Increased responsiveness of rheumatoid factor-producing B cells in seronegative and seropositive rheumatoid arthritis.

OBJECTIVE: To compare the frequencies and responsiveness of rheumatoid factor (RF)-producing B cells in the peripheral blood of patients with seronegative and seropositive rheumatoid arthritis (RA). METHODS: Frequencies of IgM+, IgG+, and RF+ B cells were determined by limiting-dilution analysis of purified peripheral blood B cells from 6 patients with seropositive RA, 8 patients with seronegative RA, and 7 normal controls. B cell help was provided by cloned T helper cells, which were stimulated by either anti-CD3 or the bacterial superantigen staphylococcal enterotoxin D (SED). IgM and IgG antibodies and RF in culture supernatants were detected by enzyme-linked immunosorbent assay. RESULTS: In the presence of anti-CD3-stimulated T helper cells, 2-10% of B cells from normal individuals secreted IgM and IgG antibodies. The frequency of RF+ B cells was low and ranged from 1:182 to 1:885 (RF+: IgM+) B cells. In patients with seropositive RA, the numbers of Ig-producing B cells were reduced by a factor of 2, while the fraction of RF+ B cell precursors was expanded by more than 50-fold (7-20% of IgM+ B cells; P = 0.004). Patients with seronegative RA had higher frequencies of RF-producing B cells (1.5-6% of IgM+ B cells) than normal individuals (P = 0.002), but not to the same extent as seropositive patients (P = 0.002). Stimulation of B cells using SED preferentially induced RF+ B cells in normal controls and in patients with seronegative and seropositive RA. CONCLUSION: B cell precursors with the potential to secrete RF were detectable in high frequencies in normal individuals and in patients with seropositive and seronegative RA. In all donors, these B cells could be stimulated with the bacterial superantigen SED. In normal individuals, RF+ B cells remained nonresponsive to help provided by anti-CD3-activated T cells, but were responsive in RA patients. Seronegative and seropositive RA form a continuous spectrum of disease, with a higher number of RF-secreting B cells in the seropositive patients.

Pilot study of antithymocyte globulin in systemic sclerosis.

OBJECTIVE: Between June 1, 1992 and August 31, 1994 we conducted an open pilot study of antithymocyte globulin (ATGAM; Upjohn, Kalamazoo, MI) in 10 patients with early systemic sclerosis (SSc) to assess whether this agent might prevent the progression of cutaneous and pulmonary involvement in this disease. METHODS: Adult patients with early SSc (< 3 years) and evidence of progressive skin and pulmonary disease were enrolled. All patients were hospitalized and received a single course of intravenous ATGAM, at a dosage of 10 mg/kg over 4 hours, on 5 consecutive days. Patients were followed up at weeks 1, 2, 3, and 4, and months 2, 4, 6, and 12. Patients were considered to be improved if the Rodnan skin score decreased > or = 25%, to be worse if the skin score increased > or = 25%, and to be not improved if the skin score was within 25% of baseline. For pulmonary involvement, patients were considered to be improved if either the diffusing capacity for carbon monoxide or the forced vital capacity was increased > or = 10%, worse if decreased by > or = 10%, and stable if within 10% of baseline. RESULTS: Most patients tolerated the treatment well, although 1 patient developed an allergic reaction necessitating discontinuation of treatment, 1 developed a serum sickness reaction after completion of therapy, and 1 developed a central venous access-related axillary vein thrombosis. Two patients died of SSc-related complications during the followup period. At 12 months, only 2 patients showed improvement in both skin and pulmonary function measures, whereas 5 patients were worse and 3 were stable. CONCLUSION: At the dosage administered in this study, ATGAM appears ineffective in improving the skin and pulmonary features of SSc.

Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis.

