Roux-en-Y gastric bypass surgery in youth with severe obesity: 1-year longitudinal changes in spexin.
Spexin is a novel peptide predominantly produced in human white adipose tissue and has recently been implicated as a potential signal in the regulation of body weight, energy homeostasis, and satiety. The effect of bariatric surgery on spexin is unknown. To study the effect of Roux-en-Y gastric bypass (RYGB) surgery on endogenous spexin concentration and various risk factors of type 2 diabetes and cardiovascular disease in youth with severe obesity. University hospital, United States METHODS: Spexin, body mass index (BMI), insulin, glucose, total and high molecular weight adiponectin, leptin, and high sensitivity C- reactive protein were measured longitudinally (baseline, 6 mo, and 12 mo) after RYGB surgery in girls with severe obesity (n = 12; age = 16.7 ± 1.5 years; BMI = 51.6 ± 2.9 kg/m2). Serum spexin concentration increased (P = .01) at 6 months after surgery and stabilized afterward. Spexin level correlated negatively with homeostatic model assessment insulin resistance, HOMA-IR (Spearman correlation r = -.796, P < .001) and positively with high molecular weight adiponectin (Spearman correlation r = .691, P = .011). The change in spexin concentration, from baseline to 6 months after surgery, was inversely correlated with the corresponding change in BMI (Spearman correlation r = -.573, P = .051). Furthermore, the 6-month changes in spexin and HOMA-IR were inversely correlated (slope [standard error, SE] = -.0084 (.0019), P = .001)], even after adjusting for the change in BMI. The enhancement of circulating spexin concentration in response to RYGB and correlations with beneficial postoperative changes in various adipokines in youth are novel findings that require further validation.


Is Predominant Clonal Evolution a Common Evolutionary Adaptation to Parasitism in Pathogenic Parasitic Protozoa, Fungi, Bacteria, and Viruses?
We propose that predominant clonal evolution (PCE) in microbial pathogens be defined as restrained recombination on an evolutionary scale, with genetic exchange scarce enough to not break the prevalent pattern of clonal population structure. The main features of PCE are (1) strong linkage disequilibrium, (2) the widespread occurrence of stable genetic clusters blurred by occasional bouts of genetic exchange ('near-clades'), (3) the existence of a "clonality threshold", beyond which recombination is efficiently countered by PCE, and near-clades irreversibly diverge. We hypothesize that the PCE features are not mainly due to natural selection but also chiefly originate from in-built genetic properties of pathogens. We show that the PCE model obtains even in microbes that have been considered as 'highly recombining', such as Neisseria meningitidis, and that some clonality features are observed even in Plasmodium, which has been long described as panmictic. Lastly, we provide evidence that PCE features are also observed in viruses, taking into account their extremely fast genetic turnover. The PCE model provides a convenient population genetic framework for any kind of micropathogen. It makes it possible to describe convenient units of analysis (clones and near-clades) for all applied studies. Due to PCE features, these units of analysis are stable in space and time, and clearly delimited. The PCE model opens up the possibility of revisiting the problem of species definition in these organisms. We hypothesize that PCE constitutes a major evolutionary strategy for protozoa, fungi, bacteria, and viruses to adapt to parasitism.


Vagal stimulation by manual carotid sinus massage to acutely suppress seizures.
Carotid sinus massage, a technique involving digital pressure on the richly innervated carotid sinus, is a time-honoured method for termination of supraventricular tachycardia due to paroxysmal atrial tachycardia. Vagal nerve stimulation, a more recent technique, employs pacemaker stimulation of the vagus as a treatment for refractory epilepsy. This case report discusses the use of carotid sinus massage to abort seizure activity. The patient used manual manipulation of the carotid sinus (similar to cardiology techniques) to suppress seizures, achieving a therapeutic neurological outcome.


Spatial and temporal variability of microplastic abundance in estuarine intertidal sediments: Implications for sampling frequency.
Microplastics (<5 mm) are well documented across shorelines worldwide; however, high variability in microplastic abundance is often observed within and among field studies. The majority of microplastic surveys to date consist of single sampling events that do not consider spatiotemporal variability as a potential confounding factor in the interpretation of their results. Therefore, these surveys may not accurately capture or reflect levels of microplastic contamination in the environment. Here, we provide the first investigation of small-scale spatial and temporal variability of microplastic abundance, distribution, and composition in the intertidal zone of an urbanized US estuary to better understand the short-term, daily spatiotemporal variability of microplastics in dynamic coastal environments. Intertidal sediment was collected from both the low and high intertidal zones of a sandy estuarine beach located in South Carolina, southeastern US every 1 to 2 days at low tide over 17 days (12 sampling events; total n = 72). Study-wide, microplastic abundance ranged from 44 to 912 microplastics/m2 and consisted primarily of polyethylene, nylon, polyester, and tire (or tyre) wear particles. High temporal variability was observed, with microplastic abundance differing significantly among sampling events (p = 0.00025), as well as among some consecutive tidal cycles occurring within 12 h of each other (p = 0.007). By contrast, low spatial variability was observed throughout the study with no significant differences in microplastic abundance detected between the low and high intertidal zones (p = 0.76). Of the environmental factors investigated, wind direction on the day of sampling had the greatest effect on temporal microplastic variability. Our results demonstrate that there can be significant temporal variability of microplastic abundance in estuarine intertidal sediments and are important for informing the methods and interpretation of future microplastic surveys in dynamic coastal environments worldwide.


Defining dosing pattern characteristics of successful tapers following methadone maintenance treatment: results from a population-based retrospective cohort study.
To identify dose-tapering strategies associated with sustained success following methadone maintenance treatment (MMT). Population-based retrospective cohort study. Linked administrative medication dispensation data from British Columbia, Canada. From 25 545 completed MMT episodes, 14 602 of which initiated a taper, 4183 individuals (accounting for 4917 MMT episodes) from 1996 to 2006 met study inclusion criteria. The primary outcome was sustained successful taper, defined as a daily dose ≤5 mg per day in the final week of the treatment episode and no treatment re-entry, opioid-related hospitalization or mortality within 18 months following episode completion. The overall rate of sustained success was 13% among episodes meeting inclusion criteria (646 of 4917), 4.4% (646 of 14 602) among all episodes initiating a taper and 2.5% (646 of 25 545) among all completed episodes in the data set. The results of our multivariate logistic regression analyses suggested that longer tapers had substantially higher odds of success [12-52 weeks versus <12 weeks: odds ratio (OR): 3.58; 95% confidence interval (CI): 2.76-4.65; >52 weeks versus <12 weeks: OR: 6.68; 95% CI: 5.13-8.70], regardless of how early in the treatment episode the taper was initiated, and a more gradual, stepped tapering schedule, with dose decreases scheduled in only 25-50% of the weeks of the taper, provided the highest odds of sustained success (versus <25%: OR: 1.61; 95% CI: 1.22-2.14). The majority of patients attempting to taper from methadone maintenance treatment will not succeed. Success is enhanced by gradual dose reductions interspersed with periods of stabilization. These results can inform the development of a more refined guideline for future clinical practice.


[Secondary syphilis with pulmonary involvement: report of a case with emphasis to the high-resolution CT and magnetic resonance findings].
A 37-year-old man presented with thoracic pain and fever. The physical examination showed reddish skin lesions. He was investigated with radiography, high- resolution computed tomography and magnetic resonance of the chest, which revealed multiple small and large nodules with random distribution, mostly in the lower lungs zones. Biopsies of lung and skin lesions was performed and the diagnosis of secondary syphilis was defined. Other laboratories tests (venereal disease laboratory and FtA-abs) corroborated the diagnosis. The patient was treated with penicillin, and the pulmonary and skin lesions regressed in the follow- up examinations.


Endoscopic ultrasound-guided ethanol ablation for the management of a symptomatic pancreatic insulinoma.
pancreatic insulinoma is a sporadic, usually benign, frequently solitary tumor that is smaller than 20 mm. When it is functioning, patients present with symptoms of hypoglycemia secondary to insulin hypersecretion. The diagnosis is clinical, with biochemical and radiological confirmation. Surgery is the management of choice, although endoscopic ultrasound-guided ablation is currently being developed. we present a prospective case series of pancreatic insulinoma patients with symptoms of severe hypoglycemia, who were treated with endoscopic ultrasound-guided ethanol ablation as an alternative to surgical management. technical and clinical success was achieved in all cases and there were no complications associated with the procedure. the treatment of symptomatic insulinoma by endoscopic ultrasound-guided ethanol ablation could be a safe and effective alternative to surgical management in non-surgical patients or those who refuse surgery.


Identification of tissue-specific regulatory region in the zebrafish lamin A promoter.
Lamins are major structural proteins present in the nuclei of metazoan cells and contribute significantly to nuclear organization and function. The expression of different types of lamins is developmentally regulated and lamin A is detectable in most differentiated tissues. Although the proximal promoter of the mammalian lamin A gene has been characterized, the tissue-specific regulatory elements of the gene have not been identified. In this study, we have cloned and functionally characterized a 2.99 kb segment upstream of exon 1 in the zebrafish lamin A gene. This fragment was able to drive GFP expression in several tissues of the developing embryo at 14-72 h post fertilization in stable transgenic lines. Deletion fragments of the 2.99 kb promoter were analyzed by microinjection into zebrafish embryos in transient assays as well as by luciferase reporter assays in cultured cells. A minimal promoter segment of 1.24 kb conferred tissue-specific expression of GFP in the zebrafish embryo as well as in a myoblast cell line. An 86 bp fragment of this 1.24 kb segment was able to activate a heterologous promoter in myoblasts. Mutational analysis revealed the importance of muscle-specific regulatory motifs in the promoter. Our results have important implications for understanding the tissue-specific regulation and functions of the lamin A gene.


Exposure to second-hand smoke at home and its associated factors: findings from the Global Adult Tobacco Use survey in Vietnam, 2010.
The paper describes the pattern of exposure to second-hand smoke (SHS) at home among the adult population of Vietnam and examines associated socio-demographic factors. A total of 11,142 households were selected for this survey using a two-phase sampling design analogous with three-stage stratified cluster sampling. The dependent variable was the status of exposure to SHS at home. Independent variables included gender, age, occupation, asset-based wealth quintile, ethnicity, marital status, residence. Logistic regression modelling was performed to examine the association with relevant factors of patterns of exposure to second-hand smoke among non-smokers. Of adults aged 15 years and above (representing approximately 47 million people) 73.1% reported they were exposed to SHS at home at least monthly. Considering non-smokers only, the prevalence of exposure to SHS at home was 67.6% (equivalent to approximately 33 million non-smokers). The significant correlates of the status of exposure to SHS at home among non-smokers were female gender, ethnic minority, low education, and lack of smoking restriction at home. The study showed that a high percentage of people are exposed to second-hand smoke at home. Disadvantaged people were more likely than the better-off to be exposed to SHS at home.


