Effect of in vitro treatment with reducing drugs on structure and function of human secretory immunoglobulin A.
Samples of unstimulated whole saliva from 15 healthy children with 0.5--6 mg/100 ml of secretory IgA and from 10 healthy adults with 4--18 mg/100 ml of secretory IgA were pooled and treated in vitro with dithiothreitol and alpha-mercaptopropionylglycine. The effect of these reducing drugs on the immunochemical properties of secretory IgA was evaluated. Dithiothreitol induced depolymerization of secretory IgA and splitting of the secretory piece from the IgA molecule; furthermore it strongly reduced the titer of secretory antibodies to Escherichia coli antigens. The drug alpha-mercaptopropionylglycine apparently did not affect either the polymeric structure of secretory IgA or the titer of secretory anti-E. coli antibodies; however it induced splitting of the secretory piece. On the whole it appers that drugs with reducing properties, currently employed for liquifying mucous secretions in clinical practice, should be carefully evaluated for possible depressive side-effects on local immunity.


Virtual repurposing of ursodeoxycholate and chenodeoxycholate as lead candidates against SARS-Cov2-Envelope protein: A molecular dynamics investigation.
Drug repurposing is an apt choice to combat the currently prevailing global threat of COVID-19, caused by SARS-Cov2in absence of any specific medication/vaccine. The present work employs state of art computational methods like homology modelling, molecular docking and molecular dynamics simulations to evaluate the potential of two widely used surfactant drugs namely chenodeoxycholate(CDC) and ursodeoxycholate (UDC), to bind to the envelope protein of SARS-Cov2(SARS-Cov2-E).The monomeric unit of SARS-Cov2-E was modelled from a close homologue (>90% sequence identity) and a pentameric assembly was modelled using symmetric docking, followed by energy minimization in a DPPC membrane environment. The minimized structure was used to generate best scoring SARS-Cov2-E-CDC/UDC complexes through blind docking. These complexes were subjected to 230 ns molecular dynamics simulations in triplicates in a DPPC membrane environment. Comparative analyses of structural properties and molecular interaction profiles from the MD trajectories revealed that, both CDC and UDC could stably bind to SARS-Cov2-E through H-bonds, water-bridges and hydrophobic contacts with the transmembrane-channelresidues.T30 was observed to be a key residue for CDC/UDC binding. CDC/UDC binding affected the H-bonding pattern between adjacent monomeric chains, slackening the compact transmembrane region of SARS-Cov2-E. Additionally, the polar functional groups of CDC/UDC facilitated entry of a large number of water molecules into the channel. These observations suggest CDC/UDC as potential candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitating the entry of solvents/polar inhibitors inside the viral cell.Communicated by Ramaswamy H. Sarma.


How the first years of motherhood impact the cardiac autonomic profile of female healthcare professionals: a study by heart rate variability analysis.
The conciliation between career and family is a relevant issue for working women, in particular during the first years of motherhood. Data about the state of the cardiac autonomic regulation in working women with preschoolers are lacking. Aim of this study was to compare the cardiac autonomic profile of female healthcare professionals with and without preschoolers via the analysis of the variability of the time distance between two consecutive R-wave peaks (RR) from standard 24-h Holter electrocardiogram (ECG). Fifty healthy active female healthcare professionals were enrolled: 25 with at least one preschooler (W_KID) and 25 without (W_NOKID). A standard Holter ECG was obtained during a regular working day. Segments of 5000 consecutive RRs were selected during daytime (DAY) and nighttime (NIGHT). Heart rate variability analysis was performed and the following parameters were considered for comparison between the two groups: mean (μRR), variance (σ2RR), and the absolute power in high frequency component (HF) of RR (HFRR) series. HFRR was considered as a marker of vagal cardiac modulation. Only µRR significantly increased from DAY to NIGHT in both groups (699 ± 88 vs 887 ± 140 ms in W_KID and 728 ± 90 vs 942 ± 166 ms in W_NOKID). Instead, σ2RR and HFRR increased from DAY to NIGHT only in W_NOKID (from 3334 ± 2153 to 4816 ± 4063 ms2 and from 356 ± 334 to 1397 ± 1629 ms2, respectively). W_KID showed lower σ2RR and HFRR during NIGHT, compared to W_NOKID (2336 ± 3170 vs 4816 ± 4063 ms2 and 556 ± 950 vs 1397 ± 1629 ms2, respectively). The perceived stress according to the visual analogue scale was similar in the two groups (4.7 ± 2.1 in W_KID, 5.7 ± 2.1 in W_NOKID). The presence of preschoolers lowered nocturnal cardiac vagal modulation in female healthcare professionals. This might represent an adaptation with a finalistic purpose, scilicet the facilitation of a prompt reaction in case of a child's need.


Effect of catheter site on the agreement of peripheral and central venous pressure measurements in neurosurgical patients.
Previous studies suggest a correlation of central venous pressure (CVP) with peripheral venous pressure (PVP) in different clinical setups. The aim of this study was to investigate the effect of measurement site on PVP and its agreement with CVP in patients undergoing general anesthesia. Prospective randomized study. University hospital. Thirty patients of American Society of Anesthesiologists physical status I and II undergoing elective craniotomy. Patients were randomly assigned into Group A (antecubital; n=15) and Group D (dorsum hand; n=15) for antecubital and hand dorsum catheterization sites, respectively. Central venous pressure and PVP were monitored throughout the study. A total of 1925 simultaneous measurements were recorded at 5-minute intervals. Bland-Altman assessment for agreement was used for CVP and PVP in 2 groups. Peripheral venous pressure measurements were within the range of +/-2 mm Hg of CVP values, in 93.9% of the measurements in Group A, and in 91.2% of the measurements in Group D. Considering all measurements, mean bias was -0.072 mm Hg (95% CI, -0.134 to -0.010). Group A measurements showed a bias (CVP-PVP) of 0.173+/-3.557 mm Hg, whereas the bias was -0.122+/-4.322 mm Hg (mean+/-SDcorrected for repeated measurements) in Group D. All of the measurements were within mean+/-2SD of bias, which means that PVP and CVP are interchangeable in our clinical setting. Peripheral venous pressure measurement may be a noninvasive alternative for estimating CVP in patients undergoing elective neurosurgical operations. Measuring PVP from hand dorsum does not interfere with the agreement of CVP and PVP.


The relationship between adolescents' externalizing and internalizing symptoms and brain development over a period of three years.
Adolescence is a crucial period for both brain maturation and the emergence of mental health disorders. Associations between brain morphology and internalizing/externalizing symptomatology have been identified in clinical or at-risk samples, but age-related developmental differences were rarely considered. The current study investigated the longitudinal relationship between internalizing/externalizing symptoms and brain development in the absence of psychiatric disorders during early and late adolescence. 98 healthy adolescents within two cohorts (younger: 9 years, older: 12 years) participated in annual assessments for three years; a clinical assessment measuring their externalizing and internalizing symptoms (SDQ) and an MRI assessment measuring their brain volume and white matter microstructure, including fractional anisotropy (FA), mean diffusivity (MD) and average path length. Linear mixed effect models and cross-lagged panel models showed that larger subcortical gray matter volume predicted more externalizing symptoms in older adolescents whereas decreases of subcortical gray matter volume predicted more externalizing symptoms for younger adolescents. Additionally, longer average white matter path length predicted more externalizing symptoms for older adolescents, while decreases in cerebral white matter volume were predictive of more externalizing symptoms for younger adolescents. There were no predictive effects for internalizing symptoms, FA or MD. Delays in subcortical brain maturation, in both early and late adolescence, are associated with increases in externalizing behavior which indicates a higher risk for psychopathology and warrants further investigations.


Engineering white light-emitting diodes with high color rendering index from biomass carbonized polymer dots.
Carbonized polymer dots (CPDs) have promise in the fields of sensing, bioimaging, and optoelectronic devices due to their excellent optical properties, favorable biocompatibility, and superior stability. Biomass CPDs present greater advantages in terms of their lack of toxicity, low cost, easy preparation, and feasibility in terms of luminescence-related applications. Here, two kinds of fluorescent CPDs were obtained through the simple hydrothermal method using biomass avocado peel (CPDs-P) and sarcocarp (CPDs-S) as carbon sources. Interestingly, these two biomass CPDs have excellent applications in ion detection and light-emitting diodes (LEDs). Analysis and results show that CPDs-P possess better sensitivity to Fe3+ because they have more oxygen-containing functional groups. After mixing with epoxy resin, warm and cold white LEDs with CIE (Commission Internationale de L 'Eclairage) coordinates (0.38, 0.39) and (0.29, 0.34) were constructed successfully from extremely stable CPDs-P and CPDs-S. The high color rendering index of the prepared white LEDs are 90.47 and 84.54. This study shows that these biomass CPDs are promising materials in sensing and white LEDs illumination.


Kinetic studies of small molecule interactions with protein kinases using biosensor technology.
Protein kinases are among the most commonly targeted groups of molecules in drug discovery today. Despite this, there are few examples of using surface plasmon resonance (SPR) for kinase inhibitor interaction studies, probably reflecting the need for better developed assays for these proteins. In this article, we present a general methodology that uses biosensor technology to study small molecule binding to eight different serine/threonine and tyrosine kinases. Mild immobilization conditions and a carefully composed assay buffer were identified as key success factors. The methodology package consists of direct binding studies of compounds to immobilized kinases, kinase activity assays to confirm inhibitory effects, detailed kinetic analyses of inhibitor binding, and competition assays with ATP for identification of competitive inhibitors. The kinetic assays resolve affinity into the rates of inhibitor binding and dissociation. Therefore, more detailed information on the relation between inhibitor structure and function is obtained. This might be of key importance for the development of effective kinase inhibitors.


Implementing a person centred collaborative health care model - A qualitative study on patient experiences.
Collaborative Health Care (CHC) is a unique model in which ambulance services, home health care, hospital care and the national telephone helpline for healthcare in Sweden - Swedish health care direct (SHD1177) collaborate to provide the fastest possible health care for inhabitants living in eleven municipalities in western region of Sweden. To explore how patients experience and perceive health care received in the CHC. Qualitative descriptive study using open-ended individual telephone interviews with fifteen community dwelling persons with experiences of care throughthe model CHC were conducted. Two main categories and six subcategories were identified. The category "Thoughts of time in regard to acute health care" include "CHC leads to shorter waiting time for health care", "Knowledge about the staff working hours" and "To alert or not alert". The category "Thoughts on unplanned health care from CHC" involved "Receiving health care in my home", "Coordination from SHD1177 surprises" and "Accessibility of health care values higher than continuity". Integrated health care models such as CHC are time saving and highly appreciated by community dwelling persons. The benefits of provision of coherent health care like in CHC, addresses the need to implement innovative integrated healthcare models in today's health care.