RA is a heterogeneous group of disorders characterized by variations in clinical manifestations, disease course, and probably response to therapeutic interventions. We have addressed the question whether genetically and potentially etiologically more homogeneous subgroups of RA patients can be defined based upon the expression of the RA-linked sequence motif in the third hypervariable region of the HLA-DRB1 gene. Genetic comparison of patients classified upon clinical manifestation and disease course demonstrated that patients with mild disease were genetically distinct from those progressing to severe and destructive disease. Specifically, rheumatoid factor (RF) negative patients preferentially expressed RA-linked HLA-DRB1 alleles with an arginine substitution in position 71, whereas the alleles with a lysine substitution in position 71 accumulated in RF+ patients. RF- patients were further subdivided based on clinical markers (time of onset of erosive disease and requirement for aggressive therapy). Clinical heterogeneity correlated with genetic heterogeneity. Patients with early erosive disease and patients requiring aggressive therapy frequently typed HLA-DRB1*04+. Patients with late erosive/nonerosive disease or a benign disease course manageable with nonaggressive treatment preferentially expressed HLA-DRB1*01 or lacked an RA-linked haplotype. These data indicate that the heterogeneity of RA reflects genetic differences. Sequence variations within the disease-linked sequence motif, as well as polymorphisms surrounding the candidate genetic element, affect pattern, course, and treatment response of RA. Amino acid position 71 in the HLA-DRB1 gene has a unique role, the understanding of which may provide important clues to disease etiology.

Endocrine effects in Asian postmenopausal women, treated with SH D 461 M and Prempak-C.

We reported the results of a randomized cross-over study comparing SH D 461 M (Climen) and Prempak-C in 38 postmenopausal women who were established users of hormone replacement therapy (HRT). Climen contains 11 tablets of 2 mg estradiol valerate (EV), and 10 tablets with 2 mg EV plus 1 mg of cyproterone acetate. Prempak-C, on the other hand, is a regimen consisting of 28 tablets of 0.625 mg conjugated equine estrogens (CEE); the last 12 tablets are taken together with 0.15 mg of norgestrel (NG) tablets. Patients in Sequence I started with Climen for 6 months and then crossed-over to Prempak-C, for the next 6 months. Patients in Sequence II followed the reverse order. Following Climen treatment, significantly higher levels (P < 0.05, t-test) of sex hormone binding globulin (SHBG) and estradiol, when compared to Prempak-C treated subjects, were noted. No significant differences in follicle stimulating hormone (FSH), corticosteroid binding globulin (CBG), renin angiotensinogen, angiotensin-I and aldosterone levels between the two treatment regimens were noted. While both regimens were effective in reducing menopausal symptoms, none of the regimens could eliminate all symptoms completely. Treatment with Climen appeared to result in less frequent occurrences of some symptoms. During periods of no estrogen (only true for Climen) as well as periods of maximum P and E, subjects on Climen had significantly lower incidence of some of the symptoms (backache, lack of concentration, lethargy and swelling) when compared to those on Prempak-C.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine effects in Asian postmenopausal women treated with SH D 461 M and Prempak-C.

We reported the results of a randomized cross-over study comparing SH D 461 M (Climen) and Prempak-C in 38 postmenopausal women who were established users of hormone replacement therapy (HRT). Climen contains 11 tablets of 2 mg estradiol valerate (EV), and 10 tablets with 2 mg EV plus 1 mg of cyproterone acetate. Prempak-C, on the other hand, is a regime consisting of 28 tablets of 0.625 mg conjugated equine estrogens (CEE); the last 12 tablets are taken together with 0.15 mg of norgestrel (NG) tablets. Patients in Sequence I started with Climen for 6 months and then crossed-over to Prempak-C, for the next 6 months; patients in Sequence II, followed the reverse order. Following Climen treatment, significantly higher levels (P < 0.05, t-test) of sex hormone binding globulin (SHBG) and estradiol, when compared to Prempak-C treated subjects, were noted. No significant differences in follicle stimulating hormone (FSH), corticosteroid binding globulin (CBG), renin, angiotensinogen, angiotensin-I and aldosterone levels between the two treatment regimes were noted. While both regimes were effective in reducing menopausal symptoms, none of the regimes could eliminate all symptoms completely. Treatment with Climen appeared to result in less frequent occurrences of some symptoms. During periods of no estrogen (only true for Climen) as well as periods of maximum progestagen and estrogen (P and E), subjects on Climen had significantly lower incidence of some of the symptoms (backache, lack of concentration, lethargy and swelling) when compared to those on Prempak-C.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrauterine devices.

