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Gonococcal infection of human fallopian tube mucosa in organ culture: relationship of mucosal tissue TNF-alpha concentration to sloughing of ciliated cells.

BACKGROUND AND OBJECTIVES: An experimental model consisting of gonococcal infection of human fallopian tube mucosa in organ culture has proven useful in studying the molecular pathogenesis of acute gonococcal salpingitis and postsalpingitis sequelae. Gonococcal infection of human fallopian tube mucosa in organ culture results in the sloughing of ciliated epithelial cells from the mucosa. This damage to the mucosa can be quantified on fallopian tube pieces by an assay of the percent of the periphery that has ciliary activity (PPCA) remaining at specific time points after infection. Although assay of the PPCA has been quite valuable, it is labor-intensive, somewhat subjective, and requires that the observers have training and experience. A more practical assay for genital mucosal damage is desirable for further investigations that employ the fallopian tube experimental model. Gonococcal infection of fallopian tube mucosa in organ culture also results in the production of easily quantified tumor necrosis factor-alpha (TNF-alpha) by the mucosa. Furthermore, treatment of the organ cultures with recombinant human TNF-alpha (rHuTNFalpha) alone also causes sloughing of ciliated cells from the mucosa. These findings strongly suggest that TNF-alpha is a mediator of the mucosal damage that attends gonococcal infection. GOALS OF THE STUDY: To determine: (1) whether the PPCA values and the TNF-alpha concentrations in fallopian tube mucosal tissues correlate closely enough to allow prediction of the PPCA from a measurement of the mucosal tissue TNF-alpha concentration; and (2) whether the correlation of the TNF-alpha mucosal tissue concentration with the sloughing of ciliated cells (measured by the PPCA) supports the hypothesis that induction of TNF-alpha by gonococcal infection, with resultant sloughing of ciliated cells, is likely to be a major pathogenic mechanism of gonococcal salpingitis and might mediate postsalpingitis infertility and ectopic pregnancy. STUDY DESIGN: A metaanalysis was performed on studies from three research groups (two laboratories in the United States and one in the United Kingdom, using identical techniques for quantifying the PPCA, TNF-alpha, or both. RESULTS: There was a close and statistically significant correlation between the TNF-alpha mucosal tissue concentration and the proportion of ciliated cells lost from the mucosa as measured by the PPCA (r = 0.95, p < 0.001). Therefore, as the mucosal tissue concentration of endogenous TNF-alpha increased, the loss of ciliated cells from the epithelium increased proportionately. CONCLUSIONS: During gonococcal infection of human fallopian tube mucosa in organ culture, the mucosal tissue concentration of TNF-alpha can be used to predict the PPCA, and therefore, the extent of mucosal damage. This finding should facilitate studies of the molecular pathogenesis of infectious diseases involving human genital mucosa. Further, the close correlation of mucosal TNF-alpha concentration with genital mucosal damage, evaluated by the PPCA, supports the hypothesis that induction of the proinflammatory cytokine, TNF-alpha, by gonococcal infection, with resultant inflammation and sloughing of ciliated cells, is an important pathogenic mechanism of gonococcal salpingitis and may mediate postsalpingitis infertility and ectopic pregnancy as well.

Cilia↗

Pelvic inflammatory disease during pregnancy.

Pelvic inflammatory disease associated with pregnancy is not commonly reported. We present three illustrative cases at ten, 13, and 26 weeks of gestation. Unlike pelvic abscess, which may be discovered at any stage of gestation, acute salpingitis during pregnancy occurs more commonly in the first trimester. Both processes are associated with substantial fetal wastage. Diagnosis may be difficult if the obstetrician is not aware that these infections can occur during pregnancy. The diagnosis is often made at laparotomy by a physician expecting appendicitis or another inflammatory condition. Since salpingitis during pregnancy, like salpingitis generally, is amenable to antibiotic therapy, surgery may be avoided if appropriate antibiotic therapy is quickly instituted. The pregnant patient and her fetus may be spared general anesthesia and the attendant risks of abdominal surgery.

Abdomen↗

Reduction in hospitalized women with pelvic inflammatory disease in Oslo over the past decade.

