Effect of homocysteine-lowering therapy on arterial elasticity and metabolic parameters in metformin-treated diabetic patients

Metformin may affect the risk of atherothrombotic disease. However, metformin increases levels of homocysteine (Hcy), considered an independent risk factor for atherosclerosis. We evaluate whether homocysteine-lowering has a beneficial effect on arterial elasticity and metabolic parameters in metformin-treated diabetic patients. In double-blind, placebo-controlled study, 60 diabetic patients treated with high dose of metformin were randomly assigned to receive daily oral supplementation with folate (1000 mcg), vitamins B12 (400 mcg) and B6 (10 mg) (group 1) or placebo (group 2). Lipid profile, HbA1C, insulin, C-peptide, hs-CRP, vitamin B12, folic acid, homocysteine, endothelin, homeostasis model assessment-insulin resistance (HOMA-IR) were measured. Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, MN). The two groups were similar at baseline in terms of hemodynamic and arterial elasticity parameters. After a 4-month small artery elasticity index (SAEI) was significantly greater in patients who received Hcy-lowering agents than in the placebo group: 4.3 ± 2.04 ml/mm Hg × 100 versus 3.2 ± 1.1 ml/mm Hg × 100, p = 0.01. Post-treatment vitamin B12 and folic acid levels were greater in group 1 versus group 2: 738.1 ± 279.9 pg/ml versus 566.1 ± 167.4 pg/ml, p = 0.007 and 14.9 ± 4.8 ng/ml versus 8.3 ± 2.9 ng/ml, p < 0.0001, respectively. Hcy level decreased significantly in the treatment group from 10.0 ± 4.4 to 7.6 ± 2.5 μmol/l, p = 0.002 and did not change in placebo group (p = 0.9). Hcy-lowering therapy improved small arterial elasticity in diabetic patients treated with high dose of metformin. The improvement was associated with a decrease in Hcy as well as an increase in folic acid and vitamin B12. These findings suggest that Hcy-lowering may have beneficial vascular effect in metformin-treated diabetic patients.     

Acute myeloid leukemia with a RUNX1-RUNX1T1 t(1;21;8)(q21;q22;q22) novel variant: a case report and review of the literature

Variants of t(8;21)(q22;q22) account for approximately 3% of all t(8;21) in acute myeloid leukemia (AML). We report a 63-year-old female patient with AML, who showed a 3-way novel variant of t(8;21), t(1;21;8)(q21;q22;q22). She presented with gastric discomfort and splenomegaly, and her complete blood count was: white blood cell count 7.96 × 10(9)/l, with 7% blasts; hemoglobin 8.3 g/dl, and platelets 66 × 10(9)/l. Her bone marrow showed increased blasts (32.5%) with a basophilic cytoplasm, salmon-pink granules and Auer rods. Cytogenetic analysis revealed a karyotype of 46,XX,t(1;21;8)(q21;q22;q22), and fluorescence in situ hybridization confirmed a RUNX1-RUNX1T1 fusion signal on the derivative chromosome 8. After induction chemotherapy, the patient achieved complete remission and has been stable for 6 months. To the best of our knowledge, this is the first report on the novel variant of t(8;21) involving the breakpoint 1q21 and the third case with a translocation among chromosomes 1, 21 and 8. Although the clinical relevance of variant t(8;21) is still unclear, a review of 24 such cases in the literature does not imply a poorer prognosis of variant t(8;21) than of the classic t(8;21).     

Toxin positivity and <Emphasis Type="Italic">tcdB</Emphasis> gene load in broad-spectrum <Emphasis Type="Italic">Clostridium difficile</Emphasis> infection

Purpose

This study aimed to evaluate the clinical significance of toxin positivity and toxin gene load, and the relation between them in the broad spectrum of Clostridium difficile infection (CDI) including colonization, significant diarrhea, and severe disease.

Methods

We included 2671 fecal samples submitted for CDI diagnosis and 180 samples from healthy individuals. The clinical spectrum was categorized as category I (toxigenic C. difficile positive without clinical CDI criteria), category II (mild CDI), and category III (severe CDI). Clinical parameters were compared based on toxin EIA and tcdB C _t values. C _t values of tcdB PCR for predicting toxin EIA positivity were assessed using receiver-operating characteristic (ROC) curves.

