Care staff training in detection of depression in residential homes for the elderly: randomised trial.
Many people with depression in residential care homes for the elderly do not receive treatment because their depression remains undetected. To determine the effects of staff training on the detection, treatment and outcome of depression in residents of ten homes. We conducted a randomised controlled trial in ten residential homes. The intervention consisted of a training programme for staff and collaborative evaluation by staff and a mental health specialist of residents with possible depression. Recognition of depression increased more in homes where staff received the training than in the control homes. Treatment rates also increased compared with control homes, but the increase was not significant. Residents with depressive symptoms had a more favourable course when staff had received training. Moreover, the prevalence of depressive symptoms decreased, but the decrease was not significant. Training of care staff results in the increased detection of depression in the elderly, a trend towards more treatment and better outcomes.


Clinical assessment of left ventricular regional contraction patterns and ejection fraction by high-resolution gated scintigraphy.
An improved, noninvasive, radionuclidic, gated blood-pool imaging technique has been developed for clinical analysis of regional contraction abnormalities of the left ventricle and determination of ejection fraction. The principal innovations include high-resolution collimation, higher information density, improved method for dynamic aortic-mitral-diaphragmatic border delineation, accurate selection of the endsystolic gating interval through the use of the phonocardiogram, and accurate end-diastole by on-line gating immediately following the electrocardiographic QRS. The results of scintigraphic studies were compared with selective radiopaque cineangiographic findings in 27 patients with cardiac disease; excellent correlations of ejection fractions (r = 0.93) and abnormal contraction patterns (17/17 patients) were demonstrated. In addition, the clinical usefulness in evaluating ventricular performance was demonstrated in 79 patients with acute and chronic coronary artery disease. This radionuclidic technique allowed assessment of reversibility of segmental dyssynergy by the response to nitroglycerin in 20 patients. These findings demonstrate the validity of this improved radionuclidic technique in the atraumatic quantification of ventricular function and suggest its usefulness in a variety of clinical conditions.


Phase I study of a continuous infusion of high-dose ara-C in conjunction with a fixed dose of 2'-deoxycytidine (IND 28108) in patients with refractory leukemia: an interim report.
A total of 16 patients with refractory leukemia have been entered on a phase I study employing escalating doses of a 96 h continuous infusion of high-dose cytosine arabinoside (ara-C) administered in conjunction with a 120 h infusion of a fixed dose (22 g/m2 per day) of 2'-deoxycytidine (IND 28108) as a host-protective agent. Extramedullary toxicities, even at the highest ara-C dose level (e.g. 14 g/m2 per day) were mild (e.g. CALGB grade I or II), and consisted of diarrhea, fluid retention, somnolence, hepatic dysfunction, and febrile episodes. Neutropenia and thrombocytopenia were noted in all patients, but no serious infections or bleeding episodes were encountered. Steady state plasma ara-C concentrations of 20-60 microM were observed in patients treated at the 14 g/m2 dose, and were associated with plasma ara-U concentrations approaching 1 mM. Although no complete remissions were obtained at the ara-C dose levels tested to date, three partial remissions were noted, and the large majority of patients experienced a clearing of peripheral blood blasts. In addition, several patients who failed to achieve objective responses exhibited atypically benign clinical courses following completion of therapy. These findings demonstrate that 2'-deoxycytidine protects humans from otherwise lethal doses of high-dose ara-C administered by continuous infusion, and substantially ameliorates the hematologic and non-hematologic toxicity of such regimens without completely abrogating antileukemic activity. Determination of the ultimate efficacy of this strategy will require identification of an ara-C maximum tolerated dose and evaluation of the antileukemic potential of this regimen in prospective phase 11 trials.


Assessing the Delivery of the Thinking for a Change Program in Modified Formats: An Experimental Approach.
This paper evaluates whether participation in the Thinking for a Change cognitive behavioral program produces improvement in social problemsolving skills in a prison context. Data are derived from a randomized experiment, with a focus on whether improvement in social problemsolving skills varies across modified delivery formats, and whether improvements are attributable to program completion or program dosage. We find that there are significant improvements in social problem solving between the pre- and post-test, and that delivery of the curriculum using video conferencing technology or inmate co-facilitated formats produces equivalent outcomes relative to traditional classroom administration. On average, significant improvements accrue to participants who receive greater program dosage. However, program completion, commonly viewed as a primary marker of satisfactory program performance, is not associated with improvement in social problem solving. Implications of the findings for rehabilitation programming are discussed, including considerations in a pandemic context.


Plasma carotenoid and vitamin E concentrations in women living in a rural west African (Gambian) community.
Vitamin E and carotenoid pigments are important nutrients for the maintenance of health and protection of tissues against free radical damage. They also play a potential role in disease-risk-prediction and -protection, but little is known about their physiological and sociodemographic correlates and determinants, especially in a West African context. As part of a study of reproductive health in rural Gambian women, blood samples were obtained from 1286 women aged 15 to 54 years, living in the Farafenni area of The Gambia. Measurement of two forms of vitamin E and six carotenoids in plasma was performed by high performance liquid chromatography. All eight components, but especially the carotenoids: lycopene, alpha- and beta-carotene, exhibited a major seasonal variation, with maximum levels between May and July, corresponding to the end of the "mango" season and the beginning of the "rainy" season. Only the tocopherols varied significantly (increasing) with age. Several unexpected ethnic group differences were observed, and canthaxanthin was present at lower concentrations in women with manual occupations, compared to those with non-manual occupations. There were also significant differences associated with pregnancy and the postpartum period, especially for the tocopherols, but fewer differences associated with marital status. The observed patterns confirm that there are important seasonal, physiological, possibly genetic, and sociodemographic determinants of these nutrients in blood plasma, which may have significance for health and longevity.


The role of oxytocin in empathy to the pain of conflictual out-group members among patients with schizophrenia.
Oxytocin (OT) is associated with our ability to empathize and has been shown to play a major role in mediating social behaviors within the context of intergroup dynamics. Schizophrenia is associated with impaired empathy, and with a dysfunctional oxytocinergic system. The effect of OT on the empathic responses of patients with schizophrenia within the context of intergroup relationships has not been studied. The present study examined the effect of OT on the patients' empathic responses to pain experienced by in-group, conflictual out-group and neutral out-group members. In a double-blind, placebo-controlled, within-subject cross-over design, the responses on the Pain Evaluation Task of 28 male patients with schizophrenia were compared to 27 healthy male controls. All participants received a single intranasal dose of 24 IU OT or placebo, 1 week apart. OT induced an empathy bias in the healthy controls towards the conflictual out-group members. Although this effect was absent in the patient group, OT seems to heighten an empathic bias in the patient group towards the in-group members when rating non-painful stimuli. The study demonstrates that the administration of OT can result in empathic bias towards adversary out-group members in healthy controls but not in patients with schizophrenia. However, the OT-induced bias in both the patients (in the no-pain condition towards the in-group members) and the healthy controls (in the no-pain and pain conditions towards the adversary out-group) suggests that OT enhances the distinction between conflictual in-group and out-group members.


Hydrodynamics of bilayer membranes with diffusing transmembrane proteins.
We consider the hydrodynamics of lipid bilayers containing transmembrane proteins of arbitrary shape. This biologically-motivated problem is relevant to the cell membrane, whose fluctuating dynamics play a key role in phenomena ranging from cell migration, intercellular transport, and cell communication. Using Onsager's variational principle, we derive the equations that govern the relaxation dynamics of the membrane shape, of the mass densities of the bilayer leaflets, and of the diffusing proteins' concentration. With our generic formalism, we obtain several results on membrane dynamics. We find that proteins that span the bilayer increase the intermonolayer friction coefficient. The renormalization, which can be significant, is in inverse proportion to the protein's mobility. Second, we find that asymmetric proteins couple to the membrane curvature and to the difference in monolayer densities. For practically all accessible membrane tensions (σ > 10(-8) N m(-1)) we show that the protein density is the slowest relaxing variable. Furthermore, its relaxation rate decreases at small wavelengths due to the coupling to curvature. We apply our formalism to the large-scale diffusion of a concentrated protein patch. We find that the diffusion profile is not self-similar, owing to the wavevector dependence of the effective diffusion coefficient.


[Appendiceal mucinous cystadenoma].
Appendiceal neoplasms are rare. Patients may present with clinical symptoms suggestive of "acute appendicitis" or other unspecific abdominal complaints. An appendiceal mucinous neoplasia is sometimes diagnosed during a laparotomy performed on another indication. Frequently, the condition remains undiagnosed until the pathologists' examination. We present the case of a 49-year-old woman who presented with symptoms suggestive of acute appendicitis. An appendectomy was performed. The appendectomy specimen revealed a mucinous cystadenoma with a diverticulum in the appendix. The case is discussed in the light of the current literature. Appendiceal tumours account for less than 0.4% of neoplasias in the gastrointestinal tract and are found in less than 1% of appendectomies. Mucinous lesions ("mucocele") are classified as mucosal hyperplasia, mucinous cystadenoma, or mucinous cystadenocarcinoma. However, there are reports of great variability in the biological behavior, especially concerning the development of pseudomyxoma peritonei. No current consensus exists as to diagnostic criteria or treatment. A radically removed appendix is curative in most cases of mucinous cystadenoma, whereas right hemicolectomy should be considered for patients with malignant mucinous lesions of the appendix.


Structure of the epiphyte community in a tropical montane forest in SW China.
Vascular epiphytes are an understudied and particularly important component of tropical forest ecosystems. However, owing to the difficulties of access, little is known about the properties of epiphyte-host tree communities and the factors structuring them, especially in Asia. We investigated factors structuring the vascular epiphyte-host community and its network properties in a tropical montane forest in Xishuangbanna, SW China. Vascular epiphytes were surveyed in six plots located in mature forests. Six host and four micro-site environmental factors were investigated. Epiphyte diversity was strongly correlated with host size (DBH, diameter at breast height), while within hosts the highest epiphyte diversity was in the middle canopy and epiphyte diversity was significantly higher in sites with canopy soil or a moss mat than on bare bark. DBH, elevation and stem height explained 22% of the total variation in the epiphyte species assemblage among hosts, and DBH was the most important factor which alone explained 6% of the variation. Within hosts, 51% of the variation in epiphyte assemblage composition was explained by canopy position and substrate, and the most important single factor was substrate which accounted for 16% of the variation. Analysis of network properties indicated that the epiphyte host community was highly nested, with a low level of epiphyte specialization, and an almost even interaction strength between epiphytes and host trees. Together, these results indicate that large trees harbor a substantial proportion of the epiphyte community in this forest.


