[Supra-selective vagotomy in the treatment of perforated duodenal ulcers. Thirty cases report (author's transl)].
Thirty patients with acute perforated duodenal ulcer were managed by supra-selective vagotomy and simple closure of the perforation. There was no operative mortality and a low morbidity. Fourteen patients have had gastric studies between four and thirty-two months after operation. Three patients had transitory epigastric fullness (21%); there was no diarrhea or dumping, but two recurrences (14%). The risk of ulcer recurrence after simple closure is high; supra-selective vagotomy as a definitive ulcer therapy, does not increase operative mortality, and has mild digestive sequelaes, for an acceptable rate of recurrence.


Bone Regeneration Using Gene-Activated Matrices.
Gene delivery to bone is a potential therapeutic strategy for directed, sustained, and regulated protein expression. Tissue engineering strategies for bone regeneration include delivery of proteins, genes (viral and non-viral-mediated delivery), and/or cells to the bone defect site. In addition, biomimetic scaffolds and scaffolds incorporating bone anabolic agents greatly enhance the bone repair process. Regional gene therapy has the potential of enhancing bone defect healing and bone regeneration by delivering osteogenic genes locally to the osseous lesions, thereby reducing systemic toxicity and the need for using supraphysiological dosages of therapeutic proteins. By implanting gene-activated matrices (GAMs), sustained gene expression and continuous osteogenic protein production in situ can be achieved in a way that stimulates osteogenesis and bone repair within osseous defects. Critical parameters substantially affecting the therapeutic efficacy of gene therapy include the choice of osteogenic transgene(s), selection of non-viral or viral vectors, the wound environment, and the selection of ex vivo and in vivo gene delivery strategies, such as GAMs. It is critical for gene therapy applications that clinically beneficial amounts of proteins are synthesized endogenously within and around the lesion in a sustained manner. It is therefore necessary that reliable and reproducible methods of gene delivery be developed and tested for their efficacy and safety before translating into clinical practice. Practical considerations such as the age, gender, and systemic health of patients and the nature of the disease process also need to be taken into account in order to personalize the treatments and progress towards developing a clinically applicable gene therapy for healing bone defects. This review discusses tissue engineering strategies to regenerate bone with specific focus on non-viral gene delivery systems.


Mycelium cultivation, chemical composition and antitumour activity of a Tolypocladium sp. fungus isolated from wild Cordyceps sinensis.
To examine and illustrate the morphological characteristics and growth kinetics of Cs-HK1, a Tolypocladium fungus, isolated from wild Cordyceps sinensis in solid and liquid cultures, and the major chemical constituents and antitumour effects of Cs-HK1 mycelium. The Cs-HK1 fungus was isolated from the fruiting body of a wild C. sinensis and identified as a Tolypocladium sp. fungus. It grew rapidly at 22-25 degrees C on a liquid medium containing glucose, yeast extract, peptone and major inorganic salts, with a specific growth rate of 1.1 day(-1), reaching a cell density of 23.0 g dw l(-1) in 7-9 days. Exopolysaccharides accumulated in the liquid culture to about 0.3 g l(-1) glucose equivalent. In comparison with natural C. sinensis, the fungal mycelium had similar contents of protein (11.7-microg) and carbohydrate (654.6-microg) but much higher contents of polysaccharide (244.2 mg vs 129.5 mg), adenosine (1116.8-microg vs 264.6 microg) and cordycepin (65.7 microg vs 20.8 microg) (per gram dry weight). Cyclosporin A, an antibiotic commonly produced by Tolypocladium sp., was also detected from the mycelium extract. The hot water extract of mycelium showed low cytotoxic effect on B16 melanoma cells in culture (about 25% inhibition) but significant antitumour effect in animal tests, causing 50% inhibition of B16 cell-induced tumour growth in mice. The Tolypocladium sp. fungus, Cs-HK1, can be easily cultivated by liquid fermentation. The mycelium biomass contained the major bioactive compounds of C. sinensis, and the mycelium extract had significant antitumour activity. The Cs-HK1 fungus may be a new and promising medicinal fungus and an effective and economical substitute of the wild C. sinensis for health care.


Epithelial-like transport of mineral distinguishes bone formation from other connective tissues.
We review unique properties of bone formation including current understanding of mechanisms of bone mineral transport. We focus on formation only; mechanism of bone degradation is a separate topic not considered. Bone matrix is compared to other connective tissues composed mainly of the same proteins, but without the specialized mechanism for continuous transport and deposition of mineral. Indeed other connective tissues add mechanisms to prevent mineral formation. We start with the epithelial-like surfaces that mediate transport of phosphate to be incorporated into hydroxyapatite in bone, or in its ancestral tissue, the tooth. These include several phosphate producing or phosphate transport-related proteins with special expression in large quantities in bone, particularly in the bone-surface osteoblasts. In all connective tissues including bone, the proteins that constitute the protein matrix are mainly type I collagen and γ-carboxylate-containing small proteins in similar molar quantities to collagen. Specialized proteins that regulate connective tissue structure and formation are surprisingly similar in mineralized and non-mineralized tissues. While serum calcium and phosphate are adequate to precipitate mineral, specialized mechanisms normally prevent mineral formation except in bone, where continuous transport and deposition of mineral occurs.


Stable phosphatidylcholine-bile salt mixed micelles enhance oral absorption of paclitaxel: preparation and mechanism in rats.
The aim of this study is to prepare a stable phosphatidylcholine/bile salt micelles with Pluronic F127-polyethylenimine conjugates (F127-PEI), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), soybean phosphatidylcholine (SPC) and sodium cholate (NaC) and to elucidate the effects and possible mechanism of micelle components on the intestinal absorption of paclitaxel (PTX) in rats. The results of intestinal absorption revealed that the PTX in SPC/NaC micelles displayed superior permeability across intestinal barrier than free drug and PTX in TPGS/SPC/NaC and F127-PEI/TPGS/SPC/NaC mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-gp and enhancement of the drug transportation across the unstirred water layer to the endothelial lining, thereby promoting the permeation across the intestinal wall. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC0→∞) of paclitaxel in F127-PEI/TPGS/SPC/NaC micelles was much greater than that in TPGS/SPC/NaC micelles. This phenomenon deviated from the results of uptake studies by cells and permeability experiments through rat intestine and revealed that the micelle stability had a great effect on intestinal absorption of paclitaxel.


Antidiarrhoeal and antimicrobial activity of Calpurnia aurea leaf extract.
In Ethiopia, Calpurnia aurea is used for the treatment of syphilis, malaria, rabies, diabetes, hypertension, diarrhoea, leishmaniasis, trachoma, elephantiasis, fungal diseases and different swellings. However, despite its traditional usage as an antidiarrhoeal and antimicrobial agent, there is limited or no information regarding its effectiveness and mode of action in diarrhoea which may be caused by Shigella flexneri, Staphylococcus aureus, Escherichia coli and Salmonella typhi. Hence, we evaluated the 80% methanol (MeOH) extract of dried and powdered leaves of C. aurea for its antidiarrhoeal and antimicrobial activities. Swiss albino mice of either sex were divided into five groups (five/group): Group I served as control and received vehicle (1% Tween 80) at a dose of 10 ml/kg orally; Group II served as standard and received loperamide at the dose of 3 mg/kg orally; Groups III, IV and V served as test groups and received the 80% MeOH leaf extract of C. aurea at doses of 100, 200 and 400 mg/kg orally, respectively. Diarrhoea was induced by oral administration of 0.5 ml castor oil to each mouse, 1 h after the above treatments. During an observation period of 4 h, time of onset of diarrhea, total number of faecal output (frequency of defecation) and weight of faeces excreted by the animals were recorded. Data were analyzed using one way analysis of variance followed by Tukey post test. Antimicrobial activity test was conducted using agar well diffusion assay. Clinical isolates tested were Salmonella typhi, Salmonella paratyphi, Salmonella typhimurium, Shigella species, Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. In castor oil induced diarrhea model, the 80% methanol leaf extract of C. aurea at 100, 200 and 400 mg/kg and the standard drug loperamide (3 mg/kg) significantly reduced the time of onset of diarrhea, the frequency of defecation (total number of faecal output) and weight of faeces. C. aurea leaf extract also showed good antimicrobial activity against all tested organisms. C. aurea possesses good antidiarrhoeal and antimicrobial activity which support the traditional use of the plant in the treatment of diarrhea in Ethiopia.


[Neuroma of the common bile duct: a rare cause of jaundice].
We report a case of neuroma of the main bile duct arising twenty years after cholecystectomy. The patient, a 82-year-old woman, was admitted for jaundice. Endoscopic retrograde cholangiography showed a regular stenosis of the main bile duct. Histologic examination demonstrated neuroma. Based on the analysis of this and 15 other previously published cases, the following features of bile duct neuroma were outlined: a) variable interval between cholecystectomy and the onset of jaundice (6 months to 35 years); b) the generally complicated postoperative course, c) the various localizations on the biliary tree (cystic, main bile duct, intrahepatic bile duct) and, d) the circumstances of onset.


Identification and DNA fingerprinting of Legionella strains by randomly amplified polymorphic DNA analysis.
The randomly amplified polymorphic DNA (RAPD) technique was used in the development of a fingerprinting (typing) and identification protocol for Legionella strains. Twenty decamer random oligonucleotide primers were screened for their discriminatory abilities. Two candidate primers were selected. By using a combination of these primers, RAPD analysis allowed for the differentiation between all different species, between the serogroups, and further differentiation between subtypes of the same serogroup. The usefulness of RAPD analysis was also evaluated with outbreak-related clinical and environmental isolates previously typed by the restriction fragment length polymorphism technique. RAPD analysis proved to be as accurate as other genotypic methods, reproducible, and highly discriminatory and is a valuable new alternative to traditional fingerprinting and identification of Legionella species and strains.


Fasting Imparts a Switch to Alternative Daily Pathways in Liver and Muscle.
The circadian clock operates as intrinsic time-keeping machinery to preserve homeostasis in response to the changing environment. While food is a known zeitgeber for clocks in peripheral tissues, it remains unclear how lack of food influences clock function. We demonstrate that the transcriptional response to fasting operates through molecular mechanisms that are distinct from time-restricted feeding regimens. First, fasting affects core clock genes and proteins, resulting in blunted rhythmicity of BMAL1 and REV-ERBα both in liver and skeletal muscle. Second, fasting induces a switch in temporal gene expression through dedicated fasting-sensitive transcription factors such as GR, CREB, FOXO, TFEB, and PPARs. Third, the rhythmic genomic response to fasting is sustainable by prolonged fasting and reversible by refeeding. Thus, fasting imposes specialized dynamics of transcriptional coordination between the clock and nutrient-sensitive pathways, thereby achieving a switch to fasting-specific temporal gene regulation.


