Development of a novel autoantibody assay for autoimmune gastritis in type 1 diabetic individuals.

BACKGROUND: Autoimmune atrophic body gastritis (ABG) and pernicious anaemia are prototypical, organ-specific autoimmune diseases whose prevalence in the general population is 2.0 vs 2 and 0.15-1%, respectively. The incidence of disease increases with age and is frequently associated with other autoimmune disorders such as type 1 diabetes mellitus (T1DM). Early diagnosis of ABG/pernicious anaemia is essential for the prevention and/or treatment before manifestations of chronic disease become irreversible. Parietal cell autoantibody detection via enzyme-linked immunosorbent assay is currently the most widely used biomarker of disease with diagnosis confirmed by subsequent immunohistochemistry via biopsy. METHODS: To improve the assay we designed a specific, molecularly defined radioimmunoprecipitation assay for early detection of ABG, targeting its major antigen, the gastric H+/K+ ATPase 4A subunit ATP4A. RESULTS: The major antigenic domain in ATP4A was tested against a panel of sera from new onset patients with T1DM which tested positive for the gold standard T1DM autoantibodies (IAA, IA2A, GAD65A, and ZnT8A). Significant immunoreactivity to ATP4A was measured (25%) while 6% of first-degree relatives of subjects with T1DM who were sero-negative for T1DM autoantigens were positive for ATP4A autoantibodies. ATP4A antibody prevalence increased with age of onset of T1DM, which is atypical of other T1DM autoantibodies. Immunoreactivity to ATP4A, unlike that of T1DM antigens, demonstrates a significant gender bias in newly diagnosed individuals with T1DM. CONCLUSION: Although the utility of the assay as a biomarker for T1DM is likely limited, it may serve as an improved indicator of ABG.

Management and outcomes after multiple corneal and solid organ transplantations from a donor infected with rabies virus.

BACKGROUND: This article describes multiple transmissions of rabies via transplanted solid organ from a single infected donor. The empirical Milwaukee treatment regimen was used in the recipients. METHODS: Symptomatic patients were treated by deep sedation (ketamine, midazolam, and phenobarbital), ribavirin, interferon, and active and passive vaccination. Viral loads and antibodies were continuously monitored. RESULTS: Recipients of both cornea and liver transplants developed no symptoms. The recipient of the liver transplant had been vaccinated approximately 20 years before transplantation. Two recipients of kidney and lung transplants developed rabies and died within days of symptomatic disease. Another kidney recipient was treated 7 weeks before he died. The cerebrospinal fluid viral load remained at constant low levels (<10,000 copies/mL) for approximately 5 weeks; it increased suddenly by almost 5 orders of magnitude thereafter. After death, no virus was found in peripheral compartments (nerve tissue, heart, liver, or the small intestine) in this patient, in contrast to in patients in the same cohort who died early. CONCLUSIONS: Our report includes, to our knowledge, the longest documented treatment course of symptomatic rabies and the first time that the virus concentration was measured over time and in different body compartments. The postmortem virus concentration in the periphery was low, but there was no evidence of a reduction of virus in the brain.

The natural history of autonomous gonadal function, adrenarche, and central puberty in gonadotropin-independent precocious puberty.

Gonadotropin-independent precocity (GIP) is a syndrome marked by precocious pubertal development in the absence of pubertal levels of gonadotropins. To investigate the discrete patterns of central nervous system, gonadal, adrenal, and skeletal maturation in this syndrome, we conducted longitudinal studies spanning up to 10 yr in two such affected individuals. A cross-sectional analysis of adrenal androgen secretion was performed in nine additional patients to assess further the time course of adrenarche in GIP. Serial evaluations revealed progression of secondary sexual characteristics, statural growth, and skeletal maturation, all consistent with ongoing exposure to pubertal gonadal steroid levels. On the other hand, adrenarche (n = 11) and spontaneous and GnRH-stimulated gonadotropin secretion (n = 2) progressed in chronological age-appropriate manners despite long term pubertal levels of gonadal sex steroid secretion. After the development of central puberty, as documented by the appearance of pulsatile gonadotropin secretion, we sought to determine whether the potential for gonadal autonomy persisted. Despite complete pituitary desensitization induced by administration of a GnRH agonist, both patients studied demonstrated an ongoing capacity to secrete pubertal levels of gonadal steroids. Our study suggests that the timing of adrenarche and central puberty in these subjects with GIP was apparently unaltered by prolonged exposure to gonadal steroids. Subsequent to the development of central puberty, pulsatile gonadotropin secretion may override and, thus, mask the underlying defect(s) in adolescents and adults with histories of GIP.

