Clinical phenotype,biochemical profile,and treatment in 19 patients with arginase 1 deficiency

Background

Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology.

Methods

Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site.

Results

Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome.

Conclusion

Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.

     

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

Introduction

Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life.

Methods

We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment.

Findings and conclusions

Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

     

Arrhythmia device lead extraction: factors that necessitate laser assistance

BACKGROUND:

The removal of pacemaker and implantable cardioverter defibrillator (ICD) leads has become a common procedure. The need for laser use has considerable implications regarding cost and expertise. It is not an option at all centres and introduces an element of risk to the procedure. Anticipation of the need for laser assistance may be of benefit to procedure planning.

METHODS:

Data on all patients undergoing lead extraction at London Health Sciences Centre (London, Ontario) between July 2001 and October 2006 were reviewed. Variables were assessed for independent association with the need for laser assistance. A prediction rule for laser use was created based on the multivariate model.

RESULTS:

From July 2001 to October 2006, 154 patients underwent lead extraction, with laser assistance required in 106 patients (68.8%). One hundred seven patients (69.5%) had pacemakers and the remainder had ICDs. The mean (± SD) device age was 7.6±5.7 years, with 1.9±0.9 leads requiring extraction. Clinical success was achieved in 152 patients (98.7%). Multivariate analysis revealed that laser use was less likely among men (OR 0.24, 95% CI 0.069 to 0.84; P=0.026) and among septic patients (OR 0.25, 95% CI 0.072 to 0.84; P=0.025), and more likely with ICDs than pacemakers (OR 4.40, 95% CI 1.50 to 12.91; P=0.0069) and with each additional year of device age (OR 1.46 per year, 95% CI 1.26 to 1.70; P<0.0001).

CONCLUSIONS:

Laser assistance was required in 68.8% of cases, with clinical success in 98.7% of patients. Laser use was less likely among septic patients and men, and more likely with ICD leads and increasing time since lead implant. It was not possible to derive an accurate prediction rule for cases that would not need laser assistance. Therefore, it is prudent to ensure that a laser and appropriate infrastructure is available for lead extractions, and that the patient is aware of the possible need for laser assistance, along with the risks entailed.     

Comparison of low-dose pegylated interferon versus standard high-dose pegylated interferon in combination with ribavirin in patients with chronic hepatitis C with genotype 3: an Indian experience

Background and Aims: In chronic hepatitis C virus (HCV) infection with genotype 3, therapy with pegylated interferon (peg‐IFN) alfa‐2b in a dose of 1.5 μg/kg/week and ribavirin (800–1000 mg/day) is recommended for 24 weeks. Reduced doses of peg‐IFN may increase compliance and decrease cost and adverse events. This study aimed to assess the safety and efficacy of two different regimens of peg‐IFN alfa‐2b, in combination with ribavirin, in genotype 3 patients. Methods: A total of 103 liver biopsy–proven chronic HCV patients with genotype 3, having alanine aminotransferase levels >1.2 × ULN and positive HCV‐RNA were randomized into two groups: group I (n = 76; age, 43.1 ± 11.4 years; male/female, 67/9) received peg‐IFN 1.0 μg/kg/week + ribavirin 10.6 mg/kg/day, while group II (n = 27; age, 37.3 ± 11.6 years; male/female, 21/6) received peg‐IFN 1.5 μg/kg/week + ribavirin 10.6 mg/kg/day. Patients in both groups were treated for 24 weeks. End of treatment viral response (ETVR) and sustained viral response (SVR) after a 6‐month follow‐up period were assessed. Results: In both groups I and II, one patient was lost to follow‐up, while one patient in group II withdrew due to side‐effects. ETVR was seen in 72/76 (94.7%) of patients in the low dose group and 24/27 (88.9%) of patients in the high dose group (P = 0.375). SVR was seen in 60/76 (78.9%) of patients in the low dose group and 25/27 (92.6%) of patients in the high dose group (P = 0.145). Age (Pearson correlation coefficient = 0.263; P = 0.008) and fibrosis (correlation coefficient, 0.263; P = 0.008) showed a significant correlation with the SVR. Conclusion: In patients with genotype 3, peg‐IFN at 1.0 μg/kg/week with ribavirin is as effective as peg‐IFN at 1.5 μg/kg/week with ribavirin.     

Calcium Status and Calcium-Regulating Hormones in Alcoholics

To elucidate effects of chronic ethanol consumption on clinical chemical parameters reflecting overall calcium homeostasis 34 hospitalized male alcoholics and 35 age-matched controls were studied during the winter season. Serum concentrations of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 were reduced by 28% (p less than 0.01) and 24% (p less than 0.02) among the alcoholics as compared to the controls, respectively. Dietary intake of vitamin D3 did not differ significantly between the groups. The calcium level was below lower limit of reference in nine alcoholics (26%). Serum concentrations of parathyroid hormone and phosphorus were within normal ranges in both groups, and no differences were observed in levels of magnesium, vitamin D-binding protein, calcitonin, or alkaline phosphatase. In conclusion, it is possible that the activities of enzymes crucial in vitamin D3 metabolism may be altered in alcoholics.     

