Do all components of the chronic care model contribute equally to quality improvement?
The Chronic Care Model (CCM) is a widely used conceptual model for improving chronic illness care, but there is limited evidence to support the validity of this model. Seventeen clinics in a single medical group used the CCM in a diabetes improvement initiative, and the study tested which CCM components at the clinic level were associated with improved glycohemoglobin (A1C) and low-density (LDL) outcomes for patients with diabetes. Three leaders from each of 17 clinics completed a survey in 2002 that assessed the presence of CCM components in their clinics. Clinic scores from this survey were correlated with change in clinic-level measures of the quality of care for their diabetes patients (A1C and LDL outcomes) during the preceding year. Delivery system design (DSD) scores were positively correlated with improvements in A1C and lipid test rates and levels at these clinics (r = 0.49-0.57, p < .05). Self-management support and clinical information systems demonstrated associations that may have substantive significance but did not reach p < 05. These data suggest that delivery system design is associated with improved A1C and LDL outcomes for people with diabetes. Additional studies are necessary to determine the association of other CCM components with improved outcomes.


Gastroenterostoma after Billroth antrectomy as a premalignant condition.
Gastric stump carcinoma (GSC) following remote gastric surgery is widely recognized as a separate entity within the group of various types of gastric cancer. Gastrectomy is a well established risk factor for the development of GSC at a long time after the initial surgery. Both exo- as well as endogenous factors appear to be involved in the etiopathogenesis of GSC, such as achlorhydria, hypergastrinemia and biliary reflux, Epstein-Barr virus and Helicobacter pylori infection, atrophic gastritis, and also some polymorphisms in interleukin-1β and maybe cyclo-oxygenase-2. This review summarizes the literature of GSC, with special reference to reliable early diagnostics. In particular, dysplasia can be considered as a dependable morphological marker. Therefore, close endoscopic surveillance with multiple biopsies of the gastroenterostomy is recommended. Screening starting at 15 years after the initial ulcer surgery can detect tumors at a curable stage. This approach can be of special interest in Eastern European countries, where surgery for benign gastroduodenal ulcers has remained a practice for a much longer time than in Western Europe, and therefore GSC is found with higher frequency.


Deep infiltrative low-grade MALT (mucosal-associated lymphoid tissue) colonic lymphomas that regressed as a result of antibiotic administration: endoscopic ultrasound evaluation.
Since 1997 we have experienced three cases of low-grade colonic mucosal-associated lymphoid tissue (MALT) lymphomas. The depth of tumor invasion was evaluated by endoscopic ultrasonography (EUS) and the mass lesions were all diagnosed as having extended beyond the deep region of the submucosal layer. Although all of these patients tested negative for gastric Helicobacter pylori, their tumor lesions regressed after antibiotic treatment in accordance with H. pylori eradication therapy. In general, consensus has been reached regarding antibiotic therapy for gastric MALT lymphomas. However, as a prerequisite for antibiotic therapy, the therapy has been deemed effective against these gastric tumors if the extent of infiltration, as evaluated by EUS, is limited to the mucosal layer or the superficial region of the submucosal layer. Based on the therapeutic outcomes seen in the three patients studied here, it is suggested that antibiotic therapy might be useful in treating MALT lymphomas of the colon, even in patients with advanced invasive tumors, in contrast to the extent of the lesions in the stomach suitable for antibiotic treatment. The success of the antibiotic treatment also suggests that MALT lymphomas may be caused by unknown luminal microorganisms, other than H. pylori.


Single-Port Retzius-Sparing Robot-Assisted Radical Prostatectomy: Feasibility and Early Outcomes.
Background: To determine safety and feasibility of single-port Retzius-sparing robot-assisted radical prostatectomy (SP-rsRARP) using the da Vinci® SP (Intuitive Surgical, Sunnyvale, CA) robotic platform in men with adenocarcinoma of the prostate. Patients and Methods: Twenty-eight consecutive men with prostate cancer underwent SP-rsRARP by one of two surgeons (J.B., S.C.). Data for perioperative, pathologic, and functional outcomes were collected prospectively and retrospectively analyzed. Results: Mean (standard deviation) follow-up was 6 (3) months. Mean age was 65.3 years old with an average body mass index of 25.2 kg/m2. Mean preoperative prostate-specific antigen (PSA) was 10.2 ng/mL. Average prostate weight was 42 g. Three patients (11%) had prior radiation to the prostate. There were no intraoperative complications or conversions of technique. Lymphadenectomy was performed in 24 (86%) patients and nerve sparing in 14 (46%) patients. Mean operative time (skin to skin) was 234 minutes with an average estimated blood loss of 148 mL. Length of hospital stay averaged 23 hours. Seventeen (61%) of the patients did not require opioids for postoperative pain. Two Clavien Grade IIIa complications occurred (lymphocele aspiration and dilation of bladder neck contracture). Pathologic grade group was group 1 (0%), group 2 (57%), group 3 (29%), and group 4-5 (14%). Pathologic stage was T2 (15/28, 54%) and T3a,b (13/28, 46%). Five patients (18%) had a positive surgical margin, four (80%) of whom had T3 disease. One patient (4%) had a detectable PSA during follow-up and opted for adjuvant radiation. Twenty-three patients (82%) were continent at foley removal. Postoperative mean sexual health inventory for men score in those who underwent nerve sparing was 18 at 3 months follow-up. Conclusions: SP-rsRARP appears safe and feasible. Early continence rates are promising. Full characterization of outcomes requires longer follow-up and larger cohort validation.


How to Correct for Computer Experience in Online Cognitive Testing?
Objective: Since computerized cognitive test performance may be influenced by computer experience, correction for this measure might be needed. This study examined how to correct for computer experience by examining its influence on online and traditional tests. Method: 248 healthy adults completed an online neuropsychological test battery and 70 adults completed traditional equivalents of the tests. Computer experience was assessed by a performance-based and a self-report measure. Regression analyses were applied to examine their influence on the online and traditional tests. Results: After correction for demographics, the performance-based measure was associated with online and traditional, predominantly speed-based, tests. The self-report measure was also associated with speed-based online tests but not with most traditional tests. Conclusions: Correcting computerized neuropsychological tests using a performance-based measure of computer experience would be unwise, because this measure also seems to tap into cognitive functions. A correction using a self-report measure might be better and is appropriate.


Influence of Job Burnout on Decision-Making and Coping With Stress Among Nurses.
Job burnout is highly prevalent among health care workers. This study determined the effect of job burnout on decision-making and coping with stress among nurses. Two hundred seventy-seven nurses in Xijing Hospital were investigated using the Job Burnout Scale, Decision Scale, and Simple Stress Coping Style Scale. The total score of job burnout was 107.8 ± 16.479 (severe burnout) and clinical decision-making consciousness was 123.75 ± 16.094 (moderate decision-making consciousness). No statistical differences existed in different gender samples (P > .05). Burnout and clinical decision-making awareness of clinical nurses were stronger than nursing interns and regular trainee nurses, but the occupational pressure of nursing interns was the highest (P < .05). Marital status also showed significant differences in job burnout; unmarried nurses were more prone to burnout (P < .05). In conclusions, burnout is a serious issue among nurses, which is closely related with clinical decision-making awareness, negative coping, and occupational stress. Nurse identity and marital status had significant effects on burnout.


Visible light induced photocatalytic inactivation of bacteria by modified titanium dioxide films on organic polymers.
Commercially available polypropylene foil was pretreated with a low temperature oxygen plasma and covered with a thin film of nanocrystalline titanium dioxide by dip coating. The films were then photosensitized by titanium(IV) surface charge transfer complexes formed by impregnation with catechol. The photoactivity of the coatings up to 460 nm was confirmed by photoelectrochemical measurements. The photoinactivation of Escherichia coli and Staphylococcus aureus was evaluated by a glass adhesion test based on ISO 27447:2009(E) in the presence of visible light. The coating showed good antimicrobial activity induced by light from a light-emitting diode (405 nm), in particular towards E. coli ATCC 25922 strain. Adaptation of ISO 27447:2009(E) to assess bacterial photoinactivation by photocatalytic coatings will allow this procedure to be applied for the comparison of photoactivity under a range of irradiation conditions.


Widespread occurrence of dosage compensation in Candida albicans.
The important human pathogen Candida albicans possesses an unusual form of gene regulation, in which the copy number of an entire specific chromosome or a large portion of a specific chromosome changes in response to a specific adverse environment, thus, insuring survival. In the absence of the adverse environment, the altered portion of the genome can be restored to its normal condition. One major question is how C. albicans copes with gene imbalance arising by transitory aneuploid states. Here, we compared transcriptomes from cells with either two copies or one copy of chromosome 5 (Ch5) in, respectively, a diploid strain 3153A and its representative derivative Sor55. Statistical analyses revealed that at least 40% of transcripts from the monosomic Ch5 are fully compensated to a disomic level, thus, indicating the existence of a genome-wide mechanism maintaining cellular homeostasis. Only approximately 15% of transcripts were diminished twofold in accordance with what would be expected for Ch5 monosomy. Another minor portion of approximately 6% of transcripts, unexpectedly, increased up to twofold and higher than the disomic level, demonstrating indirect control by monosomy. Array comparative genome hybridization revealed that only few out of approximately 500 genes on the monosomic Ch5b were duplicated, thus, not causing a global up regulation. Dosage compensation was confirmed with several representative genes from another monosomic Ch5a in the mutant Sor60. We suggest that C. albicans's unusual regulation of gene expression by the loss and gain of entire chromosomes is coupled with widespread compensation of gene dosage at the transcriptional level.


