IFN-alpha therapy is effective in suppressing the clinical experimental myasthenia gravis.
To study the therapeutic efficacy of IFN-alpha after the onset of clinical signs of experimental autoimmune myasthenia gravis (EAMG), we treated mice with clinical EAMG with recombinant human IFN-alpha or mouse IFN-alpha. In the first experiment, 7 of 16 (44%) mice had a complete clinical remission in the recombinant human IFN-alpha-treated group, in contrast to none in the placebo group (0/14) (p = 0.006). There was a higher incidence of death and severe disease in the placebo group (7/14) relative to the IFN-alpha group (4/16). In the second experiment, 6 of 18 (33%) mice in the mouse IFN-alpha-treated group had a complete clinical remission, while none of 17 (0%) mice in the placebo-treated group had remission (p = 0.011). Again, more mice died or worsened in the placebo group (11/17) compared with the IFN-alpha group (7/18). IFN-alpha treatment significantly reduced the anti-acetylcholine receptor (AChR) Ab levels, especially the IgG1 and IgG2b isotypes, and the amount of anti-AChR Abs bound to muscle AChR. IFN-alpha treatment also lowered CD4 cells in the lymph nodes and spleen, and suppressed the in vitro lymphocyte proliferative response to AChR and its dominant peptide in a dose-dependent manner.


A 4-day sodium-controlled diet reduces variability of overnight sodium excretion in free-living normotensive adolescents.
The present analysis examined changes in the variability of overnight sodium excretion in 84 free-living adolescents (ages 15 to 19 years) on a 4-day sodium-controlled diet in which foods provided were selected by adolescents from an extensive list of menu items. The only selection criterion imposed was that foods selected for each day contain 4,000+/-200 mg sodium. Adolescents collected overnight urine samples. Repeated measures analysis of variance tested the effect of diet day on overnight sodium excretion, overnight urinary sodium concentration, and overnight urinary volume. Variance ratio test evaluated changes in overnight sodium excretion variance across days. Day 4 overnight sodium excretion was statistically lower than days 1 to 3 (1.84 vs 6.54, 5.94, and 5.52 mEq/h [1.84 vs 6.54, 5.94, and 5.52 mmol/h]). Day 4 overnight urinary sodium concentration was lower than days 1 to 3 (32.16 vs 119.64, 109.61, and 111.32 mEq/L [32.16 vs 119.64, 109.61, and 111.32 mmol/L]). The variance of overnight sodium excretion from day 1 to day 4 was reduced 10-fold from 20.1 mEq/h (20.1 mmol/h) to 1.90 mEq/h (1.90 mmol/h). Daily overnight urine volumes remained constant, averaging 451.7 mL/day. The dietary protocol successfully reduced the variability of sodium intake as estimated by overnight sodium excretion in free-living adolescents. The protocol could be expanded to include baseline values, additional days of sodium control, and varying levels of dietary sodium intake.


Chromosomal and genetic imbalances in synovial sarcoma detected by conventional and microarray comparative genomic hybridization.
To analyze the relationship between chromosomal instabilities and clinicopathological factors in synovial sarcoma (SS). Twenty-two fresh-frozen SS were analyzed by metaphase comparative genomic hybridization (CGH). Additional microarray CGH was performed in 13 cases. Fourteen patients with SYT-SSX1 rearrangements and nine patients with biphasic tumor subtypes had better prognosis than the eight patients with SYT-SSX2 rearrangements and 13 patients with monophasic subtypes, respectively. Gains (average 3.0) were more frequent than losses (average 1.0). Frequent gains were identified on chromosomal regions 2, 6q, 7, 8q, 12, 17q, 18q, and 21q, whereas frequent losses were over-lapped on chromosomes 1p31-p35, 3p, 6q, 16, and 17p. High-level gains were observed on chromosomes 1q21-q31, 7, 8, 12, 17q, 18q, and 21q. Thirteen monophasic and nine biphasic tumors had an average of 5.1 and 2.8 aberrations, respectively. Patients with tumors harboring numerous aberrations (>or=3) had a worse clinical course. Microarray CGH more specifically detected genetic imbalances including gains in MDM2, MSH2, KCNK12, DCC, CDK2, ERBB3, SAS, and CDK4 and losses in HRAS, RASSF1, and CCND1. Gain of SAS was an important prognostic factor of SS. We have identified several factors influencing the prognosis of SS patients by metaphase and microarray CGH.


[Devices for the sampling of air, containing hazardous elements and biological aerosols].
A set of devices for extraction of air samples to detect chemical hazards and biologic aerosols is designed and launched into production. The devices are compact, precise (error is +/- 3 - +/- 10%) and handy, could be calibrated and tested by the same equipment, give conventional results. Samples extraction devices meet the requirements of Russian standards on protection from, control, prevention and liquidation of events caused by chemical and biologic hazards. The devices are metrologically assured, certified, included into a State Register, widely put into practice of Russian Sanitary, Epidemiologic and Ecologic Supervision.


"Yo! This is no lie, if you smoke, you die": a content analysis of anti-smoking posters created by adolescents.
Exposure to anti-smoking messages is strongly associated with lower smoking initiation by adolescents. However, few anti-smoking efforts have involved message generation by adolescents themselves. This article presents a content analysis of anti-smoking posters created by middle school students in two northeastern schools in the United States. Understanding how smoking prevention messages should be framed from the perspective of young teens will provide us with formative information about what kinds of smoking prevention messages teens believe are effective. 50 anti-smoking posters created by adolescents (11-14 years) were content analysed, with a focus around three broad areas: effects of smoking portrayed in posters, specific ways of message depiction in posters and use of slogans. Results of content analysis reveal that appearance-related factors (44%) were most commonly used to convey harmful health effects of smoking, followed by messages about death and dying (30%), before-after effects of smoking (22%), other sickness-related effects of smoking (20%) and cancer (12%). Supplemental thematic analysis revealed that in a majority of posters pictures were exaggerated and were dominant part of the posters. These results provide information about anti-smoking messages/themes perceived as efficacious by young adolescents and have implications for developing anti-smoking messages for adolescents.


Cost-effectiveness Analysis of Contralateral Prophylactic Mastectomy Compared to Unilateral Mastectomy with Routine Surveillance for Unilateral, Sporadic Breast Cancer.
Contralateral prophylactic mastectomy (CPM) rates in younger women with unilateral breast cancer have more than doubled. Studies of cost and quality of life of the procedure remain inconclusive. A cost-effectiveness analysis using a decision-tree model in TreeAge Pro 2015 was used to compare long-term costs and quality of life following unilateral mastectomy (UM) with routine surveillance versus CPM for sporadic breast cancer in women aged 45 years. A 10-year risk period for contralateral breast cancer (CBC), reconstruction, wound complications, cost of routine surveillance, and treatment for CBC were used to estimate accrued costs. In addition, a societal perspective was used to estimate quality-adjusted life years (QALYs) following either treatment for a period of 30 years. Medical costs were obtained from the 2014 Medicare physician fee schedule and event probabilities were taken from recent literature. The mean cost of UM with surveillance was $14,141 and CPM was $20,319. Treatment with CPM resulted in $6178 more in costs but equivalent QALYs (17.93) compared with UM over 30 years of follow-up. Even with worst-case scenario and varying assumptions, CPM is dominated by UM in terms of cost and quality. From this refined model, UM with routine surveillance costs less and provides an equivalent quality of life. Patients undergoing CPM may eliminate the anxiety of routine surveillance, but they face the burden of higher lifetime medical costs.


Are children with recessive dystrophic epidermolysis bullosa of low birthweight?
To compare the birthweight of children affected by recessive dystrophic epidermolysis bullosa (RDEB) to a sibling control group, we designed a questionnaire-based case-control study. As participants we used patients with RDEB attending the Great Ormond Street Hospital for Children, London, England, and their nearest unaffected siblings. We found that children with RDEB are of significantly lower birthweight than their unaffected siblings, with 30% being small for their gestational age compared to 12% of controls (McNamar chi2 = 4.9, d f = 1, p = 0.02). A conditional logistic regression model was used to examine the possible effects of confounding variables. The relationship between the RDEB and standardized birthweight groups, smoking status of the mother at the time of birth, and the previous number of live births showed that the standardized birthweight group was the only significant variable in the model and was unaffected by confounding variables. Based on these findings, we concluded that the compromise in growth seen in RDEB begins in utero.


Imaging of the lamina cribrosa in glaucoma: perspectives of pathogenesis and clinical applications.
The lamina cribrosa (LC) is a sieve-like structure in the sclera where retinal ganglion cell axons exit from the eye. The LC has been known to play a critical role in the pathogenesis of glaucoma. With the advent of imaging technologies, such as enhanced depth imaging, spectral-domain optical coherence tomography (OCT) enables us to unveil the LC in vivo features. The application of adaptive optics technology and a compensatory image-processing algorithm has further improved the visualization of the beams and pores and neural pathways of the LC and the scleral insertion sites. Monitoring the changes of these structures in relation to acute and chronic elevation of intraocular pressure would be germane to decipher the relationship between the stress and strain response of the LC and optic nerve damage and improve our understanding of glaucoma pathophysiology. While the impact of investigating the integrity of LC is substantive, considerable challenges remain for imaging the LC. Nevertheless, with the rapid development of the OCT technology, it is expected that some of these limitations can be overcome and the potentials of LC imaging will be unraveled.


Pattern recognition as rule-guided inductive inference.
The determination of pattern recognition rules is viewed as a problem of inductive inference, guided by generalization rules, which control the generalization process, and problem knowledge rules, which represent the underlying semantics relevant to the recognition problem under consideration. The paper formulates the theoretical framework and a method for inferring general and optimal (according to certain criteria) descriptions of object classes from examples of classification or partial descriptions. The language for expressing the class descriptions and the guidance rules is an extension of the first-order predicate calculus, called variable-valued logic calculus VL21. VL21 involves typed variables and contains several new operators especially suited for conducting inductive inference, such as selector, internal disjunction, internal conjunction, exception, and generalization. Important aspects of the theory include: 1) a formulation of several kinds of generalization rules; 2) an ability to uniformly and adequately handle descriptors (i.e., variables, functions, and predicates) of different type (nominal, linear, and structured) and of different arity (i.e., different number of arguments); 3) an ability to generate new descriptors, which are derived from the initial descriptors through a rule-based system (i.e., an ability to conduct the so called constructive induction); 4) an ability to use the semantics underlying the problem under consideration. An experimental computer implementation of the method is briefly described and illustrated by an example.


