A collaborative sequential meta-analysis of individual patient data from randomized trials of endovascular therapy and tPA vs. tPA alone for acute ischemic stroke: ThRombEctomy And tPA (TREAT) analysis: statistical analysis plan for a sequential meta-analysis performed within the VISTA-Endovascular collaboration.
Endovascular treatment has been shown to restore blood flow effectively. Second-generation medical devices such as stent retrievers are now showing overwhelming efficacy in clinical trials, particularly in conjunction with intravenous recombinant tissue plasminogen activator. This statistical analysis plan utilizing a novel, sequential approach describes a prospective, individual patient data analysis of endovascular therapy in conjunction with intravenous recombinant tissue plasminogen activator agreed upon by the Thrombectomy and Tissue Plasminogen Activator Collaborative Group. This protocol will specify the primary outcome for efficacy, as 'favorable' outcome defined by the ordinal distribution of the modified Rankin Scale measured at three-months poststroke, but with modified Rankin Scales 5 and 6 collapsed into a single category. The primary analysis will aim to answer the questions: 'what is the treatment effect of endovascular therapy with intravenous recombinant tissue plasminogen activator compared to intravenous tissue plasminogen activator alone on full scale modified Rankin Scale at 3 months?' and 'to what extent do key patient characteristics influence the treatment effect of endovascular therapy?'. Key secondary outcomes include effect of endovascular therapy on death within 90 days; analyses of modified Rankin Scale using dichotomized methods; and effects of endovascular therapy on symptomatic intracranial hemorrhage. Several secondary analyses will be considered as well as expanding patient cohorts to intravenous recombinant tissue plasminogen activator-ineligible patients, should data allow. This collaborative meta-analysis of individual participant data from randomized trials of endovascular therapy vs. control in conjunction with intravenous thrombolysis will demonstrate the efficacy and generalizability of endovascular therapy with intravenous thrombolysis as a concomitant medication.


Patterns of User Engagement with Mobile- and Web-Delivered Self-Care Interventions for Adults with T2DM: A Review of the Literature.
Technology-delivered interventions can improve the health behaviors and clinical outcomes of persons with diabetes, but only if end users engage with these interventions. To summarize the current knowledge on engagement with technology-based interventions, we conducted a review of recent mobile- and web-delivered intervention studies for adults with type 2 diabetes published from 2011 to 2015. Among 163 identified studies, 24 studies satisfied our inclusion criteria. There was substantial variation in how intervention engagement was reported across studies. Engagement rates were lower among interventions with a longer duration, and engagement decreased over time. In several studies, older age and lower health literacy were associated with less engagement, and more engagement was associated with intervention improvement in at least one outcome, including glycemic control. Future technology-based intervention studies should report on engagement, examine and report on associations between user characteristics and engagement, and aim to standardize how this is reported, particularly in longer trials.


Exploring the experiences of operating room health care professionals' from the challenges of the COVID-19 pandemic.
The operating room nurses have encountered several challenges during the current COVID-19 Pandemic, which subsequently impact their clinical performance. The present study aimed to investigate the experiences of operating room health care professionals' regarding the COVID-19 pandemic challenges in southern Iran. This is a descriptive qualitative study. The required data were collected using in-depth and semi-structured interviews. Accordingly, 19 operating room health care professions were included in this study through purposive sampling. The data were collected from February 2020 to August 2021 and then analyzed using the Granheim and Lundman's method. Three main themes and 9 sub-themes were presented in this study. They included: 1- Challenges of applying protocols and standards of care in the COVID-19 pandemic in the operating room (lack of specific guidelines regarding care protocols and standards for crisis management of Covid-19 in the operating room and impossibility of keeping social distance in the operating room). 2- Professional challenges (tedious and hard work, professional burnout, lack of adequate support by the managers and lack of personal protective equipment). 3-Psychological crises (indescribable anxiety and worry, parenting stress, and weakened resilience). Based on the findings of the present study, it was indicated that lack of a specific guideline in the COVID-19 pandemic led to a sense of indecision and confusion among operating room staff. In this regard, performing tedious tasks, feelings of tiredness and exhaustion, lack of support by the authorities, and lack of access to adequate facilities and equipment were reported as the professional challenges of the healthcare staff in the current COVID-19 pandemic, which consequently affected the quality of care and patient's safety. It seems that hospital officials can use the results reported in this study for efficient planning and effective management during the COVID-19 pandemic.


Facility-Level Variation of Low-Value Breast Cancer Treatments in Older Women with Early-Stage Breast Cancer: Analysis of a Statewide Claims Registry.
Since 2004, national guidelines have supported the omission of sentinel lymph node biopsy (SLNB) and radiotherapy for women ≥ 70 years of age with early-stage, hormone receptor-positive (HR+) breast cancer, but many women continue to receive at least one of these services. Provider- and patient-level factors may contribute to persistent utilization, but the role of facility-level factors is unknown. We aimed to determine facility-level variation of SLNB and adjuvant radiotherapy utilization in older women with early-stage, HR+ breast cancer undergoing breast-conserving surgery (BCS). Additionally, we aimed to explore factors associated with SLNB and radiotherapy utilization and the intra-facility correlation in their utilization. We conducted a retrospective cohort study using a statewide registry of claims data. We included women ≥70 years of age diagnosed with breast cancer who underwent BCS from 2012 to 2019 at 80 hospitals in the Michigan Value Collaborative. The main outcome was inter-facility rates and variation of SLNB and radiotherapy, as well as intra-facility correlation in their utilization. The cohort included 7253 women (median age 77 years). Only 20% (n = 1440) underwent BCS alone, whereas 71% (n = 5122) underwent SLNB and 52% (n = 3793) received radiotherapy. Inter-facility rates of SLNB ranged from 35 to 82% (median 70%), and radiotherapy ranged from 19 to 72% (median 49%). SLNB and radiotherapy were positively correlated (r = 0.27, p = 0.016). SLNB and radiotherapy rates remain high with significant variation in utilization at the facility level. High utilizers of SLNB are likely to be high utilizers of radiotherapy, suggesting the opportunity for strategic targeting of these facilities and their clinicians.


Cooperation between physicians and advisory services in a vocational rehabilitation centre.
The importance of cooperation between physicians and all other services in vocational rehabilitation is shown by demonstration of three follow-up studies. Vocational rehabilitation is understood as a new dimension in the therapy of disabled people.


An unusual case of anterior urethral injury.
We report an unusual case of straddle injury manifested by complete transection of the urethra without disruption of Buck's fascia and concomitant intussusception of the detached distal urethral segment through the external urinary meatus.


Pharmacokinetics of tolfenamic acid in patients with cirrhosis of the liver.
Six patients with alcoholic cirrhosis of the liver received 100 mg tolfenamic acid p.o. and i.v. The disposition of tolfenamic acid could be described by a two-compartment open body model, with a mean central compartment volume of 8.71, and a beta-phase volume of 25 l. The elimination rate constant ke averaged 1.13 h-1 and the half-life of the beta-phase was 1.73 h; the mean total plasma clearance was 159 ml/min. These pharmacokinetic parameters differed only slightly from those in two groups of healthy volunteers studied previously; ke was significantly reduced by about 30% in the patients but none of the other parameters differed significantly. There was good correlation between individual elimination rate constants or plasma clearances with the liver function tests, serum albumin and P-coagulation factors. Oral absorption was good and bioavailability of about 100% was shown by comparison of the areas under the plasma concentration - time curves after i.v. and p.o. administration. Metabolism was qualitatively and quantitatively very similar to previous observations in healthy volunteers. There seems no reason to reduce the dose of tolfenamic acid in patients with compensated alcoholic cirrhosis.


Psychometric properties of the OCI-R in a college sample.
Two studies examined the psychometric properties of the Obsessive-Compulsive Inventory-Revised (OCI-R; Psychol. Assessment 14 (2002) 485) in a nonclinical student sample. In Study 1, we investigated the factor structure and internal consistency of the OCI-R using a sample of 395 undergraduate students. At a second testing session 1 month later, 178 students completed the OCI-R. Test-retest reliability was examined using data from 94 students who completed the OCI-R in both sessions. Convergent validity was also assessed with the Maudsley Obsessive-Compulsive Inventory (MOCI). In Study 2, we further investigated the convergent and divergent validity of the OCI-R using a new sample of 221 students who completed a battery of measures of obsessive-compulsive symptoms, worry, and depression. There was a significant order effect for both the OCI-R and the MOCI: means of each measure were significantly lower when presented second. Despite the order effect, statistical analyses indicated that the OCI-R has adequate test-retest reliability for the full scale and subscale scores, solid factor structure, and high internal consistency. Convergent validity with other measures of obsessive-compulsive symptoms was moderate to excellent, and divergent validity was good. The results indicate that the OCI-R is a short, psychometrically sound self-report measure of obsessive-compulsive symptoms.


Dissolution of cholesterol gallstones using methyl tert-butyl ether.
Symptomatic cholelithiasis affects a large segment of the population. Several nonoperative therapeutic alternatives for treatment of these gallstones have recently been developed. We present here the technical aspects and results of gallstone dissolution in 75 patients with the use of methyl tert-butyl ether (MTBE) administered via a small percutaneously placed cholecystostomy catheter. Successful stone dissolution was achieved in 69 patients. The average time required for stone dissolution was 12.4 h over an average of 2.4 days, with the success and rate of dissolution being very dependent on technique. Six patients have developed recurrent gallstones. Future efforts will focus on decreasing the labor intensity of the procedure, dealing with the noncholesterol components of gallstones, and preventing gallstone recurrence.


