The Optic atrophy 1 protein (OPA1) is a key element in the dynamics and morphology of mitochondria. We demonstrated that the absence of IκB kinase-α, which is a key element of the nonclassical NF-κB ...pathway, has an impact on the mitochondrial network morphology and OPA1 expression. In contrast, the absence of NF-κB essential modulator (NEMO) or IκB kinase-β, both of which are essential for the canonical NF-κB pathway, has no impact on mitochondrial dynamics. Whereas Parkin has been reported to positively regulate the expression of OPA1 through NEMO, herein we found that PARK2 overexpression did not modify the expression of OPA1. PARK2 expression reduced the levels of Bax, and it prevented stress-induced cell death only in Bak-deficient mouse embryonic fibroblast cells. Collectively, our results point out a role of the nonclassical NF-κB pathway in the regulation of mitochondrial dynamics and OPA1 expression.
Ghrelin is a 28 amino acid residue peptide identified in both human and rat stomach and which acts as an endogenous ligand for the GH secretagogue receptor (GHS-R) and stimulates GH release. GHS-Rs ...are expressed in a number of tissues, including the pancreas, and ghrelin-like immunoreactivity is present in peripheral plasma, where its levels increase during fasting and decrease after food intake. The relationship between nutritional status and circulating ghrelin concentrations prompted us to investigate the effect of this peptide on pancreatic hormone secretion.
The study was performed in the isolated rat pancreas perfused in situ. Insulin, glucagon and somatostatin were measured by radioimmunoassay.
Addition of 10 nM ghrelin to the perfusate significantly reduced the insulin response to the secretagogues glucose, arginine and carbachol, which act on the B-cell via different mechanisms, as well as the somatostatin response to arginine. Ghrelin was without effect on the glucagon output induced by this amino acid. At a lower concentration (2 nM) ghrelin was also found to inhibit glucose-induced insulin release.
These findings support the proposal that the inhibitory effect of ghrelin on insulin release constitutes a tonic regulation of the B-cell, contributing to restrain its secretory activity in the state of food deprivation. On the other hand, the inhibition of pancreatic somatostatin release by ghrelin suggests a blocking effect of this hormone on the widely distributed D-cell population.
Objective: To compare the status of infants with hypoplastic left heart syndrome (HLHS) or pulmonary atresia-hypoplastic right heart (PA-HRH) before and following transport using the validated ...Transport Risk Index of Physiologic Stability (TRIPS) score.
Methods: In this retrospective review of infants with HLHS or PA-HRH transported to a Children's Hospital by a pediatric transport team, an increase in TRIPS score (temperature, blood pressure, respiratory status, and response to stimuli) following transport was defined as deterioration. Statistical analyses included t-test (paired and independent), χ
2
, and McNemar's tests for comparisons between groups with and without deterioration and before and after transport.
Results: Our cohort n = 64; 39 (61%) HLHS and 25 (39%) PA-HRH was predominantly female (61%), black (56%), and diagnosed antenatally (78%). Median transport time was 20 (10-30) min and age was <12 h in 48 (75%) infants. TRIPS scores worsened after transport in 24 (37.5%) infants, due to temperature (n = 10) or respiratory (n = 7) dysregulation. Infants who deteriorated during transport had HLH more often (83 versus 48%) and lower pH 7.27 (0.12) versus 7.33 (0.07). HLH was significantly predictive of deterioration during transport OR 5.60 (95% C.I. 1.18-26.62).
Conclusions: The physiologic deterioration in a third of infants with single ventricle following short transports is intriguing and may have implications on their optimal place of birth.
The shortfin mako shark (
) is a large pelagic predator that inhabits coastal and ocean waters. It has several teeth arranged in rows that run from the rostral to the lingual face. These teeth are in ...several stages of maturation, where the teeth closest to the rostral face are more mature and functional and the teeth closest to the lingual face are still in development. The tooth supply of the shark is unlimited throughout its life. The mechanism of tooth replacement follows that, when the front teeth are discarded physiologically, the posterior teeth replace it. This study us used a head and dental arch of
Intraoral radiographs were obtained with the aim to show details of the pulp cavity. The study concluded that the pulp diameter varies according to the stage of dental maturation.
