High risk for major nonlimb anomalies associated with lower-limb deficiency: a population-based study.
The aims of this study were to determine the prevalence of congenital lower-limb reduction defects and associated mortality, to evaluate lower-limb deficiencies by type of reduction, and to identify patterns of associated anomalies. We conducted a population-based study with use of data from the Finnish Register of Congenital Malformations and Care Register for Health Care. All cases of lower-limb deficiency among live births, stillbirths, spontaneous abortions, and terminations of pregnancy due to fetal anomalies from 1993 to 2008 were included. We analyzed medical records and classified lower-limb reduction defects. Associated major anomalies were recorded, and perinatal mortality and infant mortality were calculated. Two hundred and sixty-six cases with lower-limb deficiency were identified, with a total prevalence of 2.8 per 10,000 births, a birth prevalence of 2.2 per 10,000 births, and a live-birth prevalence of 2.1 per 10,000 live births. Terminal transverse limb reductions accounted for 44.7% of the cases; longitudinal reductions, 22.9%; intercalary reductions, 7.9%; multiple reductions, 8.3%; and split-foot malformations, 4.5%. In addition to lower-limb deficiency, 47.7% of the cases had other major anomalies; anomalies of internal organs were noted in 26.3% of the cases, anomalies of the axial skeleton in 13.5% of cases, and central nervous system anomalies in 12.8%. Upper-limb reductions were observed in 32.0% of the cases. The relative risk (RR) for associated major anomalies was 12.54 (95% confidence interval [CI], 11.06 to 14.23) compared with the general figures for major congenital anomalies in Finland. The RR for associated anomalies was higher (1.75; 95% CI, 1.20 to 2.53) for longitudinal preaxial lower-limb deficiencies than for the other types of lower-limb reductions. Perinatal mortality was seventy-eight per 1000 births. All infant deaths were associated with chromosomal abnormalities, other known syndromes, or additional congenital malformations. Nearly half of the cases with lower-limb deficiencies were found to have other major anomalies. In cases of preaxial lower-limb deficiencies, the risk for associated major anomalies was highest.


Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood.
An asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups. To characterize the asthma and atopy phenotypes in early childhood that associate with the 17q12-21 locus. The single nucleotide polymorphism (SNP), rs7216389, was genotyped in 376 of 411 children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort born to mothers with asthma together with 305 mothers and 224 fathers. Nineteen additional SNPs in the region were genotyped in the children. Investigator-diagnosed clinical endpoints were based on diary cards and clinic visits every 6 months and at acute symptoms from birth. Lung function, bronchial responsiveness, and sensitization were tested longitudinally from early infancy. rs7216389 was significantly associated with the development of wheeze (hazard ratio 1.64 [1.05-2.59], P value = 0.03), asthma (hazard ratio, 1.88 [1.15-3.07], P = 0.01), and acute severe exacerbations (hazard ratio 2.66 [1.58-4.48], P value = 0.0002). The effect on wheeze and asthma was observed for early onset but not late onset of disease. The increased risk of exacerbations persisted from 1 to 6 years of age (incidence ratio 2.48 [1.42-4.32], P value = 0.001), and increased bronchial responsiveness was present in infancy and at 4 years of age, but not at 6 years. In contrast, rs7216389 conferred no risk of eczema, rhinitis, or allergic sensitization. Variation at the chromosome 17q12-q21 locus was associated with approximately twofold increased risk of recurrent wheeze, asthma, asthma exacerbations, and bronchial hyperresponsiveness from early infancy to school age but without conferring risk of eczema, rhinitis, or allergic sensitization. These longitudinal clinical data show this locus to be an important genetic determinant of nonatopic asthma in children.


Fluorescein transport through the blood-aqueous and blood-retinal barriers in diabetic macular edema.
To investigate the integrity of the blood-aqueous barrier (BAB) and the blood-retinal barrier (BRB) in diabetic patients with clinically significant macular edema (CSME). The rate constant (Kd(F)) of the BAB and the permeability of the blood-retinal barrier for non-protein bound fluorescein were determined simultaneously by fluorometry. Results were analysed pairwise in diabetic patients (n = 25) with CSME in one eye and without CSME in the other eye. Kd(F) for the eyes with CSME was significantly increased compared to eyes without CSME (444. 10(-6) min( -1) and 387. 10(-6) min(-1) respectively, p = 0.01). The passive permeability of the BRB was also significantly increased in CSME (5.7 nm/sec and 3.5 nm/sec respectively, p = 0.009, n = 19). Both the rate constant of the BAB and the BRB permeability were significantly increased in CSME indicating that eye-specific factors are common for both barriers in diabetic patients with CSME.


[Interleukin-1 beta and interleukin-6-plasma concentrations in laparotomies. Interaction with neuroendocrine secretion and postoperative temperature regulation?].
Elevated body temperature, increased plasma cortisol concentrations, and loss of the circadian secretory pattern are typical changes observed after trauma and surgery. We investigated the hypothesis that the interleukins IL-1 beta and IL-6 are involved in these phenomena, since both are endogenous pyrogens and can induce ACTH and cortisol secretion. METHODS. Eight healthy women undergoing hysterectomy for non-malignant diseases participated in the study after having given written consent. The study had the approval of our institution's ethics committee. Anaesthesia was induced with fentanyl 0.1 mg and methohexitone 1.5 mg/kg and maintained with isoflurane in 60% N2O and 40% O2. Blood samples were drawn before induction, before incision, during surgery, at the end of surgery, and 30, 60, 120, 240 and 360 min after surgery. Cortisol, prolactin, IL-1 beta, and IL-6 concentrations were determined with commercially available ELISAs. Statistical analysis was performed with non-parametric methods. RESULTS. IL-6 increased significantly from 15 (4.3-23) to 68 (18-107) pg/ml (medians and range) at the end of surgery and peaked at 128 (52-214) pg/ml 60 min postoperatively (p < 0.01, Table 2). Baseline IL-1 beta concentrations were 20 (1-35) pg/ml with a significant increase in median postoperative concentrations in the postoperative period (p < 0.001). Prolactin increased from 22 (13-43) to 210 (115-291) ng/ml immediately after induction of anaesthesia (p < 0.001) and remained elevated until 240 min after surgery. Cortisol increased from 99 (26-167) to 384 (241-553) ng/ml during surgery and reached a maximum of 475 (246-597) ng/ml 30 min postoperatively (Table 3). Rectal and mean body temperatures increased significantly in the postoperative period (Table 1). There was a significant correlation between IL-6 and cortisol concentrations (r = 0.468; p < 0.001), but none was found between IL-6 and temperature or between IL-1 beta and cortisol or temperature. CONCLUSIONS. Surgical trauma markedly stimulates the secretion of IL-6, and to a lesser extent that of IL-1 beta. The data do not yield any evidence indicating an effect of IL-1 beta or IL-6 on body temperature. Postoperative prolactin concentrations might be influenced by IL-6. The positive correlation between plasma concentrations of IL-6 and cortisol may be coincidental, but could reflect a causal relationship, particularly in the postoperative period during which time the circadian pattern of cortisol secretion is disturbed.


A general approach to spirolactonized Si-rhodamines.
A general approach has been developed for the synthesis of spirolactonized Si-rhodamines (SiRBs). The alternative synthetic route provides a facile opportunity to access various s bearing ring-expanded scaffolds and substituents for conjugation. By click reaction, a near-infrared (NIR) mitochondrial tracker was prepared, displaying specific mitochondrial staining in cells.


Effects of physical conditioning on left ventricular ejection fraction in patients with coronary artery disease.
To address the hypothesis that physical conditioning may improve left ventricular function in patients with coronary artery disease, we performed first-pass radionuclide ventriculography in 53 patients at rest and during upright bicycle exercise before and after 6 to 12 months of exercise training. The peak bicycle workload achieved before the onset of fatigue, dyspnea, or angina increased by an average of 22% (p = .0001) after training, and mean heart rate at a workload equal to the pretraining maximum workload was decreased by 10 beats/min after training (p = .0002). Of 21 subjects with angina or exertional ST segment depression before training, 15 (71%) were able to exercise to the same workload without these manifestations of ischemia after training. Whereas neither mean resting left ventricular ejection fraction (LVEF) nor LVEF at peak exertion was significantly altered, mean LVEF at the pretraining maximum workload was increased from 0.50 to 0.54 (p = .002) after training. There was a significant correlation between the magnitude of training bradycardia and the increment in LVEF at the pretraining maximum workload (p = .009). We conclude that the relative bradycardia at comparable exercise workloads produced by exercise conditioning is associated with improvements in left ventricular performance as assessed by the LVEF. This observation is compatible with the hypothesis that training bradycardia in conditioned subjects with ischemic heart disease is associated with lower myocardial oxygen demand and lesser degrees of ischemia at comparable workloads. However, training effects on ventricular afterload or on ischemia contractile performance of the heart cannot be excluded.


The associations between dietary flavonoid intake and the prevalence of diabetes mellitus: Data from the National Health and Nutrition Examination Survey 2007-2010 and 2017-2018.
Diabetes mellitus (DM) is a prominent health concern worldwide, leading to the high incidence of disability and mortality and bringing in heavy healthcare and social burden. Plant-based diets are reported associated with a reduction of DM risk. Plant-based diets are rich in flavonoids, which possess properties such as scavenging free radicals and exerting both anti-inflammatory and antioxidant effects. However, whether dietary flavonoids are associated with the prevalence of DM remains controversial. The potential reasons for contradictory epidemiological outcomes on the association between dietary flavonoids and DM prevalence have not been determined. To address these limitations, we employed data from 22,481 participants in the National Health and Nutrition Examination Survey to explore the association between the intake of flavonoids and DM prevalence by weighted Logistic regression and weighted restricted cubic splines. We found that the prevalence of DM was inversely associated with the intake of total flavonoids in the second quartile [Odds Ratio (OR) 0.78 95% confidence interval (CI) (0.63, 0.97), p = 0.028], in the third quartile [0.76 (0.60, 0.97), p = 0.031], and in the fourth quartile [0.80 (0.65, 0.97), p = 0.027]. However, the p for trend was not significant [0.94 (0.88, 1.01), p = 0.096]. Moreover, the association between DM prevalence and the intake of total flavonoids was significantly influenced by race (p for interaction = 0.006). In Mexican Americans, there was a significant positive association between DM prevalence and total flavonoid intake within the third quartile [1.04 (1.02, 1.07), p = 0.003]. Total flavan-3-ol and subtotal catechin intake exhibited a non-linear U-shaped association with DM prevalence (p for non-linearity < 0.0001 and p for non-linearity < 0.0001, respectively). Compared to the first quartile of corresponding intakes, consumption within the third quartile of subtotal catechins [0.70 (0.55, 0.89), p = 0.005] and total flavan-3-ols [0.65 (0.50, 0.84), p = 0.002] was associated with a lower prevalence of DM. Taken together, our study may provide preliminary research evidence for personalized improvement of dietary habits to reduce the prevalence of diabetes.


