Resistance to aztreonam-avibactam due to CTX-M-15 in the presence of penicillin-binding protein 3 with extra amino acids in Escherichia coli.
Aztreonam-avibactam is a promising combination to treat carbapenem-resistant Enterobacterales including coverage for metallo-β-lactamases. Escherichia coli strains resistant to aztreonam-avibactam have emerged but resistance mechanisms remain to be elucidated. We performed a study to investigate the mechanism for aztreonam-avibactam in a carbapenem-resistant Escherichia coli clinical strain. This strain was resistant to aztreonam-avibactam (aztreonam MIC, 16 mg/L in the presence of 4 mg/L avibactam). Whole genome sequencing revealed that the strain carried metallo-β-lactamase gene bla NDM-4 and the extended-spectrum β-lactamase (ESBL) gene bla CTX-M-15 and had a YRIK four amino acid insertion in penicillin-binding protein 3 (PBP3). bla CTX-M-15 was cloned into pET-28a(+), followed by the transformation, with the gene, of E. coli strain 035125∆pCMY42 possessing the YRIK insertion in PBP3 and strain BL21 with the wildtype PBP3. bla CTX-M-14, another common ESBL gene, and bla CTX-M-199, a hybrid of bla CTX-M-14 and bla CTX-M-15 were also individually cloned into both E. coli strains for comparison. Aztreonam-avibactam resistance was only observed in the E. coli strains with the YRIK insertion in PBP3 that produced CTX-M-15 or its hybrid enzyme CTX-M-199. Checkerboard titration assays were performed to determine the synergistic effects between aztreonam-avibactam and ceftazidime or meropenem. Doubling avibactam concentration in vitro reversed aztreonam-avibactam resistance, while the combination of aztreonam-avibactam and ceftazidime or meropenem did not. In conclusion, CTX-M enzymes with activity against aztreonam, (e.g., CTX-M-15 and CTX-M-199), can confer resistance in the combination of PBP3 with YRIK insertions in metallo-β-lactamase-producing carbapenem-resistant E. coli. Doubling the concentration of avibactam may overcome such resistance.


Cost effectiveness of the Expert Patients Programme (EPP) for patients with chronic conditions.
To assess the cost effectiveness of the Expert Patients Programme (EPP) intervention compared to a treatment as usual alternative. Two-arm pragmatic randomised controlled trial design with waiting list control. Community settings in England. Patients with a wide range of self-defined long-term conditions. The EPP based on the US chronic disease self management program (CDSMP), a lay-led self-care group involving six weekly sessions to teach self-care support skills. Costs estimated over a 6-month period from a societal perspective. Health outcomes estimated in terms of quality adjusted life years (QALYs) generated by patients' response to the EQ5D at baseline and 6-month follow-up. The intervention group is associated with better patient outcomes, at slightly lower cost. Specifically, the intervention group has a 0.020 QALY gain compared with the control group, and a reduced cost of around 27 pounds per patient. The intervention would therefore be considered dominant. While the QALYs gained are small in absolute terms, an additional 0.02 QALY is equivalent to an extra one week of perfect health per year. When the value of a QALY is 20,000 pounds the EPP has a probability of 94% of being cost effective. Indeed, for all plausible values of willingness-to-pay for a QALY the EPP group is more likely to be cost effective than the control group. The EPP intervention evaluated in this trial is very likely to provide a cost effective alternative to usual care in people with long-term conditions.


Ectopic thyroid presenting as a submandibular mass.
Although extremely rare, the presence of ectopic thyroid tissue in the submandibular region should be considered in the differential diagnosis of tissue masses in the cervical region. Diagnosis is confirmed by fine-needle aspiration biopsy and exclusion of malignancy should be confirmed by histopathologic analysis of the lesion. In general, surgery is the treatment of choice. A rare case of ectopic thyroid in the right submandibular region is reported; it was diagnosed after total thyroidectomy and successfully treated through surgery.


Pharmacological Management of Common Soft Tissue Lesions of the Oral Cavity.
Soft tissue lesions commonly seen in the oral cavity tend to overlap in their onset, presentation, and location making it difficult to appreciate their etiology. In some instances, common oral soft tissue lesions can create confusion due to similar clinical appearance or unusual presentation; therefore, proper diagnosis of the lesion is key in pharmacologic management. In ulcerative conditions, topical steroids can decrease the symptoms and improve healing time, but do not affect the recurrence rate. Always be suspicious of soft tissue lesions that are nonresolving or recurrent lesions as they may warrant further investigation to rule out malignancy or associated systemic conditions. This article discusses key clinical presentations and the proper topical and systemic pharmacologic treatments.


Risk factors for primary invasive Haemophilus influenzae disease: increased risk from day care attendance and school-aged household members.
From November 1, 1981, through April 30, 1982, we performed a case-control study of primary invasive Haemophilus influenzae infections in children in Colorado. Information was collected for 121 (83%) of 146 children with positive cultures and for 196 (67%) of 292 age-matched controls selected at random from birth certificates. Infected children were more likely to have attended a day care center or nursery (DCC/N) and to have an elementary school-aged household member. For attendance at DCC/N, the relative risk was significantly increased only for children 12 months of age or older, and increased with the size of the DCC/N. After controlling for DCC/N attendance and school-aged siblings, children younger than 6 months of age with infection were significantly less likely to have been breast-fed, suggesting a protective effect of breast-feeding. We identified DCC/N attendees, especially those older than 1 year of age, to be at increased risk of primary H. influenzae disease. They could benefit from immunization.


Vertebral arterial injury due to fatal dog bites.
Dog bite-related injuries and fatalities are major public health problem worldwide. The authors present a case of a Japanese Tosa-dog bite-related fatality in an old woman who died from a vertebral arterial laceration with the C5 vertebral fracture. This was an uncommon type of injury that dog bites injured the vertebral artery only without damage to carotid artery. The identity of the Tosa-dog as an offending dog in this case was unsuccessful by a DNA analysis. Then the detection of the offending dog was made by comparisons of the dental casts of the dog with the victim's wounds. This case report describes making dental cast of the dog, and statistical data on dog-bite incidents in Japan.


Gastrointestinal bacteria generate nitric oxide from nitrate and nitrite.
Denitrifying bacteria in soil generate nitric oxide (NO) from nitrite as a part of the nitrogen cycle, but little is known about NO production by commensal bacteria. We used a chemiluminescence assay to explore if human faeces and different representative gut bacteria are able to generate NO. Bacteria were incubated anaerobically in gas-tight bags, with or without nitrate or nitrite in the growth medium. In addition, luminal NO levels were measured in vivo in the intestines in germ-free and conventional rats, and in rats mono-associated with lactobacilli. We show that human faeces can generate NO after nitrate or nitrite supplementation. Lactobacilli and bifidobacteria generated much NO from nitrite, but only a few of the tested strains produced NO from nitrate and at much lower levels. In contrast, Escherichia coli, Bacteroides thetaiotaomicron, and Clostridium difficile did not produce significant amounts of NO either with nitrate or nitrite. NO generation in the gut lumen was also observed in vivo in conventional rats but not in germ-free rats or in rats mono-associated with lactobacilli. We conclude that NO can be generated by the anaerobic gut flora in the presence of nitrate or nitrite. Future studies will reveal its biological significance in regulation of gastrointestinal integrity.


Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction.
The pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Multiple lines of evidence suggest that abnormal skeletal muscle metabolism is a key contributor, but the mechanisms underlying metabolic dysfunction remain unresolved. To evaluate the associations of skeletal muscle mitochondrial function using respirometric analysis of biopsied muscle fiber bundles from patients with HFpEF with exercise performance. In this cross-sectional study, muscle fiber bundles prepared from fresh vastus lateralis biopsies were analyzed by high-resolution respirometry to provide detailed analyses of mitochondrial oxidative phosphorylation, including maximal capacity and the individual contributions of complex I-linked and complex II-linked respiration. These bioenergetic data were compared between patients with stable chronic HFpEF older than 60 years and age-matched healthy control (HC) participants and analyzed for intergroup differences and associations with exercise performance. All participants were treated at a university referral center, were clinically stable, and were not undergoing regular exercise or diet programs. Data were collected from March 2016 to December 2017, and data were analyzed from November 2020 to May 2021. Skeletal muscle mitochondrial function, including maximal capacity and respiration linked to complex I and complex II. Exercise performance was assessed by peak exercise oxygen consumption, 6-minute walk distance, and the Short Physical Performance Battery. Of 72 included patients, 50 (69%) were women, and the mean (SD) age was 69.6 (6.1) years. Skeletal muscle mitochondrial function measures were all markedly lower in skeletal muscle fibers obtained from patients with HFpEF compared with HCs, even when adjusting for age, sex, and body mass index. Maximal capacity was strongly and significantly correlated with peak exercise oxygen consumption (R = 0.69; P < .001), 6-minute walk distance (R = 0.70; P < .001), and Short Physical Performance Battery score (R = 0.46; P < .001). In this study, patients with HFpEF had marked abnormalities in skeletal muscle mitochondrial function. Severely reduced maximal capacity and complex I-linked and complex II-linked respiration were associated with exercise intolerance and represent promising therapeutic targets.


The effect of shape and position of the oxygen equilibrium curve on extraction and ventilation requirement in fishes.
The effects of haemoglobin-oxygen affinity and of cooperativity in oxygen binding on the oxygen extraction and ventilation requirement in fish are analysed using the mathematical model of Malte and Weber (1985). It is shown that a high affinity may allow a substantial reduction in ventilatory requirement and that optimal O2 uptake depends on a delicate balance between affinity and cooperativity. Using P50 and nH values from the literature, the oxygen extraction values predicted by the model for carp and rainbow trout coincide neatly with the values found for these species, indicating that the differences in oxygen extraction are a direct result of different blood oxygen binding properties.


Effect of growth temperature on self-rectifying BaTiO3/ZnO heterojunction for high-density crossbar arrays and neuromorphic computing.
In the quest for high-density integration and massive scalability, ferroelectric-based devices provide an achievable approach for nonvolatile crossbar array (CBA) architecture and neuromorphic computing. In this report, ferroelectric-semiconductor (Pt/BaTiO3/ZnO/Au) heterojunction-based devices are demonstrated to exhibit nonvolatile and synaptic characteristics. In this study, the ferroelectric (BaTiO3) layer was modulated at various growth temperatures of 350 °C, 450 °C, 550 °C and 650 °C. Growing temperature in the ferroelectric layer has a significant impact on resistive switching. The ferroelectricity of the BaTiO3 thin film enhanced by increasing temperature causes a substantial shift in the interface state density at heterojunction interface, which is crucial for self-rectification. Furthermore, this self-rectifying property advances to reduce the crosstalk problem without any selector device. Enhanced resistive switching and neuromorphic applications have been demonstrated using BaTiO3 heterostructure devices at 550 °C. The dynamic ferroelectric polarization switching in this heterojunction demonstrated linear conductance change in artificial synapses with 91 % recognition accuracy. Ferroelectric polarization reversal with a depletion region at the heterojunction interface is the responsible mechanism for the switching in these devices. Thus, these findings pave the way for designing low power high-density crossbar arrays and neuromorphic application based on ferroelectric-semiconductor heterostructures.