The racemic metoprolol H2-antagonist interaction.
The effects of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of multiple-dose metoprolol were investigated in 12 normal, healthy male volunteers. The pharmacokinetics of metoprolol were assessed in terms of racemic metoprolol and the individual (R)- and (S)-enantiomers with a stereoselective assay. Ranitidine had no effect on the pharmacodynamics or pharmacokinetics of metoprolol. Although not affecting the pharmacodynamics of metoprolol, cimetidine did produce an increase in the bioavailability of metoprolol through inhibition of enzymes responsible for the first-pass elimination of the beta-blocker. The effect was stereoselective, with the major effect being on the less pharmacologically active (R)-enantiomer.


Bioaccumulation and Elimination of the Herbicide Clomazone in the Earthworms Eisenia fetida.
Acute toxicity, bioaccumulation, and elimination of herbicide clomazone in the earthworm Eisenia fetida were investigated in the different exposure systems. The LC50 values of clomazone on earthworms were 5.6 μg cm(-2) in the contact filter paper test (48 h), 174.9 mg kg(-1) (7 days) and 123.4 mg kg(-1) (14 days) in artificial soil test, respectively. Clomazone could rapidly bioaccumulate in earthworms and reached the highest concentration after 3 days exposure, with the maximum concentrations of 9.0, 35.3 and 142.3 mg kg(-1) at 10.0, 40.0 and 160.0 mg kg(-1) of clomazone, respectively. Clomazone uptake showed a good correlation with exposure concentration. After the 14th day, clomazone declined to minimum value. About 74%-80% of accumulated clomazone was eliminated within 1 day after exposed to clomazone-free soil. However, a trace amount of clomazone persisted for a relatively long time in earthworms.


Gender-specific associations between functional autonomy and physical capacities in independent older adults: results from the NuAge study.
Even with healthy and active aging, many older adults will experience a decrease in physical capacities. This decrease might be associated with diminished functional autonomy. However, little is known about the physical capacities associated with functional autonomy in older women and men. This study aimed to examine gender-specific associations between functional autonomy and physical capacities in independent older women and men. Secondary analyses were carried out using cross-sectional data from 652 women and 613 men who participated in the NuAge longitudinal study. The "functional autonomy measurement system" (SMAF) was used to evaluate functional autonomy. The physical capacities measured (tests used) were: biceps and quadriceps strength (Microfet dynamometer), grip strength (Martin vigorimeter), unipodal balance, changing position & walking (timed up and go), normal & fast walking (four-meter walking speed) and changing position (chair stand). Correlation and multiple linear regression analyses adjusted for age, depressive symptoms and body composition were performed. On average, participants were aged 73 years and had mild to moderate functional autonomy loss. In women, after controlling for age, depressive symptoms and body composition, greater functional autonomy was best explained by faster changing position & walking skills and superior biceps strength (R(2)=0.46; p<0.001). After controlling for depressive symptoms, faster changing position & walking skills and better unipodal balance best explained greater functional autonomy in men (R(2)=0.21; p<0.001). According to these results, physical capacities are moderately associated with functional autonomy among independent older adults, especially women.


Dorsiflexion range of motion significantly influences dynamic balance.
The purpose of this study was to examine the relationships between dorsiflexion range of motion on the weight-bearing lunge test (WBLT) and normalized reach distance in three directions on the Star Excursion Balance Test (SEBT). Thirty-five healthy adults (14 males, 21 females, age: 25.9±6.7 years, height: 166.7±22.9 cm, weight: 76.7±22.8 kg) participated. All subjects performed three trials of maximum lower extremity reach in the anterior, posteromedial, and posterolateral directions of the SEBT on each limb to assess dynamic balance. Subjects performed three trials of the WBLT to measure maximum dorsiflexion range of motion. Dependent variables included the means of the SEBT normalized reach distances in the anterior, posteromedial, and posterolateral directions and the mean of the WBLT. Only the anterior direction (mean: 79.0±5.8%) of the SEBT was significantly related to the WBLT (mean: 11.9±2.7 cm), r=0.53 (p=0.001). The r² for this simple linear regression was 0.28, indicating that the WBLT explained 28% of the variance in the anterior normalized reach distance. The WBLT explained a significant proportion of the variance within the anterior reach distance signifying this direction of the SEBT may be a good clinical test to assess the effects of dorsiflexion range of motion restrictions on dynamic balance.


[Effect of xiaoyin recipe in treatment of psoriasis patients of blood-heat syndrome type and its impact on peripheral Th1/Th2 equilibrium].
To explore the mechanism of Chinese medicinal therapy for cooling blood and removing stasis (CBRS) in treating psoriasis of blood-heat syndrome type by observing its clinical efficacy and impact on serum level of cytokines. Changes of psoriasis area and severity index (PASI) scores, scores of syndrome and serum levels of tumor necrosis factor alpha (TNF-alpha, Th1 cytokine) and interleukin-10 (IL-10, Th2 cytokine) in 32 psoriatic patients before and after treatment were observed. The total effective rate after 4 weeks of treatment and 8 weeks of treatment was 65.63% (21/32 cases) and 75.00% (24/32 cases) respectively. Scores of PASI and syndrome all improved after treatment (P < 0.05). And comparison of TNF-alpha level before and after treatment also showed significant difference (P < 0.05) , whereas that of IL-10 was insignificant (P > 0.05). Moreover, a positive correlation was found between PASI scores and secreting level of TNF-alpha in patients with psoriasis (r = 0.3709, P < 0.05). Chinese therapy for CBRS could play its effect in treating psoriasis by way of reducing TNF-alpha level.


Regulation of fetal lung disaturated phosphatidylcholine synthesis by de novo palmitate supply.
Lung surfactant disaturated phosphatidylcholine (PC) is highly dependent on the supply of palmitate as a source of fatty acid. The purpose of this study was to investigate the importance of de novo fatty acid synthesis in the regulation of disaturated PC production during late prenatal lung development. Choline incorporation into disaturated PC and the rate of de novo fatty acid synthesis was determined by the relative incorporation of [14C]choline and 3H2O, respectively, in 20-day-old fetal rat lung explants and in 18-day-old explants which were cultured 2 days. Addition of exogenous palmitate (0.15 mM) increased (26%) choline incorporation into disaturated PC but did not inhibit de novo fatty acid synthesis, as classically seen in other lipogenic tissue. Even in the presence of exogenous palmitate, de novo synthesis accounted for 87% of the acyl groups for disaturated PC. Inhibition of fatty acid synthesis by agaric acid or levo-hydroxycitrate decreased the rate of choline incorporation into disaturated PC. When explants were subjected to both exogenous palmitate and 60% inhibition of de novo synthesis, disaturated PC synthesis was below control values and 75% of disaturated PC acyl moieties were still provided by de novo synthesis. These data show that surfactant disaturated PC synthesis is highly dependent on the supply of palmitate from de novo fatty acid synthesis.


Retinal hemorrhages in a patient with dyskeratosis congenita.
Dyskeratosis congenita, also referred to as Zinsser-Cole-Engman syndrome, is characterized by reticular skin pigmentation, dystrophic nail changes, and mucosal leukoplakia. Other findings include carious teeth, premature graying of hair, and osteoporosis. Approximately 50% of patients develop pancytopenia. Ophthalmologic manifestations include blepharitis, conjunctivitis, obliteration of the lacrimal puncta, nasolacrimal duct obstruction, ectropion, and loss of eyelashes. We report bilateral retinal hemorrhages from pancytopenia in a patient with dyskeratosis congenita.


Bronchoscopic Lobar Lavage in the Treatment of a Single Lung Transplant Recipient With Pulmonary Alveolar Proteinosis: A Case Report.
Pulmonary alveolar proteinosis is a rare disorder that results from impaired clearance of surfactant. There are few case reports in lung transplant recipients. We report the case of a 57-year-old man with chronic hypersensitivity pneumonitis who underwent left single lung transplantation. Approximately 1 year after transplant, he was diagnosed as having pulmonary alveolar proteinosis by surgical lung biopsy. He was successfully treated with bronchoscopic lobar lavage of his allograft but later was diagnosed as having peritoneal mesothelioma. We highlight the challenges in the diagnosis, discuss potential etiologies, and describe a unique therapy of this rare disorder in lung transplant recipients.


Exposure to ELF magnetic field tuned to Zn inhibits growth of cancer cells.
The effects of ELF alternating magnetic fields tuned to Zn(2+) on the growth of cancer cells with different status of p53 were investigated using a cell proliferation assay. Human cancer cells HeLa (cervix cancer, p53(+/+)), Saos-2 and Saos-2-His-273 (osteosarcoma, p53(-/-) and p53 His-273 mutant, respectively), H1299tTA and H1299tTA-His175 (lung carcinoma, p53(-/-) and p53 His-175 mutant), and normal human fibroblasts VH-10 (p53(+/+)) were used. Exposure parameters were calculated for the first harmonic of Zn(2+) based either on the magnetic parametric resonance (MPR) model of Lednev or the ion parametric resonance (IPR) model of Blanchard and Blackman. ELF exposure was for 72 and 96 h. The vertical alternating field was 20 Hz at amplitudes of either 38.7 or 77.4 microT (peaks, IPR or MPR, respectively). The vertical static magnetic field was 43 microT, and the horizontal static magnetic field was zeroed. Treatments of cells with PRIMA-1 and gamma-rays were used as positive controls. Growth inhibition was observed in cells after exposure to ELF at 38.7 microT. Inhibition of HeLa, VH-10, and Saos-2-His-273 cells was statistically significant, P=0.0003, 0.02, and 0.006, respectively. No consistent ELF effects following exposure 77.4 microT were seen. PRIMA-1 inhibited the growth of all cell lines with the strongest effect in mutant p53-carrying cell line H1299tTA-His175. The effects of gamma-rays were relatively weak, suggesting that the cell proliferation assay under conditions employed in this study is not very sensitive to apoptosis. In conclusion, ELF under conditions of exposure tuned to Zn(2+) according to the IPR model inhibited the growth of cancer and normal cells. No clear relationship of the observed growth inhibition to p53 status was found. Further experiments, using complementary techniques, are required to test whether p53 reactivation by ELF is feasible.