Lactobacillus reuteri DSM 17938 changes the frequency of Foxp3+ regulatory T cells in the intestine and mesenteric lymph node in experimental necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine in premature infants. Lactobacillus reuteri DSM 17938 improves survival and reduces the incidence and severity of NEC in a rodent model. Foxp3(+) regulatory T cells (Tregs) maintain intestinal homeostasis by controlling inflammation and inducing tolerance. To determine whether there are insufficient numbers of Tregs to control inflammation in NEC and to determine if LR17938 increases the frequency of Tregs, we studied selected groups of newborn Sprague-Dawley rats according to feeding plan: dam±LR17938, formula±LR17938, and NEC±LR17938. NEC was induced by gavage feeding with special formula and exposure to hypoxic conditions. Lymphocytes isolated from ileum, mesenteric lymph nodes (MLN), spleen and thymus were labeled for T cell surface markers (CD3, CD4, CD8) and intracellular Foxp3; and labeled cells were analyzed by flow cytometry. The percentage of CD3(+) T cells and Foxp3(+) Tregs in the ileum significantly decreased in pups with NEC, compared to normal controls. Feeding LR17938 to neonatal rats with NEC increased the % of Foxp3(+) T cells in the ileum while decreasing the percentage of cells in the MLN. Administration of LR17938 to dam-fed rats significantly increased Foxp3(+)Tregs in the ileum as early as day of life (DOL)1 but did not produce an increase in Tregs in formula-fed rats on DOL1. These results suggest that factors in breast milk may enhance the early immunomodulatory effects of LR17938. An anti-inflammatory effect of LR17938 in NEC was associated with the modulation of immune responses and induction and what appears to be migration of Foxp3(+) Tregs to the diseased gut. Probiotic-facilitated development of Tregs might play an important role in the prevention of NEC.


[Spatiotemporal evolution of COVID-19 epidemic in the early phase in China].
Objective: Based on the geographic information systems, we exploreed the spatiotemporal clustering and the development and evolution of COVID-19 epidemic at prefectural level in China from the time when the epidemic was discovered to the time when the lockdown ended in Wuhan. Methods: The information and data of the confirmed COVID-19 cases from December 8, 2019 to April 8, 2020 were collected from 367 prefectures in China for a spatial autocorrelation analysis with software GeoDa, and software ArcGIS was used to visualize the results. Software SatScan was used for spatiotemporal scanning analysis to visualize the hot-spot areas of the epidemic. Results: The incidence of new cases of COVID-19 had obvious global autocorrelation and the partial autocorrelation results showed that incidence of COVID-19 had different spatial distribution at different times from December 8, 2019 to March 4, 2020. There was no significant difference in global autocorrelation coefficient from March 5, 2020 to April 8, 2020. The statistical analysis of spatiotemporal scanning identified two kinds of spatiotemporal clustering areas, the first class clustering areas included 10 prefectures, mainly distributed in Hubei, from January 13 to February 25, 2020. The secondary class clustering areas included 142 prefectures, mainly distributed in provinces in the north and east of Hubei, from January 23 to February 1, 2020. Conclusions: There was a clear spatiotemporal correlation in the distribution of the outbreaks in the early phase of COVID-19 epidemic (December 8, 2019-March 4, 2020) in China. With the decrease of the case and effective prevention and control measures, the epidemics had no longer significant correlations among areas from March 5 to April 8. The study results showed relationship with time points of start and adjustment of emergency response at different degree in provinces. Furthermore, improving the early detection of new outbreaks and taking timely and effective prevention and control measures played an important role in blocking the transmission.


Chromatin-bound protease: (3H)diisopropyl fluorophosphate labeling patterns of chromatin.
The nuclei and chromatin of rat liver contain three major proteins reacting with diisopropyl fluorophosphate (DFP). The molecular weights of the three proteins determined by gel filtration in the presence of sodium dodecyl sulfate and sodium dodecyl sulfate-polyacrylamide gel electrophoresis are 70000, 60000, and 25000. The chromatin isolated from whole liver, instead of nuclei, contains an additional DFP-binding protein whose molecular weight is 100000 in the presence of sodium dodecyl sulfate and beta-mercaptoethanol. The small molecular weight DFP-binding protein can be fractionated from chromatin by 0.25 N HC1 and was found to be a protease which is active in the most commonly used solution for chromatin dissociation, that is, 2-3 M NaCl-5 M urea. This enzyme appears to be the major DFP-binding chromatin-bound protease in the chromatin of most rat tissues. The acid-soluble protease is converted from a 25000-dalton form to a 20000-dalton form during 0.25 N HC1 acid extraction from chromatin, which retains proteolytic activity.


Development of the mouse cochlea database (MCD).
The mouse cochlea database (MCD) provides an interactive, image database of the mouse cochlea for learning its anatomy and data mining of its resources. The MCD website is hosted on a centrally maintained, high-speed server at the following URL: (http://mousecochlea.umn.edu). The MCD contains two types of image resources, serial 2D image stacks and 3D reconstructions of cochlear structures. Complete image stacks of the cochlea from two different mouse strains were obtained using orthogonal plane fluorescence optical microscopy (OPFOS). 2D images of the cochlea are presented on the MCD website as: viewable images within a stack, 2D atlas of the cochlea, orthogonal sections, and direct volume renderings combined with isosurface reconstructions. In order to assess cochlear structures quantitatively, "true" cross-sections of the scala media along the length of the basilar membrane were generated by virtual resectioning of a cochlea orthogonal to a cochlear structure, such as the centroid of the basilar membrane or the scala media. 3D images are presented on the MCD website as: direct volume renderings, movies, interactive QuickTime VRs, flythrough, and isosurface 3D reconstructions of different cochlear structures. 3D computer models can also be used for solid model fabrication by rapid prototyping and models from different cochleas can be combined to produce an average 3D model. The MCD is the first comprehensive image resource on the mouse cochlea and is a new paradigm for understanding the anatomy of the cochlea, and establishing morphometric parameters of cochlear structures in normal and mutant mice.


Cytokine induction of MIP-1 alpha and MIP-1 beta in human fetal microglia.
Leukocyte infiltration into the central nervous system (CNS) is a key event in the inflammatory processes of neuroimmunologic diseases. Microglia, resident macrophages of the CNS, may contribute to this process by elaborating chemoattractants that are capable of recruiting leukocytes across the blood-brain barrier. Such factors have been detected in the CNS of animal models of multiple sclerosis and in the brains of human and nonhuman primates with AIDS encephalitis. As the expression of these chemoattractants may play an important role in the initiation and progression of neuroimmunologic diseases, we analyzed expression of the chemokines MIP-1 alpha, MIP-1 beta, MCP-1, and RANTES in human fetal microglial cultures. Unstimulated microglia expressed minimal levels of MIP-1 alpha, MIP-1 beta, and MCP-1, while RANTES was undetectable. In response to LPS, TNF-alpha, or IL-1 beta, both MIP-1 alpha and MIP-1 beta were induced at the mRNA and protein levels in a dose- and time-dependent manner. IFN-gamma did not significantly induce chemokine expression. MCP-1 was detectable in LPS- and cytokine-treated microglia. TGF-beta, a cytokine with down-modulatory effects on other cell types, had little effect on chemokine expression in microglia when used concomitantly before or during treatment with LPS. These results illustrate the ability of certain inflammatory stimuli to induce expression of MIP-1 alpha, MIP-1 beta, and MCP-1 by human fetal microglia. The expression of these chemoattractants may function to recruit inflammatory cells into the CNS during the course of neuroimmunologic diseases and may modulate the ability of HIV to infect the CNS.


[Analysis of mental health devices in the cities of the Paraíba Valley].
This study's purpose was to identify and to analyse the relation between population about the amount and modality of existing mental health devices. That was a a descriptive-exploratory study carried out in 27 municipalities of the Regional of Health XVII of São Paulo State. Of the participant municipalities, seven had some mental health device, totalling 12 in five different modalities: two Centers of Psychosocial Attention type I; two of type II; one day-hospital; 12 beds in a general hospital; four outpatient clinics and seven beds in emergency services. High number of residents in those municipalities is without mental care coverage.


Atelectasis and neuromuscular respiratory failure.
Atelectasis occurred in 17 of 20 patients treated with assisted ventilation for respiratory failure due to neuromuscular disease. A retrospective review of chest roentgenograms and medical records indicated that atelectasis occurs early in the course of respiratory failure and has a predilection for the lower lobes. Atelectasis was associated with infection and persisted despite therapy, often for more than four weeks. This study demonstrates that atelectasis in this condition still occurs frequently despite modern practices of mechanical ventilatory assistance. Infection, occurring soon after intubation, is identified as the principal cofactor.


Administration of acetylcholine and vasoactive intestinal polypeptide to atopic eczema patients.
Responses to acetylcholine (ACh) and vasoactive intestinal polypeptide (VIP) were investigated in atopic eczema (AE) patients. To elucidate the involvement of histamine to ACh-provoked vasoreactions and sensations, we applied a selective H1-antagonist (cetirizine) 3 h prior to the ACh-administration. Solutions of acetylcholine (ACh, 0.55 M) and vasoactive intestinal polypeptide (VIP, 1.5x 10(-5) M) were injected (10 microl) intracutaneously into the volar forearm of 14 healthy subjects and 14 atopic eczema (AE) patients. The substances were applied as single stimulus as well as in combination. Sensations evoked by the stimulation were recorded using 2 visual analog scales (VAS). Vasoreactions were analyzed with the new technique of computer assisted video image analysis. With this method we measured the dynamics of the flare development and the extension of the final flare size independent of the observer's assessment. In control subjects the development and extension of the final flare size was almost similar, regardless whether ACh and VIP were applied in combination or separately. Compared to healthy controls, after injection of ACh, VIP and the combination of VIP and ACh smaller flare sizes were recorded in AE patients. After VIP was given, the control subjects reported pruritus, which was significantly augmented compared to AE patients. In contrast, controls reported a burning pain after the injection of ACh, whereas AE patients felt predominantly pruritus. Itch sensation after the combined application of VIP and ACh was significantly elevated in AE patients. Consequently, we assume that mediators of sudomotor neurons, i.e., VIP and ACh meet in AE patients apparently sensitized nociceptive primary afferents and induce exaggerated itch, pain and flare responses. When pretreated with the selective H1-antagonist cetirizine before ACh was injected, pain and erythema due to ACh was diminished in healthy controls. In contrast, cetirizine did not influence the size of erythema and the magnitude of sensation in AE patients. We conclude, that the release of histamine is not involved in ACh-induced erythema and pruritus in AE. These data provide evidence that pruritus can be elicited in atopic eczema by a cholinergic, histamine independent mechanism.