Molecular cloning, characterization and expression of miR-15a-3p and miR-15b-3p in dairy cattle.
MicroRNA (miRNA) plays an important role in modulating immune responses. We identified miR-15a-3p and miR-15b-3p which were immune related in bovine. Fourteen potential target genes were predicted. Both miR-15a-3p and miR-15b-3p showed significant differential expression patterns in healthy and mastitis infected cattle (P < 0.01). Expression patterns of the two miRNAs provide important information on the relationships between mastitis and miRNA expression.


Contraception, unintended pregnancy, and induced abortion within 24 months of delivery in China: a retrospective cohort study.
To explore the prevalence of contraceptive use, unintended pregnancy, and induced abortions within 24 months postpartum in eastern, central, and western regions of China and in China overall. We conducted a retrospective cohort study and selected women who delivered a live birth between 12 and 24 months before the survey at 60 hospitals in eastern, central, and western regions of China. We used structured questionnaires for data collection and applied life-table analyses to estimate the prevalence of contraception, unintended pregnancy, and abortions. We used clustered log-rank tests to compare trends and rate differences at each time interval between/among regions. A total of 19,939 postpartum women were contacted, and 18,045 (90.5%) of them agreed to be interviewed. The 6-, 12-, and 24-month rates for modern contraceptive methods were 62.7% (95% confidence interval [CI] 58.9-66.4), 72.4% (95% CI 68.8-75.7), and 73.2% (95% CI 69.6-76.6), respectively. Condoms accounted for 79% of contraceptive initiators. The 6-, 12-, and 24-month rates were 1.4% (95% CI 1.2-1.7), 5.3% (95% CI 4.5--6.1), and 13.1% (95% CI 11.3-14.8) for unintended pregnancy; and 1.1% (95% CI 0.8-1.3), 4.0% (95% CI 3.4-4.6), and 10.4% (95% CI 8.9-11.8) for induced abortion, respectively. By 24 months postpartum, 3-quarters of unintended pregnancies ended in abortion. The 24-month rates of modern contraceptive methods (75.2% vs73.4%, 71.1%), unintended pregnancy (15.3% vs 11.1%, 12.6%), and induced abortion (11.8% vs 9.9%, 9.4%) were higher in the western region relative to the eastern or central regions. Postpartum contraception use was relatively high in China but dominated by less-effective methods, and these may contribute to higher risks of unintended pregnancy and induced abortion during the postpartum period. Use of long-acting reversible contraceptives and effective and reliable short-acting methods should thus be fostered in postpartum family planning services in China. A national postpartum family planning program is needed in China. Service providers should work on counselling postpartum women and their partners with respect to long-acting reversible contraceptive methods, and to effectively and reliably use short-acting methods during the postpartum period.


Exploring CCL18, eczema severity and atopy.
Childhood atopic dermatitis (AD) is a distressing disease associated with pruritus, sleep disturbance, and impaired quality of life. The pathophysiology of AD is complex, and the chemokine CCL18/pulmonary and activation-regulated chemokine (PARC) may be involved. To evaluate whether CCL18 was associated with disease severity, quality of life, nocturnal scratching, serum eosinophil, and IgE levels. Patients with AD aged 20 yr or younger were recruited. Disease severity was assessed with the SCORing Atopic Dermatitis (SCORAD) index, quality of life with the Children's Dermatology Life Quality Index (CDLQI), and nocturnal scratching with a wrist motion monitor. Concentrations of plasma CCL18/PARC, serum total IgE, and eosinophil counts were measured in these patients. One hundred and eight patients with AD (mean [s.d.] age of 10.5 [4.4] yr) were recruited. The mean (s.d.) plasma concentration of CCL18/PARC was 162.2 (129.0) pg/ml, respectively. CCL18/PARC was significantly correlated with objective SCORAD (r = 0.44, p < 0.001), extent (r = 0.45, p < 0.001), intensity (r = 0.43, p < 0.001), the symptoms of pruritus (r = 0.20, p = 0.04), and sleep loss (r = 0.19, p = 0.049) but not with CDLQI or nocturnal scratching activities. CCL18/PARC levels were also correlated with eosinophil counts (r = 0.37, p < 0.001) and IgE(log) (r = 0.27, p = 0.005). Positive correlation with SCORAD was present even in patients without bronchial hyper-reactivity. Serum levels of CCL18 correlate with the clinical severity score, serum eosinophil, and IgE levels. CCL18 is associated with AD and atopy.


Association between Nonsteroidal Anti-Inflammatory Drugs and Colorectal Cancer: A Population-Based Case-Control Study.
Background: COX-2 overexpression may contribute to colorectal cancer occurrence. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce colorectal cancer recurrence, but the efficacy of primary prevention in Asian populations is still elusive. Thus, we examined the primary preventive efficacy of aspirin and NSAIDs on colorectal cancer incidence in Taiwan.Methods: A nested case-control study was conducted using the National Health Insurance Research Database (NHIRD) in Taiwan. We identified patients with diagnosis of colorectal cancer from 2005 to 2013 in the Registry of Catastrophic Illness Patient Database. We selected patients without colorectal cancer from the Longitudinal Health Insurance Database as the controls and matched them with cases. NSAID exposure was defined as at least two prescriptions 13 to 48 months prior to the index date. Conditional logistic regression models were performed to evaluate the association between NSAID use and colorectal cancer.Results: A total of 65,208 colorectal cancer cases and 65,208 matched controls were identified. Patients with aspirin use had a lower risk of colorectal cancer compared with nonusers [adjusted OR (AOR) = 0.94, 95% confidence interval (CI) = 0.90-0.99]. NSAID use was associated with lower incidence of colorectal cancer (AOR = 0.96; 95% CI = 0.92-1.00). When examining colon or rectal cancer, similar decreased risks were observed. Patients taking more cumulative days of NSAIDs use tended to experience a more protective effect on colorectal cancer, but no dose-response effects were noted.Conclusions: Aspirin and NSAIDs were associated with a reduced risk of colorectal cancer development among a study cohort in an Asian population.Impact: This study provided a possible chemoprevention for colorectal cancer in an Asian population. Cancer Epidemiol Biomarkers Prev; 27(7); 737-45. ©2018 AACR.


Aspirin use and chronic diseases: a cohort study of the elderly.
To evaluate the associations between the use of aspirin and the incidences of cardiovascular diseases, cancers, and other chronic diseases. Postal questionnaire survey to elicit details of aspirin use. Californian retirement community. All 22,781 residents of the community (white, affluent, and well educated) were sent a questionnaire that included questions on medical history and the use of drugs such as analgesics, laxatives, and vitamin supplements. In all 61% responded (13,987, 8881 women and 5106 men; median age 73). They formed the cohort that was followed up for 6 1/2 years using discharge summaries from three hospitals serving the area and death certificates from the health department. Only 13 respondents were lost to follow up but seemed not to have died. Incidences of cardiovascular diseases, cancers, gastrointestinal bleeding, ulcers, and cataracts were compared in participants who did and did not take aspirin daily. Age adjusted incidences were computed with an internal standard and five age groups. By 1 January 1988 there had been 25 incident cases of kidney cancer among all participants; 341 incident cases of stroke, 253 of acute myocardial infarction, 220 of ischaemic heart disease, and 317 of other heart disease were reported among respondents without a reported history of angina, myocardial infarction, or stroke. The incidence of kidney cancer was raised among those who took aspirin daily compared with those who did not take it, although the increase was significant only in men (relative risks = 6.3, 95% confidence interval 2.2 to 17, for men and 2.1, 0.53 to 8.5, for women). Those who took aspirin daily showed no increased risk of any other cancer, except colon cancer for both sexes combined (relative risk = 1.5, 1.1 to 2.2). The risk of acute myocardial infarction was reduced slightly among regular users of aspirin in men but not women. The risk of ischaemic heart disease was almost doubled in those who took aspirin daily compared with non-users (relative risks = 1.9, 1.1 to 3.1, for men and 1.7, 1.1 to 2.7, for women). Small, non-significant increased risks of stroke were observed in both sexes. The daily use of aspirin increased the risk of kidney cancer and ischaemic heart disease.


Stability of pyridoxal-5-phosphate semicarbazone: applications in plasma vitamin B6 analysis and population surveys of vitamin B6 nutritional status.
The determination of pyridoxal-5-phosphate (PLP) and pyridoxal (PL) in plasma requires the availability of dark room facilities, due to the photosensitivity of these vitamin B6 vitamers. The fact that the semicarbazone forms of PL and PLP are more strongly fluorescent than the underivatized B6 vitamers has been exploited in plasma analyses, but it was not previously realised that these semicarbazone forms are also very stable even under conditions that lead to rapid decomposition of free PL and PLP. The stabilisation of PLP and PL obtained in this manner is sufficient and fully adequate to meet the practical requirements of clinical field studies. We report a high-performance liquid chromatographic method for plasma PLP and PL determinations based on precolumn semicarbazone formation and fluorescence detection. The method is sensitive enough for quantitative plasma PLP determinations even in B6-deficient patients.


[War and medicine in a culture of peace. 5. Synopsis of nonlethal weapons].
Non lethal weapons may be harmful for people. The effects are accidental in some instances. For some weapons, they are clearly intentional. The eventuality of a fatal issue cannot be ruled out.


Effectiveness of an optional breastfeeding course for multidisciplinary undergraduate healthcare students: A quasi-experimental study.
This study aimed to examine and quantify the effectiveness of an optional breastfeeding course for multidisciplinary undergraduate healthcare students and to provide advice for education improvement based on students' characteristics and learning feedback. Breastfeeding has received global awareness and educating undergraduate healthcare students is a prospective way to promote breastfeeding. This is the first report from mainland China to verify the education effects and formulate a proposal for improvement. A quasi-experimental study with a one-group pretest-posttest design. An optional breastfeeding course covering eight topics based on the Health Belief Model was conducted for multidisciplinary students in a medical college. The Breastfeeding Knowledge Questionnaire, Iowa Infant Feeding Attitude Scale and Breastfeeding Promotion Intention Scale were completed for pre- and post-education comparison. The Wilcoxon signed-rank test, MannWhitney U test, KruskalWallis test and chi-square test were used for statistical analysis. The class average normalized gain and individual students' normalized gain were calculated to quantify the effectiveness from the perspective of learning gain. From March to November 2021, 102 students specialized mainly in nursing, clinical medicine, medical imaging technology and midwifery took the course. Knowledge, attitudes and intention scores improved significantly (Z = 8.70, 8.72, 7.64, respectively, p < .001) and the class average normalized gains were 81.0%, 52.3% and 70.6%, respectively. Insignificant differences were found for students of different genders and categories of specialties (p > .05). Students of first year had significantly higher individual normalized gains (p < .05). In learning feedback, the top-ranked advice for course improvement was to increase practice and experience (75.5%). This optional breastfeeding course produced medium to high learning gains for multidisciplinary healthcare undergraduates. Independent breastfeeding education based on behavioral theory for multidisciplinary students is recommended to be conducted in medical colleges. The addition of practice and experience may add value to such education.


