Fetal interleukin-1 receptor antagonist gene polymorphism, intra-amniotic interleukin-1beta levels, and history of spontaneous abortion

OBJECTIVE: The purpose of this study was to determine whether fetal carriage of specific alleles of the polymorphic interleukin-1 receptor antagonist gene is associated with variations in intra-amniotic cytokine levels and previous pregnancy outcomes. STUDY DESIGN: Fetal cells in midtrimester amniotic fluid from 189 women were tested for interleukin-1 receptor antagonist intron 2 length polymorphisms. Concentrations of cytokines in amniotic fluid were tested by enzyme-linked immunosorbent assay. Pregnancy history data were obtained subsequently. RESULTS: Homozygosity for interleukin-1 receptor antagonist allele 1 was detected in 13 of 17 fetuses (76.5%) from women whose previous pregnancies all ended in spontaneous abortions, as compared with 33 of 74 fetuses (44.6%) from women with at least 1 previous term birth ( P = .02). Fetal carriage of interleukin-1 receptor antagonist allele 2 was associated with only 1 (5.9%) previous spontaneous abortion, as opposed to 31 pregnancies (41.9%) that were associated with a previous term delivery ( P = .004). A similar relationship between interleukin-1 receptor antagonist allele 1 and spontaneous abortions was observed when pregnancies of white women only were analyzed. Median mid trimester amniotic fluid interleukin-1beta concentrations were higher in women whose previous pregnancies ended in term deliveries (15.7 pg/mL), as opposed to women with 1 to 2 (6.4 pg/mL; P = .04) or > or =3 (4.1 pg/mL; P = .007) previous spontaneous abortions. Fetal carriage of interleukin-1 receptor antagonist allele 2 was associated with elevated intra-amniotic interleukin-1beta levels (16.2 pg/mL), as compared with interleukin-1 receptor antagonist allele 1 homozygotes (10.8 pg/mL; P = .03). CONCLUSION: Fetal carriage of interleukin-1 receptor antagonist allele 1 is associated with reduced intra-amniotic interleukin-1beta concentrations and an increased occurrence of spontaneous abortions in previous pregnancies.     

Primary cardiac paraganglioma

We report a case of a 29-year-old male, who during workup of hypertension was found to have a malignant primary paraganglioma of the heart. The tumor arose from the site of the aortopulmonary window and right ventricular outflow tract (RVOT) and was removed with the aid of cardiopulmonary bypass. Reconstruction of the RVOT and pulmonary valve was necessary because of involvement by the tumor. The surgical course was uncomplicated, with normalization of catecholamine secretion and blood pressure.     

Lacrimal sac rhinosporidiosis: a case report

Rhinosporidiosis is a disease caused by Rhinosporidium seeberi. It usually affects the nasal mucosa and rarely the conjunctiva, lacrimal sac, tonsils, and skin. We present a case study of an isolated lacrimal sac rhinosporidiosis in an 8-year-old girl who was a migrant from Orissa, an Eastern coastal state of India. The mode of presentation and management of this case with a review of literature is discussed in brief.     

A comparison of the tolerability of two dilution volumes (0.5 mL and 1.0 mL) of a purified chick embryo cell rabies vaccine administered intramuscularly to healthy adult volunteers: A randomized, intraindividual, assessor-blind study

