Association between DRD2 and DRD3 gene polymorphisms and gastrointestinal symptoms induced by levodopa therapy in Parkinson's disease.

Levodopa is the most used drug to treat motor symptoms in Parkinson's disease (PD). However, dopaminergic side effects such as nausea and vomiting may occur. Several evidences indicate a major role for dopamine receptors D2 (DRD2) and D3 (DRD3) in emetic activity. The aim of this study was to investigate the relationship of DRD2 rs1799732 and DRD3 rs6280 gene polymorphisms with gastrointestinal (GI) symptoms induced by levodopa in PD patients. Two hundred and seventeen PD patients on levodopa therapy were investigated. DRD2 rs1799732 and DRD3 rs6280 polymorphisms were genotyped by PCR-based methods. Multiple Poisson regression method with robust variance estimators was performed to assess the association between polymorphisms and gastrointestinal symptoms. The analyses showed that DRD2 Ins/Ins (prevalence ratio (PR)=2.374, 95% confidence interval (CI): 1.105-5.100; P=0.027) and DRD3 Ser/Ser genotypes (PR=1.677, 95% CI 1.077-2.611; P=0.022) were independent and predictors of gastrointestinal symptoms associated with levodopa therapy. Despite all the efforts to alleviate GI symptoms, this adverse effect still occurs in PD patients. Pharmacogenetic studies of GI symptoms induced by levodopa therapy have the potential to display new ways to better understand the molecular mechanisms involved in these side effects.

Environmental determinants on the assemblage structure of Drosophilidae flies in a temperate-subtropical region.

The species composition and the relative abundance of species in an insect community can vary in time and space for many reasons, including climatic variables and habitat preferences. Drosophilids were collected each quarter from April 2011 to April 2012 (five collections in all) in a natural area of the Pampa biome, considering three environments: open field, forest edge and the interior of forest patches. Kruskal-Wallis and chi-square tests were used to examine the effects of temporal and spatial components on the drosophilid assemblage. Four diversity measures: S obs , S rar , H' and E var were used to evaluate the community structure. A total of 7164 drosophilids belonging to 51 species were collected. The interaction of species in each environment varied among sampling periods. The abundance of both Neotropical and exotic species was affected by temporal and spatial components. The species of the D. repleta group were predominantly more abundant in the open field, but they migrated to the forest patches during periods of thermal stress. Generally, diversity was greatest in the interior of forest patches. Nevertheless, temporal components appear to be the predominant environmental determinant of the characteristics of the drosophilid community of the Pampas. Furthermore, the forest patches appear to act as a center of recolonization, reinforcing their importance in the maintenance of biodiversity in the Pampas; this function will be even more important in the future, when the temperatures will, most likely, be higher.

HLA-G +3142 polymorphism as a susceptibility marker in two rheumatoid arthritis populations in Brazil.

In this study, we sought to investigate the genetic influence of two HLA-G 3'-untranslated region (3'-UTR) polymorphisms - 14 bp (rs66554220) and +3142C>G (rs1063320) and their compounding haplotypes in susceptibility to rheumatoid arthritis (RA) in a two-region Brazilian study comprising of 539 patients and 489 controls. All subjects were polymerase chain reaction (PCR) genotyped for the referred polymorphisms and logistic regression models controlling for sex, city and age were performed. Homozygozity for the +3142G allele was associated with an increased risk of RA [odds ratio (OR) = 1.45, 95% confidence interval (CI) = 1.075-1.959, P(Bonf) = 0.030], whereas no association was observed for the 14 bp polymorphism. Haplotype comparisons between patients and controls showed a decreased frequency of the delC haplotype in patients (OR = 0.70, 95% CI = 0.521-0.946, P(Bonf) = 0.040), which remained significant in the rheumatoid factor (RF)-positive group (OR = 0.66, 95% CI = 0.482-0.900, P(Bonf) = 0.018), but not in the RF-negative group. These results corroborate the hypothesis of an involvement of HLA-G in the susceptibility of RA. The +3142G allele is associated with haplotype lineages that share high identity and are regarded as low producers. The presence of the G allele in homozygosis could be responsible for a low HLA-G expression profile that could favor the triggering of RA.

Effect of nortriptyline on brain responses to painful esophageal acid infusion in patients with non-erosive reflux disease.