The efficacy of sulodexide in the prevention of postthrombotic syndrome.
The aim of this open, observational registry was to evaluate the effects of antithrombotic treatment on the development of postthrombotic syndrome (PTS): the effects of "standard management" (SM; according to International Union of Angiology guidelines) were compared to SM in association with sulodexide or aspirin. Postthrombotic syndrome occurrence was observed in 3 nonparallel groups after deep venous thrombosis (DVT); the registry started after the end of the anticoagulation period. The target was to observe the occurrence of PTS in 5 years. Three possible options were suggested to the patients, and the patients and their caregivers defined the type of management. A group of 167 patients was involved in the SM with reevaluation every 6 months; the sulodexide group included 124 patients and the aspirin group included 48 patients. The 3 groups were clinically similar and comparable for age and sex distribution. Of the 167 patients in the SM group, 154 patients completed 60 months of follow-up. The percentage of patients with PTS in the SM group ranged from 14.9% (1 year after the end of anticoagulation) to 19.5% (60 months). In the nonparallel group using sulodexide (124 comparable patients at inclusion; 115 at 60 months), the percentage of PTS was variable from 8.8% (1 year after anticoagulants) to 12.17% at 60 months. These percentages are significantly lower than those observed with SM. In the nonparallel aspirin group (48 patients at inclusion and 34 at 54 months), there was a PTS incidence of 23.5% at 54 months (vs 12.17% in the sulodexide group and 18.23% in the SM group). The incidence of PTS was significantly higher in comparison with the other 2 groups. The incidence of PTS was lower in the sulodexide group in comparison with the 2 other groups. Sulodexide administration after DVT appears to be effective in preventing PTS in association with recommended management and a number of recurrent DVTs. Modalities of treatment, dosages, and timing of administration should be explored in more comprehensive and complete studies.


Ultrasound Muscle Assessment and Nutritional Status in Institutionalized Older Adults: A Pilot Study.
Muscle thickness, measured by ultrasonography, has been investigated for nutritional assessment in older adults, however the associations between muscle ultrasound parameters in the lower limb and nutritional status have not been studied. The aim of this study was to investigate the relationship between muscle thickness echo intensity (EI), and nutritional status in home care residents. A cross sectional study was conducted involving 19 older adults from a home care in Malaga (Spain). We evaluated lower leg muscles by ultrasound, anthropometric data, physical function (measured by gait speed and the Short Physical Performance Battery), strength (handgrip and knee extensors strength) and nutritional status across the Mini-Nutritional Assessment Short-Form (MNA-SF). We found that muscle thickness assessed by ultrasonography independently predicts nutritional status by MNA-SF and after adjusting for handgrip strength or age and sex. As secondary findings, we found relations between strength, functional capacity and the MNA-SF test. These results suggest that lower leg muscle ultrasound parameters could be used as a low-cost objective method for muscle evaluation in nutritional assessment in older adults.


Nosocomial Gram-positive antimicrobial susceptibility pattern at a referral teaching hospital in Tehran, Iran.
The aim of the study was to evaluate epidemiology and susceptibility patterns of nosocomial Gram-positive infections in a referral teaching hospital. Over a 1 year period, Gram-positive microorganisms isolated from specimens of hospitalized patients with documented nosocomial infection underwent antimicrobial susceptibility testing using the disk diffusion test. In addition, possible risk factors for developing multidrug-resistant bacteria were evaluated. During the study period, a total of 137 nosocomial infections were detected. Staphylococcus aureus was the most frequently isolated microorganism (56.2%), followed by Enterococcus spp. (21.9%) and Staphylococcus epidermidis (15.3%). All S. aureus strains were sensitive to vancomycin, teicoplanin, linezolid and chloramphenicol. More than 50% of enterococci strains were resistant to vancomycin and teicoplanin. Possible risk factors for multidrug resistance among isolated pathogens were history of antibiotic use and intubation of patient for mechanical ventilation. This study showed high rates of antimicrobial resistance among nosocomial Gram-positive pathogens, complicating antibiotic therapy and its outcomes.


Adherence to a Mediterranean diet is associated with cognitive function in an older non-Mediterranean sample: findings from the Maine-Syracuse Longitudinal Study.
Background: Adherence to a Mediterranean diet is associated with higher cognitive function and reduced risk of dementia in Mediterranean populations. However, few studies have investigated the association between Mediterranean diet adherence and cognition in populations outside of the Mediterranean basin. Furthermore, it is currently unknown whether the association between Mediterranean diet adherence and cognitive function differs between middle-aged and older individuals.Methods: Cross-sectional (n = 894) and longitudinal (n = 530) multivariable analyses were undertaken using data from community-dwelling adults from the Maine-Syracuse Longitudinal Study (MSLS). Mediterranean diet adherence was measured by applying a literature-based Mediterranean diet score to food frequency questionnaire data. Cognitive function was assessed with a battery of tests and composites scores were computed for global cognitive function, Visual-Spatial Organisation and Memory, verbal memory, working memory, scanning and tracking and abstract reasoning.Results: No cross-sectional associations between Mediterranean diet adherence and cognitive function were detected. Over a period of five years, higher adherence to a Mediterranean diet was associated with improvements in Global Cognitive Function, Visual-Spatial Organisation and Memory and scanning and tracking in participants ≥70 years. No significant longitudinal associations were observed for participants <70 years.Conclusion: Our findings suggest that higher adherence to a Mediterranean diet is associated with better cognitive performance, and therefore less cognitive decline, in older but not middle-aged individuals.


Long-term active restoration of extremely degraded alpine grassland accelerated turnover and increased stability of soil carbon.
Soil nutrient contents and organic carbon (C) stability are key indicators for restoration of degraded grassland. However, the effects of long-term active restoration of extremely degraded grassland on soil parameters have been equivocal. The aims of this study were to evaluate the impact of active restoration of degraded alpine grassland on: (a) soil organic matter (SOM) mineralization; and (b) the importance of biotic factors for temperature sensitivity (Q10 ) of SOM mineralization. Soils were sampled from intact, degraded and restored alpine grasslands at altitudes ranging between 3,900 and 4,200 m on the Tibetan Plateau. The samples were incubated at 5, 15 and 25°C, and Q10 values of SOM mineralization were determined. Structural equation modeling was used to evaluate the importance of vegetation, soil physico-chemical properties and microbial parameters for Q10 regulation. The Q10 of N mineralization was similar among intact, degraded and restored soils (0.84-1.24) and was higher in topsoil (1.09) than in subsoil (0.92). The best predictive factor of CO2 -Q10 for intact grassland was microbial biomass, for degraded grassland was basal microbial respiration, and for restored grassland was soil bulk density. Restoration by planting vegetation decreased the Q10 of SOM mineralization as soil bulk density, the most important negative predictor, increased in restored grassland. The Q10 of SOM mineralization in topsoil was 14% higher than in subsoil because of higher microbial abundance and exo-enzyme activities. The NH4 + content was greatest in intact soil, while NO3 - content was greatest in degraded soil. The SOM mineralization rate decreased with grassland degradation and increased after long-term (>10 years) restoration. In conclusion, extremely degraded grassland needs proper long-term management in active restoration projects, especially for improvement of soil nutrients in a harsh environment.


Autoimmune disease in mothers with the FMR1 premutation is associated with seizures in their children with fragile X syndrome.
An increased prevalence of autoimmune diseases in family members of children with autism spectrum disorders (ASD) has been previously reported. ASD is also a common problem co-occurring in children with fragile X syndrome (FXS). Why ASD occurs in some individuals with FXS, but not all, is largely unknown. Furthermore, in premutation carrier mothers, there is an increased risk for autoimmune diseases. This study compared the rate of ASD and other neurodevelopmental/behavioral problems in 61 children with FXS born to 41 carrier mothers who had autoimmune disease and in 97 children with FXS of 78 carrier mothers who did not have autoimmune disease. There were no significant differences in the mean age (9.61 ± 5.59 vs. 9.41 ± 6.31, P = 0.836), cognitive and adaptive functioning in children of mothers with and without autoimmune disease. Among children whose mothers had autoimmune disease, the odds ratio (OR) for ASD was 1.27 (95% CI 0.62-2.61, P = 0.5115). Interestingly, the OR for seizures and tics was 3.81 (95% CI 1.13-12.86, P = 0.031) and 2.94 (95% CI 1.19-7.24, P = 0.019), respectively, in children of mothers with autoimmune disease compared to children of mothers without autoimmune disease. In conclusion, autoimmune disease in carrier mothers was not associated with the presence of ASD in their children. However, seizures and tics were significantly increased in children of mothers with autoimmune disease. This suggests a potential new mechanism of seizure and tic exacerbation in FXS related to an intergenerational influence from autoimmunity in the carrier mother.


Size-Dependent Electroporation of Dye-Loaded Polymer Nanoparticles for Efficient and Safe Intracellular Delivery.
Efficient and safe delivery of nanoparticles (NPs) into the cytosol of living cells constitutes a major methodological challenge in bio-nanotechnology. Electroporation allows direct transfer of NPs into the cytosol by forming transient pores in the cell membrane, but it is criticized for invasiveness, and the applicable particle sizes are not well defined. Here, in order to establish principles for efficient delivery of NPs into the cytosol with minimal cytotoxicity, the influence of the size of NPs on their electroporation and intracellular behavior is investigated. For this study, fluorescent dye-loaded polymer NPs with core sizes between 10 and 40 nm are prepared. Optimizing the electroporation protocol allows minimizing contributions of endocytosis and to study directly the effect of NP size on electroporation. NPs of <20 nm hydrodynamic size are efficiently delivered into the cytosol, whereas this is not the case for NPs of >30 nm. Moreover, only particles of core size <15 nm diffuse freely throughout the cytosol. While electroporation at excessive electric fields induces cytotoxicity, the use of small NPs <20 nm allows efficient delivery at mild electroporation conditions. These results give clear methodological and design guidelines for the safe delivery of NPs for intracellular applications.


