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PHARMFIT--a nonlinear fitting program for pharmacology.

A new program is presented for nonlinear fitting of data from pharmacological and chronobiological investigations. It contains functions for calculating data from ligand-binding studies and competition experiments, for the analysis of dose-response curves, for pharmacokinetic calculations, and for cosine analysis of harmonic and overlapping rhythms. In addition, it is possible to implement general equations by the user. The program allows data exchange with most spreadsheet, database, and graphics presentation programs, and accepts data from two widely used ambulatory 24-h blood-pressure monitoring systems. The fitting procedure uses the Marquardt-Levenberg algorithm. It calculates the weighted or the unweighted fit together with a great variety of statistics for estimation of goodness of fit. A graphics module permits graphical presentation of the fitted curve. Moreover, fitting of data to different models can be compared for the most likely fit and model discrimination statistics for improvement of further experiments are provided. To demonstrate the chronobiological application of the fitting program PHARMFIT, the analysis of telemetric heart rate data from rats is presented.

Binding Sites

Decision analysis: a progress report.

Since its introduction into medicine 15 years ago, decision analysis has been applied to difficult clinical problems. Several important advances have made the process more practical and acceptable: computer programs that eliminate the need for burdensome calculations, improved techniques for designing analytic models, the ability to carry out sensitivity analyses over several dimensions simultaneously, and the elaboration of clinically relevant measures of utility. Using these techniques, analysts have addressed many important clinical issues including screening for and prevention of disease, tradeoffs among tests and treatments, and the interpretation of clinical data under conditions of uncertainty. Problems with the approach remain and applications have not been extensive, but decision analysis is evolving as a powerful clinical tool and gradually is gaining acceptance in medical practice.

Bayes Theorem

Intraoperative and external radiotherapy in resected gastric cancer: updated report of a phase II trial.

From September 1984 to August 1991, 48 evaluable patients with resected gastric cancer and apparent disease confined to locoregional area were treated with intraoperative electron beam boost to the celiac axis and peripancreatic nodal areas (15 Gy) and external irradiation (40 to 46 Gy in 4 to 5 weeks) including the gastric bed and upper abdominal nodal draining regions. At the time of evaluation for IORT, the disease was primary in 38 cases, recurrent but resectable in four (anastomosis), and unresectable in four (nodal). Post operative complications were reversible. Acute tolerance to the complete treatment program was acceptable. Late complications included life-threatening events: Six episodes of gastro intestinal bleeding (three of them had an arteriographic documentation of arterioenteric fistula) and nine with severe enteritis (five required reoperation). Other long-term treatment related complications were six cases of vertebral collapse. The median follow-up time for the entire group is 22 months. Locoregional recurrence/persistence of disease has been identified in five patients (three with residual and/or recurrent postsurgical tumor). Systemic tumor progression has been detected in 15 patients (11 in intra-abdominal sites). Overall actuarial survival for patients with positive or negative serosal involvement was 33% versus 56%. It is concluded that the treatment program described is able to induce a high locoregional tumor control rate (100%) when used strictly in an adjuvant setting and might control long term, a small portion of patients not amenable for curative surgery (2 out of 8 patients with confirmed residual post-surgical disease). Gastrointestinal bleeding and enteritis are findings that indicate treatment intensity at the upper limits of tissue tolerance. Assessment of long term tolerance of pancreatic parenchyma and large blood vessels (tissues included in the IRORT field) are pending for longer follow-up and the appropriate selective studies.

Humans

Use and acceptance of the "paper pill". A novel approach to oral contraception.

A randomized, crossover study comparing the acceptance of and attitudes towards two dosage forms of the same oral contraceptive product - a paper presentation and the conventional tablet, was carried out in a network of rural and suburban research centers in the State of Durango, México. The results failed to show any significant advantage (in terms of acceptability or continuation) of the paper formulation. Although two-thirds of the participants indicated a preference for the conventional tablet, there was a high degree of acceptance of the paper formulation among new oral contraceptive acceptors.

Adolescent

Filariasis eradication on Kinmen Proper, Kinmen (Quemoy) Islands, Republic of China.

