Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients.
FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.


Effects of local anaesthetics on phospholipases.
1. The effects of six local anaesthetics have been studied on the activities of soluble phospholipases A2 (EC 184.108.40.206) and lysophospholipase (EC 188.8.131.52). 2. Phospholipase A2 activity in human seminal plasma towards sonicated radioactively-labelled phosphatidylethanolamine was slightly stimulated a low and inhibited at high concentrations of all anaesthetic compounds employed. The order of decreasing potency was chlorpromazine, dibucaine, tetracaine, lidocaine, cocaine and procaine. In line with previous findings, the mode of inhibition was seen to be competitive with respect to Ca2+. 3. Phospholipase A2 activity in crude venom of Crotalus adamanteus was not affected or slightly stimulated by local anaesthetics up to 10(-2) M concentrations, when egg yolk was used as substrate. However, with sonicated radioactively-labelled phosphatidylcholine or phosphatidylethanolamine as substrate, stimulation of phospholipase activity was seen with all local anaesthetics up to 10(-2) M, the order of decreasing potency again being chlorpromazine, dibucaine, tetracaine, lidocaine, cocaine and procaine. The mode of stimulation was seen to be un-competitive with respect to substrate and probably independent of any involvement of Ca2+. 4. As in seminal plasma phospholipase A2, the activity in crude Naja naja venom towards sonicated radioactively labelled phosphatidylcholine was stimulated at low and inhibited at high concentrations of dibucaine and chloropromazine, for example. The mode of inhibition was seen to be competitive with respect to Ca2+, whereas stimulation by the anaesthetic drugs was independent of Ca2+. Binding between drug and enzyme was demonstrated by equilibration filtration of purified phospholipase A2 of Naja naja venom through a Sephadex G 25-fine column, previously equilibrated with 0.5 mM radioactively labelled chlorpromazine. 5. Lysophospholipase activity in rat liver cytosol towards radioactively labelled lysophosphatidylcholine was inhibited by all local anaesthetics used; the order of decreasing potency was chlorpromazine, dibucaine, tetracaine, cocaine, lidocaine and procaine. The inhibition was un-competitive with respect to substrate. 6. The inhibitory and stimulatory potencies of the local anaesthetics employed closely parallel their lipid solubilities and anaesthetic potencies.


Fractional limb volume--a soft tissue parameter of fetal body composition: validation, technical considerations and normal ranges during pregnancy.
The main goals were to provide normal reference ranges for fractional limb volume as a new index of generalized fetal nutritional status, to evaluate the reproducibility of fractional fetal limb volume measurements during the second and third trimesters of pregnancy, and to demonstrate technical considerations for this technique. This was a prospective, cross-sectional study of gravid women during mid to late pregnancy. Fractional limb volumes were based on either 50% of humeral or femoral diaphysis length. Each partial volume was subdivided into five equidistant slices that were centered along the mid-arm or mid-thigh. Slices were traced manually to obtain fractional arm (AVol) or fractional thigh (TVol) volume. Reproducibility studies were performed, using Bland-Altman plots, to assess blinded interobserver and intraobserver measurement bias and agreement. Selected images were chosen to demonstrate technical factors for the acquisition and analysis of these parameters. Reference charts were established to describe normal ranges for AVol and TVol. Three hundred and eighty-seven subjects were scanned to include 380 AVol (range, 1.1-68.3 mL) and 378 TVol (range 2.0-163.2 mL) measurements between 18.0 and 42.1 weeks' menstrual age. No gender differences were found in these soft tissue measurements (AVol, P = 0.90; TVol, P = 0.91; Mann-Whitney test). Intraobserver mean bias +/- SD and 95% limits of agreement (LOA) for fractional limb volumes were: 2.2 +/- 4.2% (95% LOA, - 6.0 to 10.5%) for AVol and 2.0 +/- 4.2% (95% LOA, - 6.3 to 10.3%) for TVol. Interobserver bias and agreement were - 1.9 +/- 4.9% (95% LOA, - 11.6 to 7.8%) for AVol and - 2.0 +/- 5.4% (95% LOA, - 12.5 to 8.6%) for TVol. Technical factors were related to image optimization, transducer pressure, fetal movement, soft tissue compression and amniotic fluid volume. Fractional limb volume assessment may improve the detection and monitoring of malnourished fetuses because this soft tissue parameter can be obtained quickly and reproducibly during mid to late pregnancy. Careful attention should be placed on technical factors that can potentially affect optimal acquisition and analysis of these volume measurements.


No Statistically Apparent Difference in Antifungal Effectiveness Observed Among Trimethoprim/Sulfamethoxazole Plus Clindamycin or Caspofungin, and Trimethoprim/Sulfamethoxazole Monotherapy in HIV-Infected Patients with Moderate to Severe Pneumocystis Pneumonia: Results of an Observational Multicenter Cohort Study.
Pneumocystis pneumonia is a common opportunistic infection in patients with HIV/AIDS, and is a leading cause of death in this population. Early selection of effective treatment is therefore critical to reduce mortality. We conducted a clinical trial to compare the effectiveness and safety of three different antifungal treatment regimens in HIV-infected patients with moderate to severe PCP. Our study was a multicenter, observational prospective clinical trial. We recruited 320 HIV-infected patients with moderate to severe PCP, and stratified these subjects into a trimethoprim/sulfamethoxazole (TMP-SMX) monotherapy group, a TMP-SMX plus clindamycin group, and a TMP-SMX plus caspofungin group. Patients were invited to participate in 12 weeks of follow-up. Outcomes included the difference in overall mortality and the proportion of overall positive response to treatment in the three groups at weeks 4 and 12, the difference in treatment duration, and the proportion of adverse events among the three groups during the study period. The probability of survival not statistically different among three treatment groups. Mortality in the TMP-SMX monotherapy group (group 1) was 15/115 (13.04%) vs. 20/83 (24.10%) in the TMP-SMX plus clindamycin group (group 2) vs. 24/107 (22.43%) in the TMP-SMX plus caspofungin group (group 3) at week 12 (p = 0.092). The overall positive response rate to treatment in the three groups was 24.14%, 34.94%, and 38.32%, respectively, at week 4, and 33.91%, 38.55%, and 44.86%, respectively, at week 12. No significant difference in the overall positive response rate to treatment at either week 4 or week 12 was noted (p = 0.061, p = 0.246). Rates of changes to therapy were 6.50% (8/123) in group 1, 3.40% (3/87) in group 2, and 2.70% (3/110) in group 3, and did not differ significantly among the three groups (p = 0.376). There were also no significant differences in adverse events among the three treatment groups of patients with moderate to severe PCP. Our results indicate that there are no significant statistical differences among the three studied treatment regimens in terms of antifungal effectiveness in HIV-infected patients with moderate to severe PCP. TMP-SMX monotherapy is a convenient, cheap, and effective therapeutic drug regimen to treat HIV-infected patients with moderate to severe PCP, and is an appropriate treatment strategy in resource-limited settings. www.ClinicalTrials.gov , ID: ChiCTR1900021195. Registered on February 1, 2019.


Plasma GABA-like activity in response to ethanol challenge in men at high risk for alcoholism.
Sons of alcoholic fathers (high risk, HR) and matched control men from families without alcoholism (low risk, LR) were administered, in a randomized double-blind fashion, either a placebo beverage or an isovolemic beverage containing ethanol (0.8 g/kg). Serial blood sampling for determination of plasma gamma-aminobutyric acid (GABA)-like activity, mood, and intoxication ratings were performed. The HR subjects were found to have significantly less plasma GABA-like activity than LR during the placebo condition. The alcoholic beverage condition washed out the differences in plasma GABA between groups. Significant interactions between risk group status and beverage conditions were found with respect to plasma GABA-like activity. Alcohol produced an increase in mean GABA-like activities among HR subjects, whereas a slight decline was noted among LR subjects. Plasma GABA-like activity also had a significant inverse correlation with self-reports of perceived tension in the placebo condition, and tension, confusion, and intoxication in response to the alcoholic drink. Since previous investigators have reported reduced plasma GABA levels in alcoholic individuals, reduced plasma GABA-like activity may be a biological marker for vulnerability to alcoholism or for heightened tension as a behavioral factor that predisposes to alcoholism.


Radiofrequency catheter ablation increases mean platelet volume.
Radiofrequency ablation (RFA) may increase the risk of thromboembolic events. The objective of this study was to evaluate the effect of RFA on mean platelet volume (MPV), an indicator of platelet activity. A total of 95 patients undergoing RFA were included in the study. MPV was measured before and one month after the procedure. The control group was formed by 83 individuals of the same sex and age as those in the study group. Beta-blockers, non-dihydropyridine calcium channel blockers, and acetylsalicylic acid use was higher in the ablation group compared with the control group. Other baseline clinical characteristics and baseline hemoglobin, white blood cell count, platelet count, and MPV values were similar between the ablation and control groups. In the ablation group, baseline and post-procedural hemoglobin, white blood cell counts were similar. However, postprocedural MPV values were higher, and platelet counts were lower compared with the preprocedural values. Our results indicate that MPV values are higher after RFA compared with baseline values.


Seroepidemiology and serodiagnosis of schistosomiasis in Kenya using crude and purified egg antigens of Schistosoma mansoni in ELISA.
The performance of antibody detection for the diagnosis of schistosomiasis has been evaluated in Kenya. Approximately 1500 blood samples from 3 areas with endemic schistosomiasis (Schistosoma mansoni only, S. haematobium only, and a mixed infection area), and from a non-endemic control area, were tested for their antibody reactivity in an enzyme-linked immunosorbent assay (ELISA). The results were compared with infection status determined by parasitological examination. Two test antigens were used: unfractionated S. mansoni egg homogenate (SEA), and CEF6, a previously described, partially purified fraction of SEA containing 2 cationic antigens. The antigens prepared from eggs of Kenya and Puerto Rico S. mansoni isolates gave very similar results. Bloods from patients with S. haematobium infection cross-reacted significantly with the two S. mansoni antigen preparations, but reactivity against CEF6 appeared more specifically indicative of S. mansoni infection. Of 254 blood samples from schoolchildren in the non-endemic area, 100% gave ELISA optical density readings at 492 nm (OD492) < 0.20 against SEA, and 98% were < 0.20 against CEF6. With 887 blood samples from subjects of all ages in the area endemic for S. mansoni alone, using an ELISA OD492 cut-off point of 0.20, SEA and CEF6 had sensitivities of 94% and 97% respectively, and specificities of 64% and 59% respectively. Increasing the OD492 cut-off value reduced the sensitivity and increased the specificity of both test antigens. Specificity of both antigens was poor with samples from 234 children in an area endemic for both S. mansoni and S. haematobium (< 20% for both antigens at an OD492 cut-off value of 0.20).(ABSTRACT TRUNCATED AT 250 WORDS)


[The placebo trap].
Monodisciplinary orthopaedic pain therapy no longer measures up to international standards. In cases of chronic back pain, in particular, there is such a gulf between the clinical findings and the patient's subjective assessment that the symptoms cannot be attributed solely to so-called degenerative changes. Back pain patients are in great danger of becoming fixated on somatic symptoms due to an excess of diagnostic procedures or incorrect diagnoses, of being treated purely somatically on the basis of associated findings, and of suffering irreversible damage from invasive management of such findings. Despite the wealth of empirical evidence, it remains difficult to expand the everyday concept of illness and its causes to include not only physical and biological factors but also social and emotional disturbances. Particularly physicians with a purely biological concept of pain have not learned to take note of affective relational factors and incorporate them into their diagnostic assessment. The decision to undertake invasive diagnostic or therapeutic procedures then frequently represents the doctor's reaction to feelings of irritation or helplessness. If this situation is to change, an interdisciplinary concept of pain must be made a part of medical training, and scientific findings must be presented in such a way that they can be integrated into routine daily practice.