Involvement of multiple influx and efflux transporters in the accumulation of cationic fluorescent dyes by Escherichia coli.
It is widely believed that most xenobiotics cross biomembranes by diffusing through the phospholipid bilayer, and that the use of protein transporters is an occasional adjunct. According to an alternative view, phospholipid bilayer transport is negligible, and several different transporters may be involved in the uptake of an individual molecular type. We recognise here that the availability of gene knockout collections allows one to assess the contributions of all potential transporters, and flow cytometry based on fluorescence provides a convenient high-throughput assay for xenobiotic uptake in individual cells. We used high-throughput flow cytometry to assess the ability of individual gene knockout strains of E coli to take up two membrane-permeable, cationic fluorescent dyes, namely the carbocyanine diS-C3(5) and the DNA dye SYBR Green. Individual strains showed a large range of distributions of uptake. The range of modal steady-state uptakes for the carbocyanine between the different strains was 36-fold. Knockouts of the ATP synthase α- and β-subunits greatly inhibited uptake, implying that most uptake was ATP-driven rather than being driven by a membrane potential. Dozens of transporters changed the steady-state uptake of the dye by more than 50% with respect to that of the wild type, in either direction (increased or decreased); knockouts of known influx and efflux transporters behaved as expected, giving credence to the general strategy. Many of the knockouts with the most reduced uptake were transporter genes of unknown function ('y-genes'). Similarly, several overexpression variants in the 'ASKA' collection had the anticipated, opposite effects. Similar results were obtained with SYBR Green (the range being approximately 69-fold). Although it too contains a benzothiazole motif there was negligible correlation between its uptake and that of the carbocyanine when compared across the various strains (although the membrane potential is presumably the same in each case). Overall, we conclude that the uptake of these dyes may be catalysed by a great many transporters of putatively broad and presently unknown specificity, and that the very large range between the 'lowest' and the 'highest' levels of uptake, even in knockouts of just single genes, implies strongly that phospholipid bilayer transport is indeed negligible. This work also casts serious doubt upon the use of such dyes as quantitative stains for representing either bioenergetic parameters or the amount of cellular DNA in unfixed cells (in vivo). By contrast, it opens up their potential use as transporter assay substrates in high-throughput screening.


Effects of roadwork characteristics and drivers' individual differences on speed preferences in a rural work zone.
Work zone safety from a psychological perspective has received little attention in scientific literature. Therefore, the present study aims to explore the influence of roadwork characteristics and drivers' individual differences in terms of personality traits and self-assessment of driving skills on speed preferences in a rural work zone. Eight hundred forty-five Norwegian drivers stated their preferred speed for ten pictures of a rural work zone with a 50 km/h reduced speed limit without knowing the speed limit. The results showed that the preferred speeds were greater than the actual reduced speed limit for all pictures. The standard deviations were quite high (from 11 to 14 km/h), indicating that drivers have a rather high variation in preferred speeds. A multilevel model was used to analyse the effects of the variables on speed preference. The results indicated that preferred speeds increased with age, higher scores on the normlessness scale, and higher self-assessment of own driving skills. As for the roadwork characteristics, speed increased with the presence of road markings by 11 km/h, while it decreased by 9 km/h with the presence of road delineators and by 5 km/h with barriers. Implications for respect for the reduced speed limits in work zones were discussed, and recommendations of other countermeasures were presented.


Translocation of Escherichia coli from the gastrointestinal tract to the mesenteric lymph nodes in gnotobiotic mice receiving Escherichia coli vaccines before colonization.
Germfree mice were immunized orally or intraperitoneally for 6 weeks with heat-killed vaccines of indigenous Escherichia coli or nonindigenous E. coli O 127: B8 before colonization with these strains. The mice exhibited increases in specific serum antibodies and intestinal immunoglobulin A reacting with the E coli antigens. Prior immunization did not reduce the gastrointestinal population levels of the E. coli strains attained 3 and 7 days after colonization. Neither oral nor intraperitoneal immunization with the E. coli strains before colonization decreased the incidence of bacterial translocation to the mesenteric lymph nodes or reduced the number of viable E. coli cells per mesenteric lymph node. There also was no relation in individual mice between serum antibody titers and the numbers of viable E. coli cells translocating to the mesenteric lymph nodes. Thus, prior vaccination with E. coli in this study did not decrease the incidence or reduce the numbers of viable E. coli translocating to the mesenteric lymph nodes in gnotobiotic mice monoassociated with E. coli.


Metagenomic screening for bleomycin resistance genes.
A metagenomic library of activated sludge was screened for bleomycin resistance genes. Two genes were identified that differed greatly from each other, from the genes of bleomycin-producing actinomycetes, and from those of clinical isolates. Therefore, the nonclinical environment is a rich reservoir of new resistance elements, and metagenomics can be used to sample the resistome rapidly.


Rpg1p/Tif32p, a subunit of translation initiation factor 3, interacts with actin-associated protein Sla2p.
The yeast two-hybrid system was used to screen for proteins that interact in vivo with Saccharomyces cerevisiae Rpg1p/Tif32p, the large subunit of the translation initiation factor 3 core complex (eIF3). Eight positive clones encoding portions of the SLA2/END4/MOP2 gene were isolated. They overlapped in the region of amino acids 318-550. Subsequent deletion analysis of Sla2p showed that amino acids 318-373 were essential for the two-hybrid protein-protein interaction. The N-terminal part of Rpg1p (aa 1-615) was essential and sufficient for the Rpg1p-Sla2p interaction. A coimmunoprecipitation assay provided additional evidence for the physical interaction of Rpg1p/Tif32p with Sla2p in vivo. Using immunofluorescence microscopy, Rpg1p and Sla2p proteins were colocalized at the patch associated with the tip of emerging bud. Considering the essential role of Rpg1p as the large subunit of the eIF3 core complex and the association of Sla2p with the actin cytoskeleton, a putative role of the Rpg1p-Sla2p interaction in localized translation is discussed.


In vitro cytotoxicity tests on cultured human skin fibroblasts to predict skin irritation potential of surfactants.
Cultured human skin cells are a potentially useful model for skin irritancy testing. We have investigated the use of human skin fibroblasts for in vitro screening for skin toxicity. To assess the cytotoxic effects of surfactants, cell viability was measured by the NRU (neutral red uptake) assay and AB (Alamar blue) assay as in vitro methods. The skin irritation potential of surfactants by human skin patch test was assessed as in vivo methods. The close relationship was found between AB assay with human skin fibroblasts and human patch test (r=0.867). There was a relatively good agreement between the NRU and in vivo patch test (r=0.648). These results suggest that AB and NRU assay using cultured human fibroblast could be predictable methods for the irritancy of various surfactants in human.


Phytochrome A mediates blue light and UV-A-dependent chloroplast gene transcription in green leaves.
We characterized the photobiology of light-activated chloroplast transcription and transcript abundance in mature primary leaves by using the following two systems: transplastomic promoter-reporter gene fusions in tobacco (Nicotiana tabacum), and phytochrome (phyA, phyB, and hy2) and cryptochrome (cry1) mutants of Arabidopsis. In both dicots, blue light and UV-A radiation were the major signals that activated total chloroplast and psbA, rbcL, and 16S rrn transcription. In contrast, transcription activities in plants exposed to red and far-red light were 30% to 85% less than in blue light/UV-A, depending on the gene and plant species. Total chloroplast, psbA, and 16S rrn transcription were 60% to 80% less in the Arabidopsis phyA mutant exposed to blue light/UV-A relative to wild type, thus definitively linking phyA signaling to these photoresponses. To our knowledge, the major role of phyA in mediating the blue light/UV-A photoresponses is a new function for phyA in chloroplast biogenesis at this stage of leaf development. Although rbcL expression in plants exposed to UV-A was 50% less in the phyA mutant relative to wild type, blue light-induced rbcL expression was not significantly affected in the phyA, phyB, and cry1 mutants. However, rbcL expression in blue light was 60% less in the phytochrome chromophore mutant, hy2, relative to wild type, indicating that another phytochrome species (phyC, D, or E) was involved in blue light-induced rbcL transcription. Therefore, at least two different phytochromes, as well as phytochrome-independent photosensory pathways, mediated blue light/UV-A-induced transcription of chloroplast genes in mature leaves.


No evidence of colonization with community-acquired methicillin-resistant Staphylococcus aureus in HIV-1-infected men who have sex with men.
To assess the prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) colonization in HIV-1-infected men who have sex with men (MSM), a cross-sectional study was conducted on 104 persons attending a large STI/HIV unit in Rome, Italy in the period June 2007-June 2008. Swabs obtained from both anterior nares and S. aureus isolates were characterized by phenotypic and genotypic methods. A total of 24 individuals (23.1%) were colonized with S. aureus but none carried MRSA. No statistically significant association between colonization with S. aureus and behavioural, clinical, virological or immunological characteristics was identified. This study indicates a lack of circulation of CA-MRSA in HIV-1-infected MSM in Italy and underscores large epidemiological differences between the USA and a European country, so that only locally conducted epidemiological studies can provide insight into the local circulation of CA-MRSA in general and selected populations.


WISP2 downregulation inhibits the osteogenic differentiation of BMSCs in congenital scoliosis by regulating Wnt/β-catenin pathway.
Bone marrow mesenchymal stem cells (BMSCs) are instrumental in bone development, metabolism, and marrow microenvironment homeostasis. Despite this, the relevant effects and mechanisms of BMSCs on congenital scoliosis (CS) remain undefined. Herein, it becomes our focus to reveal the corresponding effects and mechanisms implicated. BMSCs from CS patients (hereafter referred as CS-BMSCs) and healthy donors (NC-BMSCs) were observed and identified. Differentially expressed genes in BMSCs were analyzed utilizing scRNA-seq and RNA-seq profiles. The multi-differentiation potential of BMSCs following the transfection or infection was evaluated. The expression levels of factors related to osteogenic differentiation and Wnt/β-catenin pathway were further determined as appropriate. A decreased osteogenic differentiation ability was shown in CS-BMSCs. Both the proportion of LEPR+ BMSCs and the expression level of WNT1-inducible-signaling pathway protein 2 (WISP2) were decreased in CS-BMSCs. WISP2 knockdown suppressed the osteogenic differentiation of NC-BMSCs, while WISP2 overexpression facilitated the osteogenesis of CS-BMSCs via acting on the Wnt/β-catenin pathway. Our study collectively indicates WISP2 knockdown blocks the osteogenic differentiation of BMSCs in CS by regulating Wnt/β-catenin signaling, thus providing new insights into the aetiology of CS.