[Relationship between managers and clinicians].
The relationship between managers and physicians has acquired a new importance. The evolution of different aspects of the medical practice such as technological advances, a society with a greater level of maturity and the restriction of sanitary resources show the need for a correct administration coordinates by both the managers and the physicians (who actually prescribe the use of these resources). The meeting point between physicians and managers is what we know as clinical management. The concept of clinical management is based on the figure of the patient without diminishing the role of the physician, whose cooperation in the elaboration of the programs with the managers is vital so as to achieve excellence in different aspects such as clinical assistance, investigation and medical education.


Interim mortality in pulmonary atresia with intact ventricular septum.
Recent work has focused attention on interim mortality (death after hospital discharge and before second-stage surgery) in hypoplastic left heart syndrome. This study investigates interim mortality in infants undergoing systemic-to-pulmonary artery shunts for pulmonary atresia with intact ventricular septum. At two centers in 11 years (January 1991 through December 2001), 35 infants underwent placement of shunts for palliation of pulmonary atresia with intact septum. Patients were identified from the cardiology database at each institution, and data were collected retrospectively. The infants were classified into two groups, with and without severe right ventricular hypoplasia, based on the initial surgical plan (Fontan or two-ventricle repair). The mean age and weight of the infants were 9 days and 3.1 kg. The right ventricle was severely hypoplastic in 22 of 35 infants. Hospital death occurred in 2 patients (9.1%), 1 with severe right ventricular hypoplasia. The remaining 33 patients form the study population. There were a total of 5 deaths (15%) after discharge and before second-stage operation, all in patients with severe right ventricular hypoplasia. Two patients, 1 with hypoplastic right ventricle, died after second-stage operation. These data confirm a significant incidence of interim death in infants with pulmonary atresia and hypoplastic right ventricle. The interim mortality rate in the current two-institution study of infants with pulmonary atresia with intact ventricular septum is similar to that in hypoplastic left heart syndrome if all patients are considered (15%), and is somewhat higher (24%) than that for hypoplastic left heart syndrome if only patients with severe right ventricular hypoplasia are considered. This rate of interim death must be considered when different treatment options (such as shunt or transplant) are contemplated.


Resolution of head-on collisions between the transcription machinery and bacteriophage phi29 DNA polymerase is dependent on RNA polymerase translocation.
The outcome of collisions between Bacillus subtilis phage Phi29 DNA polymerase and oppositely oriented transcription complexes has been studied in vitro. We found that the replication fork was unable to go past a transcription ternary complex stalled head-on. However, head-on collisions did not lead to a deadlock. Both DNA and RNA polymerase remained bound to the template and, when the halted transcription complex was allowed to move, the replication machinery resumed normal elongation. These results suggested that a replication fork that encounters an RNA polymerase head-on whose movement is not impeded would bypass the transcription machinery. Our results for head-on collisions between concurrently moving replication and transcription complexes are indeed consistent with the existence of a resolving mechanism. The ability of Phi29 DNA polymerase to resolve head-on collisions with itself during symmetrical replication of Phi29 DNA in vivo is likely to be related to its ability to pass a head-on oriented RNA polymerase.


The immune system and electroconvulsive therapy for depression.
Electroconvulsive therapy (ECT) remains the most effective and fast-acting treatment option for several psychiatric conditions, including treatment-resistant depression. Although ECT has been in use for 75 years, the mechanism of action is unknown. There is emerging evidence that modulation of the hypothalamic-pituitary-adrenal axis may mediate, in part, the therapeutic action of ECT. A growing body of evidence points to links between disturbances in the immune system and depression. However, the impact of ECT on immune functioning and the possible role of alterations in the immune system as a mechanism of action of ECT remain elusive. To provide a literature overview on the effects of ECT on the immune system. Relevant articles and abstracts in English were retrieved from PubMed/Medline using search terms related to ECT, inflammation, and immune system. The results of studies examining ECT-induced changes in immune functioning as well as the degree to which these represent possible mechanisms mediating the therapeutic action of ECT were summarized. Our search identified only a limited number of studies. The findings suggest that a single session of ECT induces an acute, transient immune activation, whereas repetitive ECT treatment results in long-term down-regulation of immune activation. However, inconsistency in findings and methodological issues, including sample size and lack of consideration of confounding factors affecting cytokine concentrations, precludes definitive conclusion. To elucidate the possible role of immunological changes mediating the effect of ECT, more prospective controlled studies with larger sample sizes are required.


[THE INDICATORS OF COAGULATION HEMOSTASIS AFTER CRIO-RESECTION OF LIVER].
The article presents results of comparative evaluation of indicators of coagulation hemostasis in 24 patients with focal parasitic and non-parasitic pathology of liver before and after resection of organ with and without frigotherapy. The analysis of condition of coagulation hemostasis was implemented on the basis of results of blood clotting tests and immune enzyme technique of detection of content of factors V, Xl, XII in blood plasma. It is demonstrated that after crio-resection of liver the tendency to normalization of content of factors V and XI is more expressed than in case of common resection of organ. At that, in patients with non-parasitic diseases of liver after crio-resection initially decreased concentration of factor Xl is normalized and content of factor XII keeps to be in limits of normality under its decreasing in patients after resection without frigotherapy. The plasma concentration of fibrinogen corresponds to standard. The most significant departures of international normalized ratio (increasing higher than reference values) and activated partial thromboplastin time (decreasing up to reference values) in patients with parasitic and non-parasitic diseases of liver are observed at 5th day after resection independently of technique applied (with of without frigotherapy).


Genome-Resolved Metagenomic Insights into Massive Seasonal Ammonia-Oxidizing Archaea Blooms in San Francisco Bay.
Ammonia-oxidizing archaea (AOA) are key for the transformation of ammonia to oxidized forms of nitrogen in aquatic environments around the globe, including nutrient-rich coastal and estuarine waters such as San Francisco Bay (SFB). Using metagenomics and 16S rRNA gene amplicon libraries, we found that AOA are more abundant than ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB), except in the freshwater stations in SFB. In South SFB, we observed recurrent AOA blooms of "Candidatus Nitrosomarinus catalina" SPOT01-like organisms, which account for over 20% of 16S rRNA gene amplicons in both surface and bottom waters and co-occur with weeks of high nitrite concentrations (>10 μM) in the oxic water column. We observed pronounced nitrite peaks occurring in the autumn for 7 of the last 9 years (2012 to 2020), suggesting that seasonal AOA blooms are common in South SFB. We recovered two high-quality AOA metagenome-assembled genomes (MAGs), including a Nitrosomarinus-like genome from the South SFB bloom and another Nitrosopumilus genome originating from Suisun Bay in North SFB. Both MAGs cluster with genomes from other estuarine/coastal sites. Analysis of Nitrosomarinus-like genomes show that they are streamlined, with low GC content and high coding density, and harbor urease genes. Our findings support the unique niche of Nitrosomarinus-like organisms which dominate coastal/estuarine waters and provide insights into recurring AOA blooms in SFB. IMPORTANCE Ammonia-oxidizing archaea (AOA) carry out key transformations of ammonia in estuarine systems such as San Francisco Bay (SFB)-the largest estuary on the west coast of North America-and play a significant role in both local and global nitrogen cycling. Using metagenomics and 16S rRNA gene amplicon libraries, we document a massive, recurrent AOA bloom in South SFB that co-occurs with months of high nitrite concentrations in the oxic water column. Our study is the first to generate metagenome-assembled genomes (MAGs) from SFB, and through this process we recovered two high-quality AOA MAGs, one of which originated from bloom samples. These AOA MAGs yield new insight into the Nitrosopumilus and Nitrosomarinus-like lineages and their potential niches in coastal and estuarine systems. Nitrosomarinus-like AOA are abundant in coastal regions around the globe, and we highlight the common occurrence of urease genes, low GC content, and range of salinity tolerances within this lineage.


Prevention of venous thromboembolism.
Of the various prophylactic agents evaluated, four have been found to be effective. These are oral anticoagulants, low-dose heparin, mechanical devices which increase venous blood-flow in the leg, and Dextran. Oral anticoagulants have been shown to be effective in patients having abdominal, thoracic, or hip surgery, when treatment was started either before surgery or in the immediate postoperative period. They have also been shown to be effective in medical patients. The evidence derives from studies which showed that treatment can reduce total mortality, prevents venous thromboembolism detected clinically or at autopsy, and prevents thrombosis diagnosed with venography. On the other hand, the incidence of thrombosis diagnosed by 125I-fibrinogen scanning was not reduced when oral anticoagulants were started just before or just after surgery. This suggests that oral anticoagulant treatment starting in the immediate postoperative period may not prevent formation of the initial thrombotic nidus, but is clinically effective because it prevents extension of the nidus to form a significant thrombus. Bleeding has been a significant complication in almost all studies of surgical patients, and this is the major factor which has prevented widespread use of oral anticoagulant prophylaxis. In addition, the need for careful laboratory monitoring makes this approach inconvenient and adds to its expense. Low-dose heparin has been shown to be effective in general surgical and medical patients, but results have been inconclusive in patients having elective hip surgery, and this approach is probably ineffective in patients with hip fracture. In general surgical patients, low-dose heparin prophylaxis has been shown to prevent pulmonary embolism diagnosed at autopsy examination or with lung scanning, and calf and thigh vein thrombosis diagnosed with 125I-fibrinogen leg-scanning. A slight, but statistically significant, increase in the frequency of wound hematoma and a greater postoperative hematocrit fall have been reported when heparin was given three times daily, but not with the twice daily heparin injection regimen. In these studies, low-dose heparin was given without laboratory control of its anticoagulant effect, so that this prophylactic approach is simple, but the need for subcutaneous injections is a disadvantage of this approach. Results with methods which increase venous blood-flow in the leg have varied, depending on the technic used. Active measures, such as intermittent pneumatic calf compression or peroperative electrical calf muscle stimulation, have been shown to prevent thrombosis detected with 125I-fibrinogen leg-scanning. However, while the evidence suggests that both methods are effective in relatively low risk patients, they may have limited value in the high risk patient who is confined to bed for a long time. These methods are free of side effects and relatively inexpensive, but intermittent calf compression, in particular, is slightly cumbersome...