Laryngeal Schwannoma Triggered Life-threatening Acute Airway Obstruction- A Rare Case Report with Review of Literature.
Schwannoma in larynx is a rare presentaion. Laryngeal schwannomas are characterstically slow growing benign tumour usually arising from false cord and aryepiglottic fold with globus sensation being the most common presentation. Seldom it can present as stridor which need immediate intervention for survival of the patient. We present a case of 53 year female who presented with stridor at emergency and emergency tracheostomy was done. This patient had a history of dysphagia to solid food, hoarseness of voice and symptoms of aspirations. 70 degree rigid endoscopy and CEMRI of neck was performed to see the extent of the laryngeal lesion causing stridor. Tumor was excised completely by external transcervical approach. Histopathological reports suggested this tumor as schwannoma. Large obstructive laryngeal schwannoma though a unusual presentation but with immediate tracheostomy, proper diagnostic work up and precise surgical approach can give excellent recovery and post operative outcome for the patient.


Expression of stem cell factor (SCF) and SCF receptor (c-kit) in synovial membrane in arthritis: correlation with synovial mast cell hyperplasia and inflammation.
Stem cell factor (SCF), the ligand for the SCF receptor (c-kit) expressed on precursors and mature mast cells (MC), is a major agonist for human MC (e.g., SCF induces MC development, chemotaxis, activation, proliferation of MC precursors, mediates MC adhesion, and changes MC releasability). We investigated expression of SCF and c-kit in synovial membrane with particular reference to the mechanism of local MC hyperplasia and inflammation in arthritis. We conducted single and double labeling immunohistochemistry (ABC, APAAP, indirect immunofluorescence techniques) with antibodies to SCF, c-kit, MC tryptase, Ki-67 antigen (marker for proliferating cells), and CD68 (monocyte/macrophage marker). Synovial specimens analyzed were from 31 patients: traumatic arthritis (TrA, n=9), osteoarthritis (OA, n=12), and rheumatoid arthritis (RA, n=10). Control experiments were performed on human lung, skin, and buccal mucosa tissues, on the HMC-1 mast cell line, and isolated lung MC. Morphometry was performed by computerized image analysis. Synovial c-kit expression was found to be restricted to MC, whereas SCF is detected in synovial lining cells, stromal fibroblasts, monocyte/macrophages, endothelial cells, and in vascular basement membranes. SCF staining was localized to MC as well, but it was not possible to specify whether this represents SCF produced by or bound (via c-kit) to MC. In inflamed synovial membranes/areas, SCF was found to be redistributed into the extracellular matrix. Redistribution of SCF was accompanied by degranulation and/or accumulation of c-kit+ MC, the hyperplasia of which correlated positively with histologic inflammation/inflammatory cell densities, but did not appear to involve MC proliferation in situ. These findings appeared to be common for all the conditions (TrA, OA, RA) studied. In addition to the demonstration/characterization of SCF and c-kit protein expression in human synovium, results of this study suggest the hypothesis that, in arthritis, local mobilization of SCF may play a role in the development of synovial MC hyperplasia without inducing in situ proliferation of MC, and that the synovial SCF/MC c-kit system may contribute to the local nonspecific inflammatory response/arthritic flares in TrA, OA, and RA.


Infectious diseases mimicking ovarian carcinomatosis.
Infectious diseases can present similar to ovarian cancer and occur concomitantly with ovarian pathology. With increased worldwide travel and migration of populations, infections endemic to developing countries can emerge in the United States. We present 2 cases of infectious diseases mimicking ovarian carcinomatosis. Two Filipino women presented with abdominal distension and had evaluations suggestive of advanced gynecologic malignancy. The first patient underwent surgery and was found to have peritoneal tuberculosis. Intra-operative pathology from the second case revealed ovarian carcinoma with schistosomal granulomas of the intestines. Tuberculosis and schistosomiasis should be considered when treating women with gynecologic malignancies, especially those from abroad or who have spent time overseas. Correct identification of infectious etiologies allows for pharmacological intervention and can minimize unnecessary surgical procedures.


Lipoprotein separation in a novel iodixanol density gradient, for composition, density, and phenotype analysis.
Separation of lipoproteins by traditional sequential salt density floatation is a prolonged process ( approximately 72 h) with variable recovery, whereas iodixanol-based, self-generating density gradients provide a rapid ( approximately 4 h) alternative. A novel, three-layered iodixanol gradient was evaluated for its ability to separate lipoprotein fractions in 63 subjects with varying degrees of dyslipidemia. Lipoprotein cholesterol, triglycerides, and apolipoproteins were measured in 21 successive iodixanol density fractions. Iodixanol fractionation was compared with sequential floatation ultracentrifugation. Iodixanol gradient formation showed a coefficient of variation of 0.29% and total lipid recovery from the gradient of 95.4% for cholesterol and 84.7% for triglyceride. Recoveries for VLDL-, LDL-, and HDL-cholesterol, triglycerides, and apolipoproteins were approximately 10% higher with iodixanol compared with sequential floatation. The iodixanol gradient effectively discriminated classic lipoproteins and their subfractions, and there was evidence for improved resolution of lipoproteins with the iodixanol gradient. LDL particles subfractionated by the gradient showed good correlation between density and particle size with small, dense LDL (<25.5 nm) separated in fractions with density >1.028 g/dl. The new iodixanol density gradient enabled rapid separation with improved resolution and recovery of all lipoproteins and their subfractions, providing important information with regard to LDL phenotype from a single centrifugation step with minimal in-vitro modification of lipoproteins.


Nivolumab Versus Docetaxel for Previously Treated Advanced Non-Small Cell Lung Cancer in China: A Cost-Effectiveness Analysis.
The economic assessment of immuno-oncology agents in Chinese patients is limited despite a need for new therapies. Nivolumab is the first immune checkpoint inhibitor approved for the second-line treatment of non-small cell lung cancer (NSCLC) in China, and it significantly prolongs overall survival. However, considering the high cost of nivolumab, it is urgent to assess its value in China in terms of both efficacy and cost. The objective of this study was to investigate the cost-effectiveness of nivolumab vs docetaxel in the second-line setting for NSCLC patients from the Chinese healthcare system perspective. A Markov model consisting of three health states, was designed to evaluate the lifetime cost and effectiveness of nivolumab vs docetaxel in the second-line treatment of NSCLC patients. Clinical data was derived from the CheckMate 078 phase III clinical trial, which included 504 patients predominantly from China. Parametric survival models to fit and extrapolate survival data were chosen based on clinical rationality, visual fit and statistical goodness-of-fit. Lifetime costs and health outcomes were calculated, and US$28,899 and $63,564 per quality-adjusted life-year (QALY) were selected as the willingness-to-pay (WTP) threshold values for general regions and affluent regions, respectively. One-way and probabilistic sensitivity analyses were undertaken to explore the robustness of the model. Additional subgroup analyses were performed. In base case analysis, Nivolumab yielded an additional 0.24 QALYs, at a cost of $93,307 per QALY. Sensitivity analyses suggested that the results to be most sensitive to the price of nivolumab per kg (mean $60.00; range $26.00-$60.00) and the mean patient weight (65 kg, range 52-78 kg). Utility values in progression-free survival state (mean 0.804; range 0.643-0.965) and overall survival hazard ratio (0.68; 97.7% CI 0.52-0.90) had moderate impact on the model results. Subgroup analyses indicated that nivolumab was most cost-effective for patients who were 65 years of age or older ($85,171/QALY), followed by female patients ($85,273/QALY) and patients with tumor PD-L1 expression at least 1% ($90,309/QALY). Nivolumab is unlikely to be cost-effective compared with docetaxel for patients with previously treated advanced NSCLC in China. Ensuring that nivolumab is included in the National Reimbursement Drug List (NRDL) may be a valid mean of meeting extensive treatment demands in China.


Amplicon sequencing dataset of soil fungi and associated environmental variables collected in karst and non-karst sites across Yunnan province, southwest China.
Fungi are among the most widely distributed organisms on Earth, performing key roles in nutrient cycling, disease, and the global carbon cycle. However, studies on regional-scale fungal assemblage patterns and the underlying drivers, are scarce. The aim of this research was to determine the relative importance of environmental heterogeneity and spatial distance on the metacommunity structure of soil fungi in Yunnan province, southwest China. This dataset is supplementary to research by [1] and presents 12,843 fungal operational taxonomic unit (OTU) sequences, OTU distribution and abundance across 220 samples, OTU taxonomic and ecological annotations, and environmental characteristics of the sites where the samples were collected. Differences in fungal alpha and beta diversity indices between karst and non-karst soils for the full dataset, six class-level (Agaricomycetes, Dothideomycetes, Sordariomycetes, Leotiomycetes, Tremellomycetes, and Eurotiomycetes) and four functional-level (symbiotrophs, pathotrophs, saprotrophs, and ectomycorrhizal fungi) datasets are presented.


Cortisol changes among patients with septic shock and the relationship to ICU and hospital stay.
To evaluate adrenal function in patients with severe sepsis or septic shock. A prospective study of unstimulated and high-dose ACTH stimulated cortisol levels on days 1 and 2 following ICU admission and day 28 or last day of hospitalization (herein day 28). General intensive care unit. 34 septic patients. On days 1, 2, and 28 of sepsis unstimulated and ACTH stimulated cortisol levels were evaluated. End-points were length of ICU and hospital stay and 28 day all cause mortality. Eight patients on days 1 and 2 had criteria of adrenal insufficiency defined as unstimulated cortisol levels less than 15 microg/dl. Patients with unstimulated cortisol levels less than 15 microg/dl on day 1 or change of 9 microg/dl or less had longer ICU stays. Patients with unstimulated cortisol levels less than 15 microg/dl on day 1 also demonstrated longer hospital stay. On day 1 regression analysis revealed that unstimulated cortisol levels had a significant inverse correlation with length of ICU and hospital stay. The proportional change between unstimulated cortisol and post-ACTH cortisol (Delta%) is a new modality; the higher this Delta% value, the longer is the patient's ICU and hospital stay. A significant positive correlation was found in survivors when comparing unstimulated cortisol vs. day 28 changes. The present study highlights the wide range of cortisol levels among patients with sepsis. We observed a difference in cortisol response pattern between survivors and nonsurvivors on day 28. The proportional change between unstimulated cortisol and post-ACTH cortisol was used as a method to evaluate the relative change in cortisol levels between patients.


