One-year mortality in elderly stable patients with COPD.
A retrospective study was performed to evaluate the risks of one-year mortality in very old hospitalized patients including those suffering from chronic obstructive pulmonary disease (COPD). Six hundred and fifty-eight disabled patients (M = 194, mean age 79.2 +/- 7.4 years) consecutively admitted to and discharged from a Geriatric Evaluation and Rehabilitation Unit (GERU) after a comprehensive rehabilitation program were studied and divided into two groups: COPD (n = 337, 51%) and non-COPD (n = 321, 49%). Multidimensional evaluation including information on demographics, cognitive status [Mini Mental State Examination (MMSE)], physical health [number of diseases, Greenfield's Individual Disease Severity (IDS), and number of drugs used], functional disability [Basic Activity of Daily Living (BADL), Tinetti scale, and Physical Performance Test (PPT)], and nutritional status [Prognostic Nutritional Index (PNI)] were assessed at admission. Survival rate was assessed over a 1-year period following discharge. COPD patients mainly differed from non-COPD in terms of older age, smoking habit, number of associated diseases and drugs used. Aggregating the IDS 2-3-4 COPD classes (symptoms + functional impairment), the risk of one-year mortality was double that of the IDS 1 COPD class (symptoms only) and of non-COPD subjects (IDS 0 class) after adjusting for age, sex, disability, malnutrition, and comorbility. Moreover, IDS 2-3-4 COPD patients suffering from cor pulmonale (CP) had a fourfold 1-year risk of mortality in comparison with the IDS 1 COPD group after adjusting for the same covariates. Hospitalized stable very old COPD patients presenting functional impairment have a higher 1-year risk of mortality than only symptomatic COPD or non-COPD subjects. The presence of cor pulmonale with COPD further increases this risk.


Antitumor activity of high-dose pulsatile gefitinib in non-small-cell lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). However, their clinical efficacy is limited by acquired resistance. Drug resistance may be mediated by EGFR transduction, and a number of clinical trials have demonstrated that high-dose pulsatile TKIs may be effective at treating patients with acquired resistance, though their underlying mechanisms of action remain unknown. The aim of the present study was to investigate the antitumor activity of high-dose pulsatile gefitinib in NSCLC model cell lines, namely the EGFR-TKI-sensitive cell line PC9, as a control group, and the EGFR-TKI-resistant cell lines H1975 and H1650. The cell lines were administered with different doses of gefitinib and cell viability was measured using an MTT assay. Cell apoptosis and cycling were also determined by flow cytometry and the expression of phospho (p)-EGFR, EGFR, p-AKT and AKT were measured by western blot analysis. It was observed that the apoptotic rate of H1975 cells treated with high-dose pulsatile gefitinib significantly increased, while levels of p-EGFR and p-AKT were decreased. However, there was no significant difference in the apoptotic rate or level of p-AKT in gefitinib-treated H1650 cells, while p-EGFR levels decreased. By contrast, the EGFR-TKI-sensitive cell line PC9 exhibited sensitivity to gefitinib. It was demonstrated that the apoptosis rates were markedly increased when treated with high dose pulsatile gefitinib in PC9 cell line, while a decrease was noted in p-EGFR and p-AKT. These data suggest that high-dose pulsatile gefitinib treatment may overcome acquired resistance in NSCLC, though its efficacy is dependent on the type of drug resistance mutation(s) present. Furthermore, high-dose pulsatile gefitinib may inhibit tumor growth and induce cell apoptosis by blocking the EGFR signaling pathway. Therefore, if the signaling pathways involved in drug resistance are not activated by the EGFR gene, high-dose pulsatile gefitinib may have little efficacy in the treatment of NSCLC.


Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis.
Regulatory T cells (T(reg) cells) develop from progenitor thymocytes after the engagement of T cell antigen receptors (TCRs) with high-affinity ligands, but the underlying molecular mechanisms are still unclear. Here we show that the Nr4a nuclear receptors, which are encoded by immediate-early genes upregulated by TCR stimulation in thymocytes, have essential roles in T(reg) cell development. Mice that lacked all Nr4a factors could not produce T(reg) cells and died early owing to systemic autoimmunity. Nr4a receptors directly activated the promoter of the gene encoding the transcription factor Foxp3, and forced activation of Nr4a receptors bypassed low-strength TCR signaling to drive the T(reg) cell developmental program. Our results suggest that Nr4a receptors have key roles in determining CD4(+) T cell fates in the thymus and thus contribute to immune homeostasis.


Epithelioid haemangioma--angiolymphoid hyperplasia with eosinophilia. Case report and review of literature.
Epithelioid haemangioma (angiolymphoid hyperplasia with eosinophilia: ALH) is a rare tumour most often affecting the skin and subcutaneous tissue in young adults. Unusual findings in the present case included deep location oft the lesion with involvement of striated muscle and periosteum which complicated clinical diagnosis. These tumours are generally composed of proliferating small vessels with prominent endothelial cells and heavy inflammatory infiltrate made up of lymphocytes, lymphoid follicles, plasma cells, mast cells, and especially eosinophils. The lesion is benign, and local excision is curative. Clinical manifestation and morphological characteristics of this rare lesion are described in this paper and are compared with other cases reported in the literature.


Thrombin stimulates integrin β1-dependent adhesion of human pancreatic cancer cells to vitronectin through protease-activated receptor (PAR)-1.
The aim of this study was to investigate the effect of thrombin and the thrombin receptor protease-activated receptor (PAR)-1 on adhesion of human pancreatic cancer cell lines to extracellular matrices (ECMs) and to identify related integrins with these effects. Human pancreatic cancer cell lines SUIT-2 and its four sublines, and Panc- 1, AsPC-1 and MiaPaCa-2 were treated with thrombin, PAR-1 agonist TRAP-6, PAR-1 antagonist SCH79797, or anti-integrin ±vβ3, ±vβ5 and β1 monoclonal antibodies. Cells were incubated for 45 minutes on micro titer plates that were pre-coated with ECMs (fibronectin, laminin, vitronectin, type IV collagen). The number of adherent cells was measured by the MTT method. Eight human pancreatic cancer cell lines expressed PAR-1. Thrombin significantly enhanced adhesion of SUIT-2 and its sublines and MiaPaCa-2 to vitronectin, especially in the SUIT-2 subline S2-007. We obtained similar results on S2-007 cells through treatment with TRAP-6. However, SCH79797 inhibited the effect of thrombin. Furthermore, anti-integrin β1 antibody conspicuously inhibited 1U/mL thrombin-induced enhancement of adhesion to vitronectin. Thrombin significantly enhanced adhesion of pancreatic cancer cells to vitronectin through PAR- 1 depending on the presence of integrin β1. Suppression of thrombin action by anti-integrin β1 antibody will become a useful therapy against pancreatic cancer.


Crossing the hands disrupts tactile spatial attention but not motor attention: evidence from event-related potentials.
During covert shifts of tactile spatial attention both somatotopic and external reference frames are employed to encode hand location. When participants cross their hands these frames of references produce conflicting spatial codes which disrupt tactile attentional selectivity. Because attentional shifts are triggered not only in Attention tasks but also during covert movement preparation, the present study aimed at investigating the reference frame employed during such 'motor shifts of attention'. Event related brain potentials (ERPs) were recorded during a Motor task where a visual cue (S1) indicated the relevant hand for a manual movement prior to a tactile Go/Nogo stimulus (S2). For comparison, we ran a tactile Attention task where the same cue (S1) now indicated the relevant hand for a tactile discrimination (S2). Both tasks were performed under uncrossed and crossed hands conditions. In both Attention and Motor tasks similar lateralized components were observed following S1 presentation. Anterior and posterior ERP components indicative of covert attention shifts were exclusively guided by an external reference frame, while a later central negativity operated according to a somatotopic reference frame in both tasks. In the Motor task, this negativity reflected selective activation of the motor cortex in preparation for movement execution. In the Attention task, this component might reflect activity in the somatosensory cortex in preparation for the subsequent tactile discrimination. The presence of multiple and conflicting spatial codes resulted in disruption of tactile attentional selection in the Attention task where attentional modulations of tactile processing were delayed and attenuated with crossed hands as indicated by the analysis of ERPs elicited by S2. In contrast, attentional modulations of S2 processing in the Motor task were largely unaffected by the hand posture manipulation, suggesting that motor attention employs primarily one spatial coordinate system.


Imaging of the oesophagus: beyond cancer.
Non-malignant oesophageal diseases are critical to recognize, but can be easily overlooked or misdiagnosed radiologically. In this paper, we cover the salient clinical features and imaging findings of non-malignant pathology of the oesophagus. We organize the many non-malignant diseases of the oesophagus into two major categories: luminal disorders and wall disorders. Luminal disorders include dilatation/narrowing (e.g. achalasia, scleroderma, and stricture) and foreign body impaction. Wall disorders include wall thickening (e.g. oesophagitis, benign neoplasms, oesophageal varices, and intramural hematoma), wall thinning/outpouching (e.g. epiphrenic diverticulum, Zenker diverticulum, and Killian-Jamieson diverticulum), wall rupture (e.g. iatrogenic perforation, Boerhaave Syndrome, and Mallory-Weiss Syndrome), and fistula formation (e.g. pericardioesophageal fistula, tracheoesophageal fistula, and aortoesophageal fistula). It is the role of the radiologist to recognize the classic imaging patterns of these non-malignant oesophageal diseases to facilitate the delivery of appropriate and prompt medical treatment. • Nonmalignant oesophageal disease can be categorised by the imaging appearance of wall and lumen. • Scleroderma and achalasia both cause lumen dilatation via different pathophysiologic pathways. • Oesophageal wall thickening can be inflammatory, neoplastic, traumatic, or vascular in aetiology.


Right frontotemporal activation by tonal memory in dyslexia, an O15 PET Study.
A prior study documented the failure of dyslexic men to activate left temporoparietal cortex during phonologic processing. Because of reports of an anomalous right planum temporale in developmental dyslexia, the functional implications of which are unknown, this study examined the ability of dyslexics to activate right temporal cortex. Regional cerebral blood flow was measured in 15 right-handed dyslexic men during rest and during a tonal memory task expected to activate right-sided cortex in controls. A matched control sample (n = 18) showed significant activation of several right frontotemporal regions as well as of left temporal cortex. In contrast, severely dyslexic men activated fewer right frontotemporal regions, while making many more errors than controls, but showed normal activation of left mid to anterior temporal cortex. These results support hypothesized underlying deficits in rapid temporal processing and possible involvement of right (in addition to left) temporal cortex in severe dyslexia.


