Plasma asymmetric dimethylarginine predicts restenosis after coronary angioplasty

Introduction

Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of endothelial nitric oxide synthase. Asymmetric dimethylarginine may influence the process of restenosis after coronary angioplasty. The aim of the study was to determine if initial plasma ADMA level could predict restenosis after coronary angioplasty and stenting.

Material and methods

The study group consisted of 60 consecutive patients (10 women and 50 men, average age 58.9 ±10.4 years old), who underwent percutaneous coronary angioplasty with bare metal stenting for stable coronary artery disease. All patients underwent follow-up coronary angiography after a 6-month period. Patients were divided into two groups, one with restenosis (n = 22), and the other one without restenosis (n = 38). In addition to measuring acknowledged restenosis risk factors, plasma ADMA level was measured before initial angiography.

Results

Asymmetric dimethylarginine plasma level was significantly higher in the group with restenosis than in the group without restenosis (1.94 ±0.94 µmol/l vs. 0.96 ±0.67 µmol/l; p < 0.05). L-arginine/ADMA ratio was also decreased in the group with restenosis, when compared with the group without restenosis (p < 0.05). Multivariate logistic regression revealed that independent restenosis risk factors were characterised by an initially high ADMA level (p < 0.01), advanced age (p < 0.05) and low level of HDL cholesterol (p < 0.05).

Conclusions

Pre-procedural elevated plasma ADMA level increases the risk of restenosis in patients who underwent coronary angioplasty and stenting with bare metal stents.     

Asymmetrical dimethylarginine and severity of erectile dysfunction and their impact on cardiovascular events in patients with acute coronary syndrome

Introduction

Coronary artery disease (CAD) and vascular erectile dysfunction (ED) are related to endothelial dysfunction. Elevated asymmetrical dimethylarginine (ADMA) levels and ED are common in patients with increased cardiovascular risk. Our aim was to investigate whether ADMA has a predictive role for major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS). The secondary aim of this study was to investigate whether severity of ED predicts MACE in these patients.

Material and methods

Follow-up data were available for severity of ED in 71 patients with ACS. Plasma ADMA levels were determined by ELISA in 57 patients. Erectile dysfunction was assessed by the International Index of Erectile Function-6 (IIEF-6) score. Major adverse cardiovascular events (reinfarction, all-cause hospitalisation, stroke and all-cause death) was evaluated after a median of 10 months.

Results

Severe ED had no significantly increased hazard ratio for cardiovascular events compared with mild, mild to moderate, and moderate ED (0.259 [95% CI 0.041–1.6], p = 0.147; 0.605 [95% CI 0.095–3.8], p = 0.594; 0.980 [95% CI 0.233–4.1], p = 0.978; and 0.473 [95% CI 0.052–1.3], p = 0.508). The patients who had ADMA levels ≥ 0.32 µmol/l had no significantly increased hazard ratio for cardiovascular events compared with patients who had ADMA levels < 0.32 µmol/l (2.018 [95% CI 0.615–6.6], p = 0.247).

Conclusions

Severity of ED and ADMA did not increase the risk of cardiovascular events in follow-up patients with ACS in our study. Larger prospective studies are necessary to evaluate whether ADMA predicts cardiovascular events in patients with ACS.     

Serum methylarginines and incident depression in a cohort of older adults

Background

Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in depression. This study measured serum concentrations of l-arginine, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in a representative sample of older community-dwelling adults and determined their association with incident depression over 6-years of follow-up.

Methods

Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and l-arginine (measured using LC–MS/MS) were collected from a population-based sample of older Australian adults (Median age=64 years; IQR=60–70) from the Hunter Community Study. Clinical depression was defined as a Centre for Epidemiological Studies Depression Scale (CES-D) score ≥16 or use of antidepressant medications.

Results

In adjusted analyses ADMA (Q3), SDMA (Q2), l-arginine (Q2), gender, and asthma remained statistically significant predictors of incident depression at follow-up. Quartile 3 of ADMA concentration was associated with 3.5 times the odds of developing depression compared with Q1 (OR=3.54; 95% CI: 1.25–9.99).