EGCG protects against homocysteine-induced human umbilical vein endothelial cells apoptosis by modulating mitochondrial-dependent apoptotic signaling and PI3K/Akt/eNOS signaling pathways.
Homocysteine (Hcy) induced vascular endothelial injury leads to the progression of endothelial dysfunction in atherosclerosis. Epigallocatechin gallate (EGCG), a natural dietary antioxidant, has been applied to protect against atherosclerosis. However, the underlying protective mechanism of EGCG has not been clarified. The present study investigated the mechanism of EGCG protected against Hcy-induced human umbilical vein endothelial cells (HUVECs) apoptosis. Methyl thiazolyl tetrazolium assay (MTT), transmission electron microscope, fluorescent staining, flow cytometry, western blot were used in this study. The study has demonstrated that EGCG suppressed Hcy-induced endothelial cell morphological changes and reactive oxygen species (ROS) generation. Moreover, EGCG dose-dependently prevented Hcy-induced HUVECs cytotoxicity and apoptotic biochemical changes such as reducing mitochondrial membrane potential (MMP), decreasing Bcl-2/Bax protein ratio and activating caspase-9 and 3. In addition, EGCG enhanced the protein ratio of p-Akt/Akt, endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) formation in injured cells. In conclusion, the present study shows that EGCG prevents Hcy-induced HUVECs apoptosis via modulating mitochondrial apoptotic and PI3K/Akt/eNOS signaling pathways. Furthermore, the results indicate that EGCG is likely to represent a potential therapeutic strategy for atherosclerosis associated with Hyperhomocysteinemia (HHcy).


Menstrual abnormality, maternal illiteracy, and household factors as main predictors of anemia among adolescent girls in Ethiopia: Systematic review and meta-analysis.
Adolescent girls are more likely to develop anemia as a result of physical and physiological changes that place a greater strain on their nutritional needs. Primary studies, on the other hand, may not be sufficient to provide a complete picture of anemia in adolescent girls and its major risk factors. The study aimed to describe the pooled prevalence of adolescent girls' anemia and the factors that contribute. We conducted a systematic review of observational studies using the databases CINAHL (EBSCO), PubMed, Science Direct, Cochrane Library, and Google Scholar. The Newcastle-Ottawa Scale was used to assess the quality of the articles, and studies of fair to good quality were included. We pooled anemia prevalence among adolescents and odds ratio estimates for risk factors. Subgroup analysis employing sample size and study setup was computed to determine the source of heterogeneity, and the I2 test was used to identify the existence or absence of substantial heterogeneity during subgroup analysis. The pooled prevalence of adolescent girls' anemia was calculated using a random-effects meta-analysis model. The overall pooled prevalence of anemia among adolescent girls in Ethiopia was 23.03% (95% confidence interval: 17.07, 28.98). Low dietary diversity (odds ratio: 1.56; 95% confidence interval: 1.05, 2.32), illiterate mothers (odds ratio: 1.45; 95% confidence interval: 1.13, 1.86), household size greater than five (odds ratio: 1.65; 95% confidence interval: 1.14, 2.38), food-insecure households (odds ratio: 1.48; 95% confidence interval: 1.21, 1.82), and menstrual blood flow more than 5 days (odds ratio: 6.21; 95% confidence interval: 1.67, 23.12) were the identified factors associated with anemia among adolescent girls. The pooled prevalence of anemia among adolescent girls in Ethiopia was moderately high. Therefore, to combat the burden of anemia among adolescent girls offering nutritional education is crucial. Iron supplementation is also recommended for adolescent females who have a menstrual cycle that lasts longer than 5 days.


Mortality Benefits of Antibiotic Computerised Decision Support System: Modifying Effects of Age.
Antibiotic computerised decision support systems (CDSSs) are shown to improve antibiotic prescribing, but evidence of beneficial patient outcomes is limited. We conducted a prospective cohort study in a 1500-bed tertiary-care hospital in Singapore, to evaluate the effectiveness of the hospital's antibiotic CDSS on patients' clinical outcomes, and the modification of these effects by patient factors. To account for clustering, we used multilevel logistic regression models. One-quarter of 1886 eligible inpatients received CDSS-recommended antibiotics. Receipt of antibiotics according to CDSS's recommendations seemed to halve mortality risk of patients (OR 0.54, 95% CI 0.26-1.10, P = 0.09). Patients aged ≤65 years had greater mortality benefit (OR 0.45, 95% CI 0.20-1.00, P = 0.05) than patients that were older than 65 (OR 1.28, 95% CI 0.91-1.82, P = 0.16). No effect was observed on incidence of Clostridium difficile (OR 1.02, 95% CI 0.34-3.01), and multidrug-resistant organism (OR 1.06, 95% CI 0.42-2.71) infections. No increase in infection-related readmission (OR 1.16, 95% CI 0.48-2.79) was found in survivors. Receipt of CDSS-recommended antibiotics reduced mortality risk in patients aged 65 years or younger and did not increase the risk in older patients. Physicians should be informed of the benefits to increase their acceptance of CDSS recommendations.


IL-15Rα deficiency in skeletal muscle alters respiratory function and the proteome of mitochondrial subpopulations independent of changes to the mitochondrial genome.
Interleukin-15 receptor alpha knockout (IL15RαKO) mice exhibit a greater skeletal muscle mitochondrial density with an altered mitochondrial morphology. However, the mechanism and functional impact of these changes have not been determined. In this study, we characterized the functional, proteomic, and genomic alterations in mitochondrial subpopulations isolated from the skeletal muscles of IL15RαKO mice and B6129 background control mice. State 3 respiration was greater in interfibrillar mitochondria and whole muscle ATP levels were greater in IL15RαKO mice supporting the increases in respiration rate. However, the state 3/state 4 ratio was lower, suggesting some degree of respiratory uncoupling. Proteomic analyses identified several markers independently in mitochondrial subpopulations that are associated with these functional alterations. Next Generation Sequencing of mtDNA revealed a high degree of similarity between the mitochondrial genomes of IL15RαKO mice and controls in terms of copy number, consensus coding and the presence of minor alleles, suggesting that the functional and proteomic alterations we observed occurred independent of alterations to the mitochondrial genome. These data provide additional evidence to implicate IL-15Rα as a regulator of skeletal muscle phenotypes through effects on the mitochondrion, and suggest these effects are driven by alterations to the mitochondrial proteome.


Sialic Acid Enhanced the Antistress Capability under Challenging Situations by Increasing Synaptic Transmission.
In early life, sialic acid (SA) plays a crucial role in neurodevelopment and neuronal function. However, it remains unclear whether and how SA supplementation in early life promotes behavioral response to stress in adolescence. This study aimed to examine the effects and mechanisms of SA on the antistress capability under challenging situations. In this study, C57BL/6 mice were daily supplemented with 1 μL SA solution/g body weight at the dose of 10 mg/kg/d from postnatal day (PND) 5-45. The antistress behaviors, including open field, elevated plus maze, forced swimming test, and tail suspension test, were performed at PND 46, PND 48, PND 50, and PND 52 to detect the antistress ability of SA, respectively. Our results showed that SA-treated mice were more active in facing challenging situations. The fiber photometry experiment showed that SA promoted the excitatory neuronal response in the medial prefrontal cortex (mPFC), which was extensively interconnected to stress. Besides, electrophysiological results revealed SA enhanced synaptic transmission rather than neuronal excitability of mPFC excitatory neurons. It was also supported by the increasing spine density of mPFC excitatory neurons. At the molecular amount, the SA elevated the transmitter release-related proteins of mPFC, including Synapsin 1 and vesicular glutamate transporter 1 (VGlut 1). Furthermore, SA supplementation enhanced synaptic transmission mainly by altering the kinetics of synaptic transmission. The SA supplementation enhanced the response capability to stress under challenging situations, and the enhanced synaptic transmission of mPFC excitatory neurons may be the neurological basis of active response under challenging situations. In general, our findings suggested that SA supplementation in early life can promote stress resistance in adolescence.


Benign myoclonic epilepsy in infancy with preceding afebrile generalized tonic-clonic seizures in Japan.
Benign myoclonic epilepsy in infancy (BMEI) is the youngest form of idiopathic generalized epilepsy, characterized by myoclonic seizures (MS) in the first three years of life in otherwise normal infants, and the lack of other seizure types except for rare simple febrile seizures. Although afebrile generalized tonic-clonic seizures (GTCS) have been described to develop later in the clinical course of BMEI, mostly during adolescence, an association with GTCS in the early stage of BMEI has never been recognized. We herein report seven children who satisfied the criteria of BMEI except for the recurrence of GTCS before the onset of MS. The age of onset and ictal video-polygraphic features of MS, as well as the long-term seizure and developmental outcome in these children were similar to those of children with typical BMEI. Furthermore, these GTCS mostly disappeared within several months and were replaced by MS. Our study indicates that these children may constitute a BMEI subgroup, expanding the spectrum of BMEI.


Sleeping difficulties and health-related quality of life in Parkinson's disease.
Various sleep-related symptoms occur in Parkinson's disease (PD). Their occurrence with health-related quality of life (HRQL), comorbid sleep disorders, and other comorbidities was studied. Altogether, 1447 randomly selected patients with Parkinson's disease, aged 43-89 years, participated in a questionnaire study. A structured questionnaire with 207 items was based on the Basic Nordic Sleep Questionnaire. Questions on demographics, PD, sleep disorders, and comorbidities were included. The response rate was 59.0%, and of these, 80% had answered to all questions that were used in the analyses (N=684). Occurrence of long sleep was found in 26.2% of the subjects, short sleep in 32.5%, poor sleep in 21.2%, sleep deprivation in 33.8%, disrupted sleep in 47.4%, and difficulties to fall asleep in 12.2%, respectively. Poor self-rated health and poor quality of life occurred in 44.4% and in 43.3% of all participants. In the logistic regression, age and gender differentially predicted long sleep and sleep deprivation, such that older age and being male were positively associated with long sleep but negatively associated with the report of sleep deprivation. Depression, subjective negative stress, and fatigue occurred with long sleep. On the other hand, poor sleep and excessive daytime sleepiness occurred with short sleep and sleep deprivation. The sleep difficulties in PD are frequent. The long sleeping patients have depression, stress, and fatigue.