Can anaerobes be acid fast? A novel, clinically relevant acid fast anaerobe.
Anaerobic acid fast bacilli (AFB) have not been previously reported in clinical microbiology. This is the second case report of a novel anaerobic AFB causing disease in humans. An anaerobic AFB was isolated from an abdominal wall abscess in a 64-year-old Caucasian diabetic male, who underwent distal pancreatectomy and splenectomy for resection of a pancreatic neuroendocrine tumour. The isolated bacteria were gram-variable and acid-fast, consisting of small irregular rods. The 16S rRNA gene sequence analysis showed that the isolate is a novel organism described in the literature only once before. The organism was studied at the CDC (Centers for Disease Control and Prevention) by the same group that worked with the isolates from the previous report; their findings suggest that the strain belongs to the suborder Corynebacterineae. This is the fifth reported case of an anaerobic AFB involved in clinical disease; its microbiological features and 16S RNA sequence are identical to previously reported cases. Clinical disease with this organism seems to be associated with recent history of surgery and abscess formation in deep soft tissues. Acquisition from surgical material is uncertain but seems unlikely.


Catalytic regioselective sulfonylation of alpha-chelatable alcohols: scope and mechanistic insight.
This paper describes a convenient protocol for the regioselective sulfonylation of alpha-chelatable alcohols. Typically, the reaction of alpha-heterosubstituted alcohols with 1 equiv of p-TsCl and 1 equiv of Et(3)N in the presence of 2 mol % of Bu(2)SnO leads to rapid, regioselective, and exclusive monotosylation. The pK(a) of the amine was correlated to the reaction rate. A plausible mechanism for this reaction has been proposed on the basis of (119)Sn NMR studies.


Challenges, unmet needs and future directions - a critical evaluation of the clinical trial landscape in schizophrenia research.
Developing novel antipsychotic mechanisms of action and repurposing established compounds for the treatment of schizophrenia is of utmost importance to improve relevant symptom domains and to improve the risk/benefit ratio of antipsychotic compounds. Novel trial design concepts, pathophysiology-based targeted treatment approaches or even the return to old values may improve schizophrenia outcome in the future. In this review of the clinical trial landscape in schizophrenia, we present an overview of the challenges and gaps in current clinical trials and elaborate on potential solutions to improve the outcomes of people with schizophrenia. The classic parallel group design may limit substantial advantages in drug approval or repurposing. Collaborative approaches between regulatory authorities, industry, academia, and funding agencies are needed to overcome barriers in clinical schizophrenia research to allow for meaningful outcome improvements for the patients.


Metaplasticity contributes to memory formation in the hippocampus.
Prior learning can modify the plasticity mechanisms that are used to encode new information. For example, NMDA receptor (NMDAR) activation is typically required for new spatial and contextual learning in the hippocampus. However, once animals have acquired this information, they can learn new tasks even if NMDARs are blocked. This finding suggests that behavioral training alters cellular plasticity mechanisms such that NMDARs are not required for subsequent learning. The mechanisms that mediate this change are currently unknown. To address this issue, we tested the idea that changes in intrinsic excitability (induced by learning) facilitate the encoding of new memories via metabotropic glutamate receptor (mGluR) activation. Consistent with this hypothesis, hippocampal neurons exhibited increases in intrinsic excitability after learning that lasted for several days. This increase was selective and only observed in neurons that were activated by the learning event. When animals were trained on a new task during this period, excitable neurons were reactivated and memory formation required the activation of mGluRs instead of NMDARs. These data suggest that increases in intrinsic excitability may serve as a metaplastic mechanism for memory formation.


Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice.
Circadian clock is implicated in the regulation of aging. The transcription factor CLOCK, a core component of the circadian system, operates in complex with another circadian clock protein BMAL1. Recently it was demonstrated that BMAL1 deficiency results in premature aging in mice. Here we investigate the aging of mice deficient for CLOCK protein. Deficiency of the CLOCK protein significantly affects longevity: the average lifespan of Clock-/- mice is reduced by 15% compared with wild type mice, while maximum lifespan is reduced by more than 20%. CLOCK deficiency also results in the development of two age-specific pathologies in these mice, cataracts and dermatitis, at a much higher rate than in wild type mice. In contrast to BMAL1 deficient animals, Clock-/- mice do not develop a premature aging phenotype and do not develop the multiple age-associated pathologies characteristic of BMAL1 deficiency. Thus, although CLOCK and BMAL1 form a transcriptional complex, the physiological result of their deficiency is different. Our results suggest that CLOCK plays an important role in aging, specifically; CLOCK activity is critical for the regulation of normal physiology and aging of the lens and skin.


[Surgical treatment of primary hyperparathyroidism: our experience].
The Authors report their experience on 136 patients with primary hyperparathyroidism. Nephrolitiasis was proven in 56 patients (41.3%), 20 patients (14.7%) were asyntomatic. Acute primary hyperparathyroidism was detected in 12 cases (8.8%). The preoperative localization of the diseased glands permits to minimize the procedure in terms of length and region of incision, extent of exploration and morbidity. 91.3% of the lesions were single adenoma, 7.3% double adenomas and 1.4% hyperplasia in MEN 1. The intraoperative PTH assay, performed in 90 patients (66.2%), showed a sensibility of 93.4%. Surgical treatment was successful in 93.4% of cases ( 127/136 patients), increasing to 97.0% (132/136patients) if only recurrent hyperparathyroidism was considered, with no mortality and morbidity of 4.4%.


Destruction of elastic tissue (elastolysis) as a link between atherosclerosis and the temporal arteritis/polymyalgia rheumatica syndrome. Observations on an actinic factor in vascular disease.
Destruction (elastolysis) of the internal elastic lamina is frequently observed near early atherosclerotic plaques. Elastolysis and plaque formation are also found together in the temporal arteritis/polymyalgia rheumatica syndrome. Could it be that atherosclerosis and the syndrome are more closely akin than usually thought, with elastolysis acting as the pathogenetic link between them? A kinship of this nature is in accord with the growing recognition that elastin-related autoimmunity prevails in both these forms of vascular disease. A case can also be made out for the belief that the autoimmune reactions in internal vessels may be provoked by events in the integument where a slow but ultimately massive turnover of dermal and vascular elastic tissue takes place under the harmful influence of solar and other forms of actinic radiation.


Brain Subtyping Enhances The Neuroanatomical Discrimination of Schizophrenia.
Identifying distinctive subtypes of schizophrenia could ultimately enhance diagnostic and prognostic accuracy. We aimed to uncover neuroanatomical subtypes of chronic schizophrenia patients to test whether stratification can enhance computer-aided discrimination of patients from control subjects. Unsupervised, data-driven clustering of structural MRI (sMRI) data was used to identify 2 subtypes of schizophrenia patients drawn from a US-based open science repository (n = 71) and we quantified classification improvements compared to controls (n = 74) using supervised machine learning. We externally validated the unsupervised and supervised learning models in a heterogeneous German validation sample (n = 316), and characterized symptom, cognition, and longitudinal symptom change signatures. Stratification improved classification accuracies from 68.5% to 73% (subgroup 1) and 78.8% (subgroup 2), respectively. Increased accuracy was also found when models were externally validated, and an average gain of 9% was found in supplementary analyses. The first subgroup was associated with cortical and subcortical volume reductions coupled with substantially longer illness duration, whereas the second subgroup was mainly characterized by cortical reductions, reduced illness duration, and comparatively less negative symptoms. Individuals within each subgroup could be identified using just 10 clinical questions at an accuracy of 81.2%, and differential cognitive and symptom course signatures were suggested in multivariate analyses. Our findings suggest that sMRI-based subtyping enhances the neuroanatomical discrimination of schizophrenia by identifying generalizable brain patterns that align with a clinical staging model of the disorder. These findings could be used to improve illness stratification for biomarker-based computer-aided diagnoses.


Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity.
In youths with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on β cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high-incretin effect group demonstrated a longitudinal increase in β cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of β cell function and weight in youths with obesity.


Signatures of anthocyanin metabolites identified in humans inhibit biomarkers of vascular inflammation in human endothelial cells.
The physiological relevance of contemporary cell culture studies is often perplexing, given the use of unmetabolized phytochemicals at supraphysiological concentrations. We investigated the activity of physiologically relevant anthocyanin metabolite signatures, derived from a previous pharmacokinetics study of 500 mg 13 C5 -cyanidin-3-glucoside in eight healthy participants, on soluble vascular adhesion molecule-1 (VCAM-1) and interleukin-6 (IL-6) in human endothelial cells. Signatures of peak metabolites (previously identified at 1, 6, and 24 h post-bolus) were reproduced using pure standards and effects were investigated across concentrations ten-fold lower and higher than observed mean (<5 μM) serum levels. Tumor necrosis factor-α (TNF-α)-stimulated VCAM-1 was reduced in response to all treatments, with maximal effects observed for the 6 and 24 h profiles. Profiles tested at ten-fold below mean serum concentrations (0.19-0.44 μM) remained active. IL-6 was reduced in response to 1, 6, and 24 h profiles, with maximal effects observed for 6 h and 24 h profiles at concentrations above 2 μM. Protein responses were reflected by reductions in VCAM-1 and IL-6 mRNA, however there was no effect on phosphorylated NFκB-p65 expression. Signatures of anthocyanin metabolites following dietary consumption reduce VCAM-1 and IL-6 production, providing evidence of physiologically relevant biological activity.


