Association between serum tumor necrosis factor-alpha level and the efficacy of infliximab for refractory pouchitis after restorative proctocolectomy in patients with ulcerative colitis.
Although the aetiology of pouchitis after restorative proctocolectomy in ulcerative colitis (UC) remains unknown, infliximab (IFX) is often effective for this condition. However, indicators and predictors of treatment efficacy remain unclear. In this study, the association between serum tumor necrosis factor-alpha (TNF-α) levels and refractory pouchitis was evaluated. We conducted a prospective study between January 2014 and April 2016. Patients with antibiotic-refractory pouchitis were treated with IFX. Serum TNF-α levels were measured before IFX induction. Diagnoses were confirmed using the modified Pouchitis Disease Activity Index (m-PDAI). Responders were defined as patients with an m-PDAI score lower than 5. Recurrence was defined as an m-PDAI score exceeding 5 during maintenance treatment or a need for additional treatments. Associations between serum TNF-α level and efficacy of IFX during 52 weeks of maintenance therapy were evaluated. Thirteen patients were eligible for this study. The short-term efficacy was 8/13 (61.5%). Four patients could not be maintained with IFX alone. The cumulative maintenance ratio was 30.8%/52 weeks, and the cut-off value for serum TNF-α was 1.93 pg/mL for short-term response. Although there was no significant association between serum TNF-α and treatment response, IFX treatment was unsuccessful for all five patients with TNF-α levels below 1.93 pg/mL, including four short-term non-responders and one long-term non-responder. Serum TNF-α level was not an independent predictor of IFX efficacy for refractory pouchitis. However, IFX may be effective for patients with elevated serum TNF-α. Future studies should assess this possibility.


Effects of posture on tactile localization by 4 years of age are modulated by sight of the hands: evidence for an early acquired external spatial frame of reference for touch.
Adults show a deficit in their ability to localize tactile stimuli to their hands when their arms are in the less familiar, crossed posture. It is thought that this 'crossed-hands deficit' arises due to a conflict between the anatomical and external spatial frames of reference within which touches can be encoded. The ability to localize a single tactile stimulus applied to one of the two hands across uncrossed-hands and crossed-hands postures was investigated in typically developing children (aged 4 to 6 years). The effect of posture was also compared across conditions in which children did, or did not, have visual information about current hand posture. All children, including the 4-year-olds, demonstrated the crossed-hands deficit when they did not have sight of hand posture, suggesting that touch is located in an external reference frame by this age. In this youngest age group, when visual information about current hand posture was available, tactile localization performance was impaired specifically when the children's hands were uncrossed. We propose that this may be due to an early difficulty with integrating visual representations of the hand within the body schema.


Potentiation of radioimmunotherapy with response-selective peptide agonist of human C5a.
Physiologic barriers to the delivery of macromolecules to solid tumors are a major obstacle to the clinical success of radioimmunotherapy (RIT). Only a small fraction of the injected dose of the radiolabeled monoclonal antibody (mAb) localizes at the tumor site. This situation worsens as the tumor burden increases. It is hypothesized that improvements to RIT of adenocarcinoma can be realized by inclusion of vasoactive agents, in particular agents able to increase the vascular permeability of tumor capillaries. In these studies, a response-selective peptide agonist of human C5a, GCGYSFKPMPLaR (AP), was used to transiently increase tumor vascular permeability in an effort to improve RIT of solid tumors. Athymic mice xenografted with human colorectal adenocarcinoma LS174T were treated intravenously with low doses (9.25 MBq) of 131I-labeled mAb B72.3 in combination with various intravenous doses of AP. The progression of the disease or the loss of >20% body weight was taken as the endpoint. Biodistribution and tumor uptake kinetics were studied in the same tumor-antibody system. The uptake of 125I-B72.3 in LS174T xenografts increased in a dose-dependent manner with an apparent maximal effect between 3 and 6 h after intravenous administration of AP. Augmenting the dose of 9.25 MBq 131I-B72.3 with a single administration of 0.1 mg AP delayed tumor growth nearly 2-fold; the tumor quadrupling time (T(q)) was 14.2 +/- 3.3 d for 131I-B72.3 alone versus 26.0 +/- 3.6 d for 131I-B72.3 plus 0.1 mg AP (P < 0.001). An additional dose of 0.1 mg AP 24 h after 131I-B72.3 further improved the therapeutic outcome (T(q) = 48.5 +/- 7.9 d; P < 0.001) and resulted in several cases of tumor regression. The inclusion of agonist peptides of human C5a in the RIT scheme results in improved tumor responses without any manifest side effects.


A single transcription factor regulates evolutionarily diverse but functionally linked metabolic pathways in response to nutrient availability.
During evolution, enzyme-coding genes are acquired and/or replaced through lateral gene transfer and compiled into metabolic pathways. Gene regulatory networks evolve to fine tune biochemical fluxes through such metabolic pathways, enabling organisms to acclimate to nutrient fluctuations in a competitive environment. Here, we demonstrate that a single TrmB family transcription factor in Halobacterium salinarum NRC-1 globally coordinates functionally linked enzymes of diverse phylogeny in response to changes in carbon source availability. Specifically, during nutritional limitation, TrmB binds a cis-regulatory element to activate or repress 113 promoters of genes encoding enzymes in diverse metabolic pathways. By this mechanism, TrmB coordinates the expression of glycolysis, TCA cycle, and amino-acid biosynthesis pathways with the biosynthesis of their cognate cofactors (e.g. purine and thiamine). Notably, the TrmB-regulated metabolic network includes enzyme-coding genes that are uniquely archaeal as well as those that are conserved across all three domains of life. Simultaneous analysis of metabolic and gene regulatory network architectures suggests an ongoing process of co-evolution in which TrmB integrates the expression of metabolic enzyme-coding genes of diverse origins.


Methylglyoxal in Cardiometabolic Disorders: Routes Leading to Pathology Counterbalanced by Treatment Strategies.
Methylglyoxal (MGO) is the major compound belonging to reactive carbonyl species (RCS) responsible for the generation of advanced glycation end products (AGEs). Its upregulation, followed by deleterious effects at the cellular and systemic levels, is associated with metabolic disturbances (hyperglycemia/hyperinsulinemia/insulin resistance/hyperlipidemia/inflammatory processes/carbonyl stress/oxidative stress/hypoxia). Therefore, it is implicated in a variety of disorders, including metabolic syndrome, diabetes mellitus, and cardiovascular diseases. In this review, an interplay between pathways leading to MGO generation and scavenging is addressed in regard to this system's impairment in pathology. The issues associated with mechanistic MGO involvement in pathological processes, as well as the discussion on its possible causative role in cardiometabolic diseases, are enclosed. Finally, the main strategies aimed at MGO and its AGEs downregulation with respect to cardiometabolic disorders treatment are addressed. Potential glycation inhibitors and MGO scavengers are discussed, as well as the mechanisms of their action.


A decennial study of the trend of antibiotic studies in China.
Antibiotics are one of the greatest inventions in human history and are used worldwide on an enormous scale. Besides its extensive usage in medical and veterinary arenas to treat and prevent the infection, its application is very prominent in other fields, including agriculture, aquaculture, and horticulture. In recent decades, the increased consumption of antibiotics in China saw a vast increase in its production and disposal in various environments. However, in this post-antibiotic era, the abuse and misuse of these valuable compounds could lead to the unreversible consequence of drug resistance. In China, antibiotics are given a broad discussion in various fields to reveal their impact on both human/animals health and the environment. To our knowledge, we are the first paper to look back at the development trend of antibiotic-related studies in China with qualitative and quantitative bibliometric analysis from the past decades. Our study identified and analyzed 5559 papers from its inception (1991) to December 6, 2021, from the Web of Science Core Collection database. However, with few authors and institutions focusing on long-term studies, we found the quality of contributions was uneven. Studies mainly focused on areas such as food science, clinical research, and environmental studies, including molecular biology, genetics and environmental, ecotoxicology, and nutrition, which indicate possible primary future trends. Our study reports on including potentially new keywords, studies' milestones, and their contribution to antibiotic research. We offer potential topics that may be important in upcoming years that could help guide future research.


Differential expression of three 1-deoxy-D: -xylulose-5-phosphate synthase genes in rice.
1-Deoxy-D-: xylulose-5-phosphate synthase (DXS) encoded by a multigene family in plants, catalyzes the first step in the methylerythritol 4-phosphate (MEP) pathway. Three rice DXS-related sequences (OsDXS) were identified from available rice databases. The open reading frame of three OsDXS genes (dxs1, dxs2, and dxs3) were amplified against cDNA template. Ratio of their transcript levels in etiolated rice leaf was 9:181:1. While the expression levels were not changed along the growth stages of etiolated culture, UV-irradiation of the etiolated rice induced the expression of dxs3 up to nine-fold compared with that of unirradiated control. In the case of light-illumination, the relative expression of dxs1 based on unilluminated control increased two-fold. The differential expression of three OsDXS genes suggested their distinct and complementary roles in the control of the first step of the MEP pathway in response to environmental stimuli.


Antioxidant activity and safety assessment of Tragopogon buphthalmoides hydroethanolic extract: Acute and subchronic toxicities.
Tragopogon buphthalmoides (DC.) Boiss, is widely used as a food additive with some imputed health effects in folk medicine of western Iran. Unfortunately, despite the prevalent medicinal uses of the plant, there are no reports on the toxic effects of T. buphthalmoides aerial parts. The present study evaluated the potential toxicity of dried hydroethanolic extract of the species in wistar rats. Also, we investigated antioxidant activity and total phenolic content (TPC) of the extract. In the acute study, single doses of extract were administered orally, and the rats were then monitored for 14 days. In the subchronic toxicity study, the sample was administered to the rats for 45 days. In the antioxidant capacity assays dried extract showed moderate to weak antioxidant activities. Also, the sample showed relatively notable TPC. The results of acute study indicated that the LD50 of T. buphthalmoides is higher than 2500 mg/kg. Biochemical analysis showed some significant changes including creatinine, glucose and triglyceride levels. Moreover, some significant abnormality of lung, kidney and liver organs was observed. Based on the results of this study, adverse effect level (AEL) of dried hydroethanolic extract of T. buphthalmoides considered to be less than 175 mg/kg/day for the male and female rats.


