Gastrokinetic effect of ghrelin analog RC-1139 in the rat. Effect on post-operative and on morphine induced ileus.
We aimed to confirm the gastrokinetic effect of ghrelin analog, RC-1139, in the presence of opiates. Gastric emptying was verified in rats by counting stomach residue 15 min after gavage of methylcellulose. Normal rats: RC-1139 (0, 0.25, 1.0, 2.5 mg/kg i.v.) decreased methylcellulose left in stomach (47, 36, 12, 10% of ingested solution). Post-operative ileus (post-op. ileus) ileus: gastric residue decreased from 88 to 66, 53, 51% with RC-1139 0, 1.0, 2.5, 10 mg/kg. Morphine in post-op. ileus: gastroparesis was corrected at 10 mg/kg (54%). Ghrelin analog RC-1139 is a potent gastrokinetic in rat; it reversed gastric post-op. ileus, even in the presence of opiates.


Phosphoglycerate mutase, 2,3-bisphosphoglycerate phosphatase and enolase activity and isoenzymes in lung, colon and liver carcinomas.
We have compared the levels of phosphoglycerate mutase, 2,3-bisphosphoglycerate phosphatase and enolase activities and the distribution of their isoenzymes in normal colon, liver and lung tissues, and in colon, liver and lung adenocarcinoma, lung squamous cell carcinoma and lung carcinoid. All tumours presented higher phosphoglycerate mutase and enolase activities and lower 2,3-bisphosphoglycerate phosphatase activity than the normal tissues. No changes were observed in the phosphoglycerate mutase isoenzyme patterns analysed by cellulose acetate electrophoresis. All specimens contained mainly type BB isoenzyme, traces of type MB isoenzyme and no type MM isoenzyme. However, the tumours had decreased levels of 2,3-bisphosphoglycerate mutase and 2,3-bisphosphoglycerate mutase-phosphoglycerate mutase hybrid enzyme. Determined by agarose gel electrophoresis, alpha alpha-enolase was the isoenzyme predominant in normal lung, colon and liver tissue, although alpha gamma- and gamma gamma-enolase were also present in all tissues. In colon, liver and non-endocrine lung tumours, the proportions of alpha gamma- and gamma gamma-enolase decreased. In contrast, in carcinoid tumours of the lung, the proportions of these isoenzymes increased.


In vitro anti-leishmanial activity of methanolic extracts of Calendula officinalis flowers, Datura stramonium seeds, and Salvia officinalis leaves.
The anti-leishmanial activity of methanolic extracts of Calendula officinalis flowers, Datura stramonium seeds, and Salvia officinalis leaves against extracellular (promastigote) and intracellular (amastigote) forms of Leishmania major were evaluated in this study. In the first stage, promastigote forms of L. major, were treated with different doses of the plant extracts in a 96-well tissue-culture microplate and IC50 values for each extract were measured with colorimetric MTT assay. In the second stage, macrophage cells were infected with L. major promastigotes. Infected macrophages were treated with plant extracts. Then the macrophages were stained with Gimsa and the number of infected macrophages and amastigotes were counted with a light microscope. The results indicated that the plant extracts inhibited the growth of promastigotes and amastigotes of L. major. Inhibitory concentrations (IC50) for promastigote assay were 108.19, 155.15, and 184.32 μgmL(-1) for C. officinalis flowers, D. stramonium seeds and S. officinalis, respectively. The extracts also reduced the number of amastigotes in macrophage cells from 264 for control group to 88, 97, and 102 for test groups. Although the anti-leishmanial activity of the extracts were not comparable with the standard drug, miltefosine; but they showed significant efficiency in reducing the number of amastigotes in macrophages, in comparison with the control group (P < 0.001). These plant extracts had lower toxicity compared with miltefosine. This study demonstrates the potential efficacy of the methanolic extracts of C. officinalis flowers, D. stramonium seeds, and S. officinalis leaves to control of cutaneous leishmaniasis.


Association between exposure to polycyclic aromatic hydrocarbons and lipid peroxidation in patients with chronic obstructive pulmonary disease.
Polycyclic aromatic hydrocarbons (PAHs) are toxic airborne pollutants and may cause adverse effects at high level of oxidative stress. Here we hypothesized that individuals with impaired lung function are susceptible to PAHs associated oxidative damage. Hence, we carried out a panel study and conducted four follow-up visits on 40 chronic obstructive pulmonary disease (COPD) patients and 75 healthy controls. Hydroxylated PAHs (OH-PAHs) and malonaldehyde (MDA) were measured in urine as exposure and oxidative stress markers, respectively, which showed significant association in all participants. Quantitatively, a 1-fold increase in OH-PAHs was associated with a 4.1-15.1% elevation of MDA. The association between OH-PAHs and MDA levels became stronger in participants with impaired lung function. For 1% decrease of FEV1/FVC, the increase of MDA associated with a 1-fold increase in OH-PAHs was up to 0.49%, suggesting an increased susceptibility to PAH-induced oxidative damage in individuals with worse lung function. This study observed that impaired lung function modified the association between PAH exposure and oxidative damage, which might accelerate the aggravation of COPD, and therefore highlighted the necessity of protection measures to decrease the additional adverse effects of air pollution exposure. CAPSULE: Individuals with worse lung function may be more susceptible to PAH-induced lipid peroxidation.


Synthesis and physicochemical characterization of new twin-tailed N-oxide based gemini surfactants.
New gemini surfactants (GSs) constituted by two double alkyl chain (from 7 to 17 methylenic units) N-oxide monovalent surfactants joined by a PEG spacer of different length (from 3 to 21 ethylene glycol units), thus combining the properties of both N-oxide and GS surfactants, were synthetized and characterized. The different hydrophilic/hydrophobic balance of the molecular structure strongly influences the morphology and the electrical features of the aggregates. Despite the zwitterionic nature of the polar head groups, all the aggregates are characterized by positive potential thus suggesting protonation at the interface; however, the extent of protonation was shown to strongly depend on the length of the alkyl chain and of the spacer.


Carboxylesterase: specificity and spontaneous reactivation of an endogenous scavenger for organophosphorus compounds.
The ability of carboxylesterase (CaE) to act as a bioscavenger to provide protection against organophosphorus (OP) compounds has been demonstrated in several animal models. To further evaluate the effectiveness of CaE as a bioscavenger, the specificity and stoichiometry of the detoxication of OP compounds by rat plasma CaE were examined. The specificity of CaE was evaluated by determining the bimolecular rate constants for inhibition (k(i)) of CaE by a variety of OP compounds. CaE exhibited a broad specificity for neutral OP compounds with k(i) > 10(6) M(-1) x min(-1) for paraoxon, sarin, soman, diisopropyl fluorophosphate, and diphenyl p-nitrophenyl phosphinate. CaE exhibited poor reactivity (k(i) < 10(4) M(-1) x min(-1)) with cationic OP compounds, such as echothiophate, VX, and iso-OMPA. The stoichiometry of CaE detoxication of OP compounds was evaluated by determining the rates of enzyme reactivation and ageing of OP-inhibited CaE. CaE exhibited no ageing after inhibition by any of the OP compounds, including soman. However, OP-inhibited CaE did exhibit spontaneous reactivation with reactivation rates that decreased as the size of the OP increased (i.e., VX > sarin > soman). The pH dependence of the spontaneous reactivation of sarin-inhibited CaE suggested that its reactivation was dependent on an amino acid residue with a pK(a) of 6.1, which is probably a histidine that is highly conserved in CaE but not in other esterases.


Enhanced cell death effects of MAP kinase inhibitors in propyl gallate-treated lung cancer cells are related to increased ROS levels and GSH depletion.
Propyl gallate (PG) has an anti-growth effect in lung cancer cells. The present study investigated the effects of mitogen-activated protein kinase (MAPK; MEK, JNK, and p38) inhibitors on PG-treated Calu-6 and A549 lung cancer cells in relation to cell death as well as reactive oxygen species (ROS) and glutathione (GSH) levels. PG induced cell death in both Calu-6 and A549 lung cancer cells at 24 h, which was accompanied by loss of mitochondrial membrane potential (MMP; ΔΨm). All of the tested MAPK inhibitors increased cell death in both PG-treated lung cancer cell lines. In particular, MEK inhibitor strongly enhanced cell death and MMP (ΔΨm) loss in PG-treated Calu-6 cells and p38 inhibitor had the same effects in A549 cells as well. PG increased ROS levels and caused GSH depletion in both cell lines at 24 h. MAPK inhibitors increased O2•- levels and GSH depletion in PG-treated Calu-6 cells, and JNK and p38 inhibitors increased ROS levels and GSH depletion in PG-treated A549 cells. In conclusion, MAPK inhibitors increased cell death in PG-treated Calu-6 and A549 lung cancer cells. Enhanced cell death and GSH depletion in Calu-6 cells caused by the MEK inhibitor were related to increased O2•- levels, and the effects of the p38 inhibitor in A549 cells were correlated with increased general ROS levels.


Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. I. Efficacy results.
We aimed to assess the efficacy of depot leuprolide versus danazol in the treatment of endometriosis. A double-blind randomized trial of 270 patients from 22 centers compared the pretreatment and posttreatment laparoscopic extent of endometriosis. Pretreatment and posttreatment endometriosis symptoms and signs were assessed with standardized methods. When compared with danazol, leuprolide depot caused a more rapid and profound suppression of estradiol. Leuprolide depot and danazol were similarly efficacious in decreasing the extent of endometriosis, as well as the pain and tenderness associated with endometriosis. Depot leuprolide is an effective alternative to danazol in decreasing the extent of endometriosis and endometriosis-related pain.


[Prognostic value of pretherapeutic 18F-FDG PET/CT in cancer of the uterine cervix: a retrospective study of 53 patients].
Assessment of prognostic value of pretherapeutic (18)F-FDG PET/CT (PET). Retrospective study of 53 patients with invasive uterine cervix carcinoma. Each patient has been evaluated with pretherapeutic whole-body FDG PET/CT and pelvic MRI. Minimal follow-up lasted for 1 year. On PET/CT, we have visually analyzed metabolism of primary tumor, pelvic and para-aortic lymph nodes in comparison with surrounding structures. We have compared prognostic factors as pretherapeutic haemoglobin rate, FIGO staging, MRI and PET/CT data using Mann-Whitney univariate analysis and Cox multivariate analysis. Para-aortic lymph node abnormal uptake on PET/CT was the only independent predictor of progression-free survival. Pelvic lymph node involvement on PET/CT was the only independent predictor of overall survival. MRI did not provide any additional information. Lymph node involvement visually assessed by (18)F-FDG PET/CT was the most significant prognostic factor for overall and progression-free survival.