SARS-CoV-2 ORF3a-Mediated NF-κB Activation Is Not Dependent on TRAF-Binding Sequence.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus Disease 2019 (COVID-19). Excessive inflammation is a hallmark of severe COVID-19, and several proteins encoded in the SARS-CoV-2 genome are capable of stimulating inflammatory pathways. Among these, the accessory protein open reading frame 3a (ORF3a) has been implicated in COVID-19 pathology. Here we investigated the roles of ORF3a in binding to TNF receptor-associated factor (TRAF) proteins and inducing nuclear factor kappa B (NF-κB) activation. X-ray crystallography and a fluorescence polarization assay revealed low-affinity binding between an ORF3a N-terminal peptide and TRAFs, and a dual-luciferase assay demonstrated NF-κB activation by ORF3a. Nonetheless, mutation of the N-terminal TRAF-binding sequence PIQAS in ORF3a did not significantly diminish NF-κB activation in our assay. Our results thus suggest that the SARS-CoV-2 protein may activate NF-κB through alternative mechanisms.


Gabapentin and postoperative pain and opioid consumption: A double-blind randomized controlled trial of perioperative pain management for sinus surgery.
The link between post-operative narcotic prescription and opioid misuse has spurred a nationwide effort to reduce perioperative opioid use. Previous work has suggested that perioperative gabapentin may reduce post-operative pain and opioid consumption across different procedures, although the optimal regimen remains to be defined. Chronic rhinosinusitis (CRS) patients undergoing functional endoscopic sinus surgery (FESS) with or without septoplasty were randomized to receive a 7-day pre- and post-operative course of placebo or gabapentin, starting at 300 mg daily and titrated to 300 mg three times daily, in a double-blind fashion. Primary endpoint was pain level using a validated visual analog scale (VAS). Secondary endpoints included post-operative opioid consumption and side effects, as well as modified Lund-Kennedy endoscopy, Lund-Mackay, and SNOT-22 scores. Analysis of 35 patients (20 gabapentin, 15 control) showed no significant difference in mean postoperative VAS (p = 0.18) or postoperative opioid consumption between the placebo and gabapentin groups (2.3 and 4.8 oxycodone tablets respectively, p = 0.18). 15 of 35 patients did not require any post-operative oxycodone tablets, and only two patients required more than six tablets. Preliminary results show no significant change in pain after FESS with or without septoplasty in patients taking 7-day pre- and post-operative gabapentin versus placebo. Results also showed no significant difference in opioid consumption between the treatment and placebo groups. Post-operative pain scores and opioid requirements are both quite low following FESS. Many patients do not need opioids at all, suggesting that routine initial post-operative opioid prescriptions can be limited accordingly.


Monoclonal anti-claudin 1 antibodies prevent hepatitis C virus infection of primary human hepatocytes.
Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. The tight junction protein claudin-1 (CLDN1) has been shown to be required for entry of HCV into the cell. Using genetic immunization, we produced 6 monoclonal antibodies against the host entry factor CLDN1. The effects of antibodies on HCV infection were analyzed in human cell lines and primary human hepatocytes. Competition and binding studies demonstrated that antibodies interacted with conformational epitopes of the first extracellular loop of CLDN1; binding of these antibodies required the motif W(30)-GLW(51)-C(54)-C(64) and residues in the N-terminal third of CLDN1. The monoclonal antibodies against CLDN1 efficiently inhibited infection by HCV of all major genotypes as well as highly variable HCV quasispecies isolated from individual patients. Furthermore, antibodies efficiently blocked cell entry of highly infectious escape variants of HCV that were resistant to neutralizing antibodies. Monoclonal antibodies against the HCV entry factor CLDN1 might be used to prevent HCV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.


Initial experience with an innovative endoscopic clipping system.
There are few options for the treatment of fistulas, leaks, and perforations endoscopically. Here we describe our experience with an endoscopic clipping system. A retrospective review of all cases using the Over-The-Scope-Clip system (Ovesco Endoscopy AG, Tuebingen, Germany) was performed. The system was utilized in ten patients with gastrointestinal surgical complications. Four patients had gastric leaks following sleeve gastrectomy, one had a post-operative colonic leak, two had gastro-gastric fistulas following gastric bypass, and three had esophageal perforations. Two leak patients had complete resolution, one had a contained leak following clip placement that was clinically insignificant, and the fourth patient had a persistent leak despite two clipping procedures. Two patients had gastro-gastric fistulas following roux-en-y gastric bypass surgery and, while they both had initial success, the fistulas recurred. One patient presented with anastomotic leak following colon resection but the system was unable to reach the treatment site. Three patients were successfully treated for esophageal perforation. There were no complications. This over-the-scope endoscopic clip system is simple to use, safe, and successful in approximating tissue to treat traditionally difficult surgical complications. Further experience and longer follow-up are needed to assess its indications as related to defect size and location.


Superoleophobic cotton textiles.
Common cotton textiles are hydrophilic and oleophilic in nature. Superhydrophobic cotton textiles have the potential to be used as self-cleaning fabrics, but they typically are not super oil-repellent. Poor oil repellency may easily compromise the self-cleaning property of these fabrics. Here, we report on the preparation of superoleophobic cotton textiles based on a multilength-scale structure, as demonstrated by a high hexadecane contact angle (153 degrees for 5 microL droplets) and low roll-off angle (9 degrees for 20 microL droplets). The multilength-scale roughness was based on the woven structure, with additional two layers of silica particles (microparticles and nanoparticles, respectively) covalently bonded to the fiber. Superoleophobicity was successfully obtained by incorporating perfluoroalkyl groups onto the surface of the modified cotton. It proved to be essential to add the nanoparticle layer in achieving superoleophobicity, especially in terms of low roll-off angles for hexadecane.


Botulinum toxin in the treatment of partially accommodative esotropia with high AC/A ratio.
To study the outcome of botulinum toxin (BTX) treatment (group 1) in partially accommodative esotropia with high accommodative convergence/accommodation (AC/A) ratio, in comparison with bilateral medial rectus muscles recessions and posterior fixation (group 2). In a retrospective comparative study, children aged 3-8 years old treated between 2011 and 2016, with partially accommodative esotropia with high AC/A ratio, deviation at distance of 10 prism diopters or more, and at least 1 year of follow-up, were included. Visual acuity, alternate prism and cover test, stereoacuity, biomicroscopy, and cycloplegic retinoscopy were carried out at initial, baseline visit, 6 months and 1 year after BTX injection or surgery. Main outcome variables were deviation at distance and near, improvement in stereoacuity, and percentage of success. We used multiple regression or proportional odds analysis to control for potential confounding variables. Of 95 patients, 84 were eligible, 48 children in group 1 and 36 in group 2. Deviation and stereoacuity were similar in the two groups at 6 months, but significantly better in the BTX group at 1 year (median distance deviation 0 prism diopters vs 5 prism diopters, p<0.01), although differences were not clinically relevant. Percentage of success was also significantly better only at 1 year (93% vs 72%, p = 0.01). Change in distance-near disparity was not significantly different in the two groups in the period of study. Botulinum toxin could be superior to, or as effective as surgery, at middle term, in the treatment of partially accommodative esotropia with high AC/A ratio.


Early gamma interferon production by natural killer cells is important in defense against murine listeriosis.
A spot enzyme-linked immunosorbent assay was used to show that subcutaneous inoculation of a sublethal number of Listeria monocytogenes resulted in the early appearance of gamma interferon (IFN-gamma)-producing cells in the draining lymph nodes. In contrast, inoculation of UV-killed L. monocytogenes failed to cause the appearance of IFN-gamma-producing cells. The appearance of IFN-gamma-secreting cells in response to the living organisms peaked at 24 h of infection and then declined. The draining lymph node cells responsible for secreting IFN-gamma belonged to a cell population that was positive for the NK1.1, asialo-GM1, and Thy-1 markers but negative for the CD4 and CD8 T cell subset markers. Early elimination of natural killer (NK) cells by treatment with anti-NK cell antibodies resulted in severe exacerbation of infection, as did early neutralization of endogenous IFN-gamma by treatment with a rat anti-murine IFN-gamma monoclonal antibody. In contrast, depletion of CD4+ and CD8+ T cells failed to exacerbate infection. The results serve to show that the early production of IFN-gamma by NK cells, rather than by T cells, is an essential event in resistance to listeriosis.


Sero-epidemiology of mumps in western Europe.
Six countries (Denmark, England and Wales, France, Germany, Italy and The Netherlands) conducted large serological surveys for mumps, in the mid-1990s, as part of the European Sero-Epidemiology Network (ESEN). The assay results were standardized and related to the schedules and coverage of the immunization programmes and the reported incidence of mumps. Low incidence of disease and few susceptibles amongst adolescents and young adults was observed in countries with high mumps vaccine coverage (e.g. The Netherlands). High disease incidence and large proportions of mumps virus antibody negative samples in adolescent and young adult age groups was noted in countries with poor vaccine coverage (e.g. Italy). The build-up of susceptibles in older children and adolescents in England and Wales, France, the former West Germany and Italy indicate the possibility of further mumps outbreaks in secondary school environments. To control mumps in western Europe, current MMR immunization programmes will need to be strengthened in a number of countries. Sero-surveillance of mumps is an important component of disease control and its usefulness will be enhanced by the development of an international mumps standard.