Medial acoustic neuromas: clinical and surgical implications.
Medial acoustic neuroma is a rare entity that confers a distinct clinical syndrome. It is scarcely discussed in the literature and is associated with adverse features. This study evaluates the clinical and imaging features, pertinent surgical challenges, and treatment outcome in a large series of this variant. The authors postulate that the particular pathological anatomy with its arachnoidal rearrangement has a profound implication on the surgical technique and outcome. The authors conducted a retrospective analysis of 52 cases involving 33 women and 19 men who underwent resection of medial acoustic neuromas performed by the senior author (O.A.) over a 20-year period (1993-2013). Clinical, radiological, and operative records were reviewed, with a specific focus on the neurological outcomes and facial nerve function and hearing preservation. Intraoperative findings were analyzed with respect to the effect of arachnoidal arrangement on the surgeon's ability to resect the lesion and the impact on postoperative function. The average tumor size was 34.5 mm (maximum diameter), with over 90% of tumors being 25 mm or larger and 71% being cystic. Cerebellar, trigeminal nerve, and facial nerve dysfunction were common preoperative findings. Hydrocephalus was present in 11 patients. Distinguishing intraoperative findings included marked tumor adherence to the brainstem and frequent hypervascularity, which prompted intracapsular dissection resulting in enhancement on postoperative MRI in 18 cases, with only 3 demonstrating growth on follow-up. There was no mortality or major postoperative neurological deficit. Cerebrospinal fluid leak was encountered in 7 patients, with 4 requiring surgical repair. Among 45 patients who had intact preoperative facial function, only 1 had permanent facial nerve paralysis on extended follow-up. Of the patients with preoperative Grade I-II facial function, 87% continued to have Grade I-II function on follow-up. Of 10 patients who had Class A hearing preoperatively, 5 continued to have Class A or B hearing after surgery. Medial acoustic neuromas represent a rare subgroup whose site of origin and growth patterns produce a distinct clinical presentation and present specific operative challenges. They reach giant size and are frequently cystic and hypervascular. Their origin and growth pattern lead to arachnoidal rearrangement with marked adherence against the brainstem, which is critical in the surgical management. Excellent surgical outcome is achievable with a high rate of facial nerve function and attainable hearing preservation. These results suggest that similar or better results may be achieved in less complex tumors.


Visualization of the membrane surface and cytoskeleton of oligodendrocyte progenitor cell growth cones using a combination of scanning ion conductance and four times expansion microscopy.
Growth cones of oligodendrocyte progenitor cells (OPCs) are challenging to investigate with conventional light microscopy due to their small size. Especially substructures such as filopodia, lamellipodia and their underlying cytoskeleton are difficult to resolve with diffraction limited microscopy. Light microscopy techniques, which surpass the diffraction limit such as stimulated emission depletion microscopy, often require expensive setups and specially trained personnel rendering them inaccessible to smaller research groups. Lately, the invention of expansion microscopy (ExM) has enabled super-resolution imaging with any light microscope without the need for additional equipment. Apart from the necessary resolution, investigating OPC growth cones comes with another challenge: Imaging the topography of membranes, especially label- and contact-free, is only possible with very few microscopy techniques one of them being scanning ion conductance microscopy (SICM). We here present a new imaging workflow combining SICM and ExM, which enables the visualization of OPC growth cone nanostructures. We correlated SICM recordings and ExM images of OPC growth cones captured with a conventional widefield microscope. This enabled the visualization of the growth cones' membrane topography as well as their underlying actin and tubulin cytoskeleton.


How can data visualization support interdisciplinary research? LuxTIME: studying historical exposomics in Belval.
The Luxembourg Time Machine (LuxTIME) is an interdisciplinary project that studies the historical exposome during the industrialization of the Minett region, located in the south of Luxembourg. Exposome research encompasses all external and internal non-genetic factors influencing the health of the population, such as air pollution, green spaces, noise, work conditions, physical activity, and diet. Due to the wide scope of the interdisciplinary project, the historical study of the exposome in Belval involved the collection of quantitative and qualitative data from the National Archive of Luxembourg, various local archives (e.g., the communes of Esch-sur-Alzette and Sanem), the National Library, the Library of National Statistics STATEC, the National Geoportal of Luxembourg, scientific data from other research centers, and information from newspapers and journals digitized in eluxemburgensia. The data collection and the resulting inventory were performed to create a proof of concept to critically test the potential of a multi-layered research design for the study of the historical exposome in Belval. The guiding navigation tool throughout the project was data visualization. It has facilitated the exploration of the data collected (or just the data) and the metadata. It has also been a valuable tool for mapping knowledge and defining the scope of the project. Furthermore, different data visualization techniques have helped us to reflect on the process of knowledge sharing, to understand how the relevance of certain topics changed throughout the project and why, and to learn about the publication process in different journals and the experience of the participants. Data visualization is used not only as a means to an end but also to embrace the idea of sandcastles using a speculative and process-oriented approach to advance knowledge within all research fields involved. LuxTIME has proven to be an ideal case study to explore the possibilities offered by different data visualization concepts and techniques resulting in a data visualization toolbox that could be evaluated and extended in other interdisciplinary projects.


Eye protection in interventional procedures.
Data suggest that radiation-induced cataracts may form without a threshold and at low-radiation doses. Staff involved in interventional radiology and cardiology fluoroscopy-guided procedures have the potential to be exposed to radiation levels that may lead to eye lens injury and the occurrence of opacifications have been reported. Estimates of lens dose for various fluoroscopy procedures and predicted annual dosages have been provided in numerous publications. Available tools for eye lens radiation protection include accessory shields, drapes and glasses. While some tools are valuable, others provide limited protection to the eye. Reducing patient radiation dose will also reduce occupational exposure. Significant variability in reported dose measurements indicate dose levels are highly dependent on individual actions and exposure reduction is possible. Further follow-up studies of staff lens opacification are recommended along with eye lens dose measurements under current clinical practice conditions.


Characterization of phenolic pellets for ESR dosimetry in photon beam radiotherapy.
This work deals with the dosimetric features of a particular phenolic compound (IRGANOX 1076®) for dosimetry of clinical photon beams by using electron spin resonance (ESR) spectroscopy. After the optimization of the ESR readout parameters (namely modulation amplitude and microwave power) to maximise the signal without excessive spectrum distortions, basic dosimetric properties of laboratory-made phenolic dosimeters in pellet form, such as reproducibility, dose-response, sensitivity, linearity and dose rate dependence were investigated. The dosimeters were tested by measuring the depth dose profile of a 6 MV photon beam. A satisfactory intra-batch reproducibility of the ESR signal of the manufactured dosimeters was obtained. The ESR signal proved to increase linearly with increasing dose in the investigated dose range 1-13 Gy. The presence of an intrinsic background signal limits the minimum detectable dose to a value of approximately 0.6 Gy. Reliable and accurate assessment of the dose was achieved, independently of the dose rate. Such characteristics, together with the fact that IRGANOX 1076® is almost tissue-equivalent, and the stability of the ESR signal, make these dosimeters promising materials for ESR dosimetric applications in radiotherapy.


Therapeutic angiogenesis: a new treatment approach for ischemic heart disease--part I.
Angiogenesis is the biologic process of forming new blood vessels and is being investigated as an innovative therapeutic approach to help manage ischemic heart disease and peripheral vascular disease. Research studies have identified various angiogenic growth factors and progenitor cells that can enhance new blood vessel formation. Preclinical investigations in animal models have explored the potential use of growth factors with and without progenitor cells to treat myocardial ischemia. The results of clinical trials with growth factor infusions and gene therapy techniques to enhance growth factor production have shown some promise, but therapeutic angiogenesis remains at an early stage of development.


[Therapeutic hypothermia after cardiac arrest--a new link in the chain can save life].
Sudden, unexpected cardiac arrest is a common cause of death. Among patients who are successfully resuscitated, a majority dies without regaining consciousness. Therapeutic hypothermia has recently been shown to improve neurological outcome in two randomized studies and to improve survival in one of them. Based on the two studies, international evidence-based recommendations have been proposed and published (ILCOR). In this review we discuss the theoretical background of hypothermic neuroprotection and therapeutic implications. We propose that victims of cardiac arrest with return of spontaneous circulation and persistent unconsciousness are considered for hypothermia treatment and that data from treated patients are collected in a common website database (see: www.scctg.org) to allow further evaluation of the use of ICU resources, efficacy of hypothermia treatment and potential risks.


Prognosis after acute myocardial infarction continues to improve in the reperfusion era in the community of Göteborg.
The objective of this study was to compare the prognosis of nonselected patients who had an acute myocardial infarction (AMI) during 2 time periods in the thrombolytic era and to describe coronary heart disease (CHD) mortality rates in the community of Göteborg during 1990 to 1995. Patients aged <75 years who were hospitalized in the community of Göteborg for AMI during 1990 to 1991 (period 1) and 1995 to 1996 (period 2) were compared in terms of history, treatment for AMI, and outcome. Information on CHD mortality rates in the community of Göteborg was gathered from the National Registry of Deaths. The numbers of patients in the 2 cohorts were 926 and 861, respectively. The incidence rate for AMI per 100,000 inhabitants and year was 200 for period 1 and 183 during period 2. During period 2, there was an increased use of percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angiotensin-converting enzyme inhibitors, heparin, and intravenous nitroglycerin. On the other hand, there was a decreased use of thrombolytic agents, diuretic agents, digitalis, long-acting nitrates, calcium-channel blockers, and lidocaine. The hospital case-fatality rates were 9.4% during period 1 and 6.0% during period 2 (P =.01). The adjusted risk ratio for period 2 versus period 1 was 0.65, with 95% confidence limits of 0.45 to 0.94. The mortality rate over a period of 3 years was 26.5% during period 1 and 17.8% during period 2 (P <.0001). The adjusted risk ratio for period 2 versus period 1 was 0.67, with 95% confidence limits of 0.54 to 0.82. Among inhabitants aged 30 to 74 years in the community of Göteborg, the CHD mortality rate decreased in 1995 as compared with 1990 (age-adjusted odds ratio 0.79, 95% confidence limits 0.68 to 0.92). For consecutive patients aged <75 years who were hospitalized for AMI in the community of Göteborg, we found that in the thrombolytic era, major changes in medical and nonmedical treatment still took place associated with a continuing decrease in mortality rates during 3 years of follow-up. A similar reduction of CHD mortality rates was seen in the same age group within the community of Göteborg.


