The membrane potential has no detectable effect on the phosphocholine headgroup conformation in large unilamellar phosphatidylcholine vesicles as determined by 2H-NMR.
In this study the effect of a transmembrane electrical potential on the phospholipid headgroup conformation was investigated using the 2H-NMR technique. Large unilamellar vesicles were prepared of dioleoylphosphatidylcholine, specifically 2H-labeled at the alpha- or beta-position of the choline group. No conformational change of the phosphocholine headgroup could be detected after induction of a valinomycin-induced K(+)-diffusion potential across the bilayer. However, this method could be used to measure the redistribution of tetraphenylphosphonium across the bilayer in response to delta psi, which reorients the phosphocholine headgroups in the opposite bilayer-water interfaces.


Effects of sildenafil on myocardial blood flow in humans with ischemic heart disease.
We tested the hypothesis that sildenafil increases myocardial dilator reserve in humans with ischemic heart disease. Positron emission tomography measured myocardial blood flow in 14 patients with ischemic heart disease. Patients were studied twice, in double-blind, placebo-control, cross-over design with sildenafil (or placebo) given approximately 2-3 h before measurements of hemodynamics and myocardial blood flow: at rest, with cold pressor stress and with adenosine. All myocardial segments of each patient with myocardial blood flow <1.65 ml/min per g with adenosine under placebo conditions were combined into one abnormal zone for that patient. Segments with myocardial blood flow >1.65 ml/min per g were averaged and combined into a normal zone for that patient. At rest, rate pressure product (heart rate x systolic arterial pressure, mmHg/min) was comparable, as was abnormal zone myocardial blood flow (ml/min per g; 0.76+/-0.48 placebo versus 0.64+/-0.20 sildenafil, both P=NS; mean+/-SD). Both rate pressure product and myocardial blood flow increased (P<0.01) with cold pressor stress (11+/-3 K and 1.14+/-0.59 placebo versus 10+/-3 K and 1.21+/-0.62 sildenafil). However, sildenafil failed to improve the myocardial blood flow response to cold pressor stress in abnormal or normal zones. In contrast, abnormal zone myocardial blood flow reserve with adenosine and sildenafil (2.6+/-0.7) exceeded that with adenosine and placebo (2.0+/-1.3, P<0.04, paired sign test). Sildenafil improves myocardial blood flow dilator response to adenosine in abnormal zones, possibly by augmenting nitric oxide-mediated increases in cGMP because adenosine response in part is nitric oxide dependent. Failure to improve myocardial blood flow response to cold pressor stress suggests that alpha-adrenergic constriction may offset enhanced nitric oxide effects. Clinically, the data suggest sildenafil may exert an anti-ischemic effect in patients with coronary artery disease.


A biomechanical matched-pair comparison of two different locking plates for tibial diaphyseal comminuted fracture: carbon fiber-reinforced poly-ether-ether-ketone (CF-PEEK) versus titanium plates.
Several methods have been proposed to reduce plate construct stiffness and promote secondary bone healing. In this study, we explored the stiffness and strength of the new carbon fiber-reinforced poly-ether-ether-ketone (CF 50) plate compared with the titanium alloy plate (Ti6Al4V). Titanium and CF-PEEK locking plates were tested in a tibial non-osteoporotic diaphyseal comminuted fracture model to determine construct stiffness in axial compression, torsion, and bending. Subsequently, constructs were loaded until construct failure to determine construct strength. Relative to the titanium locking plate, the stiffness of the CF-PEEK locking plate was 6.8% and 30.8% lower in 200 N and 700 N axial compression, respectively (P < 0.05), 64.9% lower in torsion (P < 0.05), and 48.9% lower in bending (P < 0.05). The strength of the CF-PEEK locking plate was only 2.6% lower under axial compression, 7.8% lower in torsion, and 4.8% lower in bending than the titanium locking plate (P > 0.05). The CF-PEEK locking plate significantly reduced axial, torsion, and bending stiffness compared with the titanium locking plate. Nonetheless, axial, torsional, and bending strength showed only a modest reduction. Considering its other advantages, which include radiolucency and artifact-free imaging, the CF-PEEK locking plate therefore deserves further clinical investigation.


Accuracy of frozen section, imprint cytology, and permanent histology of sub-nipple tissue for predicting occult nipple involvement in patients with breast carcinoma.
The sub-nipple tissue (SNT) examination has been used by surgeons to preserve, or not, the nipple in nipple-sparing mastectomy. However, it is uncertain whether SNT evaluation can predict nipple involvement. The aim of this study was to evaluate the accuracy, sensitivity, specificity, PPV, and NPV of the intraoperative frozen section and imprint cytology, and permanent histology of SNT to predict the involvement of the nipple in breast carcinoma and to compare the three exams. A prospective study was performed with 68 consecutive breast carcinoma women who had undergone mastectomy or central segmentectomy (removing nipple-areolar complex). After surgery, the nipple-areolar complex was dissected simulating a nipple-sparing flap (ex vivo). The SNT was subsequently removed and submitted to frozen section, imprint cytology, and permanent histology. The nipple was examined separately by paraffin histopathology and was considered the gold standard. The occult nipple involvement rate was 11.7 %. The frozen section, cytology, and permanent histology of SNT presented accuracy 86.8, 76.5, and 86.8 %; sensitivity 50, 37.5, and 62.5 %; specificity 91.7, 81.7, and 90 %; PPV 44.4, 21.4, and 45.5 %; and NPV 93.2, 90.7, and 94.7 %, respectively. The accuracy of the frozen section was similar to that of permanent histology (p = 0.77) and both were better than cytology (p = 0.01). False negative rates were 6.8 % for frozen section, 9.3 % for cytology and 5.3 % for paraffin. SNT evaluation is a good method for predicting occult nipple involvement; the outcomes showed a good accuracy and low false negative rate for the frozen section, cytology, and permanent histology exams. When we compared the exams, the frozen section was similar to permanent histology and more accurate than imprint cytology.


Usefulness of sampling with cotton swab for PCR-diagnosis of cutaneous leishmaniasis in the New World.
In this study, we tested the polymerase chain reaction (PCR)-method to diagnose cutaneous leishmaniasis (CL) by taking exudate materials from lesions with cotton swabs, using our previously tested (PCR) panel comprised of Leishmania (Viannia) panamensis, L. (V.) braziliensis, L. (V.) guyanensis, L. (Leishmania) mexicana and L. (L.) amazonensis. The objectives of the present study were to improve the sampling method convenient for the patients and to test the usefulness of samples taken with cotton swabs. Sixteen patients were clinically diagnosed to have CL including one case of diffuse cutaneous leishmaniasis (DCL) in Ecuador and the causative Leishmania parasites were identified by PCR. All the 12 samples from CL patients of La Mana, positive for Leishmania DNA, were identified as L. (V.) panamensis, while two from CL of Huigra and one from DCL of San Ignacio were L. (L.) mexicana. In the field condition, taking biopsy material is not only painful but sometimes causes iatrogenic bacterial infections. Considering the sensitivity of the test, and convenient sampling procedure, it may be suggested that collection of exudates using cotton swabs may be a better alternative to biopsy sample for PCR-diagnosis of CL.


The development of universal health insurance coverage in Thailand: Challenges of population aging and informal economy.
This paper quantitatively investigates the sustainability of the universal health insurance coverage (UHI) system in Thailand while taking into account the country's rapidly aging population and large informal labor sector. We examine the effects of population aging and informal employment across three tax options for financing the UHI. A modern dynamic general equilibrium framework is utilized to conduct policy experiments and welfare analysis. In the case of labor income tax being used to finance the cost of UHI, an additional 11-15% of labor tax will be required with the 2050 population age structure, compared with the 2005 benchmark economy. We also find that an expansion of income tax base to the informal sector can substantially alleviate the tax burden. Based on welfare comparisons across the alternative tax options, the labor income tax is the most preferred because the inequality between formal/informal sectors is large. If the informal sector cannot avoid labor income tax, capital tax will be preferred over labor and consumption taxes.


High Ki-67 Expression Predicts Favorable Survival in Muscle-Invasive Bladder Cancer Patients Treated With Chemoradiation-Based Bladder-Sparing Protocol.
To evaluate associations of Ki-67 expression with oncologic outcomes in muscle-invasive bladder cancer (MIBC) patients treated with chemoradiotherapy (CRT)-based bladder-sparing protocol. Between 1998 and 2011, 190 consecutive MIBC patients were treated with CRT-based bladder-sparing protocol. After transurethral resection of the bladder tumor, the patients underwent induction CRT (40 Gy with concurrent cisplatin) followed by partial cystectomy for bladder preservation or radical cystectomy (RC). Included in this study were 94 patients who were histologically diagnosed with urothelial carcinoma and whose tumor tissues before CRT were available for immunohistochemical evaluation of Ki-67 expression status. After induction CRT, 16 (17%) and 53 (56%) patients underwent partial cystectomy and RC, respectively, while the remaining 25 (27%) did not undergo cystectomy. Successful bladder preservation was achieved in 34 patients (36%). Higher Ki-67 labeling index (LI) independently predicted CRT response clinically and pathologically. Among the clinicopathologic variables available before CRT and cystectomy, high Ki-67 LI (≥ 20%) was independently associated with better cancer-specific survival (CSS) (5-year CSS rate, 78% vs. 46% for low Ki-67 LI; P = .019). The difference in CSS according to Ki-67 expression status was more remarkable in patients with cT3 disease (5-year CSS rate, 72% vs. 29%; P = .0098). High Ki-67 expression predicts favorable CSS in MIBC patients treated with CRT-based bladder-sparing protocol. MIBC patients with high Ki-67 expression status might benefit from CRT-based multimodal approaches in terms of prognosis and quality of life as a result of bladder preservation.


Genome Rearrangement Distance With a Flexible Intergenic Regions Aspect.
Most mathematical models for genome rearrangement problems have considered only gene order. In this way, the rearrangement distance considering some set of events, such as reversal and transposition events, is commonly defined as the minimum number of rearrangement events that transform the gene order from a genome G1 into the gene order from a genome G2. Recent works initiate incorporating more information such as the sizes of the intergenic regions (i.e., number of nucleotides between pairs of consecutive genes), which yields good results for estimated distances on real data. In these models, besides transforming the gene order, the sequence of rearrangement events must transform the list of intergenic regions sizes from G1 into the list of intergenic regions sizes from G2 (target list). We study a new variation where the target list is flexible, in the sense that each target intergenic region size is in a range of acceptable values. This allows us to model scenarios where the main objective is still to transform the order of genes from the source genome into the target genome, allowing flexibility in the sizes of the intergenic regions, since the nucleotides in these regions tend to undergo more changes when compared to genes. We investigate the rearrangement distance considering three sets of events, two with the exclusive use of reversals or transpositions, and the other allowing both rearrangement events. We present approximation algorithms for the problems and an NP-hardness proof. Our results rely on the Flexible Weighted Cycle Graph, adapted from the breakpoint graph to deal with flexible intergenic regions sizes.


