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PubMed2005

Risk factors associated with development of ventilator associated pneumonia.

OBJECTIVE: To assess the risk factors associated with development of ventilator associated pneumonia (VAP). DESIGN: A case control study. PLACE AND DURATION OF STUDY: Intensive Care Unit (ICU) at the Aga Khan University Hospital, Karachi, between January 1999 and June 2000. PATIENTS AND METHODS: All patients with assisted mechanical ventilation were assessed for the development of VAP. Risk factors associated with development of VAP were determined. Adult patients who developed pneumonia, 48 hours after ventilation, were called cases while those who did not develop pneumonia were called controls. RESULTS: Seventy (28%) out of 250 mechanically ventilated patients developed VAP (rate of VAP was 26 cases per 1000 ventilator days). Shock during first 48 hours of ventilation (odds ratio (OR), 5.95; 95% confidence interval (CI), 2.83-12.52), transport out of ICU during mechanical ventilation (OR, 6.0; 95% CI, 2.92-12.37), re-intubation (OR, 4.23; 95% CI, 2.53-9.85), prior episode of aspiration of gastric content (OR, 3.07; 95% CI, 1.35-7.01), and use of antibiotics prior to intubation (OR,2.55; 95% CI, 1.20-5.41) were found to be independently associated with a higher risk of developing VAP. Gram negative organisms and Staphylococcus aureus were responsible for over 90% of cases. Patients with VAP had higher crude mortality rate (57.1%) compared with controls (32.2%). CONCLUSION: Ventilator associated pneumonia is associated with a high mortality. This study has identified risk factors associated with VAP.

Adult↗
PubMed2005

Family-based association study of serotonin transporter gene polymorphisms in attention deficit hyperactivity disorder: no evidence for association in UK and Taiwanese samples.

Five independent studies have reported associations between serotonin transporter gene (5-HTT) polymorphisms and attention deficit hyperactivity disorder (ADHD). Four studies found evidence for association between the long-allele of a 44-base pair insertion/deletion polymorphism (5-HTTLPR), one of the studies found association to a variable number tandem repeat within intron 2, another to the T-allele of a single base pair substitution in the 3'-untranslated regions and another reported preferential transmission of a haplotype of the three markers (long-allele/10-repeat-allele/T-allele). One further study found no evidence for these associations. We investigated the association of these three markers in two samples of ADHD patients from the United Kingdom (n = 197) and Taiwan (n = 212), using within-family tests of association. No association was found between any of the three markers in either of the two populations. Although we found some evidence for the preferential transmission of a rare haplotype (long-allele/9-repeat-allele/T-allele; chi2 = 4.5, P = 0.034), we concluded that this most likely occurred by chance factors alone.

Adolescent↗
PubMed2006

Association between a variation in LRCH1 and knee osteoarthritis: a genome-wide single-nucleotide polymorphism association study using DNA pooling.

OBJECTIVE: To perform a large-scale association analysis of single-nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee. METHODS: We examined >25,000 SNPs located within approximately 14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case-control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression. RESULTS: The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as-yet-unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case-control groups. Additional subanalyses in case-control samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine-mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up-regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role. CONCLUSION: A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.

Aged↗
PubMed1994

Symptom severity of beet western yellows virus strain ST9 is conferred by the ST9-associated RNA and is not associated with virus release from the phloem.