Peripartum Primary Prophylaxis Inferior Vena Cava Filter Placement in a Patient with Stage IV B-Cell Lymphoma Presenting with a Pathologic Femur Fracture.
Background Pulmonary embolus (PE) remains a leading etiology of maternal mortality in the developed world. Increasing utilization of retrievable inferior vena cava (IVC) filter placement currently includes pregnant patients. Case A 22-year-old woman at 27 weeks' gestation was diagnosed with Stage IV high-grade malignant B cell lymphoma following pathologic femur fracture. Significant risk factors for PE led to placement of primary prophylaxis IVC filter before cesarean delivery, open reduction and internal fixation of the fractured femur, and chemotherapy. Conclusion This case supports that primary prophylaxis placement of IVC filters in highly selected pregnant patients may assist in decreasing PE-associated maternal mortality.


Increased glycosylphosphatidylinositol-anchored protein-deficient granulocytes define a benign subset of bone marrow failures in patients with trisomy 8.
Trisomy 8 (+8), one of the most common chromosomal abnormalities found in patients with myelodysplastic syndromes (MDS), is occasionally seen in patients with otherwise typical aplastic anemia (AA). Although some studies have indicated that the presence of +8 is associated with the immune pathophysiology of bone marrow (BM) failure, its pathophysiology may be heterogeneous. We studied 53 patients (22 with AA and 31 with low-risk MDS) with +8 for the presence of increased glycosylphosphatidylinositol-anchored protein-deficient (GPI-AP(-) ) cells, their response to immunosuppressive therapy (IST), and their prognosis. A significant increase in the percentage of GPI-AP(-) cells was found in 14 (26%) of the 53 patients. Of the 26 patients who received IST, including nine with increased GPI-AP(-) cells and 17 without increased GPI-AP(-) cells, 14 (88% with increased GPI-AP(-) cells and 41% without increased GPI-AP(-) cells) improved. The overall and event-free survival rates of the +8 patients with and without increased GPI-AP(-) cells at 5 yr were 100% and 100% and 59% and 57%, respectively. Examining the peripheral blood for the presence of increased GPI-AP(-) cells may thus be helpful for choosing the optimal treatment for +8 patients with AA or low-risk MDS.


Clonal hematopoiesis and bone marrow failure syndromes.
Bone marrow failure syndromes (BMF) are a group of conditions characterized by inefficient hematopoiesis frequently associated with extra-hematopoietic phenotypes and variable risk of progression to myeloid malignancies. They can be acquired or inherited and mediated by either cell extrinsic factors or cell intrinsic impairment of hematopoietic stem cell (HSC) function. The pathophysiology includes immune-mediated attack (e.g., acquired BMFs) or germline defects in DNA damage repair machinery, telomeres maintenance or ribosomes biogenesis. (e.g., inherited BMF). Clonal hematopoiesis (CH) that frequently accompanies BMF may provide a mechanism of improved HSC fitness through the evasion of extracellular pressure or somatic reversion of germline defects. The mechanism for the CH selective advantage differs depending on the condition in which it occurs. However, this adaptation mechanism, particularly when involving putative oncogenes or tumor suppressors, may lead to increased risk of myeloid malignancies. Surveillance and early detection of leukemogenic clones may lead to timely implementation of curative therapies and improved survival.


Lymphopenia predicts poor prognosis in patients with esophageal squamous cell carcinoma.
Lymphopenia is a useful predictive factor in several cancers. The aim of this study was to determine the prognostic value of lymphopenia in patients with esophageal squamous cell carcinoma (ESCC).A retrospective analysis of 307 consecutive patients who had undergone esophagectomy for ESCC was conducted. In our study, a lymphocyte count (LC) of fewer than 1.0 Giga/L was defined as lymphopenia. Kaplan-Meier method was used to calculate the cancer-specific survival (CSS). Cox regression analyses were performed to evaluate the prognostic factors. Receiver operating characteristic (ROC) curve was also plotted to verify the accuracy of LC for CSS prediction.The mean LC was 1.55 ± 0.64 Giga/L (range 0.4-3.7 Giga/L). The incidence of lymphopenia (LC < 1.0 Giga/L) was 16.6% (51/307). Patients with lymphopenia (LC < 1.0 Giga/L) had a significantly shorter 5-year CSS (21.6% vs 43.8%, P = 0.004). On multivariate analysis, lymphopenia (LC < 1.0 Giga/L) was an independent prognostic factor in patients with ESCC (P = 0.013). Lymphopenia had a hazard ratio (HR) of 1.579 [95% confidence interval (CI): 1.100-2.265] for CSS. ROC curve demonstrated that lymphopenia (LC < 1.0 Giga/L) predicts survival with a sensitivity of 86.2% and a specificity of 27.2%. Lymphopenia (LC < 1.0 Giga/L) is still an independent predictive factor for long-term survival in patients with ESCC.


Successful implementation of inquiry-based physiology laboratories in undergraduate major and nonmajor courses.
Recent evidence has demonstrated that inquiry-based physiology laboratories improve students' critical- and analytical-thinking skills. We implemented inquiry-based learning into three physiology courses: Comparative Vertebrate Physiology (majors), Human Physiology (majors), and Human Anatomy and Physiology (nonmajors). The aims of our curricular modifications were to improve the teaching of physiological concepts, teach students the scientific approach, and promote creative and critical thinking. We assessed our modifications using formative (laboratory exams, oral presentations, and laboratory reports) and summative evaluations (surveys, laboratory notebook, and an end of semester project). Students appreciated the freedom offered by the new curriculum and the opportunity to engage in the inquiry process. Results from both forms of evaluation showed a marked improvement due to the curricular revisions. Our analyses indicate an increased confidence in students' ability to formulate questions and hypotheses, design experiments, collect and analyze data, and make conclusions. Thus, we have successfully incorporated inquiry-based laboratories in both major and nonmajor courses.


Effect of nicotine (plant extract) on sex-ratio of Drosophila melanogaster (Meigen).
Experiments were conducted by using nicotine (plant extract) for its toxic effects on Drosophila melanogaster, LC50 estimated is 2.9552 microl/100 ml. Studies revealed that nicotine affects adult emergence of males and females (sex-ratio) of mutant form (Yellow) of Drosophila melanogaster.


An optical NMR spectrometer for Larmor-beat detection and high-resolution POWER NMR.
Optical nuclear magnetic resonance (ONMR) is a powerful probe of electronic properties in III-V semiconductors. Larmor-beat detection (LBD) is a sensitivity optimized, time-domain NMR version of optical detection based on the Hanle effect. Combining LBD ONMR with the line-narrowing method of POWER (perturbations observed with enhanced resolution) NMR further enables atomically detailed views of local electronic features in III-Vs. POWER NMR spectra display the distribution of resonance shifts or line splittings introduced by a perturbation, such as optical excitation or application of an electric field, that is synchronized with a NMR multiple-pulse time-suspension sequence. Meanwhile, ONMR provides the requisite sensitivity and spatial selectivity to isolate local signals within macroscopic samples. Optical NMR, LBD, and the POWER method each introduce unique demands on instrumentation. Here, we detail the design and implementation of our system, including cryogenic, optical, and radio-frequency components. The result is a flexible, low-cost system with important applications in semiconductor electronics and spin physics. We also demonstrate the performance of our systems with high-resolution ONMR spectra of an epitaxial AlGaAs/GaAs heterojunction. NMR linewidths down to 4.1 Hz full width at half maximum were obtained, a 10(3)-fold resolution enhancement relative any previous optically detected NMR experiment.


Clinical significance of cytogenetic findings in solid tumors.
Chromosome analysis of solid tumors is becoming an increasingly useful tool to help establish a correct diagnosis and to provide prognostically important information. Characteristic karyotypic patterns in terms of degree of cytogenetic complexity and type of nonrandom abnormalities may help to distinguish neoplasia from a nonneoplastic lesion and to differentiate between a benign and a malignant tumor. More importantly, the presence of a specific or pathognomonic change may confirm or refute a suspected diagnosis, provide an alternative, unsuspected diagnosis, and trace the origin of a metastasis. Presently, specific cytogenetic abnormalities may be of substantial, and sometimes decisive, help in four groups of differential diagnostic dilemmas: (1) Benign vs. malignant epithelial tumors of the kidney, thyroid gland, salivary glands, and ovary; (2) Benign vs. malignant mesenchymal tumors of adipose and muscle tissue; (3) Differentiation between various malignant bone and soft tissue tumors: and (4) Diagnosis of undifferentiated small-cell round-cell tumors. In addition to the diagnostic value, karyotypic findings may provide prognostic information. Thus, the presence of an abnormal clone and/or complex rearrangements is a poor prognostic sign in, e.g., carcinomas of the ovary, prostate, bladder, colon, and pancreas. Furthermore, characteristic cytogenetic aberrations are now known to be valuable prognostic parameters in malignant melanoma, malignant fibrous histiocytoma, germ cell tumors, neuroblastoma, and squamous cell carcinoma of the head and neck region. Many of the correlation analyses are preliminary, but they all point in the same direction, namely that cytogenetic studies will soon play the same essential role in the management of patients with solid tumors as they do today in hematologic oncology.


Relation between major and minor depression and heart rate, heart-rate variability, and clinical characteristics of patients with acute coronary syndrome.
This study examined the prevalence of major and minor depression in patients with acute coronary syndrome and their relation with heart rate and heart-rate variability, and clinical characteristics. The study group included 297 patients, 200 men and 97 women, between ages of 21 and 70 years (M age = 57.5 +/- 9.6), who were admitted to a coronary care unit with acute coronary syndrome and survived to discharge from the hospital. Major and minor depression were diagnosed using DSM-IV. There were 44.1% patients with acute coronary syndrome without depression, 29.3% with minor depression, and 26.6% with major depression. The prevalence of minor and major depression was more elevated in patients with non-ST-segment elevation myocardial infarction and unstable angina than in patients with ST-segment elevation myocardial infarction. Ventricular fibrillation and atrial fibrillation were more common in patients with major and minor depression than in patients without depression. The 24-hr. duration of heart-beat intervals and heart-rate variability were significantly lower in patients with major and minor depression than in patients without depression. This study implies that clinical depression was significantly comorbid with the acute coronary syndrome and was related to hypertension, diabetes mellitus, age, sex, type of acute coronary syndrome, left ventricular failure, higher heart rate, and lower heart-rate variability.


