Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer: 10-Year Results of the Randomized Controlled EORTC 10981-22023 AMAROS Trial.
The European Organisation for Research and Treatment of Cancer 10981-22023 AMAROS trial evaluated axillary lymph node dissection (ALND) versus axillary radiotherapy (ART) in patients with cT1-2, node-negative breast cancer and a positive sentinel node (SN) biopsy. At 5 years, both modalities showed excellent and comparable axillary control, with significantly less morbidity after ART. We now report the preplanned 10-year analysis of the axillary recurrence rate (ARR), overall survival (OS), and disease-free survival (DFS), and an updated 5-year analysis of morbidity and quality of life. In this open-label multicenter phase III noninferiority trial, 4,806 patients underwent SN biopsy; 1,425 were node-positive and randomly assigned to either ALND (n = 744) or ART (n = 681). Per intention-to-treat analysis, 10-year ARR cumulative incidence was 0.93% (95% CI, 0.18 to 1.68; seven events) after ALND and 1.82% (95% CI, 0.74 to 2.94; 11 events) after ART (hazard ratio [HR], 1.71; 95% CI, 0.67 to 4.39). There were no differences in OS (HR, 1.17; 95% CI, 0.89 to 1.52) or DFS (HR, 1.19; 95% CI, 0.97 to 1.46). ALND was associated with a higher lymphedema rate in updated 5-year analyses (24.5% v 11.9%; P < .001). Quality-of-life scales did not differ by treatment through 5 years. Exploratory analysis showed a 10-year cumulative incidence of second primary cancers of 12.1% (95% CI, 9.6 to 14.9) after ART and 8.3% (95% CI, 6.3 to 10.7) after ALND. This 10-year analysis confirms a low ARR after both ART and ALND with no difference in OS, DFS, and locoregional control. Considering less arm morbidity, ART is preferred over ALND for patients with SN-positive cT1-2 breast cancer.


Construction and validation of a prognostic model for kidney renal clear cell carcinoma based on podocyte-associated genes.
As the most common renal malignancy, kidney renal clear cell carcinoma (KIRC) has a high prevalence and death rate as well as a poor response to treatment. Developing an efficient prognostic model is essential for accurately predicting the outcome and therapeutic benefit of KIRC patients. Gene expression profiles of podocyte-associated genes (PAGs) were obtained from The Cancer Genome Atlas and GEO datasets. Cox regression and Lasso regression analyses were then used for filtering prognosis-associated PAGs. Risk score (RS) was computed from these genetic characteristics. Kaplan-Meier analysis and receiver operating characteristic (ROC) curves were applied for ascertaining the prognostic value. Stratified analysis was used to sufficiently validate model performance. Concordance index was used to compare the predictive ability of different models. Immuno-infiltration analysis and immunophenoscore were utilized for the prediction of patient reaction to immune checkpoint inhibitors (ICIs). WT1, ANLN, CUBN, OSGEP, and RHOA were significantly associated with KIRC prognosis. Prognostic analysis indicated that high-RS patients have a significantly poorer outcome. Cox regression analysis demonstrated a potential for RS to be an independent prognostic factor. Pathway enrichment results indicated a lower enrichment of cancer-related biological pathways in the low-RS subgroup. Immune infiltration analysis and IPS demonstrated greater responsiveness to ICIs in the high RS group. This podocyte-associated KIRC prognostic model can effectively predict KIRC prognosis and immunotherapy response, which may help to provide clinicians with more effective treatment strategies.


Surgical Complications After Thyroid Surgery: A 10-Year Experience at Jeddah, Saudi Arabia.
To evaluate the incidence and predictive risk factors of complications in patients who underwent thyroid surgery at our hospital with a residency training program. This retrospective cohort study analyzed the complications in all patients who underwent thyroid surgery between January 2008 and December 2017. Demographic data, preoperative diagnosis based on fine needle aspiration cytology, surgical approach, permanent pathology, postoperative complications, and factors associated with complications were recorded. At our hospital, 456 patients underwent thyroidectomy. The most common surgical complications were asymptomatic biochemical hypocalcemia and symptomatic hypocalcemia in 109 (23.9%) and 50 (11%) patients, respectively. Other surgical complications included permanent hypocalcemia, transient vocal cord palsy, permanent vocal cord palsy, hematoma, seroma, chyle fistula, and Horner's syndrome. Mean age > 45 years and more extensive surgery were significantly associated with overall complications (P = 0.003; < 0.001). Mean age > 50 years and vitamin D level < 25 nmol/L (< 10 ng/mL) were significantly associated with hypocalcemia (P = 0.008; < 0.001). Moreover, the extent of surgery and advanced thyroid carcinoma were significantly associated with vocal cord palsy (P < 0.001; 0.05). Hypocalcemia and vocal cord palsy are the most significant complications. Thyroid surgery can be performed safely by senior residents in the residency training program under the direct supervision of an experienced surgeon.


Intervention reporting and dissemination of information for the management of hand osteoarthritis.
A variety of exercise programs are recognized to be effective for the management of hand osteoarthritis (HOA). It is important to report the essential elements of these exercise programs for clinicians to replicate properly and facilitate their implementation with individuals who suffers from HOA, especially if they are found to be effective programs. The objective of this article was to assess content reporting using three exercise reporting standardized assessment tools among exercise interventions randomized controlled trials (RCTs) involving individuals with HOA. A descriptive study was used. Two pairs of trained assessors independently identified, selected, and scored the reporting quality of the exercise programs of RCTs on the management of HOA using three standardized assessment tools: the Consensus on Exercise Reporting Template (CERT) checklist, Consensus on Therapeutic Exercise Training (CONTENT) scale, and Template for Intervention Description and Replication (TIDieR) checklist to review the quality of reporting of 11 RCTs included in a recent Ottawa Panel guideline. Based on consensus reached by two different pairs of reviewers and an arbitrator, the mean total scores for the 11 included exercise programs were reported as follows: the mean total score for the CERT, CONTENT, and TIDieR was 10.58/19 ± 4.34, 3.27/9 ± 1.90, and 5.92/12 ± 2.54, respectively. The overall Pearson's Correlation (r) between the methodological quality and intervention reporting was 0.86, 0.71, and 0.54 for moderate-to-high RCTs and 0.47, 0.79, and 0.42 for fair-to-poor methodological quality for the CERT checklist, CONTENT scale, and TIDieR checklist, respectively. The intervention reporting in the management of HOA is poor among low-, moderate-, and high-quality clinical trials. The least reported information was intervention parameters related to behavior change. Improving reporting is recommended to ensure replication of effective exercise programs to enhance quality of life of individuals with HOA.


Transmission of SARS-CoV-2 by children and young people in households and schools: A meta-analysis of population-based and contact-tracing studies.
The role of children and young people (CYP) in transmission of SARS-CoV-2 in household and educational settings remains unclear. We undertook a systematic review and meta-analysis of contact-tracing and population-based studies at low risk of bias. We searched 4 electronic databases on 28 July 2021 for contact-tracing studies and population-based studies informative about transmission of SARS-CoV-2 from 0 to 19 year olds in household or educational settings. We excluded studies at high risk of bias, including from under-ascertainment of asymptomatic infections. We undertook multilevel random effects meta-analyses of secondary attack rates (SAR: contact-tracing studies) and school infection prevalence, and used meta-regression to examine the impact of community SARS-CoV-2 incidence on school infection prevalence. 4529 abstracts were reviewed, resulting in 37 included studies (16 contact-tracing; 19 population studies; 2 mixed studies). The pooled relative transmissibility of CYP compared with adults was 0.92 (0.68, 1.26) in adjusted household studies. The pooled SAR from CYP was lower (p = 0.002) in school studies 0.7% (0.2, 2.7) than household studies (7.6% (3.6, 15.9) . There was no difference in SAR from CYP to child or adult contacts. School population studies showed some evidence of clustering in classes within schools. School infection prevalence was associated with contemporary community 14-day incidence (OR 1.003 (1.001, 1.004), p<0.001). We found no difference in transmission of SARS-CoV-2 from CYP compared with adults within household settings. SAR were markedly lower in school compared with household settings, suggesting that household transmission is more important than school transmission in this pandemic. School infection prevalence was associated with community infection incidence, supporting hypotheses that school infections broadly reflect community infections. These findings are important for guiding policy decisions on shielding, vaccination school and operations during the pandemic.


Stimulus sensitivity and neuromodulatory properties of noisy intrinsic neuronal oscillators.
Intrinsic subthreshold oscillations in the membrane potential are a common property of many neurons in the peripheral and central nervous system. When such oscillations are combined with noise, interesting signal encoding and neuromodulatory properties are obtained which allow, for example, sensitivity adjustment or differential encoding of stimuli. Here we demonstrate that a noisy Hodgkin/Huxley-model for subthreshold oscillations, when tuned to maximum sensitivity, can be significantly modulated by even minor physiological changes in the oscillation parameters amplitude or frequency. Given the ubiquity of subthreshold oscillating neurons, it can be assumed that these findings reflect principle encoding properties which are relevant for an understanding of sensitivity and neuromodulation in peripheral and central neurons.


Estimation of P-glycoprotein-mediated efflux in the oral absorption of P-gp substrate drugs from simultaneous analysis of drug dissolution and permeation.
The purpose of this study was to establish an in vitro system that evaluates the effects of P-glycoprotein (P-gp)-mediated efflux on the oral absorption of P-gp substrates. An in vitro system (dissolution/permeation system, D/P system) was developed that consisted of apical and basal chambers and a Caco-2 cell monolayer mounted between the chambers. Both sides of the monolayer were filled with physiological solution and were stirred at 200rpm. The dissolution in the apical medium and permeation to the basal medium were monitored for 2h after P-gp substrates were applied to the apical side of the system. When erythromycin existed in the apical medium, the permeations of fexofenadine and talinolol were significantly enhanced without change in their dissolution. The prediction of oral absorptions of fexofenadine and talinolol from in vitro data indicated that co-administration of erythromycin results in 2.1- and 1.9-fold higher oral absorptions, respectively. Moreover, the D/P system could estimate the effect of cremophor EL on the oral absorption of saquinavir. These estimations corresponded well to in vivo human observations. Our in vitro system is useful in assessment of the effect of P-gp-mediated efflux on in vivo oral absorption of P-gp substrates.


