Development of intervention materials for individuals with limited English proficiency: lessons learned from "Colorectal Cancer Screening in Chinese Americans".
According to recent US census data, 52 million people reported speaking a language other than English at home, and almost 45% of this population reported limited English proficiency (LEP). Colorectal cancer (CRC) ranks among the top 3 most common cancers for several Asian ethnic groups, yet screening remains underutilized by Asian Americans. This article describes the development of culturally and linguistically appropriate intervention materials for individuals with LEP. We discuss lessons learned from this research and implications for the translation of research into practice. The Health Behavior Framework served as the conceptual model for this study, and qualitative findings guided the development of our intervention materials (a video and pamphlet). To recommend Western preventive behaviors, the research team bridged the gap between Western and Chinese values and beliefs by devoting particular attention to: (1) the target population's sociocultural values and health beliefs; and (2) unique linguistic features of the Chinese language. Key lessons learned from this study include the importance of: (1) a conceptual framework to guide intervention development; (2) incorporating sociocultural values and health beliefs into the intervention; (3) addressing and capitalizing on complex linguistics issues; (4) using qualitative methodology in cross-cultural research; and (5) contributions from a multicultural and multilingual research team. Other lessons relate to the translation of research findings into practice. We surmise that lessons learned from this study may be pertinent to the promotion of CRC screening among other patient groups with LEP and applicable to additional cancer screening tests.


Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer.
To determine the long-term clinical course of patients with metastatic breast cancer (MBC) who achieved a complete remission with doxorubicin-alkylating agent-containing combination chemotherapy programs. To assess the long-term prognosis of MBC, we reviewed our experience with 1,581 patients treated on consecutive doxorubicin and alkylating agent-containing front-line treatment protocols between 1973 and 1982. Treatment was administered for a maximum duration of 2 years. Characteristics of long-term survivors were evaluated, and hazard rates for progression were calculated. From this group, 263 (16.6%) achieved complete responses (CR) and 49 (3.1%) remained in CR for more than 5 years. After a median duration of 191 months, 26 patients remain in first CR, four patients died in CR at times ranging from 118 to 234 months, 18 patients died of breast cancer, and one is alive with metastatic disease. Compared with the overall CR and total patient populations, the long-term CR group had more premenopausal patients, a younger median age, a lower tumor burden, and better performance status. The hazard function shows a substantial drop in risk of progression after approximately 3 years from initiation of therapy. Ten long-term CR patients developed second primary cancers: breast (3), ovary (2), pancreas (1), endometrium (1), colon (1), head and neck (1), and lung (1). Most patients with MBC treated with systemic therapies have only temporary responses to treatment, but some patients continue in CR following initial treatment. These data show that a small percentage of patients achieve long-term remissions with standard chemotherapy regimens. Remission consolidation strategies are needed.


µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential.
The Conus genus includes around 500 species of marine mollusks with a peculiar production of venomous peptides known as conotoxins (CTX). Each species is able to produce up to 200 different biological active peptides. Common structure of CTX is the low number of amino acids stabilized by disulfide bridges and post-translational modifications that give rise to different isoforms. µ and µO-CTX are two isoforms that specifically target voltage-gated sodium channels. These, by inducing the entrance of sodium ions in the cell, modulate the neuronal excitability by depolarizing plasma membrane and propagating the action potential. Hyperexcitability and mutations of sodium channels are responsible for perception and transmission of inflammatory and neuropathic pain states. In this review, we describe the current knowledge of µ-CTX interacting with the different sodium channels subtypes, the mechanism of action and their potential therapeutic use as analgesic compounds in the clinical management of pain conditions.


[Influence of liposomal glucosaminyl-muramyl dipeptide on superoxide and nitric oxide production by murine macrophages].
Reactive oxygen and nitrogen intermediates are key factors in inflammatory response and antitumoral activity of macrophages. Free and liposomal N-acetylglucosaminyl-N-acetylmuramyl-L-alanyl-D-isoglutamine influence on murine macrophages ability to generate superoxide and nitric oxide were studied. The cells pretreated by GMDP increased superoxide generation in response to secondary stimuli (phorbol ether, lipopolysaccharide, zymosan). Encapsulation in the egg phosphatidylcholine liposomes enhanced cell sensitivity to priming effect of GMDP. The presence of liposomes (up to 0.5 mg/ml) in the medium inhibited superoxide release by macrophages probably due to participation of NO as redox-active metabolite. GMDP (up to 50 microg/ml) alone as well as GMDP with LPS treatment stimulated nitric oxide synthesis by macrophages. Liposomal GMDP at lower concentrations (up to 0.02 microg/ml) enhanced macrophage response to LPS. In contrast, NO-synthetic activity of LPS-stimulated cells decreased along with the increase of liposomal GMDP concentration (up to 0.5 microg/ml). The conditions for effective use of liposomal GMDP in immunotherapy are discussed.


Prediction of metabolic fluxes by incorporating genomic context and flux-converging pattern analyses.
Flux balance analysis (FBA) of a genome-scale metabolic model allows calculation of intracellular fluxes by optimizing an objective function, such as maximization of cell growth, under given constraints, and has found numerous applications in the field of systems biology and biotechnology. Due to the underdetermined nature of the system, however, it has limitations such as inaccurate prediction of fluxes and existence of multiple solutions for an optimal objective value. Here, we report a strategy for accurate prediction of metabolic fluxes by FBA combined with systematic and condition-independent constraints that restrict the achievable flux ranges of grouped reactions by genomic context and flux-converging pattern analyses. Analyses of three types of genomic contexts, conserved genomic neighborhood, gene fusion events, and co-occurrence of genes across multiple organisms, were performed to suggest a group of fluxes that are likely on or off simultaneously. The flux ranges of these grouped reactions were constrained by flux-converging pattern analysis. FBA of the Escherichia coli genome-scale metabolic model was carried out under several different genotypic (pykF, zwf, ppc, and sucA mutants) and environmental (altered carbon source) conditions by applying these constraints, which resulted in flux values that were in good agreement with the experimentally measured (13)C-based fluxes. Thus, this strategy will be useful for accurately predicting the intracellular fluxes of large metabolic networks when their experimental determination is difficult.


Lessons learned from intervertebral disc pathophysiology to guide rational design of sequential delivery systems for therapeutic biological factors.
Intervertebral disc (IVD) degeneration has been associated with low back pain, which is a major musculoskeletal disorder and socio-economic problem that affects as many as 600 million patients worldwide. Here, we first review the current knowledge of IVD physiology and physiopathological processes in terms of homeostasis regulation and consecutive events that lead to tissue degeneration. Recent progress with IVD restoration by anti-catabolic or pro-anabolic approaches are then analyzed, as are the design of macro-, micro-, and nano-platforms to control the delivery of such therapeutic agents. Finally, we hypothesize that a sequential delivery strategy that i) firstly targets the inflammatory, pro-catabolic microenvironment with release of anti-inflammatory or anti-catabolic cytokines; ii) secondly increases cell density in the less hostile microenvironment by endogenous cell recruitment or exogenous cell injection, and finally iii) enhances cellular synthesis of extracellular matrix with release of pro-anabolic factors, would constitute an innovative yet challenging approach to IVD regeneration.


Acid-triggered drug release from micelles based on amphiphilic oligo(ethylene glycol)-doxorubicin alternative copolymers.
We report a facile strategy to synthesize pH-sensitive amphiphilic oligo(ethylene glycol) (OEG)-doxorubicin (DOX) alternative conjugates. Poly[oligo(ethylene glycol) malicate] (POEGM) with numerous pendent hydroxyl groups was first synthesized by the direct polycondensation of oligo(ethylene glycol) (OEG) with malic acid under mild conditions. Then, benzaldehyde groups were introduced into the POEGM backbone via esterification between the pendant hydroxyl groups and 4-formylbenzoic acid. DOX moieties were finally attached to the polymeric backbone via benzoic imine linkages to obtain the OEG-DOX conjugates. Because of the high molecular weight and alternate architecture, this type of amphiphilic OEG-DOX alternative conjugates can form stable micelles in aqueous solution with a high DOX loading content (38.2 wt%) and low critical micelle concentrations (0.021 mg mL-1). Due to the pH-sensitive benzoic imine linkages between the DOX moieties and polymeric backbone, DOX could be rapidly released from the micelles at pH 5.8, whereas only a minimal amount of DOX was released at pH 7.4 under the same conditions. The cytotoxicity assay indicates that the OEG-DOX conjugates show cytotoxic effects to MCF-7 tumor cells, while the corresponding polymer material POEGM-CHO exhibits a great biocompatibility for MCF-7 tumor cells. These pH-sensitive and high drug loading nano-carriers based on the OEG-DOX alternative conjugates provide a promising platform for targeted cancer therapy.


Optogenetic engineering: light-directed cell motility.
Genetically encoded, light-activatable proteins provide the means to probe biochemical pathways at specific subcellular locations with exquisite temporal control. However, engineering these systems in order to provide a dramatic jump in localized activity, while retaining a low dark-state background remains a significant challenge. When placed within the framework of a genetically encodable, light-activatable heterodimerizer system, the actin-remodelling protein cofilin induces dramatic changes in the F-actin network and consequent cell motility upon illumination. We demonstrate that the use of a partially impaired mutant of cofilin is critical for maintaining low background activity in the dark. We also show that light-directed recruitment of the reduced activity cofilin mutants to the cytoskeleton is sufficient to induce F-actin remodeling, formation of filopodia, and directed cell motility.