The ST9 strain of beet western yellows virus (BWYV ST9) is unique among BWYV strains because it encapsidates not only its 5.6-kb genomic RNA but also a 2.8-kb RNA of distinct nucleotide sequence, designated as the ST9-associated RNA. We obtained isolates of BWYV ST9 that are free of the associated RNA by transfecting Nicotiana tabacum protoplasts with transcripts of an ST9 genomic cDNA clone. Aphids were fed on extracts of infected protoplasts and were transferred to young Shepherd's Purse (Capsella bursa-pastoris) plants. When the protoplast inoculum was ST9 genomic transcript or virion RNA of the L-1 strain of BWYV (free of the associated RNA), symptoms were mild and characteristic of BWYV L-1. When ST9-associated RNA was included in the inoculum with genomic RNA of either source, subsequently infected Shepherd's Purse plants showed the severe symptoms that are characteristic of BWYV ST9. Inclusion of ST9-associated RNA in the inoculum with ST9 genomic RNA increased the accumulation of capsid antigen and ST9 genomic RNA, relative to infections initiated with ST9 genomic RNA alone. Using gold-labeled antibody and electron microscopy, we assessed the distribution of virions in Shepherd's Purse plants. Regardless of whether the associated RNA was present, sites showing immunoreactivity above background levels were restricted to the phloem, suggesting that the increased BWYV ST9 titer and symptom severity that are correlated with the presence of the ST9-associated RNA are not due to escape of the infection from phloem limitation.

Animals↗
PubMed2003

Effects of dizocilpine [(+)-MK-801] on the expression of associative and non-associative sensitization to D-amphetamine.

Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225-250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine. (+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.

Animals↗
PubMed2005

CETP polymorphisms associated with HDL cholesterol may differ from those associated with cardiovascular disease.

To better understand the role of cholesteryl ester transfer protein (CETP) in cardiovascular disease, nine polymorphisms spanning the gene from the upstream promoter region to beyond the 3'UTR were genotyped in 2553 individuals from multiple ethnic groups and with different cardiovascular disease profiles. The frequency of four of these SNPs varied by 40-300% between Caucasians and African Americans. SNPs in each ethnic group fell into two haploblocks with significant linkage disequilibrium within each block. SNPs in the 5' haploblock were significantly associated with HDL cholesterol while SNPs in the 3' haploblock were, at best, only weakly associated with HDL-C. One SNP in the 3' haploblock (rs1800774 in intron 12) was highly associated with history of myocardial infarction even though it was not associated with HDL-C. This association was driven by the effect in Caucasian women where 11.9% of the women with no history of MI are homozygous for the less common allele while 23.7% of those with a history of MI share this genotype. In addition, this SNP was highly associated with BMI among Caucasians (p < 0.0001). The association of HDL-C with CETP genotype was found to be independent of smoking or alcohol consumption. These results replicate some earlier findings and also help to explain some of the apparent contradictions in the literature surrounding the role of CETP in modulating HDL-C and cardiovascular disease.

Black or African American↗
PubMed2006

A single nucleotide polymorphism at DBH, possibly associated with attention-deficit/hyperactivity disorder, associates with lower plasma dopamine beta-hydroxylase activity and is in linkage disequilibrium with two putative functional single nucleotide polymorphisms.

BACKGROUND: The DBH gene regulates plasma dopamine beta-hydroxylase activity (pDbetaH). Two single nucleotide polymorphisms (SNPs), -1021C-->T (rs1611115; SNP1) and +1603C-->T (rs6271; SNP3), independently influence pDbetaH. Another SNP, commonly known as DBH Taq1A (rs2519152; SNP2) is associated with attention-deficit/hyperactivity disorder (ADHD) in some (but not all) studies. We tested whether 1) SNP2 associates with pDbetaH; and 2) whether linkage disequilibrium (LD) between SNP2 and the other SNPs explains that association. METHODS: Plasma dopamine beta-hydroxylase activity and genotypes at the SNPs were determined in Caucasian subjects (n = 418). Associations to pDbetaH were examined using analyses of variance (ANOVAs) and LD among the SNPs using estimation maximization. RESULTS: 1) Each polymorphism analyzed alone associated with pDbetaH; 2) SNP2 was in strong LD with SNP1 and SNP3, respectively, but there was no significant LD between SNP1 and SNP3; and 3) analyzed jointly, each SNP contributed significantly and uniquely to plasma DbetaH activity. CONCLUSIONS: 1) SNP2 associates with pDbetaH; 2) SNP2 shows LD with SNP1 and SNP3; 3) most of the association between SNP2 and pDbetaH simply reflects that LD; however, 4) SNP2 also appears to exert a small independent effect on pDbetaH, suggesting that SNP2, or another variant in LD with it, uniquely influences pDbetaH.

