Multimodal therapy of cavernous sinus meningioma: Impact of surgery and 68Ga-DOTATATE PET-guided radiation therapy on tumor control and functional outcome.
Functional preservation in patients with WHO grade I meningioma involving the cavernous sinus (CSM) is crucial for long-term tumor control. Concise data on the functional outcome of an interdisciplinary, multimodal treatment are scarce. We analyzed functional outcome and tumor control in CSM patients following maximal safe resection (MSR), fractionated stereotactic radiotherapy (FSRT), or combination of them, retrospectively. Patients with WHO grade I CSM treated between 2003 and 2017 were included. Prior to FSRT, a 68Ga-DOTATATE PET/CT was performed for radiation planning. Progression-free survival (PFS) was analyzed using Kaplan-Meier method and log-rank test was performed to test differences between groups. Visual function was analyzed at baseline and follow-up. Eighty-five patients were included. MSR alone was performed in 48 patients (group A), MSR followed by FSRT in 25 patients (group B), and FSRT alone in 12 patients (group C). Intracranial tumor volumes were higher in A and B compared to C (median 9.2/10.8/4.3 ccm for A/B/C, P = .023). Median follow-up was 47/46/45 months and PFS at 5 years 55.7%, 100%, and 100% in A/B/C, respectively (P < .001). Optic nerve compression was more common in A (91.7%) and B (84.0%) than C (16.7%), P < .001. Post-therapeutic new onset or deterioration of double vision was observed in 29% (A), 17% (B), and 0% (C). Personalized treatment strategies for CSM are essential to control space-occupying or functionally compromising lesions. The additional potential side effect of radiotherapy seems to be justified under the aspect of longer tumor control with low functional risk. Without space-occupying effect of CSM, FSRT alone is reasonably possible.


[What is ultra-processed food and how is it related to diet-related diseases?]
Ultra-processed food is part of a modern lifestyle and accounts for about 46 % of daily energy intake in Germany. Cross-sectional and cohort studies indicate associations between consumption of ultra-processed food and a range of non-communicable diseases (obesity, diabetes, cancer, cardiovascular disease, and depression). As underlying mechanisms, a high energy density, altered food matrix, an unbalanced nutritional composition, high glycemic index, adverse additives, processing- and packaging contaminants are discussed. In order to understand the role of these potential mechanisms and to provide a scientifically based and risk-associated definition of ultra-processed food it is important to conduct appropriate intervention studies and to improve dietary assessment of processed food in prospective cohort studies.


Neutrophil-inspired propulsion in a combined acoustic and magnetic field.
Systems capable of precise motion in the vasculature can offer exciting possibilities for applications in targeted therapeutics and non-invasive surgery. So far, the majority of the work analysed propulsion in a two-dimensional setting with limited controllability near boundaries. Here we show bio-inspired rolling motion by introducing superparamagnetic particles in magnetic and acoustic fields, inspired by a neutrophil rolling on a wall. The particles self-assemble due to dipole-dipole interaction in the presence of a rotating magnetic field. The aggregate migrates towards the wall of the channel due to the radiation force of an acoustic field. By combining both fields, we achieved a rolling-type motion along the boundaries. The use of both acoustic and magnetic fields has matured in clinical settings. The combination of both fields is capable of overcoming the limitations encountered by single actuation techniques. We believe our method will have far-reaching implications in targeted therapeutics.Devising effective swimming and propulsion strategies in microenvironments is attractive for drug delivery applications. Here Ahmed et al. demonstrate a micropropulsion strategy in which a combination of magnetic and acoustic fields is used to assemble and propel colloidal particles along channel walls.


[Effect of lipid peroxidation and antioxidant defence system on the development of hemorrhagic complications in neonates of mothers with diabetes mellitus].
217 postmortem protocols of autopsies have been analyzed to study percentage of hemorrhagic complications. The analyzes allowed to determine frequency and localization hemorrhages happened in children bourn by mothers suffering from diabetes mellitus. The most detected localizations of hemorrhages are follows: ependyma (38.8%), ventricles of brain (30.8%), parenchyma of brain (30.8%) as well as frequently have been observed pleura, epicardium and adrenal glands hemorrhages.


Investigation of ultrasound image processing to improve perceptibility of microcalcifications.
This article describes an investigation of the detectability of breast microcalcifications by ultrasound imaging. Two kinds of experiments were performed to evaluate the spatial and contrast resolution of microstructures in an agar graphite phantom and to analyze human perception of tiny spots. The results showed that most of the difficulties in finding microstructures were not only due to lower echo levels but also to obstructions in the surrounding texture of the image. Based on these results, a new image processing method was proposed to emphasize microcalcifications in mammary glands. This method utilized statistical analysis of the echo signals and also considered the structural pattern of the mammary gland. Processed images from some clinical cases showed adequate extraction of the microcalcifications with efficient cancellation of the mammary gland structure. The results suggested that the perception of microcalcifications could be improved by the proposed method.


Serum antibodies against Saccharomyces cerevisiae: a new prognostic indicator in metastatic renal-cell carcinoma.
A recent study reported that a diet rich in bread and refined cereals might have an unfavorable role in the development of renal cell carcinoma (RCC). To test whether an underlying intolerance of bread ingredients is responsible for the unfavorable influence of bread on RCC, we examined patient sera for the presence of food-specific IgG. A commercial test was used to detect food-specific IgG directed against a panel of 113 food antigens in sera of 54 patients with metastatic RCC. Kaplan-Meier estimates were used for univariate survival analysis, and differences in survival curves were assessed with the log-rank test. Multivariate survival analysis was done using a Cox regression model. We found that RCC patients with elevated serum levels of IgG antibodies against S. cerevisiae, commonly known as baker's yeast and yet another bread component, have an unfavorable clinical course. Median survival of patients with high levels of S. cerevisiae IgG was only 17.8 months, whereas median survival of patients with low S. cerevisiae IgG was 43.8 months (P = 0.0022; log-rank). Multivariate survival analysis identified high levels of S. cerevisiae IgG as a strong and independent prognostic risk factor (risk ratio 4.6, P = 0.001; 95% CI 1.61-13.08). Our findings indicate that serum levels of IgG against S. cerevisiae may predict survival in patients with metastatic RCC. The data suggest not cereals but baker's yeast being the critical component of bread that may cause immune deviation and impaired immunosurveillance in predisposed RCC patients.


Integration of artificial intelligence into clinical patient management: focus on cardiac imaging.
Cardiac imaging is a crucial component in the management of patients with heart disease, and as such it influences multiple, inter-related parts of the clinical workflow: physician-patient contact, image acquisition, image pre- and postprocessing, study reporting, diagnostics and outcome predictions, medical interventions, and, finally, knowledge-building through clinical research. With the gradual and ubiquitous infiltration of artificial intelligence into cardiology, it has become clear that, when used appropriately, it will influence and potentially improve-through automation, standardization and data integration-all components of the clinical workflow. This review aims to present a comprehensive view of full integration of artificial intelligence into the standard clinical patient management-with a focus on cardiac imaging, but applicable to all information handling-and to discuss current barriers that remain to be overcome before its widespread implementation and integration.


Pertussis Prevalence in Korean Adolescents and Adults with Persistent Cough.
We investigated the prevalence of pertussis in Korean adolescents and adults with persistent cough. Study population was adolescents (aged 11-20 yr) and adults (≥ 21 yr old) who showed persistent cough of 1-8 weeks' duration. Pertussis was diagnosed by culture, polymerase chain reaction (PCR), and serology. A total of 310 subjects participated in this study, and 76 cases (24.5%) met the criteria for laboratory-confirmed pertussis. The majority of the pertussis cases (66/76) were confirmed by serology, while 3 cases (1.0%) were diagnosed with culture, and 10 cases (3.2%) were detected with PCR. Of the 76 subjects diagnosed with pertussis, 20/86 cases were adolescents and 56/224 cases were adults. Neither adolescents nor adults received adolescent-adult booster against pertussis within the previous 5 yr. Pertussis can be a primary cause of persistent cough in Korean adolescents and adults.


Alterations of adrenal and uterine angiotensin II receptors during variation of sodium intake and/or experimental hypertension.
1. Angiotensin II receptors from rat adrenal gland and myometrium were studied during variation of sodium intake. 2. In both target-tissues low Na+ diet increased the number of receptors whereas a high Na+ diet did not modify the adrenocortical receptors but increased the number of uterine receptors. 3. Deoxycorticosterone and one kidney Goldblatt hypertension were associated with a decrease in the number of adrenal receptors. 4. Alterations of angiotensin II receptors alone cannot explain satisfactorily the variations of sensitivity of target-cells to angiotensin II during sodium balance changes.


Seeking the sun in deep, dark places: mesopelagic sightings of ocean sunfishes (Molidae).
Evidence is presented from publicly available remotely operated vehicle (ROV) footage that suggests deep-water ranging in ocean sunfishes (family Molidae) is more common than typically thought, including a new maximum depth recorded for the southern sunfish Mola ramsayi.


An insight into predominance of pulmonary complications on right side in supracostal percutaneous nephrolithotomy.
To analyse pulmonary complications following supracostal percutaneous nephrolithotomy especially after right sided supracostal punctures, both in initial and relook PCNL. From February 2016 till date, 90 patients underwent PCNL in Government Medical College, Jammu through supracostal puncture - 53 on right side and 37 on left side. All supracostal punctures were made about 7-8.5 cm from midline. Tract dilatation was done using metal dilators and calculi were fragmented using pneumatic lithotripsy. Patients with supracostal superior calyceal punctures were evaluated for chest complications intraoperatively by fluoroscopy, X-ray chest on evening of postoperative day 0 and repeated thereafter on third and seventh postoperative days. Stone configuration included complete staghorn in 16, partial staghorn in 23, multiple stones in 16 and pelvic stone in 35 cases. Age range of patients was 07-76 years. There was 14.4% (13 out of 90) incidence of early or delayed chest complications - 20.8% (11 out of 53) on right side and 5.4% (2 out of 37) on left side. Pulmonary complications in supracostal punctures; especially on right side should not be underestimated. There are always chances of delayed hydrothorax after supracostal puncture. A chest X-ray should be repeated after 1 week in patients with supracostal PCNL punctures.