Background: The current recommendation of the manufacturer for administering purified chick embryo cell rabies vaccine (PCECV) is to reconstitute the contents with 1.0 mL of water for injection (WFI). However, it has been debated whether a lower volume of WFI (0.5 mL) is likely to cause less pain.Objectives: The aims of this study were to compare the tolerability of PCECV administered IM at a volume of 0.5 mL versus 1.0 mL of diluent and to determine the immunogenicity of the vaccine when administered according to the World Health Organization-recommended preexposure prophylaxis regimen for rabies immunization.Methods: This comparative, intraindividual, assessor-blind study was conducted at the Department of Clinical Pharmacology, Topiwala National Medical College and Bai Yamunabai Laxman Nair Charitable Hospital Mumbai, India). Healthy volunteers aged 18 to 50 years received, by randomized sequence, 3 IM injections of PCECV, diluted in 0.5 mL or 1.0 mL of WFI, on study days 0, 7, and 28. Tolerability was assessed at 30 minutes and 24 hours after injection and included assessments for local and systemic reactions. For immunogenicity assessment, rabies virus-neutralizing antibody 0RVNA) titers were assayed at baseline and on day 49 (ie, 3 weeks after the third injection).Results: Twenty-six subjects (24 men, 2 women; mean [SD] age, 22.4 [2.4] years; mean [SD] body weight, 59.0 [11.3] kg) entered the study. Twenty-five subjects were included in the tolerability assessment; 24 in the immunogenicity assessment. No statistically significant differences were found between dilutions in the frequency of local and systemic reactions. Most reactions were mild. All subjects developed RVNA titers >0.5 IU/mL (indicative of protection) by day 49.Conclusions: In this population of healthy volunteers, a full antigenic dose of PCECV in a dilution of 0.5 mL WFI is as well tolerated locally and systemically as in a dilution of 1.0 mL. All subjects developed levels of RVNA far exceeding 0.5 IU/mL, which is indicative of protection against rabies.     

Pharmacokinetics of erythromycin in rabbit corneas after single-dose infusion: role of P-glycoprotein as a barrier to in vivo ocular drug absorption

Efflux pump like P-glycoprotein (P-gp) is known to be a major barrier to drug delivery. Functional P-glycoprotein has been recently identified in cornea and corneal cell lines. Thus, it is probable that P-glycoprotein may restrict in vivo ocular drug absorption, resulting in low ocular bioavailability. Experiments were designed using New Zealand albino (New Zealand White) rabbits to assess inhibitors of P-gp efflux to increase drug absorption. Anesthetized rabbits were given constant topical infusions of [(14)C]erythromycin in the presence and absence of inhibitors. Testosterone, verapamil, quinidine, and cyclosporine A were selected as P-gp inhibitors. Transport experiments were conducted in Madin-Darby canine kidney cells transfected with the human mdr1 gene (MDCK-MDR1). Erythromycin exhibited significant efflux out of MDCK-MDR1 cells, suggesting that erythromycin is a good substrate for P-gp. Ocular pharmacokinetic studies were conducted using a topical single-dose infusion method. Maximum inhibition of P-gp mediated efflux was observed with 500 microM testosterone. Area under the curve (AUC)(0- infinity ) of erythromycin with 500 microM testosterone was almost 4 times higher than AUC(0- infinity ) without any inhibitor. Rate of elimination (k(10)) for erythromycin and those with inhibitors was found to be similar (141 +/- 23 min), suggesting that elimination pathways were not altered. All the inhibitors were found to be nontoxic. Verapamil also inhibited the efflux pump with moderate change in AUC(0- infinity ) and C(max) compared with control. Thus, P-gp is found to be active in vivo, and it restricts topical erythromycin absorption across the cornea, which can be inhibited by known P-gp inhibitors. Therefore, ocular bioavailability of P-gp substrates can be significantly enhanced by proper selection of P-gp inhibitors.     

Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor

Activation of plasma prekallikein and generation of bradykinin are responsible for the angioedema attacks observed with C1-inhibitor deficiency. Heterozygous individuals with <50% levels of active C1-inhibitor are susceptible to angioedema attacks indicating a critical need for C1-inhibitor to be present at maximum levels to prevent unwanted prekallikrein activation. Studies with purified proteins do not adequately explain this observation. Therefore to investigate why reduction of C1-inhibitor to levels seen in angioedema patients results in excessive kallikrein generation we examined the effect of endothelial cells on the inhibition of kallikrein by C1-inhibitor. Surprisingly, it was found that a C1-inhibitor concentration of greater than 1 microM was needed to inhibit 3 nM kallikrein. We propose that this apparent protection from inhibition was mediated by kallikrein binding to the cells via the heavy chain in a high molecular weight kininogen and zinc independent manner. Protection of kallikrein from inhibition was not observed when C1-inhibitor truncated in the amino-terminal domain by the StcE metalloproteinase was used, which suggests a novel function for this unique domain. The requirement for high concentrations of C1-inhibitor to fully inhibit kallikrein is consistent with the fact that reduced levels of C1-inhibitor result in the kallikrein activation seen in angioedema.     