Hypoxic 3D Tumor Model for Evaluating of CAR-T Cell Therapy In Vitro.
Solid tumors contain abnormal physical and biochemical barriers that hinder chimeric antigen receptor (CAR) T cell therapies. However, there is a lack of understanding on how the solid tumor microenvironment (e.g. hypoxia) modulates CAR-T cell function. Hypoxia is a common feature of many advanced solid tumors that contributes to reprogramming of cancer and T cell metabolism as well as their phenotypes and interactions. To gain insights into the activities of CAR-T cells in solid tumors and to assess the effectiveness of new combination treatments involving CAR-T cells, in vitro models that faithfully reflect CAR-T cell-solid tumor interactions under physiologically relevant tumor microenvironment is needed. Here we demonstrate how to establish a hypoxic 3-dimensional (3-D) tumor model using a cleanroom-free, micromilling-based microdevice and assess the efficacy of the combination treatment with CAR-T cells and PD-1/PD-L1 inhibition.


Translocation of sugars into rat liver lysosomes. Evidence against a common carrier for D-glucose and D-ribose.
A conflict exists in the literature concerning the mode of translocation of D-glucose and D-ribose across the lysosome membrane. The more rapid net uptake of ribose, when measured by the osmotic-protection technique, has been attributed either to its smaller size and lower hydrogen-bonding capacity, or to a lower affinity for a transport system shared by both sugars. The latency of acid beta-hexosaminidase in isolated rat liver lysosomes was measured after preincubation for periods up to 1 h in various solutions containing glucose and/or ribose, and in some cases sucrose. After confirmation of the superior osmotic protection afforded by glucose (than by ribose), it was shown that a solution 0.125 M in both glucose and ribose provided protection intermediate between that given by 0.25 M-glucose and that given by 0.25 M-ribose. This result is inconsistent with the common-carrier hypothesis.


Comparison of Papanicolaou test with visual detection tests in screening for cervical cancer and developing the optimal strategy for low resource settings.
To compare the sensitivity, specificity, positive and negative predictive values, and accuracy of Papanicolaou test with visual inspection with acetic acid (VIA)/VIA using magnification devices (VIAM) and develop the best strategy for screening in low resource settings. This is a prospective cross-sectional study on 408 symptomatic multiparous women in the reproductive age group, sequentially using the Papanicolaou test, the VIA, and the VIAM for screening. Women with a positive screening test underwent guided biopsy and endocervical curettage. The site of biopsy was recorded. Histopathological findings were taken as the "gold" standard in comparing the methods. The mean (SD) age was 32.3 (6.8) years (range, 15-49 years), whereas the mean (SD) parity was 2.9 (1.2) (range, 1-9). Abnormal cytological findings were detected in 2.9% patients, whereas the remaining smears were negative for any intraepithelial lesion or malignancy. A total of 113 cases were screened positive by one/all methods. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the Papanicolaou test, the VIA, and the VIAM were 24, 98, 42, 96, and 94%; 95, 78, 19, 99, and 79%; and 95, 78, 19, 99, and 79%, respectively, for high-grade lesions. The Papanicolaou test had low sensitivity but high specificity, whereas visual detection methods had a high sensitivity in addition to being cheaper. Alternative methods of screening such as VIA/VIAM can be a valuable alternative to the Papanicolaou test for cervical cancer screening in low resource settings. Visual inspection using magnification devices may be of benefit over VIA in doubtful cases.


Hemin levels in culture medium of Porphyromonas (Bacteroides) gingivalis regulate both hemin binding and trypsinlike protease production.
Washed cells and Sarkosyl-insoluble outer membrane preparations of the black-pigmented bacteroides Porphyromonas gingivalis W50 bound hemin. The amount of hemin removed from a buffered solution by both cells and outer membranes was significantly larger if bacteria had been grown in broths supplemented with 5 mg of hemin per liter rather than none. Conversely, cells grown without supplemental hemin bound relatively little. However, all preparations bound some hemin. In addition, hemin regulated the production of significantly higher levels of trypsinlike protease by P. gingivalis W50. The nonpigmented variant, W50 BE1, showed no such responses to the levels of hemin in the growth medium.


Temperature-Sensitive Reproduction and the Physiological and Evolutionary Potential for Mother's Curse.
Strict maternal transmission of mitochondrial DNA (mtDNA) is hypothesized to permit the accumulation of mitochondrial variants that are deleterious to males but not females, a phenomenon called mother's curse. However, direct evidence that mtDNA mutations exhibit such sexually antagonistic fitness effects is sparse. Male-specific mutational effects can occur when the physiological requirements of the mitochondria differ between the sexes. Such male-specific effects could potentially occur if sex-specific cell types or tissues have energy requirements that are differentially impacted by mutations affecting energy metabolism. Here we summarize findings from a model mitochondrial-nuclear incompatibility in the fruit fly Drosophila that demonstrates sex-biased effects, but with deleterious effects that are generally larger in females. We present new results showing that the mitochondrial-nuclear incompatibility does negatively affect male fertility, but only when males are developed at high temperatures. The temperature-dependent male sterility can be partially rescued by diet, suggesting an energetic basis. Finally, we discuss fruitful paths forward in understanding the physiological scope for sex-specific effects of mitochondrial mutations in the context of the recent discovery that many aspects of metabolism are sexually dimorphic and downstream of sex-determination pathways in Drosophila. A key parameter of these models that remains to be quantified is the fraction of mitochondrial mutations with truly male-limited fitness effects across extrinsic and intrinsic environments. Given the energy demands of reproduction in females, only a small fraction of the mitochondrial mutational spectrum may have the potential to contribute to mother's curse in natural populations.


Final height in girls with slowly progressive untreated central precocious puberty.
A group of six girls with slowly progressive idiopathic precocious puberty (IPP) and a good initial height prognosis was followed without treatment. At first observation the girls had a bone age advance over chronological age of no more than 18 months, a delta height age (delta HA): delta bone age (delta BA) ratio higher than 0.9 and height prognosis was unimpaired after 6 months. During the first two years of follow-up the girls maintained an acceptable height potential. The delta HA:delta BA ratio remained constant at greater than 0.9. Predicted height showed a slight increase or decrease (+/- 4 cm). The girls were reevaluated after the age of 14 years and followed-up until they reached their final height (FH). The mean FH (155.4 +/- 2.8 cm) was below the mean target height (159.3 +/- 4.2 cm) by 3.9 cm (range -2.1 to -6.7 cm); this difference was not statistically significant. The FH was more than 5 cm below the target height in only one case; this girl had the most precocious onset of puberty, at 6 years of age. In three cases FH was between the 3rd and 10th centiles. These three girls had a target height below 158 cm (< 25th centile). Girls with slowly progressive IPP and a good initial height prognosis preserved height potential with an acceptable final height without therapy.


All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes.
A positive effect of all-trans retinoic acid (ATRA) on white adipose tissue (WAT) oxidative and thermogenic capacity has been described and linked to an in vivo fat-lowering effect of ATRA in mice. However, little is known about the effects of ATRA on mitochondria in white fat. Our objective has been to characterize the effect of ATRA on mitochondria biogenesis and oxidative phosphorylation (OXPHOS) capacity in mature white adipocytes. Transcriptome analysis, oxygraphy, analysis of mitochondrial DNA (mtDNA), and flow cytometry-based analysis of mitochondria density were performed in mature 3T3-L1 adipocytes after 24 h incubation with ATRA (2 µM) or vehicle. Selected genes linked to mitochondria biogenesis and function and mitochondria immunostaining were analyzed in WAT tissues of ATRA-treated as compared with vehicle-treated mice. ATRA upregulated the expression of a large set of genes linked to mtDNA replication and transcription, mitochondrial biogenesis, and OXPHOS in adipocytes, as indicated by transcriptome analysis. Oxygen consumption rate, mtDNA content, and staining of mitochondria were increased in the ATRA-treated adipocytes. Similar results were obtained in WAT depots of ATRA-treated mice. We conclude that ATRA impacts mitochondria in adipocytes, leading to increased OXPHOS capacity and mitochondrial content in these cells.


Delivery modes in case of fetal malformations.
An estimated 276,000 babies die within 4 weeks of birth every year, worldwide, from congenital anomalies. Better quality ultrasound screening can increase the detection of these fetal malformations in the prenatal period. Prenatal counseling for the pregnant woman and her family, regarding the nature of the disease and prognosis is necessary. Options for management in prenatal, perinatal, intrapartum, neonatal, and childhood periods need to be thoroughly discussed, so that the family can make an informed decision. A multidisciplinary approach is usually needed once a decision has been made to optimize fetal outcome, to plan for the timing and location as well as the mode of delivery. In most of the cases, vaginal delivery can be attempted. An elective cesarean delivery should be reserved for maternal concern of dystocia, certain fetal conditions that cesarean delivery will optimize perinatal outcome, or if the parents have a psychosocial determination to have a live-born infant.


A phylogeographic investigation of African monkeypox.
Monkeypox is a zoonotic disease caused by a virus member of the genus Orthopoxvirus and is endemic to Central and Western African countries. Previous work has identified two geographically disjuct clades of monkeypox virus based on the analysis of a few genomes coupled with epidemiological and clinical analyses; however, environmental and geographic causes of this differentiation have not been explored. Here, we expand previous phylogenetic studies by analyzing a larger set of monkeypox virus genomes originating throughout Sub-Saharan Africa to identify possible biogeographic barriers associated with genetic differentiation; and projected ecological niche models onto environmental conditions at three periods in the past to explore the potential role of climate oscillations in the evolution of the two primary clades. Analyses supported the separation of the Congo Basin and West Africa clades; the Congo Basin clade shows much shorter branches, which likely indicate a more recent diversification of isolates within this clade. The area between the Sanaga and Cross Rivers divides the two clades and the Dahomey Gap seems to have also served as a barrier within the West African clade. Contraction of areas with suitable environments for monkeypox virus during the Last Glacial Maximum, suggests that the Congo Basin clade of monkeypox virus experienced a severe bottleneck and has since expanded its geographic range.