Structural and inflammatory heterogeneity in subcutaneous adipose tissue: relation with liver histopathology in morbid obesity.
In addition to total body fat, the regional distribution and inflammatory status of enlarged adipose tissue are strongly associated with metabolic co-morbidities of obesity. We recently showed that the severity of histological liver lesions related to obesity increases with the amount of macrophage accumulation in visceral adipose tissue (VAT), while no association was found with the subcutaneous adipose tissue (SAT). In the abdominal region, SAT is anatomically divided into two layers, i.e. superficial (sSAT) and deep (dSAT). The aim of the present study was to test the hypothesis that these distinct compartments differentially contribute to hepatic alterations in obesity. Biopsies of the liver, sSAT, dSAT, and VAT were collected in 45 subjects with morbid obesity (age 43.7±1.6 years; BMI 48.5±1.2kg/m(2)) during bariatric surgery. Large scale gene expression analysis was performed to identify the pathways that discriminate sSAT from dSAT. Adipose tissue macrophages were quantified by immunohistochemistry using HAM56 antibody in subjects scored for liver histopathology. An inflammatory gene pattern discriminates between sSAT and dSAT. dSAT displayed an intermediate level of macrophage accumulation between sSAT and VAT. The abundance of macrophages in dSAT, but not in sSAT, was significantly increased in patients with non-alcoholic steatohepatitis (NASH) and/or fibroinflammatory hepatic lesions. These data show distinct gene signature and macrophage abundance in the two compartments of SAT, with dSAT more closely related to VAT than to sSAT in terms of inflammation and relation with the severity of liver diseases in morbid obesity.


Health-related quality of life in Chinese individuals with type 2 diabetes mellitus: a multicenter cross-sectional study.
Type 2 diabetes mellitus (T2DM) is a chronic and life-threatening disease. Health-related quality of life (HRQoL) is vital for individuals with T2DM. However, little is known about the impact of psychological stability factors on HRQoL among individuals with T2DM in mainland China. This multicenter cross-sectional study was conducted in five tertiary grade-A hospitals in Chongqing, China, from January to December 2019. A total of 385 individuals with T2DM were included by the convenient sample method. Fear of Progression (FOP) Questionnaire-short Form, Hypoglycemia Fear Survey II, diabetes-management self-efficacy scale, and EuroQol-5 Dimensions were used for data collection. The mean age of the 385 individuals was 57.65 (SD = 15.15) years, three-quarters of whom had a high school or above education level. The participants in our study had moderate HRQoL and were more likely to have poor scores in the pain/discomfort dimension. The FOP level was moderate on average, and 23.1% of individuals suffered from psychological dysfunction. The participants had higher levels of fear of hypoglycemia (FOH) and self-efficacy (SE). Multiple steppage-regression analysis predicted that higher levels of FOP and FOH, reduced SE, older age, longer duration since diagnosis, lower educational attainment, higher levels of HbA1c, and living with comorbid conditions were related to lower HRQoL. This study showed that the HRQoL among Chinese T2DM patients may be impaired by increased FOP and FOH, decreased SE, and poor glycemic control. In addition, as the patient's age and duration since diagnosis increase, their HRQoL further declines. We recommend improving HRQoL by encouraging individuals to attain more health education and resilience skills to enhance SE and reduce negative emotions among individuals with T2DM.


CD8+ suppressor cells inhibit staphylococcal protein A-induced gamma interferon production by CD4+ lymphocytes.
We have previously demonstrated that purified soluble staphylococcal protein A (SpA) induces the synthesis of gamma interferon (gamma-IFN) by human peripheral blood lymphocytes (PBL), that CD4+ (T helper) cells represent the subpopulation responsible for this synthesis and that prostaglandin E2 (PGE2)-activated CD8+ (T suppressor/cytotoxic) cells have an inhibitory effect on this synthesis. The mechanisms implicated in this regulation remain to be defined, and could involve direct cell-to-cell contact among members of these subpopulations or may be due to a soluble mediator release by CD8+ suppressor cells. In this study, we explored the ability of PGE2 to activate CD8+ cells into either cytotoxic or suppressor cells and the mechanisms by which these cells regulate the SpA-induced gamma-IFN production by CD4+ cells. Peripheral blood lymphocytes from 18 healthy volunteers, prepared by centrifugation over Ficoll-Hypaque gradient, were separated into subpopulations by passage on nylon wool columns and selective depletion using specific monoclonal antibodies and rabbit complement. CD4+ cells were incubated with SpA for gamma-IFN production and CD8+ cells were incubated with 10(-6) M PGE2. After 48 h these populations were remixed and the cytotoxic or suppressor effector function of CD8+ cells was measured. No cytotoxic activity was detected against CD4+ cells. Different levels of suppression of gamma-IFN production were observed in our subjects. Suppression mediated through the release of soluble factor was observed in only 2 of the 18 cases. Taken together, these results suggest that in the present experimental system, the regulation of gamma-IFN production is mediated by suppressor CD8+ T cells and that cell-to-cell contact between both subpopulations is usually necessary.


[Trauma management under military conditions. A German field hospital in Afghanistan in comparison with the National Trauma Registry].
The German armed forces run a role-III field hospital in Kabul, Afghanistan. Emergency room (ER) management is of utmost importance as a link between pre- and in-hospital treatment. Prospective data were acquired of all patients admitted to the ER over a 3-month period. The quality of ER management was tested using established audit filters and comparing the results with those of the National Trauma Registry. A total of 353 patients were admitted to the ER (48.4% trauma cases). Fifty-nine patients were major trauma cases, and the proportion of combat-related injury was 33.2%. In comparison to the National Trauma Registry, significant differences were observed regarding age (25.2 vs 41.7 years, P<0.0001) and injury severity (NISS 18.8 vs 28.8, P<0.0001). The demands on the quality of ER management have increased. Using the audit filters of the National Trauma Registry, significant differences were observed regarding ER management. In a military setting, medical treatment of major trauma victims is influenced by multiple adverse factors significantly affecting the quality of trauma management.


The position of the patient during neurosurgical procedures on the posterior fossa.
Different parameters were measured on patients in six different positions during infratentorial surgery. One group of data served to prove that such patients were in a steady-state as far as their cardiovascular and ventilatory function was concerned. The other measured parameters concerned the intracranial pressure, the intracranial venous pressure and the cerebral perfusion pressure. It appeared from the comparison of these data, that the lateral sitting (45 degrees) position had important advantages and that in this position the possibility of unfavourable features (such as air-embolism) was minimized.


A mathematic equation derived from host-pathogen interactions elucidates the significance of integrating modern medicine with traditional Chinese medicine to treat infectious diseases.
The prognosis of infectious diseases is determined by host-pathogen interactions. Control of pathogens has been the central dogma of treating infectious diseases in modern medicine, but the pathogen-directed medicine is facing significant challenges, including a lack of effective antimicrobials for newly emerging pathogens, pathogen drug resistance, and drug side effects. Here, a mathematic equation (termed equation of host-pathogen interactions, HPI-Equation) is developed to dissect the key variables of host-pathogen interactions. It shows that control of pathogens does not necessarily lead to host recovery. Instead, a combination of promoting a host's power of self-healing and balancing immune responses provides the best benefit for host. Moreover, the HPI-Equation elucidates the scientific basis of traditional Chinese medicine (TCM), a host-based medicine that treats infectious diseases by promoting self-healing power and balancing immune responses. The importance of self-healing power elucidated in the HPI-Equation is confirmed by recent studies that the tolerance mechanism, which is discovered in plants and animals and conceptually similar to self-healing power, improves host survival without directly attacking pathogens. In summary, the HPI-Equation describes host-pathogen interactions with mathematical logic and precision; it translates the ancient wisdoms of TCM into apprehensible modern sciences and opens a new venue for integrating TCM and modern medicine for a future medicine. Sun J. A mathematic equation derived from host-pathogen interactions elucidates the significance of integrating modern medicine with traditional Chinese medicine to treat infectious diseases. J Integr Med. 2023; 21(4):324-331.


Shock wave lithotripsy not associated with development of diabetes mellitus at 6 years of follow-up.
To investigate the hypothesis that extracorporeal shock wave lithotripsy (ESWL) increases the incident risk of new-onset diabetes mellitus (DM). Studies have suggested that ESWL predisposes to DM. Using a mail survey, we collected data on the presence and onset of DM in 1947 patients treated with the Medstone-STS electrohydraulic lithotripter from 1999 to 2002. These patients were matched by age, sex, and body mass index to controls from the National Health and Nutrition Examination Survey (NHANES) database. Of the 1947 patients, 4% could not be matched and were excluded, leaving 1869 for analysis, of whom 60.0% were men. The mean age was 51.9 years at ESWL and the median follow-up was 6 years. The mean body mass index at the end of the study was 28.6 kg/m(2). At ESWL, 8.67% of matched patients had a diagnosis of DM. This had increased to 13.9% at the time of survey. In the NHANES group, 8.34% had DM at the time the ESWL group underwent treatment, and this had increased to 14.1% at the NHANES survey. Therefore, the rate of new DM cases in the ESWL group was similar to that in the NHANES group (5.2% vs 5.8%, respectively; P = .47). Multivariate analysis of the patient cohort confirmed that age, sex, body mass index, and family history correlated with development of DM and that the laterality of treatment and number of treatments or shocks given were not significant predictors of DM. The results of our study have shown that patients treated with ESWL do not develop DM at a greater rate than does the general population at 6 years of follow-up.


Inequities in Therapy for Infantile Spasms: A Call to Action.
The aim of this study was to determine whether selection of treatment for children with infantile spasms (IS) varies by race/ethnicity. The prospective US National Infantile Spasms Consortium database includes children with IS treated from 2012 to 2018. We examined the relationship between race/ethnicity and receipt of standard IS therapy (prednisolone, adrenocorticotropic hormone, vigabatrin), adjusting for demographic and clinical variables using logistic regression. Our primary outcome was treatment course, which considered therapy prescribed for the first and, when needed, the second IS treatment together. Of 555 children, 324 (58%) were non-Hispanic white, 55 (10%) non-Hispanic Black, 24 (4%) non-Hispanic Asian, 80 (14%) Hispanic, and 72 (13%) other/unknown. Most (398, 72%) received a standard treatment course. Insurance type, geographic location, history of prematurity, prior seizures, developmental delay or regression, abnormal head circumference, hypsarrhythmia, and IS etiologies were associated with standard therapy. In adjusted models, non-Hispanic Black children had lower odds of receiving a standard treatment course compared with non-Hispanic white children (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.20-0.89; p = 0.02). Adjusted models also showed that children with public (vs. private) insurance had lower odds of receiving standard therapy for treatment 1 (OR, 0.42; CI, 0.21-0.84; p = 0.01). Non-Hispanic Black children were more often treated with non-standard IS therapies than non-Hispanic white children. Likewise, children with public (vs. private) insurance were less likely to receive standard therapies. Investigating drivers of inequities, and understanding the impact of racism on treatment decisions, are critical next steps to improve care for patients with IS. ANN NEUROL 2022;92:32-44.