BACKGROUND: A tuboovarian abscess (TOA) is a common complication of pelvic inflammatory disease (PID), occurring world-wide in 15-30% of women with PID. The aim of the study was to identify changes during the last 10 years in the number of women hospitalized with PID in Oslo, as well as a change regarding the frequencies of the subdiagnoses salpingitis and tuboovarian abscess. METHODS: We performed a review of computerized diagnosis lists and manual check of the medical records of women hospitalized with PID in Oslo. The years 1990-92 and 2000-02 were included, resulting in information from two time periods 10 years apart. Cases were registered as salpingitis, oophoritis or tuboovarian abscess. Medical and demographic variables from the medical records of women diagnosed during 4 out of the 6 years were described in detail. RESULTS: We identified 523 women with the diagnosis of PID hospitalized during 1990-92 and 2000-02. There was a 35% reduction in hospitalized cases of salpingitis over the period of 10 years, but the number of cases of tuboovarian abscesses among women admitted for PID remained unchanged from 1990-92 to 2000-02. We found low frequencies of Chlamydia trachomatis and Neisseria gonorrhoea infections, although documented bacteriological sampling was insufficient. CONCLUSIONS: Fewer patients were hospitalized in Oslo for PID during the time period of 2000-02 compared with 10 years earlier, but a higher percentage of patients had developed TOA compared with the first time period (43% compared with 26%, p = 0.013), indicating a changing clinical panorama of PID.

Abscess↗

PID: clinical and laparoscopic aspects.

Clinical signs of pelvic inflammatory disease (PID) are not constant and are often limited to slight pelvic pain. Laparoscopy can lead to a rapid and correct diagnosis of PID. Intrapelvic bacteriologic samples can be obtained so as to administer the proper antibiotic. The exact nature of the lesions can be evaluated, and in severe cases, recent abscesses can be treated with good results for fecundity. Because the results in cases of long-standing abscess are not so good, laparoscopy should be performed at the onset of infection and not be reserved until after some weeks of inefficient medical treatment, especially in young women who have not completed their family. In primary chronic salpingitis, the lack of any clinical signs usually leads to a delay in diagnosis until women consult for fertility problems. The ideal point would be to detect some biologic or clinical change that may lead to diagnosis such as a positive anti-Chlamydia trachomatis (CT) serology or, in the future, positive anti-CT Hsp 60 antibody could be the key to detecting and treating silent salpingitis in young women, CT being the main microorganism involved in chronic salpingitis. Screening for C. trachomatis low genital tract infection is mandatory in young people in order to control the epidemic.

Abscess↗

Incidence, trends, and risks of ectopic pregnancy in a population of women.

In a 20-year longitudinal study on ectopic pregnancy in a defined population of women aged 15-39 years the rate of ectopic pregnancy per 1000 diagnosed conceptions increased from 5.8 during 1960-4 to 11.1 during 1975-9. The mean annual incidence of ectopic pregnancy per 1000 women increased from 0.6 to 1.2 during the same period. The numbers of ectopic pregnancies per 1000 diagnosed conceptions increased with increasing age of the women and were 4.1, in the teenage group 6.9, in women aged 20-29 years, and 12.9 in women aged 30-39. Among 20- to 29-year-old sexually active women at risk of pregnancy who had never had acute salpingitis the rates of ectopic pregnancy per 100 woman-years were the same in those who did not use contraceptives as in those using non-medicated or copper-medicated intrauterine contraceptive devices (IUCDs; 0.3/100 woman years). The risk of an ectopic pregnancy increased sevenfold after acute salpingitis. These findings confirm the increased risk of ectopic pregnancy after salpingitis and suggest that the increase in the incidence of ectopic pregnancy in Lund from 1960 to 1979 was partly accounted for by the use of IUCDs.

Adolescent↗

[Genital Chlamydia trachomatis infection in abortion seekers. Strategy of examination and treatment in order to reduce the sequelae of the infection].