Baseline thyroid hormones in depressed and non-depressed pre- and early-pubertal boys and girls.

OBJECTIVE: To examine baseline thyroid hormones in a large group of well-characterized pre- and early-pubertal boys and girls who met criteria for major depressive disorder (MDD) and a comparison group of normal children without psychiatric disorders. METHODS: 45 children with MDD (10.6 years +/- 1.4 year) and 56 healthy controls (10.0 +/- 1.7 year) who participated in a large, psychobiologic protocol are included in this report. As part of the screening for eligibility, baseline samples were drawn for thyroxine (T4), triiodothyronine (T3) uptake, and thyroid stimulating hormone (TSH). Free thyroxine index (FTI) also was computed. RESULTS: Between-group analyses were carried out controlling for various demographic variables significantly related to thyroid hormones [e.g. age, gender, body mass index (BMI) and their interactions]. For many hormones there were significant effects for age and gender. For T4, MDD boys had lower T4 compared with boys in the normal group. No differences were noted between MDD girls and normal girls. For TSH, MDD boys had lower concentrations compared with normal boys while no differences were noted in girls. For T3 uptake, the MDD group had lower uptake compared with the normal group. For FTI, there were no group differences. Similar to most studies of adults with depression, all our subjects were euthyroid. Unlike the adult studies, we found lower T4 concentrations in the MDD group rather than higher. Group differences in thyroid hormones were noted primarily in boys. The large sample size of this study allowed for the control of multiple variables, which has not been done in past studies. Without such controls, true findings may be masked in other studies of depression. Thus, our findings suggest the possibility of developmental differences in the relation of thyroid hormone and depression.

Gonadotropin-releasing hormone (GnRH) antibodies formation in hypogonadotropic azoospermic men treated with pulsatile GnRH--diagnosis and possible alternative treatment.

Five hypogonadotropic azoospermic men received pulsatile, intravenous gonadotropin-releasing hormone (GnRH) treatment over prolonged period. In three patients, the spouses were successful in achieving five pregnancies, three of which generated five healthy newborns, one ended in a first-trimester abortion, and one is ongoing. In one patient, anti-GnRH antibodies were detected, secondary to initial response. This was associated with deterioration of gonadotropin levels and diminution in testosterone to pretreatment levels. The cross-reactivity of the antibodies with five GnRH agonistic analogs was examined. Possible treatment with pulsatile GnRH analogs in such patients is discussed. In light of the relatively long period of treatment needed to achieve spermatogenesis and fertility in patients with hypogonadotropic azoospermia, monitoring the appearance of GnRH antibodies seems appropriate to assess whether therapy should be concluded. The superiority of intravenous pulsatile GnRH treatment to subcutaneous GnRH treatment or to human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) treatment is discussed.

Corneal tattooing: an alternative treatment for disfiguring corneal scars.

BACKGROUND: The performance and results of corneal tattooing are described in a case series of 11 patients suffering from a disfiguring corneal scar using a technique similar to conventional dermatography. METHODS: Drawing ink in different shades was applied into the anterior corneal stroma by punctures performed with a conventional spatula needle. RESULTS: Up to 4 years after surgery all patients still had satisfactory staining of the formerly cosmetically disfiguring corneal scar. CONCLUSION: Tattooing of unsightly corneal scars proved to be an efficient and easy to perform technique, yielding acceptable results during follow up.