Application of high-performance hydrophobic-interaction chromatography to the characterization of recombinant DNA-derived human growth hormone.
This publication analyzes different preparations of recombinant human growth hormone (rhGH) by hydrophobic-interaction chromatography (HIC). The effect of temperature on the separation was investigated as well as a series of commercially available HIC columns (TSK-phenyl-5PW, TSK-ether-PW, Beckman CAA-HIC and polypropyl A). The TSK-ether column gave the best results in the analysis of rhGH samples at different temperatures, as well as allowing an efficient separation of methionyl-hGH from rhGH. The TSK-phenyl column can be effectively used in the examination of different human growth hormone variants. The details of sample preparation have been demonstrated to be important in HIC analysis of hGH on the TSK-ether-5PW column. Injection volume and the solvent used to dissolve the protein sample are both crucial factors in this analysis. Also protein aggregation may play a role in these observations. The effect of temperature, protein concentration and spectroscopic data on the eluted protein suggest, however, that aggregation is not the cause of frontal peaks.


Structural, electrochemical and photophysical investigations of Re(I)-complexes of κ(3)N-tridentate heterocyclic ligands.
fac,fac-[Re(I)(CO)3]-complexes of new κ(3)N-tridentate ligands were synthesized and characterized by various analytical techniques including XRD. The regulation of electronic properties of the complexes upon ligand modification is discussed.


Insulin-induced factors derived from lymph node cells influence anaphylactoid reaction in the rat.
The effect of supernatants of isolated lymph node cells exposed to insulin has been studied on the anaphylactoid reaction induced by dextran in the rat paw. Native supernatants derived from rat lymphocytes were shown to increase dextran response only from April to October, while in the intermediate period no potentiation was obtained. The supernatants were filtered through sephadex G-25, G-50, and G-100 gels. Pro-inflammatory activity was recovered in the void volume of sephadex G-25 or G-50 columns, while it ran with bovine serum albumin marker suggesting an approximate mol. wt. of 70-kilodalton. Potentiation was detectable in adrenalectomized rats from November through April. A fraction of the eluate recovered from sephadex G-25 gels in the range of 1- to 6-kilodalton was found to suppress dextran edema. Supernatants of calf lymph node cells with insulin were fractionated on DEAE-sephadex A-50 and yielded two distinct fractions, one with pro-inflammatory and the other with anti-inflammatory effect. These results suggest that insulin affects anaphylactoid reaction via the release of some lymphocyte mediators.


EGFR inhibitor erlotinib plus monoclonal antibody versus erlotinib alone for first-line treatment of advanced non-small cell lung carcinoma: A systematic review and meta-analysis.
Immuno-combination therapy is emerging as an effective treatment for advanced non-small cell lung carcinoma (NSCLC). However, compared to monotherapy, such as monoclonal antibodies or kinase inhibitors, whether combination therapy can enhance antitumor efficacy or alleviate side effects remains unclear. A systematic literature search was undertaken using the PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials databases to identify eligible studies concentrating on treatment with erlotinib or erlotinib plus monoclonal antibodies in NSCLC patients published between January 2017 and June 2022. The primary outcomes included progression-free survival (PFS), overall survival (OS), response rate (RR) and treatment-related adverse events (AEs). Seven independent randomized, controlled clinical trials including 1513 patients were obtained for the final analysis. Erlotinib plus monoclonal antibodies was significantly associated with the improvement of PFS (hazards ratio [HR], 0.60; 95% CI 0.53-0.69; z = 7.59, P < 0.01) and with moderate performance regarding OS (HR, 0.81; 95% CI 0.58-1.13; z = 1.23, P = 0.22) and RR (odds ratio [OR], 1.25; 95% CI 0.98-1.59; z = 1.80, P = 0.07), irrespective of EGFR mutation status. In the safety evaluation, erlotinib plus monoclonal antibodies had a markedly higher occurrence of adverse events (AEs) of Clavien grade 3 or higher (OR, 3.32; 95% CI 2.66-4.15; z = 10.64, P < 0.01). Compared with erlotinib alone, combination therapy (erlotinib plus monoclonal antibodies) was associated with significantly improved PFS in NSCLC therapy, accompanied by increased treatment-related AEs. Our systematic review protocol was registered in the PROSPERO international register of systematic reviews (CRD42022347667).


Don't give up? It's a little complicated: Action Crisis Moderates Consequences of goal support.
Social support for goals can be beneficial for goal pursuit, but often has unintended negative consequences for the recipient. We propose that action crisis-the state in which an individual is considering disengaging from a goal they are currently pursuing-may result in people experiencing more ambivalent reactions to goal support. Drawing on both experimental and longitudinal methods, we show that action crisis increases negative consequences of goal support, but does not reduce positive consequences of goal support. In Study 1, we experimentally manipulated goal phase (action crisis, deliberative, or implemental) and had participants imagine support or neutral interactions. In Study 2, we measured experiences of action crisis and receipt of goal support in first-year pre-health students over the course of the academic year. Action crisis predicted more negative appraisals of support, but did not impact positive appraisals of support. Similarly, action crisis predicted more negative emotions and depressive symptoms among people who received goal support, but did not impact positive emotions. These results suggest that action crisis increases the extent to which support is received as a "mixed blessing". The online version contains supplementary material available at 10.1007/s11031-022-09977-8.


[Treatment of iron deficiency in predialysis state by low molecular weight iron dextran high doses intravenously].
Anemia is a common complication of chronic kidney disease (CKD) in predialysis stage. Iron deficiency is more common than in normal patients and plays a key role in the genesis of anemia. Its correction avoids the use of erythropoiesis stimulating agents (ESA) or reduces their dosage. Treatment with oral iron is often poorly tolerated and ineffective, necessitating the use of intravenous iron. New forms of injectable iron allow the use of high doses and correct iron deficiency in a single administration with consequent preservation of venous capital and lower costs. We studied the effectiveness of iron dextran of low molecular weight (LMWID) in high doses to correct iron deficiency and treat anemia in predialysis CKD patients. Twenty-nine doses of 500 to 1600 mg were administered to 25 patients followed for CKD (GFR between 60 and 10 ml/min per 1.73 m(2)), selected on biological criteria of iron deficiency defined by a ratio of transferrin saturation (TSAT) <20% and/or serum ferritin of less than 100 μg/L. Patients received treatment by ESA in 16 cases out of 29. One month after treatment, hemoglobin (Hb) increased significantly (11.4±1.6 vs 10.4±1.4 g/dL, P=0.0003) along with a significant increase in TSAT (21.3±7.3 vs 13.3±3.8%, P=0.000003) and serum ferritin (286±253 vs 91±60 μg/L, P=0.00005). Six patients had a serum ferritin greater than 500 μg/L after treatment, which may put them at risk of iron overload. Their serum ferritin was higher than the rest of the population before treatment, while the TSAT was no different, reflecting a functional deficiency. Their hemoglobin did not increase after treatment in contrast to the rest of the population suggesting the unavailability of iron for erythropoiesis with accumulation in the reticuloendothelial system. Renal function did not change significantly and there were no cases of acute renal failure. No immediate side effect was observed. Three patients presented delayed reactions to such self-limiting myalgia and arthralgia. No venous inflammatory reaction was noted. The administration of high doses of LMWID is effective in treating anemia of CKD in the predialysis stage with a satisfactory tolerance, without affecting kidney function and helps preserve the venous capital. It should be reserved for patients whose serum ferritin is less than or equal to 150 μg/L.


Novel PD-1 inhibitor prolgolimab: expanding non-resectable/metastatic melanoma therapy choice.
Prolgolimab is an IgG1 anti-PD-1 (programmed cell death protein 1) monoclonal antibody containing the Fc-silencing 'LALA' mutation. We assessed the efficacy and safety of two dosing regimens of prolgolimab in patients with advanced melanoma in a multicenter open-label parallel-arm phase II trial (MIRACULUM). We present the final analysis after 1 year of follow-up and additional efficacy results from 2 years of follow-up. Patients with advanced cutaneous or non-cutaneous melanoma, including stable brain metastasis, without autoimmune disease and who underwent no prior targeted therapy, anti-PD-(L)1 or anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) therapy were randomly assigned (1:1) to receive prolgolimab in 2 dosing regimens, 1 mg/kg every 2 weeks (arm 1) or 3 mg/kg every 3 weeks (arm 2), until disease progression or intolerable toxicity. Randomisation was stratified based on performance status (Eastern Cooperative Oncology Group 0 or 1), lactate dehydrogenase levels (elevated or normal) and prior systemic therapy (naive or previously treated). The primary outcome was the objective response rate, assessed as per immune-related Response Evaluation Criteria in Solid Tumours by independent central review. The hypothesis that each dosing regimen of prolgolimab has an overall response rate >28% was tested independently for each study arm comprising all patients who received at least one dose of prolgolimab. Exploratory assessment of efficacy, including subgroup analysis, at 2 years of follow-up was not specified in the protocol. This study is registered withClinicalTrials.gov(NCT03269565). Between August 2017 and March 2018, 126 patients with advanced melanoma were enrolled. At main 1-year data cut-off, the median follow-up was 13.8 and 14.5 months in arm 1 and 2, respectively. An objective response was observed in 38.1% of patients (arm 1) and in 28.6% (arm 2). Grade III-IV treatment-related adverse events occurred in 12.7% and 3.2% of patients in arm 1 and 2, respectively. For exploratory efficacy analysis, the median follow-up was 25.4 and 25.7 months in arm 1 and 2, respectively. The 2-year progression-free survival was 33.3% in arm 1 and 30.2% in arm 2, and the 2-year overall survival was 57.1% and 46.0%, respectively. The MIRACULUM study met its primary end-point in both the study arms. Prolgolimab showed significant antitumour activity and a manageable safety profile in patients with advanced melanoma.


