Evaluation of lung metabolism during successful twenty-four-hour canine lung preservation.
We used a canine left lung allotransplantation model to evaluate 24-hour lung preservation with two different electrolyte solutions, low-potassium dextran and low-potassium dextran with 1% glucose. To investigate changes in the energy status during preservation, we analyzed the lungs for adenosine triphosphate, phosphocreatine, and several metabolites of the glycolysis pathway and the citric acid cycle: glucose, glucose-6-phosphate, lactate, citrate, and malate. We also devised and evaluated a pulmonary cooling jacket to prevent rewarming of the lung during implantation. The lungs were divided into four groups. Groups I (n = 10) and II (n = 6) were flushed with low-potassium dextran and groups III (n = 6) and IV (n = 6) were flushed with low-potassium dextran solution with 1% glucose. The cooling jacket was used for groups II and IV only. After 24-hour preservation at 10 degrees C, the left lungs were implanted into the recipient animals. Function of the transplanted left lung was assessed during temporary (10 minutes) occlusion of the contralateral pulmonary artery while both lungs were ventilated with 100% oxygen. This assessment was performed at 1 hour and at 3, 8, and 22 days after transplantation. Immediately after transplantation the arterial oxygen tension was 279 +/- 70 mm Hg in group I, 376 +/- 56 mm Hg in group II, 523 +/- 41 mm Hg in group III, and 518 +/- 50 mm Hg in group IV. The arterial oxygen tension in groups III and IV were significantly greater than in group I (p < 0.05). Of the lungs preserved with low-potassium dextran solution with 1% glucose solution, 11 of 12 (92%) showed excellent lung function (arterial oxygen tension > 300 mm Hg) at 3 days; only 10 of 16 lungs preserved with low-potassium dextran achieved this level of function. Glucose, glucose-6-phosphate, lactate, citrate and malate levels decreased significantly during 24-hour preservation with low-potassium dextran solution; they were stable with low-potassium dextran solution with 1% glucose. Adenosine triphosphate and phosphocreatine were stable for 24 hours with both low-potassium dextran and low-potassium dextran solution with 1% glucose. The cooling jacket provided uniform cooling of the lung parenchyma during implantation, and significant increase in temperature was observed in its absence, with topical cooling by cold saline solution.(ABSTRACT TRUNCATED AT 400 WORDS)


The urokinase/urokinase receptor system mediates the IgG immune complex-induced inflammation in lung.
Immune complex (IC) deposition induces an acute inflammatory response with tissue injury. IC-induced inflammation is mediated by inflammatory cell infiltration, a process highly regulated by the cell surface-specific receptor (uPAR), a binding partner for the urokinase-type plasminogen activator (uPA). We assessed the role of the uPA/uPAR system in IC-induced inflammation using the pulmonary reverse passive Arthus reaction in mice lacking uPA and uPAR compared with their corresponding wild-type controls. Both uPA-deficient C57BL/6J (uPA(-/-)) and uPAR-deficient mice on a mixed C57BL/6J (75%) x 129 (25%) background (uPAR(-/-)) demonstrated a marked reduction of the inflammatory response due to decreased production of proinflammatory mediators TNF-alpha and Glu-Leu-Arg (ELR)-CXC chemokine MIP-2. In uPAR(-/-) animals, the reduction of inflammatory response was more pronounced because of decreased migratory capacity of polymorphonuclear leukocytes. We show that the uPA/uPAR system is activated in lung of wild-type mice, particularly in resident alveolar macrophages (AM), early in IC-induced alveolitis. This activation is necessary for an adequate C5a anaphylatoxin receptor signaling on AM that, in turn, modulates the functional balance of the activating/inhibitory IgG FcgammaRs responsible for proinflammatory mediator release. These data provide the first evidence that the uPA/uPAR plays an important immunoregulatory role in the initiation of the reverse passive Arthus reaction in the lung by setting the threshold for C5a anaphylatoxin receptor/FcgammaR activation on AM. The findings indicate an important link between the uPA/uPAR system and the two main components involved in the IC inflammation, namely, complement and FcgammaRs.


Is epidemiology correcting its vision problem? A perspective on our perspective: 2012 presidential address for American College of Epidemiology.
Epidemiology, like all disciplines, exists within and is shaped by a culture that frames its ways of understanding. In the last 60 years epidemiology as a discipline and scientific approach has undergone major transition, but remains challenged by vestiges of the limiting frameworks of our origins which shape the way we approach questions, and even the questions we choose to investigate. A part of the current transformation is a reframing of our perspective and a broadening of our methods to encourage creativity and to encompass new types of evidence and new approaches to investigation and interpretation. Epidemiologists are developing innovative ways to approach increasingly complex problems and becoming more open to multi-disciplinary approaches to solving epidemiologic challenges.


Role of HPV DNA, HPV mRNA and cytology in the follow-up of women treated for cervical dysplasia.
The aim of this study was to assess the role of cytology, human papilloma virus (HPV) DNA and human papilloma virus messenger RNA (HPV mRNA) assays in detecting cervical intraepithelial neoplasia grade 2+ (CNi 2+) (recurrences/persistence) during the follow-up of women after treatment of cervical intraepithelial lesion. This cross-sectional study was performed among 43 women treated for cervical intraepithelial neoplasia (CIN) between January 2014 and January 2017 at the Department of Obstetrics and Gynecology of Spedali Civili's Hospital, Brescia, Italy. Pap smear and cervical samples for HPV tests were collected during the follow-up visit. Furthermore, colposcopy was always performed in order to find out the persistence/recurrence of the disease. A cervical biopsy was collected when necessary. Cervical samples obtained were tested for HPV DNA using the INNO-LiPa HPV assay and for HPV mRNA using the APTIMA assay. The mean age of enrolled women was 42.5 years. Among the treated patients, more than 50% of women revealed the absence of high risk HPV DNA and HPV mRNA. We found the persistence of the disease cervical intraepithelial neoplasia grade 2 (CIN 2) only in one woman. The sensitivity of cytology, HPV DNA and HPV mRNA in detecting disease was satisfactory (100%), while the specificity was quite different for the three tests: 64.2, 52.4 and 78.9%, respectively. The HPV mRNA test has higher specificity with respect to cytology and HPV DNA, avoiding the referral to unnecessary colposcopy with an improvement of costs/benefits for healthcare system. However, given the small size sample, this study should be considered as a pilot for future larger studies.


Mutation of RORγT reveals a role for Th17 cells in both injury and recovery from renal ischemia-reperfusion injury.
To investigate T helper type 17 (Th17) cells in the setting of acute kidney injury, the gene encoding the master regulator of Th17 cell differentiation, that is, RAR-related orphan receptor-γ (RORγT), was mutated in Lewis rats using CRISPR/Cas9 technology. In response to 40 min of bilateral renal ischemia-reperfusion (I/R), RAR-related orphan receptor C (Rorc)-/- rats were resistant to injury relative to wild-type Rorc+/+ rats. This protection was associated with inhibition of IL-17 expression and reduced infiltration of CD4+ cells, CD8+ cells, B cells, and macrophages. To evaluate the effect of Th17 cells on repair, ischemia was increased to 50 min in Rorc-/- rats. This maneuver equalized the initial level of injury in Rorc-/- and Rorc+/+ rats 1 to 2 days post-I/R based on serum creatinine values. However, Rorc-/- rats, but not Rorc+/+ rats, failed to successfully recover renal function and had high mortality by 4 days post-I/R. Histological assessment of kidney tubules showed evidence of repair by day 4 post-I/R in Rorc+/+ rats but persistent necrosis and elevated cell proliferation in Rorc-/- rats. Adoptive transfer of CD4+ cells from the spleen of Rorc+/+ rats or supplementation of exogenous rIL-17 by an osmotic minipump improved renal function and survival of Rorc-/- rats following 50 min of I/R. This was associated with a relative decrease in the number of M1-type macrophages and a relative increase in the percentage of T regulatory cells. Taken together, these data suggest that Th17 cells have both a deleterious and a beneficial role in kidney injury and recovery, contributing to early postischemic injury and inflammation but also possibly being critical in the resolution of inflammation during kidney repair.


Acute urinary retention secondary to Epstein-Barr virus infection in a pediatric patient: a case report and review of causes of acute urinary retention in children.
We present the case of a 12-year-old boy with acute urinary retention presumed secondary to Epstein-Barr virus infection. Workup revealed an atonic bladder, which was refractory to medical management. The patient subsequently developed axillary lymphadenopathy, and the biopsy specimen was consistent with Epstein-Barr virus. In addition to presenting this patient with acute urinary retention secondary to EBV infection, we review the causes of acute urinary retention in children, with a focus on viral etiologies.


Structural and biological behaviors of some nonionic Schiff-base amphiphiles and their Cu(II) and Fe(III) metal complexes.
Novel series of nonionic Schiff bases was synthesized and characterized using microelemental analysis, FTIR and (1)H NMR spectra. These Schiff bases and their complexes with Cu and Fe have been evaluated for their antibacterial activity against bacterial species such as Staphylococcus aureus, Pseudomonas aureus, Candida albi, Bacillus subtilis and Escherichia coli and their fungicidal activity against Aspcrgillus niger and Aspcrgillus flavus. The results of the biocidal activities showed high potent action of the synthesized Schiff bases towards both bacteria and fungi. Furthermore, complexation of these Schiff bases by Cu(II) and Fe(III) show the metal complexes to be more antibacterial and antifungal than the Schiff bases. The results were correlated to the surface activity and the transition metal type. The mode of action of these complexes was discussed.


Effects of the Auxivo CarrySuit occupational exoskeleton when carrying front and side loads on a treadmill.
Low-cost exoskeletons can effectively support workers in physically demanding jobs, but most such exoskeletons have been developed to support repetitive lifting or uncomfortable static postures. Very few low-cost exoskeletons have been designed to support walking while carrying heavy objects, which would be beneficial for jobs such as moving furniture and warehouse work. This paper thus presents a single-session lab evaluation of the Auxivo CarrySuit, a low-cost upper-body exoskeleton designed for carrying objects that would normally be held with the arms. Twenty participants carried four loads (box or two bags, 20 or 40 lb total weight) for 2 min each on a treadmill with and without the CarrySuit. Across all loads, the CarrySuit significantly reduced the mean electromyogram of the middle trapezius (partial eta-squared = 0.74 - from 16.1% to 8.8% of maximum voluntary contraction value) and anterior deltoid (partial eta-squared = 0.26 - from 3.0% to 1.1% of maximum voluntary contraction value) with no corresponding increase in lower back muscle activation. Furthermore, maximum heart rate and Ratings of Perceived Exertion were also reduced by the CarrySuit, and discomfort was shifted from the upper body to the legs. While arm EMG was not measured, it is likely that it was also reduced due to the unloading of the arms. The CarrySuit can thus be considered beneficial in the short term, though longer-term evaluations with actual workers are needed to determine practical benefits.