Itinerant surgical and medical specialist care in Kansas: report of a survey of rural hospital administrators.

In most rural areas, specialist nonprimary care, when available, is provided by "itinerant" physicians and surgeons who periodically visit from a distant home base. Little is known about current usage and acceptability of itinerant specialists in rural communities. Administrators of hospitals in rural and frontier Kansas counties were asked to report the frequency of itinerant care in their facilities, the home base of each specialist and a listing of procedures performed during specialist visits. Administrators were also asked to respond on a Likert scale to six questions inviting their assessment of itinerant care. Responses were received from 53 of 56 hospitals. All offered at least one monthly session of itinerant medical or surgical care. The most common specialties represented were cardiology (in 87 percent of hospitals), urology (68 percent), orthopedics (68 percent) and radiology (60 percent). General surgeons consulted in over 80 percent of responding hospitals. Psychiatrists, dermatologists and neurologists were rarely available in the hospitals surveyed. Administrators generally rated itinerant care highly, though some expressed concern about revenue lost when specialists performed procedures in their home-base office or hospital. No associations were found between amount of care offered and potential explanatory variables such as hospital size, distance from subregional centers, or percentage of patients hospitalized locally. Further study is needed to better understand differences in itinerant specialist utilization and acceptance among rural Kansas hospitals. Because Kansas demographics are similar to those of many other American rural areas, such study may offer insights applicable to other regions.

Fetal biometry: a comparison of family physicians and radiologists.

BACKGROUND AND OBJECTIVES: While performance and reading of obstetric sonograms is a skill widely taught in family practice residency programs, no prior studies have compared ultrasound performance and interpretation in residency programs with that of hospital radiologists. This study compares results of fetal biometry for gestational age determination performed sequentially by faculty-supervised residents and radiologists. METHODS: This retrospective chart review selected cases from among all gravidas who had ultrasound performed in a family practice residency clinic between January 1992 and April 1999. Biometry was performed by residents under the supervision of faculty preceptors who had ultrasound training and experience. A patient was included if (1) results of both a family practice ultrasound and a radiologist-read hospital ultrasound were present in the chart, (2) both studies were done before 36 weeks gestation, and (3) the family practice examination preceded the hospital study. The difference in expected date of confinement between resident and radiologist ultrasound was calculated, and this difference was evaluated for statistical significance by a paired sample t test. RESULTS: Ninety-two ultrasound pairs were assessed, a sample size that provided .90 power to detect a gestational age estimate difference of 3 days between family practice and radiologist interpretations. The normally distributed observed mean difference in gestational age estimates was only 1.5 days. CONCLUSIONS: This study found no difference in gestational age assessment performed by closely supervised family practice residents in comparison to radiologists.

Inflammatory atypia. An apparent link with subsequent cervical intraepithelial neoplasia explained by cytologic underreading.

A review of 5,752 cervical smears done on college students at a medium-sized midwestern university in a 24-month period showed 496 cytologic diagnoses of inflammatory atypia and 132 of dysplasia (cervical intraepithelial neoplasia: CIN). Further retrospective review of a nonselected cohort (178 cases) of the 496 patients with inflammatory atypia showed that their subsequent cytologic smears were more likely to show CIN than could be explained by chance alone. Only ten cases accounted for this difference, and a case-controlled blind review of the original cytologic smears of these ten patients resulted in the reclassification to CIN (mild dysplasia) of seven who had subsequently "progressed" from inflammatory atypia to dysplasia. Only one control smear was reclassified. In this population, underreading of a small number of cervical smears explained a strong statistical apparent correlation between inflammatory atypia and the subsequent development of CIN.

Inflammatory atypia and the false-negative smear in cervical intraepithelial neoplasia.