Urbanization and maternal hormone transfer: Endocrine and morphological phenotypes across ontogenetic stages.
The phenotypes observed in urban and rural environments are often distinct; however, it remains unclear how these novel urban phenotypes arise. Hormone-mediated maternal effects likely play a key role in shaping developmental trajectories of offspring in different environments. Thus, we measured corticosterone (Cort) and testosterone (T) concentrations in eggs across the laying sequence in addition to Cort concentrations in nestling and adult female house wrens (Troglodytes aedon) at one urban and one rural site. We found that egg T concentrations were not different between birds from urban and rural sites. However, across all life stages (egg, nestling, and adult female), Cort concentrations were higher at the urban site. Additionally, urban nestling Cort concentrations, but not rural, correlated with fine-scale urban density scores. Furthermore, rural egg volume increased over the laying sequence, but urban egg volume leveled off mid-sequence, suggesting either that urban mothers are resource limited or that they are employing a different brood development strategy than rural mothers. Our study is one of the first to show that egg hormone concentrations differ in an urban environment with differences persisting in chick development and adult life stages. We suggest that maternal endocrine programing may shape offspring phenotypes in urban environments and are an overlooked yet important aspect underlying mechanisms of urban evolution.


Neuropsychological Differences Between Surgery Interns and Age-Matched Adults.
The purpose of this study was to assess how neuropsychological factors differ between general surgery interns and normative data from age-matched adults in the general population. Participants completed a comprehensive neuropsychological assessment battery. Neuropsychological factors assessed included: executive function (Behavioral Rating Inventory of Executive Function, BRIEF), working memory (Wechsler Adult Intelligence Scale, or WAIS, digit span), psychomotor speed (WAIS coding, Trails A and B), selective attention (D2 Test of Attention), and problem solving (Tower of London, TOL). Data for all measures was compared to previously published normative data for age-matched, healthy adults in the general population using one-sample t-tests. This study was completed at Indiana University School of Medicine in Indianapolis, IN, which is a large academic healthcare training institution. Postgraduate year 1 general surgery residents (PGY1s) voluntarily participated in this study. Twenty-six general surgery PGY1s completed all measures. We found that PGY1s had significantly better behavioral inhibition, working memory, selective attention, problem solving, and psychomotor speed than their counterparts in the general population (Table 1). Conversely, we found that PGY1s had significantly lower cognitive flexibility (p = 0.02) and ability to monitor task progress (p = 0.006) than the general population. The results from this study indicate that there are several neuropsychological factors that may help explain the high achievement of general surgery PGY1s. Assessment of these factors could aid general surgery programs in the selection and training of high-caliber residents. However, there are indicators that PGY1s struggle from cognitive inflexibility and task monitoring compared to the general population. These skills are needed to manage the complex and dynamic nature of surgical performance, so educators should consider methods to enhance junior residents' development of these characteristics.


Effects of the pilates method on kinesiophobia associated with chronic non-specific low back pain: Systematic review and meta-analysis.
Patients with chronic low back pain with higher levels of kinesiophobia have a 41% greater risk of developing a physical disability. The kinesiophobia model suggests that patients fear movements because of pain, associating movement with worsening of their state. Studies that apply the Pilates method for chronic low back pain achieve positive results in reducing pain and disability, and moderate results regarding kinesiophobia. The purpose of this review is to evaluate the effects of the Pilates method on kinesiophobia associated with chronic non-specific low back pain. The following databases were searched from August to October 2018: MEDLINE, PEDro, SciELO, LILACS and the Cochrane Database of Systematic Reviews (CENTRAL), without restriction of language and year of publication. Randomized clinical trials assessing the effectiveness of the Pilates method in the treatment of kinesiophobia in patients with chronic non-specific low back pain. Two authors independently selected the studies, assessed the risk of bias and extracted data. A third author was consulted in case of disagreements. The primary outcome was kinesiophobia as evaluated by the Tampa scale. Our electronic searches resulted in 314 studies; 288 studies were excluded and 27 were selected for reading in full-text. Five articles were included in this review and four in the meta-analysis. There is a favorable effect of the Pilates method compared to minimal intervention or no treatment in reducing kinesiophobia associated with chronic non-specific low back pain, with a moderate quality of evidence. Low Back Pain, Exercise Movement Techniques, Exercises, Pilates-Based.


Potential Uses of Anthropogenic Noise as a Source of Information in Animal Sensory and Communication Systems.
Although current research on the impact of anthropogenic noise has focused on the detrimental effects, there is a range of ways by which animals could benefit from increased noise levels. Here we discuss two potential uses of anthropogenic noise. First, local variations in the ambient-noise field could be used to perceive objects and navigate within an environment. Second, introduced sound cues could be used as a signal for prey detection or orientation and navigation. Although the disadvantages of noise pollution will likely outweigh any positive effects, it is important to acknowledge that such changes may benefit some species.


Couples' experiences of postnatal depression: a framing analysis of cultural identity, gender and communication.
Difficulties in communication have been associated with fathers' perceived lack of support for mothers suffering postnatal depression (PND). This paper investigates why the communication of the experience of PND is so difficult and considers how these difficulties might be linked, in part, to the diagnostic process. The study explores, through in-depth interviews, how six Australian couples talked about the new mothers' experience of mild to moderate PND. Framing analysis revealed discrepancies in the couples' explanations of the mothers' PND. The application of the concept of 'framing' has come to the study of mental health by way of Goffman's work on how experience becomes organised. Goffman used the technique of 'frame analysis' to identify and describe the taken-for-granted sociocultural elements that give meaning to a situation. This study identified that mothers and fathers used different frames, with mothers understanding their postnatal experience primarily from within an 'identity' frame and fathers understanding the mothers' experience primarily through a 'psychological' or 'physical hardship' frame. Implications for health service providers are considered.


[Stratification of cardiovascular risk in women: Optimize the medical care].
Cardiovascular diseases are become the primary cause of death in women. The cardiovascular risk of the woman has unknown specificities and remains underestimated. At equal age, women have more cardio vascular risk factors than men. All these specificities must be taken into account for an optimized evaluation of cardiovascular risk and for improvement of CV management in women. Some traditional risk factors are more deleterious in women such as hypertension, tobacco, diabetes or psycho-social stress and they are less well controlled compared to men. Women are also exposed to hormonal risk factors (contraception, pregnancy and menopause) or to emergent risk situations (migraine with aura, endometriosis, polycystic ovary syndrome, auto-immune diseases…). Conversely, lifestyle measures (regular physical activity, no smoking, healthy diet, stress management) are extremely effective in primary and secondary prevention in women. Predicting the risk of cardiovascular events in women is difficult because the classic risk scores (SCORE, Framingham…) do not take into account hormonal CV specificities and underestimate the women CV risk. Until then, only the specific women AHA stratification of CVR allowed for appropriate care for them. Recently, at the initiative of the French Society of hypertension, a consensus of experts proposed a stratification of CVR adapted to French women, to help practitioners in their care, especially for the two hormonal periods as contraception and menopause.


Different Dynamics for IgG and IgA Memory B Cells in Adolescents following a Meningococcal Serogroup C Tetanus Toxoid Conjugate Booster Vaccination Nine Years after Priming: A Role for Priming Age?
Antibody levels wane rapidly after Meningococcal serogroup C conjugate (MenCC) vaccination in young children, rendering the need for an adolescent booster dose. It is not clear whether circulating memory B cells are associated with persistence of MenC-specific antibody levels. Measurement of MenC-specific IgG and IgA memory B cells and levels of serum and salivary MenC-specific IgG and IgA in healthy 10-, 12- and 15-year-olds prior to and one month and one year after a MenCC booster vaccination. All participants had received a primary MenCC vaccination nine years earlier. The number of circulating MenC-specific IgG memory B cells prior to booster was low and not predictive for MenC-specific IgG responses in serum or saliva post-booster, whereas the number of MenC-specific IgA memory B cells pre-booster positively correlated with MenC-specific IgA levels in saliva post-booster (R = 0.5, P<0.05). The booster induced a clear increase in the number of MenC-specific IgG and IgA memory B cells. The number of MenC-PS-specific IgG memory B cells at 1 month post-booster was highest in the 12-year-olds. The number of MenC-specific memory B cells at one month post-booster showed no correlation with the rate of MenC-specific antibody decay throughout the first year post-booster. Circulating MenC-specific IgA memory B cells correlate with IgA responses in saliva, whereas circulating MenC-specific IgG memory B cells are not predictive for MenC-specific IgG responses in serum or saliva. Our results are suggestive for age-dependent differences in pre-existing memory against MenC.


α-Lactalbumin, Amazing Calcium-Binding Protein.
α-Lactalbumin (α-LA) is a small (Mr 14,200), acidic (pI 4-5), Ca2+-binding protein. α-LA is a regulatory component of lactose synthase enzyme system functioning in the lactating mammary gland. The protein possesses a single strong Ca2+-binding site, which can also bind Mg2+, Mn2+, Na+, K+, and some other metal cations. It contains several distinct Zn2+-binding sites. Physical properties of α-LA strongly depend on the occupation of its metal binding sites by metal ions. In the absence of bound metal ions, α-LA is in the molten globule-like state. The binding of metal ions, and especially of Ca2+, increases stability of α-LA against the action of heat, various denaturing agents and proteases, while the binding of Zn2+ to the Ca2+-loaded protein decreases its stability and causes its aggregation. At pH 2, the protein is in the classical molten globule state. α-LA can associate with membranes at neutral or slightly acidic pH at physiological temperatures. Depending on external conditions, α-LA can form amyloid fibrils, amorphous aggregates, nanoparticles, and nanotubes. Some of these aggregated states of α-LA can be used in practical applications such as drug delivery to tissues and organs. α-LA and some of its fragments possess bactericidal and antiviral activities. Complexes of partially unfolded α-LA with oleic acid are cytotoxic to various tumor and bacterial cells. α-LA in the cytotoxic complexes plays a role of a delivery carrier of cytotoxic fatty acid molecules into tumor and bacterial cells across the cell membrane. Perhaps in the future the complexes of α-LA with oleic acid will be used for development of new anti-cancer drugs.


