Neutrophil-lymphocyte ratio is associated with arterial stiffness in patients with peritoneal dialysis

Background

Patients with peritoneal dialysis are in the persistent inflammation state and have elevated arterial stiffness. Neutrophil-lymphocyte ratio(NLR) is a new inflammatory marker in renal and cardiac disorders. Brachial-ankle pulse wave velocity (baPWV) is a non-invasive measurement, which is widely used as a surrogate marker of arterial stiffness. However, there is little evidence to show an association between NLR and baPWV in patients with peritoneal dialysis. The aim of this cross-section study was to investigate the relationship between NLR and arterial stiffness measured by baPWV in patients with peritoneal dialysis.

Methods

In this cross-section study, 101 patients with peritoneal dialysis were enrolled from January 2014 to June 2015. According to average baPWV level (1847.54 cm/s), the patients were categorized into two groups, low group and high group. baPWV, which reflects arterial stiffness, was calculated using the single-point method. Clinical data were collected in details. NLR was calculated using complete blood count. Associations between NLR and baPWV were assessed using Pearson’s correlation and linear regression analysis.

Results

The NLR was significantly lower in the low baPWV group than in the high baPWV group (p?=?0.03). There were positive correlations between baPWV and neutrophil count (r?=?0.24, p?=?0.01) and NRL(r?=?0.43, P?<?0.01), and there was a negative correlation between baPWV and lymphocyte count (r?=?-0.23, p?=?0.01). In addition, albumin, phosphorous and intact parathyroid hormone showed negative correlations with baPWV (r?= ?0.32, p?<?0.01; r?= ?0.28, p?<?0.01; r?= ?0.25, p?=?0.01, respectively). Age and hsCRP showed positive correlations with baPWV (r?=?0.47, p?<?0.01; r?=?0.25, p?=?0.01). In multivariate analysis, NLR independently correlated with baPWV in patients with peritoneal dialysis (β?=?0.33, p?<?0.01), even after adjustment for various confounders.

Conclusion

Our study suggests that NLR was an independently associated with arterial stiffness in patients with peritoneal dialysis. However, further prospective studies are needed to confirm cause-and-effect relationship between NLR and baPWV, and to investigate whether anti-inflammatory treatment could improve arterial stiffness in patients with peritoneal dialysis.

     

Association of plasma somatostatin with disease severity and progression in patients with autosomal dominant polycystic kidney disease

Background

Somatostatin (SST) inhibits intracellular cyclic adenosine monophosphate (cAMP) production and thus may modify cyst formation in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether endogenous plasma SST concentration is associated with disease severity and progression in patients with ADPKD, and whether plasma SST concentrations change during treatment with a vasopressin V2 receptor antagonist or SST analogue.

Methods

In this observational study, fasting concentrations of SST were measured in 127 ADPKD patients (diagnosed upon the revised Ravine criteria) by ELISA. cAMP was measured in 24?h urine by Radio Immuno Assay. Kidney function was measured (mGFR) as ¹²⁵I-iothalamate clearance, and total kidney volume was measured by MRI volumetry and adjusted for height (htTKV). Disease progression was expressed as annual change in mGFR and htTKV. Additionally, baseline versus follow-up SST concentrations were compared in ADPKD patients during vasopressin V2 receptor antagonist (tolvaptan) (n?=?27) or SST analogue (lanreotide) treatment (n?=?25).

Results

In 127 ADPKD patients, 41?±?11?years, 44% female, eGFR 73?±?32?ml/min/1.73m², mGFR 75?±?32?ml/min/1.73m² and htTKV 826 (521–1297) ml/m, SST concentration was 48.5 (34.3–77.8) pg/ml. At baseline, SST was associated with urinary cAMP, mGFR and htTKV (p?=?0.02, p?=?0.004 and p?=?0.02, respectively), but these associations lost significance after adjustment for age and sex or protein intake (p?=?0.09, p?=?0.06 and p?=?0.15 respectively). Baseline SST was not associated with annual change in mGFR, or htTKV during follow-up (st. β?=???0.02, p?=?0.87 and st. β?=???0.07, p?=?0.54 respectively). During treatment with tolvaptan SST levels remained stable 38.2 (23.8–70.7) pg/mL vs. 39.8 (31.2–58.5) pg/mL, p?=?0.85), whereas SST levels decreased significantly during treatment with lanreotide (42.5 (33.2–55.0) pg/ml vs. 29.3 (24.8–37.6), p?=?0.008).