The effectiveness of cervical cytologic screening is compromised by the increasingly recognized prevalence of false-negative smears. Our previous studies suggested that some false-negative cytologies can be accounted for by smears showing cervical intraepithelial neoplasia (CIN) reported as inflammatory atypia; we found that at least 4% of 5,752 consecutive smears had been underreported in this manner. In the present study, that data was reanalyzed to derive 95% confidence limits for the number of CIN smears reported as inflammatory atypia. Using several differing estimates of cytologic screening sensitivity, it is speculated that, under certain testable assumptions, colposcopy of patients with cytologic diagnoses of inflammatory atypia may be one cost-effective approach to finding CIN cases missed by screening. If confirmed, these findings imply that laboratory quality assurance efforts, traditionally directed to the most serious cytologic diagnoses, should also focus in part on nondysplastic atypia.

Inflammatory epithelial changes and nonviral cervicovaginal pathogens.

To assess the relationship between inflammatory epithelial changes (IECs) and cervicovaginal infection, 249 women with cytologic diagnoses of IEC were studied. The findings showed a Chlamydia infection in 15.7% of the cases, Monilia in 38.1%, Trichomonas in 1.6% and a lateral vaginal wall pH of greater than 5.5 in 29.7%. These results were compared with those for 211 controls drawn from the same population; women with abnormal cytologic reports were excluded from the control group. The controls had a prevalence of yeast and trichomoniasis no different from that of the IEC group. In contrast, the prevalence of chlamydial infection (7.6%) and pH greater than 5.5 (10.7%) were significantly lower in the controls than in the IEC cases. Chlamydia was found in 30.2% of 43 women with an atypical transformation zone, equally distributed between women whose biopsies were normal and those whose biopsies showed cervical intraepithelial neoplasia. The traditional guidelines of treating cases with cytologic diagnoses of IEC prior to obtaining a repeat smear may need reevaluation in the light of these findings.

Colposcopy of patients with cytologic inflammatory epithelial changes.

Of 3,308 cervical cytologies performed at a university health service between September 1986 and September 1987, 371 were reported as showing inflammatory epithelial changes (IECs). Colposcopy was offered to all patients with this diagnosis and was actually performed on 200 (54%). Of these women, 44 had an atypical transformation zone; of the 33 who were biopsied, 23 had histologic diagnoses ranging from human papillomavirus (HPV) infection (4 cases) to grade III cervical intraepithelial neoplasia (CIN; 4 cases). Most biopsies showed CIN I. In our clinic, the 95% confidence limits for the histologic diagnosis of HPV or CIN in women with a cytologic diagnosis of IEC are 8.5% to 23.5%. Colposcopic examination of women with IEC may be able to detect patients with CIN who are missed by standard cytologic screening. Concerns about a potential bias from false-positive histology reports must be resolved before such an approach can be recommended.

Improving the sensitivity of cervical cytologic screening. A comparison of duplicate smears and colposcopic examination of patients with cytologic inflammatory epithelial changes.

During a ten-month period, 264 cervical cytologic specimens were submitted in duplicate to two separate cytology laboratories. An attempt was made to perform colposcopy on all 45 patients reported as having an abnormality by either laboratory. All but one patient with a cytologic diagnosis of cervical intraepithelial neoplasia (CIN) underwent colposcopy, as did 68% of the patients with a diagnosis of nondysplastic atypia (inflammatory epithelial changes [IEC]). Five cases of histologically verified CIN were found by colposcopic study of patients with a cytologic diagnosis of CIN; two additional cases were found by colposcopic study of patients with a cytologic diagnosis of IEC. On the assumption that patients not colposcoped were not systematically different from the others with IEC, the screening sensitivities for both laboratories and for cytology followed by colposcopy of IEC cases were estimated. A statistically significant improvement in screening sensitivity was achieved by colposcopic examination of patients with IEC. This conclusion was tempered by a Bayesian analysis that suggested that some of the apparent improved sensitivity could be due to falsely positive biopsy reports. Despite potential benefits, it is premature to recommend universal colposcopic examination of patients with cytologic reports of inflammatory epithelial changes.

Management of the abnormal Papanicolaou smear.

