High-affinity antigen association to cationic liposomes via coiled coil-forming peptides induces a strong antigen-specific CD4+ T-cell response.

Liposomes are widely investigated as vaccine delivery systems, but antigen loading efficiency can be low. Moreover, adsorbed antigen may rapidly desorb under physiological conditions. Encapsulation of antigens overcomes the latter problem but results in significant antigen loss during preparation and purification of the liposomes. Here, we propose an alternative attachment method, based on a complementary heterodimeric coiled coil peptide pair pepK and pepE. PepK was conjugated to cholesterol (yielding CPK) and pepE was covalently linked to model antigen OVA323 (yielding pepE-OVA323). CPK was incorporated in the lipid bilayer of cationic liposomes (180 nm in size). Antigen was associated more efficiently to functionalized liposomes (Kd 166 nM) than to cationic liposomes (Kd not detectable). In vivo co-localization of antigen and liposomes was strongly increased upon CPK-functionalization (35% -> 80%). CPK-functionalized liposomes induced 5-fold stronger CD4+ T-cell proliferation than non-functionalized liposomes in vitro. Both formulations were able to induce strong CD4+ T-cell expansion in mice, but more IFN-y and IL-10 production was observed after immunization with functionalized liposomes. In conclusion, antigen association via coiled coil peptide pair increased co-localization of antigen and liposomes, increased CD4+ T-cell proliferation in vitro and induced a stronger CD4+ T-cell response in vivo.

The intrauterine device and its dynamics.

In the past decade, attention has shifted from family planning (often made available through population programs) to reproductive health--a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity, in all matters related to the reproductive system and its function and processes. Reproductive health has three components: the ability to procreate, regulate fertility and enjoy sex; the successful outcome of pregnancy through infant and child survival and growth; and the safety of the reproductive process. According to Mitchell et al., the following are key elements in a reproductive health program: (a) Family planning services that offer complete and accurate information about all contraceptive methods and that make contraceptive services, supplies and counseling accessible. (b) Antenatal care, which research suggests lowers rates of maternal mortality. (c) Safe delivery services, so that all women deliver under some type of supervised care and so that referral systems are established to provide emergency treatment of life-threatening complications of delivery. (d) Postnatal care that contributes to a woman's ability to have a speedy and complete recovery from the stress of pregnancy and childbirth, to enjoy sexual relations without pain and to have safe pregnancies and deliveries in the future. (e) Management of the complications of abortion where safe abortions are not available. (f) Infertility services that enable women to achieve their reproductive goals; and effective screening for or control of reproductive tract infections (RTIs), because RTIs are the most common preventable cause of involuntary infertility and ectopic pregnancy, as well as of chronic pelvic pain and recurrent infection. (g) Management and treatment of systemic sexually transmitted diseases (STDs), such as HIV and hepatitis B. (h) Symptomatic treatment of urinary tract infections. (i) Detection and treatment of breast and reproductive tract cancers, such as cervical cancer. (j) Attention to and treatment of dysmenorhea, which in some cases is the first sign of other problems, such as pelvic inflammatory disease, endometriosis, fibroids, endometrial cancer and ectopic pregnancy. (k) Nutritional supplementation to meet the special needs of adolescents, pregnant or lactating women, and women older than 50 years. (1) Services for menopause and other health problems that women encounter as they grow older. (m) Services for adolescents, including family planning and STD prevention and treatment. It shall be clear that many institutions delivering reproductive health services operate significantly below their physical capacity to see clients, and that much of the equipment required for expanding reproductive health services may already be available for use in family planning and other health services. In this context, we would therefore like to discuss the dynamics of IUDs.

New directions in IUCD development.

In recent years, the development of improved intrauterine devices has focused on finding methods to reduce expulsion and the need for medical removal for better intrauterine retention and devices. Efforts also have been directed towards developing intracervical devices. Some of the more recent developments in intrauterine and intracervical devices are discussed.

Oral contraceptives and breast cancer risk.

Because of the continuing controversy on the breast cancer risks associated with the use of combined oral contraceptives (OCs), the medical literature was reviewed to assess the risks of this cancer to OC users. This review found that the medical literature supports the view that OC use is associated with small increased risks of premenopausal breast cancer. There is no consensus as to which subgroups of women might be at an increased risk.