A control program for bancroftian filariasis was conducted on Kinmen Proper from 1970 to 1982. The combined method of mass chemotherapy with diethylcarbamazine (DEC) for microfilarial carriers and larvicide with sumithion for mosquitoes was used on the island for 3 years (1974-76). The microfilarial rate and microfilarial density decreased from 8.4% and 14.6/20 microns in 1970-73 to 0.7% and 5.3/20 microns in 1976. The infection rate, infective rate, and larval density of Culex quinquefasciatus, the only mosquito vector of the parasite, decreased from 10.3%, 6.4%, and 6.4 in 1970-73 to 0.3%, 0.2%, and 1.3, in 1976, respectively. For final elimination of the infection, DEC medicated salt (0.33%, w/w) was then administered to the whole population for 6 months (March-September 1977). All accepted the program and no adverse side-effects were noted. Six annual follow-up surveys (1977-82) revealed only 3 out of 3853 previous carriers to be positive. These carriers were cured with a course of 5 g DEC. All family members of the 3 carriers and of the 12 neighbouring families were also given DEC medicated salt for 4 months in order to clear the only remaining source of filarial transmission. In conclusion, administration of DEC medicated salt is simple, rapid, safe, inexpensive, efficient, and practical for filariasis control or eradication.

Adolescent

Testing strategies to increase use of chloroquine chemoprophylaxis during pregnancy in Malaŵi.

The widespread problem of low and non-compliance to antimalarial chemoprophylaxis during pregnancy demands that attention be focused on alternative approaches to programming, product acceptability and demand for preventive services. This study describes the testing of three interventions to determine their effect on use of chloroquine (currently the most widely used drug for chemoprophylaxis) during pregnancy. The strategies evolved from community-based formative research undertaken to learn about the local concept of malaria and issues surrounding malaria prevention and treatment during pregnancy. The resulting interventions were tested in four clinics, and included a change in the health education message given during antenatal sessions, distribution of a sugar-coated chloroquine tablet, and an intervention combining the two strategies. The results showed a 45% increase in chloroquine use when the health education message was changed, and a 64% increase when the product was changed. High use levels were maintained with the combined intervention; an additive effect was seen. The study shows that improving the product was the most important factor in increasing the use of the program, and that changing the health education message can also make an impact on use.

Chemistry, Pharmaceutical

A breast self-examination program for high school students.

Breast self-examination (BSE) is an important adjunct to the detection of breast cancer at an early stage. High school students were instructed in the importance and methods of BSE. By use of questionnaires, the program was evaluated for interest, acceptability, and compliance. It was found that high school students were not adverse to learning about BSE, found the program acceptable, and maintained some compliance at one year.

Adolescent

Prognostic value of thyroid hormone levels in patients evaluated for liver transplantation.

The thyroid hormones T4, T3, rT3 and TSH were assayed in 134 adult patients evaluated and accepted as potential liver transplant candidates at the University of Pittsburgh from March, 1981 to December, 1983. The subsequent course of these patients was evaluated with respect to the levels of these hormones obtained at the time of acceptance for transplantation. T4 levels were increased significantly while their T3 levels were reduced (both p less than 0.01) in those who survived and were discharged home as compared to either those who died waiting to be transplanted or died following the procedure. As a result, the ratio of T3/T4 was reduced markedly (p less than 0.01) in those who were transplanted and survived as compared to those not transplanted or dying following transplantation. Importantly, the rT3 levels clearly separated (p less than 0.01) those who would die prior to transplantation from those who would survive to be transplanted. Finally, the ratio rT3/T3 even more clearly separates those who will die prior to transplantation (p less than 0.01) from the other two groups. These data suggest that thyroid hormone levels, particularly rT3 levels, might be useful in setting priorities for which patients referred for a transplantation evaluation should be accepted into the program and in determining who among accepted patients should be operated upon in preference to others also accepted and waiting to be transplanted.

Carcinoma, Hepatocellular

The television, school, and family smoking prevention and cessation project. VIII. Student outcomes and mediating variables.