Validation of the Prodromal Questionnaire-Brief in a representative sample of adolescents: Internal structure, norms, reliability, and links with psychopathology.
The main purpose of the present study was twofold: to validate the Prodromal Questionnaire-Brief (PQ-B) in a community-derived sample of adolescents and to examine the links between psychotic-like experiences and emotional and behavioral problems, prosocial behavior, suicidal ideation, and bipolar-like experiences. One thousand five hundred eighty-eight students selected by random sampling participated in a cross-sectional survey. The PQ-B, Paykel Suicide Scale, Strengths and Difficulties Questionnaire, Mood Disorder Questionnaire, Penn Matrix Reasoning Test, Family Affluence Scale-II, and Oviedo Infrequency Scale were used. The unidimensional factorial structure of the PQ-B items showed adequate goodness of fit index. This model also showed configural and strong invariance across gender. The internal consistency of the PQ-B total frequency score was 0.92. A high degree of overlap was found between psychotic-like experiences and emotional and behavioral problems, suicidal ideation, and bipolar-like experiences. The PQ-B is a brief, easy, and reliable tool for screening psychotic-like experiences in adolescents from the general population. The assessment of risk for psychosis and its relationship with other psychopathological risk factors in a close-in strategy or two-stage process model may help us to enhance the early identification for youths at heightened risk for serious mental disorders.


[Metformin for type-2 diabetes mellitus. Systematic review and meta-analysis].
To evaluate the efficacy of metformin against placebo, diet, oral anti-diabetics, or insulin in type 2 diabetes mellitus. Systematic review. MEDLINE (1966-2003), EMBASE (1974-2003), LILACS (1986-2003), Cochrane library (Issue 3, 2003). 29 randomized clinical trials of metformin in monotherapy, with results on mortality, morbidity, and biochemistry. EXTRACTION OF DATA: RevMan 4 computer program. Two reviewers extracted the data and evaluated the quality. any clinical event related to diabetes (mortality, coronary disease, stroke, arterial disease, and retinopathy). Secondary variables: weight and biochemistry. 29 clinical studies with 37 comparisons of metformin were analyzed (13 with sulphonylureas, 12 with placebo, 3 with diet, 3 with thiazolidinediones, 2 with alpha-glucosidase inhibitors, 2 with insulin, and 2 with meglitinides). Metformin was more beneficial than the sulphonylureas or insulin for any clinical event associated with diabetes (relative risk [RR]=0.78; 95% confidence interval [CI], 0.65-0.94) and than diet (RR=0.74; 95% CI, 0.60-0.90). Metformin decreased glycosylated hemoglobin A1 (weighted mean difference, -1.21%; 95% CI, -1.48 to -0.94), low density lipoprotein cholesterol (weighted mean difference, -0.24; 95% CI, -0.40 to -0.09), and weight (standardized mean difference, -0.11; 95% CI, -0.18 to -0.04). Metformin was more beneficial than the placebo, diet or the thiazolidinediones on glycosylated hemoglobin A1, and than the sulphonylureas or insulin on weight. In the long term metformin reduces the risks of clinical events associated with diabetes. There are no long term clinical trials which compare alpha-glucosidase inhibitors, meglitinides, and thiazolidinediones with metformin, in primary results. The different treatments compared with metformin did not obtain more benefit for the secondary results evaluated.


Biomolecule immobilization techniques for bioactive paper fabrication.
Research into paper-based sensors or functional materials that can perform analytical functions with active recognition capabilities is rapidly expanding, and significant research effort has been made into the design and fabrication of bioactive paper at the biosensor level to detect potential health hazards. A key step in the fabrication of bioactive paper is the design of the experimental and operational procedures for the immobilization of biomolecules such as antibodies, enzymes, phages, cells, proteins, synthetic polymers and DNA aptamers on a suitably prepared paper membrane. The immobilization methods are concisely categorized into physical absorption, bioactive ink entrapment, bioaffinity attachment and covalent chemical bonding immobilization. Each method has individual immobilization characteristics. Although every biomolecule-paper combination has to be optimized before use, the bioactive ink entrapment method is the most commonly used approach owing to its general applicability and biocompatibility. Currently, there are four common applications of bioactive paper: (1) paper-based bioassay or paper-based analytical devices for sample conditioning; (2) counterfeiting and countertempering in the packaging and construction industries; (3) pathogen detection for food and water quality monitoring; and (4) deactivation of pathogenic bacteria using antimicrobial paper. This article reviews and compares the different biomolecule immobilization techniques and discusses current trends. Current, emerging and future applications of bioactive paper are also discussed.


HCH and DDT Residues in Bivalves Anodonta woodiana from the Taihu Lake, China.
The present article attempts to use freshwater bivalves Anodonta woodiana for monitoring the pollution of hexachlorocyclohexane isomers (alpha-, beta-, gamma-, delta-HCH), dichlorodiphenyltrichloroethanes (o, p', p, p'-DDT) and metabolites (p, p'-DDE, p, p'-DDD) in the Taihu Lake, China. A total of 36 bivalves were sampled from 4 sites of Huzhou city, Dapu of Yixing city, Xueyan of Changzhou city, and Wulihu of Wuxi city around the lake in August-October 2004. The organochlorines were detected in all bivalves, and the mean concentration of SigmaDDTs (7.07 ng/g wet weight) was significantly higher than that of SigmaHCHs (2.37 ng/g wet weight). Overall, SigmaHCHs are at the highest concentrations in the bivalves from the Dapu and Huzhou site, whereas SigmaDDTs are at highest concentrations in the bivalves from the Wulihu site. Compositions of SigmaHCHs were predominated by alpha- and gamma-HCH isomers in the bivalves from all four study sites. Among these sampling sites, p, p'-DDT exhibited the highest percentage in the bivalves from Huzhou site. Furthermore, significant regional variations in compositions of both SigmaDDTs and SigmaHCHs had been identified. The residue levels of SigmaDDTs and SigmaHCHs in the bivalves of the present study were much lower than the corresponding residue limits for aquatic products of Ministry of Agriculture of China, FDA, and FAO/WHO. These findings suggest that Anodonta woodiana could serve as a unique bioindicator to monitor the HCH and DDT pollutions in the freshwater environment.


Exploring Integration of Care for Children Living with Complex Care Needs across the European Union and European Economic Area.
The aim of this paper is to report on the development of surveys to explore integration of care for children living with complex care needs across the European Union (EU) and European Economic Area (EEA). Each survey consists of a vignette and questions adapted from the Standards for Systems of Care for Children and Youth with Special Health Care Needs and the Eurobarometer Survey. A Country Agent in each country, a local expert in child health services, will obtain data from indigenous sources. We identified 'in-principle' complex problems and adapted surveys to capture care integration. We expect to get rich data to understand perceptions and to inform actions for a number of complex health issues. The study has the potential to make a wide contribution to individual countries of the EU/EEA to understand their own integration of services mapped against responses from other member states. Early results are expected in Spring 2017.


Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments.
Autism spectrum disorders (ASD) are subdivided into idiopathic (unknown) etiology and secondary, based on known etiology. There are hundreds of causes of ASD and most of them are genetic in origin or related to the interplay of genetic etiology and environmental toxicology. Approximately 30 to 50% of the etiologies can be identified when using a combination of available genetic testing. Many of these gene mutations are either core components of the Wnt signaling pathway or their modulators. The full mutation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome (FXS), the most common cause of monogenic origin of ASD, accounting for ~ 2% of the cases. There is an overlap of molecular mechanisms in those with idiopathic ASD and those with FXS, an interaction between various signaling pathways is suggested during the development of the autistic brain. This review summarizes the cross talk between neurobiological pathways found in ASD and FXS. These signaling pathways are currently under evaluation to target specific treatments in search of the reversal of the molecular abnormalities found in both idiopathic ASD and FXS.


Evaluation of echogenic emboli during total knee arthroplasty using transthoracic echocardiography.
Tranesophageal echocardiography or direct sampling of arterial and/or right atrial blood with histological evaluation are invasive techniques used to evaluate embolic material entering the heart during total knee arthroplasty (TKA). The aim of this study was to develop a non-invasive method of detecting and quantifying the embolic matter using transthoracic echocardiography and to apply this method to compare the incidence and severity of embolism between computer-navigated (N) and conventional (C) TKA done under tourniquet. Twenty-eight patients (15 N-TKA and 13 C-TKA) were enrolled. Transthoracic echocardiography was performed in all standard views prior to surgery and continuously after the tourniquet release for monitoring the echodense particulates appearing in the right atrium. To estimate the severity of echogenic embolization, maximum absolute increase in luminosity after tourniquet release (peak embolic load) and area under the curve (AUC; total embolic load) were both calculated. Twenty-four (85%) had significant particulate matter in right atrium (median time from release of thigh tourniquet to peak embolization in right atrium: 18.0 s). Peak embolic load was lower in N-TKA than C-TKA [17.0 versus 35.0 arbitrary luminosity units, p = 0.03]. Total embolic load, by area under the curve, was lower in the N-TKA group. Perioperative particulate embolization during TKA can be quantified non-invasively with the use of transthoracic echocardiography and off-line image analysis. N-TKA, by virtue of avoiding intramedullary guides, causes lesser total embolic load and hence can lead to decreased the severity and incidence of this potentially fatal phenomenon. II.


SPE and large-volume sample stacking in MEKC for determination of doxycycline in biological fluids: comparison of direct injection to SPE-MEKC.
A novel and simple method has been developed for the determination of doxycycline (DOX) in biological fluids. The method is based on SPE, large-volume sample stacking (LVSS) and MEKC with UV-DAD detection. Six SPE cartridges have been used in investigation for sample clean up and pre-concentration (Supelco LC-8, LC-18, LC-SCX, and LC-WCX, as well as Strata-X and X-C). DOX was determined on a 56 cm (effective length 50 cm) x 50 microm id fused-silica capillary. The BGE was 20 mM borate buffer, pH 9.3, containing 80 mM SDS and 7.5% v/v of methanol (30 sx50 mbar), and the temperature and voltage were 25 degrees C and 30 kV, respectively. The analytical wavelength was set at 210 nm. Under optimized conditions it is possible to determine DOX in human serum, urine, semen, tears and saliva with recovery of 97.5% (RSD 2.5%). The method was shown to be sensitive (LOD is 1 microg/L) and precise (intra-day RSD 0.2 and 2.4%; inter-days 0.4 and 3.5% for migration time and peak area, respectively). Results for developed SPE-LVSS-MEKC were compared with LVSS-MEKC method with direct sample injection. The new LVSS-MEKC method is presented as a useful technique for rapid determination without extraction procedure of DOX in human urine and serum, using 80 mM of SDS, 10% v/v of methanol and 40 mM borate buffer (pH 9.3; 30 s x 50 mbar; 25 degrees C; 30 kV; 350 nm), but not for the other biological fluids, according to lower sensitivity of the method and because of the sample composition.


