Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.

OBJECTIVE: Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in <15% of familial cSVD cases. We sought to identify novel causes of cSVD. METHODS: We used linkage analysis and exome sequencing to identify the causal mutation in a French cSVD family. The identified candidate gene was then screened in 202 cSVD unrelated probands, including 1 proband from the first reported pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) family. Sanger sequencing was used to confirm variants in all mutated probands and analyze their segregation in probands' relatives. Mutation consequences were assessed with luciferase reporter assays and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: A candidate heterozygous variant located in a predicted miR-29 microRNA binding site, within the 3' untranslated region of COL4A1, was identified in the large French cSVD family. Five additional unrelated probands, including the PADMAL proband, harbored heterozygous variants in this microRNA binding site. Variants cosegregated with the affected phenotype, and cumulative logarithm of odds score reached 6.03, establishing linkage to this locus. A highly significant difference was observed when comparing the number of variants within this binding site in cases and controls (p = 1.77 × 10E-12). RT-qPCR analyses of patients' primary fibroblasts and luciferase reporter assays strongly favor an upregulation of COL4A1 mediated by disruption of miR-29 binding to its target site. Magnetic resonance imaging features were characterized by the presence of multiple pontine infarcts in all symptomatic mutation carriers. INTERPRETATION: Mutations upregulating COL4A1 expression lead to PADMAL, a severe early onset ischemic cSVD, distinct from the various phenotypes associated with COL4A1 missense glycine mutations. Ann Neurol 2016;80:741-753.

The plasma homocysteine concentrations and prior myocardial infarction.

UNLABELLED: Elevated plasma homocysteine levels are associated with increased risk of vascular disease and with a relationship between homocysteine values and disease severity. Several studies have shown that the high plasma level of homocysteine is an important predictor for risk of cardiovascular events. We analysed the relationship between homocysteine concentrations and other risk factors into CAD progression in patients of prior myocardial infarction. METHODS: We performed a study including 208 patients (100 men and 108 women) divided into two groups: 104 patients with prior myocardial infarction and 104 without coronary artery disease. RESULTS: The patients with prior myocardial infarction had higher mean values of plasma homocysteine than the controls (18.98 +/- 4.72 vs. 14.09 +/- 3.32 micromol/L, p < or = .001). Multivariate analysis after the adjustment for age, gender and cardiovascular risk factors has identified homocysteine over 15 micromol/L as significant and independent cardiovascular risk factors (odds ratio 2.05; 95% CI 1.56-2.54). The correspondent Receiver Operator Curve shape suggested a good reliability in diagnosis of coronary artery disease for homocysteine (under curve area = 0.671, p < or = 001). CONCLUSION: Our results showed a positive correlation between plasma homocysteine levels and severity of coronary lesions (r = 0.765, p < .005). We suggest the use of homocysteine in clinical practice as marker of cardiovascular risk assessment.

Nephrotic syndrome associated with immune thrombocytopenia revealing Kimura's disease in a non-Asian male.

We report the case of a young Caucasian man presenting with diffuse oedema and nephrotic syndrome. Clinical examination revealed multiple lymphadenopathies. Histological examination was consistent with the diagnosis of Kimura's disease. A renal biopsy showed focal segmental glomerulosclerosis. Immune thrombocytopenia and signs of humoral autoimmunity were discovered. Corticosteroid treatment induced remission of nephrotic syndrome but relapses occurred 12 and 18 months after onset of treatment while the patient was receiving 20 mg prednisone once a day. To our knowledge, this is the first case of Kimura's disease and nephrotic syndrome associated with B-cell autoreactivity.

Lipoprotein (a) and lipid and non-lipid risk factors in coronaries risk assessment.

PURPOSE: Several studies showed that elevated plasma levels of lipoprotein(a) [Lp(a)] represent a predictor for cardiovascular risk. Based on already existing literature data, we aim to study the relationship between Lp(a), lipids and other cardiovascular risk factors in individuals with or without coronary heart disease. METHODS: We performed a cross-sectional transversal study on 208 patients (100 men and 108 women) aged between 37-75, with or without old myocardial infarction. In all the patients were evaluated the cardiovascular risk factors, the plasma level of the lipid fractions and Lp(a). The relationship between Lp(a) and the lipid and non-lipid risk factors were evaluated by the logistic regression method. RESULTS: The myocardial infarction group had higher values of plasma levels of Lp(a) (0.37 +/- 0.28 vs. 0.29 +/- 0.23 g/L, p < 0.05), and LDL-C (125.66 +/- 41.21 vs. 113.44 +/- 46.64 mg/dL, p < 0.05), than the group without coronary heart disease, as well as higher values of plasmatic TC/HDL-C ratio (4.31 +/- 1.55 vs. 4.08 +/- 1.29, p < 0.05), with significantly decreased plasmatic levels of HDL-C (45.88 +/- 12.04 vs. 53.22 +/- 23.12 mg/dL, p < 0.05). The association between the high Lp(a) plasma levels and the severity of coronary vessels number involved was significant. Multivariate analysis performed with adjustments for cardiovascular risk factors showed that the Lp(a), LDL-C and CT/HDL-C ratio levels are significant and independent predictive markers of coronary heart disease. CONCLUSION: The results show that the high Lp(a) plasma levels represent an independent cardiovascular risk factor, with superior risk prediction than the conventional lipid fractions. Our results confirm the Lp(a) as a marker for cardiovascular risk assessment in clinical practice.