Among women applying for termination of pregnancy, 5-17% are infected with Chlamydia trachomatis. The prevalence is higher among women under 20 years of age (12-30%), in nulliparae and when Neisseria gonorrhoeae are found simultaneously. If women applying for termination of pregnancy with Chlamydia infection are not treated, 10-60% will develop pelvic infection after abortion. Salpingitis caused by Chlamydia runs a milder clinical course than salpingitis caused by gonococci or other etiology but salpingitis due to Chlamydia is regarded as one of the most important causes of tubal infertility and extrauterine pregnancy. The symptoms may be discharge and dysuria or objective findings such as cervicitis and pathological findings in wet smears of the cervical secretion. The majority of women applying for termination of pregnancy with Chlamydia infection have no symptoms. Only few investigations have analysed Chlamydia infection in connection with sexual behaviour and association between Chlamydia infection and the number of sexual partners has been demonstrated. Direct immune fluorescent microscopic examination or enzyme immune examination of material from the cervix and urethra may be employed in women applying for termination of pregnancy on account of the rapid results. Tetracyclines and erythromycin may be employed for treatment of demonstrated Chlamydia infection. Completion of treatment prior to abortion is probably not necessary. The sexual partners should be treated.

Abortion Applicants↗

Histopathology of fallopian tubes with recurrent tubal pregnancy.

Fifteen fallopian tubes in which a previous ipsilateral eccyesis was managed by conservative surgical techniques were examined. The condition of the tube relative to the previous surgical management and the resolution of the previous implantation sites were correlated with the recurrent tubal pregnancy. All previous incisions were identified and all were well-healed, except for one fistula. Residual histologic evidence was present in only five of 16 previous implantation sites. The recurrent eccyeses were related to previous surgical management in only three women, two after anastomosis and one because of inadvertent obstruction of the tube. The cases of tubal obstruction and tuboperitoneal fistula formation were thought to reflect a lack of understanding of the pathologic changes associated with tubal pregnancy during conservative surgery. The previous tubal incision sites were all remarkably well-healed regardless of whether they were primarily closed or left open, and independent of location. Infundibular or fimbrial "milk-outs" were without histologic evidence of damage. The underlying tubal disease (chronic salpingitis, follicular salpingitis, or salpingitis isthmica nodosa) seems to be the major factor identified that is associated with, and probably the cause for, the recurrent tubal gestation.

Adult↗

A pelvic scoring system for infertility surgery.

A pelvic scoring system for infertility surgery was devised in which pelvic pathology is assessed for comparative and prognostic purposes. Pelvic pathology was divided into three areas: adhesions (ADH), salpingitis (SPG), and tubal occlusion (TOC). The extent of pathology was scored as mild (1), moderate (2), severe (3), or extensive (4). The maximum scores for adhesions, salpingitis, and tubal occlusion were 48, 24, and 28, respectively--various weightings were applied and subareas accounted for. The pelvic score (PLV#) was simply the sum of the adhesions (ADH#), salpingitis (SPG#), and tubal occlusion (TOC#) scores. The stage of pelvic pathology was arbitrarily assigned as stage 0, I, II, III, and IV with PVL#'s of 0, 1-25, 26-50, 51-75, and 76-100, respectively. A close correlation (r = .960-.990) of PLV# was noted between different observers using this system. Poorer reproductive potential was observed in the patients with higher scores and stages. This scoring system properly reflects clinical experience and can be relied on for patient counseling via prediction of prognosis. This system can be utilized to compare objectively the results of infertility surgery between surgeons as well as among institutions.

Constriction, Pathologic↗

Introductory address: microbial etiology of pelvic inflammatory disease.

The etiology of acute pelvic inflammatory disease is multifactorial, and the pattern of organisms most frequently causing the condition fluctuates. For example, tuberculous salpingitis has gradually become a rarity in many areas, and cases of nongonococcal salpingitis have started to outnumber those of gonococcal salpingitis. Chlamydia trachomatis now causes more cases than Neisseria gonorrhoeae in many regions. Mycoplasma hominis is another (often overlooked) etiologic agent infection in the upper genital tract of women. Pelvic inflammatory disease due to anaerobic microorganisms seems to occur more frequently in some areas (i.e., the United States) than in others (i.e., Europe).

Adult↗

[Morphological changes in the oviducts of infertile cows of the zebu breed].