Limitations

Limitations of our study include the use of a subjective self-reported questionnaire tool using a dichotomous cut-off, together with use of antidepressant medications, as proxies for clinical depression. Moreover, similarly to most population studies on methylated arginines, the measurement of ADMA and SDMA from blood does not necessarily reflect intracellular concentrations of these compounds. Finally, there were no measures of nitric oxide metabolites to determine if these levels were altered in the presence of elevated methylarginines and depression.

Conclusions

After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum ADMA was independently associated with incident depression at 6-years follow-up.     

Dimethylarginines in patients with intracerebral hemorrhage: association with outcome,hematoma enlargement,and edema

Background

Asymmetric dimethylarginine (ADMA)––the most potent endogenous NO-synthase inhibitor, has been regarded as mediator of endothelial dysfunction and oxidative stress. Considering experimental data, levels of ADMA and its structural isomer symmetric dimethylarginine (SDMA) might be elevated after intracerebral hemorrhage (ICH) and associated with clinical outcome and secondary brain injury.

Methods

Blood samples from 20 patients with acute ICH were taken at?≤?24 h and 3 and 7 days after the event. Nine patients had favorable (modified Rankin Scale (mRS) at 90 days 0–2) outcome, and 11 patients unfavorable outcome (mRS 3–6). Patients’ serum ADMA, SDMA, and L-arginine levels were determined by high-performance liquid chromatography–tandem mass spectrometry. Levels were compared to those of 30 control subjects without ICH. For further analysis, patients were grouped according to outcome, hematoma and perihematomal edema volumes, occurrence of hematoma enlargement, and cytotoxic edema as measured by computed tomography and serial magnetic resonance imaging.

Results

Levels of ADMA––but not SDMA and L-arginine––were elevated in ICH patients compared to controls (binary logistic regression analysis: ADMA?≤?24 h, p?=?0.003; 3 days p?=?0.005; 7 days p?=?0.004). If patients were grouped according to outcome, dimethylarginines were increased in patients with unfavorable outcome. The binary logistic regression analysis confirmed an association of SDMA levels?≤?24 h (p?=?0.048) and at 3 days (p?=?0.028) with unfavorable outcome. ADMA?≤?24 h was increased in patients with hematoma enlargement (p?=?0.003), while SDMA?≤?24 h was increased in patients with large hematoma (p?=?0.029) and perihematomal edema volume (p?=?0.023).

Conclusions

Our data demonstrate an association between dimethylarginines and outcome of ICH. However, further studies are needed to confirm this relationship and elucidate the mechanisms behind.

     

Clinical efficacy and safety of colistin treatment in patients with pulmonary infection caused by Pseudomonas aeruginosa or Acinetobacter baumannii: a meta-analysis

Introduction

The aim of this study was to evaluate the efficacy and safety of colistin treatment in patients with pulmonary infection caused by Pseudomonas aeruginosa or Acinetobacter baumannii.

Material and methods

The relevant studies were identified through a search of public databases including PubMed, MEDLINE and EMBASE up to December 2012. A meta-analysis was conducted to compare the clinical response, mortality and renal damage of colistin (colistin group) versus other effective antibiotics (control group). The odds ratio (OR) was chosen as the effect size.

Results

A total of 9 studies were eventually identified. The result of the meta-analysis showed that the pooled OR of clinical response was 1.24 (95% CI = 0.68–2.27, p > 0.05) for patients in the colistin group versus the control group, indicating no significant difference in efficacy between colistin and control groups. Similar results were obtained by the further subgroup meta-analyses by sample size, research year, ethnicity and study method. Treatment with colistin versus other agents did not affect hospital mortality (OR = 1.05, 95% CI = 0.58–1.89, p > 0.05) or renal damage (OR = 1.25, 95% CI = 0.78–2.00, p > 0.05). The combined estimate of our analysis was strong across multiple sensitivity analyses and without significant publication bias.

Conclusions

Our results suggest that colistin may be as efficacious and safe as standard antibiotics for the treatment of pulmonary infection.     