Risk Factors of Delayed Recovery of Gastrointestinal Function After Ileostomy Reversal for Rectal Cancer Patients.
The aim of this study was to identify the risk factors associated with delayed recovery of gastrointestinal function after ileostomy reversal for rectal cancer patients. In this retrospective study, the data of rectal cancer patients who underwent ileostomy reversal from January 2018 to December 2019 at the Sixth Affiliated Hospital of Sun Yat-sen University were assessed to investigate potential risk factors of delayed flatus after ileostomy reversal. A total of 282 patients were eligible for this study. Postoperative first flatus time ranged from 1 to 9 days, of which 58.8% patients presented with delayed flatus that was longer than 3 days. Univariate analysis showed that delayed postoperative flatus was significantly associated with the length of postoperative hospital stay (P<0.001) and postoperative complications (P=0.037). Multivariate analysis showed that intravenous fluid infusion at postoperative day 1 (POD1) (OR=1.001, 95% CI: 1.001-1.002, P=0.001) and duration of stoma ≥6 months (OR=2.005, 95% CI:1.155-3.657, P=0.014) were independent risk factors for delayed flatus. Increased intravenous fluid infusion at POD1 and duration of stoma ≥6 months were related to delayed recovery of gastrointestinal function after ileostomy reversal for rectal cancer patients.


International regulatory aspects of clinical periodontal research.
The Food and Drug Administration (FDA) was the pioneer regulatory agency to set standards for clinical studies aimed at approval of new drugs. For years the FDA's rules represented the most thorough, stringent, and consistent policy. Now most other developed countries have comparable requirements for the conduct of clinical trials. The European Community (EC). Canadian, and Japanese regulations are most important for United States (US) scientists attempting to globalize their research. Regulations in Eastern Europe, some Asian countries, and Latin America are of growing importance. The Pacific-Rim appears to be the fastest growing pharmaceutical market in the next decade. Currently, the EC and Japan's Good Clinical Practice (GCP) regulations are more detailed than those of the US. Moreover, the World Health Organization recently published GCP recommendations similar to the EC requirements. Well-designed and well-controlled studies done in the EC, US, and other developed countries are generally accepted throughout the world. Japan and some other countries require studies in local patients. American scientists cannot expect to conduct studies in other countries as principal investigators, but many are associated with national clinicians. Mutual recognition of marketing approvals is the ultimate goal for the globalization of drug research. While it is the objective of the Scheme for the Mutual Recognition of Evaluation Reports on Pharmaceutical Products and the EC Decentralized Procedure, it is not apparent when the FDA will totally accept another regulatory body's approval decision. The International Conference on Harmonization involves the EC, Japan, and the US. This most important series of meetings will finally align the major countries more closely in regulating clinical studies and the production of safe, effective, and quality products, especially in these times of worldwide economic considerations and health care reform. It is imperative that US dental scientists become more familiar with pertinent regulations in leading foreign countries.


Clinical decision support system for early detection of Alzheimer's disease using an enhanced gradient boosted decision tree classifier.
Alzheimer's disease (AD) is one of the most common forms of dementia contributing to more than 70% of the cases. The factors accounting for the cause and progression of neurodegenerative diseases like AD are primarily genetic, in addition to life style and environmental factors. Early and accurate diagnoses of AD empower practitioners to take timely clinical decisions and preventive actions. This being the motivation, the work proposes a novel pattern matching and scoring method on genetic material towards devising an effective classifier. We propose a distinctive disease causing gene sequence pattern identification using suffix trees as a base detection model with an accuracy of 91.5% in linear time complexity. A scoring mechanism is implemented to assign scores to genes based on the severity of the disease causing and disease resistant Single Nucleotide Polymorphisms associated with the genes. These scores are then used as a remarkable feature in the gradient boosted decision tree classifier to enhance the classification of AD versus healthy control. The efficiency of the proposed gene powered EGBDT classifier is evaluated on ADNI benchmark data set with the prediction accuracy of 94.16% and is found to be efficient compared to the recent works in the literature.


Piezoresistive Sensor with High Elasticity Based on 3D Hybrid Network of Sponge@CNTs@Ag NPs.
Pressure sensors with high elasticity are in great demand for the realization of intelligent sensing, but there is a need to develope a simple, inexpensive, and scalable method for the manufacture of the sensors. Here, we reported an efficient, simple, facile, and repeatable "dipping and coating" process to manufacture a piezoresistive sensor with high elasticity, based on homogeneous 3D hybrid network of carbon nanotubes@silver nanoparticles (CNTs@Ag NPs) anchored on a skeleton sponge. Highly elastic, sensitive, and wearable sensors are obtained using the porous structure of sponge and the synergy effect of CNTs/Ag NPs. Our sensor was also tested for over 2000 compression-release cycles, exhibiting excellent elasticity and cycling stability. Sensors with high performance and a simple fabrication process are promising devices for commercial production in various electronic devices, for example, sport performance monitoring and man-machine interfaces.


Inhibition of neuroblastoma tumor growth by targeted delivery of microRNA-34a using anti-disialoganglioside GD2 coated nanoparticles.
Neuroblastoma is one of the most challenging malignancies of childhood, being associated with the highest death rate in paediatric oncology, underlining the need for novel therapeutic approaches. Typically, patients with high risk disease undergo an initial remission in response to treatment, followed by disease recurrence that has become refractory to further treatment. Here, we demonstrate the first silica nanoparticle-based targeted delivery of a tumor suppressive, pro-apoptotic microRNA, miR-34a, to neuroblastoma tumors in a murine orthotopic xenograft model. These tumors express high levels of the cell surface antigen disialoganglioside GD2 (GD(2)), providing a target for tumor-specific delivery. Nanoparticles encapsulating miR-34a and conjugated to a GD(2) antibody facilitated tumor-specific delivery following systemic administration into tumor bearing mice, resulted in significantly decreased tumor growth, increased apoptosis and a reduction in vascularisation. We further demonstrate a novel, multi-step molecular mechanism by which miR-34a leads to increased levels of the tissue inhibitor metallopeptidase 2 precursor (TIMP2) protein, accounting for the highly reduced vascularisation noted in miR-34a-treated tumors. These novel findings highlight the potential of anti-GD(2)-nanoparticle-mediated targeted delivery of miR-34a for both the treatment of GD(2)-expressing tumors, and as a basic discovery tool for elucidating biological effects of novel miRNAs on tumor growth.


Treatment Options for Pilonidal Disease.
Pilonidal disease can be treated medically; however, surgical excision remains the gold standard. Nonetheless, all current surgical approaches are still associated with potential for tissue loss, wound healing disorders, and high rates of recurrence. Aim of this study is to assess the long-term outcomes of the minimal-invasive pit-picking operation in comparison to the well-established technique of Karydakis flap-closure. Medical records of all patients undergoing either Karydakis flap-closure or the pit-picking operation for pilonidal disease at our department were reviewed retrospectively. A total of 101 patients were treated either by excision and Karydakis flap-closure (n = 62) or by the pit-picking operation (n = 39). Mean follow-up time was 65.5 (range: 38-101) months, including data collection using a standardized questionnaire. Analysis of the outcomes revealed no significant differences between the Karydakis flap-closure- and the pit-picking groups; however, the latter was associated with faster recovery, no need for hospitalization and overall low complication rates. In summary, the main advantages of the pit-picking operation lie in its' outpatient character, the simplicity of the procedure, low complication rates, short recovery time, and predictably good results.


Image Segmentation for Image-Based Dietary Assessment: A Comparative Study.
There is a health crisis in the US related to diet that is further exacerbated by our aging population and sedentary lifestyles. Six of the ten leading causes of death in the United States can be directly linked to diet. Dietary assessment, the process of determining what someone eats during the course of a day, is essential for understanding the link between diet and health. We are developing imaging based tools to automatically obtain accurate estimates of what foods a user consumes. Accurate food segmentation is essential for identifying food items and estimating food portion sizes. In this paper, we present a quantitative evaluation of automatic image segmentation methods for food image analysis used for dietary assessment. The experiments indicate that local variation is more suitable for food image segmentation in general dietary assessment studies where the food images acquired have complex background.


Positively charged residues at positions 12, 17, and 18 of glucagon ensure maximum biological potency.
Glucagon is a peptide hormone that plays a central role in the maintenance of normal circulating glucose levels. Structure-activity studies have previously demonstrated the importance of histidine at position 1 and the absolute requirement for aspartic acid at position 9 for transduction of the hormonal signal. Site-directed mutagenesis of the receptor protein identified Asp64 on the extracellular N-terminal tail to be crucial for the recognition function of the receptor. In addition, antibodies generated against aspartic acid-rich epitopes from the extracellular region competed effectively with glucagon for receptor sites, which suggested that negative charges may line the putative glucagon binding pocket in the receptor. These observations led to the idea that positively charged residues on the hormone may act as counterions to these sites. Based on these initial findings, we synthesized glucagon analogs in which basic residues at positions 12, 17, and 18 were replaced with neutral or acidic residues to examine the effect of altering the positive charge on those sites on binding and adenylyl cyclase activity. The results indicate that unlike N-terminal histidine, Lys12, Arg17, and Arg18 of glucagon have very large effects on receptor binding and transduction of the hormonal signal, although they are not absolutely critical. They contribute strongly to the stabilization of the binding interaction with the glucagon receptor that leads to maximum biological potency.


A cross-sectional study on the ability of physicians to hypertension management in China's Sichuan Tibetan rural area.
This study aimed to investigate the hypertension management abilities of rural physicians in a high-altitude Tibetan area. A cross-sectional survey was conducted in the Ganzi Tibetan Autonomous Prefecture, China, in October 2020. Information about healthcare resources in local medical institutions, along with the knowledge, attitudes, practices, and training status of primary care physicians, was collected. Limited resources were observed in terms of equipment, drugs, and personnel in the 18 township hospitals included. A total of 132 physicians participated in this survey. The scores for hypertension-related knowledge, attitudes toward hypertension management, routine practice ability, priority given to hypertension, and confidence in performing certain tasks were 32.60%, 67.40%, 18.90%, 65.15%, and 35.60%, respectively. The most concerning issues lay in the ignorance of the healthy lifestyle, undervaluation of cardiovascular risks, and lack of confidence in optimally performing management activities. Only 9.85% of the physicians received more than 24 days of training per year; 28.79% preferred a longer training time. While training was generally provided in conference sessions (63.64% of current training programs), physicians preferred remote education (55.30%), and on-site guidance (46.21%) from professionals. The current training was centered around clinical skills (61.36%) and was identified as a major training requirement by the physicians surveyed (80.30%). This survey suggests that the medical resources may not be effective, with deficiencies present in the knowledge and practices of primary care physicians in the Sichuan Tibetan area. Hypertension education and skill-development courses based on the specific issues identified should be provided to these physicians in the future.


