Should genetic analysis in newborn screening and a heterozygote test for hyperphenylalaninaemia be recommended? An Italian study

OBJECTIVE: To determine whether the introduction of genetic analysis for phenylalanine hydroxylase (PAH) deficiency into regional screening programmes can be supported by the benefit-cost ratio. METHOD: Tests for the genetic PAH locus were carried out in 151 patients with hyperphenylalaninaemia originally from all of the Italian regions. PAH mutations were identified by extraction of genomic DNA from leucocytes (whole blood in EDTA), PAH exon amplification was determined by polymerase chain reaction, restriction enzyme analysis was carried out for some recognised mutations, and DNA sequence analysis for the other mutations. RESULTS: It was found that the eight most common mutations in the population accounted for 49% of the mutant alleles, which is well below the required standard for effective population screening (90%). CONCLUSIONS: Genetic screening for PAH deficiency in Italy does not increase the sensitivity of the methodology and the benefit-cost ratio, and thus provides no advantage, particularly as the correlation between genotype and the metabolic phenotype needed to optimise dietary intervention is still being studied

Is supercomplex organization of the respiratory chain required for optimal electron transfer activity?

AbstractThe supra-molecular assembly of the main respiratory chain enzymatic complexes in the form of “supercomplexes” has been proved by structural and functional experimental evidence. This evidence strongly contrasts the previously accepted Random Diffusion Model stating that the complexes are functionally connected by lateral diffusion of small redox molecules (i.e. Coenzyme Q and cytochrome c).This review critically examines the available evidence and provides an analysis of the functional consequences of the intermolecular association of the respiratory complexes pointing out the role of Coenzyme Q and of cytochrome c as channeled or as freely diffusing intermediates in the electron transfer activity of their partner enzymes

Genetic control of chemokines in severe human internal carotid artery stenosis

Background and purpose: Atherosclerosis is an inflammatory disease. Chemokines and chemokine receptors are known to be involved in atherogenesis. Common single nucleotide polymorphisms (SNPs) affect transcription in response to inflammatory stimuli. The aim of this study was to evaluate the correlations between MCP-1, RANTES, SDF-1, CCR2, and CCR5 gene polymorphisms with increased risk of internal carotid artery (ICA) stenosis. Methods: Hundred and twelve patients, consecutively recruited for ICA occlusive disease, and 282 controls were genotyped for MCP-1-2518G, RANTES-403A, CCR5D32, CCR2 V64I, and SDF-1-801A polymorphisms. Results: The frequency of the SDF-1A allele was significantly different between cases and controls: 0.32 vs. 0.20, respectively (OR 1.81; 95% CI 1.25\u20132.60; p = 0.007). The frequency of the RANTES-403G allele was significantly higher in patients with stenosis >70% (OR, 2.45; 95% CI 1.12\u20135.71; p = 0.015). No significant differences were observed with the other polymorphisms. Conclusion: The reported results seem to correlate the polymorphisms of the genes encoding for SDF-1, RANTES with pathogenesis and progression of ICA occlusive disease. Although suggestive, these results need confirmation in prospective cross-sectional studies

Stromelysin-1 polymorphism as a new potential risk factor in progression of chronic obstructive pulmonary disease

Background. Chronic obstructive lung disease (COPD) is characterised by partially reversible usually progressive airflow limitation caused by inflammation and remodelling. Stromelysin-1 (MMP-3) has regulatory activity on other matrix-metalloproteinases. Altered MMP-3 activity has been described in different diseases. We investigated the role of a promoter MMP-3 polymorphism in determining susceptibility and severity of COPD. Methods. We studied 147 patients with COPD in stable conditions and distinguished two groups based on FEV1 values. In 100 patients functional modifications across a two-year period were noted. 133 healthy subjects were used as controls. Genotyping for the –1171 5A/6A MMP-3 polymorphism was performed using nucleotide sequencing. Results. No difference was noted in the genotype distribution between COPD patients and controls. However, among patients with severe disease 6A/6A genotype and 6A allelic frequency were significantly more represented than among mild-moderate patients (p < 0.05). The 6A/6A genotype was also associated with a higher FEV1 decline over time. Conclusions. Our data suggests that –1171 6A allele does not represent a risk factor for the development of COPD while it is associated with more severe disease and different functional decline. We hypothesise that a disregulation of MMP-3, possibly caused by the –1171 5A/6A polymorphism or other linked variants, may lead to different progression in COPD