Visual Reasoning for Uncertainty in Spatio-Temporal Events of Historical Figures.
The development of digitized humanity information provides a new perspective on data-oriented studies of history. Many previous studies have ignored uncertainty in the exploration of historical figures and events, which has limited the capability of researchers to capture complex processes associated with historical phenomena. We propose a visual reasoning system to support visual reasoning of uncertainty associated with spatio-temporal events of historical figures based on data from the China Biographical Database Project. We build a knowledge graph of entities extracted from a historical database to capture uncertainty generated by missing data and error. The proposed system uses an overview of chronology, a map view, and an interpersonal relation matrix to describe and analyse heterogeneous information of events. The system also includes uncertainty visualization to identify uncertain events with missing or imprecise spatio-temporal information. Results from case studies and expert evaluations suggest that the visual reasoning system is able to quantify and reduce uncertainty generated by the data.


Grapevine rootstock effects on scion biomass are not associated with large modifications of primary shoot growth under nonlimiting conditions in the first year of growth.
In grapevine (Vitis vinifera L.), rootstocks are known to alter scion development by modifying stem weight and yield. The aim of this work was to evaluate the contribution of primary growth to the rootstock effects on scion biomass. The shoot growth of Vitis vinifera cv. Cabernet Sauvignon N autografted and grafted onto Vitis riparia cv. Riparia Gloire de Montpellier and Vitis berlandieri×V. rupestris cv. 1103 Paulsen was studied in young plants grown in pots trained to one stem in two experiments. Stem elongation and phytomer emergence were studied from grafting until the end of the growth season. The elongation of the Cabernet Sauvignon N leaves, tendrils and internodes of each phytomer along the stem was fitted using sigmoid curves. The rootstocks studied slightly altered the growth dynamics of the leaves, internodes and tendrils of the scion. This is the first study to examine the effect of rootstocks on shoot growth dynamics in any species. The alterations in primary growth were small, suggesting that rootstocks may alter scion biomass principally by modifying secondary growth.


Increased CDC20 expression is associated with development and progression of hepatocellular carcinoma.
Cell division cycle 20 (CDC20) encodes a regulatory protein interacting with the anaphase-promoting complex/cyclosome (APC/C) in the cell cycle and plays important roles in tumorigenesis and progression of multiple tumors. The present study aimed to investigate the clinical significance of CDC20 in hepatocellular carcinoma (HCC) and the role of CDC20 in the progression of HCC. By bioinformatics analysis, CDC20 was found to be the major node in HCC molecular interaction networks. Quantitative PCR and western blot analyses were applied to examine CDC20 expression in 16 paired primary HCC tissues. Immunohistochemistry (IHC) was performed to examine CDC20 protein expression in 132 matched paraffin-embedded HCC tissues and to analyze the relationship between CDC20 staining and clinical characteristics. Small interfering RNA (siRNA) targeting CDC20 was synthesized and transfected into HepG2 cells to investigate the role of CDC20 in cell growth and the cell cycle. Results show that CDC20 expression was upregulated in HCC tissues compared to adjacent non-tumor liver tissues. In the 132 matched HCC tissues, high expression levels of CDC20 were detected in 68.18% HCC samples, and overexpression of CDC20 was positively correlated with gender (P=0.013), tumor differentiation (P=0.000), TNM stage (P=0.012), P53 and Ki-67 expression (P=0.023 and P=0.007, respectively). Cells transfected with CDC20 siRNA showed a decrease in cell proliferation and increase in the number of cells in G2/M-phase. In conclusion, increased expression of CDC20 was demonstrated to be associated with the development and progression of HCC, and may be regarded as a promising therapeutic target for HCC.


Clearance of hepatitis C infection is associated with the early appearance of broad neutralizing antibody responses.
The contribution of humoral immune responses to spontaneous control of hepatitis C virus (HCV) infection remains unclear. We assessed neutralizing antibody (nAb) responses during acute HCV infection to determine whether infection outcome is associated with the nAb response, specifically, its timing or breadth (neutralization of multiple genotype-matched variants). A representative genotype 1 HCV pseudoparticle (HCVpp) library, consisting of 19 genetically distinct genotype 1 HCVpp that comprise the natural variability of genotype 1 E1E2 sequences, was used to assess anti-genotype 1 nAb responses during acute infection in at-risk persons followed prospectively. Neutralization of individual library HCVpp by the last viremic plasma sample obtained before clearance was compared to either 1-year post-initial viremia or clearance time-matched specimens obtained from subjects developing persistent infection. In persistently infected persons nAb responses were delayed then progressively broadened, whereas in persons who controlled viremia broader responses were detected early and contracted after clearance of viremia. Surprisingly, the breadth of anti-genotype 1 nAb responses was not dependent on subjects' infection genotype. Also, individual library HCVpp neutralization sensitivity was not associated with any known E2 sequence determinants. Interestingly, two single nucleotide polymorphisms in the HLA-DQ locus were associated with nAb breadth. Control of HCV infection is associated with more rapid development of a broad nAb response, independent of the infection viral genotype, providing further evidence for the role of nAb in controlling HCV infection and the potential benefit of generating broad anti-HCV nAb responses by vaccination.


Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms.
To define glycemic thresholds for activation of glucose counterregulatory systems and for symptoms of hypoglycemia, we measured these during stepped reductions in the plasma glucose concentration (in six 10-mg/dl hourly steps) from 90 to 40 mg/dl under hyperinsulinemic clamp conditions, and compared these with the same measurements during euglycemia (90 mg/dl) under the same conditions over 6 h in 10 normal humans. Arterialized venous plasma glucose concentrations were used to calculate glycemic thresholds of 69 +/- 2 mg/dl for epinephrine secretion, 68 +/- 2 mg/dl for glucagon secretion, 66 +/- 2 mg/dl for growth hormone secretion, and 58 +/- 3 mg/dl for cortisol secretion. In contrast, the glycemic threshold for symptoms was 53 +/- 2 mg/dl, significantly lower than the thresholds for epinephrine (P less than 0.001), glucagon (P less than 0.001), and growth hormone (P less than 0.01) secretion. Thus, the glycemic thresholds for activation of glucose counterregulatory systems during decrements in plasma glucose lie within or just below the physiologic plasma glucose concentration range, and are substantially higher than the threshold for hypoglycemic symptoms in normal humans. These findings provide further support for the concept that glucose counterregulatory systems are involved in the prevention, as well as the correction, of hypoglycemia.


Composition of the metabolomic bio-coronas isolated from Ocimum sanctum and Rubia tinctorum.
Nanoharvesting from intact plants, organs, and cultured cells is a method in which nanoparticles are co-incubated with the target tissue, which leads to the internalization of nanoparticles. Internalized nanoparticles are coated in situ with specific metabolites that form a dynamic surface layer called a bio-corona. Our previous study showed that metabolites that form the bio-corona around anatase TiO2 nanoparticles incubated with leaves of the model plant Arabidopsis thaliana are enriched for flavonoids and lipids. The present study focused on the identification of metabolites isolated by nanoharvesting from two medicinal plants, Ocimum sanctum (Tulsi) and Rubia tinctorum (common madder). To identify metabolites that form the bio-corona, Tulsi leaves and madder roots were incubated with ultra-small anatase TiO2 nanoparticles, the coated nanoparticles were collected, and the adsorbed molecules were released from the nanoparticle surface and analyzed using an untargeted metabolomics approach. Similar to the results in which Arabidopsis tissue was used as a source of metabolites, TiO2 nanoparticle bio-coronas from Tulsi and madder were enriched for flavonoids and lipids, suggesting that nanoharvesting has a wide-range application potential. The third group of metabolites enriched in bio-coronas isolated from both plants were small peptides with C-terminal arginine and lysine residues.


Terminal restriction fragment length polymorphism analysis of the gut microbiota profiles of pediatric patients with inflammatory bowel disease.
We analyzed the fecal microbiota profiles of pediatric patients with inflammatory bowel disease. Terminal restriction fragment length polymorphism analysis was performed in 10 fecal samples from Crohn's disease (CD), 14 samples from ulcerative colitis (UC) and 27 samples from healthy individuals. The bacterial diversity was evaluated by the Shannon diversity index. In CD patients, a setting of similarity generated three major clusters. The majority of CD patients were classified into CD clusters I and II (9 out of 10), but the majority of healthy individuals (21 of 27) were classified into CD cluster III. In UC patients, a setting of similarity also generated three major UC clusters, but each cluster was not characteristic for UC patients or healthy individuals. The changes in simulated bacterial composition indicated that the class Clostridia, including the genus Faecalibacterium, was significantly decreased in CD patients as compared to UC patients and/or healthy individuals. The genus Bacteroides was also decreased as compared to healthy individuals. The bacterial diversity measured by the Shannon diversity index was significantly reduced in CD patients as compared to healthy individuals. The gut microbiota profile of pediatric CD patients was different from that of healthy children.


Status report on the atopic dermatitis registry TREATgermany.
The TREATgermany registry collects data from children, adolescents, and adults with moderate-to-severe atopic dermatitis (AD) in Germany. For this purpose, clinical and patient-reported outcomes, the course of the disease, and applied therapies are observed. TREATgermany recruits patients with moderate-to-severe AD according to the diagnostic criteria of the UK Working Party, an "Objective Scoring for Atopic Dermatitis" (oSCORAD) > 20 and/or currently antiinflammatory systemic treatment for AD or previous anti-inflammatory systemic treatment for AD within past 24 months before inclusion. No study related interventions will be performed. Currently, 59 dermatological practices, clinics, and university hospitals are participating in TREATgermany (as of May 2021). Based on the interim analysis of October 13, 2020, patient characteristics were described from 4,373 documented visits of adult participants (n = 1,025). The mean age at inclusion in TREATgermany was 42 years, 57.7% of patients were men (n = 591) and 42.3% were women (n = 434). According to oSCORAD, 85.8% of those included suffered from moderate-to-severe AD. At baseline visit, 744 patients had already received one or more systemic treatments for AD (glucocorticosteroids n = 600, ciclosporin A (CSA) n = 307, dupilumab n = 98). 597 patients received dupilumab during their participation in TREATgermany, 134 patients received CSA. With the increasing number of recruitment centers (October 2020: 38 centers; May 2021: 59 centers), TREATgermany can continue to make an important contribution to health services research for patients with moderate-to-severe AD. The registry fulfills the methodological requirements of IQWiG for the collection and processing of healthcare-related data. With the successful and expected approval of further systemic treatments, these can be compared in terms of efficacy and safety in the future. In addition, with the recruitment of children and adolescents started in 2021, this patient group can also be observed.