Immunohistochemical localization of human tear lysozyme.
Possible local sources of human tear lysozyme were investigated using an indirect immunofluorescence technique. Lysozyme was identified in 20% to 50% of acinar and ductular epithelial cells of both main and accessory lacrimal glands. The staining was granular in character and confined to the apices of the cells. Cells that stained positive tended to be grouped. Interstitial tissues of main and accessory lacrimal tissues did not stain. Conjunctiva and all other ocular tissues examined were unstained by antilysozyme antisera. Our findings are compatible with lysozyme either being produced in lacrimal tissue or being concentrated from plasma. The absence of any other lysozyme-specific fluorescence in the interstitial elements of the lacrimal tissues supports the notion of local synthesis by acinar lacrimal tissue.


PHD3 Acts as Tumor Suppressor in Mouse Osteosarcoma and Influences Tumor Vascularization via PDGF-C Signaling.
Cancer cell proliferation and insufficient blood supply can lead to the development of hypoxic areas in the tumor tissue. The adaptation to the hypoxic environment is mediated by a transcriptional complex called hypoxia-inducible factor (HIF). HIF protein levels are tightly controlled by oxygen-dependent prolyl hydroxylase domain proteins (PHDs). However, the precise roles of these enzymes in tumor progression and their downstream signaling pathways are not fully characterized. Here, we study PHD3 function in murine experimental osteosarcoma. Unexpectedly, PHD3 silencing in LM8 cells affects neither HIF-1α protein levels, nor the expression of various HIF-1 target genes. Subcutaneous injection of PHD3-silenced tumor cells accelerated tumor progression and was accompanied by dramatic phenotypic changes in the tumor vasculature. Blood vessels in advanced PHD3-silenced tumors were enlarged whereas their density was greatly reduced. Examination of the molecular pathways underlying these alterations revealed that platelet-derived growth factor (PDGF)-C signaling is activated in the vasculature of PHD3-deficient tumors. Silencing of PDGF-C depleted tumor growth, increased vessel density and reduced vessel size. Our data show that PHD3 controls tumor growth and vessel architecture in LM8 osteosarcoma by regulating the PDGF-C pathway, and support the hypothesis that different members of the PHD family exert unique functions in tumors.


Binding of aflatoxin B1 metabolites in extrahepatic tissues in fetal and infant mice and in adult mice with depleted glutathione levels.
Whole-body autoradiography of 3H-labeled aflatoxin B1 (AFB1) in adult C57BL mice pretreated with the glutathione (GSH)-depleting agent phorone showed accumulation of tissue-bound radioactivity in the nasal olfactory and respiratory mucosa, the mucosa of the nasopharyngeal duct, and the tracheal and esophageal mucosa, which was not seen in unpretreated adult mice. The altered distribution pictures induced by the phorone are probably related to decreased tissue levels of GSH. The AFB1 is likely to be bioactivated locally in the extrahepatic tissues; in nonpretreated mice the reactive AFB1 metabolite formed is probably scavenged by GSH via the action of glutathione-S-transferase, whereas in the mice with depleted GSH levels a binding to tissue macromolecules will instead take place. The mechanism indicated above is supported by results of in vitro experiments in which the nasal olfactory mucosa and the esophageal mucosa were shown to have a capacity to form tissue-bound 3H-AFB1 metabolites. This formation was decreased when the incubations were performed in the presence of GSH. In addition, the treatments of mice with phorone were shown to induce a strong GSH depletion in the nasal olfactory mucosa and the esophageal mucosa. In autoradiographic studies performed with 1- and 5-day-old infant mice a marked localization of bound 3H-AFB1 metabolites was found in the nasal olfactory mucosa, and in the 5-day-old infant there was also a labeling of the mucosa of the nasopharyngeal duct, the pharyngeal and esophageal mucosa, and the tracheal mucosa. Experiments in vitro with the nasal olfactory mucosa of 5-day-old infants demonstrated a marked binding of 3H-AFB1 metabolites in this tissue. Incubations together with GSH decreased this binding, although the inhibition was less marked than in the adult animal. The in vivo accumulation of bound AFB1 metabolites in the extrahepatic tissues of the infant mice may be related to low glutathione-S-transferase (GST) activity in the tissues of the young animals. In addition, some extrahepatic tissues may have a considerable capacity to bioactivate the AFB1 at early age. Autoradiography of 3H-AFB1 in pregnant mice showed a labeling of the fetal nasal olfactory mucosa at day 18 but not at day 14 of gestation. This indicates that AFB1-bioactivating enzymes develop in the fetal nasal olfactory mucosa in late gestation.


Capitate transposition to replace necrotic lunate bone with a pedicle for Kienbock's disease: review of 30 cases.
To investigate the clinical application of capitate transposition with a pedicle in 30 cases of Kienbock's disease. The external diameter and curvature of the capitate head and proximal facet of the lunate were observed and measured in 100 specimens. The vascularity of the capitate was also investigated. Capitate transposition with a vascular pedicle was designed to treat 30 patients with advanced Kienbock's disease who were followed up for 2 to 16 years and then analyzed according to Evans's scoring system. Aseptic necrosis did not occur in the transposed capitate because the pedicle fascia including the dorsal branch of the anterior interosseous artery ensured the vascularity of proximal two thirds of the capitate. The transposed capitate reestablished a relatively pain-free radiocarpal joint. Follow-up results showed that grip strength and motion arc were up to 70% of contralateral side. Capitate transposition with a pedicle is a reliable treatment method for advanced Kienbock's disease, with favorable prognosis for at least five years postoperatively.


On the reinterpretation of resonances in split-ring-resonators at normal incidence.
We numerically study the spectral response of 'U'-shaped split-ring-resonators at normal incidence with respect to the resonator plane. Based on the evaluation of the near-field patterns of the resonances and their geometry-dependent spectral positions, we obtain a comprehensive and consistent picture of their origin. We conclude that all resonances can be understood as plasmonic resonances of increasing order of the entire structure. In particular, for an electrical field polarized parallel to the gap the so-called LC-resonance corresponds to the fundamental plasmonic mode and, contrary to earlier interpretations, the electrical resonance is a second order plasmon mode of the entire structure. The presence of further higher order modes is discussed.


Dank or not? Analyzing and predicting the popularity of memes on Reddit.
Internet memes have become an increasingly pervasive form of contemporary social communication that attracted a lot of research interest recently. In this paper, we analyze the data of 129,326 memes collected from Reddit in the middle of March, 2020, when the most serious coronavirus restrictions were being introduced around the world. This article not only provides a looking glass into the thoughts of Internet users during the COVID-19 pandemic but we also perform a content-based predictive analysis of what makes a meme go viral. Using machine learning methods, we also study what incremental predictive power image related attributes have over textual attributes on meme popularity. We find that the success of a meme can be predicted based on its content alone moderately well, our best performing machine learning model predicts viral memes with AUC=0.68. We also find that both image related and textual attributes have significant incremental predictive power over each other.


APG: an Active Protein-Gene network model to quantify regulatory signals in complex biological systems.
Synergistic interactions among transcription factors (TFs) and their cofactors collectively determine gene expression in complex biological systems. In this work, we develop a novel graphical model, called Active Protein-Gene (APG) network model, to quantify regulatory signals of transcription in complex biomolecular networks through integrating both TF upstream-regulation and downstream-regulation high-throughput data. Firstly, we theoretically and computationally demonstrate the effectiveness of APG by comparing with the traditional strategy based only on TF downstream-regulation information. We then apply this model to study spontaneous type 2 diabetic Goto-Kakizaki (GK) and Wistar control rats. Our biological experiments validate the theoretical results. In particular, SP1 is found to be a hidden TF with changed regulatory activity, and the loss of SP1 activity contributes to the increased glucose production during diabetes development. APG model provides theoretical basis to quantitatively elucidate transcriptional regulation by modelling TF combinatorial interactions and exploiting multilevel high-throughput information.


[Roaming through methodology. XXX. The capture-recapture method].
The capture-recapture method is useful for the estimation of the incidence and prevalence of a disease if there exist multiple lists that can be linked. Some assumptions have to be fulfilled for the estimate to be adequate. For example, for every list every individual should have the same probability to be on the list, and the lists should be independent. In case of two lists one has to assume that these are independent in order to get an estimate. When three or more lists are available this strong assumption may be mitigated.


Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity.
Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities.


Measurement properties of pain scoring instruments in farm animals: A systematic review protocol using the COSMIN checklist.
Society has been increasingly concerned about the impact of pain on farm animal welfare. This systematic review aims to provide evidence relating to the measurement properties (i.e. reliability, validity, and sensitivity) of pain scoring instruments used for pain assessment in farm animals. A literature search will be performed using five databases (MEDLINE, EMBASE, Web of Science, CAB abstracts and Biological Abstracts) and search terms related to pain, pain scales and different species of farm animals. Eligibility criteria will include full-text studies on the development and/or validation of acute and chronic pain scoring instruments for farm animals including bovine (beef and dairy), ovine, caprine, camel, swine and poultry. Exclusion criteria will include studies that report the use of pain scales for the validation of another instrument, or those reporting ethograms/list of behaviors potentially indicating pain without a scoring system. Study titles and their abstracts will be screened for eligibility by one investigator. Full-text articles will be independently reviewed for eligibility and evaluated by two investigators. Relevant information will be recorded and evaluated systematically according to the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist using an adapted data collection sheet. The following measurement properties and characteristics of the instruments will be assessed: content validity (internal consistency, structural and cross-cultural validity), reliability, measurement error, criterion and construct validity, responsiveness, interpretability and feasibility. Following the assessment of methodological quality and quality of the findings, evidence for each measurement property will be summarized into high, moderate, low or very low. This systematic review will provide further insights into the evidence-based measurement properties of pain scoring instruments in farm animals. It may identify possible gaps of knowledge with these tools as a potential target for future studies in farm animals with a positive impact on animal welfare.