Risk of restless legs syndrome in low socioeconomic rheumatoid arthritis patients.
Our aim was to determine the frequency of restless leg syndrome (RLS) in rheumatoid arthritis (RA) patients from a low socioeconomic area of Pakistan and compare results with a control group to evaluate the effect of variables on RLS patients. A clinical observational study was carried out on 240 RA patients form low socioeconomic group. Controls (n = 210) were frequency-matched by age group to the RA patients. We evaluated the presence of RLS and collected information on characteristics believed to be correlated with RLS in the general population. Multiple logistic regression models were used to study the association between RLS and other risk factors such as age, smoking status, and obesity. Among all rheumatic patients seen at our rheumatology clinic, 70.8% were women. Our study shows that 20% of RA patients were suffering from RLS compared with 10% of the control group with other rheumatic diseases. Multivariate logistic regression adjusted for age, obesity, and smoking also showed that women with RA were more likely to have RLS than control patients. RLS was also significantly associated with increasing age, high body mass index, and smoking status. Approximately 20% of RA patients were suffering from RLS. Hence, there is need of increase awareness of RLS among rheumatologists to enhance early RLS diagnosis and appropriate management of this treatable condition.


Distinct B-cell lineage commitment distinguishes adult bone marrow hematopoietic stem cells.
The question of whether a single hematopoietic stem cell (HSC) gives rise to all of the B-cell subsets [B-1a, B-1b, B-2, and marginal zone (MZ) B cells] in the mouse has been discussed for many years without resolution. Studies here finally demonstrate that individual HSCs sorted from adult bone marrow and transferred to lethally irradiated recipients clearly give rise to B-2, MZ B, and B-1b, but does not detectably reconstitute B-1a cells. These findings place B-2, MZ, and B-1b in a single adult developmental lineage and place B-1a in a separate lineage derived from HSCs that are rare or missing in adults. We discuss these findings with respect to known developmental heterogeneity in other HSC-derived lymphoid, myeloid, and erythroid lineages, and how HSC developmental heterogeneity conforms to the layered model of the evolution of the immune system that we proposed some years ago. In addition, of importance to contemporary medicine, we consider the implications that HSC developmental heterogeneity may have for selecting HSC sources for human transplantation.


A cis-proline to alanine mutant of E. coli aspartate transcarbamoylase: kinetic studies and three-dimensional crystal structures.
The only cis-proline residue in Escherichia coli aspartate transcarbamoylase has been replaced by alanine using site-specific mutagenesis. The Pro268-->Ala enzyme exhibits a 40-fold reduction in enzyme activity and decreased substrate affinity toward carbamoyl phosphate and aspartate compared to the corresponding values for the wild-type enzyme. The concentration of the bisubstrate analogue N-phosphonacetyl-L-aspartate (PALA) required to activate the mutant enzyme to the same extent as the wild-type enzyme is significantly increased. The heterotropic effects of ATP and CTP upon the Pro268-->Ala enzyme are also altered. Crystal structures of the Pro268-->Ala enzyme in both T- and R-states show that the cis-peptidyl linkage between Leu267 and Ala268 is maintained. However, the tertiary structure of both the catalytic and regulatory chains has been altered by the amino acid substitution, and the mobility of the active-site residues is increased for the R-state structure of Pro268-->Ala enzyme as comparison with the wild-type R-state structure. These structural changes are responsible for the loss of enzyme activity. Thus, Pro268 is required for the proper positioning of catalytically critical residues in the active site and is important for the formation of the high-activity high-affinity R-state of E. coli aspartate transcarbamoylase.


Flumequine-Mediated Upregulation of p38 MAPK and JNK Results in Melanogenesis in B16F10 Cells and Zebrafish Larvae.
Flumequine is a well-known second generation quinolone antibiotic that induces phototoxicity. However, the effect of flumequine on skin melanogenesis is unclear. Therefore, we, for the first time, investigated whether flumequine regulates melanogenesis. The present study showed that flumequine slightly inhibited in vitro mushroom tyrosinase activity but significantly increased extracellular and intracellular melanin content in B16F10 cells and promoted the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. Additionally, flumequine remarkably increased melanin pigmentation in zebrafish larvae without any toxicity. We also found that flumequine stimulated p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation; inhibition of p38 MAPK and JNK resulted in significant downregulation of extracellular and intracellular melanin content in B16F10 cells and pigmentation of zebrafish larvae accompanied with suppression of MITF and tyrosinase expression, indicating that flumequine-mediated p38 and JNK promote melanogenesis in vitro and in vivo. According to the molecular docking prediction, flumequine targeted dual-specificity MAPK phosphatase 16 (DUSP16), which is a major negative regulator of p38 MAPK and JNK. Our findings demonstrate that flumequine induces an increase in melanin content in B16F10 cells and zebrafish larvae by activating p38 MAPK and JNK. These data show the potential of flumequine for use as an anti-vitiligo agent.


South African Helichrysum species: a review of the traditional uses, biological activity and phytochemistry.
In South Africa, the genus Helichrysum is widely used in traditional medicine. The uses are well documented although renaming of species and the resulting confusing taxonomic nomenclature may cause uncertainty as to which specific species was referred to in some reports. The aim of this paper is to present a collated and coherent overview of the documented traditional uses of Helichrysum species and to update the botanical identity of previously studied species. Databases (Scifinder, ISI Web of Knowledge) and several books were used to collect in information on South African Helichrysum species. The traditional uses, chemistry and biological activity of Helichrysum species have been summarized. It was attempted to give clarity as to exactly which species is refer to in the ethnobotanical literature. Although a large number of ethnopharmacological uses have been documented and the chemistry of the genus has been studied extensively, only a few South African species have been investigated for their biological activity.


Device-independent certification of high-dimensional quantum systems.
An important problem in quantum information processing is the certification of the dimension of quantum systems without making assumptions about the devices used to prepare and measure them, that is, in a device-independent manner. A crucial question is whether such certification is experimentally feasible for high-dimensional quantum systems. Here we experimentally witness in a device-independent manner the generation of six-dimensional quantum systems encoded in the orbital angular momentum of single photons and show that the same method can be scaled, at least, up to dimension 13.


Cardiac involvement in Churg-Strauss syndrome mimicking acute coronary syndrome.
Churg-Strauss syndrome (CSS) is a rare multisystemic disorder of unknown origin and cardiac involvement is one of the most serious manifestations of the disease, accounting for approximately one-half of deaths attributable to CSS. Cardiac manifestation can be acute and mimic acute coronary syndrome (ACS). In this setting checking the blood leucocyte count can reveal hypereosinophilia and lead to a diagnosis of CSS.


[Comparative characteristics of laser-mediated and radiofrequency-powered thermal obliteration in varicose disease].
The article deals with a comparative analysis of the two most commonly used methods techniques of thermal ablation used for elimination of truncal varicosis in varicose disease, i. e., endovasal laser-mediated and radiofrequency-powered obliteration, underlining differences in the mechanisms of physical impact of the two competitive methods, clinical peculiarities of their application, as well as economic aspects of these interventions under the conditions of the present-day Russia.


Identification and control of dynamical systems using the self-organizing map.
In this paper, we introduce a general modeling technique, called vector-quantized temporal associative memory (VQTAM), which uses Kohonen's self-organizing map (SOM) as an alternative to multilayer perceptron (MLP) and radial basis function (RBF) neural models for dynamical system identification and control. We demonstrate that the estimation errors decrease as the SOM training proceeds, allowing the VQTAM scheme to be understood as a self-supervised gradient-based error reduction method. The performance of the proposed approach is evaluated on a variety of complex tasks, namely: i) time series prediction; ii) identification of SISO/MIMO systems; and iii) nonlinear predictive control. For all tasks, the simulation results produced by the SOM are as accurate as those produced by the MLP network, and better than those produced by the RBF network. The SOM has also shown to be less sensitive to weight initialization than MLP networks. We conclude the paper by discussing the main properties of the VQTAM and their relationships to other well established methods for dynamical system identification. We also suggest directions for further work.


Incidental Treatment of a Subclinical Chronic Tension-Type Headache by Cosmetic Use of Botulinum Toxin A: A Case Report.
Headache is a common disorder of the nervous system; chronic headache in particular may affect quality of life negatively. The pathophysiology is multifactorial and not completely elucidated. Studies have demonstrated the beneficial effects of botulinum toxin A on chronic migraine headaches, but failed to show the same effect on chronic tension-type headaches. We present the case of a 32-year-old woman who after receiving cosmetic injections with botulinum toxin A for fine lines of the forehead experienced relief of subclinical tension-type headaches. Although the effect of botulinum toxin A on chronic tension-type headaches is limited, several studies demonstrate its pain-modulating effects, and as such it is worth paying attention to this potential beneficial effect when performing cosmetic injections with botulinum toxin A.


Association of all-cause and cardiovascular mortality with prehypertension: a meta-analysis.
Studies of prehypertension and mortality are controversial after adjusting for other cardiovascular risk factors. This meta-analysis sought to evaluate the association of prehypertension with all-cause and cardiovascular disease (CVD) mortality. The PubMed, EMBASE, Cochrane Library databases, and conference proceedings were searched for studies with data on prehypertension and mortality. The relative risks (RRs) of all-cause, CVD, coronary heart disease (CHD), and stroke mortality were calculated and presented with 95% CIs. Subgroup analyses were conducted according to blood pressure, age, gender, ethnicity, follow-up duration, participant number, and study characteristics. Data from 1,129,098 participants were derived from 20 prospective cohort studies. Prehypertension significantly increased the risk of CVD, CHD, and stroke mortality (RR 1.28, 95% CI 1.16-1.40; RR 1.12, 95% CI 1.02-1.23; and RR 1.41, 95% CI 1.28-1.56, respectively), but did not increase the risk of all-cause mortality after multivariate adjustment (RR 1.03, 95% CI 0.97-1.10). The difference between CHD mortality and stroke mortality was significant (P < .001). Subgroup analyses showed that CVD mortality was significantly increased in high-range prehypertension (RR 1.28, 95% CI 1.16-1.41) but not in low-range prehypertension (RR 1.08, 95% CI 0.98-1.18). Prehypertension is associated with CVD mortality, especially with stroke mortality, but not with all-cause mortality. The risk for CVD mortality is largely driven by high-range prehypertension.