Conclusions

Fasting plasma SST concentration is not associated with disease severity or progression in patients with ADPKD. Treatment with lanreotide caused a decrease in SST concentration. These data suggest that plasma SST cannot be used as a biomarker to assess prognosis in ADPKD, but leave the possibility open that change in SST concentration during lanreotide treatment may reflect therapy efficacy.

     

Neuromuscular comorbidity,heart failure,and atrial fibrillation as prognostic factors in left ventricular hypertrabeculation/noncompaction

Background

There is some controversy concerning the prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT). LVHT is frequently associated with neuromuscular disorders (NMDs). The aim of this study was to assess cardiac and neurological findings as predictors of mortality in patients with LVHT.

Patients and methods

The study included patients with LVHT diagnosed between June 1995 and January 2014 in one echocardiographic laboratory. They underwent a baseline cardiologic examination and were invited for a neurological examination. Between January and February 2014, their survival status was assessed.

Results

LVHT was diagnosed in 220 patients (68 female, aged 52?±?17 years) with a prevalence of 0.35?%/year. During a follow-up of 72?±?61 months, 65 patients died. The mortality was 5?%/year. A neurological investigation was performed on 173 patients (79?%) and revealed specific NMDs in 31 (14?%), NMD of unknown etiology in 103 (47?%), and normal findings in 39 (18?%) patients. In multivariate analysis, the predictors of mortality were increased age (p?=?0.0001), presence of a specific NMD (p?=?0.0062) or NMD of unknown etiology (p?=?0.0062), heart failure NYHA III (p?=?0.0396), atrial fibrillation (p?=?0.0022), and sinus tachycardia (p?=?0.0395).

Conclusions

LVHT patients should undergo systematic neurological examinations. Whether an optimal therapy of heart failure and atrial fibrillation will improve the prognosis of LVHT patients needs to be addressed in further studies.

     

Hazelnut and cocoa spread improves flow-mediated dilatation in smokers

Hazelnut and cocoa spread is an Italian product containing cocoa and hazelnut. Several epidemiological studies suggest that cocoa and hazelnuts cocoa exert beneficial cardiovascular effects. To investigate whether in smokers, hazelnut and cocoa spread elicits artery dilatation via down-regulation of oxidative stress. Flow-mediated dilatation (FMD), oxidative stress (as assessed by serum isoprostanes excretion, Nox2 activation and NO bioavailability) and antioxidant status [as assessed by vitamin E levels, plasma total polyphenols and H₂O₂ breaking down activity (HBA)] were studied in 20 smokers in a crossover, single-blind study. Patients were randomly allocated to 60 g of Hazelnut and cocoa spread or 60 g of milk chocolate (≤?35% cocoa). FMD, serum isoprostanes, Nox2 activation, NOx, vitamin E, HBA and total polyphenols were assessed at baseline and 2 h after chocolate ingestion. After Hazelnut and cocoa spread intake, FMD and NOx significantly increased (from 4.3?±?2.8 to 8.0?±?3.2%, p?<?0.001 and from 23.1?±?5.5 to 32.0?±?12.6 µM, p?=?0.016, respectively); conversely, serum isoprostanes and Nox2 activation significantly decreased (from 302.8?±?59.8 to 240.7?±?90.8 pmol/l, p?=?0.03 and from 25?±?4.4 to 22.6?±?3.2, p?=?0.03, respectively). After Hazelnut and cocoa spread intake, serum total polyphenols, vitamin E and HBA significantly increased (from 133.8?±?49.7 to 202.5?±?69.5 mg/l GAE, p?=?0.001; from 3.56?±?1.4 to 4.5?±?1.0 μmol/mmol cholesterol, p?=?0.002 and from 63.3?±?13.2 to 74.2?±?12.4%, p?=?0.003, respectively). No changes in the above variables were observed after milk chocolate intake. A linear correlation analysis shows that Δ (expressed by difference of values between before and after chocolate intake) of FMD correlates with Δ of total polyphenols and Δ of vitamin E. This study shows that Hazelnut and cocoa spread improves FMD with a mechanism potentially involving downregulation of oxidative stress and eventually increased NO generation in smokers.     

