Female representation in intensive care medicine: Challenges and perspectives from China.
The gender gap in the practice of intensive care medicine has increasingly been recognized as a problem in recent years. Despite limited information, the available data suggest that representation of women in the physician workforce, academic positions, and leadership roles in intensive care is inadequate globally. In this article, we describe the situation of female intensive care unit (ICU) physicians from the perspective of Chinese intensivists. The proportion of female ICU physicians in China has been increasing in recent years. The biggest challenges faced by female ICU physicians include balance of work and life, difficulties in career planning, and lack of academic influence. More attention and policy support should be provided to help them play a better role in intensive care medicine.


Prolonged E-selectin induction by monocytes potentiates the adhesion of flowing neutrophils to cultured endothelial cells.
We investigated the hypothesis that the infiltration of monocytes into inflamed tissue or damaged vessels would induce a secondary accumulation of neutrophils. Confluent human umbilical vein endothelial cells (HUVEC) and blood monocytes (0.5 or 0.05 monocytes/endothelial cell) were co-incubated for 4 or 24 h. The adhesion of neutrophils flowing over HUVEC was then analysed by video microscopy. Co-incubation caused up to a 40-fold increase in neutrophil adhesion, dependent upon monocyte/HUVEC ratio and duration of incubation. At the lower monocyte/HUVEC ratio, rolling adhesion alone was induced after 4 h co-incubation; however, the full repertoire of rolling, immobilization and migration of neutrophils was observed at all other combinations of co-culture ratio and exposure time. After maximal stimulation by monocytes, antibody blockade of the neutrophil integrin CD18 inhibited neutrophil arrest and migration and revealed underlying rolling adhesion. Rolling was supported by endothelial E-selectin as demonstrated by the almost total abolition of adhesion by a blocking antibody. In a direct comparison, monocytes, tumour necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) were assessed for their ability to induce endothelial expression of E-selectin. E selectin was significantly increased by all agents at 4 h, but monocytes alone were able to maintain high levels of E-selectin expression for 24 h. We conclude that monocytes can induce prolonged neutrophil adhesion and migration by activating endothelial cells and causing expression of E-selectin.


Recombinant production and characterisation of two chitinases from Rasamsonia emersonii, and assessment of their potential industrial applicability.
Rasamsonia emersonii (previously Talaromyces emersonii) is a thermophilic filamentous fungus displaying optimum growth at 45 °C. It has a history of use in commercial food enzyme production. Its unfractionated chitinolytic secretome was partially characterised in the early 1990s; however, no individual chitinase from this source has been described in literature previously. This study describes two GH18 chitinases originating from the R. emersonii genome, expressed in the methylotrophic yeast P. pastoris. Chit1 comprises of a GH18 catalytic domain and Chit2 comprises of a GH18 catalytic domain and a chitin-binding motif at the C-terminal. The chitinases were expressed as glycoproteins. The apparent molecular weight of Chit1 was 35.8-42.1 kDa with a smearing tail associated with glyco-sidechains visible up to 72.2 kDa. This became two bands of 30.8 and 29.0 kDa upon de-glycosylation. The apparent molecular weight of Chit2 was 50.4 kDa, reducing to 48.2 kDa upon de-glycosylation. Both chitinases displayed endo-chitinase and chitobiosidase activity, temperature optima of 50-55 °C and low pH optima (pH 4.5 or lower); Chit1 displayed a pH optimum of 3.5, retaining > 60% maximum activity at pH 2.2, a pH range lower than most enzymes of fungal origin. Chit2 displayed the highest chitin-degrading ability at 3456 µmol/mg on 4-NP-triacetylchitotriose, but lost activity faster than Chit1, which displayed 403 µmol/mg on the same substrate. The predicted D values (time required to reduce the enzyme activity to 10% of its original value at 50 °C) were 19.2 and 2.3 days for Chit1 and Chit2, respectively. Thus, Chit1 can be considered one of few hyperthermostable chitinase enzymes described in literature to date. Their physicochemical properties render these chitinases likely suitable for shrimp chitin processing including one-step chitin hydrolysis and alternative sustainable protein processing and the attractive emerging application of mushroom food waste valorisation.Key points• Two GH18 chitinases originating from the industrially relevant thermophilic fungus R. emersonii were cloned and expressed in P. pastoris.• The purified recombinant chitinases showed low pH and high temperature optima and appreciable thermostability at industrially relevant temperatures.• The chitinases displayed characteristics that indicate their likely suitability to several industrial applications including sustainable alternative protein processing, food waste valorisation of commercial mushroom production and one-step shrimp chitin processing.


Bentall procedure for the treatment of aortic dissection after cardiac transplant: a case report.
Aortic dissection affecting the donor aorta after cardiac transplant is a rarely seen complication. Data on the literature about the subject is restricted to case reports. Here, we present a case of type A aortic dissection after cardiac transplant that was successfully treated by the Bentall procedure.


Arm pain and fever as an unusual presentation of lobar pneumonia in a 3-year-old girl: case report.
Children with pneumonia presenting with extrathoracic pain, such as abdominal pain, have been previously described. In this report, we describe a 3-year-old girl with fever and right arm pain who was found to have an apical lobar pneumonia.


Are spexin levels associated with metabolic syndrome, dietary intakes and body composition in children?
The aim of the present study was to investigate whether circulating levels of spexin is related to metabolic syndrome, some dietary intakes (Total energyintake, Macronutrient intakes) and body composition in children. 90 children were recruited in the present cross sectional study. Anthropometric measures, body composition, blood pressure, dietary intakes, resting metabolic rate, physical activity level, appetite status, pubertal stage, serum spexin, fasting blood glucose, high-sensitivity C-reactive protein, insulin and lipid profile were measured using standard techniques. 14 children met the criteria for metabolic syndrome. Median (IQR) of spexin levels were significantly lower in children with high fat mass and children with higher systolic blood pressure (SBP), compared to children with normal fat mass and normal SBP: (P < 0.05). A protective independent effect was detected for the highest tertile of serum spexin on metabolic syndrome in adjusted models; Crude OR (CI): 0.23 (0.04-1.2), P-trend = 0.08; Model 1: OR (CI): 0.15(0.02-1.01), P-trend = 0.05; Model 2: OR (CI): 0.10 (0.01-0.90), P-trend = 0.03. There was a significant negative association between spexin and total dietary fat intake (r= - 0.21; P < 0.04). This findings can further highlight the importance of the relationship between spexin, adipose tissue and adipose tissue metabolism.


Disentangling the rhythms of human activity in the built environment for airborne transmission risk: An analysis of large-scale mobility data.
Since the outset of the COVID-19 pandemic, substantial public attention has focused on the role of seasonality in impacting transmission. Misconceptions have relied on seasonal mediation of respiratory diseases driven solely by environmental variables. However, seasonality is expected to be driven by host social behavior, particularly in highly susceptible populations. A key gap in understanding the role of social behavior in respiratory disease seasonality is our incomplete understanding of the seasonality of indoor human activity. We leverage a novel data stream on human mobility to characterize activity in indoor versus outdoor environments in the United States. We use an observational mobile app-based location dataset encompassing over 5 million locations nationally. We classify locations as primarily indoor (e.g. stores, offices) or outdoor (e.g. playgrounds, farmers markets), disentangling location-specific visits into indoor and outdoor, to arrive at a fine-scale measure of indoor to outdoor human activity across time and space. We find the proportion of indoor to outdoor activity during a baseline year is seasonal, peaking in winter months. The measure displays a latitudinal gradient with stronger seasonality at northern latitudes and an additional summer peak in southern latitudes. We statistically fit this baseline indoor-outdoor activity measure to inform the incorporation of this complex empirical pattern into infectious disease dynamic models. However, we find that the disruption of the COVID-19 pandemic caused these patterns to shift significantly from baseline and the empirical patterns are necessary to predict spatiotemporal heterogeneity in disease dynamics. Our work empirically characterizes, for the first time, the seasonality of human social behavior at a large scale with a high spatiotemporal resolutio and provides a parsimonious parameterization of seasonal behavior that can be included in infectious disease dynamics models. We provide critical evidence and methods necessary to inform the public health of seasonal and pandemic respiratory pathogens and improve our understanding of the relationship between the physical environment and infection risk in the context of global change. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM123007.


Retrieval and monitoring of atmospheric trace gas concentrations in nadir and limb geometry using the space-borne SCIAMACHY instrument.
The Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY) onboard the European Envisat spacecraft performs continuous spectral observations of reflected, scattered and transmitted sunlight in various observation geometries. A unique feature of SCIAMACHY is the capability of probing the atmosphere in three different observation geometries:The nadir, limb, and occultation measurement modes. In nadir mode, column densities of trace gases are retrieved with a spatial resolution of typically 30 x 60 km using the Differential Optical Absorption Spectroscopy (DOAS) technique (Platt and Perner, 1983). Alternating with the nadir measurement, vertical profiles of absorber concentration in the stratosphere are derived in limb and occultation. In this paper we present an overview over some applications of SCIAMACHY data in space-based monitoring of atmospheric pollution. The DOAS algorithms for the retrieval of total column amounts from nadir spectra are briefly described and case studies of pollution events are presented. We also illustrate the technique used to derive stratospheric concentration profiles from limb observations and show comparisons with other remote sensing systems. Special emphasis will be given to techniques, which take advantage of SCIAMACHY's different viewing geometries. In particular, we will discuss the potential and limits of strategies to infer tropospheric abundances of O3 and NO2.


The effect of reversible permeabilization and post-electroporation resting on the survival of Thai basil (O. Basilicum cv. thyrsiflora) leaves during drying.
Horticultural crops have a low tolerance to dehydration. In this paper, we show that the reversible electroporation (200 monopolar, rectangular pulses of 50 µs pulse duration, 760 µs between pulses and nominal field strength of 650 V/cm) of Thai basil leaves followed by 24 h resting before hot air drying at 40 °C enhanced the survivability of the tissues at certain levels of dehydration (moisture ratio = 0.2 and 0.1). However, this increased survival was rather limited. Through measurements of metabolic heat production during resting, rehydration kinetics, respiration and photosynthesis of the rehydrated leaves, we show that resting after the application of a reversible pulse-electric field (PEF) may allow a phase of hardening that has a protective effect on the cells, thus decreasing damage during the subsequent drying phase. Increased preservation of cell vitality would be associated with a more turgid and fresh-like rehydrated product, as cells would have the capacity to retain the rehydration water.