A Cross-Platform Metabolomics Comparison Identifies Serum Metabolite Signatures of Liver Fibrosis Progression in Chronic Hepatitis C Patients.
Metabolomics offers new insights into disease mechanisms that is enhanced when adopting orthogonal instrumental platforms to expand metabolome coverage, while also reducing false discoveries by independent replication. Herein, we report the first inter-method comparison when using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS) and nuclear magnetic resonance (NMR) spectroscopy for characterizing the serum metabolome of patients with liver fibrosis in chronic hepatitis C virus (HCV) infection (n = 20) and non-HCV controls (n = 14). In this study, 60 and 30 serum metabolites were detected frequently (>75%) with good technical precision (median CV < 10%) from serum filtrate samples (n = 34) when using standardized protocols for MSI-CE-MS and NMR, respectively. Also, 20 serum metabolite concentrations were consistently measured by both methods over a 500-fold concentration range with an overall mean bias of 9.5% (n = 660). Multivariate and univariate statistical analyses independently confirmed that serum choline and histidine were consistently elevated (p < 0.05) in HCV patients with late-stage (F2-F4) as compared to early-stage (F0-F1) liver fibrosis. Overall, the ratio of serum choline to uric acid provided optimal differentiation of liver disease severity (AUC = 0.848, p = 0.00766) using a receiver operating characteristic curve, which was positively correlated with liver stiffness measurements by ultrasound imaging (r = 0.606, p = 0.0047). Moreover, serum 5-oxo-proline concentrations were higher in HCV patients as compared to non-HCV controls (F = 4.29, p = 0.0240) after adjustment for covariates (age, sex, BMI), indicative of elevated oxidative stress from glutathione depletion with the onset and progression of liver fibrosis. Both instrumental techniques enable rapid yet reliable quantification of serum metabolites in large-scale metabolomic studies with good overlap for biomarker replication. Advantages of MSI-CE-MS include greater metabolome coverage, lower operating costs, and smaller sample volume requirements, whereas NMR offers a robust platform supported by automated spectral and data processing software.


Forensic dissection of a clinical trial: lessons learned in understanding and managing interstitial cystitis.
A pharmaceutical company-sponsored post-registration clinical trial designed to determine the most effective dose of pentosan polysulfate for the treatment of interstitial cystitis (IC) reported negative results. However, because of a priori trial design features, important posthoc analyses were able to answer many of the important clinical issues on the epidemiology, diagnosis, and treatment of IC that to date had remained unanswered. Seven published follow-up reports based on data and outcomes from the original study evaluated the clinical significance of a positive Potassium Sensitivity Test, confirmed the O'Leary-Sant Interstitial Cystitis Symptom Index as a valid and sensitive outcome measure, and determined that doses of pentosan polysulfate higher than the standard US Food and Drug Administration-approved dose of 300 mg/d did not increase efficacy although increased duration of therapy increases the chance of symptom amelioration. Further analyses determined that sexual dysfunction is an important parameter to assess in IC and that successful therapy can improve sexual functioning. Finally, the data showed that symptom severity, quality of life (QoL), and sleep function are interrelated. Consequently, symptom improvement with therapy correlates with improvement in both sleep function and QoL. This post hoc forensic dissection of a clinical trial initially undertaken for simple regulatory reasons has significantly improved our understanding and management of the enigmatic condition we call IC.


Characteristics of young-onset white coat hypertension identified by targeted screening for hypertension at a university health check-up.
Previously we estimated the prevalence of essential hypertension (EH) as around 0.1% and suggested that male gender, obesity, and strong genetic background (hypertension in parents) were risk factors for EH in a young population aged less than 30 based on targeted screening for hypertension at a university health check-up. This study also revealed a high incidence of white coat hypertension (WCH) in university students, and thus, we continued this screening for four consecutive years, and examined the prognosis and clinical characteristics of young-onset WCH. Three occasions of casual blood pressure (BP) measurement and additional home BP measurement revealed 72 WCH and 15 EH students (all males) during the 4-year study period. None of the WCH students had elevated home BP to the level of hypertension during their stay at university, and 26 out of 38 WCH students participating screening in the following years showed normal casual BP. Although WCH students showed a significantly higher pulse rate than controls, WCH could not be fully differentiated from EH either by pulse rate or by correlation between casual BP value and pulse rate. These findings indicate the requirement of longer follow-up after graduation to determine the prognosis of young-onset WCH, though EH and WCH in the young population share the same risk factors and, possibly, autonomic nervous system dysfunction. Since diagnosis of WCH has limited importance for university students, screening of EH following a general health check-up would elevate the clinical validity of casual BP measurement at the university.


[MR-track pointer. A reusable device for localization during interventions].
Development of an helpful instrument for a better planning and orientation during MR guided interventions. We developed a reusable, sterilizable instrument that can be filled both with a solution of Gd-DTPA (1%) and with a sodium chloride solution (0.9%). The pointer has a diameter of 3 and 5 mm resp. and its length is 100-150 mm. The instrument can be combined with an interactive stereotactic tracking device. The MR-Track-Pointer can be fixed to the two handpieces of the integrated interactive tracking system without problems. The pointer can be seen both on T1w and T2w sequences inside and outside of the tissue. This new instrument can be interactively used for reliable planning the biopsy trajectory, planning craniotomies and identifying structures which are only visible on MR images. The MR-Track-Pointer is an ideal supplement for the integrated virtual tracking system. It permits a minimal invasive orientation and facilitates the exact localisation of suspect lesions in sensible regions during MR guided interventions, e.g. diagnostic biopsies and tumour resections.


Is social media, as a main source of information on COVID-19, associated with perceived effectiveness of face mask use? Findings from six sub-Saharan African countries.
The use of face masks as a public health approach to limit the spread of coronavirus disease 2019 (COVID-19) has been the subject of debate. One major concern has been the spread of misinformation via social media channels about the implications of the use of face masks. We assessed the association between social media as the main COVID-19 information source and perceived effectiveness of face mask use. In this survey in six sub-Saharan African countries (Botswana, Kenya, Malawi, Nigeria, Zambia and Zimbabwe), respondents were asked how much they agreed that face masks are effective in limiting COVID-19. Responses were dichotomised as 'agree' and 'does not agree'. Respondents also indicated their main information source including social media, television, newspapers, etc. We assessed perceived effectiveness of face masks, and used multivariable logistic models to estimate the association between social media use and perceived effectiveness of face mask use. Propensity score (PS) matched analysis was used to assess the robustness of the main study findings. Among 1988 respondents, 1169 (58.8%) used social media as their main source of information, while 1689 (85.0%) agreed that face masks were effective against COVID-19. In crude analysis, respondents who used social media were more likely to agree that face masks were effective compared with those who did not [odds ratio (OR) 1.29, 95% confidence interval (CI): 1.01-1.65]. This association remained significant when adjusted for age, sex, country, level of education, confidence in government response, attitude towards COVID-19 and alternative main sources of information on COVID-19 (OR 1.33, 95%CI: 1.01-1.77). Findings were also similar in the PS-matched analysis. Social media remains a viable risk communication channel during the COVID-19 pandemic in sub-Saharan Africa. Despite concerns about misinformation, social media may be associated with favourable perception of the effectiveness of face masks.


The insulin-like growth factors (IGFs) in follicular fluid are predominantly bound in the ternary complex.
The presence of IGFs and their associated binding proteins (IGFBPs) in human follicular fluid is well documented. Furthermore, most of the constituents of the IGF system in follicular fluid have been found to vary, either in total amount or by proteolytic cleavage, depending on the health status of the follicle. In this study we have examined the acid-labile subunit (ALS) and found that levels in follicular fluid (mean 146 nmol/l) were almost 50% of those in the circulation. This amount of ALS was considerably greater than that found in other extracirculatory fluids (20.9 for synovial fluid and 31.4 nmol/l for skin blister fluid). As in the circulation, ALS levels were in molar excess and did not vary between atretic and dominant follicles. Although the source of ALS is probably from blood (conditioned medium from ovarian cell cultures had no measurable ALS) it would appear that this glycoprotein is not merely diffusing from the circulation as the capillary endothelium becomes more permeable in dominant follicles and this is not reflected in the level of ALS. Analysis of the distribution of IGF-I, IGF-II and IGFBP-3 in fluid from healthy and atretic follicles revealed that the majority of these growth factors (> 80% of total IGF-II) were in the 150KDa complex, indicating that the ALS present was functional, in that it formed the ternary complex with a molecule of IGFBP-3 and IGF. No free IGF-II was found in any of the follicular fluids analysed nor was there any increase in the amount of unsaturated IGFBP-3 in atretic follicles. In summary, we have shown that the majority of IGF measured in follicular fluid, whether from healthy or atretic follicles, is bound in the ternary complex.


Structure of Self-Assembled Mn Atom Chains on Si(001).
Mn has been found to self-assemble into atomic chains running perpendicular to the surface dimer reconstruction on Si(001). They differ from other atomic chains by a striking asymmetric appearance in filled state scanning tunneling microscopy (STM) images. This has prompted complicated structural models involving up to three Mn atoms per chain unit. Combining STM, atomic force microscopy, and density functional theory we find that a simple necklacelike chain of single Mn atoms reproduces all their prominent features, including their asymmetry not captured by current models. The upshot is a remarkably simpler structure for modeling the electronic and magnetic properties of Mn atom chains on Si(001).


