Practical immunoregulation: neonatal immune response variation and prophylaxis of experimental food allergy in pigs.
The importance of environment in immune response is identified and the increase in prevalence of allergic, autoimmune and chronic inflammatory diseases reviewed. In particular, altered opportunity to acquire evolutionarily anticipated commensal microbiota is associated through the "hygiene hypothesis" with defective developmental and response signals to the innate and adaptive immune systems. Evidence of the detrimental effects of such environments is reviewed as is evidence for remediation using controlled exposure to bacteria or their active components such as LPS or peptidoglycan ligands for TLR and NOD-like receptors. Occurrence of major environmentally associated changes in porcine immune response phenotype are described. The prophylactic effects of heat-killed Escherichia coli given intramuscularly or of oral Lactococcus lactis on experimental ovomucoid-induced allergy in piglets are described in the context of altered immune response bias favouring reduced type-2 phenotypes. The high frequency of clinical tolerance to developing allergic signs even in the face of classical sensitization indicates possible function in this pig model of regulatory effectors such as Treg cells.


The film festival "AUSNAHME|ZUSTAND" (State of Emergency)--do feature films and documentaries on mental health reduce stigma and influence help-seeking attitudes?
The study aims at evaluating the impact of the Germany-wide film festival "AUSNAHME|ZUSTAND" on social distance and help-seeking attitudes of the adolescent audience. The festival, on the subject of mental health, was staged for the second time, aiming to give a podium to the topic mental health and to inform and entertain an adolescent audience that has not been in close contact with the subject before. A pre-post test was carried out to look for the effect of feature films and documentaries on social distance of the audience towards people with mental illness and on the change in help-seeking attitudes. A total of 532 young people with a mean age of 15.6 were questioned during the film festival in Leipzig. As the results show, the effect on the viewers׳ social distance and their help-seeking attitudes strongly depend on the content of the feature films and documentaries. Two films improved attitudes – one both social distance and help-seeking, one only help-seeking. One film increased social distance, and two films did not affect either outcome. Age, gender, and knowing someone with mental health problems also turned out to be decisive factors influencing the development of social distance and help-seeking attitudes. Feature films or documentaries about mental illness can reduce social distance or influence help-seeking attitudes, but effects strongly depend on the particular film.


Methodological issues on "challenges and opportunities towards the road of universal health coverage (UHC) in Nepal: a systematic review".
Systematic reviews adhere to the principle that science is cumulative and attempt to identify all empirical evidence in accordance with pre-determined eligibility criteria to answer a specific research question. Therefore, in order to achieve reliable findings, these studies must use an explicit method, as they are increasingly used to guide political decision and the direction of future research. We would like to thank the authors Chhabi Lal Ranabhat et al., for the article "Challenges and opportunities towards the road of universal health coverage (UHC) in Nepal: a systematic review". Although the authors have stated that they reported th according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, some items have not been well reported. We critically appraised it using the PRISMA guidelines. Results of the study were significantly valuable, but some important points that hamper the utility of the study need to be considered by the audors. The purpose of this letter is to improve the quality of study and present methodological issues about the search strategy, quality assessment of included studies, and data analysis and synthesis.


Synthesis and biological activity of folic acid and methotrexate analogues containing L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid.
The stereospecific syntheses of L-threo-gamma-fluoromethotrexate (1t) and L-threo-gamma-fluorofolic acid (3t) are reported. Compounds 1t and 3t have no substrate activity with folylpoly-gamma-glutamate synthetase isolated from CCRF-CEM human leukemia cells, and compound 1t inhibits human dihydrofolate reductase at similar levels as methotrexate. The synthesis of DL-3,3-difluoroglutamic acid (6) and its incorporation into DL-beta,beta-difluorofolic acid (4) are also reported. Compound 4 acts as a better substrate for human CCRF-CEM folylpoly-gamma-glutamate synthetase than folic acid (V/K = ca. 7-fold greater). Thus, replacement of the glutamate moiety of methotrexate and folic acid with 4-fluoroglutamic acid and 3,3-difluoroglutamic acid results in folates and antifolates with altered polyglutamylation activity.


Total digoxin-like immunoreactive factor(s) in healthy population, uncomplicated term pregnancies and neonates.
Free digoxin-like immunoreactive factor(s) (DLIF) which may have a homeostatic role, as documented in different physiological conditions, but is generally undetectable in plasma from normal population. Total digoxin-like immunoreactive factor(s) (protein bound and free) can be estimated after plasma is heated. In this study, total digoxin-like immunoreactive factor(s) as measured in plasma in a well defined control population and compared to healthy term pregnant women and neonates, categories known to be associated with increased free digoxin-like immunoreactive factor(s) concentrations. The mean level of this factor(s) in the control group was 706 +/- 129 pg digoxin equivalent/ml (pg/ml) and was unaffected by age and sex. Significantly increased levels of total digoxin-like immunoreactive factor(s) were found in pregnant women and neonates (928 +/- 127 and 1242 +/- 367 pg/ml, respectively). We conclude that levels of total digoxin-like immunoreactive factor(s) are increased in term pregnancies and neonates, similarly to its free form. However total digoxin-like immunoreactive factor(s) is detected in the normal population as a plasma component, contrary to its free form, which is generally undetectable.


Injury of the Thoracolumbar Posterior Ligamentous Complex: A Bibliometric Literature Review.
To conduct a bibliometric review of literature on posterior ligamentous complex (PLC) injury in thoracolumbar trauma to guide future research. A keyword-based search was conducted from January 2000 to September 2021 using the Scopus database. Relevant publications were analyzed for year of publication, authorship, publishing journal, institution and country of origin, subject matter, and article type. Content analysis of clinical articles was also performed, analyzed for sample size, retrospective versus prospective study design, single-center versus multicenter study, and level of evidence. The search yielded 262 publications published in 61 journals by 537 authors from 162 institutions and 29 countries. Thomas Jefferson University, University of Calgary, and University of Toronto had the largest number of publications related to posterior ligamentous complex injury. Authors from the United States, Canada, and China were the most frequent contributors in terms of the number of publications. Spine was the most prolific and top-cited journal, and A.R. Vaccaro was the most prolific author. The most cited publication was "A New Classification of Thoracolumbar Injuries: The Importance of Injury Morphology, the Integrity of the Posterior Ligamentous Complex, and Neurologic Status" by Vaccaro et al. Most of the publications were case studies, with diagnostic accuracy being the most frequently discussed topic. The sample size for a large portion of the case series was <50. Most case series were retrospective studies conducted at a single center. Our review provides an extensive list of the most historically significant thoracolumbar PLC injury articles, acknowledging key contributions made to the advancement of this research area.


Species distribution and conservation assessment of the black-headed night monkey (Aotus nigriceps): a species of Least Concern that faces widespread anthropogenic threats.
Deforestation rates in the Brazilian Amazon have been steadily increasing since 2007. Recent government policy, the projected growth of agriculture, and the expansion of the cattle industry are expected to further pressure primates within the Amazon basin. In this study, we examined the anthropogenic impact on the widely distributed black-headed night monkey, Aotus nigriceps, whose distribution and population status have yet to be assessed. We (1) modeled potential species distribution in A. nigriceps, (2) estimated the impact of habitat loss on population trends, and (3) highlight landscape-based conservation actions that maximize the potential for their long-term sustainability. We found the black-headed night monkey to be restricted by several biotic and environmental factors including forest cover, isothermality, precipitation, temperature, and elevation. Over the last two decades, over 132,908 km2 of tree cover (18%) has been lost within their currently recognized range based on satellite imagery. Based on a balance training omission, predicted area, and threshold values (BPTP), suitable habitat was only 67% (1,069,948 km2) of their hypothesized range, a loss of 16.5% from 2000, with just nearly a third of suitable habitat currently within protected areas. Over the last two decades, an estimated minimum 1.6 million individuals have been lost due to loss of suitable habitat. Projected deforestation rates equate to an additional loss of 94,458 km2 of suitable habitat over the next decade. Although classified as a species of Least Concern, we suggest that A. nigriceps may likely be more at risk than previously described. The future impact of the continued expansion of monoculture crops, cattle ranching, and wildfires is still unknown. However, we outline several steps to ensure the long-term viability of this nocturnal primate and other sympatric species throughout the Amazon Basin.


Localization of the gene for plasma retinol binding protein to the distal half of mouse chromosome 19.
A DNA polymorphism for the mouse retinol binding protein has been identified using the enzyme BamHI and a rat partial cDNA probe. Analysis of the polymorphism in DNA from 64 inbred mouse strains demonstrated the presence of a single gene with two alleles, Rbp-4b and Rbp-4d. Comparison of the segregation patterns of these alleles in three sets of recombinant inbred strains with allele segregation patterns of previously characterized loci shows that the Rbp-4 locus is closely linked to the locus for phenobarbital-inducible cytochrome P450-2c (Cyp-2c) that has been shown by in situ hybridization to lie on chromosome 19, bands D1-D2. The Rbp-4 locus is just proximal to Cyp-2c at the distal end of chromosome 19.


[Therapeutic modulation of the cardiotoxic action of cardiac glycosides with electromagnetic emitters alternating with magnetic and electric fields].
A model of the cardiotoxic effect of cardiac glycosides (k-strophanthin) was used in the experiments with standard frog hearts isolated in situ. Effective parameters of the cardioprotective action of electromagnetic radiations, magnetic and electric fields are examined with the model.


Independent and combined effects of ultrasound and transglutaminase on the gel properties and in vitro digestion characteristics of bay scallop (Argopecten irradians) adductormuscle.
The effects of transglutaminase (TGase) addition (0.4-1.2 g/100g), ultrasound (120-720 W, 20 min), and their combination on the gel properties and in vitro digestion characteristics of bay scallop adductor muscle were studied. The gel strength of the gel sample with TGase content of 0.8 g/100g (TG-0.8) was 58.2% higher than that of the control sample (CON). The gel sample treated with ultrasound at 480 W (UT-480) had the highest gel strength. The strength of the gel prepared by combination of 0.8 g/100g TGase and 360 W ultrasound (UT-TG) was 82.3% higher than that of CON. The whiteness and water holding capacity of the gel increased regardless of the addition of TGase or ultrasound treatment. SDS-PAGE patterns showed that the myosin heavy chain of the treated samples became thinner, and the changes of actin and tropomyosin were not significant. The scanning electron microscopy results of gel samples prepared by ultrasound combined with TGase showed a denser structure, which was related to the lowest total sulfhydryl content and TCA-soluble peptide content. The results of dynamic rheology show that the UT-TG sample had the highest G' value, followed by TG-0.8. The in vitro digestion characteristics of the selected gel samples were also discussed. The degree of protein hydrolysis and the content of free amino acids in TG-0.8 samples were the lowest, which improved after ultrasound treatment. Overall, the combination of appropriate ultrasound treatment and TGase addition provides an effective means for improving gel properties and digestibility of scallop surimi product.


