Acid control with esomeprazole and lansoprazole: A comparative dose–response study

Objective. To determine the level of acid control and the dose–response relationships achieved with esomeprazole and lansoprazole. These data are relevant in helping clinicians to decide on whether to increase a proton-pump inhibitor dose, or whether to switch to an alterative drug for increased acid control. Material andmethods. In an open-label, single-centre, randomized, six-way crossover study, 40 healthy subjects received esomeprazole 20, 40 and 80 mg, and lansoprazole 15, 30 and 60 mg once daily for 5 days. The mean time with intragastric pH >4 and mean 24-h median intragastric pH on day 5 were analyzed using a mixed-model ANOVA. Post-hoc analyses were completed for 0–12-h (daytime) and 12–24-h (night-time) post-dose intervals. Results. Increasing the dose of esomeprazole from 20 mg to 40 mg resulted in significantly improved acid control over 0–12, 12–24 and 0–24 h post-dose (p<0.001), but no significant improvement in acid control for either period was seen when further increasing the dose to 80 mg. Increasing the dose of lansoprazole from 15 mg to 30 mg or from 30 mg to 60 mg significantly improved acid control over 0–12 and 0–24 h (p<0.01) but not over 12–24 h. With the exception of the esomeprazole 20 mg versus lansoprazole 30 mg comparisons, and the esomeprazole 20 mg versus lansoprazole 15 mg during 12–24 h post-dose comparison, esomeprazole provided significantly greater acid control than lansoprazole at each dose level over 0–12, 12–24 and 0–24 h (p<0.05). Mean 24-h median intragastric pH was higher following esomeprazole dosing compared with lansoprazole at each dose level. Conclusions. For low-, standard- and double-dose comparisons, esomeprazole achieved greater elevation of gastric pH and better acid control in more subjects than lansoprazole. Use of esomeprazole may therefore reduce the need for dose adaptations or drug switching.     

Calcium and vitamin D supplementation and incident rheumatoid arthritis: the Women’s Health Initiative Calcium plus Vitamin D trial

To determine whether calcium plus vitamin D supplementation (CaD) affects incidence of rheumatoid arthritis (RA). Participants enrolled in the Women??s Health Initiative CaD trial (n?=?36,282) were randomized to 1,000?mg calcium carbonate plus 400?IU of vitamin D₃ daily or to placebo. Incident RA cases were identified via self-report and validated rheumatic medication use. Cox proportional hazards models were used to compare RA incidence in the treatment versus placebo groups. The analysis included 32,435 women without the history of RA, of which 163 incident RA cases were identified over an average of 5.1?years. No significant differences in demographics, total personal vitamin D intake [P?=?0.36], or solar irradiance [P?=?0.68] were seen between the groups. In intention-to-treat analyses, no differences were observed in RA incidence [HR 1.04, 95% CI 0.76, 1.41]. No significant modifying effects were seen for stratum of age, solar irradiance, or total vitamin D intake, overall or when adjusted for adherence. Significant effect modifications were seen between CaD and total vitamin D intake and CaD and solar irradiance that suggest increased RA incidence with high vitamin D exposure. CaD supplementation did not demonstrate a significant effect on RA incidence in postmenopausal women. Modifying effects between CaD and both solar irradiance and dietary vitamin D intake are suggestive that multiple high vitamin D exposures may increase RA incidence. Further research is needed to fully explore the benefits and possible adverse effects of vitamin D supplementation on RA.     