Treatment of laryngeal hemiplegia in horses by prosthetic laryngoplasty, ventriculectomy and vocal cordectomy.
The medical records of 80 horses treated for left laryngeal hemiplegia by prosthetic laryngoplasty, ventriculectomy and vocal cordectomy were examined, first to compare the subjective and objective success rates for groups of horses of different ages and used for different purposes, and secondly, to compare the efficacy of including vocal cordectomy in the surgical protocol with published success rates for laryngoplasty and ventriculectomy alone. Subjectively, 70 per cent of the horses were said to have had a successful surgical outcome. The success rate for thoroughbred racehorses (66 per cent) was lower than for other breeds (90 per cent) on the basis of a subjective assessment by owners and trainers. Thoroughbreds two years old or younger had a success rate of 69 per cent, but older thoroughbreds had a success rate of 61 per cent. Of the 17 horses for which an objective performance index could be calculated, 10 (59 per cent) had an improved performance postoperatively. There was a nearly significant association between the objective and subjective assessments (P=0.078). Six of 69 horses (8.7 per cent) continued to make a respiratory noise after surgery. The subjective assessment of success did not appear to correlate with the objective measure of success used in this study and age had no apparent association with a successful surgical outcome. Inclusion of a vocal cordectomy in the surgical protocol may be more important in the eradication of postoperative respiratory noise than in improving clinical success rates.


Silica-PEG gel immobilization of mammalian cells.
In this study, human foreskin fibroblasts and mouse embryonic fibroblasts were encapsulated in mechanically reversible, THEOS and THEOS-PEG gels that completely immobilized them restricting their motility, growth and proliferation. The changes in the membrane integrity and metabolic activity (MA) of the immobilized cells were measured by IR spectroscopy and fluorescence microscopy. To explore the effects of surface chemistry and porosity on immobilized cell MA, different amounts of a biocompatible polymer, polyethylene glycol PEG, was incorporated into the silica gels. To explore the effects of the proliferative stress, in selected experiments, cellular proliferation was arrested prior to immobilization by exposing the cells to irradiation. Four main factors were identified that affect the long-term survival of the cells within the immobilization matrix: (1) porosity/permeability of the gel, (2) structural homogeneity of the gel, (3) specific interactions between the cell membrane and the gel surface and (4) the proliferative stress. It was shown that the immobilized cells could easily be mechanically recovered from the gel and upon incubation, proliferated normally. It is believed that the gels and the matrix developed here have very significant potential applications in tissue engineering and in personalized cancer treatment.


Antibody-free isolation and regulation of adherent cancer cells via hybrid branched microtube-sandwiched hydrodynamic system.
The detection of circulating tumor cells (CTCs) has achieved promising progress for early diagnosis and disease analysis. Microfluidic chip techniques have recently promoted the technologies of CTC sorting and analysis, yet seldom can the microfluidic chips for CTC enrichment via antibody-free capture provide in situ regulation of both extracellular and intracellular activity, which would be advantageous for cell-based pharmaceutical therapeutics and screening. Herein, we have demonstrated a hybrid TiO2/ZnO branched microtube array (HBMTA)-sandwiched hydrodynamic device that integrates the multiple functions of selective enrichment of adherent tumor cells in an antibody-free manner and in situ delivery to the extracellular and intracellular spaces of the enriched tumor cells. More than 90% cancer cells were enriched on the device due to their preferential adhesion with the nano-branches of HBMTA, while more than 91% blood cells were eliminated from the device by constant hydrodynamic fluid shearing. For in situ regulation, temporally and spatially controlled extracellular delivery to the enriched tumor cells could be precisely achieved through the hollow structures of the HBMTA. In addition, reagents (e.g. propidium iodide) could be delivered into the intracellular spaces of enriched tumor cells by coupling an electric field to nondestructively perforate the cell membrane. Our study not only offers a promising and facile strategy for antibody-free isolation of tumor cells, but also provides unique opportunities to facilitate cancer research, including antitumor drug screening and personalized therapeutics.


Anti-HBV activity of TRL mediated by recombinant adenovirus.
To investigate the inhibitive effect of hepatitis B virus (HBV)-TRL on HBV replication. Based on previously constructed pcDNA3.1(-)/TRL, TR, TRmut, HBV core protein (HBVc) and hEDN, interest gene sequences TRL, TR, HBVc and hEDN were inserted into adenovirus shuttle plasmid pDC316 respectively and co-transfected HEK293 cells with rescue plasmid pBHGloxdeltaE1,3Cre to acquire RAd/TRL, TR, HBVc and hEDN. And then RAds were identified, amplified and the titers in HEK293 cells were determined. RAd/TRL and TR were named as the experimental groups, and others were control ones. After HepG2.2.15 cells were infected, RAd/TRL expression was identified by indirect immunofluorescence staining. Supernatant HBV-DNA content was determined by fluorescent quantification PCR. Meanwhile, metabolism of HepG2.2.15 cells was evaluated by MTT colorimetry. RAd vectors with distinct interest gene sequence were successfully constructed. Effective expression of RAd/TRL in HepG2.2.15 cells resulted in a significant decrease of supernatant HBV-DNA content compared to RAd/TR (0.63+/-0.14 vs 1.60+/-0.47, P = 0.0266, <0.05) and other control groups (0.63+/-0.14 vs 8.50+/-2.78, 8.25+/-2.26, 8.25+/-2.29, 8.50+/-1.51, 8.57+/-1.63, P<0.01). MTT assay suggested that there were no significant differences in cell metabolic activity between groups (P>0.05). The construction and expression of RAd/TRL has been achieved and it could inhibit HBV replication successfully, which has laid the foundation for further research on anti-HBV activity in vivo.


Characterization of the CPAP-treated patient population in Catalonia.
There are different phenotypes of obstructive sleep apnoea (OSA), many of which have not been characterised. Identification of these different phenotypes is important in defining prognosis and guiding the therapeutic strategy. The aim of this study was to characterise the entire population of continuous positive airway pressure (CPAP)-treated patients in Catalonia and identify specific patient profiles using cluster analysis. A total of 72,217 CPAP-treated patients who contacted the Catalan Health System (CatSalut) during the years 2012 and 2013 were included. Six clusters were identified, classified as "Neoplastic patients" (Cluster 1, 10.4%), "Metabolic syndrome patients" (Cluster 2, 27.7%), "Asthmatic patients" (Cluster 3, 5.8%), "Musculoskeletal and joint disorder patients" (Cluster 4, 10.3%), "Patients with few comorbidities" (Cluster 5, 35.6%) and "Oldest and cardiac disease patients" (Cluster 6, 10.2%). Healthcare facility use and mortality were highest in patients from Cluster 1 and 6. Conversely, patients in Clusters 2 and 4 had low morbidity, mortality and healthcare resource use. Our findings highlight the heterogeneity of CPAP-treated patients, and suggest that OSA is associated with a different prognosis in the clusters identified. These results suggest the need for a comprehensive and individualised approach to CPAP treatment of OSA.


A systematic review of loss of independence in Parkinson's disease.
Functional dependency (needing help with basic ADLs) is an important outcome in Parkinson's disease (PD). "Death or dependency", as opposed to being alive and independent, is a useful dichotomous indicator of poor outcome. We aimed to systematically review the progression to dependency in PD and what factors predicted development of dependency. Comprehensive searches were performed to identify observational studies of dependency in PD with follow-up of at least 3 years. Other forms of parkinsonism and highly selected cohorts were excluded. Descriptive analysis of included studies was performed and outcomes over time were plotted by type of cohort (inception/non-inception). Independent prognostic factors were identified. There were insufficient data for meta-analysis. Of 15,154 unique references identified, 14 studies were included. Most studies were of low quality. There was heterogeneity in definitions of dependency and the measured risk of dependency at similar time-points. Risk of dependency in inception studies was about 10-25 % at 5 years and about 20-50 % at 10 years; and risk of "death or dependency" in the inception studies was about 15-40 % at 5 years and about 35-70 % at ten years. More bradykinesia and older age were associated with more dependency, but there was little evidence for other prognostic factors. Few high-quality data on dependency are available. Heterogeneity in study populations, methodology and outcome reporting made data synthesis difficult. Few prognostic factors have been identified. Further data from representative inception studies are necessary to better understand the progression of dependency in PD.


Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1.
Pyrroloquinoline quinone (PQQ) has been shown to play a role as an anti-oxidant in neuronal cells and prevent neuronal cell death in a rodent stroke model. DJ-1, a causative gene product for a familial form of Parkinson's disease, plays a role in anti-oxidative stress function by self-oxidation of DJ-1. In this study, the expression level and oxidation status of DJ-1 were examined in SHSY-5Y cells and primary cultured neurons treated with 6-hydroxydopamine (6-OHDA) or H(2)O(2) in the presence or absence of PQQ. The pI shift of DJ-1 to an acidic point, which was observed in SHSY-5Y cells treated with 6-OHDA, was inhibited by PQQ. TOF-MS analyses showed that while the level of a reduced form of DJ-1, one of the active forms of DJ-1, was decreased in SHSY-5Y cells treated with 6-OHDA or H(2)O(2), PQQ increased the level of the reduced form of DJ-1. These results suggest that PQQ prevents oxidative stress-induced changes in oxidative status of DJ-1. Therefore, the neuroprotective effects of PQQ on oxidative stress-induced neuronal death may be at least in part involved in increased level of an active form of DJ-1.


Influenza virus and its mucoprotein substrate in the chorioallantoic membrane of the chick embryo. II. Stepwise inactivation of substrate and its relation to the mode of viral multiplication.
The fate of heat-stable inhibitors (HI) of hemagglutination by influenza viruses in the infected chorioallantoic membrane has been studied. The amount of soluble HI extractable from the normal CAM is taken as a measure of the total mucoprotein substrate derived from the allantoic cells. It has been shown that a decrease in HI is demonstrable when all or nearly all cells of the allantois are involved in the infectious process. Once this condition is fulfilled, viral multiplication in the CAM is associated with stepwise breakdown and partial restoration of HI. The periodicity of these steps is in close agreement with earlier reports by others on the duration of primary and secondary cycles of viral multiplication. Periodicity of viral multiplication and of HI breakdown with subsequent restoration is particularly pronounced in eggs pretreated with metaperiodate or with mixtures of periodate and glucose or glycerol. The stepwise nature of the HI breakdown indicates that it is in some way related to intracellular phases of viral reproduction, and that individual cells produce virus in cycles rather than continuously. A possible mechanism of this process is proposed.


