Therapeutic Factors in a Psychiatric Group Therapy: a Preliminary Validation of Therapeutic Factors Inventory-8, Italian Version.
Several studies support group therapy effectiveness due to the activation in patients of unique psychological mechanisms defined as non-specific therapeutic factors (Therapeutic Factors-TFs), which shape the setting and, at the same time, enhance the specific group therapeutic factors. The objectives of this study were to preliminarly validate Therapeutic Factors Inventory-8 (TFI-8) Italian version and identify group therapeutic factors. In a psychiatric residential facility, a weekly psychotherapeutic group was evaluated during 1 year. One scale on group process (TFI-8, Ferrara-Group Experience Scale) and three clinical scales (Brief Symptom Inventory-53, Sheehan Disability Scale, WHO Quality of Life-Bref) were administered to participating patients. Internal consistency, Exploratory Factor Analysis (EFA), convergent validity of TFI-8 were assessed. Correlations between TFI-8 and other scale scores and selected variables were pwerformed. Our sample consisted of 64 participants. TFI-8 showed good internal consistency (Chronbach's alpha = 0.84), concurrent validity with Fe-GES (Rho = 0.42, p = 0.0008). EFA highlighted a single Factor, accounting for 92% of variance. TFI-8 was not significantly related to clinical scale scores. TFI-8 Italian version proved to be a valid and reliable tool which allowed us to identify one therapeutic factor indicating relational attraction in group therapy, composed of three dimensions: infusion of hope, cohesion and social learning.


Interaction between grapefruit juice and praziquantel in humans.
After a single oral dose of praziquantel with 250 ml of grapefruit juice, the area under the concentration-time curve and the maximum concentration in plasma of praziquantel (Cmax) were significantly increased (Cmax for water treatment, 637.71 +/- 128.5 ng/ml; and Cmax for grapefruit juice treatment, 1,037.65 +/- 305.7 ng/ml, P < 0.05). No statistically significant differences were found in the time to maximum concentration of drug in plasma or elimination half-life.


Dermatofibrosarcoma protuberans of the scalp: a series of cases.
Three cases of dermatofibrosarcoma protuberans on the scalp of young women are presented. The scalp is a rare but important anatomic site for this tumor because of the possibility of direct invasion into the skull and brain. The use of DNA analysis to predict biologic aggressiveness of a tumor is discussed.


Evaluation of biotinylated cells as a source of antigens for characterization of their molecular profile.
Biotinylated lymphoid cells have been suggested as a useful source of antigen for the immunochemical characterization of their molecular profile. Labelling with biotin eliminates the problems associated with the use of radioactivity. However, this method has not been widely used. This reflects: (1) difficulties in optimizing the signal/background ratio because of the lack of a simple method to quantify biotinylated proteins in a cell lysate, (2) the loss of reactivity with monoclonal antibody of antigen following biotinylation, because of steric hindrance, and (3) the lack of information about the utility of other biotinylated cells as an antigen source. To overcome these limitations, we developed an ELISA to quantify biotinylated proteins in cell lysates and optimized the signal/background ratio. The validity of this approach was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of a number of cell surface antigens immunoprecipitated from lymphoid cells by an optimal amount of monoclonal antibody. Furthermore, we showed that biotinylated melanoma cells are a useful source of antigen for immunoprecipitation experiments and that ligation of biotin to antigen does not affect reactivity with monoclonal antibody. Lastly, biotinylated antigens in cell lysates stored at -80 degrees C for 6 months maintained their reactivity with monoclonal antibodies. Biotinylated cells thus represent a useful source of antigen for characterizing the immunochemical profile and analyzing the specificity of antibodies with immunochemical methods.


Bioactive phenylpropanoid esters of sucrose and anthraquinones from Polygonum cuspidatum.
Four new compounds including two new phenylpropanoid esters of sucrose, polygonusucroside A (1) and B (2); two new anthraquinones, 8-O-β-d-(6'-galloyl)-glucopyranoside (3) and polyanthraquinoside A (4), together with six known compounds were isolated from Polygonum cuspidatum. Their structures were established using UV, IR, HRESIMS, and NMR data. All compounds were evaluated for their α-glucosidase inhibitory activities and neuroprotective effects. Compounds 5, 7 and 9 showed significant α-glucosidase inhibitory activities with IC50 values of 27.30, 5.51, and 1.09 μmol/L, respectively (acarbose as positive control, IC50 = 6.17 μmol/L). In addition, the assessment of neuroprotective effect showed that compound 3 exhibited remarkable effect against PC12 cells injured by serum-deprivation and compounds 2, 7, and 9 exhibited moderate effects against PC12 cells injured by rotenone.


Effects of intracytoplasmic sperm injection timing and fertilization methods on the development of bovine spindle transferred embryos.
Cytoplasmic replacement by spindle transfer (ST) technique can be applied to improve the developmental competence of poor qualitied or aged oocytes. In cattle, ST technology has not been well established for producing embryos and the calves successfully using intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF). The objective of this study was to develop a novel procedure for producing bovine ST embryos, which could be fundamental to applying ST technology in other mammals. In the present study, the efficacies of performing ICSI before (ICSI-ST) or after (ST-ICSI) and IVF on the development of ST bovine embryos were investigated. Results indicated that the blastocyst rate of ST embryos produced by ICSI-ST (24.7%) was higher (P < 0.05) than that produced by ST-ICSI (5.9%). On the other hand, ST-IVF had the highest fertilization rate (97.3%), polyspermy rate (24.7%), and lowest blastocyst rate (22.7%) when compared to denuded oocytes (DO), zona cut oocytes (ZC), and cumulus-oocyte complexes (COCs)-IVF groups. Finally, the in vitro development rates of ICSI-ST (24.5%) and ST-IVF (25.2%) were not significantly different (P > 0.05). However, the pregnancy rate (46.7%) and birth rate (33.3%) of ST-IVF were higher (P < 0.05) than those of ICSI-ST (6.3% and 0%, respectively). The percentage of mitochondrial DNA (mtDNA) heteroplasmy derived from donor karyoplasts of the 5 claves was between 2% and 18%. Taken together, performing ICSI prior to ST can improve the embryonic development of ST bovine embryos. Moreover, using IVF, instead of ICSI, for ST oocyte fertilization dramatically increased the pregnancy rate and birth rate of ST calves, in which mtDNA heteroplasmy derived from donor karyoplasts exists.


Association between antiphospholipid antibodies and cardiac abnormalities in patients with systemic lupus erythematosus.
Although the antiphospholipid antibodies are well recognized to be associated with thrombosis, recurrent abortion, and thrombocytopenia in patients with systemic lupus erythematosus (SLE), their relationship with cardiac disease is less clear. The purpose of this study was to evaluate the association between anti-phospholipid antibodies and cardiac abnormalities in patients with SLE. A total of 75 consecutive SLE patients and 60 healthy sex- and age-matched control subjects were evaluated in a case-control study. All participants underwent M-mode, two-dimensional, and Doppler echocardiography. Antiphospholipid antibodies levels were assayed in each patient. The prevalence of antiphospholipid antibodies in patients with and without echocardiographic abnormalities was compared. Compared with the control group, SLE patients had significantly more pericardial abnormalities, left ventricular hypertrophy, left atrial enlargement, left ventricular dysfunction and verrucous valvular thickening, global valvular thickening with dysfunction, and mitral and aortic regurgitation. Among these abnormalities, antiphospholipid antibodies were significantly associated with isolated left ventricular (global or segmental) dysfunction (four of five positive; p less than 0.05), verrucous valvular (mitral or aortic) thickening (seven of nine positive; p less than 0.005), global valvular (mitral or aortic) thickening and dysfunction (five of six positive; p less than 0.02), as well as mitral regurgitation (16 of 19 positive; p less than 0.001) and aortic regurgitation (five of six positive; p less than 0.02). Valvular lesions and myocardial dysfunction are associated with elevated antiphospholipid antibodies. This study has important implications for the pathogenic role of anti-phospholipid antibodies in relation to these cardiac abnormalities.


Acetylcholine release from rat cortical slices during postnatal development and aging.
Acetylcholine release from cortical slices superfused with choline-enriched Krebs solution containing physostigmine was investigated at birth, at 7, 20 and 30 days, and at 3 and 24 months of age, in order to assess age influence on the functional efficiency of the cortical cholinergic network. The slices were electrically stimulated at frequencies from 1 to 10 Hz for 5 min periods, preceded and followed by rest periods. The superfusate was collected every 5 min and acetylcholine content quantified by bioassay. In the newborn and 7 day-old pups acetylcholine release was approximately 50% lower than that of the 3 month-old rats at all frequencies tested. The highest release was elicited in the 30 day-old rats. Beginning with this age the evoked ACh release underwent a decline which in the 24 month-old rats brought it back to the same level as in the newborn ones. The blockade of the muscarinic autoreceptors by atropine 1.5 X 10(-8) M caused an increase in acetylcholine release at 20 day, 3 and 24 months of age but not in the newborn and 7 day-old pups. Adenosine 3 X 10(-5) M decreased acetylcholine output in newborn and adult but had no effect in the senescent rats.


The supramammillary nucleus: is it necessary for the mediation of hippocampal theta rhythm?
Recent evidence suggests that the supramammillary nucleus of the posterior hypothalamus serves as an important relay in a brainstem to septum/hippocampus pathway involved in the generation of hippocampal theta rhythm. In order to examine the role of the supramammillary nucleus as a possible relay/mediator of hippocampal theta rhythm, electrolytic lesions and procaine injections were administered to the supramammillary nucleus of freely moving and urethane-anesthetized rats, respectively. In the urethane-anesthetized rat, it was found that procaine injections attenuated both the frequency and amplitude of theta rhythm elicited by stimulation of the pontine reticular formation. These data suggest that the pontine reticular elicitation of hippocampal theta rhythm is mediated through connections with the supramammillary nucleus. However, it was found that lesions of the supramammillary nucleus failed to produce significant changes in the hippocampal electroencephalogram of freely moving animals. Several explanations concerning this apparent discrepancy are discussed. The most compelling is that multiple brainstem to septum/hippocampus pathways may serve to generate or facilitate the generation of theta rhythm in the freely moving animal. The present report demonstrates that the supramammillary nucleus plays a questionable role in the mediation of hippocampal electroencephalogram signals which are thought to be important for mnemonic processes.


[Description of characteristics, therapy and outcome of patients older than 75 years presenting with severe renal insufficiency (eGFR below 20 mL/min/1.73 m(2): pilot study].
In France, the incidence of dialysis patients is increasing in people over 75 years and represents 40% of incident patients. In these elderly patients with many comorbidities, the benefit of dialysis in terms of survival and quality of life remains controversial. Using data from REIN, determinants of early mortality were identified and a prognostic score was provided. This approach must now be adapted to elderly with end stage renal failure (ESRF) not on dialysis for which we have little data on their clinical characteristics, therapeutic projects and outcome. We report the results of a pilot study and the prospective study protocol that resulted. In four French nephrology department, 76 patients were studied with a mean age of 83 ± 5 years, with a MDRD estimated GFR (abbreviated MDRD) of 16 ± 4 mL/min/1.73 m(2). These patients were different from the population on dialysis recorded in REIN. This pilot study has shown the feasibility of a prospective study on a larger scale, which aims to build a valuable tool for decision making in elderly patients with ESRF not yet on dialysis.