Results

The median C _t values of tcdB PCR and toxin positivity were not significantly correlated with clinical spectrum of CDI (27.5, 28.2, and 26.1 for tcdB C _t and 55.0, 56.6, and 60.9% for toxin EIA positivity in category I, II, and III, respectively, P > 0.05). There were significant differences in the tcdB C _t values between toxin EIA-positive and -negative groups (P < 0.001). Optimal cutoff for the tcdB C _t value for estimating toxin EIA positivity was 26.3 with 79.3% sensitivity and 83.6% specificity with good area under the curves (AUC, 0.848).

Conclusions

The C _t values successfully predicted toxin EIA positivity and could be used as a surrogate for toxin EIA positivity in the diagnostic algorithm and routine analysis. Further studies are needed to validate the clinical significance of tcdB PCR C _t value in toxigenic C. difficile colonization and infection.

     

Two founder mutations in the SEC23B gene account for the relatively high frequency of CDA II in the Italian population

Congenital Dyserythropoietic Anemia type II is an autosomal recessive disorder characterized by unique abnormalities in the differentiation of cells of the erythroid lineage. The vast majority of CDA II cases result from mutations in the SEC23B gene. To date, 53 different causative mutations have been reported in 86 unrelated cases (from the CDA II European Registry), 47 of them Italian. We have now identified SEC23B mutations in 23 additional patients, 17 Italians and 6 non-Italian Europeans. The relative allelic frequency of the mutations was then reassessed in a total of 64 Italian and 45 non-Italian unrelated patients. Two mutations, E109K and R14W, account for over one-half of the cases of CDA II in Italy. Whereas the relative frequency of E109K is similar in Italy and in the rest of Europe (and is also prevalent in Moroccan Jews), the relative frequency of R14W is significantly higher in Italy (26.3% vs. 10.7%). By haplotype analysis we demonstrated that both are founder mutations in the Italian population. By using the DMLE+ program our estimate for the age of the E109K mutation in Italian population is ≈2,200 years; whereas for the R14W mutation it is ≈3,000 years. We hypothesize that E109K may have originated in the Middle East and may have spread in the heyday of the Roman Empire. Instead, R14W may have originated in Southern Italy. The relatively high frequency of the R14W mutation may account for the known increased prevalence of CDA II in Italy.     

Iatrogenic hyperthyroidism does not promote weight loss or prevent ageing-related increases in body mass in thyroid cancer survivors

Context Thyroid cancer survivors represent a unique population in which the potential long‐term effects of brief periods of intentional thyroid hormone withdrawal and/or prolonged periods of iatrogenic hyperthyroidism on body weight and body mass were evaluated. Objectives The objectives of this study were to characterize body mass changes over several years in a cohort of thyroid cancer patients with iatrogenic hyperthyroidism and to compare these changes with the expected weight gain in age‐matched healthy control populations. We also evaluated the possibility that the method of preparation [thyroid hormone withdrawal (THW) vs recombinant human TSH (rhTSH)] for radioactive iodine remnant ablation may be associated with differences in body mass at the time of the final follow‐up. Design/Setting/Patients/Interventions A retrospective review identified 153 patients with thyroid cancer who underwent total thyroidectomy at one major medical centre. Of the 153 patients, 143 also had radioactive iodine remnant ablation: 70 after THW and 73 after rhTSH. Main Outcome Measures Change in weight and BMI at 1–2 and 3–5 years of follow‐up points were examined. Annualized weight variation within the cohort was compared with age‐matched population controls expressed in kilogram/year. Results Significant weight gain was noted for the full cohort after 3–5 years of follow‐up as compared to baseline (76 ± 21 kg at baseline vs 79 ± 23 kg at 3–5 years of follow‐up, P < 0·01), which represented a 3·2% increase. Female and male patients with thyroid cancer experienced 0·46 and 0·94 kg/year gain in weight, respectively, which is similar or somewhat higher than previously published age‐matched population controls (ranging from 0·23 to 0·34 kg/year). When expressed as per cent change and comparing the final weight to the pre‐operative baseline, the rhTSH group experienced approximately a 1·7% increase in weight compared with the 3·9% increase seen with THW patients (P = 0·02). When expressed as kg/year change, the rhTSH cohort had 0·34 kg/year change compared with the 0·64 kg/year change seen in the thyroid hormone withdrawal patients (P = 0·02). Conclusion In otherwise, healthy patients with differentiated thyroid cancer, significant weight gain occurred during the 3–5 years of follow‐up despite ongoing thyrotropin suppression. The data suggest that mild iatrogenic hyperthyroidism does not promote weight loss or prevent ageing‐related weight gain. Greater weight gain was seen in patients prepared for radioactive remnant ablation with THW than with rhTSH.     

