Multiple DNA variant association analysis: application to the insulin gene region in type I diabetes.

Association and linkage studies have shown that at least one of the genetic factors involved in susceptibility to insulin-dependent diabetes mellitus (IDDM) is contained within a 4.1-kb region of the insulin gene. Sequence analysis has led to the identification of 10 DNA variants in this region that are associated with increased risk for IDDM. These variants are in strong linkage disequilibrium with each other, and previous studies have failed to distinguish between the variant(s) that cause increased susceptibility to IDDM and others that are associated with the disease because of linkage disequilibrium. To address this problem, we have undertaken a large population study of French diabetics and controls and have analyzed genotype patterns for several of the variant sites simultaneously. This has led to the identification of a subset consisting of four variants (-2733AC, -23HphI, -365VNTR, and +1140AC), at least one of which appears to be directly implicated in disease susceptibility. The multiple-DNA-variant association-analysis approach that is applied here to the problem of identifying potential susceptibility variants in IDDM is likely to be important in studies of many other multifactorial diseases.

[I.U.D].

PIP: Presently about 15 million women use intrauterine contraception, but despite 15 years of clinical experimentation, the exact way the IUDs function is still relatively difficult to explain. The efficacy of the technique varies from 0 to 5.6 pregnancies/100 women for the 1st year. The most important factor affecting it is the careful, sterile insertion, deep in the uterine cavity. It should be inserted in the last days of menstruation and after pregnancy it seems preferable to wait for the return of the menstrual period. An examination 2-3 months after insertion and every 6-12 months afterward is recommended. Perforation and bleeding are the 2 major problems. Extrauterine pregnancy and spontaneous abortion are more frequent with the IUD. The former, because of the IUD protects against uterine pregnancies better than against extrauterine ones. In the case of a uterine pregnancy, it is often difficult to extract the IUD. Often a therapeutic abortion is recommended. If the doctor and patient decide to continue the pregnancy with the IUD left in place, it becomes a high risk pregnancy with serious possibility of infection and spontaneous abortion. Recent developments include a large surface IUD and a type using a bioactive element, either metal or a hormone.^ieng

[Contraception for nulliparas]. / La contraception chez la nullipare.

PIP: This panel discussion of contraception for nulliparae, in the form of questions and answers interspersed with general discussion, followed an introductory presentation by the first author (ibid: 1(1): 31-34. September 1973). The topics posed as questions were: how to judge a mature request for contraception; what are the causes of contraceptive failures and depressions; is a hypothalamic amenorrhea likely; are diaphragms, condoms, coitus interruptus, monthly pills, morning after pills, spermicides or deport injections recommended; how to prescribe contraception to a virgin; how to treat functional bleeding. There was much attention devoted to whether pills should be stopped at intervals to prevent amenorrhea. Several discussants contributed their results with IUDs and pills, and one summarized his results with 135 women under 25 years old.^ieng

[Clinical study of an estro-progestative association in low doses. Experience of 3 years (490 patients-5600 cycles)]. / Etude clinique d'une association oestro-progestative faiblement dosée. Expérience de 3 ans (490 malades-5600 cycles.

PIP: 490 women who used Stediril (.5 mg norgestrel and .05 mg ethinyl estradiol, combined) for a total of 5600 cycles or 466 woman-years over a 3 year period are presented. They all took the pills primairly for contraception; most were 20-30 years old, and took Stediril 3-6 months. Some other indications were 119 cases of menstrual irregularity, 15 of spaniomenorrhea, 14 of premenstrual syndrome and 3 of acne, all relieved. 46 of 50 cases of menorrhagia, 83 of 89 of dysmenorrhea and 32 of 34 with pelvic pain were relieved. Withdrawal bleeding was usually less than before and tended to diminish with time. There were 46 women with nausea, 3 of whom stopped Stediril. Migraines sometimes a ppeared, sometimes disappeared, but often occurred regularly on the first day between pill cycles. 52 women complained of breast congestion for the first time. Weight rose in 2301, fell in 98 and stayed constant in 134 after 3 months: weight was easily controlled with diet and appetite supressant drugs. No hypertension was observed. There were 19 single cycles of amenorrhea, several cases of persistant amenorrhea and 4 cases of amenorrhea after stopping. 2-3% of cycles were marked by metrorrhagia; 63 women had spotting, 8 had significant metrorrhagia; 7 had metrorrhagia followed by withdrawal bleeding in that cycle. 1 woman had a thromboembolism of the left leg after 2 pill cycles during which she gained 3 kg. There was 1 pregnancy due to irregular pill use.^ieng

[Clinical study of an estroprogestative agent]. / Etude clinique d'un oestro-progestatif.

PIP: 123 women took NOR 50 (1 mg norethindrone and .05 mg mestranol, combined) for a total of 1779 cycles, ranging from 1-42 months. The chief indication was contraception, but some also had menstrual irregularity (47 cases), menorrhagia (54), dysmenorrhea (41), chronic pain (11), premenstrual syndrome (13), and acne (3). There were no pregnancies, and all gynecological complaints were cured except 1 case of pain and 1 of acne. Side effects included 4 who stopped for nausea and vomiting, 28 who had transient nausea, 50 with metrorragia (according to the author, probably due to forgotten pills in severe cases), 29 with amenorrhea, 27 with breast pain, 7 with loss of libido, 1 with cholasma. The author remarked that the dimunution of menstrual flow and the improvement to those with fibroids was striking.^ieng