The incidence and risk factors for postoperative urinary retention in neurosurgical patients.
Postoperative urinary retention (POUR) is a common problem in adult neurosurgical patients. The incidence of POUR is unknown and the etiology has not been well established. POUR can lead to urogenital damage, prolonged hospital stay, higher cost, and infection. This study elucidates several risk factors that contribute to POUR in a variety of neurosurgical patients in one institution. A total of 137 neurosurgical patients were prospectively followed up for the development of POUR, which we defined as initial postvoid residual (PVR1) >250 ml 6 hours after removal of an indwelling urinary catheter (IUC). For patients with PVR >250 ml on the third check, IUCs were reinserted and kept in for 5-7 days. Of the 137 patients, 68 (50%) were male, 41% (56/137) were 60 years or older, 86% (118/137) underwent spinal surgery, and 54% (74/137) had anesthesia over 200 minutes. Overall incidence of clinical POUR was 39.4% (54/137). Significantly higher rates of PVR1 >250 were noted in males, patients older than 60 years, and those who underwent spine surgery. When considering all patient characteristics (except selective alpha blockers), only gender, surgery time, and surgery type remained significant. In addition, PVR1 >250 was positively associated with longer length of stay. Of all patients, 24 (18%) had IUCs reinserted postoperatively or should have had one (5 refused and 2 had a third PVR). The association of IUC reinsertion with male gender was significant. Male gender, time of anesthesia >200 minutes, older age, and spinal surgery are the most significant risk factors associated with POUR in neurosurgical patients.


Correlations between characteristics of some free-living Chlorella sp. and their ability to form stable symbioses with Hydra viridis.
Aposymbiotic polyps of Hydra viridis were infected with 17 strains of in vitro cultured Chlorella sp. Larvae of Artemia fed with the chlorellae were used as an infecting vector. Of the 17 strains, seven formed stable symbioses and one formed a transient infection that disappeared within several weeks. Chlorellae of the nine other strains were cleared out of the infected hydra within 2-3 days. There was a distinct correlation between the ability of the chlorellae to form stable symbioses and their ability to adapt and grow in media enriched with 0.5% proteose peptone. Only strains that grew in the latter medium formed symbioses with the hydra. The symbioses formed with the different strains of chlorellae differed from one another. Hydra infected with some strains greened completely while those infected with other strains greened only partially. The degree of infection varied also within each population, and there were differences in the distribution of the various chlorellae along the stalk and inside the digestive cells of the hydra. Growth rates of the infected hydra were all less that those of aposymbiotic hydra or of hydra hosting native zoochlorellae. We conclude that adaptability to a nutrient-rich environment inside the perialgal vacuole of the digestive cell and a sufficient growth rate therein are crucial to the ability of chlorellae to form stable symbioses with H. viridis. In time, co-adaptation of hydra and chlorellae would restore the normal growth rate of the former and bring about regularity to the form and extent of infection by the latter.


A primary care pediatrician's guide to assessing problematic interactive media use.
To review the literature and provide a guide to assessing patients with problematic interactive media use (PIMU). 0.3-1.0% of the world population meets criteria for internet gaming disorder (IGD). 26.8-83.3% of adolescents meeting criteria for internet addiction have comorbid attention-deficit/hyperactivity disorder. IGD is associated with increased anxiety and social anxiety/phobias. Group counseling, cognitive behavioral therapy, and sports intervention are associated with significant reductions in internet addiction. With the Diagnostic and Statistical Manual of Mental Disorders-5 inclusion of IGD under 'Conditions for Further Study' and the addition of gaming disorder to International Classification of Diseases (ICD)-11, the idea that PIMU is a mental health disorder gained traction. Although certain populations may be at increased risk, all children and adolescents should be screened for PIMU given now-normal heavy media usage rates. Effective treatment of PIMU starts with identification and management of comorbid mental and behavioral health problems. Depending on their degree of functional impairment, patients may benefit from various forms of psychotherapy with coordinated outpatient management or may warrant higher level of care in one of several established residential treatment programs. Few studies have evaluated pharmacologic approaches to treating PIMU, but some medications targeting comorbid mental and behavioral health conditions improve PIMU-related behaviors.


Examination of the microbiota of normal cow milk using MinIONTM nanopore sequencing.
The aim of this study was to evaluate the microbiota of normal milk in dairy cows and their relationship with host factors, such as the age of the cow (Age), somatic cell counts in milk (SCCs), and days in milk (DIM). We investigated 48 milk samples from 22 cows with no systemic or local clinical signs using MinIONTM nanopore sequencing for a 16S rRNA gene amplicon. Bacterial richness was positively correlated with the DIM (P=0.043), and both the Shannon-Wiener Index and Simpson's Index, which are metrics of alpha-diversity, were also significantly positively correlated with the SCC (P<0.001). The composition ratios of both Actinobacteria at the phylum level and Kocuria spp. at the genus level in the milk microbiota were significantly correlated with the SCC (P<0.001 and P<0.001, respectively). In the beta-diversity test, the one-way analysis of similarities test showed a significant difference (P=0.0051) between the low- and high-SCC groups. This study clarified that the composition of the normal milk microbiota in this herd was related to the SCC. It also raised the possibility of variations in bacterial genera in the normal milk microbiota between the low- and high-SCC groups. However, to clarify the actual condition of the milk microbiota and to elucidate the relationship with the SCC, it is necessary to perform further analyses taking into account not only the relative abundance, but also the absolute abundance of microbes.


The Impact of Donor-Specific Anti-Human Leukocyte Antigen (HLA) Antibody Rebound on the Risk of Antibody Mediated Rejection in Sensitized Kidney Transplant Recipients.
BACKGROUND Donor-specific anti-HLA antibody (DSA) detected on Luminex-based single antigen assay (LSA) has become the subject of desensitization based upon the results of previous studies. We retrospectively investigated the impact of preoperative DSA on the incidence of antibody mediated rejection (AMR) in patients desensitized using a protocol based on rituximab and rabbit antithymocyte globulin (rATG). MATERIAL AND METHODS Nine patients (Group 1, 9/327, 2.8%) were complement dependent cytotoxicity crossmatch (CDC-XM) positive and underwent desensitization with rituximab (375 mg/m²), intravenous immunoglobulin (IVIG; 400 mg/kg), plasmapheresis, and rATG. Twenty-two patients (Group 2, 22/327, 6.7%) were CDC-XM negative but DSA positive on LSA and had received desensitization with rituximab and rATG, while 55 patients (Group 3, 55/327, 16.8%) were CDC-XM and DSA negative with a calculated panel reactive antibody (cPRA) ≥50%. Another 241 patients (Group 4, 241/327, 73.7%) were CDC-XM and DSA negative with a cPRA <50%. RESULTS Recipients with DSA (Group 2) experienced more AMR than other groups (p<0.01). More de novo DSAs also developed in Group 2 (p<0.001). The mean fluorescence intensity (MFI) of DSA of patients with AMR tended to rebound (p=0.01). CONCLUSIONS Patients who were CDC-XM negative but DSA positive status were at a higher risk of developing AMR even though they had received desensitization with rATG and rituximab. A more intense desensitization protocol is needed for these recipients. Patients with MFI rebound of DSA should be carefully monitored for the risk of AMR.


Changes in Physical Performance and Their Association With Health-Related Quality of Life in a Mixed Nonischemic Cardiac Population That Participates in Rehabilitation.
Exercise-based cardiac rehabilitation improves physical performance and health-related quality of life (HRQoL). However, whether improvements in physical performance are associated with changes in HRQoL has not been adequately investigated in a nonischemic cardiac population. Patients who were ablated for atrial fibrillation, who underwent heart valve surgery or who were treated for infective endocarditis, and who participated in 1 of 3 randomized controlled rehabilitation trials were eligible for the current study. Change in physical performance and HRQoL were measured before and after a 12-wk exercise intervention. Physical performance was assessed using a cardiopulmonary exercise test, a 6-min walk test, and a sit-to-stand test. Health-related quality of life was assessed using the generic 36-Item Short Form Health Survey and the disease-specific HeartQoL questionnaire. Spearman correlation coefficient (ρ) and linear regressions quantified the association between changes in physical outcome measures and changes in HRQoL. A total of 344 patients were included (mean age: 60.8 ± 11.6 yr and 77% males). Associations between changes in physical outcome measures and HRQoL ranged from very weak to weak (ρ = -0.056 to 0.228). The observed associations were more dominant within physical dimensions of the HRQoL compared with mental or emotional dimensions. After adjusting for sex, age, and diagnosis, changes in physical performance explained no more than 20% of the variation in the HRQoL. The findings show that the positive improvement in HRQoL from exercise-based cardiac rehabilitation cannot simply be explained by an improvement in physical performance.


Suppression of ethanol responding by centrally administered CTOP and naltrindole in AA and Wistar rats.
Both mu- and delta-opioid receptors have been implicated in the reinforcing actions of ethanol. However, selective opioid receptor antagonists have not altered ethanol intake in all rodent strains consistently, which suggests that genotype may modulate their suppressive effects. Therefore, we tested the effects of the selective mu-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and the selective delta-antagonist naltrindole in both high-drinking AA (Alko, Alcohol) and heterogeneous Wistar rats. AA and Wistar rats were trained to respond for ethanol (10% w/v) in a two-lever operant condition by using a saccharin fading procedure. After stable baseline responding was established, rats were implanted stereotaxically either with a guide cannula above the lateral ventricle or with bilateral cannulas above the nucleus accumbens, basolateral amygdala, or ventral tegmental area. After postoperative recovery, AA and Wistar animals were tested after intracerebroventricular microinjections of either CTOP (0-3 microg) or naltrindole (0-30 microg) or subcutaneous injections of naloxone (0-1 g/kg), which was used as a reference antagonist. Effects of intracerebral microinjections of CTOP and naltrindole (both 0-500 ng) were tested only in Wistar rats. Subcutaneous naloxone and intracerebroventricular CTOP and naltrindole suppressed ethanol self-administration in a similar manner in AA and Wistar rats. Cumulative response patterns indicated that naloxone and naltrindole had no effect on the initiation of responding but suppressed it later during the session, whereas CTOP also affected initiation. In Wistar rats, naltrindole microinjections into both the nucleus accumbens and basolateral amygdala decreased ethanol responding, whereas CTOP was effective only in the amygdala. Injections of these antagonists into the ventral tegmental area had little effect on ethanol intake. The results confirm previous results which showed that both mu- and delta-opioid receptors are involved in the regulation of ethanol self-administration and indicate that genetic differences between AA and Wistar rats produced by selection do not modify the effects of opioid antagonists. The nucleus accumbens and the basolateral amygdala may be important central sites for the mediation of their suppressive effects.


