Over-expression of TATA binding protein (TBP) and p53 and autoantibodies to these antigens are features of systemic sclerosis, systemic lupus erythematosus and overlap syndromes

The aim of this study was to determine the expression levels of p53 and TATA binding protein (TBP) and the presence of autoantibodies to these antigens in Asian Indian patients with systemic sclerosis (SSc), overlap syndromes (OS) and systemic lupus erythematosus (SLE). Fifty patients with SSc, 20 with OS, including mixed connective tissue diseases (MCTD), 20 with SLE, 10 disease controls (DC) and 25 controls (C) were studied. The over-expression of p53 and TBP antigen was determined quantitatively by sandwich enzyme-linked immunosorbent assay (ELISA), varies between four- and sevenfold higher in patients with SSc, OS and SLE, in comparison to DC and C. The expressed protein antigens were not present as free antigens but as immune-complexes. Autoantibodies to p53 were detected by ELISA in 78% subjects with SSc, 100% with OS and 80% with SLE. Autoantibodies to TBP were observed in 28% patients with SSc, 25% with OS and 15% with SLE. In comparison to healthy controls, the titre of antibodies to p53 was significantly higher in patients with SSc (P = 0.00001) than the patients with OS (P = 0.00279) and SLE (P = 0.00289), whereas the titre of antibodies to TBP was higher in patients with OS (P = 0.00185) than the SLE (P = 0.00673) and the SSc (P = 0.00986) patients. Autoantibodies to p53 and TBP were detected in all these patients and the levels of these two autoantibodies showed weak negative correlation with each other. We propose that the over-expression of these antigens might be due to hyperactive regulatory regions in the p53 and TBP gene.     

Extra-cardiac collateral to an anomalous origin right coronary artery in a post-PTCA,post-CABG patient

In the context of collateral circulation of the heart, the role of extra-cardiac collateral arteries has been thought to be negligible. We present a case in which such collateral vessel acted as a rescue, subsequent to a failed revascularisation attempt. With surgeons nowadays considering ‘less is more’ in terms of grafting in coronary artery bypass grafting (CABG), and more evidence arising in favour of medical therapy, we need to re-assess the role of these collateral vessels in the coronary circulation.     

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1^asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1^asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1^asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1^asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

RTS,S/AS01E malaria vaccine induces IgA responses against CSP and vaccine-unrelated antigens in African children in the phase 3 trial

BackgroundThe evaluation of immune responses to RTS,S/AS01 has traditionally focused on immunoglobulin (Ig) G antibodies that are only moderately associated with protection. The role of other antibody isotypes that could also contribute to vaccine efficacy remains unclear. Here we investigated whether RTS,S/AS01_E elicits antigen-specific serum IgA antibodies to the vaccine and other malaria antigens, and we explored their association with protection.MethodsNinety-five children (age 5–17 months old at first vaccination) from the RTS,S/AS01_E phase 3 clinical trial who received 3 doses of RTS,S/AS01_E or a comparator vaccine were selected for IgA quantification 1 month post primary immunization. Two sites with different malaria transmission intensities (MTI) and clinical malaria cases and controls, were included. Measurements of IgA against different constructs of the circumsporozoite protein (CSP) vaccine antigen and 16 vaccine-unrelated Plasmodium falciparum antigens were performed using a quantitative suspension array assay.ResultsRTS,S vaccination induced a 1.2 to 2-fold increase in levels of serum/plasma IgA antibodies to all CSP constructs, which was not observed upon immunization with a comparator vaccine. The IgA response against 13 out of 16 vaccine-unrelated P. falciparum antigens also increased after vaccination, and levels were higher in recipients of RTS,S than in comparators. IgA levels to malaria antigens before vaccination were more elevated in the high MTI than the low MTI site. No statistically significant association of IgA with protection was found in exploratory analyses.ConclusionsRTS,S/AS01_E induces IgA responses in peripheral blood against CSP vaccine antigens and other P. falciparum vaccine-unrelated antigens, similar to what we previously showed for IgG responses. Collectively, data warrant further investigation of the potential contribution of vaccine-induced IgA responses to efficacy and any possible interplay, either synergistic or antagonistic, with protective IgG, as identifying mediators of protection by RTS,S/AS01_E immunization is necessary for the design of improved second-generation vaccines.Clinical trial registration: ClinicalTrials.gov: NCT008666191.     

