Effects of mandibular advancement device treatment on arterial stiffness and glucose metabolism in patients with mild to moderate obstructive sleep apnea: a prospective 1 year study

Study objectives

An independent association between obstructive sleep apnea (OSA) and cardiovascular events has been reported, suggesting that OSA may lead to cardiometabolic dysregulation. We prospectively investigated the effect of mandibular advancement device (MAD) treatment on arterial stiffness, glucose metabolism, and certain inflammatory markers as predictors of cardiometabolic risk in mild to moderate OSA patients.

Methods

A total of 18 patients with mild to moderate OSA were prospectively enrolled in the study to determine the effects of MAD treatment at 3 months and 1 year following initiation of the treatment. Sleep studies, arterial stiffness assessment, and laboratory analyses were obtained at the baseline and at the time of follow-up. The data collected at 1 year were compared to baseline values.

Results

There was a significant decrease in apnea-hypopnea index (AHI) after 1 year of treatment when compared to baseline (22.9?±?5.9 to 9.7?±?4.5, P?<?0.001). Furthermore, MAD treatment was associated with reduced levels of fasting plasma glucose values after 1 year of treatment (5.3?±?0.5 to 4.9?±?0.5 mmol/L, P?<?0.001), as well as fasting plasma insulin values (14.1?±?7.8 to 10.9?±?6.4 μU/mL, P?<?0.05) and HOMA-IR (3.3?±?1.8 to 2.4?±?1.4, P?<?0.001). There was significant improvement in pulse wave velocity (9.3?±?1.9 m/s at baseline to 8.1?±?1.7 m/s, P?<?0.05) after 1 year of treatment. Plasma level of an inflammatory marker fibrinogen decreased significantly from 3.4?±?0.7 at baseline to 3.0?±?0.9, (P?<?0.05) at 1-year follow-up.

Conclusions

The MAD treatment improved arterial stiffness, glucose metabolism, and insulin resistance in mild to moderate OSA patients after 1 year of treatment.

     

Obstructive sleep apnea is associated with interdialytic weight gain and increased long-term cardiovascular events in hemodialysis patients

Background

Obstructive sleep apnea (OSA) is common in hemodialysis (HD) patients. The reasons for the high prevalence and whether OSA is associated with vascular impairment, end-organ damage, and prognosis are not completely clear.

Methods

We evaluated patients with low cardiovascular risk on HD, not treated by CPAP. Laboratory tests, sleep questionnaires (Berlin and Epworth) and polysonography studies, echocardiography, and markers of arterial stiffness and atherosclerosis were performed. After the initial evaluation, patients were followed up until cardiovascular events, renal transplantation, or death.

Results

Fifty-five patients (49% male, 50?±?9 years, body mass index 24.7?±?4.5 kg/m²) were included. OSA (apnea-hypopnea index ≥?5 events/h) occurred in 73% of the patients. The proportion of patients with interdialytic weight gain >?2 kg was higher in patients with OSA than those without OSA (96 vs. 55%; p?=?0.002). Left ventricular (LV) posterior wall thickness (10.0?±?1.9 vs. 11.3?±?1.8 mm; p?=?0.04) and LV diastolic diameter (48?±?5 vs. 53?±?5 mm; p?=?0.003) were higher in patients with OSA than in patients without OSA, respectively. Sleep questionnaires did not predict OSA. No significant differences were found in pulse wave velocity, carotid intima-media thickness, and ankle-brachial index between the groups. Multivariate analysis showed that interdialytic weight gain >?2 kg and LV diastolic diameter were independently associated with OSA. On follow-up (median 45 months), OSA was found to be associated with a higher incidence of cardiovascular (CV) events (28 vs. 7%, log-rank?=?0.042).

Conclusions

OSA was associated with increased risk of CV events. Significant (>?2 kg) interdialytic weight gain was independently associated with OSA.

     

Recent-onset dilated cardiomyopathy associated with <Emphasis Type="Italic">Borrelia burgdorferi</Emphasis> infection

Background

Several recent small studies have suggested a causal link between Lyme disease and dilated cardiomyopathy (DCM) by demonstrating the presence of the Borrelia burgdorferi (Bb) genome in the myocardium of patients with recent-onset DCM. The aim of this study was to further investigate the effect of targeted antibiotic treatment of Bb-related recent-onset DCM in a larger cohort of patients.