Crystal structures of human saposins C andD: implications for lipid recognition and membrane interactions.
Human saposins are essential proteins required for degradation of sphingolipids and lipid antigen presentation. Despite the conserved structural organization of saposins, their distinct modes of interaction with biological membranes are not fully understood. We describe two crystal structures of human saposin C in an "open" configuration with unusual domain swapped homodimers. This form of SapC dimer supports the "clip-on" model for SapC-induced vesicle fusion. In addition, we present the crystal structure of SapD in two crystal forms. They reveal the monomer-monomer interface for the SapD dimer, which was confirmed in solution by analytical ultracentrifugation. The crystal structure of SapD suggests that side chains of Lys10 and Arg17 are involved in initial association with the preferred anionic biological membranes by forming salt bridges with sulfate or phosphate lipid headgroups.


Factors affecting the distribution of lumbricids (Oligochaeta) in associations at peat and mineral sites in northern England.
1. Earthworms were collected in pitfall traps from 46 moorland sites over a period of two years; mineral moorland sites were sampled by formalin solution and gave density estimates of 40-100 worms per square metre. 2. Thirteen species were found and A. chlorotica and A. caliginosa were most abundant. Sites were clustered on the basis of species present and showed mineral and peat sites clearly separate. Six species were almost confined to mineral sites and B. eiseni was virtually confined to peat sites. 3. Environmental factors measured at the sites were used in multiple regression analysis to identify those significant in governing the distribution of each species; pH, loss in wieght on ignition of soil, plant association and dominant plant were among those significant. 4. Cluster analysis showed only one cluster of seven species. The distribution of most of these had been shown to be determined by dominant plant species (or a factor associated with this) or by soil pH. 5. Species in a cluster are largely responding to the same group of environmental factors but detailed investigation of microdistribution and laboratory experiments to identify other factors which affect their population dynamics are needed to fully explain the geographical distribution of earthworms.


A sensorimotor representation impairment in dyslexic adults: A specific profile of comorbidy.
Sensorimotor disorders have been frequently reported in children and adults with dyslexia over the past 30 years. The present study aimed to determine the impact of sensorimotor comorbidity risks in dyslexia by investigating the functional links between phonological and sensorimotor representations in young dyslexic adults. Using 52 dyslexic participants and 58 normo-readers, we investigated whether the underlying phonological deficit, which is reported in the literature, was associated with a general impairment of sensorimotor representations of articulatory and bodily actions. Internal action representations were explored through motor imagery tasks, consisting of measuring and comparing the durations of performed or imagined actions chosen from their current repertoire of daily life activities. To detect sensorimotor deficits, all participants completed the extended version of the M-ABC 2, as a reference test. We found sensorimotor impairments in 27% of the young adult dyslexics, then considered as sensorimotor comorbid, as opposed to much less in the normo-reader group (5%). While motor slowdown, reflecting motor difficulty, was present in all dyslexic adults, motor imagery performance was impacted only in the specific dyslexic subgroup with sensorimotor impairments. Moreover, in contrast with slowness, only the comorbid subgroup showed an increased variability in execution durations. The present study highlights the importance of the quality of perception-action coupling, questions the relevance of investigating sensorimotor impairment profiles beyond phonological deficits and provides new arguments supporting the perspective of multiple deficits approaches in dyslexia.


Future Frontiers in Shoulder Arthroplasty and the Management of Shoulder Osteoarthritis.
Shoulder arthroplasty has advanced considerably in recent decades, but the most recently published long-term outcomes continue to have unacceptably high failure rates, especially in young patients. However, there are several future frontiers that offer the promise of improved implant longevity and function including advances in surgical approach, such as subscapularis-sparing approaches and computer-assisted surgical planning; advances in humeral component fixation, such as stemless, short-stem, and convertible implants; advances in bearing surfaces, such as pyrocarbon, ceramic, and metal-on-metal; and advances in glenoid component geometry and fixation, such as augmented components, in-growth pegs, and inlay glenoid components.


Novel antiproliferative falcarindiol furanocoumarin ethers from the root of Angelica japonica.
Four novel antiproliferative furanocoumarin ethers of falcarindiol, named japoangelols A (8.5), B (7.2), C (7.4), and D (8.4), were isolated from the root of Angelica japonica together with panaxynol (0.3), falcarindiol (3.2), (9Z)-1,9-heptadecadiene-4,6-diyne-3,8,11-triol (2.2), and 8-acetoxyfalcarinol (3.2). Structures were established from the spectroscopic evidence, and the inhibitory activities (ED50, microgram/ml, shown in the parentheses) were evaluated using the MTT assay.


The prevalence and epidemiology of gastrointestinal parasites of horses in Victoria, Australia.
A quantitative post mortem study of 150 horses from Victoria was conducted to determine the prevalence and epidemiology of gastrointestinal parasites. A total of 42 species of metazoan parasite was found. The following species of non-cyathostome parasite were found (% prevalence): Trichostrongylus axei (51%); Habronema muscae (13%); H. majus (2%); Draschia megastoma (5%); Gastreophilus intestinalis (81%); G. nasalis (29%); Parascaris equorum (5%); Anoplocephala perfoliata (29%); Fasciola hepatica (0.7%); Oxyuris equi (7%); Strongylu vulgaris (23%); S. edentatus (23%); S. equinus (3%); Craterostomum acuticaudatum (7%); Triodontophorus serratus (8%); T. tenuicollis (8%); T. brevicauda (3%). Ninety-five per cent of horses were infected with gut-wall encysted stages of cythostomes with a mean intensity of 113,000 larvae per horse. Ninety-three per cent of all horses harboured adult cyathosome worms; 24 species representing 6 genera were found. The 3 most prevalent species were Cylicostephanus longiburstatus (76%); Cyathostomum catinatum (68%) and Cylicocyclus nassatus (54%). Seventeen species of strongyle were present in high abundance, which allowed their site distribution in the large intestine to be determined. Twelve species preferred the large colon to the small colon and caecum, and the remaining 5 species preferred the caecum. Statistical analysis of the parasitological data set allowed effects of sex, age, type, and physical condition of the horse as well as the season and environment on the prevalence and mean intensity of infection to be determined.


Rise of the guardians: Gut microbial maneuvers in bacterial infections.
Bacterial infections are one of the major causes of mortality globally. The gut microbiota, primarily comprised of the commensals, performs an important role in maintaining intestinal immunometabolic homeostasis. The current review aims to provide a comprehensive understanding of how modulation of the gut microbiota influences opportunistic bacterial infections. Primarily centered around mechanisms related to colonization resistance, nutrient, and metabolite-associated factors, mucosal immune response, and commensal-pathogen reciprocal interactions, we discuss how gut microbiota can promote or prevent bacterial infections. Opportunistic infections can occur directly due to obligate pathogens or indirectly due to the overgrowth of opportunistic pathobionts. Gut microbiota-centered mechanisms of altered intestinal immunometabolic and metabolomic homeostasis play a significant role in infection promotion and prevention. Depletion in the population of commensals, increased abundance of pathobionts, and overall decrease in gut microbial diversity and richness caused due to prolonged antibiotic use are risk factors of opportunistic bacterial infections, including infections from multidrug-resistant spp. Gut commensals can limit opportunistic infections by mechanisms including the production of antimicrobials, short-chain fatty acids, bile acid metabolism, promoting mucin formation, and maintaining immunological balance at the mucosa. Gut microbiota-centered strategies, including the administration of probiotics and fecal microbiota transplantation, could help attenuate opportunistic bacterial infections. The current review discussed the gut microbial population and function-specific aspects contributing to bacterial infection susceptibility and prophylaxis. Collectively, this review provides a comprehensive understanding of the mechanisms related to the dual role of gut microbiota in bacterial infections.


Engineered CCR5 superagonist chemokine as adjuvant in anti-tumor DNA vaccination.
Chemokine receptors are promising targets for enhancing T-cell immunity and anti-cancer therapy. CCL5 is a potential adjuvant for DNA vaccination. We postulated that CCR5 superagonists could be even more effective. A CCR5 superagonist derived from natural CCL5 by directed in vitro evolution, namely 1P7, is used as a DNA vaccine adjuvant and expressed as fused chemokine-Ig (1P7-Ig). We show that OVA+1P7-Ig DNA co-inoculation induced higher frequencies of OVA-specific CD8 lymphocytes than OVA+CCL5-Ig or controls and gave an even better protection against tumor growth in a CCR5-dependant manner. Our results indicate that CCR5-superagonists may provide potent adjuvants for vaccines.


Clinical skills training of U.S. medical students.
Although there is general agreement that the teaching of clinical procedures needs vast improvement, little appears to have been done to achieve this goal, particularly with regard to medical students. In the summer and fall of 1992, 60 U.S. medical schools participated in a telephone survey about how they taught clinical procedures to medical students. The schools were in 30 states and the District of Columbia; 36 were public and 24 were private. The schools were asked to describe what procedures were taught, how, and over what duration of time, with a focus on whether students were taught procedures prior to their clinical rotations. More than three-fourths of the schools (47 of 60) offered nothing other than an introduction to phlebotomy. Only four schools offered more extensive courses (40-50 hours) that covered a variety of topics. Few schools had adopted any formal method for training students to perform clinical procedures. In light of this problem, the authors describe a solution that has proven popular at the Stanford University School of Medicine--an elective course in surgical skills developed in 1988-89 and continuing to the present. Although the content of this particular course focuses on surgical procedures, important topics from other disciplines could easily be added or substituted. The course incorporates techniques that have previously been shown to be successful, such as the use of plastic models and cadavers. It also enables students to learn by performing procedures on each other, and to benefit from continuity of supervision by being taught by one faculty member.


Synthesis and characterization of a brush-like copolymer of polylactide grafted onto chitosan.
A brush-like poly(DL)-lactide grafted onto chitosan as the backbone was investigated. The graft copolymerization was carried out with triethylaluminum as catalyst in toluene at 70 degrees C. It was found that a greater lactide content in the feeding ratio results in a higher grafting percentage. FTIR spectrometry, (1)H NMR, DSC scanning, and wide-angle X-ray scattering, respectively, are used to characterize these branch copolymers. A copolymer has a definite melting point when the molar feeding ratio of lactide to chitosan is more than 10:1, and the deltaH of the copolymers increases with the feed ratio of lactide to chitosan in feeding.