MicroRNA-124-3p promotes apoptosis and autophagy of glioma cells by down-regulating CREBRF.
This research was performed to dissect the influence of microRNA (miR)-124-3p on the apoptosis and autophagy of glioma cells and clarify its specific mechanism. RT-PCR and western blot were utilized to determine miR-124-3p and CREBRF expression in U251 and T98 cells. After loss- and gain-of-function assays in U251 and T98 cells, glioma cell proliferation, autophagy, and apoptosis were measured by MTT assay, western blot, and flow cytometry, respectively. The relationship between miR-124-3p and CREBRF was examined by dual-luciferase reporter assay. The levels of AKT pathway-related proteins were detected by western blot. MiR-124-3p was lowly expressed and CREBRF was highly expressed in U251 and T98 cells. Overexpression of miR-124-3p or knockdown of CREBRF enhanced apoptosis and autophagy and diminished proliferation of glioma cells. MiR-124-3p negatively targeted CREBRF. MiR-124-3p up-regulation repressed proliferation and facilitated apoptosis and autophagy of glioma cells by diminishing CREBRF expression and blocking the AKT pathway. MiR-124-3p accelerates apoptosis and autophagy of glioma cells via CREBRF.


Educational needs on safe motherhood from the perspective of suburban women: A qualitative study.
Maternal mortality resulting from pregnancy and delivery complications is a sensitive indicator of women's status in the society, access to care services, and sufficiency and quality of healthcare and is the major indicator of a country's developmental status. The present study aimed at determination of educational needs regarding safe motherhood from suburban women's perspective. This qualitative study with conventional content analysis approach was conducted in suburban healthcare centers of Alborz University of medical sciences from 23 October to 22 December 2019. The participants included 15 eligible Iranian suburban women who were selected through purposive sampling. The data were collected via in-depth semi-structured interviews and focus groups. Data were analyzes with MAXQDA10 software. Three main themes emerged from the analysis of the data (barriers against safe pregnancy, accountability multidimensional training, and threats and opportunities of distance learning), six categories, 11 subcategories and 547 codes. The results indicated that suburban women were less probable to be present in healthcare centers and receive the required information compared to their peers due to their conditions; provision of accessible training services appropriated to their conditions can greatly contribute to elimination of these problems.


The antimicrobial activity of embalming chemicals and topical disinfectants on the microbial flora of human remains.
The antimicrobial activity of embalming chemicals an topical disinfectants was evaluated to determine the degree of disinfection achieved during the embalming of human remains. The administration of arterial and cavity embalming chemicals resulted in a 99% reduction of the postmortem microbial population after 2 hours of contact. This level of disinfection was maintained for the 24 hours test period. Topical disinfection of the body orifices was also observed. Therefore, it is probable that present embalming practices reduce the hazard from transmission of potentially infectious microbial agents within the immediate environment of embalmed human remains.


National estimates of environmental thresholds for upland soil phosphorus in China based on a meta-analysis.
The environmental threshold for upland soil phosphorus (P) content (ETSP, i.e., inflection point of soil P content leading to enhanced P loss) provides an important metric for guiding agricultural nonpoint source P pollution control. This study achieved the first meta-analysis to determine ETSP values for upland soils in China. The estimated national-level ETSP based on 472 field experimental observations of Olsen-P content and P loss rate was 30.1 ± 4.0 mg P kg-1, which was lower than the average ETSP value (52.1 ± 5.0 mg P kg-1) but higher than the average agronomic threshold values (16.0 ± 6.4 mg P kg-1) previously reported. Lower upland ETSP values occurred in acidic soils and soils having higher organic matter content (SOM), precipitation and slope (ETSP: 30.5 for pH < 7.0 versus 46.1 for pH ≥ 7.0; >56.4 for SOM < 2%, 49.9 for SOM = 2%-3%, and <3 for SOM > 3%; 33 for precipitation < 1000 mm yr-1, 27.5 for precipitation = 1000-1200 mm yr-1 and <5 for precipitation > 1200 mm yr-1; and 39.8 for slopes < 5° versus <9 for slopes ≥ 5°). A multiple regression model that incorporates SOM, pH, precipitation and slope was developed to predict upland ETSP values (R2 = 0.73, p < 0.01). The model estimated national upland ETSP values ranging from ~0 to 100 mg P kg-1 with an areal-weighted average of 60.6 mg P kg-1 and 15% of national upland soils having ETSP values <30 mg P kg-1. Upland soil P contents in Guangdong, Fujian and Zhejiang provinces largely exceeded their corresponding ETSP values by 1-22 mg P kg-1, indicating high P loss risks. Controlling upland P loss requires integrated management of soil P content, SOM, pH and erosion control. This study provides the first national estimate of upland soil ETSP, providing critical quantitative information for designing management practices to attenuate agricultural nonpoint source P pollution.


Does parental permissiveness toward cigarette smoking and alcohol use influence illicit drug use among adolescents? A longitudinal study in seven European countries.
Adolescents' perceptions of parental norms may influence their substance use. The relationship between parental norms toward cigarette and alcohol use, and the use of illicit substances among their adolescent children is not sufficiently investigated. The purpose of this study was to analyze this relationship, including gender differences, using longitudinal data from a large population-based study. The present study analyzed longitudinal data from 3171 12- to 14-year-old students in 7 European countries allocated to the control arm of the European Drug Addiction Prevention trial. The impact of parental permissiveness toward cigarettes and alcohol use reported by the students at baseline on illicit drug use at 6-month follow-up was analyzed through multilevel logistic regression models, stratified by gender. Whether adolescents' own use of cigarette and alcohol mediated the association between parental norms and illicit drug use was tested through mediation models. Parental permissive norms toward cigarette smoking and alcohol use at baseline predicted adolescents' illicit drug use at follow-up. The association was stronger among boys than among girls and was mediated by adolescents' own cigarette and alcohol use. Perceived parental permissiveness toward the use of legal drugs predicted adolescents' use of illicit drugs, especially among boys. Parents should be made aware of the importance of norm setting, and supported in conveying clear messages of disapproval of all substances.


Mass Spectrometry and Microbial Diagnostics in the Clinical Laboratory.
Over the past decade, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry has revolutionized the practice of clinical microbiology and infectious disease diagnostics. Rapid advancement has occurred through the development and implementation of mass spectrometric protein profiling technologies that are widely available. Ease of sample preparation, rapid turnaround times, and high throughput accuracy have accelerated acceptance within the clinical laboratory. New mass spectrometric technologies centered on multiple microbial diagnostic markers are in development. Such new applications, reviewed in this article and on the near horizon, stand to greatly enhance the capabilities and utility for improved mass spectrometric microbial identification and patient care.


Pharmacotherapy for pulmonary hypertension.
Pulmonary arterial hypertension is a serious disease with significant morbidity and mortality. Although it can occur idiopathically, it is more commonly associated with other cardiac or lung diseases. While most of the available therapies have been tested in adult populations and most therapies in children remain off-label, new reports and randomized trials are emerging that inform the treatment of pediatric populations. This review discusses currently available therapies for pediatric pulmonary hypertension, their biological rationales, and evidence for their clinical effectiveness.


Dear White People in Emergency Medicine.
We, emergency physicians of color, are not okay. We are living and working through a pandemic that has disproportionately affected our communities and a year in which we cannot escape our lived experiences of police brutality. We see you, dear White people in emergency medicine, and are glad you want to support us. However, let us guide you in supporting our cause.


Reversible, activity-dependent targeting of profilin to neuronal nuclei.
The actin cytoskeleton in pyramidal neurons plays a major role in activity-dependent processes underlying neuronal plasticity. The small actin-binding protein profilin shows NMDA receptor-dependent accumulation in dendritic spines, which is correlated with suppression of actin dynamics and long-term stabilization of synaptic morphology. Here we show that following NMDA receptor activation profilin also accumulates in the nucleus of hippocampal neurons via a process involving rearrangement of the actin cytoskeleton. This simultaneous targeting to dendritic spines and the cell nucleus suggests a novel mechanism of neuronal plasticity in which profilin both tags activated synapses and influences nuclear events.


Monodisperse microspheres with poly(N-isopropylacrylamide) core and poly(2-hydroxyethyl methacrylate) shell.
Monodisperse core-shell microspheres, composed of poly(N-isopropylacrylamide) (PNIPAM) core with thermo-responsive swelling/shrinking function and biocompatible poly(2-hydroxyethyl methacrylate) (PHEMA) shell with "open/close" switching function, have been successfully prepared by microfluidic emulsification, free-radical polymerization and atom transfer radical polymerization (ATRP). The effects of grafting time for the ATRP and polyvinyl alcohol (PVA) concentration inside the core on the thermo-responsive behavior of core-shell microspheres are investigated. For the core-shell microspheres prepared with PVA concentration of 2% (w/v) and grafting time of 2 h, the PNIPAM core is in the shrunken state and the solid PHEMA shell protect the whole PNIPAM core at temperatures above the volume phase transition temperature (VPTT); as environmental temperature decreases below the VPTT, the PNIPAM core swells dramatically and the PHEMA shell ruptures a large area. The thermo-responsive function of the core-shell microspheres is reversible and the appearance/recovery of PHEMA shell crack exhibits an "open/close" switching function. Such core-shell microspheres are highly attractive for developing drug delivery systems with both biocompatible and thermo-responsive characteristics.


