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Biomedical subjects

R Menon

Publications and source records attributed to R Menon.

At least 19 recordsLinked to original sources
PubMed2005

Further evidence for LBP-1c/CP2/LSF association in Alzheimer's disease families.

OBJECTIVES: Several studies suggested chromosome 12 harbours an Alzheimer's disease (AD) risk factor gene. Significant association of a single nucleotide polymorphism (SNP) in the 3' UTR of transcription factor CP2 (LBP-1c/CP2/LSF or TFCP2) at 12q13 was reported in three independent case-control studies, but no family based analyses have been performed to date. METHODS: Genotypes for three SNPs were generated in two independent AD family samples. A meta-analysis on all published case-control studies was also performed. RESULTS: The A allele of the 3' UTR SNP was associated with increased risk for AD in one sample (odds ratio (OR) 2.1, 95% confidence interval (95% CI) 1.1 to 4.3), but not in the other, possibly due to low power. Haplotype analyses showed that this allele is part of a putative risk-haplotype overtransmitted to affected individuals in one sample and in both samples combined. Meta-analysis of the previously associated 3' UTR SNP showed a trend towards a protective effect of the A allele in AD (OR 0.73, 95% CI 0.5 to 1.1). CONCLUSIONS: This is the first study to examine LBP-1c/CP2/LSF in AD families, and the fifth to independently show significant association. While our results support a role of this gene in AD pathogenesis, the direction of the effect remains uncertain, possibly indicating linkage disequilibrium with another variant nearby.

3' Untranslated Regions↗
PubMed2004

PEN2 is not a genetic risk factor for Alzheimer's disease in a large family sample.

PEN2 is a reasonable Alzheimer's disease (AD) candidate gene because it is a necessary component of the gamma-secretase complex that generates beta-amyloid peptide. Moreover, its gene (PEN2) maps to a highly significant linkage region on chromosome 19q13. Four common polymorphisms in PEN2 were tested for genetic association with AD in a large and carefully ascertained AD family sample (789 subjects from 202 nuclear families) using single-locus and haplotype-based analyses. These results do not suggest PEN2 to be a major AD risk factor.

Aged↗
PubMed2003

Carrier dynamics in conducting polymers: case of PF6 doped polypyrrole.

The carrier dynamics in PF6 doped polypyrrole has been probed by dielectric spectroscopy (from 10(-4) to 4 eV), down to 4.2 K. The phase-sensitive sub-THz data have assisted to resolve the discrepancies in Kramers-Kronig analysis in earlier studies. Even in metallic samples, just 1% of the carriers are delocalized, at 300 K; the fraction drops down considerably as a function of disorder, carrier density, and temperature. This subtle metallic feature and the anomalies in carrier dynamics are attributed to coherent and incoherent transport between short conjugated segments.

Journal Article↗
PubMed2003

IL-1 beta is a better inducer of apoptosis in human fetal membranes than IL-6.

The objective of this study was to compare two of the inflammatory cytokines (IL-1 and IL-6) elevated in both preterm labour and preterm premature rupture of the membranes (pPROM), with respect to their ability to induce fetal membrane apoptosis. Fetal membranes collected from women at term were placed in an organ explant system and stimulated with recombinant human IL-1 beta and IL-6. The expression patterns of pro-apoptotic genes (Fas, FasL, TRADD, FADD) and caspases 2, 3, 8, 9 were studied using PCR. Caspase activity and DNA fragmentation were studied using substrate assays and TUNEL respectively. Caspase 8 and 9 expressions were induced in IL-1 beta and IL-6 treated amniochorion. Caspase 2 expression was seen only in IL-1 beta stimulated tissues. When compared to control, IL-1 beta increased caspase 2, 3, 8 and 9 activities, whereas IL-6 treated membranes did not exhibit a significant change. DNA fragmentation was seen in greater numbers after IL-1 beta treatment than after IL-6 treatment. This study demonstrates that IL-1 beta is a better inducer of apoptosis in normal human fetal membranes than IL-6.

Apoptosis↗
PubMed2001

Interleukin-10 inhibition of gelatinases in fetal membranes: therapeutic implications in preterm premature rupture of membranes.