Traumatic overbite: a restorative solution.
Deep overbite is frequently seen in the adult dentition. Although the condition is usually asymptomatic, certain factors may lead to the development of deep traumatic overbite, and in partially dentate patients loss of posterior occlusal support may be a contributory factor. Several treatment modalities, including orthodontics, orthognathic surgery and prosthodontics have been used but, as some adult patients with this problem are unwilling to avail themselves of treatment involving either orthodontics or orthognathic surgery, a restorative approach using a combination of fixed and removable restorations may provide a satisfactory solution. This paper details a case report on the restorative management of a partially dentate adult patient with a deep traumatic overbite.


Safety of a Trivalent Inactivated Influenza Vaccine in Health Care Workers in Kurdistan Province, Western Iran; A Longitudinal Follow-up Study.
We studied the safety of a trivalent inactivated surface antigen (split virion, inactivated) influenza vaccine, Begrivac® (Novartis Company), widely used in health care workers in Kurdistan. A longitudinal follow-up study was performed in Sanandaj city, west of Iran, recruiting 936 people. A questionnaire was completed for each participant, and all symptoms or abnormal physical findings were recorded. In part 1 of the study, the post-vaccination complaints were headache (5.3%), fever (7.9%), weakness (9.6%), chills (10.1%), sweating (10.5%), arthralgia (20.2%), and malaise (21.5%). Swelling of the injection site was seen in 267 (30.3%) participants, and pruritus of the injection site was seen in 290 (32.9%) participants. Redness and induration were also reported in 42.5% of the participants. Local reactions were mainly mild and lasted for 1-2 days. No systemic reactions were reported in the second part of the study. None of the participants experienced any inconvenience. We concluded that local adverse reactions after the trivalent inactivated split influenza vaccine, Begrivac®, in health care workers were far more common than expected. Continuous surveillance is needed to assess the potential risks and benefits of newly produced influenza vaccines.


Stretch reflex sensitivity: effects of postural and muscle length changes.
In this study, a combination of clinical evaluation, laboratory testing, and model simulation of spasticity is performed under various postural conditions to investigate the changes in the sensitivity and specific mechanisms of spasticity. Fifty-nine multiple sclerosis patients participated in the study and received spasticity evaluation based on both the Ashworth scale and the pendulum test. Spasticity was found to increase in the pendulum test when the subjects were tested in a supine posture, compared to when they were sitting. Three patterns of stretch reflex response were seen for similar leg swing trajectories. While it was clear that the increased stretch of rectus femoris in the supine posture contributed to the increased spasticity, the results of modeling showed that other more complex factors were also involved. The supraspinal descending modulation associated with postural control may play a more dominant role in the severity of spasticity. The results suggest that the biomechanical test of spasticity should be performed for several different postures or ranges of movement with muscle activities monitored simultaneously, so that the effect of various factors can be examined. The work also indicates that a neuromusculoskeletal model with detailed muscle dynamics and stretch reflex loops is a valuable tool for investigating the neural mechanisms of spasticity.


The performance of ice-free cryopreserved heart valve allografts in an orthotopic pulmonary sheep model.
Transplantation of cryopreserved heart valves (allografts) is limited by immune responses, inflammation, subsequent structural deterioration and an expensive infrastructure. In previous studies we demonstrated that conventional frozen cryopreservation (FC) is accompanied by serious alterations of extracellular matrix (ECM) structures. As the main culprit of the observed damages ice crystal formation was identified. Objective of this study was the application principles of cryoprotection as observed in nature, occurring in animals or plants, for ice-free cryopreservation (IFC) of heart valves. Using IFC, valves were processed and stored above the glass transition temperature of the cryoprotectant formulation (-124 degrees C) at -80 degrees C to avoid any ice formation, tissue-glass cracking and preserving ECM. After implantation in the orthotopic pulmonary position in sheep, we demonstrate that IFC resulted in cell free matrices, while maintaining crucial ECM-components such as elastin and collagen, translating into superior hemodynamics. In contrast, we reveal that FC valves showed ECM damage that was not restored in vivo, and T-cell inflammation of the stroma with significant leaflet thickening. Compared to currently applied FC practice IFC also reduced infrastructural needs for preservation, storage and shipping. These results have important implications for clinical valve transplantation including the promise of better long-term function and lower costs.


Pragmatic Home-Based Exercise after Total Hip Arthroplasty - Silkeborg: Protocol for a prospective cohort study (PHETHAS-1).
Introduction: Rehabilitation exercises are offered to patients after total hip arthroplasty (THA); however, the effectiveness and optimal type and dose of exercise remains unknown. The primary objective of this trial is to indicate the preliminary efficacy of home-based rehabilitation using elastic band exercise on performance-based function after THA, based on the relationship between the performed exercise dose and the change in performance-based function (gait speed) from 3 (start of intervention) to 10 weeks (end of intervention) after surgery. The secondary objective is to investigate if a dose-response relationship exists between the performed exercise dose and changes in: hip-related disability, lower-extremity functional performance, and hip muscle strength Methods: In this prospective cohort study, patients scheduled for THA will be consecutively included until 88 have completed the intervention period from 3 to 10 weeks postoperatively. Participants perform the standard rehabilitation program with elastic band exercises. Exercise dose (exposure) will be objectively quantified using a sensor attached to the elastic band. The primary outcome is gait speed measured by the 40-m fast-paced walk test. Secondary outcomes include: patient reported hip disability (Hip disability and Osteoarthritis Outcome Score (HOOS)), hip muscle strength (hand-held dynamometry) and lower extremity function (30-s chair stand test). Discussion: This trial will add knowledge concerning the relationship between performed exercise dose and post-operative outcomes after THA. The protocol paper describes the study design and methods in detail, including the statistical analysis plan. Trial registration: Pre-registered on March 27, 2017 at ClinicalTrails.gov (ID: NCT03109821).


A survey of membrane receptor regulation in valvular interstitial cells cultured under mechanical stresses.
Degenerative valvular diseases have been linked to the action of abnormal forces on valve tissues during each cardiac cycle. It is now accepted that the degenerative behavior of valvular cells can be induced mechanically in vitro. This approach of in vitro modeling of valvular cells in culture constitutes a powerful tool to study, characterize, and develop predictors of heart valve degeneration in vivo. Using such in vitro systems, we expect to determine the exact signaling mechanisms that trigger and mediate propagation of degenerative signals. In this study, we aim to uncover the role of mechanosensing proteins on valvular cell membranes. These can be cell receptors and triggers of downstream pathways that are activated upon the action of cyclical tensile strains in pathophysiological conditions. In order to identify mechanosensors of tensile stresses on valvular interstitial cells, we employed biaxial cyclic strain of valvular cells in culture and quantitatively evaluated the expression of cell membrane proteins using a targeted protein array and interactome analyses. This approach yielded a high-throughput screening of all cell surface proteins involved in sensing mechanical stimuli. In this study, we were able to identify the cell membrane proteins which are activated during physiological cyclic tensile stresses of valvular cells. The proteins identified in this study were clustered into four interactomes, which included CC chemokine ligands, thrombospondin (adhesive glycoproteins), growth factors, and interleukins. The expression levels of these proteins generally indicated that cells tend to increase adhesive efforts to counteract the action of mechanical forces. This is the first study of this kind used to comprehensively identify the mechanosensitive proteins in valvular cells.


Factors associated with patients' participation in rehabilitation services: a comparative injury analysis 12 months post-discharge.
To determine key characteristics or factors associated with rehabilitation participation during the first year following discharge for persons with either traumatic brain injury (TBI), spinal cord injury (SCI), intra-articular fracture (IAF), or burn injury (BURNS). Medical records and longitudinal survey [telephone questionnaire] data were collected for persons in the four injury groups and analyzed using hierarchical logistic regression procedures for each domain of factors. The only significant predictors with odds ratios greater than one were those for vocational rehabilitation participation. TBI patients lacking private insurance were 2.6 times more likely to participate in vocational rehabilitation; older SCI and TBI patients are about twice as likely to participate in vocational rehabilitation; and finally those with IAF or BURNS who are married at 12 months post discharge are 11.5 and 4.4 times respectively more likely to participate in vocational rehabilitation. Those lacking valuable socio-economic resources, such as private insurance (for TBI) and social support systems provided by marriage (for BURNS and IAF patients) are much more likely to be referred to vocational rehabilitation. This is true for older SCI and TBI patients as well. Lacking such resources, patients may be viewed by referral agents as less likely to benefit from in or outpatient rehabilitation.


[Multiresidue analysis of pesticides in tea by supercritical fluid extraction (SFE) and GC-MS].
A multiresidue analysis of pesticides in tea using supercritical fluid extraction (SFE) and GC-MS was developed. The preprocessing using SFE shortened the total analysis time. The SFE extract contained less matrices than the extract obtained with organic solvents. However, these matrices disturbed instrumental analysis. So, the extract was cleaned up with ENVI™-Carb/NH2 and InertSep™ SI cartridge. A recovery test was carried out for 245 pesticides spiked in samples at the level of 0.1 μg/g. Recovery rates of 178 pesticides ranged from 70 to 120%, the relative standard deviations (RSDs) were less than 15%, and quantitation limits were between 0.01 and 0.05 μg/g. Based on these results, this method is considered to be useful for multiresidue analysis of pesticides in tea samples.