LDL phospholipid hydrolysis produces modified electronegative particles with an unfolded apoB-100 protein.
Electronegative low density lipoprotein (LDL(-)) formation that structurally resembles LDL(-) isolated from plasma was evaluated after LDL treatment with snake venom phospholipase A(2) (PLA(2)). PLA(2) treatment of LDL increased its electrophoretic mobility in proportion to the amount of LDL(-) formed without evidence of lipid peroxidation. These changes dose-dependently correlated with the degree of phospholipid hydrolysis. Strong immunoreactivity of LDL(-) subfraction from plasma and PLA(2)-treated LDL (PLA(2)-LDL) to amyloid oligomer-specific antibody was observed. Higher beta-strand structural content and unfolding proportionate to the loss of alpha-helical structure of apolipoprotein B-100 (apoB-100) of LDL(-) isolated from both native and PLA(2)-LDLs was demonstrated by circular dichroism (CD) spectropolarimetry. These structural changes resembled the characteristics of some oxidatively modified LDLs and soluble oligomeric aggregates of amyloidogenic proteins. PLA(2)-LDL was also more susceptible to nitration by peroxynitrite, likely because of exposure of otherwise inaccessible hydrophilic and hydrophobic domains arising from apoB-100 unfolding. This was also demonstrated for plasma LDL(-). In contrast, PLA(2)-LDL was more resistant to copper-mediated oxidation that was reversed upon the addition of small amounts of unsaturated fatty acids. The observed similarities between PLA(2)-LDL(-)-derived LDL(-) and plasma LDL(-) implicate a role for secretory PLA(2) in producing modified LDL(-) that is facilitated by unfolding of apoB-100.


GTPγS-Autoradiography for Studies of Opioid Receptor Functionality.
The opioid receptors have been an interesting target for the drug industry for decades. These receptors were pharmacologically characterized in the 1970s and several drugs and peptides have emerged over the years. In 2012, the crystal structures were also demonstrated, with new data on the receptor sites, and thus new possibilities will appear. The role of opioids in the brain has attracted considerable interest in several diseases, especially pain and drug dependence. The opioid receptors are G-protein-coupled receptors (GPCR ) that are Gi coupled which make them suitable for studying the receptor functionality. The [35S]GTP γS autoradiography assay is a good option that has the benefit of generating both anatomical and functional data in the area of interest. It is based on the first step of the signaling mechanism of GPCRs. When a ligand binds to the receptor GTP will replace GDP on the a-subunit of the G-protein, leading to a dissociation of the βγ-subunit. These subunits will start a cascade of second messengers and subsequently a physiological response.


[Recent developments in technics of nuclear magnetic resonance imaging].
Three main aspects of presently developed nuclear magnetic resonance imaging techniques are pointed out in this short review: first, the importance of Fourier transform as reconstruction technique is recalled; secondly, the problem of the choice of the magnetic field value is raised and third, new trends in magnetic imaging are noticed such as the use of nuclei other than hydrogen or the improvement of phase contrast methods.


[Electrolyte homeostasis in petroleum industry workers].
Disorders in electrolyte balance of erythrocytes and plasma in petroleum industry workers are described. All examinees were divided into 3 groups with different intensity of chemical exposure: 1) workers of the plant without contacts with chemicals (21); 2) workers handling chemicals 2-3 times a week (28)--risk group; and 3) workers permanently exposed to chemicals for 3-5 years (46); control group consisted of 40 healthy subjects without occupational exposure to chemicals. Significant changes in erythrocyte and plasma electrolytes were detected in groups 2 and, more so, 3: erythrocyte K, Mg, and Ca levels were decreased and Na and P levels increased, while in the plasma K, Mg, and P concentrations were increased and Na and Ca decreased.


Adult multifocal pigmented villonodular synovitis--clinical review.
Pigmented villonodular synovitis (PVNS) is a rare, benign proliferative disease of the synovial tissue that affects a single joint or a tendon sheath. Data from the literature present only a few cases of multifocal PVNS. This paper presents multifocal PVNS in the adult. This disease can affect bilateral shoulders, hips and knees. The diagnosis may be delayed by the slow evolution of the disease (up to ten years); some patients may be seen with late-stage degenerative joints, serious complications, painful and functionally uncompensated, with significant locomotion deficit. PVNS requires a radical treatment with prosthetic arthroplasty associated with synovectomy. Complex imaging (X-Rays, magnetic resonance imaging (MRI), ultrasound) and macroscopic appearance of the lesions during surgery confirms the clinical diagnosis of multifocal PVNS with secondary bone lesions. Histology marks the final diagnosis of multifocal PVNS. The postoperative results are good, with recovery in functional parameters of the joints with endoprosthesis.


Selective serotonin-reuptake inhibitors: an update.
Selective serotonin-reuptake inhibitors (SSRIs), including fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram, represent an important advance in the pharmacotherapy of mood and other disorders. They are chemically unrelated to tricyclic, heterocyclic, and other first-generation antidepressants. SSRIs are the treatment of choice for many indications, including major depression, dysthymia, panic disorder, obsessive-compulsive disorder, eating disorders, and premenstrual dysphoric disorder, because of their efficacy, good side-effect profile, tolerability, and safety in overdose, as well as patient compliance. A review of the literature was conducted using Medline and the terms "SSRIs," "fluoxetine," "sertraline," "paroxetine," "fluvoxamine," and "citalopram." Articles were limited to those published in English within the last 15 years. The search revealed that indications for antidepressants include unipolar depression, dysthymia, bipolar depression, treatment-resistant depression, depression in the medically ill, panic disorder, obsessive-compulsive disorder, eating disorders, social phobia, and premenstrual dysphoric disorder. One SSRI, fluoxetine, has demonstrated safety in pregnancy. Side effects of SSRIs include gastrointestinal disturbances, headache, sedation, insomnia, activation, weight gain, impaired memory, excessive perspiration, paresthesia, and sexual dysfunction.


[Maternal serum gamma-glutamyltransferase and prenatal diagnosis of the fetal alcohol syndrome].
In order to investigate prospectively the relationship between maternal serum levels of a biologic marker of alcohol and the outcome of pregnancy, we measured serum gamma-glutamyltransferase in 541 women between 14 and 20 weeks of pregnancy. An abnormally elevated value was observed in 6.8% of the cases but only 16.2% of these suspected alcohol abusers admitted drinking practices during pregnancy. Analysis of obstetrical issue and blind examination of the newborns showed a significant correlation between raised gamma-glutamyltransferase levels and an increased incidence of pre-/perinatal complications, congenital anomalies and intrauterine growth retardation. However, the sensitivity of this test is weak, limiting its use in the early recognition and prevention of fetal alcohol effects.


Ion permeation in normal and batrachotoxin-modified Na+ channels in the squid giant axon.
Na+ permeation through normal and batrachotoxin (BTX)-modified squid axon Na+ channels was characterized. Unmodified and toxin-modified Na+ channels were studied simultaneously in outside-out membrane patches using the cut-open axon technique. Current-voltage relations for both normal and BTX-modified channels were measured over a wide range of Na+ concentrations and voltages. Channel conductance as a function of Na+ concentration curves showed that within the range 0.015-1 M Na+ the normal channel conductance is 1.7-2.5-fold larger than the BTX-modified conductance. These relations cannot be fitted by a simple Langmuir isotherm. Channel conductance at low concentrations was larger than expected from a Michaelis-Menten behavior. The deviations from the simple case were accounted for by fixed negative charges located in the vicinity of the channel entrances. Fixed negative charges near the pore mouths would have the effect of increasing the local Na+ concentration. The results are discussed in terms of energy profiles with three barriers and two sites, taking into consideration the effect of the fixed negative charges. Either single- or multi-ion pore models can account for all the permeation data obtained in both symmetric and asymmetric conditions. In a temperature range of 5-15 degrees C, the estimated Q10 for the conductance of the BTX-modified Na+ channel was 1.53. BTX appears not to change the Na+ channel ion selectively (for the conditions used) or the surface charge located near the channel entrances.


Acute effects of nucleus pulposus on blood flow and endoneurial fluid pressure in rat dorsal root ganglia.
An experimental study to elucidate the initial factors in the pathogenesis of lumbar pain caused by disc herniation. To evaluate the effects of autologous nucleus pulposus on blood flow and endoneurial fluid pressure in dorsal root ganglia. Human sciatica is known to be associated with compression of lumbar nerve roots and dorsal root ganglia by herniated intervertebral discs. Recently, it has been shown that application of nucleus pulposus to nerve roots induces injury and pain-related behavior in experimental animals. In this study, the authors hypothesized that nucleus pulposus applied to a nerve root would cause increased intraneural edema and reduced blood flow in the corresponding dorsal root ganglia. Studies in peripheral nerves have shown that these initial pathophysiologic disturbances initiate complex events that exacerbate nerve injury and cause pain. A total of 29 adult female Sprague-Dawley rats weighing 200 to 250 g had their left L5 nerve roots and associated dorsal root ganglia exposed. Autologous nucleus pulposus was harvested from the tail and applied to the L5 nerve root just proximally to the dorsal root ganglia (nucleus pulposus group). For control, the same volume of muscle was harvested from the surgical area in the back and applied similarly to the neural tissue (control group). Blood flow was continuously monitored using a laser Doppler flow probe for 3 hours (n = 10) or 4 hours (n = 8) in animals with indwelling cannulas for measurement of systemic arterial pressure. Endoneurial fluid pressures were recorded with a servonull micropipette system using glass micropipettes with tip diameters of 4 microns. Endoneurial fluid pressure in the dorsal root ganglia was measured before and 3 hours after application of nucleus pulposus (n = 7) or muscle (n = 4). After measurement of blood flow and endoneurial fluid pressure, the nerve root and dorsal root ganglia were processed for histology and evaluated by light microscope. Blood flow in the nucleus pulposus group was reduced by 10% to 20% from the initial value after 3 to 4 hours. This reduction was statistically significant compared with that of the control group (P < 0.01). Endoneurial fluid pressure was initially 2.6 +/- 1.2 cm H2O in the nucleus pulposus group, and 2.1 +/- 0.6 cm H2O in the control group. Three hours after application, endoneurial fluid pressure was 7.5 +/- 4.6 in the nucleus pulposus group (P > 0.05), and 2.0 +/- 0.8 in the control group (P > 0.05). Edema was the principal pathologic finding seen consistently in the nerve roots and in many of the associated dorsal root ganglia from animals treated with nucleus pulposus. Application of nucleus pulposus to nerve root increased endoneurial fluid pressure and decreased blood flow in the dorsal root ganglia. This study's acute observations in the dorsal root ganglia may thus help to explain why disc herniations without compression of neural tissue are sometimes painful because similar pathologic findings are observed after only nucleus pulposus application to the nerve root. The authors further suggest that exposure of nerve roots to nucleus pulposus may establish a "compartment syndrome" in the dorsal root ganglia.