Induction of CYP1A1 and CYP1A2 expressions by prototypic and atypical inducers in the human lung.
The inducibility of cytochrome P4501A1 gene (CYP1A1) expression was examined in human lung samples from 27 subjects, using an explant culture system and semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. CYP1A1 transcripts were present in all of the lung specimens and were induced by the prototypic inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (B[a]P), and by the atypical inducers pyridine, nicotine, and omeprazole. 2-Hydroxypyridine was a better inducer than pyridine, implicating metabolites in CYP1A1 induction by the parent compound. The prototypical inducers were the most effective inducers in many samples but were ineffective in some samples in which the atypical compounds were effective inducers. Cytochrome P4501A2 (CYP1A2) transcripts were also detected in most of the lung specimens and were inducible in some specimens. The results show the suitability of the explant culture system for examining the inducibility of human pulmonary CYP1A1 and CYP1A2, indicate the heterogeneity in individual sensitivity to the induction, and underscore the need to include atypical inducers in studies of CYP1A inducibility in humans.


[External drainage of the common bile duct. A new transcystic drain (author's transl)].
The authors present a new transcystic drain which offers the possibility of per-operative cholangiograms of excellent quality and provides an highly satisfactory means of external drainage of the common bile duct.


[Degenerative angiodysplasia of the ascending colon: a new entity frequently responsible for intestinal hemorrhage in the elderly].
The authors report a case of degenerative angiodysplasia of the right side of the colon. Regarding this they describe the two clinical features peculiar to this new nosological anatomo-clinical entity: hypochromic anaemia associated with low iron, and intestinal haemorrhage. The improvement of selective arteriography is the method which permits its description and underlines the frequence. But the authors believe that coloscopy in the presence of these lesions, should become beneficial and hold a place of special importance: in the diagnosis and concerning treatment of this disease. In effect the patients most prone to this condition are, by definition, elderly and hardly suitable subjects for surgery.


Strategies for improving hydrolytic efficiency of crude multienzyme extracts in mushroom processing.
The current study investigated and optimized key process parameters affecting mushroom hydrolysis with crude enzymatic extract. The crude enzyme was prepared by solid-state fermentation of pineapple peels using Aspergillus niger. The reaction parameters viz. time, temperature, pH and enzyme concentration were optimized using the central composite design of the response surface methodology. The model predicted glucose yield of 1.49 mg/mL at optimal pH of 6.5, temperature of 50 °C, enzyme loading of 5 % (v/v), and reaction time of 12 h. Mushroom hydrolysis at the same optimal model conditions, increased glucose yield by 10%. More so supplementing SSF media with 0.2% (w/v) Tween-80 and 0.08% (w/v) yeast extract at moisture level of 70-75% significantly (p value < 0.05) improved hydrolytic efficiency of the crude enzyme extract by 2.2-fold. This study provides baseline data that will be useful in developing a low-cost enzyme-based process for hydrolyzing mushrooms to recover high-value products.


[Hypothalamo-pituitary system controls the development of humoral immune response during prenatal ontogenesis in rats].
We studied the influence of the neuroendocrine system on the development of humoral immune response to sheep erythrocytes in rat fetuses. The removal of brain in utero by decapitation of 18-day fetuses induced a fourfold increase in the number of antibody-forming cells in the liver, as compared to the unoperated fetuses. After the removal of the forebrain, including hypothalamus (encephalectomy), the number of antibody-forming cells was comparable to that in unoperated fetuses. The observed increase in the number of antibody-forming cells in the liver was not due to a disturbed migration of precursors of B-lymphocytes in the spleen, since their content in the spleen was also four times that in the encephalectomized and unoperated fetuses. The increased number of antibody-forming cells in decapitated fetuses could be due to an enhanced proliferative activity of the lymphocytes in the liver of these fetuses. It has been proposed that humoral immunity is controlled by the hypothalamo-pituitary-adrenal system already during prenatal development; the adrenocorticotropic hormone and glucocorticoids appear to be involved in this regulation.


cGMP-dependent protein kinase anchoring by IRAG regulates its nuclear translocation and transcriptional activity.
Type I cGMP-dependent protein kinases (PKGs) translocate to the nucleus to regulate gene expression in some, but not all cell types; we hypothesized that nuclear translocation of PKG may be regulated by extra-nuclear anchoring proteins. The inositol 1,4,5-triphosphate (IP(3)) receptor-associated cGMP kinase substrate (IRAG) binds to the N-terminus of PKG Ibeta, but not PKG Ialpha, and in smooth muscle cells, IRAG and PKG Ibeta are in a complex with the IP(3) receptor at endoplasmatic reticulum membranes, where the complex regulates calcium release [Schlossmann et al., Nature, 404 (2000) 197]. We found that co-expression of IRAG and PKG Ibeta in baby hamster kidney cells prevented cGMP-induced PKG Ibeta translocation to the nucleus, and decreased cGMP/PKG Ibeta transactivation of a cAMP-response element-dependent reporter gene. These effects required the PKG Ibeta/IRAG association, as demonstrated by a binding-incompetent IRAG mutant, and were specific for PKG Ibeta, as nuclear translocation and reporter gene activation by PKG Ialpha was not affected by IRAG. A phosphorylation-deficient IRAG mutant that is no longer functionally regulated by PKG phosphorylation suppressed cGMP/PKG Ibeta transcriptional activity, indicating that IRAG's effect was not explained by changes in intracellular calcium, and was not related to competition of IRAG with other PKG substrates. These results demonstrate that PKG anchoring to a specific binding protein is sufficient to dictate subcellular localization of the kinase and affect cGMP signaling in the nucleus, and may explain why nuclear translocation of PKG I does not occur in all cell types.


Role of mFI-5 in predicting geriatric outcomes in laparoscopic cholecystectomy.
Frailty is the age-related decline contributing to adverse outcome vulnerability. This study assesses the modified 5-factor frailty index's (mFI-5) ability to predict geriatric cholecystectomy outcomes. Laparoscopic cholecystectomy patients ages ≥65 were identified from the American College of Surgeons' National Surgical Quality Improvement Program database (2018-2020). MFI-5 variables include hypertension, congestive heart failure, chronic obstructive pulmonary disease, diabetes, and functional status. Groups were stratified according to the number of comorbidities: mFI = 0, mFI = 1, mFI≥2. 32,481 cases included 27.6% mFI = 0, 46.4% mFI = 1, 26.0% mFI≥2. Highest frailty correlated with increased discharges to not home (OR 1.88, p < 0.01). Non-independent functional status was associated with mortality (OR 7.32), prolonged length of stay (LOS) (5.69), pneumonia (4.90), sepsis (3.78), readmission (2.60) (p < 0.01). AUCs were calculated for prolonged LOS (0.89), discharges to not home (0.85), mortality (0.83), pneumonia (0.76), sepsis (0.76). Healthcare teams can use mFI-5 to target at-risk cholecystectomy patients and proactively intervene to avoid complications.


Reversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) network: Study protocol and rationale of a multicentre research collaboration.
Reversible cerebral vasoconstriction syndrome (RCVS) is a rare, but increasingly recognised cerebrovascular condition with an estimated annual age-standardised incidence of approximately three cases per million. Knowledge about risk factors and triggering conditions and information about prognosis and optimal treatment in these patients are limited. The REversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) project aims to elucidate the epidemiological and clinical characteristics of RCVS by collecting individual patient data from four countries (France, Italy, Taiwan and South Korea) in the setting of a multicentric study. All patients with a diagnosis of definite RCVS will be included. Data on the distribution of risk factors and triggering conditions, imaging data, neurological complications, functional outcome, risk of recurrent vascular events and death and finally the use of specific treatments will be collected. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and geographical region of residence. Ethical approval for the REVERCE study will be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of clinical and epidemiological characteristics of RCVS patients.


Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice.
Fibromyalgia (FM) is an idiopathic disorder characterized by generalized pain and associated symptoms such as depression and anxiety. Cannabis sativa shows different pharmacological activities, such as analgesic, anti-inflammatory, neuroprotective, and immunomodulatory. Associated with this, the use of an oil with low concentrations of THC can reduce the psychomimetic adverse effects of the plant. Therefore, the present study aimed to evaluate the analgesic effect of broad-spectrum cannabis oil with low THC concentration in an experimental model of FM. Mechanical hyperalgesia, thermal allodynia, depressive- and anxious-related behavior, and locomotor activity were evaluated after reserpine (0.25 mg/kg; injected subcutaneously (s.c.) once daily for three consecutive days) administration. Our results showed that oral administration of broad-spectrum cannabis oil (0.1, 1, and 3 mg/kg, p.o.) in a single dose on the 4th day inhibited mechanical hyperalgesia and thermal allodynia induced by reserpine. Relevantly, treatment during four days with broad-spectrum cannabis oil (0.1 mg/kg, p.o.) reduced mechanical hyperalgesia 1 h after reserpine administration. Intraplantar treatment with cannabis oil significantly reversed mechanical and heat thermal nociception induced by reserpine injection. Interestingly, spinal and supraspinal administration of broad-spectrum cannabis oil completely inhibited mechanical hyperalgesia and thermal sensitivity induced by reserpine. The repeated cannabis oil administration, given daily for 14 days, markedly mitigated the mechanical and thermal sensitivity during the FM model, and its reduced depressive-like behavior induced by reserpine. In summary, broad-spectrum cannabis oil is an effective alternative to reverse the reserpine-induced fibromyalgia model.


Essential oil from herb and rhizome of Peucedanum ostruthium (L. Koch.) ex DC.
Essential oil from herb and rhizome of Peucedanum ostruthium (L.Koch.) ex DC underwent qualitative and quantitative analyses. The content of the oil obtained by hydrodistillation was 0.95% in the herb and 1.25% in the rhizome (per dry weight basis). Gas chromatography (GC) with MS detection and flame ionisation detection showed that the oil from the rhizome contains 39 compounds, of which 29 were identified. Gas chromatography with flame ionisation detection in chiral columns against standard compounds showed the presence of enantiomers of some of the components of the oil. Compounds present in largest quantities are: sabinene (35.2%) of which (+) sabinene accounts for (96.54%) and 4-terpineol (26.6%) of which (+) 4-terpineol accounts for (65.8%). 44 components were found in the herb essential oil, of which 39 compounds were identified. Compounds present in largest quantities were beta-caryophyllene (16.1%) and alpha-humulene (15.8%). The content of sabinene in the herb oil was 4.7%. The following compounds were present in the herb oil only as enantiomers: (+) sabinene (4.7%), (-) limonene (4.4%), (-) beta-pinene (0.4%). A coumarin (osthole) was detected in both essential oils (5.5% in herb oil and 5.1% in rhizome oil).