Corticosteroids in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
Glucocorticoids (GCs) have been the cornerstone of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) therapy since their advent in the 1950s. There is considerable variation in their use, both with respect to dose and duration. Given considerable treatment-related morbidity and mortality, refining the role of GCs is becoming increasingly important. This article discusses the current role of GCs in various phases of AAV treatment, including remission induction, maintenance therapy, treatment of relapses, and the use of local GCs. It discusses current controversies relating to GC use as well as research efforts that seek to reduce GC toxicity in AAV.


A history of early life parental loss or separation is associated with successful cognitive-behavioral therapy in major depressive disorder.
There is a clinical need for evidence-based psychotherapy response biomarkers in major depressive disorder (MDD). Based on previous studies, we hypothesized that lower 24-h urinary cortisol levels and a history of early life stress/trauma would predict an improved antidepressant response to cognitive-behavioral therapy (CBT). 50 currently depressed MDD subjects were enrolled. 24-h urine was collected and measured for cortisol levels by radioimmunoassay (RIA). Subjects were also administered early life stress/trauma measures at baseline: Global Perceived Early-Life Stress (GPELS), The Early Life Trauma Inventory (ELTI) and Klein Loss Scale (KLS). The efficacy of a twelve-week course of once-weekly CBT was evaluated by the primary outcome measure, the 24-item Hamilton Depression Rating Scale (HDRS24), at baseline and every four weeks, and the Beck Depression Inventory at baseline and weekly thereafter. 42 subjects had at least one complete follow-up visit (≥4 weeks of CBT), and 30 subjects completed the full 12-week course. Baseline 24-h urinary cortisol levels did not correlate with CBT's antidepressant response. Higher KLS scores, a measure of early life parental loss or separation, correlated with delta HDRS24 (rs=-0.39, padjusted=0.05). Complementary general linear model analysis revealed enhanced CBT efficacy in patients with a history of early life parental loss or separation [F(1,35)=6.65, p=0.01]. Small sample size, Treatment-naïve population. Early life parental separation or loss positively correlated with CBT's antidepressant efficacy in our sample and may warrant further study in larger clinical samples.


Intra- and interoperator variability in fetal nasal bone assessment at 11-14 weeks of gestation.
Examination of the fetal nasal bones by ultrasound between 11 and 14 weeks of gestation has been proposed as an additional tool in the detection of trisomy 21 in a high-risk population. However the variability in the identification of fetal nasal bones by ultrasound has not yet been investigated. The aim of this study was to assess the intraobserver and interobserver reproducibility of fetal nasal bone identification by ultrasound between 11 and 14 weeks of gestation. A total of 1040 consecutive ultrasound examinations were performed at 11-14 weeks of gestation for nuchal translucency (NT) measurement and nasal bone identification by ultrasound. A total of 657 consecutive video-loops were assessed by three experienced operators. Each operator assigned cases to one of three categories, namely present, uncertain or absent nasal bones, and the results were compared between operators. To assess the intraoperator variability each operator reviewed 100 randomly selected videos out of the 657 loops and again used the same classification. Results were compared by pairwise unweighted and weighted Kappa index to evaluate the inter- and intraoperator variability. Among the 1040 fetuses, there were 51 (4.9%) with an NT measurement above the 95th centile. Nasal bones were identified by ultrasound in 948, not seen in eight and impossible to assess in 84 fetuses. Four fetuses had trisomy 21 including three with absent nasal bones and increased NT and one with present nasal bones and normal NT. The Kappa and weighted Kappa values for interoperator variability between the three operators were between 0.26 and 0.37 and 0.33 and 0.44, respectively. The Kappa and weighted Kappa values for intraoperator variability were between 0.35 and 0.48 and 0.43 and 0.55, respectively. The assessment of fetal nasal bones is only fairly reproducible. Although the performance of the test in fetuses at high risk for trisomy 21 has been reported to be good, its implementation as an additional screening technique in the general population must be accompanied by teaching and quality control programs.


Anti-inflammatory principles of Suregada multiflora against nitric oxide and prostaglandin E2 releases.
The stem bark of Suregada multiflora and the isolated compounds were carried out to investigate for anti-inflammatory activity. The stem bark of Suregada multiflora and its isolated compounds were tested for their anti-inflammatory effects against lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostraglandin E(2) (PGE(2)) releases in RAW264.7 cells as well as the anti-inflammatory mechanism on mRNA expression of the active compound (5, helioscopinolide A). The extract of Suregada multiflora possessed potent NO inhibitory effect with an IC(50) value of 8.6 μg/ml. Among the isolated compounds, helioscopinolide A (5) exhibited the highest activity against NO release with an IC(50) value of 9.1 μM, followed by helioscopinolide C (6) and suremulol D (2) with IC(50) values of 24.5 and 29.3 μM, respectively. The IC(50) value of 5 against PGE(2) production was found to be 46.3 μM. The mechanism in transcriptional level of compound 5 was found to inhibit iNOS and COX-2 mRNA expressions in dose-dependent manners. The present study may support the traditional use of Suregada multiflora stem bark for treatment of inflammatory-related diseases.


Oxidative phosphorylation and aging.
This review addresses the data that support the presence and contribution of decreased mitochondrial oxidative phosphorylation during aging to impaired cellular metabolism. Aging impairs substrate oxidation, decreases cellular energy production and increases the production of reactive intermediates that are toxic to the cell. First, the basic principles of mitochondrial oxidative physiology are briefly reviewed. Second, the focus on the relationship of altered mitochondrial respiration to the increased production of reactive oxygen species that are employed by the "rate of living" and the "uncoupling to survive" theories of aging are discussed. Third, the impairment of function of respiration in aging is reviewed using an organ-based approach in mammalian systems. Fourth, the current state of knowledge regarding aging-induced alterations in the composition and function of key mitochondrial constituents is addressed. Model organisms, including C. elegans and D. melanogaster are included where pertinent. Fifth, these defects are related to knowledge regarding the production of reactive oxygen species from specific sites of the electron transport chain.


Diet quality is associated with reduced risk of hypertension among Inner Mongolia adults in northern China.
The present study investigated the association between dietary patterns and hypertension applying the Chinese Dietary Balance Index-07 (DBI-07). A cross-sectional study on adult nutrition and chronic disease in Inner Mongolia. Dietary data were collected using 24 h recall over three consecutive days and weighing method. Dietary patterns were identified using principal components analysis. Generalized linear models and multivariate logistic regression models were used to examine the associations between DBI-07 and dietary patterns, and between dietary patterns and hypertension. Inner Mongolia (n 1861). A representative sample of adults aged ≥18 years in Inner Mongolia. Four major dietary patterns were identified: 'high protein', 'traditional northern', 'modern' and 'condiments'. Generalized linear models showed higher factor scores in the 'high protein' pattern were associated with lower DBI-07 (βLBS = -1·993, βHBS = -0·206, βDQD = -2·199; all P < 0·001); the opposite in the 'condiments' pattern (βLBS = 0·967, βHBS = 0·751, βDQD = 1·718; all P < 0·001). OR for hypertension in the highest quartile of the 'high protein' pattern compared with the lowest was 0·374 (95 % CI 0·244, 0·573; Ptrend < 0·001) in males. OR for hypertension in the 'condiments' pattern was 1·663 (95 % CI 1·113, 2·483; Ptrend < 0·001) in males, 1·788 (95 % CI 1·155, 2·766; Ptrend < 0·001) in females. Our findings suggested a higher-quality dietary pattern evaluated by DBI-07 was related to decreased risk for hypertension, whereas a lower-quality dietary pattern was related to increased risk for hypertension in Inner Mongolia.


Tolerability and therapeutic effect of clozapine. A retrospective investigation of 216 patients treated with clozapine for up to 12 years.
Two hundred and sixteen psychiatric patients (183 men and 33 women) hospitalized in Sct. Hans Hospital were treated with clozapine between 1971-1983. All had been treated previously with one or more neuroleptic(s) and had either failed to respond adequately, or their response was limited by side effects. Eighty-five patients were treated exclusively with clozapine, while the remaining 131 received additional medication, mainly other neuroleptic drugs. The mean clozapine dosage was 317 mg/day (range 50-1200), and the mean duration of treatment was 23/4 years (range 1/12-12). The tolerability to clozapine was determined by an evaluation of haematological changes, pronounced side effects and mortality. One patient treated with clozapine (8 months) and nitrofurantoin (8 days) developed a reversible granulocytopenia. One patient (treated with a combination of drugs) had clinically insignificant depression of the leucocytes and three of segmented granulocytes. Seven had a reduction in thrombocytes. Two patients developed cardiac insufficiency, and four epileptic seizures. None of the patients treated exclusively with clozapine developed neurological side effects. A global estimation of therapeutic effect revealed that clozapine alone or in combination with other neuroleptic drugs was significantly better than previous antipsychotic therapy, although 47-63% of the patients showed no change. It is concluded that clozapine is a potent antipsychotic drug offering particular advantages in the treatment of schizophrenic patients with a pronounced symptomatology and tendency towards developing extrapyramidal side effects. Caution is advised in patients with cardiac insufficiency and epilepsy. There appears to be a slight risk of granulocytopenia, and therefore the present monitoring of WBC should continue in order to prevent this reaction and to obtain more complete information regarding risk of granulocytopenia.


Diabetes mellitus with mild or moderate kidney dysfunction is associated with poor prognosis in patients with coronary artery disease: A large-scale cohort study.
Both kidney dysfunction and diabetes mellitus (DM) predict long-term poor prognosis in patients with coronary artery disease (CAD). We aimed to evaluate the clinical outcomes according to the combined status of DM and different stages of kidney dysfunction in CAD patients. From January 2013 to December 2013, 9293 eligible patients hospitalized for percutaneous coronary intervention (PCI) at Fuwai hospital were followed up for major adverse cardiovascular and cerebrovascular events (MACCEs), a composite of all-cause mortality, myocardial infarction and stroke. Baseline kidney function was considered as stage I: normal or high kidney function; stage II: mild dysfunction and stage III: moderate dysfunction according to estimated glomerular filtration rate (eGFR). Upon baseline kidney function, diabetic and non-diabetic patients were divided into six groups. During a median follow-up of 2.4 years, 326 (3.5%) MACCEs occurred. Compared to patients in the stage I/non-DM group, patients in the stage II/DM and stage III/DM groups had significantly increased MACCE risk [adjusted hazard ratio (aHR), 1.53; 95% confidence interval (CI), 1.09-2.15; P = 0.014; aHR, 3.00; 95%CI, 1.74-5.18; P < 0.002, respectively]. Additionally, there were J-shaped associations of eGFR with MACCE risk regardless of glycemic metabolism status after adjusted for confounders. Furthermore, moderate kidney dysfunction conferred an increased MACCE risk in diabetic patients with uncontrolled glycemia (aHR, 2.93; 95%CI, 1.48-5.78; P = 0.002). DM with mild or moderate kidney dysfunction is associated with poor prognosis in CAD patients. Categorical classification of patients with DM and kidney dysfunction could provide prognostic information for risk stratification of CAD patients.