Early improvement in eating attitudes during cognitive behavioural therapy for eating disorders: the impact of personality disorder cognitions.
The personality disorders are commonly comorbid with the eating disorders. Personality disorder pathology is often suggested to impair the treatment of axis 1 disorders, including the eating disorders. This study examined whether personality disorder cognitions reduce the impact of cognitive behavioural therapy (CBT) for eating disorders, in terms of treatment dropout and change in eating disorder attitudes in the early stages of treatment. Participants were individuals with a diagnosed eating disorder, presenting for individual outpatient CBT. They completed measures of personality disorder cognitions and eating disorder attitudes at sessions one and six of CBT. Drop-out rates prior to session six were recorded. CBT had a relatively rapid onset of action, with a significant reduction in eating disorder attitudes over the first six sessions. Eating disorder attitudes were most strongly associated with cognitions related to anxiety-based personality disorders (avoidant, obsessive-compulsive and dependent). Individuals who dropped out of treatment prematurely had significantly higher levels of dependent personality disorder cognitions than those who remained in treatment. For those who remained in treatment, higher levels of avoidant, histrionic and borderline personality disorder cognitions were associated with a greater change in global eating disorder attitudes. CBT's action and retention of patients might be improved by consideration of such personality disorder cognitions when formulating and treating the eating disorders.


A computational approach for generating continuous estimates of motor unit discharge rates and visualizing population discharge characteristics.
Objective. Successive improvements in high density surface electromyography and decomposition techniques have facilitated an increasing yield in decomposed motor unit (MU) spike times. Though these advancements enhance the generalizability of findings and promote the application of MU discharge characteristics to inform the neural control of motor output, limitations remain. Specifically, (1) common approaches for generating smooth estimates of MU discharge rates introduce artifacts in quantification, which may bias findings, and (2) discharge characteristics of large MU populations are often difficult to visualize.Approach. In the present study, we propose support vector regression (SVR) as an improved approach for generating smooth continuous estimates of discharge rate and compare the fit characteristics of SVR to traditionally used methods, including Hanning window filtering and polynomial regression. Furthermore, we introduce ensembles as a method to visualize the discharge characteristics of large MU populations. We define ensembles as the average discharge profile of a subpopulation of MUs, composed of a time normalized ensemble average of all units within this subpopulation. Analysis was conducted with MUs decomposed from the tibialis anterior (N= 2128), medial gastrocnemius (N= 2673), and soleus (N= 1190) during isometric plantarflexion and dorsiflexion contractions.Main result. Compared to traditional approaches, we found SVR to alleviate commonly observed inaccuracies and produce significantly less absolute fit error in the initial phase of MU discharge and throughout the entire duration of discharge. Additionally, we found the visualization of MU populations as ensembles to intuitively represent population discharge characteristics with appropriate accuracy for visualization.Significance. The results and methods outlined here provide an improved method for generating estimates of MU discharge rate with SVR and present a unique approach to visualizing MU populations with ensembles. In combination, the use of SVR and generation of ensembles represent an efficient method for rendering population discharge characteristics.


Predicting detectability in radioguided surgery: a study based on physical characterization of the probe and on tissue uptake ratios of 125I-, 153Sm- and 165Er-labelled radiopharmaceuticals.
We performed measurements of the sensitivity in water of the radioguided surgery system, Neoprobe 1000. Point sources of 125I, 153Sm and 165Er were measured to a geometric accuracy of 0.1 mm. These measurements were performed with the detector uncollimated and with two different collimators; the results were used to construct three-dimensional sensitivity matrices from which isosensitivity curves could be derived. The matrices were used to simulate the reliability of detecting tumours of various sizes, at various depths, and with variable uptake ratios and activity levels of the three radionuclides investigated. Simulations showed improved tumour detection with a conical collimator, demonstrating that collimator design is important. To minimize the radiation dose during diagnostic work-up, a novel bone-seeking radiopharmaceutical, 165Er-EDTMP, was developed and tested. It showed rapid bone localization, especially in growth zones, and rapid clearance from blood and non-osseous tissues. Its biodistribution was similar to that of 153Sm-EDTMP. Based on these results and previous clinical data, the simulations predicted that lung metastases with a radius of 1 mm might be reliably detected with the Neoprobe 1000 system, if equipped with a suitable collimator.


Protective effects of piperine against copper-ascorbate induced toxic injury to goat cardiac mitochondria in vitro.
Piperine, the main alkaloid of black pepper, Piper nigrum Linn., is an important Indian spice used in traditional food and medicine in India. In the present study, we investigated the antioxidant activities of piperine against copper-ascorbate induced toxic injury to mitochondria obtained from a goat heart, in vitro. Incubation of isolated cardiac mitochondria with copper-ascorbate resulted in elevated levels of lipid peroxidation and protein carbonylation of the mitochondrial membrane, a reduced level of mitochondrial GSH and altered status of antioxidant enzymes as well as decreased activities of pyruvate dehydrogenase and the Kreb's cycle enzymes, altered mitochondrial morphology, mitochondrial swelling, di-tyrosine level and mitochondrial DNA damage. All these changes were found to be ameliorated when the cardiac mitochondria were co-incubated with copper-ascorbate and piperine, in vitro. Piperine, in our in vitro experiments, was found to scavenge hydrogen peroxide, superoxide anion free radicals, hydroxyl radicals and DPPH radicals, in a chemically defined system, indicating that this compound may provide protection to cardiac mitochondria against copper-ascorbate induced toxic injury through its antioxidant activities. The results of this study suggest that piperine may be considered as a future therapeutic antioxidant and may be used singly or as a co-therapeutic in the treatment of diseases associated with mitochondrial oxidative stress.


Prospective comparison of stereotactic core biopsy and surgical excision as diagnostic procedures for breast cancer patients.
To determine whether stereotactic core biopsy (SCNB) is the diagnostic method of choice for all mammographic abnormalities requiring tissue sampling. Stereotactic core needle biopsy decreases the cost of diagnosis, but its impact on the number of surgical procedures needed to complete local therapy has not been studied in a large, unselected patient population. A total of 1,852 mammographic abnormalities in 1,550 consecutive patients were prospectively categorized for level of cancer risk and underwent SCNB or diagnostic needle localization and surgical excision. Diagnosis, type of cancer surgery, and number of surgical procedures to complete local therapy were obtained from surgical and pathology databases. The malignancy rate was 24%. Surgical biopsy patients were older, more likely to have cancer, and more likely to be treated with breast-conserving therapy than those in the SCNB group. For all types of lesions, regardless of degree of suspicion, patients diagnosed by SCNB were almost three times more likely to have one surgical procedure. However, for patients treated with lumpectomy alone, the number of surgical procedures and the rate of negative margins did not differ between groups. Stereotactic core needle biopsy is the diagnostic procedure of choice for most mammographic abnormalities. However, for patients undergoing lumpectomy without axillary surgery, it is an extra invasive procedure that does not facilitate obtaining negative margins.


Effect of halothane on cardiac output and regional flow in the fetal lamb in utero.
We studied the effect of halothane on the fetal cardiovascular system of six lambs in utero by measuring fetal heart rate and femoral arterial blood pressure and by injecting labeled microspheres during a control period and again after 60 and 90 min of halothane anesthesia administered to six pregnant ewes at an inspired concentration of 1.5%. There were no significant effects on maternal cardiovascular function or acid-base balance, but fetal blood pressure decreased significantly by 27% after 8 min of halothane anesthesia and remained at this level for the duration of the experiment. However, there were no significant changes either in fetal regional blood flow to the vital organs or in fetal cardiac output. Fetal oxygenation and acid-base status remained stable. We conclude that in normal fetal lamb in utero the decrease in mean fetal arterial blood pressure associated with maternal halothane anesthesia is due to a decrease in peripheral vascular resistance because regional blood flow and acid-base status are well maintained.


Autopsy-determined causes of death after cardiac valve replacement.
We reviewed records of 378 patients who died after cardiac valve replacement and underwent autopsy at The Methodist Hospital, Houston, from 1962 through 1979. Patients were divided according to postoperative interval at death: within 30 days (early) or 30 days to ten years (late). Early deaths (279 patients) were due almost exclusively to cardiovascular abnormalities or operative complications (94%). Only 6% of early deaths were caused by prosthesis-associated complications. In contrast, late deaths (99 patients) were valve related in 47% of cases, including complete thrombotic occlusion or systemic thromboembolism (21%), prosthetic valve endocarditis (14%), valve dehiscence (6%), anticoagulation-related hemorrhage (3%), and mechanical degeneration (2%). Nine percent of late deaths were unrelated to cardiovascular disease. Thus, while early deaths primarily reflected the severity of preexisting or associated cardiovascular disease, prosthesis-associated complications were an important cause of late death after cardiac valve replacement.