Patients and methods

We performed endomyocardial biopsy (EMB) in 110 individuals (53?±?11 years, 34 women) with recent-onset unexplained DCM, and detected the Bb genome in 22 (20?%) subjects. Bb-positive patients were subsequently treated with intravenous ceftriaxone for 21 days in addition to conventional heart failure medication.

Results

At the 1-year follow-up, a significant improvement in left ventricular (LV) ejection fraction (26?±?6? vs. 44?±?12?%; p?<?0.01) and a decrease in LV end-diastolic (69?±?7 vs. 63?±?11 mm; p?<?0.01) and end-systolic (61?±?9 vs. 52?±?4 mm; p?<?0.01) diameters were documented. Moreover, a significant improvement in heart failure symptoms (NYHA class 3.4?±?0.6 vs. 1.5?±?0.7; p?<?0.01) was also observed.

Conclusion

Targeted antibiotic treatment of Bb-related recent-onset DCM in addition to conventional heart failure therapy is associated with favorable cardiac remodeling and improvement of heart failure symptoms.

     

Circulating Survivin Levels in Obstructive Sleep Apnoea

Introduction

Obstructive sleep apnoea (OSA) is characterised by a low-grade systemic and airway inflammation; however, the regulatory mechanisms of inflammation are poorly explored. Survivin (Birc5) is an anti-apoptotic protein which inhibits Type 1 inflammation; however, this molecule has not been investigated in OSA.

Methods

Forty-five patients with OSA and 31 non-OSA control subjects were involved. Venous blood was collected for plasma survivin measurements before and after diagnostic overnight polysomnography. Plasma survivin levels were compared between the two groups and correlated to OSA severity and comorbidities.

Results

Plasma survivin levels were lower in OSA in the evening (27.6?±?89.9 vs. 108.3?±?161.2 pg/ml, p?<?0.01) and in the morning (17.4?±?48.6 vs. 36.4?±?69.2 pg/ml, p?=?0.02) compared to the control group. This OSA-related decrease was also present when only the non-obese patients were analysed. Significant indirect relationships were observed between plasma survivin levels and measures of OSA severity such as the apnoea–hypopnoea index (r?=???0.45) or oxygen desaturation index (r?=???0.40, both p?<?0.01); however, when adjusting to BMI, these became insignificant (p?>?0.05). Low plasma survivin concentrations were associated with high BMI (r?=???0.35), high CRP (r?=???0.31), low HDL cholesterol (r?=?0.24) and high triglyceride levels (r?=???0.24, all p?<?0.05).

Conclusion

Plasma survivin levels are reduced in OSA, relate to disease severity, and are associated with high CRP levels. This suggests an impaired immunoregulation in this disorder which needs to be studied in further detail.

     

Relationship between surfactant proteins B and C and obstructive sleep apnea: is serum SP-B concentration a potential biomarker of obstructive sleep apnea?

Background

Surfactant proteins B and C are mainly synthesized, secreted by alveolar type II cells, and affected by hypoxia and mechanical stretches. We hypothesized that their serum levels might be altered by intermittent hypoxia and swing of intrathoracic pressure of obstructive sleep apnea (OSA).

Methods

Consecutive 140 middle-aged males, suspicious of OSA determined by polysomnography, were studied. Surfactant proteins B and C were determined by ELISA.

Results

Surfactant protein B (41.39?±?6.01 vs 44.73?±?7.62 ng/L, p?=?0.005), not C (32.60?±?6.00 vs 32.43?±?6.44 ng/L, p?=?0.61), significantly lowered in moderate to severe OSA subjects than in non to mild OSA subjects. Severity of OSA is inversely correlated with serum surfactant protein B. Adjusting age, body mass index, and smoking history, compared to subjects with surfactant protein B (SP-B) ≥43.35 ng/L, those with SP-B <43.35 ng/L showed significantly increased 1.528-fold risk for moderate to severe OSA (p?=?0.009), whereas no association between surfactant protein C and OSA was observed. Prevalence of moderate to severe OSA in lower SP-B group is higher than that in higher SP-B group (62.7 vs 38.4 %, p?=?0.003). Serial and parallel tests on Epworth sleep scale (ESS) and SP-B evaluation can be complementary and prove helpful with high specificity (94.44 %) and sensitivity (84.48 %) to detect moderate to severe OSA.