OBJECTIVE: To examine the effect of interleukin-10 on production and regulation of gelatinases by amniochorion in an in vitro model of infection. METHODS: We placed amniochorionic membranes collected from eight women who had elective repeat cesareans at term in an organ explant culture system. After 48 hours in culture, the membranes were stimulated with lipopolysaccharide (50 ng/mL), and some were costimulated with interleukin-10 (500 ng/mL). Tissue and media samples were collected after 24-hour stimulation. Quantitative polymerase chain reactions and enzyme-linked immunosorbent assays were used to evaluate matrix metalloproteinase 2 and matrix metalloproteinase 9 messenger RNA and proteins, respectively. RESULTS: Lipopolysaccharide stimulation induced 55.14 transcripts of matrix metalloproteinase 9, compared with 0.83 in control tissues (P <.001). Costimulation with interleukin-10 and lipopolysaccharide significantly reduced matrix metalloproteinase 9 messenger RNA levels to 10 transcripts (P <.001). Lipopolysaccharide stimulation produced 29.25 ng/mL of immunoreactive matrix metalloproteinase 9, which was reduced to 6.3 ng/mL (P(adj) =.016) after costimulation with interleukin-10. Although not significant, matrix metalloproteinase 2 messenger RNA levels were higher in lipopolysaccharide-stimulated tissues (4.37 x 10(6) transcripts) compared with control (2.8 x 10(5) transcripts; P(adj) =.08), with a significant decrease in matrix metalloproteinase 2 messenger RNA levels in interleukin-10- costimulated tissues (2.9 x 10(6); P(adj) =.007). Interleukin-10 costimulation resulted in a significant decrease in matrix metalloproteinase 2 protein production (203.1 [lipopolysaccharide] and 149.75 [with interleukin-10]; P(adj) <.001). CONCLUSION: Interleukin-10 eliminated lipopolysaccharide induction of matrix metalloproteinase 2 and 9 in amniochorion.

Amnion↗
PubMed2001

IL-18, a product of choriodecidual cells, increases during premature rupture of membranes but fails to turn on the Fas-FasL-mediated apoptosis pathway.

PROBLEM: IL-18 is a novel cytokine, which promotes inflammation and apoptosis. This study examines its expression pattern, site of production, and levels in the amniotic fluid (AF) during pregnancy complications such as preterm labor and preterm premature rupture of membranes (pPROM). The ability of IL-18 to induce the Fas-Fas ligand (FasL)/caspase-mediated apoptotic pathway is also studied. METHODS: Amniochorion collected at term was placed in an organ explant system. IL-18 mRNA expression was studied by RT-PCR. IL-18 mRNA and peptide were localized by in situ hybridization and immunohistochemistry. IL-18 in the AF of women with pPROM, with preterm labor with no rupture of membranes, and at term was measured using ELISA. Multiplex PCR was used to study the expression pattern of proapoptotic genes such as Fas, FasL, caspase 8, and Fas-associated death domain (FADD). ELISA was also used to measure the release of soluble Fas from IL-18-stimulated amniochorion in culture media. RESULTS: IL-18 is a constitutively expressed gene in human chorion and decidua but not in human amnion and increases in the AF of women with pPROM [2.9 +/- 3.3 ng/ml (SD)] compared to women with preterm labor (1.1 +/- 0.67 ng/ml; P < 0.05) and term (0.9 +/- 0.73 ng/ml; P < 0.05). IL-18 induces Fas expression, whereas FADD is a constitutively expressed gene in human fetal membranes. IL-18 failed to induce FasL or caspase 8 expressions. Soluble Fas release from amniochorion was increased after IL-18 stimulation. CONCLUSION: Chorion and decidua are a source of IL-18, whose concentrations are increased in the AF during pPROM. IL-18 induced Fas expression in amniochorion; however, it failed to turn on other genes in the Fas-FasL apoptosis pathway including FasL and caspase 8.

Amniotic Fluid↗
PubMed2001

Distinct molecular events suggest different pathways for preterm labor and premature rupture of membranes.

