Serum magnesium and the incidence of coronary artery disease over a median 27 years of follow-up in the Atherosclerosis Risk in Communities (ARIC) Study and a meta-analysis.
Low serum magnesium (Mg) concentrations have been associated with higher coronary artery disease (CAD) risk. A previous Atherosclerosis Risk in Communities (ARIC) Study article that evaluated the Mg-CAD association, based on 319 events occurring over 4-7 y, identified a sex-interaction whereby the inverse Mg-CAD association was much stronger among women than men. More than 1700 additional ARIC CAD events have since accrued. We aimed to test our hypothesis that serum Mg is inversely and independently associated with long-term CAD risk in ARIC and in a meta-analysis with other prospective studies. A total of 14,446 ARIC study participants (baseline mean ± SD age: 54 ± 6 y, 57% women, 27% African American) were followed for incident CAD through 2017. CAD events were defined by myocardial infarction or CAD mortality. Serum Mg was modeled as quintiles based on mean visit 1 (1987-1989) and visit 2 (1990-1992) concentrations. Cox regression models were used. We also conducted a random-effects meta-analysis incorporating these contemporary ARIC findings. Over a median follow-up of 27 y, 2131 incident CAD cases accrued. Overall, low serum Mg was associated with higher CAD risk after adjustment for demographics, lifestyle factors, and other CAD risk factors than was higher serum Mg (HR Q1 compared with Q5: 1.28; 95% CI: 1.11, 1.47; P-linear trend <0.001). The association was stronger among women (HR Q1 compared with Q5: 1.53; 95% CI: 1.22, 1.92) than men (HR: 1.11; 95% CI: 0.92, 1.34) (P-interaction = 0.05). In the meta-analysis including 5 studies, the pooled RR (95% CI) for CAD in the lowest compared with the highest circulating Mg category was 1.18 (1.06, 1.31) (I2 = 22%, P-heterogeneity = 0.27). In this large community-based cohort and updated meta-analysis, low circulating Mg was associated with higher CAD risk than was higher Mg. Whether increasing Mg concentrations within healthy limits is a useful strategy for CAD prevention remains to be seen.


[Effect of age and the amount of inoculate on the growth of Streptococcus lactis and its formation of nisin].
The cells of Streptococcus lactis, strain MGU, synthesize considerable amounts of nisine in the course of their growth. The rate of metabolic processes is not increased by stirring if the medium is complete and easily assimilated. Utilization of a young inoculate (1.5, 3, and 6 hours) reduces the process of nisine production by 1.5--2 times. The amount of the inoculate exceeding 1.5 volume percent has no significant effect on the biosynthesis.


In Vitro and In Vivo Anti-Cancer Activity of Lasiokaurin in a Triple-Negative Breast Cancer Model.
Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC.


A clinical water-coated antenna applicator for MR-controlled deep-body hyperthermia: a comparison of calculated and measured 3-D temperature data sets.
A magnetic resonance (MR)-compatible three-dimensional (3-D) hyperthermia applicator was developed and evaluated in the magnetic resonance (MR) tomograph Siemens MAGNETOM Symphony 1.5 T. Radiating elements of this applicator are 12 so-called water coated antenna (WACOA) modules, which are designed as specially shaped and adjustable dipole structures in hermetically closed cassettes that are filled by deionized water. The WACOA modules are arranged in the applicator frame in two transversal antenna subarrays, six antennas per subarray. As a standard load for the applicator an inhomogeneous phantom was fabricated. Details of applicator's realization are presented and a 3-D comparison of calculated and measured temperature data sets is made. A fair agreement is achieved that demonstrates the numerically supported applicator's ability of phase-defined 3-D pattern steering. Further refinement of numerical models and measuring methods is necessary. The applicator's design and the E-field calculations were performed using the finite-difference time-domain (FDTD) method. The calculation and optimization of temperature patterns was obtained using the finite element method (FEM). For MR temperature measurements the proton resonance frequency (PRF) method was used.


Immuno-spin trapping detection of antioxidant/pro-oxidant properties of zinc or selenium on DNA and protein radical formation via hydrogen peroxide.
Trace elements can participate in the catalysis of group-transfer reactions and can serve as their structural components. However, most of them including zinc and selenium have multifunctional roles in biological environments such as antioxidant and/or pro-oxidant effects, as concentration-dependent manner. Although it has been demonstrated the antioxidant actions of either selenium or zinc compounds, there are several documents pointing out their pro-oxidant/oxidant roles in biological systems. Here we have used ELISA-based immuno-spin trapping, a method for detection of free radical formation, to detect whether or not a zinc compound, Zn3(PO4)2, or a selenium compound, Na2SeO3, has antioxidant and/or pro-oxidant effect on 5,5-Dimethyl-1-Pyrroline-N-Oxide (DMPO)-DNA nitrone adducts induced with Cu(II)-H2O2-oxidizing system in in vitro preparations. Second, we examined whether this technique is capable to demonstrate the different DMPO-protein nitrone adduct productions in isolated protein crude of hearts from normal rats (CON) or rats with metabolic syndrome (MetS). Our data demonstrated that either Zn(2+) (100 µM) or SeO3(-2) (50 nM) has very strong antioxidant action against 200 µM H2O2-induced DMPO-DNA nitrone adduct production, whereas their higher concentrations have apparent pro-oxidant actions. We also used verification by Western blotting analysis whether immuno-spin trapping can be used to assess H2O2-induced DMPO-protein nitrone adducts in heart protein crudes. Our Western blot data further confirmed the ELISA-data from proteins and demonstrated how Zn(2+) or SeO3(-2) are dual-functioning ions such as antioxidant at lower concentrations while pro-oxidant at higher concentrations. Particularly, our present data with SeO3(-2) in DMPO-protein nitrone adducts, being in line with our previous observation on its dual-actions in ischemia/reperfusion-induced damaged heart, have shown that this ion has higher pro-oxidant actions over 50 nM in MetS-group compared to that of CON group.


[Boerhaave's syndrome--an unusual cause of acute retrosternal pain].
Boerhaave's syndrome or spontaneous perforation of the oesophagus is a rare condition with a severe prognosis. Adequate treatment is often delayed because of misdiagnosis of the condition as cardial, pulmonary or other gastrointestinal disease, with a concomitant rise in mortality. A case of Boerhaave's syndrome is described. An 88-year-old male presented with acute retrosternal pain, initially believed to be caused by cardiac disease. After a delay of more than 24 hours, laparotomy revealed a perforation of the oesophagus. The patient was treated with laparotomy, drainage, antibiotics, antifungal and medical supportive therapy. Surgical closure of the lesion was not performed because of the debilitated state of the patient and the delay in diagnosis. He left the hospital in his habitual state after 33 days of hospitalization. Boerhaave's syndrome is a serious condition that is often misdiagnosed. The preferred treatment is prompt surgical closure of the oesophageal defect.


The effects of thyroid hormone modulation on rat liver injury associated with ischemia-reperfusion and cold storage.
We investigated the effects of thyroid hormone modulation on liver injury associated with ischemia-reperfusion (I-R) and cold storage in rats. First, euthyroid and thyroxine (T4)-pretreated rats were exposed in vivo to 20-min global liver ischemia, then 30-min reperfusion. Liver injury was assessed by measuring serum alanine aminotransferase (ALT) levels. Liver concentrations of adenine nucleotides, reduced glutathione (GSH), and oxidized glutathione were evaluated. Second, rats were given the antithyroid drug propylthiouracil (PTU). Livers stored at 0-1 degrees C in Euro-Collins' solution for 20 h were reperfused at 37 degrees C for 15 min. Lactate dehydrogenase (LDH) in the effluent perfusate and bile flow were evaluated during reperfusion. Serum ALT levels increased after ischemia and I-R. ALT increased significantly more in T4-pretreated than in euthyroid rats after ischemia and I-R. Preischemic levels of adenosine triphosphate (ATP) were significantly lower in livers from T4-pretreated than in euthyroid rats (6.22 +/- 0.7 and 11 +/- 0.9 nmol/mg protein, respectively; P < 0.05). After ischemia, liver ATP was similarly reduced in T4-pretreated and euthyroid rats. After reperfusion, ATP partially recovered in euthyroid rats but remained low in T4-pretreated rats (6.7 +/- 1.0 and 1.91 +/- 0.7 nmol/mg protein, respectively; P < 0.05). Preischemic levels of liver GSH decreased to 44% in T4-pretreated rats. After ischemia, GSH decreased similarly in euthyroid and T4-pretreated rats. GSH recovered promptly after reperfusion in euthyroid rats but remained low in T4-pretreated rats (13.9 +/- 3.3 and 3.9 +/- 0.9 nmol/mg protein, respectively; P < 0.02). During reperfusion after cold storage, LDH in effluent perfusate was significantly lower and bile flow higher in livers from PTU-pretreated rats than from euthyroid rats. The histopathological changes observed after I-R and cold storage confirmed the biochemical findings. Our results suggest that T4 administration exacerbates pretransplant liver damage by increasing liver susceptibility to I-R, whereas PTU administration reduces the liver injury associated with cold storage. We studied the effects of thyroid hormone modulation on liver injury associated with ischemia-reperfusion and cold storage in rats. Thyroxine administration increased susceptibility to ischemia-reperfusion injury, whereas the antithyroid agent propylthiouracil reduced the deleterious effects associated with cold storage.


