The incidence of primary fallopian tube cancer in the United States.
The objective of this study was to report the incidence of primary fallopian tube carcinoma (PFTC) in the United States population and to describe associated demographic and clinical factors. A total of 3051 PFTC cases diagnosed from 1998 to 2003, reported from population-based cancer registries, were analyzed. Registries contributing data represent 83.1% of the U.S. population. Data are presented by age, race/ethnicity, U.S. census region, stage, histology, grade, and laterality. Trends in incidence over time from 1998 to 2003 are also presented. The incidence rate was 0.41 per 100,000 women from 1998 to 2003. White, non-Hispanic women and women aged 60-79 had the highest incidence rates (p<0.0001). The majority (88%) of PFTCs were adenocarcinomas; serous adenocarcinomas accounted for 44% and endometrioid adenocarcinomas for 19% of adenocarcinoma diagnoses. Essentially half (49.9%) of PFTCs were poorly differentiated; 89% were unilateral at diagnosis. Stage at diagnosis was fairly evenly distributed among localized (36%), regional (30%), and distant (32%). Overall, rates of PFTC remained stable over time. Among women aged 65-69, incidence rates increased significantly by 3.8% per year from 1998 to 2003 (p<0.05). This report provides characteristics of PFTC using the largest number of cases assembled in one study to date. Although the demographic characteristics of PFTC are similar to those of ovarian cancer, stage at diagnosis and the stable trend observed in PFTC are in contrast to ovarian cancer. Future studies should focus on examining the increasing trend of PFTC among 65- to 69-year-old women.


Vibrational spectroscopy: can density functional theory cope with highly electronegative atoms?
Vibrational properties of molecules composed solely of highly electronegative atoms are studied by means of density functional methods. Performance of different combinations of exchange and correlation functionals is tested. It is demonstrated that certain functionals can successfully simulate infrared spectra of systems containing only fluorine, oxygen and nitrogen.


Rapid screening of TCR-pMHC interactions by the YAMTAD system.
Personalized immunotherapy, such as cancer vaccine and TCR-T methods, demands rapid screening of TCR-pMHC interactions. While several screening approaches have been developed, their throughput is limited. Here, the Yeast Agglutination Mediated TCR antigen Discovery system (YAMTAD) was designed and demonstrated to allow fast and unbiased library-on-library screening of TCR-pMHC interactions. Our proof-of-principle study achieved high sensitivity and specificity in identifying antigens for a given TCR and identifying TCRs recognizing a given pMHC for modest library sizes. Finally, the enrichment of high-affinity TCR-pMHC interactions by YAMTAD in library-on-library screening was demonstrated. Given the high throughput (106-108 × 106-108 in theory) and simplicity (identifying TCR-pMHC interactions without purification of TCR and pMHC) of YAMTAD, this study provides a rapid but effective platform for TCR-pMHC interaction screening, with valuable applications in future personalized immunotherapy.


Effects of N-methylnaloxone and N-methylnaltrexone on nociception and precipitated abstinence in mice.
Subcutaneous administrations of naloxone and naltrexone have already been shown to enhance nociceptive reactions in mice. The present study was undertaken to examine the effects of N-methyl-naloxone and N-methylnaltrexone on nociception using the hot plate test (dose range: 0.3 to 30 mg kg-1s.c.). The latter compounds were selected to differentiate the central and peripheral components of hyperalgesia. Unlike naloxone, N-methyl-naloxone did not produce hyperalgesia. Similarly low doses of N-methylnaltrexone did not enhance the jumping response. However, a high dose of N-methylnaltrexone (30 mg kg-1 s.c.) significantly reduced the jumping latencies 2 h after its administration. This phenomenon indicated that it might be converted to an active metabolite. Further, N-methylnaloxone and N-methylnaltrexone were very weak in precipitating the signs of abstinence in mice rendered acutely dependent on morphine. Two factors, poorer penetration into the CNS and steric hindrance, might render the N-methylated antagonists weak. Hence, both these factors should be considered when interpreting the effects after quaternary derivatives of opioid antagonists.


Keeping It in the Family: ATRX Loss Promotes Persistent Sister Telomere Cohesion in ALT Cancer Cells.
In this issue of Cancer Cell, Ramamoorthy and Smith report that cancer cells that maintain their chromosome ends through alternative lengthening of telomeres (ALT) display persistent sister telomere cohesion. This delayed resolution of sister telomere cohesion depends upon the loss of ATRX and its histone-sequestering function and is associated with increased recombination between sister telomeres.


AlgU controls environmental stress adaptation, biofilm formation, motility, pyochelin synthesis and antagonism potential in Pseudomonas protegens SN15-2.
Pseudomonas protegens is a typical plant-growth-promoting rhizobacterium that can serve as an agricultural biocontrol agent. The extracytoplasmic function (ECF) sigma factor AlgU is a global transcription regulator controlling stress adaption and virulence in Pseudomonas aeruginosa and Pseudomonas syringae. Meanwhile, the regulatory role of AlgU in the biocontrol ability of P.protegens has been poorly studied. In this study, deletion mutations of algU and its antagonist coding gene mucA were constructed to investigate the function of AlgU in P.protegens SN15-2 via phenotypic experiment and transcriptome sequencing analysis. On the basis of phenotypic analyses, it was concluded that the AlgU whose transcription was induced by osmotic stress and oxidative stress positively regulated biofilm formation and tolerance towards osmotic, heat, and oxidation stresses, while it negatively regulated motility, pyochelin synthesis, and the ability to inhibit pathogens. On the basis of the RNA-seq analysis, compared to the wild-type strain, 12 genes were significantly upregulated and 77 genes were significantly downregulated in ΔalgU, while 407 genes were significantly upregulated and 279 genes were significantly downregulated in ΔmucA, indicating the involvement of AlgU in several cellular processes, mainly related to resistance, carbohydrate metabolism, membrane formation, alginate production, the type VI secretion system, flagella motility and pyochelin production. Our findings provide insights into the important role of AlgU of P.protegens in biocontrol, which is of value in improving the biocontrol ability of P.protegens.


Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors.
Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dose-dependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 microg/kg x min 8-Methoxymethyl-IBMX, 1 microg/kg x min sildenafil, 5 microg/kg x min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of PPA reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor.


Prospective clinical study on cochlear function after erbium:yttrium-aluminum-garnet laser stapedotomy.
To assess whether the application of the emitting erbium:yttrium-aluminum-garnet (Er:YAG) laser in stapedotomy has negative effects on vestibular and cochlear functions. Prospective, with 12 to 14 months follow-up. Academic tertiary referral center. Twenty-four patients undergoing stapedotomy (primary surgery) in otosclerosis. All patients underwent Er:YAG laser-assisted stapedotomy for otosclerosis between January 2000 and June 2002. Early (1-3 days after surgery) and late (12-14 months after surgery) postoperative bone-conduction thresholds and the presence of post-operative tinnitus and vertigo were analyzed. In addition, the relation between applied laser energy and postoperative bone-conduction thresholds was calculated. In 22 patients, unchanged preoperative minus early postoperative pure-tone bone-conduction averages at 1, 2, and 4 kHz were observed. In one patient, a slight early deterioration between 10 and 20 dB was seen. In 18 patients, unchanged preoperative minus late postoperative pure-tone bone-conduction averages at 1, 2, and 4 kHz were observed. In two patients, a slight late deterioration between 10 and 20 dB was seen. In two patients, a new postoperative tinnitus was observed. No patient suffered from vertigo at the time of second evaluation. No correlation between applied laser energy and both postoperative bone-conduction thresholds was found. The Er:YAG laser stapedotomy in otosclerosis is a safe technique. Vestibular and cochlear function is not significantly disturbed after Er:YAG laser stapedotomy.


Current practices for viability testing of cryopreserved cord blood products: an international survey by the cellular therapy team of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative.
Viability testing is a common practice in laboratories. The goal of this study was to ascertain current laboratory practices internationally for performing viability testing for cryopreserved cord blood (CB) products and glean information about how to standardize the method to improve interlaboratory reproducibility. A survey to evaluate current laboratory practices for viability testing was designed and distributed internationally. The question topics included sampling and testing methods, responses to unexpected results, and the rating of the reliability of the CB quality tests, together with expectations for standardization. There were 32 respondents to the survey, of whom 28 responded to the more detailed questionnaire about viability methods. Overall, responses indicated that various stains were used among the laboratories, and when multiple sites used the same viability stain the methods differed. The majority of the respondents were in favor of standardizing the viability testing methods. A wide variety of preferences were communicated about how to standardize the method, but a majority did advocate the use of 7-aminoactinomycin D (7-AAD) with flow cytometry. The survey results revealed a variety of tests and inconsistent interlaboratory practices for performing the viability assay. Flow cytometry with a 7-AAD dye was suggested as a first step toward standardization.


Total versus conventional robotic-assisted cyst excisions and hepaticojejunostomies in children with choledochal cysts: a case-control study.
The current study's primary aim is to compare the safety and effectiveness between total and conventional robot-assisted cyst excisions and hepaticojejunostomies in children with choledochal cysts (CCs). Patients suffering from CCs treated with either total or conventional robot-assisted procedures (TRAS or CRAS) between December 2019 and February 2021 were analyzed retrospectively. Data collected included the characteristics, operative and postoperative details. The risk factors for conversion of TRAS to CRAS were analyzed by logistic regression analysis. There were 50 patients who underwent TRAS and CRAS, respectively, and 19 patients were transferred to CRAS. The operation time in the TRAS group was significantly higher than that of the CRAS group, while the time to taking water and hospital stay were significantly shorter (p < 0.05). No significant difference was observed in complications between the groups (p = 0.325). The risk factors for conversion of TRAS to CRAS were age ≥ 48 months, thickness of abdominal wall (TAW) ≥ 1.3 cm and upper abdominal length (UAL) ≥ 9.5 cm. Both TRAS and CRAS are safe and feasible. Performing TRAS is recommended for patients whose age ≥ 48 months, TAW ≥ 1.3 cm and UAL ≥ 9.5 cm, while for others, it is recommended to perform CRAS.


