Hormonal and barrier contraception and risk of upper genital tract disease in the PID Evaluation and Clinical Health (PEACH) study.

OBJECTIVE: Among women diagnosed with pelvic inflammatory disease, we examined the associations between hormonal or barrier methods of contraception and upper genital tract infection or inflammation. METHODS: Participants were 563 patients from a treatment trial for pelvic inflammatory disease. All had pelvic pain; pelvic organ tenderness; and leukorrhea, mucopurulent cervicitis, or untreated cervicitis. Contraceptive use within the prior 4 weeks was compared among women with baseline upper genital tract gonorrhea or chlamydia, women with endometritis without upper genital tract gonorrhea or chlamydia, and women with neither upper genital tract gonorrhea or chlamydia nor endometritis. RESULTS: Inconsistent condom use was significantly and independently associated with a 2 to 3 times elevated risk for upper genital tract infection. Upper genital tract gonorrhea or chlamydia was not significantly associated with use of oral contraceptives, use of medroxyprogesterone, condoms used consistently, nor other barrier methods. CONCLUSION: No hormonal or barrier contraceptive method was related to a reduction in upper genital tract disease among women with clinical pelvic inflammatory diseases.

Douching and endometritis: results from the PID evaluation and clinical health (PEACH) study.

BACKGROUND: Douching has been related to risk of pelvic inflammatory disease (PID). GOAL: To examine the association between douching and PID in a large, multicenter, clinical trial of PID after adjustment for race/ethnicity. STUDY DESIGN: Interviews were conducted with 654 women who had signs and symptoms of PID. Vaginal Gram stains and upper genital tract pathology/cultures were obtained from all the women. Women with evidence of plasma cell endometritis and/or gonococcal or chlamydial upper genital tract infections were compared with women who had neither endometritis nor upper genital tract infection. RESULTS: Women with endometritis or upper genital tract infection were more likely to have douched more than once a month or within 6 days of enrollment than women who never douched. These associations remained after adjustment for confounding factors, after analysis of black women only; and among women with normal or intermediate vaginal flora but not bacterial vaginosis. CONCLUSION: Among a predominantly black group of women with clinical PID, frequent and recent douching was associated with endometritis and upper genital tract infection.

Clinical predictors of endometritis in women with symptoms and signs of pelvic inflammatory disease.

OBJECTIVE: Careful detection and treatment of pelvic inflammatory disease are essential for the prevention of adverse sequelae. The purpose of this study was to evaluate the diagnostic test characteristics of clinical criteria for the diagnosis of pelvic inflammatory disease. STUDY DESIGN: We performed a cross-sectional analysis of the baseline characteristics of 651 patients enrolled in a multicenter randomized treatment trial for pelvic inflammatory disease. Clinical and laboratory findings were recorded for all patients, and endometrial sampling was performed. We calculated sensitivity and specificity and performed receiver operating characteristic curve analysis and multivariate logistic regression, using histologic endometritis as the criterion standard. RESULTS: The minimal criteria for pelvic inflammatory disease, as recommended by the Centers for Disease Control and Prevention, had a sensitivity of 83%, in comparison with a 95% sensitivity for adnexal tenderness (P =.001). Of the supportive clinical criteria, the finding most highly associated with endometritis was a positive test result for Chlamydia trachomatis or Neisseria gonorrhoeae (adjusted odds ratio, 4.3; 95% confidence interval, 2.89--6.63). A multivariate logistic regression model indicated that combinations of criteria significantly improve the prediction of endometritis. CONCLUSION: Sensitivity can be maximized by using the presence of adnexal tenderness as a minimal criterion for the diagnosis of pelvic inflammatory disease, and supportive criteria are helpful in estimating the probability of endometritis.

Analysis of TCR Vbeta repertoire and cytokine gene expression in patients with idiopathic dilated cardiomyopathy.