[Forensic medical estimation of the morphological changes in the myocardium and hypothalamo-pituitary-adrenal system in case of sudden cardiac death].
This morphological, morphometric, and immunohistochemical study of the myocardium, adrenal gland, and hypothalamus included 50 corpses of men aged from 25-49 years deceased by reason of acute coronary failure associated with coronary heart disease. The commonest lesions in the myocardium were contractures (54.3 +/- 3.5% [51.2; 57.8%]), cyclic deformation (44.7 +/- 6.3% [38.2; 51.4%]), and dissociation of cardiomyocytes (61.2 +/- 2.3% [56.3; 64.8%]). The sinoatrial and atrioventricular nodes of the heart contained large amounts of adrenaline-positive cells (45.6 +/- 4.5% [40.1; 48.7%]) and 34.2 +/- 2.9% [31.2; 37.4%]). The equally large numbers of adrenaline-positive cells were detected in the adrenal medulla (67.2 +/- 6.8% [61.9; 74.3%]). The arcuate, supraoptic, and paraventricular nuclei of the hypothalamus underwent reversible changes of neutron content (the degree of damage 25.6 +/- 4.8% [21.2; 29.8%]) and contained large amounts of noradrenaline-positive and dopamine-positive neural cells (54.2 +/- 3.6% [51.4; 59.3%]) and 28.7 +/- 2.1% [23.4; 31.7%]) respectively. It is concluded that the morphometric and immunohistochemical changes detected in the present study can be used as the additional forensic medical criteria for diagnostics of death from acute coronary failure associated with coronary heart disease.


Effect of diazinon, an organophosphate insecticide, on plasma lipid constituents in experimental animals.
There has been increasing interest in studying the various effects of organophosphate insecticides in humans and experimental animals. Only a few data are available on the effect of the organophosphate insecticide, diazinon, on lipid metabolism. The aim of this study was to evaluate the effect of diazinon on plasma lipid constituents in mammalian animals. The plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and phospholipids (PL) were measured in albino rats that were orally treated with a single dose of diazinon at a level of LD(50) or with repeated daily doses at the levels of 1/2, 1/8, and 1/32 LD(50) for 2, 8, and 32 days, respectively. After a 24 h post-treatment with a single LD(50) dose of diazinon, TC was not significantly changed, the HDL-C and PL levels were significantly decreased, but the LDL-C and TG levels were significantly increased. Separate daily oral administrations of diazinon at 1/2 LD(50), 1/8 LD(50), and 1/32 LD(50) doses resulted in a significant decrease in HDL-C and PL, with no significant change in TG. The LDL-C levels were significantly increased and TC showed no significant change with 1/2 LD(50) and 1/32 LD(50) doses of diazinon, whereas a significant decrease in the levels of TC, HDL-C, as well as LDL-C, was observed with the 1/8 LD(50) dose. These data suggest that diazinon may interfere with lipid metabolism in mammals.


Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts.
In this study, we evaluated the effect of lipoic acid (LA) and N-acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal, N(epsilon)-(carboxymethyl)lysine and heme oxygenase-1] and apoptotic (caspase 9 and Bax) markers in fibroblasts from patients with Alzheimer disease (AD) and age-matched and young controls. AD fibroblasts showed the highest levels of oxidative stress, and the antioxidants, lipoic acid (1 mM) and/or N-acetyl cysteine (100 microM) exerted a protective effect as evidenced by decreases in oxidative stress and apoptotic markers. Furthermore, we observed that the protective effect of LA and NAC was more pronounced when both agents were present simultaneously. AD-type changes could be generated in control fibroblasts using N-methylprotoporphyrin to inhibit cytochrome oxidase assembly indicating that the the oxidative damage observed was associated with mitochondrial dysfunction. The effects of N-methylprotoporphyrine were reversed or attenuated by both lipoic acid and N-acetyl cysteine. These data suggest mitochondria are important in oxidative damage that occurs in AD. As such, antioxidant therapies based on lipoic acid and N-acetyl cysteine supplementation may be promising.


[Congenital components of immunity: Toll-like receptors in the normal state and in immunopathology].
This review deals with rapidly accumulating information on a highly important components of the congenital immune system: Toll-like receptors playing a leading role in the recognition of microbial patterns. The data on the main structural and functional features of Toll-like receptors and their distribution in the body are summarized. The main signal paths are characterized and the key molecules which take part in the transduction are pointed out. Special attention is paid to the activating action of lipopolysaccharides through TLR4. Pathological processes developing as the result of damages in the structure and function of Toll-like receptors in humans and experimental animals are determined.


Impaired blood rheology is associated with endothelial dysfunction in patients with coronary risk factors.
To investigate the relationship between blood rheology and endothelial function in patients with coronary risk factors, brachial arterial flow-mediated vasodilatation (FMD), an index of endothelial function and blood passage time (BPT), an index of blood rheology, and fasting blood cell count, glucose metabolism, and plasma fibrinogen, lipid, C-reactive protein, and whole blood viscosity levels were measured in 95 patients with coronary risk factors and 37 healthy controls. Brachial arterial FMD after reactive hyperemia was assessed by ultrasonography. BPT was assessed using the microchannel method. In healthy controls, BPT significantly correlated with FMD (r = - 0.325, p < 0.05), HDL cholesterol (r = - 0.393, p < 0.05), body mass index (BMI; r = 0.530, p < 0.01), and plasma fibrinogen concentration (r = 0.335, p < 0.05). In a multivariate regression analysis adjusted for all clinical variables, BPT remained significantly associated with BMI and fibrinogen, but not with FMD, in healthy controls. In patients with coronary risk factors, BPT significantly correlated with FMD (r = - 0.331, p < 0.01), HDL cholesterol (r = - 0.241, p < 0.05), BMI (r = 0.290, p < 0.01), hematocrit (r = 0.422, p < 0.001), white blood cell count (r = 0.295, p < 0.01), platelet count (r = 0.204, p < 0.05), and insulin (r = 0.210, p < 0.05). In a multivariate regression analysis adjusted for all clinical variables, BPT remained strongly associated with FMD and hematocrit in patients with coronary risk factors. These data indicate that BPT is closely associated with FMD in patients with coronary risk factors and suggest that the measurement of blood rheology using the microchannel method may be useful in evaluating brachial arterial endothelial function as a marker of atherosclerosis in these patients.


Interphase death in human peripheral blood lymphocytes after moderate and high doses of low and high LET radiation: an electron microscopic approach.
Peripheral blood lymphocytes irradiated with low and moderate doses of low linear energy transfer (LET) gamma-rays are known to die by an apoptotic process. In the present study, the type of interphase death occuring after administration of moderate and high doses of low LET gamma-rays and high LET fast neutrons was investigated. Lymphocytes were irradiated in vitro with radiation doses of 5 and 20 gray (Gy) of both radiation qualities. They were cultured for 24 or 48 hours and the type of cell death induced was determined by electron microscopy. After neutron irradiation, a slight increase in the incidence of apoptosis from 5 to 20 Gy was found, whereas after gamma-irradiation, the incidence of apoptosis was lower at 20 Gy as compared to 5 Gy. However, unlike the other radiation doses, the 20 Gy dose of gamma-rays, besides apoptosis also induced oncosis (classical necrosis). According to our experiments, membranes are probably an important target for the induction of interphase death. It is suggested that a great amount of ionisations distributed all over the cell surface, as caused by high doses of gamma-rays, lead to a high influx of Ca++ which induces oncosis instead of apoptosis.


The PEVKEK region of the pyridoxal phosphate binding domain of GAD65 expresses a dominant B cell epitope for type 1 diabetes sera.
Molecular mimicry between the 65-kDa isoform of glutamic acid decarboxylase (GAD65) and the protein 2C (P2C) of Coxsackie B4 virus (CBV) may initiate human type 1 diabetes. GAD65 contains a motif that has a 6-amino acid identity with CBV-P2C (PEVKEK), whereas the weakly autoantigenic isoform, GAD67, contains PEVKTK. A human-derived monoclonal antibody (mAb) MICA3 reacts with a surface loop of GAD65 that includes PEVKEK, and mutagenic deletion of this loop was shown to reduce reactivity of GAD with the mAb by 70%. To establish that the PEVKEK motif on GAD65 contains a major epitope for diabetes sera and to identify the amino acids involved, mutants of nucleotides of GAD65 and GAD67 at sites in the PEVKEK motif were created and the expressed proteins used for radioimmunoprecipitation (RIP) tests with sera from patients with type 1 diabetes. A potent mouse mAb (GAD6) to GAD65, and a rabbit polyclonal antibody (AB108) to GAD67, were used to standardize the reactivity of the diabetes sera with the mutant molecules. Of 45 type 1 diabetes sera tested, 30 (67%) had an 80% or greater reduction of reactivity to GAD65(delta258-270) vs. intact GAD65. Various single-surface amino acids in the PEVKEK epitope region of GAD65 were mutated, but most molecules carrying these mutations reacted similarly to the parent molecule. However after point mutation of the equivalent motif of GAD67 (PEVKTK to PEVKEK), there was an increase in the reactivity of 12 of 49 (24%) type 1 diabetes sera tested; 7 of 8 sera reactive with GAD67 showed increased reactivity with GAD67(T273E), and 5 previously negative sera gained reactivity with GAD67(T273E). Thus, the PEVKEK motif on GAD65 contributes to serologic reactivity of type 1 diabetes sera. This favors the hypothesis that CBV infection causes type 1 diabetes by the process of viral mimicry with cross-reactivity to a critical epitope of GAD65.