Influencing the properties of dysprosium single-molecule magnets with phosphorus donor ligands.
Single-molecule magnets are a type of coordination compound that can retain magnetic information at low temperatures. Single-molecule magnets based on lanthanides have accounted for many important advances, including systems with very large energy barriers to reversal of the magnetization, and a di-terbium complex that displays magnetic hysteresis up to 14 K and shows strong coercivity. Ligand design is crucial for the development of new single-molecule magnets: organometallic chemistry presents possibilities for using unconventional ligands, particularly those with soft donor groups. Here we report dysprosium single-molecule magnets with neutral and anionic phosphorus donor ligands, and show that their properties change dramatically when varying the ligand from phosphine to phosphide to phosphinidene. A phosphide-ligated, trimetallic dysprosium single-molecule magnet relaxes via the second-excited Kramers' doublet, and, when doped into a diamagnetic matrix at the single-ion level, produces a large energy barrier of 256 cm(-1) and magnetic hysteresis up to 4.4 K.


Antibodies to synthetic peptides from the pre-S1 and pre-S2 regions of one subtype of the hepatitis B virus (HBV) envelope protein recognize all HBV subtypes.
Immunodominant B and T cell epitopes have been demonstrated recently on the preS1 and PreS2 regions of the hepatitis B virus (HBV) envelope protein. Synthetic peptide analogs corresponding to the preS2 region elicit virus-neutralizing antibodies and protect chimpanzees against HBV infection. Antibodies raised by immunization with peptides derived from the preS1 sequence block the site involved in HBV attachment to cell receptors, and are expected to be virus-neutralizing. Results presented here show that antisera raised against synthetic peptide analogs carrying the immunodominant epitope of the preS1 and preS2 sequence, respectively, and corresponding to two HBV subtypes, adw2 and ayw, each recognized preS1 and preS2 specific epitopes on all serological subtypes of the HBV envelope protein. Thus, the sequence variability within the preS1 and preS2 regions does not represent an impediment to the development of synthetic peptide or genetically engineered hepatitis B preS immunogens for worldwide immunization.


Pneumococcal Vaccines: Challenges and Prospects.
Infections with the bacterium Streptococcus pneumoniae are one of the most common causes of morbidity and mortality in children less than five years of age worldwide, mostly in low- and middle-income countries (LMICs) [...].


Immune-inflammatory responses in atherosclerosis: Role of an adaptive immunity mainly driven by T and B cells.
Adaptive immune response plays an important role in atherogenesis. In atherosclerosis, the proinflammatory immune response driven by Th1 is predominant but the anti-inflammatory response mediated mainly by regulatory T cells is also present. The role of Th2 and Th17 cells in atherogenesis is still debated. In the plaque, other T helper cells can be observed such as Th9 and Th22 but is little is known about their impact in atherosclerosis. Heterogeneity of CD4(+) T cell subsets presented in the plaque may suggest for plasticity of T cell that can switch the phenotype dependening on the local microenvironment and activating/blocking stimuli. Effector T cells are able to recognize self-antigens released by necrotic and apoptotic vascular cells and induce a humoral immune reaction. Tth cells resided in the germinal centers help B cells to switch the antibody class to the production of high-affinity antibodies. Humoral immunity is mediated by B cells that release antigen-specific antibodies. A variety of B cell subsets were found in human and murine atherosclerotic plaques. In mice, B1 cells could spontaneously produce atheroprotective natural IgM antibodies. Conventional B2 lymphocytes secrete either proatherogenic IgG, IgA, and IgE or atheroprotective IgG and IgM antibodies reactive with oxidation-specific epitopes on atherosclerosis-associated antigens. A small population of innate response activator (IRA) B cells, which is phenotypically intermediate between B1 and B2 cells, produces IgM but possesses proatherosclerotic properties. Finally, there is a minor subset of splenic regulatory B cells (Bregs) that protect against atherosclerotic inflammation through support of generation of Tregs and production of anti-inflammatory cytokines IL-10 and TGF-β and proapoptotic molecules.


A rapid procedure for the isolation of human sex steroid binding protein.
A three stage procedure is described which provides a rapid, simple, and reliable means to isolate sex steroid binding protein from human serum. Purification is achieved by the sequential use of affinity chromatography, isoelectric focusing in granulated gels and ion exchange chromatography. Between 3--4 mg of protein can be recovered from one litre of pregnancy serum without four days. A molecular radius of 2.98 nm and an apparent molecular mass of 91 000 were obtained for the purified native protein by polyacrylamide gel electrophoresis. A value of 50 000 was obtained for the molecular mass of the reduced protein by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate. The purified protein was used to prepare a monospecific rabbit antiserum and a murine monoclonal antibody. Partial characterisation of the latter has been achieved.


Transcription of the non-repetitive genome in liver hypertrophy and the homology between nuclear RNA of normal and 12 H-regenerating liver.
The percentage of the non-repetitive genome transcribed and the complexity of nuclear RNA were estimated in normal and 12 h-regenerating rat liver. Nuclear RNA from normal or 12 h-regenerating liver hybridizes with approximately 6.1% of non-repetitive DNA (12.2% of the single-copy genome, assuming assymetric transcription). The estimated complexity of either of these nuclear RNA populations is 7.6 . 10(10) daltons, which is approximately 7 times higher than that calculated for polysomal mRNA. Cross hybridization experiments did not show differences between the nuclear RNA populations of normal and 12 h-regenerating liver. The results indicate that liver hypertropy (without hyperplasia) may be brought about without a large increase in the proportion of the non-repetitive genome transcribed.


Presence of Not5 and ubiquitinated Rps7A in polysome fractions depends upon the Not4 E3 ligase.
In this study, we determine that Saccharomyces cerevisiae Not4 E3 ligase ubiquitinates Rps7A in vivo and in vitro, but not its paralogue, Rps7B. Ubiquitinated Rps7A is detectable only in 80S and polysomes, but not in free 40S fractions. A different role of the Rps7 paralogues in vivo is supported by the observation that the deletion of Rps7A but not Rps7B is sensitive to translational inhibitors and leads to an accumulation of aggregated proteins. An important accumulation of aggregated proteins that include ribosomal proteins and ribosome-associated chaperones is also observed in cells lacking Not4. A contribution of Not4 to ribosomal function extending beyond Rps7A ubiquitination is supported by the observation that the deletion of Not4 displays a synthetic slow growth phenotype when combined with the deletion of either one of the two Rps7 paralogues. Not4 is detectable in polysome fractions, as are other subunits of the Ccr4-Not complex such as Not5. The optimal presence of Not5 in polysomes is dependent upon Not4 and the deletion of Not5 leads to a dramatic reduction of polysomes. These results lead us to suggest that Not4 contributes to normal polysome levels and is important for cellular protein solubility maybe in part by ubiquitination of Rps7A.


Strategies and Challenges to Myocardial Replacement Therapy.
Cardiovascular diseases account for the majority of deaths globally and are a significant drain on economic resources. Although heart transplants and left-ventricle assist devices are the solution for some, the best chance for many patients who suffer because of a myocardial infarction, heart failure, or a congenital heart disease may be cell-based regenerative therapies. Such therapies can be divided into two categories: the application of a cell suspension and the implantation of an in vitro engineered tissue construct to the damaged area of the heart. Both strategies have their advantages and challenges, and in this review, we discuss the current state of the art in myocardial regeneration, the challenges to success, and the future direction of the field. This article outlines the advantages and limitations of the cell injection and patch approaches to cardiac regenerative therapy. If the field is to move forward, some fundamental questions require answers, including the limitations to the use of animal models for human cell-transplantation studies; the best way to measure success in terms of functional improvements, histological integration, electrical coupling, and arrhythmias; and where the cells should be applied for maximal benefit-the epicardium or the myocardium.


Spontaneous Uterine Vessel Rupture During Pregnancy or in the Puerperium: A Review of the Literature.
Spontaneous perinatal rupture of a uterine vessel is a rare occurrence that may lead to severe hemorrhage and requires prompt identification and management. The aim of this study was to examine the etiologies, locations, diagnostic tools, treatment options, and risks in subsequent pregnancies when spontaneous rupture of a uterine vessel occurs in pregnancy. A literature search was performed by university research librarians using the PubMed, CINAHL, and Web of Science search engines. Identified were 78 cases of perinatal spontaneous uterine vessel rupture and formed the basis for this review. Increased uterine blood flow during pregnancy may alter the integrity of pelvic vessels leading to increased risk of spontaneous rupture. The uterine artery is the most common site of vessel rupture; the second most common site is the uterine-ovarian plexus. The most common presentation is abdominal or pelvic pain, maternal vital sign abnormalities, and an absence of vaginal bleeding. Exploratory laparotomy and embolization (interventional radiology) have been reported as management options. Spontaneous rupture of uterine vessels is a rare but potentially life-threatening complication of pregnancy that should be included in the differential diagnosis of pregnant patients presenting with an acute abdomen. Our aim is to increase the awareness of spontaneous vessel rupture during pregnancy to improve detection, management, and perinatal outcomes.


Involvement of Arp2/3 complex in the process of colorectal carcinogenesis.
Increased motility is one of the characteristics of cancer cells, and actin polymerization and disassembly are essential for cellular motility. Since actin-related protein (Arp) 2/3 complex acts as a nucleus for actin polymerization, in this study, we immunohistochemically investigated the expression of Arp2 and Arp3 in 175 colorectal tumors in various stages of neoplastic progression. Arp2 and Arp3 showed identical expression patterns, and both were expressed in the stromal cells around neoplastic tubules or glands and in the tumor cells themselves. The frequency of expression of Arp2 and Arp3 (Arp2 and 3) by the stromal cells increased with the atypia of the colorectal neoplasms, from 5.5% (3/55) in adenoma with mild or moderate atypia, to 11.8% (2/17) in adenoma with severe atypia, 53.3% (16/30) in intramucosal carcinoma, and 91.8% (67/73) in invasive carcinoma (P<0.0001). The frequency of expression of Arp2 and 3 in the tumor cells was similar and was 1.8% (1/55) in adenoma with mild or moderate atypia, 23.5% (4/17) in adenoma with severe atypia, 23.5% (7/30) in intramucosal carcinoma, and 32.9% (24/73) in invasive carcinoma. Expression of Arp2 and 3 by the stromal cells was significantly correlated with nuclear accumulation of p53 in the tumor cells and stromal expression of CD10. These results suggest that formation of Arp2/3 complex by both neoplastic and stromal cells contributes to the increased motility of both cell types and thus provides suitable conditions for invasion.