[Application of fallopian tube embolization before in vitro fertilization and embryo transfer dealing with the hydrosalpinx].
To explore the effectiveness of the fallopian tubes embolization for the hydrosalpinx before in vitro fertilization and embryo transfer (IVF-ET). The fallopian tubes embolization was performed on 46 hydrosalpinx patients. First, the hysterosalpingography was performed to show the positions and shape of the hydrosalpinx. Then the hydrops was drawn into the celiac cavity in order to be absorbed after performing fallopian tube recanalization. Finally, transvaginal therapy was performed, putting the embolization microcoils into the fallopian tube through a micro-catheter One month after the fallopian tubes embolization, hysterosalpingography was conducted to check for the effectiveness of the embolization. After 3 months, all the 46 patients received the treatment of IVF-ET. The interventional treatment of 82 fallopian tubes obtained one time success among 46 cases of fallopian tubes embolization. Among them, obvious results were achieved in 72 fallopian tubes, taking up 88% of the total; effective results were seen in 10 fallopian tubes, accounting for 12% of the total. No one was invalid. In the same period, compared with the 91 cases of non-hydrosalpinx as the control group, the embolization group of patients achieved a higher fertilization rate (69%), and clinical pregnancy rate (41%), compared with the control group (63% and 39% respectively), but without a significant difference ( P>0.05). However, the ectopic pregnancy rate (0) and the abortion rate (8%) were significantly lower than the control group (8%, 16% respectively; P<0.05). Fallopian tubes embolization used in hydrosalpinx treatment before IVF-ET is an innovative approach, simple, safe, economical, with no negative impact on ovarian function. It can significantly increase the clinical pregnancy rate and prevent the occurrence of tubal pregnancy. It is a feasible and effective method.


Safety of hyperbaric oxygen therapy in mechanically ventilated patients.
To evaluate the epidemiology of patients who require mechanical ventilation during hyperbaric oxygen therapy. One-hundred-fifty patients who required mechanical ventilation during hyperbaric oxygen therapy were prospectively studied during a 6-year period in a French university hyperbaric centre. We analysed the indication of hyperbaric oxygen therapy, agent used for sedation, presence of a chest tube, need for vasopressor agents and tolerance and appearance of side effects. Finally, we compared the outcomes of patients according to the presence or absence of acute respiratory distress syndrome (ARDS). Eleven children and 139 adult patients were included (n = 150) in the study. In both populations, carbon monoxide poisoning (51%) and iatrogenic gas embolism (33%) were the two main causes of intubation and mechanical ventilation. The combination of midazolam and sufentanil was used in 85 (67%) patients. All of the patients were given a bolus of a neuromuscular blocker during the hyperbaric session, despite the presence of ARDS in 35 patients. Patient-ventilator asynchrony was the most frequent side effect in 6 (5%) patients and was often the consequence of suboptimal sedation. Mortality was higher in the group with ARDS (23%). Carbon monoxide poisoning and iatrogenic gas embolism are the two main diseases of the patients who required mechanical ventilation during hyperbaric oxygen therapy in this study. Mechanical ventilation is a safe method for patients during hyperbaric oxygen therapy. Sedation needs to be perfected to avoid patient-ventilator asynchrony.


The association of serum choline with linear growth failure in young children from rural Malawi.
Choline is an essential nutrient for cell structure, cell signaling, neurotransmission, lipid transport, and bone formation. Choline can be irreversibly converted to betaine, a major source of methyl groups. Trimethylene N-oxide (TMAO), a proatherogenic molecule, is produced from the metabolism of dietary choline by the gut microbiome. The relation between serum choline and its closely related metabolites with linear growth in children is unknown. The aim was to characterize the relation between serum choline and its closely related metabolites, betaine and TMAO, with linear growth and stunting in young children. We measured serum choline, betaine, and TMAO concentrations by using liquid chromatography isotopic dilution tandem mass spectrometry in a cross-sectional study in 325 Malawian children, aged 12-59 mo, of whom 62% were stunted. Median (25th, 75th percentile) serum choline, betaine, and TMAO concentrations were 6.4 (4.8, 8.3), 12.4 (9.1, 16.3), and 1.2 (0.7, 1.8) μmol/L, respectively. Spearman correlation coefficients of age with serum choline, betaine, and TMAO were -0.57 (P < 0.0001), -0.26 (P < 0.0001), and -0.10 (P = 0.07), respectively. Correlation coefficients of height-for-age z score with serum choline, betaine-to-choline ratio, and TMAO-to-choline ratio were 0.31 (P < 0.0001), -0.24 (P < 0.0001), and -0.29 (P < 0.0001), respectively. Serum choline concentrations were strongly and significantly associated with stunting. Children with and without stunting had median (25th, 75th percentile) serum choline concentrations of 5.6 (4.4, 7.4) and 7.3 (5.9, 9.1) μmol/L (P < 0.0001). Linear growth failure in young children is associated with low serum choline and elevated betaine-to-choline and TMAO-to-choline ratios. Further work is needed to understand whether low dietary choline intake explains low circulating choline among stunted children living in low-income countries and whether increasing choline intake may correct choline deficiency and improve growth and development. This trial was registered in the ISRCTN registry (www.isrctn.com) as ISRCTN14597012.


One-dimensional supramolecular assemblies based on a Re2(III,III) synthon and their solid-state phosphorescence.
Reactions between Re2(DMBA)4(NO3)2 (1; DMBA is dimethylbenzamidinate) and a bidentate dianion, either tungstate (WO4(2-)) or terephthalte (1,4-(O2C)2C6H4(2-)), resulted in the one-dimensional coordination polymers [Re2(DMBA)4(mu-O,O'-WO4)](infinity) (2) and [Re2(DMBA)4(mu-O,O'-1,4-(O2C)2C6H4)](infinity) (3), respectively. Both polymers display phosphorescence from a 3(delta --> delta*) state, which is significantly blue shifted from the phosphorescence previously observed for Re2(DMBA)4Cl2 type compounds.


Sedentary Behavior, Physical Activity, Social Participation, and Loneliness Among Community-Dwelling Older Adults in China.
This study examined the relationship between loneliness, sedentary behavior, physical exercise, and social participation in Chinese older adults, and provided ideas to formulate preventive strategies that can help reduce loneliness. Data on demographics, health behavior, social participation, and loneliness were collected from a cross-sectional study of 629 older adults in Hefei, Anhui province, from June to August 2020. After adjusting for age, income, religion, marital status, and chronic illness demographic variables, sedentary behavior (β = 0.111, SE = 0.671, p = .001), physical exercise (β = -0.229, SE = 0.358, p < .001), and social participation (β = -0.329, SE = 0.086, p < .001) were found to be significantly correlated with loneliness in older adults. These findings suggest that a higher level of loneliness may be linked to greater sedentary behavior, less social engagement, and decreased physical exercise among older men and women.


Calcium Dynamics Regulate Protective Responses and Growth of Staphylococcus aureus in Macrophages.
Staphylococcus aureus (S. aureus) is a gram-positive bacteria, which causes various fatal respiratory infections including pneumonia. The emergence of Methicillin-Resistance Staphylococcus aureus (MRSA) demands a thorough understanding of host-pathogen interactions. Here we report the role of calcium in regulating defence responses of S. aureus in macrophages. Regulating calcium fluxes in cells by different routes differentially governs the expression of T cell costimulatory molecule CD80 and Th1 promoting IL-12 receptor. Inhibiting calcium influx from extracellular medium increased expression of IFN-γ and IL-10 while blocking calcium release from the intracellular stores inhibited TGF-β levels. Blocking voltage-gated calcium channels (VGCC) inhibited the expression of multiple cytokines. While VGCC regulated the expression of apoptosis protein Bax, extracellular calcium-regulated the expression of Cytochrome-C. Similarly, VGCC regulated the expression of autophagy initiator Beclin-1. Blocking VGCC or calcium release from intracellular stores promoted phagosome-lysosome fusion, while activating VGCC inhibited phagosomelysosome fusion. Finally, calcium homeostasis regulated intracellular growth of Staphylococcus, although using different mechanisms. While blocking extracellular calcium influx seems to rely on IFN-γ and IL-12Rβ receptor mediated reduction in bacterial survival, blocking either intracellular calcium release or via VGCC route seem to rely on enhanced autophagy mediated reduction of intracellular bacterial survival. These results point to fine-tuning of defence responses by routes of calcium homeostasis.


Validation of the Spanish Short Self-Regulation Questionnaire (SSSRQ) through Rasch Analysis.
Background: The aim of the study was to psychometrically characterize the Spanish Short Self-Regulation Questionnaire (SSSRQ) through Rasch analysis. Materials and Methods: 831 Spaniard university students (262 men), between 17 and 39 years of age and ranging from the first to the 5th year of studies, completed the SSSRQ questionnaire. Confirmatory factor analysis (CFA) was carried out in order to establish structural adequacy. Afterward, by means of the Rasch model, a study of each sub scale was conducted to test for dimensionality, fit of the sample questions, functionality of the response categories, reliability and estimation of Differential Item Functioning by gender and course. Results: The four sub-scales comply with the unidimensionality criteria, the questions are in line with the model, the response categories operate properly and the reliability of the sample is acceptable. Nonetheless, the test could benefit from the inclusion of additional items of both high and low difficulty in order to increase construct validity, discrimination and reliability for the respondents. Several items with differences in gender and course were also identified. Discussion: The results evidence the need and adequacy of this complementary psychometric analysis strategy, in relation to the CFA to enhance the instrument.


The intriguing case of organic impurities contained in synthetic methanol: a mass spectrometry based investigation.
The role of organic impurities in the methanol-to-olefin (MTO) industrial process catalyzed by zeolites is the subject of ongoing debate. We have found that methanol (HPLC and RPE grade) purchased from different chemical companies may contain organic impurities, whose ionization is the dominant process in the positive ion atmospheric pressure chemical ionization (APCI) spectrum of commercial CH(3)OH. Such impurities produce ions with elemental formulae C(n)H(2n+1)O(+) (n = 4, 5, 6); likewise, ionization of tetradeuterated methanol (CD(3)OD) leads to the corresponding fully deuterated series C(n)D(2n+1)O(+) (n = 4, 5, 6), an outcome which represents a clear evidence of their widespread diffusion. We suggest that their formation might be inherent to the chemical process whereby methanol is synthesized on an industrial scale. Mass spectrometry (MS) experiments, gas chromatography/mass spectrometry (GC/MS) analysis and nuclear magnetic resonance (NMR) measurements allowed us to establish that commercial methanol contains dimethyl acetals of simple alkyl ketones, such as propanone, butanone and pentanone. Ab initio calculations (DFT/B3LYP) proved useful to understanding the ionization mechanisms of such impurities.