Cartilage repair of the ankle: first results of T2 mapping at 7.0 T after microfracture and matrix associated autologous cartilage transplantation.
Both microfracture (MFX) and matrix associated autologous cartilage transplantation (MACT) are currently used to treat cartilage defects of the talus. T2 mapping of the ankle at 7 T has the potential to assess the collagen fibril network organization of the native hyaline cartilage and of the repair tissue (RT). This study provides first results regarding the properties of cartilage RT after MFX (mean follow-up: 113.8 months) and MACT (65.4 months). A multi-echo spin-echo sequence was used at 7 T to assess T2 maps in 10 volunteer cases, and in 10 cases after MFX and MACT each. Proton weighted morphological images and clinical data were used to ensure comparable baseline criteria. A significant zonal variation of T2 was found in the volunteers. T2 of the superficial and the deep layer was 39.3 ± 5.9 ms and 21.1 ± 3.1 ms (zonal T2 index calculated by superficial T2/deep T2: 1.87 ± 0.2, P < 0.001). In MFX, T2 of the reference cartilage was 37.4 ± 5.0 ms and 25.3 ± 3.5 ms (1.51 ± 0.3, P < 0.001). In the RT, T2 was 43.4 ± 10.5 ms and 36.3 ± 7.7 ms (1.20 ± 0.2, P = 0.009). In MACT, T2 of the reference cartilage was 39.0 ± 9.1 ms and 27.1 ± 6.6 ms (1.45 ± 0.2, P < 0.001). In the RT, T2 was 44.6 ± 10.4 ms and 38.6 ± 7.3 ms (1.15 ± 0.1, P = 0.003). The zonal RT T2 variation differed significantly from the reference cartilage in both techniques (MFX: P = 0.004, MACT: P = 0.001). T2 mapping at 7 T allows for the quantitative assessment of the collagen network organization of the talus. MACT and MFX yielded RT with comparable T2 properties.


Timing the First Pediatric Tracheostomy Tube Change: A Randomized Controlled Trial.
The first pediatric tracheostomy tube change often occurs within 7 days after placement; however, the optimal timing is not known. The primary objective was to determine the rate of adverse events of an early tube change. Secondary objectives compared rates of significant peristomal wounds, sedation requirements, and expedited intensive care discharges. Prospective randomized controlled trial. Tertiary children's hospital between October 2018 and April 2020. A randomized controlled trial enrolled children under 24 months to early (day 4) or late (day 7) first tracheostomy tube changes. Sixteen children were enrolled with 10 randomized to an early change. Median age was 5.9 months (interquartile range, 5.4-8.3), and 86.7% required tracheostomy for respiratory failure. All tracheostomy tube changes were performed without adverse events. There were no accidental decannulations. Significant wounds developed in 10% of children with early tracheostomy tube changes and 83.3% of children with late tracheostomy tube changes (odds ratio [OR], 45.0; 95% CI, 2.3-885.6; P = .01). This significant reduction in wound complications justified concluding trial enrollment. Hours of dexmedetomidine sedation (P = .11) and boluses of midazolam during the first 7 days (P = .08) were no different between groups. After the first change, 90% of the early group were discharged from intensive care within 5 weeks compared to 33.3% of patients in the late group (OR, 18.0; 95% CI, 1.2-260.9; P = .03). The first tracheostomy tube change in children can occur without adverse events on day 4, resulting in fewer significant peristomal wounds and earlier intensive care discharge.


Detection and isolation of protein susceptible indigenous bacteria affected by dietary milk-casein, albumen and soy-protein in the caecum of ICR mice.
In this study, we fed ICR mice with a high-sucrose diet containing 20% w/w of milk-casein (MC), egg-white (EW), or soy-protein (SP) for 14 days in order to detect the presence of protein-susceptible gut indigenous bacteria (P-SIB). The caecal microbiome was examined by 16S rDNA amplicon sequencing using a next-generation MiSeq system. Principal coordinate analysis of the operational taxonomic units (OTUs) revealed that the microbiomes differed among the three groups. Typical SIB found in the MC-fed group were Bacteroides acidifaciens-, Bacteroides sartorii-, Eisenbergiella sp., and Lachnospiraceae sp.-like; in the EW-fed group were Lactobacillus murinus and Enterococcus faecium/avium-like; and in the SP-fed group were Muribaculaceae sp.-like bacteria. We also found that a few Lachnospiraceae sp.- and Clostridium disporicum-like bacteria were suppressed in the EW-fed mice. Out of the P-SIB detected, B. acidifaciens, L. murinus, E. faecium, and E. avium could be isolated and identified using BL agar and 16S rDNA BLAST search, respectively.


Impact of the COVID-19 Pandemic on Hospitalizations for Alcoholic Hepatitis or Cirrhosis in Alberta, Canada.
Coronavirus disease 2019 (COVID-19) pandemic lockdown and restrictions had significant disruption to patient care. We aimed to evaluate the impact of COVID-19 restrictions on hospitalizations of patients with alcoholic and nonalcoholic cirrhosis as well as alcoholic hepatitis (AH) in Alberta, Canada. We used validated International Classification of Diseases (ICD-9 and ICD-10) coding algorithms to identify liver-related hospitalizations for nonalcoholic cirrhosis, alcoholic cirrhosis, and AH in the province of Alberta between March 2018 and September 2020. We used the provincial inpatient discharge and laboratory databases to identify our cohorts. We used elevated alanine aminotransferase or aspartate aminotransferase, elevated international normalized ratio, or bilirubin to identify AH patients. We compared COVID-19 restrictions (April-September 2020) with prior study periods. Joinpoint regression was used to evaluate the temporal trends among the 3 cohorts. We identified 2916 hospitalizations for nonalcoholic cirrhosis, 2318 hospitalizations for alcoholic cirrhosis, and 1408 AH hospitalizations during our study time. The in-hospital mortality rate was stable in relation to the pandemic for alcoholic cirrhosis and AH. However, nonalcoholic cirrhosis patients had lower in-hospital mortality rate after March 2020 (8.5% vs 11.5%; P = .033). There was a significant increase in average monthly admissions in the AH cohort (22.1/10,000 admissions during the pandemic vs 11.6/10,000 admissions before March 2020; P < .001). Before and during COVID-19 monthly admission rates were stable for nonalcoholic and alcoholic cirrhosis; however, there was a significant increase in AH admissions. Because alcohol sales surged during the pandemic, future impact on alcoholic liver disease could be detrimental.


Repeated antenatal corticosteroid treatments adversely affect neural transmission time and auditory thresholds in laboratory rats.
Antenatal corticosteroid (AC) treatment is given to pregnant women at risk for preterm birth to reduce infant morbidity and mortality by enhancing lung and brain maturation. However, there is no accepted regimen on how frequently AC treatments should be given and some studies found that repeated AC treatments can cause growth retardation and brain damage. Our goal was to assess the dose-dependent effects of repeated AC treatment and estimate the critical number of AC courses to cause harmful effects on the auditory brainstem response (ABR), a sensitive measure of brain development, neural transmission and hearing loss. We hypothesized that repeated AC treatment would have harmful effects on the offspring's ABRs and growth only if more than 3 AC treatment courses were given. To test this hypothesis, pregnant Wistar rats were given either a high regimen of AC (HAC), a moderate regimen (MAC), a low regimen (LAC), or saline (SAL). An untreated control (CON) group was also used. Simulating the clinical condition, the HAC dams received 0.2mg/kg Betamethasone (IM) twice daily for 6 days during gestation days (GD) 17-22. The MAC dams received 3 days of AC treatment followed by 3 days of saline treatment on GD 17-19 and GD 20-22, respectively. The LAC dams received 1 day of AC treatment followed by 5 days of saline treatment on GD 17 and GD 18-22, respectively. The SAL dams received 6 days of saline treatment from GD 17 to 22 (twice daily, isovolumetric to the HAC injections, IM). The offspring were ABR-tested on postnatal day 24. Results indicated that the ABR's P4 latencies (neural transmission time) were significantly prolonged (worse) in the HAC pups and that ABR's thresholds were significantly elevated (worse) in the HAC and MAC pups when compared to the CON pups. The HAC and MAC pups were also growth retarded and had higher postnatal mortality than the CON pups. The SAL and LAC pups showed little or no adverse effects. In conclusion, repeated AC treatment had harmful effects on the rat offspring's ABRs, postnatal growth and survival. The prolonged ABR latencies reflect slowed neural transmission times along the auditory nerve and brainstem auditory pathway. The elevated ABR thresholds reflect hearing deficits. We concluded that repeated AC treatment can have harmful neurological, sensory and developmental effects on the rat offspring. These effects should be considered when weighing the benefits and risks of repeated AC treatment and when monitoring and managing the prenatally exposed child for possible adverse effects.


Neonatal rat hypoxia-ischemia: Effect of the anti-oxidant mitoquinol, and S-PBN.
The production of oxygen free radicals after perinatal hypoxia-ischemia is thought to play a critical role in the pathogenesis of the brain injury. Administration of anti-oxidants may thus be neuroprotective. The aim of the present study was to investigate the effect of a mitochondria-targeted anti-oxidant mitoquinol (mitoQ) administered in the form of the prodrug mitoquinone, and an extracellular anti-oxidant N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN; Aldrich, St Louis, MO, USA), on neuronal survival in the rat striatum after acute perinatal hypoxia-ischemia. Mitoquinone at 17 micromol/L (n = 6) or 51 micromol/L (n = 6), or its diluent (n = 12), was continuously infused over 3 days into the right striatum of Sprague-Dawley rats. Infusion was via an Alzet micro-osmotic pump (Alza, Los Angeles, CA, USA), stereotaxically implanted on postnatal day (PN) 7 under anesthesia. In another experiment, S-PBN (100 mg/kg) (n = 8) or its diluent (n = 8) was administered in six s.c. injections every 12 h from the evening of PN7. Hypoxia-ischemia was induced on PN8 by right common carotid artery ligation under anesthesia, followed 2.5 h later by exposure to 8% oxygen for 1.5 h. On PN14 the pups were euthanased and 40 microm serial sections were cut through the entire striatum. The total number of medium-spiny neurons within the right striatum was stereologically determined using the optical disector/Cavalieri method. No significant difference was seen in the total number of striatal medium-spiny neurons between the 17 micromol/L or 51 micromol/L mitoQ-treated pups and their respective diluent-treated controls. No significant difference was seen in the total number of striatal medium-spiny neurons between the S-PBN-treated and diluent-treated pups. Solely targeting mitochondrial oxidants with mitoQ, or extracellular oxidants with S-PBN, is not protective for striatal medium-spiny neurons after perinatal hypoxia-ischemia.