A comparison of various rural wastewater treatment processes for the removal of endocrine-disrupting chemicals (EDCs).
The removal of six endocrine-disrupting chemicals (EDCs), including estrone (E1), 17β-estradiol (E2), estriol (E3), 17α-ethinyl estradiol (EE2), bisphenol A (BPA) and 4-nonylphenol (NP), was investigated in 20 rural wastewater treatment facilities (WWTFs) located in a county of Zhejiang Province, China. These WWTFs adopted one of the four treatment processes: activated sludge (AS), constructed wetland (CW), stabilization pond (SP), and micro-power biofilm reactor (MP). Results indicate that all the six EDCs were detected in wastewater samples with NP showing a maximum detection frequency (97%) and a maximum influent concentration (5002 ng L(-1)). After biological treatment, the concentrations of E2, E3 and NP decreased remarkably, while E1, EE2 and BPA exhibited varying removal efficiencies that depended on the specific treatment process and sampling season. In general, the centralized AS process outperformed those decentralized processes (i.e., CW, SP and MP) and a higher removal of E1, EE2, NP and BPA in the AS process was observed in summer (>70%) than in winter. Among the three decentralized processes, the removal of EDCs in the SP process was limited, especially for E1, EE2 and BPA (18-46%) in winter. Due to an incomplete removal, the total concentration of target EDCs increased obviously in the mixing and downstream sections of a local river receiving the effluent from a typical WWTF (practicing AS). This study reveals that the design and operation of rural WWTFs should be optimized if an effective removal of EDCs is to be achieved.


[Priorization in healthcare. An important duty, an unnecessary luxury, or playing with fire? A sociomedical point of view].
While setting priorities in healthcare has been discussed internationally for about 25 years, attempts to even start a discussion in Germany have failed for more than a decade. On the contrary, the topic was and still is actively suppressed. In this respect, one helpful mechanism is to deliberately or carelessly confuse prioritization with rationing, a German taboo-word. The national healthcare debate again and again neglects the question on what to spend Germany's still very considerable resources. This helps our health politicians to continue to live the postulate that everybody should have immediate, unrestricted access to all medically indicated healthcare. Attempts to distinguish between priority setting and rationing as two entirely distinct programs based on prioritization models from Sweden, England, and Oregon/USA are presented. While discussing possible objects, levels, criteria, ethics, and normative implications of priority setting in healthcare, recent recommendations of a permanent vaccination committee (STIKO) are used as an example.


The relationship between prenatal exposure to BP-3 and Hirschsprung's disease.
Hirschsprung's disease (HSCR) is neonatal intestinal abnormality which derived from the faliure of enteric neural crest cells migration to hindgut during embryogenesis from 5 to 12 weeks. Currenly, the knowledge of environmental factors contributing to HSCR is still scarce. Benzophenone-3 (BP-3) is one of the most widely used UV filters, and has weak estrogen and strong anti-androgenic effects. In order to examine the effect of maternal BP-3 exposure on development of offspring and explore the potential mechanism, we conducted case and control study and in vitro study. In this work, BP-3 concertrations in maternal urine was detected by ultra-high performance liquid chromatography. Besides, we investigated the cytotoxicity and receptor tyrosine kinase (RET) expression in cells exposed to BP-3. The results showed that maternal BP-3 exposure was associated with offspring's HSCR in the population as well as inhibited migration of 293T and SH-SY5Y cells. What's more, we discovered dose-response relationship between RET expression and BP-3 exposure dose, and miR-218 and some other genes involved in SLIT2/ROBO1-miR-218-RET/PLAG1 pathway were also related to BP-3 exposure. Therefore, we deduced that BP-3 influenced cell migration via SLIT2/ROBO1-miR-218-RET/PLAG1 pathway. Our study firstly revealed the relationship between maternal BP-3 exposure and HSCR as well as its potential mechanism.


Effects of copper in Daphnia are modulated by nanosized titanium dioxide and natural organic matter: what is the impact of aging duration?
During its aquatic life cycle, nanosized titanium dioxide (nTiO2) may interact with natural organic matter (NOM) ultimately altering the ecotoxicity of co-occurring chemical stressors such as heavy metals (e.g. copper (Cu)). In this context, the following hypotheses were tested: (1) aging of nTiO2 along with Cu reduces Cu toxicity, (2) nTiO2 agglomerates have a lower potential to reduce Cu toxicity and (3) aging of nTiO2 in presence of NOM reduces Cu toxicity further. A multifactorial test design crossing three nTiO2 levels (0.0, 0.6 and 3.0 mg/L) with two levels of NOM (0 versus 8 mg total organic carbon (TOC)/L) and seven nominal Cu concentrations (ranging from 0 to 1536 μg/L) aged in ASTM medium for 0, 1, 3 and 6 days was realised, while two aging scenarios were applied (type 1: nTiO2 jointly aged with Cu; type 2: Cu added after nTiO2 aging). Subsequently, Cu toxicity was assessed using the immobility of Daphnia magna after 48 h of exposure as response variable. The experiments revealed that neither aging duration nor the extent of agglomeration (type 1 vs. type 2 aging) has a substantial impact on Cu induced toxicity. Moreover, it was confirmed that the presence of NOM substantially reduced Cu induced toxicity, independent of the aging scenario and duration. More importantly, the data suggest the ingestion of Cu loaded nTiO2 as additional exposure pathway contributing to Cu toxicity. In conclusion, it seems unlikely that nTiO2 concentrations currently detected in or predicted for aquatic ecosystems, which are at least one order of magnitude below the concentration tested here, influence Cu toxicity meaningfully.


D-2-hydroxyglutaric aciduria: a case with an intermediate phenotype and prenatal diagnosis of two affected fetuses.
D-2-hydroxyglutaric aciduria (D2HGA) is a rare autosomal recessive disorder with variable clinical expression. The biochemical defect is unknown at present. Previously reported cases have either followed a severe clinical course characterized by neonatal epileptic encephalopathy, cortical blindness, and profound developmental delay, or a mild course characterized by mild developmental delay, manageable epilepsy, and mild hypotonia. To date there has been a clear distinction between these two groups. We report the second case of a child with D2HGA who has followed an intermediate course. She presented in infancy with hypotonia, manageable epilepsy and developed moderate to severe developmental delay, and cortical visual impairment. The proposita had a coarse facial appearance, flat face, broad nasal bridge, up-turned nose, and simple, anteverted ears. These facial anomalies have been noted in other children with D2HGA and this case strengthens the proposed association between this facial phenotype and D2HGA. We also report the third and fourth instances of prenatal diagnosis for D2HGA. At each prenatal diagnosis, an affected fetus was diagnosed on the basis of markedly increased levels of D-2-hydroxyglutaric acid in amniotic fluid.


The impact of receptor of advanced glycation end-products polymorphisms on prostate cancer progression and clinicopathological characteristics.
The receptor for advanced glycation end products (RAGE) overexpression was suggested to be associated with prostate cancer development and poor prognosis. In this study, we focused on the correlations between the clinicopathological characteristics and susceptibility of prostate cancer and RAGE single-nucleotide polymorphisms (SNPs). In 579 prostate cancer patients, the RAGE SNPs rs1800625, rs1800624, rs2070600 and rs184003 in patients with or without grade group upgrade were analysed with real-time polymerase chain reaction. The results demonstrated that the prostate cancer patients who carried the RAGE SNPs rs2070600 'GA' genotypic variants were significantly associated with lower risk to develop grade group upgrade. Moreover, patients with the RAGE rs1800625 'TC + CC' genotypic variants were associated with higher risk of perineural invasion. In 343 prostate cancer patients who carried the RAGE rs1800625 'TC + CC' genotype without grade group upgrade were correlated with higher risk of biochemical recurrence and perineural invasion. In the analysis of TCGA database, significant differences of the RAGE mRNA level were found between the normal controls and prostate cancer patients (p < 0.0001), and the pathologic stage N1 and N0 patients (p = 0.0027). The prostate cancer patients with high RAGE expression were associated with lower overall survival rate (p = 0.025). In conclusion, our results have revealed that the RAGE SNPs rs2070600 and rs1800625 were associated with the grade group upgrade of prostate cancer and clinical status. The RAGE polymorphisms may provide as a pivotal predictor to evaluate prostate cancer disease progression and prognosis.


Studies on novel HIF activators, A-503451s.I. Producing organism, fermentation, isolation and structural elucidation.
In the course of our screening for activators of hypoxia-inducible factor (HIF), A-503451 A and virantmycin were isolated from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 60101. From the same culture, the non-active homologs A-503451 B and D were also isolated. A-503451 A and virantmycin activated HIF-dependent reporter gene expression with EC50 values of 8 and 17 ng ml-1, respectively. They are highly potent activators of HIF and thus may be therapeutically useful for erythropoiesis and neural cell protection.


Use of texture analysis to study hydrophilic solvent effects on the mechanical properties of hard gelatin capsules.
The aim of this work was to explore texture analysis for quantitative evaluation of the effect of hydrophilic solvent systems used as capsule fills on the mechanical properties of hard gelatin capsules. For this purpose, a texture analyzer (Stable Micro Systems, model TA.XT Plus) equipped with a capsule separating rod fixture was used. The tests were conducted in a tension mode. Elastic stiffness, tensile force and elongation at break were determined from the experimental stress-strain curve in order to quantitatively describe both brittleness and softening of capsules. In this paper, it has been demonstrated that the effect of various hydrophilic solvent (i.e. propylene glycol (PG), polyethylene glycol 400 (PEG 400), ethanol) mixtures on the mechanical properties of hard gelatin capsules can be easily monitored using texture analysis. Significant counteractive effects between PG and PEG 400 or ethanol on the integrity of capsule shells were discovered in this study. Texture analysis is found to be a convenient tool for studying formulation compatibility. It can be invaluable in early screening studies of liquid filled hard gelatin capsules.


Cobalt-promoted fabrication of 3D carbon with a nanotube-sheet mutual support structure: scalable preparation of a high-performance anode material for Li-ion batteries.
Currently, the design of carbon-based composite as a high-performance anode material for lithium-ion batteries (LIBs) presents challenges for commercial application. Herein, we developed a three-dimensional carbon-based material with a nanotube-sheet mutual support structure (MS-CNTS) engineered by the catalytic effect of Co species. The present work highlights a concise 'solvent-free' synthetic method allowing for large-scale output, which is potentially available for low cost commercial use. With the readily available acetylacetonate and cobalt (II) acetylacetonate as starting chemicals, this nanostructured carbonaceous material is fabricated with aldol condensation to construct a Co-contained carbon-link network polymer precursor followed by annealing under argon. It is composed of brim-curled graphene-like carbon nanosheets and carbon nanotubes, which support each other's structures to effectively avoid agglomeration. Therefore, it enables high performance in LIBs. In spite of the trace amount of cobalt, the carbon-based MS-CNTS anode delivers a high charge capacity of 1028 mAh g-1 at 0.1 A g-1, high rate capacity of 495 mAh g-1 at 2 A g-1, and ultra-long cycling life with a very low capacity decay of 0.008% per cycle over 1000 cycles at 0.5 A g-1, accompanied by 100% Coulombic efficiency. From full cell measurements, we further confirm the considerable promise of MS-CNTS as anodes with a long cycling life.