Lessons from animal models of NASH.
Studies of animals with obesity-related liver disease have taught us much about the mechanisms that mediate this pathology. Our work with genetically obese, insulin-resistant ob/ob mice demonstrates that hepatocytes become steatotic and die at increased rates. Thus, ob/ob mice develop non-alcoholic steatohepatitis (NASH) spontaneously. NASH is intimately related to the insulin resistance (i.e., metabolic) syndrome, a constellation of disorders that result from abnormal production of hormones and cytokines that regulate inflammatory responses. Like humans with the metabolic syndrome, ob/ob mice exhibit increased tumor necrosis factor (TNF) but relatively low levels of adiponectin. Because TNF and adiponectin typically antagonize each other, the combination of increased TNF and decreased adiponectin promotes a state of high TNF activity. Consequently, hepatocytes generate excessive reactive oxygen species (ROS), have altered viability, accumulate lipid and are resistant to insulin. Treatments that inhibit TNF activity or that increase adiponectin improve NASH in ob/ob mice, other mice and humans with NASH. Hence, there is no doubt that cytokine and hormonal imbalances play a key role in the pathogenesis of NASH. However, the fundamental cellular events involved are still poorly understood. Even within very small areas of livers with NASH, most hepatocytes are merely steatotic, while others are ballooned (pre-necrotic), and still others have succumbed to apoptosis. This observation suggests cell-to-cell variability in the response to chronic inflammatory stress. In NASH, most steatotic hepatocytes survive by inducing adaptive, cytoprotective factors. However, such cells respond to super-imposed toxic and mitogenic stimuli differently than (3)naïve(2) (un-adapted) hepatocytes. Fatty hepatocytes tend to be more vulnerable to ATP depletion and less proliferative, perpetuating chronic liver injury while encouraging the expansion of liver progenitor populations that may become neoplastic. Finally, like other causes of chronic injury, NASH increases the risk for cirrhosis. Studies of ob/ob mice demonstrate that progression to cirrhosis is potentiated by leptin. Leptin probably acts at multiple levels to promote hepatic fibrosis, including direct activation of stellate cells via leptin receptors, regulation of pro- and anti-fibrogenic cytokine production by innate immune cells, and modulation of other neuronal factors that regulate stellate cell activation. The latter two mechanisms seem to dominate because stellate cell activation, fibrogenic cytokine production, collagen gene expression and fibrosis can all be induced by manipulating cytokines and neuronal factors in ob/ob mice (that are genetically deficient in leptin). Thus, studies in mice have uncovered several basic mechanisms that explain the dysfunction that occurs in different types of liver cells during the metabolic syndrome. This has important therapeutic implications for human NASH.


Is there more than one way to skin a newt? Convergent toxin resistance in snakes is not due to a common genetic mechanism.
Convergent evolution of tetrodotoxin (TTX) resistance, at both the phenotypic and genetic levels, characterizes coevolutionary arms races between amphibians and their snake predators around the world, and reveals remarkable predictability in the process of adaptation. Here we examine the repeatability of the evolution of TTX resistance in an undescribed predator-prey relationship between TTX-bearing Eastern Newts (Notophthalmus viridescens) and Eastern Hog-nosed Snakes (Heterodon platirhinos). We found that that local newts contain levels of TTX dangerous enough to dissuade most predators, and that Eastern Hog-nosed Snakes within newt range are highly resistant to TTX. In fact, these populations of Eastern Hog-nosed Snakes are so resistant to TTX that the potential for current reciprocal selection might be limited. Unlike all other cases of TTX resistance in vertebrates, H. platirhinos lacks the adaptive amino acid substitutions in the skeletal muscle sodium channel that reduce TTX binding, suggesting that physiological resistance in Eastern Hog-nosed Snakes is conferred by an alternate genetic mechanism. Thus, phenotypic convergence in this case is not due to parallel molecular evolution, indicating that there may be more than one way for this adaptation to arise, even among closely related species.


Esophageal achalasia after Roux-en-Y gastric bypass for morbid obesity.
The development of achalasia in patients with a prior Roux-en-Y gastric bypass (RYGB) is rare and it often remains unclear whether the esophageal motility disorder is a pre-existing condition in the obese patient or develops de novo after the procedure. The aim of this study was to review the available evidence regarding the management of patients with achalasia after a RYGB. Intra-sphincteric injection of botulinum toxin and pneumatic dilatation can be used to eliminate the functional obstruction at the level of the gastroesophageal junction. However, considering that achalasia patients after RYGB are often young and these treatment modalities have shown worse long-term outcomes, endoscopic or surgical myotomy is preferred. Per-oral endoscopic myotomy (POEM) is a very effective first line of treatment, and as RYGB is an excellent anti-reflux operation per se, post-POEM reflux may not be an issue in these patients. Laparoscopic Heller myotomy (LHM) is also an effective and safe therapy in achalasia patients with RYGB anatomy, and the gastric remnant can be safely used to perform a fundoplication to cover the myotomy. LHM and POEM are both acceptable primary treatment modalities in this setting. Further studies are needed to elucidate the pathophysiology and optimal management of patients with achalasia after RYGB.


Three actin-binding proteins are developmentally regulated in rat liver plasma membranes.
Actin-binding membrane proteins (linking microfilaments to the cell membrane) are involved in cytoskeleton-membrane interactions which are supposed to undergo profound changes during cell proliferation and development. In this study 8 polypeptides were shown to bind F-actin directly in the liver cell membranes of mature rats. From these, the abundance of three polypeptides, of 130, 50 and 36 kDa, was observed to increase considerably during postnatal development, which indicates a developmental change in the cytoskeleton-membrane interactions.


Serum Krebs von den Lungen-6 is associated with in-Hospital mortality of patients with severe Community-Acquired Pneumonia: A retrospective cohort study.
Currently, no ideal biomarker can accurately stratify the risk of patients with severe community-acquired pneumonia (SCAP). This study aimed to evaluate the role of serum Krebs von den Lungen-6 (sKL-6) in predicting in-hospital mortality in adults with SCAP. In this retrospective cohort study, 249 severe pneumonia adult patients were recruited between 6 May 2021 to 30 April 2023 in Xiangya Hospital of Central South University. The sKL-6 level within 48 h of admission was measured, and the primary outcome assessed was in-hospital mortality. Multivariable logistic regression analysis was performed to calculate adjusted odds ratios (OR) with 95% confidence intervals (CI). Survival curves were plotted and subgroup analyses were conducted, stratified by relevant covariates. A total of 249 patients were included in the study,with 124 patients having normal sKL-6 levels, and 125 patients having abnormal sKL-6 levels. The overall in-hospital mortality rate was 28.9% (72 out of 249 patients). Univariate and multivariate logistic regression analysis revealed that the patients with abnormal sKL-6 levels had a higher risk of in-hospital mortality compared to those with normal sKL-6 levels, both in the total SCAP patient population (OR: 5.38, 95%CI: 2.41-12.01, P < 0.001) and the non-COVID-19 SCAP patients subgroup (OR: 8.12, 95%CI: 3.16-20.84, P < 0.001). Subgroup and interaction analyses confirmed the stability of the relationship between sKL-6 levels and in-hospital mortality(P for interaction > 0.05). Kaplan-Meier survival curves showed that patients with abnormal sKL-6 levels had a higher in-hospital mortality rate than those with normal sKL-6 levels (P < 0.05). However, the results of restricted cubic spline plots(RCS) analysis demonstrated a nonlinear association between sKL-6 levels (as a continuous variable) and in-hospital mortality in patients with SCAP. Similar results were observed in non-COVID-19 SCAP patients. Furthermore, the receiver operating characteristic curve (ROC) analysis revealed that sKL-6 had superior predictive performance compared to existing biomarkers (e.g., APACHE-II, SOFA, BUN/Cr, PCT, and D-dimer) for in-hospital mortality in non-COVID-19 SCAP patients. sKL-6 is a practical and useful biomarker for predicting in-hospital mortality in patients with SCAP.


Jejunal diverticulosis - A case series and literature review.
Scant literature is available regarding in vivo jejunal diverticulosis, in part due to its typically asymptomatic course. This is made more difficult by the difficulty in establishing its diagnosis. This case series examines a number of patients presenting to our hospital with jejunal diverticular disease, and their varying clinical courses. A number of cases that had presented to our hospital with jejunal diverticulosis were reviewed retrospectively in keeping with PROCESS guidelines. Their presentations, investigations, and management rationale are discussed in brief. The presentation of jejunal diverticulosis is varies significantly along a spectrum, with a number of symptoms similar to other common intra-abdominal pathologies. The imaging modalities of choice are a barium small bowel series, CT scans, and enteroclysis, varying in sensitivity and complexity. Decision making with regards to operative vs. non-operative management is typically in line with that of colonic diverticulosis, though no strict guidelines have been established. Jejunal diverticulosis is an uncommon, with scarce data available on the appropriate investigation and management pathways. Its presentation is difficult to differentiate from other intra-abdominal pathology, and its investigations either poorly sensitive or costly and technically challenging. The general consensus on its management is similar to that of colonic diverticula, though more research needs is warranted.


Neuropeptidomic analysis of the brain and thoracic ganglion from the Jonah crab, Cancer borealis.
Mass spectrometric methods were applied to determine the peptidome of the brain and thoracic ganglion of the Jonah crab (Cancer borealis). Fractions obtained by high performance liquid chromatography were characterized using MALDI-TOF MS and ESI-Q-TOF MS/MS. In total, 28 peptides were identified within the molecular mass range 750-3000Da. Comparison of the molecular masses obtained with MALDI-TOF MS with the calculated molecular masses of known crustacean peptides revealed the presence of at least nine allatostatins, three orcokinin precursor derived peptides, namely FDAFTTGFGHS, [Ala(13)]-orcokinin, and [Val(13)]-orcokinin, and two kinins, a tachykinin-related peptide and four FMRFamide-related peptides. Eight other peptides were de novo sequenced by collision induced dissociation on the Q-TOF system and yielded AYNRSFLRFamide, PELDHVFLRFamide or EPLDHVFLRFamide, APQRNFLRFamide, LNPFLRFamide, DVRTPALRLRFamide, and LRNLRFamide, which belong to the FMRFamide related peptide family, as well as NFDEIDRSGFA and NFDEIDRSSFGFV, which display high sequence similarity to peptide sequences within the orcokinin precursor of Orconectes limosus. Our paper is the first (neuro)peptidomic analysis of the crustacean nervous system.


[Cochlear mechanics: new experimental data (author's transl)].
The goal of this research is to confirm or disprove the presently accepted theories concerning the cochlear mechanism using: -- enlarged mechanical models of the cochlea, reproducing the known anatomy as accurately as possible, -- true sinusoidal stimuli or transient, -- objective documents (photographs and films).