Asymmetric and Symmetric Dimethylarginine in Adolescents with Hyperuricemia

The purpose of this work was to investigate if in adolescents with hyperuricemia serum levels of asymmetric and symmetric dimethylarginine (ADMA, SDMA) are increased and if their levels correlate with serum uric acid (UA). Patients and Methods. The study group consisted of 58 hyperuricemic patients aged median 16.15 Q1–Q3 (14–17). The reference group contained 27 healthy individuals with normal serum UA level. ADMA and SDMA were measured by immunoenzymatic ELISA commercial kits and expressed in μmol/L. Serum UA was measured by the colorimetric method. Results. In hyperuricemic patients serum ADMA values did not differ between two estimated groups (P > 0.05); however, SDMA was significantly higher than in reference group (P < 0.01). Serum ADMA and SDMA correlated positively with UA (r = 0.34, P < 0.01) (r = 0.31, P < 0.01) and hs-CRP (r = 0.20, P < 0.05) (r = 0.36, P < 0.01), respectively. Conclusion. We demonstrated increased SDMA but not ADMA levels in adolescents with hyperuricemia and their correlation with serum uric acid levels. However, at the moment it is difficult to answer the question if it is just coexistence of these factors or any mechanism linking uric acid and methylated arginines really exists.     

The effect of combining rosuvastatin with sartans of different peroxisome proliferator receptor-γ activating capacity on plasma 8-isoprostane prostaglandin F2a levels

Introduction

Oxidative stress is associated with the development and progression of cardiovascular disease. Plasma 8-isoprostane prostaglandin F_2a (8-iso-PGF_2a) levels are a reliable marker of oxidative stress.

Material and methods

Patients (n = 151) with hypertension, dyslipidemia and impaired fasting glucose were randomly allocated to rosuvastatin (10 mg/day) plus telmisartan 80 mg/day (RT group, n = 52) or irbesartan 300 mg/day (RI group, n = 48) or olmesartan 20 mg/day (RO group, n = 51). After 6 months of treatment, changes in plasma 8-iso-PGF_2a levels were blindly evaluated.

Results

A decrease of 8-iso-PGF_2a levels vs baseline was observed only in the RT group (–8.6%; p = 0.02). A trend for decrease vs. baseline was observed in the RI (–5.7%; p = 0.40) and RO (–3.7%; p = 0.60) groups. Changes of 8-iso-PGF_2a levels between groups were not significantly different (p = 0.70).

Conclusions

The combination of rosuvastatin with sartans of different peroxisome proliferator receptor-γ activating capacity was associated with a decrease in levels of plasma 8-iso-PGF_2a. This decrease reached significance only in the telmisartan group.     

Renal vascular response to angiotensin II inhibition in intensive antihypertensive treatment of essential hypertension

Introduction

High blood pressure (BP) leads to target organ damage. It is suggested that regression of early organ lesions is possible on condition of BP normalization. The study objective was to assess whether permanent reduction of BP to the recommended values modifies renal vascular response to acute angiotensin II inhibition in the Doppler captopril test (DCT) in patients with essential hypertension (EH).

Material and methods

Twenty-nine persons (58 kidneys) were found eligible for the study: 18 patients with EH and 11 healthy volunteers constituting the control group. Glomerular filtration rate estimation (eGFR), 24-h ambulatory BP monitoring (ABPM) and DCT with evaluation of renal resistive index change (ΔRI) were performed before and after a 6-month period of intensive antihypertensive therapy (IAT). Additional ABPM was performed at the end of IAT.

Results

The mean IAT period was 8.5 ±2.4 months. The mean 24-h values of systolic and diastolic BP in the EH group were significantly lower in the IAT period than at the beginning and at the end of the study. Significantly lower systolic and diastolic BP (p < 0.05) and improvement of renal function (eGFR 121 ±38 vs. 139 ±40 ml/min, p < 0.001) were found after IAT as compared to initial values. Before IAT, ΔRI was significantly lower in the EH group as compared to the controls, but no such differences were found after IAT.

Conclusions

In EH patients, intensive BP lowering to the recommended values was associated with improvement of renal function and normalisation of renal vascular response to acute angiotensin II inhibition.     