Kisspeptins are a family of peptides encoded by the KISS1 gene, which binds to G-protein-coupled receptor (GPR54), an orphan GPR54 related to galanin receptors. Endogenous forms composed of 54, 14, ...and 13 amino acids have been identified. Kisspeptin and GPR54 mRNAs have been detected in pancreatic B and A cells. Furthermore, kisspeptin-54 has been shown to slightly stimulate the last phase of glucose-induced insulin secretion in mouse and human islets and to inhibit insulin release in MIN6 cells. We have investigated the effect of kisspeptin-13 on insulin, glucagon, and somatostatin secretion. The study was performed in the perfused rat pancreas. Glucose, arginine, carbachol, and exendin-4 were used as secretagogues. Hormones were measured by RIA. Kisspeptin-13 reduced glucose-induced insulin secretion in a dose-dependent manner (IC(50)=1.2 nM) and inhibited the insulin responses to both carbachol and exendin-4. Kisspeptin-13 blocked arginine-induced insulin secretion without affecting the glucagon or somatostatin responses to this amino acid, thus indicating that kisspeptin-13 influences B cells directly, rather than through an A- or D-cell paracrine effect. The reduction of the insulin response to exendin-4 induced by kisspeptin-13 was also observed in pertussis toxin-treated rats, thus suggesting an inhibition independent of G(i) proteins. In view of the potent insulinostatic effect of kisspeptin-13, it is tempting to speculate that kisspeptins may be implicated in the regulation of B-cell secretion.
This study aimed to estimate the prevalence of musculoskeletal disorders and rheumatic diseases among the indigenous Qom (Toba) population in the city of Rosario, Santa Fe, Argentina. An analytical ...cross-sectional study using methodology of the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) was performed. Subjects ≥18 years of age were interviewed by advanced students of medicine and nursing, bilingual translator-facilitators, and coordinators. Individuals with musculoskeletal pain (positive cases) were evaluated sequentially for 7 days by internists and rheumatologists for diagnosis and treatment. The study included 1656 individuals (77 % of the census population). Of these, 1020 (61.5 %) were female, with mean age of 35.3 (SD 13.9) years, and 1028 (62.0 %) were bilingual. The public health care system covers 87.1 % of the population. Musculoskeletal pain in the previous 7 days and/or at some time during their life was present in 890 subjects (53.7 %). Of those with pain in the last 7 days, 302 (64.1 %) subjects had an Health Assessment Questionnaire Disability Index (HAQ-DI) score ≥0.8. The most frequent pain sites were lumbar spine (19.3 %), knees (13.0 %), and hands (12.0 %). The prevalence of rheumatic diseases was as follows: mechanical back pain (20.1 %), rheumatic regional pain syndrome (2.9 %), osteoarthritis (4.0 %) rheumatoid arthritis (2.4 %), inflammatory back pain (0.2 %), systemic sclerosis (0.1 %), Sjögren syndrome (0.1 %), fibromyalgia (0.1 %), mixed connective tissue disease (0.06 %), and systemic lupus erythematosus (0.06 %). The prevalence of musculoskeletal disorders was 53.7 % and rheumatic diseases 29.6 %. Rheumatoid arthritis prevalence was 2.4 % using COPCORD methodology, one of the highest reported at present.
are respiratory pathogens comprised of three classical
species:
, and
. With recent surges in
spp. cases and antibiotics becoming less effective to combat infectious diseases, there is an imperative ...need for novel antimicrobial therapies. Our goal is to investigate the possible targets of host immunomodulatory mechanisms that can be exploited to promote clearance of
spp. infections. Vasoactive intestinal peptide (VIP) is a neuropeptide that promotes Th2 anti-inflammatory responses through VPAC1 and VPAC2 receptor binding and activation of downstream signaling cascades.
We used classical growth
assays to evaluate the effects of VIP on
spp. growth and survival. Using the three classical
spp. in combination with different mouse strains we were able to evaluate the role of VIP/VPAC2 signaling in the infectious dose 50 and infection dynamics. Finally using the
murine model we determine the suitability of VPAC2 antagonists as possible therapy for
spp. infections.
