Comparison of intestinal transit recovery between laparoscopic and open surgery using a rat model.
After laparoscopic surgery (LS), patients show faster recovery of intestinal transit than after conventional open surgery (OS). To prove the mechanism of this advantage, we compared the recovery of intestinal transit using steel carbon balls. Rats underwent either open laparotomy or were insufflated with carbon dioxide followed by the administration of steel balls (0.6 mm). An abdominal radiograph was taken 12 h after the operation. Compliance of the intestinal walls was analyzed with a computer-driven barostat device. An abdominal radiograph of 12 h after administration of the steel carbon balls showed the balls scattered in the small and large intestine of the LS patients, whereas they remained mostly in the stomach of the OS patients. Compliance of the intestinal walls was sustained at approximately 100 microl/mmHg in the LS patients, whereas it dropped to 94 microl/mmHg in the OS patients with the increase in balloon pressure. Histologically, the extent of serosal edema was more severe in the OS than in the LS patients. In terms of intestinal transit and irritation LS has advantage over OS. Intestinal transit recovery, as measured by the migration of steel carbon balls, is faster in LS, and gastric emptying is slow in OS.


GABAB Receptor Signaling in the Mesolimbic System Suppresses Binge-like Consumption of a High-Fat Diet.
Binge eating could contribute to the development of obesity, and previous studies suggest that gamma-aminobutyric acid (GABA) type B receptor (GABABR) signaling is involved in the regulation of binge eating. Here, we show that time-restricted access to a high-fat diet (HFD) induces binge-like eating behavior in wild-type mice. HFD consumption during restricted time was significantly increased in corticostriatal neuron-specific GABABR-deficient mice compared with wild-type mice. Furthermore, the GABABR agonist baclofen suppressed HFD intake during restricted time in wild-type mice but not in corticostriatal or dopaminergic neuron-specific GABABR-deficient mice. In contrast, there were no significant differences in food consumption among genotypes under ad libitum access to HFD. Thus, our data show that the mesolimbic system regulates food consumption under time-restricted but not ad libitum access to HFD and have identified a mechanism by which GABABR signaling suppresses binge-like eating of HFD.


Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors.
Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers. Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas. Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.


Poststroke "pushing": natural history and relationship to motor and functional recovery.
Patients with hemiparetic stroke have impaired balance control. Some patients ("pushers") are resistant to accepting weight on and actively "push" away from the nonparetic side. This research identified pushers from stroke patients with moderate to severe hemiparesis and examined longitudinal changes in symptoms, level of impairment, and functional independence. Prospective sample of hemiparetic stroke patients (n=65) located in Toronto, Canada. Detailed clinical assessments were performed within 10 days postonset, at 6 weeks, and at 3 months. At 1 week after stroke, 63% of patients demonstrated features of pushing. In 62% of pushers, symptoms resolved by 6 weeks, whereas in 21%, pushing symptoms persisted at 3 months. Motor recovery and functional abilities at 3 months were significantly lower among the pushers compared with the nonpushers. Pushers also had a significantly longer hospital length of stay (89 days versus 57 days). It is noteworthy that motor and functional recovery improved significantly over the 3-month study period for both pushers and nonpushers. Identification of stroke patients with pushing symptoms has prognostic implications for recovery. In light of this potential recovery, rehabilitation specialists need to refine treatment approaches for the pushers to further improve functional outcome.


The implication of Sir2 in replicative aging and senescence in Saccharomyces cerevisiae.
The target of rapamycin (TOR) pathway regulates cell growth and aging in various organisms. In Saccharomyces cerevisiae, silent information regulator 2 (Sir2) modulates cellular senescence. Moreover, Sir2 plays a crucial role in promoting ribosomal DNA (rDNA) stability and longevity under TOR inhibition. Here we review the implication of rDNA stabilizers in longevity, discuss how Sir2 stabilizes rDNA under TOR inhibition and speculate on the link between sumoylation and Sir2-related pro-aging pathways.


Benign neonatal hemangiomatosis.
Diffuse neonatal hemangiomatosis is a serious multisystem syndrome of multiple cutaneous hemangiomas, visceral hemangiomatosis with arteriovenous shunts, high output congestive heart failure, thrombocytopenia with hemorrhage and central nervous system involvement. Some neonates with multiple cutaneous hemangiomas, however, may follow a benign course of spontaneous resolution without symptomatic visceral involvement. Such cases may be called benign neonatal hemangiomatosis.


Association of growth patterns during infancy and puberty with lung function, wheezing and asthma in adolescents aged 17.5 years: evidence from 'Children of 1997' Hong Kong Chinese Birth Cohort.
Rapid growth is related to adverse respiratory outcomes although possibly confounded or limited by growth modelling methods. We investigated the association of infant and pubertal growth with lung function, wheezing and asthma in a non-Western setting. In Hong Kong's 'Children of 1997' Chinese birth cohort (n = 8327), weight during infancy and weight, height and body mass index (BMI) during puberty were modelled using a super-imposition by translation and rotation model to identify (larger or smaller) size, (earlier or later) tempo and (slower or faster) velocity. Sex-specific associations with forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC (Global Lung function Initiative z-score) and self-reported wheezing and asthma at ∼17.5 years were assessed. For each fraction higher than average weight growth velocity during infancy, FVC was higher in boys (0.90 SD, 95% CI 0.35; 1.44) and girls (0.77 SD, 95% CI 0.24; 1.30), FEV1/FVC was lower (-0.74 SD, 95% CI -1.38; -0.10) and wheezing was higher (odds ratio 6.92, 95% CI 1.60; 29.99) in boys and an inverse association with FVC was observed for tempo but not for size. Associations for weight growth velocity in puberty were similar but weaker. Greater size and higher velocity of BMI growth was associated with higher FVC, lower FEV1/FVC and higher asthma and wheezing risk. Accelerated infant and pubertal weight growth were associated with disproportionate lung size and airway growth, and higher risk of asthma; optimizing early-life growth patterns could be important.


The association between N-acetylcysteine treatment and hepatic healing in patients with non-acetaminophen-induced liver injury in pediatric intensive care: A single-center retrospective study.
The aim of this study was to determine the association between the use of intravenous N-acetylcysteine (NAC) and hepatic healing in pediatric intensive care unit (PICU) patients with non-acetaminophen-induced hepatic injury, except for acute liver failure. The data of patients who received intravenous NAC as adjuvant therapy for transaminase levels more than sixfold normal values during their PICU stay between 2010 and 2014 were retrospectively collected from the medical records database. The patients who did not receive NAC with elevated transaminase levels during their PICU stay between 2014 and 2018 were also collected as the standard of care (SOC) cohort. More than 50% of the liver injuries were secondary to acute hypoxia, hypotension, sepsis, and inflammation. The median number of elevated transaminase period (ETP) days of the NAC and SOC groups were 5 (IQR: 4) and 4 (IQR: 4), respectively (p = 0.17). There was no significant difference between the groups in terms of minimum and maximum laboratory values during ETP. There was no significant difference in terms of ETP and maximum ALT levels between the NAC and SOC groups in the hypoxia-hypotension subgroup. This study did not show an association between indirect measures of hepatic healing and post-insult use of NAC in pediatric liver injury in the PICU setting.


The interaction between personality and interpersonal needs in predicting suicide ideation.
The Interpersonal Psychological Theory of Suicide (i.e., IPTS) proposes that suicidal desire occurs when an individual simultaneously experiences thwarted belongingness (TB) and perceived burdensomeness (PB) (i.e., interpersonal needs). However, interpersonal needs have been inconsistent in predicting suicide ideation in Koreans. Therefore, we examined depressogenic personality dimensions-sociotropy and autonomy-as individual differences that may alter the effects of TB and PB on suicide ideation. We hypothesized that sociotropy will amplify the influence of TB on suicide ideation and that autonomy will regulate the degree to which PB leads to suicide ideation. This study was conducted with undergraduate students from a university located in Seoul, Korea. 313 students of whom 113 were males (36.1%) and 200 were females (63.9%) were included in the final analyses. Among the 313 participants, 42 (20.3%) endorsed suicide ideation. Significant correlations were identified between sociotropy and depression, and autonomy and depression. PB and sociotropy were valid predictors of suicide ideation even after controlling for depression. In addition, significant interactions were found between sociotropy and TB, and autonomy and PB.


Near-real-time feedback control system for liver thermal ablations based on self-referenced temperature imaging.
Our challenge was to design and implement a dedicated temperature imaging feedback control system to guide and assist in a thermal liver ablation procedure in a double-donut 0.5T open MR scanner. This system has near-real-time feedback capability based on a newly developed "self-referenced" temperature imaging method using "moving-slab" and complex-field-fitting techniques. Two phantom validation studies and one ex vivo experiment were performed to compare the newly developed self-referenced method with the conventional subtraction method and evaluate the ability of the feedback control system in the same MR scanner. The near-real-time feedback system was achieved by integrating the following primary functions: (1) imaging of the moving organ temperature; (2) on-line needle tip tracking; (3) automatic turn-on/off the heating devices; (4) a Windows operating system-based novel user-interfaces. In the first part of the validation studies, microwave heating was applied in an agar phantom using a fast spoiled gradient recalled echo in a steady state sequence. In the second part of the validation and ex vivo study, target visualization, treatment planning and monitoring, and temperature and thermal dose visualization with the graphical user interface of the thermal ablation software were demonstrated. Furthermore, MR imaging with the "self-referenced" temperature imaging method has the ability to localize the hot spot in the heated region and measure temperature elevation during the experiment. In conclusion, we have demonstrated an interactively controllable feedback control system that offers a new method for the guidance of liver thermal ablation procedures, as well as improving the ability to assist ablation procedures in an open MR scanner.


Evaluation of new automated syphilis test reagents 'IMMUNOTICLES AUTO3' series: performance, biochemical reactivity, and clinical significance.
Automated nontreponemal and treponemal test reagents based on the latex agglutination method (immunoticles auto3 RPR: ITA3RPR and immunoticles auto3 TP: ITA3TP) have been developed to improve the issues of conventional manual methods such as their subjectivity, a massive amount of assays, and so on. We evaluated these reagents in regards to their performance, reactivity to antibody isotype, and their clinical significance. ITA3RPR and ITA3TP were measured using a clinical chemistry analyzer. Reactivity to antibody isotype was examined by gel filtration analysis. ITA3RPR and ITA3TP showed reactivity to both IgM- and IgG-class antibodies and detected early infections. ITA3RPR was verified to show a higher reactivity to IgM-class antibodies than the conventional methods. ITA3RPR correlated with VDRL in the high titer range, and measurement values decreased with treatment. ITA3RPR showed a negative result earlier after treatment than conventional methods. ITA3TP showed high specificity and did not give any false-negative reaction. Significant differences in the measurement values of ITA3RPR between the infective and previous group were verified. The double test of ITA3RPR and ITA3TP enables efficient and objective judgment for syphilis diagnosis and treatments, achieving clinical availability.