Effect of secretin on stress-induced gastric bleeding in rats.
The effect of secretin on gastric bleeding induced by water (20 degrees C) immersion stress was studied by means of either perfusion of hydrochloric acid (0.13 N) or instillation of hydrochloric acid solution (0.4 N) into the rat stomach. When the stomach was perfused with acid solution, gastric bleeding occurred 20 min after the stress of water immersion and the amount of bleeding increased with time. It was found that integrated amounts of gastric bleeding after stress were more significantly decreased in the secretin-treated group (7.5 clinical units/kg/hr) than the saline control. On the other hand, intraduodenal administration of cimetidine (100 mg/kg) or propantheline (30 mg/kg) did not affect gastric bleeding. It was also revealed that the total amount of glycoprotein in the 4-hr perfusate was decreased 30% by the water immersion, but that secretin treatment prevented the 30% decrease in glycoprotein in the perfusate. In experiments on intragastric instillation of hydrochloric acid solution, it was found that gastric bleeding was seen only when the concentration of hydrochloric acid solution was higher than 0.4 N. However, the bleeding was also significantly prevented by treatment with secretin (2.5 and 7.5 clinical units/kg/hr). In conclusion, secretin prevents stress-induced gastric bleeding at least in part by increasing glycoprotein secretion in the gastric mucosa in the rat.


Metabolism of tamoxifen by isolated rat hepatocytes. Identification of 1-[4-(2-hydroxyethoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene and the dependence of N-oxidation on oxygen availability.
Metabolism of tamoxifen by rat hepatocytes and hydrolysis of the resulting polar metabolites corresponding to conjugates with beta-glucuronidase gave a major component which was identified as 1-[4-(2-hydroxyethoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene by comparison of mass spectral properties with those of synthetic material. This compound, which was not observed as a phase I metabolite, is believed to have been found previously in rat bile and in human faeces (metabolite F) but its structure had been incorrectly assigned. Its binding affinity for the estrogen receptor was greater than that of tamoxifen but less than that of 4-hydroxytamoxifen, and it possessed a corresponding degree of antitumour activity against the MCF-7 breast cancer cell line. By carrying out the hepatocyte incubation separately under oxygen and air, it has been shown that the N-oxidation of tamoxifen is favoured by a high concentration of oxygen during in vitro metabolism but that the rate of 4-hydroxylation is not dependent on oxygen availability.


Melatonin ameliorates ochratoxin A induced liver inflammation, oxidative stress and mitophagy in mice involving in intestinal microbiota and restoring the intestinal barrier function.
The mycotoxin ochratoxin A (OTA) is a widespread contaminant in human and animal food products. Previous studies in rats revealed that melatonin (Mel) exhibits a preventive effect against OTA-induced oxidative stress in liver. However, it remains unknown whether gut microbiota respond to Mel and, if so, whether it can prevent OTA-induced inflammation and mitophagy in the liver. In the present study, mice received an oral gavage of Mel and OTA for 3 weeks before harvesting colonic digesta and liver tissue for analyses. In another study, the role of intestinal microbiota on the effects of Mel on OTA-induced liver inflammation and mitophagy was assessed through clearance of intestinal microbiota with antibiotics followed by gut microbiota transplantation (GMT). Oral Mel supplementation ameliorated mitophagy in the liver and reversed gut microbiota dysbiosis. Intriguingly, in antibiotic-treated mice, Mel and OTA failed to induce mitophagy in the liver. Using the GMT approach in which mice were colonised with intestinal microbiota from control-, OTA-, or Mel + OTA-treated mice led us to elucidated the involvement of intestinal microbiota in liver inflammation and mitophagy induced by OTA. The findings suggested that intestinal microbiota play some role in the Mel-induced amelioration of liver inflammation and mitophagy induced by OTA.


Quality of life: radical prostatectomy versus radiation therapy for prostate cancer.
The impact of radical prostatectomy and external beam radiotherapy on the quality of life of patients was compared. A total of 136 patients underwent radical prostatectomy and 60 underwent external beam radiotherapy for clinically localized prostate cancer. Patients were asked to complete a questionnaire containing The Functional Living Index: Cancer, the Profile of Moods States, and a series of questions evaluating bladder, bowel and sexual function. The radical prostatectomy group had worse sexual function and urinary incontinence, while the external beam radiotherapy group had worse bowel function. Of the patients 90% from both groups stated that they would undergo the treatment again. Radical prostatectomy and external beam radiotherapy have comparable impact upon quality of life.


Effects of methaqualone on blood platelet function.
To study the mechanism whereby toxic doses of methaqualone cause a bleeding tendency in humans, the effects of methaqualone, diphenhydramine, and the combination of methaqualone plus diphenhydramine on blood platelet function were investigated. Exposure of human platelets in platelet-rich plasma in vitro to final concentrations of methaqualone ranging from 1.1 to 4.5 X 10(-4)) M resulted in nearly complete inhibition of the secondary phase and significant inhibition of the primary phase of adenosine diphosphate (ADP)--induced aggregation. Both the slope and height of collagen-induced aggregation responses were reduced significantly in vitro by the drug. When methaqualone final concentrations of 1.1, 2.3, and 4.5 X 10(-4) M were studied in the presence of diphenhydramine (1.1, 2.3, and 4.5 X 10(-5) M, respectively), the degree of inhibition of ADP-induced aggregation was only slightly greater (not significant) than that observed with methaqualone. The platelets of rabbits injected intravenously with methaqualone, 10 mg/kg, demonstrated a significantly decreased ability to aggregate with ADP and collagen 30 and 60 min after administration of the drug. These results suggest that a drug-induced defect of blood platelet function may play a role in the bleeding associated with methaqualone toxicity.


[Magnetic resonance tomography: a patient-connected system for artificial respiration and monitoring].
Physical phenomena that occur during magnetic resonance imaging (MRI) and the position of the patient inside the scanning tube necessitate adaptations of anesthetic techniques and devices. An anesthesia unit is presented that operates in close proximity to the patient without interfering with the imaging process. This unit enables the anesthesiologist to be close to the patient and his equipment, and minimizes the length of necessary tubing between patient and anesthesia apparatus. The unit consists of commonly used, commercially available devices with only minor modifications.


Supernumerary kidney.
We studied 58 case reports of patients with supernumerary kidneys to determine the morphology, vagaries and embryogenesis of this rare and poorly documented anomaly. The supernumerary kidney usually was located caudal to the ipsilateral kidney when subserved by a bifid ureter and cranially when the ureters were separate. The Weigert-Meyer law for duplex fused kidneys was obeyed by the supernumerary ureter in most fully documented cases of double ureters. Pathologic conditions of the upper urinary tract occurred in more than 50 per cent of the patients with a bifid system, who were prone to have hydronephrosis and calculous disease, and with a double system, who were prone to have complications resulting from supernumerary ureteral ectopia. Double tails to the nephrogenic cords, each induced by a branch of a bifid bud or by 1 of 2 separate buds as opposed to tandem inductions of a single metanephros, were regarded as the probable embryogenesis.


The use of a 'bleach-etch-seal' deproteinization technique on MIH affected enamel.
To ascertain whether deproteinization pretreatment of molar-incisor hypomineralization (MIH) enamel affects resin sealant infiltration. Thirty one extracted MIH teeth were divided into three sections and randomly allocated into the Control (etch and FS), Treatment 1 (5% NaOCl, etched and fissure sealed), and Treatment 2 (5% NaOCl and fissure sealed with no etch) groups. Two hundred seventy nine sealant tag/enamel grade observations were recorded by scanning electron microscopy. Control and Treatment 1 were similar in their outcomes, and Treatment 2 was markedly different. There was no statistical evidence to suggest that there was any difference between Treatment 1 and the Control Treatment (95% CI, 0.52, 1.51; P = 0.6). There was a marked difference between Treatment 2 and the Control Treatment (95% CI, 0.07, 0.25; P < 0.001). All treatments also demonstrated a high-predicted probability of obtaining 'poor' sealant tags (Control = 47%, Treatment 1 = 49%, and Treatment 2 = 40%). The findings suggest that there was no significant difference in the tag quality between the conventional technique (Control) and the 'bleach-etch-seal' technique (Treatment 1). There was no benefit in pre-treating with NaOCl alone (without etch) before sealing. This research also showed that there was a high-predicted probability of obtaining 'poor' sealant tags in MIH enamel, regardless of which of the three treatments was used.


Pharmacy services in a Federal extended care facility, as provided by a pharmacy student.
The objective of this study was to identify the role of the pharmacy student in providing health care to a Federal Nursing Home Care Unit. Under the supervision of a graduate pharmacy resident, the student was responsible for monitoring compliance in drug therapy, providing consultation services, and developing several research projects. A detailed study of allergy documentation in 78 patients showed that 25.6 percent of their records indicated drug allergies, but upon further investigation only 5.1 percent could be confirmed. Fourteen (41 percent) of the 34 reported allergy-producing substances had been administered again after the initial allergic incident, without ensuing difficulties. Evaluation of the self-medication program indicated that 71.4 percent of 14 study patients could not easily open their child-proof medicine container. A change to "tight" containers enhanced the patients' ability to open them. However, no significant conclusions could be drawn regarding improvement in the patients' compliance with prescription directions. Pharmacy students can be a valuable resource in improving documentation, testing drug prescription compliance, and participating in the general care of patients in long-term facilities.