Under the hypothesis that inhibition of VIP/VPAC2 signaling would promote clearance, we found that VPAC2
mice, lacking a functional VIP/VPAC2 axis, hinder the ability of the bacteria to colonize the lungs, resulting in decreased bacterial burden by all three classical
species. Moreover, treatment with VPAC2 antagonists decrease lung pathology, suggesting its potential use to prevent lung damage and dysfunction caused by infection. Our results indicate that the ability of
spp. to manipulate VIP/VPAC signaling pathway appears to be mediated by the type 3 secretion system (T3SS), suggesting that this might serve as a therapeutical target for other gram-negative bacteria.
Taken together, our findings uncover a novel mechanism of bacteria-host crosstalk that could provide a target for the future treatment for whooping cough as well as other infectious diseases caused primarily by persistent mucosal infections.
Background
Pediatric heart transplant patients require cardiac catheterization to monitor for coronary allograft vasculopathy. Cardiac catheterization has no safe and consistent method for measuring ...microvascular disease. Stress perfusion cardiac magnetic resonance imaging (MRI) assessing microvascular disease has been performed in adults.
Objective
To investigate the feasibility and safety of performing cardiac MRI with quantitative adenosine stress perfusion testing in pediatric heart transplant patients with and without coronary allograft vasculopathy.
Materials and methods
All pediatric heart transplant patients with coronary vasculopathy at our institution were asked to participate. Age- and gender-matched pediatric heart transplant patients without vasculopathy were recruited for comparison. Patients underwent cardiac MRI with adenosine stress perfusion testing.
Results
Sixteen pediatric heart transplant patients, ages 6–22 years, underwent testing. Nine patients had vasculopathy by angiography. No heart block or other complications occurred during the study. The myocardial perfusion reserve for patients with vasculopathy showed no significant difference with comparison patients (median: 1.43 vs. 1.48;
P
=0.49). Values for both groups were lower than expected values based on previous adult studies. The patients were also analyzed for time after transplant and the number of rejection episodes. Patients within 6 years of transplantation had a nonsignificant trend toward a higher myocardial perfusion reserve (median: 1.57) versus patients with older transplants (median: 1.47;
P
=0.46). Intra- and interobserver reproducibility were 97% and 92%, respectively.
Conclusion
Myocardial perfusion reserve is a safe and feasible method for estimating myocardial perfusion in pediatric heart transplant patients. There is no reliable way to monitor microvascular disease in pediatric patients. This method shows potential and deserves investigation in a larger cohort.
Summary
Behçet’s disease (BD) is an inflammatory disease mainly affecting men along the ancient Silk Route. In the present study we describe a Dutch family suffering from BD‐like disease with extreme ...pathergic responses, but without systemic inflammation. Genetic assessment revealed a combination of the human leukocyte antigen (HLA)‐B*51 risk‐allele together with a rare heterozygous variant in the CSF2 gene (c.130A>C, p.N44H) encoding for granulocyte–macrophage colony‐stimulating factor (GM‐CSF) found by whole exome sequencing. We utilized an over‐expression vector system in a human hepatocyte cell line to produce the aberrant variant of GM‐CSF. Biological activity of the protein was measured by signal transducer and activator of transcription 5 (STAT‐5) phosphorylation, a downstream molecule of the GM‐CSF receptor, in wild‐type peripheral mononuclear cells (PBMCs) using flow cytometry. Increased STAT‐5 phosphorylation was observed in response to mutated GM‐CSF when compared to the wild‐type or recombinant protein. CSF2 p.N44H results in disruption of one of the protein’s two N‐glycosylation sites. Enzymatically deglycosylated wild‐type GM‐CSF also enhanced STAT‐5 phosphorylation. The patient responded well to anti‐tumor necrosis factor (TNF)‐α treatment, which may be linked to the capacity of TNF‐α to induce GM‐CSF in phorbol 12‐myristate 13‐acetate (PMA)‐treated PBMCs, while GM‐CSF itself only induced dose‐dependent interleukin (IL)‐1Ra production. The identified CSF2 pathway could provide novel insights into the pathergic response of BD‐like disease and offer new opportunities for personalized treatment.
Loss of N44 glycosylation in GM‐CSF leads to increased signaling activity resulting in a BD‐like phenotype marked by extreme pathergy. The GM‐CSF pathway may provide a novel target to reshape individual patient care in the pathogenesis of pathergy in BD.
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