Since 1943, Papanicolaou (Pap) smears have been widely used to screen for cervical cancer. Over the past 25 years, new understanding of the natural history of cervical epithelial neoplasia has defined the existence and importance of dysplasia, also termed cervical intraepithelial neoplasia (CIN), and more recently, its probable link to human papilloma virus (HPV). Inflammatory atypia (IA) is a common cytological diagnosis whose significance is less understood. Current gynecological opinion strongly supports a practice of colposcopic evaluation for all women with cytology showing any degree of CIN. Data from studies in our health service and elsewhere establish that 15% to 30% of patients with IA will have CIN if evaluated by colposcopy. Although clinicians may choose to follow such patients with repeated Pap smears, there are strong arguments for offering colposcopic evaluation to patients with IA. Potential problems with false-positive cervical biopsy reports, however, may limit the utility of colposcopy in patients with IA cytology.

[Bilateral simultaneous LASIK. Pro and contra]. / Bilaterale simultane LASIK. Pro und Kontra.

Until recently simultaneous bilateral laser in situ keratomileusis (LASIK) was regarded as contraindicated in Germany. However, the procedure was sporadically performed, because it offers patient comfort and is more cost effective than sequential LASIK. Even though the complication rate is below the calculated rate of 0.01%, bilateral complications may have catastrophic effects on the patient. In addition, there is the theoretical disadvantage that the results from the first eye cannot be used for the second eye. However, this effect has yet to be clinically proven.

[Diagnosis and therapy of LASIK-induced neurotrophic epitheliopathy]. / Diagnostik und Therapie der LASIK-induzierten neurotrophen Epitheliopathie.

Laser in situ keratomileusis (LASIK) has emerged as the standard surgical procedure for the correction of refractive errors and in the last years a lot of experience has been gained. Consequently, the amount of intraoperative, early and late postoperative complications have significantly decreased. Keratitis punctata superficialis and dry eye symptoms are the most frequent postoperative complications. A decreased corneal sensitivity attributable to the cutting of the corneal sensory nerves has been described after LASIK. In addition pathological tear secretion tests and typical dry eye symptoms have been reported. Until know it has not been completely evaluated, if these symptoms are a combination of the dry eye disease and LASIK-induced symptoms or if they are due to an independent LASIK complication, the so-called LASIK-induced neurotrophic epitheliopathy. Independently of the incompletely understood etiology, much care and a sufficient therapy with artificial tears should be applied to such patients. To increase the comfort of LASIK, adequate intra- and postoperative treatment is necessary to enhance the patient satisfaction.

An analysis of and intervention in the sexual transmission of disease.

Sexually transmitted diseases are a serious threat to the public health. Indeed, when an individual seeks medical treatment for a sexually transmitted disease, health authorities frequently attempt to identify, procure, and treat that individual's sexual contact(s). We conducted a comparative analysis of three alternative approaches to tracing the sexual partners of individuals diagnosed as having a sexually transmitted disease. The first approach involved counseling individuals (n = 27) infected with either gonorrhea or nongonococcal urethritis and exhorting them to procure their sexual partners for treatment. In addition to counseling, the second and third approaches involved distributing "occasion cards" for patients to use when informing sexual contacts of the need for treatment. Moreover, in the second approach, the counselor (a nurse or physician) informed infected patients (n = 19) that they and their partners could waive the $3 clinic fee contingent upon the partners seeking treatment within 1 week. In the third approach, the counselor asked infected persons (n = 19) to accept a follow-up telephone contact if their sexual partners failed to seek treatment within 1 week. The third approach was most effective. Ninety percent of the partners identified through this approach sought treatment, versus only about 60% of the partners in the other two conditions. The third approach was also the least expensive, costing about $2.95 to procure each partner for treatment.

Does a family physician who offers colposcopy and LEEP need to refer patients to a gynecologist?