Hydralazine-induced hepatitis.
Three patients developed hepatic injury two months, ten months and two years, respectively, after hydralazine therapy for hypertension. Clinical and biochemical recovery followed discontinuation of drug therapy. Liver biopsies of the three patients revealed varying degrees of centrilobular necrosis. Complement 3 and Complement 4 levels were measured and found to be low in the patient with poor liver synthetic function, as was evident from the low serum albumin level and prolonged prothrombin time. Hydralazine-induced liver injury may be due to abnormality of drug metabolism in the liver.


Immune interferon produced in vitro as a quantitative indicator of cell-mediated immunity.
The present study was constructed to provide some information on the possibility of utilizing immune interferon as a quantitative indicator of cell-mediated immunity and to clarify some of the nature of immune interferon-producing cells (IIPC). When spleen cells derived from L cell-sensitized mice were co-cultivated with L cells, interferon appeared in the culture fluid. It was shown by additional experiments that the cells responsible for immune interferon production in this system were T-lymphocytes assisted by macrophages. The pattern of kinetics of immune interferon production in vitro was similar to that of migration inhibitory factor or T cell-mediated cytotoxicity.


Facilitatory effect of antidromic stimulation on milk ejection-related activation of oxytocin neurons during suckling in the rat.
Oxytocin neurons of the paraventricular nucleus were identified by their antidromic response to stimulation of the neurohypophysis and a short high-frequency burst of spikes displayed before reflex milk ejection in the urethane-anesthetized lactating rat. During suckling, the milk ejection-related bursts recurred at regular intervals. Stimulation of the neurohypophysis at 50-300 pulses/s for 0.5-6 s (current 1 mA) evoked additional burst(s) with the amplitude higher than those of spontaneously occurring ones. Stimulation with subthreshold current for antidromic response or constant-collision test could also facilitate the neurosecretory bursts. Possibly, oxytocin released within the magnocellular nuclei is responsible for these effects.


Can we let our patients sleep in the hospital? A randomized controlled trial of a pragmatic sleep protocol in surgical oncology patients.
Postoperative inpatients experience increased stress due to pain and poor restorative sleep than non-surgical inpatients. A total of 101 patients, undergoing major oncologic surgery, were randomized to a postoperative sleep protocol (n = 50) or standard postoperative care (n = 51), between August 2020 and November 2021. The primary endpoint of the study was postoperative sleep time after major oncologic surgery. Sleep time and steps were measured using a Fitbit Charge 4®. There was no statistically significant difference found in postoperative sleep time between the sleep protocol and standard group (median sleep time of 427 min vs. 402 min; p = 0.852, respectively). Major complication rates were similar in both groups (7.4% vs. 8.9%). Multivariate analysis found sex and Charlson Comorbidity Index to be significant factors affecting postoperative sleep time and step count. Postoperative delirium was only observed in the standard group, although this did not reach statistical significance. There were no in hospital mortalities. The use of a sleep protocol was found to be safe in our study population. There was no statistical difference in postoperative sleep time or major complications. Institution of a more humane sleep protocol for postoperative inpatients should be considered.


Neurobehavioral, autonomic nervous function and lymphocyte subsets among aluminum electrolytic workers.
The purpose of our study is to determine the alteration of neurobehavioral parameters, autonomic nervous function and lymphocyte subsets in aluminum electrolytic workers of long-term aluminum exposure. 33 men who were 35.16 +/- 2.95 (mean +/- S.D) years old occupationally exposed to aluminum for 14.91 +/- 6.31 (mean +/- S.D) years. Air Al level and urinary aluminum concentration was measured by means of graphite furnace atomic absorption spectrophotometer. Normal reference group were selected from a flour plant. Neurobehavioral core test battery (NCTB) recommended by WHO was utilized. Autonomic nervous function test battery recommended by Ewing DJ was conducted on subjects. FAC SCAN was used to measure the lymphocyte subsets of peripheral blood. The mean air aluminum level in the workshop was 6.36 mg/m3, ranged from 2.90 to 11.38 mg/m3. Urinary aluminum of the Al electrolytic workers (40.08 +/- 9.36 microgram/mg.cre) was obviously higher than that of control group (26.84 +/- 8.93 m/mg.cre). Neurobehavioral results showed that the scores of DSY, PAC and PA in Al electrolytic workers were significantly lower than those of control group, The score of POMSC, POMSF and SRT among Al exposed workers were significantly augmented in relation to those of control group. Autonomic nervous function test results showed that R-R interval variability of maximum ratio of immediately standing up in Al electrolytic workers were decreased compare with the control group, while the BP-IS, HR-V, HR-DB, R30:15 had no significant change. Peripheral blood lymphocyte subsets test showed that CD4-CD8+ T lymphocyte in Al electrolytic workers increased. This study suggests that Al exposure exerts adverse effects on neurobehavioral performance, especially movement coordination and negative mood, and parasympathetic nervous function; moreover it increase CD4-CD8+ T lymphocyte subsets.


Chromosome remodeling and differentiation of tetraploid embryos during preimplantation development.
Although it is known that the tetraploid embryo contributes only to the placenta, the question of why tetraploid embryos differentiate into placenta remains unclear. To study the effect of electrofusion on the development of mouse tetraploid oocytes, mouse two-cell embryos were fused and cultured in vitro in Chatot-Ziomek-Bavister medium. After electrofusion, two chromosome sets from the tetraploid blastomere were individually duplicated before nuclear fusion. At 8-10 hr after electrofusion, each chromosome set was condensing and the nuclear membrane was breaking down. Around 12-14 hr after electrofusion, the two chromosome sets had combined together and had reached the second mitotic metaphase, at this point with 8n sets of chromosomes. Interestingly, we discovered that expression of OCT4, an inner cell mass cells biomarker, is lost by the tetraploid expanded blastocysts, but that CDX2, a trophectoderm cells biomarker, is strongly expressed at this stage. This observation provides evidence clarifying why tetraploid embryos contribute only to trophectoderm.


Complete elimination of mitosis and DNA synthesis in the lens of the hypophysectomized frog: effects on cell migration and fiber growth.
Three weeks after hypophysectomy mitosis and DNA synthesis are absent in the lens of the leopard frog (Rana iiens). By labeling germinative zone cells in their last DNA synthetic period we were able to follow them in the absence of further proliferation. By this means it has been demonstrated that migration of epithelial cells to the equator of the lens is stopped. Based on indirect measurements it seems that lens fiber formation also ceases. A correlation coefficient of 0.86 was computed between average labeling index and average distance migrated. In hypophysectomized animals the correlation coefficient between time and migration was 0.02 while in intact animals it is 0.87.


Non-neoplastic colorectal disease biopsies: evaluation and differential diagnosis.
A wide variety of non-neoplastic conditions may be encountered on colorectal biopsy encompassing idiopathic, infectious, vascular and immune-mediated aetiologies. Although interpretation of such biopsies may be challenging, appreciation of the dominant pattern of injury and subsequent host response may allow for a more focused histological diagnosis in the correct clinical and endoscopic setting. This article aims to provide a systematic, methodical approach to the assessment of such biopsies, concentrating mainly on diagnoses other than inflammatory bowel disease.


Preservation of infected and exposed vascular grafts using vacuum assisted closure without muscle flap coverage.
The most widely used techniques for graft preservation after localized graft infections are muscle flap closure or antibacterial dressings and irrigations after débridement. Vacuum assisted closure (VAC) has been increasingly used for complex wounds in vascular surgery, including groin infections, but not directly on exposed bypass grafts as a stand-alone technique. We used the VAC system after wound débridement in four patients with fully exposed synthetic bypass grafts who were too unstable or risky for further operative interventions. Mean duration of VAC use was 22.8 days (range, 6 to 53 days), with time to total wound closure of 30 to 63 days (mean, 41 days). There were no reinfections with 11 to 25 months' follow-up (mean, 18.3 months). For high-risk surgical patients with a fully exposed infected prosthetic vascular graft, VAC therapy along with aggressive débridement and antibiotic therapy may be an effective alternative to current management strategies.


Use of particle beam liquid chromatography-electron impact mass spectrometry for structure elucidation of oxodipine and three of its metabolites.
In order to test the analytical capabilities of the particle beam liquid chromatograph-mass spectrometer interface in structural identification in drug metabolism, a liquid chromatographic-mass spectrometric (LC MS) method using this new technique was developed for oxodipine and some of its expected metabolites. After two extraction steps at pH 9 and 1.5, the separation of the compounds, which have a wide polarity range, was carried out by an isocratic high-performance liquid chromatographic method with a 25-cm cyano-bonded column. The compounds were eluted with hexane-methanol-methylene chloride (76:12:12). Mass spectra were recorded after electron impact ionization (75 eV) with a source temperature of 150 degrees C. Under these conditions, comparison of the spectra with those obtained after gas chromatography or with a direct introduction probe showed identical fragmentation patterns when a sufficient amount of product was injected for LC-MS analysis.


Incidence and survival of childhood cancer in the French islands of Reunion and Mayotte (2005-2011).
The aim of this study is to describe childhood cancer incidence and survival in the French islands of Reunion and Mayotte for the period 2005-2011. Data were taken from the population-based Cancer Registry of Reunion Island. All incident cases of malignant tumours and benign tumours of the Central Nervous System diagnosed between 2005 and 2011 in children under the age of 15 and living in Reunion or Mayotte were included. A total of 236 cases were registered (176 in Reunion, 60 in Mayotte). Age-standardised incidence rates (ASRs, world standard) for all cancers were 125.0 and 101.8 per million for Reunion and Mayotte, respectively. ASRs for the main cancer groups were lower than those described in mainland France for the same period. The 5-year overall survival rate for all patients was 78.5% (95%CI 71.9- 83.7), slightly lower than that reported in mainland France.


Comparative efficacy of psychosocial interventions for opioid-dependent people receiving methadone maintenance treatment: A network meta-analysis.
To estimate the efficacy of multiple psychosocial interventions for opioid-dependent people receiving methadone maintenance treatment (MMT). Systematic review and network meta-analysis of randomized controlled trials (RCTs) reporting the effect of psychosocial intervention for opioid-dependent people receiving MMT in outpatient clinics. We searched multiple data sources (Medline, Embase, Web of Science, PsycINFO and Cochrane Library) from inception to January 2022, finding 21 RCTs evaluating a total of 2862 people with opioid dependence receiving MMT. The primary outcome was the opioid-positive rate (assessed by urinalysis) and the secondary outcome was treatment discontinuation (the number of patients who terminated the study for any reason). We performed random-effects Bayesian meta-analysis. We used relative ranking using surface under the cumulative ranking method and certainty of evidence using grading of recommendations, assessment, development and evaluations. Cognitive-behavioral therapy (CBT) [odds ratio (OR) = 0.66, 95% credible interval (CI) = 0.66-0.96; low certainty] and educational and behavioral counseling (EBC) (OR = 0.28, 95% CI = 0.12-0.25; high certainty) were more effective than treatment as usual (TAU) in efficacy. In terms of treatment discontinuation, at the end of the follow-up period there was no statistical significance among psychosocial interventions. According to the ranking probabilities, EBC might be the most effective treatment and behavioral couples' therapy (BCT) might be the best discontinuation treatment. Educational and behavioral counseling and cognitive-behavioral therapy appear to be the most effective psychosocial interventions for opioid-dependent people receiving methadone maintenance treatment.