Nosocomial infection by Rhizomucor pusillus in a clinical haematology unit.
Three patients suffering from acute leukaemia were treated with cytotoxic agents and broad-spectrum antibiotics and received blood transfusion and nasal packing for severe epistaxis. All developed necrosis of nasal and facial tissues, with facial swelling an oedema; two biopsies showed typical phycomycete mycelium, and Rhizomucor pusillus was grown from one biopsy. Air and surfaces in the unit and the air intake and ducting were all heavily colonized by Rh. pusillus and other phycomycetes. It is suggested that Rh. pusillus spores from the air invaded the tissues in the conditions promoted by the nasal packing in these patients with impaired defences.


Clinical analysis of liver fibrosis in choledochal cyst.
Although most patients with choledochal cyst (CC) have a favorable prognosis with prompt treatment, some of them are complicated with liver fibrosis, resulting in prolonged liver dysfunction even after definitive surgery. The aim of this study was to distinguish the high-risk group of liver fibrosis in patients with CC. Fifteen patients who underwent liver biopsy during surgery for CC from 1981 to 2012 were enrolled in this study. Liver histology with H&E staining was graded according to Ohkuma's classification, and the correlation with the clinical characteristics was retrospectively assessed. Their median age at biopsy was 13.4 months (range 1-42 months), and there were 7 in Ia, 2 in Ic, and 6 in IVa of the Todani classification. There were no significant differences in serum liver function test among those cyst types. The histological grades of liver fibrosis were as follows: grade 0 (no fibrosis) in 7 patients, grade 1 (mild) in 2, grade 2 (moderate) in 3, grade 3 (severe) in 2, grade 4 (cirrhosis) in 1. All 3 patients with grade 3 and 4 had CC with IVa and were under 18-month old. A 3-month-old girl with cirrhosis presented with severe jaundice resulting in living-donor liver transplantation despite bile drainage. A 16-month-old girl with grade 3 suffered from prolonged liver dysfunction and intractable ascites after surgery. The progression of liver fibrosis is likely to be correlated with IVa, and the postoperative course might be unsatisfactory in advanced cases. The prompt surgical intervention is recommended especially for neonatal and infantile cases with type IVa cyst because irreversible liver cirrhosis could occur as early as in the infantile period.


Recent Advances in Small Molecule and Biological Therapeutic Approaches in the Treatment of Psoriasis.
New treatments continue to be developed for psoriasis. In this review, we aim to summarize the results of the major published studies on biologic and small molecule drugs for the treatment of psoriasis. We emphasize the safety, efficacy, and tolerability of these treatment options. A review of the MEDLINE database was conducted for each class of medication. Randomized controlled trials were identified for each medication; data on efficacy, safety, and tolerability were reviewed. Biologic and small molecule treatment options are more effective than placebo, although there were few head-to-head trials to assess relative efficacy between biologics and small molecule treatments. These drugs offer favorable safety profiles with only rare serious adverse events reported. Biologic and small molecule drugs offer diverse therapeutic regimens, particularly in patients with recalcitrant disease.


Effects of plastic residues and microplastics on soil ecosystems: A global meta-analysis.
Plastic pollution is one of the global pressing environmental problems, threatening the health of aquatic and terrestrial ecosystems. However, the influence of plastic residues and microplastics (MPs) in soil ecosystems remains unclear. We conducted a global meta-analysis to quantify the effect of plastic residues and MPs on indicators of global soil ecosystem functioning (i.e. soil physicochemical properties, plant and soil animal health, abundance and diversity of soil microorganisms). Concentrations of plastic residues and MPs were 1-2700 kg ha-1 and 0.01-600,000 mg kg-1, respectively, based on 6223 observations. Results show that plastic residues and MPs can decrease soil wetting front vertical and horizontal movement, dissolved organic carbon, and total nitrogen content of soil by 14%, 10%, 9%, and 7%, respectively. Plant height and root biomass were decreased by 13% and 14% in the presence of plastic residues and MPs, while the body mass and reproduction rate of soil animals decreased by 5% and 11%, respectively. However, soil enzyme activity increased by 7%441% in the presence of plastic residues and MPs. For soil microorganisms, plastic residues and MPs can change the abundance of several bacteria phyla and families, but the effects vary between different bacteria.


Gut Microbiome-Dependent Metabolic Pathways and Risk of Lethal Prostate Cancer: Prospective Analysis of a PLCO Cancer Screening Trial Cohort.
Diet and the gut microbiome have a complex interaction that generates metabolites with an unclear effect on lethal prostate cancer risk. Identification of modifiable risk factors for lethal prostate cancer is challenging given the long natural history of this disease and difficulty of prospectively identifying lethal cancers. Mass spectrometry was performed on baseline serum samples collected from 173 lethal prostate cancer cases and 519 controls enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial. Baseline serum levels of choline, carnitine, betaine, γ-butyrobetaine, crotonobetaine, phenylacetylglutamine, hippuric acid, and p-cresol sulfate were quantified and analyzed by quartile. Conditional multivariable logistic regression analysis associated analyte levels with lethal prostate cancer incidence after adjusting for body mass index and PSA. The Cochran-Armitage test evaluated analyte level trends across quartiles. Relative to those in the first quartile, cases with the highest baseline levels of choline (Q4 OR: 2.19; 95% CI, 1.23-3.90; P-trend: 0.005) and betaine (Q4 OR: 1.86; 95% CI, 1.05-3.30; P-trend: 0.11) exhibited increased odds of developing lethal prostate cancer. Higher baseline serum levels of phenylacetylglutamine (Q4 OR: 2.55; 95% CI, 1.40-4.64; P-trend: 0.003), a gut microbiome metabolite of phenylalanine with adrenergic activity, were also associated with lethal prostate cancer. Baseline serum levels of one-carbon methyl donors and adrenergic compounds resulting from human and gut microbiota-mediated metabolism are associated with increased lethal prostate cancer risk. Dietary composition, circulating metabolite levels, and downstream signaling pathways may represent modifiable risk factors associated with incident lethal prostate cancer. Beta-adrenergic blockade represents an additional target for oncologic risk reduction.


Coxiella burnetii in Tunisian dromedary camels (Camelus dromedarius): Seroprevalence, associated risk factors and seasonal dynamics.
Q fever, caused by Coxiella burnetii, is a zoonotic disease responsible of abortion in ruminants. Few studies have investigated the prevalence of this infection in camels (Camelus dromedarius). The present report aimed to highlight the epidemiological status and identify the risk factors associated with C. burnetii infection in one-humped dromedary that is the most productive livestock species in arid areas. A total of 534 sera of healthy camels were collected in eight governorates from southern and central Tunisia. Samples were tested by an indirect Enzyme linked Immunosorbent Assay (ELISA). Results were analyzed using the Chi-square test and logistic regression. Overall, 237 camels (44%, 95%CI: 0.40-0.49) were seropositive to C. burnetii. Statistical analysis pointed out four potential risk factors associated with infection. A meaningful high seropositivity was observed in female camels with a previous history of abortion (70%) (OR = 4.186, 95%CI: 2.05-8.51). Seroprevalence was higher in aged camels (>10 years-old) (48%) (OR = 2.91, 95%CI: 1.37-6.17). Besides, camels, intended for meat production from small herds showed a high level of infection (52%) (OR = 2.43, 95%CI: 1.3-4.5). Coxiellosis evolved in dromedary herds throughout the year, however infection was significantly important in autumn (60%) (OR = 4.13, 95%CI: 1.86-9.17) and winter (56%) (OR = 5.52, 95%CI: 2.50-12.16). Bioclimatic stage, gender, tick infestation and contact with other ruminants were not risk factors in camel's infection by C. burnetii. Our reports confirm that Tunisian one-humped dromedaries had been exposed to this bacterium and could contribute to its dissemination among farmers and other livestock animals. Furthers studies are required to evaluate the prevalence of Q fever among people professionally exposed like farmers, veterinarians and slaughterhouse workers.


Diagnosis of congenital Hyperinsulinism can occur not only in infancy but also in later age: a new flow chart from a single center experience.
Congenital Hyperinsulinism typically occurs with a neonatal hypoglycemia but can appear even in childhood or in adolescence with different types of glucose metabolism derangements. Current diagnostic algorithms don't take into account cases with a late presentation. Clinical and laboratory data of twenty-two subjects diagnosed at Federico II University of Naples have been described: patients have been divided according to the molecular defect into channel defects, metabolic defects and unidentified molecular defects. A particular focus has been made on three cases with a late presentation. Late presentation cases may not be identified by previous diagnostic algorithms. Consequently, it seems appropriate to design a new flow-chart starting from the age of presentation, also considering that late presentation cases can show glucose metabolism derangements other than hypoglycaemic crises such as diabetes, glucose intolerance, postprandial hypoglycaemia and gestational diabetes.


Risk factors of thromboembolism in nonvalvular atrial fibrillation patients with low CHA2DS2-VASc score.
The risk of thromboembolism in patients with CHA2DS2-VASc score of 0 to 1 was low, and the anticoagulant therapy was not recommended. Although the CHA2DS2-VASc score was low, there were still many patients suffered from thrombotic events and stroke. We aim to investigate the risk factors of thrombotic events in nonvalvular atrial fibrillation (NVAF) patients with low CHA2DS2-VASc score.We retrospectively enrolled 595 consecutive NVAF patients with low CHA2DS2-VASc score (male: CHA2DS2-VASc = 0, female: CHA2DS2-VASc = 1). The general clinical data, blood biochemical data, and echocardiography results of the 595 patients were collected. Multivariate logistic regression models were used to evaluate risk factors of thrombosis. Receiver operating characteristic curve was used to identify the optimal cut-off value of the independent risk factors. A P value of <.05 (2-sided) was considered to be statistically significant.In multivariate analysis, lipoprotein (a) (Lp(a)) plasma level and left atrium diameter (LAD) were positively related to thromboembolism in NVAF patients with CHA2DS2-VASc score of 0 to 1 after adjustment for age, gender, and other variables (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.01-1.03; OR = 1.13, 95% CI: 1.06-1.18). Lp(a) exerted a significant predictive value with area under the curve (AUC) of 0.62 (95% CI: 0.55-0.68, P < .01). The optimal cut-off value for Lp(a) predicting thrombotic events was 27.2 mg/dL (sensitivity 45.7%, specificity 73.4%). LAD showed a significant predictive value with AUC of 0.71 (95% CI: 0.64-0.78, P < .01). The optimal cut-off point for LAD predicting thrombotic events was 43.5 mm (sensitivity 47.1%, specificity 85.8%).High Lp(a) plasma level and left atrial dilatation might be independent risk factors of thrombotic events for NVAF patients with low CHA2DS2-VASc score.