BACKGROUND: Non-erosive reflux disease (NERD) patients generally present with heartburn as the main symptom. Antidepressants might help to relieve heartburn by acting on the esophagus-brain axis. We aimed to assess the effect of nortriptyline on behavioral and brain responses to painful esophageal acid infusion in NERD patients evaluated with functional magnetic resonance imaging (fMRI). METHODS: In a randomized double-blind crossover design, 20 NERD patients off proton pump inhibitors (36.1 ± 9.3 years, 75% women) were assigned to 21 days of nortriptyline and placebo, in counterbalanced order, with a 21 days washout period in between both treatment periods. Changes in acid-induced brain response on fMRI and heartburn perception were assessed and at the end of each treatment. KEY RESULTS: Nortriptyline significantly reduced the acid-induced brain response in prefrontal cortex (median [IQR]: -1.9 [-4.5 to -0.1] vs -0.3 [-2.5 to 2.3]; p = 0.050), caudate (-3.0 [-5.1 to -0.01] vs 0.48 [-1.9 to 3.1]; p = 0.029), insula (-2.4 [-4.8 to -0.6] vs -0.2 [-1.5 to 1.5]; p = 0.029), cingulate (-4.2 [-8.8 to -0.1] vs -0.6 [-1.8 to 3.0]; p = 0.017), and hippocampus (-2.7 [-6.0 to 0.5] vs -0.04 [-2.3 to 1.9]; p = 0.006) in comparison with placebo. However, there was no significant difference between nortriptyline and placebo in clinical outcomes and side effects. CONCLUSIONS & INFERENCES: Nortriptyline decreased the brain response to esophageal acid infusion more markedly than placebo, but without clinical significance.

Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson's disease patients.

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.

Distribution patterns of variability for 18 immune system genes in Amerindians--relationship with history and epidemiology.

Native American populations generally have a higher prevalence of infectious diseases than non-Native populations and this fact can induce different pressures in their immune system. We investigated the patterns of population differentiation (FST ) of 32 polymorphisms related to adaptive immune response in four Native American populations (Aché, Guarani-Kaiowá, Guarani-Ñandeva and Kaingang), and the results were compared with the three major world population data [Yoruba of Ibadan, Nigeria (YRI), Utah residents with northern and Western Europe ancestry (CEU) and Han Chinese of Beijing, China (CHB)] available in the HapMap database. The Aché clearly differentiated from the other Amerindians, but when all Native Americans were compared with the samples of other ethnic groups the lowest difference (0.08) was found with CHB (Asians), the second lowest (0.15) with YRI (Africans) and the most marked with CEU (European-derived). The considerable intra and interethnic differences found can be explained both in terms of diverse evolutionary distances and more recent environmental pathogen exposures; and they should be appropriately considered prior to any specific public health action.

N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients.

SETTING: Isoniazid (INH) is related to the development of hepatotoxicity in some patients. OBJECTIVE: To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of patients treated with INH in an Amazonian Brazilian population. DESIGN: Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods. RESULTS: Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07-8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47-12.37, P = 0.008). CONCLUSIONS: Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.

The burdened life of adults with ADHD: impairment beyond comorbidity.

Since approximately 70% of adult patients with attention-deficit/hyperactivity disorder (ADHD) have at least one comorbid disorder, rating of impairment specifically attributable to ADHD is a hard task. Despite the evidence linking environmental adversities with negative outcomes in ADHD, life events measures have not been used to rate the disorder impairment. The present study tested for the first time the hypothesis that increased ADHD severity is associated with an increase in negative recent life events, independently of comorbidity status. The psychiatric diagnoses of 211 adult ADHD outpatients were based on DSM-IV criteria assessed through structured interviews (K-SADS-E for ADHD and ODD, MINI for ASPD and SCID-IV-R for other comorbidities). ADHD severity was evaluated with the Swanson, Nolan and Pelham rating scale (SNAP-IV) and recent life events with the Life Experience Survey. Higher SNAP-IV inattention and hyperactivity scores, female gender, lower socioeconomic status and the presence of comorbid mood disorders were associated with negative life events. Poisson regression models with adjustment for possible confounders confirmed the effect of inattention and hyperactivity severity on negative life events. Our results suggest that the negative life events experienced by these patients are associated to the severity of ADHD independently from comorbid psychiatric disorders.