Although the etiopathogenesis of idiopathic dilated cardiomyopathy (IDC) is still unclear, it is widely accepted that a complex interplay between viral infections and immune mechanisms is the basis of disease genesis. Previously, we showed that heart-infiltrating T cells of patients suffering from acute, fulminant Coxsackie virus B3+-IDC shared a preferential usage of three variable gene segments of the T cell receptor beta chain-(TCR-Vbeta) encoding families Vbeta3, 7 and 13.1. This indicated the possible presence of a superantigen-driven immune response. Here, we further investigated the IDC immunological scenario by analysing different phenotypes of heart-infiltrating cells: TCR repertoires, cytokine expression and presence of enterovirus-specific antigens. IDC patients who underwent heart transplantation at different times after the onset of heart failure were studied. A cardiac infiltrate of CD4+ and CD8+ T cells was present together with activated macrophages. Furthermore, the same Vbeta gene families, previously found to be skewed in hearts from fulminant cases of CVB3+-IDC, together with two additional Vbeta gene families, Vbeta1 and 5B, were increased. IL-1beta, IL-2, IL-6 and IFN-gamma were expressed in the myocardium while others, like IL-4 were not. In conclusion, an orchestrated complex of immune mechanisms seems to be the basis of IDC etiopathogenesis.

Idiopathic dilated cardiomyopathy: a superantigen-driven autoimmune disease.

BACKGROUND: Many cases of idiopathic dilated cardiomyopathy (IDC) result from an inflammatory myocarditis. The specific immunological mechanisms are not yet defined. Various autoimmune diseases are associated with superantigen-triggered immune responses, resulting in massive T-cell activation and tissue damage. We studied 3 cases in a search for evidence that such a phenomenon is also implicated in IDC. METHODS AND RESULTS: Myocardial, lymph node, and thymic tissue samples were obtained from IDC patients who were undergoing heart transplantation. Infiltrating immune-cell phenotypes and gene expression of T-cell receptor (TCR) alpha- and beta-chain variable (Valpha and Vbeta) regions were analyzed by immunostaining and polymerase chain reaction. Similar technical approaches were used to assay the tissues for the presence of coxsackievirus B (CVB). In all the specimens analyzed, an overexpression of the TCR Vbeta3, Vbeta7, and Vbeta13.1 gene families was detected among the infiltrating T cells. These tissues were also found to be CVB3-positive. In vitro exposure of peripheral blood mononuclear cells to lysates of cells infected with CVB3 was capable of stimulating expansion of the same TCR Vbeta families. The TCR Valpha repertoire was never found to be skewed. CONCLUSIONS: A superantigen-mediated immune response is involved in human heart disease. CVB3 may directly or indirectly trigger this response, suggesting a possible mechanistic link between CVB infection and myocarditis development progressing to IDC.

Neonates with electrically confirmed seizures and possible placental associations.

Placental specimens were reviewed from 73 singleton pregnancies of women whose offspring received electroencephalogram (EEG) studies in the neonate period. A group of 43 neonates (postconception age [PCA] 23-44 weeks) with electrically confirmed seizures in the immediate neonate period were compared with 30 healthy preterm and term infants of comparable PCA who had no electrographic seizures. Pathologic placental changes were separated: Group A consisted of chorioamnionitis, edema, meconium staining, and/or retroplacental hematoma. Group B consisted of abnormal villous maturation, infarction, and/or chronic villitis. Logistic regression analyses calculated the odds ratio of having Group A or Group B placental lesions in each neonate group as a function of increasing PCA. For the seizure group, the odds of having Group B with or without Group A placental lesions increased by a factor of 1.2 for each postconception week up to 43 weeks PCA. For a 15-week interval the odds of having Group B lesions for the seizure group increased by a factor of 12.1 (P < 0.007). Ratios were not significant for Group A lesions alone in the seizure group or for either Group B or Group A findings in the neonate group without seizures. Pathophysiologic events in utero leading to Group B rather than Group A findings are associated with electrically confirmed seizures in near-term and term infants. Group A lesions were considered more likely to have intrapartum or peripartum associations, whereas Group B lesions were considered more likely to have antepartum associations.

Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus.

Fas is an apoptosis-inducing surface receptor involved in controlling tissue homeostasis and function at multiple sites. Here we show that beta cells from the pancreata of newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients express Fas and show extensive apoptosis among those cells located in proximity to Fas ligand-expressing T lymphocytes infiltrating the IDDM islets. Normal human pancreatic beta cells that do not constitutively express Fas, become strongly Fas positive after interleuken (IL)-1beta exposure, and are then susceptible to Fas-mediated apoptosis. NG-monomethyl-L-arginine, an inhibitor of nitric oxide (NO) synthase, prevents IL-1beta-induced Fas expression, whereas the NO donors sodium nitroprusside and nitric oxide releasing compound (NOC)-18, induce functional Fas expression in normal pancreatic beta cells. These findings suggest that NO-mediated upregulation of Fas contributes to pancreatic beta cell damage in IDDM.

Lymphoproliferative disorder involving the cervix in a patient being treated with FK-506.

FK-506 is an immunosuppressive agent used mainly to prevent allograft rejection in organ transplant patients. Recently, it has been applied as a treatment for patients with autoimmune disorders. An entity called posttransplant lymphoproliferative disorder (PTLD) is a well-recognized result of immunosuppression in transplant patients receiving long-term immunosuppression. This disorder is a complication of treatment with FK-506 in 0.7 to 1.6% of transplant patients and is usually of B-cell origin. A majority of patients have serologic evidence of EBV infection. We report a case of a patient receiving long-term FK-506 therapy for multiple sclerosis who developed lymphoproliferative disorder involving the cervix. We will discuss the possible role of FK-506 initiation of this tumor.

Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology.

Insulin-dependent diabetes mellitus (IDDM) is a T-cell-mediated autoimmune disease whose onset is believed to be triggered by unknown environmental factors acting on a predisposing genetic background. Islet-infiltrating T (IIT) cells from two IDDM patients, who had died at the onset of the disease from brain swelling as a complication of ketoacidosis, were analysed. The results provided evidence for the involvement of a pancreatic islet cell membrane-bound superantigen as a diabetes aetiopathogenetic factor. There was a selective expansion of a T-cell receptor (TCR) variable segment of the beta-chain (V beta 7) in these IIT cells in association with unselected V alpha-chain segments; extensive junctional diversity of the TCR V beta 7 chains; and evidence of positive selection, after exposure to diabetic islet cell membrane preparations, of V beta 7+ T-cell clones among peripheral blood lymphocytes from non-diabetic individuals.

The argyrophilic nucleolar organizer regions in ductal carcinoma in situ of the breast. The significance of ploidy and proliferative activity analysis using this silver staining technique.

BACKGROUND: Two interphase argyrophilic nucleolar organizer region (AgNOR) counts have been correlated with ploidy and proliferative activity in patients with ductal carcinoma in situ (DCIS) of the breast. The first is the mean number of AgNORs (mAgNOR); it reflects ploidy. The second is the percentage of nuclei with greater than or equal to five AgNORs/nucleus (pAgNOR); it correlates with proliferative activity. DCIS of the breast is a heterogeneous group of lesions that is not associated uniformly with invasive ductal carcinoma. A significant number of patients with DCIS will, however, progress to invasive ductal carcinoma. Factors identifying the invasive potential of DCIS in these patients have not been defined clearly. The authors postulated that pAgNOR in DCIS may predict the invasive potential of these lesions. METHODS: The authors studied 86 cases of DCIS of the breast by the AgNOR silver stain using the two above-mentioned counts. RESULTS: There were 54 comedo and 32 noncomedo DCIS cases. Forty-one cases (47%) were associated with invasive ductal carcinoma. Thirty cases of comedo DCIS (55%) showed mAgNOR counts suggestive of aneuploidy (> or = 2.4/nucleus), whereas only seven cases of noncomedo DCIS (22%) showed such counts (P = 0.001). Cases associated with invasion had higher incidence of aneuploid mAgNOR counts (P = 0.0003). The pAgNOR counts in comedo DCIS ranged from 1% to 36% (median, 11%), whereas in noncomedo DCIS pAgNOR counts ranged from 0% to 22% (median, 7%) (P = 0.007). The 41 cases associated with invasion had pAgNOR counts ranging from 3% to 36% (median, 12%), whereas those not associated with invasion had pAgNOR counts ranging from 0% to 24% (median, 5%) (P = 0.000001). This difference was irrespective of the type of DCIS or mAgNOR counts. CONCLUSIONS: Comedo DCIS of the breast may show a higher incidence of aneuploidy and increased proliferative activity and invasive ductal carcinoma than does noncomedo DCIS. Ploidy and proliferative activity, measured by AgNOR staining in DCIS, may have a significant predictive value in identifying the invasive potential of these lesions.

