Affinity chromatography of enzyme cofactors: the separation of NAD on immobilised dehydrogenase colums.
1. Alcohol dehydrogenase (EC 220.127.116.11.) has been immobilised to aminoethyl-cellulose by glutaraldehyde, to DEAE-cellulose by an s-triazine derivative and to agarose using CNBr. Lactate dehydrogenase has been immobilised to the latter two supports. 2. Their use for affinity chromatography of NAD was compared and alcohol dehydrogenase immobilised to CNBr-activated agarose chosen for detailed study due to the efficient coupling of applied enzyme and the specific nature of binding. 3. The efficiency of coupling of alcohol dehydrogenase dropped from 94.5 to 72.2% when the applied load was increased from 18 to 54 mg/g activated agarose. Activity relative to free enzyme fell from 21 to 11%. The binding of NAD was maximal between pH 5.5 and 6. With the lowest loading of enzyme, NAD binding fell from 450 to 320 mug/g support when the linear flow rate was increased from 0.84 to 3.95 cm/min. 4. NAD was completely separated from a mixture with ATP, ADP and AMP. Separation from NMN and hydrolysed RNA and DNA was evidently possible. Immobilised alcohol dehydrogenase used for 34 binding experiments over a period of weeks maintained 60% of its original enzyme activity. 5. The method was applied to yeast NAD following mechanical disruption of yeast, clarification and either ultrafiltration or hollow-fibre dialysis to permit separate purification of macromolecules and nucleotides.


Composition of whole unstimulated saliva of human infants.
Whole unstimulated saliva of 168 infants aged 3 days to 12 months was analysed. The concentration of Ca, Mg and Cl was higher in the saliva of infants than in adults. The concentration of phosphate, IgA, amylase and pH was lower in infants; Na, K and total protein did not differ significantly. A wide range of all the concentrations was observed in the saliva of infants. No significant difference was found between the salivary composition of male versus female or of breast-fed as compared to bottle-fed infants. No difference before and after eruption of teeth was detected. Significant differences between different age groups were observed in the concentrations of Na, K, Cl, phosphate, protein, amylase and pH. No significant differences were found in Ca, Mg and IgA concentrations within the first year. A negative correlation between the age of the infants and the concentrations of Na, K, Cl and total protein was observed. A positive correlation was found for phosphate and amylase as a function of age.


Overexpression, purification and enzymatic characterization of a recombinant Arabian camel Camelus dromedarius glucose-6-phosphate dehydrogenase.
In a previous study the full-length open reading frame of the Arabian camel, Camelus dromedarius liver cytosolic glucose-6-phosphate dehydrogenase (G6PD) cDNA was determined using reverse transcription polymerase chain reaction. The C. dromedarius cDNA was found to be 1545 nucleotides (accession number JN098421) that encodes a protein of 515 amino acids residues. In the present study, C. dromedarius recombinant G6PD was heterologously overexpressed in Escherichia coli BL21 (DE3) pLysS and purified by immobilized metal affinity fast protein liquid chromatography (FPLC) in a single step. The purity and molecular weight of the enzyme were analyzed on SDS-PAGE and the purified enzyme showed a single band on the gel with a molecular weight of 63.0 KDa. The specific activity was determined to be 2000 EU/mg protein. The optimum temperature and pH were found to be 60 °C and 7.4, respectively. The isoelectric point (pI) for the purified G6PD was determined to be 6.4. The apparent Km values for the two substrates NADP+ and G6P were found to be 23.2 μM and 66.7 μM, respectively. The far-UV circular dichroism (CD) spectra of G6PD showed that it has two minima at 208 and 222 nm as well as maxima at 193 nm which is characteristic of high content of α-helix. Moreover, the far-UV CD spectra of the G6PD in the presence or absence of NADP+ were nearly identical.


Effect of conversion from ciclosporin to tacrolimus on endothelial progenitor cells in stable long-term kidney transplant recipients.
Endothelial progenitor cell (EPC) counts are proposed surrogate markers for vascular function and cardiovascular risk. The effect of tacrolimus (TAC) on EPC is unknown. In this randomized controlled trial, we assigned 148 stable long-term kidney transplant recipients (KTR) to maintaining ciclosporin (CSA) or to commencing TAC-based immunosuppression at a 2:1 ratio. EPC counts (CD34/KDR) after 24 months were defined as primary endpoint. The intent-to-treat analysis included 141 KTR (estimated glomerular filtration rate, 46.7 [40.1-61.8] mL/min per 1.73 m). Median (interquartile range [IQR]) EPC counts at baseline and month 24 were 6 (2-9) and 3 (1-9) cells and 4 (2-8) and 2 (0-5) cells per 5×10 mononuclear cells in CSA and TAC, respectively. Median (IQR) circulating angiogenic cells at baseline and month 24 were 28 (10.7-57) and 44.33 (14.6-59.8) cells and 22 (10.8-41) and 21 (9.7-49.5) cells per high-power field in CSA and TAC, respectively. Median (IQR) endothelial cell colony-forming units count per well at baseline and month 24 were 10.5 (3.3-34.3) and 4.38 (1.7-26.5) in CSA and significantly declined from 9.31 (1.8-29.3) to 4.13 (1.1-9.5) in TAC (P=0.003). There were no cardiovascular events in either group. Although late conversion from CSA to TAC appears safe in KTR, conversion to TAC has no favorable effect on EPC. Low EPC levels are associated with a higher risk of subsequent cardiovascular events and are therefore of prognostic value. Their trend to decline over time deserves further examination.


Increased doxorubicin levels in hepatic tumors with reduced systemic drug exposure achieved with complete hepatic venous isolation and extracorporeal chemofiltration.
We evaluated a novel system of complete hepatic venous isolation and chemofiltration (CHVI-CF) to reduce systemic drug exposure following regional hepatic infusion of doxorubicin. Rabbits bearing hepatic VX-2 tumors were given doxorubicin via either hepatic arterial infusion (HAI) or portal venous infusion (PVI). A dual-balloon vena cava catheter and extracorporeal chemofilter were used to capture and filter hepatic venous blood in experimental animals. Control animals received chemotherapy without hepatic venous isolation and chemofiltration. Following a 5-min HAI of doxorubicin (3 or 5 mg/kg), control and experimental animals had similar doxorubicin levels in their livers and VX-2 tumors, but experimental animals showed a significant reduction in doxorubicin levels in systemic plasma, heart, and kidney tissue as compared with control animals (P < 0.01). HAI produced a 4-fold increase in doxorubicin levels in VX-2 tumors as compared with the drug levels obtained using PVI (P < 0.01). A single HAI of 3 mg/kg doxorubicin in animals treated with CHVI-CF produced marked tumor necrosis at 7 and 14 days after treatment. By increasing the total body clearance of doxorubicin, this system will allow HAI of higher doses of drug in attempts to improve the antitumor response.


Clearance of tracer albumin from peritoneal cavity to plasma at low intraperitoneal volumes and hydrostatic pressures.
To assess the clearance of radiolabeled tracer albumin (RISA) from peritoneal cavity to plasma (Cl-->P) in rats under essentially "normal" conditions, that is, when intraperitoneal hydrostatic pressure (IPP) is subatmospheric and the intraperitoneal (IP) "free" fluid volume (IPV) is low. A volume of 0.3 mL of RISA was injected IP into anesthetized Wistar rats (wt = 300 g) when the IPV was approximately 2 mL (normal) or the IPV was approximately 10 mL, and IPP was either -1.8 mmHg (normal) or +1.5 mmHg (produced by an external cuff). Plasma samples (25 microL) were obtained repeatedly during the dwell, which lasted 30-300 min, after which the peritoneal cavity was opened to recover the IPV and residual IP RISA activity. The Cl-->P was assessed as the mass transfer of RISA into plasma, occurring per unit time, divided by the calculated mean IP RISA concentration (CD). The interstitial RISA space was measured as the mass of RISA accumulated, per unit tissue weight, in peritoneal tissue samples divided by the CD. A markedly lower Cl-->P (2.47+/-0.67 microL/min), as well as total RISA clearance out of the peritoneal cavity (Cl), was found under "normal" conditions (an IPV of approximately 2 mL and an IPP of approximately -1.8 mmHg) compared to the situation during peritoneal dialysis (an IPV of approximately 20 mL and an IPP of +1 mmHg). Furthermore, the interstitial RISA space increased linearly over time even at negative IPPs and at an unchanging peritoneal interstitial fluid volume. At a low (normal) IPV the Cl-->P did not increase significantly with elevating IPP, and increased only marginally when tracer distribution was improved by artificial vibration of the rats. However the Cl-->P increased when larger volumes were infused to increase the total IPV. It is concluded that the Cl-->P and Cl at low IPPs and IPVs are not as high as during peritoneal dialysis. Increases in Cl-->P were, however, coupled to increases in IPV. This highlights the importance of the IPV per se and of a sufficient IP tracer distribution for direct lymphatic absorption to be efficient.


All-Terrain Vehicle-Related Emergency Department Visits: Interaction of Sex and Age, NEISS, 2019.
Epidemiologic patterns of all-terrain vehicle (ATV)-related emergency department (ED) visits by male and female individuals may vary at different ages. To our knowledge, this has not been researched previously. The purpose of this study was to determine the interaction of sex and age differences in their association with ATV-related ED visits. Data from the 2019 National Electronic Injury Surveillance System were extracted for ATV-related ED visits, including sex, age, race, location of crash, injured body part, and whether alcohol was involved. Descriptive statistics and logistic regression analyses were conducted. We modeled sex in separate multivariable models, adjusting for the same independent variables. There were an estimated 95,995 (unweighted n = 1999) ATV-related ED visits. There was a significant age-by-sex interaction in the association between ATV-related ED visits vs. other ED injuries, indicating that the effect of age on ATV-related ED visits differed by sex and vice versa. Overall, male individuals were 1.7 times as likely to have an ATV-related ED visit as female individuals. In the stratified analysis for female individuals, odds were substantially greater for girls younger than 18 years (adjusted odds ratio [AOR] 2.33; 95% confidence interval [CI] 1.61-3.69) and women aged 18-35 years (AOR 4.76; 95% CI 3.48-6.51) compared with woman older than 35 years. For men, odds were significant for ages 18-35 years (AOR 2.21; 95% CI 1.72-2.85) compared with men older than 35 years. As newer ATVs become more powerful and faster, there is a need to know who is at greatest risk for ATV-related ED visits to develop policies and safety measures.