Sympathetic and parasympathetic innervation of pupillary dilation during sustained processing.
The contributions of separate sympathetic and parasympathetic pathways to pupillary dilation during a sustained processing task were studied through environmental and pharmacological manipulations. In Experiment 1, 22 healthy volunteers (11 female) performed a serial Subtract 7 task while pupil diameter was recorded both during moderate room light and in darkness. In a control for verbalization, subjects performed an easier Add 1 task. In all conditions, pupil diameter increased significantly during the response period as compared to a pre-verbalization baseline period. Pupillary dilation was increased for the difficult task, and further increase in dilation was associated with recording in light. This suggests a major differential contribution to task difficulty mediated through inhibition of the parasympathetic pathway. In Experiment 2, a subgroup of 12 volunteers (seven female) repeated all conditions at three additional sessions in which one eye was instilled with tropicamide (to block the parasympathetic sphincter muscle), dapiprazole (to block the sympathetic dilator muscle) or placebo. All pharmacological conditions resulted in overall dilation during task performance. Differential performance similar to the placebo condition was seen only in the dapiprazole condition, when parasympathetic activation was intact. The findings suggest that sustained performance during a difficult task is modulated by cortical inhibition of the parasympathetic pathway at the oculomotor nucleus. Moreover, modulation of both ambient light intensity and pharmacological blockade of the final pupillary musculature were observed to provide converging approaches for quantifying the activity of identifiable central autonomic pathways.


Complexity of neurotoxicological assessment.
One of the central objections to routine behavioral testing concerns the difficulty in interpreting behavioral effects. This paper discusses the assessment of neurotoxic hazard using data from both conventional toxicity studies and behavioral studies. It describes the breadth and complex expression of neurotoxic effects, the inference of neurotoxicity from behavioral and other data, and the validity and interpretation of behavioral effects. The basic questions asked by regulatory petition reviewers include: (1) can an effect be identified; (2) can the effect be considered to be a function of exposure; (3) can the effect be considered to be a direct effect on the nervous system; and (4) can the effect be considered to be an adverse effect? Approaches and options for improving the interpretability of current testing strategies are described. These include improvements and additions to existing studies, explicit testing, and development of generic testing requirements for specific chemical classes.


The role of recombination and selection in the modifier theory of sex-ratio distortion.
The equilibrium configurations for a two-locus multialle model of sex-linked meiotic drive are studied with regard to the recombination fraction:limit cycles can occur in the case of small recombination while stable equilibrium points associated with linkage equilibrium can exist for an intermediate range of recombination values depending on the equilibrium sex ratio, linkage disequilibrium at nearby equilibrium points taking turn with loser linkage. The evolutionary dynamics in two-locus sex-ratio distortion systems is enlightened: while equilibria with a sex ratio closer to 1/2 are more likely to be stable with respect to perturbations on the frequencies of sex-ratio distorters that are represented at equilibrium, such equilibria are also more vulnerable to the invasion of mutant distorters when there is some degree of linkage with the sex-determining locus. For X-linked multimodifier systems of sex-ratio distortion, differential fertilities and viabilities are incorporated and a maximum principle is suggested.


Chronic active Epstein-Barr virus (CAEBV) enteritis.
Chronic active Esptein-Barr virus (CAEBV) enteritis if rarely observed in immunocompetent patients and can be often misdiagnosed as inflammatory bowel disease. We hereby present a case of CAEBV enteritis diagnosed with double-balloon enteroscopy and EBER in-situ hybridization. This case demonstrates the clinical presentation and diagnosis of CAEBV enteritis and highlights the importance of early recognition of the disease.


Mass cytometry analysis of blood immune cells from psoriasis patients on biological therapy.
Psoriasis is a chronic immune-mediated skin disease accompanied by systemic inflammation and comorbidities. We analyzed peripheral blood mononuclear cells (PBMCs) in the search for immune signatures and biomarkers related to psoriasis severity and treatment effect. Thirty-two patients with psoriasis and 10 matched healthy controls were included. PBMCs were collected before and after initiation of anti-TNF, anti-IL-17 or anti-IL-12/23 treatment and analyzed utilizing 26-parameter mass cytometry. The number of circulating Th17, Th22, Th9, and cytotoxic T cells were increased in severe psoriasis. Intracellular pp38 and pERK in T helper cells were associated with disease severity. Differences between responders and nonresponders regarding cell composition and intracellular signaling were identifiable already at inclusion. Biological treatment induced memory cells, restored inhibitory PD-1 function of T cells, and reduced a potential pro-atherogenic profile in monocytes. In conclusion, these results indicate amelioration of systemic inflammation in psoriasis after biological treatment. Such broad immune profiling may enable prospective stratification of patients regarding future treatment response. Successful early intervention may lead to a healthier trajectory with favorable implications on later comorbidities.


Long-Term Patient-Reported Outcomes Comparing Oncoplastic Breast Surgery and Conventional Breast-Conserving Surgery: A Propensity Score-Matched Analysis.
Oncoplastic breast surgery (OBS) combines plastic surgery techniques with conventional breast-conserving surgery (BCS) and expands BCS eligibility. Limited data are available on patient-reported outcomes (PROs) after OBS. Here we compare long-term PROs after OBS and BCS utilizing the BREAST-Q. Women undergoing OBS or BCS between 2006 and 2019 who completed ≥ 1 long-term BREAST-Q survey 3-5 years postoperatively were identified. Baseline characteristics were compared between women who underwent OBS/BCS. Women who underwent OBS were paired with those who underwent BCS using 1:2 propensity matching [by age, body mass index (BMI), race, T stage, and multifocality]. BREAST-Q scores were compared preoperatively and 3-5 years postoperatively. A total of 297 patients were included for analysis (99 OBS/198 BCS). Women who underwent OBS were younger (p < 0.001) and had higher BMI (p = 0.005) and multifocal disease incidence (p = 0.004). There was no difference between groups in nodal stage, re-excision rates, axillary surgery, chemotherapy, endocrine therapy, or radiotherapy. After propensity matching preoperatively, women who underwent OBS reported lower psychosocial well-being (63 versus 100, p = 0.039) but similar breast satisfaction and sexual well-being compared with women who underwent BCS; however, only three patients who underwent BCS had preoperative BREAST-Q scores available for review. In long-term follow-up, women who underwent OBS reported lower psychosocial scores (74 versus 93, p = 0.011) 4 years postoperatively, but not at 5 years (76 versus 77, p = 0.83). There was no difference in long-term breast satisfaction or sexual well-being. Women who undergo OBS present with a larger disease burden and may represent a group of non-traditional BCS candidates; they reported similar long-term breast satisfaction and sexual well-being compared with women who undergo BCS. While women who underwent OBS reported lower psychosocial well-being scores preoperatively and during a portion of the follow-up period, this difference was no longer seen at 5 years postoperatively.


Modeling monochloramine loss in the presence of natural organic matter.
A comprehensive model describing monochloramine loss in the presence of natural organic matter (NOM) is presented. The model incorporates simultaneous monochloramine autodecomposition and reaction pathways resulting in NOM oxidation. These competing pathways were resolved numerically using an iterative process evaluating hypothesized reactions describing NOM oxidation by monochloramine under various experimental conditions. The reaction of monochloramine with NOM was described as biphasic using four NOM specific reaction parameters. NOM pathway 1 involves a direct reaction of monochloramine with NOM (k(doc1) = 1.05 x 10(4)-3.45 x 10(4) M(-1) h(-1)). NOM pathway 2 is slower in terms of monochloramine loss and attributable to free chlorine (HOCl) derived from monochloramine hydrolysis (k(doc2) = 5.72 x 10(5)-6.98 x 10(5) M(-1) h(-1)), which accounted for the majority of monochloramine loss. Also, the free chlorine reactive site fraction in the NOM structure was found to correlate to specific ultraviolet absorbance at 280 nm (SUVA280). Modeling monochloramine loss allowed for insight into disinfectant reaction pathways involving NOM oxidation. This knowledge is of value in assessing monochloramine stability in distribution systems and reaction pathways leading to disinfection by-product (DBP) formation.


Cytoplasmic pool of U1 spliceosome protein SNRNP70 shapes the axonal transcriptome and regulates motor connectivity.
Regulation of pre-mRNA splicing and polyadenylation plays a profound role in neurons by diversifying the proteome and modulating gene expression in response to physiological cues. Although most of the pre-mRNA processing is thought to occur in the nucleus, numerous splicing regulators are also found in neurites. Here, we show that U1-70K/SNRNP70, a component of the major spliceosome, localizes in RNA-associated granules in zebrafish axons. We identify the extra-nuclear SNRNP70 as an important regulator of motor axonal growth, nerve-dependent acetylcholine receptor (AChR) clustering, and neuromuscular synaptogenesis. This cytoplasmic pool has a protective role for a limited number of transcripts regulating their abundance and trafficking inside axons. Moreover, non-nuclear SNRNP70 regulates splice variants of transcripts such as agrin, thereby controlling synapse formation. Our results point to an unexpected, yet essential, function of non-nuclear SNRNP70 in axonal development, indicating a role of spliceosome proteins in cytoplasmic RNA metabolism during neuronal connectivity.


Blood transcriptomics mirror regulatory mechanisms during hibernation-a comparative analysis of the Djungarian hamster with other mammalian species.
Hibernation enables many species of the mammalian kingdom to overcome periods of harsh environmental conditions. During this physically inactive state metabolic rate and body temperature are drastically downregulated, thereby reducing energy requirements (torpor) also over shorter time periods. Since blood cells reflect the organism´s current condition, it was suggested that transcriptomic alterations in blood cells mirror the torpor-associated physiological state. Transcriptomics on blood cells of torpid and non-torpid Djungarian hamsters and QIAGEN Ingenuity Pathway Analysis (IPA) revealed key target molecules (TMIPA), which were subjected to a comparative literature analysis on transcriptomic alterations during torpor/hibernation in other mammals. Gene expression similarities were identified in 148 TMIPA during torpor nadir among various organs and phylogenetically different mammalian species. Based on TMIPA, IPA network analyses corresponded with described inhibitions of basic cellular mechanisms and immune system-associated processes in torpid mammals. Moreover, protection against damage to the heart, kidney, and liver was deduced from this gene expression pattern in blood cells. This study shows that blood cell transcriptomics can reflect the general physiological state during torpor nadir. Furthermore, the understanding of molecular processes for torpor initiation and organ preservation may have beneficial implications for humans in extremely challenging environments, such as in medical intensive care units and in space.


