Muscle and plasma amino-acid patterns in severely depleted surgical patients.
Plasma and muscle free amino-acid concentrations were determined in 7 post-operative patients with extensive skeletal muscle protein depletion, and in a group of age- and sex-matched volunteers. All patients had a slightly positive energy balance during the study as verified by indirect calorimetry. In plasma, the concentration of phenylalanine was increased whereas threonine, isoleucine, leucine, serine, glutamine, glycine, citrulline, ornithine, histidine and arginine concentrations were reduced. In muscle, the concentrations of threonine, valine, isoleucine, leucine, phenylalanine, aspartate, glutamate, glycine, alanine and tyrosine were increased, arginine was decreased, whereas glutamine and methionine were normal. The intracellular to extracellular concentration gradients of threonine, valine, isoleucine, leucine, aspartate, serine, glycine, alanine and tyrosine were increased. The plasma concentration of amino-acids correlated inversely with the serum concentration of cortisol. The present results reconfirm some of the previously reported alterations in plasma and muscle amino-acid patterns in traumatised and infected patients. In marked contrast with most previous reports, muscle threonine, aspartate and glutamate concentrations were increased, whereas muscle glutamine concentration was normal. Taking body compositional alterations into account, the findings may in part be explicable on the basis of the high supply of energy and amino-acids in relation to the reduced skeletal muscle protein mass.


Period and cohort trends for mortality and cigarette consumption in England and Wales, 1946 to 1980, with emphasis on sex ratios.
In an earlier paper (Burch P. R. J. J Chron Dis 1981; 34: 87-103) changes in sex- and age-specific mortality from all causes of death in England and Wales were studied in relation to changes in sex- and age-specific cigarette consumption. The absence of a consistent correlation between the two variables, and the general characteristics of the data, suggested that studies of sex ratios might provide a better test of the hypothesis that the association between smoking and mortality has a causal basis. In this paper temporal changes in the sex ratio of cumulative cigarette consumption by cohort, and of smoking rates by age, are considered in relation to changes in the sex ratio of mortality. Again, no consistent correlations emerge and it is evident that factors other than smoking have played a dominant part in determining recent changes in the sex ratio of mortality in all age groups from 35-39 to 80-84 years. Among these "other factors" are birth cohort effects that can be attributed, in part, to birth cohort changes in the sex ratio of mortality from bronchitis and emphysema. The present results, together with other evidence (vide supra; and Burch P. R. J. J Chron Dis 1984; 37: 148-156), show that great care needs to be exercised when attempts are made to deduce causation from epidemiologic surveys.


[INTRAABDOMINAL HYPERTENSION AND RESPIRATORY DYSFUNCTION AFTER PLASTY OF THE ABDOMINAL WALL HERNIA].
The impact of intraabdominal pressure on postoperative state of respiratory system after surgery for abdominal wall hernia (AWH) was analyzed. The investigation was conducted in 2013-2014 yrs in 35 patients. Perioperative state of pulmonary mechanics, the gas exchange, and the indices of a spirogram were analyzed. The postoperative period course, the rate of the respiratory insufficiency occurrence were analyzed. Respiratory insufficiency was observed, as a rule, in 24 - 48 h after hernioplasty. The AWH plasty lead to the intraabdominal pressure raising, the PaCO2-EtCO2 gradient changes, and the PaO2/FiO2 ratio as well.


X-ray propagation through a kinoform lens.
Combining geometric ray tracing and wave optics propagation, a new simulation model named LWF is established to calculate the full coherent X-ray propagation through a kinoform lens. The LWF model is used to analyze the X-ray propagation through long and short kinoform lenses and calculate the intensity distribution at the focal plane. When the aperture is large, the focal spot for the long kinoform lens is smaller than that for the short kinoform lens. Due to the use of the geometric ray-tracing method to calculate the beam propagation inside the kinoform lens, the LWF model takes a low number of transversal wavefront segments, i.e. a short time, to achieve high accuracy. The simulation times for the one-dimensional and two-dimensional LWF models are 0.025 s and 5.3 s, respectively, with a calculation error of less than 0.5%. The high efficiency and high accuracy make the LWF model a strong tool in designing kinoform lenses.


Glucocorticoid receptor inactivation and activation by phosphorylation mechanisms.
The specific glucocorticoid binding capacity of cytosol preparations is rapidly lost on incubation at 25 degrees in the absence of ligand. We have examined this process in cell-free preparations from rat thymus, rat liver and mouse fibroblasts (L 929 cells), and we have found that the unoccupied receptor is inactivated by endogenous enzymes to a form that does not bind steroids. The inactivation can be prevented by inhibitors of phosphatase action such as molybdate, fluoride and glucose-1-phosphate. On the basis of this type of evidence we propose that the receptor activity of cytosol can be rendered inactive by a dephosphorylation process. We have now been able to partially reactivate the receptor in both L cell and rat thymus cytosols in an ATP dependent manner. If fibroblast (L cell) cytosol is preincubated to permit receptor inactivation by endogenous enzyme, further inactivation can be prevented by the addition of 10 mM molybdate and reactivation of the binding capacity can be obtained by adding 5 to 10 mM ATP in addition to molybdate. ATP dependent activation is prevented with EDTA and this block is overcome by added magnesium. ADP, CTP, GTP, and UTP are inactive. After inactivating the glucocorticoid binding capacity of rat thymocyte cytosol by incubation for 45 minutes at 25 degrees, considerable reactivation is obtained by addition of dithiothreitol and ATP. This system does not absolutely require the presence of a phosphatase inhibitor in order to show activation. Thymocyte cytosol can also be activated to a steroid binding state by addition of DTT and heat-treated (90 degrees for 15 min.) cytosol from a variety of cell types. The heat-treated cytosol contains ATP, reducing equivalents, and a relatively small molecular weight heat-stable activator(s) that potentiates the reactivation process. Maximum receptor activation is obtained by adding dithiothreitol, heat-stable factor, ATP, and molybdate to the inactivated thymocyte cytosol.


Editorial Commentary: In Patients With Hip-Spine Syndrome, a Single Simple Solution May Not Apply: Occam's Razor Becomes Blunt.
The importance of hip-spine syndrome in a nonarthritic population, in which patients present with coexisting symptoms in both the hip and lumbar spine, is becoming more clear. Several studies have shown inferior outcomes in patients undergoing treatment for femoral acetabular impingement syndrome with coexisting spinal symptoms. The most important factor when treating HSS patients is understanding each patient's pathology. A history and physical examination with provocative tests for spinal and hip pathology often provide the answer. Routine standing and seated lateral radiographs are required to assess spinopelvic mobility. If the cause of pain is unclear, diagnostic intra-articular hip injections with local anesthetic and further imaging of the lumbar spine are recommended. In patients with degenerative spine disease with neural impingement, these symptoms may persist after hip arthroscopy, particularly if not improved by intra-articular injections. Patients should be appropriately counseled. If hip symptoms predominate, treatment of femoroacetabular impingement syndrome results in improved outcomes, even with coexisting neural impingement. If spine symptoms predominate, referral to an appropriate specialist may be required. In patients with HSS, Occam's razor becomes blunt; thus, a single simple solution may not apply, and we may need to consider treating each pathology separately.


[Pigmentary disorders induced by anticancer agents. part I: chemotherapy].
The occurrence of hyperpigmentation during chemotherapy is one of the most frequent dermatological adverse events observed with these drugs. It may arise with numerous anticancer agents, and can be either localized or diffuse, occurring either immediately or after inflammatory dermatological lesions. Nails, mucosa and skin may all be affected. Though the incidence is high in clinical practice, such drug-induced hyperpigmentation has been only rarely individualized and characterized. Herein we describe the main clinical, histological and pathophysiological characteristics of these lesions and the most frequently incriminated chemotherapeutic agents, as well as the anatomical areas involved and the most specific clinical patterns such as flagellate dermatitis, reticulate or serpentine supravenous hyperpigmentation and eruptive naevi.


Injury narratives in occupational safety and health prevention in Italy.
Storytelling is an effective information source when coupled with technical-scientific evidence. It can promote a structured relationship between evidence-based knowledge and field experience of workplace safety and prevention services (WSPS) inspectors. This is key to identifying the causes of workplace injuries and to set priorities for prevention strategies. The main aim was to describe and report how story collection can be used for deriving validated indications for injury prevention. The specific objectives were to report the results of the creation and dissemination on the web of the story collection and the experience of setting up a community of practice (CoP) to develop preventive recommendations. WSPS inspectors from local health boards in Piedmont (northwest Italy) were asked to write injury stories. They identified the key elements of their stories and developed a narrative of witness accounts to explore the critical issues identified during the investigation. In sessions with the CoP, the inspectors validated the indications for prevention elaborated in each story to reduce bias and standardize recommendations. Between 2012 and 2017, 60 WSPS inspectors wrote 53 injury stories which were collected and published on the institutional website. Twenty-two stories were selected for discussion during peer review sessions in the CoP and the indications for prevention were transformed as preventive solutions. Occupational safety and health prevention can benefit from a narrative-based approach that provides a more comprehensive look at health and safety by facilitating knowledge improvement and sharing.


Accuracy of neutrophil lymphocyte ratio for diagnosis of acute appendicitis in children: A diagnostic study.
Many biomarkers for diagnosis of acute appendicitis in children have been reported, however, the results are still controversial. We assessed the accuracy of neutrophil-lymphocyte ratio (NLR) for diagnosis of acute appendicitis and discriminating simple and complicated appendicitis in children. We included 121 patients with acute appendicitis and 49 children with intussusception as controls who were admitted at our hospital from 2013 to 2017. White blood count (WBC), neutrophil, and NLR were compared between groups. Neutrophil and NLR were significantly higher in the acute appendicitis group than control (76.17 ± 14.41 vs. 62.43 ± 15.9%, p=<0.0001; and 8.44 ± 6.63 vs. 3.38 ± 2.84, p=<0.0001, respectively), while WBC, neutrophil, and NLR were significantly greater in complicated than simple appendicitis (15.86 ± 6.48 vs. 12.64 ± 6.27 × 103/μL, p = 0,008; 82.64 ± 8.41 vs. 68.99 ± 16.23%, p=<0.0001; and 11.32 ± 6.87 vs. 5.25 ± 4.65, p=<0.0001, respectively). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), area under the receiver operating characteristic (ROC) curve, and cutoff point of NLR for diagnosis of acute appendicitis were 83.5%, 57.7%, 81.4%, 61.2%, 0.764, and 2.87, respectively; whereas the sensitivity, specificity, PPV, NPV, area under the ROC curve, and cutoff point of NLR for differentiating complicated and simple appendicitis were 84.6%, 56.5%, 35.5%, 92.9%, 0.790, and 6.59, respectively. NLR shows a high accuracy for diagnosis of acute appendicitis and distinguishing a complicated appendicitis from the simple one.