Adenovirus-mediated transfer of the neurotrophin-3 gene into skeletal muscle of pmn mice: therapeutic effects and mechanisms of action.
Several neurotrophic factors (CNTF, BDNF, IGF-1) have been suggested for the treatment of motor neuron diseases. In ALS patients, however, the repeated subcutaneous injection of these factors as recombinant proteins is complicated by their toxicity or poor bioavailability. We have constructed an adenovirus vector coding for neurotrophin-3 (AdNT-3) allowing for stable and/or targeted delivery of NT-3 to motoneurons. The intramuscular administration of this vector was tested in the mouse mutant pmn (progressive motor neuronopathy). AdNT-3-treated pmn mice showed prolonged lifespan, improved neuromuscular function, reduced motor axonal degeneration and efficient reinnervation of muscle fibres. NT-3 protein and also adenovirus vectors, when injected into muscle, can be transported by motoneurons via retrograde axonal transport to their cell bodies in the spinal cord. Using ELISA and RT-PCR analyses in muscle, spinal cord and serum of AdNT-3-treated pmn mice, we have investigated the contribution of these processes to the observed therapeutic effects. Our results suggest that most if not all therapeutic benefit was due to the continuous systemic liberation of adenoviral NT-3. Therefore, viral gene therapy vectors auch as adenoviruses, AAVs, lentiviruses and new types of gene transfer not based on viral vectors that allow for efficient in vivo liberation of neurotrophic factors have potential for the future treatment of human motor neuron diseases.


Analyzing China's coal-related carbon emissions from economic growth perspective: Through decoupling and decomposition model.
To evaluate the relationship between coal-related carbon emissions (CCE) and economic growth, this paper analyzed the decoupling relationship between CCE and economic growth from national and provincial perspectives during period 1997-2016 through Tapio Decoupling Index. Then, to recognize its spatial characteristics during 1997-2016, gravity model was adopted to study the geographical changes of CCE. Finally, to identify the changes of (CCE) in China and reveal its internal driving forces, this paper employs the logarithmic mean Divisia index (LMDI) decomposition analysis to decompose decoupling indicator into six effects including emission factors, energy intensity, fossil energy structure, energy consumption structure, activity, and population at national and provincial levels. The results reflect that (1) CCE of China rose by 168.37% from 1997 to 2016, and reached the peak of 7948.43 Mton in 2013. The center of gravity has shifted from (114.64 E, 34.70 N) to (113.48 E, 35.06 N). (2) The decoupling curve showed an inverted "U" shape. The economic growth of 18 provinces has achieved a strong decoupling from CCE by 2016. Only Xinjiang, Shanxi, and Shaanxi's economic growth has increased the dependence on CCE. (3) Activity and energy intensity effects were the dominant factors driving and curbing the increase of decoupling indicator respectively.


Biochemical studies of pigments from a pathogenic fungus Microsporum cookei. V. Evidence for the transmembrane permeability of xanthomegnin across phospholipid bilayer membranes.
Direct evidence is provided for the transmembrane permeation of xanthomegnin across phospholipid bilayer membranes using ascorbate-loaded liposomes. This process may be associated with an uncoupling effect on the oxidative phosphorylation of mitochondria.


The effect of different carbohydrate intakes on body weight and nitrogen balance during nasogastric feeding after faciomaxillary surgery.
In order to assess the effects on body composition of different carbohydrate intakes when nitrogen supply is constant and adequate (9 g/day), we gave either no carbohydrate, sufficient to avoid ketosis (100 g) or at least enough to satisfy energy needs (600 g) to a group of six patients after major faciomaxillary surgery. Each patient was given the different feeds for 3-day periods in a randomised, cross over design. 100 g carbohydrate was effective in avoiding negative nitrogen balance, but weight loss was only prevented when 600 g was used. Differences in water balance suggest that mobilisation and repletion of body glycogen (with associated water) probably account for most of these differences in body weight changes.


Two decades of chronic kidney disease of unknown aetiology (CKDu) research: Existing evidence and persistent gaps from epidemiological studies in Sri Lanka.
Chronic Kidney Disease of unknown origin (CKDu) excludes known primary renal conditions or systemic disease (such as diabetes mellitus or hypertension). Prominence of CKDu has been noted for some decades in Sri Lanka, especially among men in particular rural areas, prompting many studies directed towards environmental causation. This article critically reviews relevant primary studies. Articles for this literature review (n = 86) were found by searching Medline, Embase, Global Health and ProQuest databases over 2000-2020 utilizing a standard algorithm. Articles were critiqued according to criteria for diagnosis of CKDu, aetiological agents investigated, analytic methods employed and findings. Criteria for diagnosis of CKDu varied significantly, including pre-selection by proteinuria, eGFR and biopsy proven interstitial nephritis. Prevalence studies have been largely conducted in the North Central Province, with recent studies demonstrating the presence of CKDu in other regions. Aetiological factors investigated in primary studies included water source, use of agrochemicals, agricultural work, heavy metals, snake bites, ayurvedic medication, heat stress, infectious diseases and usage of tobacco and betel leaf. There is no conclusive evidence for any one aetiological agent despite consistent evidence of distal factors such as male sex, rural residence and farming. The current body of evidence for any aetiological agent as the cause of CKDu in Sri Lanka is limited. Further research with stronger study designs is necessary to increase knowledge of aetiology of CKDu in Sri Lanka to identify and eliminate exposure to possible causative agent(s) prior to concluding that the disease is multifactorial.


Pharmacokinetics of varying doses of nicotinamide and tumour radiosensitisation with carbogen and nicotinamide: clinical considerations.
Plasma concentrations, after administration of varying doses of nicotinamide, were measured in CBA male mice using a newly-developed high performance liquid chromatography assay. In all dose groups, peak levels were observed within the first 15 min after an i.p. administration of 0.1, 0.2, 0.3 or 0.5 mg g-1 of nicotinamide. There was a clear dose-dependent increase in plasma concentration with increasing dose, with almost a five-fold lower concentration (1.0 vs 4.9 mumol ml-1) achieved with a dose of 0.1 mg g-1 compared with 0.5 mg g-1, respectively. The half-life of nicotinamide increased from 1.4 h to 2.2 h over the dose range (P < 0.01). Comparisons with previous pharmacokinetic data in humans show that clinically-relevant oral doses of 6 and 9 g in humans give plasma levels slightly higher than those achieved at 1 h with doses of 0.1 to 0.2 mg g-1 in mice. Tumour radiosensitisation with carbogen alone, and with carbogen combined with varying doses of nicotinamide (0.05 to 0.5 mg g-1), was investigated using a 10-fraction in 5 days X-ray schedule. Relative to air-breathing mice, a statistically significant increase in sensitisation was observed with both a local tumour control and with an in vivo/in vitro excision assay (P < or = 0.007). With the local control assay, a trend was observed towards lower enhancement ratios (ERs) with decreasing nicotinamide dose (from 1.85 to 1.55); carbogen alone was almost as effective as when combined with 0.1 mg g-1 of nicotinamide. With the excision assay, ERs for carbogen combined with nicotinamide increased with decreased levels of cell survival. At a surviving fraction of 0.02, enhancement ratios of 1.39-1.48 were obtained for carbogen plus 0.1 to 0.3 mg g-1 of nicotinamide. These were lower than those seen with the two higher doses of 0.4 to 0.5 mg g-1 (ERs = 1.63-1.69).


Retracted: Evaluation of the Quality and Effect of 360° Safe Indwelling Infusion of Peripheral Venous Indwelling Needle in Pediatric Clinic.
[This retracts the article DOI: 10.1155/2022/1499927.].


Quantitation and localization of acinar cell-specific mucin in submandibular glands of mice during postnatal development.
In this study, antiserum to acinar cell-specific mucin was utilized to determine whether mucin could be detected in the mouse submandibular gland prior to cytodifferentiation of acinar cells. Results from radioimmunoassay indicated that mucin occurs in submandibular glands from newborn mice, i.e., before the appearance of mature acinar cells. Additionally, mucin quantitated in various stages of development was found to be antigenically identical to adult mucin. After sections of glands were treated with immunohistochemical reagents, we observed that the mature acinar cell-specific mucin was present in secretory terminal-tubule cells and in proacinar cells of newborn animals. The present findings suggest that in young animals, the proacinar cells are an immediate precursor of acinar cells and that the secretory terminal-tubule cells may represent an earlier stage in development of acinar cells. In adult female glands, mucin was also detected in the granular intercalating-duct cells. This latter observation is consistent with the hypothesis that these cells are an intermediate in the acinar cell replacement process.


Ball milling - a new concept for predicting degradation profiles in active pharmaceutical ingredients.
A method for forced oxidative mechanochemical degradation of active pharmaceutical ingredients (APIs) using clopidogrel hydrogensulfate as a model compound is presented. Considerable and selective formation of degradants occurs already after very short reaction times of less than 15 minutes and the nature of the products is strongly dependent on the used oxidant.


Restraint of spreading-dependent activation of polymorphonuclear leukocyte NADPH oxidase in an acidified environment.
Elucidation of the mechanisms by which environmental pH affects or regulates the functions of polymorphonuclear leukocytes (PMNs) is important because severe acidification of the microenvironment often prevails at sites of inflammation where they act in host defense. In the present study, we investigated the effect of an acidic environment on spreading-dependent activation of O2- -producing NADPH oxidase in PMNs. We found that PMNs underwent spreading spontaneously over type I collagen and plastic surfaces at both neutral and acidic pH, although spreading over fibrinogen surfaces, for which cellular stimulation with H2O2 is required, was inhibited by acidic pH. At acidic pH, however, PMNs were unable to undergo spreading-dependent production of O2-. Pharmacological experiments showed that p38 mitogen-activated protein kinase (MAPK) was involved in the signaling pathways mediating the spreading-dependent activation of NADPH oxidase, and that its spreading-dependent phosphorylation of Thr-180 and Tyr-182, a hallmark of activation, was impaired at acidic pH. Furthermore, the inhibition by acidic pH of O2- production as well as p38 MAPK phosphorylation subsequent to spreading induction was reversible; environmental neutralization and acidification after induction of spreading at acidic and neutral pH, respectively, up- and down-regulated the two phenomena. Acidic pH did not affect the O2- production activity of NADPH oxidase pre-activated by phorbol 12-myristate 13-acetate (PMA). These results suggest that, in PMNs, the p38 MAPK-mediated signaling pathway functions as a pH-sensing regulator of spreading-dependent NADPH oxidase activation.