Persistent pulmonary hypertension after mitral valve surgery: does surgical procedure affect outcome?

BACKGROUND AND AIM OF THE STUDY: Recently published data suggest that prosthesis-patient mismatch is common after mitral valve replacement (MVR), and manifests as persistent pulmonary hypertension. The study aim was to determine the prevalence and severity of pulmonary hypertension after mitral valve surgery, including mitral valve repair, and to determine whether surgery type affects the prevalence of post-operative pulmonary hypertension. METHODS: Matched preoperative and > or =1 year postoperative Doppler estimates of right ventricular systolic pressure (RVSP) were evaluated in a cohort of 179 patients who underwent MVR or repair (33 after bioprosthetic valve replacement, 20 after mechanical valve replacement, 43 after physiological valve repair (predominantly for myxomatous disease), 78 after undersized annuloplasty for functional regurgitation, and five after repair of rheumatic stenosis). RESULTS: Patients undergoing repair of function mitral regurgitation had a lower left ventricular ejection fraction. The postoperative mean transmitral gradient was slightly higher for patients after bioprosthetic valve replacement (6.9 +/- 2.6 mmHg) compared to mechanical valve replacement (5.2 +/- 2.8 mmHg; p = 0.03), physiological repair (5.2 +/- 2.8 mmHg; p = 0.05), or repair of functional regurgitation (5.5 +/- 2.8 mmHg; p = 0.02). Pulmonary hypertension was common (present in 78% of patients before and 64% after surgery), and there were no significant differences between groups in the prevalence of postoperative pulmonary hypertension. The RVSP tended to decrease in all groups, but reached statistical significance only for patients undergoing bioprosthetic replacement (-9 +/- 24 mmHg; p = 0.04), mechanical replacement (-10 +/- 14 mmHg; p = 0.003) or physiological repair (-6 +/- 16 mmHg; p = 0.01). CONCLUSION: Pulmonary hypertension is common before and after mitral valve surgery. Although there were at least trends toward lower pulmonary artery pressures regardless of surgery type, significant decreases were noted only after MVR and physiological repair. A slightly higher postoperative mean transmitral gradient after bioprosthetic valve replacement may have contributed to postoperative pulmonary hypertension. The physiological repair of organic, non-rheumatic mitral regurgitation appears to offer favorable hemodynamics and a relatively low rate of postoperative pulmonary hypertension.     

Effect of age and sex on carotid intima-media thickness, elasticity and brachial endothelial function in healthy adults: the cardiovascular risk in Young Finns Study.

AIMS: The objective was to produce reference values and to analyse the associations of age and sex with carotid intima-media thickness (IMT), carotid compliance (CAC), and brachial flow-mediated dilatation (FMD) in young healthy adults. METHODS AND RESULTS: We measured IMT, CAC, and FMD with ultrasound in 2265 subjects aged 24-39 years. The mean values (mean +/- SD) in men and women were 0.592 +/- 0.10 vs. 0.572 +/- 0.08 mm (P < 0.0001) for IMT, 2.00 +/- 0.66 vs. 2.31 +/- 0.77%/10 mmHg (P < 0.0001) for CAC, and 6.95 +/- 4.00 vs. 8.83 +/- 4.56% (P < 0.0001) for FMD. The sex differences in IMT [95% confidence interval (CI) for sex difference -0.013 to 0.004 mm, P = 0.37] and CAC (-0.01 to 0.18%/10 mmHg, P = 0.09) became non-significant after adjustments with risk factors and carotid diameter. In FMD, the sex difference was unaltered after adjustments for risk factors, but was reversed after adjustment with brachial diameter (95% CI 0.18-1.32%, P < 0.01). With aging, IMT increased 5.7 +/- 0.4 microm/year and CAC decreased 0.042 +/- 0.003%/10 mmHg/year. The association of age with IMT and CAC was slightly attenuated (12 and 22%, respectively) after adjustments with risk factors, but remained significant (both P < 0.0001). Aging was not significantly related to brachial FMD (P = 0.16). CONCLUSION: Reference values produced in the present study can be utilized in the cardiovascular risk stratification among young people. Sex differences in the markers of subclinical atherosclerosis were mostly explained by differences in risk factors and vessel size. This emphasizes the importance of risk factor control in the prevention of atherosclerosis in young adults.