MLL-Rearranged Acute Lymphoblastic Leukemia.
Rearrangements of the histone lysine [K]-MethylTransferase 2A gene (KMT2A) gene on chromosome 11q23, formerly known as the mixed-lineage leukemia (MLL) gene, are found in 10% and 5% of adult and children ALL cases, respectively. The most common translocated genes are AFF1 (formerly AF4), MLLT3 (formerly AF9), and MLLT1 (formerly ENL). The bimodal incidence of MLL-r-ALL usually peaks in infants in their first 2 years of life and then declines thereafter during the pediatric/young adult phase until it increases again with age. MLL-rearranged ALL (MLL-r-ALL) is characterized by hyperleukocytosis, aggressive behavior with early relapse, relatively high incidence of central nervous system (CNS) involvement, and poor prognosis. MLL-r-ALL cells are characterized by relative resistance to corticosteroids (due to Src kinase-induced phosphorylation of annexin A2) and L-asparaginase therapy, but they are sensitive to cytarabine chemotherapy (due to increased levels of hENT1 expression). Potential therapeutic targets include FLT3 inhibitors, MEK inhibitors, HDAC inhibitors, BCL-2 inhibitors, MCL-1 inhibitors, proteasome inhibitors, hypomethylating agents, Dot1L inhibitors, and CDK inhibitors. In this review, we discuss MLL-r-ALL focusing on clinical presentation, risk stratification, drug resistance, and treatment strategies, including potential novel therapeutic targets.


In Vitro Evaluation of the Virucidal Activity of Different Povidone-Iodine Formulations Against Murine and Human Coronaviruses.
Polyvinylpyrrolidone-iodine (PVP-I) demonstrates broad-spectrum anti-infective activity and is available in different formulations for oral rinse and topical use in medical and personal care settings. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need to supplement available preventive strategies. We assessed virucidal activity of PVP-I formulations, including 0.5% (w/v) solution, 5.0% (w/v) solution, 7.5% (w/v) scrub, and 10.0% (w/v) solution, versus placebos when challenged with coronaviruses in two in vitro studies. Murine coronavirus strain A59 (American Type Culture Collection [ATCC]® VR-764™), human coronavirus strain OC43 (ZeptoMetrix Corp. #0810024CF), human coronavirus strain NL63 (ZeptoMetrix Corp. #0810228CF), and human coronavirus strain 229E (ATCC® VR-740™) were used as surrogates for SARS-CoV-2. Both studies used the American Society for Testing and Materials in vitro time-kill method. All active PVP-I formulations in study 1 demonstrated virucidal activity at 15 s, with mean log10 reduction of greater than 4.56 or greater than 99.99% inactivation; a cytotoxic effect against the National Collection of Type Cultures clone 1469 host cells was observed with 5.0% (w/v) solution, 7.5% (w/v) scrub, and 10.0% (w/v) solution. Active PVP-I formulations in study 2 demonstrated effective virucidal activity against coronaviruses in less than 15 s; log10 reduction in viral titer for each coronavirus strain was consistently higher for 10.0% (w/v) solution and 0.5% (w/v) solution versus 7.5% (w/v) scrub. Both studies demonstrated in vitro virucidal activity of PVP-I formulations when challenged with SARS-CoV-2 surrogate coronaviruses. Although promising, further investigations are needed to evaluate SARS-CoV-2 inactivation.


Bladder cancer is the fifth most frequently diagnosed cancer in Europe, with major healthcare costs. For patients with non-muscle invasive bladder cancer, recurrences, treatment and surveillance regimes with multiple invasive procedures are a significant burden. Muscle invasive or metastatic disease is treated with radical surgery, radiation therapy and/or systemic chemo- or immunotherapy, with a five-year overall survival of around 50% and long-term quality of life issues for survivors. We present a brief overview of bladder cancer in various stages and give examples of new developments.


A critical review on correlating active sites, oxidative species and degradation routes with persulfate-based antibiotics oxidation.
At present, numerous heterogeneous catalysts have been synthesized to activate persulfate (PS) and produce various reactive species for antibiotic degradation from water. However, the systematic summary of the correlation among catalyst active sites, PS activation pathway and pollutant degradation has not been reported. This review summarized the effect of metal-based, carbon-based and metal-carbon composite catalysts on the degradation of antibiotics by activating PS. Metal and non-metal sites are conducive to inducing different oxidation pathways (SO4•-, •OH radical oxidation and 1O2 oxidation, mediated electron transfer, surface-bound reactive complexes and high-valent metal oxidation). SO4•- and •OH are easy to attack CH, S-N, CN bonds, CC double bonds and amino groups in antibiotics. 1O2 is more selective to the structure of the aniline ring and amino group, and also to attacking CS, CN and CH bonds. Surface-bound active species can cleave CC, SN, CS and CN bonds. Other non-radical pathways may also induce different antibiotic degradation routes due to differences in oxidation potential and electronic properties. This critical review clarified the functions of active sites in producing different reactive species for selective oxidation of antibiotics via featured pathways. The outcomes will provide valuable guidance of oriented-regulation of active sites in heterogeneous catalysts to produce on-demand reactive species toward high-efficiency removing antibiotics from water.


Influence of 17β-estradiol binding by dissolved organic matter isolated from wastewater effluent on estrogenic activity.
The aims of this study were to determine the sorption coefficient (LogK(DOC)) of 17β-estradiol (E2), according to the size and composition of dissolved organic matter (DOM) isolated from wastewater effluent using a fluorescence quenching (FQ) method, and to measure the estrogenic changes due to the extent of E2 sorption onto effluent DOM (EfOM) by using an E-screen bioassay. The highest logK(DOC) of E2 for a DOM size fraction less than 0.2 μm was observed by 4.87 ± 1.87 Lkg(-1)(DOC), and its estrogenicity was the lowest among all the size fractions at 1.2 ng-EEQL⁻¹. However, E2 estrogenicity for a DOM size fraction less than 5 kDa was as high as that for the positive control due to the absence of fulvic acid- and protein-like DOM to bind with E2. The estrogenic activity for the hydrophobic fraction bound with E2 was significantly reduced to 1.6 ng-EEQL⁻¹, while that for the hydrophilic fraction having no binding with E2 was 2.6 ng-EEQL⁻¹, which was similar to that of the positive control (i.e., 2.8 ng-EEQL⁻¹). The results support a conclusion that the change in estrogenicity was due to the strong sorption affinity of E2 onto DOM.


Comparative evaluation of quantitative glomerular filtration rate measured by isotopic and nonisotopic methods.
Good correlation of glomerular filtration rate (GFR) measured isotopically from plasma disappearance of Tc-99m-DTPA (Sn) was shown with inulin clearance, creatinine clearance, and graded radionuclide imaging. The isotopic GFR is a simple, urineless technique not requiring continuous infusion that enables one to perform simultaneous renal imaging with one radiotracer.


Role of Predatory Bacteria in the Termination of a Cyanobacterial Bloom.
Changes in cyanobacterial abundance and in the occurrence of bacteria capable of lysing cyanobacteria were monitored over a period of 6 months (May to October 1998) in eutrophic Brome Lake (Quebec, Canada), in which dense cyanobacterial blooms recur regularly. By screening lake water, we isolated two strains of lytic bacteria from the family Cytophagaceae. When tested on 12 cyanobacteria and 6 heterotrophic bacteria, strain 1 lysed only Anabaena flos-aquae and strain 2 lysed only Synechococcus cedorum, Synechococcus leopoliensis, Synechococcus elongatus, and Anacystis nidulans: both liquid and agar-grown cultures of these cyanobacteria were lysed. The number of plaque-forming units of bacteria increased dramatically during the decline of the bloom. The results are consistent with an important role for these host-specific lytic bacteria in control and elimination of cyanobacterial blooms in this lake.


Obesity is Not Associated with Adverse Perioperative or Poorer Clinical Outcomes following Thoracic and Fenestrated-Branched Endovascular Aortic Repair.
Obesity is a risk factor for higher morbidity and mortality following open aortic repair but currently there is limited literature on its impact on clinical and procedural outcomes following thoracic endovascular aortic repair (TEVAR) and branched-fenestrated endovascular aortic repair (B-FEVAR). We conducted a retrospective case-control analysis of a prospectively collected nonrandomized database to evaluate the effects of obesity on procedural and clinical outcomes after B-FEVAR/TEVAR in treatment of pararenal/thoracoabdominal aortic aneurysm and dissection at the University hospital of Nantes (France) between January 2016 and December 2021. Patients were divided in 2 groups according to their body mass index (BMI) and the rate of technical success, complications (renal, pulmonary, cardiac, and neurological events), 30-day and long-term survival, freedom from target vessel instability and reintervention were compared. 195 patients were included (mean age 69.6 DS±11.2; n = 135, 69.2% men; mean BMI: 26.6 kg/m2 range 19-41) totalling n = 72 (36.8%) TEVAR, n = 107 (55.4%) FEVAR and n = 14 (7.3%) BEVAR. Patients were divided in 2 groups [obese: BMI≥30 kg/m2n = 52 (26.7%); and nonobese, BMI<30 kg/m2, n = 143 (73.3%) that statistically differed only in terms of coronary artery disease (obese 42.3% vs. 26.6% nonobese, P = 0.035) and diabetes (obese 25% vs. 12.6% nonobese, P = 0.03). No statistical differences were noted in primary technical (94.2% vs. 94.4%, P = 1.00) and clinical (92.3% vs. 95.1%, P = 0.49) success. Overall morbidity (30.8% vs. 21.1%, P = 0.16), visceral vessels instability (1.9% vs. 1.4% P = 1.00), reintervention rate within 30 days (9.6% vs. 5.6% P = 0.33), 90 days (7.7% vs. 9.8%, P = 0.78) and during follow-up (9.8% vs. 20%, P = 0.14) were comparable. No statistical difference were noted in 30-day mortality (3.8% vs. 4.9%, P = 1.00) and the 2-year follow-up survival (86.8% vs. 78.4%, P = 0.180) between the 2 groups. In this series, obesity was not associated to worst clinical outcomes or higher mortality rate following TEVAR/B-FEVAR. However, considering our small patient sample, a conclusive analysis on obesity as risk factors for adverse events after endovascular treatment is not possible. A larger sample from the collaboration of multiple centers will be required to obtain definitive conclusions.