HLA-G polymorphism influences the susceptibility to HCV infection in sickle cell disease patients.

Despite its well known monogenic etiopathogenesis, sickle cell disease (SCD) is characterized by a striking variability of clinical presentation. There is growing evidence that genetic factors may be involved in this variability. Human leukocyte antigen (HLA)-G is a non-classical HLA molecule which was shown to be expressed at sites of inflammation and in inflammatory diseases. Besides its large and highly polymorphic promoter region, the 3' UTR region seems also to play an important role on regulating HLA-G expression. We investigated the influence of the 14 pb (rs1704) and the +3142 (rs1063320) HLA-G polymorphisms in 93 SCD patients in order to evaluate its potential role on clinical parameters. Twenty-one patients presented an HCV infection. Among all SCD patients 16 (22.2%) were homozygous for the +3142C genotype, none of them hepatitis C (HCV) positive. Controlling for blood transfusions in the last year, the C allele represented a dose dependent protection effect for HCV infection (PR = 0.41; 95% CI: 0.24-0.71). The +3142C allele was also underrepresented among patients with history of respiratory-tract infections. Our results support a role of the +3142 polymorphism in the susceptibility to infections, in particular to HCV infection, and suggest a possible interference of the HLA-G molecule in the response to infections, among SCD patients.

Heartburn during sleep: a clinical marker of gastro-oesophageal reflux disease in morbidly obese patients.

Gastro-oesophageal reflux disease (GORD) and morbid obesity are entities with increasing prevalence. New clinical strategies are cornerstones for their management. The aim of this study was to assess the prevalence of heartburn during sleep (HDS) and whether this symptom predicts the presence of objective GORD parameters and increased heartburn perception in morbidly obese patients. Ninety-one consecutive morbidly obese patients underwent clinical evaluation, upper gastrointestinal endoscopy and oesophageal pH monitoring. HDS was characterized when patients replied positively to the question, 'Does heartburn wake you from sleep?'. A General Score for Heartburn (GSH) ranging between 0 and 5 was assessed with the question 'How bad is your heartburn?'. HDS was reported by 33 patients (36%). More patients with HDS had abnormal acid contact time or reflux oesophagitis than patients without HDS (94%vs 57%, P < 0.001). HDS had a positive predictive value of 94% (0.95 CI 82-98), sensitivity of 48% (0.95 CI 37-60%) and specificity of 93% (0.95 CI 77-98%) for detection of GORD. A higher proportion of patients with HDS perceived heartburn preceded by acid reflux in diurnal (39%vs 9%; P < 0.001) periods during pH-metry. HDS patients showed higher GSH (2.4 +/- 0.5 vs 1.7 +/- 0.4; P < 0.0001) compared with patients who denied HDS but reported diurnal heartburn. HDS occurs in a significant minority of patients with morbid obesity and has high positive predictive value for GORD. Symptomatic reflux during the sleep seems to be a marker of increased heartburn perception in this population.

Endoscopic implantation of polymethylmethacrylate augments the gastroesophageal antireflux barrier: a short-term study in a porcine model.

BACKGROUND AND AIMS: Endoscopic injection of filler agents into the esophagogastric junction has been developed to augment the antireflux barrier and decrease gastroesophageal reflux (GER). However, evidence of efficacy is lacking and serious complications have been reported in humans. The aim of this study was to assess whether endoscopic implantation of polymethylmethacrylate augments the antireflux barrier in a porcine model for GER. METHODS: Large White pigs underwent esophageal manometry, gastric yield pressure (GYP), and gastric yield volume (GYV) measurements and implantation of PMMA in the distal esophagus under general anesthesia. After follow-up of 28 days, esophageal manometry and gastric yield measurements were repeated and animals sacrificed. RESULTS: Implantation of PMMA was performed in 18 animals, and 14 animals survived 28 days. There was a significant increase in GYP (10.7 mmHg versus 8.1 mmHg; p = 0.017) and GYV (997 ml versus 393 ml; p < 0.001) after PMMA implantation, whereas resting LES pressure did not change significantly. Acute inflammatory changes and fibrous tissue deposits were found surrounding the PMMA implants during histology. One animal died after esophageal perforation and three others due to pneumonia (two) and colon perforation (one) in the postoperative period. CONCLUSIONS: Endoscopic implantation of PMMA in the distal esophagus augments the antireflux barrier 28 days after the procedure. However, esophageal perforation points to the need for technical refinements to make the procedure safer.