Efficacy of Acupoint Application on In Vitro Fertilization Outcome in Patients with Polycystic Ovary Syndrome: A UHPLC-MS-Based Metabolomic Study.
To explore the clinical effect of acupoint application on the outcome of in vitro fertilization-embryo transfer (IVF-ET) in patients with polycystic ovary syndrome (PCOS) of the phlegm-dampness type and elucidate its possible mechanism of action from the perspective of follicular fluid metabolomics. A total of 90 patients undergoing IVF-ET due to infertility were selected and divided into three groups: the treatment group (PCOS with acupoint application, n = 30), the control group (PCOS without acupoint application, n = 30), and the normal group (non-PCOS, n = 30). All patients received a gonadotropin-releasing hormone agonist (GnRH-a) long protocol for controlled ovarian hyperstimulation (COH). Among them, the treatment group was also given the acupoint application from the day of pituitary downregulation to the day of the human chorionic gonadotrophin (hCG) trigger. Ultrahigh-performance liquid chromatography connected with quadrupole time-of-flight mass spectrometry (UHPLC-MS) was adopted for untargeted metabolomic analysis of follicular fluid collected from the three groups of patients on the day of oocyte pick-up (OPU). The significantly differential metabolites were screened using univariate and multivariate statistical analysis, and the related metabolic pathways were identified by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Metabolomic analysis showed that the treatment group's follicular fluid samples were aggregated with the normal group and separated from the control group. A total of 34 significantly differential metabolites were found in the follicular fluid of patients with phlegm-dampness PCOS and normal people. With the intervention of acupoint application, seven metabolites (pseudouridine, phenol, 2-oxoadipic acid, 9R,10S-EpOME, DL-lactate, nicotinamide, and DL-indole-3-lactic acid) were all downregulated, mainly involving the pathways of pyruvate metabolism, nicotinate and nicotinamide metabolism, protein digestion and absorption, biosynthesis of amino acids, and pyrimidine metabolism. Acupoint application can effectively improve the clinical symptoms and the outcome of IVF-ET treatment in patients with PCOS of the phlegm-dampness type, and its mechanism of action may be related to the regulation of the pathways of pyruvate metabolism, nicotinate and nicotinamide metabolism, protein digestion and absorption, biosynthesis of amino acids, and pyrimidine metabolism.


Dynamics of different functional parts of bacteriorhodopsin: H-2H labeling and neutron scattering.
We show that dynamics of specific amino acids within a protein can be characterized by neutron spectroscopy and hydrogen-deuterium labeling, and we present data on the motions of a selected set of groups within bacteriorhodopsin (BR), the retinal-based proton pump in the purple membrane of halophilic Archaea. Elastic incoherent neutron scattering experiments allow the definition of motions in the nano- to picosecond time scale and have revealed a dynamical transition from a harmonic to a softer, anharmonic atomic fluctuation regime in the global behavior of proteins. Biological activity in proteins is correlated with this transition, suggesting that flexibility is required for function. Elastic incoherent neutron scattering is dominated by H atom scattering, and to study the dynamics of a selected part of BR, fully deuterated purple membrane with BR containing H-retinal, H-tryptophan, and H-methionine was prepared biosynthetically in Halobacterium salinarum. These amino acids cluster in the functional center of the protein. In contrast to the protein globally, the thermal motions of the labeled atoms were found to be shielded from solvent melting effects at 260 K. Above this temperature, the labeled groups appear as more rigid than the rest of the protein, with a significantly smaller mean square amplitude of motion. These experimental results quantify the dynamical heterogeneity of BR (which meets the functional requirements of global flexibility), on the one hand, to allow large conformational changes in the molecule and of a more rigid region in the protein, on the other, to control stereo-specific selection of retinal conformations.


Does music induce interbrain synchronization between a non-speaking youth with cerebral palsy (CP), a parent, and a neurologic music therapist? A brief report.
Shared emotional experiences during musical activities among musicians can be coupled with brainwave synchronization. For non-speaking individuals with CP, verbal communication may be limited in expressing mutual empathy. Therefore, this case study explored interbrain synchronization among a non-speaking CP (female, 18 yrs), her parent, and a music therapist by measuring their brainwaves simultaneously during four music and four storytelling sessions. In only the youth-parent dyad, we observed a significantly higher level of interbrain synchronization during music rather than story-telling condition. However, in both the youth-parent and youth-therapist dyad, regardless of condition type, significant interbrain synchronization emerged in frontal and temporal lobes in the low-frequency bands, which are associated with socio-emotional responses. Although interbrain synchronization may have been induced by multiple factors (e.g., external stimuli, shared empathetic experiences, and internal physiological rhythms), the music activity setting deserves further study as a potential facilitator of neurophysiological synchrony between youth with CP and caregivers/healthcare providers.


The role of defects in the reaction of chlorine atoms with alkanethiol self-assembled monolayers.
Scanning tunneling microscopy (STM) in ultra-high-vacuum is used to investigate the reaction of gas-phase atomic chlorine with octanethiolate self-assembled-monolayers on Au(111). Exposure to Cl atoms results in the formation of a variety of surface defects, and eventually leads to a complete loss of order within the alkanethiolate monolayer. X-ray photoelectron spectroscopy and thermal desorption mass spectrometry show that these morphological changes are accompanied by significant chlorination of the monolayer as well as a ~30% decrease in the amount of adsorbed sulfur. The rate of reaction is measured through the analysis of sequences of STM images, and coverage-vs.-exposure data shows that the average reactivity of any given molecule within the monolayer decreases as the reaction progresses. Working with the assumption that monolayer defects created by Cl-atom reaction will affect the reactivity of neighboring molecules, a kinetic Monte Carlo simulation shows the data are consistent with defect sites inhibiting reaction rate by a factor of 5 or more. This behavior is opposite to that found for hydrogen-atom reactions, where edge and defect sites were far more reactive. The dynamics of chlorine-atom reactivity are described primarily in terms of the formation and subsequent reaction of surface-adsorbed radicals, with surface defects providing sites where these radicals can be quenched.


A profile of lung carcinomas: study on 364 cases.
The authors have proposed to analyze retrospectively the clinical-morphological profile of a consistent group of lung carcinomas treated surgically. The studied material consisted of clinical and pathological medical records from 364 patients confirmed histopathologically with lung carcinoma after surgical intervention. Five main groups were defined based on the histopathological criteria and then compared. The assessment of clinical data, in spite of a wide range of clinical expressions, revealed some particular features for each of the defined groups. The morphological data outlined also different behavioral profiles for each of the histopathological types of lung carcinoma. These results showed that malignant epithelial tumors of the lung are still a major challenge from the detection until the therapeutic intervention and, therefore, the preoperative clinical-morphological investigation is crucial for a better adjustment of the therapeutic act according to the individual profile of each type of tumor.


Molecular data reveal spatial and temporal patterns of diversification and a cryptic new species of lowland Stenocercus Duméril & Bibron, 1837 (Squamata: Tropiduridae).
Phylogenetic studies have uncovered biogeographic patterns and the associated diversification processes of Neotropical wet forest taxa, yet the extensive open and drier biomes have received much less attention. In the Stenocercus lizard radiation, restricted sampling and phylogenetic information have limited inferences about the timing, spatial context, and environmental drivers of diversification in the open and dry lowland settings of eastern and southern South America. Based on new DNA sequence data of previously unsampled species, we provide an updated historical biogeographic hypothesis of Stenocercus. We infer phylogenetic relationships, estimate divergence times, and track ancestral distributions, asking whether cladogenetic events within the genus correlate to reported shifts in South American landscapes during the past 30millionyears, focusing in the open and drier areas. To examine correlations between genetic and ecological divergence, we extracted environmental data from occurrence records and estimated climatic envelopes occupied by lowland taxa. Our results suggest that Stenocercus began to diversify around the South American Midwest by the late Oligocene. We recovered two main lowland and two main Andean clades within the genus; within both Andean clades, most cladogenetic events date back to the Miocene, synchronously with the most intense phase of Andean uplift. In the western clade of lowland Stenocercus, species ranges and divergence times are consistent with major landscape shifts at the upper Guaporé and Paraguay River basins as a result of Andean orogeny, suggesting vicariant speciation. By contrast, in the 'horned' lowland clade, we find evidence that dispersal and ecological differentiation have shaped species divergences and current ranges in the Brazilian Cerrado, Caatinga, Pampas and Atlantic Forest, possibly under a vanishing refuge scenario. Lastly, our phylogenetic results indicate two divergent clades within the formerly recognized taxon S. sinesaccus, and further evaluation of morphological data corroborates the existence of a distinct, new species of Stenocercus, here described. The new taxon occurs in the Chapada dos Parecis massif in the Brazilian states of Mato Grosso and Rondônia.


Research on the rapid assembly algorithm of the wireless ultraviolet cooperative UAV formation.
Aiming at the problem that the strong electromagnetic interference environment restricts the communication of the Unmanned Aerial Vehicle(UAV) formation, which affects the rapid assembly of the UAV formation, a wireless ultraviolet cooperative UAV formation rapid assembly algorithm is proposed to realize the fixed-point assembly of the UAV formation in the airspace. First, the Ultraviolet(UV) light beacon model is used to realize the information interaction of the UAV formation. secondly, the UV four-node positioning algorithm is used to realize the three-dimensional positioning of the UAV formation. Combined with the method, the UAV formation can reach a consensus speed when assembling. The simulation results show that when there are more than 6 reference nodes, the three-dimensional space positioning accuracy can reach 96%. The assembly algorithm can realize the fixed-point assembly of the UAV formation, and can maintain the circular motion trajectory after the assembly is completed.


The role of infragenicular spliced vein bypass surgery in patients with chronic limb-threatening ischemia: single center long-term results.
In patients requiring infrageniculate surgical revascularization a single-segment great saphenous vein (SS-GSV) is the optimal conduit. In the absence of a SS-GSV, the small saphenous vein and arm veins can also be used to obtain an all-autologous bypass. The aim of this study was to compare the long-term results of infrageniculate SS-GSV bypasses and spliced vein bypasses in patients with chronic limb-threatening ischemia (CLTI). A total of 308 consecutive CLTI patients who underwent a primary infragenicular, autologous bypass between January 2000 and December 2016 were included. The definition of a spliced vein bypass was a graft consisting of at least two venous segments. A SS-GSV graft was used in 235 patients, and a spliced vein graft was used in 73 patients. Significantly more infrapopliteal bypasses were performed in the spliced vein group (P=0.024), and in this group the mean operation time was almost 60 minutes longer (P<0.001). The overall morbidity rate was 44%. The overall 30-day mortality was 3.2%, and overall in-hospital mortality was 4.9%. No significant differences were observed between the groups in mortality, overall morbidity or any specific complication. Comparing the SS-GSV group with the spliced vein group, no significant differences were observed between overall survival (53.2% vs. 45.7%), primary patency (55.5% vs. 53.2%), assisted primary patency (78.5% vs. 76.5%), secondary patency (87.9% vs. 90.6%) and limb salvage (83.3% vs. 82.0%). The use of infrageniculate spliced vein bypasses for the treatment of CLTI patients results in similar results compared with infrageniculate SS-GSV bypass grafts. A strict surveillance protocol in the first 2 years and a liberal reintervention strategy may result in excellent long-term patency rates.