Representation of autism in leading newspapers in china: a content analysis.
The public's lack of understanding and the public's misconceptions about autism in China contribute to the underdiagnosis and undertreatment of the disorder and the stigma associated with it. Mass media are the primary channel through which people learn about autism. This article examines how leading newspapers in China covered autism in the 10-year period of 2003 through 2012 through a framing analysis. It finds that while autism has received increased media attention, it is increasingly framed as a family problem-family members are cited or quoted more than any other sources and the responsibility of dealing with autism is ultimately assigned to families. Autistic people are largely silenced unless they are autistic savants with special talents. The use of the scientific discourse and the human-interest discourse both decrease over time in percentage, while the use of other discourses such as the public relations discourse becomes more dominant.


Flavones scaffold of Chromolaena odorata as a potential xanthine oxidase inhibitor: Induced Fit Docking and ADME studies.
Introduction: Gout is a type of painful inflammation initiated by the interactions between monosodium urate crystals and connective tissue. Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine, then to uric acid. The primary treatments for gout include XO inhibitors. At present, allopurinol is the most used XO inhibitor for the treatment of gout. However, it can cause adverse effects commonly known as allopurinol hypersensitivity syndrome, thereby limiting its usage. Consequently, it is necessary to develop potent and less toxic inhibitors of XO. Chromolaena odorata is one of such plants under investigation for its diverse health benefits. Methods: Phytochemicals of C. odorata were screened against XO receptor, using molecular docking. The top five hit compounds of glide docking yield flavones scaffold which were subjected to induced fit docking (IFD) and absorption, distribution, metabolism, and excretion (ADME) studies. Results: The result showed that flavones scaffold of C. odorata can bind with higher affinity and lower free energy values when compared to that of the standard, allopurinol. The IFD scores of the flavones scaffold range from -1525.25 to -1527.99 kcal/mol. Conclusion: Our results have shown that flavones scaffold might have the potential to act as an effective drug candidate when compared to allopurinol in treating and/or preventing gout and some inflammatory condition.


Cancer Risk After Radioactive Iodine Treatment for Hyperthyroidism: A Systematic Review and Meta-analysis.
Whether radioactive iodine (RAI) therapy for hyperthyroidism can increase cancer risk remains a controversial issue in medicine and public health. To examine site-specific cancer incidence and mortality and to evaluate the radiation dose-response association after RAI treatment for hyperthyroidism. The Medline and Cochrane Library electronic databases, using the Medical Subject Headings terms and text keywords, and Embase, using Emtree, were screened up to October 2020. Study inclusion criteria were as follows: (1) inclusion of patients treated for hyperthyroidism with RAI and followed up until cancer diagnosis or death, (2) inclusion of at least 1 comparison group composed of individuals unexposed to RAI treatment (eg, the general population or patients treated for hyperthyroidism with thyroidectomy or antithyroid drugs) or those exposed to different administered doses of RAI, and (3) inclusion of effect size measures (ie, standardized incidence ratio [SIR], standardized mortality ratio [SMR], hazard ratio [HR], or risk ratio [RR]). Two independent investigators extracted data according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Overall quality assessment followed the recommendations of United Nations Scientific Committee on the Effects of Atomic Radiation. The SIR and SMRs and the RRs and HRs were pooled using random-effects meta-analysis. Cancer incidence and mortality for exposure vs nonexposure to RAI therapy and by level of RAI administered activity. Based on data from 12 studies including 479 452 participants, the overall pooled cancer incidence ratio was 1.02 (95% CI, 0.95-1.09) and the pooled cancer mortality ratio was 0.98 (95% CI, 0.92-1.04) for exposure vs nonexposure to RAI therapy. No statistically significant elevations in risk were observed for specific cancers except thyroid cancer incidence (SIR, 1.86; 95% CI, 1.19-2.92) and mortality (SMR, 2.22; 95% CI, 1.37-3.59). However, inability to control for confounding by indication and other sources of bias were important limitations of studies comparing RAI exposure with nonexposure. In dose-response analysis, RAI was significantly associated with breast and solid cancer mortality (breast cancer mortality, per 370 MBq: 1.35; P = .03; solid cancer mortality, per 370 MBq: 1.14; P = .01), based on 2 studies. In this meta-analysis, the overall pooled cancer risk after exposure to RAI therapy vs nonexposure was not significant, whereas a linear dose-response association between RAI therapy and solid cancer mortality was observed. These findings suggest that radiation-induced cancer risks following RAI therapy for hyperthyroidism are small and, in observational studies, may only be detectable at higher levels of administered dose.


Avoiding Missing Data Biases in Phylogenomic Inference: An Empirical Study in the Landfowl (Aves: Galliformes).
Production of massive DNA sequence data sets is transforming phylogenetic inference, but best practices for analyzing such data sets are not well established. One uncertainty is robustness to missing data, particularly in coalescent frameworks. To understand the effects of increasing matrix size and loci at the cost of increasing missing data, we produced a 90 taxon, 2.2 megabase, 4,800 locus sequence matrix of landfowl using target capture of ultraconserved elements. We then compared phylogenies estimated with concatenated maximum likelihood, quartet-based methods executed on concatenated matrices and gene tree reconciliation methods, across five thresholds of missing data. Results of maximum likelihood and quartet analyses were similar, well resolved, and demonstrated increasing support with increasing matrix size and sparseness. Conversely, gene tree reconciliation produced unexpected relationships when we included all informative loci, with certain taxa placed toward the root compared with other approaches. Inspection of these taxa identified a prevalence of short average contigs, which potentially biased gene tree inference and caused erroneous results in gene tree reconciliation. This suggests that the more problematic missing data in gene tree-based analyses are partial sequences rather than entire missing sequences from locus alignments. Limiting gene tree reconciliation to the most informative loci solved this problem, producing well-supported topologies congruent with concatenation and quartet methods. Collectively, our analyses provide a well-resolved phylogeny of landfowl, including strong support for previously problematic relationships such as those among junglefowl (Gallus), and clarify the position of two enigmatic galliform genera (Lerwa, Melanoperdix) not sampled in previous molecular phylogenetic studies.


Alpha-Tocopherol and endothelial nitric oxide synthesis.
Nitric oxide (NO), a central regulator of vascular tone and homeostasis, is generated upon activation of endothelial NO synthase (eNOS), which is mediated by an increase of intracellular calcium and/or by eNOS phosphorylation. A reduction of NO bioavailability leads to endothelial dysfunction that has been shown to be improved by alpha-tocopherol in certain conditions. The underlying mechanisms, however, are not completely clarified. The present study was performed to investigate whether alpha-tocopherol is able to affect endothelial NO synthesis. The formation of NO was measured in human umbilical vein endothelial cells using citrulline (coproduct) and cGMP (product of the NO-activated soluble guanylate cyclase) as indicator molecules. alpha-Tocopherol (10-200 microM, 24 hr) increased ionomycin-induced citrulline and cGMP formation in intact cells in a concentration-dependent manner. In parallel, ionomycin-stimulated phosphorylation of eNOS at serine 1177, known to support enzyme activation, was increased by alpha-tocopherol, suggesting that this was the mechanism responsible for enhanced NO formation. The effect of alpha-tocopherol was dependent on its hydrophobic structure because it was mimicked by gamma-tocopherol but not by trolox, a hydrophilic derivative of alpha-tocopherol. Coincubation with ascorbic acid (100 microM, 24 hr) amplified the effects of alpha-tocopherol on eNOS phosphorylation and NO formation, which is possibly related to the regeneration of oxidized alpha-tocopherol by ascorbate. Our data suggest that vasoprotective effects of alpha-tocopherol in vivo may be related to an increase of NO formation. The effect of alpha-tocopherol seems to be dependent on tissue saturation with ascorbic acid, and both vitamins may act synergistically to provide optimal conditions for endothelial NO formation.


Centrally administered atrial natriuretic factor increases renal water excretion.
The effects of intracerebroventricular (ICV) infusion of atrial natriuretic factor (ANF; atriopeptin III) on renal function, plasma concentrations of antidiurectic hormone, aldosterone, and plasma renin activity (PRA) were examined in anesthetized rats and sodium-depleted conscious sheep. The results were compared with those obtained by intravenous infusion of the same dose of ANF. In both rats and sheep, urine volume was increased four- to sixfold over basal values by ICV infusion of ANF. The response was not associated with increased excretion of sodium or potassium. However, urine osmolality was decreased, and free water clearance increased. Intravenous infusion of the same dose of ANF was without effect. Neither mean arterial blood pressure nor heart rate was changed by the ICV infusion of ANF. In the sheep, renal plasma flow showed no significant changes and glomerular filtration rate was unaltered with the exception of a single experimental period out of four periods of ICV ANF infusion. Plasma concentration of ADH was decreased and PRA increased, whereas aldosterone levels remained unchanged as a function of ICV ANF. In the rat, the diuretic response to ANF was prevented by continuous intravenous infusion of a subpressor dose of ADH. These results suggest that ANF within the central nervous system inhibits secretion of ADH.


Training associated alterations in equine respiratory immunity using a multiomics comparative approach.
Neutrophilic airway inflammation is highly prevalent in racehorses in training, with the term mild to moderate equine asthma (MMEA) being applied to the majority of such cases. Our proposed study is largely derived from the strong association between MMEA in racehorses and their entry into a race training program. The objectives of this study are to characterise the effect of training on the local pulmonary immune system by defining the gene and protein expression of tracheal wash (TW) derived samples from Thoroughbred racehorses prior to and following commencement of race training. Multiomics analysis detected 2138 differentially expressed genes and 260 proteins during the training period. Gene and protein sets were enriched for biological processes related to acute phase response, oxidative stress, haemopoietic processes, as well as to immune response and inflammation. This study demonstrated TW samples to represent a rich source of airway cells, protein and RNA to study airway immunity in the horse and highlighted the benefits of a multiomics methodological approach to studying the dynamics of equine airway immunity. Findings likely reflect the known associations between race-training and both airway inflammation and bleeding, offering further insight into the potential mechanisms which underpin training associated airway inflammation.