A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies.
Germ line loss-of-function heterozygous mutations in the RUNX1 gene cause familial platelet disorder with associated myeloid malignancies (FPDMM) characterized by thrombocytopenia and a life-long risk of hematological malignancies. Although gene therapies are being considered as promising therapeutic options, current preclinical models do not recapitulate the human phenotype and are unable to elucidate the relative fitness of mutation-corrected and RUNX1-heterozygous mutant hematopoietic stem and progenitor cells (HSPCs) in vivo long term. We generated a rhesus macaque with an FPDMM competitive repopulation model using CRISPR/Cas9 nonhomologous end joining editing in the RUNX1 gene and the AAVS1 safe-harbor control locus. We transplanted mixed populations of edited autologous HSPCs and tracked mutated allele frequencies in blood cells. In both animals, RUNX1-edited cells expanded over time compared with AAVS1-edited cells. Platelet counts remained below the normal range in the long term. Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization. In conclusion, the lack of a competitive advantage for wildtype or control-edited HSPCs over RUNX1 heterozygous-mutated HSPCs long term in our preclinical model suggests that gene correction approaches for FPDMM will be challenging, particularly to reverse myelodysplastic syndrome/ acute myeloid leukemia predisposition and thrombopoietic defects.


Isolation, characterization and HPLC quantification of compounds from Aquilegia fragrans Benth: Their in vitro antibacterial activities against bovine mastitis pathogens.
The underground parts of Aquilegia fragrans are traditionally used for the treatment of wounds and various inflammatory diseases like bovine mastitis. However, there are no reports on the phytochemical characterization and antibacterial studies of A. fragrans. To isolate compounds from the methanol extract of the underground parts of A. fragrans and determine their antibacterial activity against the pathogens of bovine mastitis. The study was undertaken in order to scientifically validate the traditional use of A. fragrans. Five compounds were isolated from the methanol extract of the underground parts of A. fragrans using silica gel column chromatography. Structural elucidation of the isolated compounds was done using spectral data analysis and comparison with literature. High performance liquid chromatography (HPLC) was used for the qualitative and quantitative determination of isolated compounds in the crude methanol extract. The methanol extract and isolated compounds were evaluated for antibacterial activities against mastitis pathogens using broth micro-dilution technique. The five isolated compounds were identified as (1) 2, 4-dihydroxyphenylacetic acid methyl ester (2) β-sitosterol (3) Aquilegiolide (4) Glochidionolactone-A and (5) Magnoflorine. A quick and sensitive HPLC method was developed for the first time for qualitative and quantitative determination of four isolated marker compounds from A. fragrans. The crude methanol extract and compound 5 exhibited weak antibacterial activities that varied between the bacterial species (MIC=500-3000 µg/ml). The above results show that the crude methanol extract and isolated compounds from A. fragrans exhibit weak antibacterial activities. Further phytochemical and pharmacological studies are required for proper scientific validation of the folk use of this plant species in the treatment of various inflammatory diseases like bovine mastitis.


The Q-Trap mass spectrometer, a novel tool in the study of protein glycosylation.
The use of the recently introduced Q-Trap mass spectrometer in the study of protein glycosylation is described. The combined ion trap and triple quadrupole scan functions make it a powerful system in both oligosaccharide and glycopeptide analysis. Several oligosaccharides, both linear and branched, were analyzed to obtain information on sequence, linkage, and branching. Quadrupole like MS/MS spectra with ion trap sensitivity but without the typical ion trap low mass cut-off were obtained. To determine the origin of fragments and to reveal the existence of new ions, the MS(3) capabilities of the system proved to be useful. Glycopeptides were selectively detected in peptide mixtures using the triple quadrupole precursor ion scan function, either in off-line experiments or during LC/MS using information dependent acquisition (IDA).


[A successful conversion of failed fontan circulation to total cavopulmonary connection in a case of tricuspid atresia without pulmonary stenosis].
A 12-year-old boy was first admitted to Tokyo Metropolitan Children's Hospital at 2 days of age with the diagnosis of tricuspid atresia without pulmonary stenosis, normally related great arteries, ventricular septal defect, and persistent left superior vena cava (PLSVC). He underwent pulmonary artery banding at the age of 1 year and atrial septectomy at 2.9 years. At the age of 6.3 years, he underwent successful Bjork operation in conjunction with closure of a trial and ventricular septal defects. Late after surgery, however, he developed progressive intolerance to exercise (NYHA III), cardiomegaly, and depressed ST segments in the left precordial leads. Catheter examination at the age of 11.9 years disclosed moderately elevated pressures (15 mmHg) in the right atrium and pulmonary artery, depressed left ventricular function with ejection fraction (EF) of 0.48, and marked dilatation of the coronary sinus (CS). Right atriography revealed retrograde filling of the dilated CS up to the junction with PLSVC. With supposition that the combined elevation of the volume and pressure loads on CS had disturbed both coronary circulation and ventricular function, he, at the age of 12 years, underwent take down of the Fontan circulation and conversion to the total cavopulmonary connection (TCPC). His postoperative recovery was uneventful and, at 2.5 years after the latest surgery, he is leading a normal life. The findings of the chest roentgenogram and electrocardiogram reverted to normal and EF returned to the normal value (0.66). This experience draws us to conclude that conversion to TCPC is a safe and effective mean to salvage the patients with failed Fontan circulation. This experience also suggests that dilatation of CS is a predictor of the failed or failing Fontan circulation.


Chronic kidney disease in primary care: risk of cardiovascular events, end stage kidney disease and death.
The prevalence of chronic kidney disease (CKD) is increasing globally. Early diagnosis in primary care may have a role in ensuring proper intervention. We aimed to determine the prevalence and outcome of CKD in primary care. We performed an observational cohort study in primary care in Copenhagen (2001-2015). Outcomes were stroke, myocardial infarction (MI), heart failure (HF), peripheral artery disease (PAD), all-cause- and cardiovascular mortality. We combined individuals with normal kidney function and CKD stage 2 as reference. We conducted cause-specific Cox proportional regressions to calculate the hazard ratios for outcomes according to CKD group. We explored the associations between kidney function and the outcomes examined using eGFR as a continuous variable modelled with penalised splines. All models were adjusted for age, gender, diabetes, hypertension, existing CVD, heart failure, LDL cholesterol and use of antihypertensive treatment. We included 171,133 individuals with at least two eGFR measurements of which the majority (n = 157,002) had eGFR > 60 ml/min/1.73m2 at index date, and 0.05% were in CKD stage 5. Event rates were low in eGFR > 60 ml/min/1.73m2 but increased in those with higher stages of CKD. In adjusted analyses we observed an increase in hazard rates for every outcome with every increment in CKD stage. Compared to the reference group, individuals in CKD stage 4 had double the hazard rate of PAD, MI, cardiovascular and all-cause mortality. Our data from a large primary care cohort demonstrate an early increase in the risk of adverse outcomes already at CKD stage 3. This underlines the importance of studying early intervention in primary care.


Flexible Total Synthesis of 11-Deoxylandomycins and Their Non-Natural Analogues by Way of Asymmetric Metal Catalysis.
A de novo first collective total synthesis of 11-deoxylandomycins is reported. A signature step is featured by the Pd-catalyzed asymmetric addition of alcohol to ene-alkoxyallenes that assembles oligomeric 2,3,6-trideoxyoligosaccharides. The unique feature of the protocol is illustrated by a flexible access to various natural 11-deoxylandomycins as well as non-natural analogues.


Tumor budding as a useful prognostic marker in T1-stage squamous cell carcinoma of the esophagus.
Establishing a new prognostic factor for early-stage cancer may seem difficult due to the small number of disease-specific deaths. Tumor budding has been recognized as a useful microscopic finding reflecting biological activity of the tumor. Tumor budding stand for isolated single cancer cells and cell clusters scattered beyond the tumor margin at the invasive front. It was searched for in the resected esophagus with T1 squamous cell carcinoma (SCC), and the correlation between the tumor budding, patient survival, and various pathologic factors were analyzed to verify whether tumor budding is a prognostic factor in superficial esophageal cancer. Seventy-nine patients undergoing curative esophagectomy were assigned to frequent (n = 29) and rare (n = 50) groups according to the microscopically observed frequency of tumor budding in the tumor. Three-year survival rates after esophagectomy were 48.8% for the frequent group and 94.5% for the rare group. Multivariate analysis using the Cox proportional hazards model identified this morphological variable as a significant independent prognostic factor. Tumor budding reflects the biological activity of the tumor and may be a useful prognostic indicator even in early-stage SCC of esophagus.


First-trimester screening for aneuploidy with fetal nuchal translucency in a United States population.
To examine the detection rate of chromosomal abnormalities using a combination of nuchal translucency (NT) and maternal age in a United States population. A total of 2131 pregnancies with 2339 fetuses underwent NT screening from April 2000 to April 2002 in our ultrasound unit. Nuchal translucency was measured from 11 to 14 weeks' gestation. Fetal crown-rump length (CRL) was also measured. The risk for trisomy 21 was calculated from a combination of maternal age and fetal NT with the use of software provided by The Fetal Medicine Foundation (FMF). Sensitivity and false-positive rates were calculated for different risk cut-offs. Chromosomal defects were diagnosed in 32 cases, including 12 cases of trisomy 21 and 10 cases of trisomy 18. The estimated risk based on maternal age and fetal NT was 1 in 300 or greater in 195 (8.3%) cases and these included 10/12 (83.3%) pregnancies with trisomy 21 and 9/10 (90.0%) pregnancies with trisomy 18. A combination of maternal age and fetal NT provides an effective method of screening for chromosomal defects. Using ultrasound techniques and risk algorithms from The FMF, the performance of the test in an American population is similar to that described in international populations.


Impressions and aspirations from the FDA GREAT VI Workshop on Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis and Perspectives for Progress in the Field.
The US Food and Drug Administration hosted a workshop on July 21, 2021, to discuss the disease characteristics, natural history, and end points to assess treatment benefit in patients with eosinophilic gastrointestinal disorders (EGIDs) beyond eosinophilic esophagitis (EoE). Notably, EGIDs beyond EoE, such as eosinophilic gastritis, eosinophilic enteritis, and eosinophilic colitis, herein referred to as non-EoE EGIDs, are understudied relative to EoE. This workshop provided a forum for open discussion among stakeholders-medical professionals (including their societies and research groups), Food and Drug Administration representatives, an industry representative, and a patient representative-to facilitate drug development. Experts in many disciplines related to EGIDs, including allergy, immunology, epidemiology, gastroenterology, and pathology, and both adult and pediatric clinicians contributed. Herein, we discuss some of the insights of the material presented at the meeting and present perspectives on moving the field forward toward drug approval.