Strategies for Behaviorally Phenotyping the Transgenic Mouse.
The techniques and protocols to modify the mouse genome described in this volume allow researchers to produce genetic models of a remarkable number and breadth of human disease. The generation of gene-modified mice offers profoundly powerful approaches for bringing known or purported human gene disruptions into mouse models, but the degree to which the resultant mutant mouse recapitulates the complex physiological and behavioral features of the human disease state is a key variable in the ultimate usefulness of the mouse model organism. Accordingly, the behavioral characterization of mice with novel targeted gene mutations is an important initial step in determining the potential impact of a novel mouse model. This chapter addresses strategies useful in the initial observations of the animal that assist in directing the choice of secondary tests to assess more detailed aspects of potentially disrupted behaviors that may be relevant to the disease being modeled. An initial standardized, comprehensive screen that assesses general health, reflexes, and sensorimotor functions is the first step in characterizing behavioral phenotype, and results often suggest areas where more complex complementary behavioral assays may reveal more detailed disruption of normal behavior. This sequential, standardized approach reduces variability between subjects; this chapter also addresses approaches to reducing experimental artifacts due to handling, test order, testing facility environment, and other sources. This brief overview of behavioral phenotyping approaches is intended to provide practical information to streamline initial characterization of new mouse models and maximize the usefulness of efforts to use these models to study human health and disease.


Molecular analysis and spatial expression pattern of a low-temperature-specific barley gene, blt101.
A cDNA clone of the previously unreported low-temperature-induced gene blt101 was isolated after a differential screen of a cDNA library prepared from low-temperature (6 degrees C day/2 degrees C night) grown barley shoot meristems. Southern blot analysis of barley ditelosomic addition lines was used to assign this single-copy gene to the long arm of chromosome 4. Analysis of steady-state levels of blt101 mRNA showed the induction of this transcript in shoot meristems upon transfer of barley (cv. Igri) plants from control (20 degrees C/15 degrees C) to low (6 degrees C/2 degrees C) temperature treatment. Further, the high level of this transcript is maintained at low temperatures but is reduced on transfer from low to control temperatures. The gene is not induced by drought or by foliar application of ABA. Analysis of segregating doubled haploid lines shows that there is no specific association of this gene with either spring/winter growth habit or frost hardiness. Examination of the spatial expression pattern revealed ubiquitous expression of blt101 in low-temperature (6 degrees C/2 degrees C) grown barley shoot meristems, mature leaves and roots.


Finding a home.
A Blue Cross and Blue Shield of Texas (BCBSTX) pilot program seeks to measure how effective a patient-centered medical home can be at improving quality and controlling health care costs. The program couples what some are calling "aggressive care coordination" by participating physicians with extensive feedback from BCBSTX on several quality and patient satisfaction measures. Practices get a per-patient-per-month care management fee and share in whatever savings are achieved if they hit the cost and quality benchmarks.


Conjugated equine estrogen used in postmenopausal women associated with a higher risk of stroke than estradiol.
This study aimed to evaluate the risk of ischemic stroke (IS) in hormone therapy (HT) with oral conjugated equine estrogen (CEE) and estradiol (E2) in postmenopausal women in Taiwan. A retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database, a population-based healthcare claims dataset. Eligible women, aged 40-65 years, who received HT with E2 and CEE orally were enrolled. The primary outcome was IS. Propensity score matching with menopausal age and comorbidities was used. Cox proportional hazard regression models were used to calculate the incidence and hazard ratios (HRs) for IS. The mean menopausal ages of the E2 and CEE groups were 50.31 ± 4.99 and 50.45 ± 5.31 years, respectively. After adjusting for age and comorbidities, the incidence of IS was 1.17-fold higher in the women treated with CEE than in those treated with E2 (4.24 vs. 3.61/1000 person-years), with an adjusted HR (aHR) of 1.23 (95% confidence interval [CI] 1.05-1.44). Moreover, HT with CEE initiated within 5 years of menopause had a higher HR than E2 (aHR = 1.20; 95% CI 1.02-1.42). In conclusion, HT with oral CEE might be associated with a higher risk of IS than E2 in postmenopausal Taiwanese women. The use of HT with CEE should be cautioned with the risk of IS.


A convenient synthesis of novel pyranosyl homo-C-nucleosides and their antidiabetic activities.
A series of pyranosyl homo-C-nucleosides have been synthesized by reaction of butenonyl C-glycosides (5a-5j, and 8) and cyanoacetamide in presence of t-BuOK followed by further modifications. The reaction proceeds by Michael addition of cyanoacetamide to the butenonyl C-glycosides and subsequent dehydrative cyclization and oxidative aromatization to give glycosylmethyl pyridones (6a-6j, 7a-7j, 9, and 10). The glycosylmethyl pyridones (6a-6e) on reaction with POCl(3) under reflux gave respective glycosylmethyl pyridines (11a-11e and 12a-12e) in good yields. The synthesized compounds were screened for their in vitro α-glucosidase, glucose-6-phosphatase and glycogen phosphorylase inhibitory activities. One of the pyridylmethyl homo-C-nucleoside, compound 11d, displayed 52% inhibition of glucose-6-phosphatase as compared to the standard drug sodium orthovanadate while compound 12a showed a significant antihyperglycemic effect of 17.1% in the diabetic rats as compared to the standard drug metformin.


Effect of specific non-pharmaceutical intervention policies on SARS-CoV-2 transmission in the counties of the United States.
Non-pharmaceutical interventions (NPIs) remain the only widely available tool for controlling the ongoing SARS-CoV-2 pandemic. We estimated weekly values of the effective basic reproductive number (Reff) using a mechanistic metapopulation model and associated these with county-level characteristics and NPIs in the United States (US). Interventions that included school and leisure activities closure and nursing home visiting bans were all associated with a median Reff below 1 when combined with either stay at home orders (median Reff 0.97, 95% confidence interval (CI) 0.58-1.39) or face masks (median Reff 0.97, 95% CI 0.58-1.39). While direct causal effects of interventions remain unclear, our results suggest that relaxation of some NPIs will need to be counterbalanced by continuation and/or implementation of others.


The impact of underinsurance on bladder cancer diagnosis, survival, and care delivery for individuals under the age of 65 years.
Health insurance is a key mediator of health care disparities. Outcomes in bladder cancer, one of the costliest diseases to treat, may be especially sensitive to a patient's insurance status. The Surveillance, Epidemiology, and End Results registry and the National Cancer Data Base were used to identify individuals younger than 65 years who were diagnosed with bladder cancer from 2007 to 2014. The associations between the insurance status (privately insured, insured by Medicaid, or uninsured) and the following outcomes were evaluated: diagnosis with advanced disease, cancer-specific survival, delay in treatment longer than 90 days, treatment in a high-volume hospital, and receipt of neoadjuvant chemotherapy (NAC). Compared with those with private insurance, uninsured and Medicaid-insured individuals were nearly twice as likely to receive a diagnosis of muscle-invasive bladder cancer (odds ratio [OR] for uninsured individuals, 1.90; 95% confidence interval [CI], 1.70-2.12; OR for Medicaid-insured individuals, 2.03; 95% CI, 1.87-2.20). They were also more likely to die of bladder cancer (adjusted hazard ratio [AHR] for uninsured individuals, 1.49; 95% CI, 1.31-1.71; AHR for Medicaid-insured individuals, 1.61; 95% CI, 1.46-1.79). Delays in treatment longer than 90 days were more likely for uninsured (OR, 1.36; 95% CI, 1.12-1.65) and Medicaid-insured individuals (OR, 1.22; 95% CI, 1.03-1.44) in comparison with the privately insured. Uninsured patients had lower odds of treatment at a high-volume facility, and Medicaid-insured patients had lower odds of receiving NAC (P < .001 for both). Compared with privately insured individuals, uninsured and Medicaid-insured individuals experience worse prognoses and poorer care quality. Expanding high-quality insurance coverage to marginalized populations may help to reduce the burden of this disease.


Short-term memory in the rhesus monkey: disruption from the anti-cholinergic scopolamine.
Two separate experiments were conducted to evaluate the effects of the anti-cholinergic scopolamine on primate visual discrimination and short-term memory (STM). In the first experiment it was shown that relatively mild doses of scopolamine severly impaired visual discrimination performance, even though the test procedure provided strong stimulus control. This deficit in visual discrimination suggested that previous research which used the delayed matching to sample procedure (DMS) to evaluate the role of cholinergics in primate STM may have confounded an accurate measure of specific STM effects because the DMS is inherently dependent on accurate visual discrimination. Therefore, the second experiment evaluated the effects of scopolamine on STM, using an automated apparatus and test procedure designed to minimize the discrimination component and other confounding variables present in the earlier research. In this second experiment, an indirect delayed response (DR) procedure was used, measuring the monkeys' ability to recall simple stimulus events over retention intervals of 0, 2.5, 5, and 10 sec. The monkeys were tested under 2 doses of the anti-cholinergic scopolamine and their performance was compared to that obtained on several nondrug control days. Contrary to earlier reports using the DMS, a clear interaction of drug and retention interval occurred in this situation. Under scopolamine, greatest impairments occurred on the longest delays, with little or no effect with zero second retention. Furthermore, the impairments observed on the longer delays were even greater with the highest dose of scopolamine. These data, therefore,support the notion that cholinergic mechanisms play an important role in the expression of STM in primates.


Identification of beta2-microgloblin as a candidate for early diagnosis of imaging-invisible hepatocellular carcinoma in patient with liver cirrhosis.
Glypican-3 (GPC3) is overexpressed in hepatocellular carcinoma (HCC) but not in chronic hepatitis (CH) and liver cirrhosis (LC). We have reported the possibility of GPC3-specific cytotoxic T lymphocytes (CTLs) serving as a marker for the early diagnosis of imaging invisible HCC. In this study, to identify new early diagnostic biomarker of imaging invisible HCC, we analyzed plasma of healthy donors and patients with CH, LC and HCC using surface-enhanced laser desorption-ionaization time-of-flight mass spectrometry (SELDI-TOF-MS). The intensities of four peaks were significantly increased in HCC patients compared with healthy donors. Two of these four peaks were significantly higher in CH and LC patients with GPC3-specific CTLs than in those without. One peak (11.7 kDa) was predicted to be beta2-microglobulin (beta2-MG) by molecular mass. There was a correlation between concentration of beta2-MG by latex agglutination immunoassay in plasma and peak intensity using SELDI-TOF-MS. The 11.7 kDa protein was fractionated by gel filtration and was identified as beta2-MG by Western blot analysis. These results suggest that the level of beta2-MG in plasma from patients with CH and LC could be a useful marker for the early diagnosis of imaging invisible HCC, however further investigation is needed.