Lack of effect of spearmint on lower oesophageal sphincter function and acid reflux in healthy volunteers

BACKGROUND: Spearmint is commonly used as an antispasmodic and as a flavouring in several medications including antacids. It can produce heartburn, presumably by lowering lower oesophageal sphincter (LES) tone, but the mechanism has not previously been objectively examined. AIM: To study the effect of spearmint on LES function, acid reflux and symptoms. METHODS: In healthy volunteers, a Dent Sleeve and a pH electrode were placed in the distal oesophagus. They were then given spearmint either in a flavouring (0.5 mg), or a high (500 mg) dose, or a placebo, using a double-blind randomized crossover design. LES pressure, oesophageal pH and symptoms were recorded for 30 min before and after administration. RESULTS: LES pressure was not affected by spearmint, either high dose (19.6 vs. 16.0 mmHg), flavouring dose (20.2 vs. 19.8 mmHg) or placebo (20.5 vs. 19.2 mmHg, all N.S.). There were no differences in reflux occurrence following high dose (mean = 0.65 vs. 0.85 episodes), low dose (0.4 vs. 0.5 episodes) or placebo (0.7 vs. 1.10 episodes, all N.S.). There was a significant increase in mean symptom scores following high-dose spearmint (0 vs. 0.35, P = 0.03), but not low dose (0 vs. 0.2) or placebo (0 vs. 0.5, both N.S.). One subject reported symptoms with placebo, one with low dose, and six with high dose; all without increased reflux episodes or decreased sphincter pressure. CONCLUSION: Spearmint has no effect on LES pressure or acid reflux. Flavouring doses of spearmint do not produce more symptoms than placebo while high doses can be associated with symptoms, presumably from direct mucosal irritation but not reflux.     

Personal exposure to nitrogen dioxide and risk of airflow obstruction in asthmatic children with upper respiratory infection

BACKGROUND: Several studies have linked air pollution by nitrogen dioxide (NO(2)) with increased hospital admissions for asthma in children. Exacerbations of asthma in children are often precipitated by upper respiratory infections. It is therefore possible that NO(2) increases the risk of airways obstruction when asthmatic children develop upper respiratory infections. METHODS: To test this hypothesis a sample of 114 asthmatic children aged 7-12 years were followed for a total of up to 13 months. Probable upper respiratory infections were identified by consensus review of daily symptom diaries, and episodes of airways obstruction from serial records of peak expiratory flow (PEF). Personal exposures to NO(2) were measured with Palmes tubes that were changed weekly. Generalised estimating equations were used to assess the relative risk (RR) of an asthmatic exacerbation starting within seven days of an upper respiratory infection according to estimated NO(2) exposure during the one week period from two days before to four days after the onset of the infection. RESULTS: The children were followed for an average of 34 weeks during which 318 upper respiratory infections and 224 episodes of reduced PEF were diagnosed. PEF episodes were much more likely to occur in the seven days following the onset of an upper respiratory infection than at other times. Estimated exposures to NO(2) at the time of infections were generally low (geometric mean 10.6 microg/m(3)). Compared with exposures of < or = 8 microg/m(3), exposures of >28 microg/m(3) were associated with a RR of 1.9 (95% confidence interval 1.1 to 3.4) for the development of an asthmatic episode within seven days of an infection. CONCLUSIONS: The findings give some support to the hypothesis that NO(2) increases the risk of asthmatic exacerbations following respiratory infections, even at relatively low levels of exposure. Further studies in populations with higher exposures would be useful.