Improving emergency airway cart efficiency in compliance with Joint Commission standards.
Emergency Airway Carts (EAC) are essential for pediatric otolaryngologists to provide rapid bedside care for emergent airway scenarios. At many institutions, EAC bronchoscopy equipment is individually peal-packaged due to Joint Commission (JC) standards, creating significant inefficiency in equipment assembly during time sensitive clinical settings. The objective of this quality improvement initiative was to improve the efficiency of use of our emergency airway cart equipment. Individually peel-packaged bronchoscope equipment was replaced with JC compliant sets. Otolaryngology trainees (N = 8) and pediatric otolaryngology attending physicians (N = 11) were tested in a simulated airway emergency scenario, requiring bronchoscope assembly. Complete bronchoscope assembly and time to tracheal visualization (TTV) was measured for each participant, which started with initial clinical scenario presentation and ended with successful visualization of the trachea using the rigid bronchoscope. Pre-airway cart interventions, 68.4% of participants built a complete bronchoscope with no missing pieces, which improved to 100% with the new cart organization. Post-EAC interventions, all 19 participants reduced TTV significantly by a mean of 177.7 s (p < 0.001). Trainees reduced TTV by a mean of 251.2 s (46.2%, p < 0.0001) and attendings by 124.2 s (31.5%, p < 0.0022). All participants found the new airway cart sets easier to use and improved equipment setup efficiency. Compiling bronchoscope equipment into sterile sets allowed for improved TTV and bronchoscope quality for trainees and attending physicians while maintaining JC standards. Simulation improved confidence among both trainees and attending surgeons in providing optimal patient care in airway emergencies.


Factors Associated With the Limitation at Work Because of the Voice: Study With Teachers of Basic Education In Brazil.
The voice disorder can cause limitations at work, as it affects the communication and the performance of the teaching function. To analyze the limitation at work because of the voice and to examine possible associations with sociodemographic characteristics, life and health habits and work conditions among Basic Education teachers in Brazil. Cross-sectional epidemiological study, with a representative sample, carried out between October 2015 and March 2016, with 6,324 teachers working in Basic Education in Brazil. Data collection was carried out through the application of a questionnaire via telephone with questions regarding health and working conditions. The "limitation at work because of the voice" was considered a dependent variable, whose response options were a scale with four Likert items that varied from frequently to never. The independent variables were grouped in blocks for ordinal logistic regression analysis with hierarchical entry. The magnitude of the association was assessed by the Odds Ratio (OR) with the respective confidence intervals (95% CI). One third of Brazilian teachers (32.7%) reported some frequency of limitation at work (sometimes; rarely, frequently) because of the voice at some moment in the month before the survey and, of these, 5% declared high frequency. The factors that increased the chance of a greater frequency of limitation at work because of the voice were: being female (OR = 1.32; 95% CI = 1.15-1.51); teaching for elementary school (OR = 1.35; 95% CI = 1.02-1.78); use anxiolytic or antidepressant medications (OR = 1.46; 95% CI = 1.20-1.78); losing sleep due to concerns (OR = 1.69; CI = 95% = 1.46-1.95); high noise at school (OR = 2.09; 95% CI = 1.78-2.46); agitated environment by students' indiscipline (OR = 1.37; 95% CI =1.15-1.63); high demands at work (OR = 1.18; 95% CI = 1.02-1.36); not having social support (OR = 1.19; 95% CI = 1.04-1.38); having suffered verbal violence by the students (OR = 1.43; 95% CI = 1.23-1.67). On the other hand, the practice of regular physical activity (OR = 0.86; 95% CI = 0.75-1.00) and the fact of having enough time to complete work tasks (OR = 0.71; 95% CI = 0,62-0.82) decreased the chance of a higher frequency of limitation at work due to vocal problems. The perception that the work limits the teaching performance because of the voice was more frequent among teachers in the North (OR=1.41; 95% CI = 1.17-1.71) and Northeast (OR=1.46; 95% CI = 1.22-1.76) compared to the Southeast region. Factors associated with an increase in the chance of higher frequency of reporting work limitations due to the voice: being female, lack of physical activity, losing sleep due to concern, using anxiolytic or antidepressant medication, school location in the North and Northeast, teaching for the elementary school stage, high noise at school and psychosocial aspects of work organization. The Brazilian educational sector needs public policies that take into account regional inequalities and the health and work conditions of teachers.


Interlaboratory comparison for quantitative primary metabolite profiling in Pichia pastoris.
For the first time, an interlaboratory comparison was performed in the field of quantitative metabolite profiling in Pichia pastoris. The study was designed for the evaluation of different measurement platforms integrating different quantification strategies using internal standardization. Nineteen primary metabolites including amino acids and organic acids were selected for the study. Homogenous samples were obtained from chemostat fermentations after rapid sampling, quenching and filtration, and hot ethanol extraction. Laboratory 1 (BOKU) employed an in vivo-synthesized fully labeled U(13)C cell extracts of P. pastoris for immediate internal standardization upon cell extraction. Quantification was carried out using orthogonal reversed-phase (RP-LC) and hydrophilic interaction chromatography (HILIC) in combination with tandem mass spectrometry. Laboratory 2 (Biocrates) applied a metabolomics kit allowing fully automated, rapid derivatization, solid phase extraction and internal standardization in 96-well plates with immobilized isotopically enriched internal standards in combination with HILIC-MS-MS and RP-LC-MS-MS for organic acids and derivatized amino acids, respectively. In this study, the obtained intracellular concentrations ranged from 0.2 to 108 μmol g(-1) cell dry weight. The total combined uncertainty was estimated including uncertainty contributions from the corresponding MS-based measurement and sample preparation for each metabolite. Evidently, the uncertainty contribution of sample preparation was lower for the values obtained by laboratory 1, implementing isotope dilution upon extraction. Total combined uncertainties (K = 2) ranging from 21 to 48% and from 30 to 57% were assessed for the quantitative results obtained in laboratories 1 and 2, respectively. The major contribution arose from sample preparation, hence from repeatability precision of the extraction procedure. Finally, the laboratory intercomparison was successful as most of the investigated metabolites showed concentration levels agreeing within their total combined uncertainty, implying that accurate quantification was given. The application of isotope dilution upon extraction was an absolute prerequisite for the quantification of the redox-sensitive amino acid methionine, where no agreement between the two laboratories could be achieved.


Protocol for a parallel assignment prospective, randomised, comparative trial to evaluate the safety and efficacy of intense pulsed light (IPL) combined with 3% diquafosol (DQS) ophthalmic solution in dry eye syndrome.
Evaporative dry eye (EDE) is common and can lead to ocular pain, decreased visual quality and reduced quality of life. Intense pulsed light (IPL) and 3% diquafosol ophthalmic solution have been found to be beneficial in reducing signs and symptoms of dry eye. A randomised clinical trial will be performed at He Eye Specialist Hospital in Shenyang. 360 dry eye disease patients will be equally divided randomly into the IPL group, DQS group (3% diquafosol ophthalmic solution eye-drops) and IPL+group (IPL combined with 3% diquafosol eye-drops). All groups will be followed up for 4 weeks. The primary outcome measures will be the non-invasive tear break-up time and the Ocular Surface Disease Index change from the baseline. The secondary outcome measures willincludeconjunctival and cornea staining with fluorescein and lissamine, meibomian gland function and secretion quality, tear film lipid layer score, tear meniscus height, conjunctival hyperemia (redness score) changes . Adverse events also will be monitored and documented. This study aimed to assess whether the combination of IPL with 3% diquafosol ophthalmic solution (study group), IPL+ (study group), is more effective than IPL (active control group) or DQS (active control group) in participants with EDE. Management of dry eye with IPL combined with 3% diquafosol ophthalmic solution, registered on 23 January 2023. Ethics approval number: IRB (2022) K029.01. The study's findings will be shared regardless of the effect's direction. NCT05694026.


The treatment of giant tear detachments using retrohyaloidal perfluorocarbon gases without drainage or vitrectomy.
In a pilot study, an expanding perflurocarbon gas was injected into the retrohyaloidal space for treating giant tear detachments. Using the balloon-gas procedure with a single gas injection, a bubble was obtained that was large enough to tamponade a giant tear without prior drainage of subretinal fluid or vitrectomy. The procedure was performed under subconjunctival anesthesia in order to preserve the patient's light perception, the fading of which served as a safeguard against excessive gas injection. The posterior hyaloidal membrane was only attached to the anterior flap of the tear and to the circumference of the retina anterior to the equator. The retrohyaloidal gas injection was not followed by star-fold formation or other evidence of preretinal proliferation. During the follow-up, the detached posterior hyaloidal membrane appeared to have collapsed on the anterior retina in concertina-like folds. Reattachment occurred in four of the five cases; no retina redetached during an average follow-up of 2 years.


Immunohistochemical detection of CD133 is associated with tumor regression grade after chemoradiotherapy in rectal cancer.
CD133 has been identified as a putative cancer stem cell (CSC) marker in various cancers including colorectal cancer. The relation between CD133 expression and biological characteristics of colorectal cancer remains to be clarified. Protein expression of CD133 was immunohistochemically evaluated in surgical specimens of 225 patients with colorectal cancer who were treated by surgery, as well as those of 78 patients with rectal cancer who received preoperative chemoradiotherapy (CRT) followed by curative resection. The correlation between CD133 expression and clinicopathological features, tumor recurrence and overall survival was analyzed in both populations. Among 225 colorectal cancers without CRT, 93 (41.3%) were positive for CD133 expression, which was enhanced in cases with advanced T stage and venous invasion. Moreover, CD133 was positive in 47 (60.3%) of 78 cases with CRT, which was significantly higher than the CD133-positive rate in non-CRT specimens (P=0.05). Expression of CD133 was independently correlated with the histological tumor regression grade (P<0.01). These results suggest that CD133 is not a distinctive colorectal CSC marker; expression of CD133 is suggested to be one of the key factors associated with resistance to CRT in colorectal cancer.


[Procedural analgesia : concepts and practice].
The effect of severe pain and its hazardous stress-related cardiocirculatory consequences have been well documented for the perisurgical setting. Independently of surgical intervention however, even short and simple measures (e.g. thorax drain removal, repositioning a limb fracture) and longer diagnostic procedures such as MRI are potentially very painful or stressful to the patient. Though longer diagnostic procedures are frequently supported by systemic medication, short interventions regularly lack this aspect. Specific challenges result from the need to counteract sometimes great changes in pain intensity. Moreover procedural analgesia represents a multidisciplinary measure not restricted to anaesthesiology, as most of these measures are performed without anaesthesia. To avoid endangering the patient, the choice of drugs and patient monitoring have to meet certain professional and technical standards. Competence in respiratory management is of paramount importance. This paper outlines these requirements and serves as an orientation outside the anaesthesiological speciality.