Junctional CD8+ cutaneous lymphomas with nonaggressive clinical behavior: a CD8+ variant of mycosis fungoides?
To evaluate the clinical and prognostic features in primary cutaneous CD8+ T-cell lymphomas, which are rare and considered to be aggressive cutaneous lymphoproliferative disorders. Single-center retrospective study. Lymphoma clinic (referral center) of a university hospital. Three patients presented with CD8+ cutaneous lymphoma characterized by a patchlike pattern and hyperpigmentation. Histological analysis revealed a CD3+, CD8+ small-cell infiltrate showing a remarkable affinity to the dermoepidermal junction zone. Clonality for the T-cell receptor gamma chain was detected by polymerase chain reaction followed by denaturing gradient gel electrophoresis. The clinical presentation lasted several years (6 and 9 years, respectively) before the correct diagnosis was made. Treatment with nontoxic approaches (UV-B and local steroids) was successful. Aggressive clinical behavior was not observed. Our 3 cases of junctional CD8+ cutaneous T-cell lymphomas were characterized by hyperpigmentation and nonaggressive clinical behavior. This type of lymphoma, which can be considered a CD8+ mycosis fungoides variant, must be distinguished from other types of cutaneous CD8+ lymphomas so that overtreatment can be avoided.


Factors contributing to radiocaesium variability in upland sheep flocks in west Cumbria (United Kingdom).
Following the Chernobyl accident in 1986, restrictions were placed on the movement and slaughter of sheep within upland areas of the UK because radiocaesium activity concentrations in their meat exceeded 1000 Bq kg(-1) fresh weight. Some farms remain under restriction in 2007. From 1991 to 1993 detailed studies were conducted on three sheep farms within the restricted area of west Cumbria to systematically assess the various parameters which may contribute to the observed variability in radiocaesium activity concentrations within sheep flocks. This paper reports the spatial variation in soil and vegetation activity concentrations across the grazed areas at these farms and determines the influence of grazing behaviour on variability in (137)Cs activity concentrations between individual sheep within the flocks. Together with previously reported results, these new data are used to draw conclusions on the factors determining variability within the three flocks. However, the factors are too site specific to be able to generalise the findings to other farms within the restricted areas of the UK.


Novel variant of reversed midgut rotation - retro-arterial proximal jejunum and transverse colon: a case report and review of the literature.
Reversed rotation of the midgut is the rarest variation of midgut malrotations, which are congenital disorders that result from aberrant rotation and fixation of the midgut during embryological development. Common complications of these disorders are small bowel obstruction by volvulus or peritoneal bands, usually occurring in early infancy. A 23-year-old Caucasian woman presented with recurrent abdominal pain. A contrast-enhanced multidetector computed tomography study revealed a novel variant of reversed rotation of the midgut. Besides the specific finding of a retro-arterial transverse colon, we also found the proximal jejunum to cross posterior to the mesenteric root, a variation that has not been reported in the literature so far. In this case, substantial symptomatic relief was achieved with conservative management. The hypothesis of a double reversed rotation of the pre-arterial segment of the umbilical loop around the superior mesenteric artery axis provides a possible explanation for this anomaly. There is no evidence-based consensus on the management of patients presenting with non-symptomatic or mildly symptomatic intestinal malrotations. In this case, radiologic and clinical presentations excluded acute small bowel obstruction, and surgical intervention was avoided.


"Managing the Severe Septal Deviation Using Dorsal Preservation".
Severe septal deviations are a constant challenge for rhinosurgeons. As the septum is the most important pillar of the nasal framework, septal deformities require correction to insure a straight nose. The septum should be on the midline without any tension to ensure a correct healing of the external nasal pyramid. In certain cases, the association of a correct septoplasty and dorsal preservation allows the treatment of the crooked nose and at the same time gives natural results with rapid postoperative recovery. The aim of this article was to underline the versatility of the dorsal preservation technique for the correction of severe septal deviation.


Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability.
The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.


A new method for quantifying ventricular regularization during atrial fibrillation.
Atrial fibrillation (AF) characteristically results in random variation of the intervals between successive ventricular depolarizations. However, when a patient with AF is treated with excessive amounts of digitalis, regular junctional rhythms may occur. The detection of "regularization" of the ventricular rhythm in patients with AF may signal early digitalis toxicity. In this paper, we describe a new method for quantifying the extent of ventricular regularization by the statistical analysis of the intervals between successive ventricular depolarizations (R-R intervals). This method yields a single index (Z score) which reflects the degree to which a sequence of R-R intervals deviates from a random distribution. Simulation studies demonstrate that our method is sensitive to "regularization" of as little as two to four percent of R-R intervals, even when equal intervals occur in small groups that might easily escape detection by visual electrocardiographic interpretation. Analysis of records from six nondigitalized subjects in AF shows that the sequence of R-R intervals is usually random, or very nearly so. Records obtained from the same patients when digitalized often demonstrate more regularized activity, reflected by an index (Z score) which is higher than expected from chance deviation if a random process is assumed. Preliminary data also suggeest that exercise is associated with substantial regularization of ventricular depolarization.


Role of pulmonary intravascular macrophages in endotoxin-induced lung inflammation and mortality in a rat model.
Bile-duct ligated (BDL) rats recruit pulmonary intravascular macrophages (PIMs) and are highly susceptible to endotoxin-induced mortality. The mechanisms of this enhanced susceptibility and mortality in BDL rats, which are used as a model of hepato-pulmonary syndrome, remain unknown. We tested a hypothesis that recruited PIMs promote endotoxin-induced mortality in a rat model. Rats were subjected to BDL to induce PIM recruitment followed by treatment with gadolinium chloride (GC) to deplete PIMs. Normal and BDL rats were treated intravenously with E. coli lipopolysaccharide (LPS) with or without GC pre-treatment followed by collection and analyses of lungs for histopathology, electron microscopy and cytokine quantification. BDL rats recruited PIMs without any change in the expression of IL-1beta, TNF-alpha and IL-10. GC caused reduction in PIMs at 48 hours post-treatment (P < 0.05). BDL rats treated intravenously with E. coli LPS died within 3 hours of the challenge while the normal LPS-treated rats were euthanized at 6 hours after the LPS treatment. GC treatment of rats 6 hours or 48 hours before LPS challenge resulted in 80% (1/5) and 100% (0/5) survival, respectively, at 6 hours post-LPS treatment. Lungs from BDL+LPS rats showed large areas of perivascular hemorrhages compared to those pre-treated with GC. Concentrations of IL-1beta, TNF-alpha and IL-10 were increased in lungs of BDL+LPS rats compared to BDL rats treated with GC 48 hours but not 6 hours before LPS (P < 0.05). We conclude that PIMs increase susceptibility for LPS-induced lung injury and mortality in this model, which is blocked by a reduction in their numbers or their inactivation.


Amino acids and lactate efflux from in vitro incubated soleus muscles of suckling rats.
The net in vitro release of lactate, pyruvate, alanine, glutamate, glutamine and total amino acids from soleus muscles of suckling rats was studied. In all cases, the net output of metabolites was considerably higher in young animals than in 30 day old controls. Glutamine efflux of 1 day old pups was very low, probably due to lack of effectivity of the glutamine synthesizing system. The considerable output of amino acids in the younger animals was partly due to depletion of internal amino acid pools.


Optimization of selective pressurized liquid extraction of organic pollutants in placenta to evaluate prenatal exposure.
The early exposure to organic pollutants (OPs) related to dietary habit or environmental exposure is a concern of growing interest in environmental health. When OPs enter the body, they can accumulate in fatty tissue and even travel through the bloodstream being able to cross the placenta and reach the fetus through the substance exchange between the mother and the child. Epidemiologic and clinical data affirm that these chemicals increase the risk of adverse effects during childhood. This article reviews and addresses one of the most relevant analytical methods for determining OPs in placenta. We discuss and critically evaluate procedures, such as solid-liquid and selective pressurized liquid extraction (SPLE). Clean-up of extracts was performed by solid-phase extraction (SPE) using EZ-POP cartridges. Detection of OPs was carried out by gas chromatography (GC) coupled to tandem mass spectrometry (MS/MS). Recoveries ranged from 52% to 94% by SPLE with estimated quantification limits between 0.15 and 2.2ng/g for organochlorine pesticides (OCPs), between 0.083 and 0.50 for organophosphate pesticides (OPPs), between 0.025 and 0.15ng/g for polychlorinated biphenyl (PCBs), between 0.015 and 0.10ng/g for polybromodiphenyl ethers (PBDEs), between 0.33 and 0.66ng/g for pyrethroids and between 0.022 and 0.87ng/g for polycyclic aromatic hydrocarbons (PAHs). Most of the target OPs were detected in twenty real placenta samples studied, with pyrethroids, PAHs and OPPs representing most of the 90% of OPs with means of 13-18ng/g versus PCBs, OCPs, and PBDEs with means <4.0ng/g. The rsults of this work indicate a prenatal exposure to OPs in Galicia.


Delayed psychophysiological recovery after self-concept-inconsistent negative performance feedback.
The identification of individual differences variables and environmental conditions that may be associated with poor psychophysiological recovery from stress or may serve as protective factors may be relevant in the context of physical and psychological health maintenance. In the present study, heart rate recovery from a mental arithmetic task was examined after participants received bogus performance-related feedback that could be consistent or inconsistent with their specific self-concept about their mental arithmetic skills. That way, the participants' beliefs about their own performance in the task were experimentally manipulated. Recovery of heart rate was examined in two time windows: (1) shortly after the participants had completed the task and had received positive or negative performance feedback and (2) 10 min after the task. In order to evaluate the dynamic of changes in more detail, speed of recovery (linear slope of the continuous beat-to-beat data) was analysed in addition to the degree of recovery (average heart rate decline during the five-minute observation periods). The results indicate that negative performance-related feedback may prolong psychophysiological responses to stressful conditions, in particular when the feedback is inconsistent with the domain-specific self-concept. In conjunction with other evidence these results support the assumption that positive emotional states in the context of stressful events may contribute to poor post-stress recovery. Overall, the findings are supportive of the "perseverative cognition hypothesis" according to which psychophysiological recovery may be delayed through continued cognitive representation of a negative experience.