VEGF and IL-18 in induced sputum of lung cancer patients.
Cytokines are key players in the biological processes of malignant tumors and special interest has been focused on cytokines exerting tumor and anti-tumor properties, such as vascular endothelial growth factor (VEGF) and Interleukin-18 (IL-18). Aim of this study was to assess IL-18 and VEGF levels in induced sputum of lung cancer patients at diagnosis, and assess their possible association with the histological type of cancer, the stage and the overall patient survival. Seventy six patients with a diagnosis of lung cancer were recruited and were followed up for 48months. Thirteen healthy smokers and 16 healthy non-smokers were used as control groups. VEGF and IL-18 were measured by ELISA in sputum supernatants at the time of diagnosis. Lung cancer patients had significantly higher baseline IL-18 and VEGF levels compared to healthy controls (p<0.001). No difference was found in IL-18 and VEGF levels between the various stages in non-small cell lung cancer (NSCLC) and between limited and extended small cell lung cancer (SCLC). However, the ratio of VEGF/IL-18 was significantly higher in NSCLC compared to SCLC patients (p=0.018). In extended SCLC overall survival was inversely associated with baseline sputum VEGF levels (p=0.034) and estimated mortality risk was 1.14 (95% CI 1.006-1.283) for an increase of 100pg/ml in VEGF levels. Such association was not found regarding baseline IL-18 levels. VEGF levels in induced sputum may have a prognostic role in the survival of SCLC. The ratio VEGF/IL-18 in induced sputum differs between NSCLC and SCLC, indicating differences in angiogenesis mechanisms and/or immunological response in these two major histological types of lung cancer.


Resonance Raman spectral isolation of the a and a3 chromophores in cytochrome oxidase.
Resonance Raman spectra of reduced CO-bound cytochrome oxidase obtained at two different excitation frequencies (441.6 and 413.1 nm) are compared with the spectra of the fully reduced enzyme. In the spectra of the CO-bound complex only the cytochrome a modes are strongly enhanced with 441.6 nm excitation and only the modes of the CO-bound cytochrome a3 heme are strongly enhanced with 413.1-nm excitation. In the fully reduced complex with both excitation frequencies, modes of both cytochrome a and a3 are enhanced. By subtraction we are able to uncover the complete spectrum of the fully reduced ligand-free cytochrome a3 heme. Thus, we report the discrete resonance Raman spectra of cytochromes a2+, a2+3, and a2+3 (CO). The spectra of fully reduced cytochrome a and ligand-free cytochrome a3 are very different especially in the low frequency region. Binding CO to ferrous cytochrome a3 results in electronic structure changes in the heme analogous to those in hemoglobin and myoglobin, from which we conclude that there is nothing electronically unique in the ferrous cytochrome a3 heme to account for its catalytic properties.


Comparison of gefitinib, erlotinib and afatinib in non-small cell lung cancer: A meta-analysis.
Gefitinib, erlotinib and afatinib are three widely used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for treating advanced non-small cell lung cancer (NSCLC) with proven efficacy. We undertook a systematic review and meta-analysis to synthesize existing studies with direct comparisons of EGFR TKIs in NSCLC in terms of both efficacy and safety. Eight randomized trials and 82 cohort studies with a total of 17,621 patients were included for analysis. Gefitinib and erlotinib demonstrated comparable effects on progression-free survival (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.95 to 1.04), overall survival (HR, 0.99; 95% CI, 0.93 to 1.06), overall response rate (risk ratio [RR], 1.05; 95% CI, 1.00 to 1.11), and disease control rate (RR, 0.98; 95% CI, 0.96 to 1.01), which did not vary considerably with EGFR mutation status, ethnicity, line of treatment, and baseline brain metastasis status. Gefitinib was associated with more grade 3/4 liver dysfunction, but tended to cause lower rates of dose reduction, treatment discontinuation, total grade 3/4 adverse events (RR, 0.78; 95% CI 0.65 to 0.94), and a number of specific adverse events such as rash and diarrhea. No solid evidence was found that afatinib had greater efficacy than gefitinib or erlotinib in first-line treatment of EGFR-mutant NSCLC. However, afatinib was more effective than erlotinib as second-line treatment of patients with advanced squamous cell carcinoma. The grade 3/4 adverse events rate of afatinib was comparable to that of erlotinib but higher than that of gefitinib.


Preoperative Magnetic Resonance Imaging Abnormalities Predictive of Lumbar Herniation Recurrence After Surgical Repair.
There are currently no standard criteria for evaluating the risk of recurrent disk herniation after surgical repair. This study investigated the predictive values of 5 presurgical imaging parameters: paraspinal muscle quality, annular tear size, Modic changes, modified Phirrmann disk degeneration grade, and presence of sacralization or fusion. Between 2015 and 2018, 188 patients (89 female, 99 male, median age 50) receiving first corrective surgery for lumbar disk herniation were enrolled. Microdiskectomy was performed in 161 of these patients, and endoscopic translaminar diskectomy approach was performed in 27 patients. Clinical status was evaluated before surgery and 4, 12, and 24 months post surgery using a visual analog scale, Oswestry Disability Index, and Short Form 36. Recurrent disk herniation was observed in 21 of 188 patients. Seventeen of the recurrent disk herniations were seen in those who underwent microdiskectomy and 4 in those who underwent endoscopic translaminar diskectomy. There were significant differences in visual analog scale, Oswestry Disability Index, and Short Form 36 scores at 4, 12, and 24 months between patients with recurrence and the 167 no-recurrence patients. The median annular tear length was significantly greater in patients with recurrence than without recurrence. In addition, there were significant differences in recurrence rate according to Modic change type distribution, sacralization or fusion presence, Pfirmann disk; degeneration grade distribution, dichotomized annular tear size, dichotomized Modic change; and type and simplified 3-tier muscle degeneration classification distribution. Patients with poor clinical scores and recurrence exhibited additional radiologic abnormalities before surgery, such as poor paraspinal muscle quality, longer annular tears, higher Modic change type, higher modified Phirrmann disk degeneration grade, and sacralization or fusion. This risk evaluation protocol may prove valuable for patient selection, surgical planning, and choice of postoperative recovery regimen.


Upper and lower adjacent segment range of motion after fixation of different lumbar spine segments in the goat: an in vitro experiment.
The purpose of this study was to examine the biomechanical effects of fixation on range of motion (ROM) in the upper and lower adjacent segments of different lumbar spine segments in a goat spine model. Fifteen goat spine specimens (vertebrae T12-S1) were randomly divided into three groups: A (single-segment fixation), B (double-segment fixation), and C (triple-segment fixation). Motion in different directions was tested using a spinal motion simulation test system with five external loading forces. Transverse, forward-backward, and vertical displacement of the upper and lower adjacent segments were measured. As the external load increased, the upper and lower adjacent segment ROM increased. A significantly greater ROM in group C compared with group A was found when the applied external force was greater than 75 N. The upper adjacent segment showed a significantly greater ROM than the lower adjacent segment ROM within each group. Adjacent segment ROM increased with an increasing number of fixed lumbar segments. The upper adjacent segment ROM was greater than that of the lower adjacent segments. Adjacent segment stability after lumbar internal fixation worsened with an increasing number of fixed segments.


Rapid, free-breathing non-contrast MRI for first-line imaging evaluation of ovarian torsion in the emergency department.
Transabdominal ultrasound (US) is first-line imaging to evaluate ovaries in girls presenting to the emergency department (ED) with suspected ovarian torsion. Ovaries may be difficult to visualize sonographically; therefore, prompt diagnosis using US alone can be challenging. Rapid MRI as first-line imaging may help streamline patient throughput, especially with increasing MRI availability in the ED. To assess feasibility of rapid MRI for diagnosis of ovarian torsion. A retrospective, single-center IRB approved study of MRI performed in female pediatric patients presenting with abdominopelvic pain from August 2022 to January 2023. Imaging occurred according to one of three clinical pathways (US-first approach vs MRI-first approach vs US + MRI-second-line approach). A rapid three-sequence free-breathing MRI protocol was utilized. Frequency of ovarian torsion and secondary diagnoses was recorded. Length of MR scan time, time from ED arrival to time of diagnosis, and whether patient had US prior to MR exam were obtained. A historical cohort of patients with US only performed for assessment of ovarian torsion were evaluated for length of the US examination and time from ED arrival to time of diagnosis. Intervals were compared using the uncorrected Fisher's least significant difference and Turkey's multiple comparison tests. A total of 140 MRI exams (mean age 14.6 years) and 248 historical US exams (mean age 13.5 years) were included. Of the patients with MRI, 41 (29%) patients were imaged with US + MRI and 99 (71%) imaged with MRI only; 4% (6/140) MR exams were suspicious for ovarian torsion, with one true positive case (1/6 TP) and 5 false positive cases (5/6 FP); 26.4% (37/140) of exams had secondary diagnoses. Median MRI scan time was 11.4 min (4.4) vs median historical US scan time was 24.1 min (19.7) (P<0.001). Median time from arrival in ED to MRI read was 242 (140). Median time from arrival in ED to US only read was 268 min (148). This was not a statistically significant difference when compared to the MRI only cohort. First-line MRI imaging for evaluation of ovarian torsion is a rapid and feasible imaging modality for female patients in the emergent setting.


Members of the C/EBP transcription factor family stimulate expression of the human and rat surfactant protein A (SP-A) genes.
Members of the CCAAT enhancer binding protein (C/EBP) transcription factor family were detected in fetal lung of both human and rat. In rat lung, the level of C/EBPs increased with time of gestation, peaking around birth. In adult rat lung, C/EBPs were localized to the alveolar type II cells. The effect of C/EBPs on pulmonary surfactant protein A (SP-A), which is also expressed late in gestation, was investigated. In contrast to control plasmids, C/EBP delta expressing plasmids reversed the action of a transcriptional silencer just upstream of the rat SP-A promoter. In order to test the effect of C/EBPs on endogenous SP-A gene expression, cells that express SP-A were exposed to a phosphorothioate-substituted, double-stranded oligonucleotide matching the consensus C/EBP binding site (decoy oligonucleotide) at concentrations from 0.5 to 10 microM for 72 h. A mutant oligonucleotide with an 8-base pair (bp) substitution served as a control. The decoy oligonucleotide reduced SP-A mRNA as much as 75% compared to a mutant oligonucleotide both in the human lung cell line, NCI-H441, and in primary human fetal alveolar type II cells. The data indicate that C/EBPs facilitate SP-A gene expression, possibly by overcoming transcriptional silencing.