Evidence for the induction of cytochrome P-452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls.
We have examined the ability of a commercial mixture of polychlorinated biphenyls (Aroclor 1254) to induce hepatic cytochrome P-452-linked enzyme activities in rat and pigeon liver five days after its intraperitoneal injection. The results provide evidence that, at the doses used, Aroclor 1254 induces cytochrome P-452-linked enzyme activities in rats, but not in pigeons. This inductive effect was previously regarded as being specific for hypolipidemic drugs and phthalate ester plasticisers.


Tumor necrosis factor-alpha impairs endothelium-dependent relaxation of rat renal arteries, independent of tyrosine kinase.
We hypothesized that tumor necrosis factor-alpha (TNF-alpha) mimics endotoxin in attenuating endothelium-dependent vasodilation and smooth muscle constriction of rat renal arteries, and that tyrosine kinase is involved. Isolated rat renal arteries (n =6 per group), pretreated for 2 h by genistein (4',5,7-trihydroxyisoflavone, 10 microg/mL, a tyrosine kinase inhibitor) or vehicle, were exposed for 2 h to recombinant human (rh) TNF-alpha (100 ng/mL) or vehicle. rhTNF-alpha attenuated (P < 0.05) the constriction response to depolarizing 125 mM KCl (952.6+/-125.3 mg/mm vs. 1191.4+/-136.8 mg/mm in rhTNF-alpha-exposed and control segments, respectively), but did not affect the constriction response to norepinephrine (NE, 0.01-10 microM). Genistein did not affect the constriction response to KCl. The concentration-response relation to NE in genistein-pretreated control segments showed (P < 0.05) a rightward shift, while the maximum constriction was not affected. Genistein did not prevent a reduction (P < 0.05) by rhTNF-alpha in the maximum response to NE (721.7+/-42.4 mg/mm vs. 999.8+/-84.4 mg/mm in controls). The endothelium-dependent relaxation induced by (acetyl choline) ACh (0.001-1.0 microM) was attenuated (P < 0.05) by rhTNF-alpha (39.4%+/-6.7% and 77.4%+/-10.0% in rhTNF-alpha-exposed and control segments, respectively). The reduction (P < 0.05) in maximum ACh-induced relaxation after exposure to rhTNF-alpha was not affected by genistein (44.6%+/-3.4% and 70.8% x 2.2% in genistein-pretreated rhTNF-alpha-exposed and control segments, respectively). Hence, the attenuated endothelium-dependent relaxation and smooth muscle constriction of rat renal arteries following short-term rhTNF-alpha exposure, mimicking the effect of endotoxin, does not involve the activity of tyrosine kinase. The latter may be involved in pharmacomechanical coupling, by increasing Ca2+ sensitivity, but less in the electromechanical coupling of smooth muscle constriction.


The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis. There is an urgent need to better understand the molecular mechanisms that regulate PDAC cell aggressiveness. The transient receptor potential melastatin 7 (TRPM7) is a nonselective cationic channel that mainly conducts Ca2+ and Mg2+. TRPM7 is overexpressed in numerous malignancies including PDAC. In the present study, we used the PANC-1 and MIA PaCa-2 cell lines to specifically assess the role of TRPM7 in cell invasion and matrix metalloproteinase secretion. We show that TRPM7 regulates Mg2+ homeostasis and constitutive cation entry in both PDAC cell lines. Moreover, cell invasion is strongly reduced by TRPM7 silencing without affecting the cell viability. Conditioned media were further studied, by gel zymography, to detect matrix metalloproteinase (MMP) secretion in PDAC cells. Our results show that MMP-2, urokinase plasminogen activator (uPA), and heat-shock protein 90α (Hsp90α) secretions are significantly decreased in TRPM7-deficient PDAC cells. Moreover, TRPM7 expression in human PDAC lymph node metastasis is correlated to the channel expression in primary tumor. Taken together, our results show that TRPM7 is involved in PDAC cell invasion through regulation of Hsp90α/uPA/MMP-2 proteolytic axis, confirming that this channel could be a promising biomarker and possibly a target for PDAC metastasis therapy.


Identification of a novel Y branch structure as an intermediate in trypanosome mRNA processing: evidence for trans splicing.
We present evidence that addition of the 35 nucleotide spliced leader (SL) to the 5' end of T. brucei mRNAs occurs via trans RNA splicing. A 100 nucleotide fragment of the 135 base SL RNA (100-mer) is revealed by S1 nuclease analysis of total and poly(A)+ RNA. This 100-mer is not detected by Northern hybridization analysis, indicating that it does not exist free in the cell. The 5' end of the 100-mer maps precisely to the conserved splice junction sequence of the SL RNA. Purified debranching enzyme releases this 100-mer RNA as a free, 100 nucleotide species. This indicates that the 100-mer is covalently linked to poly(A)+ RNA by a 2'-5' phosphodiester bond, that the branched intermediate has a discontinuous intron or Y structure (rather than a lariat), which is expected of a trans-spliced mRNA, and that the SL RNA is indeed the donor of the SL sequence to trypanosome mRNAs.


FEMALE-BIASED SEX RATIOS: INDIVIDUAL OR GROUP SELECTION?
The evolution of biased sex ratios in a randomly structured population stems from individual selection acting through local parental control (LPC) of the sex ratio and hence of the mating success of the sons and/or daughters. As a general rule, the sex ratio is biased away from the sex whose fitness is most affected by changes in the local sex ratio. This is the sex whose fitness is subject to the most effective parental control. The bias acts to increase the fitness of the rarer, controlled sex and to increase parental productivity. In the specific case of the evolution of the female-biased Hamiltonian ratios, LPC can affect the mating success of sons but has no effect on the success of daughters. It is argued here and elsewhere (Nunney, unpubl.) that group selection can only promote the spread of a genotype through the maintenance of a positive association of individuals of that genotype. The importance of positive association is well established in the special case of kin selection. Given such a definition, group selection plays no part in the evolution of the Hamiltonian sex ratios, although it is possible to conceive of circumstances under which group selection could favor an even more extreme sex ratio bias. In general, such circumstances involve kin selection. It is argued that the examination of differences in group productivity is not a useful way of looking at the process of natural selection, since (i) by dividing up almost any evolving population into random groups, some groups (those with the highest frequency of the fittest individuals) will be more productive than others; and (ii) in the specific case of the evolution of the Hamiltonian ratios, it is possible to develop models either with or without a group structure and get the same result. Hamilton (1967) originally suggested that a female-biased sex ratio arose in his model because of the advantage of reducing local mate competition (specifically, reducing competition between brothers for mates). This possibility was eliminated by developing a model in which competition between the brothers was prevented regardless of the sex ratio. It was found that the optimum sex-ratio strategy was unaffected. On the other hand, the idea of local parental control has, in each case examined, been able to account for the predicted optimum strategy.


Demographic and clinical correlates of acute and convalescent SARS-CoV-2 infection among patients of a U.S. emergency department.
Emergency Departments (EDs) have served as critical surveillance sites for infectious diseases. We sought to determine the prevalence and temporal trends of acute (by PCR) and convalescent (by antibody [Ab]) SARS-CoV-2 infection during the earliest phase of the pandemic among patients in an urban ED in Baltimore City. We tested remnant blood samples from 3255 unique ED patients, collected between March 16th and May 31st 2020 for SARS-CoV-2 Ab. PCR for acute SARS-CoV-2 infection from nasopharyngeal swabs was obtained on any patients based on clinical suspicion. Hospital records were abstracted and factors associated with SARS-CoV-2 infection were assessed. Of 3255 ED patients, 8.2% (95%CI: 7.3%, 9.2%) individuals had evidence of SARS-CoV-2 infection; 155 PCR+, 78 Ab+, and 35 who were both PCR+ and Ab+. Prevalence of disease increased throughout the study period, ranging from 3.2% (95%CI: 1.8%, 5.2%) PCR+ and 0.6% (95%CI: 0.1%, 1.8%) Ab+ in March, to 6.2% (95%CI: 5.1%, 7.4%) PCR+ and 4.2% (95%CI: 3.3%, 5.3%) Ab+ in May. The highest SARS-CoV-2 prevalence was found in Hispanic individuals who made up 8.4% (95%CI: 7.4%, 9.4%) of individuals screened, but 35% (95%CI: 29%, 41%) of infections (PCR and/or Ab+). Demographic and clinical factors independently associated with acute infection included Hispanic ethnicity, loss of smell or taste, subjective fever, cough, muscle ache and fever. Factors independently associated with convalescent infection were Hispanic ethnicity and low oxygen saturation. The burden of COVID-19 in Baltimore City increased dramatically over the 11-week study period and was disproportionately higher among Hispanic individuals. ED-based surveillance methods are important for identifying both acute and convalescent SARS-CoV-2 infections and provides important information regarding demographic and clinical correlates of disease in the local community.


Endometrial stromal cell autophagy-dependent ferroptosis caused by iron overload in ovarian endometriosis is inhibited by the ATF4-xCT pathway.
Ferroptosis is an iron-dependent programmed cell death process characterised by the accumulation of lethal oxidative damage. Localised iron overload is a unique clinical phenomenon in ovarian endometriosis. However, the role and mechanism of ferroptosis in the course of ovarian endometriosis remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian endometriosis and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells. Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse endometriosis model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian endometriosis can activate autophagy-related ferroptosis in endometrial stromal cells, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the endometriosis environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian endometriosis.


[Immobilized streptokinase (streptodecase) in the treatment of traumatic intra-ocular hemorrhage].
Streptodecase was used in experiments and in clinical practice for treatment of intraocular traumatic hemorrhages. The enzyme, at a dose of 30,000-45,000 .un, did not exhibit any toxico-allergic effects on eye tissues and caused maximal lysis of the blood clot. 114 patients were treated with the enzymatic preparation and in 60% of the patients blood, liberated into vitreous body, was completely lysed.