PIP: A review of 25 clinical trials conducted at the National University in Singapore included 10,055 insertions of 16 different IUDs between 1975 and 1988. The trials were conducted to assess the safety and complications of IUD use. The IUDs were inserted either immediately after abortion or at least 4 weeks after delivery or first trimester abortion. Overall, copper-releasing IUDs performed better than inert IUDs. Copper 7/Gravigard had the poorest pregnancy rate among the copper IUDs (6.3% at 48 months vs. 4.4%) as well as the highest use-related terminations (44.8% at 48 months vs. 33.4%). Use-related terminations included expulsion and terminations for other medical and other personal reasons and pregnancy. The Levonorgestrel Nova T IUD and the Copper T 380Ag IUD had the lowest pregnancy rates (no pregnancies over 5 years and 1 pregnancy in 5 years, respectively), but they were not significantly different than those for the Multiload Copper 250 IUD, the review's standard reference point (3.8% over 4 years). Among progestogen-releasing IUDs, levonorgestrel Nova T had the longest active life. The Copper 7/Gravigard, Lippes loop (size D), Dalkon Shield (standard), and OMGA T (size 1) IUDs had significantly higher pregnancy rates that the review's standard, MLCu250 (p .0001). The Latex leaf was significantly higher only after 12 months use (p .05). The Copper 7/Gravigard, Lippes loop (size D), Nova T, OMGA T (size 1), and Copper T 380Ag IUDs had significantly higher expulsion rates than did MLCu250. Women using the Copper 7/Gravigard, Lippes loop (size D), OMGA T (size 1), and Copper T 220/Proquinsert IUDs suffered significantly more pain/bleeding than those using MLCu250. Copper-releasing IUDs had significantly fewer use-related terminations than did the inert IUDs (p .001). The 2 Multiload IUDs (MLCu250 and MLCu375) had considerably fewer use-related terminations over the first 24 months of use.^ieng

Prolactin levels in menopausal women on long-term estrogen implants.

Prolactin levels were measured in 71 menopausal women before treatment and 32 treated with steroid implants. In neither group was there any case of hyperprolactinemia. Although prolactin levels were on average 13% higher in the women who had had long-term treatment with the implants, they were, nevertheless, not significantly different from the corresponding levels in the pretreated group. Treatment with steroid implants at the dose and duration studied therefore did not significantly increase the risk of hyperprolactinemia occurring in treated as compared with pretreated menopausal women.

A prospective randomized comparative trial of the Gravigard, Latex Leaf, Dalkon Shield and Multiload Cu 250 IUDs.

This prospective randomized trial in 843 patients compared the effectiveness and complications of 4 intrauterine devices. At 24 months the gross accidental pregnancy rate for the Dalkon Shield was higher than for the 7Cu200 (p less than 0.05) and the ML Cu250 (p less than 0.05). The 7Cu200 had a higher expulsion rate than the Dalkon Shield (p less than 0.01), Latex Leaf (p less than 0.001) and ML Cu250 (p less than 0.001). Use-related terminations were higher for the 7Cu200 than for the ML Cu250 (p less than 0.01). Removal for pelvic inflammatory disease was necessary in 8 women (2 for the Latex Leaf and 3 each for the 7Cu200 and Dalkon Shield). There was no significant difference in termination rates between the ML Cu250 and Latex Leaf but subsequently the Leaf has given problems with removal particularly in women who have defaulted follow-up for several years.

PIP: The effectiveness and complications of 4 IUDs--Gravigard, Latex Leaf, Dalkon Shield, and Multiload Cu 250--were compared in a prospective randomized clinical trial involving 843 acceptors. A total of 14,373 woman-months of IUD use were analyzed. At 24 months, the gross accidental pregnancy rate for the Dalkon Shield (10.4/100) was significantly higher than that for the Gravigard (4.3/100) and Multiload IUD (4.2/100); the pregnancy rate for the Latex Leaf device was 5.1/100. The Gravigard device had a significantly higher expulsion rate at 24 months (15.6/100) than the Dalkon Shield (2.1/100), Latex Leaf (5.2/100), or Multiload (3.7/100) devices. Use-related terminations were 38.1 for the Gravigard, 28.9 for the Dalkon Shield, 31.1 for the Latex Leaf, and 28.6 for the Multiload devices. Removal for pelvic inflammatory disease was necessary in 8 women (2 Latex Leaf acceptors,3 Dalkon Shield users, and 3 Gravigard acceptors). There was no case of septic abortion in this series. Although the Latex Leaf performed comparatively well in this study, it was found that over time the rubber degenerates and becomes separated from the thread when removal is attempted. In general, the Multiload Cu 250 appears to be one of the best currently available IUDs, because of its low pregnancy and expulsion rates.