Evolution of striated muscle: jellyfish and the origin of triploblasty.
The larval and polyp stages of extant Cnidaria are bi-layered with an absence of mesoderm and its differentiation products. This anatomy originally prompted the diploblast classification of the cnidarian phylum. The medusa stage, or jellyfish, however, has a more complex anatomy characterized by a swimming bell with a well-developed striated muscle layer. Based on developmental histology of the hydrozoan medusa this muscle derives from the entocodon, a mesoderm-like third cell layer established at the onset of medusa formation. According to recent molecular studies cnidarian homologs to bilaterian mesoderm and myogenic regulators are expressed in the larval and polyp stages as well as in the entocodon and derived striated muscle. Moreover striated and smooth muscle cells may have evolved directly and independently from non-muscle cells as indicated by phylogenetic analysis of myosin heavy chain genes (MHC class II). To accommodate all evidences we propose that striated muscle-based locomotion coevolved with the nervous and digestive systems in a basic metazoan Bauplan from which the ancestors of the Ctenophora (comb jellyfish), Cnidaria (jellyfish and polyps), as well as the Bilateria are derived. We argue for a motile tri-layered cnidarian ancestor and a monophyletic descent of striated muscle in Cnidaria and Bilateria. As a consequence, diploblasty evolved secondarily in cnidarian larvae and polyps.


Cancer prevention among urban southwestern American Indian women: comparison to selected Year 2000 national health objectives.
The health issues which have historically faced American Indians are related to infectious disease, but today many chronic diseases play a large role in the health status of this special population. For example, existing data indicate that American Indians have the poorest cancer survival of any group in the U.S. (34% vs. 50% for U.S. Whites). Regular participation in cancer screening and lifestyle factors such as smoking, diet, and alcohol have been found to significantly contribute to cancer risk. However, available information about these behaviors is sparse and suffers from limitations. The purpose of this study was to assess the prevalence of cancer risk behaviors and provider recommendation for cancer screening among urban American Indian women. A random household cross-sectional survey was administered to 519 adult American Indian women in Phoenix, Arizona. Smoking and weight status, alcohol consumption, physical activity, and provider referral were assessed by self-report. The results indicate that weight (69.6% were overweight) and excessive alcohol consumption (12.1 reported chronic drinking) were significant health issues in this population. The prevalence of provider referral for smoking cessation (14.9% among ever smokers) and breast as well as cervical cancer screening (30.1% and 55.5%, respectively) were below the 75% level set forth in the Year 2000 Goals. The results of this study suggest that increased cancer prevention and control efforts are needed in this special population to address the link between diet, weight, and long-term disease prevention.


CT of renal cell carcinoma: assessment of collecting system invasion.
Although renal collecting system invasion is not considered in the current TNM staging system, this finding may be relevant in terms of treatment planning and prognosis. The objective of this study was to investigate the frequency of collecting system invasion in renal cell carcinoma (RCC) and to assess the diagnostic performance of excretory phase CT for the assessment of collecting system invasion. We conducted a retrospective study of 261 patients (171 men and 90 women; average age, 61 years; age range, 32-86 years) who underwent CT before nephrectomy for RCC between November 2008 and July 2011 at a single institution. On excretory phase contrast-enhanced CT images, two radiologists independently determined whether RCC components caused a filling defect within the collecting system and whether the RCC was in contact to the collecting system wall or separated from it. Histopathology served as the standard of reference. Interreader agreement and diagnostic performance tests for the detection of collecting system invasion were calculated. Histopathology identified collecting system invasion exclusively in clear cell RCC that showed a filling defect within the collecting system on excretory phase CT images (5.4%, 14/261). Tumors separated from or in contact with the collecting system on imaging (both readers; 94.6%, 247/261) did not show collecting system invasion on histopathology (sensitivity, 100%; specificity, 100%). Interreader agreement was excellent (κ, 0.965; 95% CI, 0.93-0.99). CT provides reliable assessment of collecting system invasion in patients with RCC, with excellent sensitivity and specificity.


Drivers to improve metal(loid) phytoextraction with a focus on microbial degradation of dissolved organic matter in soils.
Bioaugmentation of soils can increase the mobilization of metal(loid)s from the soil-bearing phases. However, once desorbed, these metal(loid)s are mostly complexed to the dissolved organic matter (DOM) in the soil solution, which can restrict their availability to plants (roots mainly taking up the free forms) and then the phytoextraction performances. Firstly the main drivers influencing phytoextraction are reminded, then the review focuses on the DOM role. After having reminding the origin, the chemical structure and the lability of DOM, the pool of stable DOM (the most abundant in the soil) most involved in the complexation of metal(loid)s is addressed in particular by focusing on carboxylic and/or phenolic groups and factors controlling metal(loid) complexation with DOM. Finally, this review addresses the ability of microorganisms to degrade metal(loid)-DOM complexes as an additional lever for increasing the pool of free metal(loid) ions, and then phytoextraction performances, and details the origin of microorganisms and how they are selected. The development of innovative processes including the use of these DOM-degrading microorganisms is proposed in perspectives.


Investigating proteins and proteases composing amniotic and allantoic fluids during chicken embryonic development.
In amniotes, the amniotic fluid is a significant contributor to fetal development and health. While numerous studies have been conducted in mammalian amniotic fluid, the composition of amniotic and other extraembryonic fluids in avian egg along with their physiological functions remain largely unexplored. In such a context, our objective was to characterize the chicken amniotic fluid (AmF) and allantoic fluid (AlF) properties, protein composition, and some associated functions from day 8 to day 16 of incubation. SDS-PAGE combined to mass spectrometry analysis revealed common and specific proteins to each fluid, suggesting distinct properties and functions. Indeed, major AlF proteins are mostly "egg yolk" proteins involved in lipid, vitamin metabolisms, and metal ion transport, while major AmF proteins resemble those of albumen. Drastic changes in the AmF protein profiles were observed during incubation, when the albumen transfers from day 12 onwards, while few changes were detected for the AlF protein profile. The decreases in osmolality (from 231 to 183 mOsm/kg) and pH (from 8.26 to 7.26) observed in the AlF during incubation are associated with water and electrolytes reallocation for the embryo needs. In contrast, AmF pH value remained stable (≈7.5). Active proteolytic enzymes have been identified in the 2 fluids using gelatin zymography, followed by mass spectrometry analysis for protease identification. A total of 12 proteases was detected in the AlF, compared to 5 in the AmF. We have shown that AlF concentrates proteolytic enzymes assumed to participate in digestive processes: aminopeptidase N, dipeptidyl peptidase-4, meprin A, and 72 kDa type IV collagenase preproprotein. The other proteases identified in both fluids also could have a role in morphogenesis (hepatocyte growth factor activator, suppressor of tumorigenicity 14, astacin-like metalloendopeptidase) and hemostasis (prothrombin and coagulation factor X). Altogether, these data suggest that the roles of chicken AlF and AmF are not merely associated with protection of the embryo and regulation of metabolic disposable wastes, but also they could have more sophisticated roles during embryonic development.


Engineering responses to pandemics.
Focusing on pandemic influenza, this chapter approaches the planning for and response to such a major worldwide health event as a complex engineering systems problem. Action-oriented analysis of pandemics requires a broad inclusion of academic disciplines since no one domain can cover a significant fraction of the problem. Numerous research papers and action plans have treated pandemics as purely medical happenings, focusing on hospitals, health care professionals, creation and distribution of vaccines and anti-virals, etc. But human behavior with regard to hygiene and social distancing constitutes a first-order partial brake or control of the spread and intensity of infection. Such behavioral options are "non-pharmaceutical interventions." (NPIs) The chapter employs simple mathematical models to study alternative controls of infection, addressing a well-known parameter in epidemiology, R0, the "reproductive number," defined as the mean number of new infections generated by an index case. Values of R0 greater than 1.0 usually indicate that the infection begins with exponential growth, the generation-to-generation growth rate being R0. R0 is broken down into constituent parts related to the frequency and intensity of human contacts, both partially under our control. It is suggested that any numerical value for R0 has little meaning outside the social context to which it pertains. Difference equation models are then employed to study the effects of heterogeneity of population social contact rates, the analysis showing that the disease tends to be driven by high frequency individuals. Related analyses show the futility of trying geographically to isolate the disease. Finally, the models are operated under a variety of assumptions related to social distancing and changes in hygienic behavior. The results are promising in terms of potentially reducing the total impact of the pandemic.


Rutin ameliorates cisplatin-induced reproductive damage via suppression of oxidative stress and apoptosis in adult male rats.
Cisplatin (CP) treatment causes damage in the male reproductive system. Rutin (RUT) is a naturally occurring flavonoid glycoside that has antioxidant and anti-inflammatory properties. This study aimed to investigate effects of RUT against cisplatin-induced reproductive toxicity in male rats. Twenty-one adult male Sprague Dawley rats were used. The control group received physiological saline with oral gavage during 14 days, and physiological saline was injected intraperitoneally (IP) in 10th days of study. CP Group received physiological saline during 14 days, and 10 mg kg-1 CP was injected IP in 10th day. RUT + CP group received RUT (150 mg kg-1 ) during 14 days, and 10 mg kg-1 CP was injected IP in 10th day. Spermatological parameters (including motility, cauda epididymal sperm density, dead sperm percentage and morphological sperm abnormalities), biochemical (MDA, GSH, GSH-px, SOD and CAT), histological (H&E dye) and immunochemistry evaluations of testicles were evaluated. CP treatment caused damage on some spermatological parameters, increased the oxidative stress and induced testicular degeneration and apoptosis when compared to the control group. However, RUT treatment mitigates these side effects when compared to the CP alone group. IT is concluded that RUT treatment may reduce CP-induced reproductive toxicity as a potential antioxidant compound.


