Myocardial infarction in patients aged 70 years and over

109 subjects aged 70 years (58 women, 51 men; average age 77 years) were hospitalized in the CICU (Cardiology Intensive Care Unit) over the period stretching from 1984 to 1986. The average length of stay in the CICU was 1 week, completed by an average stay of 5 days in the cardiology department. 100 per cent of the patients were followed up. Of the clinical parameters made evident by this study, the authors note that hypertension was the predominant risk factor (52.2 per cent); a history of coronary disease was noted in 60.5 per cent; 26.6 per cent of the patients were hospitalized before the 6th hour, chest pain being typical in 78 per cent versus painless in 11 per cent of patients; topographically, the infarction was anterior in 55 per cent, posterior in 40.4 per cent, and around the circumference in 4.6 per cent of cases; 80.8 per cent of the infarctions were transmural versus 19.2 per cent of infarctions without the Q wave--the latter accounted for a higher hospital mortality rate (38 per cent versus 27.3 per cent). The main complications were disturbances in rhythm (60.6 per cent) and LVI (56.9 per cent). Complications on the form of infections were noted in 15.6 per cent. Apart from the usual indicators of severity (cardiogenic shock, VF, LVI), infarction of the RV and AF had a serious effect on the prognosis. latrogenic disease accounted for 18.9 per cent. From the point of view of prognosis, hospital mortality was 30 per cent; mortality after one year was 44 per cent and 47.7 per cent after 2 years (in a group of 76 subjects).(ABSTRACT TRUNCATED AT 250 WORDS)     

N-terminal pro-brain natriuretic peptide predicts myocardial ischemia and is related to postischemic left-ventricular dysfunction in patients with stable coronary artery disease.

BACKGROUND: The N-terminal-pro-B natriuretic peptide (Nt-pro-BNP) is of diagnostic and prognostic value in coronary artery disease (CAD). We assessed the relationship between Nt-pro-BNP and (1) the extent of ischemia on stress myocardial perfusion imaging (MPI), and (2) changes between the basal and postexercise ejection fraction (EF), in stable patients with a normal EF. METHODS AND RESULTS: One hundred and two patients with stable, documented CAD (EF, 62% +/- 8%) underwent an exercise-rest thallium-201 gated-MPI and serial Nt-pro-BNP assays. Myocardial perfusion imaging produced abnormal results in 57 patients (56%; group 1), and normal results in 45 patients (44%; group 2). Median baseline, immediate postexercise, and 3-hour postexercise Nt-pro-BNP values were higher in group 1 than in group 2: 182 vs 85, 201 vs 86, and 212 vs 99 pg/mL, respectively (P < .001 for all). Postexercise EF decreased in group 1 (53% +/- 11% vs 62% +/- 10%, P < .001), but not in group 2 (61% +/- 9% vs 62% +/- 7%, NS). The Nt-pro-BNP ruled out significant ischemia with a negative predictive value of 0.90, whereas patients within the higher tertile of Nt-pro-BNP had a fivefold higher risk of ischemia compared with patients within the lower tertile. CONCLUSIONS: The post-stress increase in Nt-pro-BNP is related to myocardial ischemia and to postischemic left-ventricular dysfunction, and accurately predicts the presence or absence of myocardial perfusion defects.     

<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.

     

Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause

Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss‐of‐function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype–phenotype correlations. Most mutation‐negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.     

Split hand/foot malformation with long‐bone deficiency and BHLHA9 duplication: report of 13 new families

Split hand/foot malformation (SHFM) with long‐bone deficiency (SHFLD, MIM#119100) is a rare condition characterized by SHFM associated with long‐bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, the minimal critical region had been reduced, suggesting that BHLHA9 copy number gains are associated with this limb defect. Here, we report on 13 new families presenting with ectrodactyly and harboring a BHLHA9 duplication.     

Microcephaly with or without chorioretinopathy,lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM No.152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in 16 families worldwide. This is a review of the condition based on the clinical features of 37 individuals from 22 families. This report includes nine previously unreported families and additional information for some of those reported previously. The condition arose de novo in 8/20 families (40%). The parental results were not available for two probands. The mutations were varied and include missense, nonsense, frameshift, and splice site and are distributed evenly throughout the KIF11 gene. In our cohort, 86% had microcephaly, 78% had an ocular abnormality consistent with the diagnosis, 46% had lymphoedema, 73% had mild-moderate learning difficulties, 8% had epilepsy, and 8% had a cardiac anomaly. We identified three individuals with KIF11 mutations but no clinical features of MCLMR demonstrating reduced penetrance. The variable expression of the phenotype and the presence of mildly affected individuals indicates that the prevalence may be higher than expected, and we would therefore recommend a low threshold for genetic testing.     

Delineation of EFTUD2 Haploinsufficiency‐Related Phenotypes Through a Series of 36 Patients

Mandibulofacial dysostosis, Guion‐Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss‐of‐function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.     

Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole‐exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca²⁺ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca²⁺ levels and store‐operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single‐gene defect, which is consistent with Mendelian‐dominant inheritance.