OBJECTIVE: On a clinical level, the etiologies associated with premature rupture of the membranes and preterm labor are virtually identical, though these conditions end in distinctly different events. This study was designed to determine differences between preterm labor and preterm premature rupture of membranes by using molecular markers of extracellular matrix degradation and apoptosis. STUDY DESIGN: Amniochorion and amniotic fluid samples were collected from gestational age-matched groups of women undergoing cesarean delivery before term. Samples were collected from 2 groups of women, women with premature rupture of membranes and women with preterm labor with no rupture of membranes. Changes in the expression pattern of messenger ribonucleic acid for matrix metalloproteinases (MMP), tissue inhibitor of metalloproteinases (TIMP), and pro-apoptotic (p53 and Bax) and anti-apoptotic (Bcl-2) proteins were identified by quantitative polymerase chain reaction. Enzyme-linked immunosorbent assay was used to determine the levels of these proteins in the amniotic fluid. Multiplex polymerase chain reaction was performed to study the expression of Fas-Fas ligand-associated pro-apoptotic genes. Unpaired nonparametric, 2-tailed Mann-Whitney U test was used to determine statistical significance of quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (P <.05 was considered significant). RESULTS: Quantitative polymerase chain reaction results demonstrated an increased mRNA expression for MMP2, MMP9, and MT1-MMP and a decreased expression for TIMP2 in prematurely ruptured membranes compared with preterm labor membranes. Enzyme-linked immunosorbent assay documented increases in the amniotic fluid concentrations of immunoreactive and bioactive MMP2 and MMP9 and immunoreactive MMP3 and a decreased TIMP2 concentration in fluids obtained from the premature rupture of membranes group compared with the preterm labor group. The pro-apoptotic genes p53 and bax were up-regulated in premature rupture of membranes when compared with preterm labor. Anti-apoptotic gene (Bcl-2 ) expression was increased in preterm labor membranes compared with prematurely ruptured membranes. Interleukin-18 (a pro-apoptotic cytokine) was increased in the amniotic fluid during premature rupture of membranes compared with preterm labor. Prematurely ruptured membranes also demonstrated fragmented deoxyribonucleic acid and expression of Fas and caspase 8 (apoptosis initiator), which were all absent in preterm labor membranes. CONCLUSIONS: We have begun to delineate 2 divergent molecular pathways for premature rupture of membranes and preterm labor. Most likely, this is the beginning of the identification of differences that will become evident with the use of molecular biology.

Amniotic Fluid↗
PubMed2001

Support for an infection-induced apoptotic pathway in human fetal membranes.

OBJECTIVE: Lipopolysaccharide and tumor necrosis factor alpha levels are both elevated in the amniotic fluid of women during infection-associated preterm labor and premature rupture of fetal membranes. Our laboratory has shown that apoptosis is associated with premature rupture of fetal membranes but is not associated with preterm labor. The exact pathway that leads to apoptosis-mediated premature rupture of fetal membranes is still unclear. Because infection and increased inflammatory cytokine response are associated with the majority of cases of premature rupture of fetal membranes, we examined the roles of bacterial lipopolysaccharide and tumor necrosis factor alpha in inducing the proapoptotic caspase pathway in fetal membranes. STUDY DESIGN: Amniochorionic membranes collected from women undergoing elective repeat cesarean delivery at term were placed in an organ explant system. At the end of a 48-hour incubation period, membranes were stimulated with lipopolysaccharide (50 ng/mL) and recombinant tumor necrosis factor (50 ng/mL). Total ribonucleic acid extracted from these samples was subjected to reverse transcription and two separate sets of multiple polymerase chain reaction. One set studied the expression of Fas, Fas ligand, caspase 8, Fas-associated death domain, and tumor necrosis factor receptor-associated death domain genes and the second set studied the expression of caspase 2, 4, 6, 7, and 10. Caspase 2, 3, and 9 expression was also studied by reverse transcriptase-polymerase chain reaction. RESULTS: Multiple polymerase chain reactions and reverse transcriptase-polymerase chain reactions documented the induction of Fas and caspase 2, 3, 7, 8, and 9 genes in amniochorion after lipopolysaccharide and tumor necrosis factor stimulation compared with the nonstimulated controls. Neither lipopolysaccharide nor tumor necrosis factor induced Fas ligand expression in human fetal membranes. Caspase 3, 4, and 6, Fas-associated death domain, and tumor necrosis factor receptor-associated death domain expressions were constitutive in all the tissues tested; however, tumor necrosis factor receptor-associated death domain expression appeared stronger in tumor necrosis factor-stimulated tissues. CONCLUSION: The presence of the signal docking proteins tumor necrosis factor receptor-associated death domain and Fas-associated death domain and the induction of caspase cascade initiators (caspase 2, 8, and 10) and effector caspases (caspase 3, 6, 7, and 9) by lipopolysaccharide and tumor necrosis factor suggest that tumor necrosis factor-tumor necrosis factor receptor-mediated apoptosis may occur in the human fetal membrane.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Lipopolysaccharide stimulation of 70 kilo Dalton heat shock protein messenger ribonucleic acid production in cultured human fetal membranes.