Investigating the Impact of COVID-19 Lockdown on the Psychological Health of University Students and Their Attitudes Toward Mobile Mental Health Solutions: Two-Part Questionnaire Study.
The COVID-19 outbreak was first reported to the World Health Organization on December 31, 2019, and it was officially declared a public health emergency of international concern on January 30, 2020. The COVID-19 outbreak and the safety measures taken to control it caused many psychological issues in populations worldwide, such as depression, anxiety, and stress. The objectives of this study were to assess the psychological effects of the lockdown due to the COVID-19 outbreak on university students in the United Arab Emirates (UAE) and to investigate the students' awareness of mobile mental health care apps as well as their attitudes toward the use of these apps. A two-part self-administered web-based questionnaire was delivered to students at United Arab Emirates University. The first part of the questionnaire assessed the mental state of the participants using the 12-item General Health Questionnaire (GHQ-12), while the second part contained questions investigating the participants' awareness of and attitudes toward mental health care apps. Students were invited to fill out the web-based questionnaire via social media and mailing lists. A total of 154 students participated in the survey, and the majority were female. The results of the GHQ-12 analysis showed that the students were experiencing psychological issues related to depression and anxiety as well as social dysfunction. The results also revealed a lack of awareness of mental health care apps and uncertainty regarding the use of such apps. Approximately one-third of the participants (44/154, 28.6%) suggested preferred functionalities and characteristics of mobile mental health care apps, such as affordable price, simple design, ease of use, web-based therapy, communication with others experiencing the same issues, and tracking of mental status. Like many groups of people worldwide, university students in the UAE were psychologically affected by the lockdown due to the COVID-19 outbreak. Although apps can be useful tools for mental health care delivery, especially in circumstances such as those produced by the outbreak, the students in this study showed a lack of awareness of these apps and mixed attitudes toward them. Improving the digital health literacy of university students in the UAE by increasing their awareness of mental health care apps and the treatment methods and benefits of the apps, as well as involving students in the app creation process, may encourage students to use these tools for mental health care.


Morphological, molecular and biogeographic evidence support two new species in the Uroptychus naso complex (Crustacea: Decapoda: Chirostylidae).
The tropical to subtropical squat lobster Uroptychus nasoVan Dam, 1933 (Chirostylidae) is a widely distributed species originally described from Indonesia, subsequently reported from the Philippines, Taiwan, Japan and it has recently been discovered on the continental slope of north-western Australia. Populations of U. naso occur along the Indo-Pacific Ocean continental margin crossing the recently proposed marine analog of Wallace's line, responsible for past population fragmentation and ancient speciation. Sequence data from mitochondrial (COI, 16S) and nuclear (H3) DNA regions were used to assess genealogical relationships among geographically disjoint populations of the species throughout its known distribution range. Several mitochondrial lineages, corresponding to geographically isolated populations and three cryptic species were encountered, namely, U. naso sensu stricto and two new species, Uroptychus cyrano and Uroptychus pinocchio spp. nov. U. pinocchio is encountered only in Japan, Taiwan and the Philippines; U. cyrano is confined to north-western Australia; and U. naso consists of three genetically distinct populations distributed on both sides of the marine Wallace's line. Fossil-calibrated divergence time approximations indicated a most recent common ancestor (MRCA) for U. naso and U. cyrano from early Eocene whilst northern and southern populations of the former have been separated probably since the Miocene. These patterns may represent a standard distribution trend for several other deep-sea invertebrate species with similar geographical ranges.


Effect of Statins on the Risk of Poststroke Pneumonia: National Population-Based Cohort Study.
Statins are widely prescribed medications for treatment of dyslipidemia and prevention of cardiovascular disease. Beyond their lipid-lowering property, statins exhibit multiple pleiotropic and antimicrobial effects. We aimed to investigate the effect of statins on the long-term risk of pneumonia after acute ischemic stroke. This retrospective observational research was performed using South Korean National Health Insurance Service claim data, which consist of population-based random sampling. We included patients discharged with acute ischemic stroke (I63 in the ICD10) and no prior history of pneumonia. The primary outcome measure was the occurrence of pneumonia determined based on ICD10 code J09-J18. Treatment with statins during follow-up was collected as a time-dependent variable based on prescription records. A total of 7,001 subjects with acute ischemic stroke and no prior history of pneumonia were included. During the mean 3.96-year follow-up, pneumonia occurred in 1,715 subjects (24.5%). On multivariate time-dependent Cox proportional hazard-regression analyses, significant preventive benefit of treatment with statins against pneumonia was noted (adjusted HR 0.86, 95% CI 0.77-0.97). Compared to no use of statin, adjusted HRs (95% CIs) for current use of low-intermediate high-intensity statins were 0.88 (0.78-0.99) and 0.49 (0.27-0.87), respectively. Our retrospective national cohort study found reduced risk of poststroke pneumonia with statin therapy after acute ischemic stroke. Our study suggests that treatment with statins may have a preventive effect against the common complication of poststroke pneumonia.


Patterns of autobiographical memory loss in medial-temporal lobe amnesic patients.
The issue of whether the hippocampus and related structures in the medial-temporal lobe (MTL) play a temporary or permanent role in autobiographical episodic memory remains unresolved. One long-standing belief is that autobiographical memory (AM), like semantic memory, is initially dependent on the MTL but ultimately can be retained and recovered independently of it. However, evidence that hippocampal amnesia results in severe loss of episodic memory for a lifetime of personally experienced events suggests otherwise. To test the opposing views, we conducted detailed investigations of autobiographical episodic memory in people with amnesia resulting from MTL lesions of varying extent. By combining precise quantification of MTL and neocortical volumes with sensitive measures of recollection of one's personal past, we show that the severity of episodic, but not semantic, AM loss is best accounted for by the degree of hippocampal damage and less likely related to additional neocortical compromise.


Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial.
Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension. The TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600-1000 h) or in the evening (2000-0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete. Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified. Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects. British Heart Foundation.


Effect of long-term administration of berberine on scopolamine-induced amnesia in rats.
The effect of berberine (BER) on scopolamine (SCOP)-induced amnesia was investigated in a step-through passive avoidance task in rats. It was observed that BER at the doses of 0.1 and 0.5 g/kg after 7-day or 14-day administration significantly improved SCOP-induced amnesia. The anti-amnesic effect of BER after 14-day administration on the SCOP-induced amnesia was significantly augmented by physostigmine or neostigmine, and completely reversed by scopolamine N-methylbromide. These results suggest that the antiamnesic effect of BER after 14-day administration may be related to the increase in the peripheral and central cholinergic neuronal system activity.


Soft Ionization Mass Spectrometry for Studying Noncovalent Interactions.
Biochemistry and structural biology have benefited tremendously from the development of electrospray ionization and matrix-assisted laser desorption/ionization, the two most important soft ionization methods used in modern mass spectrometry. Of importance in this context is that noncovalently bound complexes can be maintained in the gas phase using appropriate sample preparation conditions and instrumental settings in ESI-MS and MALDI-MS. This allows one to determine the architecture and stoichiometry of large noncovalent complexes, the binding of small molecule ligands and cofactors, and often even noncovalent binding affinities, since bound and unbound states can be clearly resolved and quantified using MS. This article presents an overview of the research in this particular area undertaken by my research group at ETH Zurich. I will introduce a number of specialized technologies that we have available in our laboratory, including MALDI mass spectrometry with high-mass detection for measuring complexes with molecular weights in the 100s of kDa range; the so-called "gap sampler" technology for high-throughput experiments; and a temperature programmed spray source for ESI. A number of selected applications will then be presented, including the study of GPCRs and other membrane proteins and their complexes, the determination of the melting behavior of non-canonical nucleic acid structures, the investigation of heterogeneous protein complexes and protein-based capsids, and the investigation of the influence of protein post-translational modifications on noncovalent binding profiles.


The Distribution of Colorectal Surgeons in the United States.
Surgical resection is a mainstay of colorectal cancer treatment, and prior studies have shown improved outcomes in patients undergoing surgery for colorectal cancer by colorectal surgical specialists compared with nonspecialized surgeons. Here, we examine the geographic distribution of colorectal surgeons in the United States and its relationship with sociodemographic characteristics of the served population. The Area Health Resource File from 2017 to 2018 was used to identify the number and location of colorectal surgeons practicing throughout the United States and sociodemographic characteristics at the county and hospital referral region (HRR) level. The main outcomes of interest were the density of colorectal surgeons per 100,000 population and associations with sociodemographic characteristics at the county and HRR level based on multivariable linear regression. In multivariable analysis, regions with higher proportion of nonwhite individuals and college-educated individuals had significantly more colorectal surgeons per 100,000 population, whereas regions with higher proportions of uninsured individuals had significantly fewer colorectal surgeons per 100,000 population at both the county and HRR levels. Geographic and sociodemographic variability exists in the distribution of colorectal surgeons in the United States. Such variability may be contributing to disparities in access to specialized colorectal care.


Design of new anti-cancer agents based on topoisomerase poisons targeted to specific DNA sequences.
There is considerable interest in the development of sequence-selective DNA drugs. Chemical agents able to interfere with DNA topoisomerases - essential nuclear enzymes- are widespread in nature, and some of them have outstanding therapeutic efficacy in human cancer and infectious diseases. Several classes of antineoplastic drugs, such as amsacrine, daunorubicin, etoposide (acting on type II topoisomerases), camptothecin and indolocarbazole derivatives of the antibiotic rebeccamycin (acting on type IB topoisomerases), have been shown to stimulate DNA cleavage by topoisomerases leading to cell death. However, these molecules exhibit little sequence preference. A convenient strategy to confer sequence specificity consists in the attachment of these topoisomerase poisons to sequence-specific DNA binding elements. Among sequence-specific DNA ligands, oligonucleotides can bind with high specificity of recognition to the major groove of double-helical DNA, resulting in triple helix formation. In this context, derivatives of camptothecin, indolocarbazole, anthracycline and acridine poisons have been covalently tethered to triple helix-forming oligonucleotides. The use of triple-helical DNA structures offers an efficient system to target topoisomerase I and II-mediated DNA cleavage to specific sequences and to increase the drug efficacy at these sites. Chemical optimization of the conjugates is essential to the efficacy of drug targeting. Consequently, the rational design of this new class of anti-cancer agents, conceived from topoisomerase poisons and triplex-forming oligonucleotides, may be exploited to improve the efficacy and selectivity of the DNA damage induced by topoisomerases.