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.     

<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.

     

Agreement between cystatin-C and creatinine based eGFR estimates after a 12-month exercise intervention in patients with chronic kidney disease

Background

Estimation of GFR (eGFR) using formulae based on serum creatinine concentrations are commonly used to assess kidney function. Physical exercise can increase creatinine turnover and lean mass; therefore, this method may not be suitable for use in exercising individuals. Cystatin-C based eGFR formulae may be a more accurate measure of kidney function when examining the impact of exercise on kidney function. The aim of this study was to assess the agreement of four creatinine and cystatin-C based estimates of GFR before and after a 12-month exercise intervention.

Methods

One hundred forty-two participants with stage 3–4 chronic kidney disease (CKD) (eGFR 25–60?mL/min/1.73?m²) were included. Subjects were randomised to either a Control group (standard nephrological care [n?=?68]) or a Lifestyle Intervention group (12?months of primarily aerobic based exercise training [n?=?74]). Four eGFR formulae were compared at baseline and after 12?months: 1) MDRDcr, 2) CKD-EPIcr, 3) CKD-EPIcys and 4) CKD-EPIcr-cys.

Results

Control participants were aged 63.5[9.4] years, 60.3% were male, 42.2% had diabetes, and had an eGFR of 40.5?±?8.9?ml/min/1.73m². Lifestyle Intervention participants were aged 60.5[14.2] years, 59.5% were male, 43.8% had diabetes, and had an eGFR of 38.9?±?8.5?ml/min/1.73m². There were no significant baseline differences between the two groups. Lean mass (r?=?0.319, p?<?0.01) and grip strength (r?=?0.391, p?<?0.001) were associated with serum creatinine at baseline. However, there were no significant correlations between cystatin-C and the same measures. The Lifestyle Intervention resulted in significant improvements in exercise capacity (+?1.9?±?1.8 METs, p?<?0.001). There were no changes in lean mass in both Control and Lifestyle Intervention groups during the 12?months. CKD-EPIcys was considerably lower in both groups at both baseline and 12?months than CKD-EPIcr (Control?=???10.5?±?9.1 and???13.1?±?11.8, and Lifestyle Intervention?=???7.9?±?8.6 and???8.4?±?12.3?ml/min/1.73?m²), CKD-EPIcr-cys (Control?=???3.6?±?3.7 and???4.5?±?4.5, and Lifestyle Intervention?=???3.6?±?3.7 and???2.5?±?5.5?ml/min/1.73?m²) and MDRDcr (Control?=???9.3?±?8.4 and???12.0?±?10.7, Lifestyle Intervention?=???6.4?±?8.4 and???6.9?±?11.2?ml/min/1.73?m²).

Conclusions

In CKD patients participating in a primarily aerobic based exercise training, without improvements in lean mass, cystatin-C and creatinine based eGFR provided similar estimates of kidney function at both baseline and after 12?months of exercise training.

Trial registration

The trial was registered at www.anzctr.org.au (Registration Number ANZCTR12608000337370) on the 17/07/2008 (retrospectively registered).

     

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.     

Platelet hyperaggregability in patients with atrial fibrillation

Objective

Atrial fibrillation (AF) is a condition where platelet hyperaggregability is commonly present. We examined potential physiological bases for platelet hyperaggregability in a cohort of patients with acute and chronic AF. In particular, we sought to identify the impact of inflammation [myeloperoxidase (MPO) and C-reactive protein (CRP)] and impaired nitric oxide (NO) signaling.

Methods

Clinical and biochemical determinants of adenosine diphosphate (ADP)-induced platelet aggregation were sought in patients (n?=?106) hospitalized with AF via univariate and multivariate analysis.