Fourier series harmonic analysis of corneal topography following suture removal after penetrating keratoplasty.
To evaluate quantitatively the influence of suture removal after penetrating keratoplasty on corneal refraction including irregular astigmatism. Subjects were 42 eyes of 39 patients with clear corneal grafts who underwent suture removal after penetrating keratoplasty. Videokeratography data taken before and after suture removal were decomposed using Fourier harmonic analysis into spherical power, regular astigmatism, and irregular astigmatism (asymmetry and higher order irregularity). On average, spherical power significantly increased after suture removal (p < 0.0001, paired t test), and regular astigmatism did not change significantly (p = 0.247). Suture removal significantly decreased asymmetry (p < 0.0001) and higher order irregularity (p < 0.0001). Suture removal after penetrating keratoplasty induces myopic shift and reduction in irregular astigmatism of the cornea.


Creation of a model for multiple sclerosis in Callithrix jacchus marmosets.
Multiple sclerosis (MS) is an inflammatory disease of the CNS white matter characterized pathologically by the accumulation of perivascular and parenchymal T lymphocytes (T cells), and macrophage infiltration associated with myelin destruction. MS lesions are also characterized by the death of oligodendrocytes (the myelin-producing cells) and proliferation and hypertrophy of astrocytes with scar tissue (gliosis) replacing normal myelin. These changes result in the loss of axonal conduction for neurons of the CNS and in clinical disability. MS is thought to be an autoimmune disease, in particular because of its analogy with the disease model of experimental allergic encephalomyelitis (EAE). Despite extensive research and the availability of various EAE models in laboratory rodents the etiology of human MS has not been identified, and to date no effective treatment exists. Phylogenetic differences may limit the usefulness of existing EAE models, and indeed no single form of rodent EAE recapitulates all the clinical and pathological features of MS. Here we describe a novel form of EAE created in a nonhuman primate, the common marmoset Callithrix jacchus. Active immunization of these monkeys with whole myelin produces a primary demyelinating disease with a chronic relapsing-remitting course, characterized pathologically by moderate inflammation with prominent and early demyelination and gliosis reminiscent of human MS. Adoptive and passive transfer experiments have permitted definition of the mechanisms responsible for the MS-like pathology. Production of the fully demyelinated lesion requires synergism between encephalitogenic (e.g., disease-inducing) T cells and pathogenic antibody. The antigens of myelin that promote encephalitogenic T cell and antibody responses in this system have been identified. Because of the similarity between the two conditions and the high degree of conservation in immune and nervous system genes between nonhuman primates and humans, future studies of marmoset EAE will likely accelerate the development of therapies for human MS.


Reliability of measurements of a reflection coefficient index to indicate spinal bone strength on adolescents with idiopathic scoliosis (AIS): a pilot study.
To investigate the test-retest, intra- and inter-rater reliabilities of an ultrasound (US) reflection coefficient (RC) index measured in a lumbar vertebra to reflect bone strength on children with AIS. Fifty-eight participants (47F; 11M) were scanned by an US imager in standing position. Twenty-four were scanned twice for a test-retest study. The RC index measures the US signal reflected from L5 to indicate bone strength. Five measurements were obtained using three different methods: (i) the maximum RC (MRC) values on the left and right sides, (ii) the average RC (ARC) values on left and right sides, and (iii) the combined average RC (CARC) from both sides. Only rater 1 measured the 24 repeated US scans once. Raters 1 and 2 measured the RC index twice on all 58 images in 1 week apart. The intraclass correlation coefficient ICC [3, 1] for test-retest and ICC [2, 1] for intra- and inter-rater reliabilities as well as the standard error of measurements (SEM) were reported. The means of scan 1 versus scan 2 were 0.16 ± 0.08 versus 0.16 ± 0.07 for left-MRC, 0.17 ± 0.11 versus 0.18 ± 0.11 for right-MRC, 0.08 ± 0.04 versus 0.09 ± 0.04 for left-ARC, 0.09 ± 0.04 versus 0.09 ± 0.05 for right-ARC and 0.08 ± 0.04 versus 0.09 ± 0.03 for CARC and all ICC[3, 1] ≥ 0.77. Among these 5 approaches, the CARC provided the best intra-rater and inter-rater reliabilities with ICC [2, 1] ≥ 0.84 and SEM ≤ 0.01. The RC index could be measured repeatably and reliably. The high RC value may reduce the risk of progression of scoliosis.


[Influence of the physical therapy on the health and quality of life of the rheumatic patient].
To evaluate the effectiveness of a specific physical therapy treatment on stiffness, pain and quality of life (HRQL) in rheumatic patients. Experimental, prospective, longitudinal and intervention study. It involved 29 individuals with a mean age (SD) of 54.16 (11,9) years, belonging to the Salmantina Association of Rheumatoid Arthritis Patients, randomized into 2 groups: treatment (GT) and control (GC). The study analyzed the time in minutes of morning stiffness, pain -using the Downie Scale- and CVRS through the Nottingham Health Profile (NHP) and the Health Questionnaire SF-36 (SF-36). It carries out an individual treatment that includes mainly physiotherapy manual techniques in one or two sessions per week for six months. The time of early morning stiffness showed a mean (SD) 21.38 (29.99) minutes (GC=20,38, GT=22.19), increasing in GC (26.82) and decreasing in GT (12,5). Pain presented at the beginning a mean (SD) 3.6 (2.03) points (GC=2,85, GT=4.22) decreasing in GT (3.68) and increasing in GC (3.45). There was an improvement of CVRS in the GT with decreased scores on four dimensions of NHP (pain, sleep, physical mobility and emotional reactions) and increases in SF-36 (physical problems, social function, pain, function physics). In any case the results were statistically significant. The study cannot conclude the effectiveness of physiotherapy in the treatment of rheumatoid arthritis although the results show a decrease of morning stiffness and pain and increased CVRS, which is clinically interesting.


Promotion of full-scale constructed wetlands in the wine sector: Comparison of greenhouse gas emissions with activated sludge systems.
The aim of this study was to quantify and compare greenhouse gas (GHG) (i.e. carbon dioxide (CO2), nitrous oxide (N2O) and methane (CH4)) emissions from two full-scale winery wastewater and sludge treatment systems (i.e. constructed wetlands (CWs) and activated sludge system) located in Galicia (Spain). GHG fluxes were measured using the static chamber method in combination with an on-site Fourier transform infrared spectroscopy (FTIR) gas analyser in the CWs system. These on-site innovative techniques proved to be very accurate and reliable. In the activated sludge treatment systems, the floating chamber method in combination with the FTIR gas analyser was used. Measurements were carried out during the vintage season, when winery wastewater has the highest flow and loads, and the rest of the year. Emission rates of CO2, N2O and CH4 in the CWs units (i.e. vertical flow, horizontal subsurface flow and sludge treatment wetlands) ranged from 1.35E+02 to 7.54E+04, 1.70E-01 to 3.09E+01 and - 3.05E+01 to 1.79E+03 mg m-2 day-1, respectively. In the case of the activated sludge units (i.e. reactor, secondary settler and sludge storage tank) emission rates of CO2, N2O and CH4 ranged from 1.56E+04 to 1.43E+05, 1.13E+01 to 4.75E+01 and 2.52E+01 to 1.01E+03 mg m-2 day-1, respectively. Seasonally, daily and instantaneous variability in emissions as well as spatial variability was found. Comparing CWs with the activated sludge system, surface emission rates were lower in the CWs system in both seasons considered. Results highlighted that CWs are suitable technologies that can help to reduce GHG emissions associated with winery wastewater treatment.


A graphene-oxide-based fluorometric assay for norA gene transcription in MRSA using Nb.BbvCI-assisted target recycling and T7 exonuclease-triggered cascade dual recycling signal amplification.
We describe a graphene oxide (GO)-based bioassay for the fluorometric determination of norA gene transcription (mRNA) in methicillin-resistant Staphylococcus aureus (MRSA). This approach is based on Nb.BbvCI-assisted target recycling (NATR) and T7 exonuclease (T7 Exo)-triggered cascade dual-recycling signal amplification (TTCDRSA). The system included GO, a capture probe (CP), an assistant probe (AP), two carboxyfluorescein (FAM)-labeled hairpins (HP1 and HP2), endonuclease Nb.BbvcI, and exonuclease T7. In the presence of a target, AP, together with the target RNA, can hybridise with CP via partial complementarity to one another and open its hairpin structure to form a triple complex that is recognised by Nb.BbvCI. Once the CP is cleaved, the released AP and target RNA can walk on the carboxylated graphene oxide (CGO) surface to bind with another CP which induces the next round of cleavage, accumulating many trigger probes (TPs). The TPs then activate TTCDRSA with the assistance of T7 Exo, HP1, and HP2 to produce large amounts of free FAMs. These free FAMs are repelled by GO and exhibit enhanced fluorescence signals at excitation/emission wavelengths of 480/514 nm. The limit of detection (LOD) of the bioassay was calculated to be 0.37 fM, and the linear range of the method ranged from 1 fM to 1 nM. More importantly, the bioassay also exhibited high sensitivity and selectivity for target RNA detection in real samples, which may open a new promising avenue for monitoring drug efflux and studying the mechanisms of drug actions.


Annotation-free glioma grading from pathological images using ensemble deep learning.
Glioma grading is critical for treatment selection, and the fine classification between glioma grades II and III is still a pathological challenge. Traditional systems based on a single deep learning (DL) model can only show relatively low accuracy in distinguishing glioma grades II and III. Introducing ensemble DL models by combining DL and ensemble learning techniques, we achieved annotation-free glioma grading (grade II or III) from pathological images. We established multiple tile-level DL models using residual network ResNet-18 architecture and then used DL models as component classifiers to develop ensemble DL models to achieve patient-level glioma grading. Whole-slide images of 507 subjects with low-grade glioma (LGG) from the Cancer Genome Atlas (TCGA) were included. The 30 DL models exhibited an average area under the curve (AUC) of 0.7991 in patient-level glioma grading. Single DL models showed large variation, and the median between-model cosine similarity was 0.9524, significantly smaller than the threshold of 1.0. The ensemble model based on logistic regression (LR) methods with a 14-component DL classifier (LR-14) demonstrated a mean patient-level accuracy and AUC of 0.8011 and 0.8945, respectively. Our proposed LR-14 ensemble DL model achieved state-of-the-art performance in glioma grade II and III classifications based on unannotated pathological images.