Development of a human glioblastoma model using humanized DRAG mice for immunotherapy.
Glioblastoma (GBM) is the most common and lethal primary brain tumor. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. We successfully generated humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model by transplantation of human DR4+ hematopoietic stem cells (hHSCs), and effectively grafted GBM patient-derived tumorsphere cells to form xenografted tumors intracranially. The engrafted tumors recapitulated the pathological features and the immune cell composition of human GBM. Administration of anti-human PD-1 antibodies in these tumor-bearing humanized DRAG mice decreased the major tumor-infiltrating immunosuppressive cell populations, including CD4+PD-1+ and CD8+PD-1+ T cells, CD11b+CD14+HLA-DR+ macrophages, CD11b+CD14+HLA-DR-CD15- and CD11b+CD14-CD15+ myeloid-derived suppressor cells, indicating the humanized DRAG mice as a useful model to test the efficacy of GBM immunotherapy. Taken together, these results suggest that the humanized DRAG mouse model is a reliable preclinical platform for studying brain cancer immunotherapy and beyond.


Strategies for retargeted gene delivery using vectors derived from lentiviruses.
With the development of the first viral vector systems 20 years ago [Mann et al., 1983; Watanabe and Temin, 1983] gene therapy strategies have come to the forefront of novel therapeutics [Cavazzana-Calvo et al., 2000]. A deeper understanding of vector biology and the molecular mechanisms of disease alongside tremendous advances in vector technology have significantly advanced the field of human gene therapy. Over the last few years several challenges needed to be overcome in order to bring gene therapy strategies closer to the clinic. These hurdles include the preparation of large amounts of stable, high titre vectors, minimising vector-related immunology and last but not least targeting infection and transgene expression to tissue or cells, which in many cases are not or only slowly dividing. Viral vectors are useful vehicles for the delivery of foreign genes into target cells, and retroviral vectors have been popular because of their ability to integrate into the host cell genome and maintain persistent gene expression. Moreover, lentiviruses, members of the retroviral family, have the ability to infect cells at both mitotic and post-mitotic stages of the cell cycle thus opening up the possibility to target non-dividing target cells and tissues. Human immunodeficiency virus (HIV) based vectors have been used in vitro and in vivo in a number of situations, however, safety concerns still exist, and therefore the development of vector systems based on primate as well as non-primate lentiviruses is ongoing. Concomitantly with lentiviral vector design, much has been learned about the incorporation of heterologous env proteins on lentiviral cores in order to combine specific targeting properties of envelope glycoproteins with the biological properties of lentiviral vectors. In this review article we will give an overview over advantages lentiviral vector systems offer. We will then discuss the current state of our understanding of the structure and function of viral envelope glycoproteins and emerging targeting strategies based on retroviral and lentiviral vector systems.


[Forensic medical assessment of vascular and neuronal lesions in the brain associated with acute blood loss and anemia].
Brain tissues available for examination in the present study were obtained from 30 subjects who died from the blood loss following injuries to blood vessels and internal organs inflicted by sharp objects. The study revealed variable character of tanatogenesis induced by acute blood loss and anemia. Tanatogenesis associated with injuries to the heart and major blood vessels is most likely due to the deficiency of blood in the microcirculatory system developing in the terminal period. The main tanatogenic factors in subjects with multiple injuries to peripheral vessels are vascular dystonia and abnormal rheological properties of blood.


Relationships between lead absorption and peripheral nerve conduction velocities in lead workers.
The motor sensory, and mixed nerve conduction velocities of median and posterior tibial nerves were measured in 39 lead workers whose blood lead (PbB) concentrations ranged from 2 to 73 mug/100 g with anaverage of 29 mug/100 g. The PbB concentrations significantly correlated with the maximal motor nerve conduction velocities (MCV) and mixed nerve conduction velocities (MNCV) of the median nerve in the forearm and with the MCV of the posterior tibial nerve. Erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity correlated similarly with the MCV and MNCV of the median nerve in the forearm, and the 24-hour urinary lead excretion following the intravenous administration of CaEDTA (20 mg/kg) (lead mobilization test) correlated with the MNCV. But no parameter correlated with the sensory nerve conduction velocities. By multiple regression analysis, a combination of the three parameters of lead absorption was found to correlate significantly with the MCV and MNCV of the median nerve in the forearm. The MCVs of the median and posterior tibial nerves in lead workers were significantly delayed in the PbB range of 29-73 mug/100 g (mean 45), in the lead mobilization test range from 173 to 3,540 mug/day (mean 973), and the ALAD activity range from 4.4 to 19.4 u. (mean 14.0), respectively.


Investigating primary marine aerosol properties: CCN activity of sea salt and mixed inorganic-organic particles.
Sea spray particles ejected as a result of bubbles bursting from artificial seawater containing salt and organic matter in a stainless steel tank were sampled for size distribution, morphology, and cloud condensation nucleus (CCN) activity. Bubbles were generated either by aeration through a diffuser or by water jet impingement on the seawater surface. Three objectives were addressed in this study. First, CCN activities of NaCl and two types of artificial sea salt containing only inorganic components were measured to establish a baseline for further measurements of mixed organic-inorganic particles. Second, the effect of varying bubble residence time in the bulk seawater solution on particle size and CCN activity was investigated and was found to be insignificant for the organic compounds studied. Finally, CCN activities of particles produced from jet impingement were compared with those produced from diffuser aeration. Analyses indicate a considerable amount of organic enrichment in the jet-produced particles relative to the bulk seawater composition when sodium laurate, an organic surfactant, is present in the seawater. In this case, the production of a thick foam layer during impingement may explain the difference in activation and supports hypotheses that particle production from the two methods of generating bubbles is not equal.


Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma.
IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer. Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected. All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively. I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer.


Protective effects of relaxin in ischemia/reperfusion-induced intestinal injury due to splanchnic artery occlusion.
1. Splanchnic artery occlusion (SAO) followed by reperfusion causes endothelial injury and inflammation which contribute to the pathophysiology of shock. We investigated the effects of relaxin (RLX), known to afford protection against the deleterious effects of cardiac ischemia/reperfusion, given to rats subjected to splanchnic artery occlusion and reperfusion (SAO/R)-induced splanchnic injury. 2. RLX (30 ng kg(-1), 15 min. before reperfusion) significantly reduced the drop of blood pressure and high mortality rate caused by SAO/R. RLX also reduced histopathological changes, leukocyte infiltration (myeloperoxidase) and expression of endothelial cell adhesion molecules in the ileum. RLX counteracted free radical-mediated tissue injury, as judged by significant decrease in the tissue levels of peroxidation and nitration products (malondialdehyde, nitrotyrosine), DNA damage markers (8-hydroxy-2'-deoxyguanosine, poly-ADP-ribosylated DNA) and consumption of tissue antioxidant enzymes (superoxide dismutase). As a result, RLX led to a reduction of ileal cell apoptosis (caspase 3, terminal deoxynucleotidyltransferase-mediated UTP end labeling). The effects of RLX appear specific, as inactivated RLX substituted for the bioactive hormone had no effects. 3. In conclusion, these results show that RLX exerts a clear-cut protective effect in SAO/R-induced splanchnic injury, likely due to endothelial protection, decreased leukocyte recruitment and hindrance of free radical-mediated tissue injury leading to cell death, lethal complications and high mortality rate. Thus, RLX could be used therapeutically in intestinal ischemia.


The feminist perspective of intersectionality in the field of public health: a narrative review of the theoretical-methodological literature.
The intersectionality approach emerged in the late 1990s in the field of black feminist activism in the USA, as a critique of one-dimensional analyses of social inequalities. This descriptive-analytical narrative review presents the current state of theoretical-methodological inclusion of intersectionality in public health. Seven scientific literature databases were consulted: Web of Science, Embase, Cinahl, Scopus, Sociological Abstracts, Lilacs, and Medline, resulting in 1763 papers. After duplicates were eliminated and the titles and abstracts screened, 30 papers produced in five countries between 2006 and 2017 were selected. The analysis, structured into three central themes (theoretical-methodological debates, social markers - gender, race, ethnicity and sexual orientation - and health policies and practices), shows intersectionality to be a promising analytical resource for understanding and facing the global challenge of inequalities in health.


A novel ADOA-associated OPA1 mutation alters the mitochondrial function, membrane potential, ROS production and apoptosis.
Autosomal dominant optic atrophy (ADOA) is a dominantly inherited optic neuropathy, affecting the specific loss of retinal ganglion cells (RGCs). The majority of affected cases of ADOA are associated with mutations in OPA1 gene. Our previous investigation identified the c.1198C > G (p.P400A) mutation in the OPA1 in a large Han Chinese family with ADOA. In this report, we performed a functional characterization using lymphoblostoid cell lines derived from affected members of this family and control subjects. Mutant cell lines exhibited the aberrant mitochondrial morphology. A ~24.6% decrease in the mitochondrial DNA (mtDNA) copy number was observed in mutant cell lines, as compared with controls. Western blotting analysis revealed the variable reductions (~45.7%) in four mtDNA-encoded polypeptides in mutant cell lines. The impaired mitochondrial translation caused defects in respiratory capacity. Furthermore, defects in mitochondrial ATP synthesis and mitochondrial membrane potential (ΔΨm) were observed in mutant cell lines. These abnormalities resulted in the accumulation of oxidative damage and increasing of apoptosis in the mutant cell lines, as compared with controls. All those alterations may cause the primary degeneration of RGCs and subsequent visual loss. These data provided the direct evidence for c.1198C > G mutation leading to ADOA. Our findings may provide new insights into the understanding of pathophysiology of ADOA.