Intravenous magnesium sulphate provides no additive benefit to standard management in acute asthma.
Treatment of acute asthma is based on rapid reversal of bronchospasm and airway inflammation. Magnesium sulphate (MgSO(4)) is known to have a bronchodilator effect on smooth muscle but studies have shown conflicting results on its efficacy in acute asthma, although its use is recommended in national and international guidelines. To determine if intravenous MgSO(4), when used as an adjunct to standard therapy, improves the outcome in acute asthma. A double blind, randomised placebo controlled trial comparing 1.2g MgSO(4) with standard therapy in adult patients with acute asthma. Patients had a PEF <or=75% predicted and all were treated with oxygen, nebulised salbutamol and ipratropium, and IV hydrocortisone. They then received 1.2g IV MgSO(4) or placebo. Outcome measures were % predicted PEF at 60 min and hospital admission rates. One hundred and twenty nine patients were studied. Placebo and active treatment groups were well matched at baseline. MgSO(4) had no benefit with regards hospital admission rates or % predicted PEF at 60 min (p=0.48) for the whole group, or for subgroups of life-threatening (p=0.85), severe (p=0.63) and moderate (p=0.67) acute asthma. This study did not show additional benefit from 1.2g IV MgSO(4) when given as an adjunct to standard therapy for acute asthma.


A revision of Hexacanalis Perrenoud, 1931 (Cestoda: Lecanicephalidea) and description of H. folifer n. sp. from the zonetail butterfly ray Gymnura zonura (Bleeker) (Rajiformes: Gymnuridae).
Hexacanalis Perrenoud, 1931 was erected for H. abruptus (Southwell, 1911) Perrenoud, 1931 based on the presence of six excretory vessels, a unique feature among the Lecanicephalidea. The genus has since been considered a junior synonym of Cephalobothrium Shipley & Hornell, 1906 or Lecanicephalum Linton, 1890, or as a genus inquirendum. Based on examination of the syntype series of H. abruptus, this species is redescribed and a lectotype designated. Examination of cestodes from the zonetail butterfly ray Gymnura zonura (Bleeker) from off Indonesian Borneo resulted in the discovery of a second species. Hexacanalis folifer n. sp. is unique among lecanicephalideans in its possession of an ovary that is U-shaped in cross-section and craspedote proglottids with prominent posterior dorso-ventral processes in the form of large lappets. The presence of six excretory vessels, confirmed in both species, supports the validity of Hexacanalis. An additional species, H. pteroplateae (Zaidi & Khan, 1976) n. comb., also from a butterfly ray, G. micrura (Bloch & Schneider) [as Pteroplatea micrura (Bloch & Schneider)], is transferred to this genus from Cephalobothrium Shipley & Hornell, 1906. A revised diagnosis of Hexacanalis is presented. Seven species of this genus remain species inquirendae. Hexacanalis appears to parasitise species of the Gymnuridae van Hasselt; however, specific identifications of the hosts are in need of re-evaluation. A summary of the cestode parasites of the Gymnuridae is presented.


Prioritizing Child Health: Promoting Adherence to Well-Child Visits in an Urban, Safety-Net Health System During the COVID-19 Pandemic.
After discovering racial/ethnic disparities in adherence to well-child visits, UMass Memorial Health worked to identify and mitigate barriers to adherence for patients and families across 53 primary care practices in central Massachusetts. When the systemwide goal to reduce racial/ethnic disparities in well-child visit adherence was established, a multidisciplinary team of leaders from UMass Memorial Health worked together to engage patients and stakeholders to identify obstacles to adherence. Transportation, language, and scheduling were identified as barriers. The team employed a number of countermeasures to address these barriers: A new workflow was created for requesting free curb-to-curb transportation for Medicaid patients, practices were provided with tip sheets for accessing interpreter services, and a protocol for scheduling appointment reminders was developed. In addition, the team leveraged robust data analytics to communicate real-time data to practices to keep them informed of their progress toward the system's health equity goal. Primary data results are reported from October 1, 2020, to September 30, 2021. For patients who identified as Hispanic/Latinx, adherence rose from 64.3% at baseline to 74.1% (p < 0.001); and for patients who identified as Black/African American, adherence rose from 58.7% at baseline to 71.9% (p < 0.001). The gap in adherence to well-child visits for Black/African American and Hispanic/Latinx children compared to White children narrowed (12.4 percentage points to 5.1; p < 0.001; 6.8 percentage points to 2.9; p < 0.001). Through a unique partnership between health system leaders, frontline staff, and the system's informatics team and by engaging caregivers to identify and address barriers to well-child visits, UMass Memorial Health was able to improve adherence to well-child visits among patients who identify as Black/African American or Hispanic/Latinx.


Temozolomide for the treatment of recurrent supratentorial glioma: results of a compassionate use program in Belgium.
Temozolomide (TMZ) has demonstrated activity and acceptable toxicity for the treatment of recurrent high-grade gliomas in prospective phase II studies. Limited information is available on TMZ when prescribed outside a clinical trial. We conducted a retrospective study to evaluate the activity and safety of TMZ that was prescribed for the treatment of recurrent glioma in the context of a compassionate use program in Belgium. Data were obtained on 117 adult patients (from five hospitals) who received TMZ as first or second line chemotherapy. The recommended starting dose of TMZ was 200 mg/m2 x5d q28d for chemonaive patients and 150 mg/m2 x5d q28d for pre-treated patients. Toxicity was generally mild. Thrombocytopenia was the most frequent treatment related adverse event (grade 3/4 in 17% of patients). Its occurrence was correlated with a starting dose of 200 mg/m2/d and stresses the need to monitor toxicity. The overall objective response rate (complete and partial response) was 29 and 34% of patients achieved an objective disease stabilization. The median progression-free survival was 104 days (95% CI: 85-123) and the median overall survival was 215 days (95% CI: 161 269). In multivariate analysis a 'deep localization' of the glioma (as opposed to a cortico-subcortical localization) and 'the preceding history of a low-grade glioma' were respectively identified as a negative and positive independent prognostic variable for survival. No significant difference in terms of response or median survival was observed between patients with anaplastic astrocytoma or oligo-astrocytoma and chemonaive glioblastoma multiforme. This retrospective study indicates that the reported activity and toxicity profile of TMZ for the treatment of patients with recurrent glioma is reproducible outside the setting of a prospective clinical trial.


Microbial enhancement of compost extracts based on cattle rumen content compost - characterisation of a system.
Microbially enhanced compost extracts ('compost tea') are being used in commercial agriculture as a source of nutrients and for their perceived benefit to soil microbiology, including plant disease suppression. Rumen content material is a waste of cattle abattoirs, which can be value-added by conversion to compost and 'compost tea'. A system for compost extraction and microbial enhancement was characterised. Molasses amendment increased bacterial count 10-fold, while amendment based on molasses and 'fish and kelp hydrolysate' increased fungal count 10-fold. Compost extract incubated at 1:10 (w/v) dilution showed the highest microbial load, activity and humic/fulvic acid content compared to other dilutions. Aeration increased the extraction efficiency of soluble metabolites, and microbial growth rate, as did extraction of compost without the use of a constraining bag. A protocol of 1:10 dilution and aerated incubation with kelp and molasses amendments is recommended to optimise microbial load and fungal-to-bacterial ratio for this inoculum source.


An index for discrimination of mangroves from non-mangroves using LANDSAT 8 OLI imagery.
Over the last few decades several vegetation indices were used to map Mangrove forest using satellite images. Difficulty still persists in discrimination of mangroves from non-mangrove vegetation, especially in areas where mangrove species are mixed with other vegetation types. In the present study we have attempted to develop an improved index, which utilizes the information from the Normalized Difference Vegetation Index (NDVI) and the Normalized Difference Water Index (NDWI) of Bhitarkanika mangrove forest of Odisha, India. These indices are negatively correlated (r = -0.988; p < 0.01). Further, the NDWI values were subtracted from the NDVI values at the pixel level. As the outputs are negatively related, subtraction increases the upper and lower range of the overall output, also increasing the distinct values of two classes with near-similar spectral signatures. Same algorithm was applied on mangroves of Sundarbans (r = -0.987) and Andaman (r = -0.989). A comparison between four established indices [NDVI, NDWI, Soil Adjusted Vegetation Index (SAVI), Simple Ratio (SR)] and the newly developed index namely Combined Mangrove Recognition Index (CMRI) were performed. Accuracy assessment using Kappa statistics, revealing that CMRI produces better accuracy (73.43%) compared to other indices, followed by NDVI (56.29%) and SR (48.79%).


Validation of an enzyme-linked immunosorbent assay for qualitative screening of neomycin in muscle, liver, kidney, eggs and milk.
A rapid and sensitive enzyme-linked immunosorbent assay (ELISA) was used for the qualitative screening analysis of neomycin in food of animal origin (muscle, liver, kidney, eggs and milk) at levels corresponding to the European Union maximum residue limit (MRL) set for this substance. The method validation was performed according to the criteria of Commission Decision 2002/657/EC established for qualitative screening methods. In this regard, the following parameters were determined: detection capability (CCβ), specificity, detection limit (LOD), quantification limit (LOQ), recovery, precision, linearity and ruggedness. LODs ranged from 5.7 microg kg(-1) in kidney to 29.3 microg kg(-1) in milk; LOQs ranged from 11.4 microg kg(-1) in kidney to 59.7 microkg(-1) in eggs. The recoveries from spiked samples at the MRL, half the MRL and double the MRL levels ranged from 65.8% to 122.8%, with a coefficient of variation (CV) between 5.9% and 28.6%. The CCβ value was less than the MRL for all examined matrices. Moderate variations of some critical factors in the sample pretreatment for muscle, milk and eggs were deliberately introduced for ruggedness evaluation and had a slight but not statistically significant effect on method performance. The proposed method is suitable for qualitative screening analysis of neomycin in the above-mentioned food in conformity with current European Union performance requirements.


Evaluation of corneal biomechanics in patients with keratectasia following LASIK using dynamic Scheimpflug analyzer.
To investigate the corneal biomechanics in eyes with keratectasia following LASIK using a dynamic Scheimpflug analyzer. Case-Control study. The subjects in the study included 12 eyes with keratectasia after LASIK (KE), 24 eyes with keratoconus (KC), 17 eyes without keratectasia after LASIK (LASIK), and 34 eyes with normal corneas (Normal). Corneal biomechanics of the four groups were evaluated using a dynamic Scheimpflug analyzer. Compared with Normal (7.06 ± 0.54), the radius at the highest concavity (radius, mm) of LASIK (5.96 ± 0.76), KE (4.93 ± 0.61) and KC (5.39 ± 1.02) were significantly small. The Deflection Amplitude (HCDLA, mm) of Normal (0.94 ± 0.07) was significantly lower than those of KE (1.11 ± 0.10) and KC (1.06 ± 0.16), and was not significantly different from that of LASIK (0.98 ± 0.07). There were significant differences between LASIK and KE in radius and HCDLA (P < 0.05), whereas KE and KC had no differences in these parameters. Corneal biomechanical features evaluated using the dynamic Scheimpflug analyzer suggest that biomechanical properties in eyes with keratectasia, keratoconus, and LASIK are different from those of normal eyes. Although the biomechanics in eyes with keratectasia differs from that in eyes with LASIK, it is similar to that in eyes with keratoconus.