Histopathologic study of ocular changes in a syndrome of multiple congenital anomalies.
We examined a 5-month-old boy who had an iris coloboma in the left eye, persistent hyaloid artery, macular hypoplasia, left aberrant nerve palsy, and bilateral blepharoptosis. He had microcephaly and bilateral corticospinal tract dysfunction. Additionally, he had brachycephaly, a high arched palate, hypospadias, a malformed left external ear, and bilateral finger contractures. Computed tomography showed agenesis of the corpus callosum. He died at age 5 months. On histologic examination the left eye showed an iris coloboma, ciliary epithelial differentiation to the retina, undifferentiated neuroepithelium beneath the equatorial retina, persistent hyaloid artery, and optic nerve coloboma and pit. These findings may result from failure of the fetal fissure of the optic cup to close, with redundant folds of neuroepithelium and focal aberrant differentiation. The constellation of developmental defects indicates that an insult occurred during the sixth week of gestation.


[Intramural jejunal lipoma in the small intestine of a young Arabian horse causing invagination of the jejunum].
A 2-year-old Arabian horse was presented with severe colic symptoms. During explorative laparotomy, a jejuno-jejunal invagination secondary to a submucosal intestinal mass was detected. The involved jejunal segment was surgically removed and an end-to-end anastomosis was created. Opening the specimen demonstrated the presence of a nodular mass on the head of the intussusceptum, measuring 10 cm in diameter, and almost completely obliterating the intestinal lumen. Additionally, a severe hyperemia of the jejunal mucosa was visible. Histological examination, which revealed a well-demarcated mass in the submucosa of the jejunum consisting of well-differentiated adipocytes, led to the diagnosis of an intramural lipoma. The small intestinal mucosa displayed mild to moderate signs of congestion. Pedunculated lipomas in the mesentery of horses causing intestinal volvulus and obstruction are a frequent cause of small-intestine strangulation in aged horses. To the authors' knowledge, intramural intestinal lipomas to date have not been described in the horse. The mare recovered without complications and was free of colic symptoms after 6 months.


Insensible water loss and its assessment in adult patients: a review.
The nature, magnitude and factors influencing insensible water loss are discussed. A brief overview of the current practice of estimating insensible perspiration in Sweden is presented. Finally, a suggestion is put forward regarding a simplified formula for estimating insensible water loss in adult patients, based on information currently available in the literature.


The Developing Microbiome of the Preterm Infant.
To determine the importance of the neonatal microbiome in intestinal and overall health. A review of existing literature. The microbiome is increasingly understood to have a significant role in health and disease. However, the microbiome of the preterm infant is unique, with simple microbial communities exposed to a consistent diet in a regulated environment, and development from naive to stable under the influence of the neonatal intensive care unit. This early microbiome encounters a still developing host and thus has the potential to program fundamental pathways with implications for neonatal and later outcomes.


To work or not to work: labour market participation of people with spinal cord injury living in Switzerland.
Cross-sectional survey. To establish labour market participation figures of persons with spinal cord injury (SCI) living in Switzerland and to investigate determinants and consequences of having paid work. Community. A survey among members of the Swiss Paraplegic Association was performed in 2008. Inclusion criteria were: SCI of traumatic or non-traumatic origin, minimum age of 18 years, and living in the community for at least 1 year. A total of 559 persons with SCI returned the questionnaire (response rate 27%), of which 495 (24%) fulfilled the eligibility criteria. Bivariate and logistic regression analyses were performed based on theoretical considerations and relevant determinants found in the literature. Of the respondents of working age, 63.8% were involved in gainful employment. No significant difference between persons with para- and tetraplegia was observed. Logistic regression showed that employment was associated with age, time since onset of SCI, having worked at 2 years after initial rehabilitation, having received vocational counselling, having less pain, more years of education and more perceived importance of work. Working persons achieved a significantly higher total income. The most important reasons to work were not financial, but rather of social nature. Barriers to work were primarily health-related. We found a relatively high employment rate among the studied persons with SCI living in Switzerland. However, because of the low response, it is difficult to generalise this finding.


Hydrogen peroxide induces intracellular calcium overload by activation of a non-selective cation channel in an insulin-secreting cell line.
Fura-2 fluorescence was used to investigate the effects of H2O2 on [Ca2+]i in the insulin-secreting cell line CRI-G1. H2O2 (1-10 mM) caused a biphasic increase in free [Ca2+]i, an initial rise observed within 3 min and a second, much larger rise following a 30-min exposure. Extracellular calcium removal blocked the late, but not the initial, rise in [Ca2+]i. Thapsigargin did not affect either response to H2O2, but activated capacitive calcium entry, an action abolished by 10 microM La3+. Simultaneous recordings of membrane potential and [Ca2+]i demonstrated the same biphasic [Ca2+]i response to H2O2 and showed that the late increase in [Ca2+]i coincided temporally with cell membrane potential collapse. Buffering Ca2+i to low nanomolar levels prevented both phases of increased [Ca2+]i and the H2O2-induced depolarization. The H2O2-induced late rise in [Ca2+]i was prevented by extracellular application of 100 microM La3+. La3+ (100 microM) inhibited the H2O2-induced cation current and NAD-activated cation (NSNAD) channel activity in these cells. H2O2 increased the NAD/NADH ratio in intact CRI-G1 cells, consistent with increased cellular [NAD]. These data suggest that H2O2 increases [NAD], which, coupled with increased [Ca2+]i, activates NSNAD channels, causing unregulated Ca2+ entry and consequent cell death.


Epidermal growth factor receptor and cancer: control of oncogenic signalling by endocytosis.
The epidermal growth factor receptor (EGFR) and other members of the EGFR/ErbB receptor family of receptor tyrosine kinases (RTKs) are important regulators of proliferation, angiogenesis, migration, tumorigenesis and metastasis. Overexpression, mutations, deletions and production of autocrine ligands contribute to aberrant activation of the ErbB proteins. The signalling output from EGFR is complicated given that other ErbB proteins are often additionally expressed and activated in the same cell, resulting in formation of homo-and/or heterodimers. In particular, association of EGFR with ErbB2 prevents its down-regulation, underscoring the importance of the cellular background for EGFR effects. Signalling from ErbB proteins can either be terminated by dissociation of ligand resulting in dephosphorylation, or blunted by degradation of the receptors. Although proteasomal targeting of ErbB proteins has been described, lysosomal degradation upon ligand-induced endocytosis seems to play the major role in EGFR down-regulation. Preclinical and clinical data have demonstrated that EGFR is a central player in cancer, especially in carcinomas, some brain tumours and in non-small cell lung cancer. Such studies have further validated EGFR as an important molecular target in cancer treatment. This review focuses on mechanisms involved in ligand-induced EGFR activation and endocytic down-regulation. A better understanding of EGFR biology should allow development of more tumour-selective therapeutic approaches targeting EGFR-induced signalling.


Sensitivity changes in guinea-pig atria and ileum following subacute administration of dyflos.
1. Subacute administration of dyflos to guinea-pigs (1.2 mg/kg, s.c., daily for 10 days) led to the development of subsensitivity to carbachol in the ileum but not in the electrically stimulated left atrium. 2. Atria from dyflos-pretreated animals became supersensitive to acetylcholine but the ileum became subsensitive to this agonist despite marked inhibition of cholinesterases. The degree of subsensitivity was less than that for carbachol. 3. Subsensitivity also developed to histamine and was of a similar order to that observed for carbachol supporting the suggestion that subsensitivity is a nonspecific post-receptor mechanism. 4. Other changes which occurred in the ileum, together with the increase in the EC50 value to agonists were an increase in tissue mass, an increase in the slope of the concentration-response curve to agonists and an increase in the maximal response to agonists.


Mobility of microinjected rhodamine actin within living chicken gizzard cells determined by fluorescence photobleaching recovery.
Rhodamine-labeled actin microinjected into living embryonic chicken gizzard cells became associated with its characteristic cytoskeletal structures. In these domains the translational diffusion coefficients (D) of rh-actin were determined in vivo by fluorescence photobleaching recovery (FPR) measurements. Two classes of actin molecules with respect to its mobilities were detected: rh-actin with a half-time of recovery of 5-10 min in stress fibers and focal contacts (immobile on the time-scale of FPR measurements) and rh-actin with D = 2-3 X 10(-9) cm2/sec in the cytoplasm and leading lamellae. The slow recovery on stress fibers exhibited similar kinetics whether a short segment or the entire structure were photobleached, indicating that recovery occurs predominantly by exchange with the surrounding diffusable actin. We propose that a steady-state equilibrium between the soluble and cytoskeletal pool of actin exists in living cells.


Calcitriol inhibits migration and invasion of renal cell carcinoma cells by suppressing Smad2/3-, STAT3- and β-catenin-mediated epithelial-mesenchymal transition.
Low vitamin D status is associated with progression in patients with renal cell carcinoma (RCC). The present study found that vimentin, a mesenchymal marker, was accordingly upregulated, and E-cadherin, an epithelial marker, was downregulated in RCC patients with low vitamin D status. Thus, we investigated the effects of calcitriol or vitamin D3, an active form of vitamin D, on epithelial-mesenchymal transition (EMT) in RCC cells. RCC cells were treated by two models. In model 1, three RCC cell lines, ACHN, 786-O and CAKI-2, were incubated with either LPS (2.0 μg/mL) or transforming growth factor (TGF)-β1 (10 ng/mL) in the presence or absence of calcitriol (200 nmol/L). In model 2, two RCC cell lines, ACHN and CAKI-2, were incubated with calcitriol (200 nmol/L) only. Calcitriol inhibited migration and invasion not only in TGF-β1-stimulated but also in TGF-β1-unstimulated RCC cells. Moreover, calcitriol suppressed E-cadherin downregulation and vimentin upregulation not only in TGF-β1-stimulated but also in TGF-β1-unstimulated ACHN and CAKI-2 cells. Calcitriol attenuated LPS-induced upregulation of MMP-2, MMP-7, MMP-9, MMP-26 and urokinase-type plasminogen activator (u-PA) in ACHN cells. In addition, calcitriol blocked TGF-β1-induced nuclear translocation of ZEB1, Snail and Twist1 in ACHN and CAKI-2 cells. Mechanistically, calcitriol suppressed EMT through different signaling pathways: (i) calcitriol suppressed Smad2/3 phosphorylation by reinforcing physical interaction between vitamin D receptor (VDR) and Smad3 in TGF-β1-stimulated RCC cells; (ii) calcitriol inhibited signal transducer and activator of transcription (STAT)3 activation in LPS-stimulated RCC cells; (iii) calcitriol inhibited β-catenin/TCF-4 activation by promoting integration of VDR with β-catenin in TGF-β1-unstimulated RCC cells. Taken together, calcitriol inhibits migration and invasion of RCC cells partially by suppressing Smad2/3-, STAT3- and β-catenin-mediated EMT.