Determination of intraoperative plasma catecholamine concentrations using liquid chromatography with electrochemical detection.
Liquid chromatography with electrochemical detection was used for the determination of norepinephrine and epinephrine in human plasma samples obtained prior to, after, and six times during the course of spinal fusion surgery for the correction of scoliosis. The catecholamines were extracted from plasma by alumina adsorption and chromatographed isocratically using a reversed-phase, ion-pairing system. Data obtained are compared to those obtained intraoperatively by other authors using a radioenzymatic method, and the mechanism of sympathetic activation during surgery is discussed. Preliminary data using 3-micron particle size columns and dual-parallel electrochemical detection are presented.


Post-prostate biopsy infection with Escherichia coli ST131 leading to epididymo-orchitis and meningitis caused by Gram-negative bacilli.
A 57-year-old man who had recently undergone a transrectal prostate biopsy for a rising prostate-specific antigen level developed postbiopsy necrotizing epididymo-orchitis (requiring orchiectomy) and then Gram-negative meningitis, despite fluoroquinolone administration for periprocedural prophylaxis and subsequent therapy. The causative organism proved to be a fluoroquinolone-resistant Escherichia coli strain from sequence type ST131.


Fish, rice, and human hair mercury concentrations and health risks in typical Hg-contaminated areas and fish-rich areas, China.
Human exposure to methylmercury (MeHg) from consuming contaminated fish has been a major concern for decades. Besides, human MeHg exposure through rice consumption has been recently found to be important in some Asian countries. China is the largest country on mercury (Hg) production, consumption, and anthropogenic emission. However, the health risks of human Hg exposure are not fully understood. A total of 624 fish, 299 rice, and 994 human hair samples were collected from typical Hg-contaminated areas and major fish-rich areas to assess the health risks from human Hg exposure in China. Fish and rice samples showed relatively low Hg levels, except the rice in the Wanshan Hg mining area (WMMA). Human hair total Hg (THg) and MeHg concentrations were significantly elevated in WMMA, Zhoushan (ZS), Xiamen (XM), Qingdao (QD), and zinc smelting area (ZSA), and 85% of hair samples in WMMA, 62% in ZS, 40% in XM, 26% in QD, and 17% in ZSA had THg concentrations exceeding the limit set by the USEPA (1 μg/g). Rice consumption was the main pathway (>85%) for human MeHg exposure in the studied Hg-contaminated areas. Meanwhile, fish was the primary human MeHg exposure source (>85%) in coastal cities. Therefore, soil remediation in typical Hg-contaminated areas and scientific guidance for fish consumption in coastal provinces are urgently needed to reduce the health risks from human Hg exposure in China.


Neutralizing activity of human antibodies against the structural protein of human T-cell lymphotropic virus type I.
We have identified and mapped the regions responsible for neutralization in the human T-cell leukemia virus type I (HTLV-I) structural proteins by using region-specific human antibodies derived from seropositive blood donors. We have obtained 18 kinds of region-specific antibody (2 in the p19 gag, 10 in the gp46 env and 6 in the gp21 env proteins) from seropositive human plasma by means of an affinity column coupled with the synthetic peptides corresponding to the antigenic regions of the HTLV-I structural proteins. These antibodies were highly specific in ELISA using synthetic peptides as an antigen. Subsequently, we examined the neutralizing activity expressed by the inhibition of virion-induced syncytium formation by region specific antibodies. Twelve of 16 antibodies derived from the env protein were able to inhibit syncytium formation induced by co-cultivation of 8C cells with HTLV-I antigen-positive T cells. The antibodies derived from the p19 gag protein and the seronegative plasma used as the control showed no significant activity. The sequences recognized by the 10 neutralizing antibodies were sites corresponding to amino acids 20 to 49, 89 to 115, 136 to 160, 175 to 199, 213 to 236, 235 to 254, 277 to 292, 332 to 352, 350 to 386, 382 to 403, 426 to 448 and 458 to 488 from the amino terminal of the env protein. These observations suggest that the neutralizing epitopes were widely distributed in the env proteins of HTLV-I.


Histopathology of otitis media with effusion. An electron microscopic study of human temporal bones.
Ultrastructural studies of the middle ear mucosa appear to be of significant value in better understanding the pathology of otitis media with effusion (OME). Our present study was undertaken in order to take advantage of the use of electron microscopy in investigating all areas of the middle ear mucosa. Tissues studied were obtained from the fresh postmortem temporal bones of three patients with OME and terminal head and neck malignancies. In the mucoid type of effusion (cases 1 and 2), goblet cells were seen to proliferate and secretory activity was greatly enhanced. In contrast, there was no evidence of secretory cell proliferation in the serous type of effusion. It was noteworthy that accumulated fluid was not homogeneous in the same ear, as exemplified by case 1, in which both mucoid and serous effusions were present. This occurrence was possibly the result of topographic diversity involving the secretory activity of the middle ear.


Using Project ECHO to Keep Professionals Well at Work: Individual and Organizational Outcomes.
The toll of COVID-19 stress on the mental health of the workforce has been well-documented. The present study examined the use of the Project ECHO framework to provide practices and resources on stress management and emotion regulation to increase individual and organizational health and well-being. Three independent ECHOs were designed and conducted over an 18-month period. Data was collected on the implementation of new learning and comparisons of organizational efforts toward being more secondary trauma responsive from baseline to post initiative, using cloud-based survey methods. Findings suggest that the use of micro-interventions at the organizational level improved over time in the areas of resilience-building and policy-making, and that individuals were actively integrating skills related to managing their stress. Lessons learned adapting and implementing ECHO strategies in the midst of a pandemic are offered, as well as how to cultivate wellness champions in the workforce.


Decreased urinary uronic acid levels in individuals with interstitial cystitis.
The pathogenesis of interstitial cystitis currently is unknown. A possible etiology is that the transitional epithelium is defective, leading to molecular leaks that initiate the disease complex. An important surface defense mechanism is the glycosaminoglycans or polysaccharides that line the bladder epithelium and act as a nonspecific antiadherence factor blocking access of bacteria, microcrystals, proteins and ions to the underlying transitional cells. We examined the excretion of urinary macromolecular uronic acid and glycosaminoglycans in normal individuals and those with interstitial cystitis. A total of 37 controls had a mean macromolecular uronic acid level of 56 nmol. per mg. creatinine, compared to 40.2 nmol. per mg. creatinine in 43 patients with active disease (differences were significant, p equals 0.03). The median excretions of glycosaminoglycan uronate for controls and patients were 15.1 and 11.1 nmol. per mg. creatinine, respectively. (There was an over-all tendency to decrease excretion in patients with a p value of 0.06.) Specimens obtained at cystoscopy from patients with active interstitial cystitis had ureteral macromolecular uronic acid levels of 40.5 nmol. uronate per mg. creatinine compared to 43.6 nmol. uronate per mg. creatinine from the bladder. Interstitial cystitis patients had 16.0 nmol. glycosaminoglycan uronate per mg. creatinine compared to 14.6 nmol. per mg. creatinine in normal controls. Neither of these differences was statistically significant. It would appear that there is a tendency to lower macromolecular uronic acid and polysaccharide excretion in individuals afflicted with this syndrome.


Resveratrol regulates lipolysis via adipose triglyceride lipase.
Resveratrol has been reported to increase adrenaline-induced lipolysis in 3T3-L1 adipocytes. The general aim of the present work was to gain more insight concerning the effects of trans-resveratrol on lipid mobilization. The specific purpose was to assess the involvement of the two main lipases: adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in the activation of lipolysis induced by this molecule. For lipolysis experiments, 3T3-L1 and human SGBS adipocytes as well as adipose tissue from wild-type, ATGL knockout and HSL knockout mice were used. Moreover, gene and protein expressions of these lipases were analyzed. Resveratrol-induced free fatty acids release but not glycerol release in 3T3-L1 under basal and isoproterenol-stimulating conditions and under isoproterenol-stimulating conditions in SGBS adipocytes. When HSL was blocked by compound 76-0079, free fatty acid release was still induced by resveratrol. By contrast, in the presence of the compound C, an inhibitor of adenosine monophosphate-activated protein kinase, resveratrol effect was totally blunted. Resveratrol increased ATGL gene and protein expressions, an effect that was not observed for HSL. Resveratrol increased fatty acids release in epididymal adipose tissue from wild-type and HSL knockout mice but not in that adipose tissue from ATGL knockout mice. Taking as a whole, the present results provide novel evidence that resveratrol regulates lipolytic activity in human and murine adipocytes, as well as in white adipose tissue from mice, acting mainly on ATGL at transcriptional and posttranscriptional levels. Enzyme activation seems to be induced via adenosine monophosphate-activated protein kinase.


Genome DNA leakage of Adeno-Associated virus under freeze-thaw stress.
Adeno-associated virus (AAV) has become an emerging tool for human gene therapies. Currently, AAV gene therapies are subjected to multiple freeze-thaw cycles during manufacturing, storage, transportation, and administration. While studies have shown that multiple freeze-thaw cycles led to a decrease in transduction efficiency, the AAV degradation mechanism during freeze-thaw is not well understood. Here, we have characterized the impact of freeze-thaw on AAV8 by employing a variety of assays, which revealed significant increases in the amount of free single-stranded DNA (ssDNA) in AAV8 formulations after multiple freeze-thaw cycles. Subsequent analysis using Next Generation Sequencing (NGS) revealed that the ssDNA primarily consisted of genome DNA, indicating that the increased ssDNA leaked out from AAV8. Experiments performed using different serotypes of AAV confirmed the pervasiveness of such behavior amongst AAVs. In addition, formulation screening studies were performed to understand the impact on genome DNA leakage from AAV. The formulation screening results showed that the addition of 10% sucrose and 0.1% poloxamer 188 to Dulbecco's phosphate-buffered saline (DPBS) reduced the leakage of ssDNA in AAV samples after freeze-thaw cycles compared to the base formulation of DPBS alone. These findings shed new light on the degradation mechanism of AAVs and stabilization of the AAV-based gene therapies.