A general benzylic C-H activation and C-C coupling reaction of zirconocenes mediated by C-N bond cleavage in tert-butylisocyanide - unusual formation of iminoacyl complexes.
Reactions of the zirconocene alkyne complex [rac-(ebthi)Zr(η2-Me3SiC2SiMe3)] (rac-(ebthi) = rac-1,2-ethylene-1,1'-bis(η5-tetrahydroindenyl)) with tert-butylisocyanide and methylbenzenes were investigated. Depending on the stoichiometry, the solvent and the reaction temperature different products were obtained. Starting with the end-on coordination of the isocyanide to the zirconium centre (2), elevated reaction temperatures and an excess of tert-butylisocyanide resulted after the elimination of the alkyne in the formation of zirconocene η2-iminoacyl cyanide complexes 3a-d. These complexes are formed by coupling with a benzyl fragment through C-H bond activation of a methyl group of methylbenzene. The dimeric cyanide bridged zirconocene complex 4 is formed as a side-product of this process. The unexpected dimer and the heterometallacycles were fully characterised, including X-ray crystallography.


Methods for evaluating effectiveness and cost-effectiveness of a Skilled Care Initiative in rural Burkina Faso.
This paper aims to describe the design, methods and approaches used to assess the effectiveness and cost-effectiveness of the Skilled Care Initiative in reducing pregnancy-related and perinatal mortality in Ouargaye district, Burkina Faso. The evaluation used a quasi-experimental design, mixed methods and a composite of tools to compare mortality and severe morbidity (near-miss) of women in reproductive age, perinatal mortality, facility functionality, perceived quality of care, utilisation of maternal health services, and costs borne by families and the health care system for maternal health care in Ouargaye and Diapaga districts. Structured questionnaires and interview guides were developed, pre-tested and piloted prior to the main survey. The evaluation was carried out from January to July 2006. A household census was used to retrospectively assess pregnancy-related and perinatal mortality over the previous 5 years, and causes of pregnancy-related death were identified using a newly developed and tested probabilistic model for interpreting verbal autopsy data. Data were directly entered into Personal Digital Assistant devices at the point of interview. Analyses included univariate and multivariate regressions and incremental cost-effectiveness ratios. A population census covering over half a million people, three qualitative surveys and facility surveys in 47 health centres have been carried out. A partnership with key stakeholders and the use of mixed methods proved feasible for evaluating complex safe motherhood strategies, and the use of hand-held computers proved possible for direct data capture, even in this remote rural environment.


What dermatologists need to know about mast cell disease: a dermatopathologist's view.
Mast cell disease involves a group of conditions characterized by the infiltration of mast cells in the tissues and organs. Mast cell disease predominantly affects the skin, presenting in the form of urticaria pigmentosa. This concise review article defines mast cell disease. This paper presents a dermatopathologist's perspective on the diagnosis, management, and treatment of mast cell disease.


Height and reproductive success in a cohort of british men.
Two recent studies have shown a relationship between male height and number of offspring in contemporary developed-world populations. One of them argues as a result that directional selection for male tallness is both positive and unconstrained. This paper uses data from a large and socially representative national cohort of men who were born in Britain in March 1958. Taller men were less likely to be childless than shorter ones. They did not have a greater mean number of children. If anything, the pattern was the reverse, since men from higher socioeconomic groups tended to be taller and also to have smaller families. However, clear evidence was found that men who were taller than average were more likely to find a long-term partner, and also more likely to have several different long-term partners. This confirms the finding that tall men are considered more attractive and suggests that, in a noncontracepting environment, they would have more children. There is also evidence of stabilizing selection, since extremely tall men had an excess of health problems and an increased likelihood of childlessness. The conclusion is that male tallness has been selected for in recent human evolution but has been constrained by developmental factors and stabilizing selection on the extremely tall.


Cleavage of unreactive bonds with pincer metal complexes.
Since the first reports some three decades ago, the chemistry of pincer metal complexes has seen a tremendous development with impact on materials chemistry, supramolecular chemistry, bioorganometallics, and, presumably most significantly, on (catalytic) bond making and breaking processes. The remarkable progress is due to a large extent to the well-defined nature and tunability of the pincer ligand which allows the reactivity of the metal center to be modified and eventually tailored to specific needs. This Perspective summarizes the achievements in employing pincer complexes for mediating and catalyzing the cleavage of typically unreactive bonds such as C-H, C-C, C-E, and E-H bonds, arguably one of the most spectacular applications of pincer chemistry.


Individual and spousal education, mortality and life expectancy in Switzerland: a national cohort study.
Household measures of socioeconomic position may better account for the shared nature of material resources, lifestyle, and social position of cohabiting persons, but household measures of education are rarely used. We aimed to evaluate the association of combined educational attainment of married couples on mortality and life expectancy in Switzerland. The study included 3,496,163 ever-married persons aged ≥30 years. The 2000 census was linked to mortality records through 2008. Mortality by combined educational attainment was assessed by gender-age-specific HRs, with 95% CIs from adjusted models, life expectancy was derived using abridged life tables. Having a less educated partner was associated with increased mortality. For example, the HR comparing men aged 50-64 years with tertiary education married to women with tertiary education to men with compulsory education married to women with compulsory education was 2.05 (1.92-2.18). The estimated remaining life expectancy in tertiary educated men aged 30 years married to women with tertiary education was 4.6 years longer than in men with compulsory education married to women with compulsory education. The gradient based on individual education was less steep: the HR comparing men aged 50-64 years with tertiary education with men with compulsory education was 1.74 (1.67-1.81). Using individual educational attainment of married persons is common in epidemiological research, but may underestimate the combined effect of education on mortality and life expectancy. These findings are relevant to epidemiologic studies examining socio-demographic characteristics or aiming to adjust results for these characteristics.


TWIST1 plays a pleiotropic role in determining the anaplastic thyroid cancer phenotype.
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human tumors; it is characterized by chemoresistance, local invasion, and distant metastases. ATC is invariably fatal. The aim was to study the role of TWIST1, a basic helix-loop-helix transcription factor, in ATC. Expression of TWIST1 was studied by immunohistochemistry and real-time PCR in normal thyroids and well-differentiated, poorly differentiated, and ATC. The function of TWIST1 was studied by RNA interference in ATC cells and by ectopic expression in well-differentiated thyroid carcinoma cells. ATCs up-regulate TWIST1 with respect to normal thyroids as well as to poorly and well-differentiated thyroid carcinomas. Knockdown of TWIST1 by RNA interference in ATC cells reduced cell migration and invasion and increased sensitivity to apoptosis. The ectopic expression of TWIST1 in thyroid cells induced resistance to apoptosis and increased cell migration and invasion. TWIST1 plays a key role in determining malignant features of the anaplastic phenotype in vitro.


Safety of anticoagulation therapy in well-informed older patients.
In older populations, oral anticoagulation therapy (OAT) is underused by physicians, mainly because of fear of bleeding complications. The aim of this study was to determine the incidence of bleeding complications and associated risk factors in a large heterogeneous group of older patients. Combined retrospective and prospective cohort study conducted in geriatric and internal medicine departments. All patients 80 years or older discharged with the recommendation of OAT were followed up for a mean +/- SD of 28.8 +/- 36.3 months. The rate of bleeding events and the quality of anticoagulation were compared across a wide range of demographic and clinical variables and cognitive and functional status. In addition, we assessed the quality of education given to the patient or caregiver on the use of OAT. Among 15 387 patients 80 years or older, 323 (2.1%) were discharged with the recommendation of OAT. The rate of major bleedings was 2.4 events per 1000 patient-months. Socioeconomic and cognitive variables and functional impairments were not associated with an increased rate of bleeding. In multivariate analysis, insufficient education on OAT as perceived by the patient or caregiver (odds ratio [OR], 8.83), polypharmacy (OR, 6.14), and international normalized ratio values above the therapeutic range (OR, 1.08) were the only significant predictive factors for bleeding complications. The rate of bleeding complications, especially major bleedings, was low in this large group of older patients, many with comorbidities and cognitive and functional impairments. Insufficient OAT education was the major factor that predicted bleeding. Therefore, improving and fostering better methods of OAT education may further reduce bleeding complications.


Practical Strategies Using Medical Cannabis to Reduce Harms Associated With Long Term Opioid Use in Chronic Pain.
Background: Chronic non-cancer pain (CNCP) is estimated to affect 20% of the adult population. Current United States and Canadian Chronic non-cancer pain guidelines recommend careful reassessment of the risk-benefit ratio for doses greater than 90 mg morphine equivalent dose (MED), due to low evidence for improved pain efficacy at higher morphine equivalent dose and a significant increase in morbidity and mortality. There are a number of human studies demonstrating cannabis opioid synergy. This preliminary evidence suggests a potential role of cannabis as an adjunctive therapy with or without opioids to optimize pain control. Methods: In 2017, the Canadian Opioid Guidelines Clinical Tool was created to encourage judicious opioid prescribing for CNCP patients and to reevaluate those who have been chronically using high MED. Mirroring this approach, we draw on our clinical experiences and available evidence to create a clinical tool to serve as a foundational clinical guideline for the initiation of medical cannabis in the management of CNCP patients using chronic opioid therapy. Findings: Following principles of harm reduction and risk minimization, we suggest cannabis be introduced in appropriately selected CNCP patients, using a stepwise approach, with the intent of pain management optimization. We use a structured approach to focus on low dose cannabis (namely, THC) initiation, slow titration, dose optimization and frequent monitoring. Conclusion: When low dose THC is introduced as an adjunctive therapy, we observe better pain control clinically with lower doses of opioids, improved pain related outcomes and reduced opioid related harm.