Oestrogen receptor beta: what it means for patients with breast cancer.
Oestrogen receptor (ER) alpha is a well established prognostic marker in breast cancer, and all patients who are ER alpha positive receive tamoxifen as adjuvant endocrine therapy. Although ER alpha predicts a favourable disease outcome, the usefulness of ER beta as a clinical prognostic marker remains to be defined. Here, we outline the history of both ERs and discuss the implications ER beta has to patients with breast cancer.


Two-dimensional complex shear modulus imaging of soft tissues by integration of Algebraic Helmoltz Inversion and LMS filter into dealing with noisy data: a simulation study.
Elasticity and viscosity of soft tissues can be obtained from the complex shear modulus imaging (CSMI). CSMI is often used not only to investigate the structure of tissues but also to detect tumors in tissues. One of the most popular ways to categorize the methods used in CSMI is into quasi-static and dynamic methods. In the dynamic method, a force excitation is used to create the shear wave propagation, and the particle velocities are measured to extract their amplitude and phase at spatial locations. These parameters are then employed to directly or indirectly estimate the Complex Shear Modulus (CSM) represented by elasticity and viscosity. Algebraic Helmholtz Inversion (AHI) algorithm provides the direct estimation of CSM using the Finite Difference Time Domain (FDTD) technique. The limitation of this method, however, is that the noise generated from measuring the particle velocity strongly degrades the accuracy of the estimation. To overcome this problem, we proposed in this paper an adaptive AHI (AAHI) algorithm that offers a good performance in CSMI with a mean error of 2.06%.


Comparative evaluation of biocompatibility of dense nanostructured and microstructured Hydroxyapatite/Titania composites.
This work deals with the biocompatibility of dense nano- and micro-structured Hydroxyapatite/Titania composites prepared by two step and conventional sintering, respectively. By application of two step sintering, it was shown that the final grain size of HA-15 wt.% TiO2 is maintained lower than 100 nm while by the application of conventional sintering it reaches higher than 100 nm. Biocompatibility of the dense bulks was evaluated by cell attachment and proliferation experiments. Cell morphology, and viability on each nano- and micro-structured Hydroxyapatite/Titania composites were examined at different time points. The nanostructured HA/Titania dense bulk exhibited higher cell viability than a microstructured one. In addition, the effects of ionic products from nano- and micro-structured bulk dissolution on osteoblasts were studied. The MTT test confirmed that the products from nanostructured HA/Titania dense bulk significantly promoted osteoblast proliferation within a certain concentration range.


Is radical local therapy effective in postoperative recurrent EGFR-mutated non-small cell lung cancer?
Long-term survival can be achieved with radical local therapy in some cases of postoperative recurrence of non-small cell lung cancer (NSCLC). Here, we evaluated post-recurrence survival (PRS) after treatment of postoperative recurrent epidermal growth factor receptor (EGFR) mutated NSCLC and examined the effectiveness of radical local therapy. This multicenter prospective cohort study was conducted in 14 hospitals. The inclusion criteria for this study were patients with recurrence after radical resection for NSCLC. Information about the patient characteristics at recurrence, tumor-related variables, primary surgery, and treatment for recurrence was collected. After registration, follow-up data (e.g., treatment and survival outcomes) were obtained and analyzed. From 2010 to 2015, 505 patients with recurrent NSCLC were enrolled into the study, and 154 EGFR mutation-positive cases were included. As the initial treatment for recurrence, 111 patients (72%) received chemotherapy, 14 (9%) received chemoradiotherapy, 14 (9%) received definitive radiotherapy, and seven (5%) received surgical resection. The remaining eight patients (5%) received supportive care. The median PRS and 5-year survival rates for all cases were 64 months and 53.2%, respectively. The 5-year survival rate according to the initial treatment was as follows: supportive care, 0%; chemotherapy, 53.3% and radical local therapy, 60.1%. The six patients who received radical local treatment remained recurrence-free for more than 3 years after recurrence with only initial treatment. Although radical local therapy may be curative in some patients, chemotherapy including EGFR-TKI treatment is expected to provide long-term survival comparable to that of radical local therapy.


Sleeping site selection by golden-backed uacaris, Cacajao melanocephalus ouakary (Pitheciidae), in Amazonian flooded forests.
In Amazonian seasonally flooded forest (igapó), golden-backed uacaris, Cacajao melanocephalus ouakary, show high selectivity for sleeping trees. Of 89 tree species in igapó, only 16 were used for sleeping (18%). Hydrochorea marginata (Fabaceae) and Ormosia paraensis (Fabaceae) were used most frequently (41% of records) despite being uncommon (Ivlev electivity ratios were 0.76, and 0.84, respectively), though the third most commonly used species (11%), Amanoa oblongifolia (Euphorbiaceae), was selected at near parity. All three species have broad, open canopies with large horizontal limbs and uncluttered interiors. Compared with random trees, sleeping trees had above average diameter at breast height (DBH) and height, lacked lianas and wasp nests, and were more frequently within 5 m of open water. Uacaris generally slept one adult per tree or widely separated in the same canopy and on the outer third of the branch. These behaviours are interpreted as maximising detection of both aerial and arboreal predators.


Evaluation of a method of production and purification of monoclonal antibodies for clinical applications.
A procedure is described for the purification of monoclonal antibodies (Mab) from ascitic fluids, which meets the quality control required for in vivo applications of immunoglobulins (Ig) in man. Additional assays were performed to calculate viral and DNA content of the purified Mab. These studies are important to prevent the possible side effects, oncogenic events and virus-related diseases which could follow immunotherapy with Mab.


Usefulness of Adjunctive Fecal Calprotectin and Serum Procalcitonin in Individuals Positive for Clostridium difficile Toxin Gene by PCR Assay.
In 54/64 subjects with nosocomial diarrhea, fecal calprotectin levels correlated with the results of stool samples tested for Clostridium difficile toxin gene by PCR. Fecal calprotectin levels can be used as an adjunctive measure to PCR to support the diagnosis of C. difficile infection.


Induction of chromosomal aberrations in bone marrow cells of asbestotic rats.
In the present study, cytogenetic effects of Indian chrysotile asbestos in rat bone marrow cells after 290 days of intratracheal inoculation (5 mg dust/0.5 ml normal saline), when it develops massive pulmonary fibrosis, were investigated. The pulmonary fibrosis was confirmed by both histopathological studies and increased collagen content in the lung of the treated animals. In the asbestotic rats a significant increase in chromosomal aberrations was recorded and a decrease in mitotic index of bone marrow cells. The types of chromosomal aberrations in these cells were chromatid gaps and breaks. The results indicate the significant cytogenetic changes in the bone marrow cells of asbestotic rats and also suggest that these changes directly or indirectly may be one of the biological events involved in eliciting the asbestos-mediated toxic responses.


Molecular docking study and development of an empirical binding free energy model for phosphodiesterase 4 inhibitors.
In the present work, several computational methodologies were combined to develop a model for the prediction of PDE4B inhibitors' activity. The adequacy of applying the ligand docking approach, keeping the enzyme rigid, to the study of a series of PDE4 inhibitors was confirmed by a previous molecular dynamics analysis of the complete enzyme. An exhaustive docking procedure was performed to identify the most probable binding modes of the ligands to the enzyme, including the active site metal ions and the surrounding structural water molecules. The enzyme-inhibitor interaction enthalpies, refined by using the semiempirical molecular orbital approach, were combined with calculated solvation free energies and entropy considerations in an empirical free energy model that enabled the calculation of binding free energies that correlated very well with experimentally derived binding free energies. Our results indicate that both the inclusion of the structural water molecules close to the ions in the binding site and the use of a free energy model with a quadratic dependency on the ligand free energy of solvation are important aspects to be considered for molecular docking investigations involving the PDE4 enzyme family.


The reliability and validity of patient self-rating of their own voice quality.
To provide preliminary data on the reliability and validity of dysphonic patients rating their own voice quality. Prospective reliability/validity assessment of voice ratings in dysphonic patients. The Royal Free Hampstead NHS Primary Care Trust. Thirty-five adult dysphonia patients recruited from ENT referrals to a speech and language therapy department. Exclusion criteria were (i) a hearing impairment which may affect auditory discrimination and (ii) a diagnosis of cognitive impairment which may affect task comprehension. Patient intra-rater reliability was assessed by test-retest ratings, using G (Grade), R (Rough), B (Breathy), A (Asthenic), S (Strained) (GRBAS). Validity was assessed by comparing (i) patient-clinician inter-rater reliability, (ii) patients' GRBAS ratings with their Vocal Performance Questionnaire (VPQ) responses. (i) Patients had lower intrarater reliability than clinicians (for G of GRBAS, kappa = 0.51 versus 0.74); (ii) patients consistently rated their voices more severely than clinicians (for G of GRBAS, mean rating = 1.4 versus 1.0); (iii) clinician-patient inter-rater agreement was no better than chance (paired t-test, all P < 0.05); (iv) patient ratings correlated significantly with vocal performance scores (r > 0.4, P < 0.05). Patients appear to have good validity and consistency using GRBAS as a self-perception tool. However, validity measured in terms of agreement with clinician ratings is poor. Voice patients may rate what they perceive rather than what they hear. Disagreement between patient and clinician ratings has implications for therapy aims, prognosis, patient expectations and outcomes. Where disagreement persists, the clinician may have to determine whether therapy priorities need redesigning to reflect patients' perceived needs, or to evaluate whether patient perceptions and expectations are unrealistic.