Cyclin D-CDK4/6 functions in cancer.
The mammalian cell cycle is driven by a complex of cyclins and their associated cyclin-dependent kinases (CDKs). Abnormal dysregulation of cyclin-CDK is a hallmark of cancer. D-type cyclins and their associated CDKs (CDK4 and CDK6) are key components of cell cycle machinery in driving G1 to S phase transition via phosphorylating and inactivating the retinoblastoma protein (RB). A body of evidence shows that the cyclin Ds-CDKs axis plays a critical role in cancer through various aspects, such as control of proliferation, senescence, migration, apoptosis, and angiogenesis. CDK4/6 dual-inhibitors show significant efficacy in pre-clinical or clinical cancer therapies either as single agents or in combination with hormone, chemotherapy, irradiation or immune treatments. Of note, as the associated partner of D-type cyclins, CDK6 shows multiple distinct functions from CDK4 in cancer. Depletion of the individual CDK may provide a therapeutic strategy for patients with cancer.


G protein and adenylate cyclase complex-mediated signal transduction in the rat heart during sepsis.
Changes in the protein level of various subunits of GTP-binding protein and the activity of adenylate cyclase in the rat heart during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP. The protein levels of various subunits of GTP-binding protein were determined by Western blot analysis. The activity of adenylate cyclase was measured based on the rate of formation of cAMP from [alpha-32P]ATP. The results show that protein levels of G alphas and G beta remained stable during the early and the late phases of sepsis. The protein levels of G alpha i-2 and G alpha i-3 remained relatively unaltered during the early phase of sepsis, but they were increased by 46.5% (P < 0.05) and 61.3% (P < 0.01), respectively, during the late phase of sepsis. The basal adenylate cyclase activity remained unchanged during the early phase while it was decreased by 25.7% (P < 0.05) during the late phase of sepsis. The isoproterenol-stimulated adenylate cyclase activity was unchanged during early sepsis while it was decreased by 44.6% (P < 0.01) during late sepsis. These data demonstrate that during the late hypodynamic phase of sepsis, myocardial G alpha i-2 and G alpha i-3 protein levels were increased and the increases were coupled with a reduction in adenylate cyclase activity. Because GTP-binding proteins mediate sympathetic control of cardiac function, the present findings may have a pathophysiological significance in contributing to the understanding of the pathogenesis of cardiac dysfunction during the late stage of sepsis.


Use of emergency rigid bronchoscopy to reduce tumour mass prior to surgical resection.
Two patients with lung adenocarcinoma developed acute respiratory failure as a result of unilateral lung collapse. They were successfully treated by tumour de-bulking using a rigid brochoscope and subsequent radical sleeve lobectomy. Case 1 was a 46-year-old man whose carcinoma was pathological stage IIIb (P-T4N2M0), and he remains tumour-free 39 months after the surgery. Case 2 was a 79-year-old man whose carcinoma was pathological stage IIb (P-T3N0M0). Following treatment, he was able to resume his daily activities, however, his tumour recurred and he died 5 months after the surgery. Debulking of tumours with a rigid bronchoscope was useful for improving patients' quality of life and for the subsequent multidisciplinary treatment of lung carcinoma.


Home vision monitoring in patients with maculopathy: Real-life study of the OdySight application.
The goal of the present study was to analyze the implementation and clinical efficacy of OdySight, a mobile medical application for the remote monitoring of patients with maculopathy. In all, 60 patients with edematous maculopathies receiving traditional clinical treatment (PRN or Treat & Extend) were provided with OdySight to detect changes in visual acuity from home. To determine both the feasibility and reliability of the application, its use by patients (both testing and game play), as well as the processing of alerts by the clinical team, were analyzed during the first year. The female-to-male ratio was 3:2, with a mean age of 64 years. 52% of patients presented with age-related macular degeneration, 31% with high myopia, 11% with retinal vein occlusion, and 6% with diabetic maculopathy. The conversion rate (defined as the percentage of patients completing at least one test following prescription) and the nine-month retention rate (percentage of active patients) were 61% and 24% respectively. Patients aged 50 to 70 years and those whose use of the app included game play represent 75% of active patients at 9 months. The 22 active patients performed 483 visual acuity tests, completed 1,667 game sessions, and underwent 77 in-person consultations. During the trial period, the clinical team processed 19 alerts, on average in fewer than 6 days. Decreases in visual acuity were detected with a sensitivity of 92% and specificity of 99%. The use of connected and mobile devices today is widespread, as is interest in mobile medical applications. Long-term treatments for maculopathies can be a difficult burden to bear, both for patients and healthcare practitioners. Overcoming the challenges associated with the successful remote detection of recurrences thus represents a significant opportunity for improving patient care. The implementation of novel digital tools requires the cooperation of the clinical team as a whole, to both inform and motivate patients. OdySight demonstrates satisfactory detection rates, thanks to reliable and reproducible home testing, and can thus serve as a supplementary tool for patients whose consultations are often spaced several months apart. Implementation can be nonetheless improved by facilitating alert processing, a goal which necessitates active adaptation of clinical practices. In general, active patients were very satisfied with this personalized service. Improved medical support, plus the amusing nature of the tests and games, both bolster long-term use of the OdySight app. The application allows for the remote monitoring of changes in visual acuity and affords patients and practitioners an added level of protection, particularly during long intervals between treatments and at the end of a treatment course. To ensure proper implementation, clinics should focus on reinforcing and modernizing the clinical pathway, from patient intake to the injection room.


Assessment on post-harvest losses of tomato (Lycopersicon esculentem Mill.) in selected districts of East Shewa Zone of Ethiopia using a commodity system analysis methodology.
One of the main challenges facing Ethiopia today is to ensure food security for its rapidly growing population. Although Ethiopia's production is much lower than the national demand, there are high post-harvest food losses. In meeting a country's food demand, increasing production by itself is not enough unless what has been produced is properly managed. In line with this, extensive assessment of post-harvest losses of tomato along the supply chain and the associated factors were evaluated in four purposively selected districts of East Shewa Zone of Ethiopia. The assessment was made using Commodity System Assessment Methodology from "farm-to-fork" to investigate the status of post-harvest losses of tomato along the supply chain and the associated factors in the pursuit of recommending appropriate mitigation strategies. Information was gathered from a total of N = 408 sampled chain actors (producers to consumers) and related institutions. Results revealed that losses of tomato due to improper care and handling of the commodity regardless of its high production in the study area were common problems for all chain actors. A loss of 20.5%, 8.6%, 2.9%, and 7.3% at the producer, wholesalers, retailers, and hotel and café level was recorded respectively with a total loss of 39.3%. Total losses across districts ranged from 17.2-33.3. Field, transportation and market display were major critical loss points identified. Practices such as market fluctuation, lack of temperature management, no/poor sorting and mixed handling of the crop, carelessness on the loss prevention and its impact were identified among the common causes for observed losses. Therefore, creating awareness on the effect of all causes of food loss and minimizing economic loss is recommended. Moreover, affordable and appropriate technology adaptation is needed to reduce observed food losses across the districts.


Pinoresinol diglucoside ameliorates H/R-induced injury of cardiomyocytes by regulating miR-142-3p and HIF1AN.
This study is aimed to investigate the effect of pinoresinol diglucoside (PDG) in ameliorating myocardial ischemia-reperfusion injury (MIRI). Hypoxia/reperfusion (H/R)-induced H9c2 cardiomyocytes were used to establish an in-vitro ischemia-reperfusion injury model of cardiomyocytes. Cells were treated with 1 μmol/L of PDG. Reactive oxygen species (ROS) level was detected by a 2',7'-dichlorofluorescein-diacetate assay. The release of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) was examined by enzyme-linked immunosorbent assay. The viability and apoptosis of H9c2 cells were probed by MTT assay and flow cytometry. Besides this, Western blot and quantitative real-time PCR were used to detect microRNA-142-3p (miR-142-3p) and hypoxia-inducible factor 1 subunit alpha inhibitor (HIF1AN) expression levels. The binding sequence between miR-142-3p and HIF1AN 3'-untranslated region was validated by a dual-luciferase reporter gene assay. PDG treatment significantly reduced the level of ROS, LDH, and CK-MB, promoted viability, and inhibited the apoptosis of H9c2 cells. PDG treatment promoted miR-142-3p expression and inhibited HIF1AN expression in H9c2 cells. MiR-142-3p overexpression enhanced the effects of PDG on ROS, LDH, CK-MB levels, cell viability, and apoptosis in H9c2 cardiomyocytes, while overexpression of HIF1AN reversed the above effects. PDG ameliorates H/R-induced injury of cardiomyocytes by regulating miR-142-3p and HIF1AN.


High Lipoprotein(a) Levels are Associated With Long-Term Adverse Outcomes in Acute Myocardial Infarction Patients in High Killip Classes.
An elevated concentration of lipoprotein(a) {Lp(a)} is associated with an increased prevalence and increased severity of coronary artery disease. However, the relationship between Lp(a) levels and outcomes after acute myocardial infarction (AMI) is unclear. Between October 2005 and June 2007, we measured serum Lp(a) levels in 832 consecutive AMI patients (age, 62.8±12.4 years, 600 men) on admission. They were divided into tertiles according to their serum Lp(a) levels {Tertile 1 (n=276), Lp(a)<13.8 mg/dL; Tertile 2 (n=279), Lp(a)=13.8-30.6 mg/dL; Tertile 3 (n=277), Lp(a)>30.6 mg/dL}. There were no differences in baseline clinical characteristics among Tertiles 1, 2, and 3, except for proportions of Killip class III-IV patients (5.8% vs. 10.0% vs. 18.8%, respectively, p<0.001). There were significant differences in left ventricular ejection fractions (57.3±11.4% vs. 55.9±12.3% vs. 53.1±13.1%, p<0.001). Among the laboratory findings, there were significant differences in total cholesterol (173.3±37.2 vs. 183.5±38.9 vs. 185.3±43.8 mg/dL, p=0.001), low density lipoprotein-cholesterol (111.3±34.3 vs. 122.9±34.7 vs. 123.3±39.4 mg/dL, p<0.001), apolipoprotein B (92.8±25.4 vs. 100.8±26.0 vs. 101.9±28.8 mg/dL, p<0.001), and amino-terminal pro-brain natriuretic peptide levels (1805.2±4343.3 vs. 2607.9±5216.3 vs. 3981.5±7689.7 pg/mL, p<0.001). After adjusting for multiple variables in the high Killip class (III-IV) subgroup, the risk estimate for major adverse cardiovascular events (MACE) at 1-year follow-up was significantly higher in Tertile 3 than in Tertiles 1 or 2 (hazard ratio 6.723, 95% confidence interval 1.037-43.593, p=0.046). In patients in high Killip classes, high serum levels of Lp(a) were significantly associated with long-term adverse outcomes after AMI.