Correlation between metabolic controls and changes in retina in patients having diabetes.
Diabetes mellitus is as old as the human race. Retinopathy, being one of complications of diabetes mellitus, is the most common cause of blindness. This study was aimed at analyzing the correlation between retinopathy and duration of disease, metabolic control, and obesity. The study sample consisted of 135 patients divided into the experimental group of 90 patients with retinopathy and the control group of 45 patients without retinopathy. The patients were exa- mined according to standard protocols: anamneses, endocrinology, ophthalmology exams, biochemical analyses, and anthropometric measurements. The average age of patients was 60.13 +/- 9.29 in the experimental group, while it was 57.55 +/- 4.85 in the control group. The average duration of disease was 11.71 +/- 5.8 and 14.40 +/- 7.68 in the control group experimental group, respectively. The following statistically essential differences between the control and experimental group were found: in duration of disease (11.71 +/- 5.85; 14.40 +/- 7.68; r = 0.000), in glycemia (7.02 +/- 2.20; 8.34 +/- 3.18; p = 0.000), in glycosylated hemoglobin A1C (HbA1C) (7.16 +/- 1.37; 8.22 +/- 2.05; r = 0.000), in triglycerides (1.92 +/- 0.72; 2.63 +/- 1.60; r = 0.001), and in body mass index (23.94 +/- 2.65; 27.66 +/- 15.13; r = 0.000). There is a positive correlation between duration of disease, glycosylated hemoglobin A1C, triglycerides, body mass index - obesity and retinopathy. A significant statistical correlation among those parameters has been found in patients with diabetic retinopathy.


Education in radiation oncology in Europe.
The outcome of an inventory among 22 European countries with respect to the radiotherapy facilities and the training of new radiation oncologists in each country is described. The radiotherapeutic profession, which mostly prescribes also cytostatics or hormones, has become well-regulated in the last 20 years. Most radiation oncologists are also involved in the diagnostic work-up and follow-up of the cancer patient. The numbers of radiotherapists and other staff, treatment capacities, and patients are given. The training for radiation oncologists is mostly taken at the university centers, but the curricula are rather diverse.


Fetal echocardiographic markers to differentiate between a right and double aortic arch.
To describe the fetal echocardiographic features of a double aortic arch (DAA) and secondly, to assess the performance of these features to differentiate between a right aortic arch with left duct (RAA-LD) in a blinded cohort of vascular rings. Review of records to identify surgically confirmed cases of DAA diagnosed prenatally from 2014 to 2018 (cohort-A). Prenatal echocardiograms were reviewed and the segments of the aortic arches anterior and posterior to the trachea, aortic isthmuses and the presence/absence of the Z-sign were described. The utility of these markers were assessed in a separate cohort (B) of fetuses with surgically confirmed cases of DAA or RAA-LD. Cohort-A comprised 34 cases with DAA; there was a dominant RAA in 32/34 (94%) and balanced left aortic arch (LAA) and RAA in two cases. The proximal LAA was seen in 29/34 (85%), distal LAA in 15/34 (44%) and the LAA aortic isthmus in 4/34 (12%). The "Z" configuration was present in 29/34 (85%) cases. The most predictive marker for DAA in cohort-B was the Z-sign (sensitivity: 100%, specificity: 81%). The "Z" sign is a useful differentiator between RAA-LD and DAA. The absence of visualization of the left aortic isthmus does not preclude the presence of a DAA.


Randomized crossover trial of 'Roll-over' technique of abdominal paracentesis versus standard technique in suspected malignant ascites.
The sensitivity of single abdominal paracentesis for diagnosis of peritoneal carcinomatosis (PC) varies from 40-70%. We hypothesized that rolling-over the patient before paracentesis might improve the cytological yield. This was a single center pilot study with a randomized cross-over design. We compared the cytological yield of fluid obtained by roll-over technique (ROG) with standard paracentesis (SPG) in suspected PC. In the ROG group, patients were rolled side-to-side thrice, and the paracentesis was done within 1 minute. Each patient served as their own control, and the outcome assessor (cytopathologist) was blinded. The primary objective was to compare the tumor cell positivity between SPG and ROG groups. Of 71 patients, 62 were analyzed. Of 53 patients with malignancy-related ascites, 39 had PC. Most of the tumor cells were adenocarcinoma (30, 94%) with one patient each having suspicious cytology and one having lymphoma. The sensitivity for diagnosis of PC was (31/39) 79.49% in SPG group and (32/39) 82.05% in ROG group (p = 1.00). The cellularity was similar between both the groups (good cellularity in 58% of SPG and 60% of ROG, p = 1.00). Rollover paracentesis did not improve the cytological yield of abdominal paracentesis. CTRI/2020/06/025887 and NCT04232384.


A new substrate for the rapid evaluation of enteric microbial overgrowth.
The possibility of a new approach to diagnosis of intestinal bacterial overgrowth has been evaluated in laboratory animals. The diagnostic test involves oral administration of an enzyme-labile substrate consisting of para-aminobenzoic acid (PABA) conjugated to a bile acid. In the presence of enteric bacteria, PABA is split from the bile acid and is rapidly absorbed and excreted in the urine. The amount of PABA recovered during the 6 hr following the administered dose of the conjugate may be used as an index of bacterial overgrowth in the upper-gastrointestinal tract. The procedure has been shown to be a reliable index of this condition in laboratory animal models.


Characterization of Histopathology and Microbiota in Contemporary Regenerative Endodontic Procedures: Still Coming up Short.
This study aimed to investigate microbiota and the histopathology of infected immature teeth microenvironments after disinfection with calcium hydroxide, triple antibiotic paste, and a synthetic antimicrobial peptide (synthetic human beta-defensin-3-C15) for regenerative endodontic procedures (REPs). The null hypothesis was that there is no difference among intracanal medications on disinfection in REPs. Pulp necrosis and periapical lesions were induced in immature beagle dog premolars. Block randomized teeth were uninfected (negative control, n = 6), left infected (positive control, n = 6), or medicated with a disinfectant (n = 6/group). After disinfection (2 weeks), teeth were reaccessed, irrigated with 17% EDTA, blood clot induced, sealed with ProRoot MTA (Dentsply Tulsa Dental, Tulsa, OK), and restored with resin-modified glass ionomer. Animals were monitored radiographically and euthanized (12 weeks) for histopathologic and metagenomic analyses. REP-treated roots showed radiographic repair of periapical radiolucency (67.65%, 23/34), continued root development (73.53%, 25/34), and apical closure (70.59%, 24/34) regardless of the disinfectant used (P > .05). Canal microenvironments histologically devoid of bacteria contained new mineralized and pulp-like tissues in characteristic patterns that varied by disinfectant. Next-generation sequencing (16S ribosomal RNA) identified Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes as dominant phyla of microbiota in immature teeth. Infection-induced teeth showed changes in diversity and richness of microbiota from negative controls. Compared with positive controls, all treated teeth exhibited depleted operational taxonomic units, with lower phylogenic diversity from synthetic human beta-defensin-3-C15-treated teeth. There were no differences among the medicaments investigated in radiologic treatment outcomes, but disinfectants in REPs showed altered microbiota from normal and diseased immature teeth with different histologic patterns of regeneration.


Gadolinium-enhanced MR cisternography to evaluate dural leaks in intracranial hypotension syndrome.
We evaluated the use of MR cisternography after intrathecal administration of gadopentetate dimeglumine to detect the presence and localization of CSF leaks in 19 patients diagnosed with spontaneous intracranial hypotension syndrome according to the criteria of International Headache Society. Lumbar puncture with an injection of 0.5 mL of gadopentetate dimeglumine into the subarachnoid space in the lumbar area was performed. MR images of the cervical, thoracic, and lumbar regions in axial, coronal, and sagittal planes with fat-saturated T1-weighted images were acquired. We observed objective CSF leakage in 17 (89%) of 19 patients. In 14 of these 17 patients, the site of dural tear was demonstrated accurately. In 3 of these 17 patients, the contrast leakage was diffuse, and site of the leak could not be located accurately. No leakage was observed in 2 patients. No complications were detected in any of the patients during the first 24 hours after the procedure or during the 6- to 12-month follow-up. The current results demonstrate the relative safety, accuracy, and feasibility of intrathecal gadolinium-enhanced MR cisternography to evaluate dural leaks.


Incidence of sexual dysfunction in male patients treated surgically for rectal malignancy.
Sixty male patients surgically treated for colorectal cancer were interviewed by structured questionnaire to evaluate the etiology of sexual dysfunction and quality of life. Patients were divided into three groups: 20 who underwent low anterior resection, 20 subjected to Miles' abdominoperineal amputation, and 20 who underwent high anterior resection. Statistical evaluation of the three groups, by use of the chi-square test and Student's t test, showed that extent of the surgical dissection plays the most important role, although psychologic problems are also involved.


The miR-548d-5p/SP1 signaling axis regulates chondrocyte proliferation and inflammatory responses in osteoarthritis.
Chondrocyte apoptosis and dysfunction play an important role in osteoarthritis (OA), a chronic progressive arthropathy. Non-coding RNAs have been implicated in OA pathogenesis. In this study, microRNA (miR)-548d-5p was found to be downregulated in OA samples and IL-1β-stimulated chondrocytes. miR-548d-5p overexpression partially reversed IL-1β-induced chondrocyte damage in vitro, evidenced by the promotion of cell growth, the inhibition of apoptosis and inflammatory cytokine release, and the improvement in extracellular matrix (ECM) deposition. Furthermore, miR-548d-5p overexpression partially reversed papain-induced damages on OA rat's knee articular cartilage. Specificity protein 1 (SP1) was inhibited by miR-548d-5p and identified as its direct downstream target. In IL-1β-stimulated chondrocytes, SP1 overexpression significantly attenuated the protective effects of miR-548d-5p overexpression against chondrocyte damage. In conclusion, miR-548d-5p was abnormally downregulated in OA samples and IL-1β-stimulated chondrocytes. miR-548d-5p protects against IL-1β-induced chondrocyte damage via direct inhibition of SP1.