An injectable silk sericin hydrogel promotes cardiac functional recovery after ischemic myocardial infarction.
Acute myocardial infarction (MI) leads to morbidity and mortality due to cardiac dysfunction. Here we identify sericin, a silk-derived protein, as an injectable therapeutic biomaterial for the minimally invasive MI repair. For the first time, sericin prepared in the form of an injectable hydrogel has been utilized for cardiac tissue engineering and its therapeutical outcomes evaluated in a mouse MI model. The injection of this sericin hydrogel into MI area reduces scar formation and infarct size, increases wall thickness and neovascularization, and inhibits the MI-induced inflammatory responses and apoptosis, thereby leading to a significant functional improvement. The potential therapeutical mechanisms have been further analyzed in vitro. Our results indicate that sericin downregulates pro-inflammatory cytokines (TNF-α and IL-18) and chemokine (CCL2) and reduces TNF-α expression by suppressing the TLR4-MAPK/NF-κB pathways. Moreover, sericin exhibits angiogenic activity by promoting migration and tubular formation of human umbilical vessel endothelial cells (HUVECs). Also, sericin stimulates VEGFa expression via activating ERK phosphorylation. Further, sericin protects endothelial cells and cardiomyocytes from apoptosis by inhibiting the activation of caspase 3. Together, these diverse biochemical activities of sericin protein lead to a significant recovery of cardiac function. This work represents the first study reporting sericin as an effective therapeutic biomaterial for ischemic myocardial repair in vivo. Intramyocardial biomaterial injection is thought to be a potential therapeutic approach to improve cardiac performance after ischemic myocardial infarction. In this study, we report the successful fabrication and in vivo application of an injectable sericin hydrogel for ischemic heart disease. We for the first time show that the injection of in situ forming crosslinked sericin hydrogel promotes heart functional recovery accompanied with reduced inflammatory responses, attenuated apoptosis and increased microvessel density in the infarcted hearts. Further, we reveal that the improvement in those aspects is ascribed to sericin protein's functional bioactivities that are comprehensively uncovered in this study. Thus, we identify sericin, a natural protein, as a biomaterial suitable for myocardial repair and demonstrate that the in vivo application of this injectable sericin hydrogel can be an effective strategy for treating MI.


Alkali-thermal activated persulfate treatment of tetrabromobisphenol A in soil: Parameter optimization, mechanism, degradation pathway and toxicity evaluation.
The continued accumulation of halogenated organic pollutants in soil posed a potential threat to ecosystems and human health. In this study, tetrabromobisphenol A (TBBPA) was used as a typical representative of halogenated organic pollutants in soil, for alkali-thermal activated persulfate (PS) treatment. The results of response surface methodology (RSM) showed a optimal debromination efficiency of TBBPA was 88.99 % under the optimum reaction conditions. Quenching experiments and electron paramagnetic resonance (EPR) confirmed that SO4-•, HO•, O2-• and 1O2 existed simultaneously in the oxidation process. SO4-• played a major role in the initial stage of the reaction, and O2-• played a major role in the the last stage. Based on density functional theory (DFT) and intermediate products, two degradation pathways were proposed, including debromination reaction and β bond scission. Moreover, the basic physical and chemical properties of the soil were affected to a certain extent, while the soil surface structure, elements and functional group composition rarely changed. In addition, the T.E.S.T. analysis and biotoxicity tests proved that alkali-thermal activated PS can effectively reduce the toxicity of TBBPA-contaminated soil, which is conducive to the subsequent safe secondary utilization of soil.


Start-up and incremental practice expenses for behavior change interventions in primary care.
If behavior-change services are to be offered routinely in primary care practices, providers must be appropriately compensated. Estimating what is spent by practices in providing such services is a critical component of establishing appropriate payment and was the objective of this study. In-practice expenditure data were collected for ten different interventions, using a standardized instrument in 29 practices nested in ten practice-based research networks across the U.S. during 2006-2007. The data were analyzed using standard templates to create credible estimates of the expenses incurred for both the start-up period and the implementation phase of the interventions. Average monthly start-up expenses were $1860 per practice (SE=$455). Most start-up expenditures were for staff training. Average monthly incremental costs were $58 ($15 for provision of direct care [SE=$5]; $43 in overhead [SE=$17]) per patient participant. The bulk of the intervention expenditures was spent on the recruitment and screening of patient participants. Primary care practices must spend money to address their patients' unhealthy behaviors--at least $1860 to initiate systematic approaches and $58 monthly per participating patient to implement the approaches routinely. Until primary care payment systems incorporate these expenses, it is unlikely that these services will be readily available.


Open versus laparoscopic cholecystectomy for gallbladder carcinoma.
Laparoscopic surgery has replaced conventional open cholecystectomy for benign gallbladder disease. A major concern is how to handle gallbladder cancer in the laparoscopic era, since there are numerous case reports of port site metastases from gallbladder cancer after laparoscopic cholecystectomy. There are also many experimental studies favoring the opinion that the laparoscopic technique implies a higher risk of spreading malignant disease. This opinion has gained wide acceptance despite little previous clinical effort to determine the risk of tumor dissemination and the lack of comparisons between open and laparoscopic surgery. This report is a short summary of our own studies and present knowledge with special respect to the clinical aspects of the development and incidence of abdominal wall metastases. Among 270 patients with verified gallbladder carcinoma in whom 210 had open surgery and 60 a laparoscopic cholecystectomy, 12 patients (6.5%) in the open cholecystectomy group and 9 (15%) in the laparoscopic group developed incisional metastases. Although the sparse clinical documentation does not unavoidably mean that laparoscopic cholecystectomy has an increased risk of disseminating tumor cells, we recommend open surgery in cases of known or suspected gallbladder carcinoma.


Update on Valvular Heart Disease for Registered Nurses.
Over the last few decades, there have been dramatic advances in the understanding of the mechanisms of valvular heart disease and development of percutaneous treatment options. These innovations have resulted in the need for a multidisciplinary heart team approach for quality patient outcomes, a team in which nursing is an integral member. This update provides an overview of the major valve diseases, current guideline recommendations, catheter-based treatment options and key elements of nursing care: physical examination, diagnostic testing, pre- and post-procedure care protocols, and patient education elements.


Docosahexaenoic acid monoacylglyceride decreases endothelin-1 induced Ca(2+) sensitivity and proliferation in human pulmonary arteries.
Pulmonary artery vasoconstriction and vascular remodeling contribute to a sustained elevation of pulmonary vascular resistance and pressure in patients with pulmonary arterial hypertension (PH), an often fatal hemodynamic disease. The effect of docosahexaenoic acid monoacylglyceride (MAG-DHA) and the role of the 17 kDa protein kinase C-potentiated inhibitor protein (CPI-17) were determined on vasoconstriction and smooth muscle cell proliferation of human pulmonary arteries (HPA). HPA were obtained from 16 patients undergoing lung resection for carcinoma. The mechanical tension and Ca(2+) sensitivity were measured on arterial rings treated with endothelin-1 (ET-1) in the absence or presence of MAG-DHA. The effect of MAG-DHA on the level of proliferation of smooth muscle cells isolated from HPA was evaluated in order to determine the role of CPI-17 protein. MAG-DHA treatment decreased the reactivity and Ca(2+) sensitivity induced by ET-1 in HPA. MAG-DHA treatment also decreased the expression of vascular endothelial growth factor (VEGF) induced by ET-1. Moreover, both VEGF inhibitor and MAG-DHA treatments reduced Ca(2+) hypersensitivity induced by ET-1, which was associated to a reduction in CPI-17 and myosin-binding subunit of the myosin light chain phosphatase (MYPT-1) phosphorylation levels. Proliferation of ET-1-stimulated HPA smooth muscle cells (PASMc) was also decreased following CPI-17 small interfering RNA transfection and MAG-DHA treatments. Western blot analyses revealed that MAG-DHA treatment resulted in decreased phosphorylation levels of CPI-17 and extracellular signal-regulated kinases (ERK) in PASMc treated with ET-1. We have demonstrated that VEGF interacts with CPI-17 signaling pathway resulting in an increase in Ca(2+) sensitivity and proliferation of PASMc, whereas MAG-DHA treatment reversed these effects.


Effects of maternal dietary protein restriction on growth of the brain and body in the rat.
We studied the growth of the brain and body in rats born of dams fed a low-protein (8% casein) diet ad lib beginning 5 weeks prior to mating and continuing throughout gestation and lactation. Control dams were fed an isocaloric 25% casein diet. Litters were culled at birth to 8 pups. At birth, brain weights and body weights of pups of protein restricted dams were similar to those of control pups. During the period of lactation, pups of restricted exhibited severely retarded body growth but only mildly retarded brain growth resulting in an elevated brain/body weight ratio. This relative macrocephaly was maximal at 10-20 days of age, declining completely by 35 days of age. The relative macrocephaly could not be accounted for by increased retention of water in the brain of the malnourished rats. Following weaning, pups were maintained ad lib on the diets fed their mothers. At adulthood brain/body weight ratios were normal in the protein restricted group.


Importance of beta cell mass for glycaemic control in people with type 1 diabetes.
The role of beta cell mass in the balance of glucose control and hypoglycaemic burden in people with type 1 diabetes is unclear. We applied positron emission tomography (PET) imaging with radiolabelled exendin to compare beta cell mass among people with type 1 diabetes and either low glucose variability (LGV) or high glucose variability (HGV). All participants with either LGV (n=9) or HGV (n=7) underwent a mixed-meal tolerance test to determine beta cell function and wore a blinded continuous glucose monitor for a week. After an i.v. injection with [68Ga]Ga-NODAGA-exendin-4, PET images were acquired for the quantification of pancreatic uptake of radiolabelled exendin. The mean standardised uptake value (SUVmean) of the pancreas was used to determine the amount of beta cell mass. Participants with LGV had lower HbA1c (46.0 mmol/mol [44.5-52.5] [6.4% (6.3-7)] vs 80 mmol/mol [69.0-110] [9.5% (8.5-12.2)], p=0.001) and higher time in range (TIR) (75.6% [73.5-90.3] vs 38.7% [25.1-48.5], p=0.002) than those with HGV. The SUVmean of the pancreas was higher for the LGV than for the HGV group (5.1 [3.6-5.6] vs 2.9 [2.1-3.4], p=0.008). The AUCC-peptide:AUCglucose ratio was numerically, but not statistically, higher in the LGV compared with the HGV group (2.7×10-2 [6.2×10-4-5.3×10-2] vs 9.3×10-4 [4.7×10-4-5.2×10-3], p=0.21). SUVmean correlated with the AUCC-peptide:AUCglucose ratio (Pearson r=0.64, p=0.01), as well as with the TIR (r=0.64, p=0.01) and the SD of interstitial glucose levels (r=-0.66, p=0.007). Our data show higher beta cell mass in people with type 1 diabetes and LGV than in those with HGV, independent of beta cell function.