Community organization in streams: the importance of species interactions, physical factors, and chance.
Experimental studies were used to examine the mechanisms governing the distribution and abundance of two major patch types in unshaded reaches of Augusta Creek, Michigan (USA). One patch type is dominated by Cladophora glomerata, a macroalga potentially able to monopolize space, whereas the other type is comprised of a low-growing, epilithic microalgal lawn inhabited by several species of sessile grazers (especially the caddisflies Leucotrichia pictipes and Psychomyia flavida). Cladophora patches are absent from mid-channel sites characterized by current velocities ≤ ca. 50 cm s-1; caging experiments indicate that their absence is due to grazing by crayfish (Orconectes propinquus). Cladophora's presence in sites with velocities >50 cm s-1 apparently results in part because crayfish foraging activity is impaired in high flow regimes. The presence of Cladophora strongly affects various other invertebrates due to its alteration of abiotic and biotic characteristics of the microhabitat. For example, the abundance of sessile grazers (e.g. Leucotrichia and Psychomyia) that inhabit microalgal patches is negatively correlated to the abundance of Cladophora, whereas the abundance of several other invertebrates (e.g. Stenonema mayflies and Taeniopteryx stoneflies) is positively correlated to Cladophora's abundance. Therefore, in some portions of this system, crayfish act as keystone predators because of their ability to regulate the abundance of Cladophora, which in turn has strong positive and negative effects on other components of the community. Cladophora does not always monopolize space at high velocities in the absence of crayfish, however. If sessile grazers arrive at such sites before Cladophora, they can prevent its establishment. Thus, where crayfish are absent, the likelihood that a site will be dominated by either Cladophora patches or sessile grazer - microalgal lawn patches depends on two sets of stochastic processes: (1) those that create bare space (e.g. disturbance and grazer emergence); and (2) those controlling the timing of recruitment by Cladophora or grazers at these bare sites. These priority effects (i.e. the ability of grazers and Cladophora to inhibit each other's establishment) contribute to the marked spatial heterogeneity of these two patch types. Collectively, these results demonstrate how interactions between competition, predation, and physical factors can generate a complex mixture of community patterns.


CoQ10 reduces glioblastoma growth and infiltration through proteome remodeling and inhibition of angiogenesis and inflammation.
Most monotherapies available against glioblastoma multiforme (GBM) target individual hallmarks of this aggressive brain tumor with minimal success. In this article, we propose a therapeutic strategy using coenzyme Q10 (CoQ10) as a pleiotropic factor that crosses the blood-brain barrier and accumulates in cell membranes acting as an antioxidant, and in mitochondrial membranes as a regulator of cell bioenergetics and gene expression. Xenografts of U251 cells in nu/nu mice were used to assay tumor growth, hypoxia, angiogenesis, and inflammation. An orthotopic model was used to explore microglial infiltration, tumor growth, and invasion into the brain parenchyma. Cell proliferation, migration, invasion, proteome remodeling, and secretome were assayed in vitro. Conditioned media were used to assay angiogenesis, monocyte chemoattraction, and differentiation into macrophages in vitro. CoQ10 treatment decreased tumor volume in xenografts and orthotopic models, although its effect on tumor cell proliferation was not direct. Tumors from mice treated with CoQ10 were less hypoxic and vascularized, having less infiltration from inflammatory cells. Treatment-induced downregulation of HIF-1α and NF-kB led to a complete remodeling of the tumor cells proteome and secretome, impacting angiogenesis, monocyte infiltration, and their differentiation into macrophages. Besides, tumor cell migration and invasion were drastically restricted by mechanisms involving modulation of the actin cytoskeleton and downregulation of matrix metalloproteases (MMPs). CoQ10 has a pleiotropic effect on GBM growth, targeting several hallmarks simultaneously. Thus, its integration into current treatments of this fatal disease should be considered.


Community without communitarianism: HIV/AIDS research, prevention and treatment in Australia and the developing world.
The advent of HIV focussed broad social attention on the group of people most affected by it in Australia, the so-called 'gay community'. However, what a gay community actually was, and what kind of rights and duties were being attached to it remained unclear. However, it is obvious that such a community--or communities--did not fit the model proposed by communitarian writers like Michael Sandel and Charles Taylor, whereby subjects cannot stand outside their own constitutive attachments. I also consider the common criticism of communitarianism, and see what kinds of collectives can in fact be considered ethical. The first part of the paper looks at the ethical issues surrounding community attachment of this kind in Australia in relation to the ethics of HIV/AIDS clinical research. In particular I examine the way in which certain forms of gay community attachment can be used to strengthen personal autonomy and check exploitation within the prevention and research process. The second part of this paper draws upon the issues just discussed. In particular I focus on the use of 'community' in the research process in developing countries, and suggest ways in which cultural considerations might strengthen autonomy. However, I go on to suggest that in many cases the idea of community has served the opposite purpose, and has in fact been used to oppress certain individuals and groups within the developing world, in the so-called interests of the greater good. In order to avoid this, I suggest a model of social and ethical research whereby all subjects and researchers in the clinical process might stand in greater relationships of equality with each other.


Comparative aspects of sperm membrane fatty acid composition in silver (Vulpes vulpes) and blue (Alopex lagopus) foxes, and their relationship to cell cryopreservation.
Cryogenic protocols have been developed for the storage of farmed silver fox (Vulpes vulpes) spermatozoa. However, these same protocols and modifications of these protocols have failed to satisfactorily preserve spermatozoa collected from farmed blue foxes (Alopex lagopus). Because cryogenic success has been linked to membrane composition, the plasma membrane lipid composition of farmed blue fox and silver fox spermatozoa was studied. Silver fox spermatozoal membranes have significantly higher levels of docosapentaenoic acid (DPA; 22:5, n-6) compared to blue fox spermatozoa, and blue fox spermatozoal membranes have significantly higher levels of stearic acid (18:0). Silver fox spermatozoal membranes not only have a higher ratio of unsaturated/saturated membrane fatty acids, but also higher levels of membrane desmosterol and cholesterol.


Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases.
Worldwide increase incidences of allergic diseases have heightened the interest of clinicians and researchers to understand the role of neuroendocrine cells in the recruitment and activation of inflammatory cells. Several pieces of evidence revealed the association of neuropeptides in the pathogenesis of allergic diseases. Importantly, one such peptide that is secreted by neuronal cells and immune cells exerts a wide spectrum of immunological functions as cytokine/chemokine is termed as Vasoactive Intestinal Peptide (VIP). VIP mediates immunological function through interaction with specific receptors namely VPAC-1, VPAC-2, CRTH2 and PAC1 that are expressed on several immune cells such as eosinophils, mast cells, neutrophils, and lymphocytes; therefore, provide the basis for the action of VIP on the immune system. Additionally, VIP mediated action varies according to target organ depending upon the presence of specific VIP associated receptor, involved immune cells and the microenvironment of the organ. Herein, we present an integrative review of the current understanding on the role of VIP and associated receptors in allergic diseases, the presence of VIP receptors on various immune cells with particular emphasis on the role of VIP in the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. Being crucial signal molecule of the neuroendocrine-immune network, the development of stable VIP analogue and/or antagonist may provide the future therapeutic drug alternative for the better treatment of these allergic diseases. Taken together, our current review summarizes the current understandings of VIP biology and further explore the significance of neuroendocrine cells derived VIP in the recruitment of inflammatory cells in allergic diseases that may be helpful to the investigators for planning the experiments and accordingly predicting new therapeutic strategies for combating allergic diseases. Summarized graphical abstract will help the readers to understand the significance of VIP in allergic diseases.


Definition of the construct to be measured is a prerequisite for the assessment of validity. The Neck Disability Index as an example.
To determine the content, structural, and construct validity of the Dutch version of the Neck Disability Index (NDI). To assess content validity, 11 neck pain experts and 10 patients commented on the construct, comprehensiveness, and relevance of the NDI. Structural validity was assessed by item factor analysis (FA) and item response theory modeling using the generalized partial credit model. Differential item functioning (DIF) analysis for gender was examined. Pearson correlation coefficient with the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire was calculated to assess construct validity. In addition to a suboptimal translation, we found a lack of consensus on the construct the NDI intends to measure. Experts and patients suggested that the NDI measures more than physical functioning. Unidimensionality of the NDI could not be confirmed. DIF analysis for gender showed DIF for the headache item. The goodness-of-fit statistics for FA with one factor were satisfactory when the item "concentration" was omitted. A correlation of 0.75 with the DASH was found supporting construct validity. It is questionable whether in research the NDI should be the instrument of choice for use as a primary outcome measure. Definition of the construct to be measured is a prerequisite for the assessment of validity.


Novel ether lipid cardiolipins in archaeal membranes of extreme haloalkaliphiles.
The lipidome of two extremely haloalkaliphilic archaea, Natronococcus occultus and Natronococcus amylolyticus, has been examined by means of combined thin-layer chromatography and MALDI-TOF/MS analyses. The detailed investigation of lipid profiles has confirmed the presence of i) ether lipid phosphatidylglycerol and phosphatidylglycerophosphate methyl ester as main lipid components, ii) both C(20) and C(25) isopranoid chains in the lipid core and yielded new findings on membrane lipids of these unusual organisms. Besides some novel minor or trace phospholipids and glycolipids, data indicate the presence of ether lipid cardiolipin variants constituted by different combinations of C(20) and C(25) isopranoid chains, never before described in archaea. The role of C(25) isopranoid chains in the adaptation to high pH gradients in the presence of very high salt concentrations is discussed.


Optimal combination of anti-inflammatory components from Chinese medicinal formula Liang-Ge-San.
Liang-Ge-San (LGS), a traditional Chinese medicine (TCM) formula, is usually used in acute inflammatory diseases in China. This study aims to detect the optimal combination of anti-inflammatory components from LGS. Four mainly representative components (phillyrin, emodin, baicalin, and liquiritin) from LGS were chosen. The optimal combination was investigated by orthogonal design study. Zebrafish inflammation model was established by lipopolysaccharide (LPS)-yolk microinjection, and then the anti-inflammatory activities of different combinations were determined by survival analysis, changes on inflammatory cells infiltration, the MyD88/NF-κB and MAPK pathways and inflammatory cytokines production. The different combinations of bioactive ingredients from LGS significantly protected zebrafish from LPS-induced inflammation, as evidenced by decreased recruitment of macrophages and neutrophils, inhibition of the MyD88/NF-κB and MAPK pathways and down-regulation of TNF-α and IL-6. Among them, the combination group 8 most significantly protected against LPS. The combination of group 8 is: 0.1 μM of emodin, 2 μM of baicalin, 20 μM of phillyrin and 12.5 μM of liquiritin. The optimized combination group 8 exerts the most significant anti-inflammatory activity by inhibiting the recruitment of inflammatory cells, activation of the MyD88/NF-κB and MAPK pathways and the secretion of pro-inflammatory cytokines. This present study provides pharmacological evidences for the further development of new modern Chinese drug from LGS to treat acute inflammatory diseases, but indicated the use of zebrafish in the screening of components from formulas.