Division within the North American boreal forest: Ecological niche divergence between the Bicknell's Thrush (Catharus bicknelli) and Gray-cheeked Thrush (C. minimus).
Sister species that diverged in allopatry in similar environments are expected to exhibit niche conservatism. Using ecological niche modeling and a multivariate analysis of climate and habitat data, I test the hypothesis that the Bicknell's Thrush (Catharus bicknelli) and Gray-cheeked Thrush (C. mimimus), sister species that breed in the North American boreal forest, show niche conservatism. Three tree species that are important components of breeding territories of both thrush species were combined with climatic variables to create niche models consisting of abiotic and biotic components. Abiotic-only, abiotic+biotic, and biotic-only models were evaluated using the area under the curve (AUC) criterion. Abiotic+biotic models had higher AUC scores and did not over-project thrush distributions compared to abiotic-only or biotic-only models. From the abiotic+biotic models, I tested for niche conservatism or divergence by accounting for the differences in the availability of niche components by calculating (1) niche overlap from ecological niche models and (2) mean niche differences of environmental values at occurrence points. Niche background similarity tests revealed significant niche divergence in 10 of 12 comparisons, and multivariate tests revealed niche divergence along 2 of 3 niche axes. The Bicknell's Thrush breeds in warmer and wetter regions with a high abundance of balsam fir (Abies balsamea), whereas Gray-cheeked Thrush often co-occurs with black spruce (Picea mariana). Niche divergence, rather than conservatism, was the predominant pattern for these species, suggesting that ecological divergence has played a role in the speciation of the Bicknell's Thrush and Gray-cheeked Thrush. Furthermore, because niche models were improved by the incorporation of biotic variables, this study validates the inclusion of relevant biotic factors in ecological niche modeling to increase model accuracy.


Revisiting Hemicraniectomy: Late Decompressive Hemicraniectomy for Malignant Middle Cerebral Artery Stroke and the Role of Infarct Growth Rate.
Objective and Methods. The outcome in late decompressive hemicraniectomy in malignant middle cerebral artery stroke and the optimal timings of surgery has not been addressed by the randomized trials and pooled analysis. Retrospective, multicenter, cross-sectional study to measure outcome following DHC under 48 or over 48 hours using the modified Rankin scale [mRS] and dichotomized as favorable ≤4 or unfavorable >4 at three months. Results. In total, 137 patients underwent DHC. Functional outcome analyzed as mRS 0-4 versus mRS 5-6 showed no difference in this split between early and late operated on patients [P = 0.140] and mortality [P = 0.975]. Multivariate analysis showed that age ≥ 55 years, MCA with additional infarction, septum pellucidum deviation ≥1 cm, and uncal herniation were independent predictors of poor functional outcome at three months. In the "best" multivariate model, second infarct growth rate [IGR2] >7.5 ml/hr, MCA with additional infarction, and patients with temporal lobe involvement were independently associated with surgery under 48 hours. Both first infarct growth rate [IGR1] and second infarct growth rate [IGR2] were nearly double [P < 0.001] in patients with early surgery [under 48 hours]. Conclusions. The outcome and mortality in malignant middle cerebral artery stroke patients operated on over 48 hours of stroke onset were comparable to those of patients operated on less than 48 hours after stroke onset. Our data identifies IGR, temporal lobe involvement, and middle cerebral artery with additional infarct as independent predictors for early surgery.


Faecal bacterial indicators removal in various wastewater treatment plants located in Almendares River watershed (Cuba).
The Almendares River, located in Havana city, receives the wastewaters of more than 200,000 inhabitants. The high abundance of faecal bacterial indicators (FBIs) in the downstream stretch of the river reflects the very poor microbiological water quality. In this zone, the Almendares water is used for irrigation of urban agriculture and recreational activities although the microbiological standards for these uses are not met. Improvement of wastewater treatment is absolutely required to protect the population against health risk. This paper compares the removal of FBIs in three wastewater treatment plants (WWTPs) located in this watershed: a conventional facility using trickling filters, a constructed wetland (CW) and a solar aquatic system (SAS). The results indicate better removal efficiency in the two natural systems (CW and SAS) for all the measured parameters (suspended matters, biological oxygen demand, total coliforms, E. coli and enterococci). Removals of the FBIs were around two log units higher in both natural systems than in the conventional one. A longitudinal profile of the microbiological quality of the river illustrates the negative impact of the large conventional WWTP. This case study confirms the usefulness of small and natural WWTPs for tropical developing countries, even in urban and periurban areas.


A new class of thermotropic lanthanidomesogens: Eu(III) nitrate complexes with mesogenic 4-pyridone ligands.
A new class of thermotropic lanthanidomesogens has been designed and prepared. They are based on 4-pyridone ligands that possess mesogenic cyanobiphenyl groups attached to the 4-pyridone unit via a flexible long alkyl spacer and show a very high thermal stability (decomposition temperatures near 300 °C). Depending on the alkyl length spacer, these complexes exhibit a SmA phase with transition temperatures influenced by the number of mesogenic groups employed and the spacer length.


Acute aortic syndrome.
Acute aortic syndrome embraces a group of heterogenous pathological entities involving the aortic wall with a common clinical profile. The current epidemiology, clinical presentation, diagnosis and treatment strategy are discussed in this review. Besides, the importance of multidisciplinary aortic teams, aortic centers and the implementation of an aortic code are emphasized.


Simultaneous quantification of ergot and tropane alkaloids in bread in the Netherlands by LC-MS/MS.
Atropine and scopolamine are tropane alkaloids (TAs), which are regulated for cereal-based foods for children in the EU. For ergot alkaloids (EAs) in cereals and cereal-based food harmonised legislation is not yet established. A fast and straightforward method, which employs extraction by acidified water/methanol followed by ultra-filtration prior to analysis by LC-MS/MS, was validated in bread for 20 EAs and six TAs. LOQs for individual alkaloids ranged from 0.3 to 1.2 µg kg-1, while recoveries ranged from 65% to 94% and repeatability from 3.4% to 17%. A survey was conducted in the Netherlands on 40 retail samples of bread (wheat, rye, wheat-rye, multi-grain) collected in 2014 and 2018. TAs, including atropine and scopolamine, were not detected. Eighteen different EAs were detected and total levels varied between <LOQ and 335 µg kg-1. Since EAs were detected in a wide concentration range, it is recommended to monitor their occurrence in bread more regularly.


Diagnosis of Noonan syndrome and related disorders using target next generation sequencing.
Noonan syndrome is an autosomal dominant developmental disorder with a high phenotypic variability, which shares clinical features with other rare conditions, including LEOPARD syndrome, cardiofaciocutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. This group of related disorders, so-called RASopathies, is caused by germline mutations in distinct genes encoding for components of the RAS-MAPK signalling pathway. Due to high number of genes associated with these disorders, standard diagnostic testing requires expensive and time consuming approaches using Sanger sequencing. In this study we show how targeted Next Generation Sequencing (NGS) technique can enable accurate, faster and cost-effective diagnosis of RASopathies. In this study we used a validation set of 10 patients (6 positive controls previously characterized by Sanger-sequencing and 4 negative controls) to assess the analytical sensitivity and specificity of the targeted NGS. As second step, a training set of 80 enrolled patients with a clinical suspect of RASopathies has been tested. Targeted NGS has been successfully applied over 92% of the regions of interest, including exons for the following genes: PTPN11, SOS1, RAF1, BRAF, HRAS, KRAS, NRAS, SHOC, MAP2K1, MAP2K2, CBL. All expected variants in patients belonging to the validation set have been identified by targeted NGS providing a detection rate of 100%. Furthermore, all the newly detected mutations in patients from the training set have been confirmed by Sanger sequencing. Absence of any false negative event has been excluded by testing some of the negative patients, randomly selected, with Sanger sequencing. Here we show how molecular testing of RASopathies by targeted NGS could allow an early and accurate diagnosis for all enrolled patients, enabling a prompt diagnosis especially for those patients with mild, non-specific or atypical features, in whom the detection of the causative mutation usually requires prolonged diagnostic timings when using standard routine. This approach strongly improved genetic counselling and clinical management.


The COVID-19 pandemic should not jeopardize dengue control.
The concurrent circulation of dengue and coronavirus disease 2019 (COVID-19) may produce many unfavourable outcomes-such as co-infections; delays in diagnosis, treatment, and mitigation measures; overwhelming of the healthcare system; underreporting of cases; deterioration in surveillance and control interventions; and exacerbation of social inequalities. Indeed, lockdown is greatly compromising the effectiveness of vector control, especially social mobilization campaigns and preventive insecticide spraying in private spaces (indoor and peridomestic spraying). Thus, failure to appropriately implement the full range of vector control interventions can lead to a reduction in their overall effectiveness and an increasing risk of vector-borne diseases circulating. Consequently, the health community and policy makers should develop proactive policies and allocate adequate resources to prevent and manage the resurgence of dengue and other vector-borne diseases in the new era of COVID-19.


High-precision robotic microcontact printing (R-μCP) utilizing a vision guided selectively compliant articulated robotic arm.
Increased realization of the spatial heterogeneity found within in vivo tissue microenvironments has prompted the desire to engineer similar complexities into in vitro culture substrates. Microcontact printing (μCP) is a versatile technique for engineering such complexities onto cell culture substrates because it permits microscale control of the relative positioning of molecules and cells over large surface areas. However, challenges associated with precisely aligning and superimposing multiple μCP steps severely limits the extent of substrate modification that can be achieved using this method. Thus, we investigated the feasibility of using a vision guided selectively compliant articulated robotic arm (SCARA) for μCP applications. SCARAs are routinely used to perform high precision, repetitive tasks in manufacturing, and even low-end models are capable of achieving microscale precision. Here, we present customization of a SCARA to execute robotic-μCP (R-μCP) onto gold-coated microscope coverslips. The system not only possesses the ability to align multiple polydimethylsiloxane (PDMS) stamps but also has the capability to do so even after the substrates have been removed, reacted to graft polymer brushes, and replaced back into the system. Plus, non-biased computerized analysis shows that the system performs such sequential patterning with <10 μm precision and accuracy, which is equivalent to the repeatability specifications of the employed SCARA model. R-μCP should facilitate the engineering of complex in vivo-like complexities onto culture substrates and their integration with microfluidic devices.