Effects on asymmetric dimethylarginine of HMR 3339, a novel selective estrogen receptor modulator: a 12-week, randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women

OBJECTIVE: To investigate the short-term effects of three different doses of the selective estrogen receptor modulator HMR 3339 in comparison with placebo and raloxifene on asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor. DESIGN: This study was a multicenter, randomized, placebo-controlled, double-blind, dose-ranging study. Ninety-four healthy postmenopausal women received daily doses of either placebo (n=16), HMR 3339 2.5 mg (n=20), HMR 3339 10 mg (n=19), HMR 3339 50 mg (n=20), or raloxifene 60 mg (n=19) for 12 weeks. Fasting plasma concentrations of ADMA, arginine, and symmetric dimethylarginine (SDMA) were measured at baseline and after 4 and 12 weeks by high-performance liquid chromatography. RESULTS: HMR 3339 induced a dose-dependent reduction of ADMA and SDMA concentrations, with the largest effects (P<0.01 for both) in the HMR 3339 50 mg group compared with baseline and placebo (at 12 weeks: -7.0% [95% CI, -14.2% to 0.2%] for ADMA and -16.2% [95% CI, -22.4% to -10.0%] for SDMA). Twelve weeks of raloxifene 60 mg significantly reduced SDMA (P=0.03) but not ADMA concentrations. Arginine concentrations were not altered by any treatment. CONCLUSIONS: The reduction of the nitric oxide synthase inhibitor ADMA by HMR 3339 may potentially have a beneficial effect on the cardiovascular system in postmenopausal women.     

Noninvasive ventilation: Are we overdoing it?

Background:

Use of noninvasive ventilation (NIV) outside guideline recommendations is common. We audited use of NIV in our tertiary care critical care unit (CCU) to evaluate appropriateness of use and patient outcomes when used outside level I recommendations.

Materials and Methods:

Prospective observational study of all patients requiring NIV. Clinical parameters and arterial blood gases were recorded at initiation of NIV and 2 h later (or earlier if clinically warranted). NIV titration and decision to intubate were left to the discretion of treating intensivist. Patients were categorized into two groups: Group 1: Those with level I indications for use of NIV and group 2: All other levels of indications. Patients were followed until hospital discharge.

Results:

From January 2010 to June 2010, 1120 patients were admitted to the CCU. Of these 106 patients required NIV support with 40.6% (n = 43/106) being in group 1 and 59.4% (n = 63/106) in group 2. Of these 35.8% patients (38/106) failed NIV and required endotracheal intubation. NIV failure rates (41.27% vs. 27.91%; P = 0.02) and mortality (30.6% vs. 18.6%; P = 0.03) were significantly higher in group 2 patients. In a logistic regression analysis Acute Physiology and Chronic Health Evaluation (APACHE) II score (P = 0.02), time on NIV before intubation (P = 0.001) and baseline PaCO₂ levels (P = 0.01) were strongly associated with mortality.

Conclusion:

Noninvasive ventilation failure and mortality rates were significantly higher when used outside level I recommendations. APACHE II score, baseline PaCO₂ and duration on NIV prior to intubation were predictors of increased mortality.     

Dimethylarginines in chronic renal failure

BACKGROUND: Nitric oxide (NO) is a potent chemical mediator involved in many functions. In vivo production of NO is thought to be regulated by endogenous analogues of L-arginine: asymmetric dimethylarginine (ADMA). AIM: To examine the effect of renal function and dialysis on the serum concentrations of ADMA and symmetric dimethylarginine (SDMA). METHODS: Blood samples were obtained from nine healthy subjects, patients with renal failure before (n = 17) and after haemodialysis (n = 9), nine patients on chronic ambulatory peritoneal dialysis (CAPD), and 13 patients with chronic renal failure on conservative treatment. Serum samples were extracted using a solid phase cation exchange column and the extracts were analysed by high performance liquid chromatography (HPLC). RESULTS: Serum concentrations of ADMA in patients with renal failure (mean, 1.04 micromol/litre; SD, 0.17) were significantly higher than those of controls (mean, 0.61 micromol/litre; SD, 0.13). Haemodialysis significantly decreased the serum concentration by 36% (before dialysis: mean 0.99 (SD, 0.25) micromol/litre; after dialysis: mean, 0.63 (SD, 0.15) micromol/litre). Serum SDMA concentrations were higher in patients with renal failure, and haemodialysis decreased the concentration by 60%. There was no difference in serum arginine concentrations between the groups. CONCLUSION: Serum concentrations of ADMA are increased in renal failure and haemodialysis reduces the concentration.     