Inhibiting Lateral Habenula Improves L-DOPA-Induced Dyskinesia.
A systematic search of brain nuclei putatively involved in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease shed light, notably, upon the lateral habenula (LHb), which displayed an overexpression of the ∆FosB, ARC, and Zif268 immediate-early genes only in rats experiencing abnormal involuntary movements (AIMs). We thus hypothesized that LHb might play a role in LID. ∆FosB immunoreactivity, 2-deoxyglucose uptake, and firing activity of LHb were studied in experimental models of Parkinson's disease and LID. ΔFosB-expressing LHb neurons were then targeted using the Daun02-inactivation method. A total of 18 monkeys and 55 rats were used. LHb was found to be metabolically modified in dyskinetic monkeys and its neuronal firing frequency significantly increased in ON L-DOPA dyskinetic 6-hydroxydopamine-lesioned rats, suggesting that increased LHb neuronal activity in response to L-DOPA is related to AIM manifestation. Therefore, to mechanistically test if LHb neuronal activity might affect AIM severity, following induction of AIMs, 6-hydroxydopamine rats were injected with Daun02 in the LHb previously transfected with ß-galactosidase under control of the FosB promoter. Three days after Daun02 administration, animals were tested daily with L-DOPA to assess LID and L-DOPA-induced rotations. Inactivation of ∆FosB-expressing neurons significantly reduced AIM severity and also increased rotations. Interestingly, the dopaminergic D1 receptor was overexpressed only on the lesioned side of dyskinetic rats in LHb and co-localized with ΔFosB, suggesting a D1 receptor-mediated mechanism supporting the LHb involvement in AIMs. This study highlights the role of LHb in LID, offering a new target to innovative treatments of LID.


Multi-Scale Volumetric Dynamic Optoacoustic and Laser Ultrasound (OPLUS) Imaging Enabled by Semi-Transparent Optical Guidance.
Major biological discoveries are made by interrogating living organisms with light. However, the limited penetration of un-scattered photons within biological tissues limits the depth range covered by optical methods. Deep-tissue imaging is achieved by combining light and ultrasound. Optoacoustic imaging exploits the optical generation of ultrasound to render high-resolution images at depths unattainable with optical microscopy. Recently, laser ultrasound has been suggested as a means of generating broadband acoustic waves for high-resolution pulse-echo ultrasound imaging. Herein, an approach is proposed to simultaneously interrogate biological tissues with light and ultrasound based on layer-by-layer coating of silica optical fibers with a controlled degree of transparency. The time separation between optoacoustic and ultrasound signals collected with a custom-made spherical array transducer is exploited for simultaneous 3D optoacoustic and laser ultrasound (OPLUS) imaging with a single laser pulse. OPLUS is shown to enable large-scale anatomical characterization of tissues along with functional multi-spectral imaging of chromophores and assessment of cardiac dynamics at ultrafast rates only limited by the pulse repetition frequency of the laser. The suggested approach provides a flexible and scalable means for developing a new generation of systems synergistically combining the powerful capabilities of optoacoustics and ultrasound imaging in biology and medicine.


A pre and post intervention study measuring the effect of interactive education on adolescent perceptions of vaccines, vaccine safety and disease risk.
Adolescents make decisions about their own vaccinations and will be the childhood vaccine decision makers of tomorrow. It is therefore essential to educate adolescents about the risks of vaccine-preventable diseases and immunization safety. This study evaluated the impact of an interactive education initiative among adolescents at a high school in North Bay Ontario. An anonymized questionnaire to assess students' knowledge, attitudes and beliefs about immunization and vaccine-preventable diseases was administered before and after delivering an interactive session. Chi-squared and Kruskal-Wallis tests were performed to test for differences between pre and post responses. The intervention increased the students' awareness that measles is a disease that affects their generation (P < 0.05). Improvements were also noted in the perceived risk of pertussis (P < 0.05) and tetanus (0.05). After the session, respondents were also more willing to participate with their parents in decisions affecting their healthcare (P < 0.05). Students' perception of vaccine safety also improved (P < 0.001). Post survey results suggest that the interactive educational intervention had a positive effect on the adolescents' perceptions and attitudes towards immunization. Further research is required to determine the impact of this type of intervention on adolescents' future decision-making with respect to immunization.


Epidermal Langerhans' cells in children with primary T-cell immune deficiencies.
Dendritic cells are the major antigen-presenting cells, especially for naive T lymphocytes; it is conceivable therefore that their absence or dysfunction may induce an immune deficiency (ID). Few data are available, however, concerning dendritic cells in human primary ID. Langerhans' cells (LC) are intraepidermal dendritic cells which express specific markers and may therefore be studied by immunohistochemistry on paraffin-embedded skin samples. Skin samples of nine children with primary ID were studied and compared with five age-matched controls. LC were present within the epidermis of two children with X-linked severe combined ID, a condition related to the lack of the common gamma-chain of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. LC were also present in skin samples of a child with Omenn syndrome and in three children with combined ID. By contrast, no LC were detected in the skin samples of two children with alymphocytosis and of a child with reticular dysgenesis, a condition characterized by the absence of peripheral blood leukocytes.


In vivo characterization of the inflammatory infiltrate and apoptotic status in imiquimod-treated basal cell carcinoma.
Imiquimod use in the treatment of basal cell carcinoma (BCC) has proven to be successful in a large percentage of cases, inducing tumor regression; however, the exact cellular mechanism has not been fully clarified. To measure the morphological changes in the tumor microenvironment and the markers of apoptosis in skin biopsies from patients with BCC before and after imiquimod treatment. In this open label study, skin biopsies obtained from 11 patients with BCC were evaluated before and after imiquimod treatment for: (i) morphological changes in the tumor microenvironment, with specific emphasis on the immunophenotype of inflammatory cells around the tumor; and (ii) markers of apoptosis, including expression of death receptors. Imiquimod treatment induced a significant increase in the mononuclear inflammatory response. In the majority of cases, the cellular infiltrate was predominantly composed of CD3(+)/CD4(+) T cells, suggesting that the effector response is mediated by CD3(+)/CD4(+) lymphocytes, with a minor cytotoxic and natural killer (NK) component. An increase in the cytotoxic CD3(+)/CD8(+) T-cell population was also observed. Imiquimod treatment was associated with a marked increased in CD20(+) B cells, and a less pronounced enhancement in cells of monocyte-macrophage origin (CD68(+)) surrounding, or within, the tumor. This finding indicates either that macrophages play a minor role in the imiquimod-induced response, or the recruitment of these cells is related to time and dose. Imiquimod treatment decreased CD1A(+) Langerhans cells in the epidermis and increased the number of CD1A(+) dendritic cells within the tumor aggregates. Imiquimod reduced Bcl-2 expression, but no difference was found in Bax, Fas/FasL, and p53 expression in BCC cells. Our results support the hypothesis that imiquimod activity in the treatment of BCC is partly a result of a pro-inflammatory action mediated by CD3(+)/CD4(+) lymphoid cells and of a pro-apoptotic activity associated with decreased Bcl-2 expression.


Dual-monomer molecularly imprinted electrochemical sensor based on amino-functionalized MOFs and graphene for trace determination of taurine.
A molecularly imprinted electrochemical sensor (MIECS) for trace determination of taurine was developed. The sensor was constructed by electropolymerizing dopamine and o-phenylenediamine as dual monomers on the surface of amino-functionalized iron-based MOFs and graphene composite-modified electrode. The porous structure and large specific surface area of amino-functionalized iron-based MOFs not only increase the number of imprinted sites, but also facilitate the binding of molecularly imprinted films. The presence of dual monomers can increase the binding sites during the formation of imprinted films. The linear range of this sensor for taurine detection is 1.00 × 10-14-1.00 × 10-8 mol L-1 with a determination limit of 3.20 × 10-15 mol L-1. The proposed MIECS was successfully applied to quantify the amount of taurine in human serum sample with good recovery values from 97.3 to 113%.


Immunomodulatory drug- and proteasome inhibitor-backbone regimens in the treatment of relapsed multiple myeloma: an evidence-based review.
Recent advances and drug approvals in the last decade have substantially changed the landscape of relapsed and refractory multiple myeloma (RRMM), which not only improved outcomes for patients but also increased complexity of treatment decisions. The approvals are based on randomized studies of novel agents added to an immunomodulatory drug- (IMiD) or proteasome inhibitor (PI)-backbone showing an improvement in outcomes. However, differences in enrolled patient populations/study designs limit comparisons of results, making the choice and sequencing of agents challenging. This review summarizes the latest updates of key clinical trials of IMiD- and PI-backbone regimens in RRMM. Additionally, it highlights carfilzomib dosing strategies and toxicity profiles of varying carfilzomib combination regimens and provides a clinical guideline for the use of carfilzomib therapy. PubMed and relevant meeting (ASH, ASCO, EHA, IMW) databases from 2010 to 2020, as well as clinicaltrials.gov, were queried for this review. The choice of therapy for RRMM requires careful consideration of patient factors (age/frailty and comorbidities), disease factors (symptom burden/biology), and treatment-related factors (toxicities/responses to prior therapies). Importantly, a critical factor in selecting an agent based on the published data is a patient's sensitivity to lenalidomide and bortezomib at the time of relapse.


Monoamine oxidase-B in motor cortex: changes in amyotrophic lateral sclerosis.
The occurrence of monoamine oxidase-B in cerebral cortex and white matter in brains from three patients with the diagnosis of amyotrophic lateral sclerosis and three controls was quantified by means of an autoradiographical method. [3H]L-Deprenyl, an irreversible and selective monoamine oxidase-B inhibitor, was used as ligand and the autoradiographs were analysed by computer-assisted densitometry. In both amyotrophic lateral sclerosis and control cerebral cortex, lamina I showed the highest, laminae II and III intermediate, laminae IV, V and VI the lowest [3H]L-deprenyl binding. White matter showed about one-third of the binding in the cortex. Amyotrophic lateral sclerosis cases showed significantly higher binding of [3H]L-deprenyl in all the cortex laminae of the pre- and postcentral gyri. There was no difference in the binding between the amyotrophic lateral sclerosis cases and the controls in area 7 of the occipital cortex, an area which is relatively spared in amyotrophic lateral sclerosis.


Osteoporosis is a Predictive Factor for Nephrolithiasis in an Adult Free-Living Caucasian Population From Southern Italy: A Longitudinal Retrospective Study Based on a General Practice Database.
Osteoporosis and nephrolithiasis are common multifactorial disorders with high incidence and prevalence in the adult population worldwide. Both are associated with high morbidity and mortality if not correctly diagnosed and accurately treated. Nephrolithiasis is considered a risk factor for reduced bone mineral density. Aim of this retrospective longitudinal study was to evaluate if osteoporosis is a predictive factor for the nephrolithiasis occurrence. Free-living subjects referring to "COMEGEN" general practitioners cooperative operating in Naples, Southern Italy. Twelve thousand seven hundred ninety-four Caucasian subjects (12,165 female) who performed bone mineral density by dual-energy X-ray absorptiometry and have a negative personal history for nephrolithiasis. Subjects aged less than 40 years or with signs or symptoms suggestive of secondary osteoporosis were excluded from the study. In a mean lapse of time of 19.5 months, 516 subjects had an incident episode of nephrolithiasis. Subjects with osteoporosis had an increased risk of nephrolithiasis than subjects without osteoporosis (Hazard Ratio = 1.33, 95% Confidence Interval 1.01-1.74, p = 0.04). Free-living adult subjects over the age of 40 with idiopathic osteoporosis have an increased risk of incident nephrolithiasis, suggesting the advisability of appropriate investigation and treatment of the metabolic alterations predisposing to nephrolithiasis in patients with osteoporosis. The study protocol was approved by the ASL Napoli 1 Ethical Committee, protocol number 0018508/2018.