Climate change amplified the 2009 extreme landslide event in Austria.
Landslides are an important natural hazard in mountainous regions. Given the triggering and preconditioning by meteorological conditions, it is known that landslide risk may change in a warming climate, but whether climate change has already affected individual landslide events is still an open question, partly owing to landslide data limitations and methodological challenges in climate impact attribution. Here, we demonstrate the substantial influence of anthropogenic climate change on a severe event in the southeastern Alpine forelands with some estimated 952 individual landslides in June 2009. Our study is based on conditional event attribution complemented by an assessment of changes in atmospheric circulation. Using this approach, we simulate the meteorological event under observed and a range of counterfactual conditions of no climate change and explicitly predict the landslide occurrence probability for these conditions. We find that up to 10%, i.e., 95 landslides, can be attributed to climate change.


The effect of vapor pressure on stomatal control of gas exchange in Douglas fir (Pseudotsuga menziesii) saplings.
Increasing leaf to air vapor pressure deficit (VPD) caused reductions in stomatal conductance of both current year and previous season needles of Pseudotsuga menziesii saplings. The stomata of current year needles were found to be more responsive to changes in VPD than those of previous season needles. The reductions in stomatal conductance of current year needles were not associated with decreases in xylem pressure potential. In fact, the reductions in stomatal conductance of current year needles were sometimes sufficient to reduce transpiration and thus raise xylem pressure potential even though VPD was increasing. There was a decline in stomatal responsiveness to VPD in current year needles between early and late summer. Pressure-volume curves determined for different age needles at different times of the year suggested that differences and changes in stomatal responsiveness to VPD may have been caused in part by differences and changes in needle water potential components. Hexane washes of current year needles during the late summer succeeded in partially restoring their VPD sensitivity, suggesting that changes in the water permeability of the external cuticle during needle maturation may also have played a role in causing the summer decline in VPD responsiveness.In both current and previous year needles VPD-induced changes in stomatal conductance had a greater relative effect on transpiration (q w) than on net photosynthesis (PhN). In maturing needles the ratio of the sensitivities of transpiration and net photosynthesis to changes in stomatal conductance, (∂q w/∂g s)/∂PhN/∂g s), remained nearly constant as VPD was varied. This provides experimental support for a recent hypothesis that stomata respond to environmental fluctuations in such a manner as to maintain the above ratio constant, which optimizes CO2 uptake with respect to water loss.


Cytotoxicity of Shiga toxin for primary cultures of human colonic and ileal epithelial cells.
Shiga toxin purified from Shigella dysenteriae 1 was cytotoxic to cultured epithelial cells from human colon and ileum. The cytotoxicity, which affected only about 50% of treated cells, was neutralized by rabbit antiserum monospecific for Shiga toxin and mediated by protein synthesis inhibition.


MicroRNA-126 deficiency enhanced the activation and function of CD4+ T cells by elevating IRS-1 pathway.
Recent evidence has shown that microRNA-126 (miR-126) has been involved in the development and function of immune cells, which contributed to the pathogenesis of related clinical diseases. However, the potential role of miR-126 in the development and function of CD4+ T cells remains largely unknown. Here we first found that the activation and proliferation, as well as the expression of interferon (IFN)-γ, of CD4+ T cells from miR-126 knock-down (KD) mice using the miRNA-sponge technique were enhanced significantly in vitro, compared with those in CD4+ T cells from wild-type (WT) mice. To monitor further the possible effect of miR-126 deficiency on the function of CD4+ T cells in vivo, we used dextran sulphate sodium (DSS)-induced murine model of acute autoimmune colitis and found that miR-126 deficiency could elevate the pathology of colitis. Importantly, the proportion of CD4+ T cells in splenocytes increased significantly in miR-126KD mice. Moreover, the expression levels of CD69 and CD44 on CD4+ T cells increased significantly and the expression level of CD62L decreased significantly. Of note, adoptive cell transfer assay showed that the pathology of colitis was more serious in carboxyfluorescein succinimidyl ester (CFSE)-labelled miR-126KD CD4+ T cell-transferred group, compared with that in the CFSE-labelled WT CD4+ T cells transferred group. Consistently, the expression levels of CD69 and CD44 on CFSE+ cells increased significantly. Furthermore, both the proliferation and IFN-γ secretion of CFSE+ cells also increased significantly in the CFSE-labelled miR-126KD CD4+ T cell-transferred group. Mechanistic evidence showed that the expression of insulin receptor substrate 1 (IRS-1), as a functional target of miR-126, was elevated in CD4+ T cells from miR-126KD mice, accompanied by altered transduction of the extracellular regulated kinase, protein B (AKT) and nuclear factor kappa B (NF-κB) pathway. Our data revealed a novel role in which miR-126 was an intrinsic regulator in the function of CD4+ T cells, which provided preliminary basis for exploring further the role of miR-126 in the development, function of CD4+ T cells and related clinical diseases.


CD and FTIR studies of an immunogenic disulphide cyclized octadecapeptide, a fragment of a snake curaremimetic toxin.
In a previous paper, the systematic epitope screening of a snake curaremimetic toxin or toxin a was described by this group using a panel of synthetic octadecapeptides. The disulphide cyclized peptide (Cys-23,40)(23-40) corresponding to loop II of the native toxin was found to elicit, with no linkage to a carrier, neutralizing antisera against the toxin. We have now undertaken the conformational study of this immunogenic disulphide cyclized peptide by CD and FTIR. The CD study of the peptide was carried in aqueous solution under various conditions (pH, temperature, presence of micelles) and in trifluoroethanol solution. Low temperature, SDS micelles and trifluoroethanol were found to induce a beta-sheet formation (16 to 39%). FTIR spectra of the peptide in the solid state (dry film) and in D2O solution or deuterated-TFE solution (hydrated film) displayed some characteristic bands indicating the presence of beta-sheet (1623 cm-1) and beta-turn (1637 cm-1; 1694 cm-1). These studies indicate that the immunogenic disulphide cyclized peptide (23-40) can adopt in solution an ordered structure.


Adolescents react to the events of September 11, 2001: focused versus ambient impact.
This study examined the perceived impact of the events of September 11, 2001, on adolescents distant from the disaster sites and compared these perceptions with changes in everyday moods. A survey of reactions to September 11 was completed 2-5 months after the events by 171 adolescents participating in a longitudinal study of stress and health. Electronic diary ratings of contemporaneous moods before and after the attacks were also compared. Many adolescents distant from the disaster sites reported changes in everyday activities and signs of distress along with some positive outcomes. Elevated levels of negative affect emerged when adolescents were asked directly about the event (focused impact), but no changes were detected in their ongoing, momentary mood reports before and after September 11 (ambient impact). Trait and electronic diary measures of anxiety independently predicted posttraumatic distress. Refined assessments are needed to evaluate the degree to which self-reported traumatic symptoms reflect significant clinical distress versus an attentional focus generated by the question-asking process.


Isolation of a gene encoding for a class III peroxidase in female flower of Corylus avellana L.
Hazelnut is a monoecious species characterized by mid-winter blooming and sporophytic incompatibility. The molecular mechanisms at the basis of the female flower development and of the pollen-stigma interaction are little known, although pollination in this species is a critical factor to ensure good yield. Differential display technique was used to study genes expressed during the female flower development, comparing styles before emergence from the bud and styles at full bloom. The full-length cDNA clone, designated CavPrx (Corylus avellana peroxidase) and isolated in mature styles, was characterized as a sequence encoding for a 330 amino acids protein, containing all the conserved features of class III peroxidases. CavPrx resulted expressed only in styles, with a peak in mature styles pollinated with compatible pollen. Class III peroxidases are expressed in several different plant tissue types and are involved in a broad spectrum of physiological processes. Until now, four peroxidases expressed in the stigma were identified in Arabidopsis thaliana and Senecio squalidus: they were assumed to be possibly involved in pollen-pistil interaction, pollen tube penetration/growth and/or in defence against pathogens. CavPrx is the first gene for a floral peroxidase isolated in hazelnut and its expression pattern suggests a possible role in the pollination process.


Quantitative analysis of flagellar movement in hyperactivated and acrosome-reacted golden hamster spermatozoa.
Caudal epididymal spermatozoa of golden hamsters were incubated in capacitation medium. Their movement patterns changed as they became hyperactivated and underwent the acrosome reaction. To understand the basic mechanism by which changes in movement pattern are brought about, digital image analysis was carried out on the flagellar movements recorded with a video system. The degree of flagellar bending increased with incubation time, especially in the proximal midpiece. The hyperactivated spermatozoa had remarkably asymmetrical flagellar waves of large amplitude because either the bends in the same direction as the hook of the head (referred as the "pro-hook bend") or the bends in the opposite direction to the hook of the head (referred as the "anti-hook bend") extremely increased their curvature; whereas, the acrosome-reacted spermatozoa had relatively symmetrical flagellar waves of large amplitude because both the pro- and anti-hook bends remarkably increased their curvature. Beat frequency significantly decreased while wavelength of flagellar waves increased after hyperactivation and further after the acrosome reaction. These results suggest that both extreme pro- and anti-hook bends are essential in the acrosome-reacted spermatozoa even though beat frequency decreased markedly.


CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis.
Extracellular vesicles (EVs) released by neurons and glia reach the cerebrospinal fluid (CSF). Studying the proteome of CSF-derived EVs offers a novel perspective on the key intracellular processes associated with the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and a potential source from which to develop biomarkers. CSF EVs were extracted using ultrafiltration liquid chromatography from ALS patients and controls. EV size distribution and concentration was measured using nanoparticle tracking analysis and liquid chromatography-tandem mass spectrometry proteomic analysis performed. CSF EV concentration and size distribution did not differ between ALS and control groups, nor between a sub-group of ALS patients with or without an associated hexanucleotide repeat expansion (HRE) in C9orf72. Univariate proteomic analysis identified downregulation of the pentameric proteasome-like protein Bleomycin hydrolase in ALS patients, whilst Gene Ontology enrichment analysis demonstrated downregulation of proteasome core complex proteins (8/8 proteins, normalized enrichment ratio -1.77, FDR-adjusted p = 0.057) in the ALS group. The sub-group of ALS patients associated with the C9orf72 HRE showed upregulation in Ubiquitin-like modifying-activating protein 1 (UBA1) compared to non-C9orf72 cases. Proteomic analysis of CSF EVs in ALS detects intracellular alterations in protein homeostatic mechanisms, previously only identified in pathological tissues. This supports the wider use of CSF EVs as a source of novel biomarkers reflecting key and potentially druggable pathological intracellular pathway alterations in ALS.