Elevated asymmetric dimethylarginine in young adult survivors of childhood acute lymphoblastic leukemia: A preliminary report

Background: Adult survivors of childhood malignancy are predisposed to late cardiovascular (CV) complications. Our aim was to estimate plasma levels of the endogenous nitric oxide formation inhibitor asymmetric dimethylarginine (ADMA), in long-term survivors of childhood acute lymphoblastic leukemia (ALL) treated with only chemotherapy. Methods: ADMA and its isomer symmetric dimethylarginine (SDMA) were measured in 25 former ALL patients (aged 18–28 years) who had survived without recurrent disease ≥ 5 years from completing chemotherapy without cranial irradiation, and in 20 healthy controls (aged 20–31 years). Results: Characteristics of the both groups were similar, except for lower high-density lipoproteins-cholesterol (HDL-C) in ALL survivors. Compared to controls, the former ALL patients exhibited significant, albeit small, rises in levels of ADMA (0.63 ± 0.09 [SD] vs. 0.57 ± 0.07 μmol/L; p = 0.016), but not SDMA, with a consequently increased ADMA to SDMA ratio (1.08 ± 0.22 vs. 0.91 ± 0.16; p = 0.004). The effect of former ALL on ADMA was attenuated (intergroup p = 0.10 [ANCOVA]) upon adjustment for HDL-C (ADMA vs. HDL-C regression coefficient: −0.065 ± 0.030 [SEM]; p = 0.03). Conclusions: ADMA is elevated in adult childhood ALL survivors, which can reflect late detrimental chemotherapy effects, partially related to minor lipid profile changes. Whether these subtle ADMA elevations might herald future CV morbidity, remains to be elucidated.     

Bronchial hyperresponsiveness to mannitol,airway inflammation and Asthma Control Test in atopic asthmatic children

Introduction

The aim of this study was to evaluate the relationship between airway hyperresponsiveness (AHR) to mannitol and bronchial inflammation measured as exhaled nitric oxide (FeNO) and to assess whether asthma control correlates with AHR to mannitol and FeNO in atopic asthmatic children.

Material and methods

Allergy evaluation, the mannitol challenge test, FeNO levels and the Asthma Control Test (ACT) questionnaire were assessed in 40 children with intermittent and mild persistent allergic asthma.

Results

All the subjects showed positive AHR to mannitol. Pearson''s correlation test revealed a significant inverse correlation between AHR (mannitol PD₁₅) and FeNO (p = 0.020). There was also a significant positive correlation between ACT and PD₁₅ (p = 0.020) and a significant negative correlation between ACT and FeNO levels (p = 0.003). The study population was divided into two groups according to FeNO levels (group A ≥ 16 ppb vs. group B < 16 ppb). In group A mannitol PD₁₅ was significantly lower (p = 0.040) and ACT score values were significantly lower (p = 0.001) compared to group B. In group A, the ACT showed that 13.3% of subjects had well-controlled asthma, 80% had partially controlled asthma and 6.7% had uncontrolled asthma. In group B, the ACT showed that 72% of subjects had well-controlled asthma and 28% had partially controlled asthma.

Conclusions

Our findings indicate that the degree of AHR to mannitol correlates with the degree of airway inflammation in asthmatic atopic children; moreover, better control of asthma correlates with a lower degree of AHR to both mannitol and FeNO.     

Effect of 1α-25-dihydroxyvitamin D3 on intimal hyperplasia developing in vascular anastomoses: a rabbit model

Introduction

A common problem encountered in routine daily practice of cardiovascular surgery is migration of smooth muscle cells leading to intimal hyperplasia developing at vascular anastomosis sites which then causes luminal narrowing. The aim of this study was to investigate the antiproliferative effect of 1,25 (OH)₂D₃ on intimal hyperplasia.

Material and methods

Twenty-one male white New Zealand rabbits weighing 2-3 kg were selected. There were 3 groups of animals each consisting of 7 rabbits. Group 1 was the control group. Group 2 was the sham group and group 3 consisted of rabbits receiving 1,25 (OH)₂D₃. The right carotid arteries of the subjects in groups 2 and 3 were transected and re-anastomosed. A daily dose of 25 ng 1,25 (OH)₂D₃ per 100 g body weight was administered for 14 days to rabbits in group 3. Rabbits in group 2 were not subject to any pharmaceutical agent. All the subjects were sacrificed at the end of the 28^th postoperative day. Their right carotid arteries were resected and then investigated histopathologically.