Excitatory Postrhinal Projections to Principal Cells in the Medial Entorhinal Cortex.
The postrhinal cortex (POR) provides substantial input to the entorhinal cortex, mainly targeting superficial layers of the medial entorhinal cortex (MEC). Major inputs to POR originate in the visual and parietal cortex, thus providing neurons in MEC with a subset of cortical information relevant to their spatial firing properties. The POR takes a position that is comparable with that of the perirhinal cortex (PER) with regard to the lateral entorhinal cortex (LEC). Neurons in LEC and MEC show different functional properties likely reflecting differences in their respective inputs. Projections from PER to LEC exert a main inhibitory influence, which may relate to the sparse object-selective firing in LEC. In view of the continuous, spatially modulated firing properties of principal neurons in MEC, we tested in rats the hypothesis that projections from POR to MEC are functionally different from the PER-to-LEC counterpart in providing an excitatory drive to MEC. Our combined confocal and quantitative electron-microscopic observations indicated that POR projections target mainly principal cells in MEC, including neurons that project to the hippocampus. The ultrastructure of the majority of the synapses indicated that they are excitatory. Voltage-sensitive dye imaging in sagittal slices confirmed this morphologically derived conclusion, showing that the MEC network always responded with an overall depolarization, indicative for net excitatory transmission. In vitro single-cell recordings from principal cells showed only excitatory responses upon POR stimulation. These results show that POR provides an excitatory projection to MEC, differing fundamentally from the inhibitory projection of PER to LEC.


The public health threat of phthalate-tainted foodstuffs in Taiwan: the policies the government implemented and the lessons we learned.
A major incident of phthalate-contaminated foodstuffs happened in Taiwan between April and July, 2011. Phthalates were deliberately added to foodstuffs as a substitute of emulsifier. We describe the course of this incident, government response and management of the crisis, and its future implications. Five major food categories, including sports drinks, fruit beverages, tea drinks, fruit jam or jelly, and health food or supplements in tablet or powder form, were contaminated with Di-(2-ethylhexyl)phthalate and/or Di-isononyl phthalate. At least 900 different food products were affected. Like the scandal of melamine-tainted infant formula, this event represents another large deliberate food contamination incident. It is important to be reminded that many governments in developing countries make rapid economic growth as their first priority, often compromising environmental safety and public health. The administration leaders need to find a balance between economic expansion and health and environmental safety.


Electrochemistry as a screening method in determination of carotenoids in crustacean samples used in everyday diet.
Electrochemistry of carotenoids has attracted a lot of interest because it provides an understanding of their oxidative properties. We report the application of electrochemistry in the analysis of carotenoids. Voltammetry of microdroplets immobilized on paraffin impregnated graphite electrode in 0.1 mol dm-3 HClO4 and KNO3 aqueous electrolytes using square-wave voltammetry was applied. Previous studies have shown that carotenoids undergo complex oxidation process when characterized in aqueous media. In this research, the electrooxidation of carotenoid astaxanthin was confirmed. The obtained response allowed the development of an electroanalytical method with a limit of detection of 15.77 µmol dm-3, the limit of quantification of 47.80 µmol dm-3 and acceptable relative standard deviations for current (3.69%) and potential (0.41%). Extraction using DMSO and acetone has shown to be appropriate for voltammetric analysis. Astaxanthin content was determined electrochemically in shrimp and soft-shell crab samples (20.63 and 6.59 μg g-1, respectively), yielding recoveries above 90%.


Determination of the relationships between psychological stress levels and blood pressure, pulse and respiratory rates, weight and cigarette consumption.
Stress has often been invoked as the intervening variable between various patterns of environmental and psychological stimulation, and various physiological and non-physiological responses. In an attempt to document this, 71 subjects completed the Staats Stress-Vector Analysis Questionnaire yielding measures on environmental, psychogenic and somatogenic stress dimensions, as well as on an overall net stress measure. These were then correlated against the blood pressure, pulse rate, respiratory rate, weight and smoking indices of the respondents, measured under controlled circumstances. No linear correlation was apparent. The respiratory rate tended to be raised in the environmentally and overall stressed individuals as a class, while similar findings relating to weight and pulse rate applied to the psychologically stressed. Reasons are extended for these findings.


Patching Broken DNA: Nucleosome Dynamics and the Repair of DNA Breaks.
The ability of cells to detect and repair DNA double-strand breaks (DSBs) is dependent on reorganization of the surrounding chromatin structure by chromatin remodeling complexes. These complexes promote access to the site of DNA damage, facilitate processing of the damaged DNA and, importantly, are essential to repackage the repaired DNA. Here, we will review the chromatin remodeling steps that occur immediately after DSB production and that prepare the damaged chromatin template for processing by the DSB repair machinery. DSBs promote rapid accumulation of repressive complexes, including HP1, the NuRD complex, H2A.Z and histone methyltransferases at the DSB. This shift to a repressive chromatin organization may be important to inhibit local transcription and limit mobility of the break and to maintain the DNA ends in close contact. Subsequently, the repressive chromatin is rapidly dismantled through a mechanism involving dynamic exchange of the histone variant H2A.Z. H2A.Z removal at DSBs alters the acidic patch on the nucleosome surface, promoting acetylation of the H4 tail (by the NuA4-Tip60 complex) and shifting the chromatin to a more open structure. Further, H2A.Z removal promotes chromatin ubiquitination and recruitment of additional DSB repair proteins to the break. Modulation of the nucleosome surface and nucleosome function during DSB repair therefore plays a vital role in processing of DNA breaks. Further, the nucleosome surface may function as a central hub during DSB repair, directing specific patterns of histone modification, recruiting DNA repair proteins and modulating chromatin packing during processing of the damaged DNA template.


Evaluation of a prevention intervention to reduce HIV Risk among Angolan soldiers.
We developed and evaluated a military-focused HIV prevention intervention to enhance HIV risk-reduction knowledge, motivation, and behaviors among Angolan soldiers. Twelve bases were randomly assigned to HIV prevention or control conditions, yielding 568 participants. HIV prevention participants received training in preventing HIV (4.5 days) and malaria (0.5 days). Control participants received the reverse. Monthly booster sessions were available after each intervention. We assessed participants at baseline, 3 and 6 months after the training. HIV prevention participants reported greater condom use and less unprotected anal sex at 3 months, as well as greater HIV-related knowledge and perceived vulnerability at 3 and 6 months. Within-group analyses showed HIV prevention participants increased condom use, reduced unprotected vaginal sex, and reduced numbers of partners at both follow-ups, while control participants improved on some outcomes at 3 months only. A military-focused HIV prevention intervention may increase HIV-related knowledge, motivation, and risk reduction among African soldiers.


Separation and characterization of ciprofloxacin, difloxacin, lomefloxacin, norfloxacin, and ofloxacin oxidation products under potassium permanganate treatment in acidic medium by UPLC-MS/MS.
A simple, sensitive and reproducible ultra-performance liquid chromatography method for determination of ciprofloxacin, difloxacin, lomefloxacin, norfloxacin and ofloxacin oxidation stability under permanganate treatment in acidic conditions at pH from 3.0 to 6.0, was developed. Chromatographic separations were carried out using the Acquity UPLC BEH C18 column; (2.1×100 mm, 1.7 μm particle size). The column was maintained at 40°C, and eluted under isocratic conditions using 83% of eluent A and 17% of eluent B over 6.5 min, at a flow rate of 0.3 mL min(-1). Eluent A: water/formic acid (0.1 v/v%); eluent B: acetonitrile/formic acid (0.1 v/v%). An oxidation process followed kinetic of the second order reaction and depended upon solution acidity. Oxidation of fluoroquinolones proceeded at piperazine moiety yielding respective hydroxy and oxo analogs, and remaining the quinolone fragment intact. Structures of products formed were assigned on a basis of UPLC/MS/MS fragmentation pathways.


Determination of spin-orbit coupling contributions in the framework of density functional theory.
We present a noniterative method to calculate spin-orbit coupling by means of a theoretical approach that provides the use of the full Breit-Pauli operator. This method was applied to compute one and two-electron spin-orbit coupling contributions between singlet and triplet, and doublet and doublet states, respectively. These states have been represented by monodeterminantal wave functions and optimized using the PW91 gradient-corrected exchange-correlation functional and the hybrid B3LYP one. They have been supplied by the conventional density functional theory packages, and thus coupled by our spin-orbit coupling code. Different size basis sets have been employed and the obtained results have been compared with the corresponding ones provided by some of the already existing methods and with the experimental data. They have been found to be in good quantitative agreement.


Overexpression of transmembrane TNFα in brain endothelial cells induces schizophrenia-relevant behaviors.
Upregulation of genes and coexpression networks related to immune function and inflammation have been repeatedly reported in the brain of individuals with schizophrenia. However, a causal relationship between the abnormal immune/inflammation-related gene expression and schizophrenia has not been determined. We conducted co-expression networks using publicly available RNA-seq data from prefrontal cortex (PFC) and hippocampus (HP) of 64 individuals with schizophrenia and 64 unaffected controls from the SMRI tissue collections. We identified proinflammatory cytokine, transmembrane tumor necrosis factor-α (tmTNFα), as a potential regulator in the module of co-expressed genes that we find related to the immune/inflammation response in endothelial cells (ECs) and/or microglia of the brain of individuals with schizophrenia. The immune/inflammation-related modules associated with schizophrenia and the TNF signaling pathway that regulate the network were replicated in an independent cohort of brain samples from 68 individuals with schizophrenia and 135 unaffected controls. To investigate the association between the overexpression of tmTNFα in brain ECs and schizophrenia-like behaviors, we induced short-term overexpression of the uncleavable form of (uc)-tmTNFα in ECs of mouse brain for 7 weeks. We found schizophrenia-relevant behavioral deficits in these mice, including cognitive impairment, abnormal sensorimotor gating, and sensitization to methamphetamine (METH) induced locomotor activity and METH-induced neurotransmitter levels. These uc-tmTNFα effects were mediated by TNF receptor2 (TNFR2) and induced activation of TNFR2 signaling in astrocytes and neurons. A neuronal module including neurotransmitter signaling pathways was down-regulated in the brain of mice by the short-term overexpression of the gene, while an immune/inflammation-related module was up-regulated in the brain of mice after long-term expression of 22 weeks. Our results indicate that tmTNFα may play a direct role in regulating neurotransmitter signaling pathways that contribute to the clinical features of schizophrenia.