Dynamics of uS19 C-Terminal Tail during the Translation Elongation Cycle in Human Ribosomes.
Ribosomes undergo multiple conformational transitions during translation elongation. Here, we report the high-resolution cryoelectron microscopy (cryo-EM) structure of the human 80S ribosome in the post-decoding pre-translocation state (classical-PRE) at 3.3-Å resolution along with the rotated (hybrid-PRE) and the post-translocation states (POST). The classical-PRE state ribosome structure reveals a previously unobserved interaction between the C-terminal region of the conserved ribosomal protein uS19 and the A- and P-site tRNAs and the mRNA in the decoding site. In addition to changes in the inter-subunit bridges, analysis of different ribosomal conformations reveals the dynamic nature of this domain and suggests a role in tRNA accommodation and translocation during elongation. Furthermore, we show that disease-associated mutations in uS19 result in increased frameshifting. Together, this structure-function analysis provides mechanistic insights into the role of the uS19 C-terminal tail in the context of mammalian ribosomes.


A new inducible CRISPR-Cas9 system useful for genome editing and study of double-strand break repair in Candida glabrata.
In recent years, the CRISPR-Cas9 system has proven extremely useful for genome editing in many species, including the model yeast Saccharomyces cerevisiae and other yeast species such as Candida glabrata. Inducible CRISPR-Cas9 systems have the additional advantage of allowing to separate the transformation step of the organism by the CRISPR-Cas9 system, from the cutting and repair steps. This has indeed been developed in S. cerevisiae, where most inducible expression systems rely on the GAL promoters. Unfortunately, C. glabrata is gal- and lacks the GAL genes, like many other yeast species. We report here the use of a vector expressing cas9 under the control of the MET3 promoter, with the guide RNA cloned into the same plasmid. We show that it can be used efficiently in C. glabrata, for both described outcomes of CRISPR-Cas9-induced chromosome breaks; nonhomologous end joining in the absence of a homologous repair template; and homologous recombination in the presence of such a template. This system therefore allows easy editing of the genome of C. glabrata, and its inducibility may allow identification of essential genes in this asexual yeast, where spore lethality cannot be observed, as well as the study of double-strand break repair.


Cu(I)/Cu(II) Creutz-Taube Mixed-Valence 2D Coordination Polymers.
Graphene-like 2D coordination polymers (GCPs) have been of central research interest in recent decades with significant impact in many fields. According to classical coordination chemistry, Cu(II) can adopt the dsp2 hybridization to form square planar coordination geometry, but not Cu(I); this is why so far, there has been few 2D layered structures synthesized from Cu(I) precursors. Herein a pair of isostructural GCPs synthesized by the coordination of benzenehexathiol (BHT) ligands with Cu(I) and Cu(II) ions, respectively, is reported. Spectroscopic characterizations indicate that Cu(I) and Cu(II) coexist with a near 1:1 ratio in both GCPs but remain indistinguishable with a fractional oxidation state of +1.5 on average, making these two GCPs a unique pair of Creutz-Taube mixed-valence 2D structures. Based on density functional theory calculations, an intramolecular pseudo-redox mechanism is further uncovered whereby the radicals on BHT ligands can oxidize Cu(I) or reduce Cu(II) ions upon coordination, thus producing isostructures with distinct electron configurations. For the first time, it is demonstrated that using Cu(I) or Cu(II), one can achieve 2D isostructures, indicating an unusual fact that a neutral periodic structure can host a different number of total electrons as ground states, which may open a new chapter for 2D materials.


Assessment of subcutaneous adipose tissue using ultrasound in highly trained junior rowers.
There is a large variety of body fat (BF) measurements, which differ in validity and reliability. The aim of this study was to measure subcutaneous adipose tissue (SAT) using ultrasound (US) in highly trained junior rowers in a field setting, establish fat patterning profiles, and compare the profiles between male and female athletes. Skinfold thickness (SKF) measurements were also taken and compared to US measurements. Sixteen athletes participated. US measurements were taken at eight sites and reported as a sum of SAT (D): DExcl (without embedded structures) and DIncl (including embedded structures). SKF was measured at three sites and reported as a sum of adipose tissue thickness (SUMSKF). Mean SAT thickness (DIncl) was 27.6 ± 12.4 mm for males and 65.5 ± 11.8 mm for females. Females had significantly more embedded structures than males (P = .016). Significant correlations were found (P < .001, r = 0.92) comparing SUMSKF to DIncl and between SKF and US measurements at the thigh site (P < .001, r = 0.86). US is a suitable tool to measure BF in the field testing of athletes and enables measurements of SAT with an accuracy and reliability not reached before. The sum of thicknesses (DIncl or DExcl) can be used to represent subcutaneous fat based on accurate measurements of uncompressed SAT thicknesses.


Electrical stimulation of cutaneous ulcerations. A literature review.
The effect of electrical currents on living cellular systems has been studied by many researchers and is becoming useful in clinical medicine. Alteration of cellular activity with externally applied currents can positively or negatively influence the status of a healing tissue, thereby directing the healing process to a desired outcome. A review of the literature pertaining to the effect of electrical currents on tissue healing is presented and the relevance of this modality to ulcer healing is discussed.


Interval running with self-selected recovery: Physiology, performance, and perception.
This study (1) compared the physiological responses and performance during a high-intensity interval training (HIIT) session incorporating externally regulated (ER) and self-selected (SS) recovery periods and (2) examined the psychophysiological cues underpinning SS recovery durations. Following an incremental maximal exercise test to determine maximal aerobic speed (MAS), 14 recreationally active males completed 2 HIIT sessions on a non-motorised treadmill. Participants performed 12 × 30 s running intervals at a target intensity of 105% MAS interspersed with 30 s (ER) or SS recovery periods. During SS, participants were instructed to provide themselves with sufficient recovery to complete all 12 efforts at the required intensity. A semi-structured interview was undertaken following the completion of SS. Mean recovery duration was longer during SS (51 ± 15 s) compared to ER (30 ± 0 s; p < .001; d = 1.46 ± 0.46). Between-interval heart rate recovery was higher (SS: 19 ± 9 b min-1; ER: 8 ± 5 b min-1; p < .001; d = 1.43 ± 0.43) and absolute time ≥90% maximal heart rate (HRmax) was lower (SS: 335 ± 193 s; ER: 433 ± 147 s; p = .075; d = 0.52 ± 0.39) during SS compared to ER. Relative time ≥105% MAS was greater during SS (90 ± 6%) compared to ER (74 ± 20%; p < .01; d = 0.87 ± 0.40). Different sources of afferent information underpinned decision-making during SS. The extended durations of recovery during SS resulted in a reduced time ≥90% HRmax but enhanced time ≥105% MAS, compared with ER exercise. Differences in the afferent cue utilisation of participants likely explain the large levels of inter-individual variability observed.


System for time resolved spectral studies of pulsed atmospheric discharges in the visible to vacuum ultraviolet range.
Vacuum ultraviolet (VUV) emission is believed to play a major role in the development of plasma streamers in pulsed atmospheric discharges, but detection of VUV light is difficult in pulsed experiments at atmospheric pressures. Since VUV light is absorbed in most standard optical materials as well, careful attention must be given to the selection of the lens and mirror optics used in these studies. Of highest interest is the VUV emission during the initial stage of pulsed atmospheric discharges, which has a typical duration in the nanosecond regime. An experiment was designed to study this fast initial stage of VUV emission coupled with fast optical imaging of streamer propagation, both with temporal resolution on the order of nanoseconds. A repetitive solid-state high voltage pulser was constructed which produces triggered flashover discharges with low jitter and consistent pulse amplitude. VUV emission is captured utilizing both photomultiplier and intensified charge-coupled device detectors during the fast stage of streamer propagation. These results are discussed in context with the streamer formation photographed in the visible wavelength regime with 3 ns exposure time.


Epidermal mucinosis in mycosis fungoides.
In many cases of mycosis fungoides there is widening of the epidermal intercellular spaces (i.e., spongiosis) and papillary dermal fibrosis with minimal papillary dermal edema. Twenty biopsies of mycosis fungoides, stained with a modified colloidal iron procedure, were analyzed to substantiate the notion that the spongiosis resulted from the formation of an osmotic gradient because of intercellular acidic mucopolysaccharide deposition. In nineteen of twenty cases of patch-plaque mycosis fungoides, there was positive intercellular deposition of acidic mucopolysaccharides. In addition to the contribution of acidic mucopolysaccharides to the process of spongiosis, the biologic significance of epidermal mucin deposition is discussed. Mycosis fungoides should be added to the growing list of diseases in which there is epidermal mucinosis.


Patient satisfaction profiling of individual physicians: impact of panel status.
Evaluation of physician performance is increasingly based on patient satisfaction. However, few data are available regarding the extent to which individual physician profiles might be influenced by factors such as whether a physician's practice is open or closed. We evaluated whether panel status (whether or not a physician is accepting new patients) is associated with patient satisfaction with their primary care physician (PCP). Cross-sectional analysis of patient satisfaction surveys. Surveys were available for 1,750 patients cared for by 69 PCPs. Patient satisfaction with their PCP was determined based on a composite of six questions derived from the Medical Outcomes Study. We used Generalized Estimating Equations to adjust for physician level variation. Patients of closed-panel physicians were more likely to rate their satisfaction with the provider as 'Excellent' or 'Very Good' compared to patients of open-panel physicians (78% vs. 69%, P <0.0001). After adjusting for satisfaction with the practice site, provider years in practice, managed care coverage, provider productivity, and patient race, the association between a closed panel and satisfaction remained significant (odds ratio 1.60, 95% confidence interval 1.10-2.31). Individual physicians' patient satisfaction data are confounded by factors not likely to be adjusted for in available profiles. After adjusting for other variables, physicians with closed panels still had better patient satisfaction compared to physicians with open panels. Further research is necessary to determine if panel status might also confound patient satisfaction.