Synthesis of chromenochalcones and evaluation of their in vitro antileishmanial activity.
A large number of novel chromenochalcones were synthesized by pyridine-catalysed chromenylation of mono-chelated meta-dihydric acetophenones with the monoterpene, citral dimethyl acetal and subsequent Claisen-Schmidt condensation of the resultant acylchromenes with appropriate aromatic aldehydes. These chromenochalcones 1-19 were screened against in vitro extracellular promastigotes and intracellular amastigotes of Leishmania donovani. The most potent compound in this series was compound 9 with a pyridine ring-A, which showed 99% inhibition of promastigotes at 10 microg/ml, 82% at 0.25 microg/ml and 96% at 10 microg/ml concentration against amastigotes.


Measurement of the Higgs boson production rate in association with top quarks in final states with electrons, muons, and hadronically decaying tau leptons at s = 13 TeV.
The rate for Higgs ( H ) bosons production in association with either one ( t H ) or two ( t t ¯ H ) top quarks is measured in final states containing multiple electrons, muons, or tau leptons decaying to hadrons and a neutrino, using proton-proton collisions recorded at a center-of-mass energy of 13 TeV by the CMS experiment. The analyzed data correspond to an integrated luminosity of 137 fb - 1 . The analysis is aimed at events that contain H → W W , H → τ τ , or H → Z Z decays and each of the top quark(s) decays either to lepton+jets or all-jet channels. Sensitivity to signal is maximized by including ten signatures in the analysis, depending on the lepton multiplicity. The separation among t H , t t ¯ H , and the backgrounds is enhanced through machine-learning techniques and matrix-element methods. The measured production rates for the t t ¯ H and t H signals correspond to 0.92 ± 0.19 (stat) - 0.13 + 0.17 (syst) and 5.7 ± 2.7 (stat) ± 3.0 (syst) of their respective standard model (SM) expectations. The corresponding observed (expected) significance amounts to 4.7 (5.2) standard deviations for t t ¯ H , and to 1.4 (0.3) for t H production. Assuming that the Higgs boson coupling to the tau lepton is equal in strength to its expectation in the SM, the coupling y t of the Higgs boson to the top quark divided by its SM expectation, κ t = y t / y t SM , is constrained to be within - 0.9 < κ t < - 0.7 or 0.7 < κ t < 1.1 , at 95% confidence level. This result is the most sensitive measurement of the t t ¯ H production rate to date.


Apoptosis Factors of Lens Epithelial Cells Responsible for Cataractogenesis in Vitrectomized Eyes with Silicone Oil Tamponade.
The aim of this study was to determine the expression of apoptotic factors Bax, Bcl-2, and Caspase-3 in lens epithelial cells (LECs) from cataracts secondary to pars plana vitrectomy with silicone oil (SO) tamponade. We also investigated the impact of SO emulsification on the expression of apoptotic factors. Anterior capsulotomy specimens of 20 eyes in 20 patients with cataract secondary to SO tamponade (Group 2), were collected. Another 20 eyes of 20 patients with age-related cataract (Group 1) were recruited as controls. The anterior capsule specimens were obtained from the patients during cataract surgery, frozen and later analyzed with respect to immunohistochemical stains of Bax, Bcl-2, and Caspase-3 using a confocal microscope. Age, sex, and laterality did not show any difference between the 2 groups. There was a greater increase in Bax and Caspase-3 expression in LEC in Group 2 than in Group 1 (P(Bax)<0.0001, P(Caspase-3)<0.0001). The Bcl-2 expression decreased in Group 2, although the difference was not significant (P=0.616). The changes of apoptosis factors are not associated to SO emulsification (P(Bax)=0.354, P(Bcl-2)=0.728, P(Caspase-3)=0.939). The caspase-3-dependent apoptosis of LECs increased in complicated cataract patients with SO endotamponade. The Bax played a critical role in regulating apoptosis of LECs in vitrectomized eyes with SO tamponade. The SO emulsification had no significant impact on the expression of apoptosis factors.


[A case of subacute bacterial endocarditis related to Alcaligenes faecalis].
Alcaligenes faecalis was isolated from the blood culture of an 18 years old patient with subacute bacterial endocarditis and rheumatic valvular disease. Isolated strain agglutinated with patient's serum at a ratio of 1/160.


Hearing results after cholesteatoma surgery: the Iowa experience.
This study compared the hearing outcome of canal-up and canal-down mastoidectomies for removal of cholesteatoma in 455 ears. An intact canal wall procedure was performed in 92 patients while the remainder (N = 363) underwent a canal-down operation. The hearing results for both procedures are dependent on the presence of the stapes superstructure. When the stapes superstructure was intact, 52% of the patients with canal-up operations had an air-bone gap of less than 20 dB. The corresponding figure for canal-down cases was 37%. When there was no stapes superstructure, 54% of the canal-up cases and 19% of the canal-down cases obtained a similar ABG closure. Preserving the posterior external auditory canal wall results in slightly better hearing function. However, when the stapes superstructure is intact, the difference in hearing function is not remarkable, and must be weighed against the potential for residual disease or recurrence associated with canal-up procedures.


An outbreak of epidemic keratoconjunctivtis in a pediatric unit due to adenovirus type 8.
To investigate and control an outbreak of epidemic keratoconjunctivitis (EKC) occurring in a neonatal intensive care unit (NICU) and to determine signs specific for EKC in newborns. Outbreak investigation and case-control study. NICU of a 1,600-bed university hospital in Heidelberg, Germany. Case-patients were defined as individuals who had adenoviral antigen detected by ELISA or by PCR from conjunctival swabs or who had clinical signs of conjunctivitis. Twelve newborns from the NICU who had EKC between October and November 1998 were compared with 11 who had bacterial conjunctivitis. Control measures included cohorting patients in contact isolation, using gloves and gowns for patient care, and using a hand rub and disinfectants with virucidal activity. Thirteen patients, 6 healthcare and 11workers, relatives of the patients had EKC, according to our case definition. Case-patients were more likely than control-patients to develop lacrimal swelling (P < .001), eye redness (P = .004), and lacrimation (P = .037) involving both eyes (P = .002). Prior examination by an ophthalmologist was a significant risk factor for EKC (P = .004). For diagnosis or treatment of retinopathy, premature newborns were seen by an ophthalmologist from a nearby eye care center where an EKC outbreak was ongong. No new cases were diagnosed more than 10 days after the implementation of control measures. In newborns, lacrimal swelling, eye redness, and lacrimation in both eyes should evoke suspicion of EKC. Ophthalmologists who have had contact with known EKC cases should use antiseptics and disinfectants with virucidal activity before contact with newborns or abstain from examining newborns.


Single-shot noninterferometric measurement of the phase transmission matrix in multicore fibers.
A simple technique for far-field single-shot noninterferometric determination of the phase transmission matrix of a multicore fiber with over 100 cores is presented. This phase retrieval technique relies on the aperiodic arrangement of the cores.


A computational analysis of substrate binding strength by phosphorylase kinase and protein kinase A.
Protein kinases exhibit various degrees of substrate specificity. The large number of different protein kinases in the eukaryotic proteomes makes it impractical to determine the specificity of each enzyme experimentally. To test if it were possible to discriminate potential substrates from non-substrates by simple computational techniques, we analysed the binding enthalpies of modelled enzyme-substrate complexes and attempted to correlate it with experimental enzyme kinetics measurements. The crystal structures of phosphorylase kinase and cAMP-dependent protein kinase were used to generate models of the enzyme with a series of known peptide substrates and non-substrates, and the approximate enthalpy of binding assessed following energy minimization. We show that the computed enthalpies do not correlate closely with kinetic measurements, but the method can distinguish good substrates from weak substrates and non-substrates.


The effect of recombination between the X and Y chromosomes of mammals.
Recent molecular analysis has proved the hypothesis that parts of the human sex chromosomes are homologous and can recombine in male meiosis. The biological consequences of this recombination have been investigated by considering the joint effect of neutral mutation and random genetic drift on a locus that is closely linked to the non-homologous segments of the sex chromosomes, but which recombines with them in an appreciable frequency. Our model predicts that, in the absence of selection, allelic differentiation between genes carried on the X and on the Y chromosomes will develop only if the recombination rate is of the same order of magnitude as the mutation rate or smaller. Similarly, a mutation favourable in males but disadvantageous in females will increase in frequency on the Y chromosomes, while remaining rare on the X chromosomes, only if the recombination rate is smaller than the fitness advantage of the mutation. The X and Y chromosomes are, thus, not expected to show any genetic differentiation for almost all of their homologous parts. Divergence will occur only for loci that very rarely recombine between the sex chromosomes.


Embryonic statistical analyses reveal 2 growth phenotypes in mouse models of Down syndrome.
Down syndrome is associated with several comorbidities, including intellectual disability, growth restriction, and congenital heart defects. The prevalence of Down syndrome-associated comorbidities is highly variable, and intellectual disability, although fully penetrant, ranges from mild to severe. Understanding the basis of this interindividual variability might identify predictive biomarkers of in utero and postnatal outcomes that could be used as endpoints to test the efficacy of future therapeutic interventions. The main objective of this study was to examine if antenatal interindividual variability exists in mouse models of Down syndrome and whether applying statistical approaches to clinically relevant measurements (ie, the weights of the embryo, placenta, and brain) could define cutoffs that discriminate between subgroups of trisomic embryos. Three commonly used mouse models of Down syndrome (Dp(16)1/Yey, Ts65Dn, and Ts1Cje) and a new model (Ts66Yah) were used in this study. Trisomic and euploid littermate embryos were used from each model with total numbers of 102 for Ts66Yah, 118 for Dp(16)1/Yey, 92 for Ts65Dn, and 126 for Ts1Cje. Placental, embryonic, and brain weights and volumes at embryonic day 18.5 were compared between genotypes in each model. K-mean clustering analysis was applied to embryonic and brain weights to identify severity classes in trisomic embryos, and brain and placental volumetric measurements were compared between genotypes and classes for each strain. In addition, Ts66Yah embryos were examined for malformations because embryonic phenotypes have never been examined in this model. Reduced body and brain weights were present in Ts66Yah, Dp(16)1/Yey, and Ts65Dn embyos. Cluster analysis identified 2 severity classes in trisomic embryos-mild and severe-in all 4 models that were distinguishable using a putative embryonic weight cutoff of <0.5 standard deviation below the mean. Ts66Yah trisomic embryos develop congenital anomalies that are also found in humans with Down syndrome, including congenital heart defects and renal pelvis dilation. Statistical approaches applied to clinically relevant measurements revealed 2 classes of phenotypic severity in trisomic mouse models of Down syndrome. Analysis of severely affected trisomic animals may facilitate the identification of biomarkers and endpoints that can be used to prenatally predict outcomes and the efficacy of treatments.