Noninvasive in vivo detection of a fluorinated neuroleptic in the human brain by 19F nuclear magnetic resonance spectroscopy.
A fluorinated long-acting neuroleptic (fluphenazine decanoate) was detected in the human brain by fluorine nuclear magnetic resonance spectroscopy (MRS). The MRS system used had a 3 Tesla magnetic field, corresponding to a frequency of 118 MHz for the fluorine nucleus (Bruker Medspec 3 Tesla, 60-cm magnet bore width). The spectra were obtained with a surface coil having a 10-cm diameter, which was centered alternatively on the frontal lobe and basal ganglia, and on the occipital lobe. The impregnation and elimination kinetics of fluphenazine were monitored during three sessions (4 hours, 5 days, and 11 days after injection of the compound). This technique can be usefully applied to the in vivo study of the pharmacokinetics and site of action of psychiatric compounds in man.


[Comparative studies on the basic Ca2+ antagonistic activities of niludipine (Bay a 7168) and nifedipine (Bay a 1040) on the myocardium, myometrium and vessels of smooth muscles (author's transl)].
Niludipine (bis(2-propoxyethyl)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate; Bay a 7168) with respect to its specific actions on mammalian myocardium, sino-auricular or atrio-ventricular pacemakers, myometrium, and vascular smooth muscle has to be considered one of the most potent representatives of the new group of calcium antagonists. The pharmacodynamic effects of niludipine strikingly resemble those of nifedipine both qualitatively and quantitatively. Interestingly enough, niludipine is also a powerful coronary vasodilator. This is made particularly evident by the present experiments on potassium- or glycoside-contractured smooth musculature originating from large extramural coronary stem arteries.


Reconstruction of curved mandibular angle defects using a new internal transport distraction device: an experiment in goats.
A new internal distraction device, comprising a square-bodied bow, a transport plate, a traction mechanism, and two stabilisers, was developed to allow transportation of bone around an arc. Eight adult goats were studied. A curved mandibulectomy 3cm long was made on the mandibular angle. The distractor was implanted to restore the defect. The bone was distracted at a rate of 1mm per day after a 5-day latent period. Distraction lasted 25 to 32 days. Curvilinear distraction was successful in six of the eight goats. After consolidation periods of four or eight weeks, smooth curved bone masses were restored in the distracted areas. Radiographically, there was considerable bone density in the distraction area and opaque columns streamed in the direction of distraction. Histological examination showed membranous bony regeneration in the restored bone. These results suggest that restoration of curved bone defects using the new internal transport distraction device was feasible in goats.


Translational Value of Drug Discrimination with Typical and Atypical Antipsychotic Drugs.
This chapter focuses on the translational value of drug discrimination as a preclinical assay for drug development. In particular, the importance of two factors, i.e., training dose and species, for drug discrimination studies with the atypical antipsychotic clozapine is examined. Serotonin receptors appear to be an important pharmacological mechanism mediating clozapine's discriminative cue in both rats and mice, although differences are clearly evident as antagonism of cholinergic muscarinic receptors is important in rats at a higher training dose (5.0 mg/kg) of clozapine, but not at a lower training dose (1.25 mg/kg). Antagonism of α1 adrenoceptors is a sufficient mechanism in C57BL/6 and 129S2 mice to mimic clozapine's cue, but not in DBA/2 and B6129S mice, and only produces partial substitution in low-dose clozapine discrimination in rats. Dopamine antagonism produces partial substitution for clozapine in DBA/2, 129S2, and B6129S mice, but not in C57BL/6 mice, and partial substitution is seen with D4 antagonism in low-dose clozapine drug discrimination in rats. Thus, it is evident that clozapine has a complex mixture of receptor contributions towards its discriminative cue based on the data from the four mouse strains that have been tested that is similar to the results from rat studies. A further examination of antipsychotic stimulus properties in humans, particularly in patients with schizophrenia, would go far in evaluating the translational value of the drug discrimination paradigm for antipsychotic drugs.


Lenvatinib for effectively treating antiangiogenic drug-resistant nasopharyngeal carcinoma.
Nasopharyngeal carcinoma (NPC) clinical trials show that antiangiogenic drugs (AADs) fail to achieve the expected efficacy, and combining AAD with chemoradiotherapy does not show superiority over chemoradiotherapy alone. Accumulating evidence suggests the intrinsic AAD resistance in NPC patients with poorly understood molecular mechanisms. Here, we describe NPC-specific FGF-2 expression-triggered, VEGF-independent angiogenesis as a mechanism of AAD resistance. Angiogenic factors screening between AAD-sensitive cancer type and AAD-resistant NPC showed high FGF-2 expression in NPC in both xenograft models and clinical samples. Mechanistically, the FGF-2-FGFR1-MYC axis drove endothelial cell survival and proliferation as an alternative to VEGF-VEGFR2-MYC signaling. Genetic knockdown of FGF-2 in NPC tumor cells reduced tumor angiogenesis, enhanced AAD sensitivity, and reduced pulmonary metastasis. Moreover, lenvatinib, an FDA recently approved multi-kinase inhibitor targeting both VEGFR2 and FGFR1, effectively inhibits the tumor vasculature, and exhibited robust anti-tumor effects in NPC-bearing nude mice and humanized mice compared with an agent equivalent to bevacizumab. These findings provide mechanistic insights on FGF-2 signaling in the modulation of VEGF pathway activation in the NPC microenvironment and propose an effective NPC-targeted therapy by using a clinically available drug.


MPs voice concerns over IT progress.
A report by the House of Commons Committee of Public Accounts has highlighted anxieties about the way in which information technology provision for the NHS is progressing. Health Estate Journal reports.


Enhancing the thermostability, UV shielding and antimicrobial activity of transparent chitosan film by carbon quantum dots containing N/P.
The chitosan (CS) transparent film has attracted much attention in food and medicine packaging areas due to their biodegradability and good availability. A novel carbon quantum dots compound containing nitrogen and phosphorus (NP-CQDs) was obtained by reacting citric acids, with urea and phytic acids. The density of the film was increased, and the water vapor permeation was reduced by the presence of NP-CQDs. The introduction of 4 wt% NP-CQDs increased the water contact angle of the CS film from 79.2° to 105.8°. The shielding on UV-A and UV-B transmittance was increased with the NP-CQDs loading. The film containing 4 wt% NP-CQDs blocked more than 90.2% UV-A and 96.5% UV-B; however, it only blocked 26.8% visible light. It also exhibited better antibacterial activity to both E. coli and S. aureus than the control CS film. This work provided a feasible way to prepare multifunctional bio-safe film.


Interaction of human beta-endorphin with the terminal SC5b-9 and "preterminal" SC5b-7 and SC5b-8 complexes of human complement.
Human beta-endorphin (beta H-EP) is demonstrated to bind to the "preterminal" SC5b-7 and SC5b-8 complexes and to the terminal SC5b-9 complex of human complement. Detailed binding studies revealed saturability, reversibility and structural specificity of the beta H-EP interaction with high or low affinity non-opiate binding sites on SC5b-7 and SC5b-9 complexes. The high affinity binding sites seem to be located predominantly on C5b, C6 or C7 subunits of the complexes.


Polysarcosine-Coated liposomes attenuating immune response induction and prolonging blood circulation.
Liposomes coated with long polysarcosine (PSar) chains at a high density might enable long blood circulation and attenuate accelerated blood clearance (ABC) phenomenon. In this study, we controlled the length (23, 45, 68 mers) and density (5, 10, 15 mol%) of PSar on liposomal coatings and, furthermore, investigated the effects of PSar length and density on the blood circulation time, biodistribution, immune response, and ABC phenomenon induction. Length-controlled PSar-bound lipids (PSar-PEs) were synthesized using a click reaction and inserted into bare liposomes at different combinations of chain lengths and proportions. Although all PSar-coated liposomes (PSar-lipos) had similar morphological, physical, and chemical properties, they had different blood circulation times and biodistribution, and exerted varied effects on the immune system. All PSar-lipos with different PSar length and density showed a similar anti-PSar IgM response. Liposomes modified with the longest PSar chain (68 mers) at a high density (15 mol%) showed the longest blood circulation time and, additionally, attenuated ABC phenomenon compared with PEG-lipo. The ex vivo analysis of the biodistribution of liposomes revealed that a thick PSar layer enhanced the blood circulation time of liposomes due to the reduction of the accumulation of liposomes in the liver and spleen. These findings provide new insights into the relationship between IgM expression and ABC phenomenon inhibition.


Endometrioid carcinoma of the ovary: a retrospective analysis of 106 cases.
This report retrospectively analyzes 106 cases of endometrioid carcinoma of the ovary treated at the National Cancer Institute of Milan from 1974 through December 1993. In 12 of the 106 cases (11.3%) a synchronous carcinoma of the uterine body was observed. Only patients who had previously untreated disease were included in the study. Patients with synchronous tumors were staged according to their ovarian cancer and treated according to the stage of that disease. Thirty-nine patients (36.8%) had stage 1, 17 (16.0%) stage 11, 43 (40.6%) stage III, and 7 (6.6%) stage IV disease. Moderately plus poorly differentiated tumors were present in 76 of the 106 cases (71.7%). Considering the 67 patients with advanced disease, residual tumor was absent in 27 cases (40.3%), < or = 2 cm in 17 (25.4%), and > 2 cm in 23 (34.3%) cases. Systematic pelvic and para-aortic lymphadenectomy was performed in 60 patients (56.6%); selective sampling was carried out in 23 cases (21.7%). After surgery, 77 patients underwent various chemotherapy regimens. Using univariate analysis, FIGO stage, tumor grade, residual disease after surgery, lymph node status, and platinum in the chemotherapy regimen significantly influenced 5-year survival. However, when all these variables were included in a multivariate analysis only FIGO stage still had a significant impact on survival. Survival analysis also showed a trend towards longer survival in patients with synchronous tumors.


Lactobacillus-mediated inhibition of clinical toxic shock syndrome Staphylococcus aureus strains and its relation to acid and peroxide production.
The inhibitory activities of 39 strains representing 20 different species of Lactobacillus toward a menstrual toxic shock syndrome (TSS) Staphylococcus aureus archetype strain MN8 were investigated. Nearly every strain (38 of 39) produced an inhibitory effect under both aerobic and anaerobic conditions when assayed on agar medium. In addition, the MN8 inhibition was conserved against at least 10 other clinical TSS S. aureus isolates and, interestingly, required actively growing cultures of Lactobacillus (verified with a two-well co-culture system in broth medium). This general uniform inhibition could be ameliorated by organic buffer (PIPES) supplied in the growth medium and, with only one exception, MRS medium adjusted with non-organic acid (HCl) failed to support growth of TSS strains at or below pH 5.5. By comparison, the vast majority of lactobacilli in this study decreased culture pH to a range of 4-5. Hydrogen peroxide production by the lactobacilli was also assessed and verified by two different methodologies revealing a broad spectrum of phenotypes that, contrary to reports touting its effectiveness, did not seem to correspond with our inhibition studies. Furthermore, resistances to peroxide by MN8, other TSS strains, and a subset of lactobacilli used in this study were nearly identical whereas the S. aureus collection was slightly more sensitive to racemic lactic acid than the lactobacilli. Collectively, these data suggest that the underlying inhibition toward Staphylococcus is generally conserved in Lactobacillus sp. and is related to a common factor in this genus involving promotion of acidic conditions.