DNA sequence analysis and the phylogeographical history of the rodent Deltamys kempi (Sigmodontinae, Cricetidae) on the Atlantic Coastal Plain of south of Brazil.

The rodent Deltamys kempiThomas, 1917 is found on the Coastal Plain - a recently formed geographic region located on Brazil's south-east coast. Considering that Deltamys is the only South American sigmodontine with a sex chromosome system of type X(1)X(1)X(2)X(2)/X(1)X(2)Y, this investigation was focused on the phylogeographic history of this taxon by using gene sequence analysis, trying to clarify when Deltamys differentiated, what was its centre of diversification, and what were the probable routes it used to reach its present distribution. We analysed sequences of the mitochondrial cytochrome b gene and nuclear recombination activating gene 2, performed cranial measurements and searched for centric fusions in individuals collected in distinct localities. The results, clearly demonstrate that D. kempi, on the Coastal Plain, divided into two groups, one occupying a small portion to the north of this region and the other spreading widely to the south. In this process, the phenomena of marine transgression and regressions which moulded its habitat, together with the occurrence of successive chromosomal rearrangements, were certainly the fundamental factors in shaping D. kempi diversification.

Nutcracker oesophagus: association with chest pain and dysphagia controlling for gastro-oesophageal reflux.

BACKGROUND: The association between nutcracker oesophagus, gastro-oesophageal reflux and their symptoms is controversial. AIM: To evaluate the association of nutcracker oesophagus with chest pain and dysphagia controlling for gastro-oesophageal reflux. METHODS: From a database of 935 consecutive patients investigated with oesophageal manometry and pH-metry, we selected all patients with nutcracker oesophagus including diffuse and segmental patterns. Patients with normal oesophageal peristalsis served as controls. Symptoms assessment, manometry testing and 24h oesophageal pH monitoring off acid-suppressive medications were performed following a standardized protocol. The associations between nutcracker oesophagus and symptoms were assessed by logistic regression analysis. RESULTS: Nutcracker oesophagus was found in 60 patients (6.4%), of which 30 had diffuse nutcracker oesophagus and 30 had segmental nutcracker oesophagus. The control group was composed by 656 patients with normal oesophageal peristalsis. Diffuse nutcracker oesophagus was associated with chest pain (odds ratio 4.3; 95% CI 1.9-9.9; P<0.0001) and dysphagia (odds ratio 5.3; 95% CI 2.3-12.2; P<0.0001), whereas segmental nutcracker oesophagus was associated with chest pain (odds ratio 2.8; 95% CI 1.1-6.9; P=0.026), controlling for total oesophageal acid exposure, age, sex and lower oesophageal sphincter (LOS) pressure. CONCLUSION: This study suggests that both diffuse and segmental nutcracker oesophagus should be regarded as meaningful abnormalities and not mere manometric curiosities.

Genetic diversity and relatedness within and between species of the genus Oligoryzomys (Rodentia; Sigmodontinae).

A RAPD analysis on six species of the rodent genus Oligoryzomys trapped in a wide area (ranging from 01 degrees N to 32 degrees S) of Brazilian territory was performed in order to determine the levels of genetic variability within and between its populations and species. One-hundred and ninety-three animals were collected in 13 different sites (corresponding to 17 samples) located at Pampas, Atlantic Rain Forest, Cerrado, and Amazon domains. Oligoryzomys sp., O. nigripes (8 populations), O. flavescens (4 populations), O. moojeni, O. stramineus, and O. fornesi were the taxa analyzed. Of the 20 primers tested, 4 generated a total of 75 polymorphic products simultaneously amplified in 151 specimens. Various diversity estimators analyzed showed considerable differences between species and populations, indicating a great genetic variation occurring in the Oligoryzomys taxa investigated. A cluster analysis was made using Nei's standard genetic distances, however, it did not correlate the genetic heterogeneity of the species and populations with the geographical areas.