Feeding of the chewing louse Damalinia ovis (Schrank) (Phthiraptera:Trichodectidae) on sheep.
The possibility that Damalinia ovis ingests intact epidermis could explain economically important irritation behaviour by infested sheep. To test this, feeding lice were observed on sheep by hand lens and macrophotography and on light and scanning electron microscope preparations. Aspects of feeding behaviour were described, particularly an epidermal ingestion posture. Louse ingesta were examined in paraffin and frozen sections. Lipid-covered stratum corneum squames were identified in crop, midgut, rectum and faeces. Nucleated keratinocytes from inner epidermal strata were not seen, neither were wool fibres. Vertical frozen sheep skin sections, with feeding lice cryofixed by liquid nitrogen, showed mandibles engaged in the outer stratum corneum of the epidermis. The epidermal origin of some ingesta was confirmed by confirming lice over sheep whose skin was stained with Oil Red O, whose colour was seen in crop, midgut, rectum and faeces of harvested lice. Lipase was found in louse midgut. It was concluded that sebaceous secretions may form an important component of the D. ovis diet. The relative contribution from loose scurf or from stratum corneum squames was not determined. Mechanical stimuli by feeding lice did not seem to be the source of host irritation. The role of sensitising agents in louse brei filtrates was investigated with inconclusive results. Intradermal injections of louse faeces did not elicit a demonstrable response.


Rapid detection of eugenol in perch utilizing electrochemical method by transition metal substituted polyoxometalates.
Food safety concerns caused by the application of spice allergens to fish anaesthesia. In this paper, a chitosan-reduced graphene oxide/polyoxometalates/poly-l-lysine (CS-rGO/P2Mo17Cu/PLL) modified electrode was constructed by electrodeposition and successfully applied to the quantitative analysis of eugenol (EU). The detection limit was 0.4490 μM in the linear range of 2x10-6 M to 1.4x10-5 M. It was applied to the determination of EU residues in kidney, liver and meat tissues of perch with recoveries ranging from 85.43 to 93.60%. Besides, the electrodes demonstrate high stability (2.56% drop in current value after 70 days at room temperature), high reproducibility (RSD of 4.87% for 6 parallel electrodes) and extremely fast response time. This study provided a new material for the electrochemical detection of EU.


Increasing or fluctuating bispectral index values during post-resuscitation targeted temperature management can predict clinical seizures after rewarming.
To investigate whether an increasing bispectral index (BIS) value during targeted temperature management (TTM) correlates with increased clinical seizures after TTM or worse neurological prognoses after TTM. We performed a retrospective prognostication study of patients who were treated with TTM after recovery of spontaneous circulation from cardiac arrest at a tertiary care hospital. We recorded the BIS regularly during TTM and calculated the correlations of the mean BIS values, standard deviations of the BIS values, and linear regression coefficient of the trend of the BIS values over time as index tests. Study outcomes included the occurrence of clinical seizures after TTM and unfavourable neurological outcomes (defined as a Cerebral Performance Scale score of 3-5). Receiver operating characteristics (ROC) analyses evaluated the predictability of the index tests for the study outcomes. Of 534 patients with post-cardiac arrest who were admitted to the intensive care unit, 103 were enrolled in this study. Thirty-one patients (30.1%) experienced sequelae in the form of clinical seizures, and 52 (50.5%) had unfavourable neurological outcomes at 30days post-resuscitation. The standard deviation (area under the ROC curve [AUC]=0.763) and the regression coefficient (AUC=0.763) had higher predictability of clinical seizures than the mean BIS value (AUC=0.657); in contrast, the low mean BIS value best predicted unfavourable neurological outcomes (AUC=0.861) compared to the standard deviation (AUC=0.532) and regression coefficient (AUC=0.501). An increase of, or greater fluctuation in, BIS during hypothermia may predict clinical seizures after TTM.


Towards epidemiological criteria for soft-tissue disorders of the arm.
The lack of universally agreed criteria has hampered population studies of the prevalence and causation of soft-tissue disorders of the upper limb. To establish core variables for classification of the commonest disorders seen in population samples. Consecutive new cases seen in clinical practice in five different centres were evaluated with respect to 30 variables shown to have discriminatory value in univariate analysis. Multivariate analysis using logistic regression modelling was carried out with these as the independent variables and with the clinical diagnosis as the dependent variable. A total of 1382 cases of soft-tissue disorder were recorded and only those diagnostic groups with 50 or more cases were included. In multivariate logistic regression, significant variables positively discriminating for each disorder were identified for carpal tunnel syndrome (n = 56), lateral epicondylitis (n = 87), tenosynovitis (n = 63), shoulder tendonitis (n = 157), non-specific upper limb disorder (n = 458), fibromyalgia (n = 124) and inflammatory arthritis (n = 100), which was used for comparison purposes. Significant discrimination for each model was demonstrated by the construction of receiver operating characteristic (ROC) curves and appropriate area under the curve statistics. This approach to classification criteria is based on multivariate modelling rather than on a consensus statement. This includes the effects of negative as well as positive associations. Further work is required on both the reproducibility of the clinical signs and the application of the criteria to other datasets.


Ventricular extrastimulation in the mitral valve prolapse syndrome. Evidence for ventricular reentry.
Fourteen patients with mitral valve prolapse and essentially normal coronary arteries were evaluated for ventricular arrhythmias, utilizing programmed ventricular extrastimulation. Three were symptomatic with ventricular tachyarrhythmias. Application of appropriately timed ventricular extrasystoles initiated the tachyarrhythmias in these three patients. The remaining eleven mitral prolapse patients were apparently free of tachycardias. Repetitive ectopic beats were not induced by extrastimulation in these eleven patients. The initiation of ventricular tachyarrhythmias by extrastimulation suggests a reentrant mechanism for the ventricular ectopy of mitral valve prolapse.


Dissociation of the N-C(alpha) bond and competitive formation of the [z(n) - H](+) and [c(n) + 2H](+) product ions in radical peptide ions containing tyrosine and tryptophan: the influence of proton affinities on product formation.
Dissociations at the N-C(alpha) bond of tryptophan and tyrosine residues are the prevalent pathways in the fragmentations of radical cations of tripeptides that contain such as residues. This process involves a proton transfer from the beta-carbon of the tryptophan or tyrosine residue to the carbonyl oxygen of the amide group, followed by cleavage of the N-C(alpha) bond, generating low-lying proton-bound dimers that dissociate to give each an ionic and a neutral product. Formation of the [z(n) - H](*+) or [c(n) + 2H](+) ion is a competition between the two incipient fragments for the proton in a dissociating proton-bound dimer.


Clinical comparison between crestal and subcrestal dental implants: A systematic review and meta-analysis.
How the performance of dental implants is related to their occlusogingival placement, crestal or subcrestal, is unclear. The purpose of this systematic review and meta-analysis was to evaluate marginal bone loss, implant survival rate, and peri-implant soft tissue parameters between implants placed at the crestal and subcrestal bone level. Two independent reviewers searched the PubMed/MEDLINE, Embase, and Cochrane Library databases for randomized clinical trials published up to September 2020. The meta-analysis was based on the Mantel-Haenszel and the inverse variance methods (α=.05). The search identified 928 references, and 10 studies met the eligibility criteria. A total of 393 participants received 709 implants, 351 at crestal bone levels and 358 at subcrestal bone levels. Meta-analysis indicated that crestal bone level implants showed similar marginal bone loss to that seen with subcrestal bone level implants (mm) (P=.79), independent of the subcrestal level (P=.05) and healing protocol (P=.24). The bone level implant placement did not affect the implant survival rate (P=.76), keratinized tissue (mm) (P=.91), probing depth (mm) (P=.70), or plaque index (%) (P=.92). The evidence suggests that both approaches of implant placement are clinically acceptable in terms of peri-implant tissue parameters and implant-supported restoration survival.


Respiratory frequency-tunable dynamic imaging for lung function: New exam method using chest X-ray cine imaging considering various respiratory diseases.
A convenient way to conduct pulmonary function tests while preventing infectious diseases was proposed, together with countermeasures for severe coronavirus disease 2019 (COVID-19). The correlation between diagnosis result and diagnosis result was examined for patients with mild chronic obstructive pulmonary disease (COPD) of the most abounding as a subject of spirometry, and the possibility of using this method as an alternative to spirometry was examined. This study was conducted in Kanagawa, Japan. Ten normal volunteers and 15 volunteers with mild COPD participated in this study. All images were taken by EXAVISTA (Hitachi, Japan) between October 2019 and February 2020. Continuous fluoroscopic images were taken in 12.5 frames per second for 10-20 s per subject. Images that do not adopt the automatic image processing of the equipment and only carry out the signal correction of each pixel were used for the analysis. The mean total dose for all volunteers was 0.2 mGy. There was no major discrepancy in the detection of lung field geometry, and no diagnostic problems were noted by the radiologist and physician. Existing X-ray cine imaging was used to extract frequency-tunable imaging. It is possible to identify abnormal regions on the images compared to spirometry, and it does not require maximum effort respiration; therefore, it is possible to perform a stable examination because the patient's physical condition and the ability of laboratory technicians on the day are less affected. This can also be used as a countermeasure in examining patients with infectious diseases. UMIN UMIN000043868.


Demonstration of cells involved in rejection of tolerogenic grafts in tolerant Xenopus.
The J-strain (JJ) clawed frog, Xenopus laevis, can easily be made tolerant of semixenogeneic (X. laevis x X. borealis; JB) adult skin grafted onto larvae before stage 57 (larvally induced tolerance). To examine the cellular bases of this tolerance, we have established a simple and reliable method of quantifying the proliferating splenocytes in vivo by using BrdU and anti-BrdU antibody. When adult JJ frogs were injected with adult JB peripheral blood cells (PBCs), host splenic lymphocytes proliferated even in frogs that were tolerant of JB skin. Splenic lymphocytes from animals primed in vivo with JB PBCs were injected into early thymectomized (Txd) frogs that carried previously grafted JB skin. In Txd frogs injected with splenocytes from normal frogs, the rejection of JB skin grafts was initiated promptly and ended in about 10 days. Rejection was relatively delayed in the frogs injected with splenocytes depleted of proliferating cells, suggesting that the proliferating cells were actively involved in the rejection process. Early Txd frogs injected with splenocytes from undisturbed tolerant donors did not reject JB skin grafts. Quite unexpectedly, all five early Txd frogs, injected with undepleted splenocytes from tolerant donors previously stimulated with JB PBCs, rejected the JB skin grafts, four of them subacutely. In frogs injected with the splenocytes from PBC-injected tolerant donors that had been depleted of proliferating cells, the rejection was delayed. The most likely explanation is that cells actively involved in graft rejection exist in tolerant frogs and can be stimulated to proliferate, although cytotoxicity of the graft is usually suppressed or disabled by unknown mechanisms.