Severe hemolysis and methemoglobinemia following fava beans ingestion in glucose-6-phosphatase dehydrogenase deficiency: case report and literature review.
Reduced concentrations of glucose-6-phospate dehydrogenase (G6PD) render erythrocytes susceptible to hemolysis under conditions of oxidative stress. In favism, the ingestion of fava beans induces an oxidative stress to erythrocytes, leading to acute hemolysis. The simultaneous occurrence of methemoglobinemia has been reported only scarcely, despite the fact that both phenomena are the consequence of a common pathophysiologic mechanism. The presence of methemoglobinemia has important diagnostic and therapeutic consequences. We report a previously healthy boy who presented with combined severe hemolytic anemia and cyanosis due to methemoglobinemia, following the ingestion of fava beans. His condition was complicated by the development of transient acute renal failure. A G6PD-deficiency was diagnosed. We review the literature on the combination of acute hemolysis and methemoglobinemia in favism. Pathophysiologic, diagnostic, and therapeutic aspects of this disorder are discussed.


Comparative study of SmartAmp assay and reverse transcription-polymerase chain reaction by saliva specimen for the diagnosing COVID-19.
The pandemic of a novel coronavirus disease 2019 (COVID-19) caused by a severe acute respiratory coronavirus 2 (SARS-CoV-2) infection has been problematic worldwide. A new SARS-CoV-2 diagnostic test (SmartAmp) was licensed in Japan in July 2021. This method, which enables us to diagnose COVID-19 as well as a gene mutation on the virus, is promising to reduce medical costs and staff labor. To analyze the diagnostic accuracy of the SmartAmp assay for diagnosing COVID-19, we performed this retrospective study at our institute during April and May 2021. We compared the results of the SmartAmp assay and real-time reverse transcription-polymerase chain reaction (rRT-PCR) using a saliva sample from individuals suspected as having COVID-19. Out of 70 samples tested, the SmartAmp assay had 50 (71%) positive and 20 (29%) negative results. Using rRT-PCR as a reference, the diagnostic accuracy displayed a sensitivity of 84%, a specificity of 95%, a positive predictive value of 97.7%, and a negative predictive value of 70.4%. On the other hand, false-negative cases were found in 7 (10%), and there was no significant difference of Ct-value between true positive and false negative cases (Mean Ct-value 25.2 vs. 27.5 cycles, p = 0.226 by Mann-Whitney U test). The SmartAmp assay is a valuable method to diagnose COVID-19 rapidly. However, the negative predictive value is not high enough to diagnose the disease, so that negative results should be considered for rRT-PCR testing if patients are suspected of having COVID-19.


Bladder dysfunction and neuropathy in diabetes.
Established urodynamic and electrophysiological techniques have been applied to assess the frequency and extent of autonomic and peripheral neuropathy in 60 subjects with diabetes mellitus; 38 were diabetics with suggestive symptoms and the others were representative newly diagnosed (11) or treated (11) diabetics. Objective evidence neuropathic bladder dysfunction was detected in 43 of them (71.7%). The commonest abnormality was a hypotonic, insensitive large capacity bladder, which condition was usually asymptomatic. Less freuqently (15%) was this complicated by bladder decompensation and sphincter involvement, resulting in excessive residual urine and infection; some of these had bladder paralysis with chronic painless retention of urine (7%). Electrophysiological studies found a sensory defect in the lower limbs in all tested patients (100%), and in 41 patients (69%) as associated motor conduction abnormality, which was more frequent and marked in the lower than the upper limb. These functional abnormalities appeared to be related to the severity of diabetes, but less to its duration. Indeed of 11 newly diagnosed diabetics tested 7 had a peripheral neuropathy and 4 urodynamic abnormalities. The high incidence of bladder dysfunction and peripheral neuropathy in this series indicates the frequency of subclinical diabetic neuropathy and a factor needing more emphasis in diabetic uropathy.


Engineering Smart Composite Hydrogels for Wearable Disease Monitoring.
Growing health awareness triggers the public's concern about health problems. People want a timely and comprehensive picture of their condition without frequent trips to the hospital for costly and cumbersome general check-ups. The wearable technique provides a continuous measurement method for health monitoring by tracking a person's physiological data and analyzing it locally or remotely. During the health monitoring process, different kinds of sensors convert physiological signals into electrical or optical signals that can be recorded and transmitted, consequently playing a crucial role in wearable techniques. Wearable application scenarios usually require sensors to possess excellent flexibility and stretchability. Thus, designing flexible and stretchable sensors with reliable performance is the key to wearable technology. Smart composite hydrogels, which have tunable electrical properties, mechanical properties, biocompatibility, and multi-stimulus sensitivity, are one of the best sensitive materials for wearable health monitoring. This review summarizes the common synthetic and performance optimization strategies of smart composite hydrogels and focuses on the current application of smart composite hydrogels in the field of wearable health monitoring.


Safety assessment of the use of perflenapent emulsion for contrast enhancement of echocardiography and diagnostic radiology ultrasound studies.
The studies were undertaken to assess the safety of the use of perflenapent emulsion (EchoGen, SONUS Pharmaceuticals, Bothell, Wash.) for contrast enhancement of echocardiography and radiology ultrasound studies. In all, 1,001 patients or subjects were enrolled in 21 clinical studies. Clinical laboratory test, pulse oximetry, vital signs, and electrocardiograms (ECGs) were obtained in 818 patients before and after administration of perflenapent emulsion and active control [5% sonicated human albumin, (Albunex, Molecular Biosystems, Inc., San Diego, Calif.)] or placebo (saline) to determine mean changes from baseline. Adverse event rates were monitored following administration of perflenapent emulsion in 743 patients and placebo in 151 patients. No clinically significant abnormalities in clinical laboratory, pulse oximetry, vital signs, or ECG evaluations were observed. Values following administration of perflenapent emulsion were comparable with those following placebo or active control. Perflenapent emulsion (50/743; 6.7%) was comparable with placebo (4/151; 2.6%) in the overall incidence of adverse events considered related to the test article. Adverse events that occurred with a frequency of > or = 1% within 30 min after perflenapent emulsion administration were vasodilation and taste aberration. Adverse events which were mostly mild to moderate in intensity, began within 10 to 20 min after administration, and resolved spontaneously within 10 to 20 min. Perflenapent emulsion is generally well tolerated in patients undergoing echocardiography and ultrasound of other target organs.


[Transfer factor (TF) treatment of patients with HBs-Ag-positive chronic active hepatitis. A prospective, controlled study (author's transl)].
It is a clinically and experimentally well supported working hypothesis that infection with hepatitis B virus may result in chronic active hepatitis in patients with suspected immune deficiencies. On this basis, a pilot study was performed in order to evaluate the effect of "specific" transfer factor (TF) in the treatment of HBS-Ag-positive chronic active hepatitis. From the leukocytes of 500 ml venous blood each of 40 volunteers that had completely recovered from acute virus hepatitis B within the last 6 months, a unique TF pool (40 units of TF) was prepared according to the method of Lawrence. Preexaminations indicated that this preparation was able to enhance cellular immune reactions in vitro. Thirteen patients with HBS-antigenemia and chronic active hepatitis (i.e., two liver biopsies within the last 6 or more months with the histological criteria of chronic aggressive hepatitis according to de Groote, elevated serum levels of bilirubin, alkaline phosphatase, transaminase activities, and/or gamma-globulines) were randomized: Seven received s.c. injections of two units of TF each on days 1 and 15, the other six saline. Conversion of skin reactions to some ubiquitous antigens occurred in the TF group, but no significant and constant drop of HBS-Ag serum titers was observed. Although some of the biochemical parameters seemed to ameliorate in the TF group, the differences versus the control group did not prove to be significant within the limited number of patients under observation. The in vitro reactivity of patients' lymphocytes to HBS-Ag, tested by means of the 3H-thymidine uptake, was never found enhanced after TF application. In the used doses, "specific" TF was not effective in the treatment of HBS-Ag-positive chronic active hepatitis; unfavorable side-effects were not observed.


Association of mental distress with chronic diseases in 1.9 million individuals: A population-based cross-sectional study.
Mental distress has a high global prevalence and is associated with poor health outcomes. This study aimed to estimate the relationship between mental distress and the risk of 10 chronic diseases using data from the Behavioral Risk Factor Surveillance System (BRFSS). Cross-sectional data from the 2013, 2014, 2015, 2016 and 2017 BRFSS were analyzed. The association between mental distress based on the number of days of poor mental health and the risk of 10 chronic diseases, namely obesity, diabetes, asthma, chronic obstructive pulmonary disease (COPD), arthritis, kidney disease, coronary heart disease (CHD), stroke, skin cancer, and other cancers, were assessed by logistic regression models to calculate odds ratios and 95% confidence intervals. Subgroup analyses stratified by age and sex were also conducted. Positive associations between mental distress and chronic diseases were observed. We also found a dose-response gradient between mental distress levels and the risk of all chronic diseases except skin cancer. In respondents aged 18-44 years reporting ≥23 days/month of mental distress, there has the largest odds ratio between mental distress levels and each chronic disease. Moreover, mental distress was associated with higher risks of obesity and arthritis in women relative to men. Mental distress was positively associated with chronic diseases. Age and sex are crucial in this relationship. Further studies with longitudinal data are needed to clarify the direction of this association.


A regional study of the zoonotic broad tapeworm Dibothriocephalus spp. in Northwestern Patagonia (Argentina): origin of fishes and coastal cities as factors affecting infection in fishes.
Diphyllobothriosis was first recorded in humans in Argentina in 1892 and in introduced salmonids in 1952. The aim of this work is to assess factors influencing the values of prevalence and abundance of plerocercoids in fishes that could increase the risk of transmission of Dibothriocephalus spp. in Andean Patagonian lakes. We analysed two key issues potentially related to the occurrence of tapeworms in fish: the presence of cities on coastlines (as potential sources of eggs to nearby lakes) and the difference between native and exotic fishes in susceptibility to infection. We investigated the probability of finding parasites in fish, the variation in parasite abundance in different environments and the relationship between host length and occurrence of plerocercoids. A total of 3226 fishes (belonging to six autochthonous and four introduced species) were analysed between 2010 and 2019 in eight environments. Plerocercoids were counted, and a subset was determined molecularly to species level. Two species, Dibothriocephalus latus and Dibothriocephalus dendriticus, were identified from both salmonids and native fishes, this being the first molecular confirmation of these tapeworm species parasitizing native South American fishes. Salmonids had higher levels of infection than native fishes, and these levels were higher in aquatic environments with a city on their coastline. Transmission to humans seems to occur mainly through Oncorhynchus mykiss, which showed the highest infection values and is the species most captured by fishers. Based on previous data and the present results, eggs shed by humans, dogs and gulls in cities could be the principal factors in maintaining the life cycle of this parasite in surrounding aquatic environments.