Dominant-negative mutants of prgX: evidence for a role for PrgX dimerization in negative regulation of pheromone-inducible conjugation.
PrgX negatively regulates prgQ transcriptional readthrough in the pheromone-inducible enterococcal conjugative plasmid pCF10. We isolated and characterized 13 dominant-negative prgX mutants, all of which mapped in either the N- or the C-terminus of PrgX. In all mutants, the in vivo level of Qa RNA, an antisense RNA to prgQ RNA, was greatly reduced. When oligomerization of PrgX was tested with a phage lambda cI repressor fusion system, the oligomerization domain was found to be between amino acid residues 78 and 280. When histidine-tagged PrgX (His-PrgX) was purified by nickel column chromatography from a strain also expressing PrgX, PrgX was co-purified with His-PrgX. Although PrgX was expressed at a much higher level than His-PrgX, an approximately equal amount of PrgX was co-purified. Pheromone induction greatly decreased the co-purification of PrgX. Based on these data, we propose that both the N- and the C-terminal domains of PrgX are required for PrgX positive autoregulation and for the repression of prgQ transcription readthrough. In vivo, PrgX exists as a dimer, and dimerization is mediated by the central region of PrgX.


Multicomponent polyanions. 57. Large-angle X-ray scattering study of aqueous molybdophenylphosphonate solutions.
The radial distribution functions are calculated from large-angle X-ray scattering (LAXS) measurements for one concentrated aqueous molybdate/heptamolybdate solution and five aqueous molybdophenylphosphonate solutions (lithium chloride medium). Besides water and hydrated lithium, chloride, and molybdate ions, five species in all, having different nuclearities, are postulated to exist in the solutions, according to equilibrium studies using potentiometry and 31P NMR spectroscopy. The structures of the three polymolybdate species Mo7O24(6-), Mo8O26(4-), and (C6H5P)2Mo5O21(4-), for which the structures are determined crystallographically, are confirmed to exist also in aqueous solution. The principal structures of the remaining two complexes, (C6H5P)Mo6O21(OH2)5(2-) and (C6H5P)Mo7O25(OH2)4-, are elucidated with the use of structures of related species. Both anions have one group of four edge-sharing MoO6 octahedra and another group of two MoO6 octahedra connected by sharing corners, forming a bent unsymmetric six-membered ring, with the C6H5PO3 group placed on the crowded side of the ring. In the former, the group of two MoO6 octahedra is edge-shared, while in the latter, the group is face-shared, resulting in a ring small enough to tetrahedrally coordinate to the seventh molybdenum opposite the phenyl group.


Episodic memory retrieval for story characters in high-functioning autism.
The objective of this study was to examine differences in episodic memory retrieval between individuals with autism spectrum disorder (ASD) and typically developing (TD) individuals. Previous studies have shown that personality similarities between readers and characters facilitated reading comprehension. Highly extraverted participants read stories featuring extraverted protagonists more easily and judged the outcomes of such stories more rapidly than did less extraverted participants. Similarly, highly neurotic participants judged the outcomes of stories with neurotic protagonists more rapidly than did participants with low levels of neuroticism. However, the impact of the similarity effect on memory retrieval remains unclear. This study tested our 'similarity hypothesis', namely that memory retrieval is enhanced when readers with ASD and TD readers read stories featuring protagonists with ASD and with characteristics associated with TD individuals, respectively. Eighteen Japanese individuals (one female) with high-functioning ASD (aged 17 to 40 years) and 17 age- and intelligence quotient (IQ)-matched Japanese (one female) TD participants (aged 22 to 40 years) read 24 stories; 12 stories featured protagonists with ASD characteristics, and the other 12 featured TD protagonists. Participants read a single sentence at a time and pressed a spacebar to advance to the next sentence. After reading all 24 stories, they were asked to complete a recognition task about the target sentence in each story. To investigate episodic memory in ASD, we analyzed encoding based on the reading times for and readability of the stories and retrieval processes based on the accuracy of and response times for sentence recognition. Although the results showed no differences between ASD and TD groups in encoding processes, they did reveal inter-group differences in memory retrieval. Although individuals with ASD demonstrated the same level of accuracy as did TD individuals, their patterns of memory retrieval differed with respect to response times. Individuals with ASD more effectively retrieved ASD-congruent than ASD-incongruent sentences, and TD individuals retrieved stories with TD more effectively than stories with ASD protagonists. Thus, similarity between reader and story character had different effects on memory retrieval in the ASD and TD groups.


Deletion of Enigma Homologue from the Z-disc slows tension development kinetics in mouse myocardium.
Enigma Homologue (ENH) is a component of the Z-disc, a structure that anchors actin filaments in the contractile unit of muscle, the sarcomere. Cardiac-specific ablation of ENH protein expression causes contractile dysfunction that ultimately culminates in dilated cardiomyopathy. However, whether ENH is involved in the regulation of myocardial contractility is unknown. To determine if ENH is required for the mechanical activity of cardiac muscle, we analyze muscle mechanics of isolated trabeculae from the hearts of ENH +/+ and ENH -/- mice. We detected no differences in steady-state mechanical properties but show that when muscle fibers are allowed to relax and then are restretched, the rate at which tension redevelops is depressed in ENH -/- mouse myocardium relative to that in ENH +/+ myocardium. SDS-PAGE analysis demonstrated that the expression of β-myosin heavy chain is increased in ENH -/- mouse myocardium, which could partially, but not completely, account for the depression in tension redevelopment kinetics. Using top-down proteomics analysis, we found that the expression of other thin/thick filament regulatory proteins is unaltered, although the phosphorylation of a cardiac troponin T isoform, cardiac troponin I, and myosin regulatory light chain is decreased in ENH -/- mouse myocardium. Nevertheless, these alterations are very small and thus insufficient to explain slowed tension redevelopment kinetics in ENH -/- mouse myocardium. These data suggest that the ENH protein influences tension redevelopment kinetics in mouse myocardium, possibly by affecting cross-bridge cycling kinetics. Previous studies also indicate that ablation of specific Z-disc proteins in myocardium slows contraction kinetics, which could also be a contributing factor in this study.


Developing a Culture of Mentorship to Strengthen Academic Medical Centers.
Mentorship is central to academic medicine and its missions, and it has long played a critical role in the training and career development of physicians and scientists. A growing body of literature has documented the positive impact of mentorship on various outcomes, including research productivity, academic promotion, faculty retention, and career satisfaction. These benefits span academic medical centers' missions and have the potential to enhance biomedical research, patient care, education, and faculty diversity and leadership.In this Invited Commentary, the authors argue that a dynamic culture of mentorship is essential to the success of academic medical centers and should be elevated to the level of a major strategic priority. This culture of mentorship would capitalize on an institution's intellectual resources and seek to develop leaders in biomedical discovery, patient care, and education. The bidirectional transmission of knowledge between mentors and mentees, through both formal programs and informal relationships, can foster the growth of faculty members needed to meet the complex challenges currently confronting medical schools and teaching hospitals.Developing a culture of mentorship requires a strong commitment by leaders at all levels to nurture the next generation of physicians and scientists as well as grassroots efforts by trainees and faculty to seek out and create mentorship opportunities. The authors conclude by outlining possible mechanisms and incentives for elevating mentorship to the level of a strategic priority to strengthen academic medical centers across their missions.


Kimura disease: a clinicopathologic study of 21 cases.
Kimura disease is a rare form of chronic inflammatory disorder involving subcutaneous tissue, predominantly in the head and neck region and frequently associated with regional lymphadenopathy and/or salivary gland involvement. This condition has a predilection for males of Asian descent and may clinically simulate a neoplasm. Kimura disease is sometimes confused with angiolymphoid hyperplasia with eosinophilia, which occurs in the superficial skin of the head and neck region. Although sporadic cases have been reported in non-Asians, there is no large, comprehensive study of Kimura disease in the United States. We report 21 cases with nodal involvement that, histologically, are consistent with Kimura disease. There were 18 males and 3 females (male/female ratio 6:1), 8 to 64 years of age (mean, 32 years), and included 7 Caucasians, 6 Blacks, 6 Asians, 1 Hispanic, and 1 Arabic. Anatomic sites of involvement included posterior auricular (n = 10), cervical (n = 6), inguinal (n = 3), and epitrochlear (n = 2) lymph nodes, with two patients having associated salivary gland involvement. Most (n = 16) cases had peripheral blood eosinophilia. Consistent histologic features were follicular hyperplasia, eosinophilic infiltrates, and proliferation of postcapillary venules. Follow-up data on 18 patients revealed that 13 were alive without disease (3 had recurrence), mean follow-up, 10.9 years; 4 were alive with disease (2 had a recurrence), mean follow-up, 8.8 years; and 1 died with disease (12.7 years). Kimura disease has been described more often in Asians, but it does occur in non-Asians with a similar clinicopathologic presentation. It is a distinctive entity with no known etiology. Kimura disease has characteristic histologic features that are important to recognize and can be used to differentiate it from hypersensitivity and drug reactions and infections.


Core-hole-induced dynamical effects in the x-ray emission spectrum of liquid methanol.
We compute the x-ray emission spectrum of liquid methanol, with the dynamical effects that result from the creation of the core hole included in a semiclassical way. Our method closely reproduces a fully quantum mechanical description of the dynamical effects for relevant one-dimensional models of the hydrogen-bonded methanol molecules. For the liquid, we find excellent agreement with the experimental spectrum, including the large isotope effect in the first split peak. The dynamical effects depend sensitively on the initial structure in terms of the local hydrogen-bonding (H-bonding) character: non-donor molecules contribute mainly to the high-energy peak while molecules with a strong donating H-bond contribute to the peak at lower energy. The spectrum thus reflects the initial structure mediated by the dynamical effects that are, however, seen to be crucial in order to reproduce the intensity distribution of the recently measured spectrum.