[Hereditary neuroendrocrine tumors. Multiple endocrine neoplasia type 1 and 2].
Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal-dominant hereditary disease characterized by the occurrence of tumors of the parathyroids, duodenum and/or pancreas, and anterior pituitary. The syndrome is caused by germline mutations of the MEN1 tumor suppressor gene. The identification of the causative mutations is of paramount importance for the long-term management of affected individuals and their relatives. Multiple endocrine neoplasia type 2 (MEN2) is less frequent than MEN1 and represents a cancer syndrome caused by autosomal-dominant inherited mutations of the RET proto-oncogene, and displays a genotype-phenotype correlation of remarkable clinical relevance. Major components of MEN-2 comprise medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism. Since 25-30% of patients with MTC display a hereditary background, genetic testing is indicated once MTC is diagnosed. Occurrence of MTC can be avoided by prophylactic thyroidectomy in early childhood in gene carriers. Early diagnosis and therapy of simultaneous pheochromocytoma avoids the development of complications caused by acute or chronic hypertension.


Understanding mechanisms of change in the development of antisocial behavior: the impact of a universal intervention.
The association between the development of antisocial behavior, affiliation with deviant friends, and peer rejection was tested with a preventive intervention; 664 boys and girls were randomly assigned to a universal classroom-based intervention targeting disruptive behavior or a control condition. Peer nominations of antisocial behavior, friends' antisocial behavior, and peer rejection were assessed annually for 4 years. A high, a moderate, and a stable low antisocial behavior trajectory were identified. Large reductions in antisocial behavior were found among intervention children who followed the high trajectory. These reductions coincided with affiliations with nondeviant peers and with decreases in peer rejection. The affiliation between deviant and nondeviant peers was initiated by nondeviant children. The results support a causal role of deviant friends and peer rejection in the development of antisocial behavior. The implications for our understanding of the mechanisms leading to reductions in antisocial behavior are discussed.


An experimental study of the effect of nimodipine in primate subarachnoid haemorrhage.
Acute subarachnoid haemorrhage was produced in baboons by a transorbital vessel avulsion technique. Half the animals were pretreated with an intravenous infusion of the calcium antagonistic nimodipine, in a dosage comparable with clinical levels. The severity of the haemorrhage, as measured by changes in intracranial pressure, cerebral perfusion pressure, cerebral blood flow and reactivity, and evoked potentials, was not greater in the group receiving nimodipine. Changes in extracellular K+ and pH were much less marked in animals receiving nimodipine. It is suggested that nimodipine (a) has a protective effect at a cellular level against the ionic changes of ischaemia, (b) does not alter the mechanical severity of subarachnoid haemorrhage.


Lips and noses in 10-year old patients with repaired complete unilateral clefts of lip, alveolus, and palate. A prospective three-centre study of the Baltic Cleft Network.
This multicenter study aimed at comparing different techniques of lip and nose repair with or without NAM and primary anterior rhinoplasty in pre-adolescent children. Patients with unilateral clefts of lip, alveolus, and palate who had undergone cleft lip and nose repair were evaluated in a prospective three-centre study using standardized monochromatic, cropped photographs. Four cleft surgeons evaluated the aesthetics of the central part of the face when the patients had reached age ten years. Seventy-six sets of photographs out of 87 patients were evaluated. The overall ratings of lips and noses did not differ much between centres. However, noses of centres 1 (mean 0.74; SD 0.57) and 2 (mean 0.76; SD 0.60) had been rated better than centre 3 (mean 1.32; SD 0.78; p = 0.0078), especially "Deformation of upper part of nostril rim or poor position of alar cartilage". Centre 3 had produced better looking scars (mean 0.33; SD 0.48); p = 0.0036. Within the limitations of the study it seems that NAM and primary anterior rhinoplasty including postoperative nasal stents should be performed whenever possible in order to achieve a favorable shape of the nose and to reduce the need for secondary corrective surgery.


Role of NAD(P)H:quinone oxidoreductase encoded by drgA gene in reduction of exogenous quinones in cyanobacterium Synechocystis sp. PCC 6803 cells.
Insertion mutant Ins2 of the cyanobacterium Synechocystis sp. PCC 6803, lacking NAD(P)H:quinone oxidoreductase (NQR) encoded by drgA gene, was characterized by higher sensitivity to quinone-type inhibitors (menadione and plumbagin) than wild type (WT) cells. In photoautotrophically grown cyanobacterial cells more than 60% of NADPH:quinone-reductase activity, as well as all NADPH:dinoseb-reductase activity, was associated with the function of NQR. NQR activity was observed only in soluble fraction of cyanobacterial cells, but not in membrane fraction. The effects of menadione and menadiol on the reduction of Photosystem I reaction center (P700(+)) after its photooxidation in the presence of DCMU were studied using the EPR spectroscopy. The addition of menadione increased the rate of P700(+) reduction in WT cells, whereas in Ins2 mutant the reduction of P700(+) was strongly inhibited. In the presence of menadiol the reduction of P700(+) was accelerated both in WT and Ins2 mutant cells. These data suggest that NQR protects the cyanobacterial cells from the toxic effect of exogenous quinones by their reduction to hydroquinones. These data may also indicate the probable functional homology of Synechocystis sp. PCC 6803 NQR with mammalian and plant NAD(P)H:quinone oxidoreductases (DT-diaphorases).


Guideline discordant care in patients with metastatic germ cell tumors.
Despite high curability, patients with metastatic germ cell tumors (GCT) in the United States general population persistently face inferior outcomes compared with those treated in specialty referral centers. We characterized guideline discordant management in patients with metastatic GCT who experienced relapse after first-line chemotherapy and compared those who were initially treated in community practices vs. academic referral centers. Retrospective analysis of 53 patients with relapsed GCT between 2005 and 2018. First-line GCT management was assessed against the National Comprehensive Cancer Network guidelines. Guideline discordant management, predictors of discordance, and associations with outcomes were assessed. Of 53 patients with relapsed GCT, 34% received guideline discordant care in the first-line setting. Guideline discordant care was more prevalent in patients initially treated in community practices (12/30, 40%) vs. those initially treated in academic centers (3/22, 14%), though in multivariate logistic regression, this difference was not statistically significant (odds ratio: 4.07, P = 0.08). Most patients in community settings who received guideline discordant care were undertreated (10/12, 83%). There were 3 major reasons for guideline discordant care: (1) failure to resect residual masses after chemotherapy (27%, 4/15), (2) mismanagement of chemotherapy-related adverse events (27%, 4/15), and (3) under staging at diagnosis, resulting either insufficient chemotherapy regimen intensity (13%, 2/15) and/or inappropriately receiving primary surgical resection for metastatic disease (20%, 3/15). Under treatment was identified in nearly half of patients initially treated in a community setting who later developed relapsed GCT. Referral to specialized centers for a second opinion should be considered for all metastatic GCT patients in the first-line setting and all patients with post-chemotherapy residual disease. More effective methods should be developed to facilitate second opinions from expert centers in the United States.


Contribution of the fnr and arcA gene products in coordinate regulation of cytochrome o and d oxidase (cyoABCDE and cydAB) genes in Escherichia coli.
The individual and the combined effect of the fnr and arcA regulatory gene products on cytochrome o oxidase and cytochrome d oxidase gene expression in Escherichia coli were evaluated using lacZ reporter fusions to the cyo-ABCDE and cydAB operons. Fnr repressed cyo-lacZ and cyd-lacZ expression during anaerobic growth but not during aerobic growth conditions. ArcA functioned as an anaerobic repressor of cyo-lacZ expression while, in contrast, it activated cydAB expression during both aerobic and anaerobic growth. ArcA and Fnr appear to function independently of each other to control cyo-ABCDE operon expression. In contrast, FNR repression of cydAB expression was dependent on arcA+, as indicated by the inability of fnr+ plasmids to repress cyd-lacZ expression in an arcA strain. Under no conditions tested did Fnr activate cydAB expression. Most, but not all, of the observed aerobic/anaerobic regulation of cyo and cyd was accounted for by the two transcriptional regulators. These data suggest the existence of additional levels of anaerobic gene control in E. coli. Additionally, the expression of the fnr regulatory gene, and regulation of the anaerobic respiratory genes, narGHJI, dmsABC and frdABCD, was found to be independent of ArcA.


The concurrent and predictive validity of the Dutch version of the Communicative Development Inventory in children with Down Syndrome for the assessment of expressive vocabulary in verbal and signed modalities.
The expressive vocabulary of children with Down Syndrome (DS) is generally measured with parental reports, such as the Communicative Development Inventory (CDI), given that standardized tests for assessing vocabulary levels may be too difficult for most young children with DS. The CDI provides important insight into the parents' perception of their child's vocabulary development. The CDI has proven to be a valid measurement of expressive vocabulary, spoken and gestural, in typical and atypical populations. The validity in children with DS is not well established and signed vocabulary is often not included. This longitudinal study examined the concurrent and predictive validity of the Dutch version of the CDI (N-CDI) in children with DS between 2;0 and 7;6 years old to assess spoken and signed vocabulary. N-CDI scores were assessed on strength of association with mental age, an expressive vocabulary test and spontaneous language analyses in a play setting with parents at T1 and T2 (1.5 years later), and a therapy setting with speech language pathologists at T1. The results of the present study show that the N-CDI is a valuable and valid measurement of expressive vocabulary in children with DS. Strengths and weaknesses of several assessment methods for expressive vocabulary are discussed.