3' deoxycytidine, like hydroxyurea, inhibits DNA synthesis without preventing the initiation of the cell cycle.
3' Deoxycytidine, the cytidine analogue of cordycepin and selective inhibitor of pre-ribosomal RNA in HeLa cells, has been found to be a reversible inhibitor of DNA replication in RNA accumulation. Like other inhibitors of DNA replication such as hydroxyurea, it does not prevent serum-stimulated quiescent 3T3 cells from undergoing the random transition which is rate-limiting for entry into S phase.


The influence of lung metastases on the clinical course of gestational trophoblastic neoplasia: a historical cohort study.
To evaluate whether gestational trophoblastic neoplasia (GTN) patients with lung metastases have more adverse outcomes such as resistance to chemotherapy, recurrence or death of disease compared with patients without lung metastases. Historical observational cohort study. The Netherlands. We identified 434 GTN patients (72 patients with lung metastases, 362 patients without metastases) between 1990 and 2012 registered in the Dutch national databases. Baseline characteristics, recurrence rates, Methotrexate (MTX) remission rates and deaths from disease were compared between patients with lung metastases (group I) and without lung metastases (group II) using the Fisher exact test or Mann-Whitney U-test where applicable. Methotrexate resistance, recurrences and survival. Methotrexate resistance did not differ between group I and group II (62.9 versus 72.7% P = 0.19). However, the observed recurrence rate was significantly increased in patients with lung metastases compared with patients without metastases (16.7 versus 2.2% P < 0.0001), also after correction for antecedent pregnancy and interval (from the end of the antecedent pregnancy until the start of treatment). Disease-specific survival was 91.7% in the group with lung metastases and 100% in the patients without metastases (P < 0.0001). Although lung metastases are considered to be associated with a low risk of adverse outcomes, their presence appears to increase the risk for recurrence and death of disease. Further research is needed to evaluate whether the presence of lung metastases is an independent risk factor that needs adjustment in the FIGO scoring system and clinical classification system. In gestational trophoblastic neoplasia (GTN) recurrence is more often observed in the case of lung metastases.


Genomic evidence sheds new light on phylogeny of Rhabdophis nuchalis (sensu lato) complex (Serpentes: Natricidae).
Stable taxonomy and robust phylogeny are essential for the evolution and conservation of organisms. The Rhabdophis nuchalis (sensu lato) complex presently contains three species (R. nuchalis, R. chiwen, R. pentasupralabialis). Although several studies have explored the diversity and phylogeography of this group, certain issues related to systematics and taxonomy remain unresolved. Here, based on genome-wide data, including single nucleotide polymorphisms (SNPs) generated from ddRAD-seq and mitochondrial DNA (mtDNA), we re-evaluated the phylogenetic relationships and cryptic diversity of this species group. Our results are generally consistent with previous studies but provide some new insights. Phylogenetic relationship reconstruction based on SNPs and mtDNA revealed that three species in the R. nuchalis (sensu lato) complex did not form a monophyly but each species is well supported as monophyletic lineage in SNP-based analyses. Population structure analyses showed genetic admixture between several species pairs. Additionally, the population in eastern Yunnan, China, was identified as a potential cryptic species and thus described as a new species based on morphological data. From our results and previous studies, we redefined the distribution boundary for each species in the R. nuchalis (sensu lato) species complex.


First detection and quantification of N(δ)-monomethylarginine, a structural isomer of N(G)-monomethylarginine, in humans using MS(3).
The L-arginine metabolites methylated at the guanidino moiety, such as N(G)-monomethyl-L-arginine (LNMMA), asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA), and symmetric N(G),N(G')-dimethyl-L-arginine (SDMA), are long known to be present in human plasma. Far less is known about the structural isomer of LNMMA, N(δ)-monomethyl-L-arginine (δ-MMA). In prior work, it has been detected in yeast proteins, but it has not been investigated in mammalian plasma or cells. In this work, we present a method for the simultaneous and unambiguous quantification of LNMMA and δ-MMA in human plasma that is capable of detecting δ-MMA separately from LNMMA. The method comprises a simple protein precipitation sample preparation, hydrophilic interaction liquid chromatography (HILIC) gradient elution on an unmodified silica column, and triple stage mass spectrometric detection. Stable isotope-labeled D6-SDMA was used as internal standard. The calibration ranges were 25-1000 nmol/L for LNMMA and 5-350 nmol/L for δ-MMA. The intra- and inter-batch precision determinations resulted in relative standard deviations of less than 12% for both compounds with accuracies of less than 6% deviation from the expected values. In a pilot study enrolling 10 healthy volunteers, mean concentrations of 48.0 ± 7.4 nmol/L for LNMMA and 27.4 ± 7.7 nmol/L for δ-MMA were found.


PCSK9 causes inflammation and cGAS/STING pathway activation in diabetic nephropathy.
Our previous research revealed that an increase in PCSK9 is linked to aggravated inflammation in the kidneys of mice affected by a high-fat diet and streptozotocin (HFD/STZ) or in HGPA-induced HK-2 cells. Furthermore, the cGAS/STING pathway has been reported to be involved in diabetic nephropathy (DN). Therefore, in this study, we aimed to examine the correlation between the proinflammatory effect of PCSK9 and the cGAS/STING pathway in DN. We used PCSK9 mAbs to inhibit PCSK9 in vivo and PCSK9 siRNA in vitro and measured the inflammatory phenotype in HFD/STZ-treated mice or HGPA-induced HK-2 cells, and observed decreased blood urea nitrogen, creatinine, UACR, and kidney injury in response to the PCSK9 mAb in HFD/STZ-treated mice. Moreover, IL-1 β, MCP-1, and TNF-α levels were reduced by the PCSK9 mAb in vivo and PCSK9 siRNA in vitro. We observed increased mtDNA damage and activation of the cGAS-STING signaling pathway during DN, as well as the downstream targets p-TBK1, p-NF-κB p65, and IL-1β. In a further experiment with an HGPA-induced DN model in HK-2 cells, we revealed that mtDNA damage was increased, which led to the activation of the cGAS/STING system and its downstream targets. Notably, the cGAS-STING signaling pathway was inhibited by the PCSK9 mAb in vivo and PCSK9 siRNA in vitro. In addition, inhibition of STING with C-176 in HGPA-induced HK-2 cells markedly blocked inflammation. In conclusion, we report for the first time that PCSK9 triggers mitochondrial DNA damage and activates the cGAS-STING pathway in DN, which leads to a series of inflammation cascades. PCSK9-targeted intervention can effectively reduce DN inflammation and delay its progression. Moreover, the inhibition of STING significantly abrogated the inflammation triggered by HGPA in HK-2 cells.


Effects of propofol and nitrous oxide on middle cerebral artery flow velocity and cerebral autoregulation.
We studied the effects of adding 50% nitrous oxide to propofol anaesthesia administered by target-controlled infusion on middle cerebral artery flow velocity and autoregulatory indices derived from transient hyperaemic response tests. Nine healthy (ASA 1) adult patients scheduled to undergo elective surgery were recruited. A standardised anaesthetic comprising alfentanil 10 microg x kg(-1), propofol via a target-controlled infusion pump and vecuronium 0.1 mg x kg(-1) was used. Transcranial Doppler ultrasonography was used to measure middle cerebral artery (MCA) blood flow velocity and the transient hyperaemic response test was used to assess cerebral autoregulation. These measurements were performed while awake and then at an induction target concentration of propofol (the target at which consciousness was lost, mean 6.2 (SD 1.1) microg x ml(-1)). The measurements were repeated after the addition of 50% nitrous oxide to the breathing gas mixture. Propofol caused a significant decrease in MCA flow velocity and a significant increase in the strength of autoregulation. The addition of nitrous oxide had no significant effect on MCA flow velocity or cerebral autoregulation. These results suggest that addition of 50% nitrous oxide does not influence propofol-induced changes in cerebral haemodynamics.


Automated image analysis for diameters and branching points of cerebral penetrating arteries and veins captured with two-photon microscopy.
The present study was aimed to characterize 3-dimensional (3D) morphology of the cortical microvasculature (e.g., penetrating artery and emerging vein), using two-photon microscopy and automated analysis for their cross-sectional diameters and branching positions in the mouse cortex. We observed that both artery and vein had variable cross-sectional diameters across cortical depths. The mean diameter was similar for both artery (17 ± 5 μm) and vein (15 ± 5 μm), and there were no detectable differences over depths of 50-400 μm. On the other hand, the number of branches was slightly increased up to 400-μm depth for both the artery and vein. The mean number of branches per 0.1 mm vessel length was 1.7 ± 1.2 and 3.8 ± 1.6 for the artery and vein, respectively. This method allows for quantification of the large volume data of microvascular images captured with two-photon microscopy. This will contribute to the morphometric analysis of the cortical microvasculature in functioning brains.


A phase I-II trial of 4'-deoxydoxorubicin (esorubicin) in refractory or relapsed acute leukemia.
In a phase I-II study, 21 patients with relapsed or refractory acute leukemia were treated with 4'-deoxydoxorubicin (esorubicin), the 4'-deoxy derivative of doxorubicin. Four of 14 evaluable patients with acute nonlymphocytic leukemia (ANLL) in relapse or refractory to other anthracyclines achieved partial response (28.5%). Pharmacokinetics were similar to those of the parent compound, doxorubicin. Esorubicin has activity in ANLL and has pharmacologic properties comparable to those of other anthracyclines. Dose-limiting toxicity occurs in the form of mucositis, which may limit its use in combination with other antileukemic drugs.


Antigen presentation to naive CD4 T cells in the lymph node.
Although the presentation of peptide-major histocompatibility complex class II (pMHC class II) complexes to CD4 T cells has been studied extensively in vitro, knowledge of this process in vivo is limited. Unlike the in vitro situation, antigen presentation in vivo takes place within a complex microenvironment in which the movements of antigens, antigen-presenting cells (APCs) and T cells are governed by anatomic constraints. Here we review developments in the areas of lymph node architecture, APC subsets and T cell activation that have shed light on how antigen presentation occurs in the lymph nodes.