1H NMR and fluorescence studies of the complexation of DMPG by wheat non-specific lipid transfer protein. Global fold of the complex.
Plant non-specific lipid transfer proteins (LTPs) are proteins which transfer lipids between membranes in vitro and are believed to be involved in the transport of cutin monomers to the cuticle layer in vivo or in the plant defence against phytopathogens. The complexation of DMPG, a diacyl phospholipid, by wheat ns-LTP, a protein extracted from wheat seeds, was followed by 1H NMR and fluorescence spectroscopy. The global fold of the protein was calculated using the DIANA software package from a list of 968 distance constraints. The internal cavity volume, a feature common to all known ns-LTP structures, was estimated to be 750 A3 using the 'CAVITE' program. This model of the complex was obtained by inserting a lipid molecule in the cavity and was energy minimized. The study showed that the protein fold described for the free form was only weakly affected by the insertion of the bulky lipid. Observation of some intermolecular NOEs between the protein and the lipid glycerol moiety revealed that the cavity entrance was located between residues His35 and Arg44. The resulting solution structure was compared to the crystal structure of the maize ns-LTP/palmitate complex.


Biomimetic injectable hydrogel microspheres with enhanced lubrication and controllable drug release for the treatment of osteoarthritis.
The occurrence of osteoarthritis (OA) is highly associated with the reduced lubrication property of the joint, where a progressive and irreversible damage of the articular cartilage and consecutive inflammatory response dominate the mechanism. In this study, bioinspired by the super-lubrication property of cartilage and catecholamine chemistry of mussel, we successfully developed injectable hydrogel microspheres with enhanced lubrication and controllable drug release for OA treatment. Particularly, the lubricating microspheres (GelMA@DMA-MPC) were fabricated by dip coating a self-adhesive polymer (DMA-MPC, synthesized by free radical copolymerization) on superficial surface of photo-crosslinked methacrylate gelatin hydrogel microspheres (GelMA, prepared via microfluidic technology), and encapsulated with an anti-inflammatory drug of diclofenac sodium (DS) to achieve the dual-functional performance. The tribological test and drug release test showed the enhanced lubrication and sustained drug release of the GelMA@DMA-MPC microspheres. In addition, the functionalized microspheres were intra-articularly injected into the rat knee joint with an OA model, and the biological tests including qRT-PCR, immunofluorescence staining assay, X-ray radiography and histological staining assay all revealed that the biocompatible microspheres provided significant therapeutic effect against the development of OA. In summary, the injectable hydrogel microspheres developed herein greatly improved lubrication and achieved sustained local drug release, therefore representing a facile and promising technique for the treatment of OA.


The antiarrhythmic actions of bisaramil and penticainide result from mixed cardiac ion channel blockade.
Decades of focus on selective ion channel blockade has been dismissed as an effective approach to antiarrhythmic drug development. In that context many older antiarrhythmic drugs lacking ion channel selectivity may serve as tools to explore mixed ion channel blockade producing antiarrhythmic activity. This study investigated the non-clinical electrophysiological and antiarrhythmic actions of bisaramil and penticainide using in vitro and in vivo methods. In isolated cardiac myocytes both drugs directly block sodium currents with IC50 values of 13μM (bisaramil) and 60μM (penticainide). Both drugs reduced heart rate but prolonged the P-R, QRS and Q-T intervals of the ECG (due to sodium and potassium channel blockade) in intact rats. They reduced cardiac conduction velocity in isolated rat hearts, increased the threshold currents for capture and fibrillation (indices of sodium channel blockade) and reduced the maximum following frequency as well as prolonged the effective refractory period (indices of potassium channel blockade) of electrically stimulated rat hearts. Both drugs reduced ventricular arrhythmias and eliminated mortality due to VF in ischemic rat hearts. The index of cardiac electrophysiological balance (iCEB) did not change significantly over the dose range evaluated; however, different drug effects resulted when changes in BP and HR were considered. While bisaramil is a more potent sodium channel blocker compared to penticainide, both produce a spectrum of activity against ventricular arrhythmias due to mixed cardiac ion channel blockade. Antiarrhythmic drugs exhibiting mixed ion channel blockade may serve as tools for development of safer mixed ion channel blocking antiarrhythmic drugs.


[Primary structure of otter (Lutra lutra L.) myoglobin. 1. Soluble peptides of a tryptic hydrolysate].
The amino acid sequence of 24 soluble tryptic peptides has been determined for the main chromatographic component of otter myoglobin. Fractionation, identification and peptide isolation have been made by fingerprints. The isolated peptides contain in total 111 amino acid residues.


Patterns of Articular Cartilage Thickness in Pediatric and Adolescent Knees: A Magnetic Resonance Imaging-Based Study.
To establish normative values for articular cartilage thickness in pediatric and adolescent knees using magnetic resonance imaging (MRI) and investigate for any associations with age and skeletal maturity. MRI scans were analyzed in patients 7 to 18 years old without osteochondral lesions, chondral wear/pathology, intra-articular fractures, or history of knee surgery. Measurements of articular cartilage thickness at the patella (medial facet, lateral facet, median ridge), femur (medial condyle, lateral condyle, lateral trochlea), and tibia (medial plateau, lateral plateau) were made on axial, coronal, and sagittal MRI. Descriptive statistics were used to calculate mean cartilage thickness by age and sex. Analysis of variance with repeated measures, analysis of covariance, independent samples t test, and linear regression were performed to determine differences in mean cartilage thickness by anatomic location, sex, physeal status, and age, respectively. A total of 240 knee MRI scans were included. Articular cartilage was thickest at the patella and did not vary with age or skeletal maturity. On the femur, articular cartilage was thickest at the lateral trochlea with mean cartilage thickness of 4.4 ± 1.4 mm in male patients and 3.6 ± 1.3 mm in female patients (P < .001). Patients with open distal femoral physes had significantly thicker cartilage at the medial femoral condyle, lateral femoral condyle, and lateral trochlea compared to patients with closing/closed physes (P < .001). Linear regression analysis revealed a significant inverse association between cartilage thickness at the femur and age. In pediatric and adolescent knees, articular cartilage is thickest at the patella, where it does not strongly correlate with age. In contrast, there is a strong inverse association between increasing age and articular cartilage thickness of the distal femoral condyles. The longitudinal reference data presented in this study can aid in pre-operative interpretation of knee cartilage under pathologic conditions in pediatric and adolescent patients.


Bone morphogenetic protein-9 maybe an important factor which improves insulin resistance in PCOS.
Polycystic ovary syndrome (PCOS) is closely related to insulin resistance (IR). Bone morphogenetic protein-9 (BMP-9) plays an important role in maintaining glucose homeostasis, but an association between BMP-9 and PCOS has not been reported. Here, we report the changes in BMP-9 and the influence of this protein on IR in PCOS. 57 PCOS patients were selected (among them 25 received interventional treatment with exenatide (EX) for 3 months, and 32 received no treatment). 22 normal control individuals and 30 IR patients were also recruited. We evaluated IR with the euglycaemic-hyperinsulinaemic clamp (EHC) technique. IR and the glucose metabolism rate were assessed by EHC and [3-3H]glucose tracer experiments. We determined the protein expression levels of BMP-9, p-AKT (protein kinase B) and androgen receptor in the ovaries and liver by Western blotting. We found that circulating BMP-9 levels were significantly decreased in PCOS with IR patients. Circulating BMP-9 levels and p-AKT levels were decreased in HFD and PCOS rats and increased after MF and EX treatment. The glucose infusion rate, glucose disappearance rate and suppression of hepatic glucose production decreased in the HFD and PCOS groups, the opposite results were found for HGP. AR protein expression levels increased in the HFD and PCOS groups and decreased in the MF and EX groups. Our study results suggest that BMP-9 is an independent factor that influences IR in PCOS patients. The decrease in BMP-9 levels in the liver and ovaries may be involved in IR through the PI3K/AKT signaling pathway in PCOS rats.


Non-muscle myosin IIA and IIB differentially regulate cell shape changes during zebrafish brain morphogenesis.
During brain morphogenesis, the neuroepithelium must fold in specific regions to delineate functional units, and give rise to conserved embryonic brain shape. Individual cell shape changes are the basis for the morphogenetic events that occur during whole tissue shaping. We used the zebrafish to study the molecular mechanisms that regulate the first fold in the vertebrate brain, the highly conserved midbrain-hindbrain boundary (MHB). Since the contractile state of the neuroepithelium is tightly regulated by non-muscle myosin II (NMII) activity, we tested the role of NMIIA and NMIIB in regulating cell shape changes that occur during MHB morphogenesis. Using morpholino knockdown, we show that NMIIA and NMIIB are both required for normal MHB tissue angle. Quantification of cell shapes revealed that NMIIA is required for the shortening of cells specifically at the MHB constriction (MHBC), while NMIIB is required for the proper width of cells throughout the MHB region. NMIIA and NMIIB knockdown also correlated with abnormal distribution of actin within the cells of the MHBC. Thus, NMIIA and NMIIB perform distinct functions in regulating cell shape during MHB morphogenesis.


Surgivisio® and O-arm®O2 cone beam CT mobile systems for guidance of lumbar spine surgery: Comparison of patient radiation dose.
To compare patient radiation doses in cone beam computed tomography (CBCT) of two mobile systems used for navigation-assisted mini-invasive orthopedic surgery: O-arm®O2 and Surgivisio®. The study focused on imaging of the spine. Thermoluminescent dosimeters were used to measure organs and effective doses (ED) during CBCT. An ionization-chamber and a solid-state sensor were used to measure the incident air-kerma (Ki) at the center of the CBCT field-of-view and Ki during 2D-imaging, respectively. The PCXMC software was used to calculate patient ED in 2D and CBCT configurations. The image quality in CBCT was evaluated with the CATPHAN phantom. The experimental ED estimate for the low-dose 3D-modes was 2.41 and 0.35 mSv with O-arm®O2 (Low Dose 3D-small-abdomen) and Surgivisio® (3DSU-91 images), respectively. PCXMC results were consistent: 1.54 and 0.30 mSv. Organ doses were 5 to 12 times lower with Surgivisio®. Ki at patient skin were comparable on lateral 2D-imaging (0.5 mGy), but lower with O-arm®O2 on anteroposterior (0.3 versus 0.9 mGy). Both systems show poor low contrast resolution and similar high contrast spatial resolution (7 line-pairs/cm). This study is the first to evaluate patient ED and organ doses with Surgivisio®. A significant difference in organs doses was observed between the CBCT systems. The study demonstrates that Surgivisio® used on spine delivers approximately five to six times less patient ED, compared to O-arm®O2, in low dose 3D-modes. Doses in 2D-mode preceding CBCT were higher with Surgivisio®, but negligible compared to CBCT doses under the experimental conditions tested.