Medical audit after 26,711 breast imaging studies: improved rate of detection of small breast carcinomas (classified as Tis or T1a,b)
Patients with breast carcinomas 1 cm or smaller are known to have the highest long term survival rates. This pathologic measurement was used as a quality indicator of the performance of different reporting radiologists. A total of 26,711 diagnostic breast imaging studies were performed over a period of 5 years. Within the first 18 months, several general radiologists reported mammograms, whereas during the rest of the evaluated period only 1 radiologist was responsible for all mammography reporting. Radiologic findings leading to open biopsy were correlated with the histologic results. The cancer sizes from the histologic reports were recorded, and the number of Tis, T1a, and T1b cancers were correlated with all cancers found at open biopsy. The change in the relative percentage of small cancers was evaluated, along with the positive predictive value (PPV). Between 1991 and 1995, 26,711 breast imaging studies were performed. This resulted in 2698 open biopsies with 620 breast carcinomas detected. In the first 2 years, the percentages of small cancers detected (Tis or T1a,b) were 27.2% and 25.7%, respectively. In the third, fourth, and fifth years, the percentages increased to 38.8%, 34.5%, and 38.8%, respectively. At the same time, the PPV increased slightly, from 0.23 in 1991 to 0.27 in 1995. The detection of curable early stage breast carcinomas requires the dedication and commitment of a small group of radiologists who are willing to spend most of their time on this single subject. This will increase considerably the number of early stage cancers found and reduce the number of false-positive diagnoses. [See editorial counterpoint on pages 2430-1 and reply to counterpoint on pages 2432-3.]


Longer Operative Time and the Use of Anticoagulants Are Associated With Increased Blood Loss in Elderly Patients Undergoing Arthroscopic Rotator Cuff Repair.
To study the effects of rotator cuff tear size, operation time, and the use of anticoagulant on blood loss in elderly patients undergoing arthroscopic rotator cuff surgery. Patients aged older than 65 years who underwent arthroscopic rotator cuff repair with subacromial decompression at our hospital from January 2015 to December 2021 were identified. We measured hemoglobin levels preoperatively, postoperatively, and 7 days after surgery. First, subjects were divided according to the operation time (group I, <90 minutes; group II, <120 minutes; group III <150 minutes; and group IV, >150 minutes). Second, we classified the subjects by the size of the rotator cuff tear (group A, <3 cm; group B, <5 cm; and group C, >5 cm). Lastly, we categorized the subjects into 2 groups according to the use of anticoagulant medication. A total of 566 patients were included. The mean hemoglobin (Hgb) levels were 13.8 ± 1.4 g/dL preoperatively, 13.2 ± 1.4 g/dL postoperatively, and 12.8 ± 1.3 g/dL 7 days after surgery, and the differences among them were statistically significant (P < .001). The Hgb level changes 7 days after surgery showed a significant decrease in the group with a longer operation time, and the Hgb loss increased from group 1 to group 4 (P < .001). They did not show any difference in the Hgb levels among the groups according to the size of a cuff tear preoperatively, postoperatively, and 7 days after surgery. The subjects with anticoagulant use showed more decrease in Hgb levels between immediately after the surgery and 7 days after the surgery (P = .031). Still, both groups did not show a statistical difference in the Hgb level 7 days after surgery (P = .115). In this study, blood loss after arthroscopic rotator cuff repair in elderly patients was greater than expected. Bleeding increased in elderly patients who had longer surgical times or were taking anticoagulant medications after surgery. Tear size was not associated with a decrease in Hgb levels. Level III, retrospective comparative study.


Rapid measurement of fatty acid content during flour storage using a color-sensitive gas sensor array: Comparing the effects of swarm intelligence optimization algorithms on sensor features.
The fatty acid content of flour is an important indicator for determining the deterioration of flour. We propose a novel rapid measurement method for fatty acid content during flour storage based on a self-designed color-sensitive gas sensor array. First, a color-sensitive gas sensor array was prepared to capture the odor changes during flour storage. The sensor features were then optimized using genetic algorithm (GA), ant colony optimization (ACO) and particle swarm optimization (PSO). Finally, back propagation neural network (BPNN) models were established to measure the fatty acid content during flour storage. Experimental results showed that the optimization effects of the three algorithms improved in the following order: GA < ACO < PSO, for the sensor features optimization. In the validation set, the determination coefficient of the best PSO-BPNN model was 0.9837. The overall results demonstrate that the models established on the optimized features can realize rapid measurements of fatty acid content during flour storage.


BRAF inhibitor therapy in HCL.
Targeted treatment approaches are transforming the therapeutic landscape of cancer care. The discovery of the BRAF V600E mutation in most cases of classical hairy cell leukemia opens up unique opportunities for tumor specific treatment of HCL targeting the MEK/ERK signaling pathway. The discovery and biological implications of BRAF V600E in HCL are summarized to form a basis for our current understanding of the potential for clinical exploitation. There is overwhelming clinical evidence for activity of inhibitors of BRAF in the disease. The review will review current trial activity as well as discuss novel trial concepts exploiting targeted treatment focusing on BRAF inhibition in HCL.


Force acquisition frequency is less impaired compared to grip strength or hand dexterity in individuals with chronic stroke.
Despite numerous studies that show force regulation is impaired after stroke, two recent studies suggest that the ability to regulate submaximal, isometric grip forces may remain substantially intact. Here we asked how this aspect of hand motor control, measured for both a power grip and pinch grip, compares to two other key aspects of hand function-grip strength and dexterity. For 20 individuals with a range of hand impairment levels in the chronic phase of stroke (Age: 62 ± 16.0 years, Time post stroke: 958.3 ± 966.5 days, Sex: 19 M 1F) we quantified the average rate of target acquisition for force targets in the range of 3 to 30% maximum voluntary contraction as participants used the two different grips to squeeze a force sensor to control a cursor on a screen. The same force sensor was used to assess subject grip strength for the two grips, while dexterity was assessed using the Box and Blocks Test (BBT), and the Nine Hole Peg Test (NHPT) for both the paretic and non-paretic hand. On average, the relative rate of force acquisition of the paretic hand using a power grip was 74.0 ± 18.6 SD % of the non-paretic hand, a value significantly higher than the 48.6 ± 25.6 SD% for grip strength (paired t test, p < .005) or the 41.4 ± 29.1 SD % (p < .005) and 23.3 ± 30.1 SD % (p < .005) for the BBT and NHPT, respectively. Results were similar for the lateral pinch grip, suggesting similar thumb force tracking performance. Grip force tracking, measured as rate of force acquisition, is less impaired after stroke than hand strength or dexterity, a finding with implications for the neural mechanisms of stroke and the design of assistive technologies.


Uptake of 99mTc-phytate in osteosarcoma cases.
During routine liver spleen scintigraphic studies using 99mTc-phytate in patients with proven osteosarcoma, an unusual uptake of this radiopharamaeutical at the primary site was observed. In all, five cases have been investigated and we have observed the uptake of 99mTc-phytate at the primary tumor site. Early and delayed imaging showed persistant concentration of the radiopharmaceutical. Studies with 99mTc-sulfur colloid in one of the patients did not show any uptake at the tumor site.


Molecular cloning and analysis of a yeast protein phosphatase with an unusual amino-terminal region.
DNA fragments containing structural characteristics found in Ser/Thr protein phosphatases were amplified by polymerase chain reaction from yeast genome. Amplification was carried out by using degenerate oligonucleotides encoding conserved sequences found in type 1, 2A, and 2B phosphatases. A 215-base pair amplification fragment was used to screen a size-selected library, and a positive clone was isolated and sequenced. Nucleotide sequencing revealed a 2076-base pair open reading frame encoding a 692-amino acid protein. The carboxyl half of the protein is structurally related to type 1 phosphatases and virtually identical with the sequence reported as PPZ1, whereas the amino-terminal half of the protein is unrelated to sequences found in other protein phosphatases. This region is very rich in Ser residues and presents a high number of basic amino acids. Therefore, the gene product, on the basis of its unique structure, would represent a novel class of protein phosphatase. The gene, which is located at chromosome XIII, is transcribed as a mRNA of about 2.7 kilobases, and the amount of message has been found to increase 3- to 4-fold during the culture. The product of the gene PPZ1 was identified by immunoblot analysis of cell extracts as a 75-kDa protein, and the amount of immunoreactive protein was increased in cells carrying multiple copies of the gene. Disruption of the gene resulted in viable cells, with no detectable phenotypic change, indicating that the gene is not essential for growth.


Can leisure-time physical activity improve health checkup results? Evidence from Japanese occupational panel data.
We examined the extent to which changes in worker health, as measured by health checkup items, were associated with increased intensity of leisure-time physical activity (LTPA) after controlling for individual time-invariant attributes. We used panel data from two to four waves of a Japanese occupational cohort survey, focusing on 30,206 observations of 10,106 individuals (7,669 men and 2,437 women) aged 18-76 years. We estimated first-difference and mean-centered fixed effects models to examine how changes in 10 health checkup items were associated with changes in LTPA intensity. We considered four LTPA intensity levels (none, low, moderate, and vigorous), based on self-reported assessments. For men, low-density lipoprotein cholesterol levels, glycated hemoglobin levels, body mass index, and waist circumference improved when LTPA intensity was increased even at a low level, whereas triglyceride, high-density lipoprotein cholesterol, and fasting blood glucose levels improved when LTPA intensity was increased to moderate or vigorous levels. Blood pressure (both systolic and diastolic) and total cholesterol levels were only modestly responsive to changes in LTPA intensity. For women, blood pressure (both systolic and diastolic) and waist circumference were negatively associated with LTPA intensity, whereas the other variables showed more modest effects. The results suggest that even low- to moderate-intensity LTPA can improve health checkup results; however, the lowest LTPA intensity associated with improvement in health depends on health-risk factors as well as gender.