Extraction of insoluble fibrous collagen for characterization and crosslinking with phenolic compounds from pomegranate byproducts for leather tanning applications.
An environmental approach for leather manufacturing is primordial to provide a global strategy towards more sustainable biomaterials and greener tanning processing methods. The ability of collagen as a principal component of skin to combine natural phenolic compounds, especially vegetable tannins, has been proven to be eco-friendly and manageable, while making good improvement to leather properties in the tanning process. In this study, we have used pomegranate phenolic compounds and insoluble collagen as a model system to examine the effects of tanning steps on the conformation of collagen. In detail, efficient modified extraction of pure insoluble collagen (IC) was presented. The IC was successfully identified using XRD, FTIR, SEM-EDS and TGA-DSC to verify the triple helix structure, morphology and thermal properties. As a result, the as-extracted collagen exhibits a high purity, preserving the triple helix collagen structure. Besides, the IC was modified using extracted pomegranate phenolic compounds, resulting in Crosslinked Insoluble Collagen (CIC). Characterization techniques were also performed to confirm the crosslinking process. Indeed, by comparing the FTIR vibrational spectra of IC and CIC, slight shifts of amide groups were observed, indicating the presence of inter and intramolecular interaction between IC functional groups and pomegranate phenolic compounds. Moreover, the morphology of CIC was changed. XRD analysis confirms collagen conformational integrity. Finally, thermal properties were improved. The temperature at 50% weight loss (T°50) increases from 344.54 °C to 375.53 °C. CIC multifunctionality allowed utilizing pomegranate phenolic compound extracts as a tanning agent in leather processing.


The Integrative Function of Silent Synapses on Subplate Neurons in Cortical Development and Dysfunction.
The thalamocortical circuit is of central importance in relaying information to the cortex. In development, subplate neurons (SPNs) form an integral part of the thalamocortical pathway. These early born cortical neurons are the first neurons to receive thalamic inputs and excite neurons in the cortical plate. This feed-forward circuit topology of SPNs supports the role of SPNs in shaping the formation and plasticity of thalamocortical connections. Recently it has been shown that SPNs also receive inputs from the developing cortical plate and project to the thalamus. The cortical inputs to SPNs in early ages are mediated by N-methyl-D-aspartate (NMDA)-receptor only containing synapses while at later ages α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptors are present. Thus, SPNs perform a changing integrative function over development. NMDA-receptor only synapses are crucially influenced by the resting potential and thus insults to the developing brain that causes depolarizations, e.g., hypoxia, can influence the integrative function of SPNs. Since such insults in humans cause symptoms of neurodevelopmental disorders, NMDA-receptor only synapses on SPNs might provide a crucial link between early injuries and later circuit dysfunction. We thus here review subplate associated circuits, their changing functions, and discuss possible roles in development and disease.


Subcutaneous Injection Performance in Yucatan Miniature Pigs with and without Human Hyaluronidase and Auto-injector Tolerability in Humans.
Recombinant human hyaluronidase PH20 (rHuPH20) facilitates subcutaneous (SC) delivery of co-administered therapeutic agents by locally and transiently degrading hyaluronan in the SC space, and can be administered with therapeutics using a variety of devices. Two SC delivery studies were carried out to assess auto-injector (AI) performance, each in 18 Yucatan miniature pigs. Abdominal injections were administered using three auto-injectors of 1 mL (AI1) and 2 mL (AI2 and sAI2) with different injection speeds and depths (5.5-7.5 mm) and two pre-filled syringe (PFS) devices of 1 and 2 mL. The injection included a placebo buffer with and without rHuPH20 to evaluate the effect of rHuPH20 on SC injection performance. The feasibility of using similar devices to deliver a placebo buffer in humans was investigated. rHuPH20 was not studied in humans. In miniature pigs, postinjection swelling was evident for most PFS/AI injections, particularly 2 mL. Swelling heights and back leakage were typically lower with rHuPH20 co-administration versus placebo for most device configurations (1 or 2 mL PFS or AI). Auto-injections with versus without rHuPH20 also resulted in reduced swelling firmness and faster swelling resolution over time. Slow injections with rHuPH20 had shorter and more consistent injection time versus placebo. In humans, minimal injection site swelling and negligible back leakage were observed for 2-mL injections of placebo, while more erythema was observed in humans versus miniature pigs. Even at high delivery rates with PFS or AI, the addition of rHuPH20 resulted in improved SC injection performance versus placebo in miniature pigs.


Plastic Pirates sample litter at rivers in Germany - Riverside litter and litter sources estimated by schoolchildren.
Rivers are an important source of marine anthropogenic litter, but the particular origins of riverine litter itself have not been well established. Here we used a citizen science approach where schoolchildren examined litter at riversides and identified possible sources at over 250 sampling spots along large and small rivers in Germany, during autumn 2016 and spring 2017. Litter densities have an overall median of 0.14, interquartile range 0-0.57 items m-2 and an overall average (±standard deviation) of 0.54 ± 1.20 litter items m-2. Litter quantities differed only little by sampling year. The principal litter types found were plastics and cigarette butts (31% and 20%, respectively), followed by glass, paper, and metal items, indicating recreational visitors as the principal litter source. At many sites (85%), accumulations of litter, consisting principally of cigarettes and food packaging, have been found. At almost all sampling sites (89%), litter potentially hazardous to human health has been observed, including broken glass, sharp metal objects, used personal hygiene articles and items containing chemicals. In the search for litter sources, the schoolchildren identified mainly people who use the rivers as recreational areas (in contrast to residents living in the vicinity, illegal dumping, or the river itself depositing litter from upstream sources). These results indicate the urgent need for better education and policy measures in order to protect riparian environments and reduce input of riverine litter to the marine environment.


Albumin fiber scaffolds for engineering functional cardiac tissues.
In recent years attempts to engineer contracting cardiac patches were focused on recapitulation of the myocardium extracellular microenvironment. We report here on our work, where for the first time, a three-dimensional cardiac patch was fabricated from albumin fibers. We hypothesized that since albumin fibers' mechanical properties resemble those of cardiac tissue extracellular matrix (ECM) and their biochemical character enables their use as protein carriers, they can support the assembly of cardiac tissues capable of generating strong contraction forces. Here, we have fabricated aligned and randomly oriented electrospun albumin fibers and investigated their structure, mechanical properties, and chemical nature. Our measurements showed that the scaffolds have improved elasticity as compared to synthetic electrospun PCL fibers, and that they are capable of adsorbing serum proteins, such as laminin leading to strong cell-matrix interactions. Moreover, due to the functional groups on their backbone, the fibers can be chemically modified with essential biomolecules. When seeded with rat neonatal cardiac cells the engineered scaffolds induced the assembly of aligned cardiac tissues with high aspect ratio cardiomyocytes and massive actinin striation. Compared to synthetic fibrous scaffolds, cardiac cells cultured within aligned or randomly oriented scaffolds formed functional tissues, exhibiting significantly improved function already on Day 3, including higher beating rate (P = 0.0002 and P < 0.0001, respectively), and higher contraction amplitude (P = 0.009 and P = 0.003, respectively). Collectively, our results suggest that albumin electrospun scaffolds can play a key role in contributing to the ex vivo formation of a contracting cardiac muscle tissue.


The effect of transdermal scopolamine for the prevention of postoperative nausea and vomiting.
Postoperative nausea and vomiting (PONV) is one of the most common and undesirable complaints recorded in as many as 70-80% of high-risk surgical patients. The current prophylactic therapy recommendations for PONV management stated in the Society of Ambulatory Anesthesia (SAMBA) guidelines should start with monotherapy and patients at moderate to high risk, a combination of antiemetic medication should be considered. Consequently, if rescue medication is required, the antiemetic drug chosen should be from a different therapeutic class and administration mode than the drug used for prophylaxis. The guidelines restrict the use of dexamethasone, transdermal scopolamine, aprepitant, and palonosetron as rescue medication 6 h after surgery. In an effort to find a safer and reliable therapy for PONV, new drugs with antiemetic properties and minimal side effects are needed, and scopolamine may be considered an effective alternative. Scopolamine is a belladonna alkaloid, α-(hydroxymethyl) benzene acetic acid 9-methyl-3-oxa-9-azatricyclo non-7-yl ester, acting as a non-selective muscarinic antagonist and producing both peripheral antimuscarinic and central sedative, antiemetic, and amnestic effects. The empirical formula is C17H21NO4 and its structural formula is a tertiary amine L-(2)-scopolamine (tropic acid ester with scopine; MW = 303.4). Scopolamine became the first drug commercially available as a transdermal therapeutic system used for extended continuous drug delivery during 72 h. Clinical trials with transdermal scopolamine have consistently demonstrated its safety and efficacy in PONV. Thus, scopolamine is a promising candidate for the management of PONV in adults as a first line monotherapy or in combination with other drugs. In addition, transdermal scopolamine might be helpful in preventing postoperative discharge nausea and vomiting owing to its long-lasting clinical effects.