Pancreatic regeneration after ethionine-induced acute pancreatitis in rats lacking pancreatic CCK-A receptor gene expression.
We examined the effects of cholecystokinin (CCK) on the development of ethionine-induced pancreatitis and pancreatic recovery. We used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model lacking pancreatic CCK-A receptor gene expression. Ethionine-induced pancreatitis was induced in the 7-week-old male OLETF rats and in a control group that does not lack the pancreatic CCK-A receptor, Long-Evans Tokushima Otsuka (LETO) rats. The two groups were maintained on a low-protein diet for 11 days. During the last 4 days of the low-protein diet, dl-ethionine 20 mg/100 g body weight was administered intraperitoneally once daily. Histologic and biochemical examinations of the pancreas were performed, and plasma CCK concentrations were measured on days 1, 4, and 7 after the last ethionine administration. Pancreatic histologic scores for inflammation, hemorrhage, and necrosis in the LETO and OLETF rats were highest on days 1 and 4, respectively. Pancreatic weight, DNA content, and protein level per DNA content in both groups decreased during the low-protein diet, and recovery signs were delayed in the OLETF rats. The highest plasma CCK concentrations in the LETO and OLETF rats were reached on days 1 and 4, respectively. Ethionine-induced pancreatitis developed in the OLETF rats, and their pancreatic regeneration was delayed in comparison to that in the LETO rats. Our results suggested that CCK plays an important role in the development of pancreatitis as well as in the pancreatic repair process.


Evaluation of oxidative stress and antioxidant status in pregnant anemic women.
The present study was conducted to investigate the oxidant-antioxidant status in iron deficient pregnant anemic women. One hundred thirty pregnant women with iron deficiency anemia (IDA) were divided into three groups, namely mild (50), moderate (50) and severe (30) anemic along with pregnant healthy women as controls (50). The complete blood count, plasma lipid peroxidation products, enzymatic and non-enzymatic antioxidants were measured according to respective protocols. The levels of complete blood count, iron, ferritin along with antioxidant enzymes namely catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and reduced glutathione were significantly reduced in all IDA groups. However, the level of oxidized glutathione, lipid peroxides, protein carbonyls, conjugated dienes were found significantly increased in all anemic patients. Antioxidant vitamins, namely C, E and A were also found significantly decreased in IDA patients. On the basis of our results, it may be concluded that IDA tends to increase the pro-oxidant components, which may result in various complications including peroxidation of vital body molecules resulting in increased risk for pregnant women as well as fetus.


Regression-based quantitative trait loci mapping: robust, efficient and effective.
Regression has always been an important tool for quantitative geneticists. The use of maximum likelihood (ML) has been advocated for the detection of quantitative trait loci (QTL) through linkage with molecular markers, and this approach can be very effective. However, linear regression models have also been proposed which perform similarly to ML, while retaining the many beneficial features of regression and, hence, can be more tractable and versatile than ML in some circumstances. Here, the use of linear regression to detect QTL in structured outbred populations is reviewed and its perceived shortfalls are revisited. It is argued that the approach is valuable now and will remain so in the future.


Influence of the mutable kinetic parameters on the adhesion and debonding of thin viscoelastic films.
Detachment of a surface from a viscoelastic layer, such as a film of glue, engenders bridges between the surfaces until separation. Such surface instabilities arising during contact and detachment of viscoelastic films with rigid contactors have been theoretically explored by linear stability analysis and nonlinear simulations. The contact instabilities of viscoelastic materials are found to manifest in either a 'critical' or a 'dominant' mode in which the former is preferred when the contactor is slowly brought near the film while the latter manifests when the film is 'hard-pressed' against it. The nonlinear analysis considers the movement of contactor during adhesion-debonding cycle, which uncovers that the kinetic parameters can overshadow the thermodynamically predicted area of contact, average force for pull-off, energy of contactor-film separation, and pathways of debonding. Three distinct pathways of debonding - peeling, catastrophic column collapse, and column coalescence, are found to manifest with the variation in the ratio of the elastic to viscous compliances of the viscoelastic film. The study also reveals that in the dominant mode of instability, a smaller length scale with a larger area contact between the contactor and film can develop patterns having aspect ratio ∼10 times larger than the same obtained from elastic film.


The implications of Industry 4.0 on supply chains amid the COVID-19 pandemic: a systematic review.
Background: COVID-19 has caused significant disruptions in supply chains. It has increased the demand for products and decreased the supply of raw materials. This has interrupted many production processes. The emerging technologies of Industry 4.0 have the potential to streamline supply chains by improving time-sensitive customized solutions during this emergency. Purpose: This research examines the effects of the epidemic on supply chains and how these effects are reduced through Industry 4.0 technology. Design/methodology/approach: An extensive literature review using the "Preferred Reporting Items for Systematic Review and Meta-Analysis" method was carried out on the impact of the COVID-19 pandemic on supply chains and Industry 4.0 technologies. The study was undertaken by selecting keywords validated by experts and a search was conducted in the Scopus, ProQuest, and Google Scholar databases. Publications from the leading journals on these topics were selected. The bibliographical search resulted in 1484 articles followed by multiple layers of filtering. Finally, the most pertinent articles were selected for reviewing, and a total of 53 articles were analysed. Findings: This study discusses the impact of COVID-19 on the supply chain and how the emerging technologies of Industry 4.0 can help manufacturers to ease the impact. These technologies will enhance the production system through the automation and optimization of production flow convergence, enabling efficiencies and improvements among the suppliers, manufacturers, and consumers in the COVID-19 situation. Originality/value: The study summarizes the impact of the COVID-19 on supply chains and shows the potential of Industry 4.0 technologies to lessen the impact on manufacturing supply chains. This is valuable information for policymakers and practitioners so that they can get insights and take necessary actions.


Cocaine induced T cell proliferation in the rat: role of amygdala dopamine D1 receptors.
The immunomodulatory effects of local administration of cocaine into the amygdala were studied in the rat. Intra-amygdala infusion of cocaine significantly and dose-dependently increased the proliferative response of splenocytes to concanavalin A (Con A). A similar effect on the immune response was also observed in rats, microinfused into the central amygdala with the selective D1 receptor agonist SKF 38393. The increase of the proliferative response of splenocytes to Con A was inhibited by coinfusion within the central amygdala of the dopamine D1 receptor antagonist SCH 23390, together with cocaine, but not by coinfusion of the dopamine D2 receptor antagonist eticlopride. These results suggest that cocaine may produce at least some of its effects on the immune system through the activation of brain dopamine neurotransmission and that the central amygdala may represent a critical structure mediating cocaine-induced T cell proliferation.


Inversion Symmetry Breaking in Order-Disorder Transitions of Globular Ligands Coordinating to Cobalt(II) and Nickel(II) Bisacetylacetonato Complexes During Heating.
Unexpected inversion-symmetry breaking was observed in the order-disorder phase transitions of [M(acac)2 (abco)2 ] (1; M=Co2+ , 2; Ni2+ , acac- =2,4-pentanedionato, abco=1-azabicyclo-[2.2.2]-octane=quinuclidine) during heating. The isostructural, transition-free complexes [M(acac)2 (cabco)2 ] (3; M=Co2+ , 4; Ni2+ , cabco=3-chloro-1-azabicyclo-[2.2.2]-octane=3-chloroquinuclidine) were also studied for comparison. Complexes 1 and 2 crystallized in ordered phases in the centrosymmetric I2/m space group at 100 K, whereas they crystallized in disordered phases in the non-symmetric I2 space group at 300 K. The 60° step rotation disordering of the abco ligands was observed in the electron density maps of 1 and 2, which was consistent with the transition enthalpies estimated by differential scanning calorimetry (DSC). Gradual phase transitions were observed for 1 and 2 by DSC and powder X-ray diffraction (PXRD) at approximately 225 K. The inversion-symmetry disordering was likely induced by the local pseudo-symmetry of the abco ligands, increasing from trigonal to hexagonal and the increased steric repulsion pathways among them.


Flow cytometric DNA analysis: a prognostic tool in non-Hodgkin's lymphoma.
Surgical biopsies from 234 untreated patients with non-Hodgkin's lymphoma (NHL), classified according to the Kiel nomenclature, were analysed with respect to proliferative activity (S-phase) and DNA content by flow cytofluorometric (FCF-DNA) analysis. The percentage of cells in S-phase was significantly higher in lymphomas of high compared to low grade NHL (p less than 0.001). Patients with lymphomas of high grade histology and low S-phase values (less than 5.6%) achieved complete remission (CR) more often (p less than 0.05) and survived significantly longer than those with high S-phase values (p less than 0.05). In the low grade NHL group the S-phase value did not correlate to response. S-phase correlated to survival for patients with the lymphocytic (CLL & IC) (p less than 0.05) and follicle center cell (FCC) derived (p less than 0.01) but not in blastic (LB, IB, Burkitt) NHL. DNA-aneuploidy was associated with poor response to therapy and shorter CR duration in low grade NHL (p less than 0.05 for both). However, the degree of DNA-ploidy (neardiploid or aneuploid) did not correlate to survival in any of the NHL groups analysed (high- or low grade, lymphocytic, FCC derived or blastic). The Cox regression analysis indicated that the S-phase value was a stronger predictor of survival than histopathology, stage or age, especially in low grade NHL. These results suggest that S-phase analysis should be included in the clinical evaluation of NHL patients as a prognostic indicator.


Tongue Base Schwannoma.
Intraoral schwannomas account for 1% of head and neck schwannoma, with tongue base schwannoma being reported rarely. In an English literature search from 1988 to 2014, not more than 38 cases of tongue base schwannoma have been reported. Large tongue base schwannomas pose a significant risk to airway, thereby calling for an early intervention. We report a rare case of tongue base schwannoma in a 25 year old female managed surgically by lateral pharyngotomy approach.


Incomplete regression of müllerian ducts in the androgen insensitivity syndrome.
The biochemical and histological features of two related patients with the complete form of the androgen insensitivity syndrome (AIS) coexisting with incomplete regression of the Müllerian ducts are described. Both patients presented unilateral Müllerian derivatives (fallopian tube) identified by microscopic examination of surgically excised internal genital tissue. Biochemical studies performed in genital skin-derived fibroblasts from one of the affected subjects showed the existence of a specific and saturable 8.2 to 8.4 S cytosolic and 3.4 S nuclear androgen receptor exhibiting a Kd of 1.32 nmol/L. These mutant cells, however, clearly presented a significantly low maximal nuclear [3H]-5 alpha-dihydrotestosterone uptake (71.0 fmol/mg of deoxyribonucleic acid [DNA]; control strain, 284 fmol/mg DNA). Thus, an impaired uptake of the androgen receptor complex at the nuclear level was probably the cause of the complete absence of phenotypic expression of androgen action in this family. The overall findings are on line with the well-demonstrated genetic and molecular heterogeneity of the AIS.


