Active Case Finding Among Homeless People as a Means of Reducing the Incidence of Pulmonary Tuberculosis in General Population.

The incidence of tuberculosis (TB) declined more than two-fold, compared with the national average, in the northeastern region of Poland in the period of 2003-2012. During that time, four programs of active case finding of TB were conducted as part of which a total of 944 homeless individuals were examined and 21 cases of active TB were detected. The objective of the present study was to find out whether the observed beneficial epidemiological trend could be a result of those programs. We addressed the issue of how the active case finding programs in the homeless community affected the TB incidence in the general population using a modified crisscross SIS-type (Susceptible - Infected - Susceptible) model which describes the dynamics of TB spread between the homeless and non-homeless populations. The values calculated from our model proved highly congruent with the actual epidemiological data. Our analysis showed a significant decline in TB incidence within 1 year of completion of each active case finding program. The model shows that each identified and cured case in the homeless community reduced the number of new cases in the general population by 3-4 within 1 year and by up to 20 within 5 years.

Clinical presentation of early-onset Alzheimer's disease as a result of mutation in exon 12 of the PSEN-1 gene.

INTRODUCTION: Mutations in the gene for presenilin 1 (PSEN-1) cause familial, early-onset Alzheimer's disease (EOAD). Diagnosis of EOAD is often a challenge because of the high frequency of atypical presentations. Clinical manifestation of EOAD may vary depending on underlying mutation; specific genetic mutations influence development of specific clinical phenotypes; however, intrafamilial phenotypic heterogeneity has also been noted in some pedigrees. CASE PRESENTATION: We report a case of a 36-year-old woman presenting with progressive behavioral disturbances, dementia, involuntary movements, pyramidal signs, epilepsy, and a family history of early-onset dementia accompanied by involuntary movements. On genetic testing, the mutation at codon 424 (Leu→Arg) in PSEN-1 gene was identified. CONCLUSION: Our case describes a new phenotype of a known mutation of PSEN-1 at codon 424.

The adipose tissue gene expression in mice with different nitric oxide availability.

Mice with the knockout of endothelial nitric oxide synthase (eNOS ko) demonstrate symptoms resembling the human metabolic syndrome. NO has been recently demonstrated to be deeply involved in regulation of not only blood flow and angiogenesis, but also in modulation of mammalian basal energy substrate metabolism. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NOS. The enzyme dimethylarginine dimethylaminohydrolase (DDAH) catabolizes ADMA, what leads to increase of endogenous NO bioavailability. This study was aimed to compare the brown (BAT) and white (WAT) adipose tissue gene expression of age matched mice with decreased (eNOS ko) and increased (overexpressing DDAH) endogenous NO generation. The 19 week old eNOS ko mice demonstrated significantly lower weight, higher circulating glucose, insulin, leptin and cholesterol concentrations. The adiponectin as well as fasting triglyceride concentrations were not significantly altered. Animals with DDAH knock in, presented significantly increased angiogenic activity than eNOS ko mice. The microarray analysis pointed to activation of adipogenesis-related genes in eNOS ko mice in WAT, what was in contrast with the inhibition observed in the DDAH overexpressing mice. The angiogenesis related gene expression was down-regulated in both models in comparison to WT animals. This study support the multipotential role of endogenous NO in maintaining homeostasis of energy substrate catabolism.

The selected pathophysiological aspects of PPARs activation.

Peroxisome proliferator activated receptors (PPARs) belong to a subfamily of transcription nuclear factors. Three isoforms of PPARs have been identified: alpha, beta/delta and gamma, encoded by different genes and distributed in various tissues. They play important roles in metabolic processes like regulation of glucose and lipid redistribution. They also have anti-atherogenic, anti-inflammatory as well as anti-hypertensive functions. In hypertension-induced cardiac hypertrophy, both PPARa and PPARg activation reveal cardio-protective effect. Despite these beneficial functions, several recent experimental reports point to the possibille unfavorable effects of PPARs activation in lipid metabolism (lipotoxicity) in cardiomyocytes, which can lead to pathologic cardiac hypertrophy in such diseases as diabetes type 2, metabolic syndrome or obesity. This paper reviews evidences and hypotheses about the new pathophysiological aspects of PPARs activation.

Proangiogenic activity of beta-carotene is coupled with the activation of endothelial cell chemotaxis.