[The coincidence of rapidly progressing dilated cardiomyopathy and primary hyperparathyroidism. The course before and after the removal of a parathyroid adenoma].
Severe cardiac arrhythmias (Lown class IVa), rapid loss of physical capacity and dyspnoea on the slightest exertion occurred in a 55-year-old man with idiopathic dilated cardiomyopathy. In the preceding year he had recurrent diarrhoea and lost 23 kg in weight. He was found to have hypercalcaemia (3-3.2 mmol/l). The heart failure significantly improved under treatment with twice daily 12.5 mg captopril, 100 mg spironolactone daily, furosemide 40 mg twice daily, and digitoxin 0.07 mg daily. The arrhythmia responded to verapamil 80 mg and quinidine 160 mg, both drugs three times daily. Primary hyperparathyroidism was found to be the cause of the hypercalcaemia (parathormone 84 pmol/l). After the parathyroid adenoma had been removed the patient's condition again improved markedly. There were only rare monotopic extrasystoles, cardiac size regressed, and diuretics were no longer necessary. His medication at present is verapamil (80 mg three times daily), captopril (12.5 mg three times daily) and digitoxin (0.07 mg daily). It is concluded that the hypercalcaemia influenced the severity of the cardiomyopathy. It would seem that both intra- and extracellular calcium homoeostasis is of great importance in dilated cardiomyopathy.


World Heart Federation Cholesterol Roadmap 2022.
Atherosclerotic cardiovascular diseases (ASCVD) including myocardial infarction, stroke and peripheral arterial disease continue to be major causes of premature death, disability and healthcare expenditure globally. Preventing the accumulation of cholesterol-containing atherogenic lipoproteins in the vessel wall is central to any healthcare strategy to prevent ASCVD. Advances in current concepts about reducing cumulative exposure to apolipoprotein B (apo B) cholesterol-containing lipoproteins and the emergence of novel therapies provide new opportunities to better prevent ASCVD. The present update of the World Heart Federation Cholesterol Roadmap provides a conceptual framework for the development of national policies and health systems approaches, so that potential roadblocks to cholesterol management and thus ASCVD prevention can be overcome. Through a review of published guidelines and research papers since 2017, and consultation with a committee composed of experts in clinical management of dyslipidaemias and health systems research in low-and-middle income countries (LMICs), this Roadmap identifies (1) key principles to effective ASCVD prevention (2) gaps in implementation of these interventions (knowledge-practice gaps); (3) health system roadblocks to treatment of elevated cholesterol in LMICs; and (4) potential strategies for overcoming these. Reducing the future burden of ASCVD will require diverse approaches throughout the life-course. These include: a greater focus on primordial prevention; availability of affordable cholesterol testing; availability of universal cholesterol screening for inherited dyslipidaemias; risk stratification moving beyond 10-year risk to look at lifetime risk with adequate risk estimators; wider availability of affordable cholesterol-lowering therapies which should include statins as essential medications globally; use of adequate doses of potent statin regimens; and combination therapies with ezetimibe or other therapies in order to attain and maintain robust reductions in LDL-C in those at highest risk. Continuing efforts are needed on health literacy for both the public and healthcare providers, utilising multi-disciplinary teams in healthcare and applications that quantify both ASCVD risk and benefits of treatment as well as increased adherence to therapies. The adverse effects of LDL-cholesterol and apo B containing lipoprotein exposure are cumulative and result in ASCVD. These are preventable by implementation of different strategies, aimed at efficiently tackling atherosclerosis at different stages throughout the human life-course. Preventive strategies should therefore be updated to implement health policy, lifestyle changes and when needed pharmacotherapies earlier with investment in, and a shift in focus towards, early preventive strategies that preserve cardiovascular health rather than treat the consequences of ASCVD.


Structural conservation in the major facilitator superfamily as revealed by comparative modeling.
The structures of membrane transporters are still mostly unsolved. Only recently, the first two high-resolution structures of transporters of the major facilitator superfamily (MFS) were published. Despite the low sequence similarity of the two proteins involved, lactose permease and glycerol-3-phosphate transporter, the reported structures are highly similar. This leads to the hypothesis that all members of the MFS share a similar structure, regardless of their low sequence identity. To test this hypothesis, we generated models of two other members of the MFS, the Tn10-encoded metal-tetracycline/H(+) antiporter (TetAB) and the rat vesicular monoamine transporter (rVMAT2). The models are based on the two MFS structures and on experimental data. The models for both proteins are in good agreement with the data available and support the notion of a shared fold for all MFS proteins.


Efficacy of Melatonin for Sleep Disturbance in Children with Persistent Post-Concussion Symptoms: Secondary Analysis of a Randomized Controlled Trial.
Sleep disturbances are commonly reported in children with persistent post-concussion symptoms (PPCS). Melatonin treatment is often recommended, yet supporting evidence is scarce. We aimed to evaluate the efficacy of treatment with melatonin for sleep disturbance in youth with PPCS following mild traumatic brain injury (mTBI). This article is a secondary analysis of a clinical trial of melatonin compared with placebo to treat PPCS. Youth (8-18 years of age) with PPCS and significant sleep-related problems (SRPs) at 4-6 weeks post-injury were eligible. Exclusion criteria: significant medical/psychiatric history; previous concussion/mTBI within 3 months. Treatment groups were: placebo, melatonin 3 mg, or melatonin 10 mg. Primary outcome was change in SRPs measured using the Post-Concussion Symptom Inventory (PCSI) after 2 weeks of treatment. Secondary outcomes included change in actigraphy sleep efficiency, duration, onset latency, and wake-after-sleep-onset. Behavior was measured using Behaviour Assessment for Children (2nd edition). Seventy-two participants (mean age 14.0, standard deviation [SD] = 2.6) years; 60% female) with PPCS and significant sleep disturbance were included in the secondary analysis: placebo (n = 22); melatonin 3 mg (n = 25); melatonin 10 mg (n = 25). Sixty-four participants had actigraphy data. SRPs decreased across all groups over time with a significant effect of melatonin 3 mg (3.7; 95% confidence interval [CI]: 2.1, 5.4) compared with placebo (7.4; 95% CI: 4.2, 10.6) and melatonin 10 mg (6.4; 95% CI: 3.6, 9.2). Sleep duration increased in the melatonin 3 mg (43 min; 95% CI: 6, 93) and melatonin 10 mg groups (55 min; 95% CI: 5, 104) compared with placebo. A per protocol analysis demonstrated improved sleep efficiency in the melatonin 10 mg group (p = 0.029). No serious adverse events were reported. Depressive symptoms significantly decreased with melatonin 3 mg (-4.7; 95% CI: -9.2, -.2) but not with melatonin 10 mg (-1.4, 95% CI: -5.9, 3.2) treatment compared with placebo. Changes in cognition or behavior were otherwise not significantly different between treatment groups. Short-term melatonin is a well-tolerated treatment for sleep disturbance in youth with PPCS following mTBI. In this context, it may also be associated with a reduction in depressive symptoms.


Glucosamine and Chondroitin Use in Relation to C-Reactive Protein Concentration: Results by Supplement Form, Formulation, and Dose.
Objectives: Glucosamine and chondroitin supplements have been associated with reduced inflammation, as measured by C-reactive protein (CRP). It is unclear if associations vary by formulation (glucosamine alone vs. glucosamine+chondroitin), form (glucosamine hydrochloride vs. glucosamine sulfate), or dose. Design, Subjects, Setting, Location: The authors evaluated these questions using cross-sectional data collected between 1999 and 2010 on 21,917 US adults, surveyed as part of the National Health and Nutrition Examination Survey (NHANES). Exposures: Glucosamine and chondroitin use was assessed during an in-home interview; exposures include supplement formulation, form, and dose. Outcome/Analysis: CRP was measured using blood collected at interview. Survey-weighted linear regression was used to evaluate the multivariable-adjusted association between exposures and log-transformed CRP. Results: In early years (1999-2004), use of glucosamine (ratio = 0.87; 95% confidence interval [CI] = 0.79-0.96) and chondroitin (ratio = 0.83; 95% CI = 0.72-0.95) was associated with reduced CRP. However, associations significantly varied by calendar time (p-interaction = 0.04 and p-interaction = 0.01, respectively), with associations nonsignificant in later years (ratio = 1.09; 95% CI = 0.94-1.28 and ratio = 1.16; 95% CI = 0.99-1.35, respectively). Consequently, all analyses have been stratified by calendar time. Associations did not significantly differ by formulation in either set of years; however, significant associations were observed for combined use of glucosamine+chondroitin (ratioearly = 0.82; 95% CI = 0.72-0.95; ratiolate = 1.16; 1.00-1.35), but not glucosamine alone. Associations also did not significantly differ by supplement form. Even so, a significant inverse association was observed only for glucosamine sulfate in the early years (ratio = 0.78; 95% CI = 0.64-0.95); no significant association was observed for glucosamine hydrochloride. No significant trends were observed by dose. Conclusions: Although a significant inverse association was observed for glucosamine and chondroitin and CRP in early years, this association did not hold in later years. This pattern held for combined use of glucosamine+chondroitin as well as glucosamine sulfate, although associations did not significantly vary by supplement form, formulation, or dose. Further study is needed to better understand these associations in the context of calendar time.


Longly-attached cap can contribute to en bloc underwater endoscopic mucosal resection of 20-30 mm colorectal intramucosal lesions.
Background and study aims Underwater endoscopic mucosal resection (UEMR) is effective for colorectal intramucosal lesions. The aim of this study was to evaluate whether a longly-attached cap in UEMR improves the en bloc resection rate for 20-30 mm lesions. Patients and methods We performed a retrospective study at a tertiary institute. Candidates for the study were systematically retrieved from an endoscopic and pathological database from October 2016 to December 2020. We assessed the procedural outcomes with UEMR for lesions ≥ 20 mm in size and the clinical factors contributing to en bloc resection. Results A total of 52 colorectal lesions that underwent UEMR were included. The median procedure time was 271 (66-1264) seconds. The en bloc resection rate and R0 resection rate were 75 % and 73 %, respectively. Intraprocedural perforation occurred in one (1.9 %) case, but no bleeding occurred. Delayed bleeding occurred in one (1.9%) case, but no delayed perforation occurred. Regarding tumor size, macroscopic type, tumor location, and the presence or absence of a history of abdominal operation, there was no significant difference between the en bloc resection and piecemeal resection groups. The visibility of the whole lesion, a longly-attached cap, and sessile serrated lesions were more frequently observed in the en bloc resection group than in the piecemeal resection group ( P < 0.001, P = 0.01, and P = 0.04, respectively). Multivariate analysis showed that a longly-attached cap was the only independent factor associated with en bloc resection ( P = 0.02). Conclusions A longly-attached cap might contribute to en bloc resection.