Usefulness of high-frequency ultrasound to assess the healing progress of shin ulcers.
As the average lifespan becomes longer, the number of cases of chronic shin ulcers is rising, which is slowly becoming a societal problem. Currently, there no methods for objective evaluation of ulcer healing process. The aim of the study was to assess the use of high-frequency ultrasound to monitor the healing of shin ulcers subjected to laser biostimulation. The study included 8 patients (4 men and 4 women) aged from 46 to 81 years with 9 shin ulcers in whom the healing process did not progress within 8 weeks despite effective causal treatment. The ulcers were subjected to laser biostimulation. The induced changes were monitored using high-frequency ultrasound and photographic records. Ultrasound examination was used to assess the depth of ulceration and the thickness of granulation tissue, migrating epidermis, subepidermal low-echogenic band (SLEB) and epidermis in the immediate vicinity. The wound severity index and ulcer vascularity were also assessed. As a result of laser therapy, in 7 out of 9 cases the ulcers healed completely and in the remaining 2 cases ulcer size was reduced. During the ulcer healing process induced by laser therapy, ultrasound examination revealed decreasing ulcer depth, wound severity index and SLEB thickness. Granulation tissue increased in thickness and there was an epidermal formation effect (newly formed epidermis was much thicker than the one surrounding the wound and became thicker as a result of laser therapy sessions). During the healing of ulcers induced by laser therapy no significant changes were observed in ulcer vascularity and thickness of the surrounding epidermis. High-frequency ultrasound is a useful technique for the imaging of leg ulcers. It allows one to monitor their healing process induced by laser biostimulation. Further research on the subject needs to be pursued.


The Role of Serial Follow-up and Sleep Deprivation Methods in Improving Electroencephalography Diagnostic Yield in a Cohort of Omanis Aged 13 Years and Above: A Clinical Audit Study.
The aim of this audit study was to establish the utility of follow-up and sleep-deprived electroencephalography testing to improve the detection of interictal abnormalities in a tertiary referral center in Oman. As part of our ongoing auditing process, a total of 3010 EEGs were included in this study. All EEGs were routinely performed for Omanis aged 13 years and above, who were referred for possible diagnosis of seizure disorders. Each EEG was performed over an average period of 20-30 minutes. Of the 3010 EEGs, there were 553 follow-up and sleep-deprived EEGs, including initial baseline EEG studies which were analyzed for this study. The total progressive yield of serial follow-up EEGs to detect overall EEG changes was 53.5%, distributed as 8.8%, 11.4%, 0%, and 33.3% for the second, third, fourth, and fifth serial EEG studies, respectively. For the sleep deprivation EEG group, the yield was 6.5% for detecting overall EEG changes compared to the initial EEG studies. A limitation in this study was the small sample size in the subsequent follow-up and sleep deprivation EEGs. In conclusion, we found a minimal contribution of serial follow-up and sleep deprivation methods in improving the EEG abnormality detection in our study. National guidelines and an increase in awareness among physicians are required to increase the benefit of these well-established, yet not optimally utilized EEG methods.


Pericardial adipose tissue and coronary artery calcification in the Multi-ethnic Study of Atherosclerosis (MESA).
To examine the relationship of pericardial adipose tissue (PAT) with coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis. The baseline cohort comprised 6,814 Caucasian (38%), African-American (28%), Chinese American (12%), and Hispanic (22%) adults aged 45-84, without known clinical cardiovascular disease. Cardiac CT was used to measure PAT (cm(3) ) and calcification (Agatston score). We examined cross-sectional associations of PAT with the presence (score >0) and severity (continuous score if >0) of calcification using prevalence ratio (PR) (n = 6,672) and linear regression (n = 3,362), respectively. Main models were adjusted for age, age(2) , gender, race/ethnicity, field site, smoking, physical activity, alcohol, and education. PAT volume (adjusted for age, height, weight, and site) was greatest in Chinese males, whereas Black males had less PAT than all but Black females. PAT was associated with presence [PR per standard deviation (SD): 1.06 (95% CI: 1.04, 1.08)] and severity [difference in log Agatston score per SD: 0.15 (0.09, 0.21)] of calcification, but neither association varied by race/ethnicity. Adjustment for generalized adiposity attenuated but did not eliminate the associations. With further adjustment for traditional risk factors and inflammatory markers, only the association with severity remained statistically significant [PR: 1.02 (1.00, 1.04); difference: 0.10 (0.03, 0.17)]. Heterogeneity by sex was observed for the presence of calcification (PR in men: 1.04; in women: 1.08; P for interaction <0.0001). PAT was associated with the presence and severity of coronary artery calcification in this cohort, but neither association varied by race/ethnicity.


Sonographic evaluation of caudal spine anomalies in children.
Retrospective analysis of B-mode spinal sonography in 15 pediatric patients with spinal dysraphism and caudal anomalies documents a high degree of accuracy in identifying the presence, site, size, and configuration of meningoceles; and slightly less accuracy in identifying extension of neural tissue into the meningocele and presence of concurrent lipoma. B-mode sonography is capable of displaying spinal anatomy clearly enough to permit accurate retrospective interpretation of pathologic changes. When radiologists learn to interpret sonographic images well enough to achieve equal accuracy in prospective diagnosis, then B-mode spinal sonography will supplant computed tomography and myelography as the preferred screening procedure in the initial evaluation of children with selected anomalies of the caudal spine.


Cystic Fibrosis Transmembrane Conductance Regulator. Implications in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.
Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) have traditionally been viewed as two distinct entities of unrelated origins. However, molecular, cellular, and clinical studies have revealed that cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction is common to both conditions, one (CF) being defined genetically and the other (COPD) as an acquired CFTR deficiency. Multiple molecular mechanisms of cigarette smoke-induced CFTR dysfunction have been reported. More importantly, considerable evidence of cigarette smoke-induced CFTR dysfunction in several respiratory and nonrespiratory tissues have been confirmed, making CFTR a target that cannot be overlooked in our quest to understand COPD and improve therapies for individuals affected by this disease. This review summarizes the molecular, cellular, and clinical evidence that CFTR dysfunction is induced by cigarette smoke exposure both in vitro and in vivo, and explores how this may contribute to the development of COPD.


Analysis on Microstructure-Property Linkages of Filled Rubber Using Machine Learning and Molecular Dynamics Simulations.
A better understanding of the microstructure-property relationship can be achieved by sampling and analyzing a microstructure leading to a desired material property. During the simulation of filled rubber, this approach includes extracting common aggregates from a complex filler morphology consisting of hundreds of filler particles. However, a method for extracting a core structure that determines the rubber mechanical properties has not been established yet. In this study, we analyzed complex filler morphologies that generated extremely high stress using two machine learning techniques. First, filler morphology was quantified by persistent homology and then vectorized using persistence image as the input data. After that, a binary classification model involving logistic regression analysis was developed by training a dataset consisting of the vectorized morphology and stress-based class. The filler aggregates contributing to the desired mechanical properties were extracted based on the trained regression coefficients. Second, a convolutional neural network was employed to establish a classification model by training a dataset containing the imaged filler morphology and class. The aggregates strongly contributing to stress generation were extracted by a kernel. The aggregates extracted by both models were compared, and their shapes and distributions producing high stress levels were discussed. Finally, we confirmed the effects of the extracted aggregates on the mechanical property, namely the validity of the proposed method for extracting stress-contributing fillers, by performing coarse-grained molecular dynamics simulations.


Long non-coding RNA DSCAM-AS1 indicates a poor prognosis and modulates cell proliferation, migration and invasion in ovarian cancer via upregulating SOX4.
Recent studies have revealed that long noncoding RNAs (lncRNAs) play a crucial role in tumor progression. Ovarian cancer is a common type of fatal gynecological cancer worldwide. This study aims to investigate how lncRNADSCAM-AS1 functions in the progression of ovarian cancer. DSCAM-AS1 expression of both ovarian cancer cells and 56 paired of tissue samples was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Moreover, the function of DSCAM-AS1 was identified via transwell assay, wound healing assay, colony formation assay and proliferation assay in vitro. The underlying mechanism was explored through qRT-PCR and Western blot assay. DSCAM-AS1 expression was remarkably upregulated in tumor tissues compared with that in the adjacent normal tissues. Besides, ovarian cancer proliferation, migration and invasion were promoted after overexpression of DSCAM-AS1 in vitro. Moreover, after overexpression of DSCAM-AS1, SOX4 was upregulated at mRNA and protein level in vitro. Furthermore, the expression of SOX4 in tumor tissues was positively correlated with the expression of DSCAM-AS1. The above results suggested that DSCAM-AS1 can promote cell migration, invasion and proliferation in ovarian cancer by upregulating SOX4, which may offer a new therapeutic intervention for patients with ovarian cancer.


Prolactin effects on ion transport across cultured mouse mammary epithelium.
Prolactin is a known osmoregulatory hormone in lower vertebrates, and recent evidence indicates that this hormone modulates ionic concentrations in milk. In an ultrastructurally and biochemically differentiated primary cell culture system in which mouse mammary epithelium is maintained on floating collagen gels, prolactin causes an increase in short-circuit current (Isc) of monolayers of cells derived from midpregnant (24.6 to 48.0 microA . cm-2) and lactating (10.4 to 16.1 microA . cm-2) glands. Transepithelial potential differences (basal side ground) average about -12 mV and are similar to those seen in vivo. Prelactating mammary epithelial cell cultures have transepithelial resistances ranging from 374 omega . cm2 (prolactin present) to 507 omega . cm2 (prolactin absent), and lactating cell cultures have resistances averaging almost 1,000 omega . cm2. Prolactin effects require at most one day of culture maintenance in prolactin-containing medium, and the effects are not due to known contamination of prolactin preparations with arginine vasopressin or growth hormone. Medium concentrations of prolactin as low as 1 ng/ml can elicit these effects. In prelactating cell cultures not treated with prolactin, the Isc is equal to the rate of sodium absorption. Prolactin increases sodium absorption fourfold but increases Isc only twofold. Clearly, prolactin induces other active transport; neither potassium nor chloride movements can account for this additional transport. Resistance values, current-voltage plots, and permeability coefficients indicate that in vitro mammary epithelium is a moderately "tight" tissue. Comparisons with intact glands indicate that in vitro mammary epithelium closely resembles its in vivo counterpart. Floating collagen gel cultures appear suitable for elucidating transport properties in cellularly heterogeneous and structurally complex mammalian tissues.