Gross and histologic studies were carried out with a total of 118 Fallopian tubes of 59 slaughtered sterile cows of the Zebu breed originating from the Gamagüey region in Cuba. Morphologically, there were changes in 53 of the animals (89.8 per cent); of these in 29 cases both oviducts were affected, and in 24 of them only one was with lesions. In 6 of the cases (5 per cent) there were signs of acute salpingitis--hyperaemia, serous exudate, infiltration with lymphocytes and neutrophile granulocytes, and desquamation of the epithelium paving the folds. In 15 cases (13 per cent) there was subacute salpingitis--desquamation of the fold epithelium, negligible hyperaemia with oedema of the mucous membrane, and numerous plasmatic cells, fibroblasts, lymphocytes, and neutrophile granulocytes. In 61 cases (51 per cent) there were chronic salpingitis with varying fibrosis, atrophy of the folds, and cysts in the base of the folds. There were also sporadic cases of perisalpingitis.

Animals↗

Experimental pelvic inflammatory disease provoked by Chlamydia trachomatis and Mycoplasma hominis in grivet monkeys.

Pelvic inflammatory disease was produced by inoculation with Mycoplasma hominis and Chlamydia trachomatis directly into the fallopian tubes of grivet monkeys. The effects of various routes of infection were examined. The method of inoculation with the infecting agent influenced the resulting clinical spectrum. In these monkeys significant changes in humoral antibodies occurred with inflammation caused by both M. hominis and C. trachomatis. Development of cellular antibodies against M. hominis could be demonstrated in all experimentally infected monkeys, whereas no such antibodies could be detected in monkeys with chlamydia salpingitis. M. hominis in female grivet monkeys may spread from the cervix or the uterine cavity, probably via blood vessels and lymphatics, producing parametritis and "exosalpingitis." C. trachomatis may spread from the cervix via the uterine mucosa, producing endosalpingitis with destruction of the epithelium. The infection caused by M. hominis in the genital tract of female grivet monkeys resembles "nongonococcal" salpingitis while C. trachomatis produces infection resembling "gonococcal" salpingitis.

Animals↗

Reliability of clinicians versus radiologists for detecting abnormalities on hysterosalpingogram films.

OBJECTIVE: To evaluate the consistency of the identification of abnormal findings on hysterosalpingogram (HSG) and compare the reliability of clinicians to that of radiologists. DESIGN: Evaluation of reliability of diagnostic test. PATIENT(S): Women undergoing evaluation for infertility.INTEVENTION(S): Retrospective review of 50 HSG films by three reproductive endocrinologists and three radiologists. Each film was reread 30 days later in a blinded fashion. MAIN OUTCOME MEASURE(S): The consistency of each individual reader, the reliability of detecting specific abnormalities, and the consistency of clinicians compared with radiologists was evaluated with a kappa (K) statistic and interclass correlation coefficient (ICC). RESULT(S): Average intrareader reliability was high for the detection of normal uterus, normal tubes, and tubal obstruction and low for the detection of hydrosalpinx, uterine adhesions, and pelvic adhesions. Inter-reader reliability was high in the detection of normal uterine contour, normal tubal patency, and uterine filling defect and lower for the detection of a hydrosalpinx. The reliability of detecting pelvic adhesion or salpingitis isthmica nodosa was poor. CONCLUSION(S): Intrareader reliability was generally good, especially for the detection of normal findings. Agreement among different readers is lower in detecting rare outcomes such as hydrosalpinx and pelvic adhesion and salpingitis isthmica nodosa. Clinicians more reliably diagnose hydrosalpinx and tubal obstruction, while radiologists more reliably detect the more subtle findings of salpingitis isthmica nodosa or uterine adhesions.

Fallopian Tube Diseases↗

Chlamydia trachomatis reactive T lymphocytes from upper genital tract tissue specimens.