A carbon-based fluorescent probe (N-CDs) encapsulated in a zeolite matrix (NaFZ) for ultrasensitive detection of Hg (II) in fish.
In this work, a novel strategy was addressed to fabricate new sensing probe (N-CDs@NaFZ) from nitrogen doped carbon dots (N-CDs) confined in Al-free ferrisilicates zeolite (NaFZ) by hydrothermal/solvothermal method. The probe was systematically characterized by HR-TEM, FTIR, energy dispersive X-ray (EDX), powder X-ray diffraction, and UV-Vis absorption and fluorescence spectrophotometers. Characterization of the designed nanocomposite template N-CDs@NaFZ by fluorescence spectrum demonstrates a variety of important conducts as stability improvements, reasonable dispersibility in water, highly emission intensity enhancement at 435 nm when excited at 340 nm, excitation independent fluorescence behaviors, great quantum yield percentage of 91.2%, and narrow size distribution 12 nm, as a nano-space confinement effect of zeolite effectively increase the rigidity of N-CDs. Based on the fluorescence quenching mechanism, the designed approach exhibits an excellent selectivity and good sensitive response to the presence of Hg(II) ions under ambient temperature, with a wide linear range of 0.1-1500 nM and lower detection limits of 5.5 pM. Influences of variables pH and incubation time were optimized. The N-CDs@NaFZ sensor was effectively applied for the detection of Hg(II) ions in the farmed and wild rainbow trout fishes, and the results are in reasonable agreement when compared with that obtained by the cold vapor atomic absorption method.


Efficacy of Pulsatile Gonadotropin-Releasing Hormone Therapy in Male Patients: Comparison between Pituitary Stalk Interruption Syndrome and Congenital Hypogonadotropic Hypogonadism.
Pulsatile gonadotropin-releasing hormone (GnRH), widely used to induce spermatogenesis in congenital hypogonadotropic hypogonadism (CHH) patients, can restore the pituitary-testis axis function in men with pituitary stalk interruption syndrome (PSIS). This retrospective study aimed to compare the differences in the long-term efficacy of pulsatile GnRH therapy on PSIS and CHH. Patients with PSIS (n = 25) or CHH (n = 64) who received pulsatile GnRH therapy for ≥3 months were included in this retrospective study. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, total testosterone, and testicular size were compared. Baseline characteristics were comparable except for the lower basal testosterone, triptorelin-stimulated peak luteinizing hormone (LH), and follicle-stimulating hormone in patients with PSIS. With similar duration of treatment and a significantly higher GnRH dose (P < .001), small increments in LH (2.82 [1.4, 4.55] vs 5.89 [3.88, 8.02] IU/L; P < .001), total testosterone (0.38 [0, 1.34] vs 2.34 [1.34, 3.66] ng/mL; P < .001), and testicular volume (5.3 ± 4.5 vs 8.8 ± 4.8 mL, P < .05) were observed. However, spermatogenesis rate (52.0% vs 70.3%, P > .05), median time of sperm appearance (14 vs 11 months, P > .05), sperm concentration, and progressive motility were comparable. Basal testicular volume (hazard ratio, 1.13; 95% CI, 1.01-1.27) and peak LH levels (hazard ratio, 1.11; 95% CI, 1.0-1.23) were predictors for early sperm appearance. Pulsatile GnRH therapy can improve gonad function and induce spermatogenesis in men with PSIS. However, its efficacy may be inferior to that in CHH.


Serodiagnosis of Helicobacter pylori infection: an evaluation of a commercially available ELISA-IgG.
Our aim was to evaluate a commercially available ELISA (Pyloriset IgG, Orion diagnostica, Imphos B.V.) for detection of serum IgG antibodies to Helicobacter pylori. Serum samples were taken from 154 Dutch patients. As a reference method several biopsy specimens were taken from different gastric areas for histological analysis, bacterial culture and direct urease testing. The sensitivity, specificity, positive and negative predictive values of the Pyloriset IgG were calculated as compared to the reference method. Of 154 patients 126 were found to be H. pylori positive (82%), 28 were H. pylori negative (18%). Using a cut-off value at a titre of 500 U/l (as advised by the manufacturer) we found a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 81, 89, 97 and 51%, respectively. Lowering the cut-off value to 350 U/l and excluding patients aged above 70 years optimalized the performance of the Pyloriset IgG to a sensitivity, specificity, PPV and NPV of 92, 96, 99 and 72%, respectively. In the subgroup of 54 patients under the age of 45 years a sensitivity, specificity, PPV and NPV of 92, 100, 100 and 82% was found. The Pyloriset IgG is a simple and accurate method for detecting H. pylori infection in dyspeptic Dutch patients. The performance of this assay is improved by lowering the cut-off value (test becomes predominantly more sensitive) and excluding older patients (test becomes predominantly more specific). Therefore serology might eventually replace endoscopy or breath tests in the detection of H. pylori infection, especially in the younger age groups.


It's always snack time: an investigation of event scripts in young children.
This study examined whether young children include eating in their cognitive scripts for various events, and whether food-related scripts are associated with body mass index (BMI) percentile. Data were collected in a structured interview format. Participants, recruited from area preschools and day cares, provided a four-activity sequence for each of three events, and responses were recorded verbatim. Forty-four children (45% female) participated, with an average BMI percentile of 73.3% (SD = 25.9). Data were binarily coded to indicate whether each response was food-related. Frequencies were obtained, and responses were correlated with BMI percentile. Over 22% of the activities in the children's scripts involved food. The number of food-related activities reported was positively correlated with children's BMI percentile (r = 0.53, p = 0.03). Results provide preliminary evidence that food features prominently in young children's event scripts and that children with higher BMI percentiles may possess scripts that feature more food-related themes. Future researchers should investigate the causal nature of this relationship.


Penile replantation.
A case of penile amputation and replantation is presented. Partial amputation may be repaired without microsurgical technique with good results. For complete amputation, specific microneurovascular repair is recommended.


Effects of the composition of standard reference material on the accuracy of determinations of 210Pb and 137Cs in soils with gamma spectrometry.
The effect of the composition of the used standard reference material (SRM) on results of determination of fallout radionuclides in soil samples was studied. Using five soil types as SRMs, we measured the specific activity of (210)Pb and (137)Cs in six target samples of Chestnut soil. It was observed that the determination of the (210)Pb activity in the samples depended on the chemical composition of SRMs used to create the efficiency curves. Thus, using SRMs similar in chemical composition to the target samples should improve accuracy in the determination of (210)Pb in environmental samples.


An electron microscopic and cytochemical study of the cell coat of Trypanosoma cruzi in tissue cultures.
Using the cytochemical method of Thiery, a polysaccharide surface coat was demonstrated with the electron microscope in the various developmental stages of Trypanosoma cruzi maintained in tissue cultures. The cell coat was observed on the whole surface membrane system of T. cruzi. A positive reaction, similar to that observed in the cell membrane, was also obtained in the membranes of some vacuoles in the cytoplasm of the parasites. No granules were found in the parasites. No granules were found in the parasite which could represent reserve polysaccharides. The possible role of the cell coat in such phenomena as adhesion, agglutination, phago- and pinocytosis and antigenicity is discussed.


PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma.
Despite remarkable advances in treatment, most patients with hepatocellular carcinoma (HCC) respond poorly to anti-programmed cell death 1 (anti-PD1) therapy. A deeper insight into the tolerance mechanism of HCC against this therapy is urgently needed. We performed next-generation sequencing, multiplex immunofluorescence, and dual-color immunohistochemistry and constructed an orthotopic HCC xenograft tumor model to identify the key gene associated with anti-PD1 tolerance. A spontaneously tumorigenic transgenic mouse model, an in vitro coculture system, mass cytometry, and multiplex immunofluorescence were used to explore the biological function of zinc finger protein 64 (ZFP64) on tumor progression and immune escape. Molecular and biochemical strategies like RNA-sequencing, chromatin immunoprecipitation-sequencing and mass spectrometry were used to gain insight into the underlying mechanisms of ZFP64. We showed that ZFP64 is frequently upregulated in tumor tissues from patients with anti-PD1-resistant HCC. Elevated ZFP64 drives anti-PD1 resistance by shifting macrophage polarization toward an alternative activation phenotype (M2) and fostering an inhibitory tumor microenvironment. Mechanistically, we primarily demonstrated that protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and the transcriptional activation of macrophage colony-stimulating factor (CSF1). HCC-derived CSF1 transforms macrophages to the M2 phenotype to drive immune escape and anti-PD1 tolerance. Notably, Gö6976, a protein kinase inhibitor, and lenvatinib, a multi-kinase inhibitor, reset the tumor microenvironment and restore sensitivity to anti-PD1 by blocking the PKCα/ZFP64/CSF1 axis. We propose that the PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance. Inhibiting this axis with Gö6976 or lenvatinib overcomes anti-PD1 resistance in HCC. Despite remarkable treatment progress, most patients with hepatocellular carcinoma respond poorly to anti-PD1 therapy (a type of immunotherapy). A deeper insight into the tolerance mechanisms to this therapy is urgently needed. Herein, we unravel a previously unexplored mechanism linking tumor progression, macrophage polarization, and anti-PD1 resistance, and offer an attractive novel target for anti-PD1 combination therapy, which may benefit patients with hepatocellular carcinoma.


Visions for a JACIE Quality Management System 4.0.
Quality management has been part of hematopoietic stem cell transplantation (HSCT) from the very beginning. It evolved step-wise from open data exchange up to the introduction of the FACT/JACIE-based quality management system (QMS) 2 decades ago. This formal step has eased cooperation, and improved outcome for patients. Today's expansion of cellular and targeted therapies and new drugs, and the regulatory requirements for advanced therapeutic medicinal products have touched the limits of the current system. Based on the Medicine 4.0 concept, the next step should integrate novel views of QMS. The old definition "Best Quality Transplant" will be replaced by "Optimal Treatment," and encompass the entire health care journey. "Best outcome" will refer to overall survival, quality of life and costs, with or without HSCT, and will be compatible with all requirements by competent authorities. Decisions will be based on high-level evidence, supported by real-time digitized data collection, data analysis, incorporated into artificial-intelligence systems. To reach this goal, EBMT/JACIE will be challenged to start the process by further fostering harmonization within and between organizations at institutional, national, and European levels. Acceleration in information technology and modifications to working practices during the pandemic should facilitate this development to the next stage.


