This study presents the clinical findings on seven children from Malta (population 385,000). All of them had early motor delay and a significant degree of cognitive impairment. Diurnal variation of the motor impairments was clear in six out of seven of the subjects and oculogyric crises occurred from an early stage also in six out of the seven. Five out of seven had clear evidence of dystonia but the early picture was dominated by hypotonia in five. Two had early Parkinsonian tremor and chorea was seen in four, although in two this was attributable to the use of L-dopa. Three had early bulbar involvement. In all, although minor motor problems persisted, the response to L-dopa was dramatic and there was a need to balance improvement in dystonia against aggravation of chorea. The majority were not able to walk until they were treated. Increased doses of L-dopa were required in hot weather, to which they were sensitive. Despite a good response of improved motor ability and abolition of oculogyric crises, there was no obvious change in cognitive function with learning remaining in the moderate impairment range. This report widens the phenotype of dopa-responsive motor disorders and the range of young children with primary motor delay (cerebral palsy) who need a clinical trial of L-dopa. All of the subjects had the same novel mutation in the tetrahydrobiopterin pathway involving sepiapterin reductase, and no abnormality in the gene encoding guanosine triphosphate cyclohydrolase 1. Clinically and molecularly the condition shows autosomal recessive inheritance.

ObjectiveTo investigate the effect of passive smoking, active smoking and smoking cessation on inflammation, lipid profile and the risk of myocardial infarction (MI).MethodsA total of 423 cases with a first MI and 465 population controls from the Maltese Acute Myocardial Infarction (MAMI) Study were analysed. Data were collected through an interviewer-led questionnaire, and morning fasting blood samples were obtained. ORs adjusted for the conventional risk factors of MI (aORs) were calculated as an estimate of the relative risk of MI. The influence of smoking on biochemical parameters was determined among controls.ResultsCurrent smokers had a 2.7-fold (95% CI 1.7 to 4.2) and ex-smokers a 1.6-fold (95% CI 1.0 to 2.4) increased risk of MI. Risk increased with increasing pack-years and was accompanied by an increase in high-sensitivity C reactive protein levels and an abnormal lipid profile. Smoking cessation was associated with lower triglyceride levels. Exposure to passive smoking increased the risk of MI (aOR 3.2 (95% CI 1.7 to 6.3)), with the OR being higher for individuals exposed to passive smoking in a home rather than in a public setting (aOR 2.0 (95% CI 0.7 to 5.6) vs aOR 1.2 (95% CI 0.7 to 2.0)). Passive smoke exposure was associated with higher levels of total cholesterol, triglycerides and total cholesterol:high-density lipoprotein cholesterol ratio compared with individuals not exposed to passive smoking.ConclusionsBoth active and passive smoking are strong risk factors for MI. This risk increased with increasing pack-years and decreased with smoking cessation. Such effects may be partly mediated through the influence of smoking on inflammation and lipid metabolism.

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BackgroundIt is widely accepted that atherosclerosis and inflammation are intimately linked. Monocytes play a key role in both of these processes and we hypothesized that activation of inflammatory pathways in monocytes would lead to, among others, proatherogenic changes in the monocyte transcriptome. Such differentially expressed genes in circulating monocytes would be strong candidates for further investigation in disease association studies.MethodsEndotoxin, lipopolysaccharide (LPS), or saline control was infused in healthy volunteers. Monocyte RNA was isolated, processed and hybridized to Hver 2.1.1 spotted cDNA microarrays. Differential expression of key genes was confirmed by RT-PCR and results were compared to in vitro data obtained by our group to identify candidate genes.ResultsAll subjects who received LPS experienced the anticipated clinical response indicating successful stimulation. One hour after LPS infusion, 11 genes were identified as being differentially expressed; 1 down regulated and 10 up regulated. Four hours after LPS infusion, 28 genes were identified as being differentially expressed; 3 being down regulated and 25 up regulated. No genes were significantly differentially expressed following saline infusion. Comparison with results obtained in in vitro experiments lead to the identification of 6 strong candidate genes (BATF, BID, C3aR1, IL1RN, SEC61B and SLC43A3)ConclusionIn vivo endotoxin exposure of healthy individuals resulted in the identification of several candidate genes through which systemic inflammation links to atherosclerosis.

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The Ehlers-Danlos syndromes (EDS) are a collection of rare hereditary connective tissue disorders with heterogeneous phenotypes, usually diagnosed following clinical examination and confirmatory genetic testing. Diagnosis of the commonest subtype, hypermobile Ehlers-Danlos Syndrome (hEDS), relies solely on a clinical diagnosis

Despite significant advances in the diagnosis and treatment of cardiovascular diseases, recent calls have emphasized the unmet need to improve precision-based approaches in cardiovascular disease. Although some studies provide preliminary evidence of the diagnostic and prognostic potential of circulating coding and non-coding RNAs, the complex RNA biology and lack of standardization have hampered the translation of these markers into clinical practice. In this position paper of the CardioRNA COST action CA17129, we provide recommendations to standardize the RNA development process in order to catalyze efforts to investigate novel RNAs for clinical use. We list the unmet clinical needs in cardiovascular disease, such as the identification of high-risk patients with ischemic heart disease or heart failure who require more intensive therapies. The advantages and pitfalls of the different sample types, including RNAs from plasma, extracellular vesicles and whole blood, are discussed in the sample matrix, together with their respective analytical methods. The effect of patient demographics and highly prevalent comorbidities, such as metabolic disorders, on the expression of the candidate RNA is presented and should be reported in biomarker studies. We discuss the statistical and regulatory aspects to translate a candidate RNA from a research-use only assay to an in-vitro diagnostic test for clinical use. Optimal planning of this development track is required, with input from the researcher, statistician, industry and regulatory partners.

Historical studies, using Northern blot hybridization, RT-PCR and cDNA library construction have demonstrated the presence of a variety of mRNA molecules in platelets. The development of microarray technology has allowed further characterization of the transcripts represented in the platelet transcriptome. In this review, these studies will be summarized and their findings in relation to the study of platelet function and the identification of disease risk genes discussed.