High-Sensitivity C-Reactive Protein and Acute Kidney Injury in Patients with Acute Myocardial Infarction: A Prospective Observational Study

Background. Accumulating evidence suggests that inflammation plays a key role in acute kidney injury (AKI) pathogenesis. We explored the relationship between high-sensitivity C-reactive protein (hs-CRP) and AKI in acute myocardial infarction (AMI). Methods. We prospectively included 2,063 AMI patients in whom hs-CRP was measured at admission. AKI incidence and a clinical composite of in-hospital death, cardiogenic shock, and acute pulmonary edema were the study endpoints. Results. Two-hundred-thirty-four (11%) patients developed AKI. hs-CRP levels were higher in AKI patients (45 \ub1 87 vs. 16 \ub1 41 mg/L; p < 0.0001). The incidence and severity of AKI, as well as the rate of the composite endpoint, increased in parallel with hs-CRP quartiles (p for trend <0.0001 for all comparisons). A significant correlation was found between hs-CRP and the maximal increase of serum creatinine (R = 0.23; p < 0.0001). The AUC of hs-CRP for AKI prediction was 0.69 (p < 0.001). At reclassification analysis, addition of hs-CRP allowed to properly reclassify 14% of patients when added to creatinine and 8% of patients when added to a clinical model. Conclusions. In AMI, admission hs-CRP is closely associated with AKI development and severity, and with in-hospital outcomes. Future research should focus on whether prophylactic renal strategies in patients with high hs-CRP might prevent AKI and improve outcome

Oral Nutritional Supplementation in Children Treated for Cancer in Low- and Middle-Income Countries Is Feasible and Effective: the Experience of the Children's Hospital Manuel De Jesus Rivera "La Mascota" in Nicaragua.

Children with cancer are particularly vulnerable to malnutrition, which can affect their tolerance of chemotherapy and outcome. In Nicaragua approximately two-thirds of children diagnosed with cancer present with under-nutrition. A nutritional program for children with cancer has been developed at "La Mascota" Hospital. Results of this oral nutritional intervention including difficulties, benefits, and relevance for children treated for cancer in low- and middle-income countries are here reported and discussed

Diagnostic accuracy of the primary care screener for affective disorder (PC-SAD) in primary care

Background: Depression goes often unrecognised and untreated in non-psychiatric medical settings. Screening has recently gained acceptance as a first step towards improving depression recognition and management. The Primary Care Screener for Affective Disorders (PC-SAD) is a self-administered questionnaire to screen for Major Depressive Disorder (MDD) and Dysthymic Disorder (Dys) which has a sophisticated scoring algorithm that confers several advantages. This study tested its performance against a ‘gold standard’ diagnostic interview in primary care. Methods: A total of 416 adults attending 13 urban general internal medicine primary care practices completed the PC-SAD. Of 409 who returned a valid PC-SAD, all those scoring positive (N=151) and a random sample (N=106) of those scoring negative were selected for a 3-month telephone follow-up assessment including the administration of the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) by a psychiatrist who was masked to PC-SAD results. Results: Most selected patients (N=212) took part in the follow-up assessment. After adjustment for partial verification bias the sensitivity, specificity, positive and negative predictive value for MDD were 90%, 83%, 51%, and 98%. For Dys, the corresponding figures were 78%, 79%, 8%, and 88%. Conclusions: While some study limitations suggest caution in interpreting our results, this study corroborated the diagnostic validity of the PC-SAD, although the low PPV may limit its usefulness with regard to Dys. Given its good psychometric properties and the short average administration time, the PC-SAD might be the screening instrument of choice in settings where the technology for computer automated scoring is available