Ferroptosis-related small-molecule compounds in cancer therapy: Strategies and applications.
Ferroptosis is a novel type of regulated cell death which is driven by iron-dependent lipid peroxidation and subsequent plasma membrane ruptures. Since ferroptosis was coined fairly in 2012, the research in the field of ferroptosis has grown at an exponential rate. Several small-molecule drugs have been shown to trigger ferroptosis and decrease tumor growth in the last decade. Sorafenib can induce ferroptosis in human hepatocellular carcinoma cell lines (Huh7, Hep3B and HepG2), and sulfasalazine as a ferroptosis inducer can inhibit the proliferation of a series of cancer cell lines (including HT-1080 fibrosarcoma cells, Calu-1 non-small cell lung cancer cells, etc.) by specifically inhibit cystine transport which mediated by system Xc-. The purpose of this review is discussing the current crosstalk between ferroptosis and tumor-related signaling pathways, as well as comprehensively summarizing the small-molecule compounds that may regulate cancer cells death by inducing ferroptosis which will shed new light on the development of ferroptosis-related anticancer drugs in the future.


Assessment of social support and its association to depression, self-perceived health and chronic diseases in elderly individuals residing in an area of poverty and social vulnerability in rio de janeiro city, Brazil.
Social support (SS) influences the elderly ability to cope with the losses of ageing process. This study was aimed at assessing SS among elderly users of a primary healthcare unit in a poor and violent area of Rio de Janeiro City, and at verifying its association with depression, self-perceived health (SPH), marital status and chronic illnesses. A cross-sectional study was performed based on a convenience sample of 180 individuals aged 60 years or older. SS was measured with part of the Brazilian version of Medical Outcomes Study's SS scale, and SPH and depression were assessed, respectively, through one question and the Brazilian version of the Structured Clinical Interview for DSM-IV Axis I Disorders. SS medians were calculated for the categories of SPH, depression, marital status and chronic illnesses variables, and differences were evaluated with the Kruskal-Wallis and Mann-Whitney tests. Additionally, Pearson's chi-square test and logistic regression were employed to identify unadjusted and adjusted associations between SS and those variables. The participant's mean age was 73 years old, and level of education was 3 years of school education on average. They were predominantly females (73.3%), and non-married (55.0%). Among them, 74.4% perceived their SS as satisfactory, 55.0% perceived their health as good, 27.8% were diagnosed with major depression and 83.3% had hypertension. Especially for those depressed and with bad SPH, the medians of SS measure were much lower than for others, reaching an unsatisfactory level. Moreover, controlling for other factors, non-depressed individuals were more likely (OR = 2.32) to have satisfactory SS. in the violent and poor area explored in this research low SS is highly prevalent in the elderly. Depressed individuals are more likely to have low SS and this condition should be investigated in depressed elderly. The reduced scale is useful for low education individuals.


Modulation of critical brain dynamics using closed-loop neurofeedback stimulation.
EEG long-range temporal correlations (LRTCs) are a significant for both human cognition and brain disorders, but beyond suppression by sensory disruption, there are little means for influencing them non-invasively. We hypothesized that LRTCs could be controlled by engaging intrinsic neuroregulation through closed-loop neurofeedback stimulation. We used a closed-loop-stimulation paradigm where supra-threshold α-waves trigger visual flash stimuli while the subject performs the standard eyes-closed resting-state task. As a "sham" control condition, we applied similar stimulus sequences without the neurofeedback. Over three sessions, a significant difference in the LRTCs of α-band oscillations (U=89, p<0.028, Wilcoxon rank sum test) and their scalp topography (T=-2.92, p<0.010, T-test) emerged between the neurofeedback and sham conditions so that the LRTCs were stronger during neurofeedback than sham. No changes (F=0.16, p>0.69, ANOVA test) in the scalp topography of α-band power were observed in either condition. This study provides proof-of-concept for that EEG LRTCs, and hence critical brain dynamics, can be modulated with closed-loop stimulation in an automatic, involuntary fashion. We suggest that this modulation is mediated by an excitation-inhibition balance change achieved by the closed-loop neuroregulation. Automatic LRTC modulation opens novel avenues for both examining the functional roles of brain criticality in healthy subjects and for developing novel therapeutic approaches for brain disorders associated with abnormal LRTCs.


Using Informatics to Build a Digital Health Footprint of Patients Living With Inherited Metabolic Disorders Identified by Newborn Screening.
Newborn screening is a process identifying people with inherited metabolic disorders (IMDs) at birth, but these patients are often lost to follow-up, and limited data on their long-term needs are available to advocate for policies that will help this vulnerable community. Using informatics best practices, the Medical Nutrition Therapy for Prevention (MNT4P) program and the Public Health Informatics Institute successfully deployed a minimally viable product-that is, the most basic working version that is scalable-allowing for lifelong patient follow-up and outcome and needs tracking, and that can address national data gaps. The new system offers a HIPAA-compliant, efficient record-keeping system that allows data standardization and harmonization. MNT4P staff have transitioned completely away from former manual processes and are relying on this system to log and track patient information. Other programs serving patient populations burdened with rare, marginalized diseases also may benefit from this work.


Effects of organic apricot on liver regeneration after partial hepatectomy in rats.
The present study investigated the effects of (sun-dried organic apricot/SDOA) supplementation in chow on liver regeneration after partial hepatectomy/(PH) in rats. In this study, 28 female rats were randomized into four groups. On the 7th day of the study, group 1 underwent laparoscopic intervention while a PH was performed on the other three cohorts. On day 28, all rats were humanely killed. Blood and liver tissue samples were subjected to biochemical determinations, histological examinations, and measurement of tissue oxidative stress enzyme activity. Serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP), and liver tissue glutathione (GSH) activities were affected by PH and/or SDOA consumption (P < .05). Moderately staining cell counts in group 4 were significantly different from the other three groups (P < .05). However, no significant differences were detected among all groups in regard to aspartate aminotransferase (AST) serum levels or liver tissue superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT) or glutathione peroxidase (GSHpx) activities (P < .05). The 5% SDOA supplementation over a 21-day feeding period showed a beneficial effect on liver regeneration in rats, as reflects by Ki-67 finding although there was no change in ALT or ALP or in liver tissue GSH activity.


Efficacy of novel SB knife Jr examined in a multicenter study on colorectal endoscopic submucosal dissection.
Secure manipulation of forceps in endoscopic submucosal dissection (ESD) for colorectal tumors is sometimes hindered by the characteristics of that organ. SB knife Jr, which are scissor forceps using a mono-pole high frequency, were developed to avoid the difficulty of ESD operation in the colorectum. The aim of the present study was to examine the effectiveness of the SB knife Jr in colorectal ESD in 11 hospitals, mostly in northeastern Japan. One hundred and two colorectal tumors (49 non-granular laterally spreading tumor [LST] lesions, 39 granular LST lesions and 14 other lesions) that were resected by ESD operations using SB knife Jr between October 2009 and March 2010. All tumors (102/102) were resected en bloc and could be observed in detail. The mean size of the resected pieces was 40.3 mm. The mean operation time was 54.2 min. Of the complications, one case of micro-perforation occurred during the manipulation of submucosal dissection, and this case was treated with clips in that operation. The rates of resection carried out only with SB knife Jr were 74.5% (76/102). The novel ESD using SB knife Jr in the colorectum offers a breakthrough in resection techniques for not only expert endoscopists but also general endoscopists.


Correction to: Retinal oximetry and fractal analysis of capillary maps in sickle cell disease patients and matched healthy volunteers.
In the published online PDF version, Figure 3 was incorrectly captured the same as Figure 1.


A temporal study of Brazilian pregnant and postpartum women vulnerability for COVID-19: Characteristics, risk factors and outcomes.
During the COVID-19 second wave in Brazil, there has been a significant increase in the number of daily cases and deaths, including pregnant and postpartum women. We assess risk factors and outcomes for this priority group compared to the COVID-19 non-pregnant cohort in two epidemic waves. In this retrospective cohort study we evaluated data of hospitalized pregnant, postpartum, and nonpregnant women aged 15-44 years, between epidemiological weeks 2020-8 and 2021-15, who tested positive for SARS-CoV-2, retrieved from the Influenza Epidemiological Surveillance Information System maintained by Ministry of Health of Brazil. We analysed in-hospital case fatality rate, crude and adjusted risk ratios on different outcomes aiming to compare data in two waves. The study included pregnant women (n = 7,132), postpartum women (n = 2,405) and nonpregnant women (n = 76,278) hospitalized with COVID-19. Case fatality rates of pregnant women were lower in both waves compared to nonpregnant women, but higher among postpartum women. The risk for admission to the intensive care unit and invasive mechanical ventilation requirement in both waves was significantly higher among postpartum women compared to nonpregnant women. Cardiac disease, diabetes, obesity, and asthma were the most frequent underlying medical conditions in all patient groups. These comorbidities were significantly less frequent among pregnant women. Pregnant women with COVID-19 are at lower risk of poor outcome compared to nonpregnant women. On the other hand, postpartum women are at higher risk of adverse outcomes compared to pregnant and nonpregnant women, especially during the second wave. There was a significant increase in the in-hospital case fatality rate for all patient groups during the second wave of COVID-19. This study was financed in part by CAPES, CNPq, FAPEMIG and UFSJ.


Intrauterine enucleation of normal mice mimics a structural compensatory response in the geniculate of eyeless mutant mice.
Identification of a compensatory structural pathway for the retinal terminals in the glomerular configuration of the dorsal lateral geniculate nucleus (dLGN) of the adult anophthalmic mutant mouse (ZRDCT-An) led to an experimental analysis of the effect of surgical enucleation on the dLGN of normal embryonic and postnatal C57 mice. Young C57 adults were prenatally enucleated (embryonic days 14-19) or during the early postnatal period (birth to 5 days old). Light and electron microscopic observations on the dLGN of these enucleated mice were compared with the dLGN of two types of mutant mice, the bilaterally eyeless anophthalmic and the unilaterally eyeless naked splotch (NSP). A structural compensatory response, similar to that occurring naturally in these two mutant mice, is activated by prenatal experimental enucleation as shown by the appearance of large replacement terminals (LRTs) for the retinal afferents. The glomeruli in the ipsi- and/or contralateral dLGN in these 3 conditions contain extensive synaptic areas covered by compensatory large axons. This pattern of synaptic thalamic reorganization occurs after experimental prenatal and postnatal enucleation of normal mice. This structural reorganization in experimentally and genetically enucleated mice suggests a common mechanism for replacement of retinal terminals. The precise origin and function of this tract remains to be determined. This evidence demonstrates that the anophthalmic mutant mouse is a valid model system for analysis of thalamic reorganization that occurs in normal mice after perinatal enucleation.