Therapeutic effects of PEGylated insulin-like growth factor I in the pmn mouse model of motoneuron disease.
Based on its potent neurotrophic and myotrophic activities, insulin-like growth factor I (IGF-I) has been proposed for treatment of neuromuscular disorders such as muscular dystrophies and amyotrophic lateral sclerosis (ALS). However, the short half life in the circulation limits its use in vivo. At least in mouse models, beneficial effects are generally only observed by dosing regimens such as minipumps or gene therapy that are difficult to translate to patients. We have developed a polyethylene glycol coupled IGF-I (PEG-IGF-I) that could circumvent these problems by longer half-life, showing all features of a therapeutic agent supporting muscular and neuronal function. Here we investigated its effects in the pmn mutant mouse, a model with typical dying-back motoneuron degeneration. In vitro, PEG-IGF-I and rhIGF-I profoundly promoted survival axonal growth of wild-type as well as pmn mutant embryonic motoneurons, suggesting that PEG-IGF-I had a fully conserved neurotrophic activity via its receptor. In vivo, treatment of pmn mutant mice with PEG-IGF-I prolonged survival, protected against late stage weight loss and significantly maintained muscle force and motor coordination. Consistently, PEG-IGF-I treatment rescued facial and lumbar motoneurons from cell death and partially preserved phrenic nerve myelinated axons. The data support that PEG-IGF-I could be used for treatment of neuromuscular diseases in a clinically feasible manner.


Relativistic quantum thermodynamics of ideal gases in two dimensions.
In this work we study the behavior of relativistic ideal Bose and Fermi gases in two space dimensions. Making use of polylogarithm functions we derive a closed and unified expression for their densities. It is shown that both type of gases are essentially inequivalent, and only in the non-relativistic limit the spinless and equal mass Bose and Fermi gases are equivalent as known in the literature.


Influence of sports participation and menarche on bone mineral density of female high school athletes.
Weight-bearing exercise during adolescence may enhance peak bone mineral density (BMD) and reduce osteoporosis risk. The association of sports participation before and after menarche with areal BMD (by central DXA) was investigated in 99 female high school athletes (age 15.5+/-1.3 year). The frequency and duration of structured sports (school-based or other organized team) were assessed using an interviewer-assisted questionnaire. Overall, the average number of years of weight-bearing sport participation was 7.4+/-3.4 years; 72% of the athletes began sport participation before menarche. Training patterns and BMD were examined by tertiles of yearly weight-bearing sport participation (hours/year) before (WBpre), after (WBpost) menarche, and in total (WBtotal). After adjusting for chronological age, gynecological age, and BMI, compared to athletes in the WBtotal low tertile, athletes in the WBtotal high tertile had significantly greater BMD at the spine (p=0.009), total hip (p=0.03), trochanter (p=0.03), and total body (p=0.009). Similar patterns were found by WBpre or WBpost status, separately, with the exception of spine BMD which was significantly different across tertiles in WBpost only (p<0.01). While the number of years of participation was similar across tertiles of WBtotal, the number of months/year was significantly greater among athletes in the high tertile than athletes in the low tertile (9.2+/-3.4 month/year versus 5.0+/-2.9 month/year, respectively (p<0.001)). These results indicate that near year-round participation in structured weight-bearing sports during early adolescence may help young girls optimize bone mineral accrual during these critical years, and may decrease their risk of osteoporosis with advancing age.


Effect of biomechanical properties on myopia: a study of new corneal biomechanical parameters.
To assess the corneal stress-strain index (SSI), which is a marker for material stiffness and corneal biomechanical parameters, in myopic eyes. A total of 1054 myopic patients were included in this study. Corneal visualisation Scheimpflug technology was used to measure the SSI. Corneal biomechanics were assessed using the first and second applanation times (A1-and A2-times); maximum deflection amplitude (DefAmax); deflection area (HCDefArea); the highest concavity peak distance (HC-PD), time (HC-time), and deflection amplitude (HC-DefA); integrated radius (IR); whole eye movement (WEM); stiffness parameter (SP-A1;, biomechanically corrected intraocular pressure (BIOP); and Corvis biomechanical index (CBI). Scheimpflug tomography was used to obtain the mean keratometery (Km) and central corneal thickness (CCT). According to the spherical equivalent (SE) (low myopia: SE ≥ - 3.00D and high myopia: SE ≤ - 6.00D.), the suitable patients were divided into two groups. The mean SSI value was 0.854 ± 0.004. The SSI had a positive correlation with A1-time ((r = 0.272), HC-time (r = 0.218), WEM (r = 0.288), SP-A1 (r = 0.316), CBI (r = 0.199), CCT (r = 0.125), bIOP (r = 0.230), and SE (r = 0.313) (all p-values<0.01). The SSI had a negative correlation with HCDefA (r = - 0.721), HCDefArea (r = - 0.665), HC-PD(r = - 0.597), IR (r = - 0.555), DefAmax (r = - 0.564), and Km (r = - 0.103) (all p-values<0.01). There were significant differences in SSI (t = 8.960, p<0.01) and IR (t = - 3.509, p<0.01) between the low and high myopia groups. In different grades of myopia, the SSI values were lower in eyes with higher SEs. It indicates that the mechanical strength of the cornea may be compromised in high myopia. The SSI was positively correlated with the spherical equivalent, and it may provide a new way to study the mechanism of myopia.


The pharmacologic and toxicologic characterization of the potent and selective KRAS G12D inhibitors ERAS-4693 and ERAS-5024.
Two potent and selective KRASG12D inhibitors, ERAS-4693 and ERAS-5024, were generated as possible clinical candidates to treat patients harboring G12D mutations in solid tumors. Both molecules exhibited strong anti-tumor activity in the KRASG12D mutant PDAC xenograft mouse models while ERAS-5024 also showed tumor growth inhibition when administered on an intermittent dosing regimen. Acute dose-limiting toxicity consistent with an allergic reaction was observed for both molecules shortly after administration at doses just above those which demonstrated anti-tumor activity, indicative of a narrow therapeutic index. A series of studies were subsequently conducted to identify a common underlying mechanism for the observed toxicity, including CETSA® (Cellular Thermal Shift Assay) as well as several functional off-target screens. Both ERAS-4693 and ERAS-5024 were identified to agonize MRGPRX2 which has been linked to pseudo-allergic reactions. In vivo toxicologic characterization of both molecules included repeat-dose studies in the rat and dog. Dose-limiting toxicities were observed in both species with ERAS-4693 and ERAS-5024 and plasma exposure levels at the maximum tolerated doses were generally below that which caused strong anti-tumor activity, supporting the initial observation of a narrow therapeutic index. Additional overlapping toxicities included a reduction in reticulocytes and clinical pathological changes suggestive of an inflammatory response. Furthermore, increases in plasma histamine were observed in dogs administered ERAS-5024, supporting the hypothesis that MRGPRX2 agonism may be the cause of the pseudo-allergic reaction. This work highlights the importance of balancing both the safety and efficacy of KRASG12D inhibitors as this class of molecules begins to enter clinical development.


Contralateral Prophylactic Mastectomy Use After Neoadjuvant Chemotherapy.
Neoadjuvant chemotherapy (NAC) for breast cancer increases breast-conserving surgery (BCS) rates, but many women opt for mastectomy with contralateral prophylactic mastectomy (CPM). Here we evaluate factors associated with CPM use in women undergoing mastectomy post-NAC. A retrospective institutional NAC database review identified women with clinical stage I-III, unilateral invasive breast cancer undergoing unilateral mastectomy (UM) or CPM mastectomy from 9/2013 to 12/2017. Clinical/pathologic characteristics, imaging, and presence of contraindications to BCS post-NAC were compared, with subset analysis of BCS candidates. The multivariable analysis was adjusted for potential confounders. Five hundred sixty-nine women underwent mastectomy after NAC, 297 (52%) UM and 272 (48%) CPM. On univariable analysis, younger age, BRCA+, lower pre-NAC clinical stage, pathologic complete response, and axillary surgery extent were associated with CPM (all p < 0.01). Favorable post-NAC clinical factors of no residual palpable disease, clinically negative nodes, complete response on breast imaging, and no post-NAC contraindication to BCS were also associated with CPM (all p < 0.01). On multivariable analysis, young age (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.91-0.95), lower pre-NAC stage (OR 0.51, 95% CI 0.34-0.77), and no contraindication to BCS (OR 3.12, 95% CI 2.02-4.82) were significantly associated with CPM. Among the 203 (35%) women who had no contraindications to BCS post-NAC, 145 (71%) underwent CPM. BRCA+ and family history were reasons more frequently cited for mastectomy among CPM than UM (p < 0.001). CPM was performed in 48% of women undergoing mastectomy after NAC; younger women with earlier-stage cancers were more likely to undergo CPM. While increased use of CPM in women with more favorable disease is medically appropriate, our findings indicate a lost opportunity for use of BCS.


Stacked kinship CNN vs. GBLUP for genomic predictions of additive and complex continuous phenotypes.
Deep learning is impacting many fields of data science with often spectacular results. However, its application to whole-genome predictions in plant and animal science or in human biology has been rather limited, with mostly underwhelming results. While most works focus on exploring alternative network architectures, in this study we propose an innovative representation of marker genotype data and tested it against the GBLUP (Genomic BLUP) benchmark with linear and nonlinear phenotypes. From publicly available cattle SNP genotype data, different types of genomic kinship matrices are stacked together in a 3D pile from where 2D grayscale slices are extracted and fed to a deep convolutional neural network (DNN). We simulated nine phenotype scenarios with combinations of additivity, dominance and epistasis, and compared the DNN to GBLUP-A (computed using only the additive kinship matrix) and GBLUP-optim (additive, dominance, and epistasis kinship matrices, as needed). Results varied depending on the accuracy metric employed, with DNN performing better in terms of root mean squared error (1-12% lower than GBLUP-A; 1-9% lower than GBLUP-optim) but worse in terms of Pearson's correlation (0.505 for DNN compared to 0.672 and 0.669 of GBLUP-A and GBLUP-optim for fully additive case; 0.274 for DNN, 0.279 for GBLUP-A, and 0.477 for GBLUP-optim for fully dominant case). The proposed approach offers a basis to explore further the application of DNN to tabular data in whole-genome predictions.