OBJECTIVE: The 70 kilo Dalton heat shock protein is up-regulated when cells are under physiological stress. It prevents protein denaturation and incorrect polypeptide assembly, and inhibits apoptosis as well as the transcription of genes coding for pro-inflammatory cytokines. To evaluate if up-regulation of heat shock protein 70 can occur during pregnancy, we examined whether addition of bacterial lipopolysaccharide to human amniochorion membranes in vitro stimulated heat shock protein 70 gene transcription. MATERIALS AND METHODS: Amniochorionic membranes (n = 5), collected at the time of elective repeat cesarean section prior to labor from normal term gestations, were placed in an organ explant system. After 48 hour in culture, the membranes were stimulated with lipopolysaccharide for 24 hours. Total RNA was extracted and subjected to an oligo dT primed reverse transcriptase reaction followed by polymerase chain reaction (PCR) using heat shock protein 70 specific primers. PCR products were hybridized with biotinylated internal probes and identified by enzyme-linked immunosorbent assay (ELISA). Results were analyzed by Mann-Whitney U test. A p < 0.05 was significant. RESULTS: Heat shock protein 70 messenger RNA was expressed by all fetal membrane preparations both prior to and following in vitro culture. Addition of lipopolysaccharide increased the concentrations of heat shock protein 70 messenger RNA in each sample tested from a mean of 35.5 +/- 29.6 ng/milliliter (12.1-80.1 ng/milliliter) to 169.6 +/- 69.9 ng/ml (51.7-218.2 ng/milliliter) (p = 0.03). CONCLUSION: Human fetal membranes constitutively express heat shock protein 70 messenger ribonucleic acid. Bacterial lipopolysaccharide markedly stimulated heat shock protein 70 messenger RNA gene transcription in human fetal membranes. Thus, heat shock protein 70 is inducible in fetal membranes and may facilitate fetal survival under adverse conditions.

Cesarean Section↗
PubMed2001

A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection.

OBJECTIVE: Degradation of the extracellular matrix in fetal membranes has been implicated in the process of parturition and rupture of membranes. Matrix metalloproteinases (MMPs) are enzymes capable of degrading extracellular matrix including collagen. Tissue inhibitors of matrix metalloproteinases (TIMPs) inhibit the activity of MMPs by covalently binding to the enzymes. MMP-2 degrades Type IV collagen and TIMP-2 is its specific inhibitor. The objective of this study was to determine if human parturition, rupture of membranes (term and preterm) and microbial invasion of the amniotic cavity (MIAC) are associated with changes in the concentrations of MMP-2 and TIMP-2 in amniotic fluid. STUDY DESIGN: A cross-sectional study was conducted with women in the following categories: 1) term with intact membranes, in labor and not in labor; 2) preterm labor and intact membranes who delivered at term, who delivered preterm and preterm labor with MIAC; 3) preterm premature rupture of membranes (PROM) with and without infection; 4) term and preterm PROM not in labor; and 5) midtrimester. MMP-2 and TIMP-2 concentrations in amniotic fluid were determined using sensitive and specific immunoassays. RESULTS: The concentration of TIMP-2 increased with advancing gestational age (r = 0.6, p < 0.001). No correlation was found between MMP-2 concentrations and gestational age. Human parturition and rupture of membranes (term and preterm) and in patients with intact membranes were not associated with changes in the amniotic fluid MMP-2 concentrations. In contrast, 1) patients with spontaneous labor (term and preterm) had significantly lower median concentrations of TIMP-2 compared to those not in labor (p < 0.05 for both); 2) MIAC in women with preterm labor and preterm PROM was associated with a significant decrease in amniotic fluid TIMP-2 concentrations (p < 0.04 for both comparisons); 3) Rupture of the membranes (term and preterm) was also associated with a significant decrease in the amniotic fluid TIMP-2 concentrations (p < 0.05 and p < 0.03, respectively). CONCLUSIONS: Human parturition (preterm and term), rupture of fetal membranes (term and preterm) and intraamniotic infection are associated with a significant decrease in amniotic fluid TIMP-2 concentrations.