Volumetric brain tumour detection from MRI using visual saliency.
Medical image processing has become a major player in the world of automatic tumour region detection and is tantamount to the incipient stages of computer aided design. Saliency detection is a crucial application of medical image processing, and serves in its potential aid to medical practitioners by making the affected area stand out in the foreground from the rest of the background image. The algorithm developed here is a new approach to the detection of saliency in a three dimensional multi channel MR image sequence for the glioblastoma multiforme (a form of malignant brain tumour). First we enhance the three channels, FLAIR (Fluid Attenuated Inversion Recovery), T2 and T1C (contrast enhanced with gadolinium) to generate a pseudo coloured RGB image. This is then converted to the CIE L*a*b* color space. Processing on cubes of sizes k = 4, 8, 16, the L*a*b* 3D image is then compressed into volumetric units; each representing the neighbourhood information of the surrounding 64 voxels for k = 4, 512 voxels for k = 8 and 4096 voxels for k = 16, respectively. The spatial distance of these voxels are then compared along the three major axes to generate the novel 3D saliency map of a 3D image, which unambiguously highlights the tumour region. The algorithm operates along the three major axes to maximise the computation efficiency while minimising loss of valuable 3D information. Thus the 3D multichannel MR image saliency detection algorithm is useful in generating a uniform and logistically correct 3D saliency map with pragmatic applicability in Computer Aided Detection (CADe). Assignment of uniform importance to all three axes proves to be an important factor in volumetric processing, which helps in noise reduction and reduces the possibility of compromising essential information. The effectiveness of the algorithm was evaluated over the BRATS MICCAI 2015 dataset having 274 glioma cases, consisting both of high grade and low grade GBM. The results were compared with that of the 2D saliency detection algorithm taken over the entire sequence of brain data. For all comparisons, the Area Under the receiver operator characteristic (ROC) Curve (AUC) has been found to be more than 0.99 ± 0.01 over various tumour types, structures and locations.


Recent advances in human norovirus research and implications for candidate vaccines.
Noroviruses are a leading cause of acute gastroenteritis worldwide. An estimated 21 million illnesses in the United States and upwards of 684 million illnesses worldwide are attributed to norovirus infection. There are no licensed vaccines to prevent norovirus, but several candidates are in development. We review recent advances in molecular epidemiology of noroviruses, immunology, and in-vitro cultivation of noroviruses using human intestinal enteroids. We also provide an update on the status of norovirus vaccine candidates. Molecular epidemiological studies confirm the tremendous genetic diversity of noroviruses, the continuous emergence of new recombinant strains, and the predominance of GII.4 viruses worldwide. Duration of immunity, extent of cross protection between different genotypes, and differences in strain distribution for young children compared with adults remain key knowledge gaps. Recent discoveries regarding which epitopes are targeted by neutralizing antibodies using the novel in vitro culture of human noroviruses in human intestinal enteroids are enhancing our understanding of mechanisms of protection and providing guidance for vaccine development. A future norovirus vaccine has the potential to substantially reduce the burden of illnesses due to this ubiquitous virus.


An anaerobic membrane bioreactor - membrane distillation hybrid system for energy recovery and water reuse: Removal performance of organic carbon, nutrients, and trace organic contaminants.
In this study, a direct contact membrane distillation (MD) unit was integrated with an anaerobic membrane bioreactor (AnMBR) to simultaneously recover energy and produce high quality water for reuse from wastewater. Results show that AnMBR could produce 0.3-0.5L/g CODadded biogas with a stable methane content of approximately 65%. By integrating MD with AnMBR, bulk organic matter and phosphate were almost completely removed. The removal of the 26 selected trace organic contaminants by AnMBR was compound specific, but the MD process could complement AnMBR removal, leading to an overall efficiency from 76% to complete removal by the integrated system. The results also show that, due to complete retention, organic matter (such as humic-like and protein-like substances) and inorganic salts accumulated in the MD feed solution and therefore resulted in significant fouling of the MD unit. As a result, the water flux of the MD process decreased continuously. Nevertheless, membrane pore wetting was not observed throughout the operation.


Expression of the O6-methylguanine-DNA methyltransferase gene MGMT in MER+ and MER- human tumor cells.
DNA probes prepared from human O6-methylguanine-DNA methyltransferase complementary DNA were hybridized to mRNA isolated from human liver and fifteen human tumor cell lines proficient (Mer+) or deficient (Mer-) in transferase activity. Liver and Mer+ cells contained levels of transferase-specific mRNA that correlated with their transferase activity levels, whereas Mer- cells contained undetectable amounts of transferase mRNA. The mRNA levels were not induced in human cells by treatments that induce other DNA damage-inducible genes. These results demonstrate that in human cells the transferase gene is constitutively expressed, that its expression is related to activity levels, and that in Mer- tumor cells the expression of the transferase gene is probably blocked at the level of mRNA production.


Cavitation clusters in lipid systems - Ring-up, bubble population, and bifurcated streamer lifetime.
The processing of oils is vital to their ultimate use within the food industry. Control over the physical properties of such materials could be achieved through the application of high-intensity ultrasound (HIU). However, the exact mechanism, centred upon acoustic cavitation, is currently unclear. To investigate the cavitation environment in oils further, the ring-up of a HIU source in an oil media is studied in the presence and absence of a pre-existing bubble population. High-speed imaging and acoustic measurements within the system is demonstrated to be extremely useful in characterising the dynamics present under non steady-state conditions. The behaviour of the clusters generated in the first 1000 ms under these conditions is shown to be significantly different depending on the bubble population. A bifurcated streamer (BiS), originating from a unique bi-cluster event, is only observable in the presence of a bubble population during the ring-up process to higher cluster orders. In addition, the lifetime of this BiS event is highly temperature dependent and is shown to be a good marker for the viscosity of the oil employed.


[High-frequency components of the electrical activity of the dog neocortex during formation of motor alimentary conditioned reflexes].
Power spectra of electrical activity of different dogs neocortical areas within a wide frequency band (1-100 Hz) were studied by correlation-spectral analysis during elaboration of motor (pressing the pedal) alimentary conditioned reflexes (CR) to acoustic stimuli. Considerable redistribution of autospectra power (ASP) within one of the five selected frequency ranges (from I to V, 20 Hz each) was observed. The frequencies of III-V ranges (41-100 Hz) were the most reactive; the degree of power increase after CR stabilization was determined by its initial level before CR elaboration which significantly differed in various animals. The weaker were presented in the EEG high frequencies before learning, the higher was the increase of their power in the process of elaboration of the given type of CR, and on the contrary, a definite level of "saturation" was preserved. Relatively low frequencies (below 20 Hz) were characterized after CR elaboration by lowering of the power. Deliberate lowering of the alimentary motivation led to a weakening of CR and power decrease (in comparison with stabilized CR) of all frequency components; however, its level remained higher, than before CR elaboration.


Effectiveness of twice daily azelastine nasal spray in patients with seasonal allergic rhinitis.
Azelastine nasal spray (Allergodil((R)), Lastin((R)), Afluon((R)); Meda AB, Stockholm, Sweden) is a fast-acting, efficacious and well-tolerated H1-receptor antagonist for the treatment of rhinitis. In addition it also has mast-cell stabilizing and anti-inflammatory properties, reducing the concentration of leukotrienes, kinins and platelet activating factor in vitro and in vivo, as well as inflammatory cell migration in rhinitis patients. Well-controlled studies in patients with seasonal allergic rhinitis (SAR), perennial rhinitis (PR) or vasomotor rhinitis (VMR) confirm that azelastine nasal spray has a rapid onset of action, and improves nasal symptoms associated with rhinitis such as nasal congestion and post-nasal drip. Azelastine nasal spray is effective at the lower dose of 1 spray as well at a dose of 2 sprays per nostril twice daily, but with an improved tolerability profile compared to the 2-spray per nostril twice daily regimen. Compared with intranasal corticosteroids, azelastine nasal spray has a faster onset of action and a better safety profile, showing at least comparable efficacy with fluticasone propionate (Flonase((R)); GSK, USA), and a superior efficacy to mometasone furoate (Nasonex((R)); Schering Plough, USA). In combination with fluticasone propionate, azelastine nasal spray exhibits greater efficacy than either agent used alone, and this combination may provide benefit for patients with difficult to treat seasonal allergic rhinitis. In addition, azelastine nasal spray can be used on an as-needed basis without compromising clinical efficacy. Compared with oral antihistamines, azelastine nasal spray also demonstrates superior efficacy and a more rapid onset of action, and is effective even in patients who did not respond to previous oral antihistamine therapy. Unlike most oral antihistamines, azelastine nasal spray is effective in alleviating nasal congestion, a particularly bothersome symptom for rhinitis sufferers. Azelastine nasal spray is well tolerated in both adults and children with allergic rhinitis. Bitter taste which seems to be associated with incorrect dosing technique is the most common side effect reported by patients, but this problem can be minimized by correct dosing technique.


Senktide, a selective neurokinin B-like agonist, elicits serotonin-mediated behaviour following intracisternal administration in the mouse.
Behavioural responses to tachykinins were observed following intracisternal administration in mice. The synthetic NK-3 agonists senktide and L-363,851 caused behaviour typically associated with serotonergic stimulation, including head twitches, reciprocal forepaw treading and hindlimb splaying. Neurokinin B produced some features of the serotonin (5-HT) syndrome, while substance P, neurokinin A and eledoisin failed to elicit any such behaviours. Senktide-induced head twitches were prevented by pretreatment with the 5-HT2 antagonists ketanserin and ritanserin, while forepaw treading was attenuated by the 5-HT1 antagonists (-)-pindolol and methysergide. These data suggest that NK-3 agonists interact with central 5-HT mechanisms.


Mousepox in inbred mice innately resistant or susceptible to lethal infection with ectromelia virus. II. Pathogenesis.
The pathogenesis of mousepox due to infection with ectromelia virus strain NIH-79 was characterized in genetically susceptible (BALB/cAnNCr) and genetically resistant (C57BL/6NCr) mice. BALB/c mice inoculated subcutaneous (s.c.) or intranasally (i.n.) had high mortality. Most mice died within 7 days from severe necrosis of the spleen and liver. Necrotic foci in livers of BALB/c mice that survived beyond 7 days often were accompanied by mononuclear cell infiltrates and by hyperplasia of lymphoid tissues. C57BL/6 mice inoculated by either route remained asymptomatic and necrotic lesions were mild or absent, whereas focal non-suppurative hepatitis and lymphoid hyperplasia were prominent. Infectious virus and viral antigen were distributed widely in tissues of BALB/c mice, but had limited distribution in C57BL/6 mice. Both mouse strains had infection of the respiratory tract, genital tract, oral tissues and bone marrow, and BALB/c mice also had infection of the intestines. Both strains also developed serum antibody to vaccinia virus antigen after infection. The results show that ectromelia virus occurs in tissues conducive to mouse to mouse transmission and that the severity and character of mousepox lesions correlate directly with resistance and susceptibility to infection. They also support the concept that cellular immunity contributes to survival from infection.