Conclusions

Serum surfactant protein B, rather than C, is decreased in some individuals with moderate to severe OSA, compared to non to mild OSA subjects. Serum surfactant protein B might be a potential biomarker to diagnose OSA.

     

Amiodarone plus Ranolazine for Conversion of Post-Cardiac Surgery Atrial Fibrillation: Enhanced Effectiveness in Reduced Versus Preserved Ejection Fraction Patients

Purpose

Ranolazine (RAN) added to amiodarone (AMIO) has been shown to accelerate termination of postoperative atrial fibrillation (POAF) following coronary artery bypass surgery in patients without heart failure (HF). This study aimed to investigate if treatment efficacy with AMIO or AMIO + RAN differs between patients with concomitant HF with reduced or preserved ejection fraction (HFrEF or HFpEF).

Methods

Patients with POAF and HFrEF (n?=?511, 446 males; 65?±?9 years) and with HFpEF (n?=?301, 257 males; 66?±?10 years) were enrolled. Onset of AF occurred 2.15?±?1.0 days after cardiac surgery, and patients within each group were randomly assigned to receive either AMIO monotherapy (300 mg in 30 min?+?1125 mg in 36 h iv) or AMIO+RAN combination (500 mg po?+?375 mg, after 6 h and 375 mg twice daily thereafter). Primary endpoint was the time to conversion of POAF within 36 h after initiation of treatment.

Results

AMIO restored sinus rhythm earlier in HFrEF vs. in HFpEF patients (24.3?±?4.6 vs. 26.8?±?2.8 h, p?<?0.0001). AMIO + RAN converted POAF faster than AMIO alone in both HFrEF and HFpEF groups, with conversion times 10.4?±?4.5 h in HFrEF and 12.2?±?1.1 h in HFpEF patients (p?<?0.0001). Left atrial diameter was significantly greater in HFrEF vs. HFpEF patients (48.2?±?2.6 vs. 35.2?±?2.9 mm, p?<?0.0001). No serious adverse drug effects were observed during AF or after restoration to sinus rhythm in any of the patients enrolled.

Conclusion

AMIO alone or in combination with RAN converted POAF faster in patients with reduced EF than in those with preserved EF. Thus, AMIO + RAN seems to be a valuable alternative treatment for terminating POAF in HFrEF patients.

     

Arterial stiffness is associated with left ventricular dysfunction in patients with rheumatoid arthritis

Arterial stiffness (AS) has a detrimental effect on cardiovascular system particularly on left ventricle (LV). The aim of the study was to evaluate the impact of AS on LV functions in patients with rheumatoid arthritis (RA). Forty patients with RA and 25 age-sex matched control subjects (mean age 48.5?±?6.3 vs. 45.1?±?6.9 years, respectively, p?=?0.06) were enrolled in study. AS was assessed by carotid-femoral pulse wave velocity (CF-PWV) and heart rate corrected augmentation index (AIx@75) measured by applanation tonometry (SphygmoCor). LV function was evaluated using tissue Doppler-derived myocardial performance index (MPI) from lateral mitral annulus. CF-PWV (28.3?±?10.3 vs. 21.8?±?9.3 m/s, p?=?0.03), AIx@75 (10.2?±?2.3 vs. 9.2?±?1, %, p?=?0.01) and MPI (0.46?±?0.12 vs. 0.36?±?0.1, p?<?0.001) were significantly higher in patients with RA than in controls. LV MPI was found to be significantly positive correlated with CF-PWV, AIx@75, and ESR (r?=?0.360, p?=?0.005; r?=?0.334, p?=?0.009; r?=?0.293, p?=?0.023, respectively). Arterial stiffness parameters including CF-PWV and AIx@75 are associated with subclinical left ventricular dysfunction in patients with RA.     

Ferric carboxymaltose reduces transfusions and hospital stay in patients with colon cancer and anemia

Purpose

The purpose of the study was to evaluate the efficacy of preoperative intravenous (IV) ferric carboxymaltose (FCM) administration vs. no-IV iron in colon cancer (CC) anemic patients undergoing elective surgery with curative intention.

Methods

This was a multicenter, observational study including two cohorts of consecutive CC anemic patients: the no-IV iron treatment group was obtained retrospectively while FCM-treated patients were recorded prospectively.