3-Phosphoglycerate dehydrogenase: a potential target for cancer treatment.
Metabolic changes have been recognized as an important hallmark of cancer cells. Cancer cells can promote their own growth and proliferation through metabolic reprogramming. Particularly, serine metabolism has frequently been reported to be dysregulated in tumor cells. 3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step in the serine biosynthesis pathway and acts as a rate-limiting enzyme involved in metabolic reprogramming. PHGDH upregulation has been observed in many tumor types, and inhibition of PHGDH expression has been reported to inhibit the proliferation of PHGDH-overexpressing tumor cells, indicating that it may be utilized as a target for cancer treatment. Recently identified inhibitors targeting PHGDH have already shown effectiveness. A further in-depth analysis and concomitant development of PHGDH inhibitors will be of great value for the treatment of cancer. In this review we describe in detail the role of PHGDH in various cancers and inhibitors that have recently been identified to highlight progression in cancer treatment. We also discuss the development of new drugs and treatment modalities based on PHGDH targets. Overexpression of PHGDH has been observed in melanoma, breast cancer, nasopharyngeal carcinoma, parathyroid adenoma, glioma, cervical cancer and others. PHGDH may serve as a molecular biomarker for the diagnosis, prognosis and treatment of these cancers. The design and development of novel PHGDH inhibitors may have broad implications for cancer treatment. Therapeutic strategies of PHGDH inhibitors in combination with traditional chemotherapeutic drugs may provide new perspectives for precision medicine and effective personalized treatment for cancer patients.


A method to calculate the NMR spectra of paramagnetic species using thermalized electronic relaxation.
For paramagnetic species, it has been long understood that the hyperfine interaction between the unpaired electrons and the nucleus results in a nuclear magnetic resonance (NMR) peak that is shifted by a paramagnetic shift, rather than split by the coupling, due to an averaging of the electronic magnetic moment caused by electronic relaxation that is fast in comparison to the hyperfine coupling constant. However, although this feature of paramagnetic NMR has formed the basis of all theories of the paramagnetic shift, the precise theory and mechanism of the electronic relaxation required to predict this result has never been discussed, nor has the assertion been tested. In this paper, we show that the standard semi-classical Redfield theory of relaxation fails to predict a paramagnetic shift, as does any attempt to correct for the semi-classical theory using modifications such as the inhomogeneous master equation or Levitt-di Bari thermalization. In fact, only the recently-introduced Lindbladian theory of relaxation in magnetic resonance [J.Magn.Reson., 310, 106645 (2019)] is able to correctly predict the paramagnetic shift tensor and relaxation-induced linewidth in pNMR. Furthermore, this new formalism is able to predict the NMR spectra of paramagnetic species outside the high-temperature and weak-order limits, and is therefore also applicable to dynamic nuclear polarization. The formalism is tested by simulations of five case studies, which include Fermi-contact and spin-dipolar hyperfine couplings, g-anisotropy, zero-field splitting, high and low temperatures, and fast and slow electronic relaxation.


Cost-effectiveness of cataract surgery.
To review the changes in the cost-effectiveness of cataract surgery in the last few decades. Cataract surgery is the commonly performed procedure and it has evolved through various techniques, namely extracapsular cataract extraction, phacoemulsification and small or microincision cataract surgery. In this article we have reviewed the healthcare variant analysis, mainly the cost-effectiveness and cost utility over the past few years. Cost-effectiveness implies the economic analysis of relative costs and practical outcomes after cataract surgery. Cost utility is typically in terms of cost per quality-adjusted life-year gained. Cost-utility values for cataract surgery for first eye varied from US$245 to US$22000/QALY in Western countries and from US$9 to US$1600 in developing countries. There are two methods that have been used to calculate the cost utility namely the costs that are discounted at 3% for 12 years and discounted at 3% for 5 years.


Glycogen synthase can use glucose as an acceptor.
Glycogen synthase purified to homogeneity from rabbit skeletal muscle is essentially free of carbohydrate and shows no activity in the absence of added acceptor. It can use glucose as a substrate converting it to a glucose disaccharide in the presence of UDP-glucose as cosubstrate. The reaction is dependent on time, and on UDP-glucose, glucose, and enzyme concentrations. The product of the single step reaction co-chromatographs in two solvent systems with maltose. The glucose disaccharide produced in the reaction with UDP-[14-C]glucose and nonradioactive glucose as well as with nonradioactive UDP-glucoes and [14-C]glucose is labeled asymmetrically. The linkage is characterized as alpha-1,4 and therefore the disaccharide is identified as maltose.


Lactulose breath test results in patients with persistent abdominal symptoms following Giardia lamblia infection.
Bacterial overgrowth has been implicated in the pathogenesis of irritable bowel syndrome (IBS). The objective of this study was to investigate whether post-infectious IBS following Giardia lamblia infection is related to intestinal bacterial overgrowth, as diagnosed by the lactulose breath test (LBT). Seventy-seven patients with persistent gastrointestinal complaints related to a recent outbreak of G. lamblia infection were included in the study. Despite one or several courses of treatment with metronidazole during the previous months, 23 of the patients were still stool positive for G. lamblia, whereas the remaining 54 patients had cleared the infection. All patients and 42 healthy volunteers underwent a LBT with 10 g lactulose, and their customary and post-LBT abdominal symptoms were scored. Ninety-five percent of the patients had IBS. Lactulose-induced hydrogen breath excretion was not significantly different in patients and controls. Customary and post-LBT symptoms were abnormally high in the patients, irrespective of both G. lamblia infection status and LBT results. Furthermore, lactulose challenge replicated the patients' customary complaints in 70% of the patients. Gastrointestinal complaints in patients with persistent or cleared giardiasis were unrelated to hydrogen breath excretion after lactulose challenge. Post-giardiasis IBS cannot be ascribed to intestinal bacterial overgrowth, as diagnosed by LBT.


Somatic symptom progression in idiopathic Parkinson's disease.
The substantia nigra (SN) pars compacta is arranged somatotopically. Symptoms of idiopathic Parkinson's disease (IPD) are caused by a lesion in this nucleus, which spreads in a stereotyped spatio-temporal pattern during the course of the disease. We investigated the order of somatic symptom progression in a group of 30 patients with IPD to determine if progression of symptoms was consistent with ordered spread of pathology through the SN pars compacta. Thirty outpatients with IPD were interviewed retrospectively about the progression of their symptoms using a semi-structured questionnaire. All the patients experienced somatic symptom progression in one of two distinct patterns, which was dependent on the location of the initial symptom. The typical pattern of progression for patients with lower limb onset was: (i) foot, (ii) leg, (iii) arm, (iv) hand, (v) face, (vi) voice and (vii) swallowing. For patients whose first symptom was in the upper limb progression to the face and lower limbs occurred roughly simultaneously or sequentially, with the typical pattern of progression: (i) hand/arm, (ii) foot/leg and face, (iii) speech and (iv) swallowing. These patterns of disease progression may reflect two distinct patterns of neuropathology within the SN pars compacta. Although the sample size was relatively small, this is the first time this phenomenon has been described in a full-length article.


Electrostatic modifications of the human leukocyte antigen-DR P9 peptide-binding pocket and susceptibility to primary sclerosing cholangitis.
The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 × 10(-32) and P = 1.8 × 10(-22) in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket. The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DRβ chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented.


Epitope mapping of a monoclonal antibody specific to bovine dry milk: involvement of residues 66-76 of strand D in thermal denatured beta-lactoglobulin.
beta-Lactoglobulin (beta-LG) is a bovine milk protein sensitive to thermal denaturation. Previously, we demonstrated that such structural change can be detected by a monoclonal antibody (mAb) specific to denatured beta-LG. In the present study, we show a dramatic increase in beta-LG immunoreactivity when heating raw milk between 70 and 80 degrees C. To map out the specific epitope of beta-LG recognized by this mAb, we used a combined strategy including tryptic and CNBr fragments, chemical modifications (acetylation and carboxymethylation), peptide array containing in situ synthesized peptides, and a synthetic soluble peptide for immunoassays. The antigenic determinant we defined was exactly located within the D strand (residues 66-76) of beta-LG. Circular dichroic spectral analysis shows that carboxymethylation on beta-LG not only resulted in a substantial loss of beta-configuration but also exerted a 10 times increase in immunoreactivity as compared with heated beta-LG. The result suggests that a further disordered structure occurred in beta-LG and thus rendered the mAb recognition. Mutations on each charged residue (three Lys and one Glu) revealed that Lys-69 and Glu-74 were extremely essential in maintaining the antigenic structure. We also show an inverse relationship between the immunoreactivity in heated beta-LG and its binding to retinol or palmitic acid. Most interestingly, pH 9-10, which neutralizes the Lys groups of beta-LG, not only reduced its immunoreactivity but also its binding to palmitic acid implicating a role of Lys-69. Taken together, we concluded that strand D of beta-LG participated in the thermal denaturation between 70 and 80 degrees C and the binding to retinol and palmitic acid. The antigenic and biochemical roles of mAb specific to D strand are discussed in detail.