Definitive weekly hypofractionated radiotherapy in surgery-ineligible older adults with cutaneous squamous cell carcinoma of the head and neck region.
This study intends to address the impact of weekly hypofractionated radiation therapy with curative intent for cutaneous squamous cell carcinoma of the head and neck region in the elderly population.


[Secretion as a way to form enterocyte homeostasis].
The contents of K, Cl and Na in the mucus containing compartments of rat small intestine epithelium were examined with X-ray microanalysis. Measurements of concentration were made on sections prepared according to techniques based on cryofixation of soft biological tissues. The concentration of potassium and chlorine within the brush border region and in the secretion product of goblet cells is 200 mM and 90 mM, respectively, while sodium concentration was lower than the detection limit of 20 mM of the method used.


Ancestral matrilineages and mitochondrial DNA diversity of the Lidia cattle breed.
To clarify the genetic ancestry and the mitochondrial DNA (mtDNA) diversity of the Lidia cattle breed, a 521-bp D-loop fragment was sequenced in 527 animals belonging to 70 herds distributed across 29 lineages. The mtDNA diversity recorded was similar to that seen for Middle Eastern breeds and greater than that recorded for the majority of European breeds. Haplotype T3 was the most common (81%), followed by the African T1 haplotype (17%); very low frequencies were recorded for haplotypes T and T2. The results agree with there being two major ancestral lines for the Lidia breed, European and African, similar to that seen for other Mediterranean breeds. A wide range of variation in haplotype frequencies was seen between the examined lineages. Haplotype T3 was present in all those analysed; in five it was the only one present, and in only one lineage (Miura) was its frequency lower than that of T1. T1*, a haplotype reported in Criollo breeds and to date in only a single European breed (the Retinta breed from Spain), was found in a single animal belonging to the Concha y Sierra lineage. Network analysis of the Lidia breed revealed the presence of two major haplotypes: T3 and T1. The Lidia breed appears to be more closely related to prehistoric Iberian and Italian than to British aurochs.


Advanced Echocardiographic Imaging for Prediction of SCD in Moderate and Severe LV Systolic Function.
This study sought to determine the long-term prognostic value of myocardial deformation imaging by echocardiography in risk stratification of sudden cardiac death (SCD) and malignant ventricular arrhythmias (VAs) in a large consecutive cohort of patients with left ventricular (LV) systolic impairment, irrespective of its etiology. Left ventricular ejection fraction (LVEF) is limited for prediction of SCD. Echocardiographic strain-derived mechanical dispersion (MD) and global longitudinal strain (GLS) has been linked to VA and SCD. However, due to low event rates, the role of these parameters has not been fully elucidated. Consecutive clinically stable patients who underwent echocardiographic study performed in an outpatient setting from 2008 to 2014 with a Simpson left ventricular ejection fraction (LVEF) ≤45% were included in the study. Strain analysis was performed in which the LV was separated into 16 segments for regional analysis. Mechanical dispersion (MD) was calculated as the SD of the time to peak of each of the 16 regions. Outcome data were obtained from medical records. A total of 939 patients were included in the study, with median LVEF of 37% (interquartile range 30% to 42%). At follow-up (91.4 ± 23.4 months), 96 VA events had occurred. Multivariate analysis demonstrated that only MD ≥75 ms (hazard ratio: 9.45; 95% confidence interval: 4.75 to 18.81; p < 0.0001) was predictive of VA events. Low MD predicted a low event rate, irrespective of LVEF. Using LVEF alone is inferior for prediction of VA and SCD, particularly in patients with moderately reduced LVEF. MD is easily obtained from standard echocardiographic images and can be used to improve risk prognosis, particularly in patients who are currently excluded from cardiac defibrillator insertion based on LVEF.


Epidemiological study of prostatic cancer by matched-pair analysis.
In 1976, we designed an original questionnaire, consisting of 111 questions, directed at the epidemiology of prostatic disease. A case-control study by matched-pair analysis was conducted on 100 controls matched for age within 1 year and for residence in the same prefecture. Patients with prostatic cancer were distinguished from the general population of men by the following characteristics: 1) belonging to middle or lower socioeconomical class, 2) marriage at a young age and a long married life, 3) precocity, 4) vigorous sexual life followed by a fall-off of sexuality in later life, and 5) Western food habits. Based on analysis of results obtained in this case-control study, a high-risk group for prostatic cancer was outlined.


[Duodenogastric reflux in humans].
Human duodenogastric reflux (DGR) was comprehensively studied via measurement of gastric juice bile acid levels, manometric, endoscopic and X-ray study in health and benign gastrointestinal diseases and during exercise. DRG is shown to fall in the physiological events that have a biologically determined circadian rhythm. There was an association of DGR with gastric secretion. The "refluctant dilution effect" was established which along with elimination provides a relative constancy of the concentrations of bile ACIDS FROM 0.025 TO 0.422 NG/ML. DGR regulation is effected by the coordinated motor and evacuatory performance of the gastroduodenal junction and duodenum which is described as a lock two-way system. It is concluded that DGR is involved in the formation of the internal gastric environment and hence plays a role in gastric digestion. The findings may be used in studies of the physiology of digestion and in clinical practice.


Memory skills elders want to improve.
While many research studies have investigated memory training for elders, none have asked which specific memory skills elders would like to improve. This study investigates two related questions. First, which memory skills elders would like to improve? Second, is there a common set of these memory skills? Elders completed a three-part questionnaire. First, it asked for subject demographics. Second, it asked for the first, second, third, and then all other memory skills they would most like to improve. Finally, it asked elders to rate the importance of 10 specific memory skills. The results indicate that elders share a common set of memory skills they wish to improve. They are: (a) people's names, (b) important dates, (c) location of household objects, (d) recent and past events, (e) meetings and appointments, (f) information and facts, (g) general improvement, and (h) medication. One conclusion from these findings is that at least some memory training research should focus on these specific memory skills.


Investigating dielectric properties of different stages of syngeneic murine ovarian cancer cells.
In this study, the electrical properties of four different stages of mouse ovarian surface epithelial (MOSE) cells were investigated using contactless dielectrophoresis (cDEP). This study expands the work from our previous report describing for the first time the crossover frequency and cell specific membrane capacitance of different stages of cancer cells that are derived from the same cell line. The specific membrane capacitance increased as the stage of malignancy advanced from 15.39 ± 1.54 mF m(-2) for a non-malignant benign stage to 26.42 ± 1.22 mF m(-2) for the most aggressive stage. These differences could be the result of morphological variations due to changes in the cytoskeleton structure, specifically the decrease of the level of actin filaments in the cytoskeleton structure of the transformed MOSE cells. Studying the electrical properties of MOSE cells provides important information as a first step to develop cancer-treatment techniques which could partially reverse the cytoskeleton disorganization of malignant cells to a morphology more similar to that of benign cells.


Human immunodeficiency virus (HIV) type 1 Vpu induces the expression of CD40 in endothelial cells and regulates HIV-induced adhesion of B-lymphoma cells.
AIDS-related B-cell non-Hodgkin's lymphoma (AIDS-NHL) is a significant cause of morbidity and mortality among individuals infected with human immunodeficiency virus type 1 (HIV-1). AIDS-NHL is clinically and histologically heterogeneous, but common features include an aggressive clinical course and frequent extranodal presentation. HIV-1 infection of nonimmune cells that interact with malignant B cells at extranodal sites may influence both the development and the clinical presentation of disease. Our previous studies have shown that coculture of B-lymphoma (BL) cells with HIV-1-infected endothelial cells (EC) leads to contact activation of EC and firm BL-cell adhesion. The key event promoting EC-BL-cell adhesion was HIV-1 upregulation of endothelial CD40, which allowed induction of vascular cell adhesion molecule 1 (VCAM-1) in a CD40-dependent manner. The present study was designed to identify the HIV-1 protein(s) that influence EC-BL-cell adhesion. When HIV-1 proteins were individually expressed in EC by using recombinant adenoviruses, cultured BL cells adhered exclusively to Vpu-transduced EC. As with HIV-infected EC, adhesive properties were linked to the capacity of Vpu to upregulate CD40, which in turn allowed efficient expression of VCAM-1. When EC were infected with an HIV-1 pseudotype lacking the Vpu gene, CD40 upregulation and BL-cell adhesive properties were lost, indicating an essential role for Vpu in EC-BL-cell interactions. Thus, these data reveal a novel function for HIV-1 Vpu and further suggest a role for Vpu in the development of AIDS-NHL at EC-rich extranodal sites.


Toward Development of a Higher Flow Rate Hemocompatible Biomimetic Microfluidic Blood Oxygenator.
The recent emergence of microfluidic extracorporeal lung support technologies presents an opportunity to achieve high gas transfer efficiency and improved hemocompatibility relative to the current standard of care in extracorporeal membrane oxygenation (ECMO). However, a critical challenge in the field is the ability to scale these devices to clinically relevant blood flow rates, in part because the typically very low blood flow in a single layer of a microfluidic oxygenator device requires stacking of a logistically challenging number of layers. We have developed biomimetic microfluidic oxygenators for the past decade and report here on the development of a high-flow (30 mL/min) single-layer prototype, scalable to larger structures via stacking and assembly with blood distribution manifolds. Microfluidic oxygenators were designed with biomimetic in-layer blood distribution manifolds and arrays of parallel transfer channels, and were fabricated using high precision machined durable metal master molds and microreplication with silicone films, resulting in large area gas transfer devices. Oxygen transfer was evaluated by flowing 100% O2 at 100 mL/min and blood at 0-30 mL/min while monitoring increases in O2 partial pressures in the blood. This design resulted in an oxygen saturation increase from 65% to 95% at 20 mL/min and operation up to 30 mL/min in multiple devices, the highest value yet recorded in a single layer microfluidic device. In addition to evaluation of the device for blood oxygenation, a 6-h in vitro hemocompatibility test was conducted on devices (n = 5) at a 25 mL/min blood flow rate with heparinized swine donor blood against control circuits (n = 3). Initial hemocompatibility results indicate that this technology has the potential to benefit future applications in extracorporeal lung support technologies for acute lung injury.