Results

A total of 266 patients were included: 111 received FCM (median dose 1000 mg) and 155 were no-IV iron subjects. Both groups were similar in terms of demographic characteristics, tumor location, surgical approach, and intra-operative bleeding severity. The FCM group showed a significant lower need for red blood cell (RBC) transfusion during the study (9.9 vs. 38.7 %; OR: 5.9, p?<?0.001). In spite of lower hemoglobin levels at baseline diagnosis and lower transfusion rates in the FCM group, the proportion of responders was significantly higher with respect to the no-IV group both at hospital admission (48.1 vs. 20.0 %, p?<?0.0001) and at 30 days post-surgery (80.0 vs. 48.9 %, p?<?0.0001). The percentage of patients with normalized hemoglobin levels was also higher in the FCM group (40.0 vs. 26.7 % at 30 days, p?<?0.05). A lower number of reinterventions and post-surgery complications were seen in the FCM group (20.7 vs. 26.5 %; p?=?0.311). The FCM group presented a significant shorter hospital stay (8.4?±?6.8 vs. 10.9?±?12.4 days to discharge; p?<?0.001).

Conclusions

Preoperative ferric carboxymaltose treatment in patients with CC and iron deficiency anemia significantly reduced RBC transfusion requirements and hospital length of stay, reaching higher response rates and percentages of normalized hemoglobin levels both at hospital admission and 30 days post-surgery.

     

Effects of <Emphasis Type="Italic">S</Emphasis>-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback

Electromechanical coupling studies have described the intervention of nitric oxide and S-nitrosylation processes in Ca²⁺ release induced by stretch, with heterogeneous findings. On the other hand, ion channel function activated by stretch is influenced by nitric oxide, and concentration-dependent biphasic effects upon several cellular functions have been described. The present study uses isolated and perfused rabbit hearts to investigate the changes in mechanoelectric feedback produced by two different concentrations of the nitric oxide carrier S-nitrosoglutathione. Epicardial multielectrodes were used to record myocardial activation at baseline and during and after left ventricular free wall stretch using an intraventricular device. Three experimental series were studied: (a) control (n?=?10); (b) S-nitrosoglutathione 10 µM (n?=?11); and (c) S-nitrosoglutathione 50 µM (n?=?11). The changes in ventricular fibrillation (VF) pattern induced by stretch were analyzed and compared. S-nitrosoglutathione 10 µM did not modify VF at baseline, but attenuated acceleration of the arrhythmia (15.6?±?1.7 vs. 21.3?±?3.8 Hz; p?<?0.0001) and reduction of percentile 5 of the activation intervals (42?±?3 vs. 38?±?4 ms; p?<?0.05) induced by stretch. In contrast, at baseline using the 50 µM concentration, percentile 5 was shortened (38?±?6 vs. 52?±?10 ms; p?<?0.005) and the complexity index increased (1.77?±?0.18 vs. 1.27?±?0.13; p?<?0.0001). The greatest complexity indices (1.84?±?0.17; p?<?0.05) were obtained during stretch in this series. S-nitrosoglutathione 10 µM attenuates the effects of mechanoelectric feedback, while at a concentration of 50 µM the drug alters the baseline VF pattern and accentuates the increase in complexity of the arrhythmia induced by myocardial stretch.     

Type 1 diabetic patients with peripheral neuropathy have pan-enteric prolongation of gastrointestinal transit times and an altered caecal pH profile

Aims/hypothesis

We hypothesised that type 1 diabetic patients with established diabetic sensorimotor polyneuropathy (DSPN) would have segmental and/or pan-enteric dysmotility in comparison to healthy age-matched controls. We aimed to investigate the co-relationships between gastrointestinal function, degree of DSPN and clinical symptoms.

Methods

An observational comparison was made between 48 patients with DSPN (39 men, mean age 50 years, range 29–71 years), representing the baseline data of an ongoing clinical trial (representing a secondary analysis of baseline data collected from an ongoing double-blind randomised controlled trial investigating the neuroprotective effects of liraglutide) and 41 healthy participants (16 men, mean age 49 years, range 30–78) who underwent a standardised wireless motility capsule test to assess gastrointestinal transit. In patients, vibration thresholds, the Michigan Neuropathy Screening Instrument and Patient Assessment of Upper Gastrointestinal Symptom questionnaires were recorded.