Results

Hyper-responsiveness of platelets to ADP was directly (r?=?0.254, p?<?0.01) correlated with plasma concentrations of thrombospondin-1 (TSP-1), a matricellular protein that impairs NO responses and contributes to development of oxidative stress. In turn, plasma TSP-1 concentrations were directly correlated with MPO concentrations (r?=?0.221, p?<?0.05), while MPO concentrations correlated with those of asymmetric dimethylarginine (ADMA, r?=?0.220, p?<?0.05), and its structural isomer symmetric dimethylarginine (SDMA, r?=?0.192, p?=?0.05). Multivariate analysis identified TSP-1 (β?=?0.276, p?<?0.05) concentrations, as well as female sex (β?=?0.199, p?<?0.05), as direct correlates of platelet aggregability, and SDMA concentrations (β?=???0.292, p?<?0.05) as an inverse correlate.

Conclusion

We conclude that platelet hyperaggregability, where present in the context of AF, may be engendered by impaired availability of NO, as well as via MPO-related inflammatory activation.

     

Discordant association of the <Emphasis Type="Italic">CREBRF</Emphasis> rs373863828 A allele with increased BMI and protection from type 2 diabetes in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand

Aims/hypothesis

The A (minor) allele of CREBRF rs373863828 has been associated with increased BMI and reduced risk of type 2 diabetes in the Samoan populations of Samoa and American Samoa. Our aim was to test rs373863828 for associations with BMI and the odds of type 2 diabetes, gout and chronic kidney disease (CKD) in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand.

Methods

Linear and logistic regression models were used to analyse the association of the A allele of CREBRF rs373863828 with BMI, log-transformed BMI, waist circumference, type 2 diabetes, gout and CKD in 2286 adults. The primary analyses were adjusted for age, sex, the first four genome-wide principal components and (where appropriate) BMI, waist circumference and type 2 diabetes. The primary analysis was conducted in ancestrally defined groups and association effects were combined using meta-analysis.

Results

For the A allele of rs373863828, the effect size was 0.038 (95% CI 0.022, 0.055, p?=?4.8?×?10^?6) for log-transformed BMI, with OR 0.59 (95% CI 0.47, 0.73, p?=?1.9?×?10^?6) for type 2 diabetes. There was no evidence for an association of genotype with variance in BMI (p?=?0.13), and nor was there evidence for associations with serum urate (β?=?0.012 mmol/l, p_corrected?=?0.10), gout (OR 1.00, p?=?0.98) or CKD (OR 0.91, p?=?0.59).

Conclusions/interpretation

Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa.

     

Serum uric acid levels are associated with lupus nephritis in patients with normal renal function

Uric acid has been recognised as a potential marker of endothelial dysfunction and kidney disease but there are scarce data about its importance in systemic lupus erythematosus (SLE) nephritis. This study aimed to evaluate serum uric acid (UA) levels in lupus nephritis (LN), by comparing SLE patients with normal renal function, with and without nephritis. Forty-six female SLE patients were consecutively selected and divided in two groups according to renal activity at the evaluation: presence of a recently diagnosed lupus nephritis (LN+, n?=?18) and absence of lupus nephritis (LN?, n?=?28). Age-matched healthy women were selected (CONTROL, n?=?28). Patients with gout, creatinine clearance lower than 80 ml/min and use of drugs that interfere in UA were excluded. Laboratory and clinical data were analysed by appropriate tests. A multivariate analysis was performed, and a receiver operating characteristic (ROC) curve was plotted, and the area under the curve was calculated to assess the diagnostic strength of UA in LN. The mean age was similar among LN+, LN? and CONTROL groups (32.44?±?6.09 vs. 30.68?±?5.36 vs. 30.86?±?5.00 years, p?=?0.52). UA was significantly higher in LN+ compared to LN? (5.54?±?1.67 vs. 3.65?±?1.090 mg/dL, p?<?0.001) and CONTROL (5.54?±?1.67 vs. 3.92?±?0.95 mg/dL p?<?0.001). Multivariate analysis confirmed that high UA was an independent variable related to LN (p?<?0.001). The cut-off value for UA using the ROC curve was 4.47 mg/dL (AUC 0.86, p?=?0.00004, CI 95% 0.75–0.96). Lupus nephritis was associated with higher UA. Hyperuricemia as a predictor of renal damage in SLE needs to be evaluated in further studies.     