Wide distribution and subcellular localization of histamine in sympathetic nervous systems of different species.
Previous studies have demonstrated that histamine (HA) acts as a neurotransmitter in the cardiac sympathetic nervous system of the guinea pig. The aim of the current study was to examine whether HA widely exists in the sympathetic nervous systems of other species and the subcellular localization of HA in sympathetic terminals. An immunofluorescence histochemical multiple-staining technique and anterograde tracing method were employed to visualize the colocalization of HA and norepinephrine (NE) in sympathetic ganglion and nerve fibers in different species. Pre-embedding immunoelectron microscopy was used to observe the subcellular distribution of HA in sympathetic nerve terminals. Under the confocal microscope, coexistence of NE and HA was displayed in the superior cervical ganglion and celiac ganglion neurons of the mouse and dog as well as in the vas deferens, mesenteric artery axon, and varicosities of the mouse and guinea pig. Furthermore, colocalization of NE and HA in cardiac sympathetic axons and varicosities was labeled by biotinylated dextranamine injected into the superior cervical ganglion of the guinea pig. By electron microscopy, HA-like high-density immunoreactive products were seen in the small vesicles of the guinea pig vas deferens. These results provide direct cellular and subcellular morphological evidence for the colocalization of HA and NE in sympathetic ganglion and nerve fibers, and support that HA is classified as a neurotransmitter in sympathetic neurons.


A rapid method for the nonselective enumeration of Yersinia enterocolitica, a foodborne pathogen associated with pork.
An impedance method was developed as a rapid, convenient method to enumerate pure culture of Yersinia enterocolitica. Cultures were incubated in trypticase soy broth (TSB) at 30°C. The BacTrac™ 4000 microorganism growth analyser was used to detect impedance change of TSB representing bacteria cell numbers in the samples. Good correlations with standard plate counts were obtained (r(2)>0.95). This method is also reliable to enumerate Y. enterocolitica growing in biofilms attached to stainless steel. Compared with a standard plate count which involves dislodging biofilms from surfaces, this method is more convenient saving both time and effort. Therefore, it will be useful to study the conditions required for the biofilm growth and control of Y. enterocolitica that could be applied to the pork industry.


Further analysis of the monoclonal antibody H8 demonstrating a JMH-related specificity.
The monoclonal antibody H8, previously described as anti-JMH, has the same specificity as a JMH-related antibody, R.M. H8 blocks the reaction of human anti-JMH and related antibodies with JMH+ cells, suggesting that the JMH-related antigens are very closely situated to each other on the red cell membrane.


Advances in EMG measurement techniques, analysis procedures, and the impact of muscle mechanics on future requirements for the methodology.
Muscular coordination enables locomotion and interaction with the environment. For more than 50 years electromyography (EMG) has provided insights into the central nervous system control of individual muscles or muscle groups, enabling both fine and gross motor functions. This information is available either at individual motor units (Mus) level or on a more global level from the coordination of different muscles or muscle groups. In particular, non-invasive EMG methods such as surface EMG (sEMG) or, more recently, spatial mapping methods (High-Density EMG - HDsEMG) have found their place in research into biomechanics, sport and exercise, ergonomics, rehabilitation, diagnostics, and increasingly for the control of technical devices. With further technical advances and a growing understanding of the relationship between EMG and movement task execution, it is expected that with time, especially non-invasive EMG methods will become increasingly important in movement sciences. However, while the total number of publications per year on non-invasive EMG methods is growing exponentially, the number of publications on this topic in journals with a scope in movement sciences has stagnated in the last decade. This review paper contextualizes non-invasive EMG development over the last 50 years, highlighting methodological progress. Changes in research topics related to non-invasive EMG were identified. Today non-invasive EMG procedures are increasingly used to control technical devices, where muscle mechanics have a minor influence. In movement science, however, the effect of muscle mechanics on the EMG signal cannot be neglected. This explains why non-invasive EMG's relevance in movement sciences has not developed as expected.


Gap-PCR Screening for Common Large Deletional Mutations of β-Globin Gene Cluster Revealed a Higher Prevalence of the Turkish Inversion/Deletion (δβ)0 Mutation in Antalya.
Although the calculated carrier frequency for point mutations of the β-globin gene is around 10% for Antalya Province, nothing is known about the profile of large deletional mutations involving the β-globin gene. In this study, we aimed to screen common deletional mutations in the β-globin gene cluster in patients for whom direct DNA sequencing was not able to demonstrate the mutation(s) responsible for the disease phenotype. Thirty-one index cases selected with a series of selection events among 60 cases without detected β-globin gene mutation from 580 thalassemia-related cases tested by direct sequencing over the last 4 years in our diagnostic center were screened for the most common 8 different large deletional mutations of the β-globin gene cluster by gap-PCR. We detected 1 homozygous and 9 heterozygous novel unrelated cases for the Turkish inversion/deletion (δβ)0 mutation in our series of 31 cases. Our study showed that the Turkish inversion/deletion (δβ)0 mutation per se accounts for 16.6% of the unidentified causative alleles and also accounts for 1.5% of all detected mutations over the last 4 years in our laboratory. Since molecular diagnosis of deletional mutations in the β-globin gene cluster warrants different approaches, it deserves special attention in order to provide prenatal diagnosis and prevention opportunities to the families involved. We conclude that the Turkish inversion/deletion (δβ)0, as the most prevalent deletional mutation detected so far, has to be routinely tested for in Antalya, and the gap-PCR approach has valuable diagnostic potential in the patients at risk.


Dopamine neurons projecting to the medial prefrontal cortex possess release-modulating autoreceptors.
The ability of dopamine (DA) agonists and antagonists to modulate the K+-evoked overflow of radioactivity from superfused slices of prefrontal cortex of the rat, preincubated with [3H]DA in the presence of 1 microM desipramine, was examined. Apomorphine and the putative autoreceptor-selective DA agonist EMD 23 448 inhibited the K+-evoked overflow of radioactivity, while the DA antagonist sulpiride enhanced the evoked overflow in a dose-dependent and stereoselective manner. The latter effect was partially reversed by EMD 23 448. More than 95% of the radioactivity retained by the slices chromatographed with DA, while deaminated metabolites represented the majority of both the basal efflux (84% metabolites, 4-5% DA) and evoked overflow (84% metabolites, 14% DA) of radioactivity. These findings indicate that mesoprefrontal DA neurons possess release-modulating nerve terminal autoreceptors. Previous studies have shown that these neurons lack synthesis-modulating autoreceptors. Thus, autoreceptors on prefrontal DA terminals appear to be coupled to regulation of the release but not the synthesis of DA.


Experimental ultrastructural study on stimulation of the rat gastric endocrine cells. In vitro distension of the stomach by air inflation.
The effect of distension of the stomach by air (in vitro) upon the ultrastructural picture of gastric endocrine cells in rats starved for 72 hours was investigated. Distension of the stomach by air in vitro, lasting for 5, 10, 15 and 20 minutes, resulted in massive dissolution of gastrin granules that had accumulated in the course of starvation. In AL, D1, EC and ECL cells distension of the stomach by air failed to induce dissolution of granular content or release of granules by any other mechanism. In AL and D1 cells accumulation of secretory granules caused by starvation was observed, the ultrastructure of EC and ECL cells remained unchanged both under the effect of starvation and distension. Dilatation of endoplasmic reticulum profiles as well as other changes on some cell organelles observed on endocrine cells after distension of the stomach by air in vitro are due to the effect of autolysis.


Long-Term Efficacy and Safety of RNAi-Mediated Virus Resistance in 'HoneySweet' Plum.
Interfering RNA technology has been established as an effective strategy to protect plants against viral infection. Despite this success, interfering RNA (RNAi) has rarely been applied due to the regulatory barriers that confront genetically engineered plants and concerns over possible environmental and health risks posed by non-endogenous small RNAs. 'HoneySweet' was developed as a virus-resistant plum variety that is protected by an RNAi-mediated process against Sharka disease caused by the plum pox virus. 'HoneySweet' has been approved for cultivation in the United States but not in countries where the plum pox virus is endemic. In this study, we evaluated the long-term efficacy of virus resistance in 'HoneySweet,' the nature and stability of its sRNA profile, and the potential health risks of consuming 'HoneySweet' plums. Graft-challenged 'HoneySweet' trees carrying large non-transgenic infected limbs remained virus-free after more than 10 years in the field, and the viral sequences from the non-transgenic infected limbs showed no evidence of adaptation to the RNAi-based resistance. Small RNA profiling revealed that transgene-derived sRNA levels were stable across different environments and, on average, were more than 10 times lower than those present in symptom-less fruits from virus-infected trees. Comprehensive 90-day mouse feeding studies showed no adverse health impacts in mice, and there was no evidence for potential siRNA off-target pathologies predicted by comparisons of the most abundant transgene-derived sRNAs to the mouse genome. Collectively, the data confirmed that RNAi provides a highly effective, stable, and safe strategy to combat virus diseases in crop plants.


Vesicular proteins exocytosed and subsequently retrieved by compensatory endocytosis are nonidentical.
Upon exocytosis, synaptic vesicle proteins are released into the plasma membrane and have to be retrieved by compensatory endocytosis. When green fluorescent protein-labeled versions of the vesicle proteins synaptobrevin-2 and synaptotagmin-1 are overexpressed in rat hippocampal neurons, up to 30% are found on axonal membranes under resting conditions. To test whether and to what extent these plasma membrane-stranded proteins participate in exo-endocytic cycling, a new proteolytic approach was used to visualize the fate of newly exocytosed proteins separately from that of the plasma membrane-stranded ones. We found that both pools were mixed and that endocytosed vesicles were largely composed of previously stranded molecules. The degree of nonidentity of vesicular proteins exo- and endocytosed depended on stimulus duration. By using an antibody to the external domain of synaptotagmin-1, we estimated that under physiological conditions a few percent of vesicular proteins were located near the active zone, from where they were preferentially recycled upon stimulation.