How the exercise electrocardiogram is used in clinical practice in patients with suspected coronary artery disease.

Clinical use of a test should be evaluated not only on the change of pretest probability but also on the increased confidence in the judged probability, and on the decision of recommending additional tests or therapy after test results. Before and after the test, cardiologists referring a patient for exercise electrocardiogram for suspected coronary artery disease were asked to estimate the probability of coronary artery disease and the minimal and maximal value of their estimate (plausible range), to judge whether to refer the patient for coronary angiography, and to specify patient's treatment. After the test, the percentage of patients with estimated probability < or = 20% increased (from 53 to 69%; p = 0.005) and the percentage of patients with intermediate probability (between 21 and 80%) decreased (from 37 to 16%; p = 0.0001). The mean plausible range decreased from pre- to post-test assessment (31 +/- 23 to 15 +/- 16%; p = 0.0001), indicating an increase in cardiologists' confidence in their estimates. After the test, the percentage of cardiologists who wished to either refer or not refer patients for coronary angiography increased (from 4 to 13%, p < 0.005; and from 37 to 65%, p < 0.0001, respectively). Test results enable cardiologists to change the assessment of disease probability, the confidence in their own estimates, and their judgment of whether to refer patients for coronary angiography.

Prevention by tetrandrine of spontaneous development of diabetes mellitus in BB rats.

Treatment of BB rats with the plant alkaloid tetrandrine (20 mg.kg-1.day-1), a novel anti-inflammatory compound, from 35 to 120 days of age reduced the cumulative incidence of spontaneous diabetes from 75.5 to 10.9% (P less than 0.001). Dose-response studies with 0, 5, 10, and 20 mg.kg-1.day-1 of tetrandrine from 35 to 130 days resulted in spontaneous diabetes in 84.2, 63.1, 31.6, and 5.3% of the rats, respectively. When the start of treatment with 20 mg.kg-1.day-1 tetrandrine was delayed until 70 days of age, there was a significant reduction of the incidence of diabetes from 63.1 to 28.6% (P less than 0.01). Histological examination of the pancreases from tetrandrine-treated rats showed a lesser degree of insulitis than controls (P less than 0.01). Drug toxicity was not seen in the rats, as assessed by appearance, behavioral change, organ histology, and blood chemistry. These results provide some hope that tetrandrine may be of value in preventing diabetes and treating newly diagnosed diabetic subjects, either by itself or in combination with a more potent immunosuppressive agent.

A new HLA-DR2 extended haplotype is involved in insulin-dependent diabetes mellitus susceptibility.