Disease severity impacts the relationship of apelin with arterial function in patients with rheumatoid arthritis

Apelin can improve arterial function by enhancing the expression of endothelial nitric oxide synthase but this effect depends markedly on endothelial integrity. We hypothesized that inflammation influences the potential impact of apelin on arterial function in rheumatoid arthritis (RA). We assessed the associations of apelin concentrations with arterial stiffness (pulse wave velocity), wave reflection (augmentation index, reflected wave pressure, and reflection magnitude), and pressure pulsatility (central systolic pressure (CSP), central pulse pressure (CPP), peripheral pulse pressure (PPP), pulse pressure amplification (PPamp), and forward wave pressure (Pf)) among 170 RA patients without cardiovascular disease. In multivariable regression models, apelin concentrations were not independently associated with arterial function measures (p?≥?0.15) in all patients. Inflammation markers were not consistently associated with apelin levels but joint deformity counts, Disease Activity Score in 28 joints (DAS28), and erythrocyte sedimentation rate (ESR) impacted apelin-pressure pulsatility relations (interaction p?≤?0.05). In stratified analysis, apelin was associated with CSP (partial r?=???0.33, p?=?0.01), CPP (partial r?=???0.26, p?=?0.04), PPamp (partial r?=?0.27, p?=?0.03), and Pf (partial r?=???0.33, p?=?0.01) in patients without but not with joint deformities; apelin was related to CSP (partial r?=???0.24, p?=?0.05) in those with a DAS28 joint <?2.8 (median value) (partial r?=???0.24, p?=?0.05) but not ≥?2.8, and to CSP (partial r?=???0.36, p?=?0.003) in those with an erythrocyte sedimentation rate <?13 mm/h (median value) but not ≥?13 mm/h. Apelin is associated with reduced pressure pulsatility in RA patients without but not with a high inflammatory burden. A loss of apelin protective effects on arterial function may contribute to the link between RA severity and cardiovascular risk.     

Non-driver mutations in patients with <Emphasis Type="Italic">JAK2</Emphasis>V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up

JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n?=?50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations?×?100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n?=?12) with these patients having a rate of 25.6 mutations?×?100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1–6.8, p?=?0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6–57.1, p?=?0.001) with mutations in ASXL1 (p?<?0.0001), TP53 (p?=?0.01), SRSF2 (p?<?0.0001), IDH1/2 (p?<?0.0001), and RUNX1 (p?<?0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p?=?0.02) and IDH1/2 (p?<?0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4–49.1, p?=?0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.     

Factors associated with anxiety in type 2 diabetes mellitus patients in Pakistan

The aim of this study was to assess the factors associated with anxiety in type 2 diabetes mellitus patients (T2DM) by using Hamilton Anxiety Rating Scale (HAM-A). A cross-sectional quantitative study was conducted after necessary ethical approval from Medicare Hospital Rawalpindi and Capital Development Authority Hospital Islamabad in accordance with Declaration of Helsinki. Three hundred thirty-eight patients with type 2 diabetes mellitus were selected by non-stratified random sampling technique from August 2016 to February 2017. Majority of the T2DM patients (n?=?258, 66.5%) had mild anxiety, followed by mild to moderate anxiety (n?=?82, 21.1%). A significant association (p?<?0.01) was observed between anxiety and patients’ gender, education, and occupation; whereas, statistically insignificant association (p?>?0.05) was observed between HAM-A score and patients’ age, family history, and life style. Linear regression analysis revealed gender (OR?=???0.308, CI-0.57-0.299) as a significant predictor (p?<?0.01) for anxiety. Findings of this study demonstrate that large proportion of the diabetic patients is suffering with type of anxiety. A significant association of anxiety was identified with gender, education, and occupation of type 2 diabetes patients.     

An adult-based insulin resistance genetic risk score associates with insulin resistance,metabolic traits and altered fat distribution in Danish children and adolescents who are overweight or obese

Aims/hypothesis

A genetic risk score (GRS) consisting of 53 insulin resistance variants (GRS₅₃) was recently demonstrated to associate with insulin resistance in adults. We speculated that the GRS₅₃ might already associate with insulin resistance during childhood, and we therefore aimed to investigate this in populations of Danish children and adolescents. Furthermore, we aimed to address whether the GRS associates with components of the metabolic syndrome and altered body composition in children and adolescents.