H2O2 self-sufficient nanoplatform based on CeO2 QDs decorated MgO2 nanosheet for amplified chemodynamic therapy.
Chemodynamic therapy (CDT), which employs Fenton/Fenton-like agents to decompose hydrogen peroxide (H2O2) into toxic hydroxyl radical (•OH) to induce cancer cell apoptosis and necrosis, holds great promise in tumor therapy due to its high selectivity. Nevertheless, its efficiency is impaired by the insufficient intracellular H2O2 concentration and/or the insensitive response of Fenton/Fenton-like agents to the slightly acid tumor microenvironment (pH∼7.0-6.5). Herein, we develop a novel CDT reagent based on CeO2 quantum dot (QD) decorated MgO2 nanosheets engineered with cascade reactions to boost the intracellular H2O2 level and high pH-activated (pH = 6.5) characteristic for an enhanced CDT. Under the tumor microenvironment (pH = 6.5), MgO2 nanosheets that are highly reactive can react with H2O to produce nontoxic Mg2+ and abundant H2O2, boosting the intracellular H2O2 level. The self-generated H2O2 is subsequently converted into •OH by CeO2 QD, which is served as a relatively high pH-activated (pH = 6.5) Fenton-like agent. The sufficient intracellular H2O2 supply and sensitive response to the slightly acid tumor sites significantly improve the Fenton reaction, leading to the excellent in vivo CDT results with tumor growth inhibition effect. Our work presents a distinctive paradigm for self-boosting CDT efficacy.


The different role of YKL-40 in glioblastoma is a function of MGMT promoter methylation status.
Inter- and intratumoral heterogeneity is a hallmark of glioblastoma (GBM) that facilitates recurrence, treatment resistance, and worse prognosis. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a significant prognostic marker for Temozolomide (TMZ) resistance in GBM patients. YKL-40 is a molecular marker for the mesenchymal subtype of GBMs and is responsible for TMZ resistance. However, underlying mechanisms by which MGMT epigenetics impacts patient outcomes and the function of YKL-40 are not fully determined. Herein, we performed in vitro and in vivo experiments, six human IDH1/2 wild-type glioblastoma stem-like cells (GSCs) were established and studied to further determine a potential interaction of YKL-40 and MGMT promoter methylation. We demonstrated that YKL-40 functioned differently in human IDH1/2 wild-type GSCs. In MGMT promoter-methylated (MGMT-m) GSCs, it acted as a tumor suppressor gene. On the other hand, in MGMT promoter-unmethylated (MGMT-um) GSCs, it promoted tumorigenesis. Notably, the reason that YKL-40 played different roles in GSCs could not be interpreted by the molecular classification of each GSCs, but is a function of MGMT promoter methylation status and involves the RAS-MEK-ERK pathway. YKL-40 mediated TMZ sensitivity by activating DNA damage responses (DDRs) in MGMT-m GSCs, and it mediated resistance to TMZ by inhibiting DDRs in MGMT-um GSCs. Our report demonstrated that MGMT promoter methylation status might influence a gene's function in human cancer. Moreover, our data also highlight the point that gene function should be investigated not only according to the molecular tumor classification, but also the epigenetic signature.


Optimizing the clinical value of hepatic scintiphotography.
Hepatic scintiphotography serves as a highly useful anatomic liver function test. When the descriptive features of the liver scan are carefully related to underlying pathology, the resulting data base permits a detection sensitivity of 90% for metastatic cancer and for the diffuse parenchymal diseases. The consequences of false positive (FP) interpretations for patient care must be minimized by attention to perceptual and technical details, by incorporating other tests into the evaluative algorithm, and by knowledge of the distribution of diseases in the population examined. The liver scan would be more beneficially applied to patient management if referring physicians were made aware of its capabilities. They, in turn, must develop more explicit strategies for disease management in order that scintiphotography be effectively applied in clinical decision making.


Familial respiratory distress syndrome in three consecutive full-term infants. Case reports and documentation of lung enzyme activities.
Familial respiratory distress syndrome in full-term newborn infants is a rare occurrence. Our patient delivered three consecutive full-term infants who developed findings consistent with respiratory distress syndrome. All three died from autopsy-proven hyaline membrane disease. Analysis of the activities of four enzymes that play an important role in the biosynthesis of lecithin (choline kinase, choline phosphotransferase, phospholipase A and lysolecithin acyltransferase) failed to disclose an abnormality in lung samples in our patient with familial respiratory distress syndrome.


Determining the impact of unknown individuals in criminality using network analysis of DNA matches.
Criminal offenders missing from police files limit the capacity to reconstruct criminal networks for criminological research and operational purposes. Recent studies show that forensic DNA databanks offer potential to address this problem, through large-scale analysis of DNA matches, many of which involve unidentified offenders. Applying social network analysis (SNA) to 18 years of DNA match data from Québec, Canada, we found that 1400 unknowns do not occupy more marginal positions in the network than 13,000 known offenders, and explain up to 18% of SNA values (e.g., betweenness centrality) for the latter while supporting 46% of their clustering values. Our results contrast with previous studies, showing moreover that unknown individuals who are positioned centrally in a network may have a larger impact than previously expected on investigation policing with implications for forensic intelligence.


The DNA damage response in viral-induced cellular transformation.
The DNA damage response (DDR) has emerged as a critical tumour suppressor pathway responding to cellular DNA replicative stress downstream of aberrant oncogene over-expression. Recent studies have now implicated the DDR as a sensor of oncogenic virus infection. In this review, we discuss the mechanisms by which tumour viruses activate and also suppress the host DDR. The mechanism of tumour virus induction of the DDR is intrinsically linked to the need for these viruses to promote an S-phase environment to replicate their nucleic acid during infection. However, inappropriate expression of viral oncoproteins can also activate the DDR through various mechanisms including replicative stress, direct interaction with DDR components and induction of reactive oxygen species. Given the growth-suppressive consequences of activating the DDR, tumour viruses have also evolved mechanisms to attenuate these pathways. Aberrant expression of viral oncoproteins may therefore promote tumourigenesis through increased somatic mutation and aneuploidy due to DDR inactivation. This review will focus on the interplay between oncogenic viruses and the DDR with respect to cellular checkpoint control and transformation.


Relative risk of cancer in sonographically detected thyroid nodules with calcifications.
The aim of this prospective study was to evaluate the significance of sonographically detected thyroid calcifications in the diagnosis of thyroid cancer. One hundred eighty-eight patients with thyroid disease, including 37 with thyroid cancer, were included in the study. Each patient underwent preoperative, high-resolution sonography to evaluate the thyroid gland for the presence of calcifications. The highest incidence of calcification was found in thyroid cancer (54%), followed by multinodular goiter (40%), solitary nodular goiter (14%), and follicular adenomas (12%). The incidence of cancer was significantly higher in calcified nodules (29%) than in noncalcified nodules in the entire group (14%) (p = 0.019), with a relative risk of 2.5. In the group of solitary thyroid nodules, the incidence of cancer in the calcified nodules (55%) was higher than in the nodules without calcification (23%) (p = 0.016). Multiple noncalcified thyroid nodules harbored cancer in only 5% of cases. Compared with multiple noncalcified thyroid nodules, the solitary calcified nodules demonstrated a relative risk of 22.8. In both the solitary and multiple nodules, the relative risk in the presence of calcification was about the same, around 4. Patients younger than 40 years with calcified nodules constituted a high-risk group, with a relative risk of 3.8 versus 2.5 in patients older than 40 years with calcified nodules. The detection of thyroid calcifications by sonography is diagnostically valuable, especially in cases involving a solitary nodule or a young person. The presence of calcifications in these cases should raise the suspicion of malignancy. The low incidence of cancer in patients with multiple noncalcified thyroid nodules suggests that a more conservative approach may be appropriate in such cases.


D(-)3-hydroxybutyrate cotransport with Na in rat renal brush border membrane vesicles.
Which are the driving forces for D(-)3-hydroxybutyrate (HB) transport in rat renal brush border membranes (RBB)? Sodium, even in the absence of gradients, accelerates the unidirectional (1-5 s) flux of HB into rat RBB vesicles. Valinomycin (and Ki = Ko) does not significantly alter the NaCl gradient driven HB influx. Thus, the Na-dependent HB influx is driven by the chemical Na+ gradient but it is not driven by changes in the transmembrane electrical potential. Indeed, in valinomycin-treated membranes, vesicle-inside more negative potentials (K-gluconate in-Na-gluconate out) sufficient to accelerate Na-glucose cotransport, did not stimulate HB influx, in the presence of inwardly directed Na+ gradients, and did not significantly inhibit when in the absence of Na+. Thus, cotransport of HB with Na in rat RBB membranes does not involve the net transfer of positive charge and the passive conductance of this membrane for HB- is not large. However, vesicle inside more negative potentials (induced by inwardly directed NaNO3 gradients or by outwardly directed K+ gradients and valinomycin in the presence of inwardly directed Na+ gradients) inhibited HB influx, suggesting that another potential sensitive mechanism, perhaps redistribution of intramembrane charges, may influence HB influx. Acidification (pHi = pHo = 6.4 vs. 7.4) or inwardly directed H+ gradients (pHo/pHi = 6.4/7.4) did not alter HB influx, in the absence of Na+. Thus there is no evidence for a H+ driven HB influx. HB influx is significantly inhibited by high (100 mEq/l) trans concentration of Na+. Also, influx of 2.25 mM 14C-HB was significantly increased by 5-10 mM intravesicular HB under Na-equilibrated conditions.(ABSTRACT TRUNCATED AT 250 WORDS)


Intracellular free iron in liver tissue and liver homogenate: studies with electron paramagnetic resonance on the formation of paramagnetic complexes with desferal and nitric oxide.
Treatment of intact liver and liver homogenate with sodium nitrite, or desferal, brings about the appearance of g = 2.03 and g = 4.3 electron paramagnetic resonance spectroscopy (EPR) signals, respectively. The g = 2.03 signal is conditioned by the formation of dinitrosyl complexes of Fe(II); the g = 4.3 signal is related to the appearance of paramagnetic desferal-Fe(III) complexes. Desferal and sodium nitrite were administered successively into liver homogenate, resulting in only a g = 4.3 EPR signal. And, vice versa, if desferal was administered after sodium nitrite, there appeared only the signal with g = 2.03. These data testify to the fact that one and the same endogenous free iron is included in both paramagnetic centers. The concentration of iron ions was measured in intact tissue according to the formation of dinitrosyl-iron complexes and desferal-iron complexes. It was 33.2 +/- 4.6 and 20.3 +/- 4.0 nmol/g of tissue weight, respectively. The data obtained testify to the fact that free endogenous iron is present in intact tissue. Possibilities of the EPR method for estimation of the content of intracellular free iron are discussed.