The Death Zone: Lessons from History.
This Lessons from History article about the naming of the extreme altitude "Death Zone" explores the historical mountaineering and medical literature relevant to the topic. Swiss alpinist and radiologist Edouard Wyss-Dunant (1897-1983) authored several reports and books about expeditions to arctic regions, deserts, and the Himalaya. Encouraged by the success of a Swiss expedition to the Garhwal Himalaya in 1947, Wyss-Dunant joined his fellow climbers from Geneva on a 1949 expedition to several peaks in the Kanchenjunga region. Wyss-Dunant was then invited to lead the spring 1952 Swiss Everest expedition. Despite this being the first Swiss attempt on Everest and on an untried route, Raymond Lambert and Tenzing Norgay nearly summitted Everest from the Nepal side. Wyss-Dunant earned mountaineering immortality by coining the phrase the Death Zone during the expedition's foray into the upper regions of Everest. Wyss-Dunant went on to become a president of the Swiss Alpine Club and the International Climbing and Mountaineering Federation. His writings and that of others provide an evocative supporting narrative to illustrate some of the problems of living (or dying) at extreme altitude.


Mechanically stable core-shell cellulose nanofibril/sodium alginate hydrogel beads with superior cu(II) removal capacity.
Nanocellulose hydrogels are promising sustainable biosorbents for removing heavy metal ions for wastewater treatment. However, the nanocellulose hydrogels reported thus far typically suffer from inferior adsorption performance and/or poor mechanical stability, thus limiting their industrial applications. Achieving the goals of mechanical stability and high removal capability remains a crucial technical challenge, which may be addressed, as presented in this study, by developing novel core-shell carboxymethylated cellulose nanofibril (CMCNF)/sodium alginate (SA) hydrogel beads (CAbs). By immobilizing CMCNFs (shell) on the surface of the SA hydrogel bead (core) via electrostatic attractions and hydrogen bonding, a mechanically stable hydrogel bead with a core-shell configuration was constructed, which shows a Cu(II) removal capacity of up to 221 mg/g that exceeds that of CMCNFs and most other nanocellulose structural adsorbents. Furthermore, both the formation principle of the core-shell structure and the Cu(II) removal mechanism were explored in detail. Finally, we demonstrated a potential application of core-shell CAbs to treat drinking water with a low concentration of Cu(II) using a homemade column adsorption device. This work brings sustainable nanocellulose adsorbents a step closer to industrial applications for Cu(II) wastewater treatment.


Bruton tyrosine kinase inhibitors in B-cell lymphoma: beyond the antitumour effect.
Targeting B-cell receptor signalling using Bruton tyrosine kinase (BTK) inhibitors (BTKis) has become a highly successful treatment modality for B-cell malignancies, especially for chronic lymphocytic leukaemia. However, long-term administration of BTKis can be complicated by adverse on- and/or off-target effects in particular cell types. BTK is widely expressed in cells of haematopoietic origin, which are pivotal components of the tumour microenvironment. BTKis, thus, show broad immunomodulatory effects on various non-B immune cell subsets by inhibiting specific immune receptors, including T-cell receptor and Toll-like receptors. Furthermore, due to the off-target inhibition of other kinases, such as IL-2-inducible T-cell kinase, epidermal growth factor receptor, and the TEC and SRC family kinases, BTKis have additional distinct effects on T cells, natural killer cells, platelets, cardiomyocytes, and other cell types. Such mechanisms of action might contribute to the exceptionally high clinical efficacy as well as the unique profiles of adverse effects, including infections, bleeding, and atrial fibrillation, observed during BTKi administration. However, the immune defects and related infections caused by BTKis have not received sufficient attention in clinical studies till date. The broad involvement of BTK in immunological pathways provides a rationale to combine BTKis with specific immunotherapies, such as immune checkpoint inhibitor or chimeric antigen receptor-T-cell therapy, for the treatment of relapsed or refractory diseases. This review discusses and summarises the above-mentioned issues as a reference for clinicians and researchers.


Abduction contracture of the deltoid muscle in children.
Deltoid contracture is usually congenital and affects the intermediate part of the muscle. Fibrosis occurring in these fibres produces the contracture. Six patients are reported. Recovery occurred after resection of the fibrotic band.


[The university health service: Role of a mental health nurse].
University health services have been serving students for many years. During this very particular health crisis, they are actively caring for the health of their population, including psychological health. Nursing skills are essential here.


Nifedipine potentiates antinociceptive effects of morphine in rats by decreasing hypothalamic pituitary adrenal axis activity.
It has been shown that nifedipine, as a calcium channel blocker can potentiate the antinociceptive effect of morphine; however, the role of Hypothalamic-Pituitary-Adrenal (HPA) axis on this action has not been elucidated. We examined the effect of nifedipine on morphine-induced analgesia in intact and adrenalectomized (ADX) rats and on HPA activity induced by morphine. To determine the effect of nifedipine on morphine analgesia, nifedipine (2 mg/kg i.p.) that had no antinociceptive effect, was injected concomitant with sub-effective dose of morphine (1 and 2 mg/kg). The tail-flick test was used to assess the nociceptive threshold, before and 15, 30, 60, 90, 120 and 180 min after drug administration. Our results showed that, nifedipine could potentiate the antinociceptive effect of morphine and this effect of nifedipine in ADX was greater than sham operated rats which, was reversed by corticosterone replacement. Nifedipine has an inhibitory effect on morphine -induced corticosterone secretion. Thus, the data indicate that the mechanism underlying the potentiation of morphine analgesia by nifedipine involves mediation, at least in part, by attenuating the effect of morphine on HPA axis.


Stasis Dermatitis: An Overview of Its Clinical Presentation, Pathogenesis, and Management.
Stasis dermatitis is a chronic inflammatory skin disease of the lower extremities. It typically occurs in older individuals and is the cutaneous manifestation of venous hypertension caused by venous reflux. Such retrograde venous blood flow is the result of incompetent venous valves, valve destruction, or venous obstruction. Stasis dermatitis is eczematous. The associated impairment of venous valves may cause swelling of the legs, leading to serious conditions including venous ulcerations. Diagnosis can be challenging because of its clinical resemblance to other skin conditions and poor clinical recognition by physicians. The cornerstones of stasis dermatitis treatment are compression therapy to ameliorate pain and swelling, topical treatments to alleviate secondary skin changes, and interventional treatment options to correct the underlying causes of venous reflux. Given the central role of inflammation of the lower extremities in driving the cutaneous changes characteristic of stasis dermatitis, new therapeutic approaches that target the inflammation are under clinical evaluation in patients with stasis dermatitis.


Schizophrenia: from phenomenology to neurobiology.
Schizophrenia is a common and debilitating illness, characterized by chronic psychotic symptoms and psychosocial impairment that exact considerable human and economic costs. The literature in electronic databases as well as citations and major articles are reviewed with respect to the phenomenology, pathology, treatment, genetics and neurobiology of schizophrenia. Although studied extensively from a clinical, psychological, biological and genetic perspective, our expanding knowledge of schizophrenia provides only an incomplete understanding of this complex disorder. Recent advances in neuroscience have allowed the confirmation or refutation of earlier findings in schizophrenia, and permit useful comparisons between the different levels of organization from which the illness has been studied. Schizophrenia is defined as a clinical syndrome that may include a collection of diseases that share a common presentation. Genetic factors are the most important in the etiology of the disease, with unknown environmental factors potentially modulating the expression of symptoms. Schizophrenia is a complex genetic disorder in which many genes may be implicated, with the possibility of gene-gene interactions and a diversity of genetic causes in different families or populations. A neurodevelopmental rather than degenerative process has received more empirical support as a general explanation of the pathophysiology, although simple dichotomies are not particularly helpful in such a complicated disease. Structural brain changes are present in vivo and post-mortem, with both histopathological and imaging studies in overall agreement that the temporal and frontal lobes of the cerebral cortex are the most affected. Functional imaging, neuropsychological testing and clinical observation are also generally consistent in demonstrating deficits in cognitive ability that correlate with abnormalities in the areas of the brain with structural abnormalities. The dopamine and other neurotransmitter systems are certainly involved in the treatment or modulation of psychotic symptoms. These broad findings represent the distillation of a large body of disparate data, but firm and specific findings are sparse, and much about schizophrenia remains unknown.


Firework smoke: Impacts on urban air quality and deposition in the human respiratory system.
Particle number concentrations and size distributions resulting from the firework displays held in Budapest, Hungary every year on St. Stephen's Day were studied over a period of seven years. In the year most impacted, the total particle number concentration reached its peak measured level of 369 × 103 cm-3 5 min after the end of the display, and returned to the pre-event state within 45 min. The fireworks increased hourly mean concentrations by a factor of 5-6, whereas the concentrations in the diameter range of 100-1000 nm, in which the magnitude of the increase was the greatest, were elevated by a factor of 20-25. An extra particle size mode at 203 nm was manifested in the size distributions as result of the fireworks. The PM10 mass concentrations at peak firework influence and as 1-h mean increased 123 and 58 times, respectively, relative to the concentration before the display. The smoke was characterised by a relatively short overall atmospheric residence time of 25 min. Spatiotemporal dispersion simulations revealed that there were substantial vertical and horizontal concentration gradients in the firework plume. The affected area made up a large part of the city. Not only the spectators of the display at the venue and nearby areas, but the population located further away downwind of the displays and more distant, large and populous urban quarters were affected by the plume and its fallout. The fireworks increased the deposition rate in the respiratory system of females by a factor of 4, as a conservative estimate. The largest surface density deposition rates were seen in the segmental and sub-segmental bronchi, which represents an excessive risk to health. Compared to adults, children were more susceptible to exposure, with the maximum surface density deposition rates in their case being three times those of adults in the trachea.


Factors that affect recurrence after anterior colporrhaphy procedure reinforced with four-corner anchored polypropylene mesh.
The purpose of this study was to evaluate the effectiveness of the anterior colporrhaphy procedure reinforced with four-corner anchored polypropylene mesh in patients with severe (stage III or IV) anterior vaginal prolapse. Thirty-eight consecutive women were enlisted for this prospective study. The procedure consisted of an extensive vaginal dissection to join the vesicovaginal and retropubic space and an anchoring of a polypropylene mesh patch between the two Arcus Tendineus Fasciae Pelvis in a tension-free manner. The mean age of the study group was 63 (33-80) years. The success rate was 87% (33/38) at a mean follow-up interval of 21 (12-29) months. A total of eight (100%) patients were also cured of concomitant stress incontinence (five overt and three occult type) with an additional tension-free vaginal tape (TVT) operation. During follow-up, there were five de-novo stress incontinence cases (16.7%) and four vaginal erosions of mesh (10.5%). Four clinical variables--diabetes mellitus, recurrent anterior vaginal prolapse, chronic cough and vaginal erosions of mesh--were found to have a significant correlation with an unsatisfactory surgical result with large values of hazard ratios found by survival analysis. We concluded that the anterior colporrhaphy procedure reinforced with four-corner anchored polypropylene mesh was effective for most, but failed in some patients who had specific risk factors within short convalescence periods. Concomitant stress incontinence can be successfully treated by a TVT operation in combination with the anterior colporrhaphy procedure reinforced with four-corner anchored polypropylene mesh. However, the anterior colporrhaphy procedure may itself have adverse effects on urethral sphincter function.


