[Socio-economic aspects of stroke management]. / Aspects socio-économiques de la prise en charge de l'attaque cérébrale.

BACKGROUND: Stroke is the third leading cause of death and the first leading cause of disability in developed and developing countries. It is one of the most demanding public health problems to be faced in the upcoming years, particularly because of population aging. STATE OF THE ART: New therapeutic advances in the management of acute stroke have changed our perception of this condition and have had a major impact on healthcare organization and subsequently healthcare expenditures. Care required for the stroke victim is costly in both developing countries and in developed countries. Hemmorhagic events are the most costly, but their prevalence in Western countries is lower than ischemic events. Prevalence of ischemic events is higher in Asian countries. The direct costs of stroke, both for primary and secondary events, constitute the larger part of healthcare expenditures. The mean cost of stroke in France is estimated at 18,000 euros for the first 12 months. Disability accounts for 42 percent of the variable cost of stroke. During the first year, the acute phase accounts for 40 percent of the cost, rehabilitation and mid-term hospitalization for 29 percent, and ambulatory care for 8 percent. After 46 months, the cost of ambulatory care exceeds the cost of the first six months of care during and following the acute phase. CONCLUSION: Any improvement in the primary or secondary prevention of stroke will lead to a decrease in the incidence and prevalence of stroke, and any therapeutic advance capable of reducing disability will consequently reduce the overall cost of stroke.

Cost of a recurrent vs. cost of first-ever stroke over an 18-month period.

When assessing the cost-effectiveness of the secondary prevention of stroke, it is not well known whether the cost of a recurrent brain infarction (BI) is different from a first-ever BI. In a cohort of 435 consecutive prevalent cases of BI (including both recurrent and first-ever BI) we collected medical and socio-economic variables. Handicap was measured with the Rankin scale. Only the direct medical costs were considered over an 18-month period from a societal perspective. We compared first-ever to recurrent BI. Of the 435 patients 20.5% had a recurrent BI. The length of the initial hospitalization and the distribution of the patients into the three classes of handicap (Rankin 0-2, 3, and 4-5) were similar in the first-ever and recurrent BI groups. The average total cost of a first-ever BI was euro 19 725 (95% CI, 17 950-21 501) and euro 18 560 (95% CI, 15 798-21 322) for a recurrent BI (P = 0.48). There were no differences between the two groups when the costs were compared by handicap levels (P = 0.17) or when the costs were compared for each type of expenditure (initial hospitalization, rehabilitation, ambulatory services) except for long-term care, because of the small number of cases. This study suggests that the costs of recurrent BI are roughly similar to the costs of first-ever BI, which may be helpful when studying the cost-effectiveness of secondary stroke prevention trials.

Chiral bicyclic phosphoramidites--a new class of ligands for asymmetric catalysis.

The development of new ligands for catalytic asymmetric C-C bond formation is of great interest to organic synthesis. We describe here a new class of chiral phosphoramidites that embody one or two binaphthol units attached to an achiral azabicyclic [3.3.1] or [3.3.0] framework. These ligands were easily accessible from (R)1,1'-binaphthyl-2,2'-dioxaphosphorchloridite (4) and the corresponding heterobicyclic core 1, 2, or 3. They were employed in enantioselective Cu-catalyzed additions of different dialkylzinc reagents to cyclic and acyclic enones. The chiral ketones were obtained with an enantiomeric ratio up to 91:9. The choice of the best ligand proved to be strongly dependent on each substrate. In addition, ligand 6 was found to be the most suitable for Rh-catalyzed hydrogenations of a,beta-unsaturated esters, giving rise to dimethyl 2-methylsuccinate and methyl N-acetylalaninate with enantiomer ratios up to 95:5.

Potential fertility--defining the window of opportunity.

The ClearPlan Easy Fertility Monitor predicts the times of high potential fertility, i.e. the times when sexual intercourse is most likely to result in conception. The test procedure identifies the times of specified changes in the concentration of urinary hormone metabolites during each ovarian cycle. The results are displayed in terms of prior knowledge about the time-specific probabilities of conception. This paper contains a summary of the scientific background that led to the development of the ClearPlan Easy Fertility Monitor.

Public/private-sector collaboration in contraceptive research and development: summary and historical perspective.