Retinal thickness of myopic eyes determined by spectralis optical coherence tomography.
To determine the relationship between the macular thickness and volume determined by spectral domain optical coherence tomography (SD-OCT) and the refractive error (RE) and axial length (AL). 48 eyes of 24 healthy Japanese subjects were examined. The REs (spherical equivalent) were measured with the Tonoref RKT-7000 autorefractometer (Nidek Inc, Aichi, Japan), and the ALs were determined by the IOL-Master (Carl Zeiss Meditec Inc, Dublin, California, USA). The thicknesses and volumes of the central, inner, and outer macular areas were measured by Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany). The correlations between the macular thickness and volume and the RE and AL were determined by linear regression analyses. The average central foveal thickness (within 1 mm) was 278.7±10.8 μm and the volume was 0.22±0.01 mm(3). The foveal thickness was negatively correlated with the RE and positively correlated with the AL (p<0.01 for both). Similar correlations were also found for the volume of the central macular areas. The significant correlation of the foveal thickness and the RE and AL in healthy eyes should be considered when these parameters are evaluated in eyes with retinal diseases.


[Multiple traumatic intracranial hematomas].
An analysis of 133 cases furnished a background to the study of features specific for the clinical course, symptomatology, diagnosis and surgical treatment of patients with multiple traumatic intracranial hematomas. The available clinical material was scrutinized in 3 groups of cases under observation (with "floor-wise", bilateral and "neighbouring" multiple intracranial hematomas) by using a complex set of up-to-date auxilliary diagnostic methods of investigation (EEG, echoencephalography, serial angiography, etc). The results of the surgical treatment were studied depending upon the specificity marking the clinical evolution of the disease, as well as upon the method and technique of the operative intervention.


Diversity, Equity, Inclusion: Where Do You Start?
Diversity, equity, and inclusion (DEI) are corresponding values that represent the workforce makeup, ensure fair treatment for all, provide organizations with welcome and support for all employees, and empower them to make a profound impact. Being welcome, included, and valued is a fundamental human need and essential to eliminating inequities in the world. The worlds of 2 nursing leaders collided at the American Organization for Nursing Leadership (AONL) Director Fellowship. One was an African American nursing leader, and the other a White nursing leader, realizing that their worlds were very similar in leadership, yet different in many ways. This article gives the reader an inside look at the DEI journeys of both nursing leaders and their impact on DEI in the professional workplace and surrounding community. It showcases the great work of 2 health care organizations, one in the Midwest and one in the Southeast.


Fully endoscopic combined transsphenoidal and supraorbital keyhole approach for parasellar lesions.
OBJECTIVE Parasellar tumors that extend far laterally beyond the internal carotid artery or that are fibrous and adhere firmly to critical structures are difficult to remove totally via the endoscopic transsphenoidal approach alone. In such cases, a combined transsphenoidal-transcranial approach is effective to achieve maximal resection in a single stage. In this paper, a new minimally invasive surgical technique for complicated parasellar lesions, a fully endoscopic combined transsphenoidal-supraorbital keyhole approach, is presented. METHODS A retrospective review of patients who had been treated via a fully endoscopic combined transsphenoidal-supraorbital keyhole approach for complicated parasellar lesions was performed. The data for resection rate, perioperative mortality and morbidity, and postoperative outcomes were analyzed. RESULTS A total of 12 fully endoscopic combined transsphenoidal-supraorbital keyhole approaches were performed from March 2013 to February 2016; 10 were for pituitary adenomas and 2 were for craniopharyngiomas. Gross-total resection or near-total resection was achieved in 7 of 12 cases. Among the 11 patients who had presented with preoperative visual disturbances, 7 had visual improvement. However, 1 patient showed deterioration in visual function. No patient experienced postoperative hemorrhage, needed additional surgical treatment, or had postoperative CSF leakage. CONCLUSIONS In the combined transsphenoidal and transcranial approach, safe and effective cooperative manipulation with 2 surgical corridors can be performed for complicated parasellar lesions. The goal of this procedure is not to achieve gross-total resection, but to achieve safe resection. Moreover, this new surgical approach offers neurosurgeons a simpler operative field with less invasiveness than the conventional microscopic combined approach. The fully endoscopic combined endonasal-supraorbital keyhole approach is an efficacious procedure for complicated parasellar lesions with acceptable results.


Retrospective study of plasma exchange in patients with idiopathic rapidly progressive glomerulonephritis and vasculitis.
A retrospective study of 48 patients was conducted to evaluate the efficacy of plasma exchange in children with idiopathic rapidly progressive glomerulonephritis (IRPGN), and renal or non-renal vasculitis. All patients were followed up at a single centre over a 15 year period. Treatment consisted of corticosteroids and/or cytotoxic agents. Plasma exchange was used in all patients because of severe renal involvement and/or clinical deterioration. One hundred per cent of patients with renal vasculitis who started plasma exchange within one month of disease onset and 58% of cases with IRPGN had significant improvement in renal function. No relapses of vasculitis were observed after treatment with plasma exchange in patients with renal and non-renal vasculitis. The results suggest that plasma exchange associated with immunosuppressive treatment could be of benefit in cases of IRPGN or vasculitis in terms of both renal and extrarenal recovery.


Free fatty acid uptake in humans with CD36 deficiency.
Animal models have demonstrated that CD36 facilitates cell membrane free fatty acid (FFA) transport, but its role in human metabolism is not well understood. We measured heart, liver, adipose (three depots), and muscle (truncal postural and thigh locomotive) FFA uptake using [(11)C]palmitate positron emission tomography (PET) scans in a family of five carrying the Pro90Ser CD36 mutation (2 homozygotes had no CD36) and matched control volunteers. PET scans were done under conditions of suppressed and slightly increased palmitate concentrations. During suppressed palmitate conditions, muscle and adipose palmitate uptake were markedly reduced in homozygotes but not heterozygotes for the Pro90Ser CD36 mutation, whereas when palmitate concentration was slightly increased, uptake in muscle and adipose did not differ between control subjects and homozygous family members. Hepatic FFA uptake was similar in all participants regardless of palmitate concentrations, whereas myocardial FFA uptake was diminished in the Pro90Ser homozygotes during both suppressed and increased palmitate conditions. We conclude that CD36 1) facilitates FFA transport into muscle and adipose tissue in humans when extracellular concentrations are reduced but not when they are modestly elevated, 2) is not rate limiting for hepatic FFA uptake, and 3) is needed for normal cardiac FFA uptake over a range of FFA concentrations from low to slightly elevated.


Activation of endothelial TLR2 by bacterial lipoprotein upregulates proteins specific for the neutrophil response.
The vascular endothelium is integrally involved in the host response to infection and in organ failure during acute inflammatory disorders such as sepsis. Gram-negative and Gram-positive bacterial lipoproteins circulate in sepsis and can directly activate the endothelium by binding to endothelial cell (EC) TLR2. In this report, we perform the most comprehensive analysis to date of the immune-related genes regulated after activation of endothelial TLR2 by bacterial di- and triacylated lipopeptides. We found that TLR2 activation specifically induces the expression of the genes IL-6, IL-8, CSF2, CSF3, ICAM1 and SELE by human umbilical vein ECs and human lung microvascular ECs. These proteins participate in neutrophil recruitment, adherence and activation at sites of inflammation. Significantly, our studies demonstrate that TLR2-mediated EC responses are specifically geared towards recruitment, activation, and survival of neutrophils and not mononuclear leukocytes, that ECs do not require priming by other inflammatory stimuli to respond to bacterial lipopeptides and, unlike mononuclear leukocytes, TLR2 agonists do not induce ECs to secrete TNF-α. This study suggests that endothelial TLR2 may be an important regulator of neutrophil trafficking to sites of infection in general, and that direct activation of lung endothelial TLR2 may contribute to acute lung injury during sepsis.


Approaches to Demonstrating the Reliability and Validity of Core Diagnostic Criteria for Chronic Pain.
The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society Pain Taxonomy (AAPT) is designed to be an evidence-based multidimensional chronic pain classification system that will facilitate more comprehensive and consistent chronic pain diagnoses, and thereby enhance research, clinical communication, and ultimately patient care. Core diagnostic criteria (dimension 1) for individual chronic pain conditions included in the initial version of AAPT will be the focus of subsequent empirical research to evaluate and provide evidence for their reliability and validity. Challenges to validating diagnostic criteria in the absence of clear and identifiable pathophysiological mechanisms are described. Based in part on previous experience regarding the development of evidence-based diagnostic criteria for psychiatric disorders, headache, and specific chronic pain conditions (fibromyalgia, complex regional pain syndrome, temporomandibular disorders, pain associated with spinal cord injuries), several potential approaches for documentation of the reliability and validity of the AAPT diagnostic criteria are summarized. The AAPT is designed to be an evidence-based multidimensional chronic pain classification system. Conceptual and methodological issues related to demonstrating the reliability and validity of the proposed AAPT chronic pain diagnostic criteria are discussed.