Breast cancer risk among women using silicone gel breast implants.

Since their introduction in 1962, silicone gel-filled breast implants have been used by an estimated one to two million women. Questions concerning an increased cancer risk to these women have been raised. A review of the medical literature, including case reports, case series, physician surveys, case-control studies, and cohort studies, failed to turn up any evidence which associated the use of silicone breast implants with either an increased risk of breast cancer or an increased risk of a more advanced stage of cancer at the time of cancer diagnosis. The available data do not indicate any significant difference between the characteristics of the breast cancers of women with breast implants and those of women in control populations.

Autoimmune disease following the use of silicone gel-filled breast implants: a review of the clinical literature.

The association between the use of silicone breast implants and the later development of connective tissue disease was reviewed. Data from case reports (only 40 in the world literature), case series, case-control studies, surveys of plastic surgeons, and cohort studies provided no evidence of an association. In many studies, the appropriate information was not collected to evaluate the association. The case-control and cohort studies were too small to detect even moderately increased risks should they exist. Further prospective studies are required to determine the risks of connective tissue disease associated with the use of silicone breast implants.

Intracervical anchoring: a new approach to intrauterine contraception.

The intracervical device described in this paper consists of copper wire around a small plastic frame that is anchored to the inner wall of the cervix, at about 1.5 cm from the external os. The device represents a radical departure from conventional intrauterine contraception and 'frameless' IUDs, which are anchored to the uterine fundus. The device was evaluated in a preliminary study of 11 women. During the 3-month evaluation period, there were no expulsions or removals for any reason. The device was well tolerated. Expanded clinical trials are planned.

When does exposure to agent X cause disease Y?

The concept of 'cause' between exposure to agent X and the subsequent development of disease Y is reviewed briefly in terms of how it is used in experimental and clinical medicine, statistics and epidemiology, and in law. Some of the interrelationships of the definition of cause by these disciplines are considered.

Safety of intrauterine contraception.

Some of the risks which have been associated with the use of intrauterine contraception are reviewed. For users of copper-releasing IUDs, such as the Multiload Cu375 and TCu380, uterine perforations are rare, there is no evidence of an increased risk of infertility, and there probably is no increased risk of ectopic pregnancy after IUD removal. Any increased risk of pelvic inflammatory disease may be limited to the initial months of IUD use. The safety of intrauterine contraception needs to be re-evaluated for the newer IUDs, since most of the information relating to IUD safety is based on studies of devices which are no longer used or which are not in widespread use.

Contraceptive development and testing in the United States of America.

Contraceptive development, including the development of IUDs, is discussed in light of the changing regulatory role of the FDA. The paper considers how the FDA and the government affect contraceptive development. Events that led to the demise of IUD use in the United States probably will have long-lasting effects on all future contraceptive development by the pharmaceutical industry in the United States.

PIP: The changing regulatory role of the FDA has affected the development of contraceptives including the IUD. This work attempts to discuss how the FDA and the government influence contraceptive development. Particular government actions led to the demise of the IUD in the US and will have long lasting effects in the US on the future of all contraceptive development by the pharmaceutical industry. This work traces the history of government regulation of contraceptives from the Pure Food and Drug Act of 1906 through the 1976 Medical Device Amendments to the Food Drug and Cosmetic Act of 1962. This act required manufactures of nonmedicated IUDs, and any other contraceptives, to conduct similar clinical trials that are required for the development of other drugs. In the US, IUD contraception has become a legal battle ground and its future is that of a condemned product. Currently no manufacturer of IUDs is marketing products in the US. This deprives US women of a safe and effective form of contraception. This work also discusses Depo-Provera and RU-486. The author's final conclusion is that the future of contraceptive research and development in the US is in doubt. The pharmaceutical companies of Western Europe have proven their commitment and ability in this area in the last decade and will continue to do so for the next.

Duration of use of copper releasing IUDs and the incidence of copper wire breakage.