Predictors of lung function in infants at high risk of atopy: effect of allergen avoidance.
Children of atopic parents are recognised as being at higher risk of developing bronchial asthma, drawing the attention of prevention strategies towards this population. Due to recent advances, lung function abnormalities in asthmatic children may now be measured early in life. The aim ofthis investigation was to examine possible predictors of lung function development in a sub sample of high-risk infants who took part in an allergy avoidance study In 60 babies of atopic parents, measurements of upper airways inflammation were performed at 4 weeks of age, respiratory symptoms were assessed at 6 and 12 months of age, and lung function (Vmax, FRC) was measured at 18 months by the rapid thoracoabdominal compression technique. Twenty-eight babies were enrolled in an allergen avoidance program, and 32 recruited as controls. No significant differences were detected for V'max,FRC between the intervention group (mean 331 ml s(-1)) and the control group (359 ml s(-1)), P = 0.382. A multiple linear regression model could explain levels of V'max FRC by weight gain since birth (beta = -35.35 ml s(-1) kg(-1), P = 0.022) and by eosinophilic cationic protein (ECP) (beta = -0.95 ml s(-1) microl(-1), P = 0.044), but not by intervention. Lung function measured at the age of 18 months in high-risk children is associated with weight gain and nasal ECF.


Mass spectrometry (LC-MS/MS) site-mapping of N-glycosylated membrane proteins for breast cancer biomarkers.
Cancer cell membrane proteins are released into the plasma/serum by exterior protein cleavage, membrane sloughing, cellular secretion or cell lysis, and represent promising candidates for interrogation. Because many known disease biomarkers are both glycoproteins and membrane bound, we chose the hydrazide method to specifically target, enrich, and identify glycosylated proteins from breast cancer cell membrane fractions using the LTQ Orbitrap mass spectrometer. Our initial goal was to select membrane proteins from breast cancer cell lines and then to use the hydrazide method to identify the N-linked proteome as a prelude to evaluation of plasma/serum proteins from cancer patients. A combination of steps facilitated identification of the glycopeptides and also defined the glycosylation sites. In MCF-7, MDA-MB-453 and MDA-MB-468 cell membrane fractions, use of the hydrazide method facilitated an initial enrichment and site mapping of 27 N-linked glycosylation sites in 25 different proteins. However, only three N-linked glycosylated proteins, galectin-3 binding protein, lysosome associated membrane glycoprotein 1, and oxygen regulated protein, were identified in all three breast cancer cell lines. In addition, MCF-7 cells shared an additional 3 proteins with MDA-MB-453. Interestingly, the hydrazide method isolated a number of other N-linked glycoproteins also known to be involved in breast cancer, including epidermal growth factor receptor (EGFR), CD44, and the breast cancer 1, and early onset isoform 1 (BRCA1) biomarker. Analyzing the N-glycoproteins from membranes of breast cancer cell lines highlights the usefulness of the procedure for generating a practical set of potential biomarkers.


The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia.
While genetic influences in schizophrenia are substantial, the disorder's molecular genetic basis remains elusive. Progress has been hindered by lack of means to detect nonpenetrant carriers of the predisposing genes and by uncertainties concerning the extent of locus heterogeneity. One approach to solving this complexity is to examine the inheritance of pathophysiological processes mediating between genotype and disease phenotype. Here we evaluate whether deficits in neurocognitive functioning covary with degree of genetic relationship with a proband in the unaffected MZ and DZ co-twins of patients with schizophrenia. Twin pairs discordant for schizophrenia were recruited from a total population cohort and were compared with a demographically balanced sample of control twin pairs, on a comprehensive neuropsychological test battery. The following four neuropsychological functions contributed uniquely to the discrimination of degree of genetic loading for schizophrenia and, when combined, were more highly correlated within MZ pairs than within DZ pairs, in both discordant and control twins: spatial working memory (i.e., remembering a sequence of spatial locations over a brief delay), divided attention (i.e., simultaneous performance of a counting and visual-search task), intrusions during recall of a word list (i.e., "remembering" nonlist items), and choice reaction time to visual targets. Together with evidence from human and animal studies of mediation of these functions by partially distinct brain systems, our findings suggest that there are multiple independently inherited dimensions of neural deficit in schizophrenia and encourage a search for genes contributing to quantitative variation in discrete aspects of disease liability. On tests of verbal and visual episodic memory, but not on the liability-related measures, patients were more impaired than their own MZ co-twins, suggesting a preferential impact of nongenetic influences on long-term memory systems.


Etoposide-incorporated tripalmitin nanoparticles with different surface charge: formulation, characterization, radiolabeling, and biodistribution studies.
Etoposide-incorporated tripalmitin nanoparticles with negative (ETN) and positive charge (ETP) were prepared by melt emulsification and high-pressure homogenization techniques. Spray drying of nanoparticles led to free flowing powder with excellent redispersibility. The nanoparticles were characterized by size analysis, zeta potential measurements, and scanning electron microscopy. The mean diameter of ETN and ETP nanoparticles was 391 nm and 362 nm, respectively, and the entrapment efficiency was more than 96%. Radiolabeling of etoposide and nanoparticles was performed with Technetium-99m (99mTc) with high labeling efficiency and in vitro stability. The determination of binding affinity of 99mTc-labeled complexes by diethylene triamine penta acetic acid (DTPA) and cysteine challenge test confirmed low transchelation of 99mTc-labeled complexes and high in vitro stability. Pharmacokinetic data of radiolabeled etoposide, ETN, and ETP nanoparticles in rats reveal that positively charged nanoparticles had high blood concentrations and prolonged blood residence time. Biodistribution studies of 99mTc-labeled complexes were performed after intravenous administration in mice. Both ETN and ETP nanoparticles showed significantly lower uptake by organs of the reticuloendothelial system such as liver and spleen (P < .001) compared with etoposide. The ETP nanoparticles showed a relatively high distribution to bone and brain (14-fold higher than etoposide and ETN at 4 hours postinjection) than ETN nanoparticles. The ETP nanoparticles with long circulating property could be a beneficial delivery system for targeting to tumors by Enhanced Permeability and Retention effect and to brain.


[Beta globin haplotypes in hemoglobin S carriers in Colombia].
The hemoglobin S (HbS) mutation is accompanied by other mutations in the region of chromosome 11 known as "beta globin cluster". The pattern of combination of these polymorphisms giving rise to the haplotypes that co-inherit the HbS mutation, are called haplotypes bs, and are of great epidemiological and clinical significance. The frequencies of major haplotypes associated with S beta-globin gene was determined in Colombian patients heterozygous for hemoglobin S. As part of the national neonatal screening program at Clínica Colsanitas, located in major cities of Colombia, nearly 1,200 children from different areas of the country were examined for hemoglobinopathies. The sickle cell trait was identified as the most common. S beta-globin gene haplotypes were determined by PCR and restriction enzymes in 33 children with AS hemoglobin electrophoretic patterns (carrier state). In addition, electrophoretic patterns of hemoglobin, fetal hemoglobin levels and hematologic parameters of each individual were identified. The most frequent haplotypes in Colombia were the Bantú haplotype (36.4 %), followed by Senegal (30.3 %), Benin (21.2 %) and Cameroon (12.1 %) haplotypes. Hemoglobin electrophoresis confirmed the AS phenotype in all patients, and fetal hemoglobin levels below 1%. Other hematological parameters were normal in all cases. The HbS haplotypes found more frequently in the sample were of African origin, and their distribution varied according to the place of origin of the individual. The most frequent corresponded to the Bantu haplotype.


Detection of hepatitis A virus RNA in oyster meat.
Detection of low concentrations of viruses in shellfish is possible with nucleic acid amplification by PCR. Hepatitis A virus (HAV) has been detected in oyster meat by reverse transcription-PCR (RT-PCR). We developed a method to identify HAV RNA by RT-PCR of total RNA extracted from oyster meat contaminated by adsorption, bioaccumulation, or injection. With dot blot hybridization detection of amplicons from the RT-PCR, rapid screening of a large number of samples is feasible. As few as 8 PFU of HAV/g of oyster meat can be detected.


99mTc-sestamibi imaging in the assessment of toremifene as a modulator of multidrug resistance in patients with breast cancer.
Multidrug resistance (MDR) due to expression of a membrane-associated permeability glycoprotein (P-glycoprotein [Pgp]) prevents successful cytotoxic chemotherapy for breast cancer. Identification of MDR would facilitate selection of chemotherapy regimens and MDR modulators. This study aimed to evaluate (99m)Tc-sestamibi imaging for predicting overexpression of Pgp in primary breast cancer and to measure the efficacy of toremifene, the MDR modulator, in vivo. Twenty patients with untreated breast cancer had (99m)Tc-sestamibi imaging 20 and 120 min after tracer injection before and after a 3-d course of toremifene (780 mg/d). Tumor samples were obtained during surgery for correlation of imaging and Pgp immunohistochemistry. Sixteen of 20 tumors were visualized with sestamibi. Before toremifene, there was a significant inverse correlation (Spearman rank correlation coefficient [R(S)]) between staining intensity, based on the anti-Pgp monoclonal antibodies C494 and C219, and the tumor-to-background ratio (T/B) at 120 min (R(S) = -0.85; P < 0.001 and R(S) = -0.71; P < 0.001, respectively). However, the correlation between the T/B and immunohistochemistry at 20 min was significant only for C494 (R(S) = -0.57; P < 0.01). Similarly, before toremifene, there was an inverse correlation between staining intensity and the change in the T/B between 20 and 120 min (R(S) = -0.77; P < 0.001 and -0.75; P < 0.001 for C494 and C219). After toremifene, an inverse correlation between staining intensity and the T/B was seen only at 120 min and only with C494 (R(S) = -0.68; P < 0.01). However, the change in the T/B between 20 and 120 min correlated significantly with staining intensity for C494 and C219 (R(S) = -0.68; P < 0.01 and -0.7; P < 0.01 for C494 and C219, respectively). Toremifene did not significantly alter the overall T/B at either 20 or 120 min when data were compared before and after toremifene. Nevertheless, at 120 min, 8 of 8 tumors with low Pgp expression showed reduced uptake after toremifene, whereas 5 of 6 tumors with strong expression showed increased uptake (P < 0.003). Moreover, there was a significant correlation between the change in the T/B and staining intensity with C494 (R(S) = 0.59; P < 0.05) and C219 (R(S) = 0.56; P < 0.05) at 120 min but not at 20 min. (99m)Tc-Sestamibi accumulation in breast cancer correlates with Pgp expression. Toremifene has a dual effect on this accumulation, increasing it through an inhibitory effect on Pgp while at the same time reducing it by a direct competition with sestamibi. The latter implies that in response to Pgp modulation the efflux of various agents may be affected differently.