Proven immunologically-mediated drug hypersensitivity in children with a history of multiple drug intolerances.
Children may be referred to pediatric allergy clinics for reactions to multiple drugs. Multiple drug hypersensitivity (MDH) is defined as immunologically-mediated hypersensitivity to 2 or more chemically different drugs. The aim of this study is to report the allergy workup results of children who had a history of potential hypersensitivity reactions to 2 or more unrelated drugs. This study was conducted in the Pediatric Allergy and Immunology department of our hospital. Children who described hypersensitivity reactions to 2 or more drugs were included and were evaluated by allergy workup (skin and/or provocation tests) between January 2011 and July 2016. During the study period, 886 children were evaluated for a history of drug intolerance. Of these children, 73 (8.2%) had a history of drug reactions to 2 or more chemically different drugs. The median age of the children who had a history of reactions to 2 or more drugs was 7.8 (min-max: 2.5-16.4) years, and 59% (n = 43) were male. Among the suspected drugs, antibiotics (65.9%) ranked first, and nonsteroid anti-inflammatory drugs (34.1%) were the second. All 73 children were evaluated with skin or provocation tests with the suspected drugs, and MDH was confirmed in only 2 (2.7%) children. Multiple drug hypersensitivity is uncommon in children. The incidence and prevalence of MDH may vary with the specific population studied. Evaluating children with a history of MDH, by performing drug hypersensitivity testing, will help avoid the morbidity associated with unnecessary drug avoidance.


Operative versus non-operative treatment in complex proximal humeral fractures: a meta-analysis of randomized controlled trials.
Whether operative treatment for complex proximal humeral fractures (CPHFs) has a greater benefit over non-operative treatment remains controversial. There is no consensus on the optimal treatment in elderly patients with CPHFs. This updated meta-analysis of randomized controlled trials (RCTs) aims to investigate whether operative treatment is superior to non-operative treatment in CPHFs. The authors searched RCTs in the electronic databases (Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Medline, Embase, Springer Link, Web of Knowledge, OVID and Google Scholar) from their establishment to July 2015. Researches on operative and non-operative treatment for CPHFs were selected in this meta-analysis. The quality of all studies was assessed and effective data was pooled for this meta-analysis. Outcome measurements were functional status include constant scores (CS scores) and disabilities of the arm, shoulder and hand scores (DASH scores), total complication rates and healthy-related quality of life. The meta-analysis was performed with software revman 5.3. Nine articles with a total 518 patients (average age 70.93) met inclusion criteria. Patients were followed up for at least 1 year in all the studies. No statistical differences were found between operative and non-operative treatment in CS scores at 12 mo (months) [MD 1.06 95 % CI (-3.51, 5.62)] and 24 mo [MD -0.61 95 % CI (-5.87, 4.65)]. There are also no statistical differences between operative and non-operative treatment in DASH scores at 12 mo [MD -4.51 95 % CI (-13.49, 4.47)] and 24 mo [MD -7.43 95 % CI (-16.14, 1.27)]. Statistical differences were found between operative and non-operative treatment in total complication rates [RR 1.55, 95 % CI (1.24, 1.94)]. Statistical differences in EQ-5D at 24 mo [MD 0.15, 95 % CI (0.05, 0.24)] were found between operative and non-operative treatment but no statistical differences were found in ED-5D at 12 mo [MD 0.08, 95 % CI (-0.01, 0.17)], 15D at 12 mo [MD 0.02, 95 % CI (-0.68, 0.73)] and 15D at 24 mo [MD 0.02, 95 % CI (-0.07, 0.83)]. Operative treatments did not significantly improve the functional outcome and healthy-related quality of life in elderly patients. Instead, Operative treatment for CPHFs led to higher incidence of postoperative complications.


Dog-walking and sense of community in neighborhoods: implications for promoting regular physical activity in adults 50 years and older.
This study investigates whether dog-ownership and neighborhood characteristics are associated with sense of community (SC) and neighborhood-based recreational walking (NRW) for older adults. A random sample of adults ≥50 years of age (n=884) provided information on SC, dog-related factors, neighborhood walking, and socio-demographics in telephone and postal surveys. Associations between dog-ownership, neighborhood characteristics, and NRW were estimated using logistic regression (i.e., odds ratios (OR)). Frequent dog-walkers (≥4 times/wk) were more likely than those not owning a dog to report a heightened SC (OR=1.94, p<.05) and to achieve ≥150min/wk of NRW (OR=10.68, p<.05). SC was also tested but not found to mediate associations between neighborhood characteristics, dog-ownership and NRW. Older adults who walk dogs often in their neighborhoods may benefit from both increased physical activity and heightened sense of community to an extent that supports healthy aging. Longitudinal studies are needed to explore directions of associations among these factors.


E valuation of M aintained Physic A l Ca P acity 1-yr After Coronary Patient Cardiac Rehabilitation (EMAP) : A FRENCH MULTICENTER STUDY.
Data are scarce concerning the sustainable effects of cardiac rehabilitation (CR), on cardiorespiratory fitness (CRF) of patients with coronary artery disease (CAD). This study, carried out using data from a French multicenter study, aimed to clarify the evolution of the CRF of patients with CAD 1 yr after the end of a CR stay. Patients were included after an acute coronary syndrome (77%) and/or coronary revascularization, occurring <3 mo beforehand. All underwent a CR program with CRF evaluation by exercise testing (ET) on a cycle ergometer at the beginning of CR (ET1), at its end (ET2), and 1 yr later (ET3)-all ETs were performed with medication. Two hundred fifty-nine patients were included (age 60 ± 10 yr, 89% male) in 16 French CR centers. Left ventricular ejection fraction was 55.3 ± 9%. Revascularization was complete (82%). Maximal workloads were 110 ± 37 (ET1), 139 ± 43 (ET2), and 144 ± 46 W (ET3) ( P < .001). The estimated metabolic equivalents of the task (METs) were respectively 5.3 ± 1.4, 6.4 ± 1.6 ( P < .001), and 6.6 ± 1.7 ( P < .002). One year later, 163 patients (63%) improved or maintained their CRF (ET3 ≥ ET2), 73 (28%) decreased (ET1 < ET3 < ET2), and 23 (9%) lost the benefit of CR (ET3 ≤ ET1). Among completers who agreed to enroll in this study, most patients with CAD seem to maintain their CRF 1 yr after CR.


Mast cell amines and inosineinduced vasoconstriction in the rat hind limb.
Under certain circumstances injected inosine causes a net vasoconstrictive effect on the arterioles, which has been attributed to 5-hydroxytryptamine (5HT) released in response to adenosine type 3 (A(3)) receptor stimulation of mast cells residing in the adventitia. We have sought further evidence for this hypothesis using blood vessels of the rat hind limb perfused in vitro at constant rate with a gelatin-containing physiological salt solution. Injection of inosine (2.7 mg) caused a rise in perfusion pressure, which was only slightly increased by inclusion of N-nitro-L-arginine methyl ester (100 muM) in the perfusate. Inclusion in the perfusate of cyproheptadine (1 muM), compound 48 80 (1 mug ml), 8-phenyltheophylline (1 muM) or 8-cyclopentyl-1,3 dipropylxanthine (0.1 muM) greatly reduced the pressor response to inosine. The pressor effect of injected 5HT (400 mug) was abolished by pre-treatment with cyproheptadine, but not by pre-treatment with compound 48 80. These results suggest that the net pressor response to injected inosine was mainly the result of an A(1) receptor-mediated release of 5HT, most probably from mast cells. No evidence was found for an involvement of A(3) receptor stimulation.


[2 cases of psychogenic pruritus ani in the same family].
The authors present two cases of idiopathic pruritus ani in the same family in which psychological factors seem to play an etiological role.


Cetyltrimethyl ammonium mediated enhancement of the red emission of carbon dots and an advanced method for fluorometric determination of iron(III).
Red-emissive carbon dots (CDs) were synthesized by one-step hydrothermal technique using citric acid (CA), and urea in N,N-dimethylformamide (DMF) solution. The CDs has an average diameter of 2.3 nm, excitation/emission maxima at 553/606 nm, and a low photoluminescence quantum yield (4%). Fluorescence is weakly quenched by the ions Fe3+, Hg2+, Cu2+, Co2+, Zn2+, Ca2+, Ni2+, and Pb2+. After addition of cetyltrimethyl ammonium ion (CTAB), electrostatic interaction between negatively charged CDs and CTAB causes the CDs to self-aggregate. The formation of CD/CTAB increases the average particle diameter to around 13 nm and enhances the quantum yield to 24%. The hydrophobic segments of CTAB twined into a network structure can selectively trap Fe3+ and then interact with surface groups of the CDs to cause quenching. The CD/CTAB nanoprobe enables fluorometric determination of Fe3+ with a linear response in the 0.10-10 μM concentration range and a 0.03 μM limit of detection. The probe was utilized for determination of Fe3+ in human serum samples, and satisfactory results were obtained. Graphical abstractSchematic representation of fluorometric analysis of Fe(III) ion by cetyltrimethyl ammonium ion (CTAB) mediated red emission carbon dots (CDs). The hydrophobic segments of CTAB twined into a network structure can selectively trap Fe(III) and then interact with surface groups of the CDs to cause quenching.


Factors associated with time to clinical remission in pediatric luminal Crohn's disease: A retrospective cohort study.
Data on factors influencing time to remission in pediatric Crohn's disease (CD) are very limited in the literature. The aim of this retrospective cohort study was to describe the trends of time to clinical remission over the past decade and to identify factors associated with time to clinical remission in children with luminal CD. Patients under 18 years old diagnosed between 2009 and 2019 were included. All data were collected from the patients' medical records. Survival analyses and linear regression models were used to assess the impact of clinical, laboratory, endoscopic, histological, and therapeutic factors on time to clinical remission. A total of 654 patients were included in the study. There was no change in the time to clinical remission over the decade. Female sex in adolescents (adjusted bêta regression coefficient [aβ] = 31.8 days, P = 0.02), upper digestive tract involvement (aβ = 46.4 days, P = 0.04) perianal disease (aβ = 32.2 days, P = 0.04), presence of active inflammation on biopsies at diagnosis (aβ = 46.7 days, P = 0.01) and oral 5-aminosalicylates (5-ASA) exposure (aβ = 56.6 days, P = 0.002) were associated with longer time to clinical remission. Antibiotic exposure (aβ = -29.3 days, P = 0.04), increased eosinophils (aβ = -29.6 days, P = 0.008) and combination of exclusive enteral nutrition with tumor-necrosis-factor-alpha (TNF-alpha) inhibitors as induction therapy (aβ = -36.8 days, P = 0.04) were associated with shorter time to clinical remission. In children with newly diagnosed Crohn's disease, time to clinical remission did not shorten during the decade. It was associated with baseline clinical and histological data and treatment strategies. Combination of enteral nutrition and TNF-alpha inhibitors was associated with faster clinical remission.