The incidence of copper wire breakage for IUDs (Multiloads) using 0.3 and 0.4 mm diameter copper wire was evaluated by examining 969 devices that had been removed for various reasons. The IUDs were examined by light microscopy to determine the integrity of the copper wire. As expected, the incidence of breakage increased with increasing duration of IUD use. The cumulative breakage rate (life table) was significantly lower (p less than 0.05) for the Multiload 375 that used 0.4 mm diameter wire, compared to the Multiload 250 that used 0.3 mm diameter wire. The cumulative rates were 5.4 per 100 IUDs after 3 years for the Multiload 250, and 3.8 per 100 IUDs after 5 years for the Multiload 375. In only 1 (0.1%) of the 969 Multiloads examined, the breakage of the copper wire was sufficiently extensive to adversely affect the user's risk of pregnancy.

Uterine perforation and use of the Multiload IUD.

The English language literature on IUDs was reviewed to evaluate the uterine perforation rate associated with use of the Multiload. No reports of cervical perforation were found, and the uterine perforation rate was 0.12/1000 insertions compared to a rate of 0.68/1000 insertions for other copper-bearing IUDs. This lower rate may reflect an under-reporting of uterine perforations in the medical literature, or may represent a truly lower perforation rate due to factors related to the Multiload design and/or its insertion technique.

Effects of intrauterine devices on the surface ultrastructure of human endometrium before and after removal.

The effects of copper-releasing IUDs on the endometrial ultrastructure were evaluated in 101 women. Endometrial samples were obtained in the secretory phase of the menstrual cycle, both during and after IUD use, and were evaluated using both scanning and electron microscopy. The degree and extent of changes to the surface ultrastructure of the endometrium were found to be related to the copper surface area of the IUD. Regardless of the duration of IUD use, by one month after IUD removal the endometrial ultrastructure had returned to its normal state. The results of this study show that the effects of copper-releasing IUDs on the endometrial ultrastructure are essentially limited to the time the IUD is in utero.

Fifteen years' experience with the Multiload IUD.

The Multiload IUD with an exposed copper surface area of 250 mm2 (MLCu250) was developed in 1972 and has become one of the most widely used IUDs. Modifications to the MLCu250 include an increase in the area of exposed copper wire to 375 mm2 (the MLCu375) and an increase in the diameter of copper wire from 0.3 to 0.4 mm. The Multiload has been evaluated extensively in noncomparative and comparative clinical trials. In these latter studies the MLCu250 performed better than the Cu-7 and TCu-200, and the MLCu375 performed better than the Fincoid or Nova T and about equally as well as the TCu380. Pooled data from over 26,000 insertions of the MLCu250 gave the following 3-year cumulative event rates (per 100 women): pregnancy, 2.0; expulsion, 3.1; removal for pain/bleeding, 7.1. Comparative studies of the Multiload and other IUDs have shown all IUDs in current use are associated with similar rates of pelvic inflammatory disease. IUDs such as the MLCu375 that have larger copper surface areas appear to be associated with lower ectopic pregnancy rates. Follow-up studies of women who have had their Multiloads removed indicate that use of the device does not impair future fertility or affect pregnancy outcome. All IUD users, regardless of the type of IUD used, are at risk of complications. On balance, the benefits of IUD usage far exceed the associated risks.

Medical removals of the Multiload IUD.

In a follow-up evaluation of 3721 Multiload IUD users, the removal rate for medical reasons other than bleeding/pain was only 2.6 per 100 women at three years. Most of these removals were for reasons that appeared to be unrelated to IUD use. The removal rate for pelvic inflammatory disease was 0.3 per 100 woman years. Women were followed up for up to three years after removal of their IUDs. Among women with PID at least 70% of those who desired pregnancy subsequently became pregnant, a rate similar to that of women who had their IUDs electively removed to become pregnant. The study provides further data on the safety of intrauterine contraception.

The future of intrauterine contraception.

In this review paper some guidelines for IUD use are presented that if followed should reduce the incidence of IUD-related complications. Recent IUD developments are discussed including the levonorgestrel-releasing T, a new variation of the Multiload, and IUDs designed for postpartum insertion. Since significant improvements in IUD safety will most likely result from a better understanding of IUD-related side-effects and adverse reactions, the paper includes recommendations for future IUD research that could enhance the safety, effectiveness and acceptability of available IUDs.