Genetic diversity and relatedness within and between species of the genus Oligoryzomys (Rodentia; Sigmodontinae)

A RAPD analysis on six species of the rodent genus Oligoryzomys trapped in a wide area (ranging from 01° N to 32° S) of Brazilian territory was performed in order to determine the levels of genetic variability within and between its populations and species. One-hundred and ninety-three animals were collected in 13 different sites (corresponding to 17 samples) located at Pampas, Atlantic Rain Forest, Cerrado, and Amazon domains. Oligoryzomys sp., O. nigripes (8 populations), O. flavescens (4 populations), O. moojeni, O. stramineus, and O. fornesi were the taxa analyzed. Of the 20 primers tested, 4 generated a total of 75 polymorphic products simultaneously amplified in 151 specimens. Various diversity estimators analyzed showed considerable differences between species and populations, indicating a great genetic variation occurring in the Oligoryzomys taxa investigated. A cluster analysis was made using Nei's standard genetic distances, however, it did not correlate the genetic heterogeneity of the species and populations with the geographical areas.

Foram realizadas análises com RAPD em seis espécies de roedores do gênero Oligoryzomys capturados em uma ampla área (estendendo-se de 01° N a 32° S) do território brasileiro com o objetivo de determinar os níveis de variabilidade genética dentro e entre as populações e espécies. Cento e noventa e três animais foram coletados em 13 locais diferentes (correspondendo a 17 amostras) localizados nos Pampas, Floresta Atlântica, Cerrado e Amazônia. Oligoryzomys sp., O. nigripes (8 populações), O. flavescens (4 populações), O. moojeni, O. stramineus e O. fornesi foram as espécies analisadas. Vinte primers foram testados, sendo que quatro deles geraram um total de 75 produtos polimórficos amplificados simultaneamente em 151 exemplares. Várias estimativas de diversidade apresentaram diferenças consideráveis entre as espécies e as populações, indicando uma grande variação genética entre os taxa de Oligoryzomys investigados. As análises de agrupamento utilizando a distância genética de Nei, entretanto, não correlacionaram a heterogeneidade genética das espécies e populações com as áreas geográficas.

Application of an African Ancestry Index as a genomic control approach in a Brazilian population.

Ten ancestry informative markers were investigated in 101 coronary artery disease patients and 102 healthy controls from a Southern Brazilian population, in order to determine if stratification occurs in this population. The degree of African admixture detected in this population was estimated to be as high as 6%, but no differences between cases and controls were observed. Using an African Ancestry Index (AAI) that estimates admixture at the individual level it was possible to remove from the samples those individuals with evidence of African admixture. Therefore we have shown that it is possible to control for population stratification by choosing individuals, without the loss of statistical power that occurs with the use of other methods of genomic control.

Estrogen-metabolizing gene polymorphisms and lipid levels in women with different hormonal status.

Endogenous and exogenous sex steroid hormones have multiple effects on lipid and lipoprotein metabolism. It is also known that estrogen has antiatherogenic actions, therefore we considered examining whether there was any association between polymorphisms in estrogen-metabolizing genes and lipid levels in women. We investigated the association between variants in genes related to estrogen biosynthesis (CYP19-TTTA(n)) and estrogen catabolism (CYP1A1*2A, CYP1A1*2C, CYP1A2-Asn516Asn, CYP3A4*1B, and COMT-Val158Met) with serum lipid levels in a cross-sectional study with 472 Brazilian women of European descent. They were divided into three subgroups according to their hormonal status: premenopausal women (n=187), postmenopausal women exposed to hormonal replacement therapy (HRT) (n=118), and postmenopausal women unexposed to HRT (n=167). The postmenopausal women receiving HRT who were carriers of the CYP3A4*1B variant showed lower low-density lipoprotein cholesterol levels than wild-type homozygotes. Premenopausal women homozygous for the CYP1A1*2C allele had higher high-density lipoprotein cholesterol levels than heterozygotes. While the CYP1A1*2C variant probably has a higher catalytic activity, the functional implications of the CYP3A4 polymorphism are still uncertain. These data are the first attempt to associate estrogen metabolism genes to lipid levels in women.

Interaction between SREBP-1a and APOB polymorphisms influences total and low-density lipoprotein cholesterol levels in patients with coronary artery disease.