Radionuclides, heavy metals and fluorine incidence at Tapira phosphate rocks, Brazil, and their industrial (by) products.
Inorganic phosphate fertilizers may contain radionuclides, heavy metals and fluorine. This paper presents the possible environmental hazards from Tapira phosphate rocks and their (by) products (Brazil) utilized as phosphate fertilizers. The activity concentration of 238U, 234U, 226Ra and 40K in Tapira phosphate rocks is within the world range for these rock types. The 232Th activity concentration is higher than the mean reported in phosphate rocks. A value of 2184 nGy h(-1) was obtained for the exposure dose rate in Tapira phosphate deposit area, which is indicative of a high background radiation area. The flotation-separation process causes the incorporation of no more than 9%, 11% and 24% of radionuclides, heavy metals and fluorine, respectively, into the phosphate concentrate. The radionuclides and heavy metals existing in phosphate fertilizers applied in Brazilian crops according to the recommended rates, do not raise their concentration in soils to harmful levels.


Urethral reconstruction using the radial artery forearm free flap: conventional and prefabricated.
For successful reconstruction of the scarred urethra it is logical to employ well-vascularized skin flaps. The radial artery forearm free flap is ideal for this purpose. This paper describes the first seven consecutive patients in whom we have used this flap for urethral reconstruction. In one, the forearm skin was too hirsute for urethral lining, and a prefabricated hairless skin flap was created by application of a preliminary full-thickness skin graft from a nonhairy site onto the forearm fascia. The longest follow-up is 5 1/2 years.


[Is diagnostic curettage sufficient prior to endometrial ablation? Case of an early stage endometrial cancer].
To demonstrate a case of unrecognized endometrial cancer at endometrial ablation. Case report. Department of Obstetrics and Gynaecology and Department of Pathology, Jessenius Faculty Hospital, Martin, Slovakia. Authors describe a case of an early endometrial cancer diagnosed from material obtained by bipolar loop electrode during endometrial ablation. Authors poing out insufficiency of curettage as a method of endometrial biopsy prior to ablation. Using of the loop electrode may minimize the incidence of unrecognized malignancies.


Successful recycling of a previously transplanted heart: another option for limited resources.
We report a case of successful reuse of a previously transplanted heart. The organ was retransplanted 16 days after the initial transplantation into a 60-year-old man who had previously received a left ventricular assist device.


X-ray structure of domain I of the proton-pumping membrane protein transhydrogenase from Escherichia coli.
The dimeric integral membrane protein nicotinamide nucleotide transhydrogenase is required for cellular regeneration of NADPH in mitochondria and prokaryotes, for detoxification and biosynthesis purposes. Under physiological conditions, transhydrogenase couples the reversible reduction of NADP+ by NADH to an inward proton translocation across the membrane. Here, we present crystal structures of the NAD(H)-binding domain I of transhydrogenase from Escherichia coli, in the absence as well as in the presence of oxidized and reduced substrate. The structures were determined at 1.9-2.0 A resolution. Overall, the structures are highly similar to the crystal structure of a previously published NAD(H)-binding domain, from Rhodospirillum rubrum transhydrogenase. However, this particular domain is unique, since it is covalently connected to the integral-membrane part of transhydrogenase. Comparative studies between the structures of the two species reveal extensively differing surface properties and point to the possible importance of a rigid peptide (PAPP) in the connecting linker for conformational coupling. Further, the kinetic analysis of a deletion mutant, from which the protruding beta-hairpin was removed, indicates that this structural element is important for catalytic activity, but not for domain I:domain III interaction or dimer formation. Taken together, these results have important implications for the enzyme mechanism of the large group of transhydrogenases, including mammalian enzymes, which contain a connecting linker between domains I and II.


Effects of long-term discharge of acid mine drainage from abandoned coal mines on soil microorganisms: microbial community structure, interaction patterns, and metabolic functions.
More than twenty abandoned coal mines in the Yudong River Basin of Guizhou Province have discharged acid mine drainage (AMD) for a long time. The revelation of microbial community composition, interaction patterns, and metabolic functions can contribute to a better understanding of such ecosystems, which in its turn can be helpful in the development of strategies aiming at the ecological remediation of AMD pollution. In this study, reference and contaminated soil samples were collected along the AMD flow path for high-throughput sequencing. Results showed that the long-term AMD pollution promoted the evolution of γ-Proteobacteria, and the acidophilic iron-oxidizing bacteria Ferrovum (relative abundance of 15.50%) and iron-reducing bacteria Metallibacterium (9.87%) belonging to this class became the dominant genera. Co-occurrence analysis revealed that the proportion of positive correlations among bacteria increased from 51.02 (reference soil) to 75.16% (contaminated soil), suggesting that acidic pollution promotes the formation of mutualistic interaction networks of microorganisms. Metabolic function prediction (Tax4Fun) revealed that AMD contamination enhanced microbial functions such as translation, repair, and biosynthesis of peptidoglycan and lipopolysaccharide, etc., which may be an adaptive mechanism for microbial survival in extremely acidic environment. In addition, acidic pollution promoted the high expression of nitrogen-fixing genes in soil, and the discovery of autotrophic nitrogen-fixing bacteria such as Ferrovum highlights the possibility of using this taxon for bioremediation of AMD pollution.


Representation of semantic typicality in brain activation in healthy adults and individuals with aphasia: A multi-voxel pattern analysis.
This study aimed to investigate brain regions that show different activation patterns between semantically typical and atypical items in both healthy adults and individuals with aphasia (PWA). Eighteen neurologically healthy adults and twenty-one PWA participated in an fMRI semantic feature verification task that included typical and atypical stimuli from five different semantic categories. A whole-brain searchlight multi-voxel pattern analysis (MVPA) was conducted to classify brain activation patterns between typical and atypical conditions in each participant group separately. Behavioral responses were faster and more accurate for typical vs. atypical items across both groups. The searchlight MVPA identified two significant clusters in healthy adults: left middle occipital gyrus and right calcarine cortex, but no significant clusters were found in PWA. A follow-up analysis in PWA revealed a significant association between neural classification of semantic typicality in the left middle occipital gyrus and reaction times in the fMRI task. When the typicality effect was examined for each semantic category at the univariate level, significance was identified in the visual cortex for fruits in both groups of participants. These findings suggest that semantic typicality was modulated in the visual cortex in healthy individuals, but to a lesser extent in the same region in PWA.


Preseason Cerebrovascular Function in Adolescent Athletes.
The purpose of this study was to investigate the effects of sport participation, concussion history, and age of first exposure to football on preseason cerebrovascular function in adolescent athletes. Athletes (n = 53, age = 15.8 ± 1.2 years) were examined based on three exposure groupings: (1) sport participation (football vs. non-collision), (2) concussion history (none vs. ≥ 1), and (3) age of first exposure (football participants only). Transcranial Doppler assessed cerebrovascular reactivity (CVR) and neurovascular coupling (NVC), and separate independent samples t-tests evaluated group differences in CVR and NVC outcomes. Separate univariate linear regressions determined how age of first exposure related to CVR and NVC outcomes. Linear mixed effects models assessed group differences in CVR and NVC relative response curves. Differential response to NVC visual task response was significantly greater in non-collision sport athletes (F1,2946 = 38.69, p < 0.0001) and athletes without a concussion history (F1,2946 = 25.23, p < 0.0001). Older age of first exposure significantly predicted reduced breath-holding CVR response (F1,1560 = 2.92, p = 0.03). Healthy adolescent athletes have similar pre-season cerebrovascular function despite different sport participation and concussion history. However, age of first exposure may predict CVR in adolescent football athletes. Developmental literature identifies cerebrovascular function as dynamically changing throughout adolescence. Our study provides fundamental data informing the clinical meaningfulness of short- and long-term physiological function changes.


Influence of organic loading rate and temperature fluctuation caused by solar energy heating on food waste anaerobic digestion.
Anaerobic digestion, one of the most currently remarkable techniques for biogas production, has provided a method of high organic solid waste disposal. Operating temperature, especially in the winter of northern city, makes biomass degradation less efficient. The microorganisms that take on the role of gas production are greatly affected by temperature. In our study, solar energy was selected for anaerobic digestion and winter was selected as the experimental environment. Anaerobic digestion was performed with solar heating and electric heating separately. Parameters were tested (pH, soluble chemical oxygen demand, total ammonia nitrogen, total volatile fatty acids), and microbial structure was monitored. The volume of methane produced was measured over 60 days. The methane yield differed by 15.92% under different conditions. It is clearly shown that methane yield can be improved by a steady temperature environment. Nevertheless, dominant bacteria and microbial structure did not seem to be much different. This study may provide more energy-saving ideas for winter anaerobic digestion projects in northern regions.


A new technique for feeding Pseudolynchia canariensis (Macquart, 1839) (Diptera, Hippoboscidae) under laboratory conditions.
The objective of this work was to present a new technique for feeding Pseudolynchia canariensis, reducing both fly-host and researcher-host contact. Flies obtained from pigeons caught in Juiz de Fora, MG, Brazil were housed in screen top test tubes and kept at 27 degrees C 80%RH. Three infestation-free pigeons were kept in screen cages as their food source. Pigeons were restrained on a wooden frame with test tube supports and a muzzle and twine to immobilize the head and wings, respectively. To minimize bird stress, both feeding wing and birds were alternated. Using this new technique, 60 flies were kept under laboratory conditions for an average of 12 +/- 17.8 days. This method allowed up to six flies per time to be fed in a short space of time, thus helping reduce stress for the animals used.