Adult↗
PubMed2006

Association of the trace amine associated receptor 6 (TAAR6) gene with schizophrenia and bipolar disorder in a Korean case control sample.

Trace amines and their receptors may be implicated in the pathogenesis of psychiatric disorders. Previous studies have reported association of the trace amine associated receptor 6 (TAAR6) gene with susceptibility to schizophrenia and bipolar disorder but results have not been consistent. The purpose of this study was to examine these associations in Korean patients and also to test for association of TAAR6 with susceptibility to major depressive disorder (MDD). A case control sample consisting of 281 patients with schizophrenia, 190 patients with bipolar disorder, 187 patients with MDD and 288 psychiatrically healthy control subjects, was examined. Patients with schizoaffective disorder were not included in any of the psychiatric samples. Five single nucleotide polymorphisms (SNPs: rs4305745; rs8192625; rs7452939; rs6903874 and rs6937506) were genotyped in the TAAR6 gene and in the 3' regulatory region, using pyrosequencing. SNP rs6903874 was significantly associated with schizophrenia (p = 0.012) and bipolar disorder (p = 0.004). A three SNP haplotype consisting of alleles GCT from SNPs rs7452939, rs6903874 and rs6937506, respectively, was significantly over-represented in patients with schizophrenia (p = 0.0003) and bipolar disorder (p = 0.00002). A second three SNP haplotype (GTT) derived from the same SNPs was significantly under-represented in patients with bipolar disorder (p = 0.001). The GTT haplotype associations withstand the most rigorous corrections for multiple testing. These findings strongly support association of the TAAR6 gene with susceptibility to both schizophrenia and bipolar disorder in Korean patients. Further studies are needed to confirm these findings in this and other populations and to identify functional variants in TAAR6 that may be implicated in pathogenesis.

Adult↗
PubMed2006

Polymorphisms within the tumor necrosis factor-alpha promoter region in patients with HLA-B27-associated uveitis: association with susceptibility and clinical manifestations.

PURPOSE: The existence of genetic variations in a number of cytokines has been considered to influence susceptibility or relate to disease severity in various autoimmune diseases. Among these, single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor alpha (TNF-alpha) promoter at nucleotides -308 and -238 are considered to be protective against inflammation in HLA-B27-positive individuals, whereas the SNP at position -857 has been associated with disease development in anterior uveitis. We investigate a hypothesized association between the TNF-alpha -857 C-to-T, -308 G-to-A, and the TNF-alpha -238 G-to-A SNPs and the presence of HLA-B27-associated uveitis. DESIGN: Retrospective case-control study. PARTICIPANTS: One hundred fourteen Caucasian patients with HLA-B27-associated uveitis were studied. Mean age of patients was 44.9+/-14 years (range, 16-81), and mean duration of HLA-B27-associated uveitis was 115.6+/-104 months (range, 6 months-51 years). Eighty-six patients (75.4%) suffered from an additional systemic manifestation of the disease. Sixty-three unrelated healthy HLA-B27-positive blood donors and 88 unrelated healthy HLA-B27-negative individuals served as controls. METHODS: Genotypes were determined by polymerase chain reaction. MAIN OUTCOME PARAMETERS: Association of genotypes at positions -857, -308, and -238 of the TNF-alpha gene with disease development. RESULTS: Frequencies of the TNF-alpha -308GA and TNF-alpha -238GA genotypes were significantly lower in patients with HLA-B27-associated uveitis (6.1% and 0%, respectively) when compared with the HLA-B27-negative control group, 23% at -308 (P = 0.003), and 7.9% at -238 (P = 0.0003). When compared with healthy HLA-B27-positive controls, a significantly lower frequency of the TNF-alpha -238GA genotype was found among patients (6.3%, P = 0.015). The frequency of the TNF-alpha -308GA genotype was also found to be lower in patients than among HLA-B27-positive control subjects, without, however, reaching statistical significance (6.1%, P = 0.07). No difference in frequencies was seen among the different groups for the SNPs at position -857. CONCLUSION: Our data suggest that HLA-B27-positive individuals show a higher susceptibility towards development of an intraocular inflammation in the presence of an A allele at nucleotide -238 and, to a lesser degree, at nucleotide -308 of the TNF-alpha gene promoter.