A new prediction score for myocardial infarction: MINF SCORE.

UNLABELLED: The present report aims to generate a simple and efficient non-invasive prediction system of myocardial infarction as well as evaluating of the new generated score. METHODS: 208 patients (both men and women) aged 37-75 admitted at Centre Hospitalier Coulommiers, France, were included in the study. Patients were divided into two groups, according to presence (104 patients, 63.7 +/- 9.2 years) and absence of myocardial infarction (104 patients, 58.1 +/- 12.4 years). RESULTS: Based on univariate and multivariate analyses the following parameters were selected to form the prediction model: age, lipoprotein (a), C-reactive protein, systolic blood pressure, non-HDL-Cholesterol. A new score was obtained and it was validated by the area under the ROC curve of 0.745 +/- 0.034 (95% CI = 0.681-0.804), p < 0.0001. For the newly generated score, at the cut-off point (> -0.3), we obtained the following accuracy parameters: sensibility=80%, specificity=62.5%, positive predictive values=65%, negative predictive values =78%. The mentioned parameters were superior to values of each component of the score individually analyzed. CONCLUSIONS: The newly generated system can become a useful tool in coronary risk evaluation, with direct application in clinical practice.

Risk factors for heart failure in patients with one prior myocardial infarction episode.

BACKGROUND AND AIM: Myocardial infarction is an important risk factor for HF, increasing risk 2- to 3-fold. Other identified classical risk factors for HF include left ventricular hypertrophy, valvular heart disease, hypertension, diabetes mellitus, cigarette smoking, obesity, and dyslipidaemia. New mechanisms, such as insulin resistance, inflammation, and oxidative stress, have been investigated, but the importance of many of these mechanisms is largely unexplored in patients of HF. Our aim was to evaluate the factors involved in heart failure installation in patients with prior myocardial infarction. METHODS: We performed a cross-sectional study including 144 patients presenting old, certified myocardial infarction. Patients were divided into two groups according to presence/absence of heart failure, as certified by New York Heart Association (NYHA) classification of heart and of echocardiography criteria by left ventricular ejection fraction < 40%. Univariate and multivariate models were performed to identify the independent predictors of heart failure. Also, receiver operating characteristic analysis doubled by chi square test for trend was performed to analyze the risk impact of each identified predictor. RESULTS: Univariate between groups comparison was significant for hypertension (p = 0.001), diabetes mellitus (p < 0.001), smoking status (p < 0.001), obesity (p = 0.027), waist circumference (p < 0.001), and levels of C-reactive protein (p < 0.001), total cholesterol (p = 0.008), triglycerides (p = 0.003), HDL-Cholesterol (p < 0.001), glycaemia (p < 0.001) and brain natriuretic peptide (p < 0.001). Multivariate analysis selected C-reactive protein (OR = 2.7, 95% CI = 1.9-4.9, p < 0.001), glycaemia (OR = 2.1, 95% CI = 1.2-4.5, p = 0.027) and HDL-Cholesterol (OR = 0.7, 95% CI = 0.3-0.9, p = 0.035) as independent predictors. Separate across quintile test for trend revealed that the highest risk is added by levels of C-reactive protein levels > = 24mg/dL, followed by glycaemia levels > = 114 mg/dL and HDL-Cholesterol < 32 mg/dL. CONCLUSIONS: Reducing of C-reactive protein and glycaemia levels, as well as increasing the level of HDL-Cholesterol may add a great benefit in reducing heart failure installation risk in patients with myocardial infarction.

Mixed myelodysplastic syndrome and myeloproliferative disorder with bone marrow and pulmonary fibrosis: the role of megakaryocytes.

The case of an 80-year-old woman displaying myelodysplastic syndrome evolving into a myeloproliferative disorder with myelofibrosis and pulmonary fibrosis, is reported. This case is characterized by an initial presentation of a myelodysplastic syndrome with normal karyotype and moderate fibrosis, its evolution towards a myeloproliferative disorder with myelofibrosis and the worsening of pulmonary fibrosis in parallel to the acceleration of the myeloproliferative disorder and myelofibrosis. These features and the high concentration of plasma platelet factor-4 suggest a role of megakaryocyte/platelet degranulation in the development of fibrosis.