Importance of preoperative myocardial glycogen levels in human cardiac preservation. Preliminary report.
One hundred seventeen patients undergoing elective coronary bypass were divided into four groups according to prebypass myocardial glycogen levels and the use of potassium chloride cardioplegia. Myocardial glycogen levels were enhanced with a preoperative fat loading diet and overnight glucose loading. The control group (n = 27) which had mean cardiac glycogen levels of 750 mg/100 gm heart weight and no cardioplegia, had a transmural myocardial infarct rate of 14.4%; 35% had severe atrial arrhythmias 65% had severe ventricular arrhythmias, and 31% had severe vasopressor dependence. The group (n = 30) with low cardiac glycogen (736 mg/100 gm) and with potassium chloride cardioplegia had an infarct rate of 6.4%; 6.7% had severe atrial arrhythmias, 18% had severe ventricular arrhythmias, and 16.7% had severe vasopressor dependence. However, the group (n = 26) which had high cardiac glycogen levels (1,208 mg/100 gm) and no cardioplegia had no myocardial infarctions; 3.8% had severe atrial arrhythmias, 27% had severe ventricular arrhythmias, and only 7.8% had severe vasopressor need. The group (n = 34) which had high glycogen levels (1,516 mg/100 gm) and potassium chloride cardioplegia did best of all with no myocardial infarctions or no severe atrial arrhythmias; 14% had severe ventricular arrhythmias and 2.81% severe vasopressor need. The lessening of vasopressor dependence and severe atrial and ventricular arrhythmias were significant by chi square contingency tables at p less than 0.05 and p less than 0.001, respectively. One cardiac-related death each occurred in the two groups with low glycogen and none in those with high glycogen levels. This suggests that better preoperative cardiac nutrition as represented by enhanced cardiac glycogen helps that heart tolerate anoxic stress whether cardioplegia is utilized or not and is additive to potassium chloride cardioplegia.


Extracting Rules via Markov Chains for Cryptocurrencies Returns Forecasting.
With the growing popularity of digital currencies known as cryptocurrencies, there is a need to develop models capable of robustly analyzing and predicting the value of future returns in these markets. In this article, we extract behavior rules to predict the values of future returns in the Bitcoin, Ethereum, Litecoin, and Ripple closing series. We used categorical data in the analyses and Markov chain models from the first to the tenth order to propose a new way of establishing possible future scenarios, in which we analyze the dependence of memory on the dynamics of the process. We used the measurements of accuracy Mean Quadratic Error, Absolute Error Mean Percentage, and Absolute Standard Deviation for the choice of the best models. Our findings reveal that cryptocurrencies have long-range memory. Bitcoin, Ethereum, and Ripple exposed seven steps of memory, while Litecoin displayed nine memory steps. From the transitions between states that happened the most, we defined decision rules that assisted in the definition of future returns in the series. Our results can support the decisions of traders, investors, crypto-traders, and policy-makers.


Residential proximity to unconventional oil and gas development and birth defects in Ohio.
Chemicals used or emitted by unconventional oil and gas development (UOGD) include reproductive/developmental toxicants. Associations between UOGD and certain birth defects were reported in a few studies, with none conducted in Ohio, which experienced a thirty-fold increase in natural gas production between 2010 and 2020. We conducted a registry-based cohort study of 965,236 live births in Ohio from 2010 to 2017. Birth defects were identified in 4653 individuals using state birth records and a state surveillance system. We assigned UOGD exposure based on maternal residential proximity at birth to active UOG wells and a metric specific to the drinking-water exposure pathway that identified UOG wells hydrologically connected to a residence ("upgradient UOG wells"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for all structural birth defects combined and specific birth defect types using binary exposure metrics (presence/absence of any UOG well and presence/absence of an upgradient UOG well within 10 km), adjusting for confounders. Additionally, we conducted analyses stratified by urbanicity, infant sex, and social vulnerability. The odds of any structural defect were 1.13 times higher in children born to mothers living within 10 km of UOGD than those born to unexposed mothers (95%CI: 0.98-1.30). Odds were elevated for neural tube defects (OR: 1.57, 95%CI: 1.12-2.19), limb reduction defects (OR: 1.99, 95%CI: 1.18-3.35), and spina bifida (OR 1.93; 95%CI 1.25-2.98). Hypospadias (males only) was inversely related to UOGD exposure (OR: 0.62, 95%CI: 0.43-0.91). Odds of any structural defect were greater in magnitude but less precise in analyses using the hydrological-specific metric (OR: 1.30; 95%CI: 0.85-1.90), in areas with high social vulnerability (OR: 1.27, 95%CI: 0.99-1.60), and among female offspring (OR: 1.28, 95%CI: 1.06-1.53). Our results suggest a positive association between UOGD and certain birth defects, and findings for neural tube defects corroborate results from prior studies.


Antecedent immunosuppressive therapy for immune-mediated inflammatory diseases in the setting of a COVID-19 outbreak.
Finite clinical data and understanding of COVID-19 immunopathology has led to limited, opinion-based recommendations for the management of patients with immune-mediated inflammatory disease (IMID) receiving immunosuppressive (IS) therapeutics. To determine if IS therapeutic type affects COVID-19 risk among patients with IMID. We conducted a retrospective cohort analysis of Henry Ford Health System patients tested for COVID-19 between February 1 and April 18, 2020, treated with IS medication for IMID. Therapeutic class of IS medication, comorbidities, and demographic factors were combined into multivariate models to determine predictors of COVID-19 infection, admission, ventilation, and mortality. Of 213 patients with IMID, 36.2% tested positive for COVID-19, and they had no greater odds of being hospitalized or requiring ventilation relative to the general population. No IS therapeutic worsened the course of disease after multivariate correction, although multidrug regimens and biologics predicted an increased and decreased rate of hospitalization, respectively, with the latter driven by tumor necrosis factor α inhibitors. A single-center study somewhat limits the generalization to community-based settings. Only patients tested for COVID-19 were analyzed. IS therapies for IMIDs are not associated with a significantly greater risk of SARS-CoV-2 or severe sequelae when controlling for other factors, and tumor necrosis factor α inhibitors may decrease the odds of severe infection.


Fostering formative assessment: teachers' perception, practice and challenges of implementation in four Sudanese medical schools, a mixed-method study.
Formative assessment (assessment for learning) enhances learning (especially deep learning) by using feedback as a central tool. However, implementing it properly faces many challenges. We aimed to describe the perception of medical teachers towards FA, their practice, challenges of implementing FA and present applicable solutions. A mixed-method, explanatory approach study was applied by administering a validated questionnaire to 190 medical teachers in four medical schools in Sudan. The obtained results were further studied using the Delphi method. Quantitative analysis revealed that medical teachers perceived their grasping of the concept of FAs and their ability to differentiate formative from summative assessments as very well (83.7%) and (77.4%), respectively. However, in contradiction to the former results, it was noteworthy that (41%) of them mistakenly perceived FA as an approach conducted for purposes of grading and certification. The qualitative study defined the challenges into two main themes: lack of understanding of formative assessment and lack of resources. Medical teachers' development and resource allocation were the main recommendations. We conclude that there is misunderstanding and malpractice in implementing formative assessment attributed to the lack of understanding of FA as well as the lack of resources. We as well present suggested solutions derived from the perception of the medical teachers in the study and evolved around three approaches: faculty development, managing the curriculum by allocating time and resources for FA, and advocacy among stakeholders.


[Burkitt's lymphoma presenting as an intermittent limp].
Musculoskeletal pain is a frequent complaint in pediatrics usually related to benign conditions. However, it may also represent the initial symptom of serious diseases such as infections, malignancies or orthopedic emergencies. We present the case of a child diagnosed with Burkitt's lymphoma whose initial presentation was a limp. This is, to the best of our knowledge, the first case reported in the literature with this type of debut. This case illustrates the importance of including neoplasms in the differential diagnosis of atypical musculoskeletal pain, since early diagnosis can significantly improve their prognosis.


Near-Infrared Photodynamic Chemiluminescent Probes for Cancer Therapy and Metastasis Detection.
There is growing interest in the development of chemiluminescence (CL) probes for phototheranostics because of their minimized tissue autofluorescence. However, due to a lack of near-infrared (NIR)-absorbing chemiluminophores, current probes for NIR CL-guided phototherapy are based on nanoparticles made up of multiple components. We report bright unimolecular chemiluminophores with NIR absorptions and emissions, long CL half-lives and ideal photodynamic efficiency. One luminophore is modified into an activatable probe, DBPOL , with a turn-on CL signal and photodynamic activity that are specific to a cancer biomarker. The highly sensitive DBPOL allows CL-guided photodynamic therapy which completely inhibits tumor growth and lung metastasis in mouse models, and can be applied for noninvasive monitoring of lung metastasis. We provide molecular guidelines for NIR-absorbing CL probes for imaging-guided phototherapy.


Ultrasound Neuromodulation Inhibits Seizures in Acute Epileptic Monkeys.
Ultrasound stimulation has recently emerged as a non-invasive method for modulating brain activity in animal and human studies with healthy subjects. Whether brain diseases such as Alzheimer's disease, epilepsy, and depression can be treated using ultrasound stimulation still needs to be explored. Recent studies have reported that ultrasound stimulation suppressed epileptic seizures in a rodent model of epilepsy. These findings raise the crucial question of whether ultrasound stimulation can inhibit seizures in non-human primates with epilepsy. Here, we addressed this critical question. We confirmed that ultrasound stimulation significantly reduced the frequency of seizures in acute epileptic monkeys. Furthermore, the results showed that the number and duration of seizures were reduced, whereas the inter-seizure interval was increased after ultrasound stimulation. Besides, no significant brain tissue damage was observed by T2-weighted MR imaging. Our results are of great importance for future clinical applications of ultrasound neuromodulation in patients with epilepsy.