Cytokines in giant-cell arteritis.
Cytokines are small proteins that serve as chemical messengers between cells, regulating cell growth and differentiation, tissue repair and remodeling, and many aspects of the immune response. Cytokines are instrumental in determining the nature, magnitude, and duration of inflammatory reactions and, as such, represent ideal targets for interfering with pathogenic processes. In OCA and PMR, cytokines are encountered in two locations, the inflammatory infiltrates accumulating in the arterial wall and in the circulation. IL-6, a cytokine involved in stimulating acute-phase responses, is located upstream of many of the laboratory abnormalities considered helpful in diagnosing and managing GCA/PMR, including elevated ESR and CRP. IL-6 has the potential to be helpful in predicting disease severity and may allow for a tailoring of immunosuppressive therapy. There is evidence suggesting that IL-6 outperforms other chemical markers in detecting disease activity and could, therefore, have a role in monitoring treatment. Interesting pathogenic clues have been derived from studies of cytokines produced in the vascular lesions. IFN-gamma has emerged as a key regulator in determining the nature and direction of the inflammatory response. IFN-gamma appears to be critically involved in modulating the process of intimal hyperplasia, the most destructive consequence of vasculitis, and, as such, emerges as a prime target for novel therapeutic approaches.


Point mutations in Arabidopsis Cullin1 reveal its essential role in jasmonate response.
The SKP1-Cullin/Cdc53-F-box protein ubiquitin ligases (SCF) target many important regulatory proteins for degradation and play vital roles in diverse cellular processes. In Arabidopsis there are 11 Cullin members (AtCUL). AtCUL1 was demonstrated to assemble into SCF complexes containing COI1, an F-box protein required for response to jasmonates (JA) that regulate plant fertility and defense responses. It is not clear whether other Cullins also associate with COI1 to form SCF complexes, thus, it is unknown whether AtCUL1, or another Cullin that assembles into SCF(COI1) (even perhaps two or more functionally redundant Cullins), plays a major role in JA signaling. We present genetic and physiological data to directly demonstrate that AtCUL1 is necessary for normal JA responses. The homozygous AtCUL1 mutants axr6-1 and axr6-2, the heterozygous mutants axr6/AXR6, and transgenic plants expressing mutant AtCUL1 proteins containing a single amino acid substitution from phenylalanine-111 to valine, all exhibit reduced responses to JA. We also demonstrate that ax6 enhances the effect of coi1 on JA responses, implying a genetic interaction between COI1 and AtCUL1 in JA signaling. Furthermore, we show that the point mutations in AtCUL1 affect the assembly of COI1 into SCF, thus attenuating SCF(COI1) formation.


Effect of Facial Parameters in Primary Acquired Nasolacrimal Duct Obstruction.
In this study, the authors aimed to identify facial and nasal parameters, which may create an anatomic disposition toward obstruction in patients with primary acquired nasolacrimal duct obstruction. Forty-eight patients (14 males and 34 females) who presented to the ophthalmology outpatient clinic and were diagnosed with primary acquired nasolacrimal duct obstruction between January 2014 and January 2015 were included in the study. The control group comprised 59 patients (38 females and 21 males) without nasolacrimal duct obstruction. Measurements of nasal height, length, and depth, presence of a nasal hump, alar width and alar angle, distance between the maxillary bone nasal notches, and right and left distances between outer canthi and corners of the mouth were made using photographs of the patients. The presence of facial asymmetry was also assessed. Facial asymmetry (P = 0.014) and nasal hump (P = 0.048) were more common in the patient group. The patient group had smaller nasal radix depth (P < 0.001), nasal length (P = 0.001), and alar width (P < 0.001), larger distance between maxillary bone nasal notches (P < 0.001), and smaller alar angle (P < 0.001). In the current study, the authors found that primary acquired nasolacrimal duct obstruction occurred more frequently on the side of the face with shorter facial measurements. Smaller nasal radix depth, nasal length, and alar base width, presence of a nasal hump and longer distance between maxillary bone nasal notches may form an anatomic basis for nasolacrimal duct obstruction. Based on our results, the authors believe that primary acquired nasolacrimal duct obstruction is associated with facial structure.


Sympathoadrenergic regulation in elite fencers in training and competition.
In ten fencers at the top national level the adrenergic regulation was investigated by determining the free and sulfoconjugated catecholamines (CA) in a training fight and a competition for the national championship to evaluate the influence of emotional strain in this discipline. In the training fight which is physically more strenuous, norepinephrine (NE) was significantly higher (+27%) than in the championship contest after which the epinephrine (EPI) level was more increased (+76.5%). Accordingly, the systolic blood pressure (SBP) was higher during competition and correlated with EPI. The share of the sulfated CA in their total amount was reduced in both loads. Since energy production in fencing is predominantly alactacitic during maximal loads of short duration and aerobic during submaximal load intensities, the lactate level in the training fight was below the anaerobic/aerobic threshold. The significantly higher lactate, glucose, and alanine levels during the fight for the national championship, presumably induced by the additional stimulation of the anaerobic muscular and hepatic glycogenolysis as well as muscular glycolysis, may be accounted to the fortified EPI secretion caused by emotional strain. The higher cortisol and renin levels may be explained by the strong central stimulation and the direct peripheral effect of EPI respectively.


Association of chronic infection of Chlamydia pneumoniae and coronary heart disease in the Japanese.
The association of Chlamydia pneumoniae with atherosclerosis of coronary and carotid arteries and the aorta has been demonstrated by seroepidemiology and by detection of the organism in atheromata. We investigated the frequency of C. pneumoniae seropositivity in patients with acute myocardial infarction (AMI). C. pneumoniae-specific antibodies were measured by the microimmunofluorescence test in 160 AMI patients and 160 control subjects matched for age and gender. The odds ratios (ORs) were 2.2 (95% confidence interval (CI), 1.2 to 3.9) for immunoglobulin (Ig)G and 2.7 (95% CI, 1.7 to 4.3) for IgA. After adjustment for other cardiovascular risk factors of age, gender, hypertension, diabetes, cigarette smoking and serum cholesterol, the ORs were essentially unchanged. This study confirmed that the observations of an association between antibody against C. pneumoniae and coronary heart disease in Western nations is also present in Japan. Our results are comparable to the previous seroepidemiological studies reporting ORs of 2.0 or greater.


The effects of growth hormone, prolactin, corticotropin, and thyrotropin on the production and secretion of somatostatin by hypothalamic cells in vitro.
The influence of GH and several other pituitary hormones on the secretion and intracellular content of immunoreactive somatostatin (IRS) in cultured hypothalamic cells was examined. Hypothalamic cells prepared from 17-day-old rat embryos and maintained as reaggregate monolayers for 12 days in vitro were used. Short term release of IRS from these cultures was found to be stable and relatively constant. IRS release was enhanced by 60 mM K+ in a calcium-dependent fashion and by dopamine at concentrations as low as 1 nM. GH (1 microM) increased medium IRS content above baseline 12, 24, and 48 h after the incubation was begun, but had no effect after only 4 h. Hypothalamic cell content of IRS was increased by a 24-h incubation in 0.3 and 1.0 microM GH, but not by 0.1 microM GH. TSH (1 microM) induced an increase in IRS release comparable to 1 microM GH. However, intracellular IRS content was decreased after exposure to TSH. Cosyntropin, an ACTH analog, inhibited both IRS release and cell content, whereas PRL had no effect on either medium or cellular IRS content. Our results demonstrate that developing somatostatinergic neurons in the hypothalamus have the capacity to respond to pituitary hormones, indicating that short-loop feedback pathways may exist in perinatal hypothalamic cells.


Meloxicam exerts neuroprotection on spinal cord trauma in rats.
Traumatic injury to the central nervous system results in the delayed dysfunction and neuronal death. Impaired mitochondrial function, generation of reactive oxygen species (ROS), and lipid peroxidation occur soon after traumatic spinal cord injury (SCI), while the activation of compensatory molecules that neutralize ROS occurs at later time points. The aim of the current study was to investigate the putative neuroprotective effect of the COX2 inhibitor meloxicam in a rat model of SCI. In order to induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10, was used. Injured animals were given either 2 mg/kg meloxicam or saline 30 min postinjury by intraperitoneal injection. At seven days postinjury, neurological examination was performed and rats were decapitated. Spinal cord samples were taken for histological examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and DNA fragmentation. Formation of ROS in spinal cord tissue samples was monitored by using a chemiluminescence (CL) technique. SCI caused a significant decrease in spinal cord GSH content, which was accompanied with significant increases in CL, MDA levels, MPO activity, and DNA damage. On the other hand, meloxicam treatment reversed all these biochemical parameters as well as SCI-induced histopathological alterations. Furthermore, impairment of the neurological functions due to SCI was improved by meloxicam treatment. The present study suggests that meloxicam, reduces SCI-induced oxidative stress and exerts neuroprotection by inhibiting lipid peroxidation, GSH depletion, and DNA fragmentation.


Laser interstitial thermal therapy for the treatment of epilepsy: evidence to date.
Medically intractable epilepsy is associated with increased morbidity and mortality. For those with focal epilepsy and correlated electrophysiological or radiographic features, open surgical resection can achieve high rates of seizure control, but can be associated with neurologic deficits and cognitive effects. Recent innovations have allowed for more minimally invasive methods of surgical seizure control such as magnetic resonance-guided laser interstitial therapy (MRgLITT). MRgLITT achieves the goal of ablating seizure foci while preserving neuropsycho-logical function and offering real-time feedback and monitoring of tissue ablation. This review summarizes the utilization of MRgLITT for mesial temporal lobe epilepsy and other seizure disorders. Overall, the efficacy of MRgLITT is comparable to that of open surgery and offers a less invasive approach in patients with significantly less morbidity.


Expression of genes involved in lipid metabolism in men with impaired glucose tolerance: impact of insulin stimulation and weight loss.
The impaired glucose tolerance (IGT) state is characterized by insulin resistance. Disturbances in fatty acid (FA) metabolism may underlie this reduced insulin sensitivity. The aim of this study was to investigate whether the prediabetic state is accompanied by changes in the expression of genes involved in FA handling during fasting and in insulin-mediated conditions and to study the impact of weight loss. Seven IGT men and 5 men with normal glucose tolerance (NGT), comparable in terms of age and BMI, participated in the study. The 5 IGT men followed a 12-week weight loss program. Muscle biopsies were taken and the expression of 6 genes was investigated. Subjects had a reduction of 15.5 ± 4.3 kg in body weight. Baseline gene expression was not different between NGT and IGT men. After a hyperinsulinemic clamp, there was an overall upregulation of PGC1α, SREBP-1c, SREBP-2, and ACC-2. The upregulation of SREBP-2 was more pronounced in IGT men (p = 0.049). Weight loss significantly increased insulin sensitivity by 71%, which was not reflected in altered gene expression profiles. SREBP-2 shows altered insulin responsiveness in IGT men compared with NGT men, while there were no differences in basal gene expression.