This summary and historical perspective relates exclusively to contraceptive research and development during the period between the early 1970s and the present. This paper covers the raison d'être for public/private-sector collaboration in this field, provides definitions and summarizes the issues motivating and confronting both sectors, discusses and outlines a generic memorandum of understanding (MOU) that can be used to initiate collaborative research activities, and presents a time line of selected milestones in public/private-sector collaboration, many of which were initiated by the Rockefeller Foundation. Public and private-sector collaboration takes advantage of the unique strengths of both sectors and offers good opportunities for a 'win-win' situation in product development.

Pregnancy outcome in natural family planning users: cohort and case-control studies evaluating safety.

Conceptions involving aging gametes are of relevance to natural family planning (NFP) because women using NFP to avoid pregnancy abstain from intercourse during the fertile time of the cycle. To help verify the safety of pregnancies occurring among NFP practitioners, our group has, since 1986, conducted a large cohort study involving six experienced NFP centers. Timing of conception was determined from NFP charts, in which women recorded days on which intercourse occurred. The number of days from the most probable conception intercourse to probable day of ovulation was first determined, and used as an estimate of the time gametes remained in the genital tract before fertilization. Several studies have already been completed, cohort as well as case-control in nature.

An evaluation of the Bioself 110 electronic fertility indicator as a contraceptive aid.

The Bioself 110 is a hand-held electronic device that combines the BBT and calendar methods of fertility regulation for planning or preventing pregnancy. A pilot study was undertaken in three centers in the United Kingdom to evaluate the Bioself 110 as a contraceptive aid. This paper deals with 1238 cycles from 131 women. Only one unplanned pregnancy occurred where a volunteer correctly used the Bioself 110 and had intercourse on a supposedly "safe" day. A second pregnancy was experienced by a volunteer who incorrectly used the device and had intercourse on what she though was a "safe" day. Another 11 unplanned pregnancies occurred due to barrier method failures, as well as 11 pregnancies where the volunteers knowingly had unprotected intercourse during the fertile phase. There were five planned pregnancies. The Bioself 110 was correctly used in 71% of the cycles studied. Eighty-four percent of the volunteers indicated that they were satisfied with the Bioself 110 after six to twelve cycles of use. It was concluded that the Bioself 110 can serve as an effective family planning aid and should be added to the menu of contraceptive methods available to women today.

PIP: The Bioself 110 is a handheld electronic device that combines the BBT and calendar methods of fertility regulation for planning or preventing pregnancy. A pilot study was undertaken in 3 centers in the United KIngdom to evaluate the Bioself 110 as a contraceptive aid. This paper deals with 1238 cycles from 131 women. There was only 1 unplanned pregnancy which occurred when a volunteer correctly used the Bioself 110 and had intercourse on what was supposed to be a "safe" day. A 2nd pregnancy was experienced by another volunteer who incorrectly used the device and had intercourse on what was also thought to be a "safe" day. Another 11 unplanned pregnancies occurred due to barrier method failures, as well as another 11 where the volunteers knowingly had unprotected intercourse during the fertile phase. There were 5 planned pregnancies. The Bioself 110 was used correctly in 71% of the studied cycles. 84% of the volunteers indicated that they were satisfied with the Bioself 110 after 6-12 cycles of use. It was concluded that the Bioself 110 can serve as an effective family planning aid and should be added to the contraceptive choices available to women today.

Validity of the Bioself 110 fertility indicator.

The Bioself 110 (Bioself Canada, Inc., Montréal, Québec, Canada) is an electronic computerized thermometer designed to identify the fertile and infertile phases of the menstrual cycle. The purpose of this study was to evaluate the validity of the device by comparing it with a reference method, the Ovustick (Monoclonal Antibodies, Inc., Mountain View, CA) luteinizing hormone (LH) surge detection kit. The Bioself 110 identified the 6-day fertile period in 86.4% of 220 cycles studied and 5 fertile days in 93.2%. The Bioself 110 correctly identified the postovulatory infertile phase in 93.3% of 178 cycles. On average, the device identified 10.9 fertile days and 10.6 postovulatory "safe" days per cycle. It was concluded the device would be a useful aid to couples trying to conceive or prevent pregnancy.

An evaluation of the BIOSELF 110 fertility indicator.