Spatial and temporal pCO2 marine monitoring near Panarea Island (Italy) using multiple low-cost GasPro sensors.
The present paper describes the GasPro probe, a small, low-cost unit for in situ, continuous pCO2 monitoring. Laboratory tests defining its performance characteristics are reported, as are the results from a 60 h water-column deployment of 20 such units near a natural CO2 seep site off the coast of Panarea Island (Italy). The spatial-temporal evolution of dissolved CO2 movement is presented and possible origins and controlling mechanisms discussed. Results highlight the potential for this technology to be used for better understanding various dynamic physical and biochemical processes in marine environments, and for marine environmental monitoring of off-shore industrial sites. These experiments have allowed us to assess the advantages and disadvantages of the present GasPro prototype and to define areas for ongoing improvement.


Reconfigurable assemblies of shape-changing nanorods.
Reconfigurable nanostructures represent an exciting new direction for materials. Applications of reversible transformations between nanostructures induced by molecular conformations under external fields can be found in a broad range of advanced technologies including smart materials, electromagnetic sensors, and drug delivery. With recent breakthroughs in synthesis and fabrication techniques, shape-changing nanoparticles are now possible. Such novel building blocks provide a conceptually new and exciting approach to self-assembly and phase transformations by providing tunable parameters fundamentally different from the usual thermodynamic parameters. Here we investigate via molecular simulation a transformation between two thermodynamically stable structures self-assembled by laterally tethered nanorods whose rod length is switched between two values. Building blocks with longer rods assemble into a square grid structure, while those with short rods form bilayer sheets with internal smectic A ordering at the same thermodynamic conditions. By shortening or lengthening the rods over a short time scale relative to the system equilibration time, we observe a transformation from the square grid structure into bilayer sheets, and vice versa. We also observe honeycomb grid and pentagonal grid structures for intermediate rod lengths. The reconfiguration between morphologically distinct nanostructures induced by dynamically switching the building block shape serves to motivate the fabrication of shape-changing nanoscale building blocks as a new approach to the self-assembly of reconfigurable materials.


Better Cryo-EM Specimen Preparation: How to Deal with the Air-Water Interface?
Cryogenic electron microscopy (cryo-EM) is now one of the most powerful and widely used methods to determine high-resolution structures of macromolecules. A major bottleneck of cryo-EM is to prepare high-quality vitrified specimen, which still faces many practical challenges. During the conventional vitrification process, macromolecules tend to adsorb at the air-water interface (AWI), which is known unfriendly to biological samples. In this review, we outline the nature of AWI and the problems caused by it, such as unpredictable or uneven particle distribution, protein denaturation, dissociation of complex and preferential orientation. We review and discuss the approaches and underlying mechanisms to deal with AWI: 1) Additives, exemplified by detergents, forming a protective layer at AWI and thus preserving the native folds of target macromolecules. 2) Fast vitrification devices based on the idea to freeze in-solution macromolecules before their touching of AWI. 3) Thin layer of continuous supporting films to adsorb macromolecules, and when functionalized with affinity ligands, to specifically anchor the target particles away from the AWI. Among these supporting films, graphene, together with its derivatives, with negligible background noise and mechanical robustness, has emerged as a new generation of support. These strategies have been proven successful in various cases and enable us a better handling of the problems caused by the AWI in cryo-EM specimen preparation.


Embryonic Stem Cell-Like Subpopulations in Venous Malformation.
Venous malformation (VM) consists of a network of ectatic anomalous thin-walled venous channels. A role for an activating TIE2 mutation in the development of the dilated luminal vessels in VM, and its proposed involvement of embryonic stem cells (ESCs), led us to investigate the expression of ESC markers in subcutaneous VM (SCVM) and intramuscular VM (IMVM). Formalin-fixed paraffin-embedded sections of SCVM from seven patients and IMVM samples from seven patients were analyzed for the expression of Nanog, pSTAT3, OCT4, SOX2, SALL4, and CD44, using 3,3'-diaminobenzidine (DAB) immunohistochemical (IHC) staining. All these samples did not express lymphatic marker D2-40. NanoString mRNA analysis and RT-PCR were performed on snap-frozen samples of SCVM (n = 3) and IMVM (n = 3) from the respective original cohorts of patients included in DAB IHC staining. To confirm co-expression of two proteins, immunofluorescent (IF) IHC staining on two representative samples of IMVM and SCVM samples from the original cohorts of patients included for DAB IHC staining was performed. DAB IHC staining demonstrated expression of all of the above ESC markers in both SCVM and IMVM samples. IF IHC staining showed that these markers were localized to the endothelium within these lesions and that Nanog, pSTAT3, SOX2, and CD44 were also expressed by cells outside of the endothelium. NanoString mRNA analysis confirmed transcription activation of pSTAT3, OCT4, and CD44. RT-qPCR confirmed transcription activation of Nanog, SOX2, and SALL4. Our findings support the presence of two ESC-like subpopulations, one within and one outside of the endothelium, of both SCVM and IMVM. Given that the endothelial ESC-like subpopulation expresses the more primitive marker, OCT4, it is exciting to speculate that they give rise to the non-endothelial subpopulation.


Inappropriately chelated iron in the cerebrospinal fluid of amyotrophic lateral sclerosis patients.
ALS is characterized by oxidative damage in the brain and cerebrospinal fluid, which is exerted by pro-oxidative activity of iron. Such activity of iron can be drastically increased in the presence of inappropriate iron ligands that catalyze redox cycling of iron, thereby promoting hydroxyl radical generation. The aim of our study was to determine the relative level of inappropriate iron ligands in the cerebrospinal fluid of ALS patients. To determine the levels of inappropriate iron ligands and redox activity of iron in cerebrospinal fluid (10 samples from ALS patients and 10 controls), we applied electron paramagnetic resonance spectroscopy. We have shown that cerebrospinal fluid of ALS patients comprises two-fold increased level of inappropriate iron ligands, proportionally increasing iron redox activity and hydroxyl radical production compared to controls. In conclusion, our results strongly support the pro-oxidative/detrimental role of inappropriately chelated iron in ALS pathophysiology. The identification of biomolecules that form such iron complexes and their therapeutic targeting may represent the future of ALS treatment.


Anastomosis configuration and technique following ileocaecal resection for Crohn's disease: a multicentre study.
A limited ileocaecal resection is the most frequently performed procedure for ileocaecal CD and different anastomotic configurations and techniques have been described. This manuscript audited the different anastomotic techniques used in a national study and evaluated their influence on postoperative outcomes following ileocaecal resection for primary CD. This is a retrospective, multicentre, observational study promoted by the Italian Society of Colorectal Surgery (SICCR), including all adults undergoing elective ileocaecal resection for primary CD from June 2018 May 2019. Postoperative morbidity within 30 days of surgery was the primary endpoint. Postoperative length of hospital stay (LOS) and anastomotic leak rate were the secondary outcomes. 427 patients were included. The side to side anastomosis was the chosen configuration in 380 patients (89%). The stapled anastomotic (n = 286; 67%), techniques were preferred to hand-sewn (n = 141; 33%). Postoperative morbidity was 20.3% and anastomotic leak 3.7%. Anastomotic leak was independent of the type of anastomosis performed, while was associated with an ASA grade ≥ 3, presence of perianal disease and ileocolonic localization of disease. Four predictors of LOS were identified after multivariate analysis. The laparoscopic approach was the only associated with a reduced LOS (p = 0.017), while age, ASA grade ≥ 3 or administration of preoperative TPN were associated with increased LOS. The side to side was the most commonly used anastomotic configuration for ileocolic reconstruction following primary CD resection. There was no difference in postoperative morbidity according to anastomotic technique and configuration. Anastomotic leak was associated with ASA grade ≥ 3, a penetrating phenotype of disease and ileo-colonic distribution of CD.


Exercise performance in adolescents with autonomic dysfunction.
To test the hypothesis that excessive postural tachycardia is associated with deconditioning rather than merely being an independent sign of autonomic dysfunction in patients with postural orthostatic tachycardia syndrome (POTS). We retrospectively analyzed records from 202 adolescents who underwent both head up-tilt and maximal exercise testing. Patients were classified as POTS if they had ≥ 30 min(-1) rise in heart rate (HR) after tilt-table test; and deconditioned if peak O(2) uptake was < 80% predicted. Changes in HR during exercise and recovery were compared between groups. Two-thirds of patients were deconditioned, irrespective of whether they fulfilled diagnostic criteria for POTS, but peak O(2) uptake among patients with POTS was similar to patients without POTS. HR was higher at rest and during exercise; whereas stroke volume was lower during exercise, and HR recovery was slower in patients with POTS compared with patients without POTS. Most patients who presented with chronic symptoms of dizziness, fatigue, or pre-syncope, were deconditioned, but, because the proportion of deconditioned patients was similar in POTS vs non-POTS groups, we conclude that HR changes in POTS are not solely because of inactivity resulting in deconditioning.


Twelve tips for addressing medical student and resident physician lapses in professionalism.
Medical educators have gained significant ground in the practical and scholarly approach to professionalism. When a lapse occurs, thoughtful remediation to address the underlying issue can have a positive impact on medical students and resident physicians, while failure to address lapses, or to do so ineffectively, can have long-term consequences for learners and potentially patients. Despite these high stakes, educators are often hesitant to address lapses in professionalism, possibly due to a lack of time and familiarity with the process. Attention must be paid to generalizable, hands-on recommendations for daily use so that clinicians and administrators feel well equipped to tackle this often difficult yet valuable task. This article reviews the literature related to addressing unprofessional behavior among trainees in medicine and connects it to the shared experience of medical educators at one institution. The framework presented aims to provide practical guidance and empowerment for educators responsible for addressing medical student and resident physician lapses in professionalism.