To ascertain why HLA-DR2 seems to confer only a moderate resistance to insulin-dependent diabetes mellitus (IDDM) in the high-incidence population of Sardinia, Italy, 32 families having one individual affected with IDDM (the proband) and 31 families without IDDM history were randomly selected from the same geographical area and serologically and molecularly HLA typed. The 64 haplotypes of the probands were then compared with the 122 haplotypes determined in the parents from the control families. Two haplotypes were found to have the highest percentage in the general population (12.3% and 7.3%, respectively). The first is the already described "Sardinian" extended haplotype A30, Cw5, B18, 3F130, DR3, DRw52, DQw2 (39.0% in IDDM patients). The second is an extended haplotype that has not been identified before (A2, Cw7, B17, 3F31, DR2, DQw1), and, due to the DR2 allele, we expected it to be decreased in IDDM. However, a stratified analysis performed by removing the DR3 and DR4 haplotypes showed that the frequency of this haplotype is significantly increased in IDDM patients. A peculiar feature of this haplotype is its DQw1 allele, which is DQB1*0502 and has serine in position 57 of the DQ beta chain. The absence of an aspartic acid in this position seems to confer susceptibility to IDDM and not resistance. The fact that DQB1*0502 was present in 75% of the Sardinian DR2 haplotypes may explain why, in Sardinia, DR2 is not providing the commonly recognized resistance to IDDM.

Rapid detection of IDDM susceptibility with HLA-DQ beta-alleles as markers.

The allelic forms of the human leukocyte antigen (HLA)-DQ beta-chain (DQB1) have been recognized as the best markers of insulin-dependent diabetes mellitus (IDDM) susceptibility. We describe a method that allows the recognition of these DQB1 alleles without the use of either allele-specific oligonucleotide probes or radioactive material. This method determines these alleles by electrophoretically separating restriction enzyme-generated fragments from the polymerase chain-reaction-amplified second exon of the HLA-DQB1 gene, which encodes the first domain of the protein chain. This digestion method, which is simpler and more rapid than the previously adopted hybridization method, is described in detail to enable individuals at any clinical laboratory to quickly ascertain IDDM susceptibility.

Capacitation and acrosome reactions in human spermatozoa monitored by a chlortetracycline fluorescence assay.

Human spermatozoa were incubated in culture medium containing human serum albumin (HSA) to promote capacitation, which was monitored by a rapid chlortetracycline (CTC) fluorescence assay. Four CTC fluorescence patterns were readily distinguished, one of which appeared to be correlated with capacitated sperm. When capacitated sperm were treated with either ionophore A23187 or acid-solubilized mouse zonae pellucidae to induce the acrosome reaction, the CTC assay identified acrosome-reacted sperm by lack of fluorescence on the head. Fresh sperm would not undergo the induced acrosome reaction. The percentages of acrosome-reacted sperm identified by the CTC assay in induced and control populations were the same as those identified by the presently used indirect immunofluorescence and triple stain assays.

Effects of L-carnitine on exercise tolerance in chronic stable angina: a multicenter, double-blind, randomized, placebo controlled crossover study.

L-carnitine was studied in forty-four men with stable chronic angina in a multicenter, double-blind, randomized, placebo controlled crossover trial. A cycloergometer exercise test was performed after a 10-day wash-out with placebo and at the end of each 4-week treatment period with either L-carnitine (1 g twice daily) or placebo. The mean (+/- SD) exercise work load showed an increase after L-carnitine compared to placebo (102.73 +/- 22.23 and 97.05 +/- 22.77 watts respectively, p = 0.001), as did the watts to onset of angina (95.7 +/- 24.07 and 87.44 +/- 24.67, p = 0.000). On the contrary, the ST segment depression was reduced by L-carnitine compared to placebo both at the maximum work load (1.40 +/- 0.90 and 1.69 +/- 0.82 mm, p = 0.05) and at the maximum work load common to L-carnitine and placebo (1.24 +/- 0.90 and 1.66 +/- 0.79 mm, p = 0.005). 22.7% of the patients became free of angina with L-carnitine and 9.1% with placebo. Resting and exercise blood pressure, heart-rate and double product were unaffected by L-carnitine. 1 patient decided to discontinue the trial because of gastric pyrosis while taking the active drug. The results of this study show that treatment with L-carnitine increases exercise tolerance and reduces ECG indices of ischemia in stable effort-induced angina.