Safety, tolerability and immunogenicity of Biological E's CORBEVAX™ vaccine in children and adolescents: A prospective, randomised, double-blind, placebo controlled, phase-2/3 study.
After establishing safety and immunogenicity of Biological-E's CORBEVAX™ vaccine in adult population (18-80 years) in Phase 1-3 studies, vaccine is further tested in children and adolescents in this study. This is a phase-2/3 prospective, randomised, double-blind, placebo-controlled study evaluating safety, reactogenicity, tolerability and immunogenicity of CORBEVAX™ vaccine in children and adolescents of either gender between <18 to ≥12 years of age in Phase-2 and <18 to ≥5 years of age in Phase-Phase-2/Phase-3 with placebo as a control. This study has two age sub-groups; subgroup-1 with subjects <18 to ≥12 years of age and subgroup-2 with subjects <12 to ≥5 years of age. In both sub groups, eligible subjects (SARS-CoV-2 RT-PCR negative and seronegative at baseline) were randomized to receive either CORBEVAX™ vaccine or Placebo in 3:1 ratio. The safety profile of CORBEVAX™ vaccine in both pediatric cohorts was comparable to the placebo-control group. Majority of reported adverse events (AEs) were mild in nature. No severe or serious-AEs, medically attended AEs (MAAEs) or AEs of special interest (AESI) were reported during the study period and all reported AEs resolved without any sequelae. In both pediatric age groups, CORBEVAX™ vaccinated subjects showed significant improvement in humoral immune-responses in terms of anti-RBD-IgG concentrations, anti-RBD-IgG1 titers, neutralizing-antibody (nAb)-titers against Ancestral-Wuhan and Delta-strains. Significantly high interferon-gamma immune- response (cellular) was elicited by CORBEVAX™ vaccinated subjects with minimal effect on IL-4 cytokine secretion. The safety profile of CORBEVAX™ vaccine in <18 to ≥5 years' children and adolescents was found to be safe and tolerable. Significant increase in anti-RBD-IgG and nAb-titers and IFN-gamma immune-responses were observed post-vaccination in both pediatric age sub-groups. The nAb titers observed in both the pediatric age cohorts were non-inferior to the adult cohort (BECT069 study) in terms of ratio of the GMT's of both the cohorts. This study shows that CORBEVAX™ vaccine is highly immunogenic and can be safely administered to pediatric population as young as 5 years old. The study was prospectively registered with clinical trial registry of India- CTRI/2021/10/037066.


Paf1 complex homologues are required for Notch-regulated transcription during somite segmentation.
Members of the yeast polymerase-associated factor 1 (Paf1) complex, which is composed of at least five components (Paf1, Rtf1, Cdc73, Leo1 and Ctr9), are conserved from yeast to humans. Although these proteins have been implicated in RNA polymerase II-mediated transcription, their roles in vertebrate development have not been explained. Here, we show that a zebrafish mutant with a somite segmentation defect is deficient in rtf1. In addition, embryos deficient in rtf1 or ctr9 show abnormal development of the heart, ears and neural crest cells. rtf1 is required for correct RNA levels of the Notch-regulated genes her1, her7 and deltaC, and also for Notch-induced her1 expression in the presomitic mesoderm. Furthermore, the phenotype observed in rtf1-deficient mutants is enhanced by an additional deficiency in mind bomb, which encodes an effector of Notch signalling. Therefore, zebrafish homologues of the yeast Paf1 complex seem to preferentially affect a subset of genes, including Notch-regulated genes, during embryogenesis.


Pediatric abdominal pain: use of imaging in the emergency department in the United States from 1999 to 2007.
To evaluate use of imaging in children with acute abdominal pain who present to U.S. emergency departments (EDs). This study received expedited review by the institutional review board. The National Hospital Ambulatory Medical Care Survey is a government-administered yearly survey of EDs that is used to estimate ED care throughout the United States. This retrospective cohort study interrogated the database for the period from 1999 to 2007. Univariate regression analysis was performed, and a multivariate regression model was developed. From 1999 to 2007, 16 900 000 pediatric ED visits were made for acute abdominal pain. Odds of undergoing computed tomography (CT) in this population increased during each year of the study period. No significant changes occurred in use of ultrasonography, number of patients admitted to the hospital, or number of patients with acute appendicitis. A multivariate model for CT use revealed increased odds of CT use in teens, white patients, the Midwest region, urban settings, patients with private insurance, and patients who were admitted or transferred. Odds of undergoing CT were significantly lower among patients who presented to a pediatric-focused emergency department (adjusted odds ratio, 0.72; 95% confidence interval: 0.58, 0.90). The main findings of this study are that the rate of CT use in the evaluation of abdominal pain in children increased every year between 1999 and 2007 and that the use of CT was greater among children seen in adult-focused EDs. Factors affecting CT use include sex, race, age, insurance status, and geographic region.


Stroke incidence and survival in three Sicilian municipalities. Sicilian Neuro-Epidemiologic Study (SNES) Group.
We investigated the incidence of first-ever stroke in three Sicilian municipalities over the years 1984-1987. Case ascertainment involved two approaches: a door-to-door two-phase prevalence survey and a study of death certificates. Only first-ever strokes occurring within the study time interval were included, and diagnoses were based on specified criteria. We found 138 subjects who had experienced a first stroke over 73 488 person-years; the average incidence rate (new cases per 1000 population per year) was 1.9 overall, 1.7 in men, and 2.1 in women. Incidence increased steeply with age and was similar in men and women. Incidence was similar in the three study municipalities. The overall case-fatality rate was 35% at 30 days and 22% at one week. Survival after stroke was similar in men and women but better in younger compared to older stroke patients. Comparisons with previous studies suggest the absence of major geographic variations in stroke incidence within Italy.


Abbreviated Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in High Bleeding Risk Patients: LEADERS-FREE and ONYX ONE.
The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) has been the focus of much discussion. The risk of late stent thrombosis appears less with newer-generation stents, and polymer-free drug-coated stents (DCS) may improve clinical efficacy relative to a bare metal stent without the potential long-term hazards associated with a durable polymer. Based on the outcomes of recent clinical trials, risk stratification to identify high bleeding risk patients and appropriate selection of a polymer-free drug-coated or durable-polymer zotarolimus-eluting stent may optimize clinical outcomes in patients who require an abbreviated DAPT regimen.


Chromosomal aberrations as detected by array comparative genomic hybridization in early low-grade intraepithelial neoplasias of the breast.
Low-grade flat ductal intraepithelial neoplasia (DIN1a, flat epithelial atypia) is one of the earliest morphologically recognizable neoplastic lesions of the breast. Frequently, it occurs concomitantly with lobular intraepithelial neoplasia (LIN). We aimed to elucidate chromosomal aberrations in these early neoplastic breast lesions with the use of array comparative genomic hybridization analysis. Laser capture microdissection of 12 archival formalin-fixed, paraffin-embedded specimens harbouring foci of both DIN1a and LIN was performed. All analysed cases of DIN1a and LIN showed chromosomal gains and losses. The aberration encountered most often was loss of 16q, noted in seven DIN1a (70% of those successfully examined) and 10 LIN (91%) cases. The next most common alteration was a gain on 1q, noted in four DIN1a (40%) and seven LIN (64%) cases. The results show concurrent chromosomal aberrations of 1q gains and 16q losses in several cases with coexisting LIN and DIN1a. These aberrations are known to be common in low-grade invasive (ductal and lobular) carcinomas as well as in more advanced (conventional) types of low-grade ductal intraepithelial neoplasia (DIN) (low-grade ductal carcinoma in situ). Our results raise the possibility of similar molecular-genetic pathways in coexisting LIN and low-grade flat DIN.


Can computed tomography classifications of chronic obstructive pulmonary disease be identified using Bayesian networks and clinical data?
Diagnosis and classification of chronic obstructive pulmonary disease (COPD) may be seen as difficult. Causal reasoning can be used to relate clinical measurements with radiological representation of COPD phenotypes airways disease and emphysema. In this paper a causal probabilistic network was constructed that uses clinically available measurements to classify patients suffering from COPD into the main phenotypes airways disease and emphysema. The network grades the severity of disease and for emphysematous COPD, the type of bullae and its location central or peripheral. In four patient cases the network was shown to reach the same conclusion as was gained from the patients' High Resolution Computed Tomography (HRCT) scans. These were: airways disease, emphysema with central small bullae, emphysema with central large bullae, and emphysema with peripheral bullae. The approach may be promising in targeting HRCT in COPD patients, assessing phenotypes of the disease and monitoring its progression using clinical data.


Ractopamine residue in meat might protect people from Parkinson disease.
There is still no curative treatment for the exasperating Parkinson disease, the second most common neurodegenerative disorder. Intracytoplasmic Lewy body composing of phosphorylated α-synuclein in dopaminergic neuronal cells has been recognized as the characteristic pathologic change and believed to be the cause of neuronal cell loss in Parkinson disease. Recently, β-adrenoreceptor antagonist was found to be correlated with an increasing incidence of Parkinson disease and β-adrenoreceptor agonist, capable of inhibiting gene expression of α-synuclein, was associated with a reduced incidence of it. Therefore, a hypothesis is raised that ractopamine, a β-adrenoreceptor agonist used as feed additive for increasing leanness of finishing cattle and swine, might provide protective effects for Parkinson disease and lower its incidence in the population consuming meat containing ractopamine residue.


Giant teratoma with isolated intestinal duplication in adult: A case report and review of literature.
A combination of diseases is a rare phenomenon. Their clinical manifestations can vary, and the diagnosis can be challenging. Intestinal duplication is a rare congenital malformation, whereas retroperitoneal teratoma is a tumor in the retroperitoneal space, derived from the remaining embryonic tissue. There are relatively few clinical findings on adult retroperitoneal benign tumors. It is hard to believe that these two rare diseases can happen to the same person. A 19-year-old woman complaining of abdominal pain with nausea and vomiting was admitted. Abdominal computed tomography angiography was suggested for invasive teratoma. Intraoperative exploration revealed that the giant teratoma was connected to an isolated intestinal tract in the retroperitoneum. The postoperative pathological examination revealed that mature giant teratoma was present with intestinal duplication. This was a rare intraoperative finding that was successfully treated surgically. The clinical manifestations of intestinal duplication malformation are various, and difficult to diagnose before the operation. The possibility of intestinal replication should be considered when intraperitoneal cystic lesions are present.