Redifferentiation of aged human articular chondrocytes by combining bone morphogenetic protein-2 and melanoma inhibitory activity protein in 3D-culture.
Melanoma inhibitory activity (MIA) affects the differentiation to hyaline cartilage and can inhibit the osteogenic potential of bone morphogenetic protein (BMP)-2 in mesenchymal stem cells (MSC). The aim of this study was to investigate if MIA also inhibits the osteogenic potential of BMP-2 in human articular chondrocytes during redifferentiation, which may lead to a higher grade of differentiation without calcification. HAC of four female patients (mean age: 73.75 ±6.98) were seeded into 3D culture for 28 days; after adding the recombinant proteins, four groups were formed (Control, BMP-2, MIA, BMP-2+MIA). Samples were analysed for gene expression, glycosaminoglycan (GAG) content and histology on day 0, 14 and 28. Collagen type 2 (COL2A1) was significantly increased in the BMP-2 containing groups on day 28; BMP-2 (100-fold, p = 0.001), BMP-2+MIA (65-fold, p = 0.009) and similar to the level of native cartilage. Higher aggrecan (Agg) levels were present in the BMP-2 (3-fold, p = 0.007) and BMP-2+MIA (4-fold, p = 0.002) group after 14 days and in the BMP-2 (9-fold, p = 0.001) group after 28 days. Collagen type 10 (COL10A1) was increased in the BMP-2 containing groups (6-fold, p = 0.006) but these levels were significantly below native cartilage. Alkaline phosphatase (ALP), collagen type 1 (COL1A1) and the glycosaminoglycan (GAG) content did not reveal any relevant differences between groups. BMP-2 is a potent inducer for differentiation of HAC. A significant enhancement of this effect in combination with MIA could not be observed. Furthermore no significant reduction of osteogenic markers during re-differentiation of chondrocytes was present combining BMP-2 and MIA.


EMR4, a novel epidermal growth factor (EGF)-TM7 molecule up-regulated in activated mouse macrophages, binds to a putative cellular ligand on B lymphoma cell line A20.
A novel member of the EGF-TM7 family, mEMR4, was identified and characterized. The full-length mouse EMR4 cDNA encodes a predicted 689-amino acid protein containing two epidermal growth factor (EGF)-like modules, a mucin-like spacer domain, and a seven-transmembrane domain with a cytoplasmic tail. Genetic mapping established that mEMR4 is localized in the distal region of mouse chromosome 17 in close proximity to another EGF-TM7 gene, F4/80 (Emr1). Similar to F4/80, mEMR4 is predominantly expressed on resident macrophages. However, a much lower expression level was also detected in thioglycollate-elicited peritoneal neutrophils and bone marrow-derived dendritic cells. The expression of mEMR4 is up-regulated following macrophage activation in Biogel and thioglycollate-elicited peritoneal macrophages. Similarly, mEMR4 is over-expressed in TNF-alpha-treated resident peritoneal macrophages, whereas interleukin-4 and -10 dramatically reduce the expression. mEMR4 was found to undergo proteolytic processing within the extracellular stalk region resulting in two protein subunits associated noncovalently as a heterodimer. The proteolytic cleavage site was identified by N-terminal amino acid sequencing and located at the conserved GPCR (G protein-coupled receptor) proteolytic site in the extracellular region. Using multivalent biotinylated mEMR4-mFc fusion proteins as a probe, a putative cell surface ligand was identified on a B lymphoma cell line, A20, in a cell-binding assay. The mEMR4-ligand interaction is Ca2+-independent and is mediated predominantly by the second EGF-like module. mEMR4 is the first EGF-TM7 receptor known to mediate the cellular interaction between myeloid cells and B cells.


Chemoprevention of colorectal tumors: role of lactulose and of other agents.
Chemoprevention can be defined as an attempt at cancer control in which the occurrence of the disease is prevented by the administration of one (or more) chemical compounds. Main problems in chemoprevention studies are the choice of a suitable drug, the choice of an appropriate intermediate or definitive end point, and the definition of the population which should be investigated. Main classes of chemopreventive agents include vitamins, non-steroid antinflammatory drugs, minerals such as calcium or selenium, and other antioxidants such as N-acetylcysteine. Chemoprevention is particularly appealing in colorectal cancer, either because these lesions develop through a multistep process, or owing to the concept of "field carcinogenesis'. Between 1985 and 1990 we carried out a controlled study in which antioxidant vitamins or lactulose were used in an attempt to prevent the recurrence of colorectal polyps after their endoscopic removal. Among the 209 patients who could be evaluated, polyps recurred in 5.7% of the individuals who were given vitamins (A, C and E), 14.7% of patients given lactulose and 35.9% of untreated controls (chi 2 = 17.1, P < 0.001). The study suggested that either antioxidant vitamins or lactulose could be effective in reducing the recurrence rate of adenomatous polyps. In a subsequent on-going study, lower doses of the same vitamins were tested versus N-acetylcysteine (600 mg/day) or no treatment. Preliminary results showed a 40% reduction of the recurrence of polyps (versus controls) in individuals given N-acetylcysteine, while the effect of lower doses of vitamins was less appreciable. Definitive results of the study should be available by the end of 1998.


Contralateral Ovarian Metastasis of Clear-Cell Renal Carcinoma: A Rare Case Report and Review of the Literature.
Renal cell carcinoma (RCC) constitutes 2-3% of all types of cancers. RCCs metastasize into lungs (50-60%), lymph nodes (36%), bones (30-40%), liver (30-40%), and brain (5%) in respective percentages. RCC rarely metastasizes into ovary. Only 25 cases of ovarian tumor, which metastasized into kidneys, have been presented. In the literature, a kidney-ovary axis has been defined, and its interrelationship begins with embryological life. With this case report, we aimed both to present a very rarely seen metastasis of RCC into contralateral ovary and also to review the literature.


Degradation of Cep68 and PCNT cleavage mediate Cep215 removal from the PCM to allow centriole separation, disengagement and licensing.
An intercentrosomal linker keeps a cell's two centrosomes joined together until it is dissolved at the onset of mitosis. A second connection keeps daughter centrioles engaged to their mothers until they lose their orthogonal arrangement at the end of mitosis. Centriole disengagement is required to license centrioles for duplication. We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(βTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by βTrCP. We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. Cep68 and PCNT bind to different pools of Cep215. We propose that Cep68 degradation allows Cep215 removal from the peripheral PCM preventing centriole separation following disengagement, whereas PCNT cleavage mediates Cep215 removal from the core of the PCM to inhibit centriole disengagement and duplication.


MTA1, a Novel ATP Synthase Complex Modulator, Enhances Colon Cancer Liver Metastasis by Driving Mitochondrial Metabolism Reprogramming.
Liver metastasis is the most fatal event of colon cancer patients. Warburg effect has been long challenged by the fact of upregulated oxidative phosphorylation (OXPHOS), while its mechanism remains unclear. Here, metastasis-associated antigen 1 (MTA1) is identified as a newly identified adenosine triphosphate (ATP) synthase modulator by interacting with ATP synthase F1 subunit alpha (ATP5A), facilitates colon cancer liver metastasis by driving mitochondrial bioenergetic metabolism reprogramming, enhancing OXPHOS; therefore, modulating ATP synthase activity and downstream mTOR pathways. High-throughput screening of an anticancer drug shows MTA1 knockout increases the sensitivity of colon cancer to mitochondrial bioenergetic metabolism-targeted drugs and mTOR inhibitors. Inhibiting ATP5A enhances the sensitivity of liver-metastasized colon cancer to sirolimus in an MTA1-dependent manner. The therapeutic effects are verified in xenograft models and clinical cases. This research identifies a new modulator of mitochondrial bioenergetic reprogramming in cancer metastasis and reveals a new mechanism on upregulating mitochondrial OXPHOS as the reversal of Warburg effect in cancer metastasis is orchestrated.


[Dynamic skin suture for closure of the incision defect after compartment incision].
Dynamic skin suture consists of a technique that diminishes local pressure on skin and permits progressive tightening of the sutures for stepwise incisional closure. A clinical series of 28 repairs after release of compartment syndromes shows complete closure in 22 incisions, the other 6 defects could be reduced in size. Technique, results and biological basics are discussed.


Polyvinylpyrrolidone-Intercalated Mn0.07 VOx toward High Rate and Long-Life Aqueous Zinc-Ion Batteries.
Aqueous zinc-ion batteries (AZIBs) are expected to be an attractive alternative in advanced energy storage devices due to large abundance and dependable security. Nevertheless, the undesirable energy density and operating voltage still hinder the development of AZIBs, which is intimately associated with the fundamental properties of the cathode. In this work, polyvinylpyrrolidone (PVP) intercalated Mn0.07 VOx (PVP-MnVO) with a large interlayer spacing of 13.5 Å (against 12.5 Å for MnVO) synthesized by a facile hydrothermal method is adopted for the cathode in AZIBs. The experimental results demonstrate that PVP-MnVO with expanded interlayer spacing provides beneficial channels for the rapid diffusion of Zn2+ , resulting in a high discharge capacity of 402 mAh g-1 at 0.1 A g-1 , superior to that of MnVO (275 mAh g-1 at 0.1 A g-1 ). Meanwhile, the PVP molecule remains in the layer structure as a binder/pillar, which can maintain its structural integrity well during the charging/discharging process. Consequently, PVP-MnVO cathode exhibits superior rate capability and cycling stability (89% retention after 4300 cycles at 10 A g-1 ) compared to that of MnVO (≈51% retention over 500 cycles at 2 A g-1 ). This work proposes a new approach to optimize the performance of vanadium-based electrode materials in AZIBs.


Internet Technology in Magnetic Resonance: A Common Gateway Interface Program for the World-Wide Web NMR Spectrometer
A custom-written Common Gateway Interface (CGI) program for remote control of an NMR spectrometer using a World Wide Web browser has been described. The program, running on a UNIX workstation, uses multiple processes to handle concurrent tasks of interacting with the user and with the spectrometer. The program's parent process communicates with the browser and sends out commands to the spectrometer; the child process is mainly responsible for data acquisition. Communication between the processes is via the shared memory mechanism. The WWW pages that have been developed for the system make use of the frames feature of web browsers. The CGI program provides an intuitive user interface to the NMR spectrometer, making, in effect, a complex system an easy-to-use Web appliance. Copyright 1998 Academic Press.