Involvement of the Zn-binding region of tetanus toxin in B and T recognition. Influence of Zn fixation.
Tetanus toxin contains a metal-binding site for zinc, located in its light chain. The sequence accounting for Zn fixation is part of a predicted amphipathic helical secondary structure and corresponds to a putative T cell epitope according to Rothbard and Taylor (EMBO J. 7, 93-100, 1988). In this paper, we analyse the antigenic properties of two synthetic peptides (233-248 = P12 and 225-243 = P13) containing the Zn binding sequence. Our results show that peptide P13 contains a B and T epitope. The B epitope seems to be immuno-dominant whether the T epitope is at least DR2 restricted. Zn binding on P13 leads to a decrease in its recognition by both antibodies and T lymphocytes.


[3 + 2] Cycloadditions of Azides with Arynes via Photolysis of Phthaloyl Peroxide Derivatives.
Photolysis of phthaloyl peroxides yields arynes, which undergo [3 + 2] cycloadditions with azides. This reaction tolerates a variety of organic azides and phthaloyl peroxides and affords the corresponding benzotriazoles in moderate to good yields at room temperature.


Dermatomyositis as the first manifestation of a lung tumor.
Dermatomyositis (DM) is a rare disease characterised by proximal muscle weakness and a typical cutaneous rash. The muscle biopsy shows inflammatory lesions consistent with myositis, being related to an increased risk of cancer, often considered as a paraneoplastic syndrome. The authors present a case of a 63-year-old man, with progressive proximal muscle weakness and cutaneous rash, appearing in two months. The muscle and skin biopsies were consistent with DM. Chest tomography showed a nodular image in the lingular region and bronchy biopsy confirmed the diagnosis of small cell lung carcinoma (SCLC). This clinical case intends to enhance the importance of a thorough diagnostic study in patients with DM, as it is often a paraneoplastic syndrome.


Lies tell the truth about cognitive dysfunction in essential tremor: an experimental deception study with the guilty knowledge task.
Research conducted in the past decade challenges the traditional view that essential tremor (ET) is characterised exclusively by movement disorder, and increasingly shows that these patients have deficits in cognitive and behavioural functioning. The available evidence suggests that this impairment might arise from dysfunction in either the fronto-subcortical or cortico-cerebellar circuits. Although abnormalities in the fronto-subcortical circuits could imply difficulty in lying, no study has investigated deception in patients with ET. To examine the cognitive functions regulating deception in patients with ET, we used a computerised task, the Guilty Knowledge Task (GKT). We also tested a group of patients with Parkinson's disease (PD), a disease associated with a known difficulty in lie production, and a group of healthy subjects (HS). In the GKT for deception, patients with ET responded less accurately than HS (p=0.014) but similarly to patients with PD (p=0.955). No differences between groups were found in truthful responses (p=0.488). Besides confirming impaired deception in patients with PD, our results show a lie production deficit in patients with ET also. These findings suggest that difficulty in lying is an aspecific cognitive feature in movement disorders characterised by fronto-subcortical circuit dysfunction, such as PD and ET. Current knowledge along with our new findings in patients with ET--possibly arising from individually unrecognised extremely mild, cognitive difficulties--should help in designing specific rehabilitative programmes to improve cognitive and behavioural disturbances in patients.


[Effect of selective activation and blockade of the central dopaminergic system on the course of the early post-traumatic period].
Acute experiments on white rats traumatized according to Kenon demonstrated that the central administration of the dopamine receptor agonist apomorphine led a reduction in mortality rates and an increase in stroke and heart indices. The latter was due to the significant activation of the hypothalamo-hypophysis-thyroidal system. The use of sulpiride as a specific dopamine receptor blocker increased mortality rates and decreased stroke and heart indices. This was accompanied by the maximum activation of the hypothalamo-neurohypophyseal system.


Evolution Process and Controlled Synthesis of Humins with 5-Hydroxymethylfurfural (HMF) as Model Molecule.
Elucidation of the chemical structure and formation mechanism of humins is a requisite to further improve the efficiency of acid-catalyzed biomass conversion. Through a low-temperature approach, the key intermediates resulting in the formation of 5-hydroxymethylfurfural (HMF)-derived humins were captured, revealing multiple elementary reactions such as etherification, esterification, aldol condensation, and acetalization. Through humin characterization, it was found out that the aldol condensation moiety between aldehyde group and levulinic acid is critical to justify the characteristic IR peaks (1620 and 1710 cm-1 ) and aromatic fragments from pyrolysis GC-MS. Based on the investigations by means of HPLC-MS/MS, IR, pyrolysis GC-MS, and SEM, the structural models of humins at different temperatures were proposed, which are comprised of the elementary reaction types confirmed by the key intermediates. Humin structures with varying content of aldol condensation could be controllably synthesized under different reaction conditions (temperature and time), demonstrating the evolution process of HMF-derived humins.


Prenatal Diagnosis of the Right Aortic Arch: Change in Detection Rate, the Status of Associated Anomalies, and Perinatal Outcomes in 137 Fetuses.
To evaluate prenatal findings of the right aortic arch (RAA), associated cardiac, extracardiac, and genetic anomalies, its perinatal outcomes and the need for postnatal interventions in cases of isolated RAA with a view to facilitating appropriate counseling. This was a multicenter, cohort study, that was undertaken in two international major cardiac centers between 2009 and 2020. The study subjects were prenatally diagnosed RAA cases with and without other structural cardiac defects. A RAA was identified in 137 fetuses. There were 84 cases of isolated RAA. Associations with additional intracardiac malformations were found in 53 (38.7%) cases. An extracardiac anomaly was observed in 26/137 (18.9%) fetuses, 11/84 (13.0%) fetuses with isolated RAA, and 15/53 (28.3%) fetuses with an additional intracardiac anomaly. The incidence of extracardiac and chromosomal anomalies was significantly higher in cases of RAA with abnormal intracardiac anatomy (28.3-18.8%, respectively), compared with RAA with normal intracardiac anatomy (13.0-5.9%, respectively) (p < 0.05). 22q11.2 microdeletion was found higher in RAA with CHD (4/18 fetuses) than isolated RAA (2/24 fetuses) (22.2% vs. 8.3% respectively). ALSA was present in 19.3% of cases. ALSA was more frequently observed in cases of isolated RAA (23.6%), than in RAA with structural CHD (7.6%) (p < 0.05). The pregnancy was interrupted in six fetuses, and one died in utero. The mortality rate was higher in fetuses with intracardiac anomaly than RAA without cardiac anomaly (11/49 (22.4%) vs. 2/81 (2.4%). Vascular ring formation was revealed in 21/98 cases. The RAA caused symptoms of a vascular ring in only one patient (0.7%) requiring surgery in the follow-up. Overall survival after initial diagnosis in the total cohort was 85.4% with 38 of 53 (71%) RAA with CHD cases and 79 of 84 (94.0%) isolated RAA cases. Chromosomal and extracardiac anomalies are lower in isolated RAA but not negligible hence amniocentesis should be routinely offered in all cases. The requirement for postnatal intervention in the immediate neonatal period is remote, therefore delivery of these fetuses need not be undertaken at a cardiac or surgical center.


An unusual case of cutaneous feline pythiosis.
Pythiosis is frequently reported in dogs and horses inhabiting tropical, subtropical and temperate areas of the USA, but the disease is rare in domestic cats. The clinical presentation of feline pythiosis includes subcutaneous masses without ulcerated tissue and involvement of the intestinal tract. Here in we report an eight-week-old female unvaccinated stray kitten with an unusual extensive circular ulcerated lesion on her left flank. The lesion did not respond favorably to administration of systemic antibiotics. Clinical specimens submitted for culture demonstrated submerged fungal-like flat colonies later identified as Pythium insidiosum, a finding also confirmed by histopathology, serology, and DNA sequencing and thus, treated with itraconazole. Since no improvement was observed, Pythium-immunotherapy was initiated. The cat responded to the latter approach and in less than 10 days, the lesion had contracted around the edges and was crusting off to reveal healthy granulation tissue. Twenty-three days after immunotherapy was initiated the original wound had shrunken significantly to a small scabbed area. However, the cat acutely developed tachypnea, lung and intestinal complications and due to her rapid deterioration, humane euthanasia was elected. Unfortunately, necropsy was not conducted. The clinical presentation reported here suggests large ulcerative cutaneous lesions caused by P. insidiosum can also occur in domestic cats. Despite reports of unsuccessful treatment results of feline pythiosis using Pythium-immunotherapy, this report suggests this approach might be helpful in similar feline cases.


Molecular and pharmacologic profile of tinzaparin and a comparable low-molecular-weight bacterial sulfaminoheparosan.
Low-molecular-weight heparins (LMWH) represent depolymerized porcine mucosal heparin derivatives, which are commonly used for the management of thrombotic disorders. Because of their widespread usage, the supplies of the raw material namely unfractionated heparin are nearly exhausted. Porcine mucosal tissue is almost exclusively used for the preparation of these agents. Thus, there is a timely need for the production of heparin like drugs from other sources. Fermentation techniques have been used to produce carbohydrates such as dextran and innulin for therapeutic purposes. Bacterial cell wall polysaccharide mimics the linear hexose units, which constitute heparin. Utilizing Escherichia coli cell membranes produced by fermentation technology, chemical sulfation and enzymatic epimerization, sulfaminoheparosan type of polymer mimicking the structure of heparin has been produced. These semi-synthetic sulfaminoheparosans exhibit biologic actions comparable to that observed with heparin. The sulfaminoheparosan core can also be degraded to obtain low-molecular-weight (LMW) derivatives mimicking LMWHs. Using this technique, a novel LMW sulfaminoheparosan derivative (Q93C/239) was produced by Inalco, Milan, Italy. To compare this heparin analogue, a LMWH, namely tinzaparin, was used to determine the relative anticoagulant, antiprotease, and molecular profile. Additional studies were carried out to determine the susceptibility of this agent to heparinase-I. These comparative studies exhibited both antiprotease and anticoagulant properties similar to those of tinzaparin. However LMW sulfaminoheparosan resisted heparinase-I digestion at low heparinase-I concentrations. These studies demonstrate that the sulfaminoheparosan derived LMW components exhibit similar molecular and anticoagulant profile as tinzaparin and warrant additional preclinical and clinical development to determine their potential usefulness as antithrombotic agents.


Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia.
Chronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the chemokine CXCL5 on WMI and cognitive decline in chronic cerebral ischemia and the underlying mechanism. Bilateral carotid artery stenosis (BCAS) model was constructed to mimic chronic cerebral ischemia in 7-10 weeks old male mice. Astrocytic Cxcl5 conditional knockout (cKO) mice were constructed and mice with Cxcl5 overexpressing in astrocytes were generated by stereotactic injection of adeno-associated virus (AAV). WMI was evaluated by magnetic resonance imaging (MRI), electron microscopy, histological staining and western blotting. Cognitive function was examined by a series of neurobehavioral tests. The proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), phagocytosis of microglia were analyzed via immunofluorescence staining, western blotting or flow cytometry. CXCL5 was significantly elevated in the corpus callosum (CC) and serum in BCAS model, mainly expressed in astrocytes, and Cxcl5 cKO mice displayed improved WMI and cognitive performance. Recombinant CXCL5 (rCXCL5) had no direct effect on the proliferation and differentiation of OPCs in vitro. Astrocytic specific Cxcl5 overexpression aggravated WMI and cognitive decline induced by chronic cerebral ischemia, while microglia depletion counteracted this effect. Recombinant CXCL5 remarkably hindered microglial phagocytosis of myelin debris, which was rescued by inhibition of CXCL5 receptor C-X-C motif chemokine receptor 2 (CXCR2). Our study revealed that astrocyte-derived CXCL5 aggravated WMI and cognitive decline by inhibiting microglial phagocytosis of myelin debris, suggesting a novel astrocyte-microglia circuit mediated by CXCL5-CXCR2 signaling in chronic cerebral ischemia.


Short-term relation between air pollutants and hospitalizations for respiratory diseases: analysis by temporal association rules.
This study investigates the relation between exposure to critical air pollution events with multipollutant (CO, PM10, PM2.5, NO2, O3, and SO2) and hospitalizations for respiratory diseases in the metropolitan area of São Paulo (RMSP) and in the countryside and coastline, from 2017 to 2021. Data mining analysis by temporal association rules searched for frequent patterns of respiratory diseases and multipollutants associated with time intervals. In the results, pollutants PM10, PM2.5, and O3 showed high concentration values in the three regions, SO2 on the coast, and NO2 in the RMSP. Seasonality was similar between pollutants and between cities and concentrations significantly higher in winter, except for O3, which was present in warm seasons. Hospitalizations were recurrent during the transition from summer to colder periods. In approximately 35% of the total days with hospitalization greater than the annual average, one or more pollutants had a high concentration. The rules showed that PM2.5, PM10, and O3 pollutants are strongly associated with increased hospitalizations in the RMSP (PM2.5 and PM10 with 38.5% support and 77% confidence) and in Campinas (PM2.5 with 66.1% support and 94% confidence) and the pollutant O3 with maximum support of 17.5%. On the coast, SO2 was related to high hospitalizations (43.85% support and 80% confidence). The pollutants CO and NO2 were not associated with the increase in hospitalizations. The ratio delay indicates the pollutants that were associated with hospitalizations, having concentration remained above the limit for three days, oscillating in smaller hospitalizations on the 1st day and again higher on the 2nd and 3rd days of delay, in a decreasing way. In conclusion, high pollutant exposure is significantly associated with daily hospitalization for respiratory problems. The cumulative effect of air pollutants increased hospitalization in the following days, in addition to identifying the pollutants and which pollutant combinations are most harmful to health in each region.


Mortality, causes of death and risk factors for death among primary amphetamine users in the Swedish criminal justice system.
This study examined mortality and predictors of death in 1,396 primary amphetamine users (85% males) who were interviewed with the Addiction Severity Index in the Swedish criminal justice system during 2000-2006 and followed through 2008. Forty-nine clients deceased (standardized mortality ratio 4.1 [3.0-5.4]), at least 84% of deaths were violent or drug-related (12% suicides), and Cox regression analysis indicated that death was associated with frequent use of sedatives and less frequent use of amphetamine. No female deaths were observed; death and male gender were associated in binary analysis. Implications for diagnostics and treatment are discussed.


Prevalence of gestational diabetes mellitus, maternal obesity and associated perinatal outcomes over 10 years in an Australian tertiary maternity provider.
The International Association of Diabetes in Pregnancy Study Groups (IADPSG) gestational diabetes mellitus (GDM) criteria have been heavily scrutinised with concerns that the consequent GDM prevalence increase has not been associated with improved perinatal outcomes. At a tertiary hospital in Melbourne, Australia we aimed to evaluate prevalence trends for GDM, type 2 diabetes (T2DM), maternal obesity and large-for-gestational age (LGA) and assess changes in perinatal outcomes following IADPSG criteria uptake in 2015. A retrospective cohort study of singleton births from 20 weeks' gestation was conducted between 1st January 2011 and 31st December 2020. Maternal characteristics and perinatal outcomes were extracted from medical records. 52,795 pregnancies were included. GDM prevalence increased 2.7 times from 8.9% in 2011 to 23.7% in 2020 and increased annually by 8.59% (95%CI 7.77, 9.42). The rate of T2DM increased annually by 11.69% (95%CI 7.72, 16.67). Obesity prevalence increased annually by 3.18% (95%CI 2.58, 3.78). Induction of labour (IOL) prevalence increased annually by 8.35% (95%CI 5.69, 11.06). LGA prevalence remained unchanged. Increasing maternal obesity was the major contributing factor for LGA prevalence. From 2011 to 2020 GDM, obesity and T2DM prevalence increased significantly, with associated increased IOL, without change in LGA rates. Prospective studies are required to explore interactions between GDM, obesity, LGA and obstetric interventions.


FermatS: A Novel Numerical Representation for Protein Sequence Comparison and DNA-binding Protein Identification.
Based on protein sequence information, a simple and effective method was used to analyze protein sequence similarity and predict DNA-binding protein. It is absolutely necessary that we generate computational methods of low complexity to accurate infer protein structure, function, and evolution in the rapidly growing number of molecular biology data available. It is important to generate novel computational algorithms for analyzing and comparing protein sequences with the rapidly growing number of molecular biology data available. Based on global and local position representation with the curves of Fermat spiral and normalized moments of inertia of the curve of Fermat spiral, respectively, moreover, composition of 20 amino acids to get the numerical characteristics of protein sequences. It has been applied to analyze the similarity/dissimilarity of nine ND5 proteins, the analysis results are consistent with the biological evolution theory. Furthermore, we employ the Logistic regression with 5-fold cross-validation to establish the prediction of DNA-binding proteins model, which outperformed the DNAbinder, iDNA-prot, DNA-prot and gDNA-prot by 0.0069-0.609 in terms of F-measure, 0.293-0.898 in terms of MCC in unbalanced dataset. These results show that our method, namely FermatS, is effective to compare, recognition and prediction the protein sequences.


The Resurgence of Dirigent Story: Time for a Bacterial Chapter.
For several decades, dirigent (DIR) domain-containing proteins have been assumed to be green lineage-specific, responsible for the defence response and lignan/lignin biosynthesis. Despite their high potential in terms of biotechnology and chemistry, to date there have been very few well-studied plant DIRs. However, recent achievements in sequencing technologies have allowed for discovery of DIR genes in bacteria. This prospective study suggests expansion of the focus of research to consider the existence of bacterial DIRs. It also considers the outlook for understanding DIR functioning with respect to the fields of green lineage evolution, organic synthesis, and biotechnology.


Prolonged tacrolimus for pediatric gastrointestinal disorder: Double-edged sword?
Although tacrolimus (TAC) can induce remission in children with refractory inflammatory bowel disease (IBD) or autoimmune gastroenteropathy (AGE), its use in maintenance therapy remains controversial. The aim of this study was to investigate the potential nephrotoxic nature of prolonged TAC use. This retrospective study reviewed children with gastrointestinal disorder who underwent kidney biopsy for the evaluation of renal damage during TAC therapy for >1 year. The clinical and histological features of renal damage were evaluated in this single-institution cohort. Eighteen of 121 children with IBD and two children with AGE followed at a national children hospital in Tokyo, Japan, received TAC between August 2006 and April 2013. Among them, five (Crohn's disease, n = 3; autoimmune gastropathy, n = 1; autoimmune enteropathy, n = 1) received TAC for >1 year, and underwent kidney biopsy. All five had achieved remission on TAC, but had histological evidence of chronic nephrotoxicity. Renal damage in one patient with relatively low TAC trough level remained mild. Estimated glomerular filtration rate (eGFR) at the time of kidney biopsy was lower than at the initiation of TAC in all four available patients. Among them, eGFR improved in one patient after the decrease or discontinuation of TAC. TAC appeared to be effective in children with refractory gastrointestinal disorder, but long-term use seems to cause irreversible renal damage. Rigorous monitoring of eGFR and kidney biopsy in selected cases should be considered for the proper adjustment of TAC.


Debilitating folliculitis barbae candidomycetica in a trumpeter: successful treatment with fluconazole.
A 29-year-old trumpeter, suffering from debilitating folliculitis barbae candidomycetica, was successfully treated with fluconazole 50 mg daily for a period of 4 weeks. Because of the strong local inflammation, oral treatment was initially combined with topical corticosteroid application.