Methods

We examined a total of 689 children and adolescents who were overweight or obese and 675 children and adolescents from a population-based study. Anthropometric data, dual-energy x-ray absorptiometry scans, BP, fasting plasma glucose, fasting serum insulin and fasting plasma lipid measurements were obtained, and HOMA-IR was calculated. The GRS₅₃ was examined for association with metabolic traits in children by linear regressions using an additive genetic model.

Results

In overweight/obese children and adolescents, the GRS₅₃ associated with higher HOMA-IR (β?=?0.109?±?0.050 (SE); p?=?2.73?×?10^?2), fasting plasma glucose (β?=?0.010?±?0.005 mmol/l; p?=?2.51?×?10^?2) and systolic BP SD score (β?=?0.026?±?0.012; p?=?3.32?×?10^?2) as well as lower HDL-cholesterol (β?=??0.008?±?0.003 mmol/l; p?=?1.23?×?10^?3), total fat-mass percentage (β?=??0.143?±?0.054%; p?=?9.15?×?10^?3) and fat-mass percentage in the legs (β?=??0.197?±?0.055%; p?=?4.09?×?10^?4). In the population-based sample of children, the GRS₅₃ only associated with lower HDL-cholesterol concentrations (β?=??0.007?±?0.003 mmol/l; p?=?1.79?×?10^?2).

Conclusions/interpretation

An adult-based GRS comprising 53 insulin resistance susceptibility SNPs associates with insulin resistance, markers of the metabolic syndrome and altered fat distribution in a sample of Danish children and adolescents who were overweight or obese.

     

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.

     

Hemodynamic impact of percutaneous left atrial appendage closure in patients with paroxysmal atrial fibrillation

Purpose

Percutaneous left atrial appendage (LAA) closure has become a valid alternative to anticoagulation therapy for the prevention of thromboembolic events in patients with atrial fibrillation (AF). However, scarce data exist on the impact of LAA closure on left atrial and ventricular function. We sought to assess the acute hemodynamic changes associated with percutaneous LAA closure in patients with paroxysmal AF.

Methods

The study population consisted of 31 patients (mean age 73?±?10 years; 49% women) with paroxysmal AF who underwent successful percutaneous LAA closure. All patients were in sinus rhythm and underwent 2D transthoracic echocardiography at baseline and the day after the procedure. A subset of 14 patients underwent preprocedural cardiac computed tomography (CT) with 3D LA and LAA reconstruction.

Results

Left ventricular systolic function parameters and LA volumetric indexes remained unchanged after the procedure. No significant changes in left ventricular stroke volume (72.4?±?16.0 vs. 73.3?±?15.7 mL, p?=?0.55) or LA stroke volume (total 15.6?±?4.2 vs. 14.6?±?4.2 mL, p?=?0.21; passive 9.0?±?2.8 vs. 8.3?±?2.6 mL, p?=?0.31; active 10.3?±?5.6 vs. 10.0?±?6.4 mL, p?=?0.72) occurred following LAA closure. Mean ratio of LAA to LA volume by 3D CT was 10.2?±?2.3%. No correlation was found between LAA/LA ratio and changes in LA stroke volume (r?=?0.35, p?=?0.22) or left ventricular stroke volume (r?=?0.28, p?=?0.33).

Conclusions

The LAA accounts for about 10% of the total LA volume, but percutaneous LAA closure did not translate into any significant changes in LA and left ventricular function.