Is It Safe to Prep the External Fixator In Situ During Staged ORIF of Bicondylar Tibial Plateau Fractures? A Retrospective Comparative Cohort Study.
To compare the risk of deep infection and unplanned reoperation after staged open reduction internal fixation (ORIF) of bicondylar tibial plateau (BTP) fractures whether elements of the temporizing external fixator were prepped into the surgical field or completely removed before definitive fixation. Retrospective comparative cohort study. Two academic Level 1 trauma centers. One hundred forty-seven OTA/AO 41-C (Schatzker 6) BTP fractures treated with a 2-stage protocol of acute spanning ex-fix followed by definitive ORIF between 2001 and 2018. Seventy-eight fractures had retained elements of the original ex-fix prepped in situ during surgery for definitive internal fixation, and 69 had the ex-fix construct completely removed before prepping and draping. Deep infection and unplanned reoperation. Among 147 patients treated with staged ORIF, the overall deep infection rate was 26.5% and the reoperation rate was 33.3%. There were high rates of deep infection (26.9% vs. 26.1%, P = 0.909) and unplanned reoperation (30.8% vs. 36.2%, P = 0.483) in both groups, but no difference whether the ex-fix was prepped in or completely removed. Within the retained ex-fix group, there was no difference in infection with retention of the entire ex-fix compared with only the ex-fix pins (28.1% vs. 26.1%, P = 0.842). We observed high complication rates in this cohort of OTA/AO 41C BTP fractures treated with staged ORIF, but prepping in the ex-fix did not lead to a significant increase in rates of infection or reoperation. This study provides the treating surgeon with clinical data about a common practice used to facilitate definitive fixation of unstable BTP fractures. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


The structure-based optimization of δ-sultone-fused pyrazoles as selective BuChE inhibitors.
Structure-based optimization was conducted to improve the potency and selectivity of BuChE inhibitors with δ-sulfonolactone-fused pyrazole scaffold. By mimicking the hydrophobic interactions of donepezil at PAS, the introduction of a tertiary benzylamine at 5-position can significantly increase BuChE inhibitory activity. Compounds C4 and C6 were identified as high selective nanomolar BuChE inhibitors (IC50 = 8.3 and 7.7 nM, respectively), which exhibited mild antioxidant capacity, nontoxicity, lipophilicity and neuroprotective activity. Kinetic studies showed that BuChE inhibition of compound C6 was mixed-type against BuChE (Ki = 24 nM) and >2000-fold selectivity for BuChE over AChE. The proposed binding mode of new inhibitors was consistent with the results of structure-activity relationship analysis.


Functional Medicine Approaches to Neurodegeneration.
Neurodegenerative diseases impact more than 6 million Americans, and current predictions estimate the rates of neurodegenerative diseases will double in the next 30 years. These diseases are progressive with increasing loss of brain function throughout their course. Overtime, those suffering from neurodegenerative diseases will lose their ability to work and function efficiently in society. Families and society are burdened with skyrocketing costs to provide care for those who are unable to perform activities of daily living. There is an urgent need to develop treatment strategies to both reduce the incidence of neurodegenerative diseases and to delay the progression of the disease.


Repeat procedures using the second-generation cryoballoon for recurrence of atrial fibrillation after initial ablation with conventional radiofrequency.
Pulmonary vein isolation is now widely accepted for the treatment of symptomatic atrial fibrillation refractory to antiarrhythmic drugs. However, multiple procedures are often required to significantly reduce atrial fibrillation (AF) recurrence. In the present study, we analyzed the acute results and the midterm clinical outcome of a second-generation cryoballoon ablation (CB-A) performed during repeat procedures for recurrence of AF after an initial procedure performed with conventional radiofrequency (RF). Consecutive patients with paroxysmal and persistent AF who underwent pulmonary vein isolation by CB-A from June 2012 in our hospital as a redo procedure after a previous pulmonary vein isolation with RF were retrospectively included in this analysis. Forty-seven patients having undergone CB-A as a redo procedure were considered for our analysis. Pulmonary vein potentials were documented in 83 pulmonary veins (PV) that were all successfully re-isolated using the CB-A. Transient phrenic nerve palsy was the only complication occurring in our study cohort. After a mean follow-up of 15 ± 8 months, 76.6% of patients were free from recurrence of atrial fibrillation. If taking into consideration a 3-month blanking period, 83% of patients were free from recurrence. The success rate in patients affected by paroxysmal AF was 87% at final follow-up following the blanking period. The second-generation CB is effective in treating recurrence of AF after a previous ablation performed with conventional RF. Considering a 3-month blanking period, 83% of the patients were free from any atrial tachycardia recurrence during a 15-month follow-up. This approach proved particularly successful in patients affected by paroxysmal AF.


Histological and ultrastructural effects of cyclosporin A on normal human skin xenografted on to nude mice.
Cyclosporin A (CsA) is a potent immunosuppressant with a selective activity on T-helper lymphocytes. However, CsA also exerts biological effects on non-lymphoid cells (fibroblasts, endothelial and epithelial cells). CsA can inhibit in vivo and in vitro DNA synthesis of epidermal keratinocytes (EK) and induces in vivo morphological alterations of kidney epithelial cells. In the present study we investigated the in vivo effects of a short-term CsA treatment (50 mg/kg per day) on DNA synthesis (evaluated through 5-bromo-2'-deoxyuridine incorporation) and on the histological features of normal human skin xenografted (NHSX) on to congenitally athymic nude mice. When compared with control NHSX, CsA induced a statistically significant inhibition of DNA synthesis of NHSX EK. At the light- and electron-microscopic level, apart from a decrease in the thickness of the viable epidermis of NHSX (statistically non-significant), no noticeable differences between treated and control NHSX could be detected. EK, Langerhans cells and melanocytes appeared morphologically unaffected by CsA and no signs of acute toxicity (giant mitochondria, vacuolization, microcalcifications) were seen. These results suggest that CsA exerts a subtle effect on human EK; indeed, despite an unequivocal antiproliferative activity, no significant histological changes related to the acute CsA toxicity seem to be induced on the various epidermal cell types.


A Bioinformatic Pipeline to Estimate Ploidy Level from Target Capture Sequence Data Obtained from Herbarium Specimens.
Whole genome duplications (WGD) are frequent in many plant lineages; however, ploidy level variation is unknown in most species. The most widely used methods to estimate ploidy levels in plants are chromosome counts, which require living specimens, and flow cytometry estimates, which necessitate living or relatively recently collected samples. Newly described bioinformatic methods have been developed to estimate ploidy levels using high-throughput sequencing data, and these have been optimized in plants by calculating allelic ratio values from target capture data. This method relies on the maintenance of allelic ratios from the genome to the sequence data. For example, diploid organisms will generate allelic data in a 1:1 proportion, with an increasing number of possible allelic ratio combinations occurring in individuals with higher ploidy levels. In this chapter, we explain step-by-step this bioinformatic approach for the estimation of ploidy level.


The effect of Gd-DTPA on T(1)-weighted choline signal in human brain tumours.
The influence of Gd-DTPA on T(1)-weighted (T(1)W) proton MR spectra has been investigated in 19 patients with histologically verified low (n = 13) or high-grade (n = 6) gliomas. Repeat measurements were performed on 9 patients (7 low-grade and 2 high-grade), with 28 examinations performed in total. Comparison of spectra obtained before and after 0.2 mmol/kg Gd-DTPA showed contrast agent induced broadening of the choline signal without significant signal area change. Lack of enhancement of the choline signal with the T(1)-weighted acquisitions implies that the contrast agent and the trimethylamine-containing species do not undergo significant direct interaction. Contrast agent induced changes in the choline signal observed in this and previous studies may, therefore, be attributable to T2*/susceptibility-based effects.


Quality of life assessment for cost/utility studies in cancer.
The goals of cancer treatment and cancer prevention are to extend life expectancy and to improve quality of life in the years prior to death. Typically, outcomes of cancer treatment are evaluated in terms of survival time. Although quality of life is often measured, interpretation of these outcomes in relation to mortality is difficult. Survival analysis places each individual into one of two categories: alive or dead. Among those alive, all individuals are considered equivalent. Thus, a patient confined to bed with severe symptoms is scored the same as someone who is active and asymptomatic. A General Health Policy Model is proposed as a solution to this problem. The model adjusts life expectancy for diminished quality of life, which is measured using a standardized instrument known as the Quality of Well-being (QWB) scale. The model expresses the effect of treatment in a unit known as a Well-Year or Quality Adjusted Life Year (QALY). These units integrate side-effects and benefits of treatment by combining into a single number, mortality, morbidity, and duration of each health state. Similar methods, such as the Q-TWiST, have been proposed for use in cancer clinical trials. However, the Q-TWiST is a subset of the more general model and carries limitations for cross-disease comparisons. We conclude that general health outcome models can be of considerable value for analysing the costs, risks and benefits of cancer therapies.


Influence of photodynamic therapy on the periodontitis-induced bone resorption in rat.
This study aimed to evaluate the effects of toluidine blue-mediated photodynamic therapy (TB-PDT) on the periodontitis-induced bone resorption in periodontitis in rats. Periodontal disease was induced by cotton ligature around the right second maxillary molar in 64 rats. After 4 weeks, the rats were randomly divided into four groups: sterile saline solution (control group); laser therapy (laser group); TB (100 μg/mL); TB plus laser (0.15 W/cm2) irradiation every other day for 240 s (PDT group). All rats were euthanized at 15 days postoperatively. Eight gingival tissue samples were collected from each group. The expressions of receptor activator of nuclear factor kappa-Β ligand (RANKL) and osteoprotegerin (OPG) in gingival tissue samples were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The maxillae from the rest of the rats were taken for histological examination. In the PDT group, the analysis revealed less bone loss than in the control treatment (P < 0.05). No significant difference was found among the control group, TB group, and laser group (P > 0.05). Significantly higher and lower expressions of RANKL and OPG were revealed in the PDT group than that in control group, respectively (P < 0.01). When compared with the control group, the expression of RANKL was significantly reduced by 40.0% in periodontitis in rats treated with TB-PDT for 15 days (P < 0.01). The expression of OPG was increased in the PDT group with TB-PDT for 15 days, when compared with the control group (P < 0.05). TB-PDT treatment significantly reverses the abnormal expression of RANKL and OPG in periodontitis in rats.


Knowledge and exercise behavior maintenance in cardiac rehabilitation patients receiving educational interventions.
To test whether a theoretically-based education curriculum results in more sustained knowledge, higher scores on Health Action Process Approach (HAPA) constructs, and greater exercise behavior 6 months post-cardiac rehabilitation (CR) when compared to traditional CR education. Patient education is a core component of CR. No research has examined whether this education results in sustained improvements post-program. In this quasi-experimental study, participants exposed to the traditional vs HAPA-based education completed surveys pre, post-CR, and 6 months post-discharge assessing knowledge, HAPA constructs, and exercise. Ninety-three participants completed the final survey. Knowledge increases post-CR were sustained 6 months post-program, with no differences by curriculum. Many improvements in HAPA constructs observed post-CR were sustained, except for some decay in self-efficacy. Minutes of exercise per week were significantly greater in participants exposed to the HAPA-based curriculum 6 months post-program. HAPA-based education in CR has sustained effects on exercise.