Agricultural injuries in Central India: nature, magnitude, and economic impact.
A study was carried out in Madhya Pradesh (Central India) to collect data on injury-causing agricultural incidents during the period 1995-1999. The overall incidence rate was 1.25/1000 workers/year. About 9.2% of the incidents were fatal, and most of the fatal incidents were due to tractors and snakebites (42.9% each). About 77.6% of all incidents were due to farm machinery, 11.8% were due to hand tools, and the remaining 10.6% were due to other sources like snakes, wells, etc. Data on 1,911 incidents reported in 10 leading newspapers published during the five-year period (1995-1999) from different regions of the state were also collected and analyzed, which indicated that only major or roadside agricultural incidents were reported in newspapers. Based on the survey data, it was estimated that in the year 2000 there would have been about 17,480 agricultural incidents in Madhya Pradesh, causing death to about 2,050 workers and injuries to about 16,770 workers, including amputations of limbs, burns, cuts, etc. Total monetary loss due to agricultural injuries in the state of Madhya Pradesh has been estimated as US $27 million/year.


Surgical resection of cardiac myxoma-a 30-year single institutional experience.
Primary cardiac tumors are rare and myxoma constitutes the majority. The present study summarizes our 30-year clinical outcomes of surgical myxoma resection. Between January 1986 and December 2015, 93 patients (30 men, 63 women; mean age, 54.7 ± 16.6 years) underwent surgical myxoma resection. The most common origin site was the left atrium. Surgery was performed via a biatrial approach in 74.2%, atrial septotomy through right atriotomy in 17.2%, and left atriotomy only in 8.6%. Mean myxoma size based on longest length was 4.73 ± 1.92 cm (range, 1.2-11.0 cm). The mean follow-up duration was 9.9 ± 7.8 years (range, 0-29 years). In-hospital mortality was 3.2%. The most common postoperative complication was atrial fibrillation (4.3%). The 5-, 10-, and 30-year survival rates were 92.9%, 87.2%, and 75.5%, respectively. Recurrence occurred in two patients (2.1%), which were detected at 20 and 79 months after the first surgery, respectively. Long-term survival after myxoma resection was excellent and recurrence was rare. Based on our experience, surgical method did not affect the outcome.


Apparent diffusion coefficient (ADC) histogram analysis: differentiation of benign from malignant parotid gland tumors using readout-segmented diffusion-weighted imaging.
To explore the utility of whole-lesion apparent diffusion coefficient (ADC) histogram analysis for differentiating parotid gland tumors following readout-segmented diffusion-weighted imaging (RESOLVE). 80 patients (40 with pleomorphic adenomas, 14 with Warthin tumors, and 26 with malignant parotid gland tumors) who underwent routine head-and-neck MRI and RESOLVE examinations, were retrospectively evaluated. RESOLVE data were acquired from a MAGNETOM Skyra 3T MR system. Eleven whole-lesion histogram parameters derived from histogram analysis (ADC_mean, ADC_minimum, ADC_maximum, ADC_1th, ADC_10th, ADC_50th, ADC_90th, ADC_99th, skewness, variance and kurtosis) were calculated for each patient using MaZda. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of the ADC for distinguishing among the three groups. In total, nine parameters (ADC_minimum, ADC_maximum, ADC_mean, ADC_10th, ADC_50th, ADC_90th, ADC_99th, variance, skewness) were statistically significant (all p < 0.05) for all three groups, in the comparison of pleomorphic adenomas to Warthin tumors; the ADC_mean, ADC_50th, and skewness revealed high diagnostic efficiency with areas under the receiver operating characteristic curve of 0.976, 0.970, and 0.970, respectively. In the comparison of pleomorphic adenomas to malignant parotid gland tumors, these nine parameters were also found to be statistically different (all p < 0.05); the ADC_mean, ADC_10th and ADC_50th revealed high diagnostic efficiency with area under the curve of 0.851, 0.866, and 0.841, respectively. However, in the comparison of Warthin tumors to malignant parotid gland tumors, only three parameters (ADC_mean, ADC_50th, skewness) were statistically significant (all p < 0.05). Whole-lesion ADC histograms are effective in differentiating common parotid gland tumors.


Factors Affecting Implant Surface Roughness and Platform Alterations After Implantoplasty: An In Vitro Study Simulating Different Clinical Scenarios.
Purpose: To determine which clinical factors might affect the postimplantoplasty presence of residual threads, platform alterations, and level of surface roughness. Materials and Methods: A total of 60 implants were placed in 20 resin models (10 edentulous maxillary models and 10 partially dentate mandibular models), and 5-mm peri-implant bone defects were created. These models were then placed in simulation mannequins. A single researcher performed the implantoplasties, which were divided into the following groups: favorable situation (FS; maxillary incisors without adjacent teeth), unfavorable situation (US; mandibular molars with adjacent teeth), crown (C; mandibular premolars with a prosthetic crown and adjacent teeth), and noncrown (NC; mandibular premolars with adjacent teeth and without a prosthetic crown). The presence of residual threads, gaps in the implant-abutment interface, and silicone debris was assessed using a scanning electron microscope (SEM), and the surface roughness (Sa and Sz) was analyzed with a confocal optical microscope. A descriptive and bivariate analysis was conducted. Results: The postimplantoplasty surfaces were significantly smoother than the original implant surfaces. The surface roughness was significantly higher in the US group than in the FS group. Gaps in the implant-abutment interface were infrequent (6.67%; 95% CI = 2.62 to 15.93) and only appeared in the posterior zone. The odds ratio for the presence of residual threads and silicone debris (US group vs FS group) was 7.1 (95% CI = 4.15 to 12.14; P < .001) and 5.53 (95% CI = 3.21 to 9.53; P < .001), respectively. When a prosthetic crown was present, residual threads were 7 times more likely to be found (OR = 7.0; 95% CI = 3.5 to 13.99; P < .001). Conclusions: Implantoplasty leads to a significant reduction in the surface roughness of implants but is affected by several variables. Performing implantoplasty on posterior mandibular implants with adjacent teeth seems to be more challenging compared to implants placed in the anterior region of a fully edentulous maxilla. The presence of a prosthetic crown should also be considered as a relevant factor. Furthermore, implantoplasty can sometimes cause gaps in the implant-abutment interface and an accumulation of silicone debris, especially in areas with limited access.


Release of radio-isotope labelled antigens from Plasmodium knowlesi during merozoite re-invasion in vitro.
Labelled antigens sharing determinants with both membrane and cytoplasmic fractions of Plasmodium knowlesi were detected in culture medium after in vitro incubation of schizont-stage parasites previously pulse-labelled with [3H]isoleucine. Release of antigens occurred only during schizont rupture and merozoite re-invasion. Antigenic material accounted for up to a third of the total trichloroacetic acid-insoluble radioactivity released by the cells. Absorption experiments indicated that approximately two-thirds of this antibody-precipitable material shared determinants with parasite membrane antigens, with a similar quantity sharing determinants with cytoplasmic proteins. Using antisera derived against 2 different antigenic variants of P. knowlesi, no evidence for the release of variant-spcific antigens was obtained. Centrifugal analysis revealed that the majority of the radio-isotope labelled antigens were particulate in nature; however, some appeared to exist in true solution.


Errors in Aerosol Inhaler Use and Their Effects on Maternal and Fetal Outcomes among Pregnant Asthmatic Women (Subanalysis from QAKCOP Study).
Data on inhaler technique and its effects on maternal and fetal outcomes during pregnancy are seldom reported. The primary objective of this study was to evaluate inhaler technique and identify errors in inhaler use among pregnant women with asthma. Secondary objectives were to identify factors associated with poor inhaler technique and study the association between inhaler technique and maternal and fetal outcomes. This was a cross-sectional, face-to-face, prospective study of 80 pregnant women with physician-diagnosed asthma. Seventy-three and 41 asthmatic pregnant women reported using pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs), respectively. Overall, wrong inhaler technique was observed in 47 (64.4%) subjects. Among pMDI users, correct inhaler use was observed in only 26/73 (35.6%) of the patients, with lack of coordination between inhalation and generation of the aerosol and failure to breathe out gently before using the inhaler, being the most common errors. Among DPI users, 21 (51.2%) demonstrated correct inhaler use, with failure to perform a breath-hold for 10 seconds after inhaling the powder and to exhale gently before using the inhaler being the most common errors. Significant associations between inhaler technique and patient's understanding of asthma medications and the kind of follow-up clinic (respiratory versus nonrespiratory clinic) were found. No significant associations between inhaler technique and various maternal and fetal outcomes or asthma control were found. In conclusion, improper inhalation technique is significantly prevalent in pregnant asthmatic women, particularly among those being followed in nonspecialized respiratory clinics. The lack of significant association between the inhaler technique and asthma control (and hence maternal and fetal outcomes) may simply reflect the high prevalence of uncontrolled asthma and significant contribution of other barriers to poor asthma control in the current patient's cohort. Multidisciplinary management of asthma during pregnancy with particular emphasis on patient's education is imperative.


Investigating saccade programming in the praying mantis Tenodera aridifolia using distracter interference paradigms.
To investigate the saccadic system in the mantis, I applied distracter interference paradigms. These involved presenting the mantis with a fixation target and one or several distracters supposed to affect saccades towards the target. When a single target was presented, a medium-sized target located in its lower visual field elicited higher rates of saccade response. This preference for target size and position was also observed when a target and a distracter were presented simultaneously. That is, the mantis chose and fixated the target rather than a distracter that was much smaller or larger than the target, or was located above the target. Furthermore, the mantis' preference was not affected by increasing the number of distracters. However, the presence of the distracter decreased the occurrence rate of saccade and increased the response time to saccade. I conclude that distracter interference paradigms are an effective way of investigating the visual processing underlying saccade generation in the mantis. Possible mechanisms of saccade generation in the mantis are discussed.