Structure of neuroscience clerkships in medical schools and matching in neuromedicine.
Due to the burden of neurologic disease, there is high demand for neurologists, child neurologists, and neurosurgeons. Only 2.6% of graduating medical students matched in neuromedicine residencies in 2014. This number will not likely meet the needs of the population or the projected shortfall. To compensate for this, the medical education system has an obligation to ensure competence in neuromedicine for all trainees and mentorship for students pursuing training in the field. We aim to evaluate the state of the neurology clerkship in US medical schools and how this impacts graduates entering the field. Publicly available curricula of 158 US medical schools were reviewed. Presence of a required neurology clerkship, its duration, and the year offered were tabulated, as were the availability of child neurology and neurosurgery electives and affiliated neuromedicine residencies. The total graduating students from each medical school matching into neuromedicine residencies for 2011-2014 were recorded. Repeated-measure analysis of variance was used to assess the relationship of these variables to number of students matching into the collective neuromedicine. All but 4 schools (97%) published clerkship information. Neurology was a required clerkship at 56% of reporting institutions. Residency match data were not published from 53 schools (35%) and these were excluded from the analysis. In the remaining schools, all variables showed a relationship to students matching in neuromedicine residencies. The presence of a required neurology clerkship and opportunities for students to explore neuromedicine during medical school correlates with students matching into neuromedicine residencies.


Effects of iron deprivation on multidrug resistance of leukemic K562 cells.
Multidrug resistance (MDR) compromises the efficacy of chemotherapy. Many approaches have been used to reduce MDR; however, the results are poor. It has been reported that iron deprivation downregulates MDR genes. To investigate the relationship of iron with MDR and early growth response gene-1 (EGR1), we investigated the effect of iron deprivation on expression and/or function of multidrug resistance-1 (MDR1), early growth response gene-1 (EGR1), ferritin heavy chain gene (H-Fn) and MDR1-encoded P-glycoprotein (P-gp) in the K562 leukemic cell line. The cells were stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and incubated with either FeCl(3) or the iron-chelating drug DFO. The mRNA levels of MDR1, EGR1 and H-Fn were detected by RT-PCR. The protein expression and function of P-gp were measured by immunohistochemical staining and flow cytometry, respectively. DFO significantly reduced the intracellular iron level, and led to approximately 70% reduction of MDR1 mRNA, approximately 50% of reduction of H-Fn mRNA and approximately 30% reduction of P-gp protein in TPA-differentiated K562 cells. The P-gp pump function, measured by daunorubicin exclusion, was also reduced by DFO treatment. These results suggest a close relationship between iron deprivation and reduced MDR1/P-gp expression and function. DFO may be used together with chemotherapeutic drugs to achieve better clinical efficacy.


The antiferroptotic effect of indigo on ulcerative colitis.
The protective effect of indigo on intestinal epithelial cells remains unclear. Yokote Akihito et al. preliminarily investigated the anti-ferroptosis effect of indigo in inflammatory bowel disease. Here, we further discuss and evaluate the role of indigo based on the results.


Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System: JACC Review Topic of the Week.
Severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) host cell infection is mediated by binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/angiotensin 1-7 (Ang1-7)/Mas axis downregulation; increased ACE2 activity was shown to mediate disease protection. Because angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease; thus, they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, it has been hypothesized that the benefits of treatment with renin-angiotensin system inhibitors in SARS-CoV-2 may outweigh the risks and at the very least should not be withheld.


Characterization of the microbiota and chemical properties of pork loins during dry aging.
Dry aging (DA) allows for the storage of meat without packaging at 0 to 3°C for several weeks. It enhances the production of pleasant flavors, tenderness, and juiciness in meat. Due to the long storage period and roles of indigenous microbiota in the maturation of several meat products, the microbiota of DA meat is of interest in terms of microbial contributions and food hygiene but has not yet been characterized in detail. This study identified the microbiota of pork loins during DA using culturing and culture-independent meta-16S rRNA gene sequencing and elucidated its characteristics. The amounts of free amino acids and profiles of aroma-active compounds were also monitored by high-performance liquid chromatography and gas chromatography, respectively. The meta-16S rRNA gene sequencing revealed that Pseudomonas spp. generally dominated the microbiota throughout DA; however, the culturing analysis showed marked changes in the species composition during DA. Acinetobacter spp. were the second most dominant bacteria before DA in the culture-independent analysis but became a minor population during DA. The cell numbers of yeasts showed an increased tendency during DA, and Debaryomyces hansenii was the only microorganism isolated from all meat samples throughout DA. Well-known foodborne pathogens were not observed in two microbiota analyses. The amounts of free amino acids were increased by DA, and the number of aroma-active compounds and their flavor dilution values markedly changed during DA. Most microbial isolates showed positive reactions with proteolytic and lipolytic activities, suggesting their contribution to tenderness and aroma production in DA meats.


Serotonin transporters are preserved in the neocortex of anxious Alzheimer's disease patients.
Densities of serotonin transporters (5-HTT) in the postmortem neocortex of behaviorally assessed Alzheimer's disease (AD) patients and aged controls were measured by radioligand binding with [3H]citalopram. It was found that 5-HTT sites in the temporal cortex of AD patients with prominent antemortem anxiety were unaltered compared with controls, but were reduced in non-anxious AD subjects. Furthermore, homozygosity for the high activity allele of a functional polymorphism in the 5-HTT gene promoter region (5-HTTLPR) was associated with both increased [3H]citalopram binding and occurrence of anxiety in the AD subjects. Since serotonin-synthesizing neurons are known to be lost in the AD cortex, this study suggests that the preservation of 5-HTT may exacerbate serotonergic deficits and underlie anxiety symptoms in AD.


An inducible Cre mouse line to sparsely target nervous system cells, including Remak Schwann cells.
Nerves of the peripheral nervous system contain two classes of Schwann cells: myelinating Schwann cells that ensheath large caliber axons and generate the myelin sheath, and Remak Schwann cells that surround smaller axons and do not myelinate. While tools exist for genetic targeting of Schwann cell precursors and myelinating Schwann cells, such reagents have been challenging to generate specifically for the Remak population, in part because many of the genes that mark this population in maturity are also robustly expressed in Schwann cell precursors. To circumvent this challenge, we utilized BAC transgenesis to generate a mouse line expressing a tamoxifen-inducible Cre under the control of a Remak-expressed gene promoter (Egr1). However, as Egr1 is also an activity dependent gene expressed by some neurons, we flanked this Cre by flippase (Flpe) recognition sites, and coinjected a BAC expressing Flpe under control of a pan-neuronal Snap25 promoter to excise the Cre transgene from these neuronal cells. Genotyping and inheritance demonstrate that the two BACs co-integrated into a single locus, facilitating maintenance of the line. Anatomical studies following a cross to a reporter line show sparse tamoxifen-dependent recombination in Remak Schwann cells within the mature sciatic nerve. However, depletion of neuronal Cre activity by Flpe is partial, with some neurons and astrocytes also showing evidence of Cre reporter activity in the central nervous system. Thus, this mouse line will be useful in mosaic loss-of-function studies, lineage tracing studies following injury, live cell imaging studies, or other experiments benefiting from sparse labeling.


Helping women quit smoking: results of a community intervention program.
This intervention was implemented to reduce the prevalence of cigarette smoking among women. We used community organization approaches to create coalitions and task forces to develop and implement a multicomponent intervention in 2 counties in Vermont and New Hampshire, with a special focus on providing support to help women quit smoking. Evaluation was by pre-intervention and post-intervention random-digit-dialed telephone surveys in the intervention counties and the 2 matched comparison counties. In the intervention counties, compared with the comparison counties, the odds of a woman being a smoker after 4 years of program activities were 0.88 (95% confidence interval = 0.78, 1.00) (P = .02, 1-tailed); women smokers' perceptions of community norms about women smoking were significantly more negative (P = .002, 1-tailed); and the quit rate in the past 5 years was significantly greater (25.4% vs 21.4%; P = .02, 1-tailed). Quit rates were significantly higher in the intervention counties among younger women (aged 18 to 44 years); among women with household annual incomes of $25,000 or less; and among heavier smokers (those who smoked 25 or more cigarettes daily). In these rural counties, community participation in planning and implementing interventions was accompanied by favorable changes in women's smoking behavior.


Remembering one year later: role of the amygdala and the medial temporal lobe memory system in retrieving emotional memories.
The memory-enhancing effect of emotion can be powerful and long-lasting. Most studies investigating the neural bases of this phenomenon have focused on encoding and early consolidation processes, and hence little is known regarding the contribution of retrieval processes, particularly after lengthy retention intervals. To address this issue, we used event-related functional MRI to measure neural activity during the retrieval of emotional and neutral pictures after a retention interval of 1 yr. Retrieval activity for emotional and neutral pictures was separately analyzed for successfully (hits) vs. unsuccessfully (misses) retrieved items and for responses based on recollection vs. familiarity. Recognition performance was better for emotional than for neutral pictures, and this effect was found only for recollection-based responses. Successful retrieval of emotional pictures elicited greater activity than successful retrieval of neutral pictures in the amygdala, entorhinal cortex, and hippocampus. Moreover, in the amygdala and hippocampus, the emotion effect was greater for recollection than for familiarity, whereas in the entorhinal cortex, it was similar for both forms of retrieval. These findings clarify the role of the amygdala and the medial temporal lobe memory regions in recollection and familiarity of emotional memory after lengthy retention intervals.