The Influence of On-pump Versus Off-pump Surgery on Short- and Medium-term Postoperative Coronary Flow Reserve After Coronary Artery Bypass Grafting.
Although several clinical trials have compared surgical outcomes between off-pump and on-pump coronary artery bypass grafting (CABG), whether there is a difference in the early- and medium-term postoperative coronary microvascular functions is not fully understood. We compared short- and medium-term coronary microvascular function after off-pump and on-pump CABG. A prospective study of patients undergoing off-pump and on-pump CABG. Eighty-two patients scheduled for CABG were recruited: 38 underwent off-pump surgery and 44 on-pump surgery. Each participant's coronary flow reserve (CFR) and diastolic function were measured with transthoracic Doppler echocardiography six and 12 months after surgery. Baseline and hyperaemic diastolic peak flow velocity in the left anterior descending artery were similar in both groups, as was CFR (2.22±0.66) in the off-pump group compared with (2.13±0.61) in the on-pump group, (P=0.54). Coronary flow reserve was significantly and inversely correlated with high sensitivity C-reactive protein concentration (r=-0.416; P<0.001) and positively correlated with mitral E/A-wave velocity ratio (r=0.247; P=0.02). Stepwise linear regression analysis revealed that only high sensitivity C-reactive protein concentration was independently correlated with CFR (β=-0.272, P=0.02). Heart-lung bypass technique had no medium-term influence on the coronary microcirculation, despite a possible initial unfavourable effect. Serum hs-CRP concentration was an independent predictor of medium-term coronary microvascular dysfunction.


Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation.
When an antioxidant scavenges a reactive species, i.e., when it exerts its antioxidant activity, the antioxidant is converted into potentially harmful oxidation products. In this way, the antioxidant quercetin might yield an ortho-quinone, denoted as QQ, which has four tautomeric forms, i.e., the ortho-quinone and three quinonmethides. We evaluated the interaction of QQ with ascorbate or glutathione (GSH). Ascorbate recycles QQ to the parent compound quercetin, while GSH forms two adducts with QQ, i.e., 6-GSQ and 8-GSQ. When both GSH and ascorbate are present, QQ is converted exclusively into GSQ. In the absence of GSH, protein thiols will be arylated by QQ. This protein arylation is not prevented by ascorbate. Thiol arylation by quinones and quinonmethides can impair several vital enzymes. This implies that the product formed when quercetin displays its antioxidant scavenging effect is toxic in the absence of GSH. Therefore, an adequate GSH level should be maintained when quercetin is supplemented.


HIV/simian immunodeficiency virus (SIV) accessory virulence factor Vpx loads the host cell restriction factor SAMHD1 onto the E3 ubiquitin ligase complex CRL4DCAF1.
The sterile alpha motif and HD domain-containing protein-1 (SAMHD1) inhibits infection of myeloid cells by human and related primate immunodeficiency viruses (HIV and SIV). This potent inhibition is counteracted by the Vpx accessory virulence factor of HIV-2/SIVsm viruses, which targets SAMHD1 for proteasome-dependent degradation, by reprogramming cellular CRL4(DCAF1) E3 ubiquitin ligase. However, the precise mechanism of Vpx-dependent recruitment of human SAMHD1 onto the ligase, and the molecular interfaces on the respective molecules have not been defined. Here, we show that human SAMHD1 is recruited to the CRL4(DCAF1-Vpx) E3 ubiquitin ligase complex by interacting with the DCAF1 substrate receptor subunit in a Vpx-dependent manner. No stable association is detectable with DCAF1 alone. The SAMHD1 determinant for the interaction is a short peptide located distal to the SAMHD1 catalytic domain and requires the presence of Vpx for stable engagement. This peptide is sufficient to confer Vpx-dependent recruitment to CRL4(DCAF1) and ubiquitination when fused to heterologous proteins. The precise amino acid sequence of the peptide diverges among SAMHD1 proteins from different vertebrate species, explaining selective down-regulation of human SAMHD1 levels by Vpx. Critical amino acid residues of SAMHD1 and Vpx involved in the DCAF1-Vpx-SAMDH1 interaction were identified by mutagenesis. Our findings show that the N terminus of Vpx, bound to DCAF1, recruits SAMHD1 via its C terminus to CRL4, in a species-specific manner for proteasomal degradation.


Integral Isosceles Triangle-Parallelogram and Heron triangle-Rhombus Pairs with a Common Area and Common Perimeter.
In this paper we show that there are infinitely many pairs of integer isosceles triangles and integer parallelograms with a common (integral) area and common perimeter. We also show that there are infinitely many Heron triangles and integer rhombuses with common area and common perimeter. As a corollary, we show there does not exist any Heron triangle and integer square which have a common area and common perimeter.


Evaluation of knowledge-based reconstruction for magnetic resonance volumetry of the right ventricle after arterial switch operation for dextro-transposition of the great arteries.
Right ventricular (RV) volume and function evaluation is essential in the follow-up of patients after arterial switch operation (ASO) for dextro-transposition of the great arteries (d-TGA). Cardiac magnetic resonance (CMR) imaging using the Simpson's method is the gold-standard for measuring these parameters. However, this method can be challenging and time-consuming, especially in congenital heart disease. Knowledge-based reconstruction (KBR) is an alternative method to derive volumes from CMR datasets. It is based on the identification of a finite number of anatomical RV landmarks in various planes, followed by computer-based reconstruction of the endocardial contours by matching these landmarks with a reference library of representative RV shapes. The purpose of this study was to evaluate the feasibility, accuracy, reproducibility and labor intensity of KBR for RV volumetry in patients after ASO for d-TGA. The CMR datasets of 17 children and adolescents (males 11, median age 15) were studied for RV volumetry using both KBR and Simpson's method. The intraobserver, interobserver and intermethod variabilities were assessed using Bland-Altman analyses. Good correlation between KBR and Simpson's method was noted. Intraobserver and interobserver variability for KBR showed excellent agreement. Volume and function assessment using KBR was faster when compared with the Simpson's method (5.1 ± 0.6 vs. 6.7 ± 0.9 min, p < 0.001). KBR is a feasible, accurate, reproducible and fast method for measuring RV volumes and function derived from CMR in patients after ASO for d-TGA.


Effects of a self-management program on patients with early-stage chronic kidney disease: a pilot study.
Without intervention, renal function deteriorates in patients with chronic kidney disease (CKD). This pilot study aimed to develop a self-management education program based on self-regulation theory and to evaluate its effects on self-efficacy, self-management behavior, and CKD progression among patients with early-stage CKD. In this single-group, pretest-posttest, repeated-measures, longitudinal study, participants underwent baseline pretesting (T0) and posttesting at 3 (T1), 6 (T2), and 12 (T3) months after a 5-week group-session self-management program. Self-efficacy increased significantly at T2 (χ(2)=8.97, p=.02) and T3 (χ(2)=10.71, p=.01) compared with T0, but self-management behavior did not. A marginally significant decrease in serum creatinine levels was observed from T0 to T3 (χ(2)=6.29, p=.07) but estimated glomerular filtration rates remained stable throughout the 12-month period. The results of this empirical study suggest that the theory-based intervention is feasible and has potential efficacy in retarding CKD progression.


Probes for rare mRNAs reveal distributed cell subsets in canary brain.
cDNA clones of 7 low-abundance canary brain RNAs hybridize in situ to different subsets of brain cells. Although these cell sets are distinct, they are dispersed in a variety of brain regions with overlapping anatomical distributions. These cDNA clones were initially selected by their relative hybridization to forebrain and rest-of-brain RNAs and represent a sampling of a much larger population of differentially expressed RNAs present at individual concentrations of 10(-7) to 10(-4) as a fraction of polyadenylated RNA mass. Our results suggest the existence of several thousand low-abundance brain mRNAs likely to be distributed in diverse and overlapping brain cell subsets. Furthermore, our experiments define a simple and general strategy for producing and analyzing molecular probes for subsets of brain cells and provide an initial set of useful reagents for further study of brain organization and development.


Robotic Rehabilitation in Spinal Cord Injury: A Pilot Study on End-Effectors and Neurophysiological Outcomes.
Robot-aided gait training (RAGT) has been implemented to provide patients with spinal cord injury (SCI) with a physiological limb activation during gait, cognitive engagement, and an appropriate stimulation of peripheral receptors, which are essential to entrain neuroplasticity mechanisms supporting functional recovery. We aimed at assessing whether RAGT by means of an end-effector device equipped with body weight support could improve functional ambulation in patients with subacute, motor incomplete SCI. In this pilot study, 15 patients were provided with six RAGT sessions per week for eight consecutive weeks. The outcome measures were muscle strength, ambulation, going upstairs, and disease burden. Furthermore, we estimated the activation patterns of lower limb muscles during RAGT by means of surface electromyography and the resting state networks' functional connectivity (RSN-FC) before and after RAGT. Patients achieved a clinically significant improvement in the clinical outcome measures substantially up to six months post-treatment. These data were paralleled by an improvement in the stair-climbing cycle and a potentiating of frequency-specific and area-specific RSN-FC patterns. Therefore, RAGT, by means of an end-effector device equipped with body weight support, is promising in improving gait in patients with subacute, motor incomplete SCI, and it could produce additive benefit for the neuromuscular reeducation to gait in SCI when combined with conventional physiotherapy.


Effects of aqueous fluoxetine exposure on gut microbiome of adult Pimephales promelas.
The microbiome of the gut is vital for homeostasis of hosts with its ability to detoxify and activate toxicants, as well as signal to the immune and nervous systems. However, in the field of environmental toxicology, the gut microbiome has only recently been identified as a measurable indicator for exposure to environmental pollutants. Antidepressants found in effluents of wastewater treatment plants and surface waters have been shown to exhibit antibacterial-like properties in vitro, where some bacteria are known to express homologous proteins that bind antidepressants in vertebrates. Therefore, it has been hypothesized that exposure to antidepressant drugs might affect gut microbiota of aquatic organisms. In this study, the common antidepressant, fluoxetine, was investigated to determine whether it can modulate the gut microbiome of adult fathead minnows. A 28-day, sub-chronic, static renewal exposure was performed with nominal fluoxetine concentrations of 0.01, 10 or 100 μg/L. Using 16S rRNA amplicon sequencing, shifts among the gut-associated microbiota were observed in individuals exposed to the greatest concentration, with greater effects observed in females. These changes were associated with a decrease in relative proportions of commensal bacteria, which can be important for health of fish including bacteria essential for fatty acid oxidation, and an increase in relative proportions of pathogenic bacteria associated with inflammation. Results demonstrate, for the first time, how antidepressants found in some aquatic environments can influence gut microbiota of fishes.