Amniotic Fluid↗
PubMed2000

Amniochorion gelatinase-gelatinase inhibitor imbalance in vitro: a possible infectious pathway to rupture.

OBJECTIVE: To estimate the effect of lipopolysaccharide on gelatinases and tissue inhibitors of matrix metalloproteinase 2 (gelatinase inhibitor) balance in human fetal membranes. METHODS: Amniochorionic membranes in organ explant were stimulated with 1000 ng/mL lipopolysaccharide for 24 hours after a 48-hour preincubation period. Quantitative competitive polymerase chain reaction (PCR) was done to quantitate messenger RNAs for gelatinase A and B (matrix metalloproteinase 2 and 9) and tissue inhibitor of metalloproteinase 2. Protein levels were assayed by enzyme-linked immunosorbant assay. The molar ratio between gelatinases and tissue inhibitor of metalloproteinase 2 was calculated. Statistical evaluation was done by Mann-Whitney U test. RESULTS: Lipopolysaccharide stimulation produced 3.6 x 10(6) and 366 transcripts of gelatinase A and B, respectively, compared with only 5.9 x 10(4) (P = .009) and three transcripts (P = .006), respectively, in the controls. Lipopolysaccharide stimulation released 210 ng/mL compared with 7 ng/mL of gelatinase A and B proteins compared with 120 (P = .01) and 4.6 ng/mL (P = .3) in controls, respectively. Control amniochorion produced 5.7 x 10(5) transcripts of tissue inhibitor of metalloproteinase 2, whereas lipopolysaccharide stimulation produced 4.1 x 10(5) transcripts (P = .69). Lipopolysaccharide reduced the release of this inhibitor from 114 ng/mL to 68 ng/mL (P = .007). The molar ratio between gelatinases and tissue inhibitor of metalloproteinase 2 increased from a balanced ratio of 1:1 to 3.1:1 after 1000 ng/mL of lipopolysaccharide. CONCLUSION: Lipopolysaccharide increased the expression and release of gelatinases and decreased its inhibitor, which shifted the balance in favor of gelatinase activity leading to membrane degradation that predisposes to premature rupture of membranes.

Amnion↗
PubMed2000

Programmed cell death (apoptosis) as a possible pathway to metalloproteinase activation and fetal membrane degradation in premature rupture of membranes.