[Isolation and properties of endodeoxyribonuclease from the ovicells of the loach].
A new DNAase was isolated from unfertilized loach eggs. The enzyme is activated by bivalent metal ions (Mg2+, Ca2+, Mn2+) and is inhibited by Na+ and N-ethylmaleimide. The maximal activity of DNAase lies within the pH range of 9.0-9.5. The enzyme is thermostable and predominantly hydrolyzes the two-chain DNA by producing one-chain ruptures. The DNAase activity during the purification procedure and enzymatic analysis was determined by a highly sensitive method based on registration of superhelical plasmid or phage DNA conversion into open circular or linear molecules.


Pesticides in a case study on no-tillage farming systems and surrounding forest patches in Brazil.
With the growing global concern on pesticide management, the relationship between its environmental recalcitrance, food security and human health has never been more relevant. Pesticides residues are known to cause significant environmental contamination. Here, we present a case study on long-term no-tillage farming systems in Brazil, where Glyphosate (GLY) has been applied for more than 35 years. GLY and its main breakdown product, aminomethylphosphonic acid (AMPA) were determined in topsoil (0-10 cm) samples from no-tillage fields and nearby subtropical secondary forests by high-performance liquid chromatography coupled with a fluorescence detector. In addition, the presence of carbamates, organochlorines, organophosphates and triazines were also screened for. GLY and AMPA were present in all soil samples, reaching values higher than those described for soils so far in the literature. A significant decrease for AMPA was observed only between the secondary forest and the farm's middle slope for site B. GLY and AMPA were observed respectively at peak concentrations of 66.38 and 26.03 mg/kg soil. GLY was strongly associated with forest soil properties, while AMPA associated more with no-tillage soil properties. Soil texture was a significant factor contributing to discrimination of the results as clay and sand contents affect GLY and AMPA retention in soils. This was the first study to report DDT and metabolites in consolidated no-tillage soils in Brazil (a pesticide fully banned since 2009). Based on human risk assessment conducted herein and the potential risk of GLY to local soil communities, this study offers a baseline for future studies on potential adverse effects on soil biota, and mechanistic studies.


Life's Essential 8, genetic predisposition, and risk of incident adult-onset asthma: a prospective cohort study.
Adult-onset asthma (AOA) and cardiovascular diseases shared common risk factors and similar pathophysiologic resemblances. The American Heart Association (AHA) unveiled the life's essential 8 (LE8) to promote cardiovascular health (CVH). This study aimed to assess the overall impact of LE8 implementation on AOA prevention. According to the guideline of AHA's Construct of CVH in 2022, LE8 score was calculated from 8 health status concerning diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Cox proportional-hazards models were used to estimate effect sizes of associations between CVH, asthma genetic risk, and risk of incident AOA in participants selected from the UK Biobank study. A total of 6180 incident AOA cases occurred in 249,713 participants during an average of 11.60 y' follow-up. A higher LE8 score was associated with a lower risk of incident AOA with a significant linear trend (P < 0.0001). Every standard deviation increment of LE8 was associated with a 17% (HR: 0.83; 95% CI: 0.81, 0.85) lower risk of incident AOA. Compared with participants with low-CVH score, participants with moderate (HR: 0.72; 95% CI: 0.67, 0.78) and high CVH scores (HR: 0.52; 95% CI: 0.47, 0.58) were associated with a lower risk of incident AOA (P-trend < 0.0001). No significant multiplicative or additive interaction was found between LE8 score and genetic risks. Stratified analysis showed a consistent association between CVH and risk of incident AOA across different asthma polygenic risk score (PRS) levels. Compared with participants with high PRS and low CVH, participants with low PRS and high CVH experienced the lowest risk (HR: 0.28; 95% CI: 0.23, 0.34) of incident AOA. Our findings suggest that maintaining optimal CVH should be recommended as a preventive strategy for AOA, regardless of their asthma genetic risks.


Safety and efficacy of hyaluronic acid injectable filler in the treatment of nasolabial fold wrinkle: a randomized, double-blind, self-controlled clinical trial.
The injectable skin fillers available for soft tissue augmentation are constantly growing, providing esthetic surgeons with more options in the treatment of scars, lines, and wrinkles. Hyaluronic acid (HA)-derived injectable fillers are ideal to reduce the appearance of nasolabial folding. This study investigated the efficacy and safety of the commercially available HA filler from Maxigen Biotech Inc. (MBI-FD) in the treatment of nasolabial folds (NLFs). We analyzed 1,4-butanediol diglycidyl ether (BDDE) residues and injection force test and observed the protein content in MBI-FD, and then was cultured in fibroblast L929 cells and examined for cytotoxicity. Finally, 95 healthy participants underwent dermal filler injection therapy to evaluate the efficacy and safety for 24 and 52 weeks, respectively. BDDE residues in MBI-FD was <0.125 µg/mL. MBI-FD was fitted using 27- and 30-G injection needles with an average pushing force of 14.30 ± 2.07 and 36.43 ± 3.11 N, respectively. Sodium hyaluronate protein in MBI-FD was 7.19 µg/g. The cell viabilities of 1× and 0.5× MBI-FD were 83.25% ± 3.58% and 82.23% ± 1.85%, respectively, indicating MBI-FD had no cytotoxicity, and decreased NLF wrinkles with no serious adverse events. MBI-FD is an effective filler for tissue augmentation of the NLFs and may be a suitable candidate as an injectable dermal filler for tissue augmentation in humans in the future.


[Recurrent systemic arterial embolism in patients with valve prostheses].
The first 400 cases of 1,436 patients undergoing cardiac valve replacement were analysed to determine the clinical features of recurrent systemic embolism. The average follow-up period was 87 months. Three groups of patients were compared: A: 289 cases without embolic complications (72.5 p. 100) B: 78 cases with a single systemic thrombo-embolic event. (TEE) (19,5 p. 100) C: 33 cases with recurrent TEE (8.25 p. 100). The incidence of recurrence is high (30 p. 100 of cases, 8,1 p. 100 per patient year, compared to 3.8 p. 100 for the first TEE). The site of recurrent embolism was the same in 45 p. 100 of cases. The consequences were serious, 30 to 40 p. 100 of events being associated with death or invalidating sequellae. Four factors predisposed to TEE: mitral valve prosthesis, atrial fibrillation, left atrial dilatation and poor anticoagulant control. Fifty-four months after the first TEE, 60 p. 100 with inadequate anticoagulation had a recurrence compared to 20 p. 100 of patients with satisfactory control. Twenty-six patients (Groups B and C) had operative or autopsy examination of the prosthesis: thrombosis was found in 12 out of 18 cases in Group B, and in 7 out of 8 cases in Group C. Reoperation may be necessary to change the valve (27 out of 1,436 patients). Strict adherence to anticoagulant therapy remains the best prophylaxis against TEE and their recurrence.


An Interpretable Neonatal Lung Ultrasound Feature Extraction and Lung Sliding Detection System Using Object Detectors.
The objective of this study was to develop an interpretable system that could detect specific lung features in neonates. A challenging aspect of this work was that normal lungs showed the same visual features (as that of Pneumothorax (PTX)). M-mode is typically necessary to differentiate between the two cases, but its generation in clinics is time-consuming and requires expertise for interpretation, which remains limited. Therefore, our system automates M-mode generation by extracting Regions of Interest (ROIs) without human in the loop. Object detection models such as faster Region Based Convolutional Neural Network (fRCNN) and RetinaNet models were employed to detect seven common Lung Ultrasound (LUS) features. fRCNN predictions were then stored and further used to generate M-modes. Beyond static feature extraction, we used a Hough transform based statistical method to detect "lung sliding" in these M-modes. Results showed that fRCNN achieved a greater mean Average Precision (mAP) of 86.57% (Intersection-over-Union (IoU) = 0.2) than RetinaNet, which only displayed a mAP of 61.15%. The calculated accuracy for the generated RoIs was 97.59% for Normal videos and 96.37% for PTX videos. Using this system, we successfully classified 5 PTX and 6 Normal video cases with 100% accuracy. Automating the process of detecting seven prominent LUS features addresses the time-consuming manual evaluation of Lung ultrasound in a fast paced environment. Clinical impact: Our research work provides a significant clinical impact as it provides a more accurate and efficient method for diagnosing lung diseases in neonates.


Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs.
The susceptibility to infections and the strong Th2 bias observed in neonates are thought to be due to the immaturity of the dendritic cell (DC) compartment. We show that neonatal DCs, like their adult counterparts, elicit Th1 responses. We also demonstrate that during potentially harmful systemic inflammation, after Toll-like receptor (TLR) 9 triggering, neonatal B cells produce high concentrations of IL-10, preventing optimal IL-12 secretion by neonatal DCs and, thus, Th1 priming. Although both CD5+ and CD5- B cell subsets respond to CpG ODN stimulation, we found that only CD5+ B cells produce IL-10. Therefore, these results show the regulatory role of CD5+ B cells on DC activation in vivo for Th1/Th2 polarization and highlight the paradoxical effects of TLR triggering in vivo.