Integral membrane glycoprotein properties of the prohormone pro-transforming growth factor-alpha.
Transforming growth factor-alpha (TGF-alpha) is a mitogenically active polypeptide hormone produced by acutely proliferating neoplastic and embryonic tissues. Molecular cloning of TGF-alpha cDNA from human and rat has indicated that this factor is synthesized as part of a larger precursor, proTGF-alpha. An intriguing feature of proTGF-alpha is that it contains a sequence of 24 hydrophobic amino acids following the bioactive TGF-alpha sequence. Similar hydrophobic sequences present in transmembrane proteins are cotranslationally anchored into the phospholipid bilayer of the rough endoplasmic reticulum, suggesting the possibility that pro TGF-alpha might be an integral membrane protein. Other secretory proteins including all known prohormones lack membrane anchoring sequences and are completely translocated across the endoplasmic reticulum membrane. To address the question of whether proTGF-alpha is as an integral membrane protein we have translated rat proTGF-alpha mRNA transcripts in the presence of rough endoplasmic reticulum membrane vesicles. The results indicate that proTGF-alpha is synthesized as an integral membrane glycoprotein. The 50-amino-acid TGF-alpha sequence in proTGF-alpha is exposed to the fluid extracellular phase where it can be released after cleavage by the appropriate enzyme.


24-h catecholamine excretion: relationships with age and weight.
24-hour urines were obtained from groups of volunteer subjects recruited from populations in the UK, USA, Nigeria and the South Pacific. Urines were collected during the course of normal daily activities. HPLC/electrochemical detection was used to measure concentrations of adrenaline and noradrenaline in each urine. Calculated 24-h output of catecholamines was tested for significant linear regression relationships with age, weight and 24-h urine volume in each population. Noradrenaline excretion tended to be positively related to age and to body wt. Adrenaline excretion tended to show little or no relationship with either age or body wt. Relationships based on catecholamine excretion/U creatinine were notably different to those based on absolute catecholamine excretion. Differences were observed in the nature and strength of the relationships in the different populations, indicating the likely importance of interactions with other factors.


Biological synthesis of coumarins in Escherichia coli.
Coumarins are a major group of plant secondary metabolites that serves as defense compounds against pathogens. Although coumarins can be obtained from diverse plant sources, the use of microorganisms to synthesize them could be an alternative way to supply building blocks for the synthesis of diverse coumarin derivatives. Constructs harboring two genes, F6'H (encoding feruloyl CoA 6' hydroxylase) and 4CL (encoding 4-coumarate CoA:ligase), were manipulated to increase the productivity of coumarins. Escherichia coli expressing the two genes was cultured in medium supplemented with hydroxycinnamic acids (HCs) including p-coumaric acid, caffeic acid, and ferulic acid, resulting in the synthesis of the corresponding coumarins, umbelliferone, esculetin, and scopoletin. Cell concentration and initial substrate feeding concentration were optimized. In addition, umbelliferone, and esculetin were synthesized from glucose by using a ybgC deletion mutant and co-expressing tyrosine ammonia lyase and other genes involved in the tyrosine biosynthesis pathway. To produce coumarin derivatives (umbelliferone, scopoletin, and esculetin) in E. coli, several constructs containing F6'H and 4CL were made, and their ability to synthesize coumarin derivatives was tested. The solubility of F6'H was critical for the final yield. After optimization, 82.9 mg/L of umbelliferone, 79.5 mg/L of scopoletin, and 52.3 mg/L of esculetin were biosynthesized from the corresponding HCs, respectively in E. coli. Umbelliferone and esculetin were also synthesized from glucose using engineered E. coli strains. The final yields of umbelliferone and esculetin were 66.1 and 61.4 mg/L, respectively.


Exploring organizational characteristics associated with practice changes following a mentored online educational module.
Studies of health professionals' perceptions of barriers to and facilitators of research utilization in clinical practices suggest that structural and resource characteristics of service provider organizations are key determinants of the capacity of individual practitioners to provide evidence-based practices. In this pilot study, we compare health professionals' self-reported practice changes with characteristics of the structures and resources available to support research use at 4 hospitals. Data on the self-reported practice changes of stroke rehabilitation professionals at Ontario hospitals were analyzed following their participation in a mentored online educational intervention, the Rehabilitation Education Program for Stroke (REPS). In-depth interviews with a purposefully drawn subsample of REPS mentors and managers of stroke rehabilitation programs examined the participating hospitals' structural and resource characteristics. The interview data on hospital characteristics were coded descriptively and thematically, quantified, and then compared with the percentage of individual REPS participants who reported positive practice changes in each hospital. Hospitals with higher percentages of participants reporting improved practices following REPS provided better computer access, paid time to participate in REPS, had established specialized units of stroke care, strong teamwork, and were previously committed to implementing best practices. They also conducted program audits or evaluations and engaged in "bottom-up" program decision making. Continuing educators should consider the capacity of hospitals to support practice changes when planning educational interventions for rehabilitation professionals. Larger studies employing objective measures are needed to examine relationships between practice improvements and organizational characteristics following educational interventions.


Strategies to prevent ischemic optic neuropathy following major spine surgery: A narrative review.
Postoperative vision loss following a major spine operation is a rare but life-changing event. Most of reports have been linked to ischemic optic neuropathy, and patients undergoing surgery for scoliosis correction or posterior lumbar fusion seem to be at the highest risk. Despite that some key risk factors have been identified, much of the pathophysiology still remain unknown. In fact, whereas only a minority of patients at high risk will present this complication, others with similar risk factors undergoing different procedures may not develop it at all. On the other hand, even when all preventive measures have been taken, ischemic optic neuropathy may still occur. Therefore, it is appropriate for clinicians involved in these cases to inform their patients about the existence of a small but unpredictable risk of vision loss. Since ischemic optic neuropathy is deemed to be the leading cause of vision loss in the context of major spine surgery in prone position, this review will be focused on its main aspects related to the frequency, diagnosis, predisposing factors, and prevention. Regrettably, no treatment has been proved to be effective for this condition.


[Quantitative analysis of corneal subbasal nerve plexus with in vivo confocal laser scanning microscopy].
An analysis of the corneal subbasal nerve plexus (SNP) allows an evaluation of the peripheral neuropathy in cases of degenerative diseases. In order to study the SNP structures quantitatively the automatically calculated morphological and topological parameters are required. In vivo confocal laser scanning microscopy (Heidelberg Retina Tomograph II/Rostock Cornea Module) was performed in healthy volunteers as well as patients with severe diabetic neuropathy. An adapted image processing algorithm was used to preprocess, segment and evaluate quantitatively the nerve fibers of the SNP. Data sets were analysed statistically. The developed algorithm allows an automated detection of SNP structures. Furthermore, it allows the collection of data based on morphological and topological parameters. The main parameters that show significant differences between healthy cornea and cases of diabetic neuropathy are nerve fibre density and length, number of branching, tortuosity and number of terminal and crossing points. All parameters of the measurements can be used isolated, combined or weighted for quantification of the SNP networks. The presented fully automated preprocessing eliminates a large number of motion-induced artefacts. The quality of the resulting pictures allows an automated quantification using characteristic measurements. This represents an in vivo, non-invasive technology analysing degenerative changes of SNP especially in the course of diabetes mellitus.


Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial.
Sunitinib and everolimus are standard first-line and second-line therapies, respectively, in clear cell renal cell carcinoma (ccRCC). To conduct a randomized phase 2 trial comparing sunitinib and everolimus in non-clear cell RCC (non-ccRCC). Patients with metastatic, non-ccRCC, or ccRCC with >20% sarcomatoid features (ccSRCC) were randomized to receive sunitinib or everolimus with crossover at disease progression. Primary end point was progression-free survival (PFS) in first-line therapy; 108 patients were needed to show improvement in median PFS (mPFS) from 12 wk with sunitinib to 20 wk with everolimus. Interim analysis of 68 patients (papillary [27], chromophobe [12], unclassified [10], translocation [7], ccSRCC [12]) prompted early trial closure. The mPFS in first-line therapy was 6.1 mo with sunitinib and 4.1 mo with everolimus (p=0.6); median overall survival (mOS) was not reached with sunitinib and was 10.5 mo with everolimus, respectively (p=0.014). At final analysis, mOS was 16.2 and 14.9 mo with sunitinib and everolimus, respectively (p=0.18). There were four partial responses (PRs) in first-line therapy (sunitinib: 3 of 33 [9%]; everolimus, 1 of 35 [2.8%]) and four PRs in second-line therapy (sunitinib: 2 of 21 [9.5%]; everolimus, 2 of 23 [8.6%]), with mPFS of 1.8 mo and 2.8 mo, respectively. In patients without sarcomatoid features in their tumors (n=49), mOS was 31.6 mo with sunitinib and 10.5 mo with everolimus (p=0.075). Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation. In this trial, everolimus was not superior to sunitinib. Both agents demonstrated modest efficacy, underscoring the need for better therapies in non-ccRCC. This randomized phase 2 trial provides the first head-to-head comparison of everolimus and sunitinib in patients with metastatic non-clear cell renal cell carcinoma (non-ccRCC). The observed very modest efficacy underscores the need to develop more effective therapies for non-ccRCC.


Reduced risk of recurrent pneumothorax for sirolimus therapy after surgical pleural covering of entire lung in lymphangioleiomyomatosis.
Patients with lymphangioleiomyomatosis (LAM) frequently experience pneumothorax. Although sirolimus is the standard therapy for LAM, its effect on pneumothorax is controversial. Recently, total pleural covering (TPC) and modified TPC (mTPC) were introduced as surgical treatment options for pneumothorax for patients with LAM. However, the effect of sirolimus on the recurrence of pneumothorax in patients who underwent the treatments is still uncertain. We hypothesized that some clinical factors including sirolimus treatment could predict postoperative recurrence of pneumothorax. In order to clarify this hypothesis, we retrospectively analyzed the clinical data from 18 consecutive patients with LAM who underwent 24 surgical pleural covering of entire lung (SPC) as 17 TPC and 7 mTPC against pneumothoraces from surgical database between January 2005 and January 2019, and we determined the predictors of postoperative recurrence. Of the 24 surgeries of SPC, 14 surgeries (58.3%) had a history of two or more ipsilateral pneumothoraces, and 11 surgeries (45.8%) had a history of ipsilateral pleural procedures before SPC. Sixteen surgeries (66.6%) in 12 patients received treatment of sirolimus after SPC (sirolimus group). With a median follow-up time of 69.0 months after SPC, four surgeries (16.6%) in three patients had a postoperative recurrence, and the 5-year recurrence-free survival (RFS) after SPC was 82.9%. In patients with postoperative recurrence, serum level of vascular endothelial growth factors D was significantly higher than that in those with non-recurrence (3260.5 vs. 892.7 pg/mL, p = 0.02), and the rate of sirolimus treatment in the recurrence group was significantly lower than that in the no-recurrence group (0 vs. 80%, p = 0.006). The log-rank test showed that the RFS of the sirolimus group (sirolimus use after SPC) was significantly better than that of the non-sirolimus group (p = 0.001), and no significant difference was observed for other factors. We first reported sirolimus might effectively suppress the recurrence of pneumothoraces in LAM patients who received SPC. Sirolimus induction after SPC (TPC or mTPC) might be a feasible option for frequent pneumothorax in LAM.