Endothelial cells play an important role in angiogenesis (formation of new vessels from preexisting ones), which is essential for organogenesis, tissue remodeling but also inflammatory response, carcinogenesis in all periods of our life. Beta-carotene (BC) in non-toxic concentrations (up to 3 microM) had no detectable effect on HUVECs (human umbilical vein endothelial cells) proliferation or apoptosis, despite significant changes of the expression patterns of pro- and anti-apoptotic genes. However beta-carotene did not change the tubulogenic activity of HUVEC in the in vitro angiogenesis model, it potently accelerated the bFGF-induced development of microcapillaries, as well as the migration of endothelial cells, in matrigel plug injected subcutaneously to mice. Potent activation of endothelial cell migration in the in vitro model of chemotaxis was also observed. According to the microarray data, genes involved in cell/cell and cell/matrix adhesion, matrix reorganization, activation of chemotaxis, the G-protein regulated intracellular signaling as well as genes involved in the rapid remodeling of protein cytoskeleton were the most affected by BC in HUVEC. We conclude that beta-carotene in the physiological concentration range stimulates early steps of angiogenesis by the activation of cellular migration as well as matrix reorganization and decrease of cell adhesion.

Homogeneous assay based on 52 primer sets to scan for mutations of the ABCA1 gene and its application in genetic analysis of a new patient with familial high-density lipoprotein deficiency syndrome.

Familial high-density lipoprotein (HDL)-deficiency syndromes are caused by mutations of the ABCA1 gene, coding for the ATP-binding cassette transporter 1. We have developed a homogeneous assay based on 52 primer sets to amplify all 50 ABCA1 exons and approximately 1 kb of its promoter. The assay allows for convenient amplification of the gene from genomic DNA and easy mutational analysis through automatic sequencing. It obviates the need to use mRNA preparations, which were difficult to handle and posed a risk to miss splice junction or promoter mutations. The application of the test to the molecular analysis of a new patient with familial HDL-deficiency (Tangier disease) led to a discovery of two novel ABCA1 mutations: C2665del and C4457T.

Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease.

HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (< or =40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P<0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.

Two novel mutant alleles of the gene encoding neurotrophic tyrosine kinase receptor type 1 (NTRK1) in a patient with congenital insensitivity to pain with anhidrosis: a splice junction mutation in intron 5 and cluster of four mutations in exon 15.

Congenital insensitivity to pain with anhidrosis (CIPA), also called hereditary sensory and autonomic neuropathy type IV (HSAN IV), is caused by mutations of the NTRK1 gene coding for the neurotrophic tyrosine kinase receptor type 1. We report the results of the NTRK1 sequence analysis in a CIPA family from Poland. We found that the patient was in a state of compound heterozygosity. He had one mutant allele with a novel G>A substitution in the conserved splice junction donor site affecting the first base pair of intron 5 (IVS5+1G>A). In the other allele he had a cluster of four single nucleotide substitutions in exon 15: an 1876C>T change (relative to the transcription start site) and three G>T changes (1904G>T, 1909G>T and 1915G>T). All of these mutations change the sense of the codons: H598Y, G607V, E609X and V611L, respectively. Mutations E609X and V611L are novel and unique to the patient family and at least one of them, which creates a premature stop codon in position 609, should have a deleterious effect on the gene function. The other two substitutions H598Y and G607V are most likely rare polymorphisms, which are in linkage disequilibrium. They occur together with an estimated allele frequency of about 6%. Our report increases the spectrum of NTRK1 mutations in CIPA patients and describes an unusual case of a cluster of four mutations located close to each other in one exon.

The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.

Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized by absence of plasma high-density lipoprotein (HDL) and deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes. Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors. In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts, which have a reduced in vitro growth rate. The TD locus has been mapped to chromosome 9q31. Here we present evidence that TD is caused by mutations in ABC1, encoding a member of the ATP-binding cassette (ABC) transporter family, located on chromosome 9q22-31. We have analysed five kindreds with TD and identified seven different mutations, including three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the understanding of cellular HDL metabolism and reverse cholesterol transport, and its association with premature cardiovascular disease.

ATP-binding cassette transporter A1 (ABCA1) in macrophages: a dual function in inflammation and lipid metabolism?

Activated lipid-laden macrophages in the vascular wall are key modulators of the inflammatory processes underlying atherosclerosis. We demonstrate here that the ATP-binding cassette (ABC) transporter ABCA1 is induced during differentiation of human monocytes into macrophages. ABCA1 has been implicated in macrophage interleukin-1beta secretion and apoptosis. Moreover, ABCA1 mRNA and protein levels are strongly upregulated by uptake of modified LDL and downregulated by HDL(3)-mediated lipid efflux in macrophages. Mutation analysis in patients with the classical Tangier disease (TD), a monogenetic disorder characterized by hypersplenism, macrophage accumulation and deposition of cholesteryl esters in the reticuloendothelial system, low plasma HDL and premature atherosclerosis, revealed deleterious mutations in their ABCA1 gene. The localization pattern of the mutations within the ABCA1 protein appears to determine the tropism for either the reticuloendothelial system, as seen in the classical TD phenotype, or the artery wall, as in the case of HDL deficiency in the absence of splenomegaly. In a comprehensive analysis of the expression and regulation of all currently known human ABC transporters, we identified additional cholesterol-responsive genes that are induced during monocyte differentiation into macrophages. Our results indicate a dual regulatory function for ABCA1 in macrophage lipid metabolism and inflammation.