The paediatric surgeon and his working conditions in Francophone sub-Saharan Africa.
This study described the current conditions of work of paediatric surgeons in Francophone sub-Saharan Africa (FSSA) and set the debate at the level of the humanist thinking in medicine. This was a multicentre study from 1 st May to 30 th October 2008. The African Society of paediatric surgeons' directory was used to identify paediatric surgeons in the Francophone's countries in Sub Saharan Africa. The parameters studied were number of surgeons per country, means of training, working conditions, remunerations, needs for continuous training and the research. A total of 41 paediatric surgeons (68.33%) responded. The average number of paediatric surgeons per country was 5. The means of training included government scholarships among 7 paediatric surgeons (17.07%), scholarship from a non-governmental organisations in 14 (34.15%) and self-sponsorships in 20 (48.78%). The average salary was 450 Euros (€) (range: 120-1 400 Euros). Most of the paediatric surgeons (68.29%) had internet services for continuous update courses and research. Thirty six paediatric surgeons (87.80%) had no subscription to specialised scientific journals. The paediatric surgeon in FSSA faces many problems related to his working and living conditions that may have a negative impact on their competences.


Can premature luteinization in superovulation protocols be prevented by aspiration of an ill-timed leading follicle?
In 12 patients stimulated for in vitro fertilization and embryo transfer (IVF-ET), a single leading follicle developed, whereas the other follicles were 6 mm smaller. In 7 patients chosen at random (group A), the leading follicle was aspirated, whereas in the other 5 the leading follicle was allowed to continue growing (group B). Comparison of the hormonal pattern of both groups showed that a premature luteinizing hormone (LH) surge was avoided only in group A, and only in this group a second follicle aspiration for IVF-ET was done, and two pregnancies were achieved. In group B, aspiration for IVF-ET was canceled because of premature LH surge. It is suggested that aspiration of a single leading follicle during ovulation induction may be an efficient method to avoid premature LH surge enabling other follicles to develop up to the preovulatory stage.


Direct and residual antimicrobial effect of 2% chlorhexidine gel, double antibiotic paste and chitosan- chlorhexidine nanoparticles as intracanal medicaments against Enterococcus faecalis and Candida albicans in primary molars: an in-vitro study.
Thorough disinfection of root canals in primary molars may be complicated by the complex root canal morphology. This in-vitro study aimed to compare direct and residual antimicrobial effect of 2% chlorhexidine (CHX) gel, 500 mg/ml double antibiotic paste (DAP) and chitosan-chlorhexidine nanoparticles (CS-CHX NPs) as intracanal medicaments against Enterococcus faecalis (E. faecalis) and Candida albicans (C. albicans) in primary molars. Mesial roots of 63 mandibular second primary molars were infected with E. faecalis and C. albicans. Teeth were divided into 9 groups: Ia: (CS-CHX NPs), IIa: (CHX), IIIa: (DAP), IVa: chitosan nanoparticles (CSNPs) in which medicaments were placed for 3 days, groups Ib: (CS-CHX NPs), IIb: CHX, IIIb: (DAP), IVb: (CSNPs) in which medicaments were placed for 7 days, and Group V (control): teeth were infected, irrigated with saline, and sampled 3- and 7-days post-infection. Microbiological samples were obtained after infection, 3, and 7 days after medicament placement and 7 days after medicament removal for both time points. One-way ANOVA, Tukey's post hoc test and paired t-test were used at p < 0.05. CS-CHX NPs had the highest anticandidal effect which was comparable to CHX and significantly higher than other medicaments (p < 0.001) at both time points. CS-CHX NPs had the highest effect against E. faecalis which was comparable to DAP and significantly higher than other medicaments (p < 0.001) at 3 days. All medicaments showed similar effect against E. faecalis after 7 days. The 7-days placement significantly increased the antimicrobial effect against both micro-organisms in all groups, except CS-CHX NPs which showed an insignificant increase. CS-CHX NPs showed the highest residual effect against both micro-organisms that increased with 7-days placement. CSNPs and CHX combination showed a synergistic effect against both micro-organisms. CS-CHX NPs displayed a higher effect at a shorter period compared to other medicaments, yet its residual effect was higher with 7-days placement.


[Labial rubor reconstruction with a flap from the tongue].
The evolution of the method used for reconstruction of labial rubor is described laying stress on the use of tongue tissue. Two cases are reported for illustration.


Cholesterol screening in school children: is family history reliable to choose the ones to screen?
Hyperlipidemia is a major factor accompanying atherosclerosis. As the basis of atherosclerotic heart disease begins at early childhood, we aim to find out which children should be tested for hypercholesterolemia, what the high cholesterol level in children is and what cautions should be taken to avoid atherosclerosis. The study was carried on 2096 school children (1043 male, 1053 female) in Ankara. Their mean age was 9.03 years. Demographic properties of the study group and their families were determined and the serum lipid levels of the subjects were obtained. The relation between these demographic properties and lipid levels were investigated. In 135 of the subjects' serum cholesterol level was >or=200 mg/dL and in 83 subjects serum LDL-cholesterol level was >or=130 mg/dL. Despite 64.4% of the subjects reported a family history of hyperlipidemia, no relations between family history and serum lipid levels were found. We suggest that regardless of family history, all children over 5 years should be screened for hyperlipidemia. Education about hyperlipidemia and precautions for its complications should be given to both children and families. The best and easiest way to reach children is to screen them at schools. School is also a good place for education of children about hyperlipidemia and risk factors.


Some factors affecting the efficiency of settle plates.
An evaluation has been made of some of the factors which may affect the efficiency of settle plates. Water loss was found to be linear with time. Although the count was reduced over an 8 h period the reduction was not statistically significant. No difference in total bacterial counts could be detected between four, 1/2 h exposures and one, 2 h exposure. The addition of water and the surface area of the plates had no effect on the total count.


[Recurrence of intracranial aneurysms after endovascular embolization: study of 70 cases].
To evaluate the factors of recurrence of intracranial aneurysm after endovascular embolization. Seventy patients with 74 intracranial aneurysms, 37 males and 33 females, aged 47 (37-63), underwent endovascular embolization. Cerebral angiography was conducted 3 months to 1 year after the endovascular embolization on 37 patients. The geometric forms of aneurysm, method and material of endovascular embolization, and digital subtraction angiography (DSA) images before and after the recurrence were analyzed. geometry form, method and material of endovascular embolization and image. Nine recurrent aneurysms were discovered in 8 patients of which 5 were located in the posterior communicating artery; 2 in the anterior communicating artery;and 2 in the first crotch of the right middle cerebral artery. Four of the recurrent aneurysms were wide-necked aneurysms; and 5 were of irregular forms. Before recurrence, complete aneurysm occlusion was achieved in 3 aneurysms and incomplete occlusion was achieved in 6. The percentage of complete aneurysm occlusion is related to the location, size, geometric form, method and material of endovascular embolization and density of coil packing. Intracranial aneurysms located in crotch of artery, with wide-neck, large, with irregular forms, and embolized incompletely are liable to recur.


Heart failure with preserved ejection fraction: Calculating the risk of future heart failure events and death.
We sought to develop a clinical model to identify heart failure patients with preserved ejection fraction (HFpEF) at highest risk for acute HF events or death. Between 2010 and 2019, 422 patients with HFpEF were followed. Acute HF events occurred in 190 patients (45%), including 110 (58%) with recurrent hospitalizations. Those with recurrent events had worse 6-min walk test (p < 0.001), higher brain N-terminal prohormone natriuretic peptide (NT-proBNP, p < 0.001), and higher New York Heart Association functional class (NYHA, p < 0.001). Overall survival rates in patients with 1 HF event vs > 1 HF events were: at 1-year 91.6 vs. 91.8%, at 3-years 84.7 vs. 68.3% and at 5-years 67.4 vs. 42.7%, respectively (p < 0.04). The Hfpef survivAL hOspitalization (HALO) score revealed best predictive capability for all-cause mortality combining the variables age (p = 0.08), BMI (p = 0.124), NYHA class (p = 0.004), need for diuretic therapy (p = 0.06), left atrial volume index (p = 0.048), systolic pulmonary artery pressure (p = 0.013), NT-proBNP (p = 0.076), and number of prior hospitalizations (p = 0.006). HALO score predicted future HF hospitalizations in an ordinal logistic regression model (OR 3.24, 95% CI: 2.45-4.37, p < 0.001). The score performance was externally validated in 75 HFpEF patients, confirming a strong survival prediction (HR 2.13, 95% CI: 1.30-3.47, p = 0.002). We developed a model to identify HFpEF patients at increased risk of death and HF hospitalization. NYHA class and recurrent HF hospitalizations were the strongest drivers of outcome.


A Rare Case of Ameloblastic Carcinoma of Maxilla.
Ameloblastic carcinoma is an odontogenic neoplasm with combined features of ameloblastoma and carcinoma on histopathological examination. Its prognosis is dominated by risk of local recurrence and distant metastasis. We report our patient because of the rare site and to highlight the importance of early, aggressive surgical treatment and regular follow-up.


Iron casein succinylate-chitosan coacervate for the liquid oral delivery of iron with bioavailability and stability enhancement.
Iron casein succinylate (ICS) liquid oral preparation as iron supplement has uncomfortable taste after a long period of storage because of its stability, and poor bioavailability of iron compared to any other iron preparations. To improve the chemical stability of ICS and enhance the bioavailability of iron, chitosan-ICS nanoparticles (NPs) were prepared by complex coacervation method and stabilized with polyethylene glycol (PEG) 400. NPs were spherical (mean diameter of 830-1070 nm) with positive charge (+30-60 mV) depending on the composition of NPs. Addition of PEG400 (2 w/v %) increased the zeta potential (26-50 %) and physical stability of chitosan-ICS NPs suspension. Also, NPs decreased iron release compared to ICS after 7-weeks of storage at 4 °C. NPs markedly increased the permeability of iron in Caco-2 cell up to 32-38-fold compared to ICS, while physical mixture of chitosan and ICS increased the iron permeability only 2.5-fold. In summary, NPs improved the physicochemical stability and enhanced the transport of iron compared to other iron preparations in Caco-2 cell model. Thus, chitosan-ICS coacervate might be a promising candidate as a liquid oral iron delivery system for iron deficiency patients with stability and bioavailability enhancement.