First preimplantation genetic testing case of Meckel syndrome with a novel homozygous TXNDC15 variant in a non-consanguineous Chinese family.
Meckel-Gruber syndrome (MKS) is a perinatally lethal, genetically heterogeneous, autosomal recessive condition caused by defective primary cilium formation. So far, the association of TXNDC15-related MKS has been reported in only five independent families from diverse ethnic origins, including Saudi, Pakistani, Estonian, and Indian. Here, we report a fetus diagnosed with MKS at 12 weeks, exhibiting typical ultrasound findings. Low-coverage whole-genome sequencing was used to identify chromosomal abnormalities. Trio-base whole exome sequencing (trio-WES) was performed to investigate the potential pathogenic variants associated with MKS. Preimplantation genetic testing for monogenic disorders (PGT-M) was applied to prevent the transmission of the pathogenic variant. A novel homozygous pathogenic variant in the TXNDC15 gene was identified through trio-WES. The application of PGT-M successfully prevented the transmission of the pathogenic variant and resulted in an ongoing pregnancy. This is the first report of a TXNDC15 variant in the Chinese population and the first PGT case of TXNDC15-related MKS worldwide. The successful application of PGT-M in this family provides a potential approach for other monogenic diseases. Our case expands the variant spectrum of TXNDC15 and contributes to the molecular diagnosis and genetic counseling for MKS. This case underscores the importance of appropriate genetic testing methods and accurate genetic counseling in the diagnosis of rare monogenic diseases.


Comparing effectiveness of risperidone with first-generation antipsychotic medications in patients with schizophrenia-spectrum disorders.
This naturalistic retrospective study aims to compare effectiveness of a second-generation antipsychotic medication, risperidone, with first-generation antipsychotic medications (haloperidol and trifluoperazine) in an Asian population with first-episode schizophrenia-spectrum disorders. A total of 261 patients were assessed for time to discontinuation for any reason and specific reasons of discontinuation, controlling for baseline differences between groups. Some 90% of patients discontinued their antipsychotic medications before 18 months. Median time to discontinuation for any reason in risperidone was 69 days versus first-generation antipsychotic medications of 27 days. Specifically, the risperidone group had a longer time to discontinuation for any reason than haloperidol (HR = 0.61, p = 0.005) and trifluoperazine groups (HR = 0.63, p = 0.03), as well as a longer time to discontinuation due to intolerability of side effects than haloperidol (HR = 0.50, p = 0.008) and trifluoperazine groups (HR = 0.26, p = 0.001). There were no significant differences between medications for time to discontinuation due to lack of efficacy, patient's/family's decisions or other reasons. We conclude that there is a very high rate of discontinuation of the initial antipsychotic medications for various reasons, with risperidone having an overall longer time to discontinuation compared with first-generation antipsychotic medications.


Molecular organization and expression of the gtfA gene of Streptococcus mutans LM7.
The Streptococcus mutans LM7 gene gtfA was cloned in Escherichia coli along with flanking regions of the chromosome as a fragment representing 10.3 kilobases (kb) of streptococcal DNA. Restriction endonuclease mapping revealed that the cloned DNA consisted of four EcoRI fragments with gtfA sucrase activity localized to one fragment, EcoRI-B (2.4 kb). Subsequent analysis with E. coli minicells indicated that three polypeptides were encoded on the 10.3-kb insert (55 [GtfA], 45, and 35 kilodaltons). Neither the 45- nor 35-kilodalton polypeptide exhibited any detectable sucrase activity. The approximate positions and directions of transcription of the two larger proteins were determined from minicell protein profiles displaying truncated versions of these polypeptides. The restriction endonuclease data for the cloned gtfA gene were used to develop a strategy for insertional inactivation of this locus in vivo. An internal HincII fragment of the gtfA gene was removed and replaced with a DNA fragment containing a tetracycline resistance determinant. This new recombinant plasmid was linearized and then transformed into S. mutans GS5 and S. mutans V403 where it was incapable of replication. It was predicted that Tcr colonies would result from double-crossover recombinational events involving homologous regions flanking the gtfA gene. This was verified by Southern DNA hybridization analyses. The inactivation of the gtfA gene in both S. mutans GS5 and S. mutans V403 resulted in a decrease of water-soluble exopolysaccharide but no detectable changes in the amounts of water-insoluble polymers.


RPE at relative intensities after 12 weeks of resistance-exercise training by older adults.
The constant-RPE tracking model monitors progress over the course of exercise training. During aerobic exercise, prior work using this model has demonstrated similar relative intensities pre- and posttraining, while the absolute workload increases posttraining. However, the prediction equation associated with these changes has not been examined during resistance training. 22 men and 27 women (M age 64 yr.) participated in a 12-wk. resistance training. Orientation determined resistances associated with RPEs of 4, 5-6, 7-8, and 9 on the OMNI-Resistance Exercise Scale for each of seven exercises for each participant. Individuals trained 3 days a week for 12 wk. Linear regression was used to calculate percent of 1-repetition maximum (%1-RM) at RPE 4, 6, and 8 for the exercises. Paired sample t tests, comparing pre- and posttraining %1-RMs at each RPE, indicated that posttraining %1-RMs were higher for RPE 4 and 6 for each exercise, while at RPE 8, results were significant for only 3 exercises. Thus for at least the RPE 4 and 6, the constant RPE tracking model is appropriate for resistance exercise; however, the equation of prediction appears to differ from that for aerobic exercise. Development of a new prediction equation may be necessary to track relative strength in older adults.


Multichannel blind image deconvolution using the Bussgang algorithm: spatial and multiresolution approaches.
This work extends the Bussgang blind equalization algorithm to the multichannel case with application to image deconvolution problems. We address the restoration of images with poor spatial correlation as well as strongly correlated (natural) images. The spatial nonlinearity employed in the final estimation step of the Bussgang algorithm is developed according to the minimum mean square error criterion in the case of spatially uncorrelated images. For spatially correlated images, the nonlinearity design is rather conducted using a particular wavelet decomposition that, detecting lines, edges, and higher order structures, carries out a task analogous to those of the (preattentive) stage of the human visual system. Experimental results pertaining to restoration of motion blurred text images, out-of-focus spiky images, and blurred natural images are reported.


Brain abscess following endoscopic injection sclerotherapy: report of a case.
A 33-year-old male patient with hepatitis B surface antigen positive cirrhosis, received 2 courses of endoscopic injection sclerotherapy for bleeding esophageal varices. A Streptococcus viridans brain abscess developed 2 weeks after the first sclerotherapy (or 1 week after the second sclerotherapy). In cirrhotic patients, an increase in pulmonary vasodilatation and pulmonary arteriovenous shunting has been well recognized. Sclerosant as well as bacteria may pass through a pulmonary arteriovenous shunt and reach the brain, directly after an infection of esophageal varices. Brain ischemia and a bacterial infection may occur at the same time, this can accelerate the development of a pyogenic brain abscess. Careful observation for the early detection and treatment of infection following endoscopic sclerotherapy is essential.


Technical aspects of reconstruction for inadequate left atrial cuff in lung transplantation.
Lung transplantation is the only life-saving treatment for lung diseases that do not respond to medical treatment. Heart-lung harvesting requires a careful procedure to protect an adequate donor left atrial cuff around the junction of the superior and inferior pulmonary veins. This study aims to describe inadequate left atrial cuff during harvest and techniques of reconstruction at the threshold of literature. Left atrial cuff complications were retrospectively analyzed in consecutive lung transplant procedures between December 2016 and December 2021. Donor and patient demographics, reconstruction material and method of application and postoperative follow-up were examined. In the study period, 84 consecutive lung transplant procedures were performed. Reconstruction of the inadequate left atrial cuff was 3.7% (6/162) for atrial anastomoses. However, the inadequate left atrial cuff was 9.1% (5/55) in heart-lung harvesting. Donor aorta graft was used in 4 patients and Dacron mesh was used on the bilateral atrial cuff in one patient. Hospital mortality occurred in one patient. One patient died 6 months later due to antibody-mediated rejection. The follow-ups of the other three patients are continuing without any problems. Inadequate left atrial cuff complications occurring in heart-lung harvest seem to be more common than in the literature. Techniques of reconstruction for the inadequate left atrial cuff is vital for the patient who has reached irreversible progress in surgery for the recipient, as well as increasing the number of organs.


Antimalarial activity from three ascidians: an exploration of different marine invertebrate phyla.
Recent research suggests that marine organisms may produce compounds with activity against malaria parasites. Of a total of 27 aqueous extracts from different marine species, collected on the northwest Cuban coast, 20 were considered as showing no significant activity against Plasmodium falciparum F32, with minimum inhibitory concentrations (MIC) >500 microg/ml, while seven extracts (MIC < or =500 microg/ml) were selected for further investigation by determining their selectivity indices and in vivo antimalarial activity. Three species of tunicates were chosen, as more than 50% reduction of P. berghei parasitaemia was produced after administration of 250 or 500 mg/kg of their crude extracts into infected mice. The aqueous extracts of Microcosmus goanus, Ascidia sydneiensis and Phallusia nigra were partitioned between water and n-butanol; the organic phases inhibited P. falciparum growth by 50% at concentrations of 17.5 microg/ml, 20.9 microg/ml and 29.4 microg/ml respectively. In general, these results are similar to those of most ethnobotanical surveys. Further chemical studies are being undertaken in order to isolate new antimalarial compounds from these Caribbean tunicates.