Whole-brain irradiation with concomitant daily fixed-dose temozolomide for brain metastases treatment: a randomised phase II trial.
This randomised phase II study evaluated the use of Temozolomide (TMZ) concomitant with 30 Gray (Gy) of Whole-brain irradiation (WBI) for 2 weeks without adjuvant TMZ vs. WBI alone in patients with Brain metastases (BM) from solid tumours. Fifty-five patients were randomised into the following groups: 28 patients received WBI (30 Gy in 10 fractions over 2 weeks) concomitant with once-daily 200 mg TMZ on Mondays, Wednesdays, and Fridays, and 300 mg TMZ on Tuesdays and Thursdays (TMZ plus WBI arm). Twenty-seven patients received the same schedule of WBI alone (control arm). The objective response (OR) was 78.6% for the TMZ plus WBI arm, (95% confidence interval [CI], 63.4-93.8%) and 48.1% (29.3-66.9%) for the control arm (p=0.019). Median Progression-free survival (PFS) of BM was 11.8 months (CI, 4.7-8.9 months) and 5.6 months (4.9-6.2 months) for the TMZ plus WBI and control arms, respectively, (Hazard ratio [HR], 0.24; CI, 0.09-0.65; p=0.005). Overall survival (OS) of 8.0 Months for the TMZ plus WBI arm and 8.1 months for the control arm, were not significantly different. A daily fixed dose of TMZ during WBI without adjuvant TMZ was well tolerated and significantly improved local control of BM compared with WBI alone. These findings require confirmation in a phase III trial (ClinicalTrials.gov number, NCT01015534).


Identifying critical higher-order interactions in complex networks.
Diffusion on networks is an important concept in network science observed in many situations such as information spreading and rumor controlling in social networks, disease contagion between individuals, and cascading failures in power grids. The critical interactions in networks play critical roles in diffusion and primarily affect network structure and functions. While interactions can occur between two nodes as pairwise interactions, i.e., edges, they can also occur between three or more nodes, which are described as higher-order interactions. This report presents a novel method to identify critical higher-order interactions in complex networks. We propose two new Laplacians to generalize standard graph centrality measures for higher-order interactions. We then compare the performances of the generalized centrality measures using the size of giant component and the Susceptible-Infected-Recovered (SIR) simulation model to show the effectiveness of using higher-order interactions. We further compare them with the first-order interactions (i.e., edges). Experimental results suggest that higher-order interactions play more critical roles than edges based on both the size of giant component and SIR, and the proposed methods are promising in identifying critical higher-order interactions.


EEG power and coherence in autistic spectrum disorder.
Autistic spectrum disorder (ASD) has been defined as a neurodevelopmental disorder with associated deficits in executive function, language, emotional, and social function. ASD has been associated with pathophysiology in cerebral organization. The current study investigated quantitative EEG findings in twenty children diagnosed with autistic disorders as compared to 20 controls matched for gender, age and IQ. The EEG was recorded during an eyes-closed resting condition and topographical differences in cerebral functioning were examined using estimates of absolute, relative, and total power, as well as intrahemispheric and interhemispheric coherences. There were group differences in power, intrahemispheric and interhemispheric coherences. Findings included excessive theta, primarily in right posterior regions, in autistics. There was also a pattern of deficient delta over the frontal cortex and excessive midline beta. More significantly, there was a pattern of underconnectivity in autistics compared to controls. This included decreased intrahemispheric delta and theta coherences across short to medium and long inter-electrode distances. Interhemispherically, delta and theta coherences were low across the frontal region. Delta, theta and alpha hypocoherence was also evident over the temporal regions. Lastly, there were low delta, theta and beta coherence measurements across posterior regions. These results suggest dysfunctional integration of frontal and posterior brain regions in autistics along with a pattern of neural underconnectivity. This is consistent with other EEG, MRI and fMRI research suggesting that neural connectivity anomalies are a major deficit leading to autistic symptomatology. This paper reports the largest integrated study of EEG power and coherence during a resting state in children suffering autism spectrum disorder.


Homocysteine and cognitive function in institutionalised elderly A cross-sectional analysis.
Several cross-sectional, case-control and prospective studies revealed a relation between homocysteine and cognitive function or dementia. These studies included either patient populations or healthy, community- dwelling elderly people. In this study we tested the hypothesis that homocysteine was inversely associated with cognitive function in a population of institutionalised elderly (aged >/= 60 y; n = 157). For testing this hypothesis baseline data of a recently conducted intervention study in institutionalised elderly (median age 83 years) were used. Cognitive function was evaluated by the cognitive subscale of the Alzheimer's disease Assessment Scale (ADAS-cog). The association between fasting plasma homocysteine level and cognitive function was investigated by multiple linear regression analysis. In the crude model homocysteine concentration was not significantly related to ADAS-cog score (beta = 0.061; p = 0.45). Age was found to be related to ADAS-cog score (beta = 0.161; p < 0.05). Adjusting for age did however not result in a relation between homocysteine and cognitive function. In our study no association was found between homocysteine and cognitive function in a population of very old institutionalised subjects.


Accelerating protein release from microparticles for regenerative medicine applications.
There is a need to control the spatio-temporal release kinetics of growth factors in order to mitigate current usage of high doses. A novel delivery system, capable of providing both structural support and controlled release kinetics, has been developed from PLGA microparticles. The inclusion of a hydrophilic PLGA-PEG-PLGA triblock copolymer altered release kinetics such that they were decoupled from polymer degradation. A quasi zero order release profile over four weeks was produced using 10% w/w PLGA-PEG-PLGA with 50:50 PLGA whereas complete and sustained release was achieved over ten days using 30% w/w PLGA-PEG-PLGA with 85:15 PLGA and over four days using 30% w/w PLGA-PEG-PLGA with 50:50 PLGA. These three formulations are promising candidates for delivery of growth factors such as BMP-2, PDGF and VEGF. Release profiles were also modified by mixing microparticles of two different formulations providing another route, not previously reported, for controlling release kinetics. This system provides customisable, localised and controlled delivery with adjustable release profiles, which will improve the efficacy and safety of recombinant growth factor delivery.


[Not Available].
Triticale is a frequently cultivated and used in feed rations because of high yields of kernels and straw. Furthermore triticale is cosidered in a culturelandscape program. The storage of triticale and storage conditions become more and more important. In our study Triticale was remoistered to a watercontent of 14, 16, 18, und 19% as well, inoculated withP verrucosum and stored for 28 weeks from november till july in a research granary (tower silo). This experiment should simulate the storage situation in farmscale from cold wintermonths to warm spring times. Every four weeks CO2 was measured, and samples for moisture, OTA- and CT-analysis were taken. At week 20 and a MC of 19 % 22 μg OTA/kg triticale were found. The maximum of OTA-production in this humidity stage was at week 28 with 635 μg/kg. Also at a MC of 18 % OTA could be found with levels near to the detection limit. In contrast to former investigations with oatsP verrucosum produced in triticale no citrinin even when the OTA concentrations were higher than in our investigations.


Mycotoxins, mycotoxicoses, mycotoxicology and Mycopathologia.
Mycotoxins are fungal poisons. This definition does not stipulate whether fungi are the targets of poisoning or are the producers of the poisons. The following is suggested as a useful working definition: Mycotoxins are natural products produced by fungi that evoke a toxic response when introduced in low concentration to higher vertebrates and other animals by a natural route. Some mycotoxins have multiple effects, and may cause phytotoxic and antimicrobial syndromes in addition to animal toxicity. By convention, mushroom and yeast poisons are usually excluded from discussions of mycotoxins. The eclectic nature of the discipline and the international scope of the problem has attracted scientists from many different backgrounds. The publishers and editors of Mycopathologia intend for this journal to become a major forum for mycotoxin research.


Occurrence of fungi and mycotoxins in herbal medicines and rapid detection of toxin-producing fungi.
Contamination from external hazardous materials may greatly influence the safety and efficacy of herbal medicines. This paper aimed to evaluate the levels of contamination by mycotoxins and toxigenic fungi in herbal medicines and establish a rapid method for detecting toxin-producing fungi. Herein, 62.92%, 36.25%, and 64.17% of herbal medicines were contaminated by aflatoxins (AFs), ochratoxins, and fumonisins, respectively. Aspergillus (43.77%), Fusarium (5.17%), and Cladosporium (4.46%) were the three predominant genera. Spearman's correlation results showed that Aspergillus and Fusarium were significantly and positively correlated with mycotoxin content (R > 0.5, P < 0.05). In addition, 323 fungal strains were isolated from herbal medicines, and 20 species were identified, mainly belonging to Aspergillus and Penicillium. Analysis of potential mycotoxin-producing fungi showed that Aspergillus flavus can produce AFs, and Aspergillus ochraceus and Aspergillus niger can produce ochratoxin A (OTA). Multiplex real-time polymerase chain reaction showed that A. flavus harbored AF synthesis genes (aflR), and A. ochraceus and A. niger harbored OTA synthesis genes (aoksl). With these synthesis genes, 67.07% and 37.20% of 164 herbal medicines were positive for toxigenic genes. Furthermore, an excellent correlation was found between the above gene copies and mycotoxin content (R2 = 0.99). Our results confirmed the high detection rate of mycotoxins in herbal medicines and identified pivotal AF- and OTA-producing fungi. In conclusion, this paper provided the contamination status of fungi and mycotoxins in herbal medicines and established a rapid method for detecting toxigenic fungi.


The etiology of rheumatoid arthritis.
The etiology of rheumatoid arthritis has been elusive, but it finally seems to be explained by a combination of three factors: (i) a relatively mild deficiency of cortisol, the normal adrenocortical hormone that is essential for normal immunity but which has achieved a bad reputation because of the use of excessive dosages of it or its stronger derivatives, (ii) a deficiency of dehydro-epi-androsterone (DHEA), the chief androgen produced by the human adrenal cortex but which has been little studied, and (iii) infection by organisms such as mycoplasma, which have a relatively low virulence, are difficult to culture in the laboratory, and cause inflammation and destruction of tissue in periarticular and articular areas of immunocompromised hosts. The mild adrenocortical deficiency apparently is sufficient to impair immunity, especially after stress, and permit these organisms to cause inflammatory arthritis. Further studies are necessary to determine optimum therapy, but it will probably include safe physiologic dosages of cortisol and DHEA plus antibiotic treatment of infection by mycoplasma or other causative organisms.