DNA methylation at enhancer regions: Novel avenues for epigenetic biomarker development.
Biomarkers are molecules or features which can provide clinically-relevant information about a particular disease state, thus providing useful tools for oncologists. Recently, a number of studies have demonstrated that DNA methylation holds great promise as a novel source of cancer biomarkers. Although promoter regions have been the focus of most investigations thus far, mounting evidence demonstrates that enhancer sequences also undergo extensive differential methylation in cancer cells. Moreover, enhancer methylation correlates with target gene expression better than promoter methylation, providing unexplored strategies for biomarker development. Here, we review important considerations associated with the clinical analysis of DNA methylation at distal regulatory regions. Notably, we highlight emerging literature addressing the methylation status of enhancers in development and cancer, and subsequently discuss how enhancer methylation can be exploited to guide disease management. While acknowledging current limitations, we propose that the methylation state of enhancer regions has the potential to headline the next generation of epigenetic biomarkers.


A mutagenicity methodology for assessing the formation of N-dimethylnitrosamine in vivo.
The mutagenicity test methodology in vitro has been extensively used during recent years in the identification of potential carcinogenic agents. Mutagenic analyses have been applied to the study of chemical reaction products for the demonstration of the formation of mutagenic agents. Recent studies have indicated that secondary and tertiary amines, when reacted with nitrite in acidic conditions, yield N-nitroso compounds, including the potent carcinogen N-dimethylnitrosamine (NDMA). This finding raises the problem of risk evaluation of several food components of human diets for the presence of potential carcinogenic compounds. By combining a mutagenicity test procedure with yeast cells inoculated into the blood system of mice and incubated in the liver for various times (minutes or hours) we have devised a model methodology which allows the detection of the formation of N-dimethylnitrosamine (NDMA) at a level lower than 1 mg/kg. The methodology has been examined for its use in the study of activators of the nitrosation, such as thiocyanate, and of inhibitors of the nitrosation, such as ascorbic acid and tannic acid. Other food components of the human diet, such as red wine, have also been investigated by this methodology.


[Colonic diverticulosis complicated with perforation. Analysis of several prognosis variables and criteria for emergency surgery].
The aim of this study was to analyse the clinical course, surgical strategy and results in patients with perforated large bowel diverticulitis. Over a 15-year period ending in January 1997, 25 patients (13 males and 12 females; mean age 64.1 years) underwent operation for perforation of acute diverticulitis. Depending on the symptoms, the spreading of the peritonitis and the patient general state, different surgical techniques were performed: primary resection and anastomosis with and without defunctioning colostomy (5), primary left hemicolectomy (1), Hartmann's resection (13), Mikulicz's procedure (4), suture and drainage with diverting colostomy (2). The overall mortality was 16%, while morbidity rate was 44%; these results were strictly related to the severity of clinical manifestations and peritoneal contamination. Therefore it must be stressed that a good surgical timing is essential. Our experience and literature data show that primary resection and anastomosis with and without colostomy have good results when the patient is fit, the sepsis is localized and satisfactory bowel preparation is achievable. By contrast, purulent and faecal peritonitis are still usually best treated by Hartamnn's procedure. Finally, it is submitted to surgeons's experience to choose, at any situation, the best procedure regarding age and general state, local findings and extent of peritonitis.


Using the IMEDS distributed database for epidemiological studies in type 2 diabetes mellitus.
This study aimed to assess data relevancy and data quality of the Innovation in Medical Evidence Development and Surveillance System Distributed Database (IMEDS-DD) for diabetes research and to evaluate comparability of its type 2 diabetes cohort to the general type 2 diabetes population. A retrospective study was conducted using the IMEDS-DD. Eligible members were adults with a medical encounter between April 1, 2018 and March 31, 2019 (index period). Type 2 diabetes and co-existing conditions were determined using all data available from April 1, 2016 to the most recent encounter within the index period. Type 2 diabetes patient characteristics, comorbidities and hemoglobin A1c (HbA1c) values were summarized and compared with those reported in national benchmarks and literature. Type 2 diabetes prevalence was 12.6% in the IMEDS-DD. Of 4 14 672 patients with type 2 diabetes, 52.8% were male, and the mean age was 65.0 (SD 13.3) years. Common comorbidities included hypertension (84.5%), hyperlipidemia (82.8%), obesity (45.3%), and cardiovascular disease (44.7%). Moderate-to-severe chronic kidney disease was observed in 20.2% patients. The most commonly used antihyperglycemic agents included metformin (35.7%), sulfonylureas (14.8%), and insulin (9.9%). Less than one-half (48.9%) had an HbA1c value recorded. These findings demonstrated the notable similarity in patient characteristics between type 2 diabetes populations identified within the IMEDS-DD and other large databases. Despite the limitations related to HbA1c data, our findings indicate that the IMEDS-DD contains robust information on key data elements to conduct pharmacoepidemiological studies in diabetes, including member demographic and clinical characteristics and health services utilization.


Preclinical and clinical studies on naltrexone: what have they taught each other?
Proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, California; organized and co-chaired by Janice C. Froehlich and Stephanie O'Malley. The presentations were (1) Introduction, by Janice C. Froehlich and Stephanie O'Malley; (2) Preclinical studies on naloxone: genetics and site of action, by Petri Hyytiä; (3) Clinical studies on naltrexone for treating hazardous drinkers, by Dena Davidson; (4) Clinical studies on naltrexone and sertraline in the treatment of alcohol dependence, by Conor Farren; and (5) Discussion by Janice D. Froehlich, Stephanie O'Malley, and Rainer Spanagel. Both preclinical and clinical studies are critical in the development of effective pharmacotherapeutic approaches for the treatment of alcoholism. Nowhere has this been more evident than in the development of naltrexone for the treatment of alcohol relapse. As research continues on the optimal use of naltrexone for modifying alcohol intake, a number of factors have emerged that are likely to determine the efficacy of naltrexone as a pharmacotherapeutic agent for the treatment of alcoholism. Some of these factors include dose, frequency and duration of treatment, pattern and severity of alcohol drinking prior to initiation of naltrexone treatment, genetic aspects of responsive subpopulations, degree of alcohol craving, and susceptibility to adverse effects of naltrexone. New, as well as established, animal models are being used to determine the parameters that optimize the ability of naltrexone to modify alcohol drinking in acute and chronic alcohol access paradigms, under conditions of intermittent versus continuous alcohol intake, and in populations that vary in genetic predisposition toward alcohol drinking. Current clinical studies are exploring the ability of naltrexone to alter alcohol drinking when delivered in combination with pharmacotherapeutic agents that act on nonopioid transmitter systems and the difference in efficacy of naltrexone when administered in populations that differ in drinking frequency and intensity, family history of alcoholism, and alcohol craving. This symposium presented new research findings from both preclinical and clinical studies with the aim of facilitating the development of treatment regimens that optimize the therapeutic potential of naltrexone in the treatment of alcoholism.


Simultaneous use of serum IgG and IgM for risk scoring of suspected early Lyme borreliosis: graphical and bivariate analyses.
The laboratory diagnosis of early disseminated Lyme borreliosis (LB) rests on IgM and IgG antibodies in serum. The purpose of this study was to refine the statistical interpretation of IgM and IgG by combining the diagnostic evidence provided by the two immunoglobulins and exploiting the whole range of the quantitative variation in test values. ELISA assays based on purified flagella antigen were performed on sera from 815 healthy Danish blood donors as negative controls and 117 consecutive patients with confirmed neuroborreliosis (NB). A logistic regression model combining the standardized units of the IgM and IgG ELISA assays was constructed and the resulting disease risks graphically evaluated by receiver operating characteristic and 'predictiveness' curves. The combined model improves the discrimination between NB patients and blood donors. Hence, it is possible to report a predicted risk of disease graded for each individual patient, as is theoretically preferable. The predictiveness curve, when adapted to the local pretest probability of LB, allows high-risk and low-risk thresholds to be defined instead of cut-offs based on the laboratory characteristics only, and it allows the extent of under- and over-treatment to be assessed. It is shown that an example patient with low ELISA results in IgM and IgG, considered negative by the conventional cut-off, has a relatively high risk of belonging to the truly diseased population and a low risk of being false positive. Using a 20% high-risk threshold for advising the clinician to consider treatment, the sensitivity of the assay is increased from 76% to 85%, while the specificity is maintained at around 95%.


Streptococcus spp. and Fusobacterium nucleatum in tongue dorsum biofilm from halitosis patients: a fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM) study.
The present study involved a qualitative and quantitative evaluation of tongue dorsum biofilms sampled from halitosis patients and healthy volunteers. The aim of the study was to quantify the distribution of Streptococcus spp. and Fusobacterium nucleatum within the oral halitosis biofilm in order to highlight the role of these bacterial members in halitosis. Tongue plaque samples from four halitosis-diagnosed patients and four healthy volunteers were analyzed and compared. The visualization and quantification of the tongue dorsum biofilm was performed combining fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM). Eubacteria, Streptococcus spp. and Fusobacterium nucleatum were stained using specific fluorescent probes. For a comparison of the two tested biofilm groups the Wilcoxon rank-sum test was used. Morphological analysis by CLSM illustrated the distribution of the species which were tracked. Streptococcus spp. appeared to be enclosed within the samples and always associated to F. nucleatum. Furthermore, compared to the control group the biofilm within the halitosis group contained significantly higher proportions of F. nucleatum and Streptococcus spp., as revealed by the FISH and CLSM-analysis. The total microbial load and relative proportions of F. nucleatum and Streptococcus spp. can be considered as causative factors of halitosis and thus, as potential treatment targets.


Verification of key odorants in rose oil by gas chromatography-olfactometry/aroma extract dilution analysis, odour activity value and aroma recombination.
Rose oil is much too expensive but very popular. It's well known that the flower oil's aroma profile hasn't been intensively investigated. In order to verify the aroma profile of rose oil, the synthetic blend of odorants was prepared and then compared with the original rose oil using electronic nose analysis (ENA) combined with quantitative descriptive analysis (QDA). The odorants from rose oils were screened out by Gas Chromatography-Olfactometry/aroma extract dilution analysis (GC-O/AEDA) combined with odour activity value (OAV). Both ENA and QDA indicated the recombination model derived from OAV and GC-O/AEDA closely resembled the original rose oil. The experiment results show that rose oxide, linalool, α-pinene, β-pinene, nonanal, heptanal citronellal, phenyl ethyl alcohol, benzyl alcohol, eugenol, methyl eugenol, β-citronellol, hexyl acetate, β-ionone, nerol, etc. are very important constituent to rose oil aroma profile.