Time-resolved diode dosimetry calibration through Monte Carlo modeling for in vivo passive scattered proton therapy range verification.
Our group previously introduced an in vivo proton range verification methodology in which a silicon diode array system is used to correlate the dose rate profile per range modulation wheel cycle of the detector signal to the water-equivalent path length (WEPL) for passively scattered proton beam delivery. The implementation of this system requires a set of calibration data to establish a beam-specific response to WEPL fit for the selected 'scout' beam (a 1 cm overshoot of the predicted detector depth with a dose of 4 cGy) in water-equivalent plastic. This necessitates a separate set of measurements for every 'scout' beam that may be appropriate to the clinical case. The current study demonstrates the use of Monte Carlo simulations for calibration of the time-resolved diode dosimetry technique. Measurements for three 'scout' beams were compared against simulated detector response with Monte Carlo methods using the Tool for Particle Simulation (TOPAS). The 'scout' beams were then applied in the simulation environment to simulated water-equivalent plastic, a CT of water-equivalent plastic, and a patient CT data set to assess uncertainty. Simulated detector response in water-equivalent plastic was validated against measurements for 'scout' spread out Bragg peaks of range 10 cm, 15 cm, and 21 cm (168 MeV, 177 MeV, and 210 MeV) to within 3.4 mm for all beams, and to within 1 mm in the region where the detector is expected to lie. Feasibility has been shown for performing the calibration of the detector response for three 'scout' beams through simulation for the time-resolved diode dosimetry technique in passive scattered proton delivery.


Objective Evaluation of Olfactory and Taste Dysfunction Among COVID-19 Patients: A Cross Sectional Study from Tribal India.
There is a varying prevalence of olfactory and taste dysfunction (OTD) in COVID-19 patients, with a higher prevalence reported in the European population as compared to the Asian population. Psychophysical tests are crucial to determine the exact frequency, extent and clinical characteristics of these OTDs. The present study objectively evaluated the OTD for patients treated in the Dedicated COVID-19 Hospital (DCH) in Shahdol. This prospective cross-sectional study was conducted after IEC approval in DCH Shahdol for a period of four months among RT-PCR positive patients, and they were evaluated using validated chemosensitive psychophysical test during ENT consultation to identify OTD. The sample size was calculated as 92 considering prevalence (p) of OTD as 41.3% by applying formula: n = (Z1-a/2)2 × p (1-p) / d 2. The information pertaining to the subjects was kept anonymous and confidential. During data analysis, an association was significant for p value < 0.05. It was observed that 45.5% of subjects reported either loss of taste or smell. During objective evaluation, olfactory and taste dysfunction was observed among 42.4% of subjects (95/224). The Chi-square analysis reflected statistically significant difference (p < 0.05) between subjects with OTD and without OTD for the variables such as days from onset of symptoms to admission, and symptoms (fever, sore throat and shortness of breath). Taste and smell are among the important senses and in India they are mostly subjectively evaluated for COVID-19 induced OTD which results in underreporting of these symptoms. So, a gold standard objective evaluation should be taken into consideration to evaluate OTD.


Picture recognition of food by sloth bears (Melursus ursinus).
Pictures are often used in cognitive research to represent objects and many species have demonstrated the ability to recognize two-dimensional pictures as representations of their three-dimensional counterparts. However, for ursids picture recognition has been reported in only one study of a single 11-year-old female American black bear (Johnson-Ulrich et al. 2016). We tested the picture recognition abilities of an additional species, the sloth bear. After a food preference test by which the bears' food options were ranked and categorized as high-, mid-, and low-preference items, we tested a sub-adult male and an adult female sloth bear by presenting two pictures of food in each testing trial-a high-preference food and a low-preference food. Both bears met the criterion by choosing the pictures of their preferred foods in at least 80% of the trials in three consecutive testing sessions. We then presented never-before-used pictures of high-preference versus low-preference food items and they again met our criterion.


The effect of homologous local anesthetics of the 4-alkoxy- and 4-alkylamino-benzoic acid-diethylamino-esthylester- hydrochloride series on the glucose transport in human erythrocytes.
The homologous compounds of the 4-alkoxy- and 4-alkylamino-series inhibit the exchange transport of glucose in human erythrocytes; they show a competitive inhibition with one or two inhibitor molecules which become bound to a singular site of the transport system for glucose. The importance of length of hydrocarbon chain of the localanesthetics for the mode of their action is discussed.


Model-based approach to the design of pharmaceutical roller-compaction processes.
This work presents a new model based approach to process design and scale-up within the same equipment of a roller compaction process. The prediction of the operating space is not performed fully in-silico, but uses low-throughput experiments as input. This low-throughput data is utilized in an iterative calibration routine to describe the behavior of the powder in the roller compactor and improves the predictive quality of the mechanistic models at low and high-throughput. The model has been validated with an experimental design of experiments of two ibuprofen formulations. The predicted sweet spots in the operating space are in good agreement with the experimental results.


Tumour-to-tumour metastasis. A report of two unusual autopsy cases.
Two further two cases of the previously undescribed combination of tumour-to-tumour metastasis - gastric carcinoma metastatic to meningioma and pancreatic carcinoma to thymoma, are presented. The clinico-pathological characteristics of these cases are briefly discussed with a review of the literature.


Comparative central nervous system effects and pharmacokinetics of neu-metoclopramide and metoclopramide in healthy volunteers.
Metoclopramide, a drug used for the relief of nausea and emesis, is currently under development as a radio- and chemosensitizing agent. Its usefulness in high doses, however, is limited by its central nervous system side effects. Neu-metoclopramide (Neu-Sensamide), a novel, concentrated, phosphate-buffered, pH-adjusted (pH = 6.5-7.0) formulation of metoclopramide, has been shown to have an improved side-effect profile in animal studies. The present double-blind, four-way crossover study compared the central nervous system effects and pharmacokinetics of neu-metoclopramide (intravenously and intramuscularly at 1.8 mg/kg) with intravenous metoclopramide and intramuscular placebo in 19 healthy male volunteers. Eight participants withdrew from the study, one because of noncompliance and seven because of adverse events. A total of 28 central nervous system events were observed with intravenous metoclopramide administration, whereas 16, 15, and 6 such events were attributed to intravenous neu-metoclopramide, intramuscular neu-metoclopramide, and placebo, respectively. Extra-pyramidal effects occurred on 10 occasions: 7 after intravenous metoclopramide, 2 after intravenous neu-metoclopramide, and 1 after intramuscular neu-metoclopramide. No significant differences were observed in the pharmacokinetic profiles of the three formulations of metoclopramide. It may be speculated, therefore, that the molecular conformational changes inherent to neu-metoclopramide result in a reduced side-effect profile compared with conventional metoclopramide formulations.


A histomorphometric study on effects of single and concurrent intermittent administration of human PTH (1-34) and bisphosphonate cimadronate on tibial metaphysis in ovariectomized rats.
This study compared the single administration of hPTH(1-34), bisphosphonate cimadronate (YM-175), and concurrent therapy of these two for restoration of lost bone mass in ovariectomized (OVX) rats. Animals were untreated for 4 weeks after surgery, and then injected s.c. with vehicle (OVX+V), hPTH(1-34) (30 micrograms/kg) (OVX+P), YM-175 (5 micrograms/kg) (OVX+Y), or a combination of these two (OVX+P+Y), 3 days a week, for 8 weeks, and sacrificed. Their proximal tibia were processed undecalcified for quantitative bone histomorphometry. Although OVX+Y showed a reduction of bone turnover compared to OVX+V, it failed to restore lost bone mass in OVX rats. In contrast, OVX+P exhibited a stimulation of bone formation and restored cancellous osteopenia due to OVX. OVX+P+Y also resulted a recovery of osteopenia, however, stimulation of bone formation by PTH was suppressed by YM-175.


[Magnesium in the cerebral califications of the Sturge-Weber syndrome: a study using a castaing electron probe].
The so-called (calcifications) present in the brain in Sturge-Weber disease were examined with the electron probed of Castaing, in three cases of the disease and found to contain calcium, phosphorus and magnesium. This is the first report concerning the presence of magnesium in deposits in the brain.


[The lymphocyte transformation test in squamous epithelial carcinomas of the orofacial region].
In the last years cell mediated immune reactions against the antigens of human carcinomas have obtained an increasing importance. With the lymphocyte transformation tests was found on the estimate of the PHA (phythemagglutinin)-stimulation a significant difference of the T-cell stimulation of patients with squamous cell carcinoma of the orofacial region opposite to a comparison group of healthy patients.


Uncalcified cartilage resorption in human fetal cartilage canals.
In the human fetus, epiphyses appear as a solid avascular cartilaginous mass until the eleventh week of development. Around the third fetal month of development, vascular canals coming from the perichondrium are recognized in the mineralized epiphyseal cartilage. Whether cartilage canals develop by passive inclusion or active chondrolysis is still a matter of controversy. We studied the relationships between the intracanalar cells and the surrounding matrix on human fetal epiphyses embedded in glycol methacrylate. At the blind end of canals both stellate fibroblast-like cells and vacuolated macrophages are observed. These cellular foci show all characteristics of active chondrolysis (loss of metachromasia, lacunae containing cells intimately associated with matrix, and presence of granular debris). Similar resorptive foci have been observed in the pannus of rheumatoid joints and in the embryonic chick growth plate composed of uncalcified cartilage. A cellular cooperation (fibroblast/macrophage) is necessary for uncalcified cartilage breakdown. In the human fetus, monocytes/macrophages have been recognized in the peripheral blood as early as the twelfth week of gestation. Our observations support the view that chondrolysis due to both fibroblasts (of mesenchymal origin) and macrophages is the basic mechanism for cartilage canal development.


Binding and uptake of 125iodine-labelled, oxidized low density lipoprotein by macrophages: comparison of the effects of alpha-tocopherol, probucol, pyridoxal-5'-phosphate and magnesium-pyridoxal-5'-phosphate-glutamate.
Specific and unspecific binding and uptake (internalization) by macrophages of 125iodine-labelled, copper-oxidized human low density lipoprotein is differently influenced by the anti-oxidants alpha-tocopherol (alpha-Toc), probucol (Prob), pyridoxal-5'-phosphate (PP) and the magnesium-pyridoxal-5'-phosphate glutamate complex (MPPG). Binding as well as internalization, mediated by the so-called "scavenger receptor" is lower in the presence of MPPG whereas both specific binding and internalization are enhanced. The comparison of the effects in vitro allows a rating of the potentially anti-atherogenic and thus protective effects of the tested substances as follows: MPPG > PP > alpha-Toc > Prob.