Kinetic modeling of free fatty acid production in Escherichia coli based on continuous cultivation of a plasmid free strain.
The microbial production of free fatty acids (FFAs) and reduced derivatives is an attractive process for the renewable production of diesel fuels. Toward this goal, a plasmid-free strain of Escherichia coli was engineered to produce FFAs by integrating three copies of a thioesterase gene from Umbellularia californica (BTE) under the control of an inducible promoter onto the chromosome. In batch culture, the resulting strain produced identical titers to a previously reported strain that expressed the thioesterase from a plasmid. The growth rate, glucose consumption rate, and FFA production rate of this strain were studied in continuous cultivation under carbon limitation. The highest yield of FFA on glucose was observed at a dilution rate of 0.05 h(-1) with the highest specific productivity observed at a dilution rate of 0.2 h(-1). The observed yields under the lowest dilution rate were 15% higher than that observed in batch cultures. An increase in both productivity and yield (≈ 40%) was observed when the composition of the nutrients was altered to shift the culture toward non-carbon limitation. A deterministic model of the production strain has been proposed and indicates that maintenance requirements for this strain are significantly higher than wild-type E. coli.


Behavioral responses of substance-exposed newborns: a retrospective study.
This study assessed the behavior of infants whose mothers had a drug history by using the Neonatal Behavioral Assessment Scale. Data were collected via retrospective chart review (N = 103). Urine testing was only reported for 66 mothers during pregnancy and at birth. Infants performed within normally expected ranges for all items, except consolability and self-quieting. These findings support the use of NBAS in assessing newborn behavior because the information gained assists the parent in providing a supportive care giving environment that will not only help the infant recover but also enhance interaction between infant and parent.


Experimental hydrocephalus and hydrosyringomyelia in the cat. Radiological findings.
Fourty-six cats were made hydrocephalic and hydromyelic by means of an intracisternal kaolin injection. In 17 other cats hydrocephalus and syringohydromyelia were achieved by operative occlusion of the foramina Luschkae of the fourth ventricle. In both the kaolin treated animals and the animals whose outlets of the fourth ventricles were operatively obstructed a progressive dilatation of the ventricles and central canal occurred, which could be demonstrated and followed in 30 animals by ventriculography, myelography and/or contrast filling of the hydromyelic central canal. Coinciding with the dilatation of the central canal the clinical picture of a raised intracranial pressure due to obstructive hydrocephalus improved. The presented results suggest that the dilated central canal acts as a kind of natural by-pass between the ventricles and the spinal subarachnoid space. In order to determine the role of spinal kaolin arachnoiditis on spinal cyst formation and central canal dilatation in 13 animals, kaolin was locally applied in the lower thoracic region. The local spinal kaolin arachnoiditis had no influence on central canal dilatation or cyst formation.


Retroperitoneal Compartment Syndrome in Renal Transplantation: How to Salvage the Graft?
Early allograft dysfunction may be caused by several technical factors including vascular complications such as thrombosis, kinking, or extrinsic compression. Renal allograft compartment syndrome (RACS) is an unrecognized cause of early allograft dysfunction. This complication is characterized by increased pressure of the iliac fossa that reduces the blood supply to the graft with a potentially devastating consequence. The main objective when recognizing this condition is to create a tension-free muscle closure. Many approaches have been proposed involving mesh such as the mesh hood fascial closure technique.1-4 PATIENT AND METHODS: We describe in the video an RACS during an operation. The recipient is a 23-year-old young man with a body mass index of 22, with renal failure secondary to chronic reflux. Past history of failure to peritoneal dialysis currently on hemodialysis. He received a living donor's kidney. After performing a standard anastomosis, his urine output was brisk. The fascia was then closed with no force, at which point he stopped making urine. A RACS was suspected; intraoperative examination and ultrasound showed no flow in the graft, with no signs of kinking. Immediately, reexploration was performed, showing the graft with abnormal color and turgor. After relieving the pressure, the graft returned to normal. The closure was redone with a large ellipsoid piece of polypropylene mesh draped loosely and without tension over the graft. A Doppler ultrasound, after the skin closure was performed, showed good flow, and the postoperative course was unremarkable. There was minimal bulking in the right iliac area, making it cosmetically acceptable. RACS could be associated with a lack of compliance in the retroperitoneal cavity.5 The RACS required a prompt intervention. The timely suspicion is a watershed in the prognosis of this rare pathology. We propose that mesh hood fascial closure is easy, effective, and a safe method to treat these complications.


Application of laser scanning cytometry in vascular smooth muscle remodeling.
Pulmonary artery hyperplasia is the result of proliferation of the pulmonary arterial smooth muscles (PASM). Hypoxia-induced PASM proliferation in the fetus and the newborn is the primary cause of persistent pulmonary hypertension of the newborn (PPHN). This study was performed to characterize the utility of the Laser Scanning Cytometry (LSC) method in elucidating arterial cytoskeletal remodeling in an in vitro model of PPHN. The aim was to demonstrate the following: (a) LSC is a valid method for the analysis of nuclear and cytosolic fluorescence and (b) the cumulative effects of mechanical stretch together with hypoxia promote reactive oxygen species (ROS) formation. The molecular events in response to hypoxia and the mechanical overload of the pulmonary circuit were demonstrated in vitro by subjecting hypoxic cultured primary PASM or human airway smooth muscles (hASM) to repetitive stretch-relaxation cycles at rates comparable to dynamic stretch in vivo. The altered cytoskeleton in the form of filamentous to globular actin (F:G actin) ratio was imaged and quantified at the cellular level by LSC as an endpoint. LSC can remove the nuclear G-actin fluorescence from the total G-actin fluorescence. Pulsatile stretch was found to significantly increase the total endogenous ROS and superoxide anion release in normoxic and hypoxic conditions in primary PASM fibers. The effect of stretch was predominant in increasing superoxide anion release, only under hypoxic conditions. These findings, obtained by LSC in vitro are amenable to validation in any in vivo model of interest. The in vitro model is clinically relevant to human pulmonary vascular remodeling.


Usefulness of endoscopic ultrasonography with a microprobe in the diagnosis of aortoesophageal fistula.
Aortoesophageal fistula (AEF) is very rare and is associated with a high mortality rate. AEF manifests with massive gastrointestinal bleeding and is difficult to diagnose from endoscopic findings and clinical features. We encountered a patient with an AEF that was promptly diagnosed by endoscopic ultrasonography (EUS) using a microprobe. A 58-year-old man was admitted to our hospital because of hematemesis. Endoscopic examination revealed a submucosal tumor (SMT)-like lesion 2 cm in diameter 25 cm from the dental arch. EUS with a 20-MHz microprobe revealed a blood vessel-like structure with hypoechoic flowing contents and a high echoic area suggestive of a thrombus protruding into the esophageal lumen. AEF resulting from a ruptured thoracic aortic aneurysm was suggested from the EUS findings and was definitely diagnosed by computed tomography. Graft replacement of the descending aorta was successfully performed. The patient is now in good health 6 years after the first admission. This is the first report of a case of AEF diagnosed by EUS with a microprobe.


The NS5A-binding heat shock proteins HSC70 and HSP70 play distinct roles in the hepatitis C viral life cycle.
We previously identified HSP70 and HSC70 in complex with NS5A in a proteomic screen. Here, coimmunoprecipitation studies confirmed NS5A/HSC70 complex formation during infection, and immunofluorescence studies showed NS5A and HSC70 to colocalize. Unlike HSP70, HSC70 knockdown did not decrease viral protein levels. Rather, intracellular infectious virion assembly was significantly impaired by HSC70 knockdown. We also discovered that both HSC70 nucleotide binding and substrate binding domains directly bind NS5A whereas only the HSP70 nucleotide binding domain does. Knockdown of both HSC70 and HSP70 demonstrated an additive reduction in virus production. This data suggests that HSC70 and HSP70 play discrete roles in the viral life cycle. Investigation of these different functions may facilitate developing of novel strategies that target host proteins to treat HCV infection.


Effects of synthetic human gastrin-releasing peptide on pancreatic exocrine secretion and release of pancreatic polypeptide in conscious rats.
The effects of a newly synthesized peptide, human gastrin-releasing peptide (hGRP), on the pancreatic exocrine secretion and the release of pancreatic polypeptide (PP) were examined in the conscious rat. Plasma PP concentrations were determined by a recently established specific radioimmunoassay for rat PP. Amounts of 0.18, 0.35, and 3.5 nmol/kg/h hGRP significantly stimulated both pancreatic exocrine secretion and 0.35 nmol/kg/h of hGRP increased PP release. Simultaneously infused proglumide (300 mg/kg/h) did not affect either pancreatic exocrine secretion or PP release. However, simultaneous infusion of atropine (100 micrograms/kg/h) slightly inhibited PP release, but did not restrict the incremental response of pancreatic protein secretion to hGRP. These results suggest that hGRP directly stimulates pancreatic exocrine secretion and PP release.


Convenient Synthesis of a Library of Discrete Hydroxamic Acids Using the Hydroxythiophenol (Marshall) Resin.
Several resins have reportedly been used to synthesize hydroxamic acids except for the hydroxythiophenol (Marshall) resin. Herein we report the use of the Marshall resin to synthesize hydroxamic acids from carboxylic acids and its application to convert a library of fourteen discrete aliphatic and aromatic carboxylic acids including N-protected amino acids to their corresponding hydroxamic acids in good yields.


The ability of plant genotoxicity assays to predict carcinogenicity.
A number of assays have been developed which use higher plants for measuring mutagenic or cytogenetic effects of chemicals, as an indication of carcinogenicity. Plant assays require less extensive equipment, materials and personnel than most other genotoxicity tests, which is a potential advantage, particularly in less developed parts of the world. We have analyzed data on 9 plant genotoxicity assays evaluated by the Gene-Tox program of the U.S. Environmental Protection Agency, using methodologies we have recently developed to assess the capability of assays to predict carcinogenicity and carcinogenic potency. All 9 of the plant assays appear to have high sensitivity (few false negatives). Specificity (rate of true negatives) was more difficult to evaluate because of limited testing on non-carcinogens; however, available data indicate that only the Arabidopsis mutagenicity (ArM) test appears to have high specificity. Based upon their high sensitivity, plant genotoxicity tests are most appropriate for a risk-averse testing program, because although many false positives will be generated, the relatively few negative results will be quite reliable.


Induction of cellular processes containing collagenase and retinoid by integrin-binding to interstitial collagen in hepatic stellate cell culture.
Cultured hepatic stellate cells were induced to elongate long, multipolar cellular processes by interstitial collagen gel used as a substratum, as compared to flattened or round cell shapes on polystyrene surface or on Matrigel containing the basement membrane components, respectively. The process induction was inhibited by several reagents as follows: (1) anti-integrin alpha2 antibody; (2) an oligopeptide, DGEA, an integrin-binding sequence in type I collagen molecule; (3) wortmannin, a phosphatidylinositol 3-kinase inhibitor. Protein tyrosine phosphorylation was enhanced throughout cells including cellular processes by culturing on type I collagen gel. Dual fluorescence staining showed that the core of the processes contained microtubules, whereas the periphery of the processes comprised fibrillar actin. Thus, the process extension was found to depend on integrin-binding to type I collagen fibres, followed by signal transduction and cytoskeleton assembly. The cellular processes included interstitial collagenase and vitamin A-containing lipid droplets. The lipid droplets and vitamin A-autofluorescence were increased by retinyl acetate addition to the culture medium, suggesting an important role of processes in hepatic stellate cell function.