Circadian regulation of renal function.
The kidneys regulate many vital functions that require precise control throughout the day. These functions, such as maintaining sodium balance or regulating arterial pressure, rely on an intrinsic clock mechanism that was commonly believed to be controlled by the central nervous system. Mounting evidence in recent years has unveiled previously underappreciated depth of influence by circadian rhythms and clock genes on renal function, at the molecular and physiological level, independent of other external factors. The impact of circadian rhythms in the kidney also affects individuals from a clinical standpoint, as the loss of rhythmic activity or clock gene expression have been documented in various cardiovascular diseases. Fortunately, the prognostic value of examining circadian rhythms may prove useful in determining the progression of a kidney-related disease, and chronotherapy is a clinical intervention that requires consideration of circadian and diurnal rhythms in the kidney. In this review, we discuss evidence of circadian regulation in the kidney from basic and clinical research in order to provide a foundation on which a great deal of future research is needed to expand our understanding of circadian relevant biology.


Hydrodynamic assembly of conductive nanomesh of single-walled carbon nanotubes using biological glue.
A hydrodynamic phenomenon is used to assemble a large-scale conductive nanomesh of single-walled carbon nanotubes (SWNTs) with exceptional control of the nanostructure. This is accomplished by a biological material with nanoscale features and a strong binding affinity toward SWNTs. The biological material also presents a unique glue effect for the assembly. Unprecedented material characteristics are observed for the nanomesh.


A possible relationship of nocturnal blood pressure variability with coronary artery disease in diabetic nephropathy.
Evidence suggests a relationship between short-term blood pressure (BP) variability and cardiovascular target-organ damage. Although a blunted nocturnal decrease in BP and reduced heart rate variability have been shown to be associated with cardiovascular morbidity in diabetic patients, little information is available on short-term BP variability. In this study, short-term BP variability was assessed in 36 subjects with type 2 diabetes and overt nephropathy who underwent ambulatory BP monitoring, and the factors that correlated with short-term BP variability were examined. The incidence of coronary artery disease (CAD) was significantly greater in the patients with increased 24-h systolic BP variability (67% versus 11%; p < 0.0005), while that of cerebrovascular disease was not significantly affected (61% versus 50%). Multiple stepwise regression analysis revealed that serum cholesterol (cholesterol) and plasma norepinephrine (p-NE) were significant and independent contributors to nighttime systolic BP variability (partial R2 = 0.490, p < 0.001; partial R2 = 0.470, p < 0.001) and demonstrated that body mass index and p-NE were primary determinants of nighttime diastolic BP variability (partial R2 = 0.539, p < 0.0005; partial R2 = 0.304, p < 0.05). Diabetic nephropathy patients with CAD had significantly increased daytime systolic (17.8 mmHg versus 13.1 mmHg, p < 0.0005), nighttime systolic (17.4 mmHg versus 10.5 mmHg, p < 0.0001), and nighttime diastolic (10.4 mmHg versus 7.2 mmHg, p < 0.05) BP variability. Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CAD (odds ratio 3.13 [95% CI 1.02-9.61]; p < 0.05). The increase in nighttime BP variability is associated with a proportional sympathetic activation in diabetic nephropathy. Elevated short-term BP variability combined with relative sympathetic prevalence during the night might represent an important risk factor for cardiovascular events in the diabetic population.


Nano-antenna enhanced two-focus fluorescence correlation spectroscopy.
We propose two-focus fluorescence correlation spectroscopy (2fFCS) on basis of plasmonic nanoantennas that provide distinct hot spots that are individually addressable through polarization, yet lie within a single diffraction limited microscope focus. The importance of two-focus FCS is that a calibrated distance between foci provides an intrinsic calibration to derive diffusion constants from measured correlation times. Through electromagnetic modelling we analyze a geometry of perpendicular nanorods, and their inverse, i.e., nanoslits. While we find that nanorods are not suited for nano-antenna enhanced 2fFCS due to substantial background signal, a nanoslit geometry is expected to provide a di tinct cross-correlation between orthogonally polarized detection channels. Furthermore, by utilizing a periodic array of nanoslits instead of a single pair, the amplitude of the cross-correlation can be enhanced. To demonstrate this technique, we present a proof of principle experiment on the basis of a periodic array of nanoslits, applied to lipid diffusion in a supported lipid bilayer.


Inter-domain dynamics in the chaperone SurA and multi-site binding to its outer membrane protein clients.
The periplasmic chaperone SurA plays a key role in outer membrane protein (OMP) biogenesis. E. coli SurA comprises a core domain and two peptidylprolyl isomerase domains (P1 and P2), but its mechanisms of client binding and chaperone function have remained unclear. Here, we use chemical cross-linking, hydrogen-deuterium exchange mass spectrometry, single-molecule FRET and molecular dynamics simulations to map the client binding site(s) on SurA and interrogate the role of conformational dynamics in OMP recognition. We demonstrate that SurA samples an array of conformations in solution in which P2 primarily lies closer to the core/P1 domains than suggested in the SurA crystal structure. OMP binding sites are located primarily in the core domain, and OMP binding results in conformational changes between the core/P1 domains. Together, the results suggest that unfolded OMP substrates bind in a cradle formed between the SurA domains, with structural flexibility between domains assisting OMP recognition, binding and release.


Influence of flexibility and variability of working hours on health and well-being.
Flexible working hours can have several meanings and can be arranged in a number of ways to suit the worker and/or employer. Two aspects of "flexible" arrangement of working hours were considered: one more subjected to company control and decision (variability) and one more connected to individual discretion and autonomy (flexibility). The aim of the study was to analyze these two dimensions in relation to health and well-being, taking into consideration the interaction with some relevant background variables related to demographics plus working and social conditions. The dataset of the Third European Survey on working conditions, conducted in 2000 and involving 21,505 workers, was used. Nineteen health disorders and four psycho-social conditions were tested by means of multiple logistic regression analysis, in which mutually adjusted odds ratios were calculated for age, gender, marital status, number of children, occupation, mode of employment, shift work, night work, time pressure, mental and physical workload, job satisfaction, and participation in work organization. The flexibility and variability of working hours appeared inversely related to health and psycho-social well-being: the most favorable effects were associated with higher flexibility and lower variability. The analysis of the interactions with the twelve intervening variables showed that physical work, age, and flexibility are the three most important factors affecting health and well-being. Flexibility resulted as the most important factor to influence work satisfaction; the second to affect family and social commitment and the ability to do the same job when 60 years old, as well as trauma, overall fatigue, irritability, and headache; and the third to influence heart disease, stomachache, anxiety, injury, and the feeling that health being at risk because of work. Variability was the third most important factor influencing family and social commitments. Moreover, shift and night work confirmed to have a significant influence on sleep, digestive and cardiovascular troubles, as well and health and safety at work. Time pressure also showed a relevant influence, both on individual stress and social life. Therefore, suitable arrangements of flexible working time, aimed at supporting workers' coping strategies, appear to have a clear beneficial effect on worker health and well-being, with positive consequences also at the company and social level, as evidenced by the higher "feeling to be able to work until 60 years of age".


The relationship between national-level carbon dioxide emissions and population size: an assessment of regional and temporal variation, 1960-2005.
This study examines the regional and temporal differences in the statistical relationship between national-level carbon dioxide emissions and national-level population size. The authors analyze panel data from 1960 to 2005 for a diverse sample of nations, and employ descriptive statistics and rigorous panel regression modeling techniques. Initial descriptive analyses indicate that all regions experienced overall increases in carbon emissions and population size during the 45-year period of investigation, but with notable differences. For carbon emissions, the sample of countries in Asia experienced the largest percent increase, followed by countries in Latin America, Africa, and lastly the sample of relatively affluent countries in Europe, North America, and Oceania combined. For population size, the sample of countries in Africa experienced the largest percent increase, followed countries in Latin America, Asia, and the combined sample of countries in Europe, North America, and Oceania. Findings for two-way fixed effects panel regression elasticity models of national-level carbon emissions indicate that the estimated elasticity coefficient for population size is much smaller for nations in Africa than for nations in other regions of the world. Regarding potential temporal changes, from 1960 to 2005 the estimated elasticity coefficient for population size decreased by 25% for the sample of Africa countries, 14% for the sample of Asia countries, 6.5% for the sample of Latin America countries, but remained the same in size for the sample of countries in Europe, North America, and Oceania. Overall, while population size continues to be the primary driver of total national-level anthropogenic carbon dioxide emissions, the findings for this study highlight the need for future research and policies to recognize that the actual impacts of population size on national-level carbon emissions differ across both time and region.


The applications of microfluidization in cereals and cereal-based products: An overview.
Although, the consumption of food consisting of fiber presents some important nutritional, functional and health benefits, manufacturers and researchers have reported that the use of high amount of fiber worsens the product quality. Besides, consuming large quantities of dietary fiber delays intestinal gas transit. In cereal grains, phenolic compounds are covalently bound to indigestible polysaccharides thus this complex bran matrix restricts its release in small intestine resulting in low bioavailability. Therefore, in order to overcome the problems related to the characteristics of fiber, the use of large quantities of dietary fiber in cereal based products as well as the low bioavailability of phenolic compounds; food scientists explore alternative milling methods to traditional treatments. The potential use of microfluidization in cereal-based products including wheat bran, corn bran, zein, rice bran and starches has been highlighted. Functionalization through microfluidization has been applied as a prospective method for production of fibrous structures from cereal brans and it improves surface areas, water holding capacity, swelling capacity, porosity, oil-holding capacity, cation-exchange capacity and the exposure of the phenolic compounds and hence the associated antioxidant capacity of fibers. Microfluidization also offers a promising method for the formation of complexes between starches and a fatty acid, which has potential to create a new functional resistant starch ingredient with increased viscosity and improved water-holding properties. Microfluidized cereal by-products provide some important unique functional and nutritional properties to bakery products. In this perspective, this paper provides an overview of the findings on the use of microfluidization in cereals and cereal-based products.