Results

Intimal thickness and intimal area were measured as significantly lower in group 1 when compared with the other groups (p = 0.004). In group 3, the ratios of thickness of tunica intima/thickness of tunica media and area of tunica intima/area of tunica media were significantly lower than those of group 2 (p = 0.015, p = 0.003).

Conclusions

1,25 (OH)₂D₃, the active metabolite of vitamin D, reduces the intimal hyperplasia developing after vascular anastomoses.     

Searching for factors associated with resistance to acetylsalicylic acid used for secondary prevention of stroke

Introduction

The aim of the study was to evaluate the prevalence of resistance to acetylsalicylic acid (ASA), used for secondary prevention of stroke, including the assessment of risk factors associated with the lack of ASA anti-aggregatory action.

Material and methods

Patients after a transient ischaemic attack (TIA) or ischaemic stroke in the acute (n = 111) and chronic phase (n = 87) were enrolled in the study. The assessment of platelet function was performed by whole blood impedance aggregometry using a multi-channel platelet function analyser (Multiplate).

Results

A proper response to ASA was found in 121 patients (61.1%) (ASA responders), a partial response to ASA in 59 patients (29.8%) (ASA partial responders), and ASA resistance in 18 patients (9.1%) (ASA non-responders). Acetylsalicylic acid resistance was observed more frequently in the chronic phase. The mean low-density lipoprotein (LDL) concentration was higher in ASA non-responders (p = 0.02). The mean heart rate (p = 0.03) and the mean haematocrit (p = 0.03) were higher in the group of ASA partial responders and ASA non-responders. Angiotensin II receptor antagonists were more often used in the group of ASA partial responders and ASA non-responders (p = 0.04). Diuretics were more rarely used by ASA non-responders, whereas fibrates were more rarely used by ASA partial responders.

Conclusions

The method enabled the detection of ASA resistance in some patients with cerebrovascular disease. The study revealed some possible risk factors of ASA resistance: long ASA therapy, increased heart rate, higher LDL concentration, and higher haematocrit value. The relationship between the effect of ASA and other medications (angiotensin II receptor blockers, fibrates, diuretics) requires further study. Platelet function monitoring should be considered in patients at a greater risk of ASA resistance.     

Aminoguanidine cream ameliorates skin tissue microenvironment in diabetic rats

Introduction

The aim of the study was to explore the effect of aminoguanidine cream on the skin tissue microenvironment in diabetic rats.

Material and methods

A total of 51 healthy male Sprague Dawley (SD) rats were randomly divided into three groups: the diabetes group (n = 18), the aminoguanidine group (n = 18) and the control group (n = 15). Rats in the diabetes group and aminoguanidine group were injected with 65 mg/kg streptozotocin to induce the diabetes model, and in the control group with citrate buffer. After successful induction of diabetes, the back hair of all rats was stripped by barium sulfide, and the aminoguanidine group was treated with aminoguanidine cream using disinfected cotton swabs twice every day for 40 days, while the diabetes and control groups were treated with the cream matrix. The pathological changes of skin were observed by HE staining, while the content of inflammatory cytokines (TNF-α, IL-8, ICAM and IL-1α) and the antioxidant indexes (T-AOC, GSH-PX, MPO MDA H₂O₂) were examined using commercial kits.

Results

After 40 days of treatment, the diabetes group manifested tissue lesions, whereas the aminoguanidine group seemed normal. Compared with the diabetes group, the content of inflammatory cytokines TNF-α, IL-8, ICAM and IL-1α was dramatically lower in the aminoguanidine group. T-AOC in all groups underwent dramatic changes and returned to normal finally. The activities of GSH-PX and MPO and content of H₂O₂ in the diabetes group were all higher than those in the aminoguanidine group.

Conclusions

Aminoguanidine may have a good systemic effect on alleviating the pathological changes of skin tissue in diabetic rats, which may be attributed to the regulation of GSH-PX, TNF-α, IL-8, ICAM and IL-1α.     