Lipid levels and the risk of hemorrhagic stroke: A dose–response meta-analysis

Background and aimsHemorrhagic stroke (HS) could damage human health and impose heavy social and economic burden around the world. An accumulating number of studies revealed the effect of lipid levels on HS, whereas the results were inconsistent. Therefore, we conducted a dose–response meta-analysis to evaluate the relationship between lipid levels and HS.Methods and resultsWe searched the databases for relative cohort studies, which were published before April 2020. We pooled adjusted effect size and performed the dose–response analysis by random-effect model. 31 eligible studies with 2,291,643 participants and 12,147 hemorrhagic stroke cases were included. An inverse association was observed between the risk of hemorrhagic stroke and total cholesterol (TC) (RR: 0.72; 95% CI: 0.64–0.82) or low-density lipoprotein cholesterol (LDL-C) (RR: 0.69; 95% CI: 0.53–0.89). Additionally, in dose–response analysis, the non-linear trend was also found between TC, high-density lipoprotein cholesterol (HDL-C), and risk of HS. When the level of TC and HDL-C was about 6 and 1.3 mmol/L separately, the risk of HS was decreased to the lowest. And we found a linear trend that for every 1 mmol/L triglyceride (TG) increase, the risk of HS decreased by 7%.ConclusionTC and LDL-C were both inversely related to the risk of HS. In dose–response analysis of TG, we also found the inverse linear trend. Furthermore, the non-linear trend suggested the level of TC and HDL-C was about 6 and 1.3 mmol/L separately could lead to the lowest risk of HS.     

Alcohol intake and risk of stroke: A dose–response meta-analysis of prospective studies

Background

Alcohol intake is inconsistently associated with the risk of stroke morbidity and mortality. The purpose of this study was to summarize the evidence regarding this relationship by using a dose–response meta-analytic approach.

Methods

We performed electronic searches of PubMed, EMBASE, and the Cochrane Library to identify relevant prospective studies. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) of stroke morbidity and mortality for more than 2 categories of alcohol intake were included.

Results

We included 27 prospective studies reporting data on 1,425,513 individuals. Low alcohol intake was associated with a reduced risk of total stroke (risk ratio [RR], 0.85; 95% CI: 0.75–0.95; P = 0.005), ischemic stroke (RR, 0.81; 95% CI: 0.74–0.90; P < 0.001), and stroke mortality (RR, 0.67; 95% CI: 0.53–0.85; P = 0.001), but it had no significant effect on hemorrhagic stroke. Moderate alcohol intake had little or no effect on the risks of total stroke, hemorrhagic stroke, ischemic stroke, and stroke mortality. Heavy alcohol intake was associated with an increased risk of total stroke (RR, 1.20; 95% CI: 1.01–1.43; P = 0.034), but it had no significant effect on hemorrhagic stroke, ischemic stroke, and stroke mortality.

Conclusions

Low alcohol intake is associated with a reduced risk of stroke morbidity and mortality, whereas heavy alcohol intake is associated with an increased risk of total stroke. The association between alcohol intake and stroke morbidity and mortality is J-shaped.     

Calcium and vitamin D in the serrated neoplastic pathway: Friends or foes?

Sessile serrated adenoma/polyps(known as SSA/Ps) may play an important role in the development of interval colorectal cancer(CRC). These lesions are more difficult to detect with conventional endoscopy and they may quickly turn into CRC, especially when dysplasia has developed. Therefore, primary or secondary chemoprevention may be an appealing strategy at a population level. Calcium and vitamin D have been shown in epidemiological studies to reduce the risk of CRC and conventional adenomas, but the evidence regarding their effect on SSA/Ps is controversial. In this editorial we comment on the results of a recent randomized controlled trial investigating the effect of calcium and vitamin D on the development of serrated lesions, summarizing the possible antineoplastic mechanisms of calcium and vitamin D, and discussing the differences found with previous observational reports.     

Neurocognitive testing in late-onset Tay–Sachs disease: A pilot study

Summary Objectives  To test neurocognitive function in patients with late-onset Tay–Sachs disease (LOTS) using a computerized system to assess whether cognition is a clinically relevant outcome measure of possible therapeutic intervention in LOTS. Methods  Ten adults with Tay–Sachs disease were administered at least one battery of the Mindstreams Neurotrax system for evaluation of cognitive function. Six sub-scores and a Global Cognitive Score (GCS) were tabulated. A disease specific severity score was also devised with six domains. Results  Despite identical genotypes, all patients but the two oldest had ≥3/6 sub-scores one standard deviation below normal mean (100); verbal and executive functions were most affected. The severity score measured other functions. Conclusions  Because of provocative findings on re-testing in patients exposed to miglustat, and despite the very small cohort, cognitive function may be an appropriate and clinically relevant outcome measure for future therapeutic interventions in LOTS. Competing Interests: A private grant to one of us (D.E.) for LOTS-related research provided funds for transportation of patients to Jerusalem and paid for Neurotrax testing. G.M.D. and E.S. are paid employees of the Neurotrax Corporation. DE, AZ, IKL and RN had no associations during the period covered in this report such as consultancies, stock ownership, or other equity interests or patent licensing arrangements that may have posed a conflict of interest.     