Immune-Mediated Colitis.
This review addresses our current knowledge of immune-mediated colitis (IMC) and offers a practical guide to its management. Due to the similarity in clinical, endoscopic, and histologic findings between IMC and inflammatory bowel disease (IBD), gastroenterologists have tailored their approach to IMC management to that of IBD. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that augment the T-cell anti-tumor response of the immune system and have demonstrated their importance in the treatment of a wide range of malignancies. With the growing benefits of ICIs, there are immune-related adverse events (irAEs) that mirror many known autoimmune diseases. Diarrhea and IMC are the most common and severe irAEs noted. No standardized guidelines exist in the management of these irAEs.


Preparation of a very stable immobilized biocatalyst of glucose oxidase from Aspergillus niger.
Glucose oxidase (GOX) has been immobilized on different activated supports, including glyoxyl agarose, epoxy sepabeads and glutaraldehyde-activated supports. Immobilization onto supports pre-activated with glutaraldehyde rendered the most thermo-stable preparation of GOX. Therefore, as the glutaraldehyde chemistry gave a high stabilization of the enzyme, we proposed another technique for improving the multipoint attachment through glutaraldehyde: the enzyme was ionically adsorbed on cationic supports with primary amino groups and then the immobilized preparation was treated with a glutaraldehyde solution. The decrease on enzyme activity was <20%. Following this methodology, we achieved the highest stability of all the immobilization systems analyzed, showing a half-life 100 times higher than the soluble enzyme. Moreover, this derivative showed a higher stability in the presence of organic solvents (for instance methanol) or hydrogen epoxide than the ionically adsorbed enzyme or the soluble one. Therefore, the adsorption of GOX on aminated cationic support and subsequent treatment with glutaraldehyde was presented as a very successful methodology for achieving a very stable biocatalyst.


Changes in amount and intensity of physical activity over time in breast cancer survivors.
Physical activity is associated with decreased breast cancer recurrence and mortality, as well as fewer treatment-related symptoms. Nevertheless, most breast cancer survivors do not meet physical activity guidelines. The purpose of this manuscript is to characterize physical activity trends over time in breast cancer survivors. Mayo Clinic Breast Disease Registry participants received surveys at baseline and at 1 and 4 years after diagnosis; breast cancer recurrence and/or metastatic disease were exclusion criteria. Participants were considered to be meeting guidelines if they self-reported at least 150 minutes of moderate-intensity (eg, fast walking) and/or strenuous (eg, jogging) physical activity per week. Statistical analyses include analysis of covariance methods, paired t tests, conditional logistic regression models, and McNemar tests of homogeneity. A total of 171 participants were included in the analysis. The amount of total physical activity decreased over time (P = .07). Mild-intensity physical activity (eg, easy walking) decreased most over time (P = .05). Among participants aged 18-49 years, mild-intensity (P = .05) and moderate-intensity (P = .02) physical activity decreased over time. Strenuous-intensity physical activity levels decreased over time among participants with a normal body mass index (P = .002) and with obesity (P = .01). We found a trend-level decrease in total physical activity over time, driven mostly by a decrease in mild-intensity physical activity. Young breast cancer survivors are especially likely to reduce their physical activity over time. Further research on implementing physical activity guidelines in clinical practice is warranted.


Race and sex demographics in the surgical management of facial nerve palsy.
Facial palsy affects patients of all backgrounds, yet no existing studies describe differences in its treatment patterns between demographic groups. We used the National Surgical Quality Improvement Project database to investigate whether race and sex disparities exist in facial reanimation surgery. Patients were identified using CPT codes corresponding to facial-nerve procedures. Seven hundred sixty-one patients met criteria; 681 self-identified as White (89.5%), 51 as Black (6.7%), 43 as Hispanic (5.6%), 23 as Asian (3.0%), and 5 patients as other (0.61%). White patients were more than twice as likely to undergo brow ptosis repair than Non-White patients (OR 2.49, 95% CI 1.16-6.15, p = .03). After controlling for malignancy, men had longer operative times than women (480.2 vs. 413.9 min, p = .04) and higher likelihood of free tissue transfer (OR 4.1, 95% CI 1.9-9.8), fascial free tissue transfer (OR 10.7, 95% CI 2.1-195), and ectropion repair (OR 1.8, 95% CI 1.2-2.8). Most patients undergoing facial reanimation surgery in the United States are White. Men have longer operative times and a higher likelihood of undergoing free fascial grafts and cutaneous and fascial free tissue transfer than women regardless of malignancy status. 2c.


The biosynthesis of elastin by an aortic medial cell culture.
A long term culture of aortic medial cells, derived from newborn pig aorta, has been established. The ability of these cells to synthesize soluble elastin has been demonstrated by isolation and characterization of the radioactively labeled protein, using soluble elastin of copper-deficient pig aorta as the carrier. The synthesis of corsslinked elastin was shown by the isolation and identification of the lysine-derived crosslinks after incubating the cultures with [14C]-labeled lysine. The precursor relationship of soluble to insoluble elastin was demonstrated by incubating the [3H]-labeled soluble elastin from copper-deficient pig aorta with the culture and isolating labeled crosslinks from the insoluble elastin residue.


PRKAA2 variation and the clinical characteristics of patients newly diagnosed with type 2 diabetes mellitus in Yogyakarta, Indonesia.
Adenosine monophosphate (AMP)-activated protein kinase (AMPK; EC 188.8.131.52) enzymes play a pivotal role in cell metabolism. They are involved in type 2 diabetes mellitus (T2DM) pathogenesis. Genetic variation of PRKAA2 coding for the AMPK α2 catalytic subunit (AMPKα2) is reported to be associated with susceptibility for T2DM. To determine the association between PRKAA2 genetic variations (rs2796498, rs9803799, and rs2746342) with clinical characteristics in patients newly diagnosed with T2DM. We performed a cross-sectional study including 166 T2DM patients from 10 primary health care centers in Yogyakarta, Indonesia. We measured fasting plasma glucose, hemoglobin A1c, serum creatinine, glomerular filtration rate, blood pressure, and body mass index as clinical characteristics. PRKAA2 genetic variations were determined by TaqMan SNP genotyping assay. Hardy-Weinberg equilibrium was calculated using χ2 tests. There was no difference in clinical characteristics for genotypes rs2796498, rs9803799, or rs2746342 (P > 0.05). No significant association was found between PRKAA2 genetic variations and any clinical feature observed. Further subgroup analysis adjusting for age, sex, and waist circumference did not detect any significant association of PRKAA2 genetic variations with clinical characteristics (P > 0.05). PRKAA2 genetic variation is not associated with the clinical characteristics of Indonesian patients with newly diagnosed T2DM.


Bag3 Regulates Mitochondrial Function and the Inflammasome Through Canonical and Noncanonical Pathways in the Heart.
B-cell lymphoma 2-associated athanogene-3 (Bag3) is expressed in all animal species, with Bag3 levels being most prominent in the heart, the skeletal muscle, the central nervous system, and in many cancers. Preclinical studies of Bag3 biology have focused on animals that have developed compromised cardiac function; however, the present studies were performed to identify the pathways perturbed in the heart even before the occurrence of clinical signs of dilatation and failure of the heart. These studies show that hearts carrying variants that knockout one allele of BAG3 have significant alterations in multiple cellular pathways including apoptosis, autophagy, mitochondrial homeostasis, and the inflammasome.


Lactate up-regulates the expression of PD-L1 in kidney and causes immunosuppression in septic Acute Renal Injury.
This study aims to explore the mechanism of immunosuppression in septic Acute Renal Injury (AKI) and the role of programmed death-1 (PD-1/PD-L1) pathway in septic AKI. This study established a septic AKI model by Cecal ligation and puncture (CLP) in C57/B6 mice, ELISA was used to test the level of lactate and creatinine in serum, blood was collected for flow cytometry and kidney samples for Western blot analyses. This study further analyzed the expression of PD-L1 in kidney and the expression of PD-1 in CD4+, CD8+ T cell, and the number of CD3+ T cells to identify apoptosis in T cells in the blood. The CLP sepsis model induced AKI in C57/B6 mice; The expression of PD-1 and PD-L1 were increased in septic AKI mice; PD-1/PD-L1 induced apoptosis in T cells: the number of lymphocytes decreased by 64%, while the number of CD3+ T cells decreased by 27% compared with the sham group; Results also indicated that lactate up-regulates expression of PD-L1 in the kidney. Lactate activated PD-1/PD-L1 pathway can induce immunosuppression by inducing apoptosis in lymphocytes in septic AKI. Moreover, blocking the receptor of lactate or PD-1/PD-L1 might be a new therapy for septic AKI.


Radiologists and endoscopy: a survey of the attitudes and intentions of radiologists in training.
A postal survey of senior registrars in radiology in this country was carried out to assess attitudes towards radiologists taking part in endoscopy services. One hundred and ninety-six senior registrars from 37 training centres recognised by the Royal College of Radiologists completed the questionnaire (a response of 74%). Thirty-nine per cent of respondents had some practical experience of endoscopy before commencing training in radiology. Twenty-eight per cent of respondents declared a major interest in gastrointestinal radiology. Sixty four per cent felt that radiologists should perform endoscopy (87% in the case of those with a major interest in gastrointestinal radiology). Thirty-seven per cent were interested in providing, or participating in, an endoscopy service after obtaining a consultant post. Despite this level of interest, only 18% of respondents felt that they had adequate access to endoscopy training and only 3% were aware of the training recommendations of the British Society, of Gastroenterology.


[Vagotomy for the surgical treatment of severe gastroduodenal hemorrhages].
24 patients (8 female, 16 male) with severe gastroduodenal haemorrhage were treated by vagotomy; in 17 cases highly selective vagotomy was performed, in 3 case truncal vagotomy + pyloroplasty and in 4 patients vagotomy was combined with excision or purse-string suture of the ulcer. Treatment was effective in 23 patients, without recurrence of haemorrhage. In 19 patients vagotomy not only curbed the bleeding but provided definitive therapy (Visick I-II); 4 patients died (mortality rate 16%).


Unilateral Facial Nerve Palsy After Inadvertent Dural Puncture Initially Diagnosed as Bell's Palsy, Improved With Epidural Blood Patch: A Case Report.
Cranial nerve (CN) VII palsy is a rare complication of neuraxial blockade. The likely etiology of the palsy is intracranial hypotension from cerebrospinal fluid loss leading to traction on CN VII. The presentation of symptoms of CN VII palsy from intracranial hypotension closely resembles a more common cause of CN VII injury, Bell's palsy, and the 2 can be difficult to differentiate. We present a patient who had a dural puncture with development of a headache and CN VII palsy, which improved with epidural blood patch (EBP). EBP should be considered for patients with suspected CN palsy from intracranial hypotension.