Mendelian randomization study of telomere length and lung cancer risk in East Asian population.
Associations between telomere length and cancer risk have been investigated in many epidemiological studies, but the results are controversial. These associations may be biased by reverse causation or confounded by environmental exposures. To avoid potential biases, we used Mendelian randomization method to evaluate whether TL is the causal risk factor for lung cancer. We conducted Mendelian randomization analysis in two published East Asian GWAS studies (7127 cases and 6818 controls). We used both weighted genetic risk score and inverse-variance weighting method to estimate the relationship between TL and lung cancer risk. Nonlinear test also used to detect potential association trends. We observed that increased weight GRS was associated with increased risk of lung cancer (OR = 2.25, 95%CI: 1.81-2.78, P = 1.18 × 10-13 ). In different subtypes, weight GRS was significantly associated with lung adenocarcinoma risk (OR = 2.69, 95% CI: 2.11-3.42, P = 7.20 × 10-16 ); while lung squamous cell carcinoma showed a marginal association (OR = 1.45, 95% CI = 1.01-2.10, P = .047). Nonlinear analysis suggested a log-linear dose-response relationship between increased weight GRS and lung cancer risk. Our results indicated that longer TL increases lung cancer risk. Those biological mechanisms changes caused by long TL may play an important role in lung carcinogenesis.


Lymphocele in Kidney Transplantation: A Comparison of Ligation and Non-ligation Technique of Iliac Lymphatic Dissection.
To compare the incidence of lymphocele in kidney recipients following 2 lymphatic vessel division techniques: ligation and non-ligation. Retrospective reviews of the records of 402 patients with end-stage renal disease who underwent kidney transplantation from April 2015 to December 2019 at Siriraj Hospital. Four hundred two patients were included in the study: 54.9% of the patients were male, and the patient's mean age was 41 years. There were 25.1% and 74.9% that received kidney grafts from living and deceased donors, respectively. The preoperative renal replacement therapies were 83.3% hemodialysis, 12.9% peritoneal dialysis, and 3.7% preemptive transplantation. Two hundred forty-nine patients received lymphatic division with the ligation technique and 153 patients received the non-ligation. Lymphoceles were found in 31 cases (7.7%). Lymphocele occurrence in the ligation group was lower than in the non-ligation group: 5.2% compared to 11.8% (P value = .017). There were 22.6% of lymphoceles that had a spontaneous resolution with no treatment. The ligation of iliac lymphatic vessels during division reduced the incidence of lymphoceles non-ligation.


ATRA promotes alpha tocopherol succinate-induced apoptosis in freshly isolated leukemic cells from chronic myeloid leukemic patients.
We investigated the in vitro efficacy of all-trans retinoic acid (ATRA) and alpha-tocopherol succinate (alpha-TS) alone and in combination on the induction of cell death in freshly isolated leukemic cells obtained from chronic myeloid leukemia (CML) patients. In vitro cytotoxicity and induction of lipid peroxidation by ATRA (10 microM) and alpha-TS (25 or 50 microM) were evaluated in primary leukemic cells by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and malondialdehyde formation respectively. Treatment of leukemic cells with alpha-TS alone or in combination with ATRA significantly (P < 0.05) decreased the cell viability in a concentration and time dependent manner as compared to peripheral blood mononuclear cells obtained from normal healthy controls. Lipid peroxidation was enhanced by 98% (P < 0.05) on combined treatment of cells with ATRA (10 microM) and alpha-TS (50 microM). ATRA alone did not enhance the externalization of phosphatidyl serine as studied by annexin-V binding using fluorescence activated cell sorter analysis, whereas in combination with alpha-TS it increased to 400% at 12 h. The treatment of leukemic cells to combination of ATRA with alpha-TS significantly decreased (P < 0.05) mitochondrial membrane potential and enhanced lysosomal destabilization. The combination of these drugs also increased mitochondrial and cytosolic reactive oxygen species (ROS) production, nitric oxide levels, and caspase-3 activity significantly and caused DNA fragmentation at 24 h in a concentration dependent manner in the leukemic cells. Our data suggest that ATRA in combination with alpha-TS efficiently induces apoptosis in leukemic cells, which may be a useful therapeutic modality in CML patients.


Two homologues of inhibitor of NF-kappa B (IκB) are involved in the immune defense of the Pacific oyster, Crassostrea gigas.
A novel homologue of IκB was cloned from a hemocyte cDNA of Crassostrea gigas (designed as CgIκB2). The complete cDNA of CgIκB2 includes an open reading frame (ORF) of 1032 bp, and 3' and 5'untranslated regions (UTR's) of 141 bp and 279 bp, respectively. The ORF encodes a putative protein of 343 amino acids with a calculated molecular weight of approximately 37.8 kDa. Alignment analysis reveals that CgIκB2 contains a conserved degradation motif and six ankyrin repeats. A phylogenetic analysis suggests that a gene duplication event prior to the gastropod-bivalve divergence resulted in the emergence of two IκB homologues in C. gigas. Distinct maximal expression patterns of CgIκB1 in hemocytes and CgIκB2 in the gonad were observed. CgIκB1 and CgIκB2 expression in response to bacterial challenge is similar and inducible. Moreover, both CgIκB1 and CgIκB2 are able to inhibit NF-κb/Rel activating transcription in S2 or HEK293 cells. Our findings demonstrate that both CgIκB1 and CgIκB2 are involved in immune defense in C. gigas through regulation of NF-κB/Rel activity.


Regulatory role of insulin in the degradation of low density lipoprotein by cultured human skin fibroblasts.
The degradation of 125I-labeled low density lipoprotein by cultured human skin fibroblasts was enhanced 25% by preincubation of cells with insulin. This effect of insulin appeared to be mediated via stimulation of low density lipoprotein binding to its cell surface receptor, since binding and subsequent internalization of low density lipoprotein were stimulated to a similar extent as was degradation. In addition, insulin enhanced binding of low density lipoprotein at 4 degrees C, at which temperature internalization of the lipoprotein does not occur. A similar effect of insulin on the interaction of very low density lipoprotein with cultured fibroblasts was observed. Insulin-induced changes in the degradation of low density lipoprotein and very low density lipoprotein appeared to be a function of the change in lipoprotein binding. Thus, insulin may play a role in the regulation of low density lipoprotein and very low density lipoprotein degradation by peripheral cells by influencing the receptor-mediated transport of these lipoproteins.


Increase of mitosis in the tubular epithelium following intrarenal doses of various kidney homogenates and hemogenate fractions in the rat.
Earlier investigations about the consequences of experimental kidney ischemia raised the question, if there exists a substance in the renal tissue which is liberated by cell death or during regeneration of cells and which might stimulate mitosis of other cells. Therefore in recent experiments we directly injected into the left kidney parenchyma of receiver animals, homogenates, or their separated fractions from infarcted or regenerated kidneys of adult donors and from kidneys of juvenile donors. These are the results" 1. A small dose of kidney homogenate already produces a clear increase of mitoses in the tubular epithelium of the renal cortex 17-19 h after injection in the adult recipient of the same breed. The increase of proliferation is of short-duration, kidney-specific, and not to reproduce in different controls. 2. The mitogenetic effect of a unilateral intrarenal dose of kidney homogenate does not favor a special area. Without a recognizable principle of cellular selection it occurs everywhere in the kidney parenchyma. It must be understood as a "simple increase" of normal growth. The proliferation stimulus is humorally transmitted to the untouched contralateral kidney. Yet the mitotic acitivty is significantly higher in the left than in the right kidney. 3. The experiments demonstrate a much better efficiency of the sediment, especially of the mitochondrial and microsomal fraction, than of the supernatant. 4. Our results indicate that in the complicated regulation system of cell growth there must be taken into account different factors and signalizing ways for induction and termination of mitosis.


New Prenylated ortho-Dihydroxycoumarins from the Fruits of Ficus nipponica.
Two new prenylated ortho-dihydroxycoumarins, designated fipsomin (1) and fipsotwin (2), were isolated from the fruits of Ficus nipponica together with a known prenylated coumarin, apigravin (3). Their structures were established by spectroscopic data and X-ray crystallographic analysis. Compound 1 exhibited antibacterial activity against Bacillus subtilis with an MIC value of 61 μm, while 2 and 3 showed very weak activity.


MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging.
Aging is a prominent risk factor for neurodegenerative disease. Defining gene expression mechanisms affecting healthy brain aging should lead to insight into genes that modulate susceptibility to disease. To define such mechanisms, we have pursued analysis of miR-34 mutants in Drosophila. The miR-34 mutant brain displays a gene expression profile of accelerated aging, and miR-34 upregulation is a potent suppressor of polyglutamine-induced neurodegeneration. We demonstrate that Pcl and Su(z)12, two components of polycomb repressive complex 2, (PRC2), are targets of miR-34, with implications for age-associated processes. Because PRC2 confers the repressive H3K27me3 mark, we hypothesize that miR-34 modulates PRC2 activity to relieve silencing of genes promoting healthful aging. Gene expression profiling of the brains of hypomorphic mutants in Enhancer of zeste (E(z)), the enzymatic methyltransferase component of PRC2, revealed a younger brain transcriptome profile and identified the small heat shock proteins as key genes reduced in expression with age.


Differences in VA and Non-VA Pulmonary Nodules: All Evaluations Are not Created Equal.
Indeterminate pulmonary nodules present a common challenge for clinicians who must recommend surveillance or intervention based on an assessed risk of malignancy. In this cohort study, patients presenting for indeterminate pulmonary nodule evaluation were enrolled at sites participating in the Colorado SPORE in Lung Cancer. They were followed prospectively and included for analysis if they had a definitive malignant diagnosis, benign diagnosis, or radiographic resolution or stability of their nodule for > 2 years. Patients evaluated at the Veterans Affairs (VA) and non-VA sites were equally as likely to have a malignant diagnosis (48%). The VA cohort represented a higher-risk group than the non-VA cohort regarding smoking history and chronic obstructive pulmonary disease (COPD). There were more squamous cell carcinoma diagnoses among VA malignant nodules (25% vs. 10%) and a later stage at diagnosis among VA patients. Discrimination and calibration of risk calculators produced estimates that were wide-ranging and different when comparing between risk score calculators as well as between VA/non-VA cohorts. Application of current American College of Chest Physicians guidelines to our groups could have resulted in inappropriate resection of 12% of benign nodules. Comparison of VA with non-VA patients shows important differences in underlying risk, histology of malignant nodules, and stage at diagnosis. This study highlights the challenge in applying risk calculators to a clinical setting, as the model discrimination and calibration were variable between calculators and between our higher-risk VA and lower-risk non-VA groups. Risk stratification and management of indeterminate pulmonary nodules (IPNs) is a common clinical problem. In this prospective cohort study of 282 patients with IPNs from Veterans Affairs (VA) and non-VA sites, we found differences in patient and nodule characteristics, histology and diagnostic stage, and risk calculator performance. Our findings highlight challenges and shortcomings of current IPN management guidelines and tools.