The BIOSELF 110 is a hand-held, non-invasive electronic instrument that measures basal body temperature and cycle length, and automatically identifies the fertile and infertile phases of the menstrual cycle with flashing red light and green light signals, respectively. The device was evaluated in 77 cycles from 33 ovulatory women in Kuala Lumpur, Malaysia. Ultrasound monitoring of maximum follicular diameter (MFD) and urinary LH measurements with Ovustick were used as reference methods to estimate the time of ovulation and the fertile period. Based on the MFD day, the BIOSELF correctly identified the entire fertile period, and at least four fertile days, in 89% and 94% of the cycles studied, respectively. The mean duration of the fertile period as determined by the number of flashing red light days was 11.0 days (SD 2.9). The device correctly identified the onset of the postovulatory infertile phase in 94% of cycles, with a mean duration of about 10 (green light) days. The results were similar using the LH peak day as the reference method. The mean interval from the onset of the fertile period (first flashing red light day) to the MFD day was 6.9 days (SD 2.6), and from the MFD day to the end of the fertile period, 3.1 days (SD 2.2). The BIOSELF 110 showed itself to be a reliable device for identifying the fertile and infertile phases of the menstrual cycle and, thus, should be a useful aid for couples seeking pregnancy. Prospective clinical trials are underway to assess the contraceptive effectiveness of the device.

PIP: The BIOSELF 110 is a handheld, noninvasive electronic instrument that measures basal body temperature and cycle length, and automatically identifies the fertile and infertile phases of the menstrual cycle with flashing red and green light signals. The device was evaluated in 77 cycles from 33 ovulatory women in Kuala Lumpur, Malaysia. Ultrasound monitoring of maximum follicular diameter (MFD) and urinary LH measurements with Ovustick were used as reference guides to estimate the time of ovulation and the fertile period. Based on the MFD day, the BIOSELF correctly identified the entire fertile period, and at least 4 fertile days, in 89% and 94% of the cycles studied, respectively. The mean duration of the fertile period as determined by the number of flashing red light days was 11.0 days (SD 2.9). The device correctly identified the onset of the postovulatory infertile phase in 94% of cycles, with a mean duration of about 10 (green light) days. The results were similar using the LH peak day as the reference method. The mean interval from the onset of the fertile period (1st flashing red light day) to the MFD day was 6.9 days (SD 2.6), and from the MFD day to the end of the fertile period, 3.1 days (SD 2.2). The BIOSELF 110 showed showed itself to be a reliable device for identifying the fertile and infertile phases of the menstrual cycle and, thus, should be a useful aid for couples seeking pregnancy. Prospective clinical trials are underway to assess the contraceptive effectiveness of the device.

Desarrollo de métodos inmunologicos para regular la fecundidad

A new approach to fertility regulation is the development of vaccines directed against human substances required for reproduction. Potential candidates for immunological interference include reproductive hormones, ovum and sperm antigens, and antigens derived from embryonic or fetal tissue. Several vaccines targeted at the beta chain of the human chorionic gonadotrophin molecule have reached the clinical trial state in Australia, Finland, India and Sweden, and the preliminary results are very encouraging. A prototype vaccine using the beta subunit of ovine luteinizing hormone seems effective in female primates. Contradictory effects on spermatogenisis in male primates have been observed by different researchers using follicle-stimulating hormone as an antigen. Both this and gonadotrophin-releasing hormone require further basic research. Immunological interference could also be aimed at a sperm production or maturation, or at sperm-ovum interaction in the female reproductive tract. The best characterized sperm antigen to date is LDH-C4, an isoenzime of lactic dehydrogenase. The identification of new sperm antigens is being aided by monoclonal antibody techniques. Another approach is to detect, and then mimic, the antisperm antibodies found in women and men with immunologically mediated infertility. Research on ovum antigens is focusing on the zona pellucida (ZP); anti-ZP antibodies

Development of immunological methods of fertility regulation.