Chlamydia trachomatis infection is associated with pelvic inflammatory disease (PID) and tubal factor infertility (TFI). We investigated the role of C. trachomatis as a target antigen of endometrial and salpingeal tissue lymphocytes derived from PID and TFI patients. Antigen specificity of the tissue originated T lymphocyte lines (TLL) was tested against C. trachomatis elementary bodies and chlamydial heat shock protein 60 (CHSP60). C. trachomatis antigen stimulated proliferation in two out of eight endometrial TLL derived from PID patients and three out of four TLL derived from TFI patients. All (n = 4) TLL derived from the salpingeal specimens responded to CHSP60 compared with only one out of 12 TLL derived from the endometrial specimens. In-vivo expression of interferon-gamma (IFN-gamma) mRNA revealed that it was present in nine of 13 specimens obtained from PID patients. The dominant activity of type-1 T lymphocytes was confirmed by the in-vitro production of IFN-gamma (median 1007 pg/ml) from all (n = 5) C. trachomatis specific TLL while IL-5 secretion was lower (median 779 pg/ml). In conclusion, C. trachomatis reactive TLL were established from in-vivo activated lymphocytes from the upper genital tract tissue of PID and TFI patients. The reactivity of the salpingeal TLL to CHSP60 provided further evidence that immunoreactivity to CHSP60 is a predominant response in patients with tubal damage.

Adolescent↗

Randomized comparison of ceftazidime versus clindamycin-tobramycin in the treatment of obstetrical and gynecological infections.

A randomized comparison of ceftazidime versus clindamycin-tobramycin was performed for the treatment of obstetrical and gynecological infections. Entry criteria were an oral temperature of greater than or equal to 38 degrees C and a clinical diagnosis of endometritis, salpingitis, or pelvic cellulitis after hysterectomy. All patients with endometritis had cultures of intrauterine material obtained via a transcervical single-lumen catheter. The patients with pelvic cellulitis had material from the vaginal apex aspirated for culture, and all patients with salpingitis had a culdocentesis for culture of intraperitoneal material. Of 38 patients who received ceftazidime, 34 had endometritis after cesarean section, 3 had endometritis after abortion, and 1 had pelvic cellulitis. Of 39 patients who received clindamycin-tobramycin, 35 had endometritis after cesarean section, 3 had salpingitis, and 1 had pelvic cellulitis. The most common bacterial isolates were Lactobacillus sp., Bacteroides bivius, Escherichia coli, other gram-negative aerobic bacilli, group B streptococci, and other aerobic streptococci. Bacteremia occurred in 9.0% of the patients. Of the patients receiving clindamycin-tobramycin and ceftazidime, 34 (87.2%) and 34 (89.5%), respectively, responded to therapy. All the clinical failures occurred in patients with endometritis after cesarean section. Clinical failures had persistent fever despite 3 or more days of treatment. One of the patients receiving clindamycin-tobramycin developed an urticarial rash after her infection had resolved. No patient in either group developed diarrhea. In these small groups of patients, there were no significant differences in cure rate, side effects, or length of hospital stay.

Bacterial Infections↗

Repeated Chlamydia trachomatis infection of Macaca nemestrina fallopian tubes produces a Th1-like cytokine response associated with fibrosis and scarring.

Chlamydia trachomatis-associated female infertility and ectopic pregnancy are caused by postinflammatory fibrosis and scarring of the upper genital tract. Scarring of the upper genital tract is associated with multiple infectious episodes with C. trachomatis. To study the immune response that occurs with multiple infections of C. trachomatis in the female upper genital tract, a Macaca nemestrina model was used. Subcutaneous pockets containing autologous salpingeal tissue implants were inoculated three times with C. trachomatis. The inflammation after three inoculations was associated with a mononuclear infiltrate dominated by CD8 T-cell lymphocytes. Perforin mRNA was induced in infected pockets, demonstrating that activated cytolytic lymphocytes were present in the lesions. Fibrosis, as evidenced by fibroblast proliferation and connective tissue deposition, was observed by the third infection. Cytokine mRNAs induced by repeated chlamydial infection included gamma interferon, interleukin-2 (IL-2), IL-6, and IL-10 mRNAs, but IL-4 mRNA was not induced. Nearly identical findings were found in macaque fallopian tubes infected in situ repeatedly with C. trachomatis, validating the subcutaneous pocket model of chlamydial salpingitis. However, it was not possible to evaluate if there was an induction of perforin mRNA in infected salpingeal tubes in situ, because there was a high basal level of perforin mRNA in these tissues. These results suggest that repeated chlamydial infection of the female upper genital tract leads to CD8 T-cell predominance, a Th1-like cytokine milieu, and these inflammatory changes are associated with progression to fibrosis associated with female infertility.