Relationship between isocapnic buffering and maximal aerobic capacity in athletes.
This study was performed to clarify the relationship between isocapnic buffering and maximal aerobic capacity (VO2max) in athletes. A group of 15 trained athletes aged 21.1 (SD 2.6) years was studied. Incremental treadmill exercise was performed using a modified version of Bruce's protocol for determination of the anaerobic threshold (AT) and the respiratory compensation point (RC). Ventilatory and gas exchange responses were measured with an aeromonitor and expressed per unit of body mass. Heart rate and ratings of perceived exertion were recorded continuously during exercise. The mean VO2max, oxygen uptake (VO2) at AT and RC were 58.2 (SD 5.8) ml x kg(-1) x min(-1), 28.0 (SD 3.3) ml x kg(-1) x min(-1) and 52.4 (SD 6.7) ml x kg(-1) x min(-1), respectively. The mean values of AT and RC, expressed as percentages of VO2max, were 48.3 (SD 4.2)% and 90.0 (SD 5.2)%, respectively. The mean range of isocapnic buffering defined as VO2 between AT and RC was 24.4 (SD 4.5) ml x kg(-1) x min(-1), and the mean range of hypocapnic hyperventilation (HHV) defined as VO2 between RC and the end of exercise was 5.8 (SD 3.0) ml x kg(-1) x min(-1). The VO2max per unit mass was significantly correlated with AT (r = 0.683, P < 0.01). In addition, VO2max/mass was closely correlated with both the range of isocapnic buffering (r = 0.803, P < 0.001) and RC (r = 0.878, P < 0.001). However, no correlation was found between VO2max per unit mass and the range of HHV (r = 0.011, NS.). These findings would suggest that the prominence of isocapnic buffering, in addition to the anaerobic threshold, may have been related to VO2max of the athletes. The precise mechanisms underlying this proposed relationship remain to be elucidated.


Bhimamycin J, a Rare Benzo[f]isoindole-dione Alkaloid from the Marine-Derived Actinomycete Streptomyces sp. MS180069.
Chemical investigation on a Streptomyces sp. strain MS180069 isolated from a sediment sample collected from the South China Sea, yielded the new benzo[f]isoindole-dione alkaloid, bhimamycin J (1). The structure was determined by extensive spectroscopic analysis, including HRMS, 1D, 2D NMR, and X-ray diffraction techniques. A molecular docking study revealed 1 as a new molecular motif that binds with human angiotensin converting enzyme2 (ACE2), recently described as the cell surface receptor responsible for uptake of 2019-CoV-2. Using enzyme assays we confirm that 1 inhibits human ACE2 79.7 % at 25 μg/mL.


Treatment with the calcineurin inhibitor and immunosuppressant cyclosporine A impairs sensorimotor gating in Dark Agouti rats.
Calcineurin is a protein regulating cytokine expression in T lymphocytes and calcineurin inhibitors such as cyclosporine A (CsA) are widely used for immunosuppressive therapy. It also plays a functional role in distinct neuronal processes in the central nervous system. Disturbed information processing as seen in neuropsychiatric disorders is reflected by deficient sensorimotor gating, assessed as prepulse inhibition (PPI) of the acoustic startle response (ASR). Patients who require treatment with immunosuppressive drugs frequently display neuropsychiatric alterations during treatment with calcineurin inhibitors. Importantly, knockout of calcineurin in the forebrain of mice is associated with cognitive impairments and symptoms of schizophrenia-like psychosis as seen after treatment with stimulants. The present study investigated in rats effects of systemic acute and subchronic administration of CsA on sensorimotor gating. Following a single injection with effective doses of CsA, adult healthy male Dark Agouti rats were tested for PPI. For subchronic treatment, rats were injected daily with the same doses of CsA for 1 week before PPI was assessed. Since calcineurin works as a modulator of the dopamine pathway, activity of the enzyme tyrosine hydroxylase was measured in the prefrontal cortex and striatum after accomplishment of the study. Acute and subchronic treatment with the calcineurin inhibitor CsA disrupted PPI at a dose of 20 mg/kg. Concomitantly, following acute CsA treatment, tyrosine hydroxylase activity was reduced in the prefrontal cortex, which suggests that dopamine synthesis was downregulated, potentially reflecting a stimulatory impact of CsA on this neurotransmitter system. The results support experimental and clinical evidence linking impaired calcineurin signaling in the central nervous system to the pathophysiology of neuropsychiatric symptoms. Moreover, these findings suggest that therapy with calcineurin inhibitors may be a risk factor for developing neurobehavioral alterations as observed after the abuse of psychomotor stimulant drugs.


A comparative study of structural properties of fibronectin and its 180 kDa fragment.
Fibronectin from human plasma and its 180 kDa fragment which retained collagen-binding, cell-attachment and heparin-binding activities, were studied by velocity centrifugation and 1H-NMR methods. The fibronectin hydrodynamic radius strongly increased at pH 11 while the hydrodynamic properties of the fragment did not change noticeably. 1H-NMR spectroscopy also showed differences in the molecular properties of fibronectin and its 180 kDa fragment. Under physiological conditions the structure of fibronectin differs from that of its 180 kDa fragment. At pH 11 and in 4 M urea no differences in their structures are observed. It is suggested that interdomain and intersubunit interactions play an important role in maintaining the native conformation of intact fibronectin.


Recurrent calcifying odontogenic cyst (case report).
A case of calcifying odontogenic cyst is reported in which the lesion recurred after almost 7 years. We would advise a long-term follow-up for patients with this lesion.


Stereoselective uptake and metabolism of prothioconazole caused oxidative stress in zebrafish (Danio rerio).
Prothioconazole (PTA) is a novel, broad-spectrum, chiral triazole fungicide that is mainly used to prevent and control the disease of cereal crops. However, the adverse effects of PTA and its major metabolite on nontarget organisms have aroused wide concern. In the present work, the acute toxic of the metabolite prothioconazole-desthio (PTA-desthio), with an LC50 of 1.31 mg L-1, was 3.5-fold more toxic than the parent compound, indicating that the metabolism of PTA in zebrafish was toxic. The stereoselective uptake and metabolism of PTA and PTA-desthio in zebrafish was firstly investigated using LC-MS/MS. Remarkable enantioselectivity was observed: S-PTA and S-PTA-desthio were preferentially uptake with the uptake rate constants of 8.22 and 8.15 d-1 at exposure concentration of 0.5 mg L-1, respectively, and the R-PTA-desthio were preferentially metabolized. PTA-desthio was rapidly formed during the uptake processes. The antioxidant enzyme activities in the zebrafish changed significantly, and these effects were reversible. A metabolic pathway including 13 phase I metabolites and 2 phase II metabolites was firstly proposed. A glucuronic acid conjugate and sulfate conjugate were observed in zebrafish. The results of this work provide information that highlights and can help mitigate the potential toxicity of PTA to the ecological environment and humans health.


A national survey of knowledge, attitude and practices among pediatricians towards newborn hearing screening in India.
Pediatricians have a key role in ensuring that infant has undergone hearing screening and required follow-up. Attempts in various countries and centers have been made at exploring their knowledge, attitude and practices towards universal newborn hearing screening. In India, such a program is at its preliminary stage, and hence a need was felt to study this aspect in pediatricians working in India. A cross-sectional online survey was carried out among 112 pediatricians working in India. The questionnaire was framed after reviewing the existing questionnaires. Descriptive statistics was used to summarize the findings. A response rate of 7.99% (112/1402) was obtained of which only 20.5% reported of availability of screening program in their work set-up. The majority of the pediatricians (95%) were aware of the newborn hearing screening while 98.3% were affirmative about the importance of screening of all infants. Very few pediatricians reported of a screening program in their set-up or in their close locality. Overall the pediatricians were confident about their knowledge on this topic yet expressed a need to know more about several intricacies about hearing screening. The pediatricians also provided an input on the most preferred method of receiving more information. The success of the universal newborn hearing screening program lies in the support and cooperation of health care providers such as pediatricians. The present study draws attention to the positive attitude and practices exhibited by them. It also sheds light on the knowledge gaps that are present and need the due attention of the policy makers. Further, it highlights the need for having more continuing medical education program and awareness drives for ensuring a better implementation of UNHS.


Epsilon aminocaproic acid reduces transfusion requirements in patients with thrombocytopenic hemorrhage.
Epsilon aminocaproic acid (EACA) is an antifibrinolytic drug that has been used to control hemorrhage by stabilizing the thrombus. It has been used in thrombocytopenic patients largely on an empiric basis. Concerns regarding side effects have limited the use of this drug. The authors reviewed their experience with EACA at the Cleveland Clinic Foundation from 1997 to 2003. Of 77 patients with thrombocytopenic hemorrhage, 51 (66%) patients achieved a complete response and 13 (17%) patients achieved a partial response, resulting in a decrease in platelet and red blood cell transfusions. Adverse effects were manageable in this set of patients with severe underlying disease. Based on this experience, EACA may be a valuable adjunctive therapy in the treatment of patients with thrombocytopenic hemorrhage.


Enzyme based assays in a sequential injection format: a review.
Sequential injection analysis systems have been extensively exploited in the last decades for the implementation of enzyme based assays aiming the evaluation of enzyme activity or the determination of specific analytes. The most prominent aspects of the automation of enzymatic assays in these systems are discussed in this review. Special attention is devoted to the mode of enzyme manipulation in homogeneous or heterogeneous media and to the comparison with batch and flow injection enzyme methodologies. The possibility of implementing strategies for the enhancement of selectivity in specific determinations is also addressed. The more recent trends in this field are discussed focusing mainly on the miniaturization resorting to the lab-on valve platform as well as on the bead injection concept.


The effect of oxidative metabolism on spontaneous Pol zeta-dependent translesion synthesis in Saccharomyces cerevisiae.
DNA lesions can stall or block high-fidelity polymerases, thus inhibiting replication. To bypass such lesions, low-fidelity translesion synthesis (TLS) polymerases can be used to insert a nucleotide across from the lesion or extend from a lesion:base mispair. When DNA repair is compromised in Saccharomyces cerevisiae, spontaneous DNA lesions can lead to a novel mutational event in which a frameshift is accompanied by one or more base pair substitutions. These "complex frameshifts" are dependent upon the TLS polymerase Pol zeta, and provide a mutational signature for mutagenic Pol zeta-dependent activity. In the current study, we have found that a specific subset of the Pol zeta-dependent mutational events requires oxidative metabolism. These results suggest that translesion bypass of spontaneously oxidized DNA bases can be a significant source of mutagenesis in repair compromised cells.


The voltage and temperature dependence of the end-plate current in frog skeletal muscle.
The effect of membrane potential (V) on the half-time (t 1/2) of the falling phase of the end-plate current (e.p.c.) was found to obey the equation t 1/2 = A X eBV + C, where A, B and C are constants. The temperature dependence of t 1/2 was found to follow the Arrhenius equation. The activation energy (Ea) varied from about 50 kJ/mol to about 120 kJ/mol. At membrane potentials between about -40 mV and -140 mV, the Ea/V relation was similar in all end-plates investigated: Ea increased if membrane potential was made more negative. At membrane potentials between about +60 mV and -40 mV, however, the Ea/V relation was different in different end-plates: If membrane potential was made more negative, Ea was either increased, or not affected, or decreased. It is concluded that at negative levels of membrane potential the decay of the e.p.c. depends on average life-time of ionic channels, opened up by the action of acetylcholine on junctional receptors. At strongly positive levels of membrane potential, however, the decay of the e.p.c. can be determined by the average life-time of ionic channels or by the clearance of transmitter from the synaptic cleft, or both. Either of these processes can be reflected in the value of constant C in the above equation.