Treatment Time and In-Hospital Mortality Among Patients With ST-Segment Elevation Myocardial Infarction, 2018-2021.
Recognizing the association between timely treatment and less myocardial injury for patients with ST-segment elevation myocardial infarction (STEMI), US national guidelines recommend specific treatment-time goals. To describe these process measures and outcomes for a recent cohort of patients. Cross-sectional study of a diagnosis-based registry between the second quarter of 2018 and the third quarter of 2021 for 114 871 patients with STEMI treated at 648 hospitals in the Get With The Guidelines-Coronary Artery Disease registry. STEMI or STEMI equivalent. Treatment times, in-hospital mortality, and adherence to system goals (75% treated ≤90 minutes of first medical contact if the first hospital is percutaneous coronary intervention [PCI]-capable and ≤120 minutes if patients require transfer to a PCI-capable hospital). In the study population, median age was 63 (IQR, 54-72) years, 71% were men, and 29% were women. Median time from symptom onset to PCI was 148 minutes (IQR, 111-226) for patients presenting to PCI-capable hospitals by emergency medical service, 195 minutes (IQR, 127-349) for patients walking in, and 240 minutes (IQR, 166-402) for patients transferred from another hospital. Adjusted in-hospital mortality was lower for those treated within target times vs beyond time goals for patients transported via emergency medical services (first medical contact to laboratory activation ≤20 minutes [in-hospital mortality, 3.6 vs 9.2] adjusted OR, 0.54 [95% CI, 0.48-0.60], and first medical contact to device ≤90 minutes [in-hospital mortality, 3.3 vs 12.1] adjusted OR, 0.40 [95% CI, 0.36-0.44]), walk-in patients (hospital arrival to device ≤90 minutes [in-hospital mortality, 1.8 vs 4.7] adjusted OR, 0.47 [95% CI, 0.40-0.55]), and transferred patients (door-in to door-out time <30 minutes [in-hospital mortality, 2.9 vs 6.4] adjusted OR, 0.51 [95% CI, 0.32-0.78], and first hospital arrival to device ≤120 minutes [in-hospital mortality, 4.3 vs 14.2] adjusted OR, 0.44 [95% CI, 0.26-0.71]). Regardless of mode of presentation, system goals were not met in most quarters, with the most delayed system performance among patients requiring interhospital transfer (17% treated ≤120 minutes). This study of patients with STEMI included in a US national registry provides information on changes in process and outcomes between 2018 and 2021.


The STAT3 inhibitor S3I-201 suppresses fibrogenesis and angiogenesis in liver fibrosis.
Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 (NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of α-SMA, collagen I and TIMP1 in both primary HSC and in a CCl4-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGFβ1 and TGFβRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFβ1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent.


Anorexia nervosa: an immunohistochemical study of the pituitary gland.
The morphologic features of the anterior pituitary gland were studied by immunohistologic methods in 12 patients who had died of complications of anorexia nervosa, 4 patients who had died while on a "crash diet", 13 patients who had died of organic disease associated with inanition, and 5 age- and sex-matched control subjects who had been involved in sudden fatal accidents. All known pituitary hormones were found to be present. Abnormalities noted in both the patients with anorexia and those with organic inanition included relative hypogranulation of adrenocorticotropic and, to a lesser extent, growth hormone cells. These changes are of unknown importance but are likely the result of starvation in that they were not observed in patients on a "crash diet" or in control patients. We conclude that no specific or etiologic abnormalities are present in the pituitary glands of subjects with anorexia nervosa and that the altered secretion of adenohypophyseal hormones often noted in patients with this disorder cannot be attributed to a primary pituitary disorder.


Phase III study of HR-positive/HER2-negative/lymph node-positive breast cancer non-responsive to primary chemotherapy: a randomized trial.
There are few studies focus on post-neoadjuvant treatment in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-)/lymph node-positive (LN+) breast cancer, a multi-center, open-label, randomized, controlled phase III trial was conducted to evaluate pathological response-guided non-cross-resistant adjuvant chemotherapy in patients with HR+/HER2-/LN+ breast cancer who were non-responsive to primary chemotherapy. Patients received four cycles of non-cross-resistant adjuvant chemotherapy plus endocrine therapy (ET), or ET alone. Forty patients responsive to neoadjuvant chemotherapy and with Miller and Payne G4 or G5 and LN- status were assigned to the observation group. Distant disease-free survival was the primary endpoint. The final intention-to-treat analysis comprised 379 patients. After a median follow-up period of 72.4 months, the 5-year distant disease-free survival was 92% and 90% in the chemotherapy plus ET and ET-alone groups, respectively. Comparatively, the observation group showed a trend towards better distant disease-free survival. For patients non-responsive to neoadjuvant chemotherapy, adjuvant non-cross-resistant chemotherapy did not significantly improve distant disease-free survival compared to ET alone.


An analysis of uterine activity in spontaneous labour using a microcomputer.
A microcomputer was used to analyse uterine activity during spontaneous labour in 30 nulliparous and 30 parous patients. The intrauterine mean active pressure (MAP) in the nulliparous group was 1.51 kPa (SD 0.45) in the first stage and 2.71 kPa (SD 0.77) in the second stage. For the parous group, the MAP in the first stage was 1.22 kPa (SD 0.37) and in the second stage was 2.92 kPa (SD 0.98). A significant parity difference in MAP and contraction frequency was observed in the first stage but not in the second stage. Epidural analgesia did not appear to influence uterine activity in the first stage but was associated with a lower MAP, contraction frequency and intensity in the second stage. During the first stage, MAP increased by 21% in nulliparas and by 39% in multiparas. The rise in MAP was mainly due to an increase in contraction frequency.


[Functional diagnosis after anorectal injuries].
Anorectum - rectum and rectosigmoid functions can be separately investigated by employing water-filled probes which have been connected to a pressure transducer. Sphincter ani externus - internus and the puborectal muscle functions particularly well. In cases of injuries to the continent organ preoperative electromanometry clarify the extent of damage. Postoperative examination then enables the evaluation of the success or failure of the reconstruction procedure. Four select cases are presented graphically and in detail illustrating the complexity of the process.


Paradoxical pseudomyotonia in English Springer and Cocker Spaniels.
Paramyotonia congenita and Brody disease are well-described conditions in humans, characterized by exercise-induced myotonic-like muscle stiffness. A syndrome similar to Brody disease has been reported in cattle. Reports of a similar syndrome in dogs are scarce. To define and describe the clinical, diagnostic, and genetic features and disease course of paradoxical pseudomyotonia in Spaniel dogs. Seven client-owned dogs (4 English Springer Spaniels and 3 English Cocker Spaniels) with clinically confirmed episodes of exercise-induced generalized myotonic-like muscle stiffness. Sequential case study. All dogs were <24 months of age at onset. The episodes of myotonic-like generalized muscle stiffness always occurred with exercise, and spontaneously resolved with rest in <45 seconds in all but 1 dog. Extreme outside temperatures seemed to considerably worsen episode frequency and severity in most dogs. Complete blood count, serum biochemistry including electrolytes, urinalysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, electromyography, motor nerve conduction velocity, ECG, and echocardiography were unremarkable. Muscle biopsy samples showed moderate but nonspecific muscle atrophy. The episodes seemed to remain stable or decrease in severity and frequency in 6/7 dogs, and often could be decreased or prevented by avoiding the episode triggers. The underlying genetic cause is not identified yet, because no disease-causing variants could be found in the coding sequence or splice sites of the 2 major candidate genes, SCN4A and ATP2A1. Paradoxical pseudomyotonia is a disease affecting Spaniels. It is of variable severity but benign in most cases.


On chorea: possible neuronal mechanisms.
The mechanism of generation of choreic movements is a rather difficult issue to be elucidated, chiefly due to the lack of a good animal model. Recently we have succeeded to reproduce choreic movements in monkey by using kainic acid lesion of the striatum and the administration of L-dopa. Based on the morphological and biochemical findings of monkey brains, we proposed the hypothesis for the mechanism of choreic movements to be the presynaptic "activation" of the nigro-striatal dopaminergic pathways rather than the postsynaptic dopaminergic receptors in the striatum. This hypothesis coincide well with the clinical and clinico-pharmacological experience in Huntington's disease. The possible mechanisms of the dopaminergic "activation" are discussed.


Role of delayed intraaortic balloon pumping in treatment of experimental myocardial infarction.
Intraaortic balloon pumping improves coronary blood flow characteristics while simultaneously reducing myocardial oxygen demands by reducing aortic systolic pressure. Clinical application of intraaortic balloon pumping has largely been in the "high risk" patient (cardiogenic shock, postinfarction angina, left main coronary artery disease and unstable angina) for support during diagnostic studies or cardiac surgery, or both. In addition, there is some evidence that balloon pumping immediately after coronary occlusion reduces the size of experimentally induced myocardial infarcts. In this study, myocardial infarcts were produced by ligation of the left anterior descending coronary artery in 12 dogs, 6 of which were treated with balloon counterpulsation beginning 3 hours after coronary occlusion. All dogs were killed 8 hours after coronary ligation. Intraaortic balloon pumping resulted in the expected hemodynamic changes (decreased aortic systolic pressure, left ventricular end-diastolic pressure and heart rate and increased aortic peak diastolic pressure). In addition, there was a significant reduction in infarct size in the group with balloon pumping as determined with epicardial S-T segment mapping, myocardial imaging with technetium-99m-glucoheptonate and histochemical staining with nitroblue tetrazolium. These results suggest that even when instituted as long as 3 hours after coronary occlusion, intraaortic balloon pumping results in significant reduction in infarct size and, it might be speculated, the mortality and morbidity associated with acute myocardial infarction may also be decreased.


Design, Modeling, and Experimental Evaluation of a Compact Piezoelectric XY Platform for Large Travel Range.
A novel piezoelectric XY platform driven by a single actuator was presented for a large travel range and compact structure. The actuator operated at the inertial mechanism and moved the output platform step-by-step. A dynamic model of the piezoelectric actuator was established based on the Timoshenko beam theory and Galerkin procedure, which was used to aid the structure design. The dynamic model of the platform system was established based on the dynamic model of the actuator and the LuGre friction model. A prototype was fabricated and its experimental system was established; the total size was 100 × 100 × 93.5 mm3 and the travel range was 15 × 15 mm2. The measured stepper motions agreed well with the simulation results, and the correctness of the dynamic model was confirmed. The proposed platform achieved maximum speeds of 2.13 and 3.11 mm/s along the axes X and Y , respectively, and a carrying capacity of 20 kg was achieved. Furthermore, the closed-loop control experiments, including the positioning resolution and the sinusoidal trajectory tracking, were carried out, and a positioning resolution better than [Formula: see text] and a tracking error rate of 4% were achieved, which revealed the potential of the proposed piezoelectric platform in field of manipulating heavy objects with submicrometer accuracy and large travel range, especially for some specific fields including microparticle manipulation, ultraprecision manufacturing, and optical device posture adjustment where large travel range, high accuracy, and multidimension are expected.