Increased asymmetric dimethylarginine concentrations in stimulated peripheral blood mononuclear cells

Elevated concentrations of total homocysteine as well as of asymmetric dimethylarginine (ADMA) in the blood have been reported to reflect an increased cardiovascular risk. ADMA is formed by endothelial cells and is an endogenous inhibitor of NO synthase. Earlier we have found that human peripheral blood mononuclear cells (PBMC) produce homocysteine upon stimulation with mitogens concanavalin A, phytohaemagglutinin and pokeweed mitogen. In this study, the ability of PBMC to form ADMA and symmetric dimethylarginine (SDMA) was determined. Effects were compared with levels of cysteine, homocysteine and arginine in cultures. Increased concentrations of ADMA and SDMA were found in mitogen-stimulated compared with unstimulated PBMC. Arginine and cysteine concentrations did not differ between stimulated and unstimulated PBMC. There existed significant associations between concentrations of homocysteine and ADMA (Spearman rank correlation (rs) = 0.575) as well as SDMA (rs = 0.436, both P < 0.001). Treatment of stimulated PBMC with the anti-inflammatory compounds salicylic acid (5 mm) and atorvastatin (25 microm) decreased the rate of ADMA and SDMA formation. Results of these in vitro studies show that ADMA and SDMA formation coincides with homocysteine production in human PBMC. Activated PBMC not only release Th1-type cytokine gamma-interferon, which is the most important inducer of nitric oxide synthase, but also ADMA, a natural inhibitor of the enzyme.     

Long-term intense exposure to grass pollen can mask positive effects of allergenic immunotherapy on non-specific bronchial hyperresponsiveness

Introduction

There are many potential factors that can modulate bronchial reactivity, including exposure to allergens, viral infections, and medications. The aim of this study was to analyze the effect of grass pollination intensity on the bronchial reactivity in seasonal allergic rhinitis (SAR) patients subjected to subcutaneous allergenic immunotherapy (SCIT).

Material and methods

This study, performed between 2005 and 2008, included 41 patients with confirmed sensitivity to grass pollens and predominating symptoms of SAR, randomly assigned to desensitization by pre-seasonal or maintenance SCIT. Bronchial provocation challenge with histamine was performed before the onset of immunotherapy, and repeated three times after each pollen season covered by this study. Bronchial reactivity was analyzed with regard to grass pollination intensity in 2005–2008 (air concentration of grass pollen grains, seasonal number of days when air concentration of grass pollen reached at least 20 or 50 grains per 1 m³).

Results

After 3 years of SCIT, a significant decrease in bronchial responsiveness was observed in the analyzed group as confirmed by an increase in PC₂₀ FEV₁ histamine values (p = 0.001). An inverse tendency was observed after 2 years of SCIT, however. This second year of SCIT corresponded to the 2007 season, when a significantly higher number of days with at least 50 grains of pollen per 1 m³ of air was recorded.

Conclusions

Fluctuations in pollination intensity observed during consecutive years of immunotherapy can influence bronchial reactivity in patients subjected to SCIT (ISRCTN Register: ISRCTN 86562422).     

Relationship between single nucleotide polymorphisms in the 3’-untranslated region of the vascular endothelial growth factor gene and susceptibility to diabetic peripheral neuropathy in China

Introduction

This study is to elucidate the relationship between a 936C/T mutation at the 3’-untranslated region of the human vascular endothelial growth factor (VEGF) gene and diabetic peripheral neuropathy (DPN).

Material and methods

All subjects recruited in this study were divided into DM (diabetes without neuropathy, retinopathy or nephropathy), DPN (diabetes with peripheral neuropathy only) and healthy control groups. The gene polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism, as well as other clinical methods including serum VEGF by ELISA.

Results

The C allele frequency and CC genotype frequency in the DPN group were higher than those in the NC group and DM group. The T allele frequency and CT+TT genotype (carrying the T allele) frequency in the DPN group were lower than those in the NC group (χ² = 19.051 and 18.533, both p < 0.001) and DM group (χ² = 11.117 and 11.156, both p = 0.001). However, there was no statistically significant difference in the three genotype (CC/CT+TT) frequencies and allele (C/T) frequencies between the DM group and the NC group. The multivariate logistic regression analysis showed that the levels of glycated hemoglobin (HbA_1c), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and plasma VEGF positively correlated with DPN, while the 936C/T gene polymorphism of VEGF negatively correlated with DPN.

Conclusions

Allele 936C of VEGF may serve as a genetic marker susceptible to DPN, while allele 936T may be a protective genetic marker of DPN.