The msr/apj gene encoding the apelin receptor is an early and specific marker of the venous phenotype in the retinal vasculature.
Expression of the new G protein-coupled msr/apj receptor in the mouse embryo is restricted to the endothelial layer of the primary blood vessels and the newly forming heart (Mech. Dev. 84 (1999) 199). During development of the retinal vasculature, the msr/apj gene is not expressed throughout the vascular network, indicating a possible relationship between the localization of expression and the acquisition of arterial or venous identity (Mech. Dev. 110 (2002) 183). Here we first established that retinal expression of ephrin-B2 and its putative receptor EphB4 correlates with arterial and venous phenotype, respectively. Then we analyzed the expression pattern of msr/apj in the retinal vessels at various stages of postnatal development by in situ hybridization. In contrast to the expression of ephrin-B2 or EphB4, msr/apj transcripts can be detected as early as postnatal day P3. From P3 to P12, msr/apj expression in the vascular network is restricted to the venules and the associated capillaries. The msr/apj gene is thus an early and specific marker of the venous phenotype in the retinal vasculature.


Design, Synthesis and Characterization of Nickel-Functionalized Covalent Organic Framework NiCl@RIO-12 for Heterogeneous Suzuki-Miyaura Catalysis.
A series of nickel-decorated covalent organic frameworks, NiCl@RIO-12, were prepared using the post-synthetic modification strategy, that is, by reacting NiCl2 with pristine RIO-12 under alkaline conditions. Interestingly, they retained their crystallinity and the amount of nickel incorporated could be tuned from 3.6 to 25 wt % according to the reaction conditions. The incorporation of a higher amount of nickel in NiCl@RIO-12 consistently led to a lower Brunauer-Emmett-Teller surface area. Additionally, no agglomeration of nickel particles was found and a relatively homogeneous dispersion of nickel could be ascertained by SEM and TEM-EDS. The paramagnetic material exhibited promising catalytic activity in Suzuki-Miyaura cross-coupling under microwave heating. Thus, NiCl@RIO-12 notably demonstrated good thermal stability and its recyclability showed no substantial loss of activity after 3 cycles.


Efficacy of idelalisib as bridge to allogeneic stem cell transplant in relapsed follicular lymphoma: a case report.
A large number of new therapeutic agents have been studied for patients with relapsed/refractory follicular lymphoma (FL). Among new therapies, idelalisib, a novel PI3K inhibitor, shows promising results in the management of this disease. We describe the case of a 39-year-old patient with a diagnosis of grade 3a FL and a Follicular Lymphoma International Prognostic Index score of 2, who underwent several lines of therapy (including autologous stem cell transplant) with transient responses or no response at all. The patient was subsequently treated with 5 courses of idelalisib monotherapy, achieving a partial response. No relevant toxicities occurred. The patient underwent allogeneic stem cell transplant (allo-SCT) from an unrelated donor and obtained a complete response, which was confirmed after 3, 6, 9, and 12 months, and is still ongoing. As previously reported, the achievement of a good response is predictive for a better outcome after allo-SCT: idelalisib represents an effective treatment option for patients with relapsed/refractory FL, which can also be adopted as a bridge to allo-SCT.


Simultaneous use of multiplex ligation-dependent probe amplification assay and flow cytometric DNA ploidy analysis in patients with acute leukemia.
The aim of this work was to simultaneously use multiplex ligation-dependent probe amplification (MLPA) assay and flow cytometric DNA ploidy analysis (FPA) to detect aneuploidy in patients with newly diagnosed acute leukemia. MLPA assay and propidium iodide FPA were used to test samples from 53 consecutive patients with newly diagnosed acute leukemia referred to our laboratory for immunophenotyping. Results were compared by nonparametric statistics. The combined use of both methods significantly increased the rate of detection of aneuploidy as compared to that obtained by each method alone. The limitations of one method are somehow countervailed by the other and vice versa. MPLA and FPA yield different yet complementary information concerning aneuploidy in acute leukemia. The simultaneous use of both methods might be recommended in the clinical setting. © 2017 International Clinical Cytometry Society.


Rollover risk of cars and light trucks after accounting for driver and environmental factors.
Characteristics of the driver, roadway environment, and vehicle were associated with the likelihood of rollover occurrence in more than 14000 single-vehicle fatal and 78000 single-vehicle injury crashes during 1995-98. Rollovers were more likely in crashes involving young drivers or occurring on rural curves. After accounting for the effects of driver age and gender, roadway alignment and surface condition, and whether or not the crash occurred in a rural area, light trucks were still twice as likely as cars to experience rollovers. Some light truck models were much more likely than others to experience rollovers. However, while physical differences (e.g. center of gravity height) could explain some of this variability, other factors affecting vehicle stability may be evident only after dynamic testing.


Use of the rectus sternalis in augmentation mammoplasty: case report and literature search.
Breast augmentation is by far one of the most common aesthetic procedures currently performed by plastic surgeons. The plane of dissection for prosthesis placement is quite often partial submuscular. The rectus sternalis, an nomalous muscle, may interfere with the submuscular pocket dissection when an intraalveolar or submammary approach is used. The use of this muscle to cover the prosthesis in its most medial part is presented.


Prevalence of serum antibodies to hantavirus in a rural population from the Southern State of Santa Catarina, Brazil.
Rodent-borne hantaviruses cause severe human diseases. We completed a serological survey of hantavirus infection in rural inhabitants of Turvo County, in the southern State of Santa Catarina, Brazil, in which seropositivity for hantavirus was correlated to previous disease in the participants. The levels of IgG antibodies to hantavirus Araraquara in the sera of 257 individuals were determined using an immunoenzymatic assay. IgG antibodies to hantavirus were found in 2.3% of the participants. All seropositive participants reported previous disease with symptoms suggestive of hantavirus cardiopulmonary syndrome. Human infections causing unreported cardiopulmonary syndrome probably occur in the southern State of Santa Catarina.


Isoform-specific modulation of pressure-stimulated cancer cell proliferation and adhesion by α-actinin.
Intratumoral pressure may stimulate cancer proliferation whereas intravascular pressure promotes metastatic adhesion. α-Actinin proteins facilitate focal adhesion formation and link focal adhesion complexes to the cytoskeleton. We hypothesized that α-actinin is the mechanotransducer that mediates the effects of pressure on cancer cell proliferation and adhesion. We treated SW620 colon cancer cells with specific short interfering RNA to reduce α-actinin-1 and/or α-actinin-4, the 2 key epithelial isoforms. Proliferation was measured in adherent cells by microculture tetrazolium (MTT) assay after 24 hours at ambient or 40 mm Hg increased pressure. For comparison, we evaluated the effects of 30 minutes of ambient or 15-mm Hg increased pressure on adhesion of suspended SW620 cells. Because the transcription factor nuclear factor-κB (NF-κB) influences proliferation, we used co-immunoprecipitation to evaluate NF-κB-α-actinin association and a lentiviral reporter assay for NF-κB activity. A total of 40 mm Hg increased pressure increased SW620 proliferation 41% ± 6% (n = 10; P < .05) versus ambient pressure controls. Reducing α-actinin-1 and α-actinin-4 together or α-actinin-4 alone blocked this effect, but reducing α-actinin-1 alone did not (n = 6; P < .05). We observed a 72% ± 11% increase in NF-κB activity (n = 6; P < .05), and increased association between NF-κB and α-actinin-4 in adherent cells under pressure. NF-κB and α-actinin-1 did not co-immunoprecipitate. However, reducing α-actinin-4 did not prevent pressure-induced NF-κB activation (n = 8). α-actinin-4 may mediate pressure stimulation of proliferation within large rapidly growing tumors, perhaps by binding transcription factors such as NF-κB. α-actinins may be important targets to inhibit cancer proliferation and metastasis.


EEG evidence of stimulus-directed response dynamics in human somatosensory cortex.
Dense multichannel recordings of scalp electroencephalogram (EEG) were obtained in the vicinity of primary somatosensory cortex, time-locked to repetitive vibrotactile stimulation of sites on the right index finger of a single human subject. Frequency-domain analysis of cross-trial averages revealed prominent 'driving' responses in the EEG at the frequency of stimulation, which under specific stimulus conditions displayed pronounced changes in amplitude and topographic organization over brief (4 s) durations of stimulus exposure. The changes were systematic and physiologically coherent, evolving toward driving-response topographies observed in the same subject in conjunction with periodic microstimulation of single mechanoreceptive afferents whose receptive fields occupied corresponding positions on the digit. This dynamic process was orderly and reproducible, and could be controlled by manipulating factors such as the amplitude, frequency, and temporal spacing of the stimuli. The results are tentatively interpreted in light of a previously proposed neurophysiological model of stimulus-driven response plasticity in mammalian somatosensory cortex.


Magnetic resonance imaging of elbow injuries in children.
Evaluating elbow injuries is challenging because of the complex anatomy of the joint. In children, injury patterns depend on the sports-specific mechanism as well as the stage of skeletal maturity. This article reviews the anatomy of the elbow and common injury patterns seen in children, with an emphasis on MRI and the throwing athlete. Imaging pitfalls specific to children are described.


Pain in osseous metastases: results of radiotherapy.
Seventy-nine patients with osseous metastases were prospectively evaluated bone pain. The evaluation of pain has been accomplished using the Keele Scale system. All cases have been treated with radiotherapy. The therapeutic response for analgesic effect has been evaluated in complete response (CR) when total disappearance of pain was present; in partial response (PR) with the reduction of at least 1 point on the Keele Scale: in non-responsive (NR) when patients showed worsening or no change in pain symptomatology during or following therapy. 51.8% have presented complete response, 36.8% partial response and 11.3% no response. The global response (CR + PR) has been 88.6%. This response was evaluated in relation to fractionating daily dose of radiotherapy and minimum dose necessary for analgesia.


Surgical treatment of three and four-part proximal humeral fractures.
Three- and four-part fractures of the proximal humerus are usually treated surgically. Open reduction with internal fixation (ORIF) is the method of choice in younger patients. Anatomic reduction of the tuberosities is crucial to ensure that, in the event of poorly tolerated avascular necrosis of the humeral head, hemiarthroplasty can be performed under optimal conditions. Suboptimal outcomes may occur after ORIF, as less-than-perfect reduction and fixation is poorly tolerated at the shoulder. Preoperative computed tomography must be performed routinely to analyse fragment displacement and comminution, classify the fracture, assess humeral head vitality, and evaluate the mechanical properties of the underlying bone. Fracture reduction relies on principles that are shared by the various available techniques. Reduction of each fragment should be assessed separately. Reduction of the humeral head to the shaft should be performed before reduction of the tuberosities. The fixation technique should ensure stability of the anatomic reduction, with secure fixation of the tuberosities and a minimal risk of material migration into the joint. Here, we provide a detailed discussion of the various techniques, with their advantages and drawbacks, to help surgeons select the method that is most appropriate to each individual patient.