Experimental evaluation of four-dimensional Magnetic Resonance Imaging for radiotherapy planning of lung cancer.
Radiotherapy planning for lung cancer typically requires both 3D and 4D Computed Tomography (CT) to account for respiratory related movement. 4D Magnetic Resonance Imaging (MRI) with self-navigation offers a potential alternative with greater reliability in patients with irregular breathing patterns and improved soft tissue contrast. In this study 4D-CT and a 4D-MRI Radial Volumetric Interpolated Breath-hold Examination (VIBE) sequence was evaluated with a 4D phantom and 13 patient respiratory patterns, simulating tumour motion. Quantification of motion related tumour displacement in 4D-MRI and 4D-CT found no statistically significant difference in mean motion range. The results demonstrated the potential viability of 4D-MRI for lung cancer treatment planning.


Multifetal pregnancy reduction: a Belgian experience.
Multifetal pregnancy reductions were performed during the first trimester of pregnancy in 26 patients. Transabdominal intrathoracic KC1 injections were performed in 23 cases, and transcervical aspirations in 3 cases. There were 4 miscarriages (15%) during the second trimester, 18 pregnancies ended in 33 births, 4 pregnancies are going on uneventfully and are beyond 32 weeks. There was no maternal morbidity related to the procedure; fetal morbidity has been mild.


Long TSLP transcript expression and release of TSLP induced by TLR ligands and cytokines in human keratinocytes.
Thymic stromal lymphopoietin (TSLP), highly expressed in keratinocytes in atopic dermatitis patients and bronchial epithelial cells in asthma patients, plays a key role in allergic diseases. Two forms of TSLP mRNA (long and short) have been reported. We compared the expression of the long-form and total TSLP transcripts in primary human keratinocytes. Primary human keratinocytes were stimulated with Toll-like receptor (TLR) ligands, cytokines, and vitamin D receptor agonists. Gene expression was analyzed by quantitative real-time PCR. The amount of TSLP released was measured by ELISA. PolyI:C (TLR3 ligand), FSL-1 (TLR2-TLR6 ligand) and flagellin (TLR5 ligand) upregulated long-form TSLP expression, which predominantly contributed to upregulation of total TSLP expression. A glucocorticoid or an endosomal acidification inhibitor inhibited the polyI:C-dependent upregulation of total TSLP and the decrease of the total TSLP was due to the decrease of the long-form. An atopic cytokine milieu (TNF-α+IL-4+IL-13) or TNF-α alone also upregulated the long-form. These stimuli also induced the release of TSLP. In contrast, a high concentration of calcitriol (1,25-dihydroxyvitamin D(3), the active form of vitamin D(3)) or its analog MC903 upregulated total TSLP significantly but not the long-form, and did not induce the release of TSLP. TLR ligands or cytokines predominantly upregulate the gene expression of the long TSLP form, which contributes to the TSLP protein production, in primary human keratinocytes. Specific measurement of the long-form rather than total TSLP should be useful for accurate detection of functional human TSLP gene expression.


Pineal graft in old rats improves erythrocyte resistance to peroxyl radical-induced hemolysis.
Pineal graft from young to old rats was performed and red blood cell hemolysis, induced by the water-soluble radical initiator 2,2'-azobis (2-amidino-propane) dihydrochloride (AAPH), was evaluated 6 months after graft. Pineal graft modified the hemolysis curve kinetic profile in grafted rats versus age-matched controls, the 50% hemolysis time as well as the lag time were longer, whereas the maximal amount of hemolysis was lower, and it occurred over a longer period of time. Thiobarbituric acid reactive substances production was lower in pineal-grafted rats than in controls and the age-related decrease of erythrocyte membrane fluidity was prevented by pineal graft. The present findings support an important physiological role of pineal gland in preventing age-related alterations of erythrocyte membranes and suggest a possible antioxidant action of melatonin.


Thromboxane receptor activation enhances striatal dopamine release, leading to suppression of GABAergic transmission and enhanced sugar intake.
The extracellular dopamine level is regulated not only by synaptic inputs to dopamine neurons but also by local mechanisms surrounding dopaminergic terminals. However, much remains to be investigated for the latter mechanism. Thromboxane A(2) is one of the cyclooxygenase products derived from arachidonic acid, and acts on its cognate G protein-coupled receptor [thromboxane receptor (TP)]. We show here that TP in the striatum locally facilitates dopamine overflow. Intrastriatal injection of a TP agonist increased extracellular dopamine levels in the striatum as measured by in vivo microdialysis. TP stimulation also augmented electrically evoked dopamine overflow from striatal slices. Conversely, TP deficiency reduced dopamine overflow evoked by N-methyl-d-aspartic acid (NMDA) and acetylcholine in striatal slices. TP immunostaining showed that TP is enriched in vascular endothelial cells. Pharmacological blockade of nitric oxide (NO) synthesis and genetic deletion of endothelial NO synthase (eNOS) suppressed NMDA/acetylcholine-induced dopamine overflow. This involvement of NO was abolished in TP-deficient slices, suggesting a role for eNOS-derived NO synthesis in TP-mediated dopamine overflow. As a functional consequence of TP-mediated dopamine increase, a TP agonist suppressed GABAergic inhibitory postsynaptic currents in medium spiny neurons through a D2-like receptor-dependent mechanism. Finally, TP is involved in sucrose intake, a dopamine-dependent motivational behavior. These data suggest that TP stimulation in the striatum locally facilitates dopamine overflow evoked by synaptic inputs via NO synthesis in endothelial cells.


[Relational dealing with crisis of youth welfare professionals in casework regarding the effects of the Covid 19 pandemic].
There is still little empirical knowledge about the impact of the Covid 19 pandemic on the casework of youth welfare offices. However, qualitative studies provide a number of indications on the importance of teamwork, on explicit and implicit ways of acting as well as on decision-making practices (sense-making) of professionals in child protection. These aspects were largely limited by the lockdowns and the pandemic-related protective measures. This leads to the question of the present study about how these restrictions are dealt with and the coping strategies related to them.The analysis is based on the contrastive interpretation of telephone interviews with professionals from two youth welfare offices. From a relational perspective in the sense of Bruno Latour, which does not focus on the actors, but rather on their connections and relations, some transformations in the network in which the cases are usually processed become visible. These transformations were elaborated based on the interviews as crisis-like restrictions of the usual practice of action. In the analyzed data, ways of acting can be reconstructed that can be understood as dealing with these crises. The results show that the actual crisis is not to be found in the abstract idea of a virus pandemic, but above all in the breaking away of case work habits.


Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models.
Therapeutic concepts exploiting tumor-specific antibodies are often established in pre-clinical xenograft models using immuno-deficient mice. More complex therapeutic paradigms, however, warrant the use of immuno-competent mice, that more accurately capture the relevant biology that is being exploited. These models require the use of (surrogate) mouse or rat antibodies to enable optimal interactions with murine effector molecules. Immunogenicity is furthermore decreased, allowing longer-term treatment. We recently described controlled Fab-arm exchange (cFAE) as an easy-to-use method for the generation of therapeutic human IgG1 bispecific antibodies (bsAb). To facilitate the investigation of dual-targeting concepts in immuno-competent mice, we now applied and optimized our method for the generation of murine bsAbs. We show that the optimized combinations of matched point-mutations enabled efficient generation of murine bsAbs for all subclasses studied (mouse IgG1, IgG2a and IgG2b; rat IgG1, IgG2a, IgG2b, and IgG2c). The mutations did not adversely affect the inherent effector functions or pharmacokinetic properties of the corresponding subclasses. Thus, cFAE can be used to efficiently generate (surrogate) mouse or rat bsAbs for pre-clinical evaluation in immuno-competent rodents.


Breastfeeding knowledge and health behavior among Mayan women in rural Guatemala.
Guatemala has the fourth highest infant mortality rate in Latin America, which makes the support and protection of breastfeeding especially critical. Traditional health-promoting practices like breastfeeding may be protected by increasing knowledge of its benefits. Yet there is a dearth of research documenting breastfeeding knowledge (i.e., knowledge of its benefits for infant health and development) in communities where breastfeeding is already practiced. Our aim was to assess degree of breastfeeding knowledge among Mayan mothers in the rural highlands of North-Western Guatemala and compare knowledge of breastfeeding - a practice promoted by local health centers - and other traditional yet non-promoted infant care practices. We conducted a survey of maternal-infant health knowledge and behavior among mothers in rural Guatemala (N = 300) from six communities with a non-governmental organization (NGO) health program and one comparison community. Overall, mothers displayed more knowledge of the benefits of breastfeeding in comparison with other traditional infant care practices not promoted by a community health program. Mothers in communities with a health program demonstrated increased knowledge of breastfeeding, regardless of whether they personally participated in the program. This health knowledge predicted participation in novel health-promoting behaviors (family planning, prenatal care, exclusive breastfeeding). Understanding breastfeeding knowledge as a proxy for community health exposure may increase the efficacy and diffusion of community health messaging.


Thyroid function abnormality induced by PD-1 inhibitors have a positive impact on survival in patients with non-small cell lung cancer.
Thyroid function abnormality (TFA) is a common immune-related adverse event (irAEs), but the association between it and the efficacy of programmed cell death protein 1 (PD-1) inhibitor in advanced non-small cell lung cancer (NSCLC) is finitely understood. We conducted a single center, retrospective study of advanced NSCLC patients who were treated with PD-1 inhibitors between 10 October 2016 and 1 April 2020. TFA was characterized as new onset subclinical hypothyroidism, overt hypothyroidism, subclinical hyperthyroidism and overt hyperthyroidism. Frequency of development of TFA-irAEs, and its relationship with overall survival (OS) and progression free survival (PFS) were evaluated. In our study, 191 patients were treated with PD-1 inhibitors. Among them, forty patients (20.9%) developed TFA, of whom 10 (5.2%) presented with subclinical hypothyroidism, 15 (7.9%) with overt hypothyroidism, 6 (3.1%) with subclinical hyperthyroidism and 9 (4.7%) with overt hyperthyroidism. Survival analysis showed that the OS (16.8 months vs. 11.1 months, p < 0.001) and PFS (10.4 months vs. 5.5 months, p < 0.001) were significantly longer in patients with TFA-irAEs than in those without TFA-irAEs. In subgroup analysis of hypothyroidism and hyperthyroidism groups, similar trends were also obtained for both OS and PFS. After adjusting for potential confounding variables, patients with TFA-irAEs had a lower mortality risk (HR 0.334, 95%CI 0.196-0.571) than those without TFA-irAEs. TFA-irAEs is associated with enhanced PD-1 inhibitor efficacy in advanced NSCLC patients and it may be a biomarker for antitumor immune response.