Radiation dose to the low axilla in patients treated for early-stage breast cancer by locoregional intensity-modulated radiotherapy (IMRT).
To determine the dose received by the low axilla during locoregional radiotherapy (RT) for early-stage breast cancer and to assess the impact of the treatment technique (three-dimensional conformal radiotherapy (3D-CRT) or rotational IMRT (VMAT) or helical tomotherapy (HT). The dosimetric study was performed on patients receiving normofractionated (NFRT - 50Gy in 25 fractions) or hypofractionated (HFRT - 40Gy in 15 fractions) locoregional radiotherapy (breast or chest wall and internal mammary, supraclavicular and infraclavicular nodes±axillary nodes) by 3D-CRT or VMAT or HT at the Institut Curie Paris. Patients treated by breast-conserving surgery received a boost dose of 16Gy and 10Gy to the tumour bed, respectively. Sixty-eight patients treated by RT from February 2017 to January 2019 were studied. The mean dose received by the low axilla when it was not part of the target volume was 30.8Gy, 41.0Gy and 44.4Gy by 3D-CRT, VMAT and HT, respectively for NFRT and 24.2Gy, 33.0Gy and 34.9Gy, respectively, for HFRT. With NFRT, 4.1% of the axilla received 95% (V95) of the prescribed dose by 3D-CRT compared to 24.5% and 33.6% by VMAT and HT, respectively; with HFRT, V95 was 3.9%, 19.5% and 24.1%, respectively. The axilla receives a non-negligible dose during locoregional radiotherapy; this dose is greater when VMAT or HT are used. Prospective studies must be conducted to assess the impact of this axillary dose in terms of morbidity, which currently remains unknown.


Thermodynamic first order transition and inverse freezing in a 3D spin glass.
We present a numerical study of the random Blume-Capel model in three dimensions. The phase diagram is characterized by spin-glass-paramagnet phase transitions of both first and second order in the thermodynamic sense. Numerical simulations are performed using the exchange Monte Carlo algorithm, providing clear evidence for inverse freezing. The main features at criticality and in the phase coexistence region are investigated. We are not privy to other 3D short-range systems with quenched disorder undergoing inverse freezing.


Plasmodium falciparum PFI1625c offers an opportunity to design potent anti-malarials: Biochemical characterization and testing potentials in drug discovery.
Putative PFI1625c was cloned, over-expressed and purified to homogeneity. It is a 56.2 kDa monomeric protease which preferentially catalyzes the degradation of gelatin with a Km = 30μM. It is a slow acting enzyme with optimal pH 8.5 and temperature 37 °C, and activity is sensitive to metalloprotease inhibitor 1,10-phenanthroline. PFI1625c active site was probed with a series of heterocyclic compounds and three molecules namely, BNPC-Inh2, DDBM-Inh1 and BHPM-Inh1 from the series were inhibiting PFI1625c protease activity. These heterocyclic compounds were found to irreversible inhibiting PFI1625c protease activity. Parasite culture was treated with these inhibitors and PFI1625c isolated from culture was found to be inactive without affecting other gelatinases present in the parasite. These inhibitors were used to generate chemically knockout PFI1625c in the parasite. PFI1625c knockout parasite remained at ring stage and was unable to complete its erythrocytic schizogony. Also, these knockout parasites were incapable to multiply. More careful analysis indicate these parasites develop oxidative stress as evident by the increase in lipid peroxidation, protein-carbonyl and a decrease of GSH level. In summary, the current study has employed biochemical, computational and pharmacological approaches to explore the role of PFI1625c in the parasite, its utility as a potential drug target to develop anti-malarials.


Clinicopathologic features of pregnancy luteoma.
This study aimed to explore the clinicopathological characteristics, immunophenotype, histological occurrence, diagnosis, and differential diagnosis of ovarian luteoma tumor of pregnancy. The clinical features, histomorphology, immunohistochemistry, and reticular fiber staining results of 18 cases of luteoma tumors of pregnancy were analyzed, and related published studies were reviewed. The 18 cases of luteoma tumors were all women who had undergone multiple pregnancies. The tumors were 1.3-15 cm in size and brownish yellow or reddish brown in color, with a soft texture. Microscopic examination revealed the eosinophilic cytoplasm of tumor cells and diffuse hyperplasia. The results of the immunohistochemical analysis were as follows: α-inhibin, AE1/AE3, CD99, and vimentin were positive, while epithelial membrane antigen, S-100, HMB45, and MelanA were negative. One case was positive for MelanA. The staining results of reticular fibers showed that the argyrophilic reticular fibers were black surrounding the tumor cell nests. Luteoma tumor of pregnancy is a rare tumor-like lesion mostly appearing in late pregnancy. The gross, immunohistochemical staining, and reticular fiber staining results may help diagnose this disease. The disease needs to be differentiated from other diseases.


Endometrial carcinoma stage I--comparison of two different treatment regimes--evaluation of risk factors and its influence on prognosis; suggested step by step treatment protocol.
Two hundred twenty-four patients with stage I endometrial carcinoma were treated between the years 1964 and 1978. One hundred and fifteen patients were classified as clinical stage Ia (51.3%) and 109 patients as clinical state Ib (48.7%). For stage Ia the standard treatment protocol was total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH + BSO). In stage Ib disease, preoperative irradiation was performed followed by TAH + BSO after an interval of 4 to 6 weeks. Postoperative irradiation to the pelvis and vaginal vault was given when extrauterine spread was found and in cases of myometrial penetration beyond the inner one-third of the myometrium. At evaluation in May 1983, the rate of disease recurrence in stage Ia was 20% and in stage Ib 9.1%. Five-year survival in stage Ia was 77.3% and 72.4% in stage Ib. Preoperative irradiation was found justified for G3 disregarding the clinical stage, therefore the approach of routine preoperative irradiation in stage Ib is not recommended. The uterine cavity depth was found to be an inaccurate prognostic parameter. According to the data collected in our material the histological grade and myometrial invasion are much better prognostic parameter and should be taken into consideration while planning the treatment regime.


A Dendritic Substrate for the Cholinergic Control of Neocortical Output Neurons.
The ascending cholinergic system dynamically regulates sensory perception and cognitive function, but it remains unclear how this modulation is executed in neocortical circuits. Here, we demonstrate that the cholinergic system controls the integrative operations of neocortical principal neurons by modulating dendritic excitability. Direct dendritic recordings revealed that the optogenetic-evoked release of acetylcholine (ACh) transformed the pattern of dendritic integration in layer 5B pyramidal neurons, leading to the generation of dendritic plateau potentials which powerfully drove repetitive action potential output. In contrast, the synaptic release of ACh did not positively modulate axo-somatic excitability. Mechanistically, the transformation of dendritic integration was mediated by the muscarinic ACh receptor-dependent enhancement of dendritic R-type calcium channel activity, a compartment-dependent modulation which decisively controlled the associative computations executed by layer 5B pyramidal neurons. Our findings therefore reveal a biophysical mechanism by which the cholinergic system controls dendritic computations causally linked to perceptual detection.


Changes in the tonotopic map of the dorsal cochlear nucleus in hamsters with hair cell loss and radial nerve bundle degeneration.
Hamsters were exposed to an intense tone (10 kHz) at levels and durations sufficient to cause hair cell loss and radial nerve bundle degeneration. A previous study reported changes in the tonotopic map of the dorsal cochlear nucleus (DCN) in hamsters with tone-induced stereocilia loss. Such changes appear similar to those observed by others in the auditory nerve following acoustic trauma, and suggest that the map alterations have a peripheral origin. However, the potential for tonotopic map reorganization after more severe lesions involving cellular degeneration in the cochlea has not yet been determined. The purpose of the present study was to determine how the tonotopic map of the DCN appears in animals with severe cochlear injury involving hair cell loss and radial nerve bundle degeneration. Neural population thresholds and tonotopic organization were mapped over the surface of the DCN in normal unexposed animals and those showing tone-induced lesions. The results indicate that cochlear lesions characterized mainly by radial bundle degeneration in a restricted portion of the organ of Corti cause changes in a corresponding region of the tonotopic map which reflect primarily changes in the shape and thresholds of neural tuning curves. In many cases the center of the lesion was represented in the DCN as a distinct characteristic frequency (CF) gap in the tonotopic map in which responses were either extremely weak or absent. In almost all cases the map area representing the center of the lesion was bordered by an expanded region of near-constant CF, a feature superficially suggestive of map reorganization (i.e., plasticity). However, these expanded map areas had abnormal tip thresholds and showed other features suggesting that their CFs had been shifted downward by distortion and deterioration of their original tips. Such changes in neural tuning following tone-induced loss of anatomical input to the central auditory pathway are similar to those observed in our previous study and by others in the auditory nerve following less severe acoustic trauma, and thus would seem to have a peripheral origin. Thus, changes in the DCN tonotopic map can be explained by peripheral modifications and do not seem to involve plastic changes (i.e., reorganization).


The prevalence and characterisation of Cryptosporidium spp. in beef abattoir water supplies.
The prevalence of Cryptosporidium spp. in 50 l samples of water used to wash beef carcasses at (a) an abattoir with a borehole water (BH) supply (n = 46) and (b) an abattoir with a river water (RW) supply (n = 48) was determined. In addition, a 100 l water sample and post-wash carcass samples (n = 24) were collected from the RW supply on a single day in July. Cryptosporidium spp. was detected in 0% and 26.1% of samples from the BH and RW supply abattoirs, respectively, with oocyst concentrations ranging from 0.02 to 8.6/l. Cryptosporidium spp. was not isolated from post-wash beef carcasses, while it was detected in water samples from that day at a concentration of 0.06 oocysts/l. The species of 3/5 isolates were identified as C. parvum, and the remaining were C. andersoni. This study has demonstrated that water used to wash beef carcasses can be contaminated with Cryptosporidium of human health importance and is a potential source of carcass contamination.


Severe neonatal hypercalcemia revealing congenital mesoblastic nephroma: A case report and management of neonatal hypercalcemia: Severe neonatal hypercalcemia revealing congenital mesoblastic nephroma.
Congenital mesoblastic nephroma is a rare pediatric renal tumor and has been reported in patients presenting with palpable abdominal mass, arterial hypertension, hematuria, polyuria, or hypercalcemia. Here we present the case of a 1-month-old neonate with suspected parathyroid hormone (PTH)-related peptide (PTH-rp)-mediated severe hypercalcemia revealing congenital mesoblastic nephroma. Preoperatively, hypercalcemia was corrected with hydration, furosemide, pamidronate, and low-calcium infant formula. Unilateral nephrectomy led to the resolution of hypercalcemia, transient hyperparathyroidism, and transient vitamin D and mineral supplementation. We conclude that congenital mesoblastic nephroma can secrete PTH-rp that can cause severe hypercalcemia.