Optimizing drug delivery in COPD: The role of inhaler devices.
Inhaled medication is the cornerstone of the pharmacological treatment for patients with asthma and chronic obstructive pulmonary disease (COPD). Several inhaler devices exist, and each device has specific characteristics to achieve the optimal inhalation of drugs. The correct use of inhaler devices is not granted and patients may incur in mistakes when using pressurized metered-dose inhalers (pMDIs) or dry-powder inhaler (DPIs). The incorrect use of inhaler devices can lead to a poorly controlled disease status. Unfortunately, guidelines provide limited guidance regarding the choice of devices. This article presents a review of the literature on different inhaler device requirements. Data from literature (PubMed and Google Scholar) on the commercially available inhaler devices have been evaluated and the history of inhaler medicine described. Furthermore, advantages and disadvantages of each type of device have been analyzed. The evaluation of literature indicated the availability of robust data on the devices characteristics and factors influencing selection of delivery devices. Each type of device has its own pro and cons. The age, cognitive status, visual acuity, manual dexterity, manual strength and ability to coordinate the inhaler actuation with inhalation may be as important as the disease severity in determining the correct approach to delivery of respiratory medication. The administration of effective therapies via a device that is simple to use and accepted by patients may help to improve treatment outcomes in patients with COPD.


Comparison between ultrasound-guided pericapsular nerve group block and anterio quadratus lumborum block for total hip arthroplasty: a double-blind, randomized controlled trial.
Peripheral nerve block can provide effective postoperative analgesia to patients undergoing total hip arthroplasty (THA). This study aimed to compare ultrasound-guided pericapsular nerve group (PENG) block against anterior quadratus lumborum (AQL) block for pain management in primary THA. In this prospective, double-blind, randomized controlled trial, 90 patients undergoing primary THA under general anesthesia were randomly allocated to receive ultrasound-guided PENG block + sham AQL block ("PENG group") or ultrasound-guided AQL block + sham PENG block ("AQL" group). The primary outcome was the highest pain score on a visual analogue scale while the patient was in the recovery room. Secondary outcomes included pain scores after transfer out of the recovery room, morphine consumption, quadricep strength, duration of hospitalization, pain level one year after surgery, and incidence of complications. Patients in the PENG group reported significantly lower maximum pain scores in the recovery room (31.3±9.1 vs. 37.3±7.4, p=0.001), as well as significantly lower pain scores at rest at 3 h after surgery and during motion at 3 and 6 h after surgery. The two groups did not differ significantly in postoperative morphine consumption, length of hospitalization, pain level at one year after surgery, or incidence of complications. Neither block significantly weakened the quadriceps. PENG block may provide slightly more effective postoperative analgesia than AQL block during the early recovery period after primary THA.


Mental health knowledge and classroom experiences of school teachers in Aragon, Spain.
Research shows that many mental disorders begin in childhood but are sometimes not diagnosed until later years. School-age children spend much of their time in schools and have daily interactions with school teachers. Examine school teachers' experiences of mental disorders in school going children and adolescents and their associated mental health training needs. A descriptive cross-sectional study was carried out with teachers in Infant-Primary and Secondary Education-Baccalaureate schools. A convenience sample of 685 teachers responded to the online survey. Participants worked in both urban and rural areas and in Infant-Primary and Secondary Education-Baccalaureate schools. Over half of participants reported classroom experiences of learner mental disorders such as ADHD, anxiety, conduct disorders or autism. Most participants acknowledged a training need, both in recognition of symptoms of mental disorders and in care resources and processes. However, 80% of respondents reported having not received any training in this regard. Participant preferences for training included face-to-face or hybrid - combined online learning. Participants also considered the management of their own mental health to be deficient, therefore any training should incorporate personal mental health awareness and self-help strategies. In Aragón (Spain), teachers of children and adolescents with mental disorders, recognize a need for training in the identification of symptoms and other aspects of mental healthcare, such as availability and access to services. Protocols for early identification and referral would promote mentally healthy school environments and reduce stigma which could be a barrier to timely intervention. In addition, any training should include mental health self-care for teachers.


A pilot study of cerebral metabolism and serotonin 5-HT2A receptor occupancy in rats treated with the psychedelic tryptamine DMT in conjunction with the MAO inhibitor harmine.
Rationale: The psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are often attributed to agonism at brain serotonin 5-HT2A receptors by N,N-dimethyltryptamine (DMT). To reduce first pass metabolism of oral DMT, ayahuasca preparations additionally contain reversible monoamine oxidase A (MAO-A) inhibitors, namely β-carboline alkaloids such as harmine. However, there is lacking biochemical evidence to substantiate this pharmacokinetic potentiation of DMT in brain via systemic MAO-A inhibition. Objectives: We measured the pharmacokinetic profile of harmine and/or DMT in rat brain, and tested for pharmacodynamic effects on brain glucose metabolism and DMT occupancy at brain serotonin 5-HT2A receptors. Methods: We first measured brain concentrations of harmine and DMT after treatment with harmine and/or DMT at low sub-cutaneous doses (1 mg/kg each) or harmine plus DMT at moderate doses (3 mg/kg each). In the same groups of rats, we also measured ex vivo the effects of these treatments on the availability of serotonin 5-HT2A receptors in frontal cortex. Finally, we explored effects of DMT and/or harmine (1 mg/kg each) on brain glucose metabolism with [18F]FDG-PET. Results: Results confirmed that co-administration of harmine inhibited the formation of the DMT metabolite indole-3-acetic acid (3-IAA) in brain, while correspondingly increasing the cerebral availability of DMT. However, we were unable to detect any significant occupancy by DMT at 5-HT2A receptors measured ex vivo, despite brain DMT concentrations as high as 11.3 µM. We did not observe significant effects of low dose DMT and/or harmine on cerebral [18F]FDG-PET uptake. Conclusion: These preliminary results call for further experiments to establish the dose-dependent effects of harmine/DMT on serotonin receptor occupancy and cerebral metabolism.


Agreement of offspring-reported parental smoking status: the RHINESSA generation study.
With increasing interest in exposure effects across generations, it is crucial to assess the validity of information given on behalf of others. To compare adult's report of their parent's smoking status against parent's own report and examine predictors for discrepant answers. We studied 7185 offspring (18-51 years) and one of their parents, n = 5307 (27-67 years) participating in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study. Information about parent's smoking status during offspring's childhood and mother's smoking status during pregnancy was obtained by questionnaires from parents and their offspring. We calculated sensitivity, specificity and Cohen's Kappa [κ] for agreement using parent's own report as the gold standard. We performed logistic regression to examine if offspring's sex, age, educational level, asthma status, own smoking status or parental status, as well as the parent's sex and amount of smoking during childhood predicted disagreement. The sensitivity for offspring's correct report of parent's smoking status during childhood (0-10 years) was 0.82 (95% CI 0.81-0.84), specificity was 0.95 (95% CI 0.95-0.96) and a good agreement was observed, κ = 0.79 (95% CI 0.78-0.80). Offspring's report of mothers' smoking status during pregnancy showed a lower sensitivity, 0.66 (95% CI 0.60-0.71), a slightly lower specificity, 0.92 (95% CI 0.90-0.95) and a good agreement, κ = 0.61 (95% CI 0.55-0.67). In multivariate logistic regression analysis, offspring not having children was a predictor for discrepant answers (odds ratio [OR] 2.11 [95% CI 1.21-3.69]). Low amount of parents' tobacco consumption, < 10 cigarettes/day (OR 2.72 [95% CI 1.71-4.31]) also predicted disagreement compared to ≥10 cigarettes per day, and so did offspring's reports of fathers' smoking status (OR 1.73 [95% CI 1.09-2.74]) compared to mothers' smoking status. Offspring's sex, asthma status, educational level, smoking status or age was not related to discrepant answers. Adults report their parent's smoking status during their childhood, as well as their mother' smoking status when pregnant with them, quite accurately. In the absence of parents' direct report, offspring's reports could be valuable.


N,N-Dimethylformamide inhibits high glucose-induced osteoporosis via attenuating MAPK and NF-κB signalling.
The role of N,N-dimethylformamide (DMF) in diabetes-induced osteoporosis (DM-OS) progression remains unclear. Here, we aimed to explore the effect of DMF on DM-OS development. Diabetic models of mice, RAW 264.7 cells, and bone marrow macrophages (BMMs) were established by streptozotocin stimulation, high glucose treatment, and receptor activator of nuclear factor-κB ligand (RANKL) treatment, respectively. The effects of DMF on DM-OS development in these models were examined by micro-CT analysis, haematoxylin and eosin (H&E) staining, osteoclast differentiation of RAW 264.7 cells and BMMs, H&E and tartrate-resistant acid phosphatase (TRAP) staining, enzyme-linked immunosorbent assay (ELISA) of TRAP5b and c-terminal telopeptides of type 1 (CTX1) analyses, reactive oxygen species (ROS) analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), Cell Counting Kit-8 (CCK-8) assay, and Western blot. The established diabetic mice were more sensitive to ovariectomy (OVX)-induced osteoporosis, and DMF treatment inhibited the sensitivity. OVX-treated diabetic mice exhibited higher TRAP5b and c-terminal telopeptides of type 1 (CTX1) levels, and DMF treatment inhibited the enhancement. DMF reduced RAW 264.7 cell viability. Glucose treatment enhanced the levels of TRAP5b, cathepsin K, Atp6v0d2, and H+-ATPase, ROS, while DMF reversed this phenotype. The glucose-increased protein levels were inhibited by DMF in cells treated with RANKL. The expression levels of antioxidant enzymes Gclc, Gclm, Ho-1, and Nqo1 were upregulated by DMF. DMF attenuated high glucose-caused osteoclast differentiation by targeting mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signalling in BMMs. DMF inhibits high glucose-induced osteoporosis by targeting MAPK and NF-κB signalling. Cite this article: Bone Joint Res 2022;11(4):200-209.


[The efficacy and safety of daratumumab in relapsed and refractory multiple myeloma].
Objective: To investigate the efficacy and safety of daratumumab in relapsed and refractory multiple myeloma (RRMM). Methods: The efficacy and adverse events (AEs) of daratumumab based regimens were retrospectively analyzed in 37 patients with RRMM from Peking University People's Hospital, Beijing Hospital and Fu Xing Hospital affiliated to Capital Medical University in China. The deadline for inclusion was December, 2019. Results: Among the 37 patients, 35 patients were available for response evaluation. The overall response rate (ORR) was 68.6%, which was better in patients receiving 16 mg/kg daratumumab than in those with fixed doses of 800 mg daratumumab [ORR: 78.3%(18/23) vs. 40.0%(4/10)]. The percentage of infusion related reactions of daratumumab was 27.0%(10/37). The most common hematological AEs were lymphocytopenia and thrombocytopenia, with the incidences of grade 3 or more severe 59.5%(22/37) and 43.2%(16/37) respectively. Pulmonary infections(37.8%, 14/37) were the most common non-hematological AEs. One patient with positive hepatitis B surface antigen (HBsAg) and two patients dependent on dialysis were safely treated with daratumumab. Conclusion: Daratumumab is highly effective in relapsed and refractory multiple myeloma. Adverse reactions are mild and well tolerable.