Double resection for patients with pancreatic cancer and a second primary renal cell cancer.
Reports of synchronous or metachronous double kidney-pancreas cancers are very rare. We present 2 patients with renal cell carcinoma and synchronous (1 patient) or metachronous (1 patient) primary pancreatic ductal adenocarcinoma. The patients underwent resection for both cancer types with a worthwhile outcome. The appearance of different primaries in an individual may indicate a genetic predisposition to different neoplasms. The study of double primary cancers is important because it might provide understanding of a shared genetic basis of different solid tumors. The association between these two cancers demands more detailed epidemiological and molecular investigation. From a clinical viewpoint a resectional policy is recommended.


Objective and subjective attractiveness and early adolescent adjustment.
Using data from the Pennsylvania Early Adolescent Transitions Study (PEATS), this study assessed how objective physical attractiveness (PA), indexed by appraisals from others, and subjective PA, indexed by self-appraisals, relate to each other and, in turn, to early adolescent adjustment (indexed by self-esteem and anxiety). Findings indicated a low relationship between objective and subjective PA. Only subjective PA was associated with adjustment.


Development of a DNA double-strand break-free base editing tool in Corynebacterium glutamicum for genome editing and metabolic engineering.
As a traditional amino acid producing bacterium, Corynebacterium glutamicum is a platform strain for production of various fine chemicals. Based on the CRISPR (Clustered regularly interspaced short palindromic repeats)-Cas9 system, gene editing tools that enable base conversion in the genome of C. glutamicum have been developed. However, some problems such as genomic instability caused by DNA double-strand break (DSB) and off-target effects need to be solved. In this study, a DSB-free single nucleotide genome editing system was developed by construction of a bi-directional base conversion tool TadA-dCas9-AID. This system includes cytosine base editors (CBEs): activation-induced cytidine deaminase (AID) and adenine deaminase (ABEs): tRNA adenosine deaminase (TadA), which can specifically target the gene through a 20-nt single guide RNA (sgRNA) and achieve the base conversion of C-T, C-G and A-G in the 28-bp editing window upstream of protospacer adjacent motif. Finally, as a proof-of-concept demonstration, the system was used to construct a mutant library of zwf gene in C. glutamicum S9114 genome to improve the production of a typical nutraceutical N-acetylglucosamine (GlcNAc). The GlcNAc titer of the mutant strain K293R was increased by 31.9% to 9.1 g/L in shake flask. Here, the developed bases conversion tool TadA-dCas9-AID does not need DNA double-strand break and homologous template, and is effective for genome editing and metabolic engineering in C. glutamicum.


Synthesis of salicylaldehyde-modified mesoporous silica and its application as a new sorbent for separation, preconcentration and determination of uranium by inductively coupled plasma atomic emission spectrometry.
A new functionalized mesoporous silica (MCM-41) using salicylaldehyde was utilized for the separation, preconcentration and determination of uranium in natural water by inductively coupled plasma atomic emission spectrometry (ICP-AES). Experimental conditions for effective adsorption of trace levels of U(VI) were optimized. The preconcentration factor was 100 (1.0 mL of elution for a 100 mL sample volume). The analytical curve was linear in the range 2-1000 microg L(-1) and the detection limit was 0.5 ng mL(-1). The relative standard deviation (R.S.D.) under optimum conditions was 2.5% (n=10). Common coexisting ions did not interfere with the separation and determination of uranium at pH 5. The sorbent exhibited excellent stability and its sorption capacity under optimum conditions has been found to be 10mg of uranium per gram of sorbent. The method was applied for the recovery and determination of uranium in different water samples.


Comparison of the epidemiology of invasive pneumococcal disease between Australia and New Zealand in 2017-2021: an observational study based on surveillance data.
The Australian immunisation schedule uses 13-valent pneumococcal conjugate vaccine (PCV13), while New Zealand (NZ) changed from PCV13 to 10-valent PCV (PCV10) in 2017. In NZ, cases of serotype 19A (not in PCV10) have been increasing since 2017. We compared invasive pneumococcal disease (IPD) epidemiology between Australia and NZ in 2017-2021. We collated IPD notification data from national surveillance systems. Between Australia and NZ, we compared IPD incidence rates and assessed the proportion of serotype 19A, and stratified for ethnicity and age. Between 2017 and 2021, the crude IPD incidence per 100,000 in Australia ranged from 4.3 to 8.4, and ranged from 6.9 to 11.4 in NZ. The highest age-adjusted IPD rates were observed in Australian Indigenous people (range: 27.3-35.5) followed by NZ Māori/Pacific peoples (range 19.7-30.4). For children <2 years, ethnicity-adjusted IPD rates were similar between Australia and NZ in 2017-2020. In 2021, however, the ethnicity-adjusted incidence in children <2 years was higher in NZ (30.2; 95% CI 21.1-39.4) than in Australia (23.3 95% CI: 19.5-27.1) (p < 0.01). In Australia, the proportion of serotype 19A remained 5%, whereas in NZ serotype 19A increased from 11.5% to 29.5% with the largest increase in children <2 years and 2-4 years. Despite higher risks in Indigenous populations in Australia compared to all other groups, the overall IPD rate in NZ is increasing, particularly among children. The numbers and proportions of IPD due to serotype 19A are increasing in NZ especially in children. These data support the NZ decision from December 2022 to change to PCV13. This research received no specific funding.


Cross table lateral radiography for measurement of acetabular cup version.
Appropriate orientation of the acetabular cup is an important factor for long-term results of total hip arthroplasty. For measurement of cup version cross-table lateral radiography is frequently used, but the reliability has been questioned. We compared cross table lateral radiography with computed tomography in patients that had undergone primary total hip arthroplasty. The study was prospectively done in 117 patients (117 hips). At 3 months after total hip replacement the acetabular version was measured by cross table lateral radiography and compared to measurements by computed tomography. By cross table lateral radiography acetabular anteversion was on mean 13.9° with a standard deviation of 10.1° as compared to 17.8°±12.6° by computed tomography. Mean difference was -3.8 with a distribution of measurements of ±13 degrees for 95% of the cases. Our study shows that cross table radiography provides acceptable information for clinical use, but has limited use for precise analysis of acetabular cup version.


Acute and repeated dose oral toxicity of N-acetyl-l-aspartic acid in Sprague-Dawley rats.
N-acetyl-l-aspartic acid (NAA) is a constituent of the mammalian central nervous system (CNS) that has been identified in a number of commonly consumed foods. The current study reports the outcome of acute and repeated dose oral toxicology studies conducted with NAA in Sprague-Dawley (SD) rats. No mortalities or evidence of adverse effects were observed in SD rats following acute oral administration of 2000mg/kg NAA. In a separate study, NAA was added to the diets of SD rats (n=10/sex group) at concentrations corresponding to daily doses of 10, 100, or 1000mg/kg/day for 14 consecutive days and 100, 500, and 1000mg/kg/day for another 14 days. All rats survived until scheduled sacrifice and no differences in body weights, feed consumption values, or clinical signs were observed in any of the treatment groups. No biologically significant differences were observed in functional observational battery (FOB), motor activity evaluations, ophthalmologic examinations, hematology, coagulation, clinical chemistry, or organ weights of any of the NAA treatment groups. Further, no test substance-related gross or microscopic changes were observed in NAA exposure groups. Based on these results, NAA was not considered acutely toxic following oral exposure to 2000mg/kg and the no-observed-adverse-effect-level (NOAEL) for systemic toxicity from repeated dose dietary exposure to NAA is 1000mg/kg/day.


Determination of biomarkers of protein oxidation in tissue and plasma.
Oxidative and nitrosative stress cause changes in proteins which can alter their structure and/or function. However, these changes especially in specific amino acid residues have proven to be reliable biomarkers of oxidative stress and inflammation. The aim of this study was to develop and validate a rapid method for the quantification of five selected biomarkers orto-tyrosine (o-tyr), meta-tyrosine (m-tyr), 3NO2-tyrosine (3NO2-tyr), 3I-tyrosine (3I-tyr) and 3Chloro-tyrosine (3Cl-tyr) in liver, brain and plasma, thus providing a snapshot of the oxidative stress status of the organism. The extraction and cleanup method entails protein precipitation, followed by digestion with pronase. Biomarker quantification is carried out using an Ultra Performance Liquid Chromatography-tandem Mass Spectrometry employing positive electrospray ionization and a reversed phase chromatographic separation. Liver, brain and plasma samples from hypoxic (FiO2: 8%) vs. normoxic newborn piglets (n=5) were studied employing the developed analytical method. m-tyrosine/phenylalanine, orto-tyrosine/phenylalanine, 3Cl-tyrosine/p-tyrosine and 3I-tyrosine/p-tyrosine ratios in liver of hypoxic animals were significantly increased as compared to normoxic. Although no significant differences were found for brain and plasma samples, a clear tendency to increased ratios was observed under hypoxic conditions. This analytical tool has proofed its suitability for the analysis of tissue and plasma samples from newborn piglets. The analysis of biomarkers of protein oxidation in bigger cohorts will be the topic of future studies with the aim of gaining a deeper insight into the mechanisms of oxidation-derived protein modification caused during hypoxia.


Factors associated with concussion-symptom knowledge and attitudes toward concussion care seeking in a national survey of parents of middle-school children in the US.
Developing appropriate concussion prevention and management paradigms in middle school (MS) settings requires understanding parents' general levels of concussion-related knowledge and attitudes. This study examined factors associated with concussion-symptom knowledge and care-seeking attitudes among parents of MS children (aged 10-15 years). A panel of 1224 randomly selected U.S. residents, aged ≥ 18 years and identifying as parents of MS children, completed an online questionnaire capturing parental and child characteristics. The parents' concussion-symptom knowledge was measured using 25 questions, with possible answers being "yes", "maybe", and "no". Correct answers earned 2 points, "maybe" answers earned 1 point, and incorrect answers earned 0 point (range: 0-50; higher scores = better knowledge). Concussion care-seeking attitudes were also collected using five 7-point scale items (range: 5-35; higher scores = more positive attitudes). Multivariable ordinal logistic regression models identified predictors of higher scores. Models met proportional odds assumptions. Adjusted odds ratios (aORs) with 95% confidence intervals (95%CIs) (excluding 1.00) were deemed statistically significant. Median scores were 39 (interquartile range: 32-44) for symptom knowledge and 32 (interquartile range: 28-35) for care-seeking attitude. In multivariable models, odds of better symptom knowledge were higher in women vs. men (aOR = 2.28; 95%CI: 1.71-3.05), white/non-Hispanics vs. other racial or ethnic groups (aOR = 1.88; 95%CI: 1.42-2.49), higher parental age (10-year-increase aOR = 1.47; 95%CI: 1.26-1.71), and greater competitiveness (10%-scale-increase aOR = 1.24; 95%CI: 1.13-1.36). Odds of more positive care-seeking attitudes were higher in white/non-Hispanics vs. other racial or ethnic groups (aOR = 1.45; 95%CI: 1.06-1.99) and in older parental age (10-year-increase aOR = 1.24; 95%CI: 1.05-1.47). Characteristics of middle school children's parents (e.g., sex, race or ethnicity, age) are associated with their concussion-symptom knowledge and care-seeking attitudes. Parents' variations in concussion knowledge and attitudes warrant tailored concussion education and prevention.