Individual differences in neural responses to social rejection: the joint effect of self-esteem and attentional control.
Individuals with low self-esteem have been found to react more negatively to signs of interpersonal rejection than those with high self-esteem. However, previous research has found that individual differences in attentional control can attenuate negative reactions to social rejection among vulnerable, low self-esteem individuals. The current fMRI study sought to elucidate the neurobiological substrate of this buffering effect. We hypothesized and found that while looking at scenes of social rejection (vs negative scenes) low self-esteem high attentional control individuals engaged the rostral anterior cingulate cortex (rACC), an area of the brain associated with emotional control, more than their low self-esteem low attentional control peers. Furthermore, we found that low self-esteem high attentional control individuals evaluated social rejection as less arousing and less rejecting in a separate behavioral task. Importantly, activation in the rACC fully mediated the relationship between the interaction of self-esteem and attentional control and emotional evaluations, suggesting that the rACC activation underlies the buffering effects of attentional control. Results are discussed in terms of individual differences in emotional vulnerability and protection and by highlighting the role of rACC in emotion regulation.


The ability of single screening questions for unhealthy alcohol and other drug use to identify substance dependence in primary care.
Single screening questions (SSQs) are recommended for the evaluation of unhealthy alcohol use and other drug use (risky use through dependence). In addition, SSQs could provide information on severity that is necessary for brief intervention, information thought to be available only from longer questionnaires. We assessed SSQ accuracy for identifying dependence. In a cross-sectional study, 286 primary care patients were administered SSQs for alcohol and for other drugs (each asks how many times they were used in the past year), the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), the Drug Abuse Screening Test (DAST), and a diagnostic interview reference standard for dependence. For each test, we calculated area under the receiver operating characteristic (ROC) curve and the ability to discriminate dependence at an optimal cutoff. The prevalence of alcohol and other drug dependence was 9% and 12%, respectively. Optimal cut points were eight or more times for the alcohol SSQ, a score of three or more for AUDIT-C, three or more times for the other drug SSQ, and a score of four or more for the DAST. The areas under the ROC curve ranged from 0.87 to 0.96. Sensitivity, specificity, and positive and negative likelihood ratios at optimal cut points for the alcohol SSQ were 88%, 84%, 5.6, and 0.1, respectively; for the other drug SSQ were 97%, 79%, 4.6, 0.04, respectively; for the AUDIT-C were 92%, 71%, 3.2, 0.1, respectively; and for the DAST were 100%, 84%, 6.3, 0, respectively. Alcohol SSQ and AUDIT-C positive likelihood ratio 95% confidence intervals did not overlap. SSQs can identify substance dependence as well as and sometimes better than longer screening tools. SSQs may be useful for both screening and preliminary assessment, thus overcoming a barrier (seen with lengthy questionnaires) to dissemination of screening and brief intervention in primary care settings.


Performance evaluation of polycrystalline HgI2 photoconductors for radiation therapy imaging.
Electronic portal imaging devices based on megavoltage (MV), active matrix, flat-panel imagers (AMFPIs) are presently regarded as the gold standard in portal imaging for external beam radiation therapy. These devices, employing indirect detection of incident radiation by means of a metal plate plus phosphor screen combination, offer a quantum efficiency of only approximately 2% at 6 MV, leading to a detective quantum efficiency (DQE) of only approximately 1%. In order to significantly improve the DQE performance of MV AMFPIs, a strategy based on the development of direct detection imagers incorporating thick films of polycrystalline mercuric iodide (HgI2) photoconductor was undertaken and is reported. Two MV AMFPI prototypes, one incorporating an approximately 300 microm thick HgI2 layer created through physical vapor deposition (PVD) and a second incorporating an approximately 460 microm thick HgI2 layer created through screen-printing of particle-in-binder (PIB) material, were quantitatively evaluated using a 6 MV photon beam. The reported measurements include empirical determination of x-ray sensitivity, lag, modulation transfer function (MTF), noise power spectrum, and DQE. For both prototypes, MTF and DQE results were found to be consistent with theoretical expectations and the MTFs were also found to be higher than that measured from a conventional MV AMFPI. In addition, the DQE results exhibit input-quantum-limited behavior, even at extremely low doses. Compared to PVD, the PIB prototype exhibits much lower dark current, slightly higher lag, and similar DQE. Finally, the challenges associated with this approach, as well as strategies for achieving considerably higher DQE through thicker HgI2 layers, are discussed. The DQE of each of the prototypes is found to be comparable to that of conventional MV AMFPIs, commensurate with the modest photoconductor thicknesses of these early samples. It is anticipated that thicker layers of HgI2 based on PIB deposition can provide higher DQE while maintaining good material properties.


Hysteresis of the venous pressure-volume relationship in the forearm of borderline hypertensive subjects.
1. The forearm venous pressure-volume relationship was studied in 14 young men with borderline hypertension and in 16 control subjects of the same age and sex. Strain-gauge plethysmography was used to evaluate volume changes after slow increases and decreases in distention, in order to estimate the amplitude of the hysteresis curve. 2. Compared with normotensive control subjects, subjects with borderline hypertension had significantly higher values of blood pressure, heart rate and forearm blood flow. 3. Baseline forearm venous tone was slightly, but not significantly, increased in borderline hypertensive subjects (21.35 +/- 6.53 versus 18.75 +/- 5.95 mmHg ml-1 100 ml-1) and was significantly enhanced after a cold pressor test. The increase was no higher in the borderline hypertensive subjects than in the normotensive control subjects. 4. The area of the hysteresis curve was significantly decreased (7.58 +/- 3.58 versus 10.34 +/- 5.67 arbitrary units; P = 0.0092) as was the extent of isotonic relaxation (creep) (0.28 +/- 0.11 versus 0.39 +/- 0.22 ml/100 ml; P = 0.0098) in borderline hypertensive subjects compared with control subjects. Both parameters were unaffected by the cold pressor test. 5. The study suggests that the viscous component of the venous wall is altered in young patients with borderline hypertension, indicating intrinsic changes in vascular segments which are not exposed to increased intraluminal pressure.


Gamma globulin and antibody formation in vitro. I. Gamma globulin formation in tissues from immature and normal adult rabbits.
Gamma globulin formation in vitro by various tissues was studied using the incorporation of C(14)-L-lysine into a protein precipitable by a specific anti rabbit gamma globulin serum prepared in a sheep. It was demonstrated that the rate of gamma globulin formation in similar numbers of spleen cells is much higher if taken from an immunized rabbit at the height of antibody formation than that in normal spleen cells. Besides spleen, other tissues shown to form gamma globulin in normal adult rabbits were: peripheral lymph nodes, bone marrow, lung, mesenteric lymph nodes, appendix, and thymus. In tissues from newborn rabbits gamma globulin formation could not be demonstrated. Rabbits 1 week old already showed a beginning of significant gamma globulin formation in appendix tissue, followed approximately 3 weeks later by gamma globulin synthesis in spleen and thymus. Histological observations on these tissues were described and correlated with findings on gamma globulin formation. In the discussion an attempt has been made to relate these observations on newborn and immature rabbits to those available in the literature on antibody formation in newborn animals.


Molecular analysis of T-DNA insertion mutants identified putative regulatory elements in the AtTERT gene.
Analysis of plants bearing a T-DNA insertion is a potent tool of modern molecular biology, providing valuable information about the function and involvement of genes in metabolic pathways. A collection of 12 Arabidopsis thaliana lines with T-DNA insertions in the gene coding for the catalytic subunit of telomerase (AtTERT) and in adjacent regions was screened for telomerase activity [telomere repeat amplification protocol (TRAP) assay], telomere length (terminal restriction fragments), and AtTERT transcription (quantitative reverse transcription-PCR). Lines with the insertion located upstream of the start codon displayed unchanged telomere stability and telomerase activity, defining a putative minimal AtTERT promoter and the presence of a regulatory element linked to increased transcription in the line SALK_048471. Lines bearing a T-DNA insertion inside the protein-coding region showed telomere shortening and lack of telomerase activity. Transcription in most of these lines was unchanged upstream of the T-DNA insertion, while it was notably decreased downstream. The expression profile varied markedly in mutant lines harbouring insertions at the 5' end of AtTERT which showed increased transcription and abolished tissue specificity. Moreover, the line FLAG_385G01 (T-DNA insertion inside intron 1) revealed the presence of a highly abundant downstream transcript with normal splicing but without active telomerase. The role of regulatory elements found along the AtTERT gene is discussed in respect to natural telomerase expression and putative intron-mediated enhancement.


Antenatal palliative care consultation: implications for decision-making and perinatal outcomes in a single-centre experience.
Some pregnant patients with complex fetal anomalies meet with paediatric palliative care subspecialists prior to delivery, but referral to antenatal palliative care consultation (APCC) is not standard. Little is known about its role in perinatal decision-making. A single-centre retrospective cohort study was undertaken for patients referred for outpatient antenatal counselling by a neonatologist over a two-and-half-year period. Patients also receiving APCC were compared with infants with similar prognoses who did not. Outcomes assessed included antenatal decision-making, obstetric and neonatal outcomes. 24 (17%) of the 144 referred fetuses received APCC; nearly all had been given the prognoses of 'non-survivable' or 'uncertain, likely poor'. Fetal or neonatal outcome included: fetal demise 5 (21%), in-hospital death 16 (67%) and survival to discharge (DC) 3(12%). 24 fetuses with similarly poor prognoses were not referred, but had similar outcomes: fetal demise 5 (21%), in-hospital death 16 (67%) and survival to DC 3 (12%). Those with APCC were more likely to choose comfort care than those without (67% vs 17%, p<0.01) and those who died in hospital had a shorter time to death than those who did not receive APCC. Less racial diversity was noted in the group receiving APCC. Infants with identified/suspected genetic syndromes were more likely to receive consultation despite similar mortality to the remaining cohort. Long-term outcomes with and without APCC were similar for infants with poor prognoses, though non-survivors with APCC were more likely to have a comfort care plan and shorter time to in-hospital death.


MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.
Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.