Comparison of bovine cysticercosis prevalence detected by antigen ELISA and visual inspection in the North East of Spain.
A cross-sectional serological study on cattle less than 2 years old, using an antigen ELISA for the detection of bovine cysticercosis was carried out between November 2009 and February 2010 in 10 slaughterhouses from the Catalonia region (North-Eastern Spain). Circulating antigen was detected in 23 of 2073 animals, i.e. a sero-prevalence of 1.11% (CI95%: 0.76-1.75%). The determined sero-prevalence was about 50 times higher than the prevalence obtained by visual inspection within the same period: 19 positive animals of 90,891 slaughtered animals (0.02%) in the same slaughterhouses. None of the animals with positive result in the Ag-ELISA was detected by meat inspection.


Midwall shortening after coarctation repair: the effect of through-plane motion on single-plane indices of left ventricular function.
Left ventricular midwall function is increased after repair of coarctation of the aorta (CoA). The cause is unclear. This study aimed to examine the variance between fiber shortening derived from 3-dimensional models of myocardial deformation, and 1- and 2-dimensional indices of left ventricular systolic function. In all, 15 young adults after CoA and 15 matched control subjects were recruited. Endocardial and midwall fractional shortening were calculated using M-mode echocardiography. Ejection fraction, midwall fractional shortening, and myocardial deformation were calculated or measured from magnetic resonance (MR) imaging. Echocardiographic and cine-MR imaging midwall fractional shortening were increased after CoA (P = .02 and < .001). In contrast, 3-dimensional MR tagging demonstrated normal midwall circumferential shortening and decreased longitudinal shortening in the CoA group (P < .01). Cine MR midwall shortening, recalculated to allow for through-plane motion, was similar to tagged midwall shortening, with no difference between the CoA and control groups. After CoA, measures of left ventricular function systematically overestimate midwall fiber shortening unless the methodology accounts for through-plane motion.


Childhood cancer mortality and radon concentration in drinking water in North Carolina.
We explored the association between groundwater radon levels and childhood cancer mortality in North Carolina. Using data from two state-wide surveys of public drinking water supplies, counties were ranked according to average groundwater radon concentration. Age and sex-adjusted 1950-79 cancer death rates among children under age 15 were calculated for counties with high, medium, and low radon levels. Overall cancer mortality was increased in counties with medium and high radon levels. The strongest association was for the leukaemias, but risks were also suggested for other sites. These associations could be due to confounding or other biases, but the findings are consistent with other recent reports.


A Tutorial for Implementing Matrix Training in Practice.
Matrix training consists of arranging targets for instruction to promote fine-grained stimulus control resulting in the establishment of skills without direct training. Recent reviews of the matrix training literature (Curiel et al., 2020a, b.; Kemmerer et al., 2021) highlighted the efficacy and efficiency of the approach with learners with and without disabilities. These reviews noted substantial variations in procedures across studies, suggesting the approach may be flexibly deployed across content areas and teaching procedures. This outcome is positive for practitioners as they may customize matrix training to meet the unique needs of their clients. However, it also necessitates decision making to sort through the variations in the literature. This tutorial was developed to help practitioners weigh various considerations when using matrix training. Tools and resources are provided to illustrate and accelerate adoption into practice settings. The online version contains supplementary material available at 10.1007/s40617-022-00733-5.


Mortality in severely injured elderly patients: a retrospective analysis of a German level 1 trauma center (2002-2011).
Demographic change is expected to result in an increase in cases of severely injured elderly patients. To determine special considerations in treatment and outcome, patients aged 75 years and older were studied. All patients in the included age group with an Injury Severity Score (ISS) ≥ 16 upon primary admission to hospital between July 2002 and December 2011 were included in this mortality analysis. The data used for this study was gained partly from data submitted to the German Trauma Register and partly from patients' hospital records. A comparison between survivors and decedents was performed, as well as age-adjusted and ISS-adjusted analyses. The odds ratio and relative risk were used to determine predictors for mortality. One-hundred eight patients met the inclusion criteria. The overall mortality proportion was 57.4%. The decedents were more severely injured (ISS 26 vs. 20, p < 0.001) and suffered more severe head traumas (GCS 4 vs. 12, p < 0.001; AIS head 5 vs. 4, p = 0.006). No differences were found in vital parameters measured at the accident scene or trauma room. Decedents had deranged coagulation with a prolonged PTT (41.1 sec vs. 27.6 sec, p = 0.008) and reduced prothrombin ratio (66.5% vs. 82.8%, p = 0.016). The treatment of severely injured elderly patients is challenging. The most common cause of accident is falling from less than 3 m with head injuries being determinant. We identified deranged coagulopathy as an important predictor for mortality, suggesting rapid normalization of coagulation might be a key to reducing mortality.


The action of arterial hypertension on lipid and lipoprotein metabolism. II. Qualitative and quantitative alterations of blood serum, liver and aortic lipids and lipoproteins in Okamoto-Aoki rats with spontaneous hypertension.
The purpose of the study was to investigate alterations in the content of the basic lipid fractions, and of the low density lipoproteins (LDL) in the liver, the blood serum and aorta, as well as to determine by acrylamide disc electrophoresis the hyperlipoproteinaemic type of spontaneously hypertensive rats (SHR) which are considered as the most suitable model of essential hypertension. The experiments were carried out on 25 normotensive control Wistar rats and 30 SHR (Okamoto-Aoki strain). An augmentation of lipid metabolism in the liver and a moderate hyperlipidaemia mainly due to an increase in triglycerides was found. The quantitative alterations of the lipid fractions corresponded with the qualitative alterations of the lipoproteins, an intensive and permanent pre-beta-LP fraction being established. In all the SHR a peculiar pattern of hyperlipoproteinaemia differing from the basic Fredickson-Lees patterns by a LP-fraction located between tha alpha- and beta-LP fractions was also established. The alterations in the lipid and lipoprotein metabolism in SHR are considered as connected with the hypertensive state itself since no accompanying atherosclerosis was observed.


Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity.
One of the most significant challenges in the development of clinically viable delivery systems for RNA interference therapeutics is to understand how molecular structures influence delivery efficacy. Here, we have synthesized 1,400 degradable lipidoids and evaluate their transfection ability and structure-function activity. We show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations on IV administration to mice (siRNA EC50 values as low as 0.01 mg kg(-1)). We identify four necessary and sufficient structural and pKa criteria that robustly predict the ability of nanoparticles to mediate greater than 95% protein silencing in vivo. Because these efficacy criteria can be dictated through chemical design, this discovery could eliminate our dependence on time-consuming and expensive cell culture assays and animal testing. Herein, we identify promising degradable lipidoids and describe new design criteria that reliably predict in vivo siRNA delivery efficacy without any prior biological testing.


Calpain-mediated impairment of Na+/K+-ATPase activity during early reperfusion contributes to cell death after myocardial ischemia.
Na+ overload and secondary Ca2+ influx via Na+/Ca2+ exchanger are key mechanisms in cardiomyocyte contracture and necrosis during reperfusion. Impaired Na+/K+-ATPase activity contributes to Na+ overload, but the mechanism has not been established. Because Na+/K+-ATPase is connected to the cytoskeleton protein fodrin through ankyrin, which are substrates of calpains, we tested the hypothesis that calpain mediates Na+/K+-ATPase impairment in reperfused cardiomyocytes. In isolated rat hearts reperfused for 5 minutes after 60 minutes of ischemia, Na+/K+-ATPase activity was reduced by 80%, in parallel with loss of alpha-fodrin and ankyrin-B and detachment of alpha1 and alpha2 subunits of Na+/K+-ATPase from the membrane-cytoskeleton complex. Calpain inhibition with MDL-7943 during reperfusion prevented the loss of these proteins, increased Na+/K+-ATPase activity, attenuated lactate dehydrogenase release, and improved contractile recovery, and these beneficial effects of MDL-7943 were reverted by ouabain. The impairment of Na+/K+-ATPase was not a mere consequence of cell death because it was not altered in hearts in which contracture and cell death had been prevented by contractile blockade with 2,3-butanedione monoxime. In these hearts, concomitant calpain inhibition preserved Na+/K+-ATPase content and function and attenuated cell death occurring on withdrawal of 2,3-butanedione monoxime. In vitro assay showed no detectable degradation of Na+/K+-ATPase subunits after 10 minutes of incubation with activated calpain. Thus, we conclude that calpain activation contributes to the impairment of Na+/K+-ATPase during early reperfusion and that this effect is mainly mediated by degradation of the anchorage of Na+/K+-ATPase to the membrane cytoskeleton.


[Prevalence of common allergies in children and adolescents in Germany: results of the KiGGS study: first follow-up (KiGGS Wave 1)].
The first follow-up of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 1) was conducted from 2009 to 2012 as a combined cross-sectional and longitudinal study and provides, among other things, data on allergic diseases. Data collection was carried out by telephone interviews. In total, 6,093 girls and 6,275 boys were included, among them 4,455 newly recruited 0- to 6-year-olds (response 38.8%) and 7,913 KiGGS follow-up participants aged 7-17 years (response 72.9%). Based on parent reports, 15.6% (95% confidence interval 14.7-16.5) of children and adolescents aged 0-17 years were currently affected by at least one atopic disease. The 12-month prevalence rates of hay fever, atopic dermatitis, and asthma were 9.1% (8.4-9.8), 6.0% (5.4-6.6), and 4.1% (3.6-4.6), respectively. In all, 2.2% (1.9-2.6) of the children and adolescents were currently suffering from contact dermatitis. Compared with the baseline KiGGS survey from 2003 to 2006, a higher percentage of participants reported the occurrence of asthma within the past 12 months in the recent KiGGS Wave 1 (4.1 vs. 3.2%; p = 0.0034). The total increase is mainly due to higher prevalence rates among 0- to 6-year-olds, especially in girls. Higher 12-month prevalence rates can be also observed for hay fever among 0- to 6-year-olds, especially in girls, although the total increase is not statistically significant (9.1 vs. 8.3%; p = 0.08). There was a declining trend for atopic dermatitis: 6.8% (2003-2006) vs. 5.4% (2009-2012); p = 0.0015.


Amalgam or composite fillings--which material lasts longer?
Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and LILACS. Hand searched relevant journals and attempted contact with authors of unpublished studies and manufacturers. Randomised controlled trials comparing dental resin composites with dental amalgams in permanent posterior teeth with a minimum follow up of three years were eligible. Data were extracted independently by a minimum of two review authors using specially designed data extraction forms. Risk of bias was assessed using the Cochrane risk of bias tool. Relative risks and 95% CIs were extracted for dichotomous data and mean difference (MD) or standardised mean difference (SMD) for continuous data. Relative risk was combined in a meta-analysis. Seven studies were included. Two were parallel and five split-mouth design. Data from 871 participants were available from the two parallel studies but several of the split-mouth studies did not report the number of participants. All studies were considered at high risk of bias. Only data from the two parallel studies were included in the primary meta-analysis. Failure rates in these studies were recorded for between five and seven years. The risk ratio of failure for composite versus amalgam was 1.89 with 95% CI of 1.52-2.35. The increased failure was primarily due to caries rather than fracture. There is low-quality evidence to suggest that resin composites lead to higher failure rates and risk of secondary caries than amalgam restorations.