Results

Compared with healthy controls, patients showed prolonged gastric emptying (299?±?289 vs 179?±?49 min; p?=?0.01), small bowel transit (289?±?107 vs 224?±?63 min; p?=?0.001), colonic transit (2140, interquartile range [IQR] 1149–2799 min vs 1087, IQR 882–1650 min; p?=?0.0001) and whole-gut transit time (2721, IQR 1196–3541 min vs 1475 (IQR 1278–2214) min; p?<?0.0001). Patients also showed an increased fall in pH across the ileocaecal junction (?1.8?±?0.4 vs ?1.3?±?0.4 pH; p?<?0.0001), which was associated with prolonged colonic transit (r?=?0.3, p?=?0.001). Multivariable regression, controlling for sex, disease duration and glycaemic control, demonstrated an association between whole-gut transit time and total GCSI (p?=?0.02).

Conclusions/interpretation

Pan-enteric prolongation of gastrointestinal transit times and a more acidic caecal pH, which may represent heightened caecal fermentation, are present in patients with type 1 diabetes. The potential implication of delayed gastrointestinal transit on the bioavailability of nutrition and on pharmacotherapeutic and glycaemic control warrants further investigation.

Trial registration

EUDRA CT: 2013-004375-12

     

Increased serum levels of adhesion molecules ICAM-1 and VCAM-1 in systemic sclerosis are not specific for pulmonary manifestations

Studies suggest elevated serum intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels may be markers of pulmonary arterial hypertension in systemic sclerosis (SSc-PAH). We sought to evaluate whether ICAM-1 and VCAM-1 levels are useful screening biomarkers for incident SSc-PAH. In this cross-sectional study, four groups were selected from the Australian Scleroderma Cohort Study: group 1 (n?=?15) had definite PAH; group 2 (n?=?19) had interstitial lung disease (ILD); group 3 (n?=?30) were SSc-controls; and group 4 (n?=?34) were healthy controls. Serum ICAM-1 and VCAM-1 levels were measured using the Millipore Milliplex MAP Human 2-Plex Panel. There were no differences in ICAM-1 levels in the PAH versus ILD group (263.0?±?85.4 vs 380.4?±?168.3 ng/mL, p?=?0.136), SSc-controls (263.0?±?85.4 vs 253.1?±?98.0 ng/mL, p?=?1.00), or healthy controls (263.0?±?85.4 vs 201.8?±?57.2 ng/mL, p?=?0.093). Similarly, there were no differences in VCAM-1 level in PAH versus ILD groups (1476.2?±?434.9 vs 1424.8?±?527.6 ng/mL, p?=?1.00) and SSc-controls (1476.2?±?434.9 vs 1409.5?±?341.1 ng/mL, p?=?1.00). SSc subjects had significantly higher levels of ICAM-1 (297.4?±?134.0 vs 201.8?±?57.2 ng/mL, p?<?0.0001) and VCAM-1 compared to healthy controls (1432.7?±?427.4 vs 1125.6?±?273.4 ng/mL, p?<?0.0001). Neither ICAM-1 nor VCAM-1 is a specific screening biomarker of SSc-PAH. Instead, increased levels of these adhesion molecules in SSc, irrespective of pulmonary complications, suggest that they may play a role in SSc pathogenesis.     

Electrocardiographic characteristics for predicting idiopathic right ventricular outflow tract premature ventricular complex-induced cardiomyopathy

Purpose

In spite of several proposed predictors for premature ventricular complex (PVC)-induced cardiomyopathy (PVC-CMP), the specific ECG features of idiopathic right ventricular outflow tract (RVOT) PVC-CMP remain unknown.

Methods

A total of 130 patients (49 males, mean age 44 years) with symptomatic and drug-refractory idiopathic RVOT PVCs undergoing radiofrequency catheter ablation (RFCA) were enrolled. The patients were categorized into two groups, including those with and without RVOT PVC-CMP (left ventricular ejection fraction (LVEF) <?50%, n?=?25 and LVEF ≥?50%, n?=?105, respectively). The 12-lead PVC morphologies were assessed.