Taste masking microspheres for orally disintegrating tablets.
The purpose of this study was to evaluate the potential of microspheres for taste masking when incorporated into orally disintegrating tablets. The microspheres were produced by spray drying a mixture of the model compound (famotidine) with taste masking material. The spray process was optimized using a central composite design for two variables to obtain microspheres with desirable characteristics. Then the microspheres were mixed with other excipients to form orally disintegrating tablets. The optimal spray-drying process parameters were 34mg/ml for solid concentration and 7ml/min for feed rate. The drug encapsulation efficiency of the spray-dried microspheres ranges from of 37.59 to 61.56%, with a mean diameter of less than 10microm size and low moisture content (less than 4%). Results from an evaluation by a panel of six human volunteers demonstrated that the orally disintegrating tablets with taste masking microspheres improved the taste significantly. Furthermore, an in vivo study in rats showed that the microspheres neither decrease the bioavailability nor retard the release of famotidine significantly. In conclusion, spray-dried microspheres can effectively mask the bitter taste of the active pharmaceutical ingredients in combination with the orally disintegrating tablets.


Ternary Nanocomplexes of Metallic Nanoclusters and Recombinant Peptides for Fluorescence Imaging and Enhanced Gene Delivery.
The efficient carrier design for transferring therapeutic genes into target cells as well as tracking the delivered agents has attracted lots of attention in the field of DNA-based therapeutics. Here, we demonstrate this concept by a fast and facilitated method using BSA gold nanocluster (BSA AuNcs) conjugated with chimeric peptide with ability of DNA binding/packaging, endosome disruption and cell nuclear localization. An extensive characterization of photoluminescence properties, electrophoresis mobility and size distribution of the nanocarrier demonstrating the stable complexes composed of plasmid DNA, chimeric peptide and BSA AuNcs were successfully formed through electrostatic interactions. In the hybrid complexes, chimeric peptide could effectively decrease the cytotoxicity of AuNcs as well as enhance internalization of plasmid harboring firefly luciferase gene into HEK 293 T. The designed nanocarrier could be a promising vector in gene delivery systems for improved theranostics applications.


PICC vs. midline catheter use for short-term indications was linked to major complications at ≤30 d.
Swaminathan L, Flanders S, Horowitz J, et al. Safety and outcomes of midline catheters vs peripherally inserted central catheters for patients with short-term indications: a multicenter study. JAMA Intern Med. 2022;182:50-8. 34842905.


Stimulation by hydrogen peroxide of DNA synthesis, competence family gene expression and phosphorylation of a specific protein in quiescent Balb/3T3 cells.
Treatment of quiescent Balb/3T3 clone A31-1-1 cells with 0.1-0.2 mM H2O2 in the presence of 1 microM insulin induced DNA synthesis 20-24 h later at almost the same level as that in cells treated with 10% serum. Treatment with 0.1-0.2 mM H2O2 alone did not induce DNA synthesis and was not toxic to the cells. Cell cycle analysis indicated that treatment with H2O2 plus insulin induced progression of the cell cycle from the quiescent state. The amounts of mRNA for competence family genes such as c-fos, KC and JE were increased by the addition of H2O2. Under these conditions H2O2 caused rapid phosphorylation of a protein of 78 kDa with a pI of 6.3 (p78). Phosphorylation of p78 increased on treatment with TPA and serum as well. Catalase reduced the increase in phosphorylation of p78 induced by TPA and serum. Endogenous production of H2O2 was observed within 10 min after treatment of quiescent cells with platelet derived growth factor (PDGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA). These results indicate that H2O2 at certain concentrations mimics the action of competence factors on resting Balb/3T3 cells.


Karyotype instability with multiple 7/14 and 7/7 rearrangements.
Chromosomes were studied in a mentally retarded boy with microcephaly, growth retardation, facial erythema, café-au-lait spots, and IgA deficiency. In the lymphocytes there was a remarkable tendency to exchange parts of the chromosomes Nos. 7 and 14, the translocations almost exclusively taking place in bands 7p13, 7q32 and 14q11. Seven different types of rearrangements between Nos. 7 and 14, and some other chromosomal aberrations were found. No abnormalities could be detected in the bone marrow. The patient somewhat resembles those affected with ataxia-telangiectasia or with Bloom's syndrome, but on clinical and cytogenetic grounds these disorders could be excluded. 7/14 Translocations similar to those found in our patient's lymphocytes have been reported to occur very rarely in the lymphocyte cultures of individuals with apparently normal chromosome constitution. A relationship between these phenomena may exist.


Effect of visceral afferent activation on leg extension induced by sciatic afferent stimulation.
In cats under light chloralose and sodium pentobarbital anesthesia the effects of electrical stimulation of various visceral afferent nerves on leg extension induced by sciatic afferent stimulation were studied. Stimulation of the central end of the cervical vagus and stellate ganglion produced inhibition of induced leg extension while stimulation of the distal end of the thoracic vagus, coeliac ganglion, and splanchnic nerves produced facilitation. Decortication slightly reduced the inhibitory effect and greatly reduced the facilitatory effect. Additional decerebration greatly reduced the inhibitory effect and almost abolished the facilitatory effect. Spinal transection at C1 completely abolished the inhibitory and facilitatory effects on induced leg extension. These results suggest that visceral afferents facilitate sciatic induced leg extension principally through the cortex while they inhibit extension through the midbrain and hypothalamus.


Morbidity, mortality and coronavirus antigen in previously coronavirus free kittens placed in two catteries with feline infectious peritonitis.
Serologically coronavirus free kittens were placed in 2 catteries with a history of feline infectious peritonitis (FIP), each cattery representing 1 of the 2 different predominant clinical characteristics of FIP--effusive and granulomatous. The kittens were clinically observed for 100 days. A 100% morbidity and a 90% mortality was observed. The first signs were observed after 14 and 27 days respectively. The clinical pattern of the disease was similar in all kittens and showed a pattern of recurrent periods of conjunctivitis, upper respiratory and gastrointestinal signs. Once developed, wasting and signs of CNS disturbances were consistent. The "effusive strain" had a 2 weeks earlier onset of signs and death, and a 40% outcome of effusive FIP. Mean survival times during the observation period were 57 +/- 26 and 57 +/- 16 (mean +/- SD in days), respectively. The death rates were similar in both groups. Feline coronavirus (FCoV) antigen was immunohistochemically detected using indirect immunofluorescence and was present in all kittens and in 93% of the 5 investigated organs (lung, liver, spleen, kidney, and mesenteric lymph node).


A study of the photochemical behaviour and relaxation mechanisms of anti-syn isomerisation around quinazolinone -N-N[double bond, length as m-dash] bonds.
High-resolution NMR experiments revealed that differently substituted quinazolinone-based Schiff bases undergo anti to syn isomerisation on exposure to ultraviolet light in DMSO solution. The degree anti to syn conversion varied significantly upon substitution (between 5% and 100%) and also showed two noteworthy features: that relaxation back to the anti-form goes far faster (by at least 3 orders of magnitude) when the C6 rings B and C have ortho-OH substituents, and that relaxation can also be significantly sped up by addition of acid. Two possible mechanisms explaining the differences in relaxation process have been proposed: (I) the interaction of the azomethine hydrogen with the carbonyl oxygen results in slower reversion to the anti-form and/or (II) suppression of conjugation of the N3 lone pair with the N[double bond, length as m-dash]CH double bond by protonation and/or internal H-bonding. Both of these mechanisms have been analysed theoretically.


Ice (photo)chemistry. Ice as a medium for long-term (photo)chemical transformations--environmental implications.
This review accounts for the current knowledge about the distribution, accumulation, and chemical/photochemical transformations of persistent, bioaccumulative, and toxic compounds (PBTs) in water ice, especially in the connection with polar regions and atmospheric cloud particles. (Photo)reactions on/in ice are discussed in terms of photochemistry, photobiology, paleochemistry, as well as astrophysics. Authors propose a model, in which a significant amount of some PBTs are generated by (photo)chemistry of primary pollutants in ice, which may subsequently be released to the environment. It is argued that ice photochemistry might play an important role in the chemical transformations in cold ecosystems and in the upper atmosphere, particularly now when the ozone layer is partially depleted.


A survey on the future of radiology among radiologists, medical students and surgeons: Students and surgeons tend to be more skeptical about artificial intelligence and radiologists may fear that other disciplines take over.
To evaluate the opinion and assessment of radiologists, surgeons and medical students on a number of important topics regarding the future of radiology, such as artificial intelligence (AI), turf battles, teleradiology and 3D-printing. An online questionnaire was created using the SurveyMonkey platform targeting radiologists, students and surgeons throughout the German speaking part of Switzerland. A total of 170 people participated in the survey (59 radiologists, 56 surgeons and 55 students). Statistical analysis was carried out using the Kruskal-Wallis test with Dunn's multiple comparison post-hoc tests. While the majority of participants agreed that AI should be included as a support system in radiology (Likert scale 0-10: Median value 8), surgeons were less supportive than radiologists (p = 0.001). Students saw a potential threat of AI as more likely than radiologists did (p = 0.041). When asked whether they were concerned about "turf losses" from radiology to other disciplines, radiologists were much more likely to agree than students (p < 0.001). Of the students that do not intend to specialize in radiology, 26 % stated that AI was one of the reasons. Surgeons advocate the use of teleradiology. With regard to AI, radiologists expect their workflow to become more efficient and tend to support the use of AI, whereas medical students and surgeons tend to be more skeptical towards this technology. Medical students see AI as a potential threat to diagnostic radiologists, while radiologists themselves are rather afraid of turf losses.


Effect of total lumbar disc replacement on the treatment of discogenic low lumbar pain: preliminary outcomes.
Lumbar pedicle screw fixation and fusion are major procedures for treating discogenic low back pain (DLBP). However, due to its advantages of preserving the segmental motion and biomechanical simulation, artificial total lumbar disc replacement (TDR) is increasingly popular. From 2007 to 2010, 68 DLBP patients were enrolled. TDR were performed on 34 patients and the other 34 controls underwent the traditional fixation procedure. Qualitative and quantitative evaluations were followed including the changes in range of motion (ROM) and interpedicle height (IPH) at the posterior intervertebral body of operated level, in 6 and 12 months, and 3 years, postoperatively. Qualitative results showed satisfying improvement in the two groups after 6 and 12 months, respectively, and the inter-group differences were significant (P > 0.05). The results of ROM and IPH have shown significant differences between the TDR and spinal fusion groups (P < 0.05). With similar clinical improvements as the traditional spinal fusion method, TDR offered significantly better ROM and intervertebral foramen height.