A feedback loop comprising PRMT7 and miR-24-2 interplays with Oct4, Nanog, Klf4 and c-Myc to regulate stemness.
Self-renewal and pluripotency are two fundamental characteristics of embryonic stem cells (ESCs) and are controlled by diverse regulatory factors, including pluripotent factors, epigenetic regulators and microRNAs (miRNAs). Although histone methyltransferases are key epigenetic regulators, whether and how a histone methyltransferase forms a network with miRNAs and the core pluripotent factor system to regulate ESC stemness is little known. Here, we show that the protein arginine methyltransferase 7 (PRMT7) is a pluripotent factor essential for the stemness of mouse ESCs. PRMT7 repressed the miR-24-2 gene encoding miR-24-3p and miR-24-2-5p by upregulating the levels of symmetrically dimethylated H4R3. Notably, miR-24-3p targeted the 3' untranslated regions (UTRs) of the major pluripotent factors Oct4, Nanog, Klf4 and c-Myc, whereas miR-24-2-5p silenced Klf4 and c-Myc expression. miR-24-3p and miR-24-2-5p also targeted the 3'UTR of their repressor gene Prmt7 miR-24-3p and miR-24-2-5p induced mouse ESC differentiation, and their anti-sense inhibitors substantially reversed spontaneous differentiation of PRMT7-depleted mouse ESCs. Oct4, Nanog, Klf4 and c-Myc positively regulated Prmt7 expression. These findings define miR-24-3p and miR-24-2-5p as new anti-pluripotent miRNAs and also reveal a novel epigenetic stemness-regulatory mechanism in which a double-negative feedback loop consisting of PRMT7 and miR-24-3p/miR24-2-5p interplays with Oct4, Nanog, Klf4 and c-Myc to control ESC stemness.


Improving the Prescription Process Information Support with Structured Medical Prospectuses Using Neural Networks.
To provide the best treatment, a physician needs information about both the patient and the medicines matching the patient status and improving it. In this article, we present three methods for structuring the sections of medical prospectuses using neural networks. To structure the information from a medical prospectus we use 3 web sources with structured data from sections (with names sections from prospectuses and with uniformized names of sections) to train as input for neural networks. The tests were conducted on Romanian prospectuses. After running the three algorithms, the prospectuses were compared in terms of accuracy and execution time for each source. It was concluded that the accuracy is higher in convolutional networks and in the case of uniform name sections. The output data is used in applications with decision support for the treatment, matching best treatment with the patient's status.


Radiological and Thermal Dose Correlations in Pallidothalamic Tractotomy With MRgFUS.
Background: MR-guided focused ultrasound (MRgFUS) offers the possibility of safe and accurate lesioning inside the brain. Until now, most MRgFUS thermal applications have been based on temperature or energy protocols. Experimental studies support however an approach centered on thermal dose control. Objective: To show the technical feasibility and lesion size predictability of a thermal dose approach during MRgFUS pallidothalamic tractotomy (PTT) against chronic therapy-resistant Parkinson's disease (PD). Methods: MR and thermal dose data were analyzed in 31 MRgFUS interventions between January and December 2017 in patients suffering from chronic therapy-resistant Parkinson's disease (PD) using a standardized PTT target covered by 5 to 7 target lesion sub-units. Results: Good correlations were found between (1) the mean axial T2 lesion diameter intraoperatively and the mean 240 cumulative equivalent min at 43°C (240 CEM) thermal dose diameter (r = 0.52), (2) the mean axial T2 diameter 48 h post-treatment and the mean 18 CEM thermal dose diameter (r = 0.62), and (3) the mean axial T2 diameter intraoperatively and 48 h post-treatment (r = 0.62). Conclusion: Our current approach using a thermal dose steering for multiple target lesion sub-units could be reproduced in 31 interventions with a good lesion size predictability.


Nevirapine for the prevention of mother-to-child transmission of HIV: a nation-wide coverage survey in Côte d'Ivoire.
Single-dose nevirapine (NVP) is the simplest antiretroviral regimen for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. We evaluated NVP coverage among HIV-infected delivering women in Côte d'Ivoire. A cross-sectional survey of mother-infant pairs was conducted between November 2007 and September 2008 in 10 randomly selected facilities providing delivery services in the country. All sites used at least NVP for PMTCT. Anonymous HIV test and blood collection for NVP concentration measurement were performed in labor wards. NVP coverage was defined as the proportion of maternal and infant NVP intake confirmed by cord blood chromatography and direct observation. A total of 9953 deliveries were enrolled. Median maternal age was 25 years, and the median number of antenatal care (ANC) visits was 3. Of the 9747 women (97.9%) who made at least 1 ANC visit, 5880 (60.3%) received an HIV test proposal, 5135 (87.3%) accepted it, and 251 (4.9%) were diagnosed HIV infected; 176 of them (70.1%) received antiretroviral prophylaxis according to the medical record. Using anonymous cord blood surveillance, HIV prevalence was 5.9% (570 of 9646), maternal NVP coverage was 24.3% (138 of 570), and maternal and infant NVP coverage was 17.9% (102 of 570). In multivariate analysis, maternal NVP coverage was associated with 2-3 ANC visits [adjusted odds ratio (aOR): 2.61; 95% confidence interval (CI): 1.27 to 5.39] or ≥ 4 ANC visits (aOR: 3.84; 95% CI: 1.86 to 7.90) (ref. ≤ 1), and giving birth in clinic of first ANC visit (aOR: 2.21; 95% CI: 1.43 to 3.40). Maternal and infant NVP coverage was low irrespective of the method. Anonymous cord blood surveillance is more reliable for documenting PMTCT coverage.


Gender and arch effects on the use of non-opioid analgesics for post endodontic pain reduction.
This study aimed to evaluate the secondary outcomes of gender and arch and their impact on pain reduction following initial endodontic therapy. 185 medications, including placebo were prepared, and 170 participants completed the trial. Group 1, received a single dose of Paracetamol alone (G-1), Group 2 received combined Ibuprofen/Paracetamol (G-2). Group 3 received combined Mefenamic acid/Paracetamol (G-3), group 4 received combined Diclofenac K/Paracetamol (G-4) and Group 5 received a placebo (G-5). There were no statistically significant differences in pain reduction between males and females whilst there were statistically significant differences between them and the placebo group. All combinations of Paracetamol performed better in pain reduction than the placebo among females, while there were no statistically significant differences among males. In conclusion, there were no differences in pain reduction between males and females, and arch for the tested analgesics taken immediately following initial endodontic therapy in teeth with irreversible pulpitis.


A reactive oxygen species-generating, cancer stem cell-potent manganese(ii) complex and its encapsulation into polymeric nanoparticles.
Intracellular redox modulation offers a viable approach to effectively remove cancer stem cells (CSCs), a subpopulation of tumour cells thought to be responsible for cancer recurrence and metastasis. Here we report the breast CSC potency of reactive oxygen species (ROS)-generating manganese(ii)- and copper(ii)-4,7-diphenyl-1,10-phenanthroline complexes bearing diclofenac, a nonsteriodial anti-inflammatory drug (NSAID), 1 and 3. Notably, the manganese(ii) complex, 1, exhibits 9-fold, 31-fold, and 40-fold greater potency towards breast CSCs than 3, salinomycin (an established breast CSC-potent agent), and cisplatin (a clinically approved anticancer drug) respectively. Encouragingly, 1 displays 61-fold higher potency toward breast CSCs than normal skin fibroblast cells. Clinically relevant epithelial spheroid studies show that 1 is able to selectively inhibit breast CSC-enriched HMLER-shEcad mammosphere formation and viability (one order of magnitude) over non-tumorigenic breast MCF10A spheroids. Mechanistic studies show that 1 prompts breast CSC death by generating intracellular ROS and inhibiting cyclooxygenase-2 (COX-2) activity. The manganese(ii) complex, 1, induces a greater degree of intracellular ROS in CSCs than the corresponding copper(ii) complex, 3, highlighting the ROS-generating superiority of manganese(ii)- over copper(ii)-phenanthroline complexes. Encapsulation of 1 by biodegradable methoxy poly(ethylene glycol)-b-poly(d,l-lactic-co-glycolic) acid (PEG-PLGA) copolymers at the appropriate feed (5%, 1 NP5 ) enhances breast CSC uptake and greatly reduces overall toxicity. The nanoparticle formulation 1 NP5 indiscriminately kills breast CSCs and bulk breast cancer cells, and evokes a similar cellular response to the payload, 1. To the best of our knowledge, this is the first study to investigate the anti-CSC properties of managense complexes and to demonstrate that polymeric nanoparticles can be used to effectively deliver managense complexes into CSCs.


Oxidation of lipids. 7. Oxidation of phosphatidylcholines in homogeneous solution and in water dispersion.
The rates and products of the oxidations of phosphatidylcholines (PCs) in organic homogeneous solutions and as multilamellar liposomes in an aqueous dispersion were studied at 50 degrees C initiated by oil-soluble and water-soluble azo compounds and with the aim primarily of elucidating the effect of substrate and the reaction medium. Polyunsaturated fatty acids were oxidized exclusively among the fatty acids in PC. The product distribution was determined by the number of double bonds: in the oxidation of methyl linoleate and dilinoleoyl PC, the conjugated diene hydroperoxides were formed almost quantitatively, whereas in the oxidation of PC and polyunsaturated fatty acids having three or more double-bonds, cyclic peroxides were also formed. The oxidizability of PC was dependent on the content of doubly allylic hydrogens and their reactivities were suggested to be similar, independent of parent substrate and reaction medium, although the oxidizability of PC in nonpolar organic solvents is markedly enhanced by the formation of reverse-phase micelles.


[Identification of adenovirus associated with conjunctivitis by molecular methodology].
To identify adenovirus in patients with conjunctivitis by molecular methods such as the Polymerase Chain Reaction (PCR) and DNA sequencing. Samples of scrapings from the inferior fornix of 51 patients (39 diagnosed with Follicular Conjunctivitis and 12 diagnosed with Vernal Conjunctivitis) were processed by generic PCR to identify adenovirus. All the samples that were PCR positive were cultured on VERO cells for virus isolation, with this being demonstrated by immunofluorescence. For the identification of the isolated serotype, the multiplex PCR was utilized and DNA automated sequencing was employed to identify the genetic variants. Twenty-eight of the individuals diagnosed with Follicular Conjunctivitis and six of those diagnosed with Vernal Conjunctivitis, had positive results to adenovirus (67%). The cultures in VERO cells allowed the isolation of eight samples. Only three of the isolated viruses (one Ad1 and two Ad2) were identified by the multiplex PCR used to identify the subgenus C adenovirus. An Ad1 genetic variant was identified by automated sequencing while the Ad2 serotypes were identical to the ones reported by Genbank. The Polymerase Chain Reaction and DNA sequencing are useful tools to identify and characterize microorganisms responsible for diseases such as conjunctivitis caused by adenoviruses.