Results

Patients with RVOT PVC-CMP had a lower LVEF (42?±?5% vs. 60?±?7%, P?<?0.01) and higher PVC burden (24?±?14% vs. 15?±?11%, P?=?0.02) when compared to patients without RVOT PVC-CMP. The PVC features in those with PVC-CMP displayed a significantly wider QRS duration (143?±?14 ms vs. 132?±?17 ms, P?<?0.01) and higher peak deflection index (PDI; 0.60?±?0.07 vs. 0.55?±?0.08, P?<?0.01). A multivariate analysis demonstrated that the QRS duration (odds ratio (OR) 1.130, 95% confidence interval (CI) 1.020–1.253, P?=?0.02) and PDI (OR 1.240, 95% CI 1.004–1.532, P?=?0.04) were independently associated with RVOT PVC-CMP. Based on the receiver-operating characteristic analysis, a QRS duration >?139 ms and PDI >?0.57 could predict RVOT PVC-CMP (area under the curve (AUC) 0.710 and AUC 0.690, respectively). The elimination and suppression of PVCs by RFCA resulted in the recovery of the LVEF in RVOT PVC-CMP.

Conclusions

The ECG parameters, including a wider QRS duration and higher PDI, could predict the development of RVOT PVC-CMP, which could be effectively treated by RFCA.

     

Increased prevalence of obstructive lung disease in patients with obstructive sleep apnea

Study purposes

This study aims to determine whether there is an increased prevalence of obstructive lung diseases (OLDs) in patients with obstructive sleep apnea (OSA). We also determined whether among the OLD patients there is a difference in the prevalences of specific chronic disease co-morbidities between patients with and without OSA.

Methods

The prevalences of COPD, asthma, and COPD combined with asthma (ICD-9 coding) were compared between 1,497 adult OSA patients and 1,489 control patients, who were matched for age, gender, geographic location, and primary care physician. The prevalences of specific co-morbidities were measured in the OLD groups between patients with OSA and the matched control group.

Results

COPD, asthma, and COPD combined with asthma were found to be more prevalent among OSA patients compared to the matched controls. Prevalences among patients with and without OSA, respectively, were COPD—7.6 and 3.7 % (P?<?0.0001), asthma—10.4 and 5.1 % (P?<?0.0001), COPD plus asthma—3.3 and 0.9 % (P?<?0.0001). The Charlson Comorbidity Index was greater for OSA patients (2.3?±?0.2) than for controls (1.9?±?1.8; P?<?0.0001). These trends held for all severity ranges of OSA. Patients with OSA and COPD were characterized by more severe hypoxia at night compared with the OSA patients without OLD.

Conclusion

OSA was associated with an increased prevalence of OLDs.     

Early deficits in insulin secretion,beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats

Aims/hypothesis

Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available.

Methods

We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells.

Results

DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3?±?121.3 vs 633.3?±?148.7; p?<?0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5–7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9?±?1593.7 vs 4416.8?±?1230.5 pg islet^?1 h^?1; p?<?0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1?×?10⁹?±?9.5?×?10⁷ vs 3.8?×?10⁹?±?5.8?×?10⁷ μm³; p?=?0.044) and small sized islets (1.6?×?10⁹?±?5.1?×?10⁷ vs 1.4?×?10⁹?±?4.5?×?10⁷ μm³; p?=?0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1?±?16.8 vs 76.9?±?11.8 μl min^?1 [g pancreas]^?1; p?=?0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats.

Conclusions/interpretation

The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

     

Cardiovascular autonomic dysfunction in patients with idiopathic diabetes insipidus

Introduction

Central diabetes insipidus (DI) is a rare disease characterized by the excretion of excessive volumes of dilute urine due to reduced levels of the antidiuretic hormone arginine vasopressin (AVP), caused by an acquired or genetic defect in the neurohypophysis. The aim of this study was to identify any autonomic dysfunction (AD) in patients with DI as a possible cofactor responsible for their reportedly higher mortality.

Methods

The study involved 12 patients (6 females) with central idiopathic DI and a well-controlled electrolyte balance, and 12 controls matched for age, sex and cardiovascular risk factors, who were assessed using the tilt, lying-to-standing, hand grip, deep breath, Valsalva maneuver and Stroop tests.