Aggregated network centrality shows non-random structure of genomic and proteomic networks.
Network analysis is a powerful tool for modelling biological systems. We propose a new approach that integrates the genomic interaction data at population level with the proteomic interaction data. In our approach we use chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) data from human genome to construct a set of genomic interaction networks, considering the natural partitioning of chromatin into chromatin contact domains (CCD). The genomic networks are then mapped onto proteomic interactions, to create protein-protein interaction (PPI) subnetworks. Furthermore, the network-based topological properties of these proteomic subnetworks are investigated, namely closeness centrality, betweenness centrality and clustering coefficient. We statistically confirm, that networks identified by our method significantly differ from random networks in these network properties. Additionally, we identify one of the regions, namely chr6:32014923-33217929, as having an above-random concentration of the single nucleotide polymorphisms (SNPs) related to autoimmune diseases. Then we present it in the form of a meta-network, which includes multi-omic data: genomic contact sites (anchors), genes, proteins and SNPs. Using this example we demonstrate, that the created networks provide a valid mapping of genes to SNPs, expanding on the raw SNP dataset used.


Review of difficult airway management in thoracic surgery.
The management of difficult airway (DA) in thoracic surgery is more difficult due to the need for lung separation or isolation and frequent presence of associated upper and lower airway problems. We performed an article review analysing 818 papers published with clinical evidence indexed in Pubmed that allowed us to develop an algorithm. The best airway management in predicted DA is tracheal intubation and independent bronchial blockers guided by fibroscopy maintaining spontaneous ventilation. For unpredicted DA, the use of videolaryngoscopes is recommended initially, and adequate neuromuscular relaxation (rocuronium/sugammadex), among other maneuvers. In both cases, double lumen tubes should be reserved for when lung separation is absolutely indicated. Finally, extubation should be a time of maximum care and be performed according to the safety measures of the Difficult Arway Society.


Molecular cloning, characterization and expression analysis of adenylosuccinate lyase gene in grass carp (Ctenopharyngodon idella).
Adenylosuccinate lyase (ADSL) is a bifunctional enzyme acting in de novo purine synthesis and purine nucleotide recycling. In the present study, we have constructed a grass carp (Ctenopharyngodon idella) intestinal cDNA library that has over 2.3 × 10(5) primary clones. An expressed sequence tag (EST) of grass carp adenylosuccinate lyase (gcADSL) gene was screened from this library. Both 5'-RACE and 3'-RACE were carried out in order to obtain the complete cDNA sequence, which contains a 1,446 bp open reading frame encoding 482 amino acids about 54.552 kDa. The deduced amino acid sequence shares high homology with its vertebrate counterparts, which shares 94% similarity with zebrafish, 81% with African clawed frog as well as chicken, 77% with human and 76% with mouse. This gcADSL genomic sequence, consisted of 13 exons and 12 introns, is 8,557 bp in size. Real-time quantitative PCR analysis revealed that the highest expression level of gcADSL was detected in muscle and the lowest in gill. In western blotting analysis, His(6)-tagged gcADSL protein expressed in Escherichia coli could be recognized not only by an anti-His(6)-tag monoclonal antibody but also by an anti-human ADSL polyclonal antibody, indicating immunological crossreactivity occurs between grass carp and human ADSL protein. 1,082 bp 5'-flanking region sequence was cloned and analyzed.


Legal and ethical implications of medically enforced feeding of detained asylum seekers on hunger strike.
The current practice of non-consensual medical treatment of hunger-striking asylum seekers in detention needs closer inquiry. An Australian Government regulation empowers the Department of Immigration and Multicultural and Indigenous Affairs (DIMIA) to authorise non-consensual medical treatment for a person in immigration detention if they are at risk of physical harm, but there are doubts about whether the regulation would withstand legal challenge. Authorisation by DIMIA does not compel medical practitioners to enforce treatment if such action is contrary to their "ethical, moral or religious convictions". The World Medical Association has established guidelines for doctors involved in managing people on hunger strikes. The Declaration of Tokyo (1975) and the Declaration of Malta (1991) both prohibit the use of non-consensual force-feeding of hunger strikers who are mentally competent. If called upon to treat hunger strikers, medical practitioners should be aware of their ethical and legal responsibilities, and that they should act independently of government or institutional interests.


Interleukins and their antagonists but not TNF and its receptors are released in post-ERP pancreatitis.
Usually it is not possible to study the initial systemic response in patients with acute pancreatitis in the first hours after onset of the disease. We used postendoscopic retrograde pancreatography (ERP) pancreatitis as a model to study cytokine and anticytokine release in the early phase of human acute pancreatitis. Post-ERP pancreatitis was defined as a threefold increase in serum amylase and at least two of the following clinical symptoms: abdominal pain, nausea, vomiting or peritonism 24 h after ERP. Serum levels of pro-inflammatory cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor alpha (TNF), as well as endogenous antagonistic mediators of the systemic inflammatory response such as soluble tumour necrosis factor alpha receptors p55 (TNFR p55) and p75 (TNFR p75), and IL-1-receptor antagonist (IL-1-RA) and interleukin-2-receptor (IL-2R) as indicators of lymphocyte activation were measured before and 0, 1, 4, 12, 24 and 48 h after ERP. In nine patients with acute post-ERP pancreatitis, these parameters were monitored daily until C-reactive protein (CRP) was within normal ranges and were compared to patients without pancreatitis after ERP. IL-1beta was not detectable in five patients with and four patients without post-ERP pancreatitis. The values of the remaining patients in both groups were lower than 3.9 pg/ml. IL-8 and IL-1-RA serum concentrations peaked 12 h after ERP (132.9 and 3245.0 pg/ml respectively) compared to patients without post-ERP pancreatitis (25.8 and 389.9 pg/ml respectively). The IL-6 concentration increased to 81.6 pg/ml (8.0 pg/ml in control patients) 24 h after ERP, while the peak values for CRP were measured 72 h after ERP (164.0 versus 7.7 mg/l). IL-2R content was maximally elevated 144 h after ERP (688.8 versus 255.9 U/ml), while concentrations of TNF and its receptors showed no significant change over time. The initial response of the cytokine network to damage of the human pancreas leading to acute pancreatitis includes the release of IL-8 and the IL-1 antagonist IL-1-RA, while IL-1beta is not found in the systemic circulation. The TNF system does not seem to be involved as indicated by the lack of detectable changes in TNF and the soluble TNFR p55 and p75 serum concentrations. Lymphocyte activation as indicated by elevated IL-2R levels occurred days after the initial trauma. Even mild post-ERP pancreatitis leads to significant systemic release of cytokines and their biological counterparts.


Label-free X-ray estimation of brain amyloid burden.
Amyloid plaque deposits in the brain are indicative of Alzheimer's and other diseases. Measurements of brain amyloid burden in small animals require laborious post-mortem histological analysis or resource-intensive, contrast-enhanced imaging techniques. We describe a label-free method based on spectral small-angle X-ray scattering with a polychromatic beam for in vivo estimation of brain amyloid burden. Our findings comparing 5XFAD versus wild-type mice correlate well with histology, showing promise for a fast and practical in vivo technique.


The effects of greater occipital nerve blockage with lidocaine on sleep characteristics in chronic migraine patients.
The aim of our study was to determine the effects of greater occipital nerve block (GONB) with lidocaine on sleep characteristics in patients with chronic migraine. Twenty female patients who underwent GONB with lidocaine were included in the study. The Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), Pre-Sleep Arousal Scale (PSAS), Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS), Restless Legs Syndrome Severity Scale (RLSSS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and headache diary results before and after the treatment of the patients were compared. We included 20 patients (all females) in our study. The mean age was 35.80 ± 8.82 years (range 24-50). After GON blockade, the number of days with pain (p < 0.001), duration of pain (p < 0.001), and Visual Analog Scale (VAS) score (p < 0.001) were significantly lower than before. After GONB, BDI (p = 0.007), BAI (p = 0.022), ISI (p = 0.009), and PSQI (p = 0.026) scores were significantly lower than before. After GONB, sleep quality was better than before (p = 0.035). This study showed that GONB with lidocaine can improve sleep quality, insomnia, and symptoms of depression and anxiety while reducing migraine headache.


Incidence and impact of perioperative complications in 175 fetoscopy-guided laser coagulations of chorionic plate anastomoses in fetofetal transfusion syndrome before 26 weeks of gestation.
The purpose of this study was to evaluate the perioperative complications in fetoscopy-guided laser therapy in fetofetal transfusion syndrome. Details of fetofetal transfusion syndrome cases who were delivered between 1999 and 2004 in a single center were reviewed retrospectively. One hundred seventy-five procedures were performed percutaneously with the use of local anesthesia. Survival at 6 months of at least 1, 1, and 2 babies was 73%, 38%, and 35%, respectively. Placental abruption and miscarriage was diagnosed in 3 and 12 cases, respectively. Premature rupture of membranes occurred in 49 cases (28%) and including 12, 29, and 46 cases that occurred before 24, 28, and 34 weeks of gestation, respectively. The entry of the trocar was transplacental in 48 cases (27%), but it was not associated with miscarriage (P = .26), premature rupture of membranes (P = .58), or placental abruption (P = .37). Fetoscopic laser treatment of fetofetal transfusion syndrome can be performed percutaneously with local anesthesia without significant maternal morbidity. Transplacental entry was not associated with premature rupture of membranes or miscarriage.


Aerobic exercise and cognitive functioning in schizophrenia: An updated systematic review and meta-analysis.
This study serves as an update to a recent systematic review and meta-analysis to summarize the effect of aerobic exercise on cognition in schizophrenia and determine the most effective method of aerobic exercise. We searched for controlled studies investigating the effect of aerobic exercise on cognition in schizophrenia published until January 2021. Fifteen studies were included. A random-effects model was used to estimate the standardized mean differences (SMDs) between cognitive outcomes of aerobic exercises and controls. Compared with controls, aerobic exercises resulted in significant improvements in global cognition (SMD = 0.21), attention/vigilance (SMD = 0.32), working memory (SMD = 0.27), and verbal learning (SMD = 0.30). Significant improvements in global cognition were observed with group exercise (SMD = 0.28), exercise supervised by exercise professionals (SMD = 0.27), as well as with ≥ 90 min/week (SMD = 0.26) and ≥ 12 weeks duration (SMD = 0.22). Our findings provide information beneficial for determining the most effective aerobic exercise method to improve cognition in schizophrenia.