Gastroesophageal Reflux Disease and Barrett Esophagus in the Elderly.
As our population continues to age, the early diagnosis and optimal management of patients with gastroesophageal reflux disease becomes paramount. Maintaining a low threshold for evaluating atypical symptoms in this population is key to improving outcomes. Should patients develop complications including severe esophagitis, peptic stricture, or Barrett esophagus, then a discussion of medical, endoscopic, and surgical treatments that accounts for patient's comorbidities and survival is important. Advances in screening, surveillance, and endoscopic treatment of Barrett esophagus have allowed us to dispel concerns of futility and treat a larger subset of the at-risk population.


Naloxone-associated pulmonary edema following recreational opioid overdose.
Describe a series of patients who developed naloxone-associated pulmonary edema after recreational opioid use. Single center retrospective case series of patients who developed pulmonary edema following the prehospital administration of naloxone. Academic, urban safety-net hospital. Adults with recreational opioid overdose who developed naloxone-associated pulmonary edema, defined as the acute onset of respiratory distress, hypoxemia, and radiographic pulmonary edema after naloxone administration for opioid intoxication, provided that gas exchange and chest imaging rapidly improved and pulmonary aspiration of gastric contents was not clinically suspected. Ten adults (median age 23 years, 90% male) met our case definition for naloxone-associated pulmonary edema. Implicated opioids were heroin in 8 patients and methadone and oxycodone in 1 patient each. The median total dose of naloxone was 4.25 mg (interquartile range [IQR] 3.3-9.8) prior to the onset of clinically-apparent pulmonary edema. Seven patients received invasive mechanical ventilation for a median of two days (IQR 0.8-5), one of whom received veno-venous extracorporeal membrane oxygenation support, and all survived to hospital discharge. Severe acute pulmonary edema may follow naloxone administration after recreational opioid overdose. Acute care clinicians should be aware of this potentially life-threatening adverse effect of naloxone.


The Impact of a 20-Minute Animal-Assisted Activity Session on the Physiological and Emotional States in Patients With Fibromyalgia.
To study the direct physiological and emotional impact of an animal-assisted activity (AAA) session (a form of complementary and integrative medicine) in patients with fibromyalgia (FM). The study population consisted of 221 participants with FM who were attending Mayo Clinic's Fibromyalgia Treatment Program between August 5, 2017, and September 1, 2018. This was a randomized controlled trial. Participants were randomly assigned to either the treatment group (a 20-minute session with a certified therapy dog and handler) or the control group (a 20-minute session with a handler only). To gain a better understanding of the direct physiological and emotional effects of AAA in patients with FM, we used multiple noninvasive physiologic-emotional biomarkers, including salivary cortisol and oxytocin concentrations, tympanic membrane temperatures, and various cardiac parameters, in addition to standardized pain and mood-based questionnaires. Results show a decrease in heart rate, an increase in heart rate variability, an increase in well-being survey scores, an increase in salivary oxytocin, and subsequent tympanic membrane temperature changes, suggesting that participants in the treatment group were in a more positive emotional-physiologic state as a result of the AAA session compared with the control group. Our results suggest that a 20-minute therapy dog visit in an outpatient setting can significantly and positively impact the physical and mental health of patients with FM.


Exogenous ACTH stimulus during the preovulatory period alters patterns of leukocyte recruitment in the ovary of dairy cows.
Before ovulation, the ovary exhibits signs of local inflammation. However, the effects of adrenocorticotropin (ACTH) on the complexity of this inflammatory response are not yet well described. Thus, the aim of this study was to evaluate the effects of ACTH administered to dairy cows during the preovulatory period on the local distribution of different subsets of leukocytes infiltrated in the ovary, along with the gene expression of relevant chemokines (C-C motif chemokine ligand-2 (CCL2), C-X-C motif chemokine ligand-8 (CXCL8), CCL25 and CXCL1) involved in leukocyte chemotaxis and blood perfusion on the follicular wall of dominant follicles. Also, the direct effect of ACTH on chemokine gene expression was addressed in cultured antral follicular walls. For this purpose, both an in vivo and an in vitro experiment were performed. For the in vivo experiment, exogenous ACTH (100 IU) was administered intramuscularly to Holstein cows (n = 12) during proestrus every 12 h for four days before ovulation, when ovariectomy was performed (day 18). Daily ovarian Doppler ultrasonography was used to evaluate the percentage of irrigated area, the pulsatility index and the resistance index in the dominant follicles. The distribution of monocytes-macrophages (CD14), T- (CD2) and B-lymphocytes (CD79a) and granulocytes (CH138A) in the ovary was analyzed by immunohistochemistry. In follicular wall samples, gene expression of CCL2, CXCL8, CXCL1 and CCL25 was evaluated, whereas IL-17A expression was analyzed by Western blot. The total number of CD14, CD79a and CD2 infiltrated cells was lower in the ACTH-treated group than in the control group (p < 0.05). Chemokine gene expression showed lower mRNA of CCL2, CCL25 and CXCL1 (p < 0.05) in the ACTH-treated group. Meanwhile, IL-17A protein expression and hemodynamic parameters were similar between groups (p > 0.05). In the in vitro assay, antral follicular walls were stimulated with ACTH to corroborate the gene expression profile of chemokines. mRNA expression of CCL2 tended to be lower in the stimulated follicular walls (p = 0.092). Our results suggest that exogenous ACTH stimulus during the preovulatory period reduces the number of infiltrated leukocytes in the bovine ovary and this could be due to a lower chemotaxis capacity of the ovary.


From text to knowledge: a unifying document-centered view of analyzed medical language.
Although medical language processing (MLP) has achieved some success, the actual use and dissemination of data extracted from free text by MLP systems is still very limited. We claim that the adoption of an 'enriched-document' paradigm (or 'document-centered' view) can help to address this issue. We present this paradigm and explain how it can be implemented, then discuss its expected benefits both for end-users and MLP researchers.


Biparametric versus Multiparametric MRI with Non-endorectal Coil at 3T in the Detection and Localization of Prostate Cancer.
To assess the sensitivity of biparametric magnetic resonance imaging (bpMRI) with non-endorectal coil in the detection and localization of index (dominant) and non-index lesions in patients suspected of having prostate cancer. We carried-out a retrospective analysis of multiparametric MRI (mpMRI) of 41 patients who underwent radical prostatectomy. Results of MRI for detection and localization of index and non-index lesions were correlated with those of histology. No statistically significant difference in size was seen between tumor lesion at histology and index lesion at MRI. In 41 patients, a total of 131 tumors were identified at histology, while bpMRI (T2-weighted and diffusion-weighted MRI) approach detected 181 lesions. bpMRI gave 27.6% false-positives and 3.3% false-negatives. Sensitivity in lesion detection by bpMRI increased with lesion size assuming high values for lesions ≥10 mm. For bpMRI and mpMRI, the sensitivity for detecting index lesions was the same and equal: 100% in the peripheral zone 97.6% and 94.7% in the entire prostate and transitional zone, respectively. bpMRI can be used alternatively to mpMRI to detect and localize index prostate cancer.


Alkaline elution of DNA from stomach pyloric mucosa of rats treated with glyoxal.
DNA damage in the pyloric mucosa of the stomach of male F344 rats was determined by the alkaline elution method after administration of glyoxal, a direct-acting mutagen present in various heated foods, by gastric intubation. Glyoxal at doses of 50-550 mg/kg body weight induced DNA damage in the pyloric mucosa of rat stomach, detected by a 5- to 12-fold increase in the elution rate constant 2 h after its administration. N-Methyl-N'-nitro-N-nitrosoguanidine, a glandular stomach carcinogen, used as a positive control at doses of 1-100 mg/kg body weight induced a 11- to 24-fold increase in the elution rate constant, while 2-acetylaminofluorene, which is not a gastric carcinogen, given as a negative control at doses of 200-400 mg/kg body weight did not increase the elution rate constant. Thus glyoxal, which was previously suggested to induce unscheduled DNA synthesis in the pyloric mucosa of rat stomach, was confirmed to be genotoxic in this region.


Exploring complex and heterogeneous correlations on hypergraph for the prediction of drug-target interactions.
The continuous emergence of drug-target interaction data provides an opportunity to construct a biological network for systematically discovering unknown interactions. However, this is challenging due to complex and heterogeneous correlations between drug and target. Here, we describe a heterogeneous hypergraph-based framework for drug-target interaction (HHDTI) predictions by modeling biological networks through a hypergraph, where each vertex represents a drug or a target and a hyperedge indicates existing similar interactions or associations between the connected vertices. The hypergraph is then trained to generate suitably structured embeddings for discovering unknown interactions. Comprehensive experiments performed on four public datasets demonstrate that HHDTI achieves significant and consistently improved predictions compared with state-of-the-art methods. Our analysis indicates that this superior performance is due to the ability to integrate heterogeneous high-order information from the hypergraph learning. These results suggest that HHDTI is a scalable and practical tool for uncovering novel drug-target interactions.


Effects of dissolved oxygen, salinity, nitrogen and phosphorus on the release of heavy metals from coastal sediments.
Great amounts of nutrients discharged into the urbanized coastal areas, which are continuously subject to violently anthropogenic metal contamination, will result in eutrophication and hypoxic episode. In order to study the effects of dissolved oxygen (DO), salinity, nitrogen and phosphorus on the release of six metals including Zn, Pb, Cd, Cu, As and Cr from coastal sediments, a series of 60-days microcosm experiments consisting of sediments and seawater were conducted. Severe hypoxia could result in the enhanced peak values of Pb, Cd, Cu and Cr concentrations in the overlying water. A higher level of water salinity could elevate the peak value of As concentration in water column, and a higher level of nitrogen could increase the peak value of Zn concentration in water. The exchange fluxes demonstrated that the diffusion from the sediments was a dominant process during the first 10 days, However, a relative equilibrium of adsorption and precipitation in the sediment-water interface reached during the later periods. In addition, the bioavailability of the studied metals in sediments was elevated under severe hypoxia, or a high level of water salinity, or high levels of nitrogen and phosphorus. The results of linear regression analysis suggested that higher metal bioavailability in sediments could facilitate the metal release, but the process could be restrained by the higher aqueous phosphorus due to the precipitation of metal phosphates.