Targeting the HIF-1α-IGFBP2 axis therapeutically reduces IGF1-AKT signaling and blocks the growth and metastasis of relapsed anaplastic Wilms tumor.
For patients with anaplastic Wilms tumor (WiT), metastasis and recurrence are common, and prognosis is generally poor. Novel therapies are needed to improve outcomes for patients with this high-risk WiT. A potential contributor to WiT development is constitutive activation of AKT by insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) signaling pathway, but the complete underlying mechanism remains unclear. Here, we demonstrate that the hypoxia-inducible factor 1α (HIF-1α)-IGF binding protein 2 (IGFBP2) axis and the tumor-specific IGF1A are key players for constitutive activation of IGF1-AKT signaling leading to the tumor malignancy. HIF-1α and IGFBP2 are highly expressed in a majority of WiT patient samples. Deficiency of either HIF-1α or IGFBP2 or IGF1 in the tumor cells significantly impairs tumor growth and nearly abrogates metastasis in xenografted mice. Pharmacologic targeting of HIF-1α by echinomycin delivered via nanoliposomes can efficiently restrain growth and metastasis of patient-derived relapsed anaplastic WiT xenografts. Liposomal echinomycin is more potent and effective in inhibiting WiT growth than vincristine in an anaplastic WiT mouse model, and eliminates metastasis by suppressing HIF-1α targets and the HIF-1α-IGFBP2 axis, which governs IGF1-AKT signaling.


Response rates to mail surveys published in medical journals.
The purpose of this study was to characterize response rates for mail surveys published in medical journals; to determine how the response rate among subjects who are typical targets of mail surveys varies; and to evaluate the contribution of several techniques used by investigators to enhance response rates. One hundred seventy-eight manuscripts published in 1991, representing 321 distinct mail surveys, were abstracted to determine response rates and survey techniques. In a follow-up mail survey, 113 authors of these manuscripts provided supplementary information. The mean response rate among mail surveys published in medical journals is approximately 60%. However, response rates vary according to subject studied and techniques used. Published surveys of physicians have a mean response rate of only 54%, and those of non-physicians have a mean response rate of 68%. In addition, multivariable models suggest that written reminders provided with a copy of the instrument and telephone reminders are each associated with response rates about 13% higher than surveys that do not use these techniques. Other techniques, such as anonymity and financial incentives, are not associated with higher response rates. Although several mail survey techniques are associated with higher response rates, response rates to published mail surveys tend to be moderate. However, a survey's response rate is at best an indirect indication of the extent of non-respondent bias. Investigators, journal editors, and readers should devote more attention to assessments of bias, and less to specific response rate thresholds.


Laser-assisted in situ keratomileusis complications in diabetes mellitus.
To report the incidence of complications and the refractive results in patients with diabetes mellitus treated with laser-assisted in situ keratomileusis (LASIK). A retrospective review of the charts, focusing on 6-month postoperative data, was performed on 30 eyes from patients with diabetes and 150 age- and gender-matched control eyes operated on during the same period. The incidence of complications and postoperative refractive results were compared. The data analyzed include UCVA, spherical equivalent, astigmatism power, astigmatism axis, and vector astigmatism change. Diabetic eyes treated with LASIK had an overall complication rate of 47% compared with the control population complication incidence of 6.9% (p< 0.01). The most frequent complications occurring in the diabetic population are punctate epithelial erosions and persistent epithelial defects. Spherical correction change was -4.64 diopters (D) for diabetic eyes and -4.98 D for control eyes (p= 0.49). Mean spherical equivalent change was -4.69 D for diabetic eyes and -4.75 D for control eyes (p= 0.9). Mean change in uncorrected visual acuity (LogMAR) was 1.5 for diabetic eyes and 1.65 for control eyes (p= 0.18). Mean astigmatism magnitude change was 0.31 in diabetic eyes and 0.57 in control eyes (p= 0.12). Mean vector corrected astigmatism change was 0.97 for diabetic eyes and 1.12 for control eyes (p= 0.31). Mean vector-corrected astigmatism axis for patients with diabetes was 18.17 for diabetic eyes and 6.20 for control eyes (p= 0.30). Patients with diabetes who undergo LASIK are at a significantly higher risk of developing postoperative epithelial complications. In addition, this study revealed poorer refractive results in the eyes of patients with diabetes treated with LASIK.


Erratum to evaluation of long-term breast shape in inferior versus superomedial pedicle reduction mammoplasty: a comparative study.
[This corrects the article DOI: 10.21037/gs-20-440.].


A machine learning approach for modelling the occurrence of Galba truncatula as the major intermediate host for Fasciola hepatica in Switzerland.
Fasciolosis caused by the trematode Fasciola hepatica is an important parasitosis in both livestock and humans across the globe. Chronic infections in cattle are associated with considerable economic losses. As a prerequisite for an effective control and prevention of fasciolosis in cattle fine-scale predictive models on farm-level are needed. Since disease transmission will only occur where the mollusc intermediate host is present, the objective of our research was to develop a regression model that allows to predict the local presence or absence of Galba truncatula as principal intermediate host for Fasciola hepatica in Switzerland. By implementing generalized linear mixed models (GLMMs) a total amount of 70 variables were analysed for their potential influence on the likelihood πi of finding Galba truncatula at a certain site. Important site-specific features could be considered by selecting suitable modelling procedures. The statistical software R was used to conduct regression analysis, performing the grplasso and the glmmLasso method. The selection of parameters was based on 10-fold cross validation and the Bayesian Information Criterion (BIC). This yielded a total number of 19 potential predictor variables for the grplasso and 13 variables for the glmmLasso model, which also included random effects. Nine variables appeared to be relevant predictors for the occurrence of Galba truncatula in both models. These included reed/humid area, spring water, water bodies within a 100 m radius, and trees/bushes as powerful positive predictors. High soil depth, temperatures frequently exceeding 30 °C in the year preceding the search for snails and temperatures below 0 °C especially in the second year before were identified to exert an adverse effect on the occurrence of Galba truncatula. Temperatures measured near ground level proved to be more powerful predictors than macroclimatic parameters. Precipitation values seemed to be of minor impact in the given setting. Both regression models may be convenient for a fine-scale prediction of the occurrence of Galba truncatula, and thus provide useful approaches for the development of future spatial transmission models, mapping the risk of fasciolosis in Switzerland on farm-level.


Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma.
This study investigates aberrant DNA methylations as potential diagnosis and prognosis markers for esophageal squamous-cell carcinoma (ESCC), which if diagnosed at advanced stages has <30% five-year survival rate. Comparing genome-wide methylation sites of 91 ESCC and matched adjacent normal tissues, we identified 35,577 differentially methylated CpG sites (DMCs) and characterized their distribution patterns. Integrating whole-genome DNA and RNA-sequencing data of the same samples, we found multiple dysregulated transcription factors and ESCC-specific genomic correlates of identified DMCs. Using featured DMCs, we developed a 12-marker diagnostic panel with high accuracy in our dataset and the TCGA ESCC dataset, and a 4-marker prognostic panel distinguishing high-risk patients. In-vitro experiments validated the functions of 4 marker host genes. Together these results provide additional evidence for the important roles of aberrant DNA methylations in ESCC development and progression. Our DMC-based diagnostic and prognostic panels have potential values for clinical care of ESCC, laying foundations for developing targeted methylation assays for future non-invasive cancer detection methods.


Evaluation of accuracy of 3-dimensional printed dental models in reproducing intermaxillary relational measurements: Based on inter-operator differences.
Although, digital models have recently been used in orthodontic clinics, physical models are still needed for a multitude of reasons. The purpose of this study was to assess whether the printed models can replace the plaster models by evaluating their accuracy in reproducing intermaxillary relationships and by appraising the clinicians' ability to measure the printed models. Twenty sets of patients' plaster models with well-established occlusal relationships were selected. Models were scanned using an intraoral scanner (Trios 3, 3Shape Dental System) by a single operator. Printed models were made with ZMD-1000B light-curing resin using the stereolithography method 3-dimensional printer. Validity, reliability, and reproducibility were evaluated using measurements obtained by three operators. In evaluation of validity, all items showed no significant differences between measurements taken from plaster and printed models. In evaluation for reliability, significant differences were found in the distance between the gingival zeniths of #23-#33 (DZL_3) for the plaster models and at #17-#43 (DZCM_1) for the printed models. In evaluation for reproducibility, the plaster models showed significant differences between operators at midline, and printed models showed significant differences at 7 measurements including #17-#47 (DZR_7). The validity and reliability of intermaxillary relationships as determined by the printed model were clinically acceptable, but the evaluation of reproducibility revealed significant inter-operator differences. To use printed models as substitutes for plaster models, additional studies on their accuracies in measuring intermaxillary relationship are required.


Theory helps experiment to reveal VOCs in human breath.
Volatile organic compounds (VOCs) present in human breath not only provide information about the internal chemistry of the body but can also be specific to diseases. Therefore, detection and analysis of specific VOCs can be used for medical diagnostics. However, up until today in spite of several existing VOC-based detection techniques and significant efforts, breath analysis is not a diagnostic method available for clinicians. Infrared absorption spectroscopy is a promising technique to fill this gap, with tens of identified VOCs in breath. Currently, a lack of digital spectral databases and several masking effects make difficult reliable molecular identification of observed absorption features. We demonstrate that calculations of rotational bands of vibrational spectra could serve as a basic method for molecular identification of spectral features observed in experiment. Results of comparison of several known VOCs spectra with the predictions of the theoretical model are presented.


Novel and highly potent histamine H3 receptor ligands. Part 2: exploring the cyclohexylamine-based series.
Synthesis and biological evaluation of novel and potent cyclohexylamine-based histamine H3 receptor inverse agonists are described. Compounds in this newly identified series exhibited subnanomolar binding affinities for human receptor and no significant interaction with hERG channel. One derivative (10t) demonstrated enhanced in vivo efficiency and preferential brain distribution, both properties suitable for potential clinical evaluation.