ATP stimulates interleukin-6 production via P2Y receptors in human HaCaT keratinocytes.
We evaluated the role of ATP in functions of human HaCaT keratinocytes. ATP was released from HaCaT cells by changing the culture medium. Reverse transcription-polymerase chain reaction analysis revealed that HaCaT cells expressed multiple P2 purinergic receptor mRNAs. UTP was the most potent agonist to increase the intracellular Ca2+ concentration ([Ca2+]i). UTP and ATP caused the accumulation of [3H]inositol phosphates, suggesting that UTP binds to the Gq/11-coupled P2Y receptor. UTP increased IL-6 mRNA and protein levels, and the increases were inhibited by a P2 purinergic receptor antagonist (suramin, 300 microM). While a protein kinase C inhibitor (GF109203X, 10 microM) was without effect, an intracellular free Ca2+ chelator (BAPTA-AM, 50 microM) suppressed UTP-mediated IL-6 induction. These results suggest that 1) ATP is released from HaCaT cells upon physical stimulation and may act as an autocrine molecule, and 2) the stimulation of P2Y receptors causes IL-6 production via mRNA expression through [Ca2+]i elevation.


Pulsed field gradient electrophoresis of DNA digested in agarose allows the sizing of the large duplication unit of a surface antigen gene in trypanosomes.
Intact chromosome-sized DNA molecules from eukaryotes may be prepared by performing lysis and enzymic deproteinization on cells embedded in agarose [Schwartz and Cantor, Cell 37 (1984), 67-75]. Here we show that DNA prepared by this method may be cut with restriction enzymes, or modified with site-specific methylases and cut by DpnI. As the DNA remains incorporated in the gel matrix, shear degradation of large fragments is avoided. The fragments can then be sized by conventional or pulsed field gradient gel electrophoresis. Phage lambda genomic oligomers are used as size markers, allowing the estimation of fragment sizes up to about 1200 kb. We apply these techniques to show that activation of the telomeric gene encoding variant surface antigen 1.3 in Trypanosoma brucei strain 427, involves the duplication of a DNA segment that starts between 29 and 42 kb upstream of the gene and to assign a chromosomal fragment into which the duplicated 1.3 gene may have transposed.


The melanopsin-directed white noise electroretinogram (wnERG).
The white noise electroretinogram (wnERG) provides a measure of the impulse response function under conditions of retinal equilibrium; it is yet to be determined how the electrical response generated by melanopsin ganglion cell photoreception is expressed in the impulse response. To this end, we recorded the human wnERG to continuous temporal white noise (TWN) stimuli that were melanopsin-directed (rod and cone silent) or cone-directed (rod and melanopsin silent). The impulse response of the electroretinogram was derived by cross-correlating the TWN stimulus with the wnERG response. We observed that the LMS-cone directed wnERG contained the expected N1 wave (24.1 ± 2.4 ms; mean ± SEM) and P1 wave (49.7 ± 1.8 ms). Melanopsin-directed stimuli produced a unique wnERG with a slower negative deflection (Nm) at 62.9 ± 3.3 ms followed by a positive deflection (Pm) at 126.3 ± 5.1 ms. Additional experiments indicated this melanopsin-directed wnERG response was not due to cone intrusion. The Nm and NmPm amplitudes increased with illuminance (32,000-80,000 Td; no rod intrusion) and melanopsin contrast (10-36% Michelson contrast). As there are known pathways connecting melanopsin cells to the outer retina, we then measured the wnERG to combined melanopsin and cone-directed stimuli to quantify melanopsin interactions with cone signalling. With the combined stimuli, the N1P1 amplitudes were suppressed by ~59%, which may be a result of a destructive interference between the positive (P1) and negative (Nm) waves generated by the cone and melanopsin pathways. We conclude that the human wnERG to melanopsin-directed stimuli may reflect the combined response of intra-retinal melanopsin pathways, independent of rod and cone photoreception.


Exacerbation of psoriasis precipitated by an oestradiol-testosterone implant.
A 47-year-old woman developed widespread psoriasis following insertion of a combined oestradiol-testosterone implant into her anterior abdominal wall for post-oophorectomy symptoms. The rash did not resolve until the effects of the implant had worn off and recurred following insertion of a second oestradiol-testosterone implant. Implants containing oestradiol alone were tolerated. We have found no previous reports suggesting a relationship between testosterone implants and psoriasis.


The membrane-lytic peptides K8L9 and melittin enter cancer cells via receptor endocytosis following subcytotoxic exposure.
We investigate the cell entry mechanism of the membrane-lytic peptides K8L9 and melittin in cancer cell lines. K8L9 and melittin interacted with the highly expressed endocytic receptors neuropilin-1, low-density lipoprotein-related protein receptor 1 (LRP1), and transferrin receptor. Silencing of these receptors by small interfering RNAs (siRNAs) attenuated the cytotoxic activity of K8L9 in four cancer cell lines. Intracellular K8L9 and melittin triggered enlargement of the lysosomal compartments and cytosolic translocation of cathepsin B. Hsc70 was identified as a melittin-interactive molecule using coimmunoprecipitation and mass spectrometry, and Hsc70-siRNA attenuated the cellular uptake of K8L9 and cytotoxic activity by K8L9 and melittin. These findings suggest that K8L9 and melittin can enter cancer cells via receptor endocytosis following subcytotoxic treatment and subsequently affect lysosomal compartments.


Electrosurgery using insulated needles: epilation.
This paper deals mainly with histologic findings and clinical aspects of epilation using insulated needles. Patients were checked for hair regrowth after "thermolysis" epilation--a cycle of three to four treatments at roughly 3-month intervals, within an observation period of 2 1/2 years. The results for 39 patients, compiled 6 months to 1 year after the final epilations, showed almost no or extremely reduced hair regrowth with almost no scarring.


Andrographolide induces apoptosis in B16F-10 melanoma cells by inhibiting NF-κB-mediated bcl-2 activation and modulating p53-induced caspase-3 gene expression.
Cancer is a disorder characterized by uncontrolled proliferation and reduced apoptosis. Inducing apoptosis is an efficient method of treating cancers. In this study, we investigated the effect of andrographolide on the induction of apoptosis as well as its regulatory effect on the activation of transcription factors in B16F-10 melanoma cells. Treatment of B16F-10 cells with nontoxic concentration of andrographolide showed the presence of apoptotic bodies and induced DNA fragmentation in a dose-dependent manner. Cell cycle analysis and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays also confirmed the observation. The proapoptotic genes p53, Bax, caspase-9, and caspase-3 were found upregulated in andrographolide-treated cells, whereas the antiapoptotic gene bcl-2 was downregulated. This study also reveals that andrographolide treatment could alter the production and expression of proinflammatory cytokines and could inhibit the activation and nuclear translocation of p65, p50, and c-Rel subunits of nuclear factor-κB (NF-κB), and other transcription factors such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein in B16F-10 melanoma cells. These results suggest that andrographolide induces apoptosis via inhibiting NF-κB-induced bcl-2-mediated survival signaling and modulating p53-induced caspase-3-mediated proapoptotic signaling.


The role of CRF receptors in anxiety and depression: implications of the novel CRF1 agonist cortagine.
Corticotropin-releasing factor (CRF), a 41 amino acid peptide exhibits its actions through two pharmacologically distinct CRF receptor subtypes CRF(1) and CRF(2). Regulation of the relative contribution of the two CRF receptors to central CRF activity may be essential in coordinating physiological responses to stress. To facilitate the analysis of their differential involvement, we recently developed a CRF(1)-selective agonist cortagine by synthesis of chimeric peptides derived from human/rat CRF, ovine CRF, and sauvagine. Cortagine was analyzed in behavioral experiments using male wild type and CRF(2)-deficient C57BL/6J mice for its action on anxiety- and depression-like behaviors. In contrast to the current hypothesis that increased CRF(1) activity facilitates the expression of anxiety- and depression-like behavior, cortagine combines anxiogenic properties with antidepressant effects. In this article, we show that antidepressant effects are partially mediated by CRF(1) of the dorsal hippocampus. Possible pathways responsible for the paradoxical antidepressant effects observed after CRF(1) activation are discussed.


Relationship between polyvictimization and overweight among adolescents from São Paulo city, Brazil.
This study is to identify victimization patterns and analyze the association between the experience of polyvictimization and overweight or obesity among adolescent girls and boys. The sample consisted of 2680 Brazilian ninth-graders enrolled in public and private schools, taken from the São Paulo Project for the social development of children and adolescents (SP-PROSO). Victimization was explored in two ways: (i) as per Finkelhor and (ii) by latent class analysis (LCA). The interest outcomes were overweight and obesity. Multinomial logistic regression models were used to study the relationship between victimization and overweight or obesity, controlling for confounders. LCA grouped boys and girls adolescents into three classes. These classes received the same labels, but the patterns differed between sexes. Class 1 was characterized by fewer types of victimization suffered and lower endorsement values in the analyzed items and was named bullying and indirect victimization (♀: 42.7%, n = 546; ♂: 21.6%, n = 293). Class 2 included more victimization types than Class 1 and less than Class 3. This class was labeled family violence and peer victimization (♀: 29.1%, n = 356; ♂: 47.9%, n = 652). Class 3 was named high polyvictimization (♀: 28.2%, n = 345; ♂: 30.5%, n = 418). According to Finkelhor, polyvictimization was not associated with overweight or obesity in both sexes. Only the class of high polyvictimization was associated with being overweight (ORadj: 1.60, 95%CI: 1.01-2.54) in girls. In this study, polyvictimization was associated with being overweight only among adolescent girls. Longitudinal studies in different contexts and populations are needed to understand this relationship.