Seroprevalence of bovine leukemia virus in cattle, buffalo, and camel in Egypt.
Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis. It causes significant economic losses associated with losses due to slaughter and eradication of infected animal from infected area and other indirect economic losses such as restriction on importation of animals and semen from infected area. The main objective of this study was to determine the seroprevalence of BLV antibodies in cattle, buffaloes, and camels in Egypt using ELISA test. Serum samples were collected from 350 cattle, 100 buffaloes, and 100 camels during 2018. The seropositivity for BLV-specific antibody was 20.8%, 9%, and 0% in cattle, buffaloes, and camels, respectively. The result revealed significant association (p < 0.05) between age and seroprevalence of BLV infection in cattle > 4 years (24%) compared with those < 4 years (13%). We found no significant association between pregnancy and herd size and seroprevalence of BLV infection in this study (p > 0.05). Furthermore, the age, pregnancy state, and herd size had significant effect on seroprevalence of BLV infection in buffaloes. This study contributes that BLV is detected in cattle and buffaloes in Egypt and confirms that the camels has resistance against BLV infection. Hence, the control measures are very necessary to combat the transmission of the disease and reduce its economic impact.


Obesity Interventions in the Community : Engaged and Participatory Approaches.
Obesity is a pervasive global public health concern of utmost priority. Effective and efficient interventions are urgently needed to reverse current trends, especially among children. The past decade has witnessed increasing adoption and implementation of community-engaged and -participatory interventions that employ a bottom-up approach to identifying and realizing sustainable solutions within communities. It is argued herein that community-based approaches are most effective when implemented via a systems perspective that integrates across societal sectors. This approach seizes upon the synergistic effects that result from simultaneously mobilizing community assets at multiple levels. This paper provides an overview of the evolution and theory behind community-engaged, community-participatory, and systems-level interventions, discusses recent findings in the field, offers reflections based on first-hand experience, outlines advances in relevant resources, and lays forth potential and promising directions for future research. It emphasizes the centrality and necessity of community-engaged systems-level interventions in halting and reversing the obesity epidemic.


Motor Control-based Group Exercise: Can It be Delivered as Effectively by Lay Leaders?
On the Move (OTM), a motor control-based group exercise program for community-dwelling older adults, has produced greater gains in mobility than a standard group exercise program when delivered by research leaders. The purposes of this study were:1) to examine the effectiveness of OTM versus a standard program when delivered by lay leaders and 2) to compare the outcomes of OTM when delivered by research versus lay leaders. Community-dwelling, medically stable older adults who could walk household distances participated. OTM consisted of warm-up, timing and coordination, strengthening, and stretching exercises. The seated standard program consisted of warm-up, aerobic, strengthening and stretching exercises. The primary outcome(s) of function and disability was the Late Life Function and Disability Instrument (LLFDI), and for walking ability were the Six Minute Walk Test and gait speed. 126 participants (mean age = 80.7±7.8 years, gait speed = 0.91 m/s) were randomized to OTM (n=49) or standard (n=77) programs. When taught by lay leaders, there were no significant between-intervention group differences in any of the outcomes (p>0.10). Comparing OTM outcomes between leaders, there was a statistical but not clinically meaningful difference in LLFDI disability (1.87±0.89, p=0.04) when taught by research versus lay leader, and moderate differences (p=0.06) in LLFDI overall function (1.89±1.02) and gait speed (0.05±0.03). Qualitative interview responses suggest that instructor-related concerns may have impacted program outcomes. When delivered by lay leaders OTM was not more effective than a standard program for improving function, disability, and mobility in older adults. Health promotion programs designed to improve mobility in community-dwelling older adults and based on a motor control theoretical background, may be best taught by rehabilitation professionals.


Causal agency and the perception of force.
In the Michotte task, a ball (X) moves toward a resting ball (Y). In the moment of contact, X stops und Y starts moving. Previous studies have shown that subjects tend to view X as the causal agent ("X launches Y") rather than Y ("Y stops X"). Moreover, X tends to be attributed more force than Y (force asymmetry), which contradicts the laws of Newtonian mechanics. Recent theories of force asymmetry try to explain these findings as the result of an asymmetrical identification with either the (stronger) agent or the (weaker) patient of the causal interaction. We directly tested this assumption by manipulating attributions of causal agency while holding the properties of the causal interaction constant across conditions. In contrast to previous accounts, we found that force judgments stayed invariant across conditions in which assignments of causal agency shifted from X to Y and that even those subjects who chose Y as the causal agent gave invariantly higher force ratings to X. These results suggest that causal agency and the perception of force are conceptually independent of each other. Different possible explanations are discussed.


Capillary electrophoresis of the electrochemical oxidation products of Ng-hydroxy-l-arginine at physiological pH.
Ng-hydroxy-l-arginine has been described as an intermediate in the nitric oxide pathway. Its electrochemical oxidation was studied by capillary electrophoresis using either electrospray ionisation mass spectrometry or diode array detection. Three stable end products and unstable intermediates were found using these techniques. These results permitted to propose an electrochemical oxidation scheme of this molecule.


Human behavioral flexibility: a psychogenetic study.
Forty-seven two-children families from Moscow were used in a study to assess genetic determination of behavior flexibility, which was measured by eight laboratory tests. Flexibility is regarded as a temperament trait. There was no age- or sex-specific differentiation of human behavioral flexibility. Genetic determination of indices was used as a criterion for construct validization of flexibility tests. Factor analysis produced two principal components of flexibility: "operational flexibility" and "afferent flexibility." The study showed that a considerable part of the phenotypic variability of the flexibility indices included in different factors is under approximately equal genetic control. The flexibility factors differ in their genetic determination. In the inheritance of the first factor the leading role belongs to the additive component, whereas the dominance effects are more prominent in the second factor of flexibility.


Discovery of new and highly effective quadruple FFA1 and PPARα/γ/δ agonists as potential anti-fatty liver agents.
Non-alcoholic fatty liver disease (NAFLD) has become the most common hepatic disease, while no drug was approved until now. The previous study reported that the quadruple FFA1/PPAR-α/γ/δ agonist RLA8 provided better efficacy than obeticholic acid on NASH. In the present study, two design strategies were introduced to explore better quadruple FFA1/PPAR-α/γ/δ agonists with improved metabolic stability. These efforts ultimately resulted in the identification of ZLY18, a quadruple FFA1/PPAR-α/γ/δ agonist with twice higher metabolic half-life than RLA8 in the liver microsome. In the triton-1339W-induced hyperlipidemic model, ZLY18 reversed hyperlipidemia to an almost normal level, which exhibited far stronger lipid-lowering effects than that of RLA8. Moreover, ZLY18 significantly decreased steatosis, hepatocellular ballooning, inflammation and liver fibrosis in NASH model even better than RLA8. Further mechanism studies suggested that ZLY18 exerts stronger effects than RLA8 on the regulation of the gene related to lipid synthesis, oxidative stress, inflammation and fibrosis. In addition, ZLY18 is more effective than pirfenidone in the prevention of CCl4-induced liver fibrosis. Besides, ZLY18 has an acceptable safety profile in the acute toxicity study at a high dose of 500 mg/kg. Therefore, ZLY18 represents a novel and highly promising quadruple FFA1/PPAR-α/γ/δ agonist worth of further investigation and development.


A novel method for the efficient entrapment of calcium in large unilamellar phospholipid vesicles.
A technique for the efficient entrapment of high concentrations of Ca2+ in large unilamellar phospholipid vesicles (LUVs), using the carboxylic acid antibiotic ionophore A23187 (calcimycin) is demonstrated. It is shown that rapid A23187-mediated entrapment of Ca2+, corresponding to essentially 100% sequestration of the extravesicular cation may be achieved for egg yolk phosphatidylcholine LUVs (100 nm) in the presence of a transmembrane proton gradient (acidic interior). Interior-exterior concentration cation gradients of over 400-fold may be readily achieved, with interior Ca2+ concentrations in excess of 250 mM. It is shown that the extent and efficiency of the A23187-mediated uptake process is affected by the intravesicular buffering capacity and the extravesicular Ca2+ concentration in a manner that is consistent with a Ca2(+)-H+ exchange process. In the absence of a pH gradient, or the presence of a reversed gradient (basic interior), only background levels of cation uptake are detected. The driving force for A23187-mediated uptake of Ca2+ is shown to depend on the intravesicular proton pool rather than on a chelation process. This protocol provides a novel method for the efficient entrapment of high concentrations of Ca2+ and other cations in phospholipid vesicles.


Say it right: measuring the impact of different communication strategies on the decision to get vaccinated.
Vaccine hesitancy is a concerning menace to the control of vaccine-preventable diseases. Effective health communication could promote an overall understanding of the importance, risks, and benefits of vaccination and reduce vaccine hesitancy. In this survey, four fictitious newspaper articles addressing an emerging bogus disease and its vaccine were randomly assigned to participants. The first version focused on information about the disease; the second was akin to the first, including a case description and image. The third version focused on vaccine safety/efficacy; the fourth version was like the third, including a case description and image. After reading a single version of the article, participants responded if they would take the vaccine and if they would vaccinate their children. We used chi-squared tests for comparisons and investigated interactions with vaccine-hesitant attitudes. We included 5233 participants between August/2021 and January/2022; 790 were caregivers of a child ≤ 5 years old, and 15% had prior vaccine hesitancy. Although most declared intention to take the vaccine, the percentage was highest among those exposed to the newspaper article focusing on the vaccine safety/efficacy with the case description and picture (91%; 95% confidence interval 89-92%), and lowest among participants exposed to the article focusing on the disease with no case description (84%; 95% confidence interval 82-86%). Similar trends were observed in the intention of offspring vaccination. We found evidence of effect modification by vaccine-hesitant attitudes, with a higher impact of communication focusing on vaccine safety/efficacy compared to that focusing on disease characteristics among hesitant participants. Communication strategies focusing on different aspects of the disease-vaccine duet may impact vaccine hesitancy, and storytelling/emotive imagery descriptions may improve risk perception and vaccine uptake. Moreover, the effect of message framing strategies may differ according to previous vaccine hesitant attitudes.