A nonradiographic system for assessing pressure for the Codman-Hakim Programmable Valve.
The Codman-Hakim Programmable Valve is widely used in shunting hydrocephalus and other conditions. To establish an accurate valve verification system for the Codman-Hakim programmable valve that does not require radiographic exposure. Prospective clinical trial tested a new valve verification system at 9 research sites. The Valve Programming and Verification System allowed us to establish the valve setting in 62% of subjects with a programmable valve. The Valve Programming and Verification System avoids radiation exposure, is cost-effective, and time efficient for the patient and provider. In approximately one third of subjects, those in whom "adjustment complete" is not achieved, cranial radiographs are still needed.


Pi sigma* excited states in molecular photochemistry.
The last few years have seen a surge in interest (both theoretical and experimental) in the photochemistry of heteroaromatic molecules (e.g. azoles, phenols), which has served to highlight the importance of dissociative excited states formed by electron promotion to sigma* molecular orbitals. Such excited states--which, for brevity, are termed pi sigma* states in this Perspective article--may be populated by direct photo-excitation (though the transition cross-sections are intrinsically small), or indirectly, by non-adiabatic coupling from an optically 'bright' excited state (e.g. an excited state resulting from pi* <--pi excitation). The analogous pi sigma* excited states in prototypical hydride molecules like H(2)O and NH(3) have long been recognised. They have served as test-beds for developing concepts like Rydbergisation, conical intersections (CIs) between potential energy surfaces, and for investigating the ways in which non-adiabatic couplings at such CIs influence the eventual photofragmentation dynamics. This Perspective article seeks to highlight the continuity of behaviour revealed by the earlier small molecule studies and by the more recent studies of heteroaromatic systems, and to illustrate the photochemical importance of pi sigma* excited states in many broad families of molecules. Furthermore, the dynamical influence of such excited states is not restricted to closed shell species; the Article concludes with a brief consideration of the consequences of populating sigma* orbitals in free radical species, in molecular cations, and in dissociative electron attachment processes.


Hippocampal slices in experimental and human epilepsy.
Many models of epileptiform activity have been developed using in vitro slices, particularly the in vitro hippocampal slice preparation. Using this preparation, investigators have elucidated some of the intrinsic neuronal and synaptic properties that appear to be involved in the generation of burst activity and hyperexcitability typical of epileptic brain. A variety of potassium and calcium conductances, in dendritic as well as somatic membrane, have been found in hippocampal neurons that produce burst discharges; appropriate channel blockers can modulate the firing patterns of these neurons. Receptor antagonists, particularly those which interact with the gamma-aminobutyric acid (GABA) receptor-chloride channel complex, have also been found to be very effective in producing epileptiform activity in the reduced central nervous system (CNS) slice preparation. In most acutely produced epileptogenic slice tissues, it appears that blockade of inhibition, intrinsic mechanisms of excitability, and recurrent excitatory synaptic connections interact to synchronize the cell population. Slice preparations of brain tissue taken from epileptic foci induced in chronic animals have been studied. The kainic acid model, kindling model, and other chronic models of epileptiform activity (alumina gel, freeze lesions) have been studied in vitro; results of these studies suggest that in these tissues there is an alteration in PSP efficacy. Seizure sensitivity in immature CNS tissue may also be produced, in part, by a late development of inhibitory postsynaptic potentials (IPSPs). Studies of cortical slices taken from human epileptic brain during surgery for intractable seizures have begun to reveal some interesting clues about cellular mechanisms underlying discharge in abnormal tissue. Spontaneous, rhythmic post-synaptic potential (PSP) activity has been recorded particularly in slices taken from mesial temporal lobe structures involved in epileptic foci. It is still unclear, however, whether such activity is a reflection of epileptogenicity of this tissue, or is rather characteristic of even normal tissue from mesial temporal cortex. We have learned much about the cellular and synaptic properties of CNS neurons using the in vitro slice preparation and have developed a variety of animal preparations in which we can model epileptiform activity. However, it is still unclear if any of these preparations accurately model human epileptiform abnormalities. A major challenge for modern epilepsy research is to build a bridge between experimental animal models of epilepsy and the epilepsies that occur in the clinical human population.


Response of the mechanical and chiral character of ethane to ultra-fast laser pulses.
A pair of simulated left and right circularly polarized ultra-fast laser pulses of duration 20 femtoseconds that induce a mixture of excited states are applied to ethane. The response of the electron dynamics is investigated within the next generation quantum theory of atoms in molecules (NG-QTAIM) using third-generation eigenvector-trajectories which are introduced in this work. This enables an analysis of the mechanical and chiral properties of the electron dynamics of ethane without needing to subject the C-C bond to external torsions as was the case for second-generation eigenvector-trajectories. The mechanical properties, in particular, the bond-flexing and bond-torsion were found to increase depending on the plane of the applied laser pulses. The bond-flexing and bond-torsion, depending on the plane of polarization, increases or decreases after the laser pulses are switched off. This is explainable in terms of directionally-dependent effects of the long-lasting superpositions of excited states. The chiral properties correspond to the ethane molecule being classified as formally achiral consistent with previous NG-QTAIM investigations. Future planned investigations using ultra-fast circularly polarized lasers are briefly discussed.


Test of catechol, tannic acid, Bidens pilosa, croton oil, and phorbol for cocarcinogenesis of esophageal tumors induced in rats by methyl-n-amylnitrosamine.
Catechol (CAS: 120-80-9), given in drinking water to rats, was the most effective of 5 phenols in enhancing [3H]thymidine incorporation [( 3H]dThd-l) into esophageal DNA. To test for esophageal cocarcinogenesis, groups of 30 male MRC-Wistar rats received 3 weekly ip injections of 25 mg methyl-n-amylnitrosamine [(MNAN) CAS: 13256-07-0]/kg. From the time of the first MNAN injection, each group also received catechol, tannic acid (CAS: 1401-55-4), dried leaves of Bidens pilosa L., or croton oil (CAS: 8001-28-3) (respectively, 2, 10, 50, and 2 g/kg semipurified diet), or were given 20 ip injections of 6 mg phorbol (CAS: 17673-25-5)/rat. The rats were killed after 20-45, 46-52, or 53-72 weeks (subgroups A, B, and C). In the group given MNAN alone, most esophageal papillomas developed during the first 45 weeks. Both catechol and B. pilosa significantly increased the esophageal papilloma multiplicity (No. of papillomas/rat) induced by MNAN, with a maximum tumor yield of 2.2 times that in the corresponding subgroup treated with MNAN alone. Papilloma multiplicity increased from subgroup A to subgroup C in the MNAN plus B. pilosa group but not in the MNAN plus catechol group. No tumors were induced by the test cocarcinogens given without MNAN. We concluded that a) an increased esophageal [3H]dThd-I indicates potential cocarcinogenicity and b) catechol and B. pilosa were weak esophageal cocarcinogens. These results support the view that catechol in cigarette smoke and B. pilosa as eaten in South Africa contribute to the etiology of human esophageal cancer.


The establishment of evidence-based practice competencies for practicing registered nurses and advanced practice nurses in real-world clinical settings: proficiencies to improve healthcare quality, reliability, patient outcomes, and costs.
Although it is widely known that evidence-based practice (EBP) improves healthcare quality, reliability, and patient outcomes as well as reduces variations in care and costs, it is still not the standard of care delivered by practicing clinicians across the globe. Adoption of specific EBP competencies for nurses and advanced practice nurses (APNs) who practice in real-world healthcare settings can assist institutions in achieving high-value, low-cost evidence-based health care. The aim of this study was to develop a set of clear EBP competencies for both practicing registered nurses and APNs in clinical settings that can be used by healthcare institutions in their quest to achieve high performing systems that consistently implement and sustain EBP. Seven national EBP leaders developed an initial set of competencies for practicing registered nurses and APNs through a consensus building process. Next, a Delphi survey was conducted with 80 EBP mentors across the United States to determine consensus and clarity around the competencies. Two rounds of the Delphi survey resulted in total consensus by the EBP mentors, resulting in a final set of 13 competencies for practicing registered nurses and 11 additional competencies for APNs. Incorporation of these competencies into healthcare system expectations, orientations, job descriptions, performance appraisals, and clinical ladder promotion processes could drive higher quality, reliability, and consistency of healthcare as well as reduce costs. Research is now needed to develop valid and reliable tools for assessing these competencies as well as linking them to clinician and patient outcomes.


The association of infant feeding with parent-reported infections and hospitalisations in the West Australian Aboriginal Child Health Survey.
To examine infant feeding associations with parent-reported infections and hospitalisations in Western Australian Aboriginal infants and children. Families in Western Australia with children under 18 years of Aboriginal or Torres Strait Islander descent were included. A stratified multi-stage sample using an area-based sampling frame was compiled. Survey weights produced unbiased estimates for the population of families with Aboriginal children. Data were collected on demographic variables, maternal and infant characteristics and parent-reported recurring chest, ear and gastrointestinal infections. The data were linked to the Hospital Morbidity System to identify hospitalisations for infections for the same children. Twenty-seven per cent of Aboriginal children were breastfed for less than three months. Parent-reported recurring chest, ear and gastrointestinal infections were reported in 47% of the 0-3 age group. Hospitalisations due to upper respiratory and gastrointestinal infections were most common in the older children, but wheezing lower respiratory infections were most common in younger children. Breastfeeding for less than three months and birth weight less than 2,500 g were risk factors for parent-reported chest infections and hospitalisations for upper and wheezing lower respiratory infections (p<0.05). Rates of parent-reported chest infections and hospitalisations due to these infections continue to be high in Aboriginal infants and children. Because breastfeeding for less than three months and low birth weight are risk factors for these infections, interventions to reduce the prevalence of low birth weight and to increase breastfeeding rates should be primary health goals in Aboriginal communities for the benefits of Aboriginal infants and children.