Efficacy of paired tumor and germline testing in evaluation of patients with Lynch-like syndrome in a large integrated healthcare setting.
Patients with mismatch repair (MMR) deficient colorectal cancer (CRC) without detectable germline pathogenic variants (PVs) or likely pathogenic variants (LPVs) in MMR genes are often labeled as Lynch-like syndrome (LLS). We sought to evaluate the efficacy of paired tumor and germline testing in risk stratification of patients with LLS in a large, community-based, integrated healthcare setting. Through the universal screening program for Lynch syndrome at Kaiser Permanente Northern California, we identified all patients with MMR deficient colorectal tumors without detectable germline PVs or LPVs between April 2011 and October 2018. These patients were categorized as LLS and were offered paired tumor and germline testing. Risk stratification and patient management were assessed upon completion of all testing. Of the 50 patients with LLS who underwent paired tumor and germline testing, 62% (n = 31) were categorized as sporadic, 6% (n = 3) had Lynch syndrome, and 32% (n = 16) remained inconclusive. Among the sporadic cases, 65% (n = 20) had a PV (n = 18) or LPV (n = 2) in combination with loss of heterozygosity while 35% (n = 11) had two somatic PVs/LPVs involving the same MMR gene. Our findings showed paired tumor and germline testing resolved the etiology in the majority of patients and is a valuable strategy in risk stratification and management of patients with LLS. Further studies are needed to assess the optimal application of paired testing in different practice settings, particularly with evolving technology and decreasing cost of molecular sequencing.


Simvastatin reduced infiltration of memory subsets of T lymphocytes in the lung tissue during Th2 allergic inflammation.
Lymphocytes infiltration is a key mechanism that drives asthma lung inflammation. Our previous results demonstrated a significant increase in the frequency and persistence of central memory T (TCM) cells in inflamed lung tissue. This could be due to an increase in the infiltration of TCM in the lung tissue, or the possible differentiation of lung effector memory T (TEM) cells into TCM during lung inflammation. Thus, targeting the accumulation of memory T cells provides a potential approach for asthma treatment. Simvastatin and other statins were shown to impact both the structural and immune lung cells, presenting a distinct immunomodulatory effect on T lymphocyte activation, infiltration, and function. Therefore, we sought to evaluate the effect of simvastatin on the frequency and function of CD4 and CD8 TEM and TCM cells in an ovalbumin (OVA)-induced mouse model of asthma. Simvastatin treatment significantly attenuated the infiltration of both TEM and TCM memory subtypes, along with their production of IL-4 and IL-13 cytokines in a T helper 2 (Th2) OVA-sensitized mouse model. Furthermore, we detected a reduction in ICAM-1 and VCAM-1 levels in the lung homogenate of OVA-sensitized and challenged mice, as well as in human umbilical vein endothelial cells (HUVECs) following treatment with simvastatin. The reduction in leucocyte homing receptors following simvastatin treatment might have contributed to the observed decrease in infiltrated memory T cell numbers. In conclusion, this study demonstrated how statin drug may attenuate allergic asthma lung inflammation by targeting memory T cells and reducing their numbers, whilst limiting their cytokine production at the site of inflammation. Longer clinical trials are required to assess the effectiveness and safety of statin treatment in different asthma phenotypes.


Prostaglandin E (Sulproston) is neither luteolytic nor luteotrophic during the estrous cycle in the pig.
Prostaglandin E2 (Sulproston, S) can induce parturition and luteolysis during late pregnancy in the pig. We now tested whether Sulproston is able to interfere with the duration of the pig's estrous cycle. Sulproston was given i.m. in two injections (0.008 mg/kg each) at 12-hour-intervals to ten gilts day 10, to five gilts day 14 and to five gilts day 16 of the estrous cycle. Blood was collected shortly before and up to 48 hrs after the onset of treatment; further daily blood samples were taken from day 0 (1st day of standing heat) to the end of the cycle. Sulproston-administration did not shorten or lengthen the duration of the estrous cycle, nor were plasma-progesterone levels altered when compared to controls. In a second study five gilts received the tenfold amount of S on day 10 of the cycle. A significant decrease in plasma-progesterone (8.52 +/- 2.8 SEM ng, treatment vs. 32.95 +/- 1.86 SEM ng/ml, control) occurred on day 11, which had returned by day 16 to the level of controls (19.22 +/- 6.28 ng/ml vs. 26.75 +/- 2.10 SEM ng/ml, respectively). No alteration in cycle length occurred. Therefore the PGE2-analogue Sulproston - though luteolytic in late pregnancy - is neither luteolytic nor luteotrophic during the estrous cycle of the pig.


Green synthesis of stable hybrid biocatalyst using a hydrogen-bonded, π-π-stacking supramolecular assembly for electrochemical immunosensor.
Rational integration of native enzymes and nanoscaffold is an efficient means to access robust biocatalyst, yet remains on-going challenges due to the trade-off between fragile enzymes and harsh assembling conditions. Here, we report a supramolecular strategy enabling the in situ fusion of fragile enzymes into a robust porous crystal. A c2-symmetric pyrene tecton with four formic acid arms is utilized as the building block to engineer this hybrid biocatalyst. The decorated formic acid arms afford the pyrene tectons high dispersibility in minute amount of organic solvent, and permit the hydrogen-bonded linkage of discrete pyrene tectons to an extended supramolecular network around an enzyme in almost organic solvent-free aqueous solution. This hybrid biocatalyst is covered by long-range ordered pore channels, which can serve as the gating to sieve the catalytic substrate and thus enhance the biocatalytic selectivity. Given the structural integration, a supramolecular biocatalyst-based electrochemical immunosensor is developed, enabling the pg/mL detection of cancer biomarker.


Saikosaponin d contributed to cancer chemotherapy induced neutropenia therapy by promoting neutrophil differentiation via activation CBL-dependent ERK pathway.
Cancer chemotherapy induced neutropenia (CCIN) is one of the most common toxicity caused by cytotoxic anticancer agents. Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical practice, the infection and infection-related mortality rate is still high for lack of functionally mature neutrophils. Saikosaponin d (SSD) is one of the major bioactive constituents of Radix Bupleuri (RB), which exerts immune-modulatory properties. We explored the function of SSD in CCIN therapy, we found that SSD contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo. Network pharmacology was employed to explore the mechanism, 61 signal pathways might play an important role in CCIN treatment. Western Blot was employed to further confirm the potential pathway involved. We found CBL-ERK1/2 pathway was activated by SSD, followed by upregulating PU.1 and CEBPβ expression and leading to neutrophil differentiation. Our findings suggest a natural regimen SSD which could regenerate microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2, providing a rationale for future therapeutic approaches.


The second-look operation and surgical reexploration in ovarian tumor of low malignant potential.
Patients at the University of Michigan Medical Center who were reoperated on for either operative staging, suspected disease, or a second-look procedure with the diagnosis of ovarian tumor of low malignant potential are reported. At the time of initial surgery, 29 patients were thought to have benign disease based on visual inspection of the ovarian mass, and seven patients had a frozen-section report of benign disease. Fifteen patients underwent restaging operation, and disease was found in seven patients. One patient remained as stage Ia, one patient was upstaged to stage Ib, and five patients were upstaged to either stages II or III. Thirteen patients underwent 22 operations for suspected disease. Malignancy was encountered in 19 of these 22 operations. A second-look operation was performed on 20 patients, and 17 of these were negative. All patient with original stages I or II disease had negative second-look operations, whereas three of the eight patients with stage III disease had positive second-look operations. Reexploration for staging in the ovarian tumor of low malignant potential will yield a reasonable number of positive results, whereas the second-look operation in early-stage disease has a very low yield.


Observations on the permeability of the choriocapillaris of the eye.
The choriocapillaris is a fenestrated capillary bed located posterior to the retinal pigment epithelium. It serves as the main source of supply to the photoreceptors, retinal pigment epithelium, and other cells of the outer retina. The permeability of these capillaries to intravenously injected ferritin (MW - approx. 480,000; mol. diam. 11 nm) was examined in the mouse, rabbit, and guinea pig, each of which is characterized by a different type of retinal vascularization. In all three species, the bulk of the ferritin remained in the capillary lumina, where it appeared to be blocked at the level of the diaphragmed fenestrae. Some ferritin was present in endothelial cell vacuoles. The results confirm previous work on the rat choriocapillaris and indicate that the barrier function of the choriocapillary endothelium is present even among species in which the retinal circulation differs significantly.


PAX8 pathogenic variants in Chinese patients with congenital hypothyroidism.
The clinical presentation of patients with congenital hypothyroidism (CH) caused by paired box gene 8 (PAX8) pathogenic variants is variable and PAX8 mutation rates differ significantly among different populations. This study was set to examine the PAX8 mutation spectrum and prevalence among patients with CH in Guangxi Zhuang Autonomous Region, China. Peripheral venous blood samples were collected from the patients. Genomic DNA was extracted from peripheral blood leukocytes. All exons of the 11 known CH associated genes including PAX8 together with their exon-intron boundaries were screened by next-generation sequencing (NGS). Permanent or transient CH was determined using the results of thyroid function tests after temporary withdrawal of L-thyroxine (L-T4) therapy at approximately 2 years of age. Next generation sequencing analysis of PAX8 in 378 CH patients revealed five different mutations in nine individuals (two are siblings). The mutations included two known missense variants, namely c.92G>A (p.R31H) and c.91C>T (p.R31C), and one novel missense variant c.68G>T (p.G23V), as well as two novel nonsense variants c.1090C>T (p. R364X) and c.658C>T (p.R220X). The variant c.92G>A (p.R31H) is highly recurrent in our patient cohort but the clinical phenotypes vary greatly among those carrying this variant. PAX8 pathogenic variants were mainly associated with permanent CH. The prevalence of PAX8 pathogenic variants was 2.38% among patients with CH in Guangxi. Our study expanded the PAX8 mutation spectrum and provided the best estimation of PAX8 mutation rate among CH patients in Guangxi, China.