Adolescent↗
PubMed1992

Optimal association-saturation procedure for estimating association and dissociation rate parameters in receptor studies. Application to solubilized A1 adenosine receptors.

A method of obtaining estimates of the maximum binding and association and dissociation rate constants for a receptor-ligand interaction is described. This new procedure, the association-saturation method, is based on an exact mathematical equation which defines the model without simplifications. The method proposed is readily applicable to any system consisting of one ligand and one receptor. With only four determinations, each involving one ligand concentration and an association time, it is possible to determine the number of specific binding sites, the dissociation and association rate constants and the equilibrium dissociation constant with accuracy. No dissociation curve is required, and only one point of the association curve for each ligand concentration is necessary. In addition to the higher confidence in the estimates of the parameter values obtained, this method leads to important savings in radiolabelled compounds and experimental time. The results were compared with those obtained with standard association-dissociation curves and saturation isotherms. The optimum number of replicates of each experimental point to obtain reliable estimates of different parameters is discussed on the basis of simulation studies. The performance of the procedure is analysed by means of association-saturation experiments with the agonist [adenine-2,8-3H,ethyl-2-3H]N6-phenylisopropyladenosine and solubilized A1 adenosine receptors from pig brain cortex.

Animals↗
PubMed1999

Association of FcepsilonR1-beta polymorphisms with asthma and associated traits in Australian asthmatic families.

BACKGROUND: Asthma is a genetically complex disease, and is characterized by elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts and increased airway responsiveness. Polymorphisms in the beta subunit of the high affinity receptor for IgE (FcepsilonR1-beta) have been previously associated with these phenotypes and with an increased risk of asthma. OBJECTIVE: To investigate the association of all known bi-allelic polymorphisms in FcepsilonR1-beta to asthma and quantitative traits associated with asthma in a selected sample of Australian asthmatic children and their nuclear families. METHODS: Australian Caucasian nuclear families (n = 134 subjects) were recruited on the basis of a child proband with current, severe, symptomatic asthma. The quantitative traits assessed included serum levels of total IgE and specific IgE to house dust mite and mixed grass, blood eosinophil counts and the dose-response slope of the forced expiratory volume in 1 s to histamine provocation. RESULTS: Neither the Leu181 nor the E237G mutations were detected in this population. Allele B of RsaI intron 2 (RsaI_in2*B) was significantly associated with physician-diagnosed asthma (ever) (P = 0.002). Alleles of both the RsaI_in2 and RsaI exon 7 (RsaI_ex7) polymorphisms were significantly associated with loge total serum IgE levels and the combined RAST index. RsaI_ex7 was also associated with loge blood eosinophil counts. These associations were independent of age, sex and familial correlations. CONCLUSION: This study supports a role for the FcepsilonR1-beta gene or a nearby gene in the pathogenesis of asthma.

Adolescent↗
PubMed2003

Association between leg length and offspring birthweight: partial explanation for the trans-generational association between birthweight and cardiovascular disease: findings from the British Women's Heart and Health Study.