Dynamics and seasonal abundance of stink bugs (Heteroptera: Pentatomidae) in a cotton-soybean ecosystem.
Two soybean varieties (early-maturing group V and late-maturing group VII) and two cotton varieties (conventional and transgenic (Bt) were grown in adjacent replicated large field plots (approximately 0.1 ha each) at two locations for 3 yr. The dynamics and relative abundance of phytophagous stink bugs within these two crops were observed. The most abundant pentatomid species in both crops for all 3 yr were Nezara viridula (L.), Acrosternum hilare (Say), and Euschistus servus (Say). Several other species also were commonly collected. This is the first record of Mormidea lugens (F.) on soybean and E. quadrator Rolston, E. obscurus (Palisot), Holcostethus limbolarius (Stål), and Oebalus pugnax (F.) on cotton. Stink bugs began arriving in soybean when plant growth stages ranged from pod formation to full seed development. Peak numbers of these insects were found in soybean from the time of full-size seeds in the pods until early maturity. The bugs were first attracted to the earlier maturing cultivar (group V), where they remained until plants began to mature (R7). The pentatomids then moved to the later-maturing cultivar (group VII) as it reached full pod to full seed. Stink bugs began arriving in cotton from the time of the earliest flowers until after the first bolls formed. Peak numbers in cotton occurred during the time when all stages of developing bolls were present. Stink bug numbers were much greater in soybean than in cotton over all three seasons. This preference for soybean over cotton indicates the potential use of soybean as a trap crop for attracting stink bugs away from cotton. Additionally, the coordinated use of early- and late-maturing soybean cultivars as a trap crop could minimize the area requiring insecticides, as well as the number of insecticide applications to cotton.


Impact of PET/CT on Staging and Treatment of Advanced Head and Neck Squamous Cell Carcinoma.
To understand the effects of positron emission tomography/computed tomography (PET/CT) evaluation on patients with previously untreated head and neck squamous cell carcinoma (HNSCC) with clinical evidence of regional lymph node involvement. Prospective blinded study. Tertiary care cancer center. Informed consent was obtained and data collected from 52 consecutive previously untreated patients with HNSCC and clinical evidence of cervical metastasis. All patients underwent conventional evaluation for HNSCC and whole body PET/CT. Data were evaluated by 5 independent reviewers, who performed TNM staging per the American Joint Committee on Cancer (seventh edition) manual and proposed a treatment plan prior to viewing, and after reviewing, PET/CT. Cases where at least 3 of 5 reviewers agreed were considered significant. There were 0 patients for whom review of the PET/CT altered the T-class assessment (95% CI, 0-6.8), 12 (23.1%) for whom PET/CT altered N classification (95% CI, 12.5-34.5), and 2 (3.8%) for whom PET/CT altered the M classification (95% CI, 0.5-13.2). For 5 patients (9.6%), overall stage was altered per PET/CT review (95% CI, 3.2-21). For 3 patients (5.8%), PET/CT findings prompted reviewers to alter treatment recommendations (95% CI, 1.2-15.9). When added to more conventional patient evaluation, PET/CT results in changes to the TNM categories, but overall staging and treatment were less frequently affected. Whether PET/CT should be used routinely for patients with stage III and IV HNSCC is still subjective and merits further study.


[A novel SMOreg algorithm based on instance cloned and its research on spectral modeling for hydromica in uranium deposit].
Hydromica is a typical alteration mineral in granite-type uranium deposit, and also an important indication of uranium. The amount of hydromica to some extent reflects the strength of hydromicasization in uranium deposit. Because of the bad performance of the traditional modelling methods in prediction, in the present paper, the authors' adopt SMOreg in the spectral modelling for hydromica, and validate its effectiveness. The authors' also propose a novel method called ICSMOreg. In this method the authors' employ instance cloned method to learn the samples selected by having a strong affinity with the test sets, and then get the new samples into SMOreg to build the spectral model. Finally, we experimentally compare ICSMOreg with SMOreg, artificial neural network, model tree and the common modelling methods like linear regression, multiple linear regression. The result shows that the new method improves the accuracy of prediction, and also reduces the negative impact of noise.


Low superior vena cava flow and intraventricular haemorrhage in preterm infants.
To document the incidence, timing, degree, and associations of systemic hypoperfusion in the preterm infant and to explore the temporal relation between low systemic blood flow and the development of intraventricular haemorrhage (IVH). 126 babies born before 30 weeks' gestation (mean 27 weeks, mean body weight 991 g) were studied with Doppler echocardiography and cerebral ultrasound at 5, 12, 24, and 48 hours of age. Superior vena cava (SVC) flow was assessed by Doppler echocardiography as the primary measure of systemic blood flow returning from the upper body and brain. Other measures included colour Doppler diameters of ductal and atrial shunts, as well as Doppler assessment of shunt direction and velocity, and right and left ventricular outputs. Upper body vascular resistance was calculated from mean blood pressure and SVC flow. SVC flow below the range recorded in well preterm babies was common in the first 24 hours (48 (38%) babies), becoming significantly less common by 48 hours (6 (5%) babies). These low flows were significantly associated with lower gestation, higher upper body vascular resistance, larger diameter ductal shunts, and higher mean airway pressure. Babies whose mothers had received antihypertensives had significantly higher SVC flow during the first 24 hours. Early IVH was already present in 9 babies at 5 hours of age. Normal SVC flows were seen in these babies except in 3 with IVH, which later extended, who all had SVC flow below the normal range at 5 and/or 12 hours. Eight of these 9 babies were delivered vaginally. Late IVH developed in 18 babies. 13 of 14 babies with grade 2 to 4 IVH had SVC flow below the normal range before development of an IVH. Two of 4 babies with grade 1 IVH also had SVC flow below the normal range before developing IVH, and the other 2 had SVC flow in the low normal range. In all, IVH was first seen after the SVC flow had improved, and the grade of IVH related significantly to the severity and duration of low SVC flow. The 9 babies who had SVC flow below the normal range and did not develop IVH or periventricular leucomalacia were considerably more mature (median gestation 28 v 25 weeks). Low SVC flow may result from an immature myocardium struggling to adapt to increased extrauterine vascular resistances. Critically low flow occurs when this is compounded by high mean airway pressure and large ductal shunts out of the systemic circulation. Late IVH is strongly associated with these low flow states and occurs as perfusion improves.


A theory for polymicrogyria and brain arteriovenous malformations in HHT.
Hereditary hemorrhagic telangiectasia (HHT) is generally considered a disorder of endothelial dysfunction, characterized by the development of multiple systemic arteriovenous malformations (AVMs), including within the brain. However, there have recently been a number of reports correlating HHT with malformations of cortical development, of which polymicrogyria is the most common type. Here we present 7 new cases demonstrating polymicrogyria in HHT, 6 of which demonstrate a brain AVM (bAVM) in close spatial proximity, with the aim of providing a common origin for the association. Upon reviewing patient genetics and imaging data and comparing with previously reported findings, we form 2 new conclusions: (1) polymicrogyria in HHT appears exclusively associated with a subset of mutations in the transmembrane protein endoglin that is involved with blood flow-related mechanotransduction signaling during angiogenesis and (2) the polymicrogyria is characteristically unilateral, typically focal, and correlates with vascular regions experiencing low fluid shear stress during corticogenesis in utero. Integrating these with findings in the literature from genetics and molecular biology experiments, we propose a theory suggesting haploinsufficient endoglin mutations, especially those that are dominant-negative, may predispose focal, aberrant hypersprouting angiogenesis during corticogenesis that leads to the production of polymicrogyria. This hypoxic insult may further serve as the revealing trigger for later development of a spatially coincident bAVM. This hypothesis suggests an essential role for endoglin-mediated hemodynamic mechanotransduction in normal corticogenesis.


Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies.
Amoxicillin is recommended for anthrax prevention in pregnancy. The objective of this study was to evaluate the pharmacokinetics of amoxicillin during pregnancy and postpartum (PP). Sixteen women received amoxicillin during gestation (18-22 weeks (T2) and 30-34 weeks (T3)) as well as 3 months postpartum (PP) to evaluate single-dose pharmacokinetics. Amoxicillin compartmental pharmacokinetic parameters were used to simulate amoxicillin concentration-time profiles following different dosage strategies. Amoxicillin CL(renal) (T2: 24.8+/-6.7 l/h, P<0.001; T3: 24.0+/-3.9 l/h, P<0.001; and PP: 15.3+/-2.6 l/h) and renal CL(secretion) (T2: 280+/-105 ml/min, P<0.002; T3: 259+/-54 ml/min, P<0.001; and PP: 167+/-47 ml/min) were higher during pregnancy than postpartum. Simulations suggest that amoxicillin concentrations adequate to prevent anthrax may be difficult to achieve during pregnancy and postpartum. Increases in amoxicillin CL(renal) and renal CL(secretion) reflect increases in filtration and secretory transport or diminished reabsorption in the kidneys. Amoxicillin may not be an appropriate antibiotic for post-anthrax exposure prophylaxis.


Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells.
The release of cytokines by T cells strongly defines their functional activity in vivo. The ability to produce multiple cytokines has been associated with beneficial immune responses in cancer and infectious diseases, while their progressive loss is associated with T-cell exhaustion, senescence and anergy. Consequently, strategies that enhance the multifunctional status of T cells are a key for immunotherapy. Dendritic cells (DCs) are professional antigen presenting cells that regulate T-cell functions by providing positive and negative co-stimulatory signals. A key negative regulator of T-cell activity is provided by binding of programmed death-1 (PD-1) receptor on activated T cells, to its ligand PD-L1, expressed on DCs. We investigated the impact of interfering with PD-L1/PD-1 co-stimulation on the multifunctionality of T cells, by expression of the soluble extracellular part of PD-1 (sPD-1) or PD-L1 (sPD-L1) in human monocyte-derived DCs during antigen presentation. Expression, secretion and binding of these soluble molecules after mRNA electroporation were demonstrated. Modification of DCs with sPD-1 or sPD-L1 mRNA resulted in increased levels of the co-stimulatory molecule CD80 and a distinct cytokine profile, characterized by the secretion of IL-10 and TNF-α, respectively. Co-expression in DCs of sPD-1 and sPD-L1 with influenza virus nuclear protein 1 (Flu NP1) stimulated Flu NP1 memory T cells, with a significantly higher number of multifunctional T cells and increased cytokine secretion, while it did not induce regulatory T cells. These data provide a rationale for the inclusion of interfering sPD-1 or sPD-L1 in DC-based immunotherapeutic strategies.