Region-specific and agent-specific dilation of intracerebral microvessels by volatile anesthetics in rat brain slices.
Volatile anesthetics are potent cerebral vasodilators. Although the predominant site of cerebrovascular resistance is attributed to intracerebral arterioles, no studies have compared the actions of volatile anesthetics on intraparenchymal microvessels. The authors compared the effects of halothane and isoflurane on intracerebral arteriolar responsiveness in hippocampal and neocortical microvessels using a brain slice preparation. After Institutional Review Board approval, hippocampal or neocortical brain slices were prepared from anesthetized Sprague-Dawley rats and placed in a perfusion-recording chamber, superfused with artificial cerebrospinal fluid. Arteriolar diameters were monitored with videomicroscopy before, during, and after halothane or isoflurane were equilibrated in the perfusate. PGF2alpha preconstricted vessels before anesthetic administration. A blinded observer using a computerized videomicrometer analyzed diameter changes. Baseline microvessel diameter and the degree of preconstriction were not different between groups. In the hippocampus, the volatile agents produced similar, concentration-dependent dilation (expressed as percent of preconstricted control +/- SEM) of 68 +/- 6% and 79 +/- 9% (1 MAC) and 120 +/- 3% and 109 +/- 5% (2 MAC) (P < 0.05) during halothane and isoflurane, respectively. In the cerebral cortex, isoflurane caused significantly less vasodilation than did similar MAC levels of halothane (84 +/- 9% vs. 42 +/- 5% dilation at 1 MAC; 121 +/- 4% vs. 83 +/- 5% dilation at 2 MAC halothane vs. isoflurane, respectively). Halothane and isoflurane differentially produce dose-dependent dilation of intraparenchymal cerebral microvessels. These findings suggest that local effects of the volatile anesthetics on intracerebral microvessel diameter contribute significantly to alterations in cerebrovascular resistance and support previously described heterogeneous actions on cerebral blood flow produced by these agents.


Health promotion in emerging collectivist communities: A study of dietary acculturation in the South Sudanese community in Logan City, Australia.
Understanding dietary acculturation within collectivist communities is required to develop and tailor appropriate health promotion strategies to prevent diet-related chronic diseases. This research explores the journey of the South Sudanese community living in Logan City, Australia in establishing new norms around food choices and practices over time. Three semi-structured group interviews and a final community forum of women (n = 20) from the South Sudanese community were conducted. These explored changes in and influences on dietary practices post-settlement. Sessions were recorded, transcribed and thematically analysed using inductive and deductive approaches. Feedback on findings from participants and community members was incorporated. Participants reported dietary acculturation phases, including assimilation, reflection and separation, with a return to traditional foods over time. Factors influencing the transition between phases included; the characteristics of the collectivist community such as shared knowledge, experiences and resources, increased accessibility to traditional foods, and increased food and health literacy as responses to emerging diet-related health issues. The Logan City South Sudanese community has navigated a new and complex food environment with positive long-term dietary outcomes; however, the initial decline in health due to poor diet on arrival may have been prevented. SO WHAT?: Early intervention and culturally appropriate health promotion strategies that are co-designed and tailored to the characteristics and strengths of newly settled collectivist communities are needed. These should promote the benefits of healthy traditional food habits, while assisting communities to successfully navigate a new food environment.


Shellfish from Todos os Santos Bay, Bahia, Brazil: treat or threat?
This study determined the concentrations of major and trace elements in shellfish (oysters, clams and mussels) and conducted an assessment of the health risks due to the consumption of contaminated seafood. Samples were collected at 34 sites along Todos os Santos Bay, Brazil. The elements were determined by ICP OES and Hg by Direct Mercury Analysis. Relatively high concentrations of trace elements (As, Zn, Se and Cu) were found in seafood tissues. Potential daily intake of As, Co, Se, Zn and Cu associated to shellfish consumption suggested relevant non-carcinogenic risk for all studied locations. Copper was the element that posed the greatest non-carcinogenic risk, while Pb posed the highest carcinogenic risk. Health risks for humans were greatest from the consumption of mussels. Contaminated shellfish offer the greatest risk for children, subsistence fishers and subsistence shellfish consumers.


Secretoglobin superfamily protein SCGB3A2 deficiency potentiates ovalbumin-induced allergic pulmonary inflammation.
Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, which may play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2, Scgb3a2(-/-) mice were generated and characterized. Scgb3a2(-/-) mice did not exhibit any overt phenotypes. In ovalbumin- (OVA-) induced airway allergy inflammation model, Scgb3a2(-/-) mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenic Scgb3a2(-/-) mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates. These results indicate that the loss of SCGB3A2 function was influenced by a modifier gene(s) in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent.


Long-term quality of life after hernioplasty using a Prolene hernia system in adult inguinal hernia.
Most surgeons favour the use of a mesh for open inguinal hernia repair as it has a low recurrence rate. Procedures used most frequently are the Lichtenstein method, mesh plug repair and the Prolene hernia system (PHS). The choice of technique may be influenced by effects on postoperative pain and quality of life. In this retrospective study, results from inguinal hernia repair with the PHS in a regional training hospital were analysed. Thirty primary inguinal hernias were treated with PHS. The primary endpoint was the recurrence rate. Secondary endpoints were short-term and long-term complications. Pain was evaluated by use of a visual analog scale (VAS, 0-100), and a short-form 36-item questionnaire was used to assess postoperation quality of life. All patients visited the outpatient clinic for a physical examination (100% follow up). After a median follow up of 8 years, one patient was diagnosed with recurrent herniation (3.3%). Three self-limited wound discharge (10%), and one haematoma needing surgical evacuation (3.3%) were diagnosed. Two patients (6.6%) suffered from persistent pain (VAS > 40). Average VAS score was 21 (0-80) 8 years after surgery. In a regional training hospital, primary inguinal hernias were treated with low recurrence and few complications by use of the PHS.


A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein.
Respiratory syncytial virus (RSV) infection is the leading cause of hospitalization and infant mortality under six months of age worldwide; therefore, the prevention of RSV infection in all infants represents a significant unmet medical need. Here we report the isolation of a potent and broadly neutralizing RSV monoclonal antibody derived from a human memory B-cell. This antibody, RB1, is equipotent on RSV A and B subtypes, potently neutralizes a diverse panel of clinical isolates in vitro and demonstrates in vivo protection. It binds to a highly conserved epitope in antigenic site IV of the RSV fusion glycoprotein. RB1 is the parental antibody to MK-1654 which is currently in clinical development for the prevention of RSV infection in infants.


Comparative analysis of antioxidative systems in malignant and benign brain tumours.
Comparison of redox conditions in malignant and benign tumours is essential for understanding the role of reactive oxygen species in the pathophysiology of aggressive cancer profiles. Here we compare antioxidative systems in highly malignant brain tumour - glioblastoma multiforme (GBM), and in meningioma, a benign brain tumour. Tumour tissues and blood of 67 GBM patients (mean age: 52.9 ± 11.5 years) and 67 meningioma patients (59.2 ± 10.2 years), and blood of 30 control subjects (50.8 ± 12.8 years) were analysed via biochemical assays. Components of glutathione system, which is responsible for H2O2 removal, showed lower activity/level in GBM: glutathione peroxidase (GBM: 9.90 ± 0.22; meningioma: 11.78 ± 0.23 U/mg of proteins; P < 0.001), glutathione reductase (GBM: 3.83 ± 0.13; meningioma: 4.67 ± 0.11 U/mg of proteins; P < 0.001), and glutathione (GBM: 6.70 ± 0.12; meningioma: 7.58 ± 0.14 μmol/g of tissue; P < 0.001). In contrast, the rank order of glutathione reductase activity and glutathione level in erythrocytes was: GBM > meningioma > control. Superoxide dismutase and catalase activities were lower in the blood of cancer patients compared to controls. Cells of malignant brain tumour show down-regulated antioxidative system which might result in increased levels of H2O2 compared to benign tumour tissue.


The developing gut-lung axis: postnatal growth restriction, intestinal dysbiosis, and pulmonary hypertension in a rodent model.
Postnatal growth restriction (PNGR) in premature infants increases risk of pulmonary hypertension (PH). In a rodent model, PNGR causes PH, while combining PNGR and hyperoxia increases PH severity. We hypothesized that PNGR causes intestinal dysbiosis and that treatment with a probiotic attenuates PNGR-associated PH. Pups were randomized at birth to room air or 75% oxygen (hyperoxia), to normal milk intake (10 pups/dam) or PNGR (17 pups/dam), and to probiotic Lactobacillus reuteri DSM 17938 or phosphate-buffered saline. After 14 days, PH was assessed by echocardiography and right ventricular hypertrophy (RVH) was assessed by Fulton's index (right ventricular weight/left ventricle + septal weight). The small bowel and cecum were analyzed by high-throughput 16S ribosomal RNA gene sequencing. PNGR with or without hyperoxia (but not hyperoxia alone) altered the microbiota of the distal small bowel and cecum. Treatment with DSM 17938 attenuated PH and RVH in pups with PNGR, but not hyperoxia alone. DSM 17938 treatment decreased α-diversity. The intestinal microbiota differed based on oxygen exposure, litter size, and probiotic treatment. PNGR causes intestinal dysbiosis and PH. Treatment with DSM 17938 prevents PNGR-associated RVH and PH. Changes in the developing intestine and intestinal microbiota impact the developing lung vasculature and RV.


Guided Growth for the Treatment of Cubitus Varus in Children: Medium- to Long-Term Results.
Correction of cubitus varus is commonly attempted through supracondylar humeral osteotomy. We hypothesized that lateral distal humeral hemiepiphysiodesis (LDHH) could be used to gradually correct this deformity in children. We conducted a retrospective study including all patients who underwent LDHH with the eight-Plate system between 2008 and 2018, with a minimum 4-year follow-up. We collected demographic, fracture-related, pre- and postoperative clinical (carrying angle (CA), ROM), and radiological data (humeral-ulnar angle (HUA), Baumann angle (BA), shaft-condylar angle (SCA), lateral capitellohumeral angle (LCHA)), as well as data on complications and satisfaction at last follow-up. Fifteen patients were included, with a median follow-up of 81 (64-103) months. All the variables had improved significantly as follows: CA -16 (-18 to -9)°, HUA -16 (-19 to -12)°, BA -11 (-17 to -7)°, SCA 7.5 (3.3 to 13.8)°, LCHA -4.8 (-6.8 to 0.6), flexion 10 (0 to 24)°, and extension 10 (0 to 10)°. The annual correction rate in terms of HUA was 2.41° (1.9 to 3.2). There were 5 cases of aseptic screw loosening, 4 of them requiring replacement, without relation to age at surgery (p = 0.324). Most patients (86.67%) were satisfied, and a relationship was found with younger age at surgery (p = 0.037). In conclusion, preliminary results show that LDHH with the eight-Plate system is an effective technique for mild to moderate cubitus varus deformity correction in children. Patients should be advised of the relatively long duration of implant retention and the possibility of reoperation for screw replacement or implant removal.