Racial disparity in meconium-stained amniotic fluid and meconium aspiration syndrome in the United States, 1989-2000

OBJECTIVE: To estimate the prevalence of meconium-stained amniotic fluid and meconium aspiration syndrome, as well as the differences in case fatality from meconium aspiration syndrome, between non-Hispanic black and non-Hispanic white infants. METHODS: We studied non-Hispanic black and non-Hispanic white live births with weights greater than 2.5 kg and gestational ages greater than 35 weeks, using the linked US birth and infant death cohorts for three periods: 1989-1991, 1995-1997, and 1998-2000. We used logistic regression to estimate the risks of meconium-stained amniotic fluid and meconium aspiration syndrome and to estimate the case fatality of meconium aspiration syndrome by maternal race, birth weight, period, and pregnancy complications. RESULTS: Risk of meconium-stained amniotic fluid was 80% higher in non-Hispanic blacks when compared with non-Hispanic whites (birth weight-adjusted odds ratio [OR], 1.81, 95% confidence interval [CI] 1.80, 1.82). The prevalence of pregnancy complications did not explain this racial disparity. Risk of meconium aspiration syndrome in non-Hispanic blacks was 67% higher when compared with non-Hispanic whites (birth weight-adjusted OR 1.67, 95% CI 1.64, 1.70). The case fatality rate of meconium aspiration syndrome was similar between non-Hispanic blacks and non-Hispanic whites in the three periods, with rates of 15.5, 15.2, and 11.2 per 1000 in non-Hispanic blacks and 13.5, 11.2, and 10.1 per 1000 in non-Hispanic whites in 1989-1991, 1995-1997, and 1998-2000, respectively. CONCLUSION: Our results suggest that when compared with non-Hispanic whites, non-Hispanic blacks are at significantly greater risk for meconium-stained amniotic fluid and meconium aspiration syndrome but not for meconium aspiration syndrome case fatality.     

Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinases TIMP-3 and -4 in benign endometrium and endometrial cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) and their physiological inhibitors, the tissue inhibitors of MMPs (TIMPs), play a key role in tumor cell invasion, angiogenesis, and growth. The aim of this study was to determine the expression and cellular distribution of MMP-26, TIMP-3, and TIMP-4 in endometrial cancers and benign endometrium throughout the menstrual cycle and the correlation with tumor histological subtype, stage, and grade. METHODS: Immunohistochemical analysis using polyclonal antibodies generated against pro- and active MMP-26, and mono- and polyclonal antibodies specific to TIMP-3 and TIMP-4, respectively, was performed. RESULTS: MMP-26, TIMP-3, and TIMP-4 are expressed in endometrial carcinomas (N = 86) and benign endometrium (N = 50) from various stages of the menstrual cycle. Semi-quantitative analysis of staining intensity indicated that endometrial carcinomas expressed more MMP-26, TIMP-3, and TIMP-4 compared to benign endometrium from the postmenopausal period, but not from the secretory phase of the menstrual cycle. The highest staining intensity was associated with endometrial epithelial cells, followed by vascular endothelial cells, myometrial smooth muscle cells, and endometrial stromal cells. Increased staining intensity of MMP-26 and TIMP-3 correlated with grade III tumors and MMP-26 and TIMP-4 with the depth of myometrial invasion in tumors histologically characterized as endometrioid adenocarcinoma, clear-cell, and papillary serous carcinoma staged/graded based on FIGO criteria. CONCLUSION: MMP-26 and TIMP-4 are expressed in endometrium and endometrial carcinoma and their elevated expression and correlation with myometrial invasion suggests that MMP-26 and TIMP-4 may play a key role in endometrial tumor progression.