Low birthweight individuals not only have increased risk of cardiovascular disease themselves, but cardiovascular disease risk is also increased in their parents. The mechanisms underlying these trans-generational associations are not fully understood. We hypothesise that, in part, they reflect the trans-generational effects of poor maternal environmental circumstances in early childhood. Adverse environmental factors acting early in the mother's life will not only influence her own predisposition to cardiovascular disease but will also result in adverse consequences - low birthweight and increased cardiovascular disease risk in later life - for her offspring. Adult leg length is a valid indicator of early life environmental circumstances, in particular of infant nutrition. If our hypothesis is correct, then adult leg length should be positively associated with offspring birthweight. In this study of 4286 randomly selected women aged 60-79 years from 23 towns across England, Scotland and Wales, the magnitude of the association between leg length and offspring birthweight was greater than the association between trunk length and offspring birthweight. After control for potential confounding factors, offspring birthweight increased by 89.8 g [95% confidence interval 66.1, 113.5 g] for each standard deviation increase in maternal leg length, and by 55.2 g [32.2, 78.1 g] for each standard deviation increase in maternal trunk length. The association between leg length and offspring birthweight was unaffected by adjustment for maternal birthweight, but the association between trunk length and offspring birthweight was attenuated to 38.0 g [1.0, 74.9 g]. These findings support the hypothesis that adverse early childhood environmental circumstances affect not only the vitality and health of the woman in later life but also the birthweight of her offspring, and suggest that the trans-generational association between birthweight and cardiovascular disease is in part explained by early childhood maternal environmental circumstances.

Aged↗
PubMed2001

Protein kinase C-associated kinase (PKK), a novel membrane-associated, ankyrin repeat-containing protein kinase.

A novel murine membrane-associated protein kinase, PKK (protein kinase C-associated kinase), was cloned on the basis of its physical association with protein kinase Cbeta (PKCbeta). The regulated expression of PKK in mouse embryos is consistent with a role for this kinase in early embryogenesis. The human homolog of PKK has over 90% identity to its murine counterpart, has been localized to chromosome 21q22.3, and is identical to the PKCdelta-interacting kinase, DIK (Bahr, C., Rohwer, A., Stempka, L., Rincke, G., Marks, F., and Gschwendt, M. (2000) J. Biol. Chem. 275, 36350-36357). PKK comprises an N-terminal kinase domain and a C-terminal region containing 11 ankyrin repeats. PKK exhibits protein kinase activity in vitro and associates with cellular membranes. PKK exists in three discernible forms at steady state: an underphosphorylated form of 100 kDa; a soluble, cytosolic, phosphorylated form of 110 kDa; and a phosphorylated, detergent-insoluble form of 112 kDa. PKK is initially synthesized as an underphosphorylated soluble 100-kDa protein that is quantitatively converted to a detergent-soluble 110-kDa form. This conversion requires an active catalytic domain. Although PKK physically associates with PKCbeta, it does not phosphorylate this PKC isoform. However, PKK itself may be phosphorylated by PKCbeta. PKK represents a developmentally regulated protein kinase that can associate with membranes. The functional significance of its association with PKCbeta remains to be ascertained.

Amino Acid Sequence↗
PubMed2001

Insulin-like growth factor I increases alpha Vbeta 3 affinity by increasing the amount of integrin-associated protein that is associated with non-raft domains of the cellular membrane.

Insulin-like growth factor I (IGF-I) stimulates an increase in alpha(V)beta(3) ligand binding. Stimulation of smooth muscle cells by IGF-I requires alpha(V)beta(3) ligand occupancy, and enhanced alpha(V)beta(3) ligand occupancy augments IGF-I actions. Therefore, IGF-I-induced changes in alpha(V)beta(3) ligand binding may act to further enhance IGF-I actions. Integrin-associated protein (IAP) has been shown to be associated with alpha(V)beta(3) and is required for the binding of alpha(V)beta(3) to vitronectin-coated beads. We therefore investigated whether IGF-I could stimulate IAP-alpha(V)beta(3) association resulting in enhanced ligand binding. IGF-I stimulated an increase in IAP-alpha(V)beta(3) association. This was due, at least in part, to an IGF-I-stimulated redistribution of IAP from the Triton-insoluble fraction of the cell to the Triton-soluble fraction of the cell, where most of the alpha(V)beta(3) was located. Inhibition of the phosphatidylinositol 3-kinase pathway blocked both the redistribution of IAP and the increase in IAP-alpha(V)beta(3) association, providing further evidence that the redistribution of IAP is essential for the increase in association. An anti-IAP monoclonal antibody, blocked both the IGF-I-stimulated increase in IAP-alpha(V)beta(3) complex formation and cell migration. IGF-I-stimulated translocation of IAP and increase in IAP-alpha(V)beta(3) association represent an important process by which IGF-I modulates alpha(V)beta(3) ligand binding and cellular responses.