Highly efficient miniaturized coprecipitation screening (MiCoS) for amorphous solid dispersion formulation development.
Microprecipitated bulk powder (MBP) is a novel solid dispersion technology to manufacture amorphous formulations of poorly soluble compounds that cannot be processed by spray drying or melt extrusion. An efficient high-throughput screening method has been developed to aid the selection of polymer type, drug loading and antisolvent to solvent ratio for MBP formulation development. With a 96-well platform, the miniaturized coprecipitation screening (MiCoS) includes mixing of drug and polymer in dimethylacetamide, controlled precipitation to generate MBP, filtration/washing, drying and high throughput characterization. The integrated MiCoS approach has been demonstrated with a model compound, glybenclamide. Based on the solid state stability and kinetic solubility of the MBP, hydroxypropylmethylcellulose acetate succinate polymer with 40% or lower drug loading, and antisolvent (0.01 N HCl) to solvent (dimethylacetamide) ratio of 5:1 or higher were selected to make glybenclamide MBP. MiCoS can be applied to both early and late stage formulation processing. In early stage research programs, the system can be used to enable efficacy, pharmacokinetics or mini-toxicology studies for poorly water soluble molecules using minimal amount of drug substance (2-10mg). In late stage development programs, MiCoS can be used to optimize MBP formulation by expanding the experimental design space to include additional formulation variants.


Loss of PBAF promotes expansion and effector differentiation of CD8+ T cells during chronic viral infection and cancer.
During chronic viral infection and cancer, it has been established that a subset of progenitor CD8+ T cells continuously gives rise to terminally exhausted cells and cytotoxic effector cells. Although multiple transcriptional programs governing the bifurcated differentiation trajectories have been previously studied, little is known about the chromatin structure changes regulating CD8+ T cell-fate decision. In this study, we demonstrate that the chromatin remodeling complex PBAF restrains expansion and promotes exhaustion of CD8+ T cells during chronic viral infection and cancer. Mechanistically, transcriptomic and epigenomic analyses reveal the role of PBAF in maintaining chromatin accessibility of multiple genetic pathways and transcriptional programs to restrain proliferation and promote T cell exhaustion. Harnessing this knowledge, we demonstrate that perturbation of PBAF complex constrained exhaustion and promoted expansion of tumor-specific CD8+ T cells resulting in antitumor immunity in a preclinical melanoma model, implicating PBAF as an attractive target for cancer immunotherapeutic.


7q11.23 Microduplication: a recognizable phenotype.
Williams-Beuren syndrome is a well-known microdeletion syndrome with a recognizable clinical phenotype. The subtle phenotype of the reciprocal microduplication of the Williams-Beuren critical region has been described recently. We report seven further patients, and a transmitting parent, with 7q11.23 microduplication. All our patients had speech delay, autistic features and facial dysmorphism consistent with the published literature. We conclude that the presence of specific dysmorphic features, including straight, neat eyebrows, thin lips and a short philtrum, in our patients with speech delay and autistic features provides further evidence that the children with 7q11.23 microduplication have a recognizable phenotype.


Addisonian pigmentation associated with acute lymphoblastic leukemia: A rare paraneoplastic phenomenon.
Addisonian pigmentation usually presents with nonspecific symptoms and signs, which are often ignored or misdiagnosed as a sign of other more common diseases. We present a case of 12-year-old child in whom diffuse Addisonian hyperpigmentation of skin was associated with underlying acute lymphoblastic leukemia (B-type), a rare paraneoplastic phenomenon in hematological malignancies.


Adverse outcome pathways during zebrafish embryogenesis: a case study with paraoxon.
Using paraoxon as a reference acetylcholinesterase (AChE) inhibitor, the objective of this study was to develop an adverse outcome pathway (AOP) that provided quantitative linkages across levels of biological organization during zebrafish embryogenesis. Within normal zebrafish embryos, we first demonstrated that ache transcripts and AChE activity increased in a stage-dependent manner following segmentation. We then showed that static exposure of embryos to paraoxon (31.2-500 nM) from 5 to 96 hpf resulted in significant stage- and concentration-dependent AChE inhibition, albeit these effects were fully reversible within 48 h following transfer to clean water. However, even in the presence of significant AChE inhibition, exposure to non-teratogenic paraoxon concentrations (≤250 nM) did not adversely impact secondary motoneuron development at 96 hpf. Therefore, we investigated the potential effects of paraoxon exposure on spontaneous tail contractions at 26 hpf - an early locomotor behavior that results from innervation of primary (not secondary) motoneuron axons to target axial muscles. Based on these studies, the frequency of spontaneous tail contractions at 26 hpf - a developmental stage with minimal AChE expression and activity - was significantly higher following exposure to paraoxon concentrations as low as 31.2 nM. Overall, our data suggest that (1) normal AChE activity is not required for secondary motoneuron development and (2) spontaneous tail contractions at 26 hpf are sensitive to paraoxon exposure, an effect that may be independent of AChE inhibition. Using a well-studied reference chemical, this study highlights the potential challenges in developing quantitative AOPs to support chemical screening and prioritization strategies.


Multi-year optimization of malaria intervention: a mathematical model.
Malaria is a mosquito-borne, lethal disease that affects millions and kills hundreds of thousands of people each year, mostly children. There is an increasing need for models of malaria control. In this paper, a model is developed for allocating malaria interventions across geographic regions and time, subject to budget constraints, with the aim of minimizing the number of person-days of malaria infection. The model considers a range of several conditions: climatic characteristics, treatment efficacy, distribution costs, and treatment coverage. An expanded susceptible-infected-recovered compartment model for the disease dynamics is coupled with an integer linear programming model for selecting the disease interventions. The model produces an intervention plan for all regions, identifying which combination of interventions, with which level of coverage, to use in each region and year in a 5-year planning horizon. Simulations using the model yield high-level, qualitative insights on optimal intervention policies: The optimal intervention policy is different when considering a 5-year time horizon than when considering only a single year, due to the effects that interventions have on the disease transmission dynamics. The vaccine intervention is rarely selected, except if its assumed cost is significantly lower than that predicted in the literature. Increasing the available budget causes the number of person-days of malaria infection to decrease linearly up to a point, after which the benefit of increased budget starts to taper. The optimal policy is highly dependent on assumptions about mosquito density, selecting different interventions for wet climates with high density than for dry climates with low density, and the interventions are found to be less effective at controlling malaria in the wet climates when attainable intervention coverage is 60 % or lower. However, when intervention coverage of 80 % is attainable, then malaria prevalence drops quickly in all geographic regions, even when factoring in the greater expense of the higher coverage against a constant budget. The model provides a qualitative decision-making tool to weigh alternatives and guide malaria eradication efforts. A one-size-fits-all campaign is found not to be cost-effective; it is better to consider geographic variations and changes in malaria transmission over time when determining intervention strategies.


Calcium dependency of inhibition by arachidonic acid of compound 48/80-induced histamine release from mast cells.
Compound 48/80 ( compd 48/80)-induced histamine secretion from rat mast cells was inhibited almost completely by pretreatment of the cells at 37 degrees with 25 microM arachidonic acid in the presence of 1.8 mM Ca2+. As the Ca2+ concentration was reduced below 1.8 mM, 25 microM arachidonic acid became less inhibitory and, then, progressively more stimulatory for histamine release with or without compd 48/80. No additive effect on histamine release was obtained by combining compd 48/80 and arachidonic acid. Pretreatment of mast cells with lidocaine, an inhibitor of Ca2+ binding to phospholipid, or with nordihydroguaiaretic acid, an inhibitor of Ca2+ flux and lipoxygenase, stimulated arachidonic acid-induced histamine release. Arachidonic acid also inhibited a compd 48/80-induced spike increment of intracellular 45Ca2+ uptake and a decrease of total 45Ca2+ uptake by 45Ca2+-preloaded mast cells. Arachidonic acid and Ca2+ also suppressed melittin-induced histamine release and compd 48/80-induced release of radioactivity from mast cells preloaded with [3H]arachidonic acid. These results suggest that exogenous arachidonic acid or its metabolite(s) may interact with membrane-associated Ca2+, disturbing Ca2+ availability for the trigger mechanism of compd 48/80-induced histamine release or inhibiting the subsequent metabolism of arachidonic acid via the lipoxygenase pathway to form active metabolites involved in the histamine liberating mechanism.


Effect of universal adhesive etching modes on bond strength to dual-polymerizing composite resins.
Information is lacking as to the effect on bond strength of the etching modes of universal adhesives when they are used to bond dual-polymerizing composite resins to dentin. The purpose of this in vitro study was to investigate the bonding of dual-polymerizing foundation composite resins to dentin when universal bonding agents are used in self-etch or etch-and-rinse modes. Sixty caries-free, extracted third molar teeth were sectioned transversely in the apical third of the crown and allocated to 12 groups (n=5). Three different bonding agents (Scotchbond Universal, OptiBond XTR, All-Bond Universal) were used to bond 2 different dual-polymerizing composite resins (CompCore AF or CoreFlo DC) to dentin, using 2 different etching approaches (etch-and-rinse or self-etch). The specimens were sectioned into sticks (1×1×8 mm) with a precision saw. The bond strength of the specimens was tested under microtensile force at a crosshead speed of 0.5 mm/min. The data were analyzed using a 3-way ANOVA, a Games-Howell post hoc comparisons model, and Student t tests with Bonferroni corrections (α=.05). In the overall model, the composite resin used had no effect on bond strength (P=.830). The etching protocol by itself also did not have a significant effect (P=.059), although a trend was present. The bonding agent, however, did have an effect (P<.001) on bond strength. Also, a significant interaction effect was found for the bonding agent and etching protocol on bond strength (P<.001). The etching protocol influenced the bond strength when Scotchbond Universal (P<.008) and All-Bond Universal (P<.004) were used but not when OptiBond XTR was used (P=1.00). A self-etch protocol provided significantly higher bond strength when Scotchbond Universal was used, whereas with All-Bond Universal, an etch-and-rinse protocol, provided higher bond strength. When universal bonding agents were used to secure dual-polymerizing composite resins to dentin, no single etching protocol is better than another. Depending on which bonding agent is being used, one etching mode may perform better.


The treatment of Lewisite burns with laser debridement---'lasablation'.
Lewisite (dichloro (2-chlorovinyl) arsine) was first synthesised in 1918 and its potential for use in military confrontations as a vesicant agent has been widely recognised. These agents cause blistering skin reactions with resultant full thickness burns. Effective treatments to date have been delayed by the lack of suitable animal models. Porcine skin has recently been used successfully to model the development and natural history of these burn injuries. A large white pig model (n=6) was employed to investigate the effectiveness of CO(2) and Erbium-YAG lasers (EYL) in laser dermabrasion of established Lewisite burns. Burns underwent treatment at 4 days post-exposure and were assessed at 1, 2 and 3 weeks, thereafter, for the rate of epithelial healing. The re-epithelialisation rates in the laser dermabraded groups were accelerated by a factor of four compared to untreated controls by the first week (analysis of vartiance, ANOVA, P=0.006 for pulsed CO(2) and P=0.011 for Erbium-YAG). Ablation of the burn eschar was thought to accelerate the rate of healing by causing partial debridement. This method has been termed 'lasablation' and represents a significant advance in the clinical management of this type of injury.