Trichoscopy in Healthy Adult Egyptian Females: Normal Values of Hair Measurable Parameters.
Documenting normal hair values through trichoscopy can provide a useful baseline when evaluating and treating hair loss in different populations. The aim of our study was to document normal values for measurable parameters of hair in adult Egyptian females. This cross-sectional study involved 90 Egyptian females (age range 18-48 years), with no symptoms or signs of hair or scalp disease. Trichoscopy was performed in different scalp areas using FotoFinder Medicam 1000 videodermoscopy. Trichoscopy images were subjected to statistical processing using TrichoLAB system. The frontal area demonstrated the highest number of hairs (190 ± 29/cm2), greatest average hair shaft thickness (63 ± 8 μm), greatest percentage of thick hairs (71% ± 12), highest mean cumulative hair thickness (12 ± 2 mm/cm2), and highest mean number of follicular units (82 ± 8/cm2). The temporal area showed the highest percentage of thin hairs (9% ± 5) and single-hair pilosebaceous units (23% ± 7), lowest mean number of hairs (154 ± 25/cm2), least average hair shaft thickness (60 ± 9 μm), least mean cumulative hair thickness (9 ± 2 mm/cm2), and least mean number of follicular units (70 ± 8/cm2). The occipital area showed the greatest percentage of triple-hair follicles (43% ± 12). Based on trichoscopy, the norms for hair parameters were calculated. Normal hair parameters in adult Egyptian females differ from those documented from other ethnicities. Evaluating and treating hair loss in clinical practice should be done in reference to documented normal values, which can be set through trichoscopy.


Usefulness of segmental and comparative tests in the electrodiagnosis of carpal tunnel syndrome: the Italian multicenter study. Italian CTS Study Group.
The Italian CTS Study Group performed a wide multicentric and multiparametric study to quantify the increase of electrodiagnostic sensitivity using an extended neurophysiological protocol and particularly segmental and comparative tests. The study also evaluated the clinical features of carpal tunnel syndrome (CTS) diagnosed by these tests, using validated physician- and patient-oriented measurements. The study group was composed of 740 patients for a total of 1123 idiopathic CTS hands. Overall, the sensitivity of standard tests (median digit-wrist sensory conduction velocity and wrist-thenar distal motor latency) was 83.5%. Comparative/segmental tests disclosed abnormal findings in a further 11.4% of cases, providing CTS electrodiagnosis in about 7 of 10 "standard negative" cases. The overall sensitivity of the electrodiagnostic protocol was 94.9%. The CTS population diagnosed by segmental/comparative tests had a clinical picture characterized by a high percentage of pain, and severe discomfort but no limitation in functional daily activity. Our data confirm the usefulness of a complete neurophysiological assessment by using segmental/comparative tests when standard tests yield normal results.


A controlled clinical trial of L-tryptophan in acute mania.
In a 2-week study, 24 newly admitted manic patients were treated for 1 week with L-tryptophan (12 g/day); during the second week, half the patients, chosen at random, continued to receive tryptophan, while placebo was substituted in the other half under double-blind conditions. In the open phase of the study, there was a clinically and statistically (p less than 0.001) significant reduction in manic symptom scores, with little need for haloperidol prn. Patients who continued to be treated with tryptophan showed no significant change in mean scores during the second week, but those who were switched to placebo tended (p less than 0.10) to show an increase in the mean scores for manic symptoms. There was a significant (p less than 0.05) increase in the geometric mean of morning fasting total and free plasma tryptophan concentrations in men, but not in women. These results suggest that increasing the synthesis of 5-hydroxytryptamine has some therapeutic effect in mania.


[Prostate cancer: how do patients choose their treatment?].
Prostate cancer remains a public health concern in France for men between 50 and 70 years old. Low-risk or intermediate-risk localised prostate cancer can be treated by a number of therapeutic options. Identify, in patients' discourse, the mechanisms and the logic involved in therapeutic decision-making. Qualitative study involving 15 men aged between 53 and 70 years, treated for early-stage prostate cancer, via interviews examining diagnosis pathway, how patients perceive and cope with the illness, and how they choose a treatment. The men made their choices using their own initiative during a multiple-stage process. The determining factors were: quality of relationship with physicians, wish to benefit from the available technological advances in medical care, and minimum impairment to their sexual and reproductive identity. Chances of survival did not appear to be their primary concern. This qualitative study reveals that men make their own decisions in terms of choice of therapy, whether encouraged by their physicians to participate or not.


Markers of remodeling in subcutaneous adipose tissue are strongly associated with overweight and insulin sensitivity in healthy non-obese men.
Alteration in extracellular matrix (ECM) in adipose tissues (AT) has been associated with insulin resistance, diabetes and obesity. We investigated whether selected biomarkers of ECM remodeling in AT in healthy subjects associated with the amount and distribution of AT and with glucometabolic variables. Subcutaneous AT and fasting blood samples from 103 middle-aged healthy non-obese men were used. AT gene expression and circulating levels of the biomarkers were quantified. Distribution of AT was assessed by computed tomography, separated into subcutaneous, deep subcutaneous and visceral AT. Insulin sensitivity was measured by glucose clamp technique. Metalloproteinase (MMP)-9, tissue inhibitor of MMP (TIMP)-1 and plasminogen activator inhibitor (PAI)-1 expression in AT correlated significantly to the amount of AT in all compartments (rs = 0.41-0.53, all p ≤ 0.01), and to insulin sensitivity, insulin, C-peptide, waist circumference and body mass index (BMI) (rs = 0.25-0.57, all p ≤ 0.05). MMP-9 was 5.3 fold higher in subjects with insulin sensitivity below median (p = 0.002) and 3.1 fold higher in subjects with BMI above median level (p = 0.013). In our healthy non-obese middle-aged population AT-expressed genes, central in remodeling of ECM, associated strongly with the amount of abdominal AT, overweight and insulin sensitivity, indicating AT-remodeling to play a role also in non-obese individuals. The remodeling process seems furthermore to associate significantly with glucometabolic disturbances.Trial registration: ClinicalTrials.gov, NCT01412554. Registered 9 August 2011, https://clinicaltrials.gov/ct2/show/NCT01412554?term=NCT01412554 .


Improving iron, zinc and vitamin A nutrition through plant biotechnology.
Recent understanding of plant metabolism has made it possible to increase the iron, zinc and beta-carotene (provitamin A) content in staple foods by both conventional plant breeding and genetic engineering. Improving the micronutrient composition of plant foods may become a sustainable strategy to combat deficiencies in human populations, replacing or complementing other strategies such as food fortification or nutrient supplementation.


Exome sequencing and subsequent association studies identify five amino acid-altering variants influencing human height.
Height is a highly heritable trait that involves multiple genetic loci. To identify causal variants that influence stature, we sequenced whole exomes of four children with idiopathic short stature. Ninety-five nonsynonymous single-nucleotide polymorphisms (nsSNPs) were selected as potential candidate variants. We performed association analysis in 740 cohort individuals and identified 11 nsSNPs in 10 loci (DIS3L2, ZBTB38, FAM154A, PTCH1, TSSC4, KIF18A, GPR133, ACAN, FAM59A, and NINL) associated with adult height (P < 0.05), including five novel loci. Of these, two nsSNPs (TSSC4 and KIF18A loci) were significant at P < 0.05 in the replication study (n = 1,000) and five (ZBTB38, FAM154A, TSSC4, KIF18A, and FAM59A loci) were significant at P < 0.01 in the combined analysis (n = 1,740). Together, the five nsSNPs accounted for approximately 2.5% of the height variation. This study demonstrated the utility of next-generation sequencing in identifying genetic variants and loci associated with complex traits.


Factor Structure and Measurement Invariance of the Spanish Burnout Inventory Among Professionals Across 17 Countries and Regions.
Studies on the prevalence of burnout in professionals in service organizations who work in direct contact with the clients or users of the organization have concluded that burnout is a serious health disorder that has increased due to the COVID-19 pandemic. A significant advantage of the Spanish Burnout Inventory (SBI) over other instruments is that it provides a broader conceptualization of burnout by including feelings of guilt as a dimension of burnout to explain its development. However, the measurement invariance of the SBI across countries has not been investigated. The purpose of this study was to test the measurement invariance of the SBI among professionals across 17 countries and regions in Europe, Latin America, and Asia, and in different languages. All the countries showed a good fit to the four-factor model, except the Indian sample, which was excluded from the measurement invariance study. Using the alignment method, it was possible to verify the scalar measurement invariance of the four SBI factors across 15 countries and one Spanish region (16 samples). The comparison of estimated latent means indicates that France is the country with the lowest scores on the Enthusiasm factor and the highest scores on the negative factors (Exhaustion, Indolence, and Guilt). In contrast, the Andean countries, Colombia, Peru, and Ecuador, show the highest latent means on the Enthusiasm factor and the lowest means on the negative factors. These results support the validity of the SBI in the countries and regions in Europe and Latin America included in this study.


Expression, purification and characterization of the sulfite reductase hemo-subunit, SiR-HP, from Acidithiobacillus ferrooxidans.
Sulfite reductase (SiR) is a large and soluble enzyme which catalyzes the transfer of six electrons from NADPH to sulfite to produce sulfide. The sulfite reductase flavoprotein (SiR-FP) contains both FAD and FMN, and the sulfite reductase hemoprotein (SiR-HP) contains an iron-sulfur cluster coupled to a siroheme. The enzyme is arranged so that the redox cofactors in the FAD-FMN-Fe(4)S(4)-Heme sequence make an electron pathway between NADPH and sulfite. Here we report the cloning, expression, and characterization of the SiR-HP of the sulfite reductase from Acidithiobacillus ferrooxidans. The purified SiR-HP contained a [Fe(4)S(4)] cluster. Site-directed mutagenesis results revealed that Cys427, Cys433, Cys472 and Cys476 were in ligating with the [Fe(4)S(4)] cluster of the protein.