A prospective randomized study of the copper 7, Multiload Cu 250 and copper 220C IUDS in Singapore.

PIP: A randomized prospective trail was conducted to assess the comparative complication rates of the 7Cu200 and 2 newer copper bearing IUDs -- the TCu220C and the MLCu250 -- in Singapore. Recruitment for this 2-year trail began in 1976. These results represent the Singapore component of a 3-center (Singapore, Medan, Kuala Lumpur) trial, conducted in conjunction with the International Development Research Center in Ottawa, Canada. The 600 patients recruited between April 1976 and November 1978 were allocated randomly to 1 of the 3 IUDs using a series of presealed envelopes. All volunteers were healthy and ranged in age from 19-35 years. They were of proven fertility and exposed to the risk of pregnancy. There were no significant differences in the age, parity, race, or immediate past contraceptive use in the 3 groups. Insertions were performed at least 8 weeks postpartum (or 4 weeks postabortion) by 1 of 20 different physicians. Followup appointments were scheduled for 6 weeks and 3, 6, 12, and 24 months. Data was recorded for all unscheduled visits, and when necessary, letters, telephone calls, and home visits were used to trace defaulters. 98 (49%) 7C8200 users completed the study compared with the 116 (58%) for both the TCu220C and the MLCu250 users. 4% of the patients were lost to followup, and 1% were withdrawn by the investigators. There were significant differences in the pregnancy rates between the 3 devices. Pregnancy was more common with the 7Cu200 than with the TCu220C and MLCu250. Expulsion was significantly less frequent with the MLCu250 when compared with the 7Cu200 and the TCu220C. There were significant differences in both use-related and total termination rates between the 3 IUDs, but no one IUD was significantly better than either of the other 2 devices.^ieng

Post-abortion insertion of MLCu 250 and MLCu 375--a comparative trial.

This randomized prospective trial compared the use effectiveness and side effects of the MLCu 250 and MLCu 375 inserted immediately post-abortion. Five-hundred-and-forty-nine patients were followed-up over a two-year period involving 9890 woman-months of use with a loss to follow-up rate of only 5.1%. Both IUDs gave good protection against pregnancy (gross rates at 24 months, 1.8 and 2.1). There were no significant differences between the two devices in pregnancies or other termination events.

A randomized comparative trial of the Lippes Loop D, Gravigard and TCu 220C IUDs.

This randomized prospective trial compared the use-effectiveness and pregnancy rates in 3 IUDs following immediate postabortal insertion in 199 women over 3107 months of use. At 24 months the Gravgard (Cu 7) was not significantly different from either of the other 2 devices. However, the Lippes Loop D when compared with the TCu 220C had a higher expulsion rate (P less than 0.05) and a higher use-related termination rate (P less than 0.001). Further details of accidental pregnancies, removal for incomplete abortion or pelvic inflammatory disease and within 48 hours after insertion are presented.

Intrauterine devices in Singapore today.

PIP: The IUD has been selected by less than 1% of contraceptive users in Singapore in the past 15 years, largely because of concerns about uterine perforation and a lack of professional training in insertion techniques. However, increased public awareness of the possible complications of oral contraceptives has led to an interest in the IUD as a family planning method and the Singapore Family Planning and Population Board has introduced the Multiload Cu 250 device at its clinic. The IUD is now considered a feasible method of contraception for women in Singapore, many of whom achieve their ideal family size of 2 children between the ages of 20-25 years. Successful use of the IUD is dependent upon placement of the device at the top of the uterine cavity by an experienced physician. All devices should be changed after 4 years to reduce the risk of complications. The newer IUDs have many advantages over inert and early copper-bearing IUDs in terms of safety and efficacy.^ieng

Research and development in obstetrics & gynaecology in the Department of Obstetrics & Gynaecology at the National University of Singapore.