In this study, we examined the insertion/deletion (Ins/Del) and XbaI polymorphisms of the apolipoprotein B (APOB) gene and the -36delG polymorphism in the sterol regulatory element binding protein-1a (SREBP-1a) gene in 298 patients with non-diabetic angiographically assessed coronary artery disease (CAD), and 188 healthy controls, from a Brazilian population of European descent. Del/X+ haplotype carriers had higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in patients (TC, p = 0.05; LDL-C, p = 0.049) and controls (TC, p = 0.004; LDL-C, p = 0.013). No association was detected between the SREBP-1a-36delG polymorphism and lipid levels, but a significant interaction effect between APOB and SREBP-1a polymorphisms was observed in the patient sample on TC (p = 0.005) and on LDL-C (p = 0.019) levels. Carriers of the APOB Del/X+ haplotype and SREBP-1a G-G- genotype showed the highest levels of these lipid parameters. This effect of interaction was not observed in the control sample. Despite the associations with lipids, these polymorphisms were not associated with CAD risk or severity in this sample.

Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome.

OBJECTIVE: To determine whether there is a relationship between the presence of histological signs of inflammation in the extraplacental membranes and umbilical cord and the concentrations of fetal plasma interleukin-6 (IL-6). METHODS: The study examined a cohort of patients who were admitted with preterm labor or preterm premature rupture of the membranes (PROM) and who underwent cordocentesis. Inclusion criteria included fetal plasma available for IL-6 determination, histological examination of the umbilical cord and placenta, and delivery within 48 h of the procedure. This last criterion was used to preserve a meaningful temporal relationship between fetal plasma IL-6 and the results of histological examination of the placenta. Fetal plasma IL-6 was determined by a high sensitivity ELISA. Forty-five patients were available for study: 18 patients had preterm labor with intact membranes and 27 had preterm PROM. RESULTS: The incidence of funisitis was 44.4% (20/45): 27.8% (5/18) in patients with preterm labor and intact membranes and 55.6% (15/27) in patients with preterm PROM. The median values of fetal plasma IL-6 in patients with funisitis, chorioamnionitis without funisitis, and non-inflamed membranes were 51.4, 18.4 and 5.2 pg/ml, respectively. After log transformation of the fetal plasma IL-6 concentration, the means differed significantly from each other (ANOVA, p < 0.02). There was no difference in log fetal plasma IL-6 concentration between patients with funisitis and those with chorioamnionitis without funisitis. The difference in mean concentration of log fetal plasma IL-6 between patients with funisitis or chorionic vasculitis and those without inflammation was highly significant (post-hoc test, p = 0.01 and p < 0.01, respectively). Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of histological signs of inflammation in the extra-placental membranes and umbilical cord than those with fetal plasma IL-6 < 11 pg/ml (funisitis: 55.6% (15/27) vs. 27.8% (5/18), p < 0.05; chorionic vasculitis: 55.6% (15/27) vs. 12.5% (2/16), p < 0.01; chorioamnionitis only: 25.9% (7/27) vs. 16.7% (3/18), p < 0.05; no inflammation: 18.5% (5/27) vs. 55.6% (10/18), p < 0.05, respectively). Fetuses with funisitis had significantly higher rates of clinical and histological chorioamnionitis, and neonatal infectious morbidity (proven + suspected sepsis) than fetuses without funisitis (40% (8/20) vs. 8% (2/25), 90% (18/20) vs. 36% (9/25), and 40% (8/20) vs. 4% (1/25), respectively; p < 0.01 for each). Fetuses with chorionic vasculitis had significantly higher rates of clinical and histological chorioamnionitis as well as neonatal infectious morbidity (proven + suspected sepsis) than fetuses without chorionic vasculitis (100% (17/17) vs. 42.3% (11/26), p < 0.01; 82.4% (14/17) vs. 50.0% (13/26), p = 0.05; and 41.2% (7/17) vs. 7.7% (2/26), p = 0.01). CONCLUSION: Fetal plasma IL-6 concentration is significantly associated with the presence of inflammatory lesions in the extraplacental membranes and umbilical cord. Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of funisitis and/or chorionic vasculitis than fetuses with fetal plasma IL-6 < 11 pg/ml. These findings suggest that funisitis/chorionic vasculitis is the histological manifestation of the fetal inflammatory response syndrome.