Evaluation of the immunogenicity and in vivo toxicity of the antimicrobial peptide P34.
Immunogenicity and toxicity of antimicrobial peptide P34 were evaluated in vivo. BALB/c mice were inoculated intraperitoneally with peptide P34 alone and associated with Freund's adjuvant. For acute toxicity testing, different concentrations of the peptide P34 (82.5, 165.0, 247.5 and 330.0mg/kg) were orally administered. To evaluate the sub-chronic toxicity the tested dose of 0.825 mg/kg/day of the peptide P34 or nisin were administered for 21 days. There were no hypersensitivity reactions or significant increase in antibody titer during the immunogenicity experiment or death of animals during the acute or sub-chronic toxicity tests. The LD(50) was higher than 332.3 ± 0.76 mg/kg. No significant changes in serum biochemical parameters were observed in the animals treated with the peptide P34 unlike nisin-treated group showed a significant increase in alanine transaminase levels in comparison to controls. The group treated with 0.825 mg/kg/day of nisin showed histological changes in the spleen, skin and liver. In the group treated with peptide P34 histological changes in the spleen were observed, with the presence of megakaryocytes. Few studies report the use of animal models to evaluate the in vivo toxicity of antimicrobial peptides and such investigation is an essential step to ensure it safe use in foods.


Shift Workers With Shift Work Disorder Have Worse Lower Urinary Tract Symptoms.
To examine the association between shift work or shift work disorder (SWD) and lower urinary tract symptoms (LUTS). Nonstandard shift workers are defined as those working shifts outside of a normal 7 AM-6 PM work day. Men presenting to a single andrology clinic between July 2014 and June 2017 completed questionnaires that included questions about work schedules, shift work status, SWD[1][1], personal well-being via the Patient Health Questionnaire-9, and LUTS (International Prostate Symptom Score [IPSS]). Men who had previously undergone prostate surgery were excluded. Shift work and SWD on IPSS was assessed via multivariate linear regression. Of the 2571 men who completed all questionnaires, 619 (24.1%) reported working nonstandard shifts in the past month. Of these, 196 (31.7%) had high risk of SWD as determined by a questionnaire. When controlling for age, medications, surgical intervention for benign prostatic hyperplasia, comorbidities, and testosterone (T) levels, nonstandard shift work overall was not associated with worse LUTS (P = .82). However, nonstandard shift workers at high risk for SWD had IPSS scores that were clinically significantly higher (3.74 points ± 0.57 standard error) than nonstandard shift workers without SWD (P <.0001). Nonstandard shift workers at high risk for SWD have worse LUTS than those without SWD. However, no association between nonstandard shift work and LUTS was found.


Separation of carbon nanotubes in aqueous medium by capillary electrophoresis.
A robust and reproducible method for the dispersion of carbon nanotubes, either single-walled or multi-walled is presented. Dispersion of nanotubes was achieved as surfactant-coated species of sodium dodecyl sulphate. The addition of small amounts of hydroxypropyl methyl cellulose (HPMC) together with the surfactant, sodium dodecyl sulphate, was found critical to achieve reproducible nanotubes dispersion and to obtain an homogeneous and stable solution. This solution is further analyzed by capillary electrophoresis using a background electrolyte solution containing a polymer, 0.025% (w/v) HPMC solution prepared in 5 mM ammonium acetate at pH 8.03. This electrophoretic method presents a high reproducibility between runs, being an interesting alternative to study nanotube size distribution or characterization after synthesis. In addition, the methodology developed allowed the study of the interaction of the different types of carbon nanotubes with a molecular probe such as pentachlorophenol. This procedure was showed effective to detect small differences on the chemical/physical surface properties of the nanotubes. The different interaction behavior found within the two SWNTs selected was critically discussed.


Functional impact of HIV-1 Tat on cells of the CNS and its role in HAND.
Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) is a potent mediator involved in the development of HIV-1-associated neurocognitive disorders (HAND). Tat is expressed even in the presence of antiretroviral therapy (ART) and is able to enter the central nervous system (CNS) through a variety of ways, where Tat can interact with microglia, astrocytes, brain microvascular endothelial cells, and neurons. The presence of low concentrations of extracellular Tat alone has been shown to lead to dysregulated gene expression, chronic cell activation, inflammation, neurotoxicity, and structural damage in the brain. The reported effects of Tat are dependent in part on the specific HIV-1 subtype and amino acid length of Tat used. HIV-1 subtype B Tat is the most common subtype in North American and therefore, most studies have been focused on subtype B Tat; however, studies have shown many genetic, biologic, and pathologic differences between HIV subtype B and subtype C Tat. This review will focus primarily on subtype B Tat where the full-length protein is 101 amino acids, but will also consider variants of Tat, such as Tat 72 and Tat 86, that have been reported to exhibit a number of distinctive activities with respect to mediating CNS damage and neurotoxicity.


Infection control measures for public transportation derived from the flow dynamics of obstructed cough jet.
During the COVID-19 pandemic, WHO and CDC suggest people stay 1 m and 1.8 m away from others, respectively. Keeping social distance can avoid close contact and mitigate infection spread. Many researchers suspect that suggested distances are not enough because aerosols can spread up to 7-8 m away. Despite the debate on social distance, these social distances rely on unobstructed respiratory activities such as coughing and sneezing. Differently, in this work, we focused on the most common but less studied aerosol spread from an obstructed cough. The flow dynamics of a cough jet blocked by the backrest and gasper jet in a cabin environment was characterized by the particle image velocimetry (PIV) technique. It was proved that the backrest and the gasper jet can prevent the front passenger from droplet spray in public transportation where maintaining social distance was difficult. A model was developed to describe the cough jet trajectory due to the gasper jet, which matched well with PIV results. It was found that buoyancy and inside droplets almost do not affect the short-range cough jet trajectory. Infection control measures were suggested for public transportation, including using backrest/gasper jet, installing localized exhaust, and surface cleaning of the backrest.


Renewable marine polysaccharides for microenvironment-responsive wound healing.
Marine polysaccharides (MPs) are an eco-friendly and renewable resource with a distinctive set of biological functions and are regarded as biological materials that can be in contact with tissues and body fluids for an extended time and promote tissue or organ regeneration. Skin tissue is easily invaded by the external environment due to its softness and large surface area. However, the body's natural physiological healing process is often too slow or suffers from the incomplete restoration of skin structure and function. Functional wound dressings are crucial for skin tissue engineering. Herein, popular MPs from different sources are summarized systematically. In particular, the structure-effectiveness of MP-based wound dressings and the physiological remodeling process of different wounds are reviewed in detail. Finally, the prospect of MP-based smart wound dressings is stated in conjunction with the wound microenvironment and provides new opportunities for high-value biomedical applications of MPs.


Automated analytical microsystem for the spectrophotometric monitoring of titratable acidity in white, rosé and red wines.
The design, construction and evaluation of a low-cost cyclic olefin copolymer (COC)-based continuous flow microanalyzer with optical detection to determine the titratable acidity content of wine is here presented. The analysis method is based on the monitoring of the blue coloration decrease of a buffered bromothymol blue (BTB) solution in the presence of the acidic compounds of wine. The microanalyzer monolithically integrates the required microfluidic motifs as well as an optical flow cell where the measurements are performed by using a miniaturized and versatile photometric detection system. Fluid management is totally automated by the use of computer-controlled microvalves, permitting the automatic calibration of the system as well as the automatic sampling, including in-line dilution and analysis. The reduced size of the whole system along with its high simplicity and automation make it suitable for its application to the on-line monitoring of titratable acidity during wine-making processes. With the optimal conditions, a linear range up to 0.50 g L-1 tartaric acid, a quantification limit (LOQ) of 0.01 g L-1 and a detection limit (LOD) of 0.004 g L-1 were obtained, covering the most common acidity content of musts and wines. A sampling rate up to 26 h-1 could be achieved, consuming less than 3 mL of inexpensive reagents per analysis and requiring no pretreatment of the sample. The microsystem has been successfully applied to the quantification of the titratable acidity content of several wine samples, being the results in excellent agreement with the ones obtained by the reference method.


Drug-protein conjugates--XV. A study of the disposition of D-penicillamine in the rat and its relationship to immunogenicity.
The disposition of [14C]D-penicillamine (PA) was investigated in vitro and in vivo with male Wistar rats. Irreversible binding of [14C]PA to isolated rat plasma proteins in vitro reached a maximum of 20.6% of total radioactivity at 6 hr. Irreversibly bound [14C]PA could be dissociated with dithiothreitol, demonstrating that conjugation was via disulphide linkage. Three hours after i.v. administration of [14C]PA (27 mumol/kg) to rats 100% of plasma radioactivity was irreversibly bound, representing approximately 3.5% of the dose. Further studies on the disposition of PA-plasma protein conjugates showed that dissociation occurred readily in vivo: the plasma half-life of the conjugate was approximately 3 hr. Free [14C]PA was the major urinary metabolite after administration of both free and conjugated drug. These studies show that the disposition of PA is similar to that reported for the structurally related sulphydryl drug captopril (CP). Free PA (340 mumol/kg and 3.4 mmol/kg) administered i.p. and i.m. daily for 4 days at one monthly intervals, and also PA-KLH conjugate (100 micrograms/rat) administered by single i.p. injection at monthly intervals with and without Freund's complete adjuvant, failed to induce PA-specific IgG or IgM antibody responses detectable by ELISA. In contrast, CP (270 mumol/kg), administered by the same protocol as free PA, induced a CP-specific IgG antibody response after the third series of monthly injections. These data suggest that the difference in immunogenicity between PA and CP arises from a difference in the intrinsic immunogenicity of the haptens, rather than from their disposition.


Structurally diverse steroids from an endophyte of Aspergillus tennesseensis 1022LEF attenuates LPS-induced inflammatory response through the cholinergic anti-inflammatory pathway.
The emerging cholinergic anti-inflammatory pathway plays a key role in regulating inflammation. Steroids are known to possess remarkable anti-inflammatory activity. However, the links between steroids and the cholinergic anti-inflammatory pathway remain unidentified. In this study, eight steroids (1-8) featuring five different structural types were characterized from an endophytic fungus Aspergillus tennesseensis 1022LEF, and were subsequently evaluated for their potential role in regulating the cholinergic anti-inflammatory pathway. As a result, compound 8, with the best potency, showed remarkable anti-inflammatory activity at the nanomolar to low micromolar level. Further pharmacological study indicated that 8 notably increased α7nAchR expression and inhibited the activation of its down-stream signaling pathways. Collectively, the present study not only highlighted the potential correlation between steroids and the cholinergic anti-inflammatory pathway, but also identified 8 as a dual-functional modulator via directly inhibition to acetylcholinesterase as well as up-regulation of α7nAchR expression.