To Do or Not to Do: The cerebellum and neocortex contribute to predicting sequences of social intentions.
Humans read the minds of others to predict their actions and efficiently navigate social environments, a capacity called mentalizing. Accumulating evidence suggests that the cerebellum, especially Crus 1 and 2, and lobule IX are involved in identifying the sequence of others' actions. In the current study, we investigated the neural correlates that underly predicting others' intentions and how this plays out in the sequence of their actions. We developed a novel intention prediction task, which required participants to put protagonists' behaviors in the correct chronological order based on the protagonists' honest or deceitful intentions (i.e., inducing true or false beliefs in others). We found robust activation of cerebellar lobule IX and key mentalizing areas in the neocortex when participants ordered protagonists' intentional behaviors compared with not ordering behaviors or to ordering object scenarios. Unlike a previous task that involved prediction based on personality traits that recruited cerebellar Crus 1 and 2, and lobule IX (Haihambo et al., 2021), the present task recruited only the cerebellar lobule IX. These results suggest that cerebellar lobule IX may be generally involved in social action sequence prediction, and that different areas of the cerebellum are specialized for distinct mentalizing functions.


Ion Channels as a Potential Target in Pharmaceutical Designs.
Voltage-gated ion channels are integral membrane proteins that respond to changes in membrane potential with rapid variations in membrane permeability to ions [...].


A case report of cerebral infarction caused by polycythemia vera.
Polycythemia vera (PV) is a cloned erythrocytotic disease manifested by high proliferation and apoptosis in the bone marrow. The clinical symptoms of PV are occult. In practice, patients with cerebral infarction caused by PV are prone to misdiagnosis and missed diagnosis. Here, we report a misdiagnosis of PV leading to cerebral infarction. The patient was a middle-aged woman who was diagnosed with acute cerebral infarction in the outpatient hospital. After treatment, the patient still had left hemiplegia, dizziness and other symptoms and was admitted to our hospital. We did not find sufficient evidence of atherosclerotic processes in the brain infarction. However, the patient's signs and laboratory examination indicated a high suspicion of PV. A series of further examinations confirmed the final diagnosis. Bone marrow suppression medications (oral hydroxyurea and subcutaneous injection of interferon) were given and subsequent prevention of cerebral infarction was implemented. Routine blood reexamination was normal and no further cerebral infarction occurred. Patients with acute cerebral infarction should be considered comprehensively, and rare causes should not be ignored. It is crucial that PV be diagnosed and treated as early as possible, which can significantly improve the prognosis of patients.


Cardiopulmonary resuscitation in hospitalized patients: continuing problems of decision-making.
Disturbingly low survival rates after CPR prompted us to carry out a series of studies. Of 272 patients receiving CPR at our 600-bed community hospital in 1984, 102 (37.5%) patients survived initial resuscitation and 30 (11%) survived their hospitalization. Of the 102 initial survivors, only 15 patients had received full CPR including cardiac compression and/or defibrillation, endotracheal intubation, and cardiotonic drugs. These data were compared with those for 129 patients admitted to our critical care units in 1982 and 1983 in whom CPR was withheld. These patients had been designated "No CPR" primarily because of their poor response to therapy. There was an 11% survival rate for patients who had received CPR compared to a 16% survival rate for the "No CPR" group. These data suggest that criteria for administering CPR to hospitalized patients should be improved.


2-Chloro-5-(chloro-meth-yl)pyridine.
The title compound, C(6)H(5)Cl(2)N, is almost planar, with an r.m.s. deviation of 0.0146 Å for all atoms except for the 5-choloromethyl Cl atom. The offset Cl atom lies above this plane with a Cl-C-C angle of 111.11 (17)°. In the crystal, mol-ecules are connected via inter-molecular C-H⋯N hydrogen bonds, forming dimers.


Biliary IgA secretion in obstructive jaundice: the effects of endoscopic drainage.
Immunoglobulin A is the predominant immunoglobulin in the bile. Data on the effects of biliary obstruction on IgA secretion are few. The serum and bile IgA levels in patients with common duct stones (n = 27) or with malignant obstructive jaundice (n = 20) were collected by insertion of nasobiliary catheters. Single samples of common duct bile from patients with gallstones (n = 24) were collected as controls. Bile samples collected were measured for total IgA, secretory IgA, and free secretory component levels by sandwich enzyme-linked immunosorbent assays. Bile total IgA, secretory IgA, and free secretory component in the common duct stones group (82.7 +/- 11.4 microgram/ml, 18.4 +/- 1.7 microgram/ml, 0.74 +/- 0.15 microgram/ml) and the malignant obstructive jaundice group (81.6 +/- 10.7 microgram/ml, 18.2 +/- 2.4 microgram/ml, 0.57 +2- 0.12 microgram/ml) were found to be significantly lower than those of the control gallstone patients (104.8 +/- 3.4 microgram/ml, 33.2 +/- 2.9 microgram/ml, 1.03 +/- 0.12 microgram/ml) (P < 0.05). Serum secretory IgA levels in the common duct stones (26.53 +/- 1.75 microgram/ml) and malignant obstructive jaundice groups (26.03 +/- 3.48 microgram/ml) were significantly higher than the gallstone group (18.45 +/- 4.56 microgram/ml). The bile-to-serum concentration ratio of total IgA, secretory IgA, and free secretory component levels rose significantly within 48 hours after relief of obstruction. Biliary obstruction secondary to both calculus or malignancy of the hepatobiliary system causes suppression of bile IgA secretion and elevated serum level of secretory IgA. Bile secretory IgA secretion recovers with endoscopic drainage of the obstructed system.


Acoustic analysis of snoring sounds originating from different sources determined by drug-induced sleep endoscopy.
To discuss the possibility of fundamental frequency (F0) and formant frequency (FF) to generally differentiate the sources of snoring sounds determined by drug-induced sleep endoscopy (DISE). A total of 74 snoring subjects underwent DISE and snoring sounds were recorded simultaneously. The noise-suppressed snoring sounds were analyzed and classified into different groups based on the sources of vibration identified by DISE. F0 and FFs were calculated. Totally, 516 snoring sounds from three vibrating sources (the palate, combined the palate and the lateral wall, the lateral wall) of 47 patients were divided into three groups then analyzed. The levels of F0 and FFs for each group follow the order: Group 1 < Group 2 < Group 3. There was statistical difference between Group 1 and other groups in F0 and F2 (p < .05). The area under the receiver-operator curves (AUC) was F0, at 0.727, and the cut-off value was 134.2 Hz; and F2, at 0.654, and the cut-off value was 2028.0 Hz. F0 and the second formant frequency (F2) are found to be significantly lower in palatal snoring sound. F0 might be a significant in distinguishing palatal snoring sound from non-palatal snoring sound. F2 is more significant than F1 and F3 in identifying the sources of the snoring sounds but is less sensitive than F0.


Reductive cleavage of permethylated polysaccharides with borane-methyl sulfide complex and butyltin trichloride.
Several per-O-methylated monosaccharides and polysaccharides were used as models in an attempt to identify more convenient reagents for accomplishing reductive cleavage of glycosidic linkages. Included in the model studies were methyl alpha- and beta-D-glucopyranoside, methyl alpha- and beta-D-mannopyranoside, and methyl alpha- and beta-D-ribofuranoside. These studies led to the identification of a new promoter, butyltin trichloride, for carrying out reductive cleavage when borane-methyl sulfide complex was used as the reducing agent. These reagents were found to accomplish the reductive cleavage of per-O-methylated amylose, cellulose, and pullulan to give only the expected derivatives of 1,5-anhydro-D-glucitol. These reagents also accomplished reductive cleavage of per-O-methylated insulin to give only the expected derivatives of 2,5-anhydro-D-mannitol and 2,5-anhydro-D-glucitol. Reductive cleavage using these reagents is easy to perform, and subsequent acetylation of the products is readily accomplished in situ.


Cardiological effects of catecholamine-secreting tumours.
Correlations between endocrine and cardiological findings were investigated in 106 patients with catecholamine-secreting tumours during the florid phase of their illness. Endocrine data showed an elevation of urinary catecholamine or vanillylmandelic acid excretion in all but one subject. Hypertension was found in 78%, symptoms of coronary heart disease in 26% and arrhythmias in 20% of the patients. Twelve per cent of the patients came to the hospital with heart attacks, 7% with acute left heart failure and 6% with myocardial infarction. At admission electrocardiograph (ECG) analysis showed a sinus rhythm in 98%, tachycardia > 100 min-1 in 14% and bradycardia < 60 min-1 in 10%. In 16% of the ECGs cQT was increased, in 17% the ST segment was lowered and in 37% abnormal T waves occurred. Indices of myocardial hypertrophy such as the Sokolow index, the modified Romhilt-Estes score and the Murphy score were raised in 29%, 19% and 38% respectively. In 23 of 51 (45%) patients echocardiography showed left ventricular hypertrophy, in 16% mitral valve insufficiency and in 24% disturbances of contractility. Comparison of cardiac and endocrine parameters confirm in vitro and animal studies indicating that, in particular, the alpha-mimetic noradrenaline (NA) has deleterious effects on the cardiovascular system. Urinary NA, but not adrenaline or dopamine, excretion was significantly higher in constantly hypertensive than in normotensive patients and associated with an elevation of the Sokolow index and the Romhilt-Estes score. Both indices and plasma NA were higher in patients with myocardial hypertrophy and we found a significant correlation between the Romhilt-Estes score and NA excretion.


Simultaneous Screening of the FRAXA and FRAXE Loci for Rapid Detection of FMR1 CGG and/or AFF2 CCG Repeat Expansions by Triplet-Primed PCR.
Moderate to hyper-expansion of trinucleotide repeats at the FRAXA and FRAXE fragile sites, with or without concurrent hypermethylation, has been associated with intellectual disability and other conditions. Unlike molecular diagnosis of FMR1 CGG repeat expansions in FRAXA, current detection of AFF2 CCG repeat expansions in FRAXE relies on low-throughput and otherwise inefficient techniques combining Southern blot analysis and PCR. A novel triplet-primed PCR assay was developed for simultaneous screening for trinucleotide repeat expansions at the FRAXA and FRAXE fragile sites, and was validated using archived clinical samples of known FMR1 and AFF2 genotypes. Population samples and FRAXE-affected samples were sequenced for the evaluation of variations in the AFF2 CCG repeat structure. The duplex assay accurately identified expansions at the FMR1 and AFF2 trinucleotide repeat loci. On Sanger sequencing of the AFF2 CCG repeat, the single-nucleotide polymorphism variant rs868914124(C) that effectively adds two CCG repeats at the 5'-end, was enriched in the Malay population and with short repeats (<11 CCGs), and was present in all six expanded AFF2 alleles of this study. All expanded AFF2 alleles contained multiple non-CCG interruptions toward the 5'-end of the repeat. A sensitive, robust, and rapid assay has been developed for the simultaneous detection of expansion mutations at the FMR1 and AFF2 trinucleotide repeat loci, simplifying screening for FRAXA- and FRAXE-associated disorders.