The lactate dehydrogenases in malignant and non-malignant diseases.
The objective of this paper was to determine different patterns of Lactate Dehydrogenase(LD) isoenzymes in serum, pleural effusions and ascitic fluid collections and their usefulness in the differential diagnosis of malignant and non-malignant diseases. It was a case control study carried out at the Lagos University Teaching Hospital. Forty- six patients with pleural or ascitic fluid collection (male and female, age range between 18 and 65 years) made up of Twenty-two patients with malignant diseases and twenty-four with non- malignant diseases were recruited. Control group comprised 50 apparently healthy subjects of both sexes with age ranging between 18 and 65 years. Serum, pleural and ascitic fluid collections were assayed for total lactate dehydrogenase(LD) and it s isoenzymes. Total LD was estimated using the pyruvate to lactate reaction. LD isoenzyme analysis was estimated by cellulose acetate electrophoresis and stained with formazan. The mean total serum LD activity in the disease groups (malignant and non-malignant) was significantly higher than the mean total serum LD activity in the control group. The pleural fluid LD was highest in patients with empyema thoracis. Five isoenzymes of LD (LD1 - LD5) were present in both control and patient sera. The serum LD1 and LD2 isoenzymes were predominant in the controls. The serum LD4 and LD5 isoenzymes were predominant in the disease groups (malignant and non-malignant). LD4 and LD5 were the predominant isoenzymes in both pleural and ascitic fluids obtained in malignant and non-malignant diseases. Serum LD4 was significantly higher than serum LD5 in non-malignant disease while serum LD5 was significantly higher than serum LD4 in malignant disease. The types of malignancies could not be differentiated by serum and effusion fluid LD isoenzyme pattern. Pleural fluid total LD estimation is useful in monitoring patients on chest tubes and may be used to determine when to insert them. Serum LD4 and LD5 differentiates malignant from non-malignant disease but the effusion LD isoenzyme pattern does not.


Interaction of PRK1 receptor-like kinase with a putative elF2B beta-subunit in tobacco.
PRK1, a receptor-like kinase that is expressed in pollen, pollen tubes, and ovaries, has been shown to play important roles in pollen development and embryo sac development in Petunia inflata. We have used the kinase domain of PRK1 as a bait in the yeast two-hybrid system to identify PRK1-interacting proteins. The screening resulted in isolation of a cDNA encoding a protein highly homologous to the human and yeast beta-subunit of translation initiation factor 2B (eIF2B-beta), which was designated NeIF2Bbeta. eIF2B is a guanine nucleotide exchange protein that functions in the regulation of translation in eukaryotic cells. Deletion mutants of NeIF2Bbeta were analyzed for their interaction with PRK1, and the results suggested that the N-terminal half of NeIF2Bbeta, especially the region between residue 103 and 235, is important for the interaction. This protein association was confirmed by in vitro binding assay of the recombinant NeIF2Bbeta and PRK1 proteins. Despite high sequence homology between NeIF2Bbeta and its yeast counterpart, the NeIF2Bbeta cDNA could not rescue the phenotype of the yeast mutant strain lacking the GCD7 gene encoding eIF2B-beta, when transferred into the mutant strain.


Examining associations between sexual behaviours and quality of life in older adults.
while sexual behaviours are potentially important for quality of life in older adults, they are under-researched. The current study examined associations between frequency and importance of sexual behaviours and quality of life in older adults. one hundred and thirty-three participants (mean 74 years, SD = 7.1) provided information about the frequency with which they participated in six sexual behaviours and the perceived importance of these: touching/holding hands, embracing/hugging, kissing, mutual stroking, masturbating and intercourse. Participants also completed the WHO Quality of Life scale, providing an overall quality of life score, in addition to the domains of physical health, psychological health, social relationships and environment. Participants provided information on their marital status, living arrangements and self-reported health. both the frequency and importance of sexual behaviours were moderately positively correlated with quality of life (r = 0.52 and 0.47, respectively, both P < 0.001). In separate regression analyses, the frequency of sexual behaviours was a significant predictor of quality of life in the social relationships domain (β = 0.225, P < 0.05), and the importance of sexual behaviours was associated with the psychological domain (β = 0.151, P < 0.05), independent of the presence of a spouse/partner and self-reported health. with ageing trends, a broader understanding of the factors that influence quality of life in older adults is increasingly important. The current findings suggest that aspects of sexual behaviour and quality of life were positively associated. Researchers are encouraged to consider aspects of sex and sexuality when exploring determinants of well-being in later life.


A cellular automaton to model the development of primary shoot meristems of Arabidopsis thaliana.
Development of organisms is a very complex process in which a lot of gene networks of different cell types are integrated. Development of a cellular automaton (Ermentrout and Edelshtein-Keshet, J Theor Biol 160:97-133, 1993) that models the morphodynamics of different cell types is the first step in understanding and analysis of the regulatory mechanisms underlying the functioning of developmental gene networks. A model of a cellular automaton has been developed, which simulates the embryonic development of shoot meristem in Arabidopsis thaliana. The model adequately describes the basic stages in development of this organ in wild and mutant types.


A tagging-via-substrate approach to detect the farnesylated proteome using two-dimensional electrophoresis coupled with Western blotting.
Prenylation is a post-translational modification critical for the proper function of multiple physiologically important proteins, including small G-proteins, such as Ras. Methods allowing rapid and selective detection of protein farnesylation and geranylgeranylation are fundamental for the understanding of prenylated protein function and for monitoring efficacy of drugs such as farnesyltransferase inhibitors (FTIs). Although the natural substrates for prenyltransferases are farnesyl pyrophosphate and geranylgeranyl pyrophosphate, farnesyltransferase has been shown to incorporate isoprenoid analogues into protein substrates. In this study, protein prenyltransferase targets were labeled using anilinogeraniol, the alcohol precursor to the unnatural farnesyl pyrophosphate analogue 8-anilinogeranyl diphosphate in a tagging-via-substrate approach. Antibodies specific for the anilinogeranyl moiety were used to detect the anilinogeranyl-modified proteins. Coupling this highly effective labeling/detection method with two-dimensional electrophoresis and subsequent Western blotting allowed simple, rapid analysis of the complex farnesylated proteome. For example, this method elucidated the differential effects induced by two chemically distinct FTIs, BMS-214,662 and L-778,123. Although both FTIs strongly inhibited farnesylation of many proteins such as Lamins, NAP1L1, N-Ras, and H-Ras, only the dual prenylation inhibitor L-778,123 blocked prenylation of Pex19, RhoB, K-Ras, Cdc42, and Rap1. This snapshot approach has significant advantages over traditional techniques, including radiolabeling, anti-farnesyl antibodies, or mass spectroscopy, and enables dynamic analysis of the farnesylated proteome.


Augmented Endoscopic Images Overlaying Shape Changes in Bone Cutting Procedures.
In microendoscopic discectomy for spinal disorders, bone cutting procedures are performed in tight spaces while observing a small portion of the target structures. Although optical tracking systems are able to measure the tip of the surgical tool during surgery, the poor shape information available during surgery makes accurate cutting difficult, even if preoperative computed tomography and magnetic resonance images are used for reference. Shape estimation and visualization of the target structures are essential for accurate cutting. However, time-varying shape changes during cutting procedures are still challenging issues for intraoperative navigation. This paper introduces a concept of endoscopic image augmentation that overlays shape changes to support bone cutting procedures. This framework handles the history of the location of the measured drill tip as a volume label and visualizes the remains to be cut overlaid on the endoscopic image in real time. A cutting experiment was performed with volunteers, and the feasibility of this concept was examined using a clinical navigation system. The efficacy of the cutting aid was evaluated with respect to the shape similarity, total moved distance of a cutting tool, and required cutting time. The results of the experiments showed that cutting performance was significantly improved by the proposed framework.


Effect of ultrasonic treatment on reduction of Esherichia coli ATCC 25922 and egg quality parameters in experimentally contaminated hens' shell eggs.
In this study, hen eggs which were experimentally contaminated with Esherichia coli ATCC 25922 were used. Contaminated eggs were washed statically (S5 to S30; 0 kHz) and by ultrasonic waves (U5 to U30; 35 kHz) for given applications of time (5, 15 and 30 min), then the eggs were stored at 22°C for 14 days. Depending on the time of ultrasonic application, a significant increase in egg shell strength (P < 0.01) was recorded. The highest value of the Haugh unit (67.93, 1 day) was observed on the eggs which were washed by ultrasonic waves. Yolk width values of ultrasonic washed eggs diminished. E. coli was completely removed by 30 min of ultrasonic application. During storage E. coli growth was not detected on the eggs which were washed by ultrasonic waves except the eggs in U5 group (2.04 log CFU eggshell⁻¹) on the first day of storage. Depending on the time of ultrasonic application a significant increase in egg quality parameters (shell strength, albumen height, Haugh units, and yolk height) were observed. The application of ultrasound led to a significant reduction in E. coli numbers on egg shells.


Inositol (1,4,5)-trisphosphate activates a calcium channel in isolated sarcoplasmic reticulum membranes.
Sarcoplasmic reticulum membrane vesicles isolated from frog skeletal muscle display high conductance calcium channels when fused into phospholipid bilayers. The channels are selective for calcium and barium over Tris. The fractional open time was voltage-independent (-40 to +25 mV), but was steeply dependent on the free cis [Ca2+] (P0 = 0.02 at 10 microM cis Ca2+ and 0.77 at 150 microM Ca2+; estimated Hill coefficient: 1.6). Addition of ATP (1 mM; cis) further increased P0 from 0.77 to 0.94. Calcium activation was reversed by addition of EGTA to the cis compartment. Magnesium (2 mM) increased the frequency of rapid closures and 8 mM magnesium decreased the current amplitude from 3.4 to 1.2 pA at 0 mV, suggesting a reversible fast blockade. Addition of increasing concentrations of inositol (1, 4, 5)-triphosphate (cis), increased P0 from 0.10 +/- 0.01 (mean +/- SEM) in the control to 0.85 +/- 0.02 at 50 microM in an approximately sigmoidal fashion, with an apparent half-maximal activation at 15 microM inositol (1, 4, 5)-trisphosphate in the presence of 40 microM cis Ca2+. Lower concentrations of this agonist were required to produce a significant increase in P0 when 10 microM or less cis Ca2+ were used. The channel was blocked by the addition to the cis compartment of either 0.5 mM lanthanum, 0.5 microM ruthenium red, or 200 nM ryanodine, all known inhibitors of Ca2+ release from sarcoplasmic reticulum vesicles. These results demonstrate the presence of calcium channels in the sarcoplasmic reticulum from frog skeletal muscle with a pharmacological profile consistent with a role in excitation contraction coupling and with the hypothesis that inositol ( 1,4,5)-trisphosphate is a physiological agonist in this process.


