affected, as medical schools throughout the United States have implemented remote learning-based curriculums and withdrawn third- and fourth-year students from in-hospital clerkships. Of particular importance is the impact of COVID-19 on current orthopaedic surgery residents applying to subspecialty fellowship programs. Because of the highly transmissible nature of the virus and current social distancing restrictions, orthopaedic sports medicine fellowship interviews are being held virtually during the 2020-2021 application cycle. This transition to videoconference interviewing may de-emphasize an applicant's unique personality or interpersonal interactions that are traditionally captured in a variety of settings during the interview day. In turn, this may lead to increased prioritization of various aspects of the application, such as the applicant's residency program, letters of recommendation, and research productivity. Matching to a sports medicine fellowship program is an inherently competitive process and the COVID-19 pandemic presents novel challenges to orthopaedic residents in their efforts to successfully match. The purpose of this review is to describe the changes made to the orthopaedic sports medicine fellowship interview process resulting from COVID-19 during the 2020-2021 application cycle and discuss how these changes may impact the future fellowship application process. This review discusses the changes made to the orthopaedic sports medicine fellowship interview process caused by COVID-19 during the 2020-2021 application cycle. This review also assesses how such changes may impact the future application process and proposes potential adaptations to the current virtual interview format if it should become the new standard moving forward.


Interview with Janet Woodcock: progress on the FDA's critical path initiative.
Janet Woodcock is the Director of the US FDA's Center for Drug Evaluation and Research. Dr Woodcock has held various positions within the FDA's Office of the Commissioner from October 2003 until 1 April, 2008, as Deputy Commissioner and Chief Medical Officer, Deputy Commissioner for Operations and Chief Operating Officer and Director of the Critical Path Programs. She oversaw scientific and medical regulatory operations for the FDA. Dr Woodcock served as Director of the Center for Drug Evaluation and Research at the FDA from 1994 to 2005. She previously served in other positions at the FDA including Director of the Office of Therapeutics Research and Review and Acting Deputy Director of the Center for Biologics Evaluation and Research. Dr Woodcock received her MD from Northwestern Medical School (IL, USA), and completed further training and held teaching appointments at the Pennsylvania State University (PA, USA)and the University of California in San Francisco (CA, USA). She joined the FDA in 1986.


Tipranavir/Ritonavir (500/200 mg and 500/100 mg) Was Virologically Non-Inferior to Lopinavir/Ritonavir (400/100 mg) at Week 48 in Treatment-Naïve HIV-1-Infected Patients: A Randomized, Multinational, Multicenter Trial.
Ritonavir-boosted tipranavir (TPV/r) was evaluated as initial therapy in treatment-naïve HIV-1-infected patients because of its potency, unique resistance profile, and high genetic barrier. Trial 1182.33, an open-label, randomized trial, compared two TPV/r dose combinations versus ritonavir-boosted lopinavir (LPV/r). Eligible adults, who had no prior antiretroviral therapy were randomized to twice daily (BID) 500/100 mg TPV/r, 500/200 mg TPV/r, or 400/100 mg LPV/r. Each treatment group also received Tenofovir 300 mg + Lamivudine 300 mg QD. The primary endpoint was a confirmed viral load (VL) <50 copies/mL at week 48 without prior antiretroviral regimen changes. Primary analyses examined CD4-adjusted response rates for non-inferiority, using a 15% non-inferiority margin. At week 48, VL<50 copies/mL was 68.4%, 69.9%, and 72.4% in TPV/r100, TPV/r200, and LPV/r groups, respectively, and TPV/r groups showed non-inferiority to LPV/r. Discontinuation due to adverse events was higher in TPV/r100 (10.3%) and TPV/r200 (15.3%) recipients versus LPV/r (3.2%) recipients. The frequency of grade ≥3 transaminase elevations was higher in the TPV/r200 group than the other groups, leading to closure of this group. However, upon continued treatment or following re-introduction after treatment interruption, transaminase elevations returned to grade ≤2 in >65% of patients receiving either TPV/r200 or TPV/r100. The trial was subsequently discontinued; primary objectives were achieved and continuing TPV/r100 was less tolerable than standard of care for initial highly active antiretroviral therapy. All treatment groups had similar 48-week treatment responses. TPV/r100 and TPV/r200 regimens resulted in sustained treatment responses, which were non-inferior to LPV/r at 48 weeks. When compared with the LPV/r regimen and examined in the light of more current regimens, these TPV/r regimens do not appear to be the best options for treatment-naïve patients based on their safety profiles.


[The area of dentinal diffusion at the time of the manual preparation of root canals].
In this current piece of work we study the area of dentinal diffusion obtained with various irrigating agents which eliminate the smear layer: critic acid at concentrations of 10, 25 and 50%, 15% ethylene-diamino-tetraacetic acid (EDTA), and REDTA (compound of EDTA). All the agents proved their efficiency in eliminating the smear layer, which was corroborated by use of the sweep electron microscope and objectified using computerized image analysis, thus obtaining different diffusion areas with the various irrigating solutions used.


Variability in Preferred Management of Electrographic Seizures in Neonatal Hypoxic Ischemic Encephalopathy.
Seizures may cause added harm in neonates with hypoxic-ischemic encephalopathy (HIE). Specific recommendations about seizure treatment in this context are lacking. We sought to determine the scope of practice regarding management of non-status epilepticus electrographic-only seizures in this setting. A case-based survey was distributed to members of the Child Neurology Society. Providers were asked about their preferred management strategy for sequential clinical scenarios. A total of 177 child neurologists responded to the survey. Seventy-seven percent of providers would treat 20 seconds or less of electrographic seizure activity. In a neonate with mild HIE and an electrographic-only seizure, there was no agreement among providers regarding whether to start maintenance therapy in addition to a one-time anti-seizure drug load. In a neonate with moderate HIE on phenobarbital for early electro-clinical seizures, most providers would escalate treatment for ongoing electrographic-only seizures by increasing phenobarbital dosing. In a neonate with severe HIE complicated by status epilepticus on phenobarbital who subsequently develops recurrent electrographic-only seizures, providers varied substantially in their management preferences. For all three cases, 75% to 85% of providers would not change their management preferences based on the absence of a clinical correlate with the electrographic seizure. We found marked variability among providers regarding preferred management of non-status epilepticus electrographic-only seizures after HIE. Our results identified specific aspects of electrographic-only seizure management in neonatal HIE where there is limited consensus. These discrepancies may serve as opportunities for future investigation.