Vitamin D: 3-deoxy-lalpha-hydroxyvitamin D3, biologically active analog of lalpha-dihydroxyvitamin D3.
The ability of chemically synthesized 3-deoxy-lalpha-hydroxyvitamin D3, an analog of the biologically active form of vitamin D3, (lalpha,25-dihydroxyvitamin D3), to stimulate intestinal calcium transport was assessed. The 3-deoxy analog acted significantly more rapidly than vitamin D3 and only slightly slower than lalpha,25-dihydroxyvitamin D3. Comparison of the dose-response curves of these three vitamin D derivatives emphasizes the importance of the 3beta-hydroxyl group to biological activity.


Historical Perspectives and Advances in Mesenchymal Stem Cell Research for the Treatment of Liver Diseases.
Liver transplantation is the only effective therapy for patients with decompensated cirrhosis and fulminant liver failure. However, due to a shortage of donor livers and complications associated with immune suppression, there is an urgent need for new therapeutic strategies for patients with end-stage liver diseases. Given their unique function in self-renewal and differentiation potential, stem cells might be used to regenerate damaged liver tissue. Recent studies have shown that stem cell-based therapies can improve liver function in a mouse model of hepatic failure. Moreover, acellular liver scaffolds seeded with hepatocytes produced functional bioengineered livers for organ transplantation in preclinical studies. The therapeutic potential of stem cells or their differentiated progenies will depend on their capacity to differentiate into mature and functional cell types after transplantation. It will also be important to devise methods to overcome their genomic instability, immune reactivity, and tumorigenic potential. We review directions and advances in the use of mesenchymal stem cells and their derived hepatocytes for liver regeneration. We also discuss the potential applications of hepatocytes derived from human pluripotent stem cells and challenges to using these cells in treating end-stage liver disease.


Nickel-based electrochemical sensor with a wide detection range for measuring hydroxyl ions and pH sensing.
The importance of hydroxyl ions concentration measurement in solution necessitates the development of suitable and simple sensing methods for online detection. To address this need, an electrochemical sensor was developed using nickel as the working electrode that enabled specificity towards hydroxyl ions and their successfully quantification. The electrochemical reaction between nickel and hydroxyl ions in solution generates a current which is proportional to the concentration of hydroxyl ions and consequently is also correlated to the pH of the solution. Cyclic voltammetry and chronoamperometry techniques were used to prepare and activate the nickel electrode for detection. The analysis of chronoamperometric experiments in different solutions exhibited three calibration curves between the current and hydroxyl ion concentrations for three regions in the range of 0.3 µM to 4.8 M with a short response time of 14 s. Up to now, no other hydroxyl ion sensor has been reported that can reach this detection limit. This sensor also holds promise to work perfectly in highly alkaline environments where only costly commercial electrodes are available to quantify pH. The results show three linear calibration curves between the current and pH of the solution over the pH range of 7.4 to 14.6. In addition to the wide detection range, the sensor exhibits a relative standard deviation percentage lower than 7% over 9 months of experiments, confirming repeatability of measurements and stability of the electrode. The potential of the proposed method to measure pH in real applications was demonstrated by testing the sensor in solutions containing urea, nitrates, phosphates, and sulfates.


The effect of transcutaneous electric nerve stimulation on chronic postoperative pain and long-term quality of life.
This study aims to investigate the effects of transcutaneous electrical nerve stimulation on early-stage postoperative pain and long-term quality of life in patients undergoing thoracotomy. Between January 2019 and September 2019, a total of 100 patients (76 males, 24 females; mean age: 57.9±11.9 years; range, 51 to 79 years) who underwent thoracotomy due to benign or malignant lesions were included. The patients were divided into two groups: 50 patients who received transcutaneous electrical nerve stimulation (Group 1) and a control group of 50 patients who did not receive transcutaneous electrical nerve stimulation (Group 2). The Short Form-36 life quality scale was used to evaluate patients' quality of life at one month before and after surgery. The mean length of hospital stay was 4.9±3.1 days in Group 1 and 6.2±4.6 days in Group 2 (p=0.008). There were no statistically significant differences in early-stage postoperative pain scores between the groups (p>0.05). Compared to Group 2, Group 1 had significantly lower pain scores and higher life quality scores pre- and postoperatively (p<0.05). Transcutaneous electrical nerve stimulation is an effective method to manage chronic pain in the postoperative period. On the other hand, it does not effectively reduce early-stage postoperative pain or affect complication rates. The prevention of chronic postoperative pain by transcutaneous electrical nerve stimulation improves long-term quality of life of patients.


Health care transformation and the case for a community-wide health information management environment.
The transformation of the health care delivery system in local, metropolitan, and regional markets is progressing rapidly. This transformation is fueled by competition, the shift of financial risk to the provider continuum, employer demands for cost containment, and the breadth and depth of state and federal government reform initiatives. However, information systems do not yet exist to support these transformations. We propose establishing a new community-level information management environment and new measures of health care system performance.


Aboriginal trephination: case from southern New England?
The skull of a young adult male Amerind from a grave at a coastal site in southern Connecticut bears a largely cicatrized elliptical anomaly near bregma. Some evidence suggests deliberate antemortem trephination of the scraping type. The specimen is of interest since perhaps fewer than twenty human skulls have been advanced as putative cases of trephining by North American aborigines.


The potential of PSMA-targeted alpha therapy in the management of prostate cancer.
Alpha emitters present several advantages for cancer therapy. The radiopharmaceutical 223Ra-dichloride has been recently introduced for the targeted alpha therapy (TAT) of metastastic castration-resistant prostate cancer (mCRPC). However, since 223Ra-dichloride targets only skeletal lesions, its use in clinical practice is recommended only in subjects without visceral metastases. To overcome this, several efforts have been made to develop radiopharmaceuticals suitable for TAT and specifically directed toward the biomarker prostate specific membrane antigen (PSMA), overexpressed by both skeletal and visceral metastases from mCRPC. The radiobiological principles concerning TAT applications are covered, with particular emphasis on its pros and cons, especially in comparison with beta-emitter radionuclide therapy. Furthermore, the role of PSMA as a theranostic target for imaging and therapy is reviewed. Lastly, the pre-clinical and clinical applications of TAT through 225Actinium (225AC) and 213Bismuth (213Bi) are discussed. PSMA-based TAT holds the promise of becoming a powerful tool for the management of mCRPC. Nevertheless, several issues have still to be addressed, especially concerning TAT toxicity. Furthermore, several efforts have to be made for identifying the more adequate alpha-emitter (225Ac vs 213Bi) with a view to the patient's tailored therapeutic approach.


Chronic pain after caesarean delivery: an Australian cohort.
We investigated the incidence of and risk factors for persistent pain after caesarean delivery. Over a 12-month period, women having caesarean delivery were recruited prospectively at an Australian tertiary referral centre. Demographic, anaesthetic and surgical data were collected and at 24 hour follow-up, women were assessed for immediate postoperative pain and preoperative expectations of pain. Long-term telephone follow-up was conducted at two and 12 months postoperatively. Complete data were obtained from 426 of 469 women initially recruited (90.6%). The incidence of persistent pain at the abdominal wound at two months was 14.6% (n=62) but subsequently reduced to 4.2% (n=18) at 12 months. At two months, 33 patients (7.8%) experienced constant or daily pain. At 12 months, five patients (1.1%) continued to have constant or daily pain which was mild. There was no apparent increase in incidence of persistent pain associated with general versus regional anaesthesia (relative risk [RR] 0.89, 95% confidence interval [CI] 0.49 to 1.6); emergency vs elective procedure (RR 0.65, 95% CI 0.39 to 1.07); higher acute pain scores (RR 1.1, 95% CI 0.69 to 1.75); or history of previous caesarean delivery (RR 0.81, 95% CI 0.50 to 1.33). Persistent pain, usually of a mild nature, is reported by some women two months after their caesarean delivery, but by 12 months less than 1% of women had pain requiring analgesia or affecting mood or sleep. All declined a pain clinic review. Clinicians and patients can be reassured that caesarean delivery is unlikely to lead to severe persistent pain in the long-term.


Role of the co-stimulatory molecule inducible T-cell co-stimulator ligand (ICOSL) in the progression of experimental metabolic dysfunction-associated steatohepatitis.
Inducible T-cell Co-Stimulator (ICOS) present on T-lymphocytes and its ligand ICOSL expressed by myeloid cells play multiple roles in regulating T-cell functions. However, recent evidence indicates that reverse signalling involving ICOSL is also important in directing the differentiation of monocyte-derived cells. In this study, we investigated the involvement of ICOS/ICOSL dyad in modulating macrophage functions during the evolution of metabolic dysfunction-associated steatohepatitis (MASH). In animal models of MASH, ICOS was selectively up-regulated on CD8+ T-cells in parallel with an expansion of ICOSL-expressing macrophages. An increase in circulating soluble ICOSL was also evident in patients with MASH as compared to healthy individuals. ICOSL knockout (ICOSL-/-) mice receiving choline/methionine deficient (MCD) diet for 6 weeks had milder steatohepatitis than wild type mice. MASH improvement was confirmed in mice fed with cholesterol-enriched Western diet for 24 weeks in which ICOSL deficiency greatly reduced liver fibrosis along with the formation of crown-like macrophage aggregates producing the pro-fibrogenic mediators osteopontin (OPN) and galectin-3 (Gal-3). These effects associated with a selective shewing of F4-80+/CD11bhigh monocyte-derived macrophages (MoMFs) expressing the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) to CD11blow/F4-80+ cells positive for the Kupffer cell marker C-type lectin-like type 2 receptor (CLEC-2), thus indicating an increased MoMF maturation toward monocyte-derived Kupffer cells. These results suggest that CD8+ T-cells interaction with monocyte-derived macrophages through ICOS/ICOSL critically supports a specific subset of TREM2+-expressing cells contributing to the evolution of steatohepatitis. The data also point ICOS/ICOSL dyad as a possible target for therapeutic interventions in MASH.


More than Medication-Achieving Goals through Psychotherapy in Patients with Obsessive Compulsive Disorder.
There are numerous variables to consider when planning treatment for a psychiatric disorder as complex as obsessive compulive disorder (OCD). Beyond the efficacy of the medications, one must take into account patient preferences and beliefs, as well as the impact of the disease and treatment on social and occupational functioning. Psychotherapy, specifically cognitive behavioral therapy (CBT), can serve as an addition to pharmacotherapy or as an alternative treatment, if necessary, for OCD. However, psychotherapy remains under-utilized. In this article, the authors review the available evidence supporting various treatment options for OCD and describe how psychotherapy (specifically CBT) can be used as monotherapy for OCD or as an adjunct to medication. Effective strategies for delivering CBT via its two modalities (exposure-response prevention and cognitive therapy) are described and illustrated by a composite case.