PIP: Birth control vaccines both would increase the choice of methods open to women and men and additionally would offer specific advantages, including the development of vaccines that are unlikely to disrupt the menstrual cycle or cause the side-effects associated with oral contraceptive (OC) use. For a birth control vaccine to be acceptable for use in human beings, it must meet several criteria: the antigen must be unique to the reproductive target; the antigen must have a fertility-related function that can be blocked by antibody or is susceptible to cell-mediated immunity, and alternatively, the function should be located on a cell that can be lysed by complement; an acceptable level of effectiveness should be achieved by no more than 1 or 2 injections for the primary immunization, with booster injections at intervals of no less than 6-12 months; and the vaccine must undergo sufficient testing in animals to ensure its safety for longterm use. For the vaccine to be widely acceptable, its effects need to be reversible. Before a fertility-regulating vaccine can be envisaged for widespread use in men or women, animal models must be found for thorough testing of toxicity, teratogenicity, effectiveness, duration, and reversibility of immunity and specificity for the target. Theoretically, the mammalian reproductive system is susceptible to immunological intervention at several points. Many reproductive hormones, as well as several antigens could be isolated from the ovum, sperm, embryonic tissue, and fetal tissue, could be candidate targets. Human chorionic gonadotropin (hCG) is a major candidate for vaccine development. The World Health Organization's (WHO) Special Program of Research, Development and Research Training in Human Reproduction, through its Task Force on Vaccines for Fertility Regulation, has been supporting research on a synthetic vaccine directed against the last 37 amino acids of the C-terminal end of the beta hCG molecule. A 2nd approach, being followed by the National Institute of Immunology, New Delhi, and the Population Council, New York, involves developing a vaccine against the entire beta chain of the hCG molecule. A prototype vaccine using the beta subunit of ovine luteinizing hormone emulsified with Freund's complete adjuvant has been studied extensively in female primates by the Population Council, but as yet there is no evidence of acute or chronic health hazards in this heterologous immunization model. The development of a vaccine based on sperm antigens will require considerable basic research. Interference with fertility could occur at several points: during sperm production in the testes, during sperm maturation in the epididymis, or during interaction with the egg in the female reproductive tract. Most research on ovum antigens is directed towards the zona pellucida, the acellular, gelatinous layer surrounding the ovum. It is estimated that vaccines that interfere with sperm function and fertility will be available for human testing by the early 1990s.^ieng

Prediction and detection of ovulation by the measurement of urinary pregnanetriol-3 alpha-glucuronide. A multicentre study.

The urine excretion pattern of pregnanetriol 3 alpha-glucuronide (PT-3G) throughout the menstrual cycle in 26 normal ovulating women was evaluated in a multicentre study. The concentration of PT-3G was measured by radioimmunoassay in daily samples of early morning urine (EMU) from 20 women for three consecutive cycles and from 6 women who conceived during the period of study. PT-3G was also measured in 24-h urine samples from 5 additional women. The peak of urine LH was used as a reference point for ovulation (Day 0). The EMU concentration of PT-3G in the follicular phase of 60 normal ovulatory cycles was 5.10 mumol/l +/- 0.11 (arithmetic mean +/- SE). The first PT-3G defined rise (CUSUM analysis) occurred during the late follicular phase (Days -3 to 0) with a PT-3G maximum excretion (9.69 mumol/1 +/- 0.55) on Day 0, whereas a PT-3G excretion peak occurred during mid-luteal phase (Days +5 to +9). The overall PT-3G excretion during the luteal phase (8.06 mumol/1 +/- 0.17) was significantly higher than that of the follicular phase (P less than 0.001). A further sustained increase in PT-3G excretion was noted after day +11 in the conceptional cycles. The 24-h excretion profile of PT-3G was similar to that obtained in EMU samples. No inter-centre significant variation was noticed in terms of PT-3G concentration values. The results were interpreted as demonstrating that the PT-3G excretion profile throughout the cycle exhibits a close resemblance to that of serum 17-OH progesterone. The data also indicates that although the immunoanalytical measurement of this urine steroid metabolite does not give an early sign for the occurrence of ovulation, it can be used for both the immediate prediction and the detection of ovulation.

Natural family planning in 1985: a status report.