Cylindrocladium buxicola, a new species affecting Buxus spp., and its phylogenetic status.
A leaf and twig blight disease of Buxus spp. was found to be associated with a new species of Cylindrocladium. The novel species status was confirmed using morphological characters, sequencing of the ribosomal 5.8S RNA gene and the flanking internal transcribed spacers (ITS), the β-tubulin gene, and the high mobility group (HMG) of the MAT2 mating type gene. Cylindrocladium buxicola is proposed as a new name. Fifteen isolates from the UK and one isolate from New Zealand were paired in all combinations but no fertile perithecia were obtained suggesting that C. buxicola is heterothallic and all isolates belonged to one mating type. AFLP analysis showed that the isolates collected in the UK and New Zealand are genetically homogenous. Phylogenetic analyses indicated that this species falls within a new lineage.


Multiscale segmentation of the skull in MR images for MRI-based attenuation correction of combined MR/PET.
Combined magnetic resonance/positron emission tomography (MR/PET) is a relatively new, hybrid imaging modality. MR-based attenuation correction often requires segmentation of the bone on MR images. In this study, we present an automatic segmentation method for the skull on MR images for attenuation correction in brain MR/PET applications. Our method transforms T1-weighted MR images to the Radon domain and then detects the features of the skull image. In the Radon domain we use a bilateral filter to construct a multiscale image series. For the repeated convolution we increase the spatial smoothing in each scale and make the width of the spatial and range Gaussian function doubled in each scale. Two filters with different kernels along the vertical direction are applied along the scales from the coarse to fine levels. The results from a coarse scale give a mask for the next fine scale and supervise the segmentation in the next fine scale. The use of the multiscale bilateral filtering scheme is to improve the robustness of the method for noise MR images. After combining the two filtered sinograms, the reciprocal binary sinogram of the skull is obtained for the reconstruction of the skull image. This method has been tested with brain phantom data, simulated brain data, and real MRI data. For real MRI data the Dice overlap ratios are 92.2%±1.9% between our segmentation and manual segmentation. The multiscale segmentation method is robust and accurate and can be used for MRI-based attenuation correction in combined MR/PET.


Effect of deoxycytidine on the metabolism and cytotoxicity of 5-aza-2'-deoxycytidine and arabinosyl 5-azacytosine in normal and leukemic human myeloid progenitor cells.
The effect of deoxycytidine (dCyd) on the inhibitory effects of two antileukemic nucleoside analogs, 5-aza-2'-deoxycytidine and ara-5-aza-Cyd, toward the clonogenic growth of normal human bone marrow progenitors (CFU-GM) and leukemic blast progenitors (L-CFU) was examined. Continuous exposure of cells to 10(-6)-10(-5) M 5-aza-deoxycytidine or 10(-5)-5 x 10(-5) M ara-5-aza-Cyd in conjunction with a 10- 100-fold excess of dCyd resulted in significantly greater restoration of CFU-GM growth than L-CFU colony formation at each dose relationship. Normal bone marrow mononuclear cells exposed to 10(-3) M dCyd for 4 hr (along with 5-aza-dCyd or ara-5-aza-Cyd) exhibited intracellular deoxycytidine triphosphate (dCTP) pools 20-fold higher than their leukemic counterparts. However, this finding was not associated with enhanced analog incorporation into leukemic cell DNA. These results suggest that high concentrations of dCyd preferentially protect normal versus leukemic progenitor cells from the inhibitory actions of 5-aza-dCyd and ara-5-aza-Cyd. They also raise the possibility that this in vitro selectivity may be related to enhanced expansion of dCTP pools in normal bone marrow elements and involves factors other than differential short-term analog incorporation into DNA.


Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage.
Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1β demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate. Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent. Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.


Improved rapid molecular diagnosis of multidrug-resistant tuberculosis using a new reverse hybridization assay, REBA MTB-MDR.
Rapid diagnosis of multidrug-resistant tuberculosis (MDR-TB) is essential for the prompt initiation of effective second-line therapy to improve treatment outcome and limit transmission of this obstinate disease. A variety of molecular methods that enable the rapid detection of mutations implicated in MDR-TB have been developed. The sensitivity of the methods is dependent, in principle, on the repertoire of mutations being detected, which is typically limited to mutations in the genes rpoB, katG and the promoter region of inhA. In this study, a new reverse hybridization assay, REBA MTB-MDR (M&D), that probes mutations in the oxyR-ahpC intergenic region, in addition to those in rpoB, katG and the inhA promoter region, was evaluated. A set of 240 Mycobacterium tuberculosis clinical isolates from patients receiving retreatment regimens was subjected to conventional phenotypic drug-susceptibility testing (DST) and the REBA MTB-MDR assay. The nucleotide sequences of the loci known to be involved in drug resistance were determined for comparison. In brief, the results showed that the REBA MTB-MDR assay efficiently recognized nucleotide changes in the oxyR-ahpC intergenic region as well as those in rpoB, katG and the inhA promoter region with higher sensitivity, resulting in an 81.0 % detection rate for isoniazid resistance. Inclusion of the oxyR-ahpC intergenic region in the REBA MTB-MDR assay improved the overall sensitivity of molecular DST for MDR-TB from 73.1 to 79.9 %.


Rotator Cuff Tear Susceptibility Is Associated With Variants in Genes Involved in Tendon Extracellular Matrix Homeostasis.
Rotator cuff tears (RCT) is a multifactorial disease with genetic factors contributing for the disease etiology. We hypothesized that genetic variants in genes involved in extracellular matrix (ECM) homeostasis may alter susceptibility to RCT. We evaluated 20 polymorphisms of genes involved in ECM homeostasis in 211 cases of full-thickness tears of the supraspinatus (Nfemales = 130; Nmales = 81) and 567 age-matched controls (Nfemales = 317; Nmales = 250). Multivariate logistic regressions were carried out with age, gender, genetic ancestry (based on the analysis of 61 biallelic short insertion/deletion polymorphisms), and common co-morbidities (diabetes, dyslipidemia, and smoking habits) as covariates. We observed that carriers of the rare allele of both studied variants of TGFB1, as well as their G/A (rs1800470/rs1800469) haplotype, were less susceptible to RCT (p < 0.05). In contrast, carriers of the G allele of MMP9 rs17576 (p = 0.014) or G/G haplotype (rs17576/rs17577; p < 0.001) had an increased risk for tendon tears. The presence of the T allele of MMP2 rs2285053 (p = 0.033), the T allele of MMP3 rs679620 (p = 0.024), and the TT-genotype of TIMP2 rs2277698 (p = 0.01) was associated with susceptibility to tears, especially in females. In males, the A allele of COL5A1 rs3196378 (p = 0.032) and the G allele of TGFBR1 rs1590 (p = 0.039) were independent risk factors for RCT. The C/T COL5A1 (rs3196378/rs11103544) haplotype was associated with a reduced risk of tears in males (p = 0.03). In conclusion, we identified the genetic variants associated with RCT susceptibility, thereby reinforcing the role of genes involved in the structure and homeostasis of the ECM of tendons in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:192-201, 2020.


Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis.
Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown. Here we show that IEC-intrinsic IkappaB kinase (IKK)-beta-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ T cells in the GI tract. Mice with an IEC-specific deletion of IKK-beta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4+ T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4+ T(H)2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.


The hypotensive effect of intravenous streptokinase in patients with acute myocardial infarction.
We studied the hypotensive effect of a rapid intravenous infusion of high-dose streptokinase in 98 patients with an acute myocardial infarction. The systolic blood pressure fell from 132 +/- 20 (range 90 to 174) to 97 +/- 21 mm Hg (range 58 to 152) at 15 +/- 8 min (range 4 to 40) after the commencement of the streptokinase infusion (p less than .001). A fall in diastolic blood pressure from 80 +/- 16 (range 51 to 105) to 61 +/- 15 mm Hg (range 32 to 92) accompanied the fall in systolic pressure (p less than .001). The fall in blood pressure was associated with an increase in heart rate (73 +/- 14 to 78 +/- 17 beats/min, p less than .001), preceded the appearance of clinical signs of reperfusion by 37 +/- 38 min and was similar in magnitude and timing in patients with anterior and inferior infarction. There were direct relationships between the rate of infusion of streptokinase and both the magnitude (r = .49, p less than .001) and the rate of fall of systolic blood pressure (r = .67, p less than .001) as well as both the magnitude and rate of fall of diastolic blood pressure. In most patients, the fall in blood pressure was transient (9 +/- 6 min, range = 2 to 30) and easily managed by slowing or stopping the infusion, placing the patient in the Trendelenburg position, or by administering an infusion of low-dose norepinephrine or dopamine. However, in four patients with severe left ventricular dysfunction, severe hypotension persisted for more than 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)


Supporting the pursuit of professionalism during a crisis.
Crisis plans for healthcare organisations most often focus on operational needs including staffing, supplies and physical plant needs. Less attention is focused on how leaders can support and encourage individual clinical team members to conduct themselves as professionals during a crisis. This qualitative study analysed observations from 79 leaders at 160 hospitals that participate in two national professionalism programmes who shared their observations in focus group discussions about what they believed were the essential elements of leading and addressing professional accountability during a crisis. Analysis of focus group responses identified six leadership practices adopted by healthcare organisations, which were felt to be essential for organisations to navigate the crisis successfully. Unique aspects of maintaining professionalism during each phase of the pandemic were identified and described. Leaders need a plan to support an organiation's pursuit of professionalism during a crisis. Leaders participating in this study identified practices that should be carefully woven into efforts to support the ongoing safety and quality of the care delivered by healthcare organisations before, during and after a crisis. The lessons learnt from the COVID-19 pandemic may be useful during subsequent crises and challenges that a healthcare organisation might experience.