Modulating human procedural learning by cerebellar transcranial direct current stimulation.
Neuroimaging studies suggest that the cerebellum contributes to human cognitive processing, particularly procedural learning. This type of learning is often described as implicit learning and involves automatic, associative, and unintentional learning processes. Our aim was to investigate whether cerebellar transcranial direct current stimulation (tDCS) influences procedural learning as measured by the serial reaction time task (SRTT), in which subjects make speeded key press responses to visual cues. A preliminary modeling study demonstrated that our electrode montage (active electrode over the cerebellum with an extra-cephalic reference) generated the maximum electric field amplitude in the cerebellum. We enrolled 21 healthy subjects (aged 20-49 years). Participants did the SRTT, a visual analogue scale and a visual attention task, before and 35 min after receiving 20-min anodal and sham cerebellar tDCS in a randomized order. To avoid carry-over effects, experimental sessions were held at least 1 week apart. For our primary outcome measure (difference in RTs for random and repeated blocks) anodal versus sham tDCS, RTs were significantly slower for sham tDCS than for anodal cerebellar tDCS (p = 0.04), demonstrating that anodal tDCS influenced implicit learning processes. When we assessed RTs for procedural learning across the one to eight blocks, we found that RTs changed significantly after anodal stimulation (interaction "time" × "blocks 1/8": anodal, p = 0.006), but after sham tDCS, they remained unchanged (p = 0.094). No significant changes were found in the other variables assessed. Our finding that anodal cerebellar tDCS improves an implicit learning type essential to the development of several motor skills or cognitive activity suggests that the cerebellum has a critical role in procedural learning. tDCS could be a new tool for improving procedural learning in daily life in healthy subjects and for correcting abnormal learning in neuropsychiatric disorders.


Greenhouse gas emission in the whole process of forest fire including rescue: a case of forest fire in Beibei District of Chongqing.
In the context of global high temperature, the harm of greenhouse gases (GHG) emissions caused by frequent forest fires to the environment cannot be ignored. Existing research only calculates the GHG generated by the burning of forest vegetation, ignoring the GHG generated by the fire-driven social rescue activities. Taking the forest fire in Beibei District, Chongqing City, China, as an example, this paper studies and establishes the GHG emission accounting method for the whole process of forest fire from ignition to fire extinguishing through three processes: vegetation burning, rescue transportation, and on-site fire extinguishing. It covers three GHG calculation types: biomass burning, traffic activity level comprehensive energy consumption, and machine energy consumption. Among them, the CO2 produced by the burning of coniferous forest, the support transportation of rescue teams in Yunnan province, and the motorcycle transportation at the fire extinguishing site accounted for a relatively high proportion in the corresponding processes, reaching 12,761.445 t, 118.750 t, and 1056.980 t, respectively. Finally, through data analysis, suggestions on GHG emission reduction related to forest tree regulation and optimization of rescue and fire extinguishing management are put forward, which provides a direction for future research on carbon reduction in the whole process of forest fire events.


Becoming lesbian: Monique Wittig's queer-trans-feminism.
Inspired by Lynne Huffer's queer feminist genealogy, this article explores queer-trans-feminism as a project that would bring together queer, feminist, and transgender theory and politics into a shared critical lineage. I suggest that Monique Wittig is a neglected thinker who could re-enliven connections and debates within queer, feminist, and trans theory and politics. Utilizing recent historiographies of queer and feminist theory, I imagine what it would mean to hold on to the figure of the lesbian as a figure for queer-trans-feminist politics rather than render the lesbian anachronistic. I then explore the implications of Wittig's notion that "lesbians are not women" for a queer-trans-feminism. I argue that Wittig's critique of the language of the social sciences offers queer-trans-feminist scholars a source for contemporary self-critique and coalition.


Comparison of radiation-induced hydrocarbons for the identification of irradiated perilla and sesame seeds of different origins.
Perilla and sesame seeds, a rich source of energy, are commonly utilized in different forms in many countries. During the post-harvest period, they are contaminated with insects as well as microbes that may have importance for keeping quality and quarantine, and thus they can be treated with ionizing radiation for insect disinfestation and microbial decontamination. Reliable and routine methods to identify whether or not a food has been irradiated are needed to help consumers' understanding of irradiated food and promote international trade. In the present study, fat-derived hydrocarbons from irradiated perilla seeds and sesame seeds of Korean and Chinese origin were analyzed in order to identify irradiation treatment by comparing their properties during the post-irradiation period. Gas chromatographic-mass spectrometric analysis showed that several saturated hydrocarbons, such as tetradecane, pentadecane, hexadecane and heptadecane, were found in the non-irradiated control samples, while four radiation-induced unsaturated hydrocarbons (R(2) = 0.647-0.997), such as 1,7,10-hexadecatriene (C(16:3)), 1,7-hexadecadiene (C(16:2)), 6,9-heptadecadiene (C(17:2)) and 8-heptadecene (C(17:1)), were detected in all irradiated samples at 0.5 kGy or higher, with variations according to sample and origin. Concentrations of all hydrocarbons were reduced during storage and could not be detected in 0.5 kGy irradiated Chinese sample of either seed after 8 months. Radiation-induced hydrocarbons (C(16:3, 16:2, 17:2, 17:1)) could be used as markers to identify irradiated perilla and sesame seeds of both Korean and Chinese origin at 1 kGy or higher for 8 months' storage at room temperature.


The influence of cytomegalovirus on the natural history of HIV infection: evidence of rapid course of HIV infection in HIV-positive patients infected with cytomegalovirus.
We studied a cohort of 299 HIV-positive individuals with known date of seroconversion to evaluate the role of Cytomegalovirus (CMV) in the natural history of HIV. The study population consisted of 236 initially CMV-positive patients, 55 CMV-negative subjects and 8 CMV seroconverters. The study endpoints were the decline to CD4+ < 200 x 10(6) cells/l, AIDS, and death. The cumulative risk of CMV disease and the survival after CMV disease were also investigated. At intake, there was no inter-group difference in sex, age, risk behaviours, history of hairy leucoplakia or herpes zoster and antiretroviral treatment. During the follow-up, 108 patients fell below 200 CD4+ x 10(6) cells/l, 72 developed AIDS and 63 died. Twenty-one subjects had CMV disease. The cumulative incidence of CMV disease in the cohort was 18.9%, and 23.3% within 8 and 9 years for the initially CMV-positive patients and 33.3% and 66.7% for the CMV seroconverters (log-rank test: p = 0.101). The median survival after CMV disease was 153 days (range: 28-855, interquartile range: 261), with a cumulative survival of 45.1%, 16.9% and 4.3% within 6, 12 and 18 months, respectively. On Cox's regression, the acute HIV seroconversion was an independent predictor of each endpoint, history of hairy leucoplakia or herpes zoster being associated only with CD4+ cell decline. Baseline CMV seropositivity was related to short survival (p = 0.037) and 2 x 2 inter-group comparison showed that older individuals with sexually acquired HIV who seroconverted to CMV had higher rates of progression to the study endpoints. Our data suggest that CMV infection influences the natural history of HIV disease and that CMV disease strongly affects the survival of the HIV-positive patients.


Military environmental health on Operation RUMAN.
Operation RUMAN was the British government's combined military and humanitarian operations to provide relief to the British Overseas Territories in the Caribbean. This paper provides a short summary of the role played by environmental health during the operation and the importance of environmental health considerations at all stages of disaster management.


From independence to interdependence. Creating synergistic healthcare teams.
As the structure of healthcare institutions changes, nurse administrators frequently are being called on to lead interdisciplinary programs. To be successful in this new health paradigm, teams must strive to create total stakeholder satisfaction by adopting a mindset that work is interdependent, not independent, and then striving to work synergistically. The author presents 12 themes that emerged from a study investigating the essential elements of synergistic team relationships.


Effect of mechanical weeding on wild chamomile (Matricaria chamomilla L.) populations in winter wheat crop (Triticum aestivum L.).
Currently, economic, agronomic and environmental concerns lead to reduce the use of herbicides. Mechanical weeding can help to reach this objective. Dynamics and biology of wild chamomile (Matricaria chamomilla L.) populations were assessed as well as dynamic of winter wheat (Triticum aestivum L.) for four level of application of a weeder-harrow (0, 1, 2, 3 treatment(s)). After each treatment, an effect of mechanical weeding on wild chamomile density was observed. Density of wild chamomile decreased significantly with intensification of mechanical weeding. A third treatment allowed eliminating late emerged plants.


Comparing clinician use of three ankle fracture classifications.
This study evaluated the accuracy and interrater reliability of US Army physician assistants (PAs) in identifying ankle fracture patterns using existing classification schemes. Twenty-eight PAs reviewed criteria for stability, Danis-Weber, and Lauge-Hansen ankle fracture classification systems. Participants reviewed 45 ankle radiographs and independently rated each radiograph using these classification schemes. Participants were able to successfully identify ankle fracture stability in 82.1% of cases (95% CI, 77.6, 86.6) with established criteria. Using the Danis-Weber classification, accurate classification was achieved in 77.8% of cases (95% CI, 72.8, 82.7). The Lauge-Hansen classification system was least reliable, with accuracy of 54.5% (95% CI, 46, 63). Referring PAs can reliably discern unstable ankle fractures in more than 80% of cases. Lauge-Hansen classification was significantly less accurate than the Danis-Weber system or criteria for stability. Good communication between orthopedic surgeons and PAs and an emphasis on PA orthopedic education can improve patient care.


The visual perception of accelerated motion.
The present research is an investigation of how changes in the rate of motion are percieved. Five separate experiments were performed with the use of filmed stimulus material and a variety of response measures, including both categorical judgments and reporduction techniques. It was found that (a) the smaller the ratio of terminal to initial velocity, the less frequent the judgments of acceleration or deceleration, (b) deceleration was significantly easier to perceive than acceleration, (c) the perception of acceleration was facilitated when the velocity of a lead-in segment was the same as the velocity at onset of motion, (d) a short tunnel centered in the motion path facilitated the perception of acceleration and deceleration, and (e) instantaneous changes in velocity were much more easily perceived than gradual changes. A one-event model for the perception of motion change in which there is a continuous interplay between earlier, later, and interpolated motion segments is favored over a two-event model in which earlier and later segments of velocity are compared.