Large Ca(2+)-activated K+ channels responsive to angiotensin II in cultured human mesangial cells.
The patch-clamp method was used to determine the properties and response to angiotensin II (ANG II) of K+ channels in subpassages of human mesangial cell cultures. In cell-attached patches, with 140 mM KCl in the bath and cell potential equal to 40 mV, the open probability (Po) of large K+ channels (MKCa) was 0.8 with 0.5 mM Ca2+ in the bath and < 0.05 if the bath Ca2+ concentration was reduced to 1.0 microM. Open and closed dwell-time histograms of MKCa displayed both fast and slow time constants. Addition of ANG II (100 nM) to the bath solution (Ca2+ = 1.0 microM) increased the Po of MKCa in cyclic bursts by decreasing the time constant of the slow closed state. In excised inside-out patches, the mean single-channel conductance of MKCa was 206 pS in symmetrical 140 mM KCl. The selectivity sequence, established in asymmetrical cationic solutions, was K+ (1.0) > Rb+ (0.54) > NH+4 (0.11) > > Cs+ = Na+ (< 0.05). The Po of MKCa was increased by depolarizing potentials and high bath Ca2+. The Boltzmann distribution was consistent with an effective valence of 1.0, and the Hill coefficient for Ca2+ activation was 0.52. We conclude that MKCa has properties similar to large Ca(2+)-activated K+ channels and may act to repolarize the membrane of mesangial cells in response to an agonist-induced mobilization of intracellular Ca2+.


Evolutionary biology and chemical geology: a timely marriage.
For more than 150 years natural selection has been perceived to be the overwhelming force in evolution. Only in recent decades have we obtained new insights into environmental and physicochemical factors that participate with selection in a synergic way. Far from denying Darwin's theory, such neglected factors put order to the bewildering range of genotypes and morphologies found in living organisms and, more importantly, they place evolution in a planetary context where biology, geology, and chemistry can easily be integrated.


Normative Scores for the NIH Toolbox Dynamic Visual Acuity Test from 3 to 85 Years.
As part of the National Institutes of Health Toolbox initiative, a computerized test of dynamic visual acuity (cDVA) was developed and validated as an easy-to-administer, cost- and time-efficient test of vestibular and visual function. To establish normative reference values, 3,992 individuals, aged 3-85 years, without vestibular pathology underwent cDVA testing at multiple clinical research testing facilities across the United States. Test scores were stratified by sociodemographic characteristics. cDVA was worse in males (p < 0.001) and those subjects 50 years or older, while there was no difference in dynamic visual acuity across age groups binned from 3 to 49 years. Furthermore, we used these normative cDVA data as a criterion reference to compare both the long (validated) and short versions of the test. Both versions can distinguish between those with and without vestibular pathology (p = 0.0002 long; p = 0.0025 short). The intraclass correlation coefficient between long- and short-cDVA tests was 0.86.


Development and Validation of HPTLC Method for Simultaneous Determination of Amlodipine Besylate and Metoprolol Succinate in Bulk and Tablets.
A simple, selective, precise high-performance thin-layer chromatographic method for simultaneous determination of amlodipine besylate and metoprolol succinate in bulk and pharmaceutical combined dosage form was developed and validated. The method employed HPTLC aluminum plates precoated with silica gel 60F-254 (10×10) as the stationary phase. The solvent system consisted of toluene:ethyl acetate:methanol:triethylamine (4:1:1:0.4 v/v/v). The system was found to give a compact spot for amlodipine besylate (R(f) = 0.39±0.02) and metoprolol succinate (R(f) = 0.59±0.02). Densitometric analysis of amlodipine besylate and metoprolol succinate was carried out in the absorbance mode at 254 nm. Linear regression analysis data for the calibration plots showed good linear relationship with r(2) = 0.9990±0.0013 with respect to peak area in the concentration range 400-1400 ng per spot for amlodipine besylate and r(2) = 0.9993±0.0013 with respect to peak area in the concentration range 3800-13300 ng per spot for metoprolol succinate. The method was validated for precision, recovery and robustness. The limits of detection and quantitation were 39.99 and 121.20 ng per spot for amlodipine besylate and 234.31 and 710.03 ng per spot for metoprolol succinate, respectively. Statistical analysis proved that the method is selective, precise and accurate for the estimation of amlodipine and metoprolol.


Disruption of actin cytoskeleton causes internalization of Ca(v)1.3 (alpha 1D) L-type calcium channels in salamander retinal neurons.
To study the influence of actin cytoskeleton reorganization on the subcellular distribution of Ca(v)1.3 L-type Ca2+ channels in salamander retinal third-order neurons. Immunocytochemistry with confocal microscopy was used to demonstrate internalization of the Ca(v)1.3 isoform of L-type voltage-gated Ca2+ channels in third-order retinal neurons. A specificity of antibody was confirmed with Western blotting and in control experiments preabsorbing antibody wit its respective peptide. Whole-cell patch clamp technique was applied to record L-type currents from ganglion cells in slice preparations in the presence of N- and P/Q type Ca2+ channel blockers. A high level of Ca(v)1.3 labeling was present in cone photoreceptor terminals in the outer plexiform layer (OPL), as aggregates of puncta. Punctate Ca(v)1.3 labeling was evident throughout the IPL and around the cell bodies in the outer nuclear (ONL), inner nuclear (INL) and on somas and axons of ganglion cells labeled with rhodamine-conjugated dextran. Doubly labeled sections for synaptophysin and Ca(v)1.3 revealed colocalization in the OPL and IPL. Depolymerization of the actin cytoskeleton caused a dynamin-dependent internalization of Ca(v)1.3 but not Ca(v)1.2 subtype of voltage-gated Ca2+ channels in dissociated neurons. In ganglion cells, the inhibition of L-type Ca2+ currents by F-actin disrupters was mediated by Ca2+ channel internalization. Treatment with cytochalasin D protected retinal neurons against kainate-induced excitotoxicity. Actin cytoskeleton dynamics plays an important role in the regulation of subcellular distribution and function of Ca(v)1.3 L-type Ca2+ channels in salamander retinal neurons. Ca2+-dependent actin depolymerization may serve as a negative feedback mechanism to reduce excessive Ca2+ influx and thereby protect neurons against glutamate-induced excitotoxicity.


Changes in uterine protein secretion during luteal and follicular phases and detection of phosphatases during luteal phase of estrous cycle in buffaloes (Bubalus bubalis).
Changes in uterine proteins during different reproductive states and their functional significance though known in other species have not been established in buffaloes. An attempt has been made to unravel the changes in composition of buffalo uterine secretion with growth and regression of corpora-lutea during early, mid and late luteal and follicular phase of estrous cycle using gel filtration and electrophoresis techniques. Also the phosphatases activities in luteal phase uterine secretions have been studied. Gel filtration chromatography analysis revealed a protein peak in void volume of the column, the intensity of which was more in all the luteal phase samples than follicular phase samples. Alkaline phosphatase was also found eluted in the void volume. The other three uterus-specific peaks (Peaks V-VII) were detected below 13.7 kd molecular weight. There were at least five peaks of acid phosphatases activity in chromatogram. Silver staining of SDS-PAGE gel detected as many as 40 protein bands in the uterine fluid of which nine proteins were glycoproteins. Molecular weight (MW) comparison revealed the major protein band at 66 kd which could be serum albumin. Comparison of uterine proteins with serum protein bands revealed a 93.5 kd glycoprotein in buffalo serum that did not appear in uterine fluid and at least 11 uterus-specific protein bands (506, 470, 241, 114, 49, 38, 33, 26, 19.2, 16, and 14.3 kd). The 38 and 19.2 kd bands were luteal-stage specific. Intense periodic acid Schiff's (PAS) stained bands in uterine proteins compared to serum indicated glycosylation process in endometrial epithelial cells. The study suggested that buffalo uterine secretion contained mainly serum and several uterus-specific proteins of which few were luteal phase specific. Further study on characterizing the unique or most abundant proteins and defining their role in uterine functions would help to address the cause of low reproduction rate in buffaloes.


Novel Coronavirus disease (COVID-19) in newborns and infants: what we know so far.
Recently, an outbreak of viral pneumonitis in Wuhan, Hubei, China successively spread as a global pandemia, led to the identification of a novel betacoronavirus species, the 2019 novel coronavirus, successively designated 2019-nCoV then SARS-CoV-2). The SARS-CoV-2 causes a clinical syndrome designated coronavirus disease 2019 (COVID19) with a spectrum of manifestations ranging from mild upper respiratory tract infection to severe pneumonitis, acute respiratory distress syndrome (ARDS) and death. Few cases have been observed in children and adolescents who seem to have a more favorable clinical course than other age groups, and even fewer in newborn babies. This review provides an overview of the knowledge on SARS-CoV-2 epidemiology, transmission, the associated clinical presentation and outcomes in newborns and infants up to 6 months of life.


Flavimonas oryzihabitans bacteremia: clinical features and microbiological characteristics of isolates.
Flavimonas oryzihabitans is rarely reported as a pathogen in humans. Twelve cases of F. oryzihabitans bacteremia were diagnosed at National Taiwan University Hospital over a 3-year period. The clinical features of these patients were analyzed, and antimicrobial susceptibilities and random amplified polymorphic DNA (RAPD) patterns of the 12 isolates were studied. Among these 12 patients, eight (67%) had underlying neoplastic diseases and all acquired F. oryzihabitans bacteremia while hospitalized. The clinical syndromes included primary bacteremia in 5 patients (42%), biliary tract infection in 3 (25%), and peritonitis, subdural empyema, infusion-related bacteremia, and pneumonia in 1 each. Polymicrobial bacteremia or concomitant fungemia was seen in three patients (25%). All the patients survived after antibiotic treatment. All isolates were susceptible to piperacillin, third-generation cephalosporins, aminoglycosides, and quinolones but resistant to cephalothin, cefuroxime, and trimethoprim. Susceptibility to aztreonam was variable (25%). The RAPD patterns differed among the isolates, indicating the epidemiological unrelatedness of these infections. F. oryzihabitans should be included as an etiology of severe nosocomial infection in patients with underlying debilitating diseases.


Correlation between stages of breast cancer and BMI in females: a multi-centre study.
To determine the link between breast cancer and obesity in women by using body mass index at the time of diagnosis. The cross-sectional study was conducted from October 2019 to April 2020 at Pakistan Ordinance Factories Hospital, Wah Cantt, and Islamabad Medical Complex National Engineering and Scientific Commission Hospital, Islamabad, Pakistan. The sample comprised women aged 40-70 years with a recent diagnosis of breast cancer. Patients' body mass index values were calculated after they were diagnosed and additional staging examinations were carried out. Data was analysed using SPSS 21. There were 100 cases with a mean age of 52.24±7.47 years. There was a significant link between obesity and breast cancer (p=0.002), with higher body mass index carrying a higher risk of advanced breast cancer. Obesity may contribute to postmenopausal breast cancer in women.