The Ras/Raf-1/MEK1/ERK signaling pathway coupled to integrin expression mediates cholinergic regulation of keratinocyte directional migration.
The physiologic mechanisms that determine directionality of lateral migration are a subject of intense research. Galvanotropism in a direct current (DC) electric field represents a natural model of cell re-orientation toward the direction of future migration. Keratinocyte migration is regulated through both the nicotinic and muscarinic classes of acetylcholine (ACh) receptors. We sought to identify the signaling pathway mediating the cholinergic regulation of chemotaxis and galvanotropism. The pharmacologic and molecular modifiers of the Ras/Raf-1/MEK1/ERK signaling pathway altered both chemotaxis toward choline and galvanotropism toward the cathode in a similar way, indicating that the same signaling steps were involved. The galvanotropism was abrogated due to inhibition of ACh production by hemicholinium-3 and restored by exogenously added carbachol. The concentration gradients of ACh and choline toward the cathode in a DC field were established by high-performance liquid chromatographic measurements. This suggested that keratinocyte galvanotaxis is, in effect, chemotaxis toward the concentration gradient of ACh, which it creates in a DC field due to its highly positive charge. A time-course immunofluorescence study of the membrane redistribution of ACh receptors in keratinocytes exposed to a DC field revealed rapid relocation to and clustering at the leading edge of alpha7 nicotinic and M(1) muscarinic receptors. Their inactivation with selective antagonists or small interfering RNAs inhibited galvanotropism, which could be prevented by transfecting the cells with constitutively active MEK1. The end-point effect of the cooperative signaling downstream from alpha7 and M(1) through the MEK1/ERK was an up-regulated expression of alpha(2) and alpha(3) integrins, as judged from the results of real-time PCR and quantitative immunoblotting. Thus, alpha7 works together with M(1) to orient a keratinocyte toward direction of its future migration. Both alpha7 and M(1) apparently engage the Ras/Raf/MEK/ERK pathway to up-regulate expression of the "sedentary" integrins required for stabilization of the lamellipodium at the keratinocyte leading edge.


Taking sides: interferons in leprosy.
In a recent Science paper, Teles et al. (2013) show that type I and II interferons (IFNs) are reciprocally expressed in the polar immune forms of leprosy, with type I IFNs inducing IL-10 that interferes with the antimycobacterial effects of type II IFNs (IFNγ) at the site of infection.


Biosynthesized silver nanoparticles (Ag NPs) from isolated actinomycetes strains and their impact on the black cutworm, Agrotis ipsilon.
Nanomaterials have been produced with the use of bio-nanotechnology, which is a low-cost approach. Currently, research is being conducted to determine whether actinomycetes isolated from Egyptian soil can biosynthesize Ag nanoparticles (Ag NPs) and characterized by using the following techniques: Transmission electron microscopy (TEM), Dynamic light scattering (DLS), Fourier transforms infrared (FT-IR), Energy-dispersive X-ray spectroscopy (EDX), UV-Vis spectroscopy and X-ray diffraction (XRD). The most promising actinomycetes isolate were identified, morphologically, biochemically, and molecularly. Streptomyces avermitilis Azhar A.4 was found to be able to reduce silver metal nanoparticles from silver nitrate in nine isolates collected from Egyptian soil. Toxicity of biosynthesized against 2nd and 4th larval instar of Agrotis ipsilon (Hufn.) (Lepidoptera: Noctuidae) was estimated. In addition, activity of certain vital antioxidant and detoxifying enzymes as well as midgut histology of treated larvae were also investigated. The results showed appositive correlations between larval mortality percentage (y) and bio-AgNPs concentrations (x) with excellent (R2). The 4th larval instar was more susceptible than 2nd larval instar with LC50 (with 95% confirmed limits) =8.61 (2.76-13.89) and 26.44(13.25-35.58) ppml-1, respectively of 5 days from treatment. The initial stages of biosynthesized AgNps exposure showed significant increases in carboxylesterase (CarE) and peroxidases (PODs) activity followed by significant suppression after 5 days pos-exposure. While protease activity was significantly decreased by increasing time post-exposure. Midgut histology showed abnormality and progressive damage by increasing time post exposure leading to complete destruction of midgut cells after 5 days from exposure. These results make biosynthesized AgNPs an appropriate alternative to chemical insecticide in A. ipsilon management.


Autism phenotype versus registered diagnosis in Swedish children: prevalence trends over 10 years in general population samples.
To compare the annual prevalence of the autism symptom phenotype and of registered diagnoses for autism spectrum disorder during a 10 year period in children. Population based study. Child and Adolescent Twin Study and national patient register, Sweden. 19, 993 twins (190 with autism spectrum disorder) and all children (n=1,078,975; 4620 with autism spectrum disorder) born in Sweden over a 10 year period from 1993 to 2002. Annual prevalence of the autism symptom phenotype (that is, symptoms on which the diagnostic criteria are based) assessed by a validated parental telephone interview (the Autism-Tics, ADHD and other Comorbidities inventory), and annual prevalence of reported diagnoses of autism spectrum disorder in the national patient register. The annual prevalence of the autism symptom phenotype was stable during the 10 year period (P=0.87 for linear time trend). In contrast, there was a monotonic significant increase in prevalence of registered diagnoses of autism spectrum disorder in the national patient register (P<0.001 for linear trend). The prevalence of the autism symptom phenotype has remained stable in children in Sweden while the official prevalence for registered, clinically diagnosed, autism spectrum disorder has increased substantially. This suggests that administrative changes, affecting the registered prevalence, rather than secular factors affecting the pathogenesis, are important for the increase in reported prevalence of autism spectrum disorder.


Transmission heterogeneities, kinetics, and controllability of SARS-CoV-2.
A long-standing question in infectious disease dynamics concerns the role of transmission heterogeneities, driven by demography, behavior and interventions. Based on detailed patient and contact tracing data in Hunan, China we find 80% of secondary infections traced back to 15% of SARS-CoV-2 primary infections, indicating substantial transmission heterogeneities. Transmission risk scales positively with the duration of exposure and the closeness of social interactions and is modulated by demographic and clinical factors. The lockdown period increases transmission risk in the family and households, while isolation and quarantine reduce risks across all types of contacts. The reconstructed infectiousness profile of a typical SARS-CoV-2 patient peaks just before symptom presentation. Modeling indicates SARS-CoV-2 control requires the synergistic efforts of case isolation, contact quarantine, and population-level interventions, owing to the specific transmission kinetics of this virus. Public health measures to control SARS-CoV-2 could be designed to block the specific transmission characteristics of the virus.


Seizure Outcome After Battery Depletion in Epileptic Patients Submitted to Deep Brain Stimulation.
We studied patients treated with chronic DBS in whom there was depletion of the generator's battery, in order to get insight on the modulatory potential of chronic DBS in refractory epilepsy. Nine adult patients with refractory epilepsy treated with at least three years of deep brain stimulation (DBS), and who were followed up for at least six months after battery depletion were studied. One patient was treated with hippocampal DBS (Hip-DBS), two to centro-median DBS (CM-DBS) and six to anterior nucleus stimulation (AN-DBS). Two patients did not have seizure's frequency modification after battery depletion; the other seven patients had seizure frequency increase, including those three patients that were seizure-free. Five of those seven patients who had seizure frequency increase after battery's depletion had seizure's frequency lower than their pre-DBS baseline seizure frequency; two of such patients returned to their pre-DBS baseline seizure frequency. In the majority of the patients, three years of chronic DBS did not show a permanent effect on epileptogenesis. On the other hand, the post-battery depletion seizure's frequency was usually much lower than the baseline (pre-DBS) seizure's frequency, suggesting that there was actual network neuromodulation.


Characterization and localization of Opisthorchis viverrini fructose-1,6-bisphosphate aldolase.
Opisthorchis viverrini (Ov) infection is a long-time public health problem in Thailand that can lead to bile duct cancer, cholangiocarcinoma (CCA). Characterization of the Ov proteins at a molecular level will increase our knowledge of host-parasite interaction that can be applied to new drug, vaccine, or immunodiagnostic development. In this study, an important enzyme in the Ov glycolytic pathway, fructose-1,6-bisphosphate aldolase (FBPA), that had been obtained from a previous study was characterized and immunolocalized. The full-length sequence of OvFBPA gene is 1089bp and encodes 362 amino acids with a predicted molecular weight and isoelectric point of 39.54kDa and 7.61, respectively. Additionally, three OvFBPA isoforms were identified by sequence analysis. The amino acid sequence of OvFBPA-1 characterized in this study shared 98% identity to FBPA isoform 1 of Clonorchis sinensis that was classified based on highly conserved active residues to class-I FBPA. The recombinant OvFBPA-1 protein was expressed as a soluble form in Escherichia coli at 25°C with N-terminal His-tagged fusion protein and the purified OvFBPA-1 protein was used to generate polyclonal antibody in mice. Antibody against rOvFBPA-1 protein was able to detect the native OvFBPA-1 protein in both Ov infected hamster liver section and Ov excretory-secretory (ES) products by immunohistochemistry and western blotting, respectively.


Augmented axonal defects and synaptic degenerative changes in female GRK5 deficient mice.
Recent studies suggested that G protein-coupled receptor kinase 5 (GRK5) deficiency plays a significant role in early Alzheimer's disease (AD) pathogenesis, and that the GRK5 knockout (GRK5KO) mouse displays an early Alzheimer-like cognitive deficit associated with increased hippocampal axonal defects and synaptic degenerative changes. Gender is known to play a role in AD, with females showing more extensive pathologic changes in brain compared to males. Although GRK5 deficiency is linked to AD, it is unknown whether the pathologic changes solely driven by the GRK5 deficiency are gender-dependent. To determine this, extent of the pathologic changes in aged GRK5KO mice was compared between genders. We find that female GRK5KO mice had a 2.5-fold increase in hippocampal swollen axonal clusters compared to male GRK5KO mice. Moreover, hippocampal levels of several synaptic proteins, including synaptophysin, were significantly lower in the female than the male. In addition, although increased Luteinizing hormone (LH) activity is believed to play a significant role in the gender phenomenon in AD, we found that desensitization of LH receptor is not affected by the GRK5 deficiency. Therefore, the worsened pathologic changes in the female mice cannot be attributed to an impaired LH receptor desensitization. Taken together, this study demonstrates a synergistic interaction between GRK5 deficiency and gender in promoting early AD-like pathologic changes in the female GRK5KO mice, although the underlying molecular mechanisms remain to be elucidated.