A new risk model based on a 11-m6A-related lncRNA signature for predicting prognosis and monitoring immunotherapy for gastric cancer.
N6-methyladenosine (m6A) mRNA modification triggers malignant behaviors of tumor cells and thereby drives malignant progression in gastric cancer (GC). However, data regarding the prognostic values of m6A RNA methylation-related long non-coding RNAs (lncRNAs) in GC are very limited in the literature. We aimed to investigate the prognostic potential of m6A-related lncRNAs in predicting prognosis and monitoring immunotherapy efficacy in GC patients. Transcriptome and clinical data were obtained from GC biopsies from Cancer Genome Atlas (TCGA). M6A-related lncRNAs associated with GC were identified by constructing a co-expression network, and the gene pairs differentially expressed in GC were selected using univariate analysis. We constructed a risk model based on prognosis-related lncRNA pairs selected using the LASSO algorithm and quantified the best cutoff by comparing the area under the curve (AUC) for risk stratification. A risk model with the optimal discrimination between high- and low-risk GC patients was established. Its feasibility for overall survival prediction and discrimination of clinicopathological features, tumor-infiltrating immune cells, and biomarkers of immune checkpoint inhibitors between high- and low-risk groups were assessed. Finally, we identified 11 m6A-related lncRNA pairs associated with GC prognosis based on transcriptome analysis of 375 GC specimens and 32 normal tissues. A risk model was constructed with an AUC of 0.8790. We stratified GC patients into high- and low-risk groups at a cutoff of 1.442. As expected, patients in the low-risk group had longer overall survival versus the high-risk group. Infiltration of cancer-associated fibroblasts, endothelial cells, macrophages, particularly M2 macrophages, and monocytes was more severe in high-risk patients than low-risk individuals, who exhibited high CD4+ Th1 cell infiltration in GC. Altered expressions of immune-related genes were observed in both groups. PD-1 and LAG3 expressions were found higher in low-risk patients than high-risk patients. Immunotherapy, either single or combined use of PD-1 or CTLA4 inhibitors, had better efficacy in low-risk patients than high-risk patients. The new risk model based on a 11-m6A-related lncRNA signature can serve as an independent predictor for GC prognosis prediction and may aid in the development of personalized immunotherapy strategies for patients.


Bioglass attenuates a proinflammatory response in mouse peritoneal endotoxicosis.
Bioglass is a bioactive, resorbable ceramic particle that was developed to assure binding to living tissues. Bioglass is currently employed to fill osseus defects in oral surgery, and it possesses both unique anti-inflammatory and antimicrobial properties. In an effort to determine whether Bioglass may be useful as an adjunct anti-inflammatory device in local inflammatory processes, we examined whether exposure of the peritoneal cavity to Bioglass would induce a pro- or anti-inflammatory response, and then modulate a subsequent proinflammatory response to endotoxin. Three- to fifty-milligram doses of 5 pm Bioglass were administered intraperitoneally in C57BL/6 mice. Total leukocyte, myeloperoxidase, and cytokine levels in the peritoneal wash fluid were determined. In addition, the peritoneal cavity was preexposed to Bioglass, and was then subjected to a subsequent endotoxin administration. All doses of Bioglass were found to induce a significant peritoneal IL-6 response; however, Bioglass did not induce a TNF-alpha, IL-1alpha, IL-10, or a white cell recruitment into the peritoneal lavage fluid. Pretreatment of the peritoneal cavity with Bioglass produced a transient reduction in the proinflammatory response to endotoxin. We conclude that exposure to Bioglass produces an IL-6 response without concurrent expression of TNF-alpha or IL-1alpha. Bioglass appears to transiently suppress the inflammatory response to endotoxin, possibly through the early induction of IL-6. These findings suggest that Bioglass may offer a unique approach in modifying the inflammatory response in local tissue compartments.


Localized role of CRMP1 and CRMP2 in neurite outgrowth and growth cone steering.
Collapsin response mediator protein 1 (CRMP1) and CRMP2 have been known as mediators of extracellular guidance cues such as semaphorin 3A and contribute to cytoskeletal reorganization in the axonal pathfinding process. To date, how CRMP1 and CRMP2 focally regulate axonal pathfinding in the growth cone has not been elucidated. To delineate the local functions of these CRMPs, we carried out microscale-chromophore-assisted light inactivation (micro-CALI), which enables investigation of localized molecular functions with highly spatial and temporal resolutions. Inactivation of either CRMP1 or CRMP2 in the neurite shaft led to arrested neurite outgrowth. Micro-CALI of CRMP2 in the central domain of the growth cones consistently arrested neurite outgrowth, whereas micro-CALI of CRMP1 in the same region caused significant lamellipodial retraction, followed by retardation of neurite outgrowth. Focal inactivation of CRMP1 in its half region of the growth cone resulted in the growth cone turning away from the irradiated site. Conversely, focal inactivation of CRMP2 resulted in the growth cone turning toward the irradiated site. These findings suggest different functions for CRMP1 and CRMP2 in growth cone behavior and neurite outgrowth.


Sodium Orthovanadate Inhibits Proliferation and Triggers Apoptosis in Oral Squamous Cell Carcinoma in vitro.
Sodium orthovanadate (SOV) is a general inhibitor of tyrosine phosphatases, a large family of enzymes that catalyze the removal of phosphate groups from tyrosine residues. SOV is commonly used in the laboratory to preserve the protein tyrosyl phosphorylation state of proteins under study. It has shown promising antineoplastic activity in some human cancer cell lines; this effect has not been fully investigated in head and neck squamous cell carcinoma. In this study, the effect of SOV on cell growth, proliferation, viability, and apoptosis was assessed in Cal27 cells, an oral squamous cell carcinoma (OSCC) cell line. SOV exhibited dose-dependent inhibition of cell growth and decrease in cell viability and colony formation. The IC50 values for treatment lasting 72 h and 7 days were 25 and 10 µM, respectively. The cytotoxic effect of the drug was associated with poly(ADP-ribose)polymerase cleavage detected by immunoblot. Flow cytometry of Cal27 cells stained with annexin V-FITC and propidium iodide showed a dose-dependent increase in apoptosis that reached approximately 40% at 25 µM SOV. These findings demonstrate that SOV has in vitro antiproliferative and proapoptotic effect on OSCC cells.


Dry matter and nitrogen in the duodenal contents of growing pigs: a discrepancy explained.
1. Discrepancies between the results obtained from experiments on pigs with re-entrant duodenal cannulas have been investigated with reference to diet, cannula site and collection procedure. 2. The results obtained from a sealed automatic collection system were different from those obtained from an open manual method and it was concluded that the maintenance of gut intra-luminal pressure in the automatic system was the causative factor.


Convulsant properties of cyclotrimethylenetrinitramine (RDX): spontaneous audiogenic, and amygdaloid kindled seizure activity.
Dose-effect and time course relationships were determined for the effects of the explosive cyclotrimethylenetrinitramine (RDX) on seizure susceptibility. Male Long Evans rats treated with 0-60 mg/kg RDX po were monitored for spontaneous seizures during an 8-hr interval between dosing and audiogenic (AG) seizure testing. Blood samples for analyzing plasma RDX concentrations were obtained immediately thereafter. Spontaneous and AG seizures were observed at dosages as low as 10-12.5 mg/kg, with significant seizure incidence induced by dosages of 25.0 mg/kg (5.34 micrograms RDX/ml plasma) and 50.0 mg/kg (8.28 micrograms RDX/ml plasma), respectively. Spontaneous seizure incidence peaked at 2 hr for all RDX treatment groups, then decreased (12.5 and 25.0 mg/kg) or remained elevated (50.0 mg/kg) for the remaining 6 hr. In contrast, AG seizures (37.5 mg/kg) could be elicited only at 8 and 16 hr, despite significant elevation of plasma RDX concentrations at 2 and 4 hr. Because limbic system involvement was suggested by spontaneous seizure characteristics, the rate of amygdaloid kindling was measured following daily treatment with 6.0 mg/kg. This dosage significantly accelerated kindling development without inducing spontaneous seizures or producing an accumulation of RDX in plasma. These data provide preliminary evidence that limbic structures may participate in RDX-induced seizure susceptibility.


Preparation of a conjugate of mitomycin C and anti-neural cell adhesion molecule monoclonal antibody for specific chemotherapy against biliary tract carcinoma.
To develop a specific chemotherapy modality for the perineural invasion of neural cell adhesion molecule (NCAM) positive biliary tract cancer, an anticancer drug, mitomycin C (MMC), was covalently bound to anti-NCAM monoclonal antibody (anti-NCAM MoAb) to form a conjugate using the cyanogen bromide method. The substitution ratio of the conjugate determined spectrophotometrically was 3.5 (MMC mol/immunoglobulin G mol). The cytotoxic activity of the conjugate, which was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test in the growth inhibition of the neuroblastoma cell line with NCAM expression, was maintained at 65.8% to 94.5% compared with the same concentration of MMC solution. The binding activity of the conjugate to the NCAM-positive bile duct cancer was examined by immunohistochemical staining and proved to be the same level as that of free anti-NCAM MoAb. The conjugate prepared in this study therefore appeared to be a potentially useful tool for immunotargeting specific chemotherapy against biliary tract cancer with NCAM expression.


Alterations in levels of mRNAs coding for neurofilament protein subunits during regeneration.
Animal models of neuronal injury can be used to explore mechanisms that regulate the expression of genes coding for cytoskeletal proteins and transmitter-related markers. In the present study, in situ hybridization was used to measure levels of messenger ribonucleic acid (mRNA) encoding each of the neurofilament subunits and beta-tubulin in spinal motor neurons at intervals (4 to 56 days) following a unilateral crush of the sciatic nerve. Levels of beta-tubulin mRNA increased (approximately twofold), peaked at 28 days postaxotomy, and returned to control values by 56 days postaxotomy. In contrast, levels of mRNA encoding neurofilament subunits were reduced and returned to control values at 56 days following the lesion. There were significant differences among relative levels of mRNAs coding for each subunit. Other studies have demonstrated that the ratio of pulse-labeled neurofilament subunits in motor axons remained unaltered during regeneration. Therefore, the ratios of neurofilament subunits in axons must be regulated at one of the steps that intervenes between the control of levels of mRNA and the anterograde axonal transport of assembled neurofilaments.


Good vibrations, bad vibrations: Oscillatory brain activity in the attentional blink.
The attentional blink (AB) is a deficit in reporting the second (T2) of two targets (T1, T2) when presented in close temporal succession and within a stream of distractor stimuli. The AB has received a great deal of attention in the past two decades because it allows to study the mechanisms that influence the rate and depth of information processing in various setups and therefore provides an elegant way to study correlates of conscious perception in supra-threshold stimuli. Recently evidence has accumulated suggesting that oscillatory signals play a significant role in temporally coordinating information between brain areas. This review focuses on studies looking into oscillatory brain activity in the AB. The results of these studies indicate that the AB is related to modulations in oscillatory brain activity in the theta, alpha, beta, and gamma frequency bands. These modulations are sometimes restricted to a circumscribed brain area but more frequently include several brain regions. They occur before targets are presented as well as after the presentation of the targets. We will argue that the complexity of the findings supports the idea that the AB is not the result of a processing impairment in one particular process or brain area, but the consequence of a dynamic interplay between several processes and/or parts of a neural network.