Activation of MAP-2 kinase activity by the CD2 receptor in Jurkat T cells can be reversed by CD45 phosphatase.
We have recently characterized a serine kinase in T lymphocytes which phosphorylates microtubule-associated protein-2 (MAP-2) in vitro. This kinase is activated in a rapidly reversible fashion during ligation of CD3/Ti by a process which involves tyrosine phosphorylation of the enzyme itself. We show that the stimulatory anti-CD2 mAb combination, anti-(T11(2) + T11(3), stimulates MAP-2K activity in Jurkat cells with kinetics that are more prolonged than during anti-CD3 treatment. The principal difference is not in the rate of response induction, but in the decline of the response beyond the peak, to which end anti-CD2 stimulation resembles the sustained phytohaemagglutin (PHA) response. Parallel immunoblotting, utilizing anti-phosphotyrosine antibodies, also revealed differences in the rate at which tyrosine phosphorylation of pp43 (MAP-2K) disappears after induction. In spite of these differences, CD2 was absolutely dependent on the presence of CD3 for inducing a MAP-2K response in Jurkat cells. These results indicate that, even though CD2 and CD3 are using a common signalling pathway in Jurkat cells, additional differences such as the involvement of a tyrosine phosphatase may have to be considered in response generation. We also demonstrate that the common CD45 isoform, when cross-linked to CD2 by mAb, could inhibit the MAP-2K response during both induction as well as the disappearing phase of the response.


Concordance of National Insurance Criteria with WPATH Standards of Care for Gender-Affirming Surgery.
Given that gender-affirming surgery (GAS) is considered medically necessary for transgender and gender diverse (TGD) individuals who desire it, the aim of this study is to assess the concordance of insurance criteria for GAS with the most recent World Professional Association for Transgender Health (WPATH) Standards of Care Version 8 (SOC-8). Insurance policies for coverage of gender-affirming genital ("bottom surgery"), chest ("top surgery"), and facial reconstruction from companies representing 80% of the market coverage in each state were evaluated. Policies were classified into three categories: no-coverage (NC), case-by-case (CC), and preauthorization (PA). Among PA policies, criteria for coverage of specific surgeries were analyzed for adherence to WPATH SOC-8. Bottom surgery policies were most concordant for age and gender dysphoria criteria, and transmasculine top surgery policies were most concordant for hormone therapy, continuous living in a congruent gender role, and referral criteria. transfeminine top surgery criteria were more restrictive than transmasculine criteria. The most discordant criteria was for hormone therapy, being required for at least 12 months prior to surgery in the majority of surveyed policies. Many specific procedures and treatments were excluded, especially facial GAS with cosmetic overlap. Additionally, reversal and revisionary surgeries were covered in less than 25% of policies. Compared to previous literature, insurance coverage and criteria alignment are becoming more concordant with medical guidelines. However, significant barriers to care are still present for GAS.


Causative impact of air pollution on evapotranspiration in the North China Plain.
Atmospheric dispersion conditions strongly impact air pollution under identical surface emissions. The degree of air pollution in the Jing-Jin-Ji region is so severe that it may impose feedback on local climate. Reference evapotranspiration (ET0) plays a significant role in the estimation of crop water requirements, as well as in studies on climate variation and change. Since the traditional correlation analysis cannot capture the causality, we apply the convergent cross mapping method (CCM) in this study to observationally investigate whether the air pollution impacts ET0. The results indicate that southwest regions of Jing-Jin-Ji always suffer higher PM2.5 concentration than north regions through the whole year, and correlation analysis suggests that PM2.5 concentration has a significant negative effect on ET0 in most cities. The causality detection with CCM quantitatively demonstrates the significantly causative influence of PM2.5 concentration on ET0, higher PM2.5 concentration decreasing ET0. However, CCM analysis suggests that PM2.5 concentration has a relatively weak causal influence on ET0 while the correlation analysis gives the near zero correlation coefficient in Zhangjiakou city, indicating that the causative influence of PM2.5 concentration on ET0 is better revealed with CCM method than the correlation analysis. Considering that ET0 is strongly associated with crop water requirement, the amount of water for agricultural irrigation could be reduced at high PM2.5 concentrations. These findings can be utilized to improve the efficiency of water resources utilization, and reduce the exploiting amount of groundwater in the Jing-Jin-Ji region, although PM2.5 is detrimental to human health.


Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor.
Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC50 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI50 < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of 11d for advancement in clinical studies.


Laser speckle contrast imaging: age-related changes in microvascular blood flow and correlation with pulse-wave velocity in healthy subjects.
In the cardiovascular system, the macrocirculation and microcirculation—two subsystems—can be affected by aging. Laser speckle contrast imaging (LSCI) is an emerging noninvasive optical technique that allows the monitoring of microvascular function and can help, using specific data processing, to understand the relationship between the subsystems. Using LSCI, the goals of this study are: (i) to assess the aging effect over microvascular parameters (perfusion and moving blood cells velocity, MBCV) and macrocirculation parameters (pulse-wave velocity, PWV) and (ii) to study the relationship between these parameters. In 16 healthy subjects (20 to 62 years old), perfusion and MBCV computed from LSCI are studied in three physiological states: rest, vascular occlusion, and post-occlusive reactive hyperaemia (PORH). MBCV is computed from a model of velocity distribution. During PORH, the experimental results show a relationship between perfusion and age (R(2) = 0.67) and between MBCV and age (R(2) = 0.72), as well as between PWV and age at rest (R(2) = 0.91). A relationship is also found between perfusion and MBCV for all physiological states (R(2) = 0.98). Relationships between microcirculation and macrocirculation (perfusion-PWV or MBCV-PWV) are found only during PORH with R(2) = 0.76 and R(2) = 0.77, respectively. This approach may prove useful for investigating dysregulation in blood flow.


Risk factors for deep vein thrombosis in short-haul cockpit crews: a prospective study.
Venous thrombosis is a concern receiving international attention, especially for passengers traveling on long distance flights. However, there are no data on the effect on cockpit crew of multiple short duration flights. Cockpit crew flew two or more internal flights per day. At sign on, 15 ml of blood was venesected from the subjects; at sign off, 20 ml of blood was venesected. All flights originated and terminated at Johannesburg Airport. A full blood count, differential, and D-dimer levels were determined. All participants completed detailed questionnaires stating their ages, alcohol consumption 24 h prior to flight duty, the amount of liquid consumed during flying time, the number of times they went to the toilet, and the amount of time spent sitting during flights. Blood tests on 27 cockpit crew were performed. D-dimers were reduced from 163 ng x ml(-1) to 133 ng x ml(-1) (p = 0.03). Hemoglobin levels dropped from 16.0 g x dl(-1) to 15.8 g x dl(-1) (p = 0.004). Hematocrit levels decreased from 47.2 ml x 100 ml(-1) to 46.9 ml x 100 ml(-1) (p = 0.04). Platelets increased from 221 x 10(9) x L(-1) to 241 x 10(9) x L(-1) (p = 0.001). White cell counts increased from 6.4 x 10(9) x L(-1) to 7.01 x 10(9) x L(-1) (p = 0.0063). Correlation analysis was performed between blood test results and the parameters of the questionnaire. No correlation was found between any of the parameters and the blood results. There is no evidence of sub-clinical thrombotic events in this group of subjects. Cockpit crew who fly multiple short duration flights do not suffer sub-clinical thrombotic events as evidenced by an absence of increased D-dimers.


Exclusion of ribulose-1,5-bisphosphate carboxylase/oxygenase from chloroplasts by specific bodies in naturally senescing leaves of wheat.
Immunocytochemical electron-microscopic observation indicated that ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco, EC 184.108.40.206) and/or its degradation products are localized in small spherical bodies having a diameter of 0.4-1.2 micro m in naturally senescing leaves of wheat (Triticum aestivum L.). These Rubisco-containing bodies (RCBs) were found in the cytoplasm and in the vacuole. RCBs contained another stromal protein, chloroplastic glutamine synthetase, but not thylakoid proteins. Ultrastructural analysis suggested that RCBs had double membranes, which seemed to be derived from the chloroplast envelope, and that RCBs were further surrounded by the other membrane structures in the cytoplasm. The appearance of RCBs was the most remarkable when the amount of Rubisco started to decrease at the early phase of leaf senescence. These results suggest that RCBs might be involved in the degradation process of Rubisco outside of chloroplasts during leaf senescence.


Multicriteria analysis of sewage sludge-based biodiesel production.
There is increasing attention on developing efficient processes including circular economy principles, and obtaining fuels from wastewater treatment feedstocks is among the most promising. As a wastewater treatment byproduct, sewage sludge is a source of lipids that can be converted to biodiesel in a transesterification process. Economic and environmental analysis have been applied to a 60 m3/h sewage sludge plant, exploring 32 process alternatives. Using solvent extraction from wet sewage sludge, the high cost associated with the drying step is skipped. The wet alternatives with low amounts of solvent and acid usage depicted higher performance compared to the dry ones. Incorporating additional extraction stages increases both the financial gains and environmental impacts. As a result, a multicriteria analysis is implemented to ascertain the optimum process based on different priorities. The case with 0.5:1 (v/v) of hexane to biomass ratio, 3-stage extractor, 60 min residence time and pH 4 was the optimum alternative in most criteria.


Reciprocal patterns of allergen-induced GATA-3 expression in peripheral blood mononuclear cells from atopics vs. non-atopics.
T helper (Th)2 cytokines are considered to play a central role in the induction and expression of allergic disease. However, the relative importance of individual cytokines is unclear, and overall disease pathogenesis appears to involve the coordinate activities of a range of Th2 cytokines acting in sequence or in parallel. The present study examines an alternative approach to the study of cytokine gene function in atopy, focusing instead upon T cell transcription factors (TFs) which play a role in the regulation of multiple cytokine genes. To investigate the allergen-induced expression of the TF GATA-3 and c-Maf in peripheral blood mononuclear cells (PBMCs) and in cytokine-driven Th polarization. PBMC from house dust mite (HDM)-atopic and non-atopics were stimulated in vitro with allergen or anti-CD3/IL-2. TF expression was analysed by semiquantitative RT-PCR and major findings were validated by real-time PCR. Cell separations were performed to analyse the contribution of CD45RO+ cells. CD4+ cord blood cells were Th1 or Th2 polarized in vitro by exogenous cytokines and TF expression analysed by Northern blot and real-time PCR. Results We demonstrate for the first time that during differentiation of CD4+ CD45RA+ naïve human T cells towards Th2 commitment, and during allergen-specific reactivation of peripheral CD4+ CD45RO+ Th2 memory cells in established atopics, expression of the Th2-associated TF GATA-3 is rapidly up-regulated, whereas T cells from non-atopics display equally rapid GATA-3 down-regulation under identical conditions of allergen stimulation. These findings identify Th2-associated TFs as key determinants of the atopic phenotype, suggesting their unique potential as therapeutic targets for disease control.