Common lupus anti-DNA antibody idiotypes in chronic liver diseases.
Chronic liver diseases may be associated with the appearance of antinuclear antibodies. To further analyze the relationship between connective tissue and liver diseases the sera of 88 patients with chronic liver disorders were examined for the presence of common lupus anti-DNA idiotypes (16/6-id, 134-id, and 32/15-id), using an enzyme-linked immunosorbent assay. The 16/6-id was found in 58 (65.9%), the 134-id in 43 (48.9%), and the 32/15-id in 13 (14.8%) of the patients' sera. Distinct diagnostic groups displayed different lupus anti-DNA idiotype profiles. Patients with primary biliary cirrhosis (PBC) and chronic active hepatitis (CAH) had mainly the 16/6 idiotype, while in alcoholic (AC) and in cryptogenic cirrhosis (CC) the 16/6-id and 134-id were the main idiotypes recorded. There was considerable correlation among the different anti-DNA idiotypes but not between any of these idiotypes and an unrelated common anti-HBsAg idiotype. The occurrence of the various idiotypes was not found to be correlated with increased serum immunoglobulin levels. It can be concluded that the similarities between chronic liver diseases and connective tissue diseases are extended also to the presence of specific common anti-DNA antibody idiotypes.


Relief from pain in Sudeck's posttraumatic syndrome by fasciotomy. A clinical, radiographic, and scintigraphic study.
Twenty-three consecutive patients aged 33-80 years with a presumed Sudeck's syndrome of one hand or one foot were seen. A fracture initiated the syndrome in three-quarters of them, and the median duration of suffering was 3.5 months in the hand and 7 months in the foot. Osteoporosis and marked 99mTc-labeled methylene diphosphonate uptake were seen in radiographs and scintigrams respectively. Thirteen of the patients were operatively treated; distal fasciotomy on the volar aspect of the forearm or the ventral aspect of the lower leg gave rapid relief from pain at rest in nine of ten patients thus affected. All the patients became symptom-free, except two who underwent closed treatment. At follow-up 2-8 years later radiographic and scintigraphic findings were usually normal.


Surface area of chorionic villi of placentas: an index of intrauterine growth restriction of fetuses.
Histomorphometric studies of placentas from idiopathic intrauterine growth restricted (IUGR) fetuses as well as normal-weight (control) fetuses were performed to determine surface area of chorionic villi (mostly terminal and few intermediate) using stereological technique. The results were compared to determine the difference in the values of surface area of chorionic villi, and to establish any relationship between placental histomorphometric changes and IUGR. Placentas from fifty (50) full-term, uncomplicated deliveries were collected; twenty eight (28) of them were associated with IUGR babies and twenty two (22) were from normal-weight babies. Placental weights and volumes were measured. Pieces of placental tissues were formalin-fixed, processed and embedded in paraffin. Seven-micron sections were cut and stained with HE stain. Histomorphometric and stereological studies were performed. IUGR placental weights and volumes were lower than those of controls. Surface areas of villi of IUGR placentas had a mean of 8.19 m(2) (SD +/- 2.88). For control placentas, the mean was 10.02 m(2) (SD +/- 1.83). The mean value of the surface area of villi of the IUGR group was significantly lower than that of the control group. These findings pointed to a defect in the normal interaction between trophoblast and maternal tissue, leading to a reduced surface area of villi. Because the surface area of the villi presents the interface between maternal and fetal circulation, its reduction might be the cause of idiopathic intrauterine growth restriction.


Derivation and culture of canine embryonic stem cells.
The derivation of canine embryonic stem cells (cESCs) represents a significant achievement and opens the door to further stem cell research and therapies in the dog. Canines share a common environment with humans and exhibit a host of genetic diseases, many of which have human parallels. Thus, the canine model presents unique advantages over other currently used organisms to help develop stem cell therapies in humans. To reveal the therapeutic potential of cESCs further basic research on the molecular mechanisms controlling their pluripotency and self-renewal characteristics is needed. Herein, we present the methods for derivation and culture of cESCs. Following collection of the canine blastocyst, two derivation methods are presented; immunodissection and whole blastocyst explant. These two methods lead to cESCs differing in morphology and subculture techniques. Additional protocols for subculture of established lines, feeder-free culture, and cryopreservation protocols are also described.


Simultaneous determination of pirprofen and its metabolite, the pyrrole derivative, in plasma by high-performance liquid chromatography.
A method for the simultaneous determination of pirprofen and its metabolite, the pyrrole derivative, in human plasma is described. The two compounds and the butyric acid analogue of the pyrrole derivative used as internal standard are extracted from plasma with chloroform, then back-extracted into an alkaline buffer. After addition of acid, the aqueous phase is assayed by high-performance liquid chromatography using a fixed-wavelength ultraviolet detector at 254 nm. The limit of quantitation is 0.1 micrograms/ml (0.396 mumol/l for pirprofen and 0.400 mumol/l for the pyrrole derivative).


Changes in microchip position after implantation of a subretinal vision prosthesis in humans.
Retinal prosthetic devices have been developed to partially restore very low vision in legally blind patients with end-stage hereditary retinal dystrophies. Subretinal implants, unlike epiretinal implants, are not fixated by a tack. The aim of this study was to assess and analyse possible changes over time in the subretinal position of the RETINA IMPLANT Alpha IMS and Alpha AMS (ClinicalTrials.gov NCT01024803). Imaging studies were performed on fundus photographs using GIMP (Version 2.8.14). Postoperative photographs of the implanted eye were scaled and aligned. Landmarks were chosen and distances between landmarks were measured to then calculate the displacement of the microchip using a transformation matrix for rotational and translational movements. Analyses were performed using MATLAB 8.6 (The MathWorks Inc., Natick, MA). Of the 27 datasets with the Alpha IMS device, 12 (44%) remained stable without displacement of the microchip relative to the optic disc and the major blood vessels, whereas in 15 (56%), displacement occurred. The mean ± SD displacement in those 15 eyes was 0.66 ± 0.35 mm (range, 0.24-1.67 mm). Of the eight datasets with the Alpha AMS device, 1 (13%) remained stable without displacement of the microchip relative to the optic disc and the major blood vessels, whereas in 7 (87%), displacement occurred. The mean ± SD displacement in those seven eyes was 0.66 ± 0.26 mm (range, 0.32-0.97 mm). Calculated from all eyes (including those in which no displacement occurred), the mean displacement was 0.36 mm in the IMS cohort, and 0.58 mm in the AMS cohort, however, the difference was not statistically significant (p = 0.17). We have shown that the position of the subretinal implant changes in the majority of the cases after implantation. While the overall mean displacement of the chip was not significantly different in either of the cohorts, the maximum displacement was smaller in the Alpha AMS cohort.


Biomodification to dentin by a natural crosslinker improved the resin-dentin bonds.
Transient collagen cross-linking treatment by proanthocyanidins (PA), a natural crosslinker, was proved to increase the cross-linking degree and ultimate tensile strength of demineralised dentin. The present study aimed to investigate whether transient pretreatment by PA-based preconditioner can improve the resin-dentin bonds of various etch and rinse adhesives. The influence of solvent type, PA concentration and treatment duration were examined. PA-based preconditioners were prepared by adding powdered grape seed extract, rich in PA, to various solvents at different concentrations. They were used on demineralised dentin before the application of the bonding agent. Bond strength, failure modes and degree of conversion were evaluated via microtensile testing, field emission scanning electron microscopy and Fourier transform infrared spectroscopy, respectively. Collagen cross-linking treatment by PA-based preconditioners presented a concentration- and time-dependent increase in dentin bond strength even in reduced, clinically applicable treatment duration. PA preconditioning improved bond strength of the tested water/ethanol-based adhesive better than the water/acetone-based system. Mixed fracture was the most prevalent failure mode happened on the top of the hybrid layer in PA-pretreated specimens, whilst at the bottom in non-treated controls. The degree of conversion was not significantly affected by PA pretreatment. Transient PA preconditioning improved resin-dentin bonds without compromise on the curing behaviours of the tested adhesives.


An Open Label, Phase 1, Randomized, Seven-treatment, Seven-period, Crossover Study to Assess the Relative Bioavailability, pH Effect, Food Effect, and Dose Proportionality of CC-292, a Potent and Orally Available Bruton's Tyrosine Kinase Inhibitor.
CC-292 is a potent, selective, orally administered small molecule inhibitor of Bruton's tyrosine kinase (BTK). To support the clinical investigation of CC-292, a randomized, seven-treatment, seven-period, crossover study was conducted to assess the relative bioavailability, pH effect, food effect, and dose-proportionality of two formulated tablets of CC-292. Healthy subjects (n = 24) were enrolled in the study and randomly assigned into different treatment sequences. Blood samples were collected at pre-specified time points to measure the drug concentrations in plasma. Statistical analyses were performed to compare the pharmacokinetics of CC-292 under different conditions. The relative bioavailability of the newly developed formulation [spray-dried dispersion (SDD)] to the reference formulation (P22) was 1.24. When a single dose of CC-292 SDD tablet was administered under fed conditions, the area under the plasma concentration-time curve from time zero to infinity (AUC∞) increased by 10.9% and the maximum plasma drug concentration Cmax) decreased by 19.4% compared to when CC-292 was administered under fasted conditions. When a single dose of CC-292 SDD tablet was administered after multiple doses of omeprazole, the area under the plasma concentration-time curve from time zero to infinity (AUC∞) decreased by 36.8% and the maximum plasma drug concentration Cmax) decreased by 48.1% compared to when CC-292 was administered alone. Over a dose range of 100-300 mg (SDD formulation), CC-292 exhibited more than dose-proportional increases of drug exposures. CC-292 was well tolerated when administered to healthy subjects as single oral doses under all conditions. Food intake had no clinically relevant impact on CC-292 pharmacokinetics compared to fasted conditions. Therefore, CC-292 can be administered with or without food. Co-administration of CC-292 with multiple doses of omeprazole (40 mg) decreased the pharmacokinetic exposure of CC-292. However, the effect was not clinically relevant. NCT02433457.


Structure identification of natural rhamnolipid mixtures by fast atom bombardment tandem mass spectrometry.
Two rhamnobiose-lipid preparations have been studied by fast atom bombardment (FAB) tandem mass spectrometry. The principal rhamnobiose-lipids contain the beta-hydroxydecanoyl-beta-hydroxydecanoate Rha-Rha-C10-C10 and the beta-hydroxytetradecanoyl-beta-hydroxytetradecanoate Rha-Rha-C14-C14. Both preparations contain minor components which are heterogenous in beta-hydroxy fatty acid composition. FAB ionization of rhamnobiose-lipids in the presence of Na+ shows the formation of both [M + Na]+, [M +2Na-H]+, [M + 3Na-2H]+ and [M - H]- ions. Tandem mass spectrometry of the [M + 2Na-H]+ and [M - H]- ions give information about the sequence of the building blocks. Particularly, heterogeneity in beta-hydroxy fatty acid composition is determined for the principal components and all the minor components present in the preparations.