Animals↗
PubMed1997

Influences of transporter associated with antigen processing (TAP) on the repertoire of peptides associated with the endoplasmic reticulum-resident stress protein gp96.

The endoplasmic reticulum (ER)-resident stress protein gp96 induces protective immunity and specific cytotoxic T lymphocyte (CTL) responses against antigens expressed in those cells it has been isolated from. This ability is based on peptides associated with gp96. Because gp96 is located inside the ER, our experiments address the question whether or not the repertoire of peptides associated with gp96 is influenced by the transporter associated with antigen processing (TAP). For this purpose, gp96 was isolated from cells with and without a TAP defect and used for immunization of mice. We found that for some antigens the association of peptides with gp96 required functional TAP molecules, whereas the association of peptides from other antigens was TAP independent. In the case of a TAP-dependent association of peptides with gp96, our results prove that peptide binding by gp96 in vivo occurs inside the ER and is not an artifact induced by cell lysis during the gp96 purification. The finding that some antigens can also associate with gp96 in the absence of functional TAP molecules indicates that the repertoire of peptides bound by gp96 truly reflects the entire repertoire of peptides present inside the ER and not only those peptides transported by TAP. These results, together with the earlier finding that the gp96 peptide repertoire is independent of the major histocompatibility complex molecules expressed by the cell gp96 is isolated from, give the theoretical foundation for the ability of gp96 to induce CTL responses against all kinds of intracellular antigens.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Quantitative analysis of Kaposi sarcoma-associated herpesvirus (KSHV) in KSHV-associated diseases.

BACKGROUND: Accurate numbers of copies of Kaposi sarcoma-associated herpesvirus (KSHV) and numbers of virus-infected cells in lesions caused by KSHV-associated diseases are unknown. METHODS: Quantitative polymerase chain reaction (PCR) and computerized imaging of immunohistochemical analysis were performed on pathologic sections of samples from persons with KSHV-associated diseases. RESULTS: Real-time PCR and semiquantitative PCR-Southern blotting demonstrated that DNA extracted from biopsy samples of KS lesions contained approximately 1-2 viral copies/cell. KSHV-associated lymphoma contained 10-50 viral copies/cell. Computerized-image analysis demonstrated that approximately 49% of cells expressed KSHV-encoded latency-associated nuclear antigen in KS biopsy samples. On the basis of results of real-time PCR and computerized-image analysis, the predicted number of viral copies was 3.2 viral copies/cell in KS lesions. Computerized-image analysis also revealed that the expression of open-reading frame (ORF)-50 protein, an immediate early protein of KSHV, was very rare in KS lesions, which implies that they were mainly composed of proliferating cells latently infected with KSHV. In multicentric Castleman disease lesions, 25% of virus-infected cells expressed ORF50 protein, which suggests the frequent lytic replication of KSHV. CONCLUSIONS: Numbers of viral copies and of virus-positive cells vary among KSHV-associated diseases, which suggests different mechanisms of viral pathogenesis. The combination of real-time PCR and computerized-image analysis provides a useful tool for the assessment of the number of viral copies in KSHV-associated diseases.

Herpesviridae Infections↗
PubMed1988

Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work.