Conceptual framework for support of caregivers of children diagnosed with intellectual disabilities in Gauteng.
children. Their needs are not met. There is lack of support for caregivers and no existing conceptual framework of support. There was therefore a need to develop a conceptual framework of support for caregivers. The purpose of this study was to develop a conceptual framework of support for caregivers of children diagnosed with intellectual disabilities in the Gauteng province. Three phases were followed: an empirical phase, a classification of concepts and a development phase. A conceptual framework was developed based on the results of the empirical phase, after concepts were classified. The conceptual framework of support for caregivers of children diagnosed with intellectual disabilities in the Gauteng province was developed, consisting of six components, namely agents, recipients, context, procedures, dynamics and terminus. A framework will guide all stakeholders on how to support caregivers of children diagnosed with intellectual disabilities in the Gauteng province.Contribution: The framework serves as a guide for future studies aiming at developing support programmes and models for caregivers, and further provide guidance on how caregivers can effectively be supported when used in mental healthcare institutions.


Ammonia nitrogen recovery from biogas slurry by SCP production using Candida utilis.
The safe and robust yeast Candida utilis was employed for nitrogen recovery as single cell protein from biogas slurry. The maximum biomass of 6.2 g/L with protein content of 53.5% was produced in batch cultivation with glucose as the carbon source, C/N ratio of 3:1, NH4+-N concentration of 3000 mg/L, initial pH of 8.0, and the addition of 0.35% (w/v) Na2HPO4. It was speculated that C. utilis can grow well with free ammonia below 197 mg/L. In fed-batch fermentation, a biomass of 14.8 g/L was obtained, and the maintenance of aerobic conditions was critical to improving the production of single cell protein. The sterilized and non-sterilized biogas slurry can be used as an effective pH regulator. The obtained single cell protein was a nutritious, safe, and reliable protein source. This study provides novel insights into nitrogen recovery via C. utilis as a single cell protein from biogas slurry.


Tracing the fate of microplastic in wastewater treatment plant: A multi-stage analysis of treatment units and sludge.
Microplastic (MP) pollution is ubiquitous in the environment presenting a global problem for both scientists and the general public. One of the major pathways of MPs entering the natural environment is through wastewater treatment plants (WWTPs). Once MPs reach the natural environment, they are posing threat to aquatic ecosystems and public health. The aim of this study is to investigate the concentration, morphology, and composition of MPs in different treatment units of a WWTP. Sampling included different points across WWTP in the water and sludge lines. Pre-treatment of the samples consists of advanced Fenton oxidation, and alkaline and enzymatic digestion followed by density separation. Once the particles were isolated, their morphology and size were studied using a stereoscopic and optical microscope followed by final confirmation with ATR-FTIR and micro-FTIR spectroscopy. Microplastic particle concentrations exhibit significant reductions as water undergoes treatment in the WWTP. For summer sampling, concentrations decreased from 351 MP/L (influent) to 35 MP/L (primary clarifier), 32 MP/L (biological reactor), and 13 MP/L (2.3 MP/L) (secondary clarifier). Similarly, winter sampling showed reductions from 403 MP/L (influent) to 159 MP/L (primary clarifier), 178 MP/L (biological reactor), and 26 MP/L (5.6 MP/L) (secondary clarifier). Removal efficiency of WWTP is high and exceeds 96%. The most abundant morphology is fibers followed by fragments and films. Polymers such as PE, synthetic cellulose, PP, PVC, PE-PP, PEEA, PA, acrylamide, and PES are widely detected in different units of WWTP. The number of MPs that are avoided from being emitted into the environment through direct water discharge was estimated to be 9.1 × 1012 MP/year. Removed MPs tend to accumulate in the sludge that is used for agricultural purposes although it should be managed as waste properly, avoiding the transition of MPs pollutants to terrestrial ecosystems adding to the number of MPs that will inevitably end up in receiving water bodies through direct WWTP effluent discharge that was set in 5.1 × 1010 MP/year in the studied WWTP.


Timing of secondhand smoke, pet, dampness or mould exposure and lung function in adolescence.
The relevance of timing of exposure in the associations of secondhand tobacco smoke (SHS), pets, and dampness or mould exposure with lung function is unclear. We investigated the relevance of timing of these exposures for lung function in adolescence. We used data from participants of the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort with spirometric measurements at ages 12 and 16 years (n=552). Data on residential exposure to SHS, pets, and dampness or mould were obtained by repeated parental questionnaires. We characterised timing of exposure through longitudinal patterns using latent class growth modelling and assessed associations of these patterns with FEV1 and FVC at ages 12 and 16 and FEV1 and FVC growth between ages 12 and 16 using linear regression models. Childhood SHS exposure was associated with reduced FEV1 growth/year (95% CI) (-0.34% (-0.64% to -0.04%)). Late childhood and early life pet exposure was associated with increased FEV1 growth (0.41% (0.14% to 0.67%)) and reduced FVC growth (-0.28% (-0.53% to -0.03%)), respectively, compared with very low exposure. Early life dampness or mould exposure was associated with reduced lung function growth. All time windows of SHS exposure tended to be associated with lower attained lung function and pet exposure tended to be associated with higher FEV1. SHS exposure during childhood could lead to reduced lung function growth and lower attained lung function in adolescence. While pet exposure in late childhood may not adversely affect lung function, early childhood pet exposure may slow down FVC growth in adolescence.


Determination of Metoclopramide Hydrochloride in Pharmaceutical Formulations using N-Oxidation Caroate.
To develop two (titrimetric and spectrophotometric) simple, rapid, sensitive and cost-effective methods for the determination of metoclopramide (MCP) in pharmaceutical dosage forms. The titrimetric method (A) was based on the N-oxidation reaction involving the use of potassium hydrogen peroxymonosulfate and subsequent iodometric back titration of a known residual reagent. The spectrophotometric method (B) was based on derivatization of MCP with potassium hydrogen peroxymonosulfate in the presence of iodide to produce a chromogen (triiodide) with a wavelength of maximum absorption at 350 nm. Method "A" was applicable over the concentration range of 0.25-3.5 mg to end volume 10 mL. In method "B", Beer's law was obeyed over the concentration range of 0.3-3.5 μg/mL with molar absorptivity of 24600 L/mol cm. The limits of quantification were calculated to be 0.25 mg/10 mL (A) and 0.2 μg/mL (B), respectively. The proposed methods were suitable for determination of MCP as a pure substance in tablets and injection.


Physical activity, cardiovascular health and mood state in older adults.
Many older adults eat poorly balanced diets and are physically inactive, posing a risk to their cardiovascular and mental health. The benefits of healthful living extend beyond cardiovascular health and disease risk reduction such that physical activity has been shown to positively affect mood state. This was a cross-sectional investigation completed at three senior lunch program sites in Charlotte, NC to assess the status and relationship of nutrition, physical activity patterns, and mood state in older adults, prior to the center offering a new nutritional and physical activity intervention. Some significant relationships between cardiovascular indicators and mood were found.


Summary of major radiation fractionation and chemotherapy trials for organ preservation therapy in locally advanced head and neck squamous cell carcinoma.
To review radiation fractionation and chemotherapy trials for patients undergoing organ preservation therapy for locally advanced head and neck squamous cell carcinoma. Radiation therapy fractionation and chemotherapy trial results as well as historical evidence are systematically reviewed. Trial results, which involve nearly 30,000 patients, have been interpreted, compared, and presented in a structured manner to demonstrate the changing approaches in treatment over the years from the 1960s to the present. The review includes data from the split-course radiation therapy era, meta-analyses of chemotherapy and radiation therapy fractionation trials, cetuximab trials, "triple-drug trials," and modern trials of induction chemotherapy followed by concomitant chemotherapy and radiation therapy. This summary will be useful to clinicians making treatment decisions today and to investigators designing trials in the future.


Distinct signaling pathways activated by "extracellular" and "intracellular" serotonin in heart valve development and disease.
Cardiac valve diseases are often due to developmental anomalies that progressively lead to the abnormal distribution and organization of extracellular matrix proteins overtime. Whereas mechanisms underlying adult valvulopathies are unknown, previous work has shown a critical involvement of the monoamine serotonin in disease pathogenesis. In particular, the interaction of serotonin with its receptors can activate transforming growth factor-β1 (TGF-β1) signaling, which in turn promotes extracellular matrix gene expression. Elevated levels of circulating serotonin can lead to aberrant TGF-β1 signaling with significant effects on cardiac valve structure and function. Additional functions of serotonin have recently been reported in which internalization of serotonin, through the serotonin transporter SERT, can exert important cytoskeletal functions in lieu of simply being degraded. Recent findings demonstrate that intracellular serotonin regulates cardiac valve remodeling, and perturbation of this pathway can also lead to heart valve defects. Thus, both extracellular and intracellular mechanisms of serotonin action appear to be operative in heart valve development, functionality, and disease. This review summarizes some of the salient aspects of serotonin activity during cardiac valve development and disease pathogenesis with an understanding that further elaboration of intracellular and extracellular serotonin pathways may lead to beneficial treatments for heart valve disease.


Preparation and FTIR, Raman and SEM characterizations of konjac glucomannan-KCl electrogels.
Konjac glucomannan (KGM) electrogels were successfully prepared under alternating current (AC) in the presence of potassium chloride (KCl). The structure of the gels was studied using Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, and scanning electron microscopy (SEM). A single-factor experiment was performed to optimize the preparation of the gels. Our results showed that KGM was degraded under AC and partially deacetylated. KGM and KCl formed the structure , and electrogels with porous structures retained some acetyl groups. Furthermore, as the KCl concentrations, voltages, time, and KGM concentrations increased, the viscoelastic moduli of the gels increased; the moduli decreased when the KCl concentrations, voltages, and time exceeded critical values.


Bioactive stability of microalgal protein hydrolysates under food processing and storage conditions.
The stability of antioxidant protein hydrolysates from Spirulina sp. LEB 18 was evaluated under food processing conditions and after in vitro digestion. Protein hydrolysates with degrees of hydrolysis of 50.6% and 60% were obtained after 90 and 120 min of reaction, respectively, with Protemax 580 L. The results indicated that the antioxidant activity of protein hydrolysates was maintained following application of heat treatment (- 18 °C, 63 °C, and 100 °C). Moreover, the ability of protein hydrolysates to inhibit the 2,2-diphenyl-1-picrylhydrazyl radical was increased by nearly 25% upon exposure to acidified media (pH 4 and pH 6). In general terms, the protein hydrolysates were bioavailable after digestion with pepsin and pancreatin. This study supports the incorporation of bioactive peptides from microalgae into functional foods by demonstrating the maintenance of their biological activities in the face of food processing conditions and gastrointestinal digestion.