Efficient introduction of an isogenic homozygous mutation to induced pluripotent stem cells from a hereditary hearing loss family using CRISPR/Cas9 and single-stranded donor oligonucleotides.
Heterozygous purinergic receptor p2x gene ( P2RX2) c.178G>T (p.V60L) mutations can lead to progressive hearing loss (HL) and increased susceptibility to noise. However, the underlying mechanisms remain unclear. A combination of human induced pluripotent stem cell (hiPSC) technology with clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9-mediated gene editing may provide a promising tool to study gene function and treat hereditary deafness in humans. hiPSC technology and CRISPR/Cas9-mediated gene editing were used to generate heterozygous and homozygous P2RX2 c.178G>T (p.V60L) cell models. We generated non-integrative hiPSCs from urine samples derived from three members of a large Chinese family carrying heterozygous P2RX2 c.178G>T mutations (designated P2RX2+/-) as a model to study P2RX2-mediated hereditary HL. Furthermore, we used CRISPR/Cas9 and single-stranded donor oligonucleotides to genetically establish homozygous P2RX2 c.178G>T hiPSCs (designated P2RX2-/-) from heterozygous patient-specific hiPSCs as a control to further study the pathological gene function. Heterozygous and homozygous P2RX2-mutated hiPSC lines are good models to investigate the pathological mechanisms of P2RX2 mutations in HL pathogenesis. Our findings confirmed our hypothesis that it is feasible and convenient to introduce precise point mutations into genomic loci of interest to generate gene-mutated hiPSC models.


A multi-layer method to study genome-scale positions of nucleosomes.
The basic unit of eukaryotic chromatin is the nucleosome, consisting of about 150 bp of DNA wrapped around a protein core made of histone proteins. Nucleosomes position is modulated in vivo to regulate fundamental nuclear processes. To measure nucleosome positions on a genomic scale both theoretical and experimental approaches have been recently reported. We have developed a new method, Multi-Layer Model (MLM), for the analysis of nucleosome position data obtained with microarray-based approach. The MLM is a feature extraction method in which the input data is processed by a classifier to distinguish between several kinds of patterns. We applied our method to simulated-synthetic and experimental nucleosome position data and found that besides a high nucleosome recognition and a strong agreement with standard statistical methods, the MLM can identify distinct classes of nucleosomes, making it an important tool for the genome wide analysis of nucleosome position and function. In conclusion, the MLM allows a better representation of nucleosome position data and a significant reduction in computational time.


Induction of sister-chromatid exchange (SCE) and cell-cycle inhibition in mouse peripheral blood B lymphocytes exposed to mutagenic carcinogens in vivo.
To determine the sensitivity of the mouse peripheral blood lymphocyte (PBL) culture system, male B6C3f1 mice were injected i.p. with either 2-acetylaminofluorene (AAF) (20, 40, 80, 160 mg/kg), benzo[a]pyrene (BP) 25, 75, 150, 300 mg/kg), dichlorvos (DCV) (5, 15, 25, 35 mg/kg), ethyl methanesulfonate (EMS) (10, 30, 90, 180, 270 mg/kg), or N-nitrosomorpholine (NM) (37.5, 75, 150, 300 mg/kg) dissolved in either RPMI 1640 (DCV, EMS, NM) or sunflower oil (AAF, BP). 24 h later blood was removed by cardiac puncture, and the lymphocytes were cultured in the presence of lipopolysaccharide for analysis of SCE in B lymphocytes. All 4 mutagenic carcinogens (AAF, BP, EMS, NM) induced significant dose-related increases in SCE frequency. DCV, a potent neurotoxicant, caused no change in the baseline SCE frequency. At the highest concentration of each chemical examined, AAF caused a 1.6-fold increase, EMS a 1.8-fold increase, NM a 3.0-fold increase, and BP a 3.1-fold increase in SCE frequency compared to concurrent controls. A comparison of these results for PBLs with those reported in the literature for bone marrow cells indicates that PBLs offer a good quantitative and qualitative estimate of the SCE-inducing potential for these 5 compounds in bone marrow cells.


The hollow denture: an alternative treatment for atrophic maxillae.
This technique is an adaptation of the double-flask technique that is well-known for the fabrication of the hollow bulb portion of a maxillary obturator. It can be used only for patients with both an atrophic maxillary alveolar ridge and a greater than usual interocclusal distance. Anything less will not permit fabrication of a hollow denture.


Definitive pelvic radiation therapy improves survival in stage IVB neuroendocrine cervical carcinoma: A NeCTuR study.
To evaluate the survival impact of adding definitive pelvic radiation therapy (RT) to chemotherapy among patients with stage IVB neuroendocrine cervical carcinoma (NECC). We retrospectively studied patients with FIGO 2018 stage IVB NECC diagnosed during 1998-2020 who received chemotherapy with or without definitive whole pelvic RT (concurrent or sequential). Demographic, oncologic, and treatment characteristics were summarized. Progression-free (PFS) and overall survival (OS) were plotted using the Kaplan-Meier method, and hazard ratios (HRs) were calculated using Cox regression. The study included 71 patients. Median age was 43 years (range, 24-75). Fifty-nine patients (83%) had pure neuroendocrine histology, and 57 (80%) had pretreatment tumor size >4 cm. Fifty-six patients (79%) received chemotherapy alone with (n = 15) or without (n = 41) palliative pelvic RT, and 15 (21%) received chemotherapy and definitive pelvic RT (chemo+RT). Median follow-up time was 20.1 months (range, 11.3-170.3) for the chemo+RT group and 13.5 months (range, 0.9-73.6) for the chemotherapy-alone group. Median PFS was 10.3 months (95% CI, 7.5-∞) for the chemo+RT group vs 6.6 months (95% CI, 6.1-8.7) for the chemotherapy-alone group (p = 0.0097). At 24 months, the PFS rate was 24% for chemo+RT vs 7.8% for chemotherapy alone. Median OS was 20.3 months (95% CI, 18.5-∞) for the chemo+RT group vs 13.6 months (95% CI, 11.3-19.2) for the chemotherapy-alone group (p = 0.0013). At 24 months, the OS rate was 49.2% for chemo+RT vs 21.5% for chemotherapy alone. In a Cox regression model, definitive RT was associated with improved PFS (HR, 0.44; 95% CI, 0.23-0.83; p = 0.0119) and OS (HR, 0.31; 95% CI, 0.14-0.65; p = 0.0022). Addition of definitive pelvic RT to chemotherapy may improve survival in patients with stage IVB NECC.


Immunofluorescence staining of thin-filament sections not participating in actomyosin crossbridges: studies by use of a monoclonal antibody specific to actin.
Monoclonal antibodies (mcab) were produced in vitro by fusing mouse X63-Ag8.653 plasmacytoma cells with spleen cells from a Balb/c mouse immunized with primary cultures of chick skeletal muscle (pmcc). After cloning on agar, stable clones were obtained, the antibodies of which stain specifically the I-band of myofibrils in the immunofluorescence (IF) procedure. For further characterization of these mcab their affinities to muscle proteins were tested by immunoblotting and by enzyme-linked immunosorbent assay (ELISA). Mcab specific for actin were revealed by these criteria. One of the anti-actin antibodies, mcab 647, reveals a variety of IF-staining patterns on myofibrils. On rest-length myofibrils the I-band is labeled only. However, at sarcomere lengths below 2 micrometers, where the thin filaments meet in the middle of the A-band and form a region of double overlap, an additional fluorescent band appears in this position. The fluorescence intensity of this band is increased significantly in shorter sarcomeres. Finally, when the I-band has disappeared at a sarcomere length of 1.5 micrometer, fluorescence is located exclusively in the middle of the A-band. These IF-staining patterns suggest that only those sections of the thin filament are stained that do not participate in actomyosin crossbridges.


Chondrocyte ultrastructure in exercise and experimental osteoarthrosis. A stereologic morphometric study of articular cartilage of young rabbits using transmission electron microscopy.
The effects of physical exercise (running) and immobilization (splinting) on chondrocyte ultrastructure were studied in the knee joint articular cartilage of 24 young rabbits. Synthetic activity of the chondrocytes was quantified by measuring the amount of rough endoplasmic reticulum (RER) from electron micrographs using a sterologic point-counting method. Extra loading of the joint by running, or by increased weight-bearing after splinting of the contralateral limb, caused a 20% and 30% increment of RER in the middle and deep zones of the cartilage, respectively, while immobilization decreased the amount of RER by 30% in the superficial zone. Some attempts to repair and regenerate were observed, especially in the deep zone of articular cartilage. Hypertrophy of cells and organelles, and cell replication were considered as signs of reparative processes. The accumulation of fine intracytoplasmic filaments (FIF) in chondrocytes, regarded as a sign of cell degeneration, was reduced in the exercise group. FIF also decreased in the deep zone chondrocytes of the immobilized group, which could be indicative of improved or retained viability of the chondrocytes.


Upper airway and tracheal obstruction in infants and children.
The radiologist plays a key role in the diagnosis of airway obstruction in children. Most diagnoses are made on the basis of plain films. In more complicated or complex entities, CT and MRI give excellent anatomic detail in defining the airway, associated soft tissues, and vascular relationships.


Cultivation of human immunodeficiency virus from whole blood: effect of anticoagulant and inoculum size on virus growth.
Human immunodeficiency virus (HIV) was cultivated directly from whole blood treated with anticoagulant by cocultivation with phytohaemagglutinin-stimulated cord blood lymphocytes. When heparin was used as the anticoagulant, isolation rates were low (10% to 56%, depending on the patient group); but when EDTA was used, isolation rates were much higher (50% to 100%). Culture of whole blood gave results identical to those of culture of separated peripheral mononuclear cells, and in some cases virus could be isolated from as little as 10 microliters of unseparated EDTA anticoagulated blood.


Clathrin-mediated endocytosis persists during unperturbed mitosis.
How does mitosis influence the critical process of endocytosis? Some experiments lead to the conclusion that endocytosis arrests completely during mitosis, whereas others indicate that endocytosis persists. We have resolved this apparent discrepancy by showing how conditions of the experiment influence its outcome. The dynamics of clathrin-coated pit formation and the uptake of transferrin are maintained in naturally dividing cells but are nearly absent in mitotic cells arrested chemically by treatment with nocodazole, S-Trityl-L-cysteine, or RO-3306. Moreover, sequentially incubating cells at 4°C and then shifting them to 37°C or to serum starvation artificially increases the amount of transferrin receptor at the surface of naturally dividing cells, leading to the incorrect conclusion that endocytosis has ceased during mitosis. Thus, our data show that endocytosis is unaffected during all stages of natural cell division.