A J-shaped relation of BMI and stroke: Systematic review and dose–response meta-analysis of 4.43 million participants

Background and aim

Many studies have shown increased risk of stroke with greater adiposity as measured by body mass index (BMI), but questions remain about the shape of the dose–response relation. We conducted a systematic review and meta-analysis of prospective studies to clarify the strength and shape of the dose–response relation between BMI and risk of stroke.

A novel role for vitamin D: modulation of expression and function of the local renin–angiotensin system in mouse pancreatic islets

Aims/hypothesis  

The aim of this study was to demonstrate that hormonal vitamin D (calcitriol) modulates the local pancreatic islet renin-angiotensin system (RAS) whilst improving islet beta cell secretory function.     

Effect of Low Level Laser Therapy on serum vitamin D and magnesium levels in patients with diabetic peripheral neuropathy – A pilot study

BackgroundDiabetic Peripheral neuropathy (DPN) is the most distressing complication of diabetic population leading to loss of sensation, pain, and amputation. Low-level laser therapy (LLLT) has been used to manage nerve injuries as it holds the potential to induce a biostimulatory effect with no side effects. Hence we planned to study the biochemical effect and therapeutic outcomes of LLLT on patients with painful diabetic peripheral neuropathy as a preliminary work.Materials and methodsPre-posttest analysis was done on 40 patients diagnosed with DPN confirmed using 10 g Monofilament test and Michigan Neuropathy Screening Instrument (MNSI). Vibration sensation and pain measured by Vibration perception threshold (VPT) and Numeric pain rating scale (NPRS). All patients were given LLLT (3.1 J/cm²) on plantar and dorsal of the foot for 10 days. Serum samples were collected at baseline and 4 weeks after LLLT to estimate Vitamin D and Magnesium and compared the results.ResultsThere was a significant increase in Vitamin D and Magnesium levels after LLLT. We observed a considerable improvement in the quality of life after LLLT demonstrated by a decrease in VPT and MNSI and a reduction in NPRS in DPN patients.ConclusionIn this study, we found that LLLT improved the QL and hence may be a useful therapeutic option in treating peripheral neuropathic pain in type 2 diabetic patients. The progress in the serum Magnesium and Vit. D levels were proportional to the QL and may be a good indicator of the prognosis of DPN after LLLT.     

Breastfeeding and the maternal risk of type 2 diabetes: A systematic review and dose–response meta-analysis of cohort studies

Background and aimsBreastfeeding has been associated with reduced risk of maternal type 2 diabetes in some cohort studies, but the evidence from published studies have differed with regard to the strength of the association. To clarify this association we conducted a systematic review and dose–response meta-analysis of breastfeeding and maternal risk of type 2 diabetes.Methods and resultsWe conducted a systematic review and dose–response meta-analysis of prospective studies of breastfeeding and maternal risk of type 2 diabetes. We searched the PubMed, Embase and Ovid databases up to September 19th 2013. Summary relative risks were estimated using a random effects model. Six cohort studies including 10,842 cases among 273,961 participants were included in the meta-analysis. The summary RR for the highest duration of breastfeeding vs. the lowest was 0.68 (95% CI: 0.57–0.82, I² = 75%, p_{heterogeneity} = 0.001, n = 6). The summary RR for a three month increase in the duration of breastfeeding per child was 0.89 (95% CI: 0.77–1.04, I² = 93%, p_{heterogeneity} < 0.0001, n = 3) and the summary RR for a one year increase in the total duration of breastfeeding was 0.91 (95% CI: 0.86–0.96, I² = 81%, p_{heterogeneity} = 0.001, n = 4). There was little difference in the summary estimates whether or not BMI had been adjusted for. The inverse associations appeared to be nonlinear, p_nonlinearity < 0.0001 for both analyses, and in both analyses the reduction in risk was steeper when increasing breastfeeding from low levels.ConclusionThis meta-analysis suggests that there is a statistically significant inverse association between breastfeeding and maternal risk of type 2 diabetes.     