Horizontal and Vertical Distributions of Chromium in a Chromate Production District of South Central China.
To study the horizontal and vertical distribution of chromium (Cr) in the soil of a chromate production site (CPS) and its nearby area (NA-CPS) in south central China, 61 profiles (depth: 14 m) in the CPS and 69 samples (topsoil) were excavated following a grid-sampling method. The geographic coordinates, elevation, and types of soil layers were recorded, and the total Cr in the soil and the total Cr and Cr(VI) in the leachate of the soil and in the groundwater were determined. Migration of Cr in surface soils may be represented in terms of a multiple linear regression equation (R²adj = 0.632). Distance, elevation, and pH are the primary factors that influence the horizontal distribution of Cr content in the surface soils, while the Cr concentration in different soil profiles mostly obeys the positive or negative binomial distributions. For a positive distribution, the Cr concentration decreases with increasing depth in the 0.0-8.0 m soil layer, under the fixing effect of soil. However, it shows an upward trend with a depth in the 8-14 m soil layer under the influence of Cr-polluted phreatic water. Under a negative distribution, Cr content is stable in the 0-6 m layer because of the influence of chromite ore processing residue mixed with miscellaneous fills, but it decreases obviously in the 6-14 m layer under the fixing effect of soil. Similar vertical distributions were observed for pH, LCr, LCr6+, and PCr6+. The decreasing amplitude of the Cr concentration for binomial distributions is mainly affected by the Cr concentration, pH, and LRCr of the soil. Moreover, PCr6+ of soil increases with pH, and the type of soil layer is the primary factor influencing LRCr in the soil profiles. Our results of the horizontal and vertical distributions of Cr could be used to guide investigations that are focused on reducing the number of samples in the horizontal and vertical directions at CPSs, and to improve risk assessments of CPSs and nearby areas.


Exploring the potential of FDA approved anti-diabetic drugs for repurposing against COVID-19: a core combination of multiple computational strategies and integrated artificial intelligence.
The latest variant of coronavirus is omicron. The World Health Organization (WHO) designated variation 'B.1.1.529' named omicron as a variant of concern (VOC) on 26 November 2021. By September 2020, it will have infected over 16 million patients and killed over 600,000 people over the world. This very infectious viral illness still poses a danger to world health; it has also become the greatest problem the world is facing and become the main area of research. The development of vaccines is insufficient to stop their spread and serious effects. Despite several reputable pharmaceutical firms claiming to have developed a cure for COVID-19. For that purpose, the field-based 3D-QSAR model has been used to analyze a series of anti-diabetic drugs to repurpose them against COVID-19. The LOO verified partial least square (PLS) model generates satisfactory q2 (0.4) and r2 (0.5) values. By using this model 10 compounds were screened out of 55 FDA approved anti-diabetic drugs (built-up library). Additionally, these substances were examined using molecular docking screening and ADMET. Finally, the drugs L8, and L23 were discovered to be the lead drugs. Density functional theory at the B3LYP/6-311G* technique was used to examine structural geometries, electronic characteristics, and molecular electrostatic potential (MEP). This work will greatly assist in the detection and development of leads for early drug development to control COVID-19.Communicated by Ramaswamy H. Sarma.


Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability.
Aurora kinases are key regulators of chromosome segregation during mitosis. We have previously shown by microarray analysis of primary lung carcinomas and matched normal tissue that AURKB (22 out of 37) and AURKA (15 out of 37) transcripts are frequently over-represented in these tumours. We now confirm these observations in a second series of 44 carcinomas and also show that aurora B kinase protein levels are raised in the tumours compared to normal tissue. Elevated levels of expression in tumours are not a consequence of high-level amplification of the AURKB gene. Using a coding sequence polymorphism we show that in most cases (seven out of nine) tumour expression is predominantly driven from one AURKB allele. Given the function of aurora B kinase, we examined whether there was an association between expression levels and genetic instability. We defined two groups of high and low AURKB expression. Using a panel of 10 microsatellite markers, we found that the group showing the higher level of expression had a higher frequency of allelic imbalance (P=0.0012). Analysis of a number of other genes that are strongly and specifically expressed in tumour over normal lung, including SERPINB5, TERT and PRAME, showed marked allelic expression imbalances in the tumour tissue in the context of balanced or only marginally imbalanced relative allelic copy numbers. Our data support a model of early carcinogenesis wherein defects in the process of inactivation of lung stem-cell associated genes during differentiation, contributes to the development of carcinogenesis.


Antiproliferative effect of boldine on neural progenitor cells and on glioblastoma cells.
The subventricular zone (SVZ) is a brain region that contains neural stem cells and progenitor cells (NSCs/NPCs) from which new neurons and glial cells are formed during adulthood in mammals. Recent data indicate that SVZ NSCs are the cell type that acquires the initial tumorigenic mutation in glioblastoma (GBM), the most aggressive form of malignant glioma. NSCs/NPCs of the SVZ present hemichannel activity whose function has not yet been fully elucidated. In this work, we aimed to analyze whether hemichannel-mediated communication affects proliferation of SVZ NPCs and GBM cells. For that purpose, we used boldine, an alkaloid derived from the boldo tree (Peumus boldus), that inhibits connexin and pannexin hemichannels, but without affecting gap junctional communication. Boldine treatment (50 μM) of rat SVZ NPCs grown as neurospheres effectively inhibited dye uptake through hemichannels and induced a significant reduction in neurosphere diameter and in bromodeoxyuridine (BrdU) incorporation. However, the differentiation pattern was not modified by the treatment. Experiments with specific blockers for hemichannels formed by connexin subunits (D4) or pannexin 1 (probenecid) revealed that probenecid, but not D4, produced a decrease in BrdU incorporation similar to that obtained with boldine. These results suggest that inhibition of pannexin 1 hemichannels could be partially responsible for the antiproliferative effect of boldine on SVZ NPCs. Analysis of the effect of boldine (25-600 μM) on different types of primary human GBM cells (GBM59, GBM96, and U87-MG) showed a concentration-dependent decrease in GBM cell growth. Boldine treatment also induced a significant inhibition of hemichannel activity in GBM cells. Altogether, we provide evidence of an antimitotic action of boldine in SVZ NPCs and in GBM cells which may be due, at least in part, to its hemichannel blocking function. These results could be of relevance for future possible strategies in GBM aimed to suppress the proliferation of mutated NSCs or glioma stem cells that might remain in the brain after tumor resection.


The process of adaptation of a community-level, evidence-based intervention for HIV-positive African American men who have sex with men in two cities.
We describe the process of adapting a community-level, evidence-based behavioral intervention (EBI), Community PROMISE, for HIV-positive African American men who have sex with men (AAMSM). The Centers for Disease Control and Prevention (CDC) Map of the Adaptation Process (MAP) guided the adaptation process for this new target population by two community-based organizations (CBOs) working in partnership with two research organizations. We describe five steps of the MAP, assessment, selection, preparation, pilot, and implementation, and the use of qualitative interviews, field observations, and a cross-sectional survey. We recommend: (1) development of a centralized interactive website, listserv, or other resources where agencies adapting EBIs can share tools, materials, experiences, lessons learned, and best practices; (2) strengthening Funding Opportunity Announcements by funding incrementally in phases linked to the MAP; and (3) research should examine (a) whether EBIs adapted by CBOs remain efficacious and (b) the best "fit" between the cultural and climate characteristics of effective collaborations between community- and research-based organizations.


Detection of active human papilloma virus-16 in head and neck cancers of Asian North Indian patients.
Head and neck cancers (HNC) are one of the most common cancers in India. Human papillomavirus (HPV) has been identified as an emerging risk factor for HNC. The present study was carried out to determine the active form of HPV-16 using a combination of PCR, viral load determination, HPV-16 E7 mRNA expression, p16, p53, and pRB immuno-histochemistry (IHC). A total of 226 HNC patients were enrolled in the present study. Sixty-seven (29.7%) of HNC cases were found to be HPV DNA positive. Thirty-two (14%) cases were HPV-16 DNA positive and 20 (9%) cases expressed HPV-16 E7 mRNA. HPV-16 mRNA/p16 positive cases had significantly increased viral load and integrated HPV-16 DNA. In summary, of total HNC patients, 6% cases were positive for both HPV-16 DNA and p16, and 5% were positive for both E7 mRNA and p16 IHC. We observed similar HPV-16 DNA/E7mRNA prevalence in oropharynx and oral cavity sites, however, oropharynx SCC had significantly higher viral load. Our results show low prevalence of active HPV-16 in North Indian HNC patients. HPV-16 E7 mRNA expression correlated with p16 nuclear positivity and increased viral load. Therefore, E7 mRNA expression may be used as a good surrogate indicator for active form of HPV-16 infection.


[Relationship between the expression of matrix metalloproteinase-13 protein and other biomarkers, prognosis in invasive breast cancer].
The study was designed to investigate the expression patterns of metalloproteinase (MMP)-13 protein in invasive breast carcinoma and to determine the clinicopathological and prognostic values of its various localization and relation to the tumor phenotypes. Immunohistochemistry was performed on paraffin-embedded tissue array from 263 invasive breast carcinomas to investigate the protein expressions of MMP-13, estrogen receptor, progesterone receptor, HER2, MMP-2, MMP-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1, TIMP-2. MMP-13 protein was detected in the cytoplasm of carcinoma cells and peritumoral fibroblasts. High level expression of MMP-13 protein in tumor cells was associated with more lymph node involvement and higher tumor grade (both P < 0.01), and positively correlated with HER2 (P = 0.015) and TIMP-1 protein (P < 0.01) expression in carcinoma cells. Moreover, high expression of MMP-13 was associated with shortened overall survival for the entire patient population and the patient group with positive lymph node. Tumor cell derived MMP-13 had different impact on patients with different HER2 status. Peritumoral fibroblasts derived MMP-13 protein, although correlated with tumor cell derived MMP-13 and associated with lymph node stage and HER2 expression, was found having less prognostic impact. Univariate survival analysis showed that the tumor size, grade, lymph node status, PR status, HER2 expression, tumors TIMP-1 and MMP-13 expression were prognostic factors. However, multivariate survival analysis showed that only tumor size, lymph node status, HER2 expression, tumors TIMP-1 and MMP-13 were independent prognostic factors. MMP-13 protein expressed by tumor cells correlates with the invasion and metastasis of breast carcinoma, and therefore, may serve as a poor prognostic marker for the patient.