Sustainable Development Goals: Challenges and the Role of the International Society of Nephrology in Improving Global Kidney Health.
The United Nations 2030 agenda for sustainable development includes 17 sustainable development goals (SDGs) that represent a universal call to end poverty and protect the planet, and are intended to guide government and private sector policies for international cooperation and optimal mobilization of resources. At the core of their achievement is reducing mortality by improving the global burden of noncommunicable diseases (NCDs), the leading causes of death and disability worldwide. CKD is the only NCD with a consistently rising age-adjusted mortality rate and is rising steadily up the list of the causes of lives lost globally. Kidney disease is strongly affected by social determinants of health, with a strong interplay between CKD incidence and progression and other NCDs and SDGs. Tackling the shared CKD and NCD risk factors will help with progress toward the SDGs and vice versa . Challenges to global kidney health include both preexisting socioeconomic factors and natural and human-induced disasters, many of which are intended to be addressed through actions proposed in the sustainable development agenda. Opportunities to address these challenges include public health policies focused on integrated kidney care, kidney disease surveillance, building strategic partnerships, building workforce capacity, harnessing technology and virtual platforms, advocacy/public awareness campaigns, translational and implementation research, and environmentally sustainable kidney care.


Cerebral arterial air embolism due to an esophago-atrial fistula seen on CT.
A case of cerebral air embolism from a rather unusual cause is reported; an esophago-cardiac fistula permitted food particles and air to enter the systemic arterial circulation. Massive embolization caused the patient to become deeply comatose rather suddenly. The computed tomogram (CT) revealed massive cerebral edema with the contradictory finding of wide superficial subarachnoid spaces. These subarachnoid spaces on further evaluation proved to be air in the cerebral vessels.


Changes in electroretinogram oscillatory potentials during dark adaptation.
To investigate changes in the oscillatory potentials (OPs) of electroretinograms (ERGs) during dark adaptation (DA). ERGs were recorded from ten normal subjects. Following 15 min of light adaptation, ERGs were recorded every 30 s for 20 min to follow the changes in the OPs during the course of DA. A 20-ms, 560-nm rectangular pulse of light was presented at 3.3 Hz to elicit the ERGs. The latencies of OP1 and OP2 did not change significantly, but the amplitudes decreased slightly during DA. OP3 was not observed at 30 s, but appeared after 1 min of DA between OP2 and OP4. Similar results were obtained with stimulus durations of 10 to 100 ms in 10-ms steps. The amplitude of OP3 increased to 10 min of DA and then plateaued. The characteristics of OP3, which increases during DA, indicate that it is probably related to rod activity.


Rumen Fermentation Characteristics in Pre- and Post-Weaning Calves upon Feeding with Mulberry Leaf Flavonoids and Candida tropicalis Individually or in Combination as a Supplement.
Although flavonoids or yeast have been used as feed additives to improve the production efficiency and health of adult cattle, little information is available on their effects on rumen fermentation in calves. The objective of this study was to investigate the effects of feed supplementation with mulberry leaf flavonoids and Candida tropicalis on performance, blood parameters, and rumen fermentation characteristics during pre-weaning and post-weaning periods. Forty-eight Holstein calves were used in a four-groups trial and were supplemented with (1) no yeast or flavonoids (CON), (2) active dry yeast (ADY; C. tropicalis, 5.0 × 109 CFU/d), (3) flavonoids (FLA; 3 g/d), or (4) yeast and flavonoids (YF; C. tropicalis, 5.0 × 109 CFU/d; flavonoids, 3 g/d). The feeding strategy was as follows: milk replacer was offered at 12% of body weight in two meals per calf each day at age 21 d, and a gradual weaning process was adopted at age 50 to 56 days. Data of daily feed intake, body weight, and serum and rumen fermentation parameters were obtained at 28, 42, 56, and 80 d ages, respectively. A significant time effect and interaction between treatment and time was found for average daily gain, feed efficiency, total volatile fatty acid concentration, and proportion of propionate in calves (p < 0.05). Average daily gain and feed efficiency increased during post-weaning and overall periods for calves in FLA and YF groups compared with CON and ADY groups (p < 0.05). A reduction of fecal scores with supplementation was found in FLA and YF groups (p < 0.05). Rumen fluid pH and ammonia nitrogen concentration remained constant across the groups, whereas total volatile fatty acid concentration and molar proportion of propionate significantly increased during the pre-weaning and overall periods in FLA and YF groups (p < 0.05). Calves in YF group had the highest serum concentrations of IgG and IgA during the overall period (p < 0.05). Additionally, serum β-hydroxybutyric acid concentration was higher in ADY and FLA groups during the post-weaning period (p < 0.05). Supplementation with C. tropicalis showed little effect on increasing growth performance and health compared with flavonoids alone. Meanwhile, the combination of C. tropicalis and flavonoids was not synergistic with respect to improving health and rumen fermentation compared with use of flavonoids alone in pre- and post-weaning calves (p > 0.05).


FMRFamide-like activity in the female locust during vitellogenesis.
The control of oviposition in the locust involves the expulsion of eggs from the lateral oviducts, a process believed to be under neurohormonal control. In this paper we have attempted to identify this putative hormone. Immunohistochemical staining of the brain retrocerebral complex and suboesophageal ganglion of Locusta migratoria with antiserum against FMRFamide revealed a number of FMRFamide-immunopositive cells. FMRFamide-like immunoreactivity was present in median neurosecretory cells and lateral neurosecretory cells of the protocerebrum. Other FMRFamide-immunoreactive cells were detected in the deutocerebrum and tritocerebrum. Immunoreactive cell processes were observed in the mushroom bodies, the central body, the optic lobes, and in the axon tracts leaving the pars intercerebralis and tritocerebrum. FMRFamide-like material was also seen in the circumoesophageal commissures. Further FMRFamide-like material was present in cell bodies of the suboesophageal ganglion. FMRFamide-like staining activity changed dramatically during the oviposition cycle in mature adult females. The median neurosecretory cells stained lightly immediately after oviposition and remained pale until the third day, when staining of perikarya and axon tracts increased. The staining intensity decreased on days 4 and 5. The titre of FMRFamide-like material in the hemolymph increased during the vitellogenic cycle but plummeted after oviposition. A single band of FMRFamide-like material was evident on immunoblot following sodium dodecyl sulphate-polyacrylamide gel electrophoresis of adult female hemolymph. The approximate molecular weight of this molecule was 8,000. Gel permeation chromatography of hemolymph revealed a FMRFamide-immunoreactive fraction with a molecular weight of 8,000. This fraction possessed myotropic activity when applied to the locust oviduct.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of Gaussian curvature modulus on the shape of deformed hollow spherical objects.
A popular description of soft membranes uses the surface curvature energy introduced by Helfrich, which includes a spontaneous curvature parameter. In this paper we show how the Helfrich formula can also be of interest for a wider class of spherical elastic surfaces, namely with shear elasticity, and likely to model other deformable hollow objects. The key point is that when a stress-free state with spherical symmetry exists before subsequent deformation, its straightforwardly determined curvature ("geometrical spontaneous curvature") differs most of the time from the Helfrich spontaneous curvature parameter that should be considered in order to have the model being correctly used. Using the geometrical curvature in a set of independent parameters unveils the role of the Gaussian curvature modulus, which appears to play on the shape of an elastic surface even though this latter is closed, contrary to what happens for surfaces without spontaneous curvature. In appendices, clues are given to apply this alternative and convenient formulation of the elastic surface model to the particular case of thin spherical shells of isotropic material (TSSIMs).


Intracoronary physiology-guided percutaneous coronary intervention in patients with diabetes.
The risk of vessel-oriented cardiac adverse events (VOCE) in patients with diabetes mellitus (DM) undergoing intracoronary physiology-guided coronary revascularization is poorly defined. The purpose of this work is to evaluate the risk of VOCE in patients with and without DM in whom percutaneous coronary intervention (PCI) was performed or deferred based on pressure-wire functional assessment. This is a retrospective analysis of a multicenter registry of patients evaluated with fractional flow reserve (FFR) and/or non-hyperaemic pressure ratio (NHPR). Primary endpoint was a composite of VOCE including cardiac death, vessel-related myocardial infarction (MI), and ischemia-driven target vessel revascularization (TVR). A large cohort of 2828 patients with 3353 coronary lesions was analysed to assess the risk of VOCE at long-term follow-up (23 [14-36] months). Non-insulin-dependent-DM (NIDDM) was not associated with the primary endpoint in the overall cohort (adjusted Hazard Ratio [aHR] 1.18, 95% CI 0.87-1.59, P = 0.276) or in patients with coronary lesions treated with PCI (aHR = 1.30, 95% CI 0.78-2.16, P = 0.314). Conversely, insulin-dependent diabetes mellitus (IDDM) demonstrated an increased risk of VOCE in the overall cohort (aHR 1.76, 95% CI 1.07-2.91, P = 0.027), but not in coronary lesions undergoing PCI (aHR 1.26, 95% CI 0.50-3.16, P = 0.621). Importantly, in coronary lesions deferred after functional assessment IDDM (aHR 2.77, 95% CI 1.11-6.93, P = 0.029) but not NIDDM (aHR = 0.94, 95% CI 0.61-1.44, P = 0.776) was significantly associated with the risk of VOCE. IDDM caused a significant effect modification of FFR-based risk stratification (P for interaction < 0.001). Overall, DM was not associated with an increased risk of VOCE in patients undergoing physiology-guided coronary revascularization. However, IDDM represents a phenotype at high risk of VOCE.


Wheel running sleep in two strains of mice: plasticity and rigidity in the expression of circadian rhythmicity.
The effects of 12--12 h, 6--6 h, 3--3 h and 1--1 h light--dark (L-D) cycles and of constant light (L--L) on wheel-running activity and electrograhically defined sleep were studied in two strains of mice, C57BL/6 and SEC/1Re. Wheel-running activity was inhibited by light and enhanced by darkness; however, in the C57 strain the L-D-induced changes were less pronounced and superimposed to a clear circadian rhythm. Under the L-L schedule clear patterns of daily rhythmicity were evident in the C57 strain but not in the SEC strain. Sleep was enhanced by light and inhibited by darkness. The L-D-induced changes of sleep were superimposed on the circadian rhythm in both strains; however, in the C57 strain these changes were larger in the circadian phase in which the animals were active. Under the L-L-schedule the C57 strain was characterized by more clear-cut patterns of daily rhythmicity than SEC mice. These phenomena are discussed in terms of plasticity of free-running rhythms of sleep and activity and of the genetic factors involved in the expression of circadian rhythmicity.