Regulation of intestinal blood flow with increased intraluminal pressure.
To better characterize the mechanisms which regulate intestinal blood flow (IBF), we studied the effects of gradual and rapid increases in intraluminal pressure (LP) in anesthetized canines. Polarographic measurements of hydrogen washout allowed repeated assessment of IBF (ml/min X g) in control (CL) and distended (DL) autoperfused small intestinal loops. In group I (n = 7) graded increases in LP (mm Hg) were produced by saline inflation. In group II (n = 4), IBF was measured before and after intraarterial aminophylline (adenosine blockade); LP was then rapidly raised to 24 mm Hg. IBF was unchanged by time (CL 0.64 +/- 0.24) or gradual distension (DL 0.65 +/- 0.28 at mean maximal LP = 26). Aminophylline did not change IBF at LP = 0. Rapid distension after adenosine blockade was accompanied by immediate increases in IBF (0.96 +/- 0.41, P less than 0.05) and decreased resistance (50 +/- 25% control). IBF is maintained despite gradual increases in luminal pressure. Blockade of adenosine, an intestinal vasodilator, does not inhibit this response; hyperemia associated with rapid distension is not impaired. We conclude that autoregulation of IBF during distension is not accomplished by an adenosine mediated metabolic mechanism.


Novel Therapeutic Strategies in Asthma-Chronic Obstructive Pulmonary Disease Overlap.
The term asthma-chronic obstructive pulmonary disease (COPD) overlap applies where there are features of asthma and COPD. Agents targeting eosinophilic inflammation have transformed asthma management and indicate promise across airways disease, whereas agents targeting neutrophilic inflammation have demonstrated limited efficacy. Successful treatment of airway dysbiosis, mucous hypersecretion, or airway remodeling may occur with better understanding of the impact of current agents on specific clinical end points or through novel approaches. Biomarkers indicating specific disease mechanisms are key to select appropriate populations for clinical trials and identify subgroups likely to benefit from targeted treatments.


Double-blind, crossover comparison of olopatadine and cetirizine versus placebo: suppressive effects on skin response to histamine iontophoresis.
Olopathadine, a newly developed histamine H1-receptor antagonist, was compared with cetirizine in its suppressive effects on histamine-induced wheal and flare reaction using an iontophoresis technique in a double-blind, crossover, placebo-controlled fashion. As a result, olopathadine was found to have effects comparable to cetirizine. This finding may predict the efficacy of this new H1-antagonist in treating pruritic skin diseases.


Deep learning-based classification and spatial prognosis risk score on whole-slide images of lung adenocarcinoma.
Classification of histological patterns in lung adenocarcinoma (LUAD) is critical for clinical decision-making, especially in the early stage. However, the inter- and intraobserver subjectivity of pathologists make the quantification of histological patterns varied and inconsistent. Moreover, the spatial information of histological patterns is not evident to the naked eye of pathologists. We establish the LUAD-subtype deep learning model (LSDLM) with optimal ResNet34 followed by a four-layer Neural Network classifier, based on 40 000 well-annotated path-level tiles. The LSDLM shows robust performance for the identification of histopathological subtypes on the whole-slide level, with an area under the curve (AUC) value of 0.93, 0.96 and 0.85 across one internal and two external validation data sets. The LSDLM is capable of accurately distinguishing different LUAD subtypes through confusion matrices, albeit with a bias for high-risk subtypes. It possesses mixed histology pattern recognition on a par with senior pathologists. Combining the LSDLM-based risk score with the spatial K score (K-RS) shows great capacity for stratifying patients. Furthermore, we found the corresponding gene-level signature (AI-SRSS) to be an independent risk factor correlated with prognosis. Leveraging state-of-the-art deep learning models, the LSDLM shows capacity to assist pathologists in classifying histological patterns and prognosis stratification of LUAD patients.


Molecular epidemiology of human rotavirus infections.
Recognition of rotaviruses as a major aetiological agent of acute gastroenteritis in infants and young children has prompted the investigation of their epidemiology by molecular techniques. Genome analysis by electrophoretic separation of the RNA segments has been widely used to distinguish virus isolates and to monitor patterns of virus transmission. Examination of virus isolates from different epidemics has clearly demonstrated the existance of extensive genomic variation in viruses circulating in large communities; with the co-circulation of a number of viruses of differing electrophoretype. Preliminary studies using the more advanced techniques of oligonucleotide mapping and hybridization analysis have suggested that variation among the viruses may occur by processes involving both "drift" and "shift". Because of their ease and specificity the new hybridization analysis techniques should greatly facilitate both the rapid diagnosis of rotavirus infections, and the solution of many epidemiological and evolutionary questions. Continued and expanded use of molecular techniques for the study of the epidemiology of rotavirus infections will be required to manage future outbreaks and to effect long term control measures.


Docosahexaenoic Acid therapy of experimental ischemic stroke.
We examined the neuroprotective efficacy of docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, in acute ischemic stroke; studied the therapeutic window; and investigated whether DHA administration after an ischemic stroke is able to salvage the penumbra. In each series described below, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo). In series 1, DHA or saline was administered i.v. at 3, 4, 5, or 6 h after stroke. In series 2, MRI was conducted on days 1, 3 and 7. In series 3, DHA or saline was administered at 3 h, and lipidomic analysis was conducted on day 3. Treatment with DHA significantly improved behavior and reduced total infarct volume by a mean of 40% when administered at 3 h, by 66% at 4 h, and by 59% at 5 h. Total lesion volumes computed from T2-weighted images were reduced in the DHA group at all time points. Lipidomic analysis showed that DHA treatment potentiates neuroprotectin D1 (NPD1) synthesis in the penumbra 3 days after MCAo. DHA administration provides neurobehavioral recovery, reduces brain infarction and edema, and activates NPD1 synthesis in the penumbra when administered up to 5 h after focal cerebral ischemia in rats.


Kinetics of atropine inhibition of pentagastrin-stimulated H+, electrolyte, and pepsin secretion in the dog.
The effects of atropine on pentagastrin-stimulated gastric secretion of water, H, Cl, Na, K, and pepsin were determined by kinetic analysis of dose-response studies in 5 dogs with esophagostomy and gastric cannula. First a dose-response study was done using 7 doses of pentagastrin (1-6 mug/kg hr), each dose given by I.V. infusion for 4 hr at a separate time. The same series of doses was used with atropine sulfate 10 mug/kg hr as background. Atropine inhibited pentagastrin-stimulated secretion competively with a dose ratio change of 20. In a third set of studies pentagastrin was infused alone for 4 hrs in the dose of 1.5 mug/kg hr and then with each of 7 doses of atropine (0.625-40 mug/kg hr), each dose used separately. Atropine competitively inhibited water, H, Cl, and K secretion, with Ki (dose of atropine giving 50% inhibition) of 1.0 mug/kg hr. Pepsin secretion was much more strongly inhibited than acid secretion by atropine with Ki 0.27 mug/kg hr and the inhibition was uncompetitive. Calculated maximal inhibition of H+ secretion by atropine was 89% and of pepsin 95%. Furthermore the shape of the response to pentagastrin was altered by atropine so that the peak response was delayed to the third and fourth hour of pentagastrin infusion.


Epibulbar choristoma and microphthalmia: a report of two cases.
The simultaneous ipsilateral presence of an epibulbar choristoma and microphthalmia has rarely been reported. We present two such cases, one of which is associated with bone formation, and we consider a possible pathogenetic mechanism.


Transcranial color-coded sonography of vertebral artery for diagnosis of right-to-left shunts.
It is unknown whether contrast transcranial color-coded sonography of vertebral artery monitoring via the foramen magnum window (cTCCS-VA) is useful to detect right-to-left shunt (RLS). We investigated whether cTCCS-VA can be proposed as an alternative to middle cerebral artery monitoring via the temporal bone window (cTCCS-MCA) for RLS detection, as compared with contrast transesophageal echocardiography (cTEE). We evaluated 112 patients with ischemic stroke or transient ischemic attack. We compared the sufficiency of both acoustic windows in each age tertile. Then, we analyzed the accuracy of cTCCS in diagnosing an RLS for a patent foramen ovale (PFO) detected by cTEE. In the higher-age tertile, the foramen magnum window was significantly more sufficient than the temporal bone window (100% vs. 71%, p<0.001). In 94 patients having both windows, diagnosis of an RLS using cTCCS-MCA revealed a specificity of 42%, and a sensitivity of 84%. Diagnosis of an RLS using cTCCS-VA revealed a specificity of 40%, and a sensitivity of 91%. Analysis of the subgroup with large PFOs revealed a specificity of 71% using both cTCCS-MCA and cTCCS-VA. cTCCS-VA should play an important role in detecting an RLS, especially in elderly stroke patients having large PFOs.


Comparison of clinical profiles and associated factors for acute myocardial infarction among young and very young patients with coronary artery disease.
This study aimed to compare the profiles of young and very young patients with coronary artery disease (CAD) and explore the factors associated with acute myocardial infarction (AMI) based on age. Young CAD patients aged between 18 and 44 years diagnosed by angiography were enrolled retrospectively. They were divided into two groups according to age: young CAD was defined as patients aged between 36 and 44 years, and very young CAD was defined as patients aged between 18 and 35 years. Demographic and clinical characteristics of the patients were collected. In total, 9286 patients were included in the final database. Most were assigned to the young CAD group (86.5%), and 1250 (13.5%) had very young CAD. Most demographic and clinical characteristics of the young and very young patients with CAD differed significantly. The proportion of patients with CAD in the total population increased with age, whereas the incidence of AMI showed a decreasing trend. A previous percutaneous coronary intervention (PCI) was negatively associated with AMI. Dyslipidemia, current smoking, and hyperhomocysteinemia were positively associated with AMI in the overall and young population with CAD. The clinical profiles and factors associated with AMI in CAD patients of different ages were significantly different. Lifestyle-related factors were significantly associated with AMI in young patients with CAD.


Association of sleep patterns and cardiovascular disease risk is modified by glucose tolerance status.
To investigate whether the association between sleep patterns and cardiovascular disease (CVD) risk differs according to glucose tolerance status. This prospective study included 358,805 participants initially free of CVD from the UK Biobank. We created a sleep score based on five sleep factors (sleep duration, chronotype, insomnia, snoring, and daytime sleepiness) with one point for each unhealthy factor. Cox proportional hazards models were used to examine the association between sleep and incident CVD, including coronary heart disease (CHD) and stroke, according to normal glucose tolerance (NGT), prediabetes, and diabetes. During a median follow-up of 12.4 years, 29,663 incident CVD events were documented. There was a significant interaction between sleep score and glucose tolerance status on CVD (P for interaction = 0.002). Each 1 point increment in sleep score was associated with a 7% (95% confidence interval 6%-9%), 11% (8%-14%), and 13% (9%-17%) higher risk of CVD among participants with NGT, prediabetes, and diabetes, respectively. Similar interaction patterns were observed for CHD and stroke. Among the individual sleep factors, sleep duration and insomnia significantly interacted with glucose tolerance status on CVD outcomes (all P for interaction <0.05). All five unhealthy sleep factors accounted for 14.2% (8.7%-19.8%), 19.5% (7.4%-31.0%), and 25.1% (9.7%-39.3%) of incident CVD cases among participants with NGT, prediabetes, and diabetes, respectively. The CVD risk associated with a poor sleep pattern was exacerbated across glucose intolerance status. Our findings emphasise the importance of integrating sleep management into a lifestyle modification programme, particularly in people with prediabetes or diabetes.