A global analysis of COVID-19 infection fatality rate and its associated factors during the Delta and Omicron variant periods: an ecological study.
The Omicron variant of SARS-CoV-2 is more highly infectious and transmissible than prior variants of concern. It was unclear which factors might have contributed to the alteration of COVID-19 cases and deaths during the Delta and Omicron variant periods. This study aimed to compare the COVID-19 average weekly infection fatality rate (AWIFR), investigate factors associated with COVID-19 AWIFR, and explore the factors linked to the increase in COVID-19 AWIFR between two periods of Delta and Omicron variants. An ecological study has been conducted among 110 countries over the first 12 weeks during two periods of Delta and Omicron variant dominance using open publicly available datasets. Our analysis included 102 countries in the Delta period and 107 countries in the Omicron period. Linear mixed-effects models and linear regression models were used to explore factors associated with the variation of AWIFR over Delta and Omicron periods. During the Delta period, the lower AWIFR was witnessed in countries with better government effectiveness index [β = -0.762, 95% CI (-1.238)-(-0.287)] and higher proportion of the people fully vaccinated [β = -0.385, 95% CI (-0.629)-(-0.141)]. In contrast, a higher burden of cardiovascular diseases was positively associated with AWIFR (β = 0.517, 95% CI 0.102-0.932). Over the Omicron period, while years lived with disability (YLD) caused by metabolism disorders (β = 0.843, 95% CI 0.486-1.2), the proportion of the population aged older than 65 years (β = 0.737, 95% CI 0.237-1.238) was positively associated with poorer AWIFR, and the high proportion of the population vaccinated with a booster dose [β = -0.321, 95% CI (-0.624)-(-0.018)] was linked with the better outcome. Over two periods of Delta and Omicron, the increase in government effectiveness index was associated with a decrease in AWIFR [β = -0.438, 95% CI (-0.750)-(-0.126)]; whereas, higher death rates caused by diabetes and kidney (β = 0.472, 95% CI 0.089-0.855) and percentage of population aged older than 65 years (β = 0.407, 95% CI 0.013-0.802) were associated with a significant increase in AWIFR. The COVID-19 infection fatality rates were strongly linked with the coverage of vaccination rate, effectiveness of government, and health burden related to chronic diseases. Therefore, proper policies for the improvement of vaccination coverage and support of vulnerable groups could substantially mitigate the burden of COVID-19.


Plate versus screws fixation for the posterior malleolar fragment in trimalleolar ankle fractures.
The fixation methods of posterior malleolar fracture (PMF) in trimalleolar ankle fractures is still controversial. We aim to compare clinical and radiological outcomes between plate fixation and screws fixation for PMF in trimalleolar ankle fractures. Literature search was performed through PubMed, EMBASE, Cochrane Library and CNKI database from databases inception to May 2022 to identify randomized controlled trial (RCT) and comparative clinical study in English or Chinese. A meta-analysis was performed using RevMan 5.1 software, and systematic review was performed when the data extracted from included studies could not be synthesized. Two RCTs and six cohort studies were included. The meta-analysis results showed that articular step-off or gap in plate fixation was superior to antero-posterior screws fixation (RR = 0.28; 95%CI: 0.11, 0.76; P = 0.01). there were no significant differences in American Orthopaedic Foot & Ankle Society scores (MD = -0.19; 95%CI: -2.43, 2.05; P = 0.87), arthritis (RR = 1.67; 95%CI: 0.61, 4.55; P = 0.32), infection and total complication (RR = 1.42; 95%CI: 0.89, 2.25; P = 0.14). Plate fixation might have better articular step-off or gap, compared with "A to P" screws fixation for the posterior malleolus in trimalleolar ankle fractures. Screw fixation could achieve shorter surgical time than plate fixation. However, no significant differences were found in AOFAS scores, arthritis, infection, sural nerve injury and total complication during the comparisons.


Concomitant chronic spontaneous urticaria treatment might hinder the diagnosis of occupational latex-induced anaphylaxis: A case report.
Cutaneous manifestations of chronic spontaneous urticaria (CSU) are identical to type 1 hypersensitivity reactions. The daily occurrence of rash from occupational allergy could be misinterpreted as CSU exacerbation. We aim to report a nurse with concomitant CSU suffering from latex-induced anaphylaxis. Skin tests, specific IgE using ImmunoCAP, and gloves challenge were performed. A 27-year-old nurse with CSU suffered from several episodes of severe urticarial flare. H1-antihistamine up-dosing and oral corticosteroid burst were given. Unfortunately, she developed 3 episodes of anaphylaxis during her routine nursing care work on a medical ward, leading to allergist consultation. She had positive latex-specific IgE (6.86 kUA/L) and positive gloves challenge test. Concomitant CSU treatment might hinder the recognition of latex allergy by masking or delaying skin manifestations. IgE-mediated allergy should be suspected if there was a change in severity or frequency of previously controlled CSU or the presence of systemic symptoms.


Air Pollution and the Dynamic Association Between Depressive Symptoms and Memory in Oldest-Old Women.
Exposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest-old (aged 80 and older) women. Prospective cohort data from the Women's Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes. Geographically diverse community-dwelling population. A total of 1,583 dementia-free women aged 80 and older. Women completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15-item Geriatric Depression Scale (GDS-15). We estimated 3-year average exposures to regional particulate matter with aerodynamic diameter below 2.5 μm (PM2.5 ) (interquartile range [IQR] = 3.35 μg/m3 ) and gaseous nitrogen dioxide (NO2 ) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging. Latent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO2 (β = .287 per IQR; P = .002) and PM2.5 (β = .170 per IQR; P = .019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS-15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (β = -.372; P = .001), with a significant indirect effect of remote NO2 and PM2.5 exposure on EM declines mediated by DS. There were no other significant indirect exposure effects. These findings in oldest-old women point to potential adverse effects of late-life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women.


Thermal tolerance of the hermatypic coral Acropora tenuis elucidated by RGB analysis and expression of heat shock proteins in coral and symbiotic dinoflagellates.
Increased seawater temperature has resulted in mass coral bleaching events globally. Acropora tenuis, the dominant hermatypic coral species in southern Japan, was exposed to four temperature treatments [28 °C, 30 °C, 32 °C, and >32 (=33.3 °C)] for 7 d. The coral colour was converted to R (red), G (green), and B (blue) values, each ranging from 0 (darkest) to 255 (brightest). RGB values exposed to 28 °C and 30 °C decreased slightly, whereas those exposed to 32 °C increased significantly after day 3-6, and those exposed to 33.3 °C changed to white within 2 d. Quantitative RT-PCR analysis revealed no significant changes in heat shock proteins in Acropora and symbiotic dinoflagellates at 28 °C and 30 °C after a 7 d exposure. Our findings revealed that 30 °C, higher than the mean temperature of the warmest month in southern Japan, was an inhabitable temperature for A. tenuis.


The role of genetic and environmental factors in the development of T-cell mediated allergic disease in early life.
Cognate immunity to inhalant allergens is virtually universal within the adult population, but in the majority of cases this does not progress to the development of persistent asthma. Accumulating evidence suggests that progression from moderate to severe allergic disease is associated with a series of host and environmental factors operative during early childhood which interact to increase risk for both allergic sensitisation and severe respiratory infection, within the same subjects.


Neutrophil extracellular traps promote keratinocyte inflammation via AIM2 inflammasome and AIM2-XIAP in psoriasis.
The infiltration of neutrophils in the epidermis and the release of neutrophil extracellular traps (NETs) are important events in the pathogenesis of psoriasis, but the regulatory roles and internal mechanism of NETs in psoriasis are largely unknown. Here, we demonstrate that NETs can activate the absent-in-melanoma-2 (AIM2) inflammasome in keratinocytes through the p38-MAPK signalling pathway, and targeting NETs with CI-amidine in vivo reduces AIM2 expression and ameliorates imiquimod-induced psoriasis-like phenotype in mice. Notably, NETs-activated AIM2 in keratinocytes not only promotes IL-1β production through the classical inflammasome pathway but also promotes IFN-γ production via X-linked inhibitor of apoptosis protein (XIAP), thereby mediating the immune responses of keratinocytes. In conclusion, our study demonstrates that the NETs-AIM2 axis exerts multiple pro-inflammatory effects on keratinocytes and may serve as a potential target for psoriasis therapy.


Accumulation of circulating endogenous and exogenous immunoglobulins by hypothalamic magnocellular neurons.
Rat monoclonal antibodies, used in immunocytochemistry of normal rat brain, result in a granular reaction product within neurons innervating areas lacking a blood-brain barrier. Immunocytochemical characterization shows that the staining is independent of the primary antibody and exclusively dependent on the presence of anti-rat immunoglobulin. This granular staining could be selectively eliminated by pre-adsorption of the anti-rat immunoglobulin with purified rat immunoglobulin or disruption of microtubule retrograde transport systems by intraventricular injection of colchicine. A dependence on retrograde transport and complete independence from local synthesis was further substantiated by the rapid uptake and accumulation of intravenously administered rabbit or rat [125I]immunoglobulins by the supraoptic-neurohypophysial system. Immunoelectron microscopy was used to identify the endogenous rat immunoglobulin within lysosome-like organelles in the cytoplasm of magnocellular neuroendocrine cells. The uptake and incorporation of plasma macromolecules into the lysosomal system of magnocellular and other neurons projecting to regions with a weak blood-brain barrier may represent a novel mode of blood-central nervous system interactions.