Animals↗

Epidemiology and therapy of Chlamydia trachomatis infections.

Chlamydia trachomatis infections are exceedingly prevalent, and can be associated with significant sequelae. The major infections are urethritis, cervicitis, salpingitis, and ocular infection. Chlamydial genital infections present as syndromes, where C. trachomatis is one of the causes of the syndrome. Because specific laboratory diagnosis of a chlamydial infection is often not available, and even if available does not exclude the concurrent presence of other pathogens, therapy should usually be directed at all the major causes of the syndrome. Thus, although C. trachomatis is readily eradicated by tetracyclines, macrolides, sulphonamides, and rifampicin, for most situations tetracyclines are the drugs of choice. Penicillins have some activity when used in multiple-dose therapy, but are not reliable for eradication of chlamydiae. Aminoglycosides, nitroimidazoles, and the newer cephalosporins have minimal or no useful activity. Seven days of tetracycline hydrochloride 500mg 4 times daily or doxycycline 100mg twice daily are the optimum regimens for uncomplicated urethritis, cervicitis (except in pregnancy), and gonorrhoea. These regimens should be extended to 10 days for epididymitis and salpingitis. Additional antimicrobials should be added to the salpingitis regimen. For chlamydial infection during pregnancy, erythromycin 500mg 4 times daily for 1 week or 250mg 4 times daily for 2 weeks should be utilised. Neonatal infection requires 2 to 3 weeks of systemic treatment with erythromycin. Inclusion conjunctivitis responds well to antimicrobials, but improved sanitation has a greater effect than antimicrobial therapy in the management of trachoma.

Adult↗

[Significance of vaginal and cervix flora with reference to ascending infections].

The role of the vaginal and cervical flora and the extent of alterations in the flora in ascending infections of the female genital tract were evaluated in a microbiological study of 86 patients with a clinical diagnosis of pelvic inflammatory disease (PID). The patients were classified as having acute salpingitis (n = 15), an acute inflammatory adnexal tumour (n = 21), subacute salpingitis (n = 38), or chronic salpingitis (n = 12). 100 symptom-free women formed a control group. The spectrum of microorganisms found in the two groups was similar. However, there were significant differences in the distribution of pathogenic and apathogenic organisms. Negative cultures and cultures with exclusively apathogenic organisms were found in 16% of the patients with PID and 43% of the healthy women. Growth of exclusively apathogenic aerobic organisms was seen in 3.5% of the patients with PID and 18% of the controls. Exclusively apathogenic anaerobic organisms were found in 7% of the patients with PID and 32% of the controls. Mycoplasmas were significantly more common in the PID group than in the controls (31% v. 10%). The rates of Chlamydia trachomatis did not differ significantly (13% v. 10%). Patients with pathogenic organisms had a 3.88 (odds ratio) or 2.27 (col-2 risk) higher risk of PID than those with negative cultures or exclusively apathogenic organisms. There were no significant associations between the microbiologic results and individual parameters of inflammation. The microbiologic results did not reflect the course or severity of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Chlamydia trachomatis oculogenital infection in the subcutaneous autotransplant model of conjunctiva, salpinx and endometrium.

The subcutaneous pocket model of salpingeal, endometrial, and conjunctival autografts for studying Chlamydia trachomatis infection in monkeys is described. Portions of the salpinx that were transplanted included fimbria, ampulla, and isthmus. The model is an extension of the original model which consists of either salpingeal fimbria or conjunctive autografts. Transplantation of the ampulla portion of the Fallopian tube enabled us to increase the number of pockets or test sites. Salpingeal and conjunctival autografts could be established during a single surgery. In addition, it is possible to autotransplant endometrium and provoke endometritis. The autografts were shown to be susceptible to C. trachomatis infection. Preliminary rechallenge experiments showed infection of the subcutaneous transplants may induce immunity, indicating the model may be used for immunity and vaccine studies. Simultaneous transplantation of different parts of the oviduct, endometrium, and conjunctive should expand the usefulness of the subcutaneous model in other studies on mixed infections or immune responses to infection.

Animals↗