Differential neuropsychological functioning between adolescents with attention-deficit/hyperactivity disorder with and without conduct disorder.
This study aimed to evaluate neuropsychological functioning of attention-deficit/hyperactivity disorder (ADHD) with and without comorbidities of oppositional defiant disorder (ODD) and/or conduct disorder (CD) and the mediation effects of the neuropsychological functions in the relationship between ADHD and ODD/CD symptoms to increase our understanding about these frequently co-occurring disorders. Adolescents aged 11-18 years were interviewed by the Kiddie epidemiologic version of the Schedule for Affective Disorders and Schizophrenia to confirm their previous and current ADHD status and other psychiatric diagnoses. The performance of the Cambridge Neuropsychological Testing Automated Battery was compared among four groups: (1) ADHD with CD (ADHD+CD), regardless of ODD; (2) ADHD with ODD (ADHD+ODD) without CD; (3) ADHD without ODD/CD (ADHD-only); and (4) typically developing controls. Mediation effects of neuropsychological functioning were tested. All three ADHD groups had impaired spatial working memory and short-term memory. Deficits in verbal memory and response inhibition were found in ADHD+ODD, but not in ADHD-only. ADHD+CD did not differ from typically developing controls in verbal working memory, signal detectability, and response inhibition. Spatial working memory partially mediated the association between ADHD and CD symptoms and alerting/signal detectability of arousal partially mediated the association between ADHD and ODD symptoms. There were both common and distinct neuropsychological deficits between adolescents with ADHD who developed ODD only and who developed CD. ADHD comorbid with CD may be a different disease entity and needs different treatment strategies in addition to treating ADHD, while ADHD+ODD may be a severe form of ADHD and warrants intensive treatment for ADHD symptoms.


Completely intracorporeal robotic renal autotransplantation.
We describe a technique of complete intracorporeal renal autotransplantation with donor nephrectomy and transplantation performed in a minimally invasive fashion without extracting the kidney. We developed this technique of a completely intracorporeal robotic renal autotransplantation and determined the feasibility of this novel procedure. This includes a method of intracorporeal transarterial hypothermic renal perfusion using a perfusion catheter through a laparoscopic port. The procedure was successfully applied in a 56-year-old man with extensive left ureteral loss after failed ureteroscopy for ureterolithiasis. Robotic donor nephrectomy was performed with a warm ischemia time of 2.3 minutes. Subsequently cold ischemia was achieved by intracorporeal hypothermic renal perfusion for 95.5 minutes. Vascular anastomoses and ureteroureterostomy in the ipsilateral pelvis were completed after donor nephrectomy with a total overall surgeon console time of 334 minutes. Venous and arterial anastomosis times were 17.3 and 21.3 minutes, respectively. Estimated blood loss was less than 50 ml. There were no complications and the patient was discharged home on postoperative day 1 after normal Doppler transplant renal ultrasound. Postoperative renal scan at 6 weeks, intravenous urogram at 8 weeks and computerized tomography urography at 5 months revealed normal function and successful ureteral reconstruction. We report the feasibility of a technique of a completely intracorporeal robotic renal autotransplantation. This operation may be considered in select patients in the hands of experienced robotic surgeons. However, further refinement is required as this novel procedure is cautiously reproduced and adopted by others.


Iron(II) triflate as a catalyst for the synthesis of indoles by intramolecular C-H amination.
A practical iron-catalyzed intramolecular C-H amination reaction and its application in the synthesis of indole derivatives are presented. As a catalyst, commercially available iron(II) triflate is used.


MRI utilization during the diagnostic and post-diagnostic phases in multiple sclerosis.
Magnetic resonance imaging (MRI) plays an important role in the diagnosis and monitoring of people with multiple sclerosis (MS). MRI rates in MS populations are poorly understood. Although Canada has universal health care, socioeconomic status (SES) is associated with MRI use. It is unknown if such disparities persist for specific conditions such as MS when care is managed centrally, or how disease-specific characteristics may affect MRI use. To assess magnetic resonance imaging (MRI) use in MS and control participants and its association with participant characteristics. Using administrative and clinical data from Manitoba, Canada, we assessed MRI use in MS and control participants during the five years pre-index (first demyelinating claim in the administrative cohort or symptom onset in the clinical cohort), between index and diagnosis (third demyelinating claim in the administrative cohort or diagnosis date in the clinical cohort), and the five years post-diagnosis. Using zero-inflated Poisson regression, we assessed associations between participant characteristics and index year, and MRI use during these three phases. We included 2,763 MS cases and 13,815 controls in the administrative cohort, and 961 MS cases in the clinical cohort. MRI use increased over time, but more in cases than in controls. Pre-index, individuals aged <50 years at the index date had lower MRI rates than those aged ≥50 years. Sex, socioeconomic status and region were not associated with MRI use. Disease-modifying therapy use was associated with 25% more MRIs post-diagnosis (adjusted rate ratio: 1.25; 95%CI:1.09-1.43) in the clinical cohort. Our findings suggest equity of access to MRI across sex, region and socioeconomic status in MS.


Dominant negative mutants of TRAF3 reveal an important role for the coiled coil domains in cell death signaling by the lymphotoxin-beta receptor.
Ligation of the lymphotoxin-beta receptor (LTbetaR) recruits tumor necrosis factor receptor-associated factor-3 (TRAF3) and initiates cell death in HT29 adenocarcinoma cells. The minimal receptor binding domain (TRAF-C) defined by two hybrid analyses is not sufficient for direct recruitment to the ligated receptor. A series of TRAF3 deletion mutants reveal that a subregion of the coiled coil motif is required for efficient recruitment to the LTbetaR. Furthermore, the ability of TRAF3 to self-associate maps to an adjacent subregion. A TRAF3 deletion mutant that lacks the N-terminal zinc RING and zinc finger motifs, but retains the coiled coil and TRAF-C motifs, competitively displaces endogenous TRAF3 from the LTbetaR. A second TRAF3 mutant that lacks the receptor binding domain, yet contains the TRAF3 self-association domain, prevents TRAF3 homodimers from being recruited to the LTbetaR. Both of these mutants have a dominant negative effect on cell death and demonstrate that the recruitment of TRAF3 oligomers is necessary to initiate signal transduction that activates the cell death pathway.


Hydrus Microstent malposition with uveitis-glaucoma-hyphema syndrome.
Intraocular implants, specifically those used in the treatment of glaucoma, are each associated with various implant related risks and complications of which surgeons placing these devices must be aware. Here we present a case of uveitis-glaucoma-hyphema (UGH) syndrome associated with the Hydrus Microstent.


Sliding resistance of polycarbonate self-ligating brackets and stainless steel esthetic archwires.
To compare the sliding resistance forces produced by polycarbonate self-ligating brackets with esthetic archwires. Samples of Opal, Oyster and conventional Blonde brackets were tested each one with 30 segments of .018x.025-in wires. The archwires were slipped at 8mm/min for 40 seconds with an universal testing machine. Two way ANOVA with Bonferroni correction were used. Blonde brackets presented the highest sliding resistance, followed in decreasing order by Oyster and Opal. The TP Shiny Bright Wire produced the highest surface friction, while the lowest was observed for Imagination archwires (except for Opal brackets where the TP Pearltone Wire achieved the best performance). Self-ligating system is more effective to reduce the sliding force resistance than conventional brackets. Esthetic stainless steel archwires produce less friction resistance than those without surface treatment. Polycarbonate self-ligating brackets are more effective to reduce the frictional forces than esthetic archwires with surface treatment.


Differentiation of pre- and post-synaptic high affinity serotonin receptor binding sites using physico-chemical parameters and modifying agents.
The two 3H-labeled agonists [3H]8-hydroxy-2-(di-n-propylamino) tetralin ([3H]8-OH-DPAT) and [3H]serotonin ([3H]5-HT) have been used to examine the effects of physico-chemical parameters and modulatory agents on the high affinity 5-HT receptor binding sites in various regions of the rat central nervous system. Sites labeled by [3H]8-OH-DPAT and [3H]5-HT were differentially sensitive to changes in incubation temperature and pH, such that the optimal interaction of [3H]8-OH-DPAT with specific sites in the striatum was at 30 degrees C and pH 7.4, whereas [3H]5-HT sites in the same region were most easily labeled at 2-23 degrees C and pH 8.2. Micromolar concentrations of Mn2+ enhanced [3H]5-HT binding but inhibited markedly [3H]8-OH-DPAT binding to striatal membranes. In contrast, both [3H]5-HT and [3H]8-OH-DPAT binding were increased by the cation in hippocampal membranes. Conversely, GTP reduced the binding of either ligand in the hippocampus but affected only [3H]5-HT binding in the striatum. Furthermore, N-ethylmaleimide inhibited equally [3H]5-HT and [3H]8-OH-DPAT binding to hippocampal membranes, but was markedly less potent against [3H]8-OH-DPAT binding to striatal membranes. These results led to the definition of assay conditions for studying separately [3H]8-OH-DPAT binding to "hippocampal-like" (HL) and "striatal-like" (SL) sites. [3H]8-OH-DPAT HL binding sites were particularly abundant in the hippocampus, septum and cerebral cortex, and exhibited pharmacological properties typical of the postsynaptic 5-HT1A subsites previously characterized with [3H]5-HT as the ligand. The regional distribution of [3H]8-OH-DPAT SL binding sites was strikingly different from that of HL sites, but similar to that of serotoninergic terminals identified by their capacity to take up [3H]5-HT. The selective lesion by 5,7-dihydroxytryptamine of serotoninergic projections induced a marked loss of [3H]8-OH-DPAT SL binding sites in the striatum and the cerebral cortex, indicating that these sites were located presynaptically. In contrast, [3H]5-HT binding sites remained unchanged in lesioned rats, which confirmed further their exclusive postsynaptic location in brain.


Osteosclerotic metaphyseal dysplasia.
A new sclerosing bone disease in two Japanese siblings born to first-degree cousin parents is reported. Clinically the disease is characterized by early developmental delay, hypotonia and later spastic paraplegia. The unique radiographic changes consist of peripheral osteosclerosis affecting predominantly metaphyses of the long bones and to a lesser degree ends of the ribs and clavicles, iliac crests, acetabulae, ischio-pubic synchondroses and vertebrae. The epiphyses are sclerotic in early life. The round bones, short tubular bones and the skull are little affected. The shafts of the tubular bones are osteopenic. Increased serum alkaline phosphatase was the only laboratory abnormality detected. We suggest the name "osteosclerotic metaphyseal dysplasia" for this disorder.