     

Malnutrition and sarcopenia in a large cohort of patients with systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune disease which may lead to malnutrition. Previous studies have defined it with different criteria. No thorough evaluations of sarcopenia in SSc are available. The aim of the present study was to assess the prevalence and the potential association of malnutrition and sarcopenia in a large cohort of SSc cases. A total of 141 SSc consecutive outpatients were enrolled. Body composition was analyzed by densitometry. Malnutrition was defined according to recently published ESPEN criteria, whereas sarcopenia was diagnosed in patients with reduced skeletal muscle index. Malnutrition was diagnosed in 9.2% of patients (95% CI, 4.4–14.0%). Malnourished patients had worse gastrointestinal symptoms according to UCLA SCTC GIT 2.0 questionnaire (p?=?0.007), lower physical activity (p?=?0.028), longer disease duration (p?=?0.019), worse predicted DLCO/VA and FVC (p?=?0.009, respectively), worse disease severity according to Medsger severity score (p?<?0.001), lower hemoglobin (p?=?0.023), and fat-free mass (p?<?0.001) and were more often sarcopenic (p?<?0.001). In multivariate analysis, only FVC (p?=?0.006) and disease severity (p?=?0.003), in particular for the lungs (p?=?0.013), were confirmed to be worse in malnourished patients. Sarcopenia was diagnosed in 29\140 patients (20.7%; 95% CI, 14.0–27.4%); 11\29 were also malnourished. In multivariate analysis, sarcopenic patients had longer disease duration (p?=?0.049), worse DLCO/VA (p?=?0.002), and lung (p?=?0.006) and skin (p?=?0.014) involvement. In SSc, malnutrition defined with ESPEN criteria was found to be lower than previously reported. Sarcopenia was found to be somewhat common. Lung involvement was significantly associated with nutritional status and may not be explained only by muscle weakness.     

Aberrant intestinal microbiota in individuals with prediabetes

Aims/hypothesis

Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1–7.0 mmol/l or HbA_1c of 42–48 mmol/mol [6.0–6.5%]) and a range of clinical biomarkers of poor metabolic health.

Methods

In the present case–control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age- and sex-matched individuals with normal glucose regulation.

Results

We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log₂ fold change ?0.64 (SEM 0.23), p _adj ?=?0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log₂ fold change 0.51 (SEM 0.12), p _adj ?=?5?×?10^?4; 0.51 (SEM 0.11), p _adj ?=?1?×?10^?4; 0.60 (SEM 0.21), p _adj ?=?0.0497; and 0.92 (SEM 0.21), p _adj ?=?4?×?10^?4, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log₂ fold change ?1.74 (SEM 0.41), p _adj ?=?2?×?10^?3 and ?1.65 (SEM 0.34), p _adj ?=?4?×?10^?4, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice.

Conclusions/interpretation

Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.

     

Expression of α-Defensins,CD20+ B-lymphocytes,and Intraepithelial CD3+ T-lymphocytes in the Intestinal Mucosa of Patients with Liver Cirrhosis: Emerging Mediators of Intestinal Barrier Function

Aim

The present study investigates the role of innate and adaptive immune system of intestinal mucosal barrier function in cirrhosis.

Methods

Forty patients with decompensated (n?=?40, group A), 27 with compensated cirrhosis (n?=?27, group B), and 27 controls (n?=?27, group C) were subjected to duodenal biopsy. Expression of α-defensins 5 and 6 at the intestinal crypts was evaluated by immunohistochemistry and immunofluorescence. Serum endotoxin, intestinal T-intraepithelial, and lamina propria B-lymphocytes were quantified.

Results

Cirrhotic patients presented higher endotoxin concentrations (p?<?0.0001) and diminished HD5 and HD6 expression compared to healthy controls (p?=?0.000287, p?=?0.000314, respectively). The diminished HD5 and HD6 expressions were also apparent among the decompensated patients compared to compensated group (p?=?0.025, p?=?0.041, respectively). HD5 and HD6 expressions were correlated with endotoxin levels (r?=?-0.790, p?<?0.0001, r?=???0.777, p?<?0.0001, respectively). Although intraepithelial T-lymphocytes were decreased in group A compared to group C (p?=?0.002), no notable alterations between groups B and C were observed. The B-lymphocytic infiltrate did not differ among the investigated groups.

Conclusions

These data demonstrate that decreased expression of antimicrobial peptides may be considered as a potential pathophysiological mechanism of intestinal barrier dysfunction in liver cirrhosis, while remodeling of gut-associated lymphoid tissue as an acquired immune response to bio-pathogens remains an open field to illuminate.