This is a review of the research and achievements of the Department of Obstetrics and Gynaecology, National University of Singapore since 1949. The research activities reviewed are Fertility Control, Subfertility, Reproductive Endocrinology, In-Vitro Fertilization, Trophoblastic Disease, Prostaglandins and Perinatal Medicine. The University Department has kept abreast with the Singapore norm of two-child families by providing the most sophisticated technology and expertise. The perinatal mortality and stillbirth rates have been reduced to 11 and 6 per thousand births. Prostaglandin research in the Department includes an investigation of the involvement of these substances in various physiological processes, pharmacological studies with different prostaglandins and development of clinical applications. Between 1974 and 1981 we had studied 12 intrauterine contraceptive devices, both on a departmental basis and in conjunction with international agencies. The newer medicated devices have proved to offer significant advantages over the original inert plastic configuration. Metabolic changes in Singapore women on the oral pill and injection Depoprovera were studied. Impaired glucose tolerance and raised fasting total lipids were found in women on the pill. Marginal changes in carbohydrate metabolism only were found in women on injection Depoprovera. Hypercoagulation changes in the blood occurring in Singapore women varied with the dose of the synthetic or natural oestrogen medication. Initially, the fibrinolytic activity was enough to compensate for these changes; however after two years there were signs of decompensation. Progestogens affect coagulation via their influence on the liver functions. Hypercoagulation changes also occurred in pregnancy and was of a greater magnitude than oestrogen or progestogen medication. In many obstetric disorders, including hydatidiform mole, there was evidence of intravascular coagulation. The introduction of endocrine function tests has greatly improved patient care in our Department, in particular those related to endocrine disorders. Application of the immunoassays to basic research has shown that physiological levels of oestradiol exert a negative feedback effect on both FSH and LH secretions in men. The greater suppression of LH than of FSH secretion by pharmacological doses of estradiol is possibly due to different control mechanisms in the pituitary for the synthesis and release of both gonadotrophins. Physiological level of testosterone per se has a definite negative feedback effect on the secretion of LH but not on FSH. Pharmacological doses of the 5-alpha-reduced metabolites of testosterone have been shown to suppress both LH and FSH indicating that some of the actions of testosterone could be medicated by these metabolites of which the 3 alpha-androstanediol and 3 beta-androstanediol are the more likely candidates.

Cervical diameter after suction termination of pregnancy.

The diameter of the internal cervical os was measured in several groups of patients in an attempt to assess any damage caused by suction termination of pregnancy. Pregnant women who had had a previous abortion by vacuum aspiration had significantly greater cervical diameters than those who had not, and there was a statistically significant correlation between dilatation of the cervix at operation and cervical diameter at six weeks' follow-up. Cervical dilatation to 10 mm or less was subsequently associated with a normal cervical diameter, but the diameter was often large when the extent of dilatation was greater than 12 mm or not known. Cervical dilatation at termination of pregnancy should, if possible not exceed 10 mm.

The relationship of a "short period" to conception.

The case records were examined of 918 patients delivered in 1963 at a London hospital. Comparisons were made between 52 patients who had a "short period" following the presumed date of conception and 155 randomly selected control patients. Patients who had a "short period" showed a significantly higher rate for the induction of labour (p smaller than 0-025) and a lower infant birthweight (0-1 smaller than p smaller than 0-2). Calculation of the menstruation-delivery interval using the "short period" rather than the last full period, gave a closer approximation to the duration of pregnancy found in the random control series of 155 patients.

Successful pregnancy after conservative surgery and radiotherapy for disgerminoma of the ovary.

A 19-year-old patient was treated for disgerminoma of the right ovary by right salpingo-oophorectomy and pelvic radiotherapy in 1967. The left ovary was shielded after the first two treatments and the patient has since conceived three times and has shown no evidence of recurrence of the tumour.