PIP: The current status of natural family planning (NFP) was reviewed. There is renewed interest in NFP, and many couples who find other methods unacceptable for medical, safety, or personal reasons are turning to NFP methods. The percent of contraceptive users who rely on behavioral methods in developing countries in 35% in Peru, 20%-25% in Haiti, Philippines, and Sri Lanka, and average 7.5% for the remaining 23 developing countries. IN the US about 4.7% of all contraceptive users rely on behavioral methods. Worldwide, rhythm is the most commonly used form of behavior fertility control, but this method is not promoted by most NFP programs. The 3 modern methods of NFP are 1) the basal body temperature method, 2) the cervical mucus, or Billings method, and 3) the sympto-thermal method. All these methods rely on physical signs and symptoms to detect ovulation and require sexual abstinence during the fertile phase of the menstrual cycle. The basal body temperature method requires women to detect the slight rise in temperature which occurs at the time of ovulation. The method is 94%-97% effective if intercourse is restricted to the postovulatory phase of the cycle. Disadvantages of the method are that intercourse must be restricted to only 7-13 days of the cycle, women must take their temperature daily, the method cannot be used during fever episodes, and the method is inappropriate for use during lactation or near menopause. The cervical mucus method is based on observing cervical mucus changes during the cycle. These changes signal the fertile and infertile phases of the cycle. According to a World Health Organization study, 93% of the women instructed in the method were able to detect mucus changes, and illiterate women were as adept at identifying these changes as university graduates. Findings also indicated that the method was 97% effective if abstinence was practiced during 15 days of the cycle, but use-effectiveness was only about 80%. This method has the advantage of not requiring ovulatory regularity. The sympto-thermal method uses a combination of symptoms including temperature shifts and mucus changes to detect ovulation. Some studies indicate that the combined method is more effective than those methods based on only 1 symptom, but many individuals find the combined method difficult and confusing. The advantages of NFP methods are that they require no medical supervision and that they have no side effects. Family planning providers often have negative attitudes toward NFP and many programs do not provide NFP services. Many providers maintain that the methods are ineffective and difficult to apply and that there is little demand for NFP. Research should be undertaken to determine if these opinions are valid. The major source of funding for NFP programs and projects is the US Agency for International Development (USAID). The agency is currently supporting 22 NFP projects under USAID grants and another 16 bilateral NFP programs. The research undertaken in connection with these projects should provide needed information on NFP advantages, disadvantages, effectiveness, and demand.^ieng

Immunological Methods of Fertility Regulation: report of a workshop.

PIP: A workshop on Research and Development of Immunologic Methods of Fertility Regulation, held April 16-18, 1984, under the joint sponsorship of the National Institutes of Health, US Agency for International Development, and the Program for Applied Research on Fertility Regulation, affirmed the need to stimulate and support basic and applied research. Particular emphasis was placed on research on sources of antigens that have the potential for eliciting an immune response and can interfere with reproductive processes in both males and females. Efforts to develop vaccines based on gonadotropins or their subunits and fragments, sperm antigens, and antigens derived from the zona pellucida were evaluated. A vaccine that is at least 90% effective should be sought. However, vaccines that do not meet this level of effectiveness should not be abandoned; rather, techniques for improving the response by modifying the immunogen, carrier, adjuvant, or dilevery schedule should be explored. It was further recommended that the 1977 document developed by the World Health Organization Task Force on Birth Control Vaccines for testing vaccine efficacy and safety should be updated. There was particular concern about 4 potential complications: 1) induction of organ-specific autoimmune disease, 2) induction of antibodies to hormone receports, 3) enhancement of the risk of neoplasia to organs that carry antigens involved in a vaccine, and 4) genetically controlled variation in the immune response. It was noted that recombinant DNA technology will become increasingly important in contraceptive vaccine development, especially in the identification of new antigens specific to the ovary or testis. Finally, it should be possible to produce a microcapsula deliv^ieng

The measurement of urinary steroid glucuronides as indices of the fertile period in women. World Health Organization, Task Force on Methods for the Determination of the Fertile Period, special programme of research, development and research training in human reproduction.

The concentrations of various estrogen glucuronides and pregnanediol-3 alpha-glucuronide have been measured in daily samples of early morning urine (EMU) and 24 h pooled collections throughout a total of 70 menstrual cycles (58 subjects). The immediate objective was to identify and assess the potential value of measuring hormone metabolites to locate the fertile period in women, with the ultimate aim of developing a non-invasive immunochemical test. The project was undertaken in five centres and the results showed that: (i) there was good agreement in the patterns and mean concentrations of metabolites between the centres; (ii) estrone-3-glucuronide should be the estrogen glucuronide selected for further study; (iii) the analysis of EMU provided information that was as useful as the corresponding measurements on pooled collections for 24 h; (iv) a rise in the concentration of estrone-3-glucuronide (50% over the mean of three preceding values) could be used to locate the start of the fertile period in greater than 90% of the ovarian cycles (from day LHmax -- 3 to day LHmax -- 7); attempts to locate the end of the fertile period by a threshold value or a defined rise in the level of pregnanediol-3 alpha-glucuronide were disappointing. A 50% rise over the mean of three preceding values in the derived concentration ratio of estrone-3-glucuronide/pregnanediol-3 alpha-glucuronide could be used to indicate the start of the fertile period, and a 50% decrease plus two days the start of the infertile period in greater than 80% of the ovarian cycles. The limitations, implications and future developments are discussed.