Identifying non-accidental injury in children presenting to A&E departments: an overview of the literature.
The need for an effective system of child protection, which is able to detect children at risk of physical abuse, has never been more urgent. The level of reporting of non-accidental injury (NAI) in young children is lower than would be expected from official statistics, which means that Accident and Emergency (A and E) nurses and clinicians have a special responsibility to improve detection of possible abuse, in what has become a very challenging area of medicine. In this paper, we review the main issues facing clinicians and nurses in the identification of children at risk of NAI and discuss the policy implications affecting A and E departments. In particular we ask the question: what are the factors that influence the identification and reporting of suspected NAI in young children and how can the under-recognition of NAI be improved? We conclude that organisational changes, such as the creation of a shared national database and improved training for A and E staff so that they are aware of social as well as clinical risk factors, are needed to address the under-reporting of non-accidental injury in young children.


A monoclonal antibody reactive with Marek's disease tumor-associated surface antigen.
An antibody-secreting hybridoma, RPH-6, to Marek's disease tumor-associated surface antigen (MATSA) was produced by somatic-cell hybridization between the mouse myeloma SP2/O-Ag/14 and spleen cells from MSB1 immunized mice. The antibody reacted with 95 to 100% of the cells from eight of 10 chicken MD cell lines and one of two turkey MD cell lines. It did not react with chicken MD cell lines RP1 and SK3, turkey MD cell line RP19, lymphoid leukosis (LL) cell lines, RP9 and RP12, and reticuloendotheliosis virus (REV) cell line RP14. A weak reaction was observed with REV cell line RP13 (10 to 20%), and a very slight reaction with normal chicken spleen cells (1 to 5%). RPH-6 produces immunoglobulin of the IgM class. Cell culture and mouse ascitic fluids have titers of 10(2) and 10(6), respectively, by fluorescent antibody (FA) test against MD tumor cell lines. The antibody did not react with Marek's disease virus (MDV) internal antigen or membrane antigen as detected by indirect FA test on chicken embryo fibroblast cultures grown on coverslips. The 51Cr release assay showed RPH-6 is highly cytotoxic (60% release) only against MD lymphoblastoid cell lines, with antibody prepared from mouse ascites having a cytotoxic titer approaching 10(6). Results from using RPH-6 for differential diagnosis of chicken lymphoid tumors of unknown origin were in complete agreement with those obtained with rabbit anti-MATSA reference serum and pathologic diagnosis.


A Bayesian Approach for Evaluation of Determinants of Health System Efficiency Using Stochastic Frontier Analysis and Beta Regression.
In today's world, Public expenditures on health are one of the most important issues for governments. These increased expenditures are putting pressure on public budgets. Therefore, health policy makers have focused on the performance of their health systems and many countries have introduced reforms to improve the performance of their health systems. This study investigates the most important determinants of healthcare efficiency for OECD countries using second stage approach for Bayesian Stochastic Frontier Analysis (BSFA). There are two steps in this study. First we measure 29 OECD countries' healthcare efficiency by BSFA using the data from the OECD Health Database. At second stage, we expose the multiple relationships between the healthcare efficiency and characteristics of healthcare systems across OECD countries using Bayesian beta regression.


The Authoritative Parenting Index: predicting health risk behaviors among children and adolescents.
Public health research demonstrates increasing interest in mobilizing parental influence to prevent health risk behaviors among children and adolescents. This research focuses on authoritative parenting, which previous studies suggest can prevent health risk behaviors among youth. To evaluate the reliability and validity of a new survey measure of authoritative parenting, data from studies of (1) substance use in a sample of 1,236 fourth- and sixth-grade students; (2) weapon carrying and interpersonal violence in a sample of 1,490 ninth- and tenth-grade students, and (3) anger, alienation, and conflict resolution in a sample of 224 seventh- and eighth-grade students were analyzed. The Authoritative Parenting Index had a factor structure consistent with a theoretical model of the construct; had acceptable reliability; showed grade, sex, and ethnic differences consistent with other studies; and identified parenting types that varied as hypothesized with multiple indicators of social competence and health risk behaviors among children and adolescents.


Plasma aldosterone levels and development of insulin resistance: prospective study in a general population.
Aldosterone plays a role in hypertension, and hypertension is prevalent in patients with insulin resistance. Cross-sectional studies have reported that plasma aldosterone levels are higher in patients with insulin resistance. However, it is not known whether plasma aldosterone levels predict the development of insulin resistance. Subjects of the present study were 1235 local residents (490 men and 745 women) who participated in health screenings in Japan in 1999. Plasma aldosterone levels were measured by radioimmunoassay. We investigated the cross-sectional relationship between plasma aldosterone levels and insulin resistance (homeostasis model assessment index ≥1.73 according to the diagnostic criteria used in Japan) in 1088 nondiabetic participants. At the 10-year follow-up, 141 subjects had died, and 260 subjects refused re-examination. We performed a prospective analysis of 564 subjects to predict incident insulin resistance. We found a significant (P<0.001) cross-sectional relationship between plasma aldosterone and homeostasis model assessment index at baseline. In the prospective analysis, a significantly higher (P<0.05) relative risk (1.71 [95% CI: 1.03-2.84]) was observed in the highest tertile versus lowest tertile of plasma aldosterone for the development of insulin resistance, after adjustment for confounding factors. This 10-year prospective study demonstrated that plasma aldosterone levels predicted the development of insulin resistance in a general population.


Statin regulation of CYP3A4 and CYP3A5 expression.
CYP3A4 and CYP3A5 are cytochrome P450 enzymes that are highly expressed in the liver and gut and metabolize endogenous compounds and xenobiotics. Statins are cholesterol-lowering drugs that are extensively metabolized by CYP3A4 and CYP3A5. The bioavailability of statins is affected by CYP3A4 and CYP3A5 and glucuronidases metabolism as well as uptake and efflux transporters that affect drug disposition. CYP3A4 and CYP3A5 variants have been demonstrated to influence the pharmacokinetics, efficacy and safety of statins. Inducers and inhibitors of CYP3A4 and CYP3A5 play an important role in reducing statin efficacy and increase the risk of adverse effects, respectively. Statins have been demonstrated to increase CYP3A expression in vitro, most likely because they are ligands to nuclear receptors (pregnane X receptor and constitutive androsterone receptor) that form heterodimers with retinoid X receptors and bind to responsive elements in the CYP3A4 and CYP3A5 promoter regions. This special report outlines the earlier studies on variability of response to statins owing to CYP3A variants and highlights findings on the induction of CYP3A4 and CYP3A5 expression by statins.


T cell requirements for the rejection of renal allografts bearing an isolated class I MHC disparity.
This study has examined the cellular and humoral responses underlying the rejection of rat renal allografts bearing an isolated RT1Aa class I MHC disparity. RT1Aa disparate kidneys were rejected promptly by high responder RT1u but not by low responder RT1c recipients (median survival time 10 d and greater than 100 d, respectively). The magnitude and phenotype of the cellular infiltrate were similar in rejecting and nonrejecting RT1Aa disparate kidneys. Paradoxically, graft infiltrating cells and spleen cells from RT1u recipients showed minimal ability to lyse donor strain lymphoblasts in vitro, whereas effector cells from RT1c recipients showed modest levels of cytotoxicity. Injection of RT1u rats with MRC OX8 mAb was highly effective at selectively depleting CD8+ cells from graft recipients but had no effect in prolonging the survival of RT1Aa disparate grafts despite the complete absence of CD8+ cells from the graft infiltrate, which included numerous CD4+ T cells and macrophages. RT1u, but not RT1c, recipients mounted a strong alloantibody response against RT1Aa disparate kidneys. Immune serum obtained from RT1u recipients that had rejected a RT1Aa disparate graft was able, when injected into cyclosporin-treated RT1u recipients, to restore their ability to reject a RT1Aa, but not a third-party RT1c, kidney. These results suggest that CD8+ cells in general and CD8+ cytotoxic effector cells in particular are unnecessary for the rapid rejection of RT1Aa class I disparate kidney grafts by high responder RT1u recipients. By implication, CD4+ T cells alone are sufficient to cause prompt rejection of such grafts and they may do so by providing T cell help for the generation of alloantibody.


Inhibitors of ceramide de novo biosynthesis rescue damages induced by cigarette smoke in airways epithelia.
Exposure to cigarette smoke represents the most important risk factor for the development of chronic obstructive pulmonary disease (COPD). COPD is characterized by chronic inflammation of the airways, imbalance of proteolytic activity resulting in the destruction of lung parenchyma, alveolar hypoxia, oxidative stress, and apoptosis. Sphingolipids are structural membrane components whose metabolism is altered during stress. Known as apoptosis and inflammation inducer, the sphingolipid ceramide was found to accumulate in COPD airways and its plasma concentration increased as well. The present study investigates the role of sphingolipids in the cigarette smoke-induced damage of human airway epithelial cells. Lung epithelial cells were pre-treated with sphingolipid synthesis inhibitors (myriocin or XM462) and then exposed to a mixture of nicotine, acrolein, formaldehyde, and acetaldehyde, the major toxic cigarette smoke components. The inflammatory and proteolytic responses were investigated by analysis of the mRNA expression (RT-PCR) of cytokines IL-1β and IL-8, and matrix metalloproteinase-9 and of the protein expression (ELISA) of IL-8. Ceramide intracellular amounts were measured by LC-MS technique. Ferric-reducing antioxidant power test and superoxide anion radical scavenging activity assay were used to assess the antioxidant power of the inhibitors of ceramide synthesis. We here show that ceramide synthesis is enhanced under treatment with a cigarette smoke mixture correlating with increased expression of inflammatory cytokines and matrix metalloproteinase 9. The use of inhibitors of ceramide synthesis protected from smoke induced damages such as inflammation, oxidative stress, and proteolytic imbalance in airways epithelia.