Unsocial hours pay is a question of fairness.
Should you be paid extra for working weekends? What about nights, or public holidays? Unsocial hours go with the job for most nurses, but the issue of whether and how staff should be rewarded is currently being scrutinised by the NHS Pay Review Body. In the past week there has also been a heated political discussion, as the parties vie for nurses' votes.


Inhibition by ibudilast of leukotriene D4-induced formation of inositol phosphates in guinea-pig lung.
1. The effects of a novel anti-asthmatic drug, 3-isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (ibudilast, KC-404) on leukotriene D4 (LTD4)-induced formation of inositol phosphates were studied in slices of guinea-pig lung and hippocampus. 2. In guinea-pig lung, ibudilast inhibited LTD4 (0.01-1 microM)-induced formation of inositol monophosphate (IP1) in a concentration-dependent manner (IC50 = 10 microM) without affecting LTD4 receptor binding. 3. Ibudilast (10 microM) inhibited histamine (0.1-1 mM)-induced formation of IP1 in guinea-pig lung slices but not in hippocampal slices. 4. Inhibition of agonist-induced formation of IP1 by ibudilast was non-competitive. 5. Ibudilast had no effect on either GTP- or calcium-stimulated phosphatidylinositol specific-phospholipase C activity of lung membranes. 6. These results suggest that ibudilast has no direct effect on LTD4 receptors, GTP binding proteins (G proteins) or phospholipase C, but inhibits inositol phosphate formation, possibly by interfering with the coupling between receptors and G proteins.


Cloning of novel bombesin precursor cDNAs from skin of Bombina maxima.
Amphibian skin is a rich resource of bioactive peptides like proline-rich bombesin from frog Bombina maxima. A novel cDNA clone encoding a precursor protein that comprises proline-rich bombesin and a novel peptide, designated as bombestatin, was isolated from a skin cDNA library of B. maxima. The predicted primary structure of the novel peptide is WEVLLNVALIRLELLSCRSSKDQDQKESCGMHSW, in which two cysteines form a disulfide bond. A BLAST search of databases did not detect sequences with significant similarity. Bombestatin possesses dose-dependent contractile activity on rat stomach strips. The differences between cDNAs encoding PR-bombesin plus bombestatin and PR-bombesin alone are due to fragment insertions located in 3'-coding region and 3'-untranslational region, respectively.


Effect of the aqueous extract of Chrysanthellum indicum on calcium mobilization and activation of rat portal vein.
The effects of the aqueous extract of Chrysanthellum indicum (CI) on calcium activation and mobilization were studied using the rat portal vein. The extract caused a concentration-dependent contraction of the portal vein. KCl (80 mM), norepinephrine (NA, 10(-6)M) and CI (4 mg/ml) evoked sustained contraction of the portal vein. In Ca-free medium (with EGTA) the contractions evoked by these agents were reduced significantly. The times-to-peak of KCl, NA and CI were similar -in normal PSS, but in Ca-free medium the times-to-peak for KCl and CI were greatly increased. The contractions induced by CI were not inhibited by chlorpropamide and prazosin, but were blocked by verapamil. The data obtained suggest that the aqueous extract of CI utilizes extracellular calcium pools to bring about contractile response and this effect might be mediated through the activation of potential-sensitive channels.


Outcomes of the Bethesda system for reporting thyroid cytopathology in community- vs. institution-performed cytology.
Despite the important role of the community in the assessment and risk stratification of patients with thyroid nodules, evidence-based data on the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) performance in community clinics is lacking. We aim to evaluate BSRTC performance of aspirations taken in community clinics compared with primary referral center. Patients who underwent thyroid surgery between 2013 and 2018 at our institution were divided according to the fine needle aspirations (FNA) settings: community FNA (cFNA) vs. institutional FNA (iFNA). Demographics, BSRTC results and final pathology were collected. Diagnostic values were calculated for BSRTC categories (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]), and were compared between the groups. A total of 268 nodules were included in the study; 77% (207) cFNA and 23% (61) iFNA. Patients in the community were younger (51.7 ± 15.1 vs. 56.6 years±14.8, p = 0.03) and with less epidemiology risk factors for thyroid cancer (1.9% vs 13.1%, p < 0.001). cFNA malignancy rate for BSRTC I-VI was 0%, 6.4%, 11.8%, 32.1%, 91.6% and 93.8% respectively. Best sensitivity was found for BSRTC III-VI in both groups (88% and 83%, cFNAs and iFNAs, respectively). Overall best performance was obtained for BSRTC V-VI for both groups (cfNA: 85%, 97%, 93%, 94% and 93%; iFNAs: 81%, 100%, 100%, 87% and 91%, for sensitivity, specificity, PPV, NPV and accuracy, respectively). Community-performed FNAs demonstrate acceptable BSRTC distribution and malignancy rates, comparable with a primary referral academic hospital. This supports the universality of the BSRTC 2017 and its recommendations also in the community.


Leukocyte cell surface proteinases: regulation of expression, functions, and mechanisms of surface localization.
A number of proteinases are expressed on the surface of leukocytes including members of the serine, metallo-, and cysteine proteinase superfamilies. Some proteinases are anchored to the plasma membrane of leukocytes by a transmembrane domain or a glycosyl phosphatidyl inositol (GPI) anchor. Other proteinases bind with high affinity to classical receptors, or with lower affinity to integrins, proteoglycans, or other leukocyte surface molecules. Leukocyte surface levels of proteinases are regulated by: (1) cytokines, chemokines, bacterial products, and growth factors which stimulate synthesis and/or release of proteinases by cells; (2) the availability of surface binding sites for proteinases; and/or (3) internalization or shedding of surface-bound proteinases. The binding of proteinases to leukocyte surfaces serves many functions including: (1) concentrating the activity of proteinases to the immediate pericellular environment; (2) facilitating pro-enzyme activation; (3) increasing proteinase stability and retention in the extracellular space; (4) regulating leukocyte function by proteinases signaling through cell surface binding sites or other surface proteins; and (5) protecting proteinases from inhibition by extracellular proteinase inhibitors. There is strong evidence that membrane-associated proteinases on leukocytes play critical roles in wound healing, inflammation, extracellular matrix remodeling, fibrinolysis, and coagulation. This review will outline the biology of membrane-associated proteinases expressed by leukocytes and their roles in physiologic and pathologic processes.


[Transoral approach for sublingual-plunging ranula].
The case of a 7-year-old boy suffering from progressive submental/submandibular swelling is reported. Following clinical and imaging diagnostics (MRI), the suspected diagnosis of a sublingual-plunging ranula was made. Surgery was performed with transoral excision of the sublingual gland in combination with excision of the ranula. Additional submandibular gland excision should be avoided.


Therapeutic potential and challenges of bitter taste receptors on lung cells.
Airway smooth muscle (ASM) hyperresponsiveness and airway remodeling are pathological drivers of disease progression and mortality in asthma. Importantly, approximately 50% of affected individuals are unable to reliably manage disease symptoms using the current standard of care. Recently, T2Rs have been identified as a novel class of G protein-coupled receptors expressed in the airway that on activation can induce ASM relaxation and reduction in airway tone. Further, agonists of T2Rs may also remedy airway remodeling, which has been difficult to manage with currently available medications. In this review, we will discuss the recent developments in T2R biology and their role in cellular physiology (particularly ASM) and expand on the therapeutic potential of T2R agonists in treatment of asthma.


Gastric antral vascular ectasia--a cause of refractory anaemia in systemic sclerosis.
Recurrent gastrointestinal haemorrhage is an uncommon manifestation of systemic sclerosis. We report a case of gastrointestinal bleeding due to gastric antral vascular ectasia (GAVE) in a patient with systemic sclerosis. Failure to recognise the condition as a cause of gastrointestinal bleeding may delay the instigation of appropriate treatment. GAVE should be considered in the differential diagnosis of anaemia in patients with autoimmune conditions such as systemic sclerosis and primary biliary cirrhosis.


Calculate protein-ligand binding affinities with the extended linear interaction energy method: application on the Cathepsin S set in the D3R Grand Challenge 3.
We participated in the Cathepsin S (CatS) sub-challenge of the Drug Design Data Resource (D3R) Grand Challenge 3 (GC3) in 2017 to blindly predict the binding poses of 24 CatS-bound ligands, the binding affinity ranking of 136 ligands, and the binding free energies of a subset of 33 ligands in Stage 1A and Stage 2. Our submitted predictions ranked relatively well compared to the submissions from other participants. Here we present our methodologies used in the challenge. For the binding pose prediction, we employed the Glide module in the Schrodinger Suite 2017 and AutoDock Vina. For the binding affinity/free energy prediction, we carried out molecular dynamics simulations of the complexes in explicit water solvent with counter ions, and then estimated the binding free energies with our newly developed model of extended linear interaction energy (ELIE), which is inspired by two other popular end-point approaches: the linear interaction energy (LIE) method, and the molecular mechanics with Poisson-Boltzmann surface area solvation method (MM/PBSA). Our studies suggest that ELIE is a good trade-off between efficiency and accuracy, and it is appropriate for filling the gap between the high-throughput docking and scoring methods and the rigorous but much more computationally demanding methods like free energy perturbation (FEP) or thermodynamics integration (TI) in computer-aided drug design (CADD) projects.


Concurrent radiochemotherapy for patients with stage III non-small-cell lung cancer (NSCLC): long-term results of a phase II study.
To investigate the feasibility and activity of concurrent radiochemotherapy in patients with Stage III nonsmall-cell lung cancer (NSCLC). Forty-one patients were treated with hyperfractionated radiation therapy (HfxRT) using 1.2 Gy bid, to a total of 69.6 Gy and concurrent low-dose daily chemotherapy (CHT) consisting of 30 mg of carboplatin (CBDCA) and 30 mg of etoposide (VP-16) given Mondays to Fridays during the RT course. On Saturdays and Sundays during the RT course, CBDCA and VP-16 were both given in a daily dose of 100 mg each. Median survival time was 25 months, and 3- and 5-year survival rates were 34% and 29%, respectively. Median relapse-free survival time was 22 months, and 3- and 5-year relapse-free survival rates were 32%, and 29%, respectively. Median time to local recurrence was 24 months and 3- and 5-year local recurrence-free survival rates were 41% and 38%, respectively. Median time to distant metastasis was 28 months, and 3- and 5-year distant metastasis-free survival rates were 44% and 44%, respectively. Acute high-grade (> or = 3) toxicity was mostly hematological (30%), esophageal (15%), and bronchopulmonary (12%). Late high-grade toxicity was infrequent. This combined radiochemotherapy regimen produced promising results and warrants further studies with more patients before testing it in a prospective randomized fashion.