OBJECTIVE: Increased matrix metalloproteinase 2 expression and activity are associated with premature rupture of fetal membranes. A proapoptotic protein produced in response to deoxyribonucleic acid fragmentation, p53, can bind to the matrix metalloproteinase 2 gene promoter and cause increased gene expression. It promotes apoptosis by inducing the expression of the proapoptotic bax gene and inhibiting the antiapoptotic bcl-2 gene. This study was undertaken to investigate the expression pattern of apoptotic elements in pregnancy complications that may cause increased expression of the gene for matrix metalloproteinase 2. STUDY DESIGN: Amniochorial membranes were collected from the following groups of women: (1) women with premature rupture of fetal membranes, (2) women with preterm labor and intact membranes, and (3) women with term labor after vaginal delivery. Deoxyribonucleic acid fragmentation was tested with ligation-mediated polymerase chain reaction and the terminal deoxynucleotidyl transferase-mediated biotinylated deoxyribonucleoside triphosphate end-labeling assay. Matrix metalloproteinase 2, p53, bcl-2, and bax gene expression patterns were studied with quantitative competitive polymerase chain reaction. Statistical analysis was performed with the Tukey-Kramer multiple comparison test. RESULTS: Quantitative competitive polymerase chain reaction documented a 10-fold increase in the expression of the gene for matrix metalloproteinase 2 in premature rupture of fetal membranes with respect to term and preterm labor. This induction coincided with an increase in the expressions of the proapoptotic genes p53 and bax and a drop in the expression of the antiapoptotic gene bcl-2. Ligation-mediated polymerase chain reaction revealed deoxyribonucleic acid fragmentation in specimens from premature rupture of fetal membranes and not in those from preterm labor or labor at term. Histochemical analysis documented fragmented deoxyribonucleic acid in chorionic and amniotic cells. CONCLUSION: This study suggests that apoptosis is associated with premature rupture of fetal membranes. Deoxyribonucleic acid fragmentation, associated with elevations in the levels of the two proapoptotic gene products evaluated (p53 and bax ) and a drop in the level of the antiapoptotic bcl-2, was seen in premature rupture of the fetal membranes. Induction of matrix metalloproteinase 2 may be a function of p53 gene expression increase in premature rupture of fetal membranes.

Apoptosis↗
PubMed2000

Il-1 beta, Il-6, Il-8 and G-CSF in the diagnosis of early-onset neonatal infections.

OBJECTIVE: To determine whether inflammatory cytokine concentrations (Il-1 beta, Il-6, Il-8 and G-CSF) in umbilical cord blood are useful predictors of an early-onset neonatal infection. MATERIAL AND METHODS: 240 women and their newborns were enrolled in our study and umbilical cord blood samples collected from neonates (n = 240) were subjected to ELISA for Il-1 beta, Il-6, Il-8 and G-CSF. Clinical outcome of the neonates was followed and documented. Placenta histology was also available in majority of the cases (n = 195). RESULTS: Early-onset neonatal infection was diagnosed in 5.4% of neonates (13/240) and placental examination showed histologic chorioamnionitis in 17.9% (35/195). Both Il-1 beta and Il-6 cord blood concentrations were elevated in association with histologic chorioamnionitis (Il-1 beta-2.7 vs. 2.1 pg/ml, p < 0.05 and Il-6 15.6 vs. 12.8 pg/ml, p < 0.005). Only Il-6 was elevated (16.0 vs. 13.2 pg/ml, p < 0.05) in neonates with early-onset bacterial infections. ROC analysis showed acceptable diagnostic performance of Il-6 in the identification of acute histologic chorioamnionitis and clinical neonatal infection. CONCLUSION: Il-6 in umbilical cord blood seems to be a promising predictor for early-onset neonatal infections.

Chorioamnionitis↗
PubMed1999

The carnage wrought by major economic change: ecological study of traffic related mortality and the reunification of Germany.

OBJECTIVE: To document the effects of sudden economic change on death rates for occupants of cars in the former German Democratic Republic (East Germany). DESIGN: Ecological time series study of East Germany in comparison with the former Federal Republic of Germany (West Germany) before and after reunification in 1990. SETTING: East and West Germany from 1985 to 1996. SUBJECTS: Populations of East and West Germany between 1985 and 1996. MAIN OUTCOME MEASURES: Death rates for occupants of cars. RESULTS: After the reunification of Germany, East Germany experienced a sudden, temporary affluence and a concomitant fourfold increase in death rates for car occupants between 1989 and 1991. Although death rates increased in all age groups, young adults (aged 18-24) were most affected. The death rate per 100 000 population for those aged 18-20 years increased 11-fold between 1989 and 1991; for those aged 21-24 years the increase was eightfold. CONCLUSION: A tragic consequence of the reunification of Germany was a dramatic increase in the death rate for car occupants. Sudden economic change and availability of cars resulted in both a rise in vehicle ownership and an increase in the number of inexperienced drivers on roads that were ill prepared for the increased traffic. The lesson learnt from Germany is that during times of economic change and modernisation, measures to prevent the predictable injury deaths that will result need to be considered.

Accidents, Traffic↗