Biological markers in body fluids for activity and progression in multiple sclerosis.
Reliable biological markers in body fluids for disease activity and progression are important for our understanding of the pathophysiology and therapeutic decisions in various subtypes of multiple sclerosis. Sampling from body fluids such as cerebrospinal fluid, blood, and urine constitutes the problem that the local immuno-inflammatory process takes place in the central nervous system whereas the disease activity is only to some extent reflected in the systemic immune compartment. Promising results have been obtained in studies of adhesion molecules, pro-inflammatory cytokines, co-stimulatory molecules and neopterin as markers of disease activity in relapsing-remitting multiple sclerosis. However, these results apply to groups of patients but not necessarily to individual patients. Currently no single body fluid marker is sufficiently correlated to disease activity to be used in the individual patient in monitoring disease activity, progression, or therapeutic effects.


TNM: principles, history, and relation to other prognostic factors.
The TNM classification system describes the anatomic extent of cancer. The ability of TNM to separately classify the individual tumor (T), lymph node (N), and metastatic (M) elements and then group them into stages differs from other cancer staging classifications, which are concerned only with summarized groups. The objectives of TNM classification are to aid the clinician in the planning of treatment, to give some indication of prognosis, to assist in the evaluation of the results of treatment, and to facilitate the exchange of information. The most important challenge facing TNM is how to interface with the great numbers of nonanatomic prognostic factors that are currently in use or under study. As nonanatomic prognostic factors become widely used, TNM provides an inviting foundation upon which to build a prognostic classification; however, there is a risk that TNM will be overwhelmed by such a variety of prognostic data. An anatomic extent of disease classification is needed to select the initial therapeutic approach, stratify patients for therapeutic studies, evaluate nonanatomic prognostic factors at specific anatomic stages, compare the weight of nonanatomic factors with extent of disease, and communicate extent of disease data in a uniform manner. Methods are needed to express overall prognosis without losing the vital anatomic content of TNM. These methods should be able to integrate multiple prognostic factors, including TNM, yet permit TNM to remain intact and distinct.


Comparison of 3 different analytic approaches for determining risk-related active and sedentary behavioral patterns in adolescents.
Much of the research conducted to date implies overweight youth exhibit uniform active and sedentary behavioral patterns. This approach negates the possibility that multiple co-occurring, and seemingly contrasting, behaviors may manifest within the same individual. We present a substantive dialogue on alternative analytical approaches to identifying risk-related active/sedentary behavioral patterns associated with overweight in adolescents. Comparisons were made among latent profile analysis (LPA), cluster analysis (CA), and multinomial logistic regression (MLR). A cross sectional sample of youth (N = 6603; 12-18 yrs) completed a questionnaire assessing: physical activity (PA); competing activities (COMP); and sedentary activities (SED). Demographics associated with PA (age, sex, BMI) were used as covariates/predictors. Comparisons among methods revealed that LPA and CA detected subgroupings of behavioral patterns associated with overweight, each unique in regards to behaviors and demographic characteristics, whereas MLR results followed established associations of low PA and high SED without subgroup separation. Use of LPA and CA provides a rich understanding of behavioral patterns and the related demographic characteristics. Decisions guiding the selection of analytical techniques are discussed.


Tgf-beta signaling pathway in lung adenocarcinoma invasion.
The histologic distinction between bronchioloalveolar carcinoma and other adenocarcinomas is tissue invasion. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in nonmucinous bronchioloalveolar carcinoma is significantly lower than that of pure invasive tumors and in tumors with greater than 0.5 cm of fibrosis or linear invasion. Using microarray gene expression profiling of human tumors, dysregulation of transforming growth factor-beta signaling was identified as an important mediator of tumor invasion. Subsequent studies showed that the CC chemokine regulated on activation, normal T cell expressed, and presumably secreted was up-regulated in invasive tumors and was required for invasion in cells with repressed levels of the transforming growth factor-beta type II receptor. Taken together, these studies illustrate how information gained from global expression profiling of tumors can be used to identify key pathways and genes mediating tumor growth, invasion, and metastasis.


Neuroimmune mechanisms of cytokine-induced depression: current theories and novel treatment strategies.
The relationships between immune and neural function are an increasingly important area of study for neuropsychiatric disorders, in particular depression. This is exemplified by the growing number of publications on cytokines and depression during the last 10 years, as compared to earlier decades. This review summarizes the current theories and novel treatment strategies for depression, with a focus on cytokine-induced depression. Neuroimmune mechanisms are now viewed as central to the development of depressive symptoms and emerging evidence is beginning to identify the neural circuits involved in cytokine-induced depression. The current diagnostic categories for depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, however, are not etiologically or biologically derived, and it has been proposed that "depression", likely reflects multiple pathogeneses leading to varying symptom constellations. As we move toward a better biological understanding of depression-related symptom constellations or syndromes, the term "depression" may prove inadequately broad, and an integration of interdisciplinary literatures will increase in importance. Future research should aim to characterize these depression-related symptom constellations or syndromes better with the goal of optimizing treatment strategies.


Young Stroke Patients Treated with Intravenous Thrombolysis have a More Favorable Outcome and Mortality Compared with Older Patients.
Previous clinical studies suggest that intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator benefits stroke patients, but the efficacy of IVT in young stroke patients is not well-studied in China. We compared the safety and efficacy of IVT with recombinant tissue plasminogen activator between Chinese young stroke patients (18-50 years old) and older patients (51-80 years old). We analyzed data from the Soochow Stroke Registry for 373 stroke patients (18-50 years, n=74 vs. 51-80 years, n=299) who received IVT between May 2009 and January 2016. Main outcomes included symptomatic intracerebral hemorrhage (sICH) within 7 days, and mortality and favorable outcome (modified Rankin scale 0-2) at 3 months. Associations between baseline characteristics and outcomes for the two groups were analyzed by logistic regression. Favorable outcome at 3 months was significantly higher in young adults (adjusted odds ratio 2.09; 95% confidence interval 1.09-3.99, p=0.026). The incidence of sICH and mortality was low for young adults compared with older patients, but there were no statistically significant differences between the two groups. Multivariable analysis showed that baseline National Institutes of Health Stroke Score was associated with favorable outcome (p=0.026) in young adults. Our analysis indicated that young stroke patients treated with IVT had a more favorable outcome without an increased risk of sICH and mortality compared with older patients. We conclude that IVT is safe and at least as beneficial for Chinese young adults with acute ischemic stroke compared with older patients.


A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17.
Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha). Moreover, the only R to G mutation at position 76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bond network. This generates a conformational shift in the p17 R76G mutant which enables a functional epitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a still unknown receptor(s). Our findings offer new opportunities to understand the molecular mechanisms accounting for the B-cell growth-promoting activity of vp17s.


Effect modification of the association between total cigarette smoking and ALS risk by intensity, duration and time-since-quitting: Euro-MOTOR.
We investigated the association between cigarette smoking and risk of amyotrophic lateral sclerosis (ALS) in a pooled analysis of population-based case-control studies and explored the independent effects of intensity, duration and time-since-quitting. ALS cases and controls, matched by age, sex and region, were recruited in the Netherlands, Italy and Ireland (*Euro-MOTOR project). Demographics and detailed lifetime smoking histories were collected through questionnaires. Effects of smoking status, intensity (cigarettes/day), duration (years), pack-years and time-since-quitting (years) on ALS risk were estimated using logistic regression models, adjusting for age, sex, alcohol, education and centre. We further investigated effect modification of the linear effects of pack-years by intensity, duration and time-since-quitting using excess OR (eOR) models. Analyses were performed on 1410 cases and 2616 controls. Pack-years were positively associated with ALS risk; OR=1.26 (95% CI: 1.03 to 1.54) for the highest quartile compared with never smokers. This association appeared to be predominantly driven by smoking duration (ptrend=0.001) rather than intensity (ptrend=0.86), although the trend for duration disappeared after adjustment for time-since-quitting. Time-since-quitting was inversely related to ALS (ptrend<0.0001). The eOR decreased with time-since-quitting smoking, until about 10 years prior to disease onset. High intensity smoking with shorter duration appeared more deleterious than lower intensity for a longer duration. Our findings provide further support for the association between smoking and ALS. Pack-years alone may be insufficient to capture effects of different smoking patterns. Time-since-quitting appeared to be an important factor, suggesting that smoking may be an early disease trigger.


Identification of Quiescent LGR5+ Stem Cells in the Human Colon.
In the mouse intestinal epithelium, Lgr5+ stem cells are vulnerable to injury, owing to their predominantly cycling nature, and their progenies de-differentiate to replenish the stem cell pool. However, how human colonic stem cells behave in homeostasis and during regeneration remains unknown. Transcriptional heterogeneity among colonic epithelial cells was analyzed by means of single-cell RNA sequencing analysis of human and mouse colonic epithelial cells. To trace the fate of human colonic stem or differentiated cells, we generated LGR5-tdTomato, LGR5-iCasase9-tdTomato, LGR5-split-Cre, and KRT20-ERCreER knock-in human colon organoids via genome engineering. p27+ dormant cells were further visualized with the p27-mVenus reporter. To analyze the dynamics of human colonic stem cells in vivo, we orthotopically xenotransplanted fluorescence-labeled human colon organoids into immune-deficient mice. The cell cycle dynamics in xenograft cells were evaluated using 5-ethynyl-2'-deoxyuridine pulse-chase analysis. The clonogenic capacity of slow-cycling human stem cells or differentiated cells was analyzed in the context of homeostasis, LGR5 ablation, and 5-fluorouracil-induced mucosal injury. Single-cell RNA sequencing analysis illuminated the presence of nondividing LGR5+ stem cells in the human colon. Visualization and lineage tracing of slow-cycling LGR5+p27+ cells and orthotopic xenotransplantation validated their homeostatic lineage-forming capability in vivo, which was augmented by 5-FU-induced mucosal damage. Transforming growth factor-β signaling regulated the quiescent state of LGR5+ cells. Despite the plasticity of differentiated KRT20+ cells, they did not display clonal growth after 5-FU-induced injury, suggesting that occupation of the niche environment by LGR5+p27+ cells prevented neighboring differentiated cells from de-differentiating. Our results highlight the quiescent nature of human LGR5+ colonic stem cells and their contribution to post-injury regeneration.