An extended Shine-Dalgarno sequence in mRNA functionally bypasses a vital defect in initiator tRNA.
Initiator tRNAs are special in their direct binding to the ribosomal P-site due to the hallmark occurrence of the three consecutive G-C base pairs (3GC pairs) in their anticodon stems. How the 3GC pairs function in this role, has remained unsolved. We show that mutations in either the mRNA or 16S rRNA leading to extended interaction between the Shine-Dalgarno (SD) and anti-SD sequences compensate for the vital need of the 3GC pairs in tRNA(fMet) for its function in Escherichia coli. In vivo, the 3GC mutant tRNA(fMet) occurred less abundantly in 70S ribosomes but normally on 30S subunits. However, the extended SD:anti-SD interaction increased its occurrence in 70S ribosomes. We propose that the 3GC pairs play a critical role in tRNA(fMet) retention in ribosome during the conformational changes that mark the transition of 30S preinitiation complex into elongation competent 70S complex. Furthermore, treating cells with kasugamycin, decreasing ribosome recycling factor (RRF) activity or increasing initiation factor 2 (IF2) levels enhanced initiation with the 3GC mutant tRNA(fMet), suggesting that the 70S mode of initiation is less dependent on the 3GC pairs in tRNA(fMet).


Psychologic and psychoeducational consequences of thyroxine therapy for juvenile acquired hypothyroidism.
The observation of severe behavioral reactions or learning problems in three teenagers treated with L-thyroxine for juvenile acquired hypothyroidism prompted us to conduct a prospective study of achievement and behavioral characteristics of patients with newly diagnosed juvenile acquired hypothyroidism. On diagnosis of juvenile acquired hypothyroidism and before treatment with L-thyroxine, 23 children and adolescents underwent a comprehensive battery of psychoeducational tests, which was repeated after 3, 12, and 24 months of replacement therapy. Results revealed that adverse behavioral reactions and learning problems were relatively rare in these children, although symptoms of juvenile acquired hypothyroidism were associated with increased distractibility, hyperactivity, and poorer achievement. The least gain in achievement was made by children with more severe hypothyroidism at diagnosis; children with the best psychologic outcome were those who achieved euthyroidism more slowly. We conclude that severe behavioral manifestations of L-thyroxine therapy for juvenile acquired hypothyroidism are uncommon, but mild behavioral symptoms and poorer school achievement may occur in about 25% of patients, who represent the most severe cases at diagnosis.


Evaluation framework for carotid bifurcation lumen segmentation and stenosis grading.
This paper describes an evaluation framework that allows a standardized and objective quantitative comparison of carotid artery lumen segmentation and stenosis grading algorithms. We describe the data repository comprising 56 multi-center, multi-vendor CTA datasets, their acquisition, the creation of the reference standard and the evaluation measures. This framework has been introduced at the MICCAI 2009 workshop 3D Segmentation in the Clinic: A Grand Challenge III, and we compare the results of eight teams that participated. These results show that automated segmentation of the vessel lumen is possible with a precision that is comparable to manual annotation. The framework is open for new submissions through the website http://cls2009.bigr.nl.


Therapeutic Impact of Initial Treatment for Chlamydia trachomatis Among Patients With Pelvic Inflammatory Disease: A Retrospective Cohort Study Using a National Inpatient Database in Japan.
Pelvic inflammatory disease (PID) is common among women of reproductive age and can be complicated by tuboovarian abscess (TOA), which is a serious and potentially life-threatening disease. However, recent mortality rates from PID on hospital admission and the short-term therapeutic usefulness of initial treatment for Chlamydia trachomatis remain unknown. Using the Diagnosis Procedure Combination database, we identified patients who were diagnosed with PID on admission from July 2010 to March 2016 in Japan. We excluded patients who were pregnant, had cancer, or had missing data. Propensity score-adjusted analyses were performed to compare short-term outcomes between patients administered initial treatment for C. trachomatis and those without this treatment. The primary outcome was surgical intervention (laparotomy, laparoscopic surgery, and/or drainage procedure) during hospitalization. In total, 27841 eligible patients were identified. Of these patients, 2463 (8.8%) had TOA on admission. Mortality during hospitalization was 0.56% and 0.28% in the groups without and with TOA, respectively. Propensity score matching created 6149 pairs. A significant difference was observed in the primary outcome between those receiving initial treatment for C. trachomatis and the control group after propensity score matching (11.5% vs 13.4%; risk difference, -1.9%; 95% confidence interval, -3.1 to -0.7). The group that received initial treatment for C. trachomatis also had a significantly lower mortality rate. In this retrospective nationwide study, initial treatment for C. trachomatis among hospitalized patients diagnosed with PID had clinical benefits in terms of improved short-term outcomes.


Usefulness of MRI in the follow-up of patients with repaired aortic coarctation and bicuspid aortic valve.
The long-term outcome of repaired aortic coarctation may be complicated by dilatation of the ascending aorta notably in patients with bicuspid aortic valve. Magnetic resonance imaging was used to compare the size of the ascending aorta in patients with bicuspid or tricuspid aortic valve. In 50 patients with a repair of aortic coarctation, the size of the ascending aorta was measured in a bicuspid aortic valve group (n=11) and a tricuspid aortic valve group (n=39). The aortic diameter was measured at the level of the sinus of Valsalva and at the widest part of the ascending aorta using magnetic resonance imaging. The mean age of patients at surgical repair was respectively 2.2+/-3.3 years for the bicuspid aortic valve group and 2.5+/-3.5 years for the tricuspid aortic valve group (p=NS) and the mean age at the time of the magnetic resonance imaging was 10.2+/-4.7 years and 9.3+/-5.9 years (p=NS) respectively. A significant difference in the aortic diameter was found between the bicuspid aortic valve group and the tricuspid aortic group both at the level of sinus of Valsalva (34.8+/-8.2 mm, 19.5+/-4.4 mm, respectively, p<0.01) and at the level of the ascending aorta (36.8+/-7.2 mm, 16.9+/-3.4 mm, respectively, p<0.01). The occurrence of ascending aortic dilatation is significantly associated with the presence of a bicuspid aortic valve. This requires long-term follow-up, which can be effectively performed by magnetic resonance imaging.


Involvement of gangliosides in proliferation of immortalized neural progenitor cells.
The CNS consists of neuronal and glial cells generated from common neural progenitor cells during development. Cellular events for neural progenitor cells, such as proliferation and differentiation, are regulated by multiple intrinsic and extrinsic cell signals. Although much is known on the importance of the proteinous factors in regulating the fate of neural progenitor cells, the involvement of other molecules such as gangliosides, sialic acid-containing glycosphingolipids, remains to be clarified. To elucidate the biological functions of gangliosides in neural progenitor cells, we transfected an immortalized neural progenitor cell line, C17.2, which does not express GD3 ganglioside, with a fusion protein of GD3-synthase (ST-II) and enhanced green fluorescent protein (ST-II-EGFP). Analysis of the ST-II transfectants revealed the ectopic expression of b- and c-series gangliosides. In the ST-II transfectants, proliferation induced by epidermal growth factor (EGF) was severely retarded. EGF-induced proliferation of C17.2 cells was dependent on the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway, and the EGF-induced activation of this pathway was significantly repressed in the transfectants. Thus, ST-II overexpression retarded proliferation of C17.2 cells via repression of the Ras-MAPK pathway. The result supports the concept that gangliosides may play an important role in regulating the proliferation of neural progenitor cells.


A Divergent Synthetic Route to the Vallesamidine and Schizozygine Alkaloids: Total Synthesis of (+)-Vallesamidine and (+)-14,15-Dehydrostrempeliopine.
The total synthesis of representative members of the schizozygine alkaloids, (+)-vallesamidine and (+)-14,15-dehydrostrempeliopine, were completed from a late-stage divergent intermediate. The synthesis took advantage of efficient nitro-group reactions with the A/B/C ring skeleton constructed concisely on a gram scale through an asymmetric Michael addition, nitro-Mannich/lactamisation, Tsuji-Trost allylation, and intramolecular C-N coupling reaction. Other key features of the synthesis are a novel [1,4] hydride transfer/Mannich-type cyclisation to build ring E and a diastereoselective ring-closing metathesis reaction to construct ring D. This approach gave access to a late-stage C14,C15 alkene divergent intermediate that could be simply transformed into (+)-vallesamidine, (+)-14,15-dehydrostrempeliopine, and potentially other schizozygine alkaloids and unnatural derivatives.


Power-assisted pedicle screws placement: Is it as safe and as effective as manual technique? Narrative review of the literature and our technique.
Pedicle screws are the gold standard in spine surgery, allowing a solid tricolumnar fixation which is unmatched by hooks and wires. The freehand technique is the most widely adopted for pedicle screws placing. While freehand technique has been classically performed with manual tools, there has been a recent trend toward the use of power tools. The aim of this review is to summarize and expose potential risks and advantages of power pedicle screws placing. The literature showed that the use of power tools offers an acceptable safety profile, comparable to manual technique. With an adequate training, the power technique may speed up the screw placing, reduce the fluoroscopy time and the physical stress to the spine surgeon. Regarding differences in pull-out strength between power and manual techniques, the literature is still uncertain and inconsistent, both in clinical and preclinical studies. The choice between the use of power and manual freehand pedicle screws placing is still based on the surgeon's own preference.


[3H] cocaine labels a binding site associated with the serotonin transporter in guinea pig brain: allosteric modulation by paroxetine.
We studied the characteristics of [3H]cocaine binding to membranes prepared from whole guinea pig brain. Cocaine binding was specific and saturable. A one-site binding model fit the data adequately: the Kd value of [3H]cocaine was 44 nM with a Bmax value of 280 fmol/mg protein. The rank order of potency for the [3H]cocaine binding site was paroxetine > clomipramine > (-)-cocaine > fluoxetine > mazindol > desipramine > GBR12909 > phencyclidine > benztropine > GBR12935 > (+)-cocaine. The IC50 values of these drugs for inhibition of [3H]cocaine binding were highly correlated with their IC50 values for inhibition of [3H]5-HT uptake into synaptosomes prepared from whole guinea pig brain. High affinity 5-HT uptake inhibitors produced dose-dependent wash-resistant (pseudoirreversible) inhibition of [3H]cocaine binding. The wash-resistant inhibition produced by paroxetine was due to an increase in the Kd of [3H]cocaine binding sites, and was accompanied by an increase in the dissociation rate, consistent with an allosteric mechanism. These studies suggest that, using membranes prepared from whole guinea pig brain, [3H]cocaine labels a binding site associated with serotonin transporter and that paroxetine and cocaine bind to different sites on the serotonin transporter.