Fenestrated endovascular repair for pararenal abdominal aortic aneurysms: a systematic review and meta-analysis.
The development of endovascular technology has led to the introduction of fenestrated endovascular repair (f-EVAR) to treat pararenal abdominal aortic aneurysms (PRAAAs) that have been deemed unsuitable for standard endovascular repair. We performed a systematic review and meta-analysis of data from the literature to determine the outcomes of the fenestrated technology. The MEDLINE, EMBASE, and Cochrane databases were searched to identify all studies published in English between January 1996 and May 2011 that reported on f-EVAR for PRAAAs. Separate meta-analyses were performed for primary outcomes (i.e., 30-day mortality, technical success rate, primary target vessel patency rate, and 12-month patency rate) and secondary outcomes (i.e., reintervention rate, target renal artery occlusion rate, and postoperative permanent dialysis rate). Subgroup analyses were performed to determine whether there were differences in outcomes between varying types of studies (prospective or retrospective). Regression analyses were performed to explore associations between outcomes and varying factors (i.e., mid-date of study, study size, and procedure time). Twelve studies conducted between 2006 and 2011 and consisting of a total of 776 cases of f-EVAR were enrolled. The pooled estimate for 30-day mortality was 2.52% (95% confidence interval [CI]: 1.55-4.08). Technical success was measured to be 92.8% (95% CI: 87.5-96.0). Primary target vessel patency was 98.3% (95% CI: 97.4-98.8). Twelve-month target vessel patency was 94.5% (95% CI: 92.1-96.2). The postoperative reintervention rate was 17.6% (95% CI: 12.0-25.1). The target renal artery occlusion rate was 6.1% (95% CI: 4.1-8.8). The postoperative permanent dialysis rate was 2.6% (95% CI: 1.5-4.4). Subgroup analyses found no significant differences between the major outcomes of the retrospective studies and the prospective studies. Regression analyses suggested that large series had higher 12-month target vessel patency rates than small series. This study revealed that f-EVAR treatment for PRAAAs has acceptable early and mid-term outcomes.


Plasma antioxidants and human aging: a study on healthy elderly Tunisian population.
The aging has been described by several theories. It was proposed that free radicals are the major factor involved in this process. This gave birth to the free radical theory of aging. This current theory provides the most popular explanation for how aging occurs at the biochemical/molecular level. Ever since 1956, this theory has received widespread attention and a large body of evidence has been accumulated in support of its hypotheses which were subsequently refined. The free radical theory of aging postulates that age-associated reductions in physiological functions are caused by an irreversible accumulation of oxidative alterations to macromolecules. This accumulation increases with age and is associated with the life expectancy of organisms. Moreover, this theory suggests the existence of an imbalance between reactive oxygen species (ROS)-producing pathways and (ROS)-scavenging pathways, which is responsible for the generation of oxidative stress syndrome. In this article, we evaluate the antioxidant status in a population of healthy elderly Tunisians in comparison with a group of healthy young Tunisian subjects. This study sets out to investigate the age-related changes in glutathione peroxidase (GPx), superoxide dismutase (SOD) activities, and in total antioxidant status (TAS) of human plasma. We have concluded that healthy aging is accompanied with a disturbed antioxidant status.


Prevalence of dental caries in school children of the province of Granada (Spain).
A sample of 3,347 students between 5 and 14 years of age was selected from the entire student population in the province of Granada (Spain) to study the prevalence of dental caries and several risk factors for the disease. Decay was ascertained in the study population by means of the following indices: df, DMF, and DMFS. Risk factors considered were the level of oral hygiene, number of between-meal sugar-containing food, and flouride concentration in drinking water. The indices mentioned showed a clear relationship to the age of the participants in the study. The level of oral hygiene did not show a clear association with dental caries measured through the df and DMF indices. Curiously, a higher correlation was noted between the disease in deciduous teeth and fluoride concentration than between the disease in permanent teeth and the latter factor.


Effects of water restriction on social behavior and 5-HT neurons density in the dorsal and median raphe nuclei in mice.
We explored here the hypothesis that temporary chronic water restriction in mice affects social behavior, via its action on the density of 5-HT neurons in dorsal and median raphe nuclei (DRN and MRN). For that, we submitted adult C57BL/6 J mice to mild and controlled temporary dehydration, i.e., 6 h of water access every 48 h for 15 days. We investigated their social behavior in a social interaction task known to allow free and reciprocal social contact. Results showed that temporary dehydration increases significantly time spent in social contact and social dominance. It also expands 5-HT neuron density within both DRN and MRN and the behavioral and neuronal plasticity were positively correlated. Our findings suggest that disturbance in 5-HT neurotransmission caused by temporary dehydration stress unbalances choice processes of animals in social context.


Lifestyle Medicine and the Management of Cardiovascular Disease.
Evidence has clearly demonstrated the importance of lifestyle factors (e.g., diet, physical activity, smoking) in the development of cardiovascular disease (CVD). Interventions targeting these behaviors may improve outcomes for CVD patients. The aim of this review is to summarize the effects of lifestyle interventions in individuals with established CVD. Most recent trials focused on diet, physical activity, stress reduction, or a combination of these. Findings were mixed, but most interventions improved at least some markers of cardiovascular risk. Few studies measured long-term clinical outcomes, but some suggested a possible benefit of stress reduction and multifaceted interventions on cardiovascular events. The benefits of lifestyle change for CVD patients have been established by decades of evidence. However, further research is needed to determine the optimal intensity, duration, and mode of delivery for interventions. Additional studies with long-term follow-up and measurement of clinical outcomes are also needed.


15-year Borrelia prevalence and species distribution monitoring in Ixodes ricinus/inopinatus populations in the city of Hanover, Germany.
Lyme borreliosis, caused by Borrelia burgdorferi sensu lato (s.l.) spirochaetes, is the most common tick-borne disease (TBD) in the Northern Hemisphere. Rising incidences indicate that its epidemiology may be affected by global changes. Therefore, the current study aimed to assess changes in tick infection rates with Borrelia spp. over a 15-year monitoring period in the city of Hanover, Germany, as a follow-up to previous prevalence studies (years 2005, 2010 and 2015). To assess the epidemiological risk, ticks of the Ixodes ricinus/inopinatus-complex were sampled from April to October 2020 by the flagging method at 10 frequently visited recreation areas in Hanover. Analysis by quantitative real-time PCR of 2100 individual ticks revealed an overall Borrelia prevalence of 25.5% (535/2100). Regarding different tick developmental stages, nymphs showed a significantly lower Borrelia prevalence (18.4% [193/1050]) than adult ticks (32.6% [342/1050]). Comparison with previous years revealed a stable total Borrelia prevalence along with consistent infection rates in the different developmental stages over the 15-year monitoring period. Borrelia species differentiation by Reverse Line Blot was successful in 67.3% of positive ticks collected in 2020, with B. afzelii being the dominating species (59.2% of the differentiated infections), besides B. burgdorferi sensu stricto (s.s.), B. garinii, B. valaisiana, B. spielmanii, B. bavariensis and B. bissettiae and the relapsing fever spirochaete B. miyamotoi. Additionally, the proportion of infections attributed to B. afzelii showed a significant increase in 2020 compared to 2005 and 2015 (59.2% vs. 37.6% and 32.0% of successfully differentiated infections, respectively). Coinfections with Anaplasma phagocytophilum and Rickettsia spp. stayed stable comparing 2020 with previous years. Therefore, although changes in the Borrelia prevalence in questing ticks were not observed throughout the 15-year monitoring period, shifts in Borrelia species distribution may alter the epidemiological risk.


Imatinib trough plasma levels do not correlate with the response to therapy in patients with chronic myeloid leukemia in routine clinical setting.
Association of trough imatinib plasma levels (IPL) with cytogenetic or molecular response to treatment in patients with chronic myeloid leukemia (CML) was repeatedly reported. We analyzed their value in the routine clinical setting in 131 patients with chronic phase CML in whom imatinib was applied as first- or second-line treatment. A total of 1,118 measurements were obtained by ultra-performance liquid chromatography-tandem mass spectrometry assay in patients treated with daily dose of imatinib ranging from 100 to 800 mg. Samples were obtained from 1 to 96 h after drug ingestion. High inter (36%) and intraindividual variability (9-33%) of IPL was observed. For analysis of correlation of IPL with treatment response, two sets of samples were selected according to the European LeukemiaNet (ELN) criteria. The first set consisted of 241 samples taken 24 ± 2 h after dosing in 54 patients, and the second one consisted of 329 samples taken 24 ± 4 h after imatinib ingestion in 84 patients. In both sets, only patients treated with 400 mg imatinib once daily for at least 18 months were included. From multiple measurements in individual patients, mean IPL were used. In both sets, we were not able to demonstrate a statistically significant correlation between IPL and response to treatment according to the ELN. We believe that this was due to the differences in patients' compliance, leukemia biology, and other variables that are difficult to eliminate in the routine clinical practice. The use of IPL for prognostic estimation in CML treatment outside the clinical trials is probably limited.


Assessment of fetal cardiac functions in pregnant women with asthma.
This study aims to investigate the effects of maternal asthma on fetal cardiac functions. The study was planned with 30 pregnant women who presented to a tertiary health center and were diagnosed with asthma and 60 healthy controls with similar gestational ages. The fetal echocardiographic assessment was assessed between 33 and 35 weeks of gestation with pulsed-wave Doppler (PW), M-mode, and tissue Doppler imaging (TDI). Fetal cardiac functions were compared between maternal asthma and the control group. Cardiac functions were assessed according to the duration of maternal asthma diagnosis, as well. Early diastolic function parameters, tricuspid E wave (p = .001), and tricuspid E/A ratio (p = .005) were significantly lower in the group with maternal asthma. Tricuspid annular plane systolic excursion (TAPSE) and measurements of mitral annular plane systolic excursion (MAPSE) values were statistically lower in the study group than in the control group; p = .010 and p = .012, respectively. Parameters assessed with TDI (E', A', S', E/E', and MPI' of tricuspid valves) and global cardiac function parameters assessed with PW like myocardial performance index (MPI) and left cardiac output (LCO) were similar between groups (p > .05). Although, MPI did not change between groups, and the isovolumetric relaxation time (IVRT) value was prolonged in maternal asthma cases (p = .025). We found that maternal asthma disease causes alteration in fetal diastolic and early systolic cardiac functions, but the global fetal cardiac function does not change. Diastolic heart function values also varied with the duration of maternal asthma. Prospective studies are needed to compare fetal cardiac functions with additional patient groups according to disease severity and type of medical treatment.