Regression and Random Forest Machine Learning Have Limited Performance in Predicting Bowel Preparation in Veteran Population.
Inadequate bowel preparation undermines the quality of colonoscopy, but patients likely to be affected are difficult to identify beforehand. This study aimed to develop, validate, and compare prediction models for bowel preparation inadequacy using conventional logistic regression (LR) and random forest machine learning (RFML). We created a retrospective cohort of patients who underwent outpatient colonoscopy at a single VA medical center between January 2012 and October 2015. Candidate predictor variables were chosen after a literature review. We extracted all available predictor variables from the electronic medical record, and bowel preparation from the endoscopy database. The data were split into 70% training and 30% validation sets. Multivariable LR and RFML were used to predict preparation inadequacy as a dichotomous outcome. The cohort included 6,885 Veterans, of whom 964 (14%) had inadequate preparation. Using LR, the area under the receiver operating characteristic curve (AUC) for the validation cohort was 0.66 (95% CI 0.62, 0.69) and the Brier score, in which a lower score indicates better performance, was 0.11. Using RFML, the AUC for the validation cohort was 0.61 (95% CI 0.58, 0.65) and the Brier score was 0.12. LR and RFML had similar performance in predicting bowel preparation, which was modest and likely insufficient for use in practice. Future research is needed to identify additional predictor variables and to test other machine learning algorithms. At present, endoscopy units should focus on universal strategies to enhance preparation adequacy.


Formation, toxicity, and mechanisms of halonitromethanes from poly(diallyl dimethyl ammonium chloride) during UV/monochloramine disinfection in the absence and presence of bromide ion.
Bromide ion (Br-) is known as a prevalent component in water environments, which exhibits significant impacts on halonitromethanes (HNMs) formation. This study was performed to explore and compare the formation, toxicity, and mechanisms of HNMs from poly(diallyl dimethyl ammonium chloride) (PDDACl) in the absence and presence of Br- in the UV/monochloramine (UV/NH2Cl) disinfection process. The results showed that chlorinated HNMs were found in the absence of Br-, while brominated (chlorinated) HNMs and brominated HNMs were found in the presence of Br-. Furthermore, the peaks of total HNMs were promoted by 2.0 and 2.4 times, respectively when 1.0 and 2.0 mg L-1 Br- were added. Also, the peaks of total HNMs were enhanced with the increase of the NH2Cl dosage, which were reduced with the increase of pH. It should be noted that Br- induced higher toxicity of HNMs, and the cytotoxicity and genotoxicity of HNMs with the addition of 2.0 mg L-1 Br- were 78.0 and 3.7 times those without the addition of Br-, respectively. Meanwhile, both the reaction mechanisms of HNMs produced from PDDACl were speculated in the absence and presence of Br-. Finally, different HNMs species and yields were discovered in these two real water samples compared to those in simulated waters. These findings of this work will be conducive to understanding the significance of Br- affecting HNMs formation and toxicity in the disinfection process.


Ecotoxicity of PM10 emissions generated during controlled burning of waste PET.
Domestic waste is often burned either as fuel for winter heating or in open areas, simply to get rid of waste. Polyethylene terephthalate (PET) represents an important component of plastics usage as well as of plastic waste produced. While most studies attempt to characterize environmental risk of open burning of mixed household waste, present work evaluates chemical and ecotoxicological parameters of particulate matter (PM) produced during controlled burning of PET samples. In the PM10 samples, polycyclic aromatic hydrocarbon and heavy metal concentrations were measured, ecotoxicity was evaluated using the kinetic Vibrio fischeri bioassay. Both chemical composition and ecotoxicity of the 4 samples showed significant correlation, regardless of the colored or colorless nature of the original PET sample. Antimony was found in considerable concentrations, in the range of 6.93-16.9 mg/kg. PAHs profiles of the samples were very similar, showing the dominance of 4-and 5-ring PAHs, including carcinogenic benzo(a)pyrene.


What Do These Findings Tell Us? Comment on Tinella et al. Cognitive Efficiency and Fitness-to-Drive along the Lifespan: The Mediation Effect of Visuospatial Transformations. Brain Sci. 2021, 11, 1028.
Tinella et al.'s recent article [...].


Comprehensive analysis of novel cancer prediction genes and tumor microenvironment infiltration in colon cancer.
Colon cancer with high incidence and mortality is a severe public health problem. As an emerging therapy, immunotherapy has played an active clinical role in tumor treatment, but only a small number of patients respond. By univariate Cox regression analysis of 165 novel cancer prediction genes (NCPGs), 29 NCPGs related to prognosis were screened. Based on these 29 NCPGs and 336 differentially expressed genes, we constructed two colon cancer subgroups and three gene clusters and analyzed prognosis, activation pathways, and immune infiltration characteristics under various modification patterns. Then each patient was scored and divided into high or low NCPG_score groups. A comprehensive evaluation between NCPG_score and clinical characteristics, tumor microenvironment (TME), tumor somatic mutations, and the potential for immunotherapy was conducted. Patients with high NCPG_score were characterized by high tumor mutation burden and high microsatellite instability and were more suitable for immunotherapy. This study screened 29 NCPGs as independent prognostic markers in colon cancer patients, demonstrating their TME, clinicopathological features, and potential roles in immunotherapy, helping to assess prognosis and guiding more personalized immunotherapy.


Efficient fitting of single-crystal diffuse scattering in interaction space: a mean-field approach.
The diffraction patterns of crystalline materials with strongly correlated disorder are characterized by the presence of structured diffuse scattering. Conventional analysis approaches generally seek to interpret this scattering either atomistically or in terms of pairwise (Warren-Cowley) correlation parameters. Here it is demonstrated how a mean-field methodology allows efficient fitting of diffuse scattering directly in terms of a microscopic interaction model. In this way the approach gives as its output the underlying physics responsible for correlated disorder. Moreover, the use of a very small number of parameters during fitting renders the approach surprisingly robust to data incompleteness, a particular advantage when seeking to interpret single-crystal diffuse scattering measured in complex sample environments. As the basis of this proof-of-concept study, a toy model is used based on strongly correlated disorder in diammine mercury(II) halides.


Does phacoemulsification under topical anesthesia affect retrobulbar blood flow?
To investigate with color Doppler imaging the effects of phacoemulsification surgery under topical anesthesia on retrobulbar vessels hemodynamics. In this prospective study, color Doppler imaging was used to measure the maximum (Vmax) and minimum flow velocity (Vmin) of the central retinal vein, and the Vmax and Vmin, pulsatility index and resistance index of the central retinal artery, nasal, and temporal posterior ciliary arteries, and ophthalmic artery blood flow before and 1 day after phacoemulsification surgery under topical anesthesia. After phacoemulsification surgery under topical anesthesia, Vmin of the central retinal artery increased (p ≤ 0.05), whereas the other variables showed no significant change. Phacoemulsification surgery under topical anesthesia has a minor effect on retrobulbar blood flow. Therefore topical anesthesia should be suitable for patients with ocular perfusion disorders (eg, glaucoma).


Characterization of a mouse factor IX cDNA and developmental regulation of the factor IX gene expression in liver.
A mouse factor IX cDNA was isolated and characterized. The cDNA was 1,837 bp in length and contained the coding region as well as short 5' and 3' untranslated sequences. Northern blot analysis of liver RNA showed two mRNA species of 3.2 kb (major) and 2.2 kb (minor) for the mouse factor IX. An antisense RNA probe prepared from the mouse cDNA was employed to determine the steady state level of factor IX mRNA in mouse liver at various developmental stages. The factor IX mRNA level was very low (2-5% of the adult level) during the gestational period until day -3 (gestational day 17) followed by a rapid increase at day -2 through birth. This phase of rapid increase was followed by a gradual increase before it reached the adult level at around 20 to 24 days. At birth, the factor IX mRNA level was found to be at about 43% of that of the adult. The mRNA levels in mouse liver agreed well with the plasma factor IX activity levels. These results indicate that reduced factor IX activity in newborns is due to the low levels of factor IX mRNA available for translation.


Effect of emergency department in-hospital tele-electrocardiographic triage and interventional cardiologist activation of the infarct team on door-to-balloon times in ST-segment-elevation acute myocardial infarction.
Current guidelines recommend that >75% of patients with ST-elevation myocardial infarction (STEMI) receive primary percutaneous coronary intervention (PPCI) within 90 minutes. The goal has been hardly achievable, so we conducted a 2-year before-and-after study to determine the impact of emergency department (ED) tele-electrocardiographic (tele-ECG) triage and interventional cardiologist activation of the infarct team at door-to-balloon time (D2BT) and the proportion of patients undergoing PPCI within 90 minutes since arrival. In total 105 consecutive patients with acute STEMI (mean age 62 ± 13 years, 82% men) were studied, 54 before and 51 after the change in protocol. The 51patients in the tele-ECG group underwent tele-electrocardiography at the ED and electrocardiograms were transmitted to a third-generation mobile telephone of an on-call interventional cardiologist within 10 minutes of ED arrival. The infarct team was activated and PPCI was performed by the interventional cardiologist. Fifty-four patients with acute STEMI who underwent PPCI in the year before implementation of tele-electrocardiography served as control subjects. Median D2BT of the tele-ECG group was 86 minutes, significantly shorter than the median time of 125 minutes of the control group (p <0.0001). The proportion of patients who achieved a D2BT <90 minutes increased from 44% in the control group to 76% in the tele-ECG group (p = 0.0001). In conclusion, implementation of ED tele-ECG triage and interventional cardiologist activation of the infarct team can significantly shorten D2BT and result in a larger proportion of patients achieving guideline recommendations.