In vitro synergistic activity of fosfomycin in combination with other antimicrobial agents against carbapenem-resistant Klebsiella pneumoniae isolated from patients in a hospital in Thailand.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes high morbidity and mortality worldwide. The purpose of the study was to assess the synergistic activity of fosfomycin in combination with other antimicrobial agents against CRKP isolated from patients in Songklanagarind Hospital, Thailand. A total of 35 K. pneumoniae isolates were obtained from patients in Songklanagarind Hospital. The MICs of imipenem and meropenem were determined in all isolates by broth microdilution. In all CRKP isolates, the presence of carbapenemase and extended-spectrum β-lactamase (ESBL) genes was investigated by PCR, while the production of these enzymes was determined by combined disk test. In the carbapenemase-genes-negative CRKP isolates, the porin loss and efflux pump were characterized by SDS-PAGE and broth microdilution, respectively. Finally, the synergistic effects of fosfomycin and other antimicrobial agents were evaluated by checkerboard analysis. Twenty-one of 35 K. pneumoniae isolates were classified as CRKP. Most of CRKP isolates carried blaNDM-1 (n = 18), blaSHV (n = 21), blaCTX-M (n = 21), and blaTEM (n = 16). In fosfomycin-based combination, the result showed that the highest synergistic activity in this study was observed in the combination of fosfomycin and gentamicin (61.9%). These findings suggested that the fosfomycin and gentamicin combination might be useful as a possible treatment option for CRKP infection.


Wedge-shaped slice-selective adiabatic inversion pulse for controlling temporal width of bolus in pulsed arterial spin labeling.
In pulsed arterial spin labeling (PASL) methods, arterial blood is labeled by inverting a slab with uniform thickness, resulting in different temporal widths of boluses in vessels with different flow velocities. This limits the temporal resolution and signal-to-noise ratio (SNR) efficiency gains in PASL-based methods intended for high temporal resolution and SNR efficiency, such as turbo-ASL and turbo-QUASAR. A novel wedge-shaped (WS) adiabatic inversion pulse is developed by adding in-plane gradient pulses to a slice-selective (SS) adiabatic inversion pulse to linearly modulate the inversion thicknesses at different locations while maintaining the adiabatic properties of the original pulse. A hyperbolic secant (HS)-based WS inversion pulse was implemented. Its performance was tested in simulations and in phantom and human experiments and compared with an SS HS inversion pulse. Compared with the SS inversion pulse, the WS inversion pulse was capable of inducing different inversion thicknesses at different locations. It could be adjusted to generate a uniform temporal width of boluses in arteries at locations with different flow velocities. The WS inversion pulse can be used to control the temporal widths of labeled boluses in PASL experiments. This should benefit PASL experiments by maximizing labeling duty cycle and improving temporal resolution and SNR efficiency. Magn Reson Med 76:838-847, 2016. © 2015 Wiley Periodicals, Inc.


Tail state limited photocurrent collection of thick photoactive layers in organic solar cells.
We analyse organic solar cells with four different photoactive blends exhibiting differing dependencies of short-circuit current upon photoactive layer thickness. These blends and devices are analysed by transient optoelectronic techniques of carrier kinetics and densities, air photoemission spectroscopy of material energetics, Kelvin probe measurements of work function, Mott-Schottky analyses of apparent doping density and by device modelling. We conclude that, for the device series studied, the photocurrent loss with thick active layers is primarily associated with the accumulation of photo-generated charge carriers in intra-bandgap tail states. This charge accumulation screens the device internal electrical field, preventing efficient charge collection. Purification of one studied donor polymer is observed to reduce tail state distribution and density and increase the maximal photoactive thickness for efficient operation. Our work suggests that selecting organic photoactive layers with a narrow distribution of tail states is a key requirement for the fabrication of efficient, high photocurrent, thick organic solar cells.


The nature and origin of DNA single-strand breaks determined with the comet assay.
After treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methyl methanesulfonate (MMS) and hydrogen peroxide, the level of alkali-labile sites and single-strand breaks (ssb) in DNA was investigated, using the comet assay. The ability of antioxidant pre-treatment to decrease DNA damage was assessed. Results showed the following. (a) All single-strand (ss) DNA breaks detected immediately after MNNG- and MMS-treatment in hamster V79 cells had the character of alkali-labile sites while true ssb of DNA were represented only as a minor statistically significant (p < 0.01) fraction at the highest MMS concentration. (b) Most ss DNA breaks detected immediately after H2O2-treatment had the character of true breaks in DNA and alkali-labile sites represented only a minor fraction. (c) Pre-treatment of hamster V79 and human CaCo2 cells with vitamin E significantly reduced the number of breaks induced by hydrogen peroxide, but has no effect on the level of breaks induced by MNNG or MMS. We suggest that MNNG and MMS do not induce significant oxidative damage of DNA. Most of breaks induced by hydrogen peroxide have the nature of oxidative lesions of DNA. (d) In contrast to the effect of vitamin E, stobadine (STB) decreased not only the breaks induced by hydrogen peroxide but also those induced by MNNG and MMS. The reduced level of DNA damage in STB pre-treated samples could be due to inactivation of these alkylating agents by STB.


Zebrafish atonal homologue zath3 is expressed during neurogenesis in embryonic development.
Basic helix-loop-helix (bHLH) transcriptional activators function in development of various cell lineages, including the central nervous system. One of the bHLH proteins, Math3/Xath3/NeuroM, was suggested to act as a late proneural gene in the mouse, Xenopus, and chick. Here, we isolated a zebrafish homologue, named zath3, and analyzed its expression pattern in zebrafish embryos. In the neural plate, zath3 is expressed first in the primordia of the tegmentum and trigeminal ganglia and three classes of primary neurons: sensory neurons, interneurons, and motor neurons. During later development, zath3 transcripts were localized along the boundaries of the optic tectum in the midbrain and rhombomeres of the hindbrain. Analyses of zath3 expression in three mid-hindbrain boundary mutants, acerebellar, no isthmus, and spiel-ohne-grensen, indicated that distribution of zath3 mRNAs in the midbrain and hindbrain was dramatically disturbed. In addition, these mutants also affect expression of zath3 in the neuroretina.


Cohort study on the prognosis of acute cerebral infarction in different circulatory systems at 1-year follow-up.
To evaluate the prognosis of acute cerebral infarction at 1-year follow-up in different circulation infarctions. Clinical data of 858 consecutive patients with acute cerebral infarction were collected. Of the 858 cases, 21 (2.45%) were lost to follow-up and 837 completed follow-up and thus were enrolled in this study. At 1-year follow-up, death or moderate-to-severe dysfunction (modified Rankin Scale (mRS) ≥ 3 points) was regarded as the poor prognostic endpoint. Univariate analysis and multivariate logistic stepwise regression analysis were performed to assess the prognosis. The prediction probability of indicators was obtained for the multivariate model, and the receiver operating characteristic curve was delineated to calculate the area under the curve (AUC) to predict the fitness of the model. The older the age, the greater the probability of a poor prognosis. Patients with previous diabetes and cerebral infarction had a poor prognosis. The higher the National Institutes of Health Stroke Scale and mRS scores and the lower the Barthel index at admission, the worse the prognosis of the patients. The longer the hospital stay, the worse the prognosis of the patients. The prognosis of different circulation infarctions was different. The AUC of the multivariate model was AUC = 0.893, and the 95% confidence interval was 0.870-0.913, indicating a good fit. The prognosis of anterior circulation infarction (ACI) was worse than that of posterior circulation infarction (PCI) (P < 0.05). The prognosis of patients with ACI and PCI was not significantly different from that of patients with ACI or PCI alone (P > 0.05). Diabetes, the Barthel index at admission and previous cerebral infarction are poor prognostic factors of acute cerebral infarction. The prognosis of ACI is worse than that of PCI. Different factors affect the prognosis of different circulatory system infarctions.


Apoptotic sperm biomarkers and their correlation with conventional sperm parameters and male fertility potential.
To investigate the relationship between sperm apoptotic biomarkers and patient clinical characteristics, conventional sperm parameters and fertility potential. Sperm analysis, phospholipid asymmetry, mitochondrial membrane potential (MMP) and DNA denaturation were assessed in 142 males of infertile couples. Seventy-three couples were allocated to the natural conception group, and 55 couples underwent IVF or ICSI. DNA denaturation correlated positively with age and negatively with testicular volume (TV). MMP correlated negatively with BMI and FSH and positively with TV. Normal viable sperm correlated positively with TV and negatively with age, BMI and FSH. DNA denaturation was associated with a significantly lower natural pregnancy rate (OR 5.4, 95% CI:1.3-22, p = 0.011). Sperm apoptosis is related to male age, BMI, testicular volume and FSH. Among the apoptotic markers, only DNA denaturation has been found to predict natural pregnancy better than conventional sperm parameters.


Prostate cancer metastasis mimicking appendicitis-A rare but important differential diagnosis in PET/CT imaging.
Prostate cancer most commonly metastasizes to lymph nodes, bones, the liver, and the lungs. Prostate cancer carcinomatosis with an affinity for the appendix is not well described in current literature and is usually reported with acute appendicitis as the primary presentation. A 65-year-old male with a history of recurrent prostate cancer presented with an increase in PSA value. 18F-PSMA-1007 PET/CT showed nodular tissue growth and increased PSMA uptake in the prostate, on the appendix, in the umbilicus, and in several intra- and extra pelvic lymph nodes. The patient had no symptomatic complaints at time of referral. Imaging findings of the appendix resembling characteristic findings of acute appendicitis raised doubts about the interpretation of these as inflammatory disease or peritoneal carcinomatosis secondary to prostate cancer. This case demonstrates the importance of correct differentiation between the 2 conditions based on imaging, clinical symptomatology, and patient history to provide proper care in time.


Activity stain for pyruvate decarboxylase in polyacrylamide gels.
A method for the localization of pyruvate decarboxylase bands in polyacrylamide gels after electrophoresis using 1,2-dianilinoethane in dilute acetic acid as reagent for acetaldehyde formed from pyruvate by the holoenzyme is described. A white condensation product forms in the bands and precipitates within a few minutes. The more or less opaque bands can be viewed and photographed against a dark background and scanned in a densitometer. The detection limit is at about 10 mU pyruvate decarboxylase when the gels are bathed in the staining solution for 20 min. Several other methods were tested and failed to produce satisfactory results.