The expression of transforming growth factor alpha receptor protein and its activation in chicken ovarian granulosa cells of maturing follicles.
Epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) are structurally related growth factors that exert their biological actions by binding to the same cell-surface receptor, EGF receptor. However, in chicken cells, human EGF binds with approximately 100-fold lower affinity than human TGF-alpha. In a previous study, we localized EGF/TGF-alpha receptor immunohistochemically in the granulosa and theca of the developing follicles of laying hens. We have also shown that TGF-alpha binds to cell-surface receptors of the granulosa cells. The present study characterizes the nature of the EGF/TGF-alpha receptor. Immunoprecipitation of receptor proteins from cultured granulosa cells with an anti-EGF receptor antibody (12E) shows the expression of a 170-kDa receptor protein. The expression of the receptor protein decreases with follicular enlargement between the F3 and F1. Incubation of the cells with [125I]TGF-alpha followed by cross-linking with bis(sulphosuccinimidyl)suberate showed that TGF-alpha binds a similar (170 kDa) receptor protein immunoprecipitated with the 12E anti-EGF receptor antibody. The binding of TGF-alpha to granulosa cells caused receptor protein oligomerization, yielding the monomeric (170 kDa) and dimeric (340 kDa) protein forms. Oligomerization seemed to favour the formation of the dimeric rather than the monomeric form. Culturing granulosa cells with luteinizing hormone or follicle-stimulating hormone increased the expression of both monomer and dimer forms of the receptor proteins compared with the control. Western blotting analysis with anti-phosphotyrosine antibody revealed that the lysates of TGF-alpha-stimulated cells express phosphotyrosine-containing receptor proteins of 170 kDa and 340 kDa. The results show that chicken granulosa cells express the 170-kDa EGF/TGF-alpha receptor protein, which dimerizes on binding to TGF-alpha, suggesting that the receptor protein may be involved in the signal transduction of TGF-alpha actions in the chicken granulosa cells.


Promising practices to eliminate tobacco disparities among Asian American, native Hawaiian and Pacific Islander communities.
Tobacco use continues to be the single most preventable cause of death for all groups in the United States, including Asian Americans (AAs) and Native Hawaiians and Pacific Islanders (NHPIs). Despite efforts in tobacco control over the past two decades, tobacco-related health disparities remain in some priority population groups, including AAs and NHPIs. This special supplement features strategies and promising practices for addressing the critical problem of tobacco in the AA and NHPI communities.


Double-blind controlled trial of molsidomine in hypertension.
Molsidomine (M), a new long-lasting antianginal compound, was studied in 38 hypertensive patients to assess its antihypertensive properties. Six patients were selected for an acute, single dose comparative trial with placebo over 8 h after treatment. The remaining 32 patients were used in a 1 month trial to study the effect on BP of more prolonged treatment. Systolic, diastolic and mean BP were significantly reduced after a single dose of M 4 mg, and the effect lasted for about 8 h. M also inhibited the hypertensive response to isometric exercise in handgrip tests performed 1 and 8 h after M ingestion. A dose-related decrease in systolic and diastolic BP in the one month trial was also observed. In addition to its antianginal properties, M appears to possess an interesting effect on BP in mildly to moderately hypertensive patients. A fall in BP is also a valuable effect in coronary patients with augmented metabolic demands of the heart.


Perceived food hypersensitivity relates to poor asthma control and quality of life in young non-atopic asthmatics.
The relationship between perceived food hypersensitivity in asthmatics, food allergen sensitization, asthma control and asthma-related quality of life has not been studied. Our aim was to study the prevalence of perceived food hypersensitivity in a cohort of young asthmatics, its relation to food allergen sensitization, and any correlation to asthma control and asthma-related quality of life. Perceived food hypersensitivity, as well as IgE sensitization to common food allergens, levels of exhaled nitric oxide (FeNO), and blood eosinophil counts (B-Eos) were assessed in 408 subjects (211 women) with asthma, aged (mean ± SEM) 20.4 ± 0.3 years. Subjects filled out the Asthma Control Test (ACT) and the Mini Asthma Quality of Life Questionnaire (Mini-AQLQ). Inflammation was assessed by means of FeNO and B-Eos. Fifty-three per cent of subjects reported food hypersensitivity. A corresponding food allergen sensitization was found in 68% of these subjects. Non-atopic subjects with perceived food hypersensitivity (n = 31) had lower ACT (19 (15 - 22) vs. 21 (20 - 23), p < 0.001) and Mini-AQLQ -scores (5.3 (4.3 - 6.1) vs. 6.1 (5.5 - 6.5), p < 0.001) than subjects with no food hypersensitivity (n = 190), despite lower levels of FeNO and B-Eos (p < 0.05). Food hypersensitivity was commonly reported among young asthmatics. In a majority of cases, a corresponding food allergen sensitization was found. A novel and clinically important finding was that non-atopic subjects with perceived food hypersensitivity were characterized by poorer asthma control and asthma-related quality of life.


Multilevel ordinal model for CD4 count trends in seroconversion among South Africa women.
Ordinal health longitudinal response variables have distributions that make them unsuitable for many popular statistical models that assume normality. We present a multilevel growth model that may be more suitable for medical ordinal longitudinal outcomes than are statistical models that assume normality and continuous measurements. The data is from an ongoing prospective cohort study conducted amongst adult women who are HIV-infected patients in Kwazulu-Natal, South Africa. Participants were enrolled into the acute infection, then into early infection subsequently into established infection and afterward on cART. Generalized linear multilevel models were applied. Multilevel ordinal non-proportional and proportional-odds growth models were presented and compared. We observed that the effects of covariates can't be assumed identical across the three cumulative logits. Our analyses also revealed that the rate of change of immune recovery of patients increased as the follow-up time increases. Patients with stable sexual partners, middle-aged, cART initiation, and higher educational levels were more likely to have better immunological stages with time. Similarly, patients having high electrolytes component scores, higher red blood cell indices scores, higher physical health scores, higher psychological well-being scores, a higher level of independence scores, and lower viral load more likely to have better immunological stages through the follow-up time. It can be concluded that the multilevel non-proportional-odds method provides a flexible modeling alternative when the proportional-odds assumption of equal effects of the predictor variables at every stage of the response variable is violated. Having higher clinical parameter scores, higher QoL scores, higher educational levels, and stable sexual partners were found to be the significant factors for trends of CD4 count recovery.


COMRADES determines in vivo RNA structures and interactions.
The structural flexibility of RNA underlies fundamental biological processes, but there are no methods for exploring the multiple conformations adopted by RNAs in vivo. We developed cross-linking of matched RNAs and deep sequencing (COMRADES) for in-depth RNA conformation capture, and a pipeline for the retrieval of RNA structural ensembles. Using COMRADES, we determined the architecture of the Zika virus RNA genome inside cells, and identified multiple site-specific interactions with human noncoding RNAs.


Assessing blocks after spinal anaesthesia for elective caesarean section: how different questions affect findings from the same stimulus.
A block to touch to T5 is widely used to indicate an adequate level of block for caesarean section with spinal anaesthesia. However, two studies using a "block to light touch" to T5 as their end-point, had a high requirement for intraoperative analgesia and their results cast doubt on the adequacy of a block to touch to T5. On enquiry, these two papers did not assess complete block to touch, but asked mothers when the touch sensation "was the same as" a control stimulus. The difference between these two assessment methods is unknown. The current study presents prospectively collected sensory block data which included both block to touch and the level when touch was the same as a control stimulus. The levels of block were assessed using a Neurotip®. The mother was asked four questions to assess the block: first touch level, first sharp level, touch same as control and sharp same as control. The first touch level was a median of two dermatomes lower than the touch same as a control level [IQR 0-3, range 0-6]. Block level assessment methods using first sharp and touch same as control were equivalent. When describing a sensory block, not only is it necessary to indicate the exact stimulus used, but it is important to define the actual question asked of the patient. Clinically, block assessment using the first sharp level and touch same as control are equivalent.


Exposure considerations in human safety assessment: Report from an EPAA Partners' Forum.
Understanding and estimating the exposure to a substance is one of the fundamental requirements for safe manufacture and use. Many approaches are taken to determine exposure to substances, mainly driven by potential use and regulatory need. There are many opportunities to improve and optimise the use of exposure information for chemical safety. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a Partners' Forum (PF) to explore exposure considerations in human safety assessment of industrial products to agree key conclusions for the regulatory acceptance of exposure assessment approaches and priority areas for further research investment. The PF recognised the widescale use of exposure information across industrial sectors with the possibilities of creating synergies between different sectors. Further, the PF acknowledged that the EPAA could make a significant contribution to promote the use of exposure data in human safety assessment, with an aim to address specific regulatory needs. To achieve this, research needs, as well as synergies and areas for potential collaboration across sectors, were identified.


The effects of Japan's National Action Plan on Antimicrobial Resistance on antimicrobial use.
The aim of this study was to estimate the effects of Japan's National Action Plan on Antimicrobial Resistance 2016-2020 (NAP) on antimicrobial use (AMU). Monthly AMU from January 2013 to December 2019 was calculated using sales data, and time-series charts of AMU were then created for the total antimicrobials and target drug categories shown in the NAP (oral cephalosporins, oral fluoroquinolones, oral macrolides, and parenteral antimicrobials). Twelve-month predictions were generated to evaluate AMU in 2020. The publication of the NAP was associated with an AMU reduction in total antimicrobials, cephalosporins, fluoroquinolones, and macrolides. Parenteral AMU showed an upward trend, although it was not significantly associated with the intervention effect. AMU reductions of 15.0% for total antimicrobials, 26.3% for cephalosporins, 23.5% for fluoroquinolones, and 24.6% for macrolides were predicted for 2020 relative to 2013. However, there was a predicted increase of 17.4% for parenteral AMU. While Japan's NAP has contributed to the reduction in national AMU over the past 5 years, sustained action is still needed to further improve antimicrobial stewardship and promote countermeasures to antimicrobial resistance.