Feeding Jejunostomy after esophagectomy cannot be routinely recommended. Analysis of nutritional benefits and catheter-related complications.
Patients undergoing esophagectomy for cancer usually deal with malnourishment which increases postoperative morbimortality. The objective of this paper is to analyze the nutritional benefits of feeding jejunostomy (FJ) for early postoperative enteral nutrition (EN) and directly-related complications. Retrospective study of 100 patients undergoing esophagectomy for cancer between 2008 and 2016. FJ was placed in 47 patients. 82.98% reached EN requirements in FJ group, with a median EN re-start of 1.9 days and median days to objective requirements of 5 days. 51.06% developed directly-related FJ complication, 91.66% of them mild ones (gastrointestinal or catheter-related). 2 patients (4.25%) required re-intervention. No significant differences were shown in total protein and albumin seric levels during first postoperative week and in anastomotic leak rate between both groups (p > 0.05). Feeding jejunostomies are associated with a great number of complications although most are not life-threatening. Since its nutritional benefit is not proven FJ cannot routinely recommended after esophagectomy. However, the optimal pathway for EN reintroduction, including direct oral intake, is still a matter of debate.


Trans--pulmonary artery repair of ventricular septal defect associated with congenitally corrected transposition of the great arteries.
This report documents successful trans-pulmonary artery repair of ventricular septal defect (VSD) in 2 patients with congenitally corrected transposition of the great arteries, one patient having associated subpulmonic stenosis. In selected cases, the method of repair that is described offers significant advantages over techniques employing transventricular or transatrial access to the VSD.


Analysis of conformation and function of the chromatin of the brain of young and old rats.
Digestion of nuclei of the cerebral hemisphere of young (18-20 week) and old (90-97 week) rats by DNase I shows that the rate and extent of digestion is lower in the old. Time course analysis of the DNA fragments produced by DNase I by polyacrylamide gel electrophoresis shows that more of the lower base pair fragments are produced in the young. Also, the rate of production of these fragments is higher in the young than in the old. Assay of template-engaged RNA polymerase II (alpha-amanitin sensitive) shows that in the old it is only about 50% of that of the young. Addition of exogenous eukaryotic (wheat germ) RNA polymerase II is not able to restore transcription of the chromatin in the old to the level of the young. These data show that chromatin undergoes increasing condensation as a function of age, resulting in decreased transcriptional activity in old age.


Corrigendum to "Raman enhancement effect of different silver nanoparticles on salbutamol" [Heliyon 8 (6), (June 2022) Article e09576].
[This corrects the article DOI: 10.1016/j.heliyon.2022.e09576.].


Anatomic study of the pre- and neonatal hip. Physiopathologic considerations on dysplasia and congenital dislocation of the hip.
Therapeutic success in dysplasia and congenital dislocation of the hip depends on an early diagnosis. The physiopathology remains very debatable and several concepts are propounded. For a better physiopathologic understanding, the authors have carried out a study of the morphology and development of 22 pre- and neonatal hips. At first, the acetabulum is cartilaginous and distorted by the moving femoral head; this acetabulum is histologically affected by the femoral pressure. The pathologic hip is characterized by defective posterior bony coverage of the femoral head by the acetabulum. The acetabulum ossifies during the 3 months following birth, forming a cup-like cavity under the pressure of the femoral head. Therefore, neonatal screening tests such as sonography must take place in the first weeks of life.


Dominant-negative retinoic acid receptors elicit epidermal defects through a non-canonical pathway.
Previous work has shown that a dominant-negative retinoic acid receptor alpha (dnRARalpha), expressed under the K14 promoter, causes severe epidermal defects. Similar defects are, however, not seen in RARalphagamma double null mutant mice, which lack the entire complement of RARs expressed in the epidermis. To investigate the mechanism of action of these dominant-negative receptors, dnRARalpha or a DNA binding-deficient variant, dnRARalpha(DBD), were targeted to the basal epidermis. Expression of either receptor type led to similar epidermal phenotypes suggesting that both RAR mutants acted through a common mechanism. The epidermal phenotype was reminiscent of defects seen in p63(-/-) mice. Consistent with this, reduced p63 expression was observed in transgenic offspring expressing either RAR mutant, suggesting that down-regulation of p63 might underlie the effects of these receptors on epidermal development. By contrast, expression of p63 in the epidermis of RARalphagamma(-/-) offspring was unaffected, indicating that RARs were not essential for p63 expression. These findings suggest that dnRARs may impact on epidermal development through one or more non-canonical pathways, which are independent of receptor-DNA interaction.


Dopamine is not involved in the opioid control of luteinizing hormone secretion in man.
The aim of this study was to examine the role of the central dopaminergic system in the mechanisms by which opioid peptides exert their influence on luteinizing hormone (LH) secretion in man. The effects of sulpiride and naloxone on the changes in LH secretion induced by a metenkephalin analog (D-Ala2-MePhe4-Met-(o)-ol-Enkephalin, FK 33824, Sandoz, Basel, Switzerland) (DAMME) and dopamine infusion in four castrated men (21 to 25 years of age) were studied. In these patients, sulpiride pretreatment counteracted the inhibitory effect of dopamine but did not alter the fall of LH plasma levels that DAMME induced. Moreover, in these subjects naloxone reduced the inhibitory effects induced by DAMME but did not change the inhibitory effect of dopamine on LH secretion. These findings confirm that central dopaminergic and opiatergic systems play a role in the control of LH secretion; the data also exclude any interaction between these systems in regulating LH secretion.


Perioperative Chemotherapy for Liver Metastasis of Colorectal Cancer: Lessons Learned and Future Perspectives.
Colorectal cancer (CRC) is a major public health problem and the 2nd leading-cause of cancer-related death worldwide. Around 30% of patients present with metastatic disease and 50% of those with early disease will eventually relapse. The metastatic spread occurs mainly to the liver, which is the exclusive site in 30-40% of the cases. Surgery is the main curative option for liver recurrence, but only one out of five patients are eligible for resection. Moreover, even if surgery is feasible, recurrence rate is high, occurring in up to 75% of patients. Therefore, additional treatment to improve these disappointing outcomes has been sought. Adjuvant and perioperative chemotherapy aim to eradicate early micrometastatic disease, decreasing recurrence rates, and improving survival outcomes. Different chemotherapy regimens, mainly extrapolated from the adjuvant experience, have showed conflicting results, with improvements in disease free but not in overall survival. The addition of targeted therapies to chemotherapy has improved response rates and resectability when administered preoperatively, but did not have an impact on survival in the adjuvant setting. There is a need to critically synthetize the available evidence on perioperative and conversion therapy from the past years, and appraise areas of current research and potential future directions.


Impaired coronary blood flow in patients with metabolic syndrome: documented by Thrombolysis in Myocardial Infarction (TIMI) frame count method.
Endothelium plays an important role in regulating coronary vascular tone. In addition, several of cardiovascular risk factors that are associated metabolic syndrome have been reported to be associated with endothelial dysfunction. In the present study we aimed to evaluate the coronary blood flow in patients with metabolic syndrome by means of the Thrombolysis in Myocardial Infarction (TIMI) frame count. Forty-two patients with metabolic syndrome (group I) and 42 control subjects without metabolic syndrome (group II) were included in the study. All subjects had angiographically proven normal coronary arteries. Diagnosis of metabolic syndrome was based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines published in 2001. Coronary flow rates of all subjects were documented by TIMI frame count method. TIMI frame counts for each of the major epicardial coronary arteries were found to be significantly higher in patients with metabolic syndrome compared with control subjects (corrected TIMI frame count for left anterior descending coronary artery: 35 +/- 7 vs 25 +/- 7, respectively; left circumflex coronary artery: 32 +/- 9 vs 25 +/- 7, respectively; right coronary artery: 31 +/- 9 vs 24 +/- 5, respectively; P < .001 for all). Statistically significant independent relationships were found between TIMI frame count and body mass index (R(2) = 0.480, P = .009), waist circumference (R2 = 0.551, P = .001), and triglyceride level (R2 = 0.434, P = .036). We have shown for the first time that patients with metabolic syndrome and angiographically normal coronary arteries have higher TIMI frame counts for all 3 coronary vessels, indicating impaired coronary blood flow, compared to control subjects without metabolic syndrome.


Acute coronary occlusion following blunt injury to the chest in the absence of coronary atherosclerosis.
A 35-year-old man suffered transmural diaphragmatic wall infarction immediately after receiving a nonpenetrating trauma to his chest. During subsequent months crippling angina pectoris developed and coronary arteriography was performed. A complete obstruction of the left circumflex coronary artery was demonstrated 2 cm. distal to its origin. In contrast to most cases previously published, in this case no signs of atherosclerosis were observed in the other coronary arteries. It must be assumed, therefore, that blunt trauma can induce complete coronary occlusion with infarction, even in subjects with normal coronary arteries.


Total and regional relationship between lean and fat mass with increasing adiposity--impact for the diagnosis of sarcopenic obesity.
Besides the effect of age used to define sarcopenia, there is need to understand the impact of adiposity on the relationship between lean (fat-free mass, FFM) and fat mass (FM) in order to diagnose sarcopenic obese phenotypes. More importantly, the regional distribution of skeletal muscle (SM) to adipose tissue (AT) or the composition of FFM (that is, SM proportion of lean mass) may also depend on adiposity. In a large database (n=1737) of healthy males and females (age 11-84 years, BMI 13.5-52.5 kg/m(2)) we investigated changes in the relationship between FFM and FM (normalized by height as fat-free mass index and fat mass index: FFMI and FMI, kg/m(2) assessed by densitometry) with increasing adiposity and age. In a subgroup (n=263) we analyzed the relationship between regional SM and (i) AT (by magnetic resonance imaging) or (ii) lean soft tissue (by dual X-ray absorptiometry) with increasing adiposity. The relationship between lean and FM was influenced by adiposity, age and gender. With increasing adiposity, SM/AT declined faster at the trunk in men and at the extremities in women. The contribution of appendicular SM to lean soft tissue of arms and legs tended to decrease at a higher adiposity in both genders (FMI >6.97 kg/m(2) in women; FMI>7.77 kg/m(2) in men). Besides age and gender, adiposity and body region should be considered when evaluating the normal relationship between lean and FM, SM/FFM and SM/AT.