Tricuspid Annulus Disjunction: Novel Findings by Cardiac Magnetic Resonance in Patients With Mitral Annulus Disjunction.
This study aimed to assess whether patients with MAD also have disjunction of the tricuspid annulus. Mitral annulus disjunction (MAD) is an abnormal atrial displacement of the mitral annulus. Whether the disjunction extends to the right side of the heart is not known. In a cohort of patients with MAD, we assessed the presence of tricuspid annulus disjunction (TAD) with the use of cardiac magnetic resonance. We explored the associations between TAD and MAD characteristics and the relationship to ventricular arrhythmias (nonsustained/sustained ventricular tachycardias and aborted cardiac arrest). We included 84 patients (mean age: 48 ± 16 years; 63% female). We observed TAD in 42 (50%). Patients with TAD were older (age 52 ± 16 years vs. 43 ± 15 years; p = 0.02), had greater circumferential extent of MAD (164 ± 57° vs. 115 ± 58°; p = 0.002), greater maximum longitudinal MAD distance (9.4 ± 2.9 mm vs. 6.2 ± 2.8 mm; p < 0.001), and more frequent mitral valve prolapse (n = 39 [92%] vs. n = 24 [57%]; p < 0.001). Ventricular arrhythmias had occurred in 34 patients (41%), who were younger (age 39 ± 14 years vs. 54 ± 14 years; p < 0.001) and had lower prevalence of TAD (n = 22 [29%] vs. n = 12 [52%]; p = 0.03). TAD was not associated with ventricular arrhythmias when adjusted for age (odds ratio adjusted for age: 0.54; 95% confidence interval: 0.20 to 1.45; p = 0.22). We report for the first time the existence of right-sided annulus disjunction as a common finding in patients with MAD. TAD was associated with more severe left-sided annulus disjunction and mitral valve prolapse, but not with ventricular arrhythmias.


Developmental potencies of nuclei from cleavage, preblastoderm, and syncytial blastoderm transplanted into unfertilized eggs ofDrosophila melanogaster.
Wild-type nuclei from eggs ofDrosophila melanogaster at various developmental stages and from different regions of the egg-cleavage nuclei, pole nuclei from preblastoderm, and lateral nuclei from syncytial blastoderm-were singly implanted into unfertilizedy w sn 3 lz 50e eggs to determine their developmental potencies.All three types of transplanted nuclei were almost equally effective in initiating development of unfertilized eggs. Development was arrested in one of five critieal embryonic stages or in one of the three larval instars. The frequency of individuals reaching a distinct stage was approximately the same for all three types of donor nuclei. The stage-specific pattern of defects was independent of the type of nucleus transplanted.The deviations from normal development were broadly similar to those seen in controls developing from fertilized eggs which had only been punctured or into which cytoplasm had been injected. Many defective embryos also occurred in these control experiments. These and other observations indicate that a large proportion of irregularly developed individuals found after nuclear transfer can be ascribed to loss of egg material, disturbances in the internal organization of the egg during nuclear implantation, and the difficulty the implanted nucleus has in adjusting to the autonomous processes within the egg, such as the formation and migration of cytoplasmic islands.Some of the defective embryos and larvae originating from nuclear transfer were implanted into adult hosts. After culture for 14 days the early embryonic stages had formed several larval structures, and the late embryonic and larval stages had developed all larval organs. The proliferated imaginal primordia of thesein vivo cultured embryos and larvae, as well as the imaginal disks of the third instar larva, were then implanted into larval hosts with which they passed through metamorphosis and differentiated into imaginal structures. All three types of donor nuclei were capable of producing all adult structures derivedin situ from imaginal disks. The phenotype of these structures waswild-type, thus demonstrating their origin from the transplanted nuclei.The problem as to why not all transplanted nuclei initiated development, and why development after nuclear transplantation was arrested at the third larval instar, at the latest, is discussed.


Effects of hyperventilation and hypoventilation on stress-induced intestinal vasoconstriction.
The combined effects of defined changes in ventilation and stress-induced vasoconstriction were studied in the intestinal vascular bed in cats (n = 20) anaesthetized with fentanyl, nitrous oxide and diazepam. Intestinal reflex vasoconstriction was induced by stimulation either of the hypothalamic defence-alarm area or of somatic and visceral pain afferents. The volume-controlled ventilation was changed by altering the tidal volume, and stimulations were performed during either control conditions (Paco2 4.5-5.0 kPa), hyperventilation (Paco2 3.0-3.5 kPa) or hypoventilation (Paco2 6.5-7.5 kPa). The increase in intestinal vascular resistance (IVR) elicited by defence-alarm area stimulation was potentiated during hyperventilation (306 +/- 83% vs 198 +/- 62%; P less than 0.01) and attenuated during hypoventilation (176 +/- 62% vs 240 +/- 44%; P less than 0.05). The increase in IVR elicited by pain fibre stimulation was potentiated during hyperventilation (73 +/- 21% vs 54 +/- 19%; P less than 0.01), but not significantly changed during hypoventilation (47 +/- 19% vs 68 +/- 34% during control ventilation). Our data indicate that the ventilatory pattern can be decisive for the vasoconstrictor response during experimental stress. We suggest that remote neurogenic mechanisms account for the increased responsiveness during hyperventilation. The decreased responsiveness during hypoventilation, on the other hand, seems to correlate with the local vasodilator effects of carbon dioxide.


Oestrogen receptors revisited: long-term follow up of over five thousand breast cancer patients.
The oestrogen receptor status of a breast tumour predicts the response to hormonal treatment and is an important prognostic marker; women with oestrogen receptor positive tumours having a better short-term survival outcome. Kaplan-Meier estimates and Cox proportional hazard model were used to estimate the association between oestrogen receptor levels and long-term breast cancer-specific survival outcomes in 5735 women diagnosed with breast carcinoma from 1970 to 1997 in Western Australia. Further analysis was performed on a subset of women for whom biochemical and tumour characteristics were also available. Five-year breast cancer-specific survival estimates for women with oestrogen receptor positive tumours was 0.85 (95% CI 0.84-86) compared to 0.72 (95% CI 0.70-74) for women with oestrogen receptor negative tumours. The relative survival advantage of an oestrogen positive tumour over oestrogen negative tumours disappeared by the fourth year (0.8, 95% CI 0.6-1.0). Conditional upon surviving 5 years, long-term breast cancer-specific survival was better for women with oestrogen receptor and progesterone receptor negative tumours compared to other women (log rank test P-value <0.05). Despite an earlier survival advantage for women diagnosed with oestrogen receptor positive tumours, after 5 years of survival, women with oestrogen receptor negative and progesterone receptor negative tumours had better long-term survival outcomes from breast cancer compared to other women.


Modulation of respiratory sinus arrhythmia in rats with central pattern generator hardware.
We report on the modulation of respiratory sinus arrhythmia in rats with central pattern generator (CPG) hardware made of silicon neurons. The neurons are made to compete through mutually inhibitory synapses to provide timed electrical oscillations that stimulate the peripheral end of vagus nerve at specific points of the respiratory cycle: the inspiratory phase (φ(1)), the early expiratory phase (φ(2)) and the late expiratory phase (φ(3)). In this way the CPG hardware mimics the neuron populations in the brainstem which through connections with cardiac vagal motoneurones control respiratory sinus arrhythmia (RSA). Here, we time the output of the CPG hardware from the phrenic nerve activity recorded from rats while monitoring heart rate changes evoked by vagal nerve stimulation (derived from ECG) controlled by the CPG. This neuroelectric stimulation has the effect of reducing the heart rate and increasing the arterial pressure. The artificially induced RSA strongly depends on the timing of pulses within the breathing cycle. It is strongest when the vagus nerve is stimulated during the inspiratory phase (φ(1)) or the early expiratory phase (φ(2)) in which case the heart rate slows by 50% of the normal rate. Heart rate modulation is less when the same exact stimulus is applied during the late expiratory phase (φ(3)). These trials show that neurostimulation by CPG hardware can augment respiratory sinus arrhythmia. The CPG hardware technology opens a new line of therapeutic possibilities for prosthetic devices that restore RSA in patients where respiratory-cardiac coupling has been lost.


The feasibility of ST-segment monitoring with a subcutaneous device.
We have developed a subcutaneous cardiac monitor/alarm for patients at high risk that alerts companions or bystanders if cardiac arrest occurs. The leadless device has 4 electrodes mounted on its corners. An added feature of the implantable monitor/alarm is the ability to detect ST-segment deviations present in acute ischemia. We obtained acute ischemia electrocardiogram (ECG) data of 30 patients from the Utah 192-site body surface maps and determined the left precordial region where our device would be implanted. (The device is implanted at the location where its electrodes yield maximum QRS amplitude.) Unipolar body surface potentials from the chosen area were further interpolated so that closely spaced bipolar electrocardiograms can be derived by performing algebraic subtraction of these "unipolar" ECGs. Results show that the summation of the absolute values of ST-deviations from a pair of diagonal bipolar leads from the optimal subarea (3 x 6 cm rectangle) provides a measure comparable to the maximum ST-deviation among the 4 corner unipolar leads of the same area. This suggests that ST-segment deviations seen at neighboring precordial sites are sufficiently different that significant cancellation of these deviations does not occur in forming close bipolar ECGs. Our conclusion is that during acute ischemia, bipolar ECG recordings between neighboring precordial sites can present ST-segment deviations that are large enough for automatic detection in many patients. Furthermore, the same electrodes used by our subcutaneous device in monitoring R-waves in arrhythmia detection can also be used in monitoring ST-segment deviations for acute ischemia detection.


A multiple health behaviour change intervention to prevent depression: A randomized controlled trial.
To examine the effectiveness of a 12-month MHBC intervention in the prevention of onset depression in primary health care (PHC). Twenty-two PHC centres took part in the cluster-randomized controlled trial. Patients were randomized to receive either usual care or an MHBC intervention. The endpoints were onset of major depression and reduction of depressive symptoms in participants without baseline depression at a 12-month follow-up. 2531 patients agreed and were eligible to participate. At baseline, around 43% were smokers, 82% were non-adherent to the Mediterranean diet and 55% did not perform enough physical activity. The intervention group exhibited a greater positive change in two or more behaviours (OR 1.75 [95%CI: 1.17 to 2.62]; p = 0.006); any behaviour (OR 1.58 [95%CI: 1.13 to 2.20]; p = 0.007); and adherence to the Mediterranean diet (OR 1.94 [95%CI: 1.29 to 2.94]; p = 0.002), while this increase was not statistically significant for smoking and physical activity. The intervention was not effective in preventing major depression (OR 1.17; [95% CI 0.53 to 2.59)]; p = 0.690) or reducing depressive symptoms (Mean difference: 0.30; [95% CI -0.77 to 1.36]; p = 0.726) during follow-up. As compared to usual care, the MHBC intervention provided a non-significant reduction in the incidence of major depression. ClinicalTrials.gov, NCT03136211.