Phospholipase C controls chloride-dependent short-circuit current in human bronchial epithelial cells.
Chloride secretion by airway epithelial cells is primordial for water and ion homeostasis and airways surface prevention of infections. This secretion is impaired in several human diseases, including cystic fibrosis, a genetic pathology due to CFTR gene mutations leading to chloride channel defects. A potential therapeutic approach is aiming at increasing chloride secretion either by correcting the mutated CFTR itself or by stimulating non-CFTR chloride channels at the plasma membrane. Here, we studied the role of phospholipase C in regulating the transepithelial chloride secretion in human airway epithelial 16HBE14o- and CFBE cells over-expressing wild type (WT)- or F508del-CFTR. Western blot analysis shows expression of the three endogenous phospholipase C (PLC) isoforms, namely, PLCδ1, PLCγ1, and PLCβ3 in 16HBE14o- cells. In 16HBE14o- cells, we performed Ussing chamber experiments after silencing each of these PLC isoforms or using the PLC inhibitor U73122 or its inactive analogue U73343. Our results show the involvement of PLCβ3 and PLCγ1 in CFTR-dependent short-circuit current activated by forskolin, but not of PLCδ1. In CFBE-WT CFTR and corrected CFBE-F508del CFTR cells, PLCβ3 silencing also inhibits CFTR-dependent current activated by forskolin and UTP-activated calcium-dependent chloride channels (CaCC). Our study supports the importance of PLC in maintaining CFTR-dependent chloride secretion over time, getting maximal CFTR-dependent current and increasing CaCC activation in bronchial epithelial cells.


Location-dependent analysis of porosity and pore direction in tablets.
Several phenomena in tablets indicate that an inhomogeneous pore distribution is formed during the compaction process. Examples are lamination and the capping of corners. In order to gain an understanding of the relation between structure and compact properties, analyzing the structure in a location dependent manner would be extremely useful. Our aim was to visualize and to quantitatively analyze the pore distribution in compacts. This was done by embedding a cubic (sodium chloride) compact with polymer, allowing the compact to be cut without disrupting the structure. By doing so, it was possible to make scanning electron microscopic images from different angles at different locations in the compact. These images were made binary with a two-means cluster algorithm (Isodata) after which the porosity could be calculated. Counting the number of transitions from the pixels in the pores to the pixels in the sodium chloride particles in two perpendicular directions allows us to construct a measure for the anisotropic connectivity of the particles. The results show an increase in porosity toward the bottom of the compact and showed a preferred orientation of the pores in the direction of compression. The proposed method is suitable for analyzing the pore distribution quantitatively and for evaluating anisotropy.


Improved solid-state NMR quantifications of active principles in pharmaceutical formulations.
The facility of implementation reached by solid-state nuclear magnetic resonance (ssNMR) spectroscopy makes this technique increasingly popular in pharmaceutical sciences, and more specifically for the dosage of active principles in pharmaceutical formulations, since about 80% of the formulations currently available on the market are present in the solid form. In this case, analysis by MAS NMR allows faster and simplified protocols, as a solubilization step is not required. However, the specificity of the ssNMR experiments should be explicitly taken into account when designing an accurate measurement procedure. In this work we show that, by using a combination of external concentration referencing and a properly designed sample preparation optimized for quantitative determinations, quantification of active principles in pharmaceutical formulations can be performed with both speed and precision. The method is illustrated by reinvestigating the dosage of Meprobamate, an anxiolytic agent typically prescribed in case of anxiety or muscular soreness, present in a commercial formulation (Equanil). Specifically, with respect to previously proposed analytical protocols, the procedure outlined here allows fast quantification with excellent precision.


Effect of prebiotic supplementation and calcium intake on body mass index.
To assess the effects of a prebiotic supplement and usual calcium intake on body composition changes during pubertal growth. We measured anthropometry and body fat with dual-energy X-ray absorptiometry in 97 young adolescents who were randomized to receive either a daily prebiotic supplement or maltodextrin (control) for 1 year. Subjects who received the prebiotic supplement had a smaller increase in body mass index (BMI) compared with the control group (BMI difference 0.52 +/- 0.16 kg/m2, P = .016), BMI Z-score (difference 0.13 +/- 0.06, P = .048) and total fat mass (difference 0.84 +/- 0.36 kg, P = .022). The prebiotic group maintained their baseline BMI Z-score (0.03 +/- 0.01, paired t test, P = .30), although BMI Z-score increased significantly in the control group (0.13 +/- 0.03, P < .001). In considering subjects whose usual calcium intake was > or = 700 mg/d, those who received the prebiotic supplement had a relative change in BMI that was 0.82 kg/m2 less than control subjects (P < .01), and BMI Z-score that was 0.20 less than control subjects (P = .003). Differences tended to be maintained 1 year after supplementation was stopped. Prebiotic supplementation and avoidance of a low calcium intake can have significant effects in modulating BMI and other body composition changes during puberty.


Fostering a culture of land. Commentary on "Agrarian philosophy and ecological ethics".
Paul Thompson's essay, "Agrarian Philosophy and Ecological Ethics," [1] usefully highlights some of the defects in the now-dominant strands of environmental ethics. It offers an agrarian alternative that solves many of them. Thompson's agrarianism, in turn, has its own limitations, yet it nonetheless merits close attention.


Multimodality imaging: Bird's eye view from the European Society of Cardiology Congress 2019 Paris, August 31st-September 4th, 2019.
At the European Society of Cardiology (ESC) congress of this year 2019, held in Paris from August 31st to September 4th, 4509 abstracts were presented. Of those, 414 (9%) belonged to an imaging category. Experts in echocardiography (VD), nuclear imaging (AS), cardiac computed tomography (CT) (MD) and cardiovascular magnetic resonance (CMR) (CBD), have selected the abstracts in their areas of expertise that were of most interest to them and are summarized in this bird's eye view from this ESC meeting. These abstracts were integrated by one of the Editors of the Journal (JB).


SUMOylation of Syntaxin1A regulates presynaptic endocytosis.
Neurotransmitter release from the presynaptic terminal is under very precise spatial and temporal control. Following neurotransmitter release, synaptic vesicles are recycled by endocytosis and refilled with neurotransmitter. During the exocytosis event leading to release, SNARE proteins provide most of the mechanical force for membrane fusion. Here, we show one of these proteins, Syntaxin1A, is SUMOylated near its C-terminal transmembrane domain in an activity-dependent manner. Preventing SUMOylation of Syntaxin1A reduces its interaction with other SNARE proteins and disrupts the balance of synaptic vesicle endo/exocytosis, resulting in an increase in endocytosis. These results indicate that SUMOylation regulates the emerging role of Syntaxin1A in vesicle endocytosis, which in turn, modulates neurotransmitter release and synaptic function.


Collision of endometrioid carcinoma and stromal sarcoma of the uterus: a report of two cases.
Two uterine collision tumors are reported, one in an 85-year-old woman and the other in a 47-year-old woman. Each tumor was composed of a smaller grade 1 endometrioid adenocarcinoma that was distinct from a larger component of high-grade stromal sarcoma. The separate components in these tumors could be detected on gross, microscopic, and immunohistochemical studies. The clinicopathologic features and indolent behavior of these tumors suggest that they should be distinguished from malignant mullerian mixed tumors.


Iron oxide particles are the active sites for hydrogen peroxide sensing at multiwalled carbon nanotube modified electrodes.
We demonstrate that the "electrocatalytic" hydrogen peroxide detection reported at multiwalled carbon nanotube modified electrodes is due to iron oxide particles arising from the chemical vapor deposition nanotube fabrication process rather than due to intrinsic catalysis attributable to the carbon nanotubes arising, for example, from edge plane-like sites/defects.


Therapeutic Decision-Making Under Uncertainty in the Management of Spinal Muscular Atrophy: Results From DECISIONS-SMA Study.
There are many uncertainties about treatment selection and expectations regarding therapeutic goals and benefits in the new landscape of spinal muscular atrophy (SMA). Our aim was to assess treatment preferences and expectations of pediatric neurologists caring for patients with SMA. DECISIONS-SMA is a non-interventional, cross-sectional pilot study that assessed pediatric neurologists with expertise in SMA from across Spain. Participants were presented with 11 simulated case scenarios of common encounters of patients with SMA type 1 and 2 to assess treatment initiation, escalation, or switches. We also asked for the expected benefit with new therapies for four simulated case scenarios. Participants completed a behavioral battery to address their tolerance to uncertainty and aversion to ambiguity. The primary outcome was therapeutic inertia (TI), defined as the number of simulated scenarios with lack of treatment initiation or escalation when warranted over the total (11) presented cases. A total of 35 participants completed the study. Participants' mean (SD) expectation for achieving an improvement by starting a new therapy for SMA type 1 (case 1, a 5-month-old) and SMA type 2 (case 6, a 1-year-old) were both 59.6% (± 21.8), but declined to 20.2% (± 12.2) for a case scenario of a 16-year-old treatment-naïve patient with long-standing SMA type 2 with severe disability. The mean (SD) TI score was 4.2 (1.7), and 3.29 (1.5) for treatment initiation. Of a total 385 individual responses, TI was observed in 147 (38.2%) of treatment choices. The multivariable analysis showed that lower aversion to ambiguity (p = 0.019) and lower expectation of treatment response (p = 0.007) were associated with higher TI after adjustment for participants' age and years of experience. Older age (p = 0.019), lower years of experience (p = 0.035), lower aversion to ambiguity (p = 0.015), and lower expectation of treatment benefits (p = 0.006) were associated with inertia for treatment initiation. Pediatric neurologists managing patients with SMA were optimistic regarding treatment improvement in cases with early diagnosis, but had lower expectations when treatment delays and advanced patient age were present. Low aversion to ambiguity, low expectation of treatment benefits, and lower clinical experience were more likely to make suboptimal decisions, resulting in lack of treatment initiation, escalation, and TI.