Does reproductive isolation reflect the segregation of color forms in Spiranthes sinensis (Pers.) Ames complex (Orchidaceae) in the Chinese Himalayas?
Isolation between species, or taxa sharing a common lineage, depends primarily on the relative strengths of various reproductive barriers. Previous studies on reproductive isolation between orchids emphasized mechanical and ethological barriers in flowers of species showing food and/or sexual mimicry. In this study, we investigated and quantified a series of prepollination and postpollination barriers between pink and white forms of Spiranthes sinensis sl, a nectar-secreting complex. We generated ML trees based on trnS-G and matK to explore phylogenetic relationships in this species complex. Spiranthes sinensis sl segregated from some other congeners, but the white form constituted a distinct clade in relation to the pink form. The white form secreted 2-Phenylethanol as it is a single-scent compound and was pollinated almost exclusively by native, large-bodied Apis cerana and Bombus species (Apidae). Apis cerana showed a high floral constancy to this form. The scentless, pink form was pollinated primarily by smaller bees in the genera Ceratina (Apidae), and members of the family Halictidae, with infrequent visits by A. cerana and Bombus species. Fruit set and the production of large embryos following interform pollination treatments were significantly lower compared to intraform pollination results for the white form. Our results suggested that pollinator isolation, based on color and scent cues, may result in greater floral constancy in white populations when both forms are sympatric as two different, guilds of pollinators forage selectively preventing or reducing prospective gene flow. Postpollination barriers appear weaker than prepollination barriers but they also play a role in interform isolation, especially in the white form. Our findings suggest that floral color forms in S. sinensis do not represent an unbalanced polymorphism. Interpretations of the evolutionary status of these forms are discussed.


Study protocol for 'The Project About Loneliness and Social networks (PALS)': a pragmatic, randomised trial comparing a facilitated social network intervention (Genie) with a wait-list control for lonely and socially isolated people.
Loneliness and social isolation have been identified as significant public health concerns, but improving relationships and increasing social participation may improve health outcomes and quality of life. The aim of the Project About Loneliness and Social networks (PALS) study is to assess the effectiveness and cost-effectiveness of a guided social network intervention within a community setting among individuals experiencing loneliness and isolation and to understand implementation of Generating Engagement in Network Involvement (Genie) in the context of different organisations. The PALS trial will be a pragmatic, randomised controlled trial comparing participants receiving the Genie intervention to a wait-list control group. Eligible participants will be recruited from organisations working within a community setting: any adult identified as socially isolated or at-risk of loneliness and living in the community will be eligible. Genie will be delivered by trained facilitators recruited from community organisations. The primary outcome will be the difference in the SF-12 Mental Health composite scale score at 6-month follow-up between the intervention and control group using a mixed effects model (accounting for clustering within facilitators and organisation). Secondary outcomes will be loneliness, social isolation, well-being, physical health and engagement with new activities. The economic evaluation will use a cost-utility approach, and adopt a public sector perspective to include health-related resource use and costs incurred by other public services. Exploratory analysis will use a societal perspective, and explore broader measures of benefit (capability well-being). A qualitative process evaluation will explore organisational and environmental arrangements, as well as stakeholder and participant experiences of the study to understand the factors likely to influence future sustainability, implementation and scalability of using a social network intervention within this context. This study has received NHS ethical approval (REC reference: 18/SC/0245). The findings from PALS will be disseminated widely through peer-reviewed publications, conferences and workshops in collaboration with our community partners. ISRCTN19193075.


A semi-automatic method for developing an anthropomorphic numerical model of dielectric anatomy by MRI.
Complex permittivity values have a dominant role in the overall consideration of interaction between radiofrequency electromagnetic fields and living matter, and in related applications such as electromagnetic dosimetry. There are still some concerns about the accuracy of published data and about their variability due to the heterogeneous nature of biological tissues. The aim of this study is to provide an alternative semi-automatic method by which numerical dielectric human models for dosimetric studies can be obtained. Magnetic resonance imaging (MRI) tomography was used to acquire images. A new technique was employed to correct nonuniformities in the images and frequency-dependent transfer functions to correlate image intensity with complex permittivity were used. The proposed method provides frequency-dependent models in which permittivity and conductivity vary with continuity--even in the same tissue--reflecting the intrinsic realistic spatial dispersion of such parameters. The human model is tested with an FDTD (finite difference time domain) algorithm at different frequencies; the results of layer-averaged and whole-body-averaged SAR (specific absorption rate) are compared with published work, and reasonable agreement has been found. Due to the short time needed to obtain a whole body model, this semi-automatic method may be suitable for efficient study of various conditions that can determine large differences in the SAR distribution, such as body shape, posture, fat-to-muscle ratio, height and weight.


Oligoclonal T-cell receptor usage of melanocyte differentiation antigen-reactive T cells in stage IV melanoma patients.
Ex vivo ELISPOT analysis of peripheral blood lymphocytes obtained from stage IV melanoma patients demonstrated reactivity against peptides derived from MART-1 and gp100. However, the number of reactive T cells was < 1% that of total lymphocytes as detected by flow cytometry using tetrameric MHC/peptide complexes. Despite this low frequency, we were able to directly isolate these populations ex vivo by means of magnetic beads coated with MHC/peptide complexes and to subject these cells to T-cell receptor clonotype mapping. This analysis revealed that the MART-1/A*0201- and gp100/A*0201-reactive T-cell populations are composed of oligoclonal T cells that engage several T-cell receptor beta chain families. Longitudinal studies using this approach may result in a better correlation between T-cell reactivity and the course of neoplastic disease.


Cercyon hungaricus, a new junior subjective synonym of C. bononiensis (Coleoptera: Hydrophilidae).
Cercyon bononiensis Chiesa, 1964 was described from two specimens collected in northern Italy in 1924-1925. For some time, these specimens were identified as C. inquinatus Wollaston, 1854. Only 40 years later, having examined the type of the latter species, Chiesa (1964) realized that the two specimens belonged to an undescribed species that he then described as Cercyon bononiensis. Based on the chagrined elytra mentioned in the original description, C. bononiensis has been placed in the Cercyon tristis group by subsequent authors. Recently, we examined a small number of Cercyon specimens from northern Italy and surprisingly found two specimens of C. hungaricus Endrödy-Younga, 1967, an easily recognizable member of the C. tristis group which was previously considered a Pannonian endemic by Fikáček et al. (2009) but was recently also found in northern Germany (Bäse 2010). The presence of this unusual species led us to question whether C. hungaricus might be conspecific with C. bononiensis. This was subsequently confirmed by the study of the types of both species. Here, we provide a summary of our studies and synonymize C. hungaricus with C. bononiensis. Examined specimens are deposited in the following collections: Hungarian Natural History Museum, Budapest, Hungary (HNHM), Museo Civico di Storia Naturale Milano, Italy (MSNM), collection of S. Rocchi at the Museo di Storia Naturale dell'Università di Firenze, Sezione di Zoologia "La Specola" (CRO).


Automated multi-subject fiber clustering of mouse brain using dominant sets.
Mapping of structural and functional connectivity may provide deeper understanding of brain function and disfunction. Diffusion Magnetic Resonance Imaging (DMRI) is a powerful technique to non-invasively delineate white matter (WM) tracts and to obtain a three-dimensional description of the structural architecture of the brain. However, DMRI tractography methods produce highly multi-dimensional datasets whose interpretation requires advanced analytical tools. Indeed, manual identification of specific neuroanatomical tracts based on prior anatomical knowledge is time-consuming and prone to operator-induced bias. Here we propose an automatic multi-subject fiber clustering method that enables retrieval of group-wise WM fiber bundles. In order to account for variance across subjects, we developed a multi-subject approach based on a method known as Dominant Sets algorithm, via an intra- and cross-subject clustering. The intra-subject step allows us to reduce the complexity of the raw tractography data, thus obtaining homogeneous neuroanatomically-plausible bundles in each diffusion space. The cross-subject step, characterized by a proper space-invariant metric in the original diffusion space, enables the identification of the same WM bundles across multiple subjects without any prior neuroanatomical knowledge. Quantitative analysis was conducted comparing our algorithm with spectral clustering and affinity propagation methods on synthetic dataset. We also performed qualitative analysis on mouse brain tractography retrieving significant WM structures. The approach serves the final goal of detecting WM bundles at a population level, thus paving the way to the study of the WM organization across groups.


[Antifungal treatment: Recent advances in dermatology.].
In this paper we discuss the published relevant mycology dermatological reports which appeared in 1997 and 1998. The aims of this review is to give an actual view on antifungal therapy with a critical discussion on the efficacy of antifungals.


Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks.
Recent genome-wide association studies have identified numerous loci associated with neuropsychiatric disorders. The majority of these are in non-coding regions, and are commonly assigned to the nearest gene along the genome. However, this approach neglects the three-dimensional organisation of the genome, and the fact that the genome contains arrays of extremely conserved non-coding elements termed genomic regulatory blocks (GRBs), which can be utilized to detect genes under long-range developmental regulation. Here we review a GRB-based approach to assign loci in non-coding regions to potential target genes, and apply it to reanalyse the results of one of the largest schizophrenia GWAS (SWG PGC, 2014). We further apply this approach to GWAS data from two related neuropsychiatric disorders-autism spectrum disorder and bipolar disorder-to show that it is applicable to developmental disorders in general. We find that disease-associated SNPs are overrepresented in GRBs and that the GRB model is a powerful tool for linking these SNPs to their correct target genes under long-range regulation. Our analysis identifies novel genes not previously implicated in schizophrenia and corroborates a number of predicted targets from the original study. The results are available as an online resource in which the genomic context and the strength of enhancer-promoter associations can be browsed for each schizophrenia-associated SNP.


[Complex method for epizootiological and epidemiological surveillance].
A complex method for the epizootological and epidemiological surveillance of a number of bacterial and viral infections on the territories inside and outside their natural foci has been developed. The investigation techniques are described and the data on the isolation rate of each causative agent in different geographical zones are presented. In the natural foci of plague and tularemia, as well as on the territories outside such foci, the causative agents of intestinal yersiniosis, pseudotuberculosis, salmonellosis, erysipeloid, staphylococci and streptococci, arena- and arboviruses have been isolated from the rodents and ectoparasites under study. The results of this investigation suggest that the method may be recommended for use in medical institutions dealing with the problems of infections originating from natural foci.


Human Factors and Organizational Issues.
To select the best papers that made original and high impact contributions in the area of human factors and organizational issues in biomedical informatics in 2019. A rigorous extraction process based on queries from Web of Science® and PubMed/Medline was conducted to identify the scientific contributions published in 2019 that address human factors and organizational issues in biomedical informatics. The screening of papers on titles and abstracts independently by the two editors led to a total of 30 papers. These papers were discussed for a selection of 15 finalist papers, which were then reviewed by the two editors and by three external reviewers from internationally renowned research teams. The query process resulted in 626 papers that reveal interesting and rigorous methods and important studies in human factors that move the field forward, particularly in clinical informatics and emerging technologies such as brain-computer interfaces. This year three papers were clearly outstanding and help advance the field. They provide examples of applying existing frameworks together in novel and highly illuminating ways, showing the value of theory development in human factors. The selected papers make important contributions to human factors and organizational issues, expanding and deepening our knowledge of how to apply theory and applications of new technologies in health.