Beneficial effect of tripterine on systemic lupus erythematosus induced by active chromatin in BALB/c mice.
The aim of this study was to determine whether tripterine, isolated from Tripterygium wilfordii Hoog f. in China, had beneficial effects on experimental systemic lupus erythematosus induced by active chromatin in BALB/c mice. BALB/c mice were immunized with active chromatin isolated from concanavalin A-activated syngenetic spleno-lymphocytes on day 0. Tripterine 6 or 12 mg kg(-1) day(-1), or prednisone 5 mg kg(-1) day(-1) was given to BALB/c mice intragastrically from day 35 to day 50. Treatment with tripterine 12 mg kg(-1) day(-1) for 15 days protected renal from glomerular injury with a concomitant reduction of serum autoantibodies and total immunoglobulin G (IgG) also with a improvement of splenocyte proliferation stimulated with concanavalin A and lipopolysaccharide. The effects were associated with reduced interleukin-10 production and serum nitric oxide (NO) level but not interferon-gamma compared with vehicle-treated control group. Tripterine 6 mg kg(-1) day(-1) had no significant protective effect against glomerular injury. It inhibited autoantibodies and interleukin-10 production but had no effect on splenocyte proliferation, serum NO level, and interferon-gamma production. These findings suggested that tripterine had a beneficial effect on systemic lupus erythematosus induced by active chromatin in BALB/c mice.


Prospective associations between joint categories of physical activity and insomnia symptoms with onset of poor mental health in a population-based cohort.
Physical inactivity and insomnia symptoms are independently associated with increased risk of depression and anxiety; however, few studies jointly examine these risk factors. This study aimed to prospectively examine the joint association of physical activity (PA) and insomnia symptoms with onset of poor mental health in adults. Participants from the 2013 to 2018 annual waves of the Household Income and Labour Dynamics in Australia panel study who had good mental health (Mental Health Inventory-5 >54) in 2013, and who completed at least 1 follow-up survey (2014-2018), were included (n = 10,977). Poor mental health (Mental Health Inventory-5 ≤ 54) was assessed annually. Baseline (2013) PA was classified as high/moderate/low, and insomnia symptoms (i.e., trouble sleeping) were classified as no insomnia symptoms/insomnia symptoms, with 6 mutually exclusive PA-insomnia symptom groups derived. Associations of PA-insomnia symptom groups with onset of poor mental health were examined using discrete-time proportional-hazards logit-hazard models. There were 2322 new cases of poor mental health (21.2%). Relative to the high PA/no insomnia symptoms group, there were higher odds (odds ratio and 95% confidence interval (95%CI)) of poor mental health among the high PA/insomnia symptoms (OR = 1.87, 95%CI: 1.57-2.23), moderate PA/insomnia symptoms (OR = 1.93, 95%CI: 1.61-2.31), low PA/insomnia symptoms (OR = 2.33, 95%CI: 1.96-2.78), and low PA/no insomnia symptoms (OR = 1.14, 95%CI: 1.01-1.29) groups. Any level of PA combined with insomnia symptoms was associated with increased odds of poor mental health, with the odds increasing as PA decreased. These findings highlight the potential benefit of interventions targeting both PA and insomnia symptoms for promoting mental health.


Inhibition of glioblastoma cell proliferation, invasion, and mechanism of action of a novel hydroxamic acid hybrid molecule.
Glioblastoma multiforme is one of the most aggressive brain tumors and current therapies with temozolomide or suberoylanilide hydroxamic acid (SAHA, vorinostat) show considerable limitations. SAHA is a histone deacetylase (HDAC) inhibitor that can cause undesirable side effects due to the lack of selectivity. We show here properties of a novel hybrid molecule, sahaquine, which selectively inhibits cytoplasmic HDAC6 at nanomolar concentrations without markedly suppressing class I HDACs. Inhibition of HDAC6 leads to significant α-tubulin acetylation, thereby impairing cytoskeletal organization in glioblastoma cells. The primaquine moiety of sahaquine reduced the activity of P-glycoprotein, which contributes to glioblastoma multiforme drug resistance. We propose the mechanism of action of sahaquine to implicate HDAC6 inhibition together with suppression of epidermal growth factor receptor and downstream kinase activity, which are prominent therapeutic targets in glioblastoma multiforme. Sahaquine significantly reduces the viability and invasiveness of glioblastoma tumoroids, as well as brain tumor stem cells, which are key to tumor survival and recurrence. These effects are augmented with the combination of sahaquine with temozolomide, the natural compound quercetin or buthionine sulfoximine, an inhibitor of glutathione biosynthesis. Thus, a combination of agents disrupting glioblastoma and brain tumor stem cell homeostasis provides an effective anti-cancer intervention.


Androluteoma syndrome of pregnancy.
The clinical course of a 26-year-old primigravid woman with a virilizing luteoma of pregnancy is described. It was demonstrated by endocrine studies that the tumor secreted an excessive amount of testosterone. After removal of the luteoma in week 32 of pregnancy, the virilizing symptoms of the mother completely regressed. A normal male infant was delivered in week 39. From 100 luteomas of pregnancy described in the literature, 26 cases have been cited to elicit endocrine virilizing activity. An evaluative synopsis indicates that including the case described in this paper only 13 can be regarded as a clinical, morphologic, and functional entity. This entity should be differentiated from the inhomogeneous group of luteomas as the "androluteoma syndrome of pregnancy." It is characterized by the following major criteria: virilization, beginning with the second trimester of pregnancy; histologic criteria of a luteoma of pregnancy; production of testosterone, leading to excessive plasma levels (exceeding the concentration of androstenedione), and masculinization of female fetuses.


Modelling osmotic stress by Flux Balance Analysis at the genomic scale.
Predictive microbiology for food safety is still primarily based on empirical models describing the effect of the environmental conditions of the food on the kinetics of the growth of foodborne pathogens. One way to make these models more mechanistic is to use systems biology methods such as Flux Balance Analysis (FBA). FBA consists of evaluating the possible fluxes through the metabolic reactions taking place in a cell. Using this method, the specific growth rate of Escherichia coli can be predicted by assuming, as an objective function, that the cells maximise their biomass production during balanced growth. Whilst this works under favourable environmental conditions, our simulations show that this objective function is not sufficient to explain the decrease of the growth rate due to osmotic stress. One feature of the FBA models is that the parameters and objective function in general refer to chemostat experiments where the carbon source is the main limiting factor. This may be relevant to some foods where the carbon to nitrogen balance is limiting but, in general, it is the physico-chemical conditions which are the most stringent. We therefore need to examine the effect of such constraints on the fluxes and/or modify the objective function, or to elaborate the metabolic model by taking into account other functional levels of the cell in order to develop mechanistic predictive models for osmotic stress conditions.


Participation in age-related activities and influence of cultural factors--comments from youth and parents of children with postnatal post infectious hemiplegia in Stockholm, Sweden.
To investigate whether children with postnatal post-infectious hemiplegic cerebral palsy, and their parents, felt that participation in activities typical for the child's age and gender was affected. To identify factors, intra- and extra-personal that influenced disability with emphasis on factors related to immigration. Interviews with six youths and 15 caregivers regarding the child's ability to participate in age-related activities, the consequences of disability in their home country compared to Sweden, and whether immigration influenced being a parent to a disabled child. All reported large difficulties participating in age-related activities. Positive and negative differences in participation in different cultures were described. War, culture, eating habits, hygiene habits, and school could differ and create difficulties when in Sweden. Language skills and intra personal factors influenced information gathering and participation in parental activities. Surprisingly large difficulties in participation may separate those with a postnatal post-infectious aetiology from hemiplegia of other aetiologies. High degrees of additional impairments may influence participation more than the physical disability. Language skills and cultural factors influence ability to seek and gain information. A mutual process where both Swedes and immigrants know traditions of care for disabled in both places may create understanding and improved dialogue.


Myosteatosis as a novel prognostic biomarker after radical cystectomy for bladder cancer.
This study aims to evaluate the influence of myosteatosis on survival of patients after radical cystectomy (RC) for bladder cancer. We retrospectively identified 230 patients who underwent RC for bladder cancer at our three institutions between 2009 and 2018. Digitized free-hand outlines of the left and right psoas muscles were made on axial non-contrast computed tomography images at level L3. To assess myosteatosis, average total psoas density (ATPD) in Hounsfield Units (HU) was also calculated as an average of bilateral psoas muscle density. We compared cancer-specific survival (CSS) between high ATPD and low ATPD groups and performed cox regression hazard analyses to identify the predictors of CSS. Median ATPD was 44 HU (quartile: 39-47 Hounsfield Units). Two-year CSS rate in overall patients was 76.6%. Patients with low ATPD (< 44 HU) had significantly lower CSS rate (P = 0.01) than patients with high ATPD (≥ 44 HU). According to multivariate analysis, significant independent predictors of poor CSS were: Eastern Cooperative Oncology Group performance status ≥ 1 (P = 0.03), decreasing ATPD (P = 0.03), non-urothelial carcinoma (P = 0.01), pT ≥ 3 (P < 0.01), and pN positive (P < 0.01). In conclusion, myosteatosis (low ATPD) could be a novel predictor of prognosis after RC for bladder cancer.


Nasopharyngeal and adjacent neoplasms: a clinico-pathologic and immunologic study.
Thirteen cases of nasopharyngeal carcinoma (NPC) and 16 cases of non-NPC tumors in the nasopharynx or in adjacent locations were investigated clinically, immunologically, and pathologically. All tumors were classified according to the TNM classification, and the stage and course of the disease was correlated with the histological tumor type, the T- and B-cell distribution in tumor tissue and in the peripheral blood, as well as with antibody titers against Epstein-Barr virus (EBV). The results showed a positive correlation of decreased T- and B-cells in tumor tissue and of decreased T-cells in the peripheral blood with the extend of the tumor in both NPC and non-NPC cases, with some exceptions of lymphocyte rich neoplasms (lymphoepithelial carcinoma and malignant lymphoma). Antibodies against EBV (early antigen and capsid antigen) became progressively elevated with increasing tumor stage in NPC-cases but not in non-NPC cases. The latter, however, was observed only in two histological types of NPC's: anaplastic carcinoma and lymphoepithelial carcinoma; titers in the remaining tumor types stayed insignificant.