Results

The tilt test showed a significantly more pronounced decrease in both systolic (??20.67?±?18 vs. ??1.92?±?6.99 mmHg, p?=?0.0009) and diastolic blood pressure (??10.5?±?14.29 vs. ??1.5?±?5 mmHg, p?=?0.012) in patients than in controls. Three patients with DI had to suspend the test due to the onset of syncope. The lying-to-standing test also revealed a marked reduction in blood pressure in patients with DI (1.05?±?0.13 vs. 1.53?±?0.14, p?=?0.0001). Similar results emerged for the Valsalva maneuver (Valsalva ratio, 1.24?±?0.19 vs. 1.79?±?0.11, p?<?0.0001) and deep breath test (1.08?±?0.11 vs. 1.33?±?0.08, p?<?0.0001).

Conclusions

All the principal autonomic tests performed in the study were concordant in indicating that patients with central DI have an impaired autonomic nervous system function despite a normal hydroelectrolytic balance under desmopressin therapy. This impairment may reflect damage to the autonomic system per se and/or the absence of any vasoactive effect of AVP on vascular smooth muscle. In our opinion, patients with central DI should be educated on how to prevent orthostatic hypotension, and pharmacological treatment should be considered for patients with a more marked impairment.

     

Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology

Purpose

Mechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch.

Methods

Atrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n?=?28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3 μM).

Results

On comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3 μM. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3 μM diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (138 ± 26 ms vs 95 ± 9 ms; p?<?0.01), ventricular refractoriness (155 ± 18 ms vs 124 ± 16 ms; p?<?0.01) and increments in spectral concentration (23 ± 5% vs 17 ± 2%; p?<?0.01), the fifth percentile of ventricular activation intervals (46 ± 8 ms vs 31 ± 3 ms; p?<?0.05), and wavelength of ventricular fibrillation (2.5 ±0.5 cm vs 1.7 ± 0.3 cm; p?<?0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control?=?38%, 0.03 μM?=?33%, 0.1 μM?=?33%, 0.3 μM?=?14%; p?<?0.01) and the stretch-induced increments in arrhythmia complexity index (control?=?62%, 0.03μM?=?41%, 0.1 μM?=?32%, 0.3 μM?=?16%; p?<?0.05) progressively decreased on increasing the GS967 concentration.

Conclusions

GS967 attenuates stretch-induced changes in cardiac electrophysiology.

     

<Emphasis Type="Italic">Vegf-A</Emphasis> mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation

Aims/hypothesis

The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment.

Methods

Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice.

Results

At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean?±?SEM: 0.118?±?0.01 [n?=?3] in Vegf-A mRNA transfected group (VEGF) vs 0.056?±?0.01 [n?=?3] in no RNA [p?<?0.05] vs 0.063?±?0.02 [n?=?4] in Gfp mRNA transfected group (GFP) [p?<?0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085?±?0.02 [n?=?4] in VEGF vs 0.030?±?0.004 [n?=?4] in no RNA [p?<?0.05] vs 0.034?±?0.01 [n?=?5] in GFP [p?<?0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048?±?0.013 [n?=?3] in VEGF vs 0.015?±?0.0051 [n?=?4] in no RNA [p?<?0.01] vs 0.013?±?0.0046 [n?=?4] in GFP [p?<?0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049?±?0.0042 [n?=?8] in VEGF vs 0.029?±?0.0052 [n?=?5] in no RNA [p?<?0.05] vs 0.027?±?0.0056 [n?=?4] in GFP [p?<?0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292?±?0.0032 μl [n?=?7] in VEGF vs 0.0178?±?0.0021 μl [n?=?5] in no RNA [p?<?0.01] vs 0.0129?±?0.0012 μl [n?=?4] in GFP [p?<?0.001]).

Conclusions/interpretation

Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.

     

Increased Sputum IL-17A Level in Non-asthmatic Eosinophilic Bronchitis

Background

Non-asthmatic eosinophilic bronchitis (NAEB) is one common cause of chronic cough which is characterized as airway eosinophilic inflammation like asthma but lack of airway hyper-responsiveness. Previous studies showed that Th2-pathway plays a role in NAEB, but the role of non-Th2 pathway in mechanism of NAEB remains unknown. Recently, IL-17A, a Th17-pathway cytokine, has been demonstrated to be involved in asthma development. However, the relationship between Th17-pathway and NAEB is unknown.