BACKGROUND: Many family physicians perform colposcopy and provide treatment when biopsy reveals dysplasia. Before the adoption of loop electrical excision procedure (LEEP) gynecologic referral following colposcopy was required for a small percentage of women--most commonly for cold cone procedures. The use of LEEP and LEEP cones may obviate the need for cold conization, so we sought to assess the pattern of gynecologic referral in the practice of family physicians skilled in this procedure. METHODS: We reviewed the referral practices of a family medicine residency practice that routinely provides LEEP for biopsy-proven cervical intraepithelial neoplasia requiring treatment. Colposcopy and, when indicated, LEEP were performed primarily by the senior author or by residents under close faculty supervision. The computerized clinic log was reviewed for all patients from its 1993 inception through November 1999, and all treatment decisions were evaluated. RESULTS: During the study period, 283 women were seen in the clinic, and 26 individuals (9%) were referred by the family physician colposcopist to a consulting gynecologist. CONCLUSIONS: Despite use of LEEP, a minority of patients continues to need gynecologic referral. Large acetowhite lesions extending onto the vaginal fornix accounted for the majority of referrals, and some patients were referred exclusively for cold cone biopsy. Although LEEP can allow family physicians to manage cases previously requiring referral, we urge that this procedure be employed only by those with the technical and decision-making skills required for safe and effective treatment.

Cervicography: an intermediate triage test for the evaluation of cervical atypia.

BACKGROUND: A substantial number of abnormal Papanicolaou (Pap) smears are reported as demonstrating "cytologic atypia." This finding may actually represent premalignant cervical disease. Some of these patients may not be able to afford definitive colposcopic examinations, and simply repeating cytologic testing may result in missed treatable disease. The purpose of this study was to evaluate the use of cervicography as an intermediate triage test for women with atypical cervical cytology. METHODS: Women with a recent smear demonstrating cytologic atypia were evaluated using colposcopy, biopsy, and cervicography. RESULTS: Colposcopically directed cervical biopsies were obtained from 224 of 685 women with cytologic atypia. The histologic specimens confirmed evidence of cervical dysplasia for 166 women. Of these women, cervicography detected 74.7% of those who had mild dysplasia, 87.5% of those who had moderate dysplasia, 75% of those who had severe dysplasia, and the one patient who had cervical cancer. Most (93%) of the women with dysplasia that was undetected by cervicography had mild dysplasia. CONCLUSIONS: Cervicography may be an effective intermediate triage test for the evaluation of young women with Pap smears demonstrating cytologic atypia.

Naked-eye inspection of the cervix after acetic acid application may improve the predictive value of negative cytologic screening.

BACKGROUND: The purpose of this study was to assess the predictive value of naked-eye inspection of the cervix (NIC) after acetic acid application as an adjunct to Papanicolaou (Pap) testing for cervical cancer screening. METHODS: Study subjects were women attending a medical college student health clinic either for cervical cytologic screening (67%) or because of a recent atypical cytologic screening result (33%). All study participants received cytologic screening, cervicography, and NIC. RESULTS: Of the 95 patients, 71 (75%) had abnormal findings on NIC. Fifty-one patients underwent colposcopy with biopsy, including 48 of the 71 with an abnormal finding on NIC. The results of 40 of the biopsies were abnormal: 36 showed human papillomavirus or low-grade squamous intraepithelial lesions, 3 showed high-grade squamous intraepithelial lesions, and 1 showed invasive cervical cancer. Sixty-five percent (26) of the abnormal biopsy findings occurred in women with normal cytologic test results. NIC and cervicography both were effective in identifying patients with abnormalities, but the combination of NIC followed by cervicography referred fewer women for colposcopy than did a positive result on NIC alone (52% vs 75%). The combination of a negative Pap smear and a negative NIC result had a 91% predictive value for the absence of cervical intraepithelial neoplasia. This was a significant improvement over cytologic screening alone. CONCLUSIONS: In this study, the combination of cytologic screening (Pap smear) and NIC increased the screening yield as compared with a Pap smear alone but with some loss of positive predictive value. NIC significantly improved the predictive value of negative cytologic screening results.