Low expression of microRNA-204 (miR-204) is associated with poor clinical outcome of acute myeloid leukemia (AML) patients.
Acute myeloid leukemia (AML) is a heterogeneous neoplasm of the bone marrow with poor prognosis. In clinical practice new prognostic factors are still needed. MicroRNAs (miRs), small endogenous noncoding RNAs, play an essential role in the development and progression of acute leukemia. The aim of the study was to evaluate miR-204 expression in patients with AML at diagnosis and after induction chemotherapy, in comparison to healthy controls. We also investigated, if miR-204 expression correlates with clinical features of AML patients. miR-204 expression has been analyzed using RT-PCR in 95 bone marrow specimens from newly diagnosed AML patients in comparison to 20 healthy subject. We showed down-regulated miR-204 expression in AML patients, which was associated with shorter patients' survival. Higher expression of miR-204 in patients after induction therapy was correlated with complete remission achieving. We showed low miR-204 expression in AML and found it to be an independent prognostic factor in this patient population.


[Opinion Survey of Paediatricians on Vaccination Status of Refugee Children - Challenges of a Medical Connection to the Regular Outpatient Care System].
In addition to the primary health care of refugees, their integration into the regular outpatient care system should be ensured. Initial data suggest that a gap of vaccination among (school) children of refugee families might have emerged in the period between the first general inspection on arrival (the first central health measure) and the transition to the local health care system. The aim of this study was to obtain the opinion of practicing paediatricians regarding the vaccination status of refugee children to examine whether a variance in the measles, mumps, rubella (varicella) vaccination schedule might have emerged between the periods of initial admission and school enrolment examination. Evaluations of both inhibiting and promoting conditions should generate fields of action regarding the systematic integration into the regular health care system. Qualitative interviews with experts as well as a quantitative questionnaire survey to measure the opinion of registered paediatricians in Münster were analyzed. The assessments showed that there was no clear vaccination gap among (school) children of refugee families. One challenge was the systematic integration into the local outpatient care system. Critical issues were inadequate vaccination education, language barriers, and frequent changes in location. The vaccination engagement and vaccination behaviour of refugees were assessed as most positive. International standards, in particular the sphere standards, attracted insufficient attention in practical implementation within the refugee relief programs. Based on the results, it is possible to identify fields of action for the prevention of vaccination gaps among refugees as well as for their systematic integration into the regular outpatient care system. The sphere standards as international standards should be incorporated more consciously.


The pharmacokinetic profile of inhaled and oral salbutamol in elite athletes with asthma and nonasthmatic subjects.
Data on pharmacokinetics of inhaled and oral salbutamol in elite athletes with asthma are needed to differentiate between therapeutic use and doping in doping control. An interventional open-label crossover. Respiratory Research Unit, Copenhagen University Hospital, Bispebjerg. Eight elite athletes with asthma and 10 nonasthmatic subjects aged 18 to 33 years. Administration of 0.8 mg of inhaled salbutamol and 8 mg of oral salbutamol separated by 14 days. Urine concentration of free salbutamol. Maximum urine concentrations peaked in the period of 0 to 4 hours after the administration of inhaled and oral salbutamol in both groups. Median concentrations after inhaled salbutamol and oral salbutamol were 401.6 and 2108.1 ng/mL in healthy subjects and 334.9 and 2975.2 ng/mL in elite athletes with asthma. There were no significant statistical differences between the groups. One sample exceeded the World Anti-Doping Agency threshold value of 1000 ng/mL with a urinary salbutamol concentration of 1057 ng/mL 4 hours after inhalation, when no correction for urine specific gravity was done. When this sample was corrected for urine specific gravity, the result was 661 ng/mL. We found no significant difference in pharmacokinetic profile of inhaled and oral salbutamol between elite athletes with asthma and nonasthmatic subjects. Our results indicate that urine salbutamol concentrations should be corrected for urine specific gravity when evaluating doping cases.


Identifying the Rate-Limiting Step in Total Laparoscopic Hysterectomy in a Training Hospital.
To identify the lengthiest step of total laparoscopic hysterectomy (TLH) in a teaching hospital and to determine which clinical factors affect the duration of this step. The University of Louisville Hospital. Single institution retrospective case series. This is a retrospective chart and video review that included 135 benign, elective TLHs performed at The University of Louisville. TLH was divided into 5 steps: (1) insertion of laparoscopic ports and adhesiolysis to restore normal anatomy; (2) identification of the ureter and resection of adnexal structures to transection of the round ligament; (3) transection of the round ligament to transection of the uterine artery; (4) lateralization of the uterine vessel pedicle to completion of colpotomy; and (5) completion of vaginal cuff closure. The random intercept and slope model was used to identify the lengthiest step of TLH, and the backward elimination procedure was used to evaluate which clinical factors affected this step. Mean ± SD total length of TLH was 81 ± 30 min. The lengthiest step was colpotomy, with a mean duration of 24 ± 13 min. Uterine weight significantly increased the length of time required for colpotomy (p = .001). The primary energy source (ultrasonic scalpel vs monopolar hook) used to perform colpotomy did not influence the length of time (p = .539 vs p = .583). Uterine weight (p < .001) and adhesiolysis (p = .003) significantly increased the total time of TLH. At a teaching institution where surgeries are performed by residents and fellows, colpotomy is the lengthiest step of TLH and is influenced by uterine weight. This finding may reflect the training levels of the surgeons performing these cases and the learning curve associated with a challenging surgical skill. Further research should focus on simulation models and/or tools for colpotomy that may result in greater efficiency in the operating room.


[Invasive carcinoma of the uterine cervix associated with pregnancy (author's transl)].
In 4,396 invasive cervix carcinomas treated between 1934 and 1973, 52 occurred during pregnancy or within 3 months post partum. Stages I were more frequent among pregnant women (24%) than without pregnancy (8%) and stages II were as frequent (50%). Stages I and II were more frequent among pregnant women treated during 1963-1973 than 1934-1962. The 3 years' survival rate, all stages combined, for pregnant women (42%) was lower than for matched control non-pregnant women (62%). This difference was significant at P = 0.05, but at 5 and 10 years, the difference was not significant for patients treated between 1963-1973. At an equal stage, survival rate seemed lower for stages IIb and III (P = 0.02 for these two stages combined.) The lymph node involvement was not more frequent; the decrease of global survival rate could be associated to some factors and especially incomplete therapy and an under-estimation of the tumor extension because of the pregnancy. Our results are compared to the data literature and therapeutic schedules are discussed.


Associations Between Vitamin D Levels and Depressive Symptoms in Later Life: Evidence From the English Longitudinal Study of Ageing (ELSA).
A possible role of vitamin D in depression has received considerable attention, especially given the significant disability, mortality, and healthcare costs associated to depression and the high prevalence of vitamin D deficiency. We investigated the cross-sectional associations between serum 25-hydroxyvitamin D (25OHD) levels and depressive symptoms (CES-D) in 5,607 older adults from the English Longitudinal Study of Ageing (ELSA). Overall, there was a significant association between low 25OHD levels and elevated depressive symptoms (odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.20-2.07 for the lowest quartile; OR = 1.45, 95% CI = 1.15-1.83 for <30 nmol/L cut-off and OR = 1.34, 95% CI = 1.10-1.62 for the ≤50 nmol/L cut-off) after adjustment for a wide range of covariates of clinical significance. Fully adjusted models showed that women in the lowest (OR = 1.67, 95% CI = 1.20-2.34) and second lowest (OR = 1.68, 95% CI = 1.20-2.35) quartiles of 25OHD as well as those with 25OHD levels <30 nmol/L (OR = 1.40, 95% CI = 1.06-1.86) and ≤50 nmol/L (OR = 1.35, 95% CI = 1.07-1.72) were more likely to report elevated depressive symptoms. For men, however, this association only remained significant for those with 25OHD levels of <30 nmol/L (OR = 1.60, 95% CI = 1.06-2.42) in the fully adjusted models. The independent and inverse association found between low 25OHD levels and elevated depressive symptoms suggests that vitamin D deficiency may be a risk factor for late-life depression, particularly among women. Whether our findings have any clinical meaning or not, additional data are needed from well-designed randomized controlled trials of vitamin D for the prevention and treatment of late-life depression.


Ultrasound characteristics of bruises and their correlation to cutaneous appearance.
The primary objective of this study was to compare the cutaneous size of a bruise on gross exam to the subcutaneous depth and height of the hematoma ascertained by ultrasound. The hypothesis was that there would be little correlation between the area of the bruise on cutaneous exam and the height when measured with ultrasound. Adult and pediatric patients with bruising were prospectively identified in the emergency department. Photographs and ultrasound images were collected of the bruises and epidemiologic information collected from the patients. The cutaneous area of the bruise was compared with the sonographic characteristics. The subcutaneous depth and height of the hematomas defined by ultrasound did not correlate with the cutaneous area. The cutaneous appearance of a bruise gives little indication of the depth and size of the subcutaneous bruise. Ultrasound can add information regarding these parameters.


Bioassay-directed purification of an acidic phospholipase A(2) from Agkistrodon halys pallas venom.
Relying on ex vivo and in vitro platelet anti-aggregation assays, a tail bleeding time assay, and an anti-thrombotic assay, we have purified the fraction of venom from Agkistrodon halys pallas which, in all of these assays, is the most active. There were two major steps in the purification: gel filtration chromatography on Sephadex G-100, and ion exchange chromatography on DEAE Sephadex A-50. Sequencing of the most active fraction by mass spectrometry revealed that it is a known acidic phospholipase A(2). Prior expectations by others about the in vivo anti-thrombotic activity of this enzyme are confirmed.