Nucleophosmin: from structure and function to disease development.
Nucleophosmin (NPM1) is a critical cellular protein that has been implicated in a number of pathways including mRNA transport, chromatin remodeling, apoptosis and genome stability. NPM1 function is a critical requirement for normal cellular biology as is underlined in cancer where NPM1 is commonly overexpressed, mutated, rearranged and sporadically deleted. Consistent with a multifunctional role within the cell, NPM1 can function not only as a proto-oncogene but also as a tumor suppressor. The aim of this review is to look at the less well-described role of NPM1 in the DNA repair pathways as well as the role of NPM1 in the regulation of apoptosis and its mutation in cancers.


Evidence for two-dimensional solitary sound waves in a lipid controlled interface and its implications for biological signalling.
Biological membranes by virtue of their elastic properties should be capable of propagating localized perturbations analogous to sound waves. However, the existence and the possible role of such waves in communication in biology remain unexplored. Here, we report the first observations of two-dimensional solitary elastic pulses in lipid interfaces, excited mechanically and detected by FRET. We demonstrate that the nonlinearity near a maximum in the susceptibility of the lipid monolayer results in solitary pulses that also have a threshold for excitation. These experiments clearly demonstrate that the state of the interface regulates the propagation of pulses both qualitatively and quantitatively. Finally, we elaborate on the striking similarity of the observed phenomenon to nerve pulse propagation and a thermodynamic basis of cell signalling in general.


A systematic review and meta-analyses on C-reactive protein in relation to periodontitis.
Elevated plasma C-reactive protein (CRP) is regarded as a risk predictor for cardiovascular diseases. This systematic review explored the robustness of observations that CRP is elevated in periodontitis. Similarly, the effect of periodontal therapy on CRP levels was investigated. Selection of publications was based on: (1) cross-sectional (case-control) studies; (2) longitudinal (treatment) studies; (3) high-sensitivity CRP measurement; (4) median and/or mean (+/-SD) values presented; and (5) subjects with no systemic disorders. Screening of the initially 448 identified studies and reference checking resulted in 18 suitable papers. The majority of the studies showed that CRP levels are higher in patients than in controls. Often, studies showed that patients had CRP levels >2.1 mg/l. A meta-analysis of 10 cross-sectional studies showed that the weighted mean difference (WMD) of CRP between patients and controls was 1.56 mg/l (p<0.00001). Evidence from available treatment studies (n=6) showed lower levels of CRP after periodontal therapy. Eligible treatment studies in a meta-analysis demonstrated a WMD of reductions of CRP after therapy of 0.50 mg/L (95% CI 0.08-0.93) (p=0.02). There is strong evidence from cross-sectional studies that plasma CRP in periodontitis is elevated compared with controls. There is modest evidence on the effect of periodontal therapy in lowering the levels of CRP.


Surgical robot system for single-port surgery with novel joint mechanism.
Single-port surgery is a new surgical method performed by inserting several surgical tools and a laparoscope through an umbilical incision. Compared with conventional laparoscopic surgery, the smaller incision in this procedure produces a lower amount of trauma, which leads to shorter hospitalization. However, with the current laparoscopic tools and surgical robots, the surgeon must overcome several difficulties, such as a limited range of motion and collisions between the surgical instruments and the laparoscope. This paper proposes a new surgical robot system for single-port surgery that uses a novel joint mechanism. The proposed joint mechanism is suitable for surgical instruments with multiple degrees of freedom (DOF). Thus, it can prevent hysteresis of the joint and achieve more accurate motion with a large force. A 6-DOF surgical instrument with this joint mechanism can avoid collisions between surgical tools or arms and approach the surgical target more easily than a conventional straight surgical tool. The external arm with 2-DOF passive joints can extend the workspace of the system during surgery. Preliminary tests and validations were performed with a prototype of the system.


Israeli mothers' willingness to use corporal punishment to correct the misbehavior of their elementary school children.
The present study theoretically and methodologically specifies and expands the concept of child misbehavior of the study of corporal punishment (CP). It introduced a new concept and measure designated "Willingness to Use CP." The findings of this study provide initial support for the validity and reliability of this measure among 204 Israeli mothers with at least one child in the first or second elementary school grade. These findings also indicate that the measure is affected by the extent to which the misbehavior offends the mother and by the risk it puts the child in. However, the weight of the former was higher than the latter. It appears that the extent to which the mother feels offended depends on the distance between her and the focus of offense of her child's misbehavior: The closer it is to the mother, the more offended she feels and her willingness to use CP increases. Findings also indicate that there is a strong association between willingness to use and actual use of CP, regardless of appropriateness of child behavior, child gender, and family socioeconomic status. These findings support not only the reliability and validity of this new measure but also its relevance for the study of CP.


Bioprospecting for microbial endophytes and their natural products.
Endophytic microorganisms are to be found in virtually every plant on earth. These organisms reside in the living tissues of the host plant and do so in a variety of relationships, ranging from symbiotic to slightly pathogenic. Because of what appears to be their contribution to the host plant, the endophytes may produce a plethora of substances of potential use to modern medicine, agriculture, and industry. Novel antibiotics, antimycotics, immunosuppressants, and anticancer compounds are only a few examples of what has been found after the isolation, culture, purification, and characterization of some choice endophytes in the recent past. The potential prospects of finding new drugs that may be effective candidates for treating newly developing diseases in humans, plants, and animals are great.


Workflow modeling in critical care: piecing together your own puzzle.
The intensive care unit (ICU) is an instance of a very dynamic health care setting where critically ill patients are being managed. To provide good care, an extensive and coordinated communication amongst the role players, use of numerous information systems and operation of devices for monitoring and treatment purposes are required. The purpose of this research is to study error evolution and management within this environment. The focus is on representing the workflow of critical care environment, which emphasizes the importance such a representation may play in strategizing the management of medical errors. We used ethnographic observation and interview data to build individual pieces of the workflow, dependent on the individual and the activity concerned. Key personnel were intensively followed during their respective patient care activities and the related actions. All interactions were recorded for analysis. These clinicians and nurses were interviewed to complement the observation data and to delineate their individual workflows. These pieces of the ICU workflow were used to develop a generalize-able cognitive model to represent the intricate workflow applicable to other health care settings. The proposed model can be used to identify and characterize medical errors and for error prediction in practice.


Systemic lupus erythematosus complicated with macrophage activation syndrome mimicking COVID-19 multisystemic inflammatory syndrome in children.
Macrophage activation syndrome (MAS) is characterized by excessive activation of macrophages and lymphocytes, leading to multiorgan dysfunction. As the initial manifestation of systemic lupus erythematosus (SLE), MAS is rare in children. Due to the COVID-19 pandemic, it is vital to identify the MAS as it shares similar characteristics with the multisystem inflammatory syndrome in children (MIS-C). We report the case of an 11-year-old male adolescent with symptoms of MIS-C. Although with negative results of RT-PCR (reverse transcription-polymerase chain reaction) and serology for SARS-CoV-2, contact with a positive COVID-19 relative was reported. When admitted to a referral hospital center, the patient received standard treatment for MIS-C. Although the same scheme was given on three occasions, the patient showed no response to initial therapy. Thus, the patient was classified as a refractory case. When the study was extended to other differential diagnoses, we found MAS associated with SLE. Therefore, the patient was treated with etoposide, cyclosporine, dexamethasone, and methotrexate and showed a good clinical response. MAS associated with SLE is rare in the pediatric population. MAS shares inflammatory markers with the MIS-C and is often confused with rheumatologic, infectious, and neoplastic entities. Reporting this case is important to identify differential diagnoses in patients presenting as MIS-C and decide on timely treatment, as it could be harmful or even fatal if a definitive diagnosis is not obtained on time.


A study protocol for the cardiac effects of a single dose of either oxytocin 2.5 IU or carbetocin 100 µg after caesarean delivery: a prospective randomized controlled multi-centre trial in Norway.
Background: Both oxytocin and carbetocin are used to prevent uterine atony and post-partum haemorrhage after caesarean delivery in many countries, including Norway. Oxytocin causes dose-dependent ST-depression, troponin release, prolongation of QT-time and arrythmia, but little is known about myocardial effects of carbetocin. We have previously demonstrated comparable vasodilatory effects of oxytocin and carbetocin and are now undertaking a Phase 4 trial to investigate whether carbetocin causes similar changes to myocardial markers compared with oxytocin. Methods: Our randomized controlled trial will be conducted at three obstetrics units at Oslo University Hospital and Akershus University Hospital, Norway. Planned enrolment will be of 240 healthy, singleton pregnant women aged 18 to 50 years undergoing planned caesarean delivery. Based on pilot study data, each participant will receive a one-minute intravenous injection of either oxytocin 2.5 IU or carbetocin 100 µg during caesarean delivery. The prespecified primary outcome is the change from baseline in high-sensitive troponin I plasma concentrations at 6-10 hours after study drug administration. Secondary outcomes include uterine tone grade at 2.5 and five minutes after study drug administration, adverse events for up to 48 hours after study drug administration, estimated blood loss within eight hours of delivery, need for rescue treatment and direct/indirect costs. Enrolment and primary analysis are expected to be completed by the end of 2021. Discussion: Women undergoing caesarean delivery should be assessed for cardiovascular risk particularly as women with an obstetric history of pregnancy induced hypertension, gestational diabetes mellitus, preterm birth, placental abruption, and stillbirth are at increased risk of future cardiovascular disease. Any additional ischaemic myocardial risk from uterotonic agents will need to be balanced with the benefit of reducing the risk of postpartum haemorrhage. Any potential cardiotoxicity difference between oxytocin and carbetocin will help inform treatment decisions for pregnant women. Registration: Clinicaltrials.gov NCT03899961 (02/04/2019).