The authors used data from the United States first national Health and Nutrition Examination Survey of 1971-1975 (HANES I) to explore the cross-sectional associations between radiographic osteoarthritis of the knee and a variety of putative risk factors. A total of 5,193 black and white study participants aged 35-74 years, 315 of whom had x-ray-diagnosed osteoarthritis of the knee, were available for analysis. After controlling for confounders, the authors found significant associations of knee osteoarthritis with overweight, race, and occupation, all of which have been suggested by smaller cross-sectional studies. They then focused specifically on those factors. For overweight, they found a strong association between current obesity and osteoarthritis of the knee, with a dose-response effect not previously assessed. This association was also seen for self-reported minimum adult weight, a proxy for long-term obesity, and was present in persons with asymptomatic osteoarthritis of the knee. These findings strongly suggest that obesity is causative. HANES I was the first study in which racial differences in osteoarthritis of the knee could be assessed within the same country. The black women who were studied had an increased risk of disease (odds ratio (OR) = 2.12, 95% confidence interval (CI) = 1.39-3.23) after controlling for age and weight, although the black men did not. Finally, the authors used the US Department of Labor Dictionary of Occupational Titles to obtain characterizations of the physical demands and knee-bending stress associated with occupations and to study the relation between physical demands of jobs and osteoarthritis of the knee. They found for persons aged 55-64 years an association between knee-bending demands and osteoarthritis of the knee (men, OR = 2.45, 95% CI = 1.21-4.97; women, OR = 3.49, 95% CI = 1.22-10.52). Since such occupational physical demands are common, the authors conclude that they may be associated with a substantial proportion of osteoarthritis of the knee.

Adult↗
PubMed2002

Type III protein secretion is associated with poor clinical outcomes in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

OBJECTIVE: Pseudomonas aeruginosa is a frequent cause of ventilator-associated pneumonia. Recent evidence suggests that production of type III secretion proteins is correlated with increased pathogenicity in both cellular and animal models of infection. The objective of this study was to determine whether this system contributes to disease severity in humans with ventilator-associated pneumonia. DESIGN: Retrospective pilot cohort study. SETTING: University hospital. PATIENTS: Thirty-five mechanically ventilated patients with bronchoscopically confirmed ventilator-associated pneumonia caused by P. aeruginosa. MEASUREMENTS AND MAIN RESULTS: Ventilator-associated pneumonia was categorized as severe (patients died or had a recurrence of their pneumonia despite appropriate antibiotic therapy) or mild (patients uneventfully recovered from their pneumonia). The type III secretion genotypes and phenotypes of isolates cultured from the patients with ventilator-associated pneumonia were determined. Whereas every examined isolate harbored type III secretion genes, only 27 (77%) were capable of secreting detectable amounts of type III proteins in vitro. Twenty-two (81%) of the patients infected with these 27 isolates had severe disease. Of the eight isolates that did not secrete type III proteins, only three (38%) were cultured from patients with severe disease. Thus, infection with a type-III-secreting isolate correlated with severe disease (p < .05). In vitro assays indicated that ExoU, the type III effector protein most closely linked to mortality in animal models, was secreted in detectable amounts in vitro by 10 (29%) of the 35 examined isolates. Nine (90%) of these 10 isolates were cultured from patients with severe disease (p < .05 when compared with the nonsecreting isolates). In contrast, ExoS was secreted by 16 (46%) of the 35 examined isolates. Twelve (75%) of these 16 isolates were cultured from patients with severe disease (p = .14 when compared with the nonsecreting isolates). CONCLUSIONS: In patients with ventilator-associated pneumonia, type-III-secreting isolates were associated with worse clinical outcomes, suggesting that this secretion system plays an important role in human disease. Our findings support the hypothesis that antibodies targeted against these proteins may be useful as adjunctive therapy in intubated patients with P. aeruginosa colonization or infection.

Bacterial Proteins↗