An evaluation of excellence in primary healthcare units after the introduction of a performance management innovation in two regional states of Ethiopia: a facility based comparative study.
The Ethiopian Ministry of Health strives to achieve universal health coverage (UHC) through increasing the number of its high-performing primary healthcare units. Although the Ethiopian health system is managed within a decentralized political system, the Ministry of Health works towards institutionalizing performance management innovations and organizational cultures that increase the excellence of primary healthcare entities. To date, there has been little evidence gathered on the factors influencing the excellence of primary healthcare units in Ethiopia. Therefore, the aim of this study was to assess and compare how the introduction of performance management and organizational culture innovations through project support affect the excellence of primary healthcare units in Ethiopia. A facility-based comparative study was conducted in USAID Transform: Primary Health Care project supported and non-supported primary healthcare units located in the Oromia and Southern Nations Nationalities and Peoples' (SNNP) regions of Ethiopia. Quantitative data were collected from randomly selected health workers using interviewer-administered questionnaires. In addition, primary healthcare unit excellence measurements were extracted from routine health information databases over eight quarters. The data were analyzed using the Statistical Package for Social Science (SPSS IBM v 20) research software package. Results were presented in frequency tables and graphs. After checking the data for homogeneous distribution, a paired sample t-test for equal variances, otherwise known as the Mann-Whitney U test was analyzed to claim statistically significant difference at P < 0.05. Out of 368 invited health workers, 364 participated in this study, (a response rate of 98.9%). Slightly higher than two-thirds of participants were enrolled from the Jimma Zone of Oromia Region. Orientations on performance management standards were provided to 101 (68.2%) and 45 (48.3%) health workers from project-supported and non-supported facilities, respectively. The mean perceived organizational culture score with [± Standard Deviation (SD)] was 3.72 ± 0.75 among project-supported health workers and 3.385 ± 0.75 among non-supported health workers, respectively. An independent sample t-test showed statistically significant differences, where project-supported health workers had higher mean scores on perceived organizational culture than their non-supported counterparts, with t = 433, df = 362, P = 0.001. The mean baseline primary healthcare unit excellence score was 63.2% and 50.5% for project-supported and non-supported health facilities, respectively. The end line excellence scores increased to 93.3% for project-supported and 79.1% for non-supported facilities. The end line overall primary healthcare units' mean rank excellence scores were 257.67 for the project supported and 105.66 for non-project supported facilities. This result of a non-parametric test, i.e. the Mann-Whitney U test revealed that project-supported facilities were higher and had a positive statistically significant difference (U = 2,728, z = -13.78, P = 0.001). The findings of this study underscore a direct relationship between implementing performance management innovations and enhancing organizational cultures for excellence at primary healthcare units. Project-supported primary healthcare units had higher organizational culture and excellence scores than their counterpart non-supported facilities. Therefore, achieving UHC through excellence in primary healthcare facilities requires scaling up of performance management innovation interventions.


Self-Sustained Resistance to Suppression of CD8+ Teff Cells at the Site of Autoimmune Inflammation Can Be Reversed by Tumor Necrosis Factor and Interferon-γ Blockade.
Resistance of Teff cells to Treg cell-mediated suppression contributes to the breakdown of peripheral tolerance in the inflamed joints of patients with juvenile idiopathic arthritis (JIA). However, unanswered questions are whether this resistant phenotype is self-sustained and whether CD8+ and CD4+ Teff cells share the same mechanism of resistance to suppression. We undertook this study to investigate intrinsic resistance of CD8+ Teff cells to suppression and to determine how this can be targeted therapeutically. CD8+ or CD4+ Teff cells were cultured with or without antigen-presenting cells (APCs) in Treg cell-dependent and -independent suppression assays. Synovial fluid (SF)-derived Teff cells were crosscultured with peripheral blood (PB) Treg cells from JIA patients or healthy controls. Tumor necrosis factor (TNF) or interferon-γ (IFNγ) blocking agents were used to restore Teff cell responsiveness to suppression. Suppression of cell proliferation and cytokine production in CD8+ Teff cells from the SF of JIA patients was severely impaired compared to that in CD8+ Teff cells from the PB of JIA patients, regardless of the presence of APCs and CD4+ Teff cells. Similar to CD4+ Teff cells, impaired suppression of CD8+ Teff cells was shown to be an intrinsic feature of this cell population. While TNF blockade restored both CD8+ and CD4+ Teff cell susceptibility to suppression, autocrine release of IFNγ selectively sustained CD8+ Teff cell resistance, which could be relieved by IFNγ blockade. Unlike CD4+ Teff cells, resistance of CD8+ Teff cells to suppression at the site of autoimmune inflammation is maintained by autocrine release of IFNγ, and blockade of IFNγ restores CD8+ Teff cell responsiveness to suppression. These findings indicate a potential therapeutic value of blocking IFNγ to restore immune regulation in JIA.


Controversies in clinical pancreatology: should the sphincter of Oddi be measured in patients with idiopathic recurrent acute pancreatitis, and should sphincterotomy be performed if the pressure is high?
The risk benefit ratio of measuring the sphincter of Oddi pressure and performing sphincterotomy in patients with idiopathic acute pancreatitis with high sphincter pressures has not been assessed. Few healthy controls have had sphincter measurements so that the definition of an abnormal sphincter remains understudied. The procedures involved have significant risks and the benefits are hard to measure considering the variable natural history of this disorder. No prospective, randomized investigations have been performed to evaluate efficacy of these invasive procedures. It is the author's opinion that until appropriate studies prove efficacy that these interventions be considered experimental.


Exposure to calcium-free medium protects sensory fibers by capsaicin desensitization.
Capsaicin (1 microM) produces a tetrodotoxin-resistant contraction of the rat isolated urinary bladder ascribable to neuropeptide release from sensory nerves. A second application of capsaicin (1-10 microM) up to 5 h from the first one was ineffective, indicating complete desensitization. However, if the first exposure to capsaicin was made after a prolonged incubation in a Ca-free medium containing EDTA (0.1 mM), a second application of capsaicin (1 microM) was still able to induce a contraction, thus indicating protection from desensitization.


Association of Hard Ticks (Ixodidae) Infestation with Milk Production and Udder Health of Extensively Reared Dairy Goats.
Extensively reared ruminants are seasonally exposed to ticks. Tick-related production losses and health issues have been well documented in cows and sheep but not in goats where relevant literature is scarce. The objective here was to investigate the association of hard tick infestation with milk production and udder health of dairy goats reared extensively. A cross-sectional study was carried out during May and June, in two dairy goat farms. The farms were located in Central and Northern Greece and were representative of typical extensive production systems. A total of 304 goats (n = 152 from each farm) were randomly selected. Each goat was examined for presence of hard ticks. Daily milk yield and quality characteristics were recorded. Udder health status was determined by milk somatic cell count (SCC) and total viable count (TVC). Tick infestation prevalence was 28.6%; it was associated with a significant (p < 0.001) increase in SCC and TVC (84.0% and 78.6%, respectively). The latter meant that infested goats were 3.7 times more prone to udder health problems (p < 0.001). There were not any significant effects (p > 0.05) on milk production. Overall, results suggest that control of tick infestation in extensively reared dairy goat herds is important for enhancing health and welfare status.


K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo.
Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1(K45A) mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1(K45A) macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli.


Effect of electrical stunning on somatosensory evoked potentials in chickens.
The spontaneous EEG and somatosensory evoked potentials (SEPs) were examined in chickens before and after electrical stunning using a waterbath stunner. Fifty-four per cent of the birds became epileptic and lost their SEPs, and 17% were non-epileptic and appeared to retain their SEPs. It was concluded that there was a reasonably close association between the presence of epileptiform activity in the EEG and the absence of SEPs following electrical stunning, but that the absence of SEPs could be preferred as an indicator of an effective stun on conceptual grounds.


DNA methylation changes in epithelial ovarian cancer histotypes.
Survival after a diagnosis of ovarian cancer has not improved, and despite histological differences, treatment is similar for all cases. Understanding the molecular basis for ovarian cancer risk and prognosis is fundamental, and to this end much has been gleaned about genetic changes contributing to risk, and to a lesser extent, survival. There's considerable evidence for genetic differences between the four pathologically defined histological subtypes; however, the contribution of epigenetics is less well documented. In this report, we review alterations in DNA methylation in ovarian cancer, focusing on histological subtypes, and studies examining the roles of methylation in determining therapy response. As epigenetics is making its way into clinical care, we review the application of cell free DNA methylation to ovarian cancer diagnosis and care. Finally, we comment on recurrent limitations in the DNA methylation literature for ovarian cancer, which can and should be addressed to mature this field.


Calf thymus DNA binding studies of the new neodymium-naproxen complex.
Fluorescence spectroscopy in combination with UV absorption spectroscopy was carried out to investigate the interaction between the neodymium-naproxen complex (Nd-NAP) and calf thymus DNA (ctDNA). The experimental results showed that Nd-NAP intercalated with the ctDNA base pairs. Analysis of fluorescence quenching data of Nd-NAP by ctDNA at different temperatures using a Stern-Volmer equation revealed that dynamic and static quenching occurred simultaneously. The binding constants and the number of binding sites at 293 and 310 K were obtained as 2.904 × 10(4) L mol(-1), 1.172 and 2.432 × 10(4) L mol(-1), 1.143, respectively. The thermodynamic parameters ΔG, ΔH, and ΔS calculated at different temperatures indicated that hydrogen bonding and van der Waals force were the main binding forces.


Release of platelets into the circulation induced by gamma globulin treatment in a case of idiopathic thrombocytopenic purpura.
The kinetics and distribution in vivo of 111In-labelled platelets prior to and during intravenous high-dose gamma globulin therapy in a 3-months-old child with idiopathic thrombocytopenic purpura were evaluated. Concomitantly with a prompt increase in platelet concentration we found evidence for release of platelets into the circulation, presumably to a large extent originating from the spleen and liver. Our results support the concept that, in response to high-dose gamma globulin therapy, platelets are not only forced to remain in but are also released into the circulation, presumably as a result of mobilization of platelets adhering to cells of the monocyte-macrophage system.


[Synthesis and properties of membrane-addressed antioxidants based on phosphorylated pyrocatechols].
Amphiphilic membrane-addressed antioxidants differing in their hydrophobic-hydrophilic balance, 3,5-di-tert-butyl-2-hydroxyphenyl phosphate, (3,5-di-tert-butyl-2-hydroxyphenyl)hexadecyl phosphate, and (3,5-di-tert-butyl-2-hydroxyphenyl)-5-cholesten-3 beta-yl phosphate, were synthesized starting from 3,5-di-tert-butyl-o-quinone. Even at 10(-8) M concentration, 3,5-di-tert-butyl-2-hydroxyphenyl phosphate and (3,5-di-tert-butyl-2-hydroxyphenyl)hexadecyl phosphate inhibit formation of malonic aldehyde during peroxidation of lipids from rat brain homogenate initiated with a Fe(2+)-ascorbate system. At 10(-4) M and higher concentrations of antioxidants in the brain homogenate, the formation of malonic aldehyde is inhibited more efficiently than with tocopherol at the same concentrations.