[Water-electrolyte balance and functional state of the kidneys in cosmonauts after a 185-day space flight].
Fluid-electrolyte metabolism and renal function of the crewmembers of the 185-day space flight were examined. Various changes in fluid-electrolyte metabolism and its regulation were seen in the Commander and Flight-Engineer. As most other crewmembers who performed similar flights, Cr showed fluid and sodium retention, whereas FE displayed higher than preflight sodium excretion in the urine. These differences were associated with individual variations of regional hemodynamics which modified the renin-angiotensin-aldosterone system in a different manner. Postflight both crewmembers showed a higher excretion of bivalent ions. The higher excretion of calcium was accompanied by a lower concentration of total and ionized calcium in the serum as well as by a lower concentration of PTH and calcitonin. The loading KC1 test made it possible to assess variations in potassium metabolism that occurred during flight. They included the inability of tissues to retain potassium due to atrophic processes which developed in the weightless state and due to the unloading of the musculoskeletal system.


A 3D printing approach toward targeted intervention in telerehabilitation.
Neuromuscular impairment requires adherence to a rehabilitation regimen for maximum recovery of motor function. Consumer-grade game controllers have emerged as a viable means to relay supervised physical therapy to patients' homes, thereby increasing their accessibility to healthcare. These controllers allow patients to perform exercise frequently and improve their rehabilitation outcomes. However, the non-universal design of game controllers targets healthy people and does not always accommodate people with disability. Consequently, many patients experience considerable difficulty assuming certain hand postures and performing the prescribed exercise correctly. Here, we explore the feasibility of improving rehabilitation outcomes through a 3D printing approach that enhances off-the-shelf game controllers in home therapy. Specifically, a custom attachment was 3D printed for a commercial haptic device that mediates fine motor rehabilitation. In an experimental study, 25 healthy subjects performed a navigation task, with the retrofit attachment and without it, while simulating disability of the upper limb. When using the attachment, subjects extended their wrist range of motion, yet maintained their level of compensation. The subjects also showed higher motivation to repeat the exercise with the enhanced device. The results bring forward evidence for the potential of this approach in transforming game controllers toward targeted interventions in home therapy.


Effect of cellular de-differentiation on the dynamics and evolution of tissue and tumor cells in mathematical models with feedback regulation.
Tissues are maintained by adult stem cells that self-renew and also differentiate into functioning tissue cells. Homeostasis is achieved by a set of complex mechanisms that involve regulatory feedback loops. Similarly, tumors are believed to be maintained by a minority population of cancer stem cells, while the bulk of the tumor is made up of more differentiated cells, and there is indication that some of the feedback loops that operate in tissues continue to be functional in tumors. Mathematical models of such tissue hierarchies, including feedback loops, have been analyzed in a variety of different contexts. Apart from stem cells giving rise to differentiated cells, it has also been observed that more differentiated cells can de-differentiate into stem cells, both in healthy tissue and tumors, aspects of which have also been investigated mathematically. This paper analyses the effect of de-differentiation on the basic and evolutionary dynamics of cells in the context of tissue hierarchy models that include negative feedback regulation of the cell populations. The models predict that in the presence of de-differentiation, the fixation probability of a neutral mutant is lower than in its absence. Therefore, if de-differentiation occurs, a mutant with identical parameters compared to the wild-type cell population behaves like a disadvantageous mutant. Similarly, the process of de-differentiation is found to lower the fixation probability of an advantageous mutant. These results indicate that the presence of de-differentiation can lower the rates of tumor initiation and progression in the context of the models considered here.


Analysis of pregnancy-associated plasma protein A production in human adult cardiac progenitor cells.
IGF-binding proteins (IGFBPs) and their proteases regulate IGFs bioavailability in multiple tissues. Pregnancy-associated plasma protein A (PAPP-A) is a protease acting by cleaving IGFBP2, 4, and 5, regulating local bioavailability of IGFs. We have previously shown that IGFs and IGFBPs are produced by human adult cardiac progenitor cells (haCPCs) and that IGF-1 exerts paracrine therapeutic effects in cardiac cell therapy with CPCs. Using immunofluorescence and enzyme immunoassays, we firstly report that PAPP-A is produced and secreted in surprisingly high amounts by haCPCs. In particular, the homodimeric, enzymatically active, PAPP-A is secreted in relevant concentrations in haCPC-conditioned media, while the enzymatically inactive PAPPA/proMBP complex is not detectable in the same media. Furthermore, we show that both homodimeric PAPP-A and proMBP can be detected as cell associated, suggesting that the previously described complex formation at the cell surface does not occur easily, thus positively affecting IGF signalling. Therefore, our results strongly support the importance of PAPP-A for the IGFs/IGFBPs/PAPP-A axis in CPCs biology.


Occupational exposures and male breast cancer: A nested case-control study in the Nordic countries.
Male breast cancer (MBC) is a rare and understudied disease. There is limited evidence on association between environmental and occupational agents and MBC. Some similarities in risk factors may be shared with female breast cancer. We evaluated solvents, metals, exhaust gases and other agents in relation to MBC within the large Nordic Occupational Cancer Study (NOCCA). The study included 1469 MBC cases and 7345 controls from Finland, Iceland and Sweden, matched for the date of birth, sex and country. Cases were identified through national cancer registries. Data on occupation and other demographic indicators were collected from census records and population registries. Overall, 24 occupational exposures were assessed. Exposure estimates were assigned by linking job titles to job-exposure matrices (NOCCA-JEM). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by using conditional logistic regression models. Significantly decreased overall OR was observed for physical workload (OR = 0.78, 95% CI 0.67-0.91). Protective effect of physical workload was stronger by increasing exposure level with significant dose-response relationship (p-trend<0.01). Non-significantly increased ORs were observed for trichloroethylene, iron, lead, chromium, welding fumes and wood dust, and decreased ORs for asbestos, silica dust and perchloroethylene. However, these results were not consistent across all analyses. The current study showed 20-25% protective effect for physical workload at work, while no strong evidence for other agents was observed.


Tri-state toxic-state syndrome study. I. Epidemiologic findings.
Eighty women who had onset of toxic-shock syndrome (TSS) between October 1, 1979, and September 19, 1980, and 160 age- and sex-matched neighborhood controls participated in this study to evaluate risk factors associated with TSS in women. Of the 80 women, 76 had onset of illness during their menstrual periods. The odds ratio for developing menses-associated TSS with any use of tampons compared with no use of tampons was 18.01 (P less than 0.001). The odds ratios ranged from 5.29 to 27.5 for individual brand use compared with no use. When exclusive use of a particular tampon brand was compared with exclusive use of all other brands. Rely (Procter and Gamble, Cincinnati, Ohio) was the only brand with a significantly increased odds ratio (2.49; P = 0.005). By multiple logistic regression analysis, the risk of TSS was more closely associated with tampon fluid capacity (absorbency) than with the use of all tampon brands.


Microbiota-Centered Interventions: The Next Breakthrough in Immuno-Oncology?
The cancer-immune dialogue subject to immuno-oncological intervention is profoundly influenced by microenvironmental factors. Indeed, the mucosal microbiota-and more specifically, the intestinal ecosystem-influences the tone of anticancer immune responses and the clinical benefit of immunotherapy. Antibiotics blunt the efficacy of immune checkpoint inhibitors (ICI), and fecal microbial transplantation may restore responsiveness of ICI-resistant melanoma. Here, we review the yin and yang of intestinal bacteria at the crossroads between the intestinal barrier, metabolism, and local or systemic immune responses during anticancer therapies. We discuss diagnostic tools to identify gut dysbiosis and the future prospects of microbiota-based therapeutic interventions. SIGNIFICANCE: Given the recent proof of concept of the potential efficacy of fecal microbial transplantation in patients with melanoma primarily resistant to PD-1 blockade, it is timely to discuss how and why antibiotics compromise the efficacy of cancer immunotherapy, describe the balance between beneficial and harmful microbial species in play during therapies, and introduce the potential for microbiota-centered interventions for the future of immuno-oncology.


Brain microRNAs dysregulation: Implication for missplicing and abnormal post-translational modifications of tau protein in Alzheimer's disease and related tauopathies.
MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional gene expression by targeting specific mRNAs for degradation or translation repression. Changes in miRNAs expression profiles have been reported in several neurodegenerative disorders such as Alzheimer's disease (AD) and related tauopathies, which are characterized by tau aggregation and neurofibrillary tangle formation (NFTs) in the brain. There is a fundamental challenge in determining how dysregulation of miRNAs can promote a pathological condition. Therefore, identifying the target genes of dysregulated miRNAs, signaling pathways and biological processes, as well as pathogenic factors which trigger miRNA dysregulation may be helpful for subsequent therapeutic development. This article reviews studies focused on the presently known roles of miRNAs in the regulation of alternative splicing and post-translational modifications of tau, events associated with the development of AD and related tauopathies. We hope this review will help readers understand the pathogenesis and the most recent therapeutic approaches to treat tauopathies.


[Reconstruction of total portosystemic shunt into selective portosystemic shunt in a child].
To date, side-to-side splenorenal shunt (SRS) and its analogues (splenosuprarenal shunts (SSRS)) are mainly used for portal hypertension. These are total portosystemic shunts characterized by total blood shunt from portal vein into inferior vena cava. The latter is fraught with a significant risk of complications such as pulmonary hypertension, decreased portal liver perfusion, liver failure and hepatic encephalopathy. Prevention of these complications is still an urgent problem in modern surgery. However, we proposed a new method of treatment, i.e. reconstruction of SRS and SSRS into selective shunt. This procedure was performed in 37 patients after 2020. We present laparoscopic reconstruction in an 11-year-old girl with portal hypertension and signs of hepatic encephalopathy identified after previous SSRS.