Microarchitectural parameters and bone mineral density in patients with tumour-induced osteomalacia by HR-pQCT and DXA.
Tumour-induced osteomalacia (TIO) is a rare paraneoplastic condition characterised by decreased tubular phosphate reabsorption. The purpose of this study is to evaluate bone mineral density (BMD) and microarchitecture in six TIO patients, compared with 18 healthy controls. Volumetric BMD and microarchitecture were evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT), and areal BMD by dual-energy X-ray absorptiometry (DXA). Differences between groups were significant for p < .05. All TIO subjects were healthy until the development of diffuse bone pain and multiple skeletal fractures and deformities. At baseline, sPi and TmPi/GFR were low and patients were on vitamin D and phosphate replacement at the study. Compared with controls, TIO patients had lower aBMD at lumbar spine and hip, and lower vBMD at trabecular, cortical and entire bone, at distal radius (R) and distal tibia (T): trabecular vBMD (R = 118.3 × 177.1; T = 72.3 × 161.3 gHA/cm3 ); cortical vBMD (R = 782.3 × 866.5; T = 789.1 × 900.9 gHA/cm3 ); total region vBMD (R = 234.5 × 317; T = 167.1 × 295.8 gHA/cm3 ). Bone microarchitecture was very heterogeneous among patients and significantly different from controls: lower cortical thickness (R = 0.59 × 0.80; T = 0.90 × 1.31 mm), bone volume-to-total volume ratio (R = 0.09 × 0.14; T = 0.06 × 0.13) and Tb.N (R = 1.46 × 2.10; T = 0.93 × 1.96 mm-1 ) and also higher Tb.Sp (R = 0.70 × 0.41; T = 1.28 × 0.45 mm) and Tb.1/N.SD (R = 0.42 × 0.18; T = 0.87 × 0.20 mm). In this original study of TIO patients, DXA and HR-pQCT evaluation identified lower areal and volumetric BMD and severely impaired microarchitecture at cortical and trabecular bones, which probably contribute to bone fragility and fractures.


Rapid containment of coincident outbreaks with 2 carbapenem-resistant Klebsiella pneumoniae strains in an intensive care unit.
In our intensive care unit, coincident outbreaks were caused by concomitant cross-transmission of 2 carbapenem-resistant Klebsiella pneumoniae strains harboring distinct mechanisms of resistance. One strain produced extended-spectrum ß-lactamase in combination with reduced permeability. The other produced oxacillinase-48 carbapenemase. Rapid phenotypic detection of carbapenemase production allowed timely implementation of appropriate infection control measures.


The physical activity experience of prostate cancer patients: a multicentre peer motivation monitoring feasibility study. The Acti-Pair study.
Although the benefits of physical activity (PA) on health are recognised, prostate cancer patients do not follow PA recommendations. The barriers to PA, whether physical, environmental or organisational, are known. Furthermore, even when such barriers are overcome, this achievement is not systematically accompanied by a change in lifestyle habits. The proposal of a programme enabling the integration of PA in the patient's everyday life represents a new challenge in the personalized management of cancer patients. Peer-mentoring interventions have demonstrated their effectiveness in increasing adherence to PA by patients. This study aimed (1) to assess the feasibility of a peer-mentoring intervention: the Acti-Pair program in a local context and (2) to assess the effectiveness of the intervention in this context. A pre-post design pilot study will be used to evaluate feasibility, potential effectiveness and implementation outcomes overs in prostate cancer patients. We performed a mixed quantitative and qualitative prospective study to assess means and process indicators and the implementation of the Acti-Pair program. This study will be performed in cancer centres of Loire district and will be comprised of three successive stages (1) diagnosis of the target population, (2) recruitment and training of peers, and (3) implementation of this intervention in the Loire department. This study will allow us to extend the peer-mentoring intervention to other contexts and assess the effectiveness of this intervention and its generalisability.


In vitro comparison of synergism between cefamandole and gentamicin or tobramycin by the triple layer agar method with enzymatic inactivation.
A synergistic effect was shown with gentamicin and tobramycin by means of a triple layer agar technique and enzymatic inactivation of cefamandole after only four hours' incubation. When the strain is sensitive to cefamandole and aminoglycosides, synergy is observed against all the strains studied (Staphylococcus aureus, Proteus, Klebsiella, Escherichia coli, Enterobacter, and Haemophilus influenzae). No significant difference was noted between the cefamandole-tobramycin and the cefamandole-gentamicin combinations when the microbial strains were sensitive to the three antibiotics.


Identification and characterization of a fatty acid binding protein in bovine mammary gland.
A fatty acid binding protein (FABP) was isolated from bovine mammary cytosol by gel filtration and ion exchange chromatography. Polyacrylamide gel electrophoresis in sodium dodecyl sulfate indicated a mol. wt. of 12,000. Isoelectric focusing showed two bands at pH 5.6 and 5.8. FABP bound long chain fatty acids and their CoA thioesters, but not medium or short chain fatty acids. Affinity constant (Ka) for 18:1 was about 2 micromolar. Endogenously bound fatty acids included 16:0, 18:0 and 18:1, in both covalent and noncovalent association with FABP. Activities of microsomal phosphatidic acid phosphatase, fatty acid:CoA ligase or diacylglycerol acyltransferase were not affected by purified FABP in vitro.


Immediate and delayed effects of in vitro ischemia on glutamate efflux from guinea-pig cerebral cortex slices.
Immediate and delayed effects of glucose deprivation, oxygen deprivation (hypoxia) and both oxygen and glucose deprivation (in vitro ischemia) on glutamate efflux from guinea pig cerebral cortex slices were studied. Immediate effects were evaluated by measuring changes of glutamate efflux during the metabolic insults. Delayed effects were evaluated by measuring the response of the tissue to a 50 mM KCI pulse applied 60 min after the metabolic insults. Deprivation of glucose in the medium did not induce either immediate or delayed effects, while hypoxic condition produced an immediate slight stimulation of glutamate efflux without any delayed effect. Conversely, in vitro ischemia produced both immediate and delayed effects on glutamate efflux. During in vitro ischemia glutamate efflux dramatically increased in a calcium-independent and tetrodotoxin-sensitive manner; this effect was potentiated by a low sodium containing medium. The blockade of the sodium/potassium ATPase exchanger by ouabain caused a glutamate outflow similar to that induced by in vitro ischemia. On the whole, these data demonstrate the central role played by the sodium electrochemical gradient and by the membrane glutamate uptake system in the glutamate overflow induced by in vitro ischemia. Moreover, in slices previously exposed to both oxygen and glucose deprivation the effect of KCI on glutamate efflux was potentiated. This in vitro ischemia-induced delayed potentiation of neurotransmitter efflux, until now unreported in the literature, was found to be selectively restricted to glutamatergic structures and to be mainly due to an enhancement of the exocytotic component of glutamate release.


Spinal changes in the neuropathy of thallium poisoning. A case with neuropathological studies.
Thallium poisoning in a man of 32 years resulted in typical peripheral neuropathy, skin rash and alopecia. Post-mortem studies showed widespread loss of peripheral nerve fibres and chromatolysis in spinal neurones. The distal nature of the nerve fibre degeneration in thallium poisoning and the sensitivity of long fibres is emphasized in this case.


Structure and thermodynamics of aqueous urea solutions from ambient to kilobar pressures: From thermodynamic modeling, experiments, and first principles simulations to an accurate force field description.
Molecular simulations based on classical force fields are a powerful method for shedding light on the complex behavior of biomolecules in solution. When cosolutes are present in addition to water and biomolecules, subtle balances of weak intermolecular forces have to be accounted for. This imposes high demands on the quality of the underlying force fields, and therefore force field development for small cosolutes is still an active field. Here, we present the development of a new urea force field from studies of urea solutions at ambient and elevated hydrostatic pressures based on a combination of experimental and theoretical approaches. Experimental densities and solvation shell properties from ab initio molecular dynamics simulations at ambient conditions served as the target properties for the force field optimization. Since urea is present in many marine life forms, elevated hydrostatic pressure was rigorously addressed: densities at high pressure were measured by vibrating tube densitometry up to 500 bar and by X-ray absorption up to 5 kbar. Densities were determined by the perturbed-chain statistical associating fluid theory equation of state. Solvation properties were determined by embedded cluster integral equation theory and ab initio molecular dynamics. Our new force field is able to capture the properties of urea solutions at high pressures without further high-pressure adaption, unlike trimethylamine-N-oxide, for which a high-pressure adaption is necessary.


Ectodysplasin-A2 induces dickkopf 1 expression in human balding dermal papilla cells overexpressing the ectodysplasin A2 receptor.
Androgenetic alopecia (AGA) is a common genetic disorder, and a X-chromosomal locus that contains the androgen receptor (AR) and ectodysplasin A2 receptor (EDA2R) genes represents a major susceptibility locus for AGA. In our previous study, we reported that ectodysplasin-A2 (EDA-A2) induces apoptosis in cultured human hair follicle (HF) cells and promotes the regression of HFs in mice. However, the role of the EDA-A2/EDA2R in AGA remains unknown, as the causative gene in this pathway has not yet been identified and potential functional connections between EDA-A2 signaling and the androgen pathway remain unclear. In this study, we investigated the expression of EDA2R in balding HFs and matched with non-balding HFs. The EDA2R level was upregulated in the balding dermal papilla (DP) cells compared with non-balding DP cells derived from patients with AGA. However, EDA2R was strongly expressed in both balding and non-balding outer root sheath (ORS) cells. We screened EDA-A2-regulated genes in balding DP cells and identified dickkopf 1 (DKK-1) as catagen inducer during the hair cycle. The mRNA and protein expression levels of DKK-1 were both upregulated by EDA-A2. In addition, DKK-1 expression was induced by EDA-A2 both in cultured human HFs and in mouse HFs. Moreover, the EDA-A2-induced apoptosis of DP and ORS cells was reversed by the antibody-mediated neutralization of DKK-1. Collectively, our data strongly suggest that EDA-A2 induces DKK-1 secretion and causes apoptosis in HFs by binding EDA2R, which is overexpressed in the bald scalp. EDA-A2/EDA2R signaling could inhibit hair growth through DKK-1 induction, and an inhibitor of EDA-A2/EDA2R signaling may be a promising agent for the treatment and prevention of AGA.