Clinical and morphological effects of hyperbaric oxygen therapy in patients with interstitial cystitis associated with fibromyalgia.
Interstitial Cystitis (IC) is a debilitating disorder of the bladder, with a multifactorial and poorly understood origin dealing with microcirculation repeated damages. Also Fibromyalgia (FM) is a persistent disorder whose etiology is not completely explained, and its theorized alteration of pain processing can compromise the quality of life. Both these conditions have a high incidence of conventional therapeutic failure, but recent literature suggests a significant beneficial response to Hyperbaric Oxygen Therapy (HBOT). With this study, this study we evaluated the effects of HBOT on quality of life, symptoms, urodynamic parameters, and cystoscopic examination of patients suffering from both IC and FM. We structured an observational clinical trial design with repeated measures (questionnaires, urodynamic test, and cystoscopy) conducted before and 6 months after a therapeutic protocol with hyperbaric oxygen for the treatment of patients suffering from both IC and FM. Patients were exposed to breathing 100% oxygen at 2 atm absolute (ATA) in a multiplace pressure chamber for 90 min using an oro-nasal mask. Patients undertook a cycle of 20 sessions for 5 days per week, and a second cycle of 20 sessions after 1 week of suspension. Twelve patients completed the protocol. Changes after HBOT were not significant, except for hydrodistension tolerance (mean pre-treatment: 409.2 ml; mean post-treatment: 489.2 ml; p < 0.05). A regression of petechiae and Hunner's ulcers was also noted 6 months after the completion of HBOT. Our study showed no improvement of symptoms, quality of life, and urodynamic parameters, except for hydrodistension, and a slight improvement in cystoscopic pattern. However, to date, we could not demonstrate the significance of overall results to justify the use of HBOT alone in patients with IC and FM. This observation suggests that additional studies are needed to better understand if HBOT could treat this subset of patients. NCT03693001 ; October 2, 2018. Retrospectively registered.


[In-home respite for the families of Alzheimer's patients].
An innovative and unique model of respite and support at home for people with Alzheimer's and their carers has been created. The quality of the service provided is based on the principle of home assistance, 24 hours a day and for several consecutive days, provided by a single specialised care assistant.


Bifurcation of subcortical afferents to visual areas 17, 18, and 19 in the cat cortex.
We have examined the pattern of axon bifurcation in the thalamic and claustral afferents to visual areas 17, 18, and 19 in the adult cat neocortex. This was achieved by injecting two fluorescent retrograde tracers, fast blue and diamidino yellow, in retinotopically corresponding regions of two of these three cortical areas. The pattern of single- and double-labelled cells was then examined in subcortical structures and the presence of double-labelled cells was interpreted as indicating that these neurons send bifurcating axons to the two injected areas. The size of the cortical region surrounding the injection site where each fluorescent dye is taken up was studied by making side-by-side injections of the two tracers in area 17 and examining the size and the separation of the two groups of labelled cells in the lateral geniculate nucleus (LGN). From these experiments we conclude that the uptake region is smaller than 1 mm and is included in the region of dense coloring surrounding the track of the injection needle. Injections were made in cortical regions which were in retinotopic correspondence as determined by electrophysiological recording. The double-labelled neurons were always found in the zone of overlap of the two populations of colored cells and no double-labelled neurons were found when there was no overlap between these populations. This indicates that the bifurcating axons send branches to strictly retinotopically corresponding regions in the two cortical areas. After injections in areas 18 and 19, numerous double-labelled cells were observed in laminae C of the LGN, in the medial interlaminar nucleus (MIN), the posterior nucleus (PN), and the lateral part of the lateral posterior nucleus (LP), in the retinorecipient zone of the pulvinar (RRZ-Pul), the intralaminar nuclei (ILN), and the claustrum. The proportions of double-labelled cells with respect to the total number of labelled neurons were computed in the region of overlap of the two populations of labelled cells. These percentages ranged between 5 and 20% and were highest in the C laminae of the LGN, the intralaminar nuclei, and the claustrum. After injection of areas 17 and 18, similar proportions of double-labelled cells were observed in the same structures, as well as in the A laminae of the LGN. Here again, the intralaminar nuclei and the claustrum tended to have slightly higher (20-30%) proportions of double-labelled cells. When the nonadjacent areas 17 and 19 were injected, doubled-labelled neurons were also observed in all these structures, except the A laminae of the LGN.(ABSTRACT TRUNCATED AT 400 WORDS)


Comparing In-Person and Synchronous Online Training for an Evidence-Based Treatment.
Online trainings in evidence-based treatments (EBT) can be effective platforms and may provide better access to community providers as compared with traditional in-person trainings. However, questions remain as to whether online trainings can achieve similar rates of training engagement and model application to traditional in-person trainings. We compared training engagement and model application (e.g., extent of use, fidelity) between participants attending in-person (n = 127) and synchronous online (n = 277) trainings for an EBT (Alternatives for Families: a Cognitive Behavioral Therapy; AF-CBT). Data were collected through pre- and post-training questionnaires and trainers' records. Chi-square analyses and t-tests were used to test for differences between groups. Engagement regarding attendance at workshops and consultation calls was high for both groups, with no significant differences. A total of 81% and 76% presented at least one case and submitted at least one audio recording of an actual AF-CBT session, respectively. Participants rated the training workshop as high quality (M > 4.5/5), and the consultation calls as medium-to-high quality (M > 4/5) across both modalities, indicating good training engagement. In-person training participants were significantly more likely to submit two or more audio recorded sessions than online training participants. This was the only training requirement outcome that differed between the two groups. In examining model application, there were no significant differences between in-person and online training participants in self-reported delivery of AF-CBT, the number of clients with whom it was implemented, the extent they used the model, or the fidelity with which they delivered it. Both groups reported similar improvements in comfort when working with aggressive families, being directive, and using learning techniques like role plays. Online evidence-based treatment skills training appears to be feasible, efficient, and beneficial, with engagement and performance comparable to in-person training. We discuss potential advantages of online training (e.g., fewer costs, greater flexibility for staff from independent practices) and disadvantages (e.g., less satisfaction).


Assignment of the human skeletal muscle alpha actin gene (ACTA1) to 1q42 by fluorescence in situ hybridisation.
The human skeletal muscle alpha actin gene (ACTA1) has previously been localized to 1p21-->qter using somatic cell hybrids and a specific probe from the 3' untranslated region of the gene. Using fluorescence in situ hybridization the localization has been confirmed and the ACTA1 gene precisely mapped to 1q42.


Psychological consequences of neonatal screening for alpha 1-antitrypsin deficiency. Parental reactions to the first news of their infants' deficiency.
Medical record information and retrospective parental reports at interview indicated that the 61 families were typically first contacted about the child's alpha 1-antitrypsin deficiency (ATD) during its first 6 months of life, when a physician called the mother on the telephone and told her at least something about the child's ATD. Most parents felt they had received unclear or inadequate information. A majority initially conceived of ATD as representing an imminent, serious danger to the child's health. Most of the mothers (78%) and many of the fathers (58%) reported having immediately had negative emotional reactions, most often worry, anxiety and fear. These reactions were often long-lasting and, in mothers, typically strong.


Effects of long term polyarthritis and subsequent NSAID treatment on activity with disassociation of tactile allodynia in the mouse.
Chronic pain has profound effects on activity. Previous reports indicate chronic inflammatory conditions result in reduced activity which normalizes upon pain treatment. However, there is little systematic investigation of this process. Rheumatoid arthritis is an autoimmune disorder that causes significant joint pain. The K/BxN serum transfer mouse has been characterized as a model for rheumatoid arthritis and chronic pain. We investigated the activity of mice following K/BxN serum transfer vs. control serum and observed the activity changes following delivery of an NSAID, ketorolac. Previous studies have used running wheels and laser beams to monitor activity; we chose to validate a model using cost-effective infrared sensors on individual cages. Each mouse had its baseline activity obtained, which showed significant variation between individual C57Bl/6 mice. Arthritic mice had significantly decreased activity for only the first 11 nights. Conversely, previous work has shown that these animals display tactile allodynia that persists for at least 45 days. Mice were treated with ketorolac in their drinking water (10mg/kg, 15mg/kg, or 20mg/kg) for nights 6-8. The two highest doses showed significant normalization of activity levels. Four nights after ketorolac was stopped, treated animals were still significantly more active than control. The reversal of the reduced activity provides support that the depression relates to the arthritic pain state of the animal. These results indicate the efficacy of activity monitoring to better investigate behavior in persistent pain states. However, insofar as depressed activity reflects pain and disability, the present work raises questions as to the relevance of the tactile thresholds in defining behaviorally relevant pain states.


Recruitment barriers in rural community hospitals: a comparison of nursing and nonnursing factors.
Despite encouraging signs suggesting that many rural hospitals are experiencing less severe staff shortages, the challenge of successfully recruiting nurses to rural practice settings continues to be a major obstacle. Based on a 1993 survey of 164 directors of nursing (DONs) practicing in rural community hospitals, exploratory factor analysis (EFA) was used to cluster 21 DON-rated recruitment barriers into factors associated with nursing delivery, local community, and professional interaction. DONs, most notably those practicing in the smallest rural facilities (< or = 25 beds), reported community-related barriers such as spouse's employment as the most severe obstacles to successful registered nurse (RN) recruitment. However, upon examination conducted by using multiple regression analyses, only those factors related to nursing delivery and professional interaction were found to be statistically significant predictors of existing staff RN full-time equivalency vacancy rates. Given that barriers related to individual nursing staffs are likely to be far more amenable to change than those associated with rural environments, these findings offer encouragement to nursing administrators who are faced with the difficulties of attracting RNs to rural practice settings.


Identification of a retinoic acid responsive aldoketoreductase expressed in HL60 leukaemic cells.
Neutrophil and monocyte differentiation can be induced in HL60 leukaemia cells by all-trans-retinoic acid (ATRA) and 1alpha,25-dihydroxyvitamin D3 (D3), respectively, whose differentiating effects can be enhanced by exposure to 'anti-inflammatory agents' and steroids. We have provided evidence that this potentiation is via inhibition of the activity of an enzyme of the aldoketoreductase (AKR) family, but had failed to identify expression of known AKRs in HL60 cells. In this study, we have identified a previously unclassified aldoketoreductase family member (termed HAKR e) that is expressed in HL60 cells. HAKR e is dramatically and transiently up-regulated in HL60 cells within 24 h of exposure to ATRA, further supporting the proposition that a member(s) of this family of enzymes play(s) a role in controlling cell growth and/or differentiation.


Perturbation theory for evolution of cooperation on networks.
Network structure is a mechanism for promoting cooperation in social dilemma games. In the present study, we explore graph surgery, i.e., to slightly perturb the given network, towards a network that better fosters cooperation. To this end, we develop a perturbation theory to assess the change in the propensity of cooperation when we add or remove a single edge to/from the given network. Our perturbation theory is for a previously proposed random-walk-based theory that provides the threshold benefit-to-cost ratio, [Formula: see text], which is the value of the benefit-to-cost ratio in the donation game above which the cooperator is more likely to fixate than in a control case, for any finite networks. We find that [Formula: see text] decreases when we remove a single edge in a majority of cases and that our perturbation theory captures at a reasonable accuracy which edge removal makes [Formula: see text] small to facilitate cooperation. In contrast, [Formula: see text] tends to increase when we add an edge, and the perturbation theory is not good at predicting the edge addition that changes [Formula: see text] by a large amount. Our perturbation theory significantly reduces the computational complexity for calculating the outcome of graph surgery.