Liquid chromatographic-mass spectrometric studies on the enzymatic degradation of beta-endorphin by endothelial cells.
An on-line HPLC-mass spectrometric procedure with an electrospray atmospheric pressure ionization (ESI-API) ion source was developed to identify the enzymatic degradation products (peptides) generated by incubation of human beta-endorphin (h beta E) with cultured aortic endothelial cells. The samples from the complex incubation mixture were prepurified and enriched using a small reversed-phase (RP) perfusion precolumn. Flow switching was applied to transfer the peptides from this precolumn to the analytical RP column of 2 or 0.32 mm I.D. and to separate them by gradient elution. The peptides were detected by means of an on-line coupled triple quadrupole mass spectrometer (TSQ 700) with an ESI-API ion source operated in the positive ion mode. This MS system behaves as a concentration sensitive detector at flow-rates from 5 to 150 microliters/min. MS-MS experiments supported the unambiguous assignment of the peptide structures. Thus most of the peptide fractions were identified and the region 16-17-18 (-L-F-K-) of h beta E was found to be primarily attacked by the enzymes of the endothelial cells.


American, European and international hypertension guidelines: Time to shake hands?
Following evidence-based medicine through guidelines is the first step to successfully treat hypertension and prevent cardiovascular outcomes. This study compares the recommendations of the most recent American College of Cardiology (ACC)/American Heart Association (AHA), European Society of Cardiology (ESC)/European Society of Hypertension (ESH) blood pressure and International Society of Hypertension (ISH) focusing on prevalent contrasts among guidelines on when, how and in whom start the treatment, which is a major health implications of guidelines. The three guidelines disagree for the cut-off values in the definition of hypertension. Due to the different cut-off values of BP at the definition of hypertension, a patient may be misclassified to one of the four phenotypes of BP from office and out of office measurements, based to which guidelines are followed by the physicians. In addition to this, each society propose different risk score to evaluate the cardiovascular risk in patients with hypertension. These differences cause a confusion not only to the general practitioners, but also the hypertension experts about the correct approach. The poor agreement between guidelines and diagnostic tools implies a huge number of patients remained unknown whether they should receive treatment.


Monitoring and Reversal of Anticoagulation and Antiplatelets.
Since percutaneous transluminal coronary angioplasty was first described and the breakthrough studies of the role of stents were reported, the evolution in anticoagulation and antiplatelet therapy used during percutaneous coronary intervention (PCI) has reduced periprocedural ischemic events and stent thrombosis. Although greater combinations and doses of anticoagulation with antiplatelets seem to provide the best protection against thrombogenic and embolic events, there is a significant trade-off with a higher risk of major and minor bleeding episodes. This review article expands on each of the commonly used antiplatelet and anticoagulants used at time of PCI, focusing on drug monitoring and reversal.


Factors influencing association of glucocorticoid receptor-steroid complexes with nuclei, chromatin, and DNA: interpretation of binding data.
Attempts to reconstruct, in a test tube, the steroid-hormone system of a responsive cell are fraught with enumerable difficulties. In this chapter I have attempted to point out some of the factors that affect receptor-steroid complexes and their interactions with acceptors. In most cases there is a quantitative influence of these factors on the level of steroid complex binding to acceptors. In some cases, selected experimental designs that neglect these factors and methods of presenting the observed data may lead to artifactual conclusions. Several of these problems should disappear when the prospect of pure receptor-steroid complexes [127, 147, 150, 181, 247, 248] becomes a common occurrence. Nevertheless much has already been learned about the interactions of complexes with acceptors, which in turn have been used to help formulate models of steroid-hormone action.


Update on SARS-CoV-2 seroprevalence: regional and worldwide.
With limited vaccine supplies, an informed position on the status of SARS-CoV-2 infection in people can assist the prioritization of vaccine deployment. We performed a systematic review and meta-analysis to estimate the global and regional SARS-CoV-2 seroprevalences around the world. We systematically searched peer-reviewed databases (PubMed, Embase and Scopus), and preprint servers (medRxiv, bioRxiv and SSRN) for articles published between 1 January 2020 and 30 March 2021. Population-based studies reporting the SARS-CoV-2 seroprevalence in the general population were included. People of different age groups, occupations, educational levels, ethnic backgrounds and socio-economic status from the general population. There were no interventions. We used the random-effects meta-analyses and empirical Bayesian method to estimate the pooled seroprevalence and conducted subgroup and meta-regression analyses to explore potential sources of heterogeneity as well as the relationship between seroprevalence and socio-demographics. We identified 241 eligible studies involving 6.3 million individuals from 60 countries. The global pooled seroprevalence was 9.47% (95% CI 8.99-9.95%), although the heterogeneity among studies was significant (I2 = 99.9%). We estimated that ∼738 million people had been infected with SARS-CoV-2 (as of December 2020). Highest and lowest seroprevalences were recorded in Central and Southern Asia (22.91%, 19.11-26.72%) and Eastern and South-eastern Asia (1.62%, 1.31-1.95%), respectively. Seroprevalence estimates were higher in males, persons aged 20-50 years, in minority ethnic groups living in countries or regions with low income and human development indices. The present study indicates that the majority of the world's human population was still highly susceptible to SARS-CoV-2 infection in mid-2021, emphasizing the need for vaccine deployment to vulnerable groups of people, particularly in developing countries, and for the implementation of enhanced preventive measures until 'herd immunity' to SARS-CoV-2 has developed.


Neural mechanisms of subliminal priming for traumatic episodic memory: an ERP study.
Event-related brain potentials (ERPs) were measured to study the electrophysiological mechanisms of subliminal priming of traumatic episodic memory. Twenty-four Chinese subjects who had experienced the great Sichuan earthquake in 2008 were classified either as normal control or as post-traumatic stress disorder (PTSD) subjects. Results showed that subliminally presented earthquake-related words elicited two significantly more positive ERP deflections (P2 and P300) than did earthquake-unrelated words between 250-300 ms and 340-400 ms post-stimulus periods for the PTSD group, but not for the control group. Dipole source analysis showed that the P2 was mainly generated in the posterior cingulate cortex (PCC), which appeared to be related to unconscious attentional resource allocation to the earthquake-related words. In addition, the P300 was found to be generated in the parahippocampal gyrus, which seemed to be related to the involuntary activation of traumatic episodic memory. These results indicated that catastrophic earthquake experiences made some subjects extremely sensitive and hyper-responsive to trauma-related information.


Novel bioactive dental restorations to inhibit secondary caries in enamel and dentin under oral biofilms.
To provide the first review on cutting-edge research on the development of new bioactive restorations to inhibit secondary caries in enamel and dentin under biofilms. State-of-the-art bioactive and therapeutic materials design, structure-property relationships, performance and efficacies in oral biofilm models. Researches on development and assessment new secondary caries inhibition restorations via in vitro and in vivo biofilm-based secondary caries models were included. The search of articles was carried out in Web of Science, PubMed, Medline and Scopus. Based on the found articles, novel bioactive materials are divided into different categories according to their remineralization and antibacterial biofunctions. In vitro and in vivo biofilm-based secondary caries models are effective way of evaluating the materials efficacies. However, new intelligent and pH-responsive materials were still urgent need. And the materials evaluation should be performed via more clinical relevant biofilm-based secondary caries models. Secondary caries is a primary reason for dental restoration failures. Biofilms produce acids, causing demineralization and secondary caries. To inhibit dental caries and improve the health and quality of life for millions of people, it is necessary to summarize the present state of technologies and new advances in dental biomaterials for preventing secondary caries and protecting tooth structures against oral biofilm attacks. In addition, suggestions for future studies are provided.


Lymphomatous intracardiac mass detected by radionuclide ventriculography.
A case of non-Hodgkin's lymphocytic lymphoma with cardiac involvement shown as an intracardiac-filling defect on the radionuclide ventriculogram is presented. The non-invasive diagnostic methods for cardiac lymphoma work-up are discussed. The known causes of cardiac-chamber filling defect(s) are reviewed.


Overexpression of RtSYP121 confers cadmium colerance by promoting vesicle trafficking, maintaining ion homeostasis, and alleviating photosynthetic inhibition in Arabidopsis.
Cadmium (Cd) is a toxic heavy metal in soil that seriously threatens crop production, food security, and human health. Syntaxins, a prototype family of Soluble N-ethyl-maleimide-associated protein receptors (SNAREs) involved in vesicle trafficking, are implicated in resistance to abiotic stresses, including Cd stress, but the molecular mechanisms underlying the involvement of syntaxins in Cd tolerance in plants are unclear. In this study, we isolated and functionally characterized the syntaxin gene RtSYP121 from Reaumuria trigyna to evaluate its potential for phytoremediation. RtSYP121 resides in the plasma membrane. The transcriptional level of RtSYP121 was strongly increased by salt, drought, and Cd stress. Overexpression of RtSYP121 significantly enhanced the Cd tolerance of transgenic Arabidopsis. The Cd tolerance of transgenic plants mainly depended on elevated vesicle trafficking, which increased the content of K+ and Ca2+ and thus decreased the accumulation of Cd2+ by regulating the delivery or activity of ion transporters, channels, and pumps. Moreover, overexpression of RtSYP121 in Arabidopsis ameliorated Cd stress-induced phytotoxic effects, including growth inhibition, ROS burst, photosynthetic impairment, and cell death. Therefore, we suggest that RtSYP121 plays multiple roles in the plant response to Cd stress by promoting vesicle trafficking, maintaining ion homeostasis, and alleviating photosynthetic inhibition.


[Coronary artery disease in hypertensive patients: improvement of the diagnostic value of exercise test by heart rate adjusted ST segment depression].
Hypertensive patients complaining of chest pain often have a normal coronary angiogram despite a pathological exercise tolerance test. The aim of the present study was to establish whether the prevalence of these "false-positive" tests could be lowered by adjusting ST segment depression for exercise-induced increase in heart rate. 60 hypertensive patients, mean age 59 years, with typical or atypical chest pain, underwent both a symptom-limited exercise test and a coronary angiogram within a median period of 1 day. The ST segment depression was measured every 20 ms from the J point. A stepwise discriminant analysis was performed: a canonical variable took into account the Detrano index, the quantified rate-recovery loop index (QRL index) as well as the presence of a LV hypertrophy (Romhilt Estes Score). [table: see text] in hypertensive patients with chest pain, the specificity and the positive predictive value of exercise test are significantly improved by adjusting ST segment depression for heart rate both during effort and recovery and by taking into account the score of Romhilt Estes on the baseline ECG recording.