Dietary cholesterol consumption and incidence of type 2 diabetes mellitus: A dose–response meta-analysis of prospective cohort studies

Background and aimThe purpose of this meta-analysis was to evaluate the dose–response relationship between dietary cholesterol (DC) consumption and the incidence of type 2 diabetes mellitus (T2DM).Methods and resultsProspective studies with the endpoint of T2DM were included. The Random-effect model weighted by inverse variance was used. Meta-regression and subgroup analyses were conducted to explore the potential sources of heterogeneity by specified study characteristics. Restricted cubic splines regression models were used to estimate the dose–response relationship. 11 prospective studies comprising of 355 230 subjects were included. Compared to lowest DC consumption, highest DC consumption was associated with an increased risk of T2DM (RR 1.15, 95% CI 1.03 to 1.28, P = 0.012; chi-squared = 31.41, I-squared 58.6%, P _{heterogeneity} = 0.003). Subgroup analyses have shown that this positive association was more evident in western countries than in eastern countries (RR 1.19, 95% CI 1.06 to 1.36 VS 1.34, 95% CI 0.84 to 1.29; P _{subgroup difference} = 0.02). For 100 mg/d increment in DC intake, the pooled RR was 1.05, (95% CI 1.04 to 1.07, P_linearity = 0.000, P_nonlinearity = 0.02), 1.06 (95% CI 1.04 to 1.07, P_linearity=0.000), and 1.01 (95% CI 0.98 to 1.05, P_linearity = 0.525) for the incidence of T2DM, in western and eastern countries, respectively.ConclusionsOur study suggests that there is a positive dose–response association between DC consumption and the incidence of T2DM, especially in western countries.Systematic review registrationPROSPERO CRD42020216318.     

Prospective, open-label, uncontrolled pilot study to study safety and efficacy of sildenafil in systemic sclerosis–related pulmonary artery hypertension and cutaneous vascular complications

Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud’s phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud’s phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud’s phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud’s phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud’s phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6-min walk test, WHO class of dyspnoea, severity of Raynaud’s phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud’s phenomenon, and digital infarcts/ulcers.     

Recombinant N–terminal fragments of chromogranin–A modulate cardiac function of the Langendorff–perfused rat heart

In this study we tested the hypothesis that vasostatins could act as myocardial modulators in the mammalian heart. Using the Langendorff–perfused rat heart, the cardiac effects of the two recombinant human CGA N–terminal fragments STA–CGA1–78 and STA–CGA1–115, containing the vasostatin–1 (CGA 1–76) and vasostatin–2 (CGA 1–113) sequences, respectively, were evaluated at concentrations of 11 ÷ 165 nM. Cardiac performance was evaluated by analyzing left ventricular pressure (LVP) and the rate pressure product (RPP: HR × LVP), used as indexes of contractile activity and cardiac work, respectively. Under basal conditions, STA–CGA1–78 at all concentrations tested elicited a dose–dependent negative inotropism (LVP variations ranging from –9.6% ± 2 to –23% ± 2.9) without affecting coronary pressure (CP). In contrast, STA–CGA1–115 increased CP at 110 and 165 nM without affecting inotropism. Both STA–CGA1–78 and STA–CGA1–115 counteracted the cardio–stimulatory effects of isoproterenol (ISO). The ISO–dependent positive chronotropism was unaffected by STA–CGA1–78, while being reduced by STA–CGA1–115. Both peptides abolished the ISO–induced positive inotropism without modifying either the β–adrenergic–dependent coronary dilation or the ouabain–induced positive inotropism. The analysis of the percentage of variations of RPP in terms of EC₅₀ values of ISO alone (–8.5 ± 0.3; r² = 0.88) and in presence of STA–CGA1–78 (11, or 33, or 65 nM: –7.7 ± 0.15, r² = 0.97; –7.7 ± 0.15, r² = 0.97; –7.8 ± 0.78, r² = 0.55, respectively) revealed a non–competitive type of antagonism of STA–CGA1–78. Taken together, these data suggest vasostatins as novel cardioregulatory peptides in mammals.