Prediction of distant metastatic recurrence by tumor-infiltrating lymphocytes in hormone receptor-positive breast cancer.
Breast cancer subtypes are known to have different metastatic recurrence sites. Distant metastases are often observed during the post-operative course in patients with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer and triple-negative breast cancer, but are relatively rare in those with hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. Tumor-infiltrating lymphocytes (TILs) serve as an index to monitor tumor immune microenvironment and may possibly predict the prognosis and therapeutic effect in breast cancer. This study aimed to investigate the correlation between TIL density and recurrence site in HR+/HER2- breast cancer. In stages I-II of HR+/HER2- breast cancer patients who underwent surgery as the first treatment and received adjuvant endocrine therapy (except adjuvant chemotherapy), forty-two patients relapsed after surgery. TILs were evaluated using needle biopsy specimens for the diagnosis of breast cancer. Morphological assessment was conducted using conventional hematoxylin and eosin staining. Six patients had no TILs density. In them, local recurrence was significantly less (p = 0.022), while distant metastases were significantly more (p = 0.015) compared to those in patients with TIL density. Therefore, for the prediction of distant metastases in HR+/HER2- breast cancer without chemotherapy, TILs could be used as predictors in univariate analysis (p = 0.015, odds ratio [OR] = 0.127), although not as independent factors (p = 0.285, OR = 0.144). Our findings indicate that TILs may predict distant metastatic recurrence in stages I-II of HR+/HER2- breast cancer in patients who do not undergo chemotherapy.


Left ventricular systolic dyssynchrony in patients with isolated symptomatic myocardial bridge.
The impact of myocardial bridge (MB) on left ventricular (LV) systolic synchrony is insufficiently understood. Thirty-five subjects with isolated mid-left, anterior, descending artery (LAD) MB, preserved LV ejection fraction (LVEF > 50%), and otherwise, normal coronary angiogram were identified from 3607 patients who underwent diagnostic coronary angiography and were evaluated by tissue Doppler imaging and real-time three-dimensional echocardiography (RT3DE). Control subjects consisted of 26 age and sex-matched coronary angiographically "normal" subjects. MB patients were characterized by reduced, early, diastolic strain rate in LAD-supplied apical segments (lateral and anterior), with prevalence of LV systolic dyssynchrony of 25.7% (9/35). MB patients were further classified by the medians of MB stenosis and length. For MB stenosis < 52.5%, Class I: length < 17 mm (n = 7), Class II: length ≥ 17 mm (n = 10); for stenosis ≥ 52.5%, Class III: length < 17 mm (n = 10), Class IV: length ≥ 17 mm (n = 8). Binary Logistic regression model revealed that higher MB lesion classification (odds ratio: 4.944, 95%CI 1.174-20.82, P < 0.05) and hypertension (odds ratio: 15.32, 95%CI: 1.252-187.6, P < 0.05) are statistically associated with LV systolic dyssynchrony, which was independent of LV mass. MB in the mid LAD is associated with myocardial dyssynchrony. Hypertensive individuals and those with more severe bridging (determined by length and stenosis) tend to have an increased incidence of dyssynchrony.


Platelet-Rich Plasma Has Better Results for Retear Rate, Pain, and Outcome Than Platelet-Rich Fibrin After Rotator Cuff Repair: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) in the literature to ascertain the extent to which platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) improved patient outcomes in arthroscopic rotator cuff repair. Two independent reviewers performed the literature search based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, with a third author resolving any discrepancies. RCTs comparing PRP or PRF to a control in rotator cuff repair were included. Quality of evidence was assessed using the Cochrane Collaboration risk of bias tool. Clinical outcomes were compared using the risk ratio for dichotomous variables and the mean difference for continuous variables. A P value <.05 was deemed statistically significant. Included in this review are 23 RCTs with 1440 patients. PRP resulted in significantly decreased rates of retear (15.9% versus 29.0%, respectively; P < .0001). Significant results were noted in favor of PRP compared with control based on the Constant score (83.9 versus 81.2, respectively; P = .0006); the University of California, Los Angeles score (31.1 versus 30.2; P < .00001); the American Shoulder and Elbow Surgeons score (87.3 versus 84.5; P = .04); and the visual analog scale score (1.3 versus 1.6; P = .01). PRF resulted in an improved Constant score (80.1 versus 80.0, respectively; P = .04) compared with control. The current evidence shows that using PRP in arthroscopic rotator cuff repair can improve pain levels and functional outcome scores while reducing the retear rate after surgery. PRF injection, on the other hand, improves only the Constant score. II; systematic review and meta-analysis of level I and II evidence.


Fabrication and modeling of high-frequency PZT composite thick film membrane resonators.
High-frequency, thickness mode resonators were fabricated using a 7 microm piezoelectric transducer (PZT) thick film that was produced using a modified composite ceramic sol-gel process. Initial studies dealt with the integration of the PZT thick film onto the substrate. Zirconium oxide (ZrO2) was selected as a diffusion barrier layer and gave good results when used in conjunction with silicon oxide (SiO2) as an etch stop layer. Using these conditions, devices were produced and the acoustic properties measured and modeled. The resonators showed a resonant frequency of about 200 MHz, an effective electromechanical coupling coefficient of 0.34, and a Q factor of 22. Modeling was based on a Mason-type model that gave good agreement between the experimental data and the simulations. The latter showed, for the PZT thick film, an electromechanical coupling coefficient of 0.35, a stiffness of 8.65 x 10(10) N x m(-2) and an e33,f piezoelectric coefficient of 9 C x m(-2).


Management of Organophosphorus Poisoning: Standard Treatment and Beyond.
Organophosphorus (OP) compounds remain a leading cause of self-poisoning and mortality, especially in South East Asia, China, and Africa. Organophosphorus causes an acute cholinergic syndrome by inhibiting acetylcholinesterase. Atropine remains the mainstay of treatment, but recently some promising therapies are in the pipeline. Oximes are used widely in the management of organophosphorus poisoning, however clinical efficacy remains to be established. Magnesium sulfate, calcium channel blockers (nimodipine), plasma alkalinizing agents, β-2 agonists, nicotinic receptor antagonists, clonidine, and lipid emulsions are promising treatment alternatives. However, large phase III trials are required to establish their efficacy.


Cerebral oxidative metabolism in the fetal lamb: relationship to electrocortical state.
Cerebral oxidative metabolism and blood flow were measured in 14 chronically prepared fetal lambs with changes in fetal electrocortical activity. Myocardial blood flow was also measured with changes in fetal state in order to determine whether metabolic changes observed were organ specific. Samples of preductal arterial and sagittal vein blood were analyzed for oxygen content, blood gases, and pH. Blood flow was measured with a radioactive microsphere technique. Cerebral oxidative metabolism increased significantly from 126 +/- 7 mumol/100 gm/min during the high-voltage electrocortical state to 152 +/- 7 mumol/100 gm-1/min-1 (p less than 0.05) during the low-voltage electrocortical state. The increase in cerebral oxidative metabolism was sustained by an increase in blood flow, 148 +/- 7 ml/100 gm/min to 173 +/- 10 ml/100 gm/min (p less than 0.01), whereas the arterial venous oxygen difference remained unchanged. Changes in myocardial blood flow were in the opposite direction, with a decrease noted during the low-voltage electrocortical state, and were correlated with changes in fetal heart rate. We conclude that cerebral oxidative metabolism is increased during the fetal low-voltage electrocortical state and suggests an important role for the increased incidence of this state during the accelerated growth and development of the brain during the perinatal period.


Stimulation of protein kinase C activity by tumor necrosis factor-alpha in bovine bronchial epithelial cells.
Bronchial epithelial cell migration, attachment, and proliferation are important processes in response to airway injury. We have shown that tumor necrosis factor (TNF)-alpha stimulates the migration of bovine bronchial epithelial cells (BBEC) in vitro. We hypothesized that protein kinase C (PKC) may be one of the intracellular signaling mediators of TNF-alpha in BBEC. In this study, we have identified multiple PKC isoforms in BBEC and measured total cellular PKC activity. Polyclonal antibodies to the PKC-alpha, -beta 2, -delta, and -epsilon isoforms recognized protein bands around 80-90 kDa. BBEC primary cultures treated with either 500 U/ml TNF-alpha for 2-4 h or 100 ng/ml 12-O-tetradecanoylphorbol 13-acetate for 15 min resulted in three-to fivefold increases in PKC activity in the particulate fractions of crude cell lysates. This activity was inhibited by 1 microM calphostin C or 10 microM H-7. Similarly, TNF-alpha-stimulated BBEC migration was reduced at least twofold in the presence of H-7 or calphostin C. These studies suggest that the activation of PKC is necessary for TNF-alpha-stimulated BBEC migration.


Plasmodium cynomolgi as Cause of Malaria in Tourist to Southeast Asia, 2018.
We report human infection with simian Plasmodium cynomolgi in a tourist from Denmark who had visited forested areas in peninsular Malaysia and Thailand in August and September 2018. Because P. cynomolgi may go unnoticed by standard malaria diagnostics, this malaria species may be more common in humans than was previously thought.


Meta-analysis: the significance of screening for JAK2V617F mutation in Budd-Chiari syndrome and portal venous system thrombosis.
It is important to evaluate whether screening for JAK2V617F mutation should be routinely performed in patients with Budd-Chiari syndrome (BCS) and portal venous system thrombosis (PVST). However, the prevalence of JAK2V617F mutation in such patients is substantially varied, and its association with development of myeloproliferative disorders (MPD) is deficiently identified. To estimate the prevalence of JAK2V617F mutation and to explore the significance of screening for JAK2V617F mutation in these patients. All observational studies regarding the prevalence of JAK2V617F mutation in patients with BCS and PVST were identified via PubMed and MEDLINE databases. Primary items were the proportions of JAK2V617F mutation and MPD. Twenty-three studies fulfilled the inclusion criteria. Regardless of underlying aetiological factors, the pooled prevalence of JAK2V617F mutation was 37% and 24% in patients with BCS and PVST respectively. After pre-existing MPD was excluded, the pooled prevalence was decreased to 26% and 19%. Heterogeneity among studies was significant for the prevalence of JAK2V617F mutation. Compared with healthy subjects and patients with thrombosis in other sites, the prevalence of JAKV617F mutation was significantly higher in patients with BCS and PVST. The prevalence of MPD was significantly higher in patients with JAK2V617F mutation than those without. JAK2V617F mutation is frequently found in patients with BCS and PVST, but there is a huge variation of prevalence among the included studies. Additionally, it is more specific to thrombosis in splanchnic areas and strongly associated with the development of MPD in these patients. Further studies are needed to evaluate whether the screening test should be widely performed in Asian countries and cirrhotic patients.


Cryptosporidium: evidence for a single-species genus.
Cryptosporidium, isolated from calves with diarrhea, infected, with or without causing enteritis, seven different species of animals.