Clonal analysis reveals laminar fate multipotency and daughter cell apoptosis of mouse cortical intermediate progenitors.
In developing cerebral cortex, most pyramidal-projection neurons are produced by intermediate progenitors (IPs), derived in turn from radial glial progenitors. Although IPs produce neurons for all cortical layers, it is unknown whether individual IPs produce multiple or single laminar fates, and the potential of IPs for extended proliferation remains uncertain. Previously, we found that, at the population level, early IPs (present during lower-layer neurogenesis) produce lower- and upper-layer neurons, whereas late IPs produce upper-layer neurons only. Here, we employed mosaic analysis with double markers (MADM) in mice to sparsely label early IP clones. Most early IPs produced 1-2 neurons for deep layers only. Less frequently, early IPs produced larger clones (up to 12 neurons) spanning lower and upper layers, or upper layers only. The majority of IP-derived clones (∼66%) were associated with asymmetric cell death after the first division. These data demonstrate that laminar fate is not predetermined, at least in some IPs. Rather, the heterogeneous sizes and laminar fates of early IP clones are correlated with cell division/death/differentiation choices and neuron birthdays, respectively.


Global shockwaves of the Hunga Tonga-Hunga Ha'apai volcano eruption measured at ground stations.
The eruption of the Tonga volcano created globally propagating spherical shockwaves in the atmosphere. Analyses are done to data from two southern U.S. stations of the author sampling at 3-21 s intervals and 189 weather stations at 1-5 min intervals. The shockwaves arrived from two routes in the atmosphere: the shortest spherical arc and the longer spherical arc through the antipole. In most stations, signals up to the 6th path of shockwaves were recorded as the waves traveled around the globe multiple times. The speed of shockwaves is estimated to be 309.5 ± 2.9 m/s, consistent with the speed of sound at the top of the troposphere where a waveguide exists. Discussion is made on the post-shockwave ringing of 4-8 min as higher amplitude oscillations above the level of pre-shockwaves background noise. A theoretical wave dispersion is derived which verifies that the spherical shockwave's phase speed is the same as the speed of sound.


Evidence of the emergence of illicit benzodiazepines from online drug forums.
Illicit or 'designer' benzodiazepines are a growing contributor to overdose deaths. We employed natural language processing (NLP) to study benzodiazepine mentions over 10 years on 270 online drug forums (subreddits) on Reddit. Using NLP, we automatically detected mentions of illicit and prescription benzodiazepines, including their misspellings and non-standard names, grouping relative mentions by quarter. On a collection of 17 861 755 posts between 2012 and 2021, we searched for 26 benzodiazepines (8 prescription; 18 illicit), detecting 173 275 mentions. The rate of posts about both prescription and illicit benzodiazepines increased consistently with increases in deaths involving both drug classes, illustrating the utility of surveillance via Reddit.


Comprehensive structured training on occupational health hazards and vaccination: A novel initiative toward employee safety.
Healthcare providers are vulnerable to occupational health hazards. However, they do not appropriately apprehend the serious health consequences of occupational exposures. This study was conducted to assess the effectiveness of "Occupational health hazards and vaccination" workshop organized periodically in institute. We validated the questionnaire prior to assess the effectiveness of workshop. Expert performed "key check" of questionnaire. Item analysis of one best item questions was performed using difficulty index (p value), discrimination indices (DI), distractor efficiency (DE), and reliability using Kuder-Richardson 20 coefficients (KR20). Pre-test and post-test scores of study participants were compared. Effectiveness of workshop was determined using class average normalized gain. The 14 item one-best questions had acceptable difficulty level (60.35 ± 9.46%) and ideal discriminating power (0.75 ± 0.17) with mean DE 73.81 ± 22.46%. The test was found highly reliable with KR20 as 0.90. Mean score in pre-test and post-test were 6.47 ± 3.38 and 13.69 ± 1.51, respectively, and significant improvement in post-test score was found compared to pre-test score. Class average normalized gain was 0.84. The Occupational health hazards and vaccination workshop effectively improved healthcare providers' knowledge regarding workplace safety protocols. Questionnaire was found to be valid and reliable. Low baseline knowledge highlights the fact that implementation of such training on regular basis is the need of hour.


Pattern EPS in endocrine orbitopathy.
Since delayed pattern evoked potentials (EPs) are a sensitive symptom of demyelination or compression of the optic nerve, a group of 33 patients with endocrine orbitopathy were examined in order to see whether or not, in this disease too, damage to the optic nerve could be detected at an early stage. Below a visual acuity of 0.4, all patients had delayed responses. Most interesting was the group of patients with normal visual acuity and delayed responses. Before conclusions can be drawn this group will have to be enlarged and followed up.


Oxygen-independent bactericidal systems. Mechanisms and disorders.
Neutrophils contain microbicidal proteins packaged in numerous cytoplasmic granules. During phagocytosis, granules fuse to phagolysosomes where the granule contents contribute to the destruction and dissolution of ingested bacteria. The properties of the microbicidal proteins cathepsin G, BPI, and defensins are described and contrasted.


Influence of Aloe vera on collagen turnover in healing of dermal wounds in rats.
Treatment of full-thickness wounds with A. vera, on rats resulted in increased biosynthesis of collagen and its degradation. A corresponding increase in the urinary excretion of hydroxyproline was also observed. Elevated levels of lysyl oxidase also indicated increased crosslinking of newly synthesised collagen. The results suggest that A. vera influences the wound healing process by enhancing collagen turnover in the wound tissue.


Cardiac magnetic resonance imaging in the evaluation of the late effects of anthracyclines among long-term survivors of childhood cancer.
This study sought to examine the left ventricular (LV) and right ventricular (RV) function and signs of focal fibrosis among long-term survivors of childhood cancer with the use of cardiac magnetic resonance (CMR) imaging. Increased myocardial fibrosis has been detected in the endomyocardial biopsies of survivors. CMR has established its role in the assessment of both cardiac function and structure, and focal fibrosis of the myocardium is detectable with late gadolinium enhancement (LGE). Sixty-two anthracycline-exposed long-term survivors of childhood cancer were studied at a mean age of 14.6 years. The LV and RV ejection fractions (EFs) and volumes were measured, and LGE was assessed using CMR. An abnormal LV function (EF <45%) was detected in 18% (11 of 62) of the survivors, and an abnormal RV function was detected in 27% (17 of 62) of the survivors. Subnormal (45% ≤ EF <55%) LV function were demonstrated in 61% (38 of 62) and subnormal RV function in 53% (33 of 62) of the survivors, respectively. Both the LV and RV end-systolic and LV end-diastolic volumes were increased compared with reference values. None of the study patients showed LGE. A considerable proportion of the long-term survivors of childhood cancer with anthracycline exposure demonstrate signs of cardiac dysfunction detectable by CMR, with the RV also being involved. Yet, myocardial fibrosis does not seem to be detectable at a median of 7.8 years after anthracycline therapy.


Effect of prior chemotherapy on hematopoietic stem cell mobilization.
A number of studies have suggested that prior chemotherapy correlates negatively with the efficiency of hematopoietic stem cell mobilization. However, little data exist with regard to the relative effects of the specific chemotherapeutic drug classes. We retrospectively reviewed the records of 201 consecutive patients with nonmyeloid malignancies undergoing CD34+ cell mobilization with chemotherapy+granulocyte colony-stimulating factor (G-CSF). The number of prior chemotherapy courses correlated negatively with the peripheral CD34+ cell concentration (pCD34) on the first day of collection (P<0.001). No significant correlation was found for age, gender, tumor primary, mobilization chemotherapy regimen, disease status, marrow involvement, prior radiation therapy, or dose and timing of G-CSF administration. When the number of courses of individual classes of chemotherapeutic agents was correlated with pCD34, only exposures to platinum compounds (P=0.001) and alkylating agents (P=0.01) were found to be independent negative predictive factors for pCD34. Within classes, DNA crosslinking agents and etoposide appeared possibly more damaging than DNA methylating agents and doxorubicin, respectively. None of the drug classes showed evidence of recovery. We conclude that exposure to chemotherapy, especially platinum compounds and alkylating agents, should be minimized prior to mobilization.


Modulation of p66Shc impairs cerebrovascular myogenic tone in low renin but not low nitric oxide models of systemic hypertension.
Cerebral blood flow and perfusion are tightly maintained through autoregulation despite changes in transmural pressure. Oxidative stress impairs cerebral blood flow, precipitating cerebrovascular events. Phosphorylation of the adaptor protein p66Shc increases mitochondrial-derived oxidative stress. The effect of p66Shc gain or loss of function in nonhypertensive rats is unclear. We hypothesized that p66Shc gain of function would impair autoregulation of cerebral microcirculation under physiological and pathological conditions. Three previously established transgenic [salt-sensitive (SS) background] p66Shc rats were used, p66-Del/SS (express p66Shc with a nine-amino acid deletion), p66Shc-knockout (KO)/SS (frameshift premature termination codon), and p66Shc signaling and knock-in substitution of Ser36Ala (p66Shc-S36A)/SS (substitution of Ser36Ala). The p66Shc-Del were also bred on Sprague-Dawley (SD) backgrounds (p66-Del/SD), and a subset was exposed to a hypertensive stimulus [NG-nitro-l-arginine methyl ester (l-NAME)] for 4 wk. Active and passive diameters to increasing transmural pressure were measured and myogenic tone was calculated in all groups (SS and SD). Myogenic responses to increasing pressure were impaired in p66Shc-Del/SS rats relative to wild-type (WT)/SS and knock-in substitution of Ser36Ala (S36A; P < 0.05). p66-Del/SD rats did not demonstrate changes in active/passive diameters or myogenic tone relative to WT/SD but did demonstrate attenuated passive diameter responses to higher transmural pressure relative to p66-Del/SS. Four weeks of a hypertensive stimulus (l-NAME) did not alter active or passive diameter responses to increasing transmural pressure (P = 0.86-0.99), but increased myogenic responses relative to p66-Del/SD (P < 0.05). Collectively, we demonstrate the functional impact of p66Shc within the cerebral circulation and demonstrate that the genetic background of p66Shc rats largely drives changes in cerebrovascular function.NEW & NOTEWORTHY We demonstrate that the modulation of p66Shc signaling impairs cerebral artery myogenic tone in a low renin model of hypertension. This impairment is dependent upon the genetic background, as modulated p66Shc signaling in Sprague-Dawley rats does not impair cerebral artery myogenic tone.