Early-onset ophthalmoplegia, cervical dyskinesia, and lower extremity weakness due to partial deletion of chromosome 16: A case report.
We explored the genotype-phenotype correlation of the novel deletion 16p13.2p12.3 in an 8-year-old child with progressive total ophthalmoplegia, cervical dyskinesia, and lower limb weakness by comparing the patient's clinical features with previously reported data on adjacent copy number variation (CNV) regions. Specifically, we first performed whole-exome sequencing, CNV-sequencing, and mitochondrial genome sequencing on the patient and his parents, then applied "MitoExome" (the entire mitochondrial genome and exons of nuclear genes encoding the mitochondrial proteome) analysis to screen for genetic mitochondrial diseases. We identified a de novo 7.23 Mb deletion, covering 16p13.2p12.3, by both whole-exome sequencing and CNV sequencing. We also detected 16p13.11 in the deleted region, which is the recurrent distinct region associated with neurodevelopmental disorder. However, the patient only displayed features of progressive total ophthalmoplegia, cervical dyskinesia, and weakness in his lower limbs without neurodevelopmental disorder. The "MitoExome" sequencing was negative. Brain magnetic resonance imaging revealed non-specific sporadic changes in the occipital parietal lobe and basal ganglia. Taken together, these results indicated that 16p13.2p12.3 deletion causes a syndrome with the phenotype of early-onset total ophthalmoplegia. The "MitoExome" analysis is powerful for the differential diagnosis of mitochondrial diseases. We report a novel copy number variant in this case, but further confirmation is required.


Acetylcholinesterase and cholinesterase activities in the mouse cerebellum following misonidazole treatment.
The acetylcholinesterase and cholinesterase activities in the mouse cerebellum were unchanged following misonidazole treatment. Inhibition of acetylcholinesterase activity only occurred at concentrations of misonidazole which were in excess of those obtained clinically. These findings indicate that the clinical neurotoxicity of the drug cannot be attributed to an effect on cholinesterases.


Methylsulfonylpyrazolyl oxadiazoles and thiadiazoles as potent, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.
Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity. The structure-activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.


Hepatocyte growth factor acutely perturbs actin filament anchorage at the epithelial zonula adherens.
Cadherin adhesion molecules function in close cooperation with the actin cytoskeleton. At the zonula adherens (ZA) of polarized epithelial cells, E-cadherin adhesion induces the cortical recruitment of many key cytoskeletal regulators, which act in a dynamic integrated system to regulate junctional integrity and cell-cell interactions. This capacity for the cytoskeleton to support the ZA carries the implication that regulators of the junctional cytoskeleton might also be targeted to perturb junctional integrity. In this report, we now provide evidence for this hypothesis. We show that hepatocyte growth factor (HGF), which is well-known to disrupt cell-cell interactions, acutely perturbs ZA integrity much more rapidly than generally appreciated. This is accompanied by significant loss of junctional F-actin, a process that reflects loss of filament anchorage at the junctions. We demonstrate that this involves uncoupling of the unconventional motor myosin VI from junctional E-cadherin, a novel effect of HGF that is mediated by intracellular calcium. We conclude that regulators of the junctional cytoskeleton are likely to be major targets for cadherin junctions to be acutely modulated in development and perturbed in disease.


Cascaded logic gates in nanophotonic plasmon networks.
Optical computing has been pursued for decades as a potential strategy for advancing beyond the fundamental performance limitations of semiconductor-based electronic devices, but feasible on-chip integrated logic units and cascade devices have not been reported. Here we demonstrate that a plasmonic binary NOR gate, a 'universal logic gate', can be realized through cascaded OR and NOT gates in four-terminal plasmonic nanowire networks. This finding provides a path for the development of novel nanophotonic on-chip processor architectures for future optical computing technologies.


Recessive Mutations in AP1B1 Cause Ichthyosis, Deafness, and Photophobia.
We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the β subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 β subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.


Effects of exercise on cardiovascular risk factors in type 2 diabetes: a meta-analysis.
Exercise is a cornerstone of diabetes management and the prevention of incident diabetes. However, the impact of the mode of exercise on cardiovascular (CV) risk factors in type 2 diabetes is unclear. We conducted a systematic review of the literature between 1970 and October 2009 in representative databases for the effect of aerobic or resistance exercise training on clinical markers of CV risk, including glycemic control, dyslipidemia, blood pressure, and body composition in patients with type 2 diabetes. Of 645 articles retrieved, 34 met our inclusion criteria; most investigated aerobic exercise alone, and 10 reported combined exercise training. Aerobic alone or combined with resistance training (RT) significantly improved HbA(1c) -0.6 and -0.67%, respectively (95% CI -0.98 to -0.27 and -0.93 to -0.40, respectively), systolic blood pressure (SBP) -6.08 and -3.59 mmHg, respectively (95% CI -10.79 to -1.36 and -6.93 to -0.24, respectively), and triglycerides -0.3 mmol/L (95% CI -0.48 to -0.11 and -0.57 to -0.02, respectively). Waist circumference was significantly improved -3.1 cm (95% CI -10.3 to -1.2) with combined aerobic and resistance exercise, although fewer studies and more heterogeneity of the responses were observed in the latter two markers. Resistance exercise alone or combined with any other form of exercise was not found to have any significant effect on CV markers. Aerobic exercise alone or combined with RT improves glycemic control, SBP, triglycerides, and waist circumference. The impact of resistance exercise alone on CV risk markers in type 2 diabetes remains unclear.


Brain Lateralization and Cognitive Capacity.
One way to increase cognitive capacity is to avoid duplication of functions on the left and right sides of the brain. There is a convincing body of evidence showing that such asymmetry, or lateralization, occurs in a wide range of both vertebrate and invertebrate species. Each hemisphere of the brain can attend to different types of stimuli or to different aspects of the same stimulus and each hemisphere analyses information using different neural processes. A brain can engage in more than one task at the same time, as in monitoring for predators (right hemisphere) while searching for food (left hemisphere). Increased cognitive capacity is achieved if individuals are lateralized in one direction or the other. The advantages and disadvantages of individual lateralization are discussed. This paper argues that directional, or population-level, lateralization, which occurs when most individuals in a species have the same direction of lateralization, provides no additional increase in cognitive capacity compared to individual lateralization although directional lateralization is advantageous in social interactions. Strength of lateralization is considered, including the disadvantage of being very strongly lateralized. The role of brain commissures is also discussed with consideration of cognitive capacity.


On-resin N-formylation of peptides: a head-to-head comparison of reagents in solid-phase synthesis of ligands for formyl peptide receptors.
4-Nitrophenyl formate was found to be the most convenient reagent in solid-phase formylation of peptides with a high formylation degree within 20 min to 3 h depending on reaction temperature and length of peptide.


Effect of stimuli in right hemispace on left-sided neglect in a line cancellation task.
Twenty-seven patients with right cerebral infarcts resulting in left-sided neglect in a line cancellation task were also tested for line cancellation when the lines were confined to the left half of sheets. All but one patient (whose neglect in the former condition was minimal) were still impaired in the latter condition, a finding that indicates that hyperattraction to test stimuli in the unneglected (right) hemispace was not the crucial factor preventing them from completing the standard version of the cancellation task, although it may have played some role. The results are consistent with the conclusion that hyperattention to stimuli in the unneglected hemifield, and possibly to stimuli in the unneglected hemispace, together with other factors, could account for the patients' impairment in line cancellation.


Oxygen transport system before and after exposure to chronic hypoxia.
Maximal VO2 on the treadmill (VO2max) and on the bicycle ergometer (VO2peak), maximal cardiac output (Qmax), by a CO2 rebreathing method, maximal heart rate (HRmax), blood hemoglobin concentration (Hb), and hematocrit (Hct) were measured on six subjects before (B) and 3 weeks after (A) prolonged exposure to chronic hypoxia. It was observed that after high-altitude exposure VO2max, VO2peak, and Qmax were lower (P less than 005) than before [A: 4.13 +/- 0.67; 3.28 +/- 0.41 and 16.89 +/- 2.49 (l/min +/- SD); B: 4.39 +/- 0.39; 3.53 +/- 0.34 and 21.81 +/- 1.27, respectively], whereas Hb and Hct were larger (A: 162 +/- 8 g/l and 0.46 +/- 0.02; B: 142 +/- 7 and 0.41 +/- 0.02) and HRmax was unchanged (178 +/- 7 vs 175 +/- 9 bts/min). Thus, the calculated stroke volume of the heart and the Hb flow at VO2 peak were lower in A than in B (95 +/- 15 vs 124 +/- 7 ml and 2,723 +/- 307 vs 3,129 +/- 196 g/min) (P less than 0.05, respectively), whereas the arteriovenous O2 difference was greater in A than in B (195 +/- 16 vs 162 +/- 19 ml O2/l; P less than 0.05). At any given submaximal work load, VO2 and HR were the same in B and in A, whereas Q was lower in A by approximately 2-3 l/min. However, because of the increased Hb, leading to a higher arterial O2 content, at any work load the O2 flow remained unchanged.


Is insulin the preferred treatment in persons with type 2 diabetes and liver cirrhosis?
Insulin is highly recommended for diabetes management in persons with liver cirrhosis. However, few studies have evaluated its long-term effects in these persons. We conducted this study to compare the risks of mortality, liver-related complications, and cardiovascular events in persons with type 2 diabetes mellitus (T2DM) and compensated liver cirrhosis. From January 1, 2000, to December 31, 2012, we selected 2047 insulin users and 4094 propensity score-matched nonusers from Taiwan's National Health Insurance Research Database. Cox proportional hazard models were used to assess the risks of outcomes. The mean follow-up time was 5.84 years. The death rate during the follow-up period was 5.28 and 4.07 per 100 person-years for insulin users and nonusers, respectively. In insulin users, the hazard ratios and 95% confidence intervals (CIs) of all-cause mortality, hepatocellular carcinoma, decompensated cirrhosis, hepatic failure, major cardiovascular events, and hypoglycemia were 1.31 (1.18-1.45), 1.18 (1.05-1.34), 1.53 (1.35-1.72), 1.26 (1.42-1.86), 1.41 (1.23-1.62), and 3.33 (2.45-4.53), respectively. This retrospective cohort study indicated that among persons with T2DM and compensated liver cirrhosis, insulin users were associated with higher risks of death, liver-related complications, cardiovascular events, and hypoglycemia compared with insulin nonusers.