Reversal of cardiac complications in thalassemia major by long-term intermittent daily intensive iron chelation

OBJECTIVES: In patients with thalassemia major (TM) who are non-compliant with long-term deferoxamine (DFO) chelation, survival is limited mainly because of cardiac complications of transfusional siderosis. It was recently shown in a small group of TM patients with established cardiac damage that continuous 24-h DFO infusion via an indwelling intravenous (i.v.) catheter is effective in reversing cardiac toxicity. The aim of the present study was to evaluate the results with intermittent daily (8-10 h) i.v. DFO. PATIENTS: Eight TM patients with cardiac complications treated with intensive intermittent DFO were retrospectively evaluated by the mean annual serum ferritin, radionucleated ventriculography and 24-h electrocardiography recordings. RESULTS: The median age at diagnosis of cardiac disease was 17.5 yr (range 14-21), and the median follow-up time was 84 months (range, 36-120). In the majority of patients (seven of eight) high-dose DFO (mean 95 +/- 18.3 mg/kg/d) was administered via a central venous line. During follow-up, there was a significant decrease in the mean ferritin levels (5828 +/- 2016 ng/mL to 1585 +/- 1849 ng/mL, P < 0.001). Both cardiac failure (mean ejection fraction 32 +/- 5) and cardiac arrhythmias were resolved in four of five patients. One non-compliant patient died during the follow-up. Following discontinuation of the i.v. therapy, compliance with conventional DFO therapy improved. The complications of this regimen, mainly catheter-related infections and catheter-related thrombosis, were similar to those described earlier. CONCLUSIONS: These results with the longest follow-up period in the literature suggest that i.v. high-dose DFO for 8-10 h daily may be as effective as continuous 24-h infusion for the reversal of established cardiac disease in TM.     

Outcome and management of pregnancies in severe chronic neutropenia patients by the European Branch of the Severe Chronic Neutropenia International Registry

Long-term granulocyte-colony stimulating factor treatment has been shown to be safe and effective in severe chronic neutropenia patients. However, data on its use during pregnancy are limited. To address this issue, we analyzed all pregnancies reported to the European branch of the Severe Chronic Neutropenia International Registry since 1994. A total of 38 pregnancies in 21 women with chronic neutropenia (16 pregnancies in 10 women with congenital, 10 in 6 women with cyclic, 12 in 5 women with idiopathic neutropenia) were reported. Granulocyte-colony stimulating factor was administered throughout pregnancy in 16 women and for at least one trimester in a further 5 women. No major differences were seen between treated and untreated women with respect to pregnancy outcome, newborn complications and infections. In addition, we evaluated the genetic transmission of known or suspected genetic defects in 16 mothers having 22 newborns as well as in 8 men fathering 15 children. As a proof of inheritance, neutropenia was passed on to the newborn in 58% from female and in 62% from male patients with ELANE mutations, but also to some newborns from parents with unknown gene mutation. Based on our results, granulocyte-colony stimulating factor therapy has been shown to be safe for mothers throughout pregnancies and for newborns without any signs of teratogenicity. With an increasing number of adult patients, genetic counseling prior to conception and supportive care of mothers during pregnancy are crucial. The acceptance of having affected children may reflect the high quality of life obtained due to this treatment.