Methods

We aim to assess the airway level of IL-17A in the subjects with NAEB. Relationships between the IL-17A level and airway function in NAEB or asthma are also observed. We measured IL-17A concentrations in the sputum supernatant from 12 subjects with EB, 16 subjects with asthma [9 eosinophilic asthmatic (EA) and 7 non-eosinophilic asthmatic (NEA) according to the sputum eosinophil ≥?3%], and 9 healthy control subjects.

Results

Increasing IL-17A level was found in NAEB group (29.65?±?8.13 pg/ml), EA group (32.45?±?3.22 pg/ml), and NEA group (29.62?±?6.91 pg/ml) compared with the healthy control group (17.05?±?10.30 pg/ml) (P?<?0.05, P?<?0.01, P?<?0.05, respectively). The sputum IL-17A level was correlated with FENO (r?=?0.44, P?<?0.01), FEV1/FVC% (r?=???0.38, P?<?0.05), MMEF%pred (r?=???0.34, P?<?0.05), and sputum neutrophil% (r?=?0.33, P?<?0.05) in total.

Conclusion

Th17-pathway may play a role not only in asthmatics, but also in subjects with NAEB, as reflected by increasing IL-17A concentrations in sputum supernatant.

     

Diabetes and pregnancy: national trends over a 15 year period

Aims/hypothesis

We aimed to examine time trends in national perinatal outcomes in pregnancies complicated by pre-existing type 1 or type 2 diabetes.

Methods

We analysed episode-level data on all obstetric inpatient delivery events (live or stillbirth) between 1 April 1998 and 31 March 2013 (n?=?813,921) using the Scottish Morbidity Record (SMR02). Pregnancies to mothers with type 1 (n?=?3229) and type 2 (n?=?1452) diabetes were identified from the national diabetes database (Scottish Care Information-Diabetes), and perinatal outcomes were compared among women with type 1 diabetes, type 2 diabetes and those without diabetes.

Results

The number of pregnancies complicated by diabetes increased significantly, by 44% in type 1 diabetes and 90% in type 2 diabetes, across the 15 years examined, to rates of 1 in 210 and 1 in 504 deliveries, respectively. Compared with women without diabetes, delivery occurred 2.6 weeks earlier (type 1 diabetes 36.7?±?2.3 weeks) and 2 weeks earlier (type 2 diabetes 37.3?±?2.4 weeks), respectively, showing significant reductions for both type 1 (from 36.7 weeks to 36.4 weeks, p?=?0.03) and type 2 (from 38.0 weeks to 37.2 weeks, p?<?0.001) diabetes across the time period. The proportions of preterm delivery were markedly increased in women with diabetes (35.3% type 1 diabetes, 21.8% type 2 diabetes, 6.1% without diabetes; p?<?0.0001), and these proportions increased with time for both groups (p?<?0.005). Proportions of elective Caesarean sections (29.4% type 1 diabetes, 30.5% type 2 diabetes, 9.6% without diabetes) and emergency Caesarean sections (38.3% type 1 diabetes, 29.1% type 2 diabetes, 14.6% without diabetes) were greatly increased in women with diabetes and increased over time except for stable rates of emergency Caesarean section in type 1 diabetes. Gestational age-, sex- and parity-adjusted z score for birthweight (1.33?±?1.34; p?<?0.001) were higher in type 1 diabetes and increased over time from 1.22 to 1.47 (p?<?0.001). Birthweight was also increased in type 2 diabetes (0.94?±?1.34; p?<?0.001) but did not alter with time. There were 65 perinatal deaths in offspring of mothers with type 1 diabetes and 39 to mothers with type 2 diabetes, representing perinatal mortality rates of 20.1 (95% CI 14.7, 24.3) and 26.9 (16.7, 32.9) per 1000 births, respectively, and rates 3.1 and 4.2 times, respectively, those observed in the non-diabetic population (p?<?0.001). Stillbirth rates in type 1 and type 2 diabetes were 4.0-fold and 5.1-fold that in the non-diabetic population (p?<?0.001). Perinatal mortality and stillbirth rates showed no significant fall over time despite small falls in the rates for the non-diabetic population.

Conclusions/interpretation

Women with diabetes are receiving increased intervention in pregnancy (earlier delivery, increased Caesarean section rates), but despite this, higher birthweights are being recorded. Improvements in rates of stillbirth seen in the general population are not being reflected in changes in stillbirth or perinatal mortality in our population with diabetes.