Autonomic manifestations in acute sensory ataxic neuropathy: a case report.
Acute sensory ataxic neuropathy (ASAN) is known to occur with acute and monophasic sensory ataxia. Although autonomic dysfunctions have been reported, no detailed descriptions are currently available. We describe a case of ASAN in which the autonomic manifestations were systematically investigated. Although the patient did not complain of any autonomic symptoms, except for photophobia due to mydriasis, autonomic testing revealed widespread autonomic dysfunctions. Norepinephrine and dobutamine infusion test indicated the presence of sympathetic dysfunction. Additionally, the pupillary response to pilocarpine revealed the presence of parasympathetic dysfunction. In conclusion, widespread, subclinical autonomic dysfunctions may be present in ASAN patients.


Using Pre-Exercise Photobiomodulation Therapy Combining Super-Pulsed Lasers and Light-Emitting Diodes to Improve Performance in Progressive Cardiopulmonary Exercise Tests.
Skeletal muscle fatigue and exercise performance are novel areas of research and clinical application in the photobiomodulation field, and positive outcomes have been reported in several studies; however, the optimal measures have not been fully established. To assess the acute effect of photobiomodulation therapy (PBMT) combining superpulsed lasers (low-level laser therapy) and light-emitting diodes (LEDs) on muscle performance during a progressive cardiopulmonary treadmill exercise test. Crossover study. Laboratory. Twenty untrained male volunteers (age = 26.0 ± 6.0 years, height = 175.0 ± 10.0 cm, mass = 74.8 ± 10.9 kg). Participants received PBMT with either combined superpulsed lasers and LED (active PBMT) or placebo at session 1 and the other treatment at session 2. All participants completed a cardiopulmonary test on a treadmill after each treatment. For active PBMT, we performed the irradiation at 17 sites on each lower limb (9 on the quadriceps, 6 on the hamstrings, and 2 on the gastrocnemius muscles), using a cluster with 12 diodes (four 905-nm superpulsed laser diodes with an average power of 0.3125 mW, peak power of 12.5 W for each diode, and frequency of 250 Hz; four 875-nm infrared LED diodes with an average power of 17.5 mW; and four 640-nm red LED diodes with an average power of 15 mW) and delivering a dose of 30 J per site. Distance covered, time until exhaustion, pulmonary ventilation, and dyspnea score. The distance covered (1.96 ± 0.30 versus 1.84 ± 0.40 km, t19 = 2.119, P < .001) and time until exhaustion on the cardiopulmonary test (780.2 ± 91.0 versus 742.1 ± 94.0 seconds, t19 = 3.028, P < .001) was greater after active PBMT than after placebo. Pulmonary ventilation was greater (76.4 ± 21.9 versus 74.3 ± 19.8 L/min, t19 = 0.180, P = .004) and the score for dyspnea was lower (3.0 [interquartile range = 0.5-9.0] versus 4.0 [0.0-9.0], U = 184.000, P < .001) after active PBMT than after placebo. The combination of lasers and LEDs increased the time, distance, and pulmonary ventilation and decreased the score of dyspnea during a cardiopulmonary test.


Comprehensive assessment of the associations between maternal diabetes and structural birth defects in offspring: a phenome-wide association study.
Our objective was to comprehensively evaluate the risk of a broad range of birth defects among offspring of women with diabetes, overall and stratified by pregestational versus gestational diagnosis, using the phenome-wide association (PheWAS) methodology. We performed a registry linkage study of all live births (>6,500,000) and birth defects cases (>290,000) in Texas, 1999-2015. We ascertained diabetes from birth and fetal death certificates. We calculated prevalence rate ratios (PRR) for phenotypes with ≥10 cases among exposed offspring (n = 130). Diabetes was associated with the prevalence of any defect (PRR 1.40, 95% confidence interval [CI] 1.38-1.42), multiple defects (PRR 1.86, 95% CI 1.81-1.91), and 60 specific phenotypes, including novel (hypospadias, mitral stenosis) and previously reported phenotypes (renal a-/dysgenesis, spinal anomalies). Pregestational diabetes was a stronger risk factor for any defect (PRR 2.00, 95% CI 1.93-2.07), multiple defects (PRR 3.27, 95% CI 3.11-3.44), and the 60 specific phenotypes evaluated. Gestational diabetes was associated with any defect (PRR 1.21, 95% CI 1.19-1.23) and 47 specific birth defects phenotypes, although associations were weaker than for pregestational diabetes. The PheWAS is an efficient way to identify risk factors for disease using population-based registry data. Pregestational diabetes is associated with a broader range of phenotypes than previously reported. Because diabetes is diagnosed in 1% of women prior to pregnancy and 6%-9% during pregnancy, our results highlight a significant public health concern.


Non-specific effects of aquaMEPHYTON (vitamin K1) on prothrombin expression in human hepatoblastoma (HepG2) cells.
In order to determine the effects of vitamin K1 on prothrombin production, we have treated cultures of human hepatoblastoma cells with an aqueous colloidal suspension of vitamin K1. Dose-response analysis demonstrated increases in secreted prothrombin antigen levels ranging from 3 to 3.7-fold over controls. Time-course analysis demonstrated increases in secreted prothrombin antigen levels over controls up to 6 hours of treatment. Between 6 and 24 hours, secreted prothrombin antigen levels increased at a rate parallel to controls. Vitamin K1 treatment also resulted in a parallel increase in total secreted protein levels. Prothrombin mRNA size (approximately 2.1 kb) and levels (ranging from 390-480 prothrombin mRNA molecules per cell) were determined by Northern and quantitative solution hybridization analysis, respectively, and were unaffected by vitamin K1 treatment. The increases in secreted prothrombin antigen levels most likely result from non-specific effects of vitamin K1 or agents used to emulsify vitamin K1 on protein release from HepG2 cells.


Benign adenoidal hypertrophy caused by adenovirus presenting as a nasopharyngeal mass concerning for malignancy.
Benign adenoidal hypertrophy is the most common cause of nasopharyngeal obstruction. However, depending on size and location, masses may cause nasopharyngeal obstruction. We present our experiences with a ten-year-old female who presented with what appeared to be a large nasopharyngeal mass that was initially favored to be malignant and was ultimately found to be adenoid hypertrophy related to acute infection with adenovirus.


Methods to reveal domain networks.
The development and application of high-throughput technology to study protein interactions has led to the construction of complex interaction maps, the correct interpretation of which is crucial to the identification of targets for drug development. Here we propose that a more informative description of protein interaction networks can be achieved by considering explicitly the modular nature of proteins. In this representation, proteins are drawn as covalently linked modular domains binding to their target sites in partner proteins. Families of conserved modules that bind to relatively short peptides mediate a large fraction of the non-covalent interactions linking different proteins in the network. As these interactions are often involved in the propagation of signal transduction, determining the recognition specificity of each domain family member is an essential step toward a functional description of the global interactome.


[The observation of palatopharyngeal histopathologic characteristic on the patients with obstructive sleep apnea-hypopnea syndrome].
To observe the histopathologic characteristic of the palatopharyngeal tissue and study the effect of ectopic accumulation of lipid on the pathogenesis and development of OSAHS. Thirty-eight cases were selected from the patients in hospital and divided into two groups. Each group had 19 cases, coupled according to Body Mass Index (BMI). HE staining, Oil red O lipid staining and the electro microscope technology were used to observe the pathologic characteristic of the palatopharyngeal tissue, especially the ectopic accumulation of lipid. There existed obvious fatty infiltration in the palatopharyngeal tissue of OSAHS patients, and the type of the minor salivary glands changed. The ultrastructure showed the corresponding changes and the cellular anoxic changes. Fatty infiltration in the palatopharyngeal tissue of OSAHS patients may play an important role in the pharyngeal airway sinking during sleep. There is a closely correlated between fatty infiltration and the pathogenesis and development of OSAHS.


Radical redo surgery for local rectal cancer recurrence improves overall survival: a single center experience.
To date, the survival benefit of redo surgery in locally recurrent rectal adenocarcinoma remains unclear. In an institutional study, operations for recurrence were retrospectively analyzed. Survival was calculated using the Kaplan-Meier plot and Cox regression analysis. A total of 72 patients with local recurrence were explored or resected. In 38 patients, there was synchronous distant organ recurrence. Forty-five of 72 were re-resected and in 37 of 45 cases, R0 situations were achieved. In 11 of 38 metastasized patients, both local and distant organ recurrence were successfully removed. For obtaining tumor control, resections of inner genitals, bladder, and sacral bone were necessary in 10, 4, and 11 patients, respectively. Survival was better for patients re-resected with a median overall survival of 54.9 months, as compared with 31.1 months among non-resected patients (p = 0.0047, log-rank test). Subgroup analysis revealed that a benefit of re-resection was observed to a lesser extent in synchronous local and in distant disease. Cox analysis showed that initial Dukes stage and complete resections of local recurrences were independently determining prognosis (relative risk 1.762 and 0.689, p = 0.008 and p = 0.002, respectively). Radical surgery for local recurrence can improve survival if complete tumor clearance is achieved, and concomitant distant tumor load should not principally preclude re-resection.


A novel response-regulator is able to suppress the nodulation defect of a Bradyrhizobium japonicum nodW mutant.
The two-component regulatory system Nod-VW of Bradyrhizobium japonicum is essential for the nodulation of the legume host plants Vigna radiata, V. unguiculata and Macroptilium atropurpureum. The NodV protein shares homology with the sensor-kinases, whereas the NodW protein is a member of the response-regulator class. We report here the identification of a new B. japonicum DNA region that is able to suppress the phenotypic defect of a nodW mutant, provided that this region is expressed from a foreign promoter. The minimal complementing region, which itself is not essential for nodulation in a nodW+ background, consists of one gene designated nwsB (nodW-suppressor). The deduced amino acid sequence of the nwsB gene product shows a high degree of homology to NodW. The nws B gene is preceded by a long open reading frame, nwsA, whose putative product appears to be a sensor-kinase. Downstream of nwsB, an open reading frame encoding a second putative response-regulator was identified. Interspecies hybridization revealed the presence of nwsAB-like DNA also in other Bradyrhizobium strains. Using nwsB'-'lacZ fusions, the nwsB gene was found to be expressed rather weakly in B. japonicum. This low level of expression is obviously not sufficient to compensate for a nodW- defect, whereas strong overexpression of nwsB is a condition that leads to suppression of the nodW- mutation.