Hyaluronic acid embedded cellulose acetate phthlate core/shell nanoparticulate carrier of 5-fluorouracil.
Aim of this research was to prepare hyaluronic acid-modified-cellulose acetate phthalate (HAC) core shell nanoparticles (NPs) of 5-fluorouracil (5-FU). HAC copolymer was synthesized and confirmed by fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. HAC NPs with 5-FU were prepared using HAC copolymer and compared with 5-FU loaded cellulose acetate phthalate (CAP) NPs. NPs were characterized by atomic force microscopy (AFM), particle size, zeta potential, polydispersity index, entrapment efficiency, in-vitro release, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). HAC NPs were found slower release (97.30% in 48h) than (99.25% in 8h) CAP NPs. In cytotoxicity studies, showed great cytotoxic potential of 5-FU loaded HAC NPs in A549, MDA-MD-435 and SK-OV-3 cancer cellline. HAC NPs showing least hemolytic than CAP NPs and 5-FU. Area under curve (AUC), maximum plasma concentration (Cmax), mean residence time (MRT) and time to reach maximum plasma concentration Tmax), were observed 4398.1±7.90μgh/mL, 145.45±2.25μg/L, 45.74±0.25h, 72±0.50h, respectively of HAC NPs and 119.92±1.78μgh/mL, 46.38±3.42μg/L, 1.2±0.25h, 0.5±0.02h were observed in plain 5-FU solution. In conclusion, HAC NPs is effective deliver carrier of 5-FU for lung cancer.


Network-pharmacology-based research on protective effects and underlying mechanism of Shuxin decoction against myocardial ischemia/reperfusion injury with diabetes.
Patients with diabetes mellitus are at higher risk of myocardial ischemia/ reperfusion injury (MI/RI). Shuxin decoction (SXT) is a proven recipe modi-fication from the classic herbal formula "Wu-tou-chi-shi-zhi-wan" according to the traditional Chinese medicine theory. It has been successfully used to alleviate secondary MI/RI in patients with diabetes mellitus in the clinical setting. However, the underlying mechanism is still unclear. To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes. This paper presents an ensemble model combining network pharmacology and biology. The Traditional Chinese Medicine System Pharmacology Database was accessed to select key components and potential targets of the SXT. In parallel, therapeutic targets associated with MI/RI in patients with diabetes were screened from various databases including Gene Expression Omnibus, DisGeNet, Genecards, Drugbank, OMIM, and PharmGKB. The potential targets of SXT and the therapeutic targets related to MI/RI in patients with diabetes were intersected and subjected to bioinformatics analysis using the Database for Annotation, Visualization and Integrated Discovery. The major results of bioinformatics analysis were subsequently validated by animal experiments. According to the hypothesis derived from bioinformatics analysis, SXT could possibly ameliorate lipid metabolism disorders and exert anti-apoptotic effects in MI/RI associated with diabetes by reducing oxidized low density lipoprotein (LDL) and inhibiting the advanced glycation end products (AGE)-receptor for AGE (RAGE) signaling pathway. Subsequent animal experiments confirmed the hypothesis. The treatment with a dose of SXT (2.8 g/kg/d) resulted in a reduction in oxidized LDL, AGEs, and RAGE, and regulated the level of blood lipids. Besides, the expression of apoptosis-related proteins such as Bax and cleaved caspase 3 was down-regulated, whereas Bcl-2 expression was up-regulated. The findings indicated that SXT could inhibit myocardial apoptosis and improve cardiac function in MI/RI in diabetic rats. This study indicated the active components and underlying molecular therapeutic mechanisms of SXT in MI/RI with diabetes. Moreover, animal experiments verified that SXT could regulate the level of blood lipids, alleviate cardiomyocyte apoptosis, and improve cardiac function through the AGE-RAGE signaling pathway.


Effects of acute sleep deprivation on H reflex and V wave.
The impact of sleep deprivation on muscular strength and power remains poorly understood. We aimed to determine the acute effects of 24 hr of sleep deprivation on H-reflex and V-wave excitability. Fourteen healthy young adults (eight men, six women) were included. Participants visited the laboratory on two different occasions, without and with 24 hr of sleep deprivation. In each session, participants were tested for maximal voluntary contraction (MVC) of the plantar flexors and dorsiflexors, soleus H- and M-recruitment curves, and evoked V wave, as well as tibialis anterior/soleus electromyographic co-activation. Twenty-four hours of sleep deprivation did not affect either plantarflexion MVC or soleus electromyographic normalized amplitude (p > .05). Moreover, H-reflex and V-wave peak-to-peak normalized amplitude did not change with sleep deprivation (p > .05). Conversely, we obtained a significant increase in antagonist/agonist level of co-activation during MVC post-sleep deprivation (6.2 ± 5.2%, p < .01). In conclusion, we found that H-reflex and V-wave responses are well preserved after 24 hr of sleep deprivation, revealing that descending neural drive and/or modulation in Ia afferent input remains largely unaffected under these circumstances. Yet, sleep deprivation affects motor control by exacerbating the magnitude of antagonist/agonist co-activation during forceful muscle contractions and this is novel.


Chondroma in a sesamoid bone of the thumb: case report.
Sesamoid tumors of the hand are uncommon. We report a 50-year-old man presenting with a right thumb sesamoid chondroma. Surgical excision was successfully performed. At 12-month follow-up, the thumb function is normal, and there is no evidence of other lesions or recurrence.


Contentious problems in bioscience and biotechnology: a pilot study of an approach to ethics education.
This manuscript describes a pilot study in ethics education employing a problem-based learning approach to the study of novel, complex, ethically fraught, unavoidably public, and unavoidably divisive policy problems, called "fractious problems," in bioscience and biotechnology. Diverse graduate and professional students from four US institutions and disciplines spanning science, engineering, humanities, social science, law, and medicine analyzed fractious problems employing "navigational skills" tailored to the distinctive features of these problems. The students presented their results to policymakers, stakeholders, experts, and members of the public. This approach may provide a model for educating future bioscientists and bioengineers so that they can meaningfully contribute to the social understanding and resolution of challenging policy problems generated by their work.


A minimal input-output configuration for a priori identifiability of a compartmental model of leucine metabolism.
To develop a model describing the structure and function of a metabolic system using data from an input-output experiment, it is useful to design a pilot tracer study first which contains a predicted maximal amount of information. Having postulated a physiologically reasonable model structure from the pilot data, two questions arise. First, are the model parameters a priori uniquely identifiable? That is, assuming an error-free model structure and data, can the parameters be uniquely identified from the information content of the pilot experiment? Second, if the model parameters are uniquely identifiable, is the pilot experiment a minimal one? That is, is the pilot experiment necessary and sufficient, in the sense of information content, among feasible experiments to guarantee a priori unique identifiability? The purpose of this paper is to determine a minimal input-output configuration for the a priori unique identifiability of a compartmental model describing the metabolism of leucine, an essential amino acid. The original pilot tracer experiment was a two-stage experiment consisting first of a two input-five output experiment followed by a single input-single output experiment. Here we show to guarantee a priori unique identifiability of the leucine model that the single input-single output experiment is not necessary, and that two of the outputs of the multi-input-multi-output experiment are not required.


Indigenous Muscovy ducks in Congo Brazzaville. 2. Preliminary observations on indigenous Muscovy ducks reared under moderate inputs in Congolese conditions.
To evaluate the potential of the native Muscovy ducks in Congo, a trial was conducted with closed housing, commercial feeding and veterinary care. The characterization included reproductive performance, daily weight gain, live body weight, feed conversion ratio, body live weight productivity, and meat productivity. The experimental genetic stock was bred under natural mating and natural incubation. The number of eggs recorded per female and per clutch was 14.6 +/- 3 eggs with 2 clutches per year. The average (+/-SD) hatchability was 75% +/- 3% and the average egg weight was 72 +/- 8 g. The sexual dimorphism for body weight appeared after 3 weeks (p < 0.05). The maximum daily weight gain in males reached 55 +/- 8 g/day and occurred at 5 weeks, whereas in females it occurred at 4 weeks and reached 35 +/- 5 g/day. The carcass yield was 70% +/- 5% and 51 +/- 8% in males and females, respectively. The meat productivity was 26.7 and 11.5 kg/m2 per year in males and females, respectively. From these findings, it can be concluded that the incubation by mother duck is preferred in the small farming duck and that males should be raised for meat and females for egg production. Further studies including local poultry-related issues are needed to optimize the performance of the native Muscovy duck in Congo-Brazzaville.


Nurses and ventilators.
In the previous issue of Critical Care, Rose and colleagues report the results of a survey on the frequency with which ICU nurses are involved in decision-making in ventilator management. About 63 to 88% of the decisions were made by nurses in collaboration with physicians, and as much as 68% of ventilator adjustments were performed by nurses independent of physicians. Nurse involvement in decision-making was twice as likely in ICUs that use weaning protocols. The ICU nurse performs many roles, the most important being the continuous observation of a patient. The diversion of a nurse's attention from constant vigilance by performing tasks of no benefit, such as the use of weaning protocols, would be a most unfortunate turn of events.


Management of Graves' orbitopathy in Latin America: an international questionnaire study compared with Europe.
Management of Graves' orbitopathy (GO) and dysthyroid optic neuropathy (DON) continues to be challenging. Other surveys have been successful in elucidating trends in GO management. Knowledge of current practice by members of the Latin American Thyroid Society (LATS) who manage patients with GO was targeted by distribution of a questionnaire. We compared our results with a previously reported European Thyroid Association (ETA) survey. To determine how endocrinologists in Latin America access and treat patients with GO and compare the results with the same European survey. One hundred and two responders representing endocrinologists from 10 countries participated in the survey. Most (57%) participate in a multidisciplinary setting for GO management. Access to a surgeon for orbital decompression was available only 'within months' according to 48.3% of responders. Despite suspected DON, 32.4% were reluctant to recommend urgent referral to an eyecare physician. Steroids were preferred as the first-option therapy by 88.2% of responders (by intravenous route by 57.8% of these). The presence of diabetes reduced the use of steroids to 64.7% (P < 0.001) and increased the use of other immunosuppressive agents (from 1% to 9.8%, P < 0.01). Development of cushingoid features resulted in a reduction in steroid use to 40.2% (P < 0.001), with increased preference for irradiation (from 23.5% to 52.9%, P < 0.001) and nonsteroidal immunosuppressive drugs (from 1% to 10.8%, P < 0.01), along with a nonsignificant trend to higher indication of orbital surgery (from 24.5% to 34.3%). Some potential deficiencies in the diagnosis and management of DON and hyperthyroidism were observed in our survey, highlighting the need for improvement in specialist education and the quality of care offered to patients with GO in Latin America.