BACKGROUND: This paper presents the student outcomes of a large-scale, social-influences-based, school and media-based tobacco use prevention and cessation project in Southern California. METHODS: The study provided an experimental comparison of classroom delivery with television delivery and the combination of the two in a 2 x 2 plus 1 design. Schools were randomly assigned to conditions. Control groups included "treatment as usual" and an "attention control" with the same outcome expectancies as the treatment conditions. Students were surveyed twice in grade 7 and once in each of grades 8 and 9. The interventions occurred during grade 7. RESULTS: We observed significant effects on mediating variables such as knowledge and prevalence estimates, and coping effort. The knowledge and prevalence estimates effects decayed partially but remained significant up to a 2-year follow-up. The coping effort effect did not persist at follow-ups. There were significant main effects of both classroom training and TV programming on knowledge and prevalence estimates and significant interactions of classroom and TV programming on knowledge (negative), disapproval of parental smoking, and coping effort. There were no consistent program effects on refusal/self-efficacy, smoking intentions, or behavior. CONCLUSIONS: Previous reports demonstrated successful development and pilot testing of program components and measures and high acceptance of the program by students and parents. The lack of behavioral effects may have been the result of imperfect program implementation or low base rates of intentions and behavior.

Child

CD40 ligation in B cell activation, isotype switching and memory development.

Interaction of CD40 on B cells with its ligand on activated T helper cells is crucial for the generation of mature T-dependent antibody responses. Experimental observations suggest that CD40 ligation acts at several points in B cell differentiation; however, it is not clear whether the consequences of ligation are direct or indirect. While its role in B cell activation is clearly direct we discuss the several ways in which it might drive isotype switching, the influence that it has on the development of memory B cells and the possibility that certain types of T-dependent antibody response are CD40L-independent. Experiments in which the ligation of CD40 is blocked in vivo reveal that early CD40 signals are important for the development of memory B cells but this may only reflect the ability of 'memory precursors' generated by CD40 ligation to accept subsequent programming or survival signals.

Animals

Concomitant adjuvant chemotherapy and radiotherapy for high risk breast cancer patients.

Thirty four patients treated with mastectomy and axillary node dissection for potentially curable breast cancer received a seven month combined adjuvant chemotherapy and radiation therapy program. These patients were considered to be at high risk for recurrence because they had either three or more positive axillary lymph nodes or their primary tumor was greater than 5 cm in diameter. The chemotherapy given at 3-week intervals consisted of cyclophosphamide, 600 mg/m2, Adriamycin 40 mg/m2, and methotrexate 40 mg/m2 during cycles 1 through 3 and 7 through 9. Radiation therapy was administered during cycles 4 through 6 with concomitant administration of 5-fluorouracil 600 mg/m2, vincristine 1.4 mg/m2, and prednisone 40 mg/m2 for 7 days. Median follow up time from initiation of study is 60 months (range 36-93). Seventeen of 34 patients (50%) remain free of recurrent breast cancer. Distant metastases and local-regional recurrence have occurred in 16 (47%) and 4 (12%) patients, respectively. Significant myelosuppression and infections requiring hospitalization were seen in 4 patients, with 1 treatment-related death. Adriamycin-containing chemotherapy and post-operative radiotherapy can thus be combined in an adjuvant treatment program with acceptable toxicity.

Adult

A conversational microcomputer-based health risk appraisal.

We have developed a conversational microcomputer-based health risk appraisal program. This appraisal has been tested on over 200 users at 3 locations in urban and suburban Minneapolis. It was considered helpful by 92% of its users, and 25% stated that they would probably or definitely change a living habit based on its use. All 3 populations considered it comparably helpful, irrespective of their different age and sex distributions. A complex health appraisal, which was formerly assumed to require batch processing on a large computer, can be carried out on a small personal system in an interactive mode. Such a program is acceptable to users and has the potential to motivate change in risky behavior.

Adult

Pregnancy, childbirth, mother and child care among the indigenous people of Zimbabwe.

Even in areas of Zimbabwe with easy access to Western-type delivery care, the majority of women are cared for and delivered by traditional birth attendants who are members of their extended family. To understand the social, cultural context of pregnancy, childbirth and subsequent maternal and child care and to use this information for the improvement of maternal and child-health care an anthropological investigation was conducted in an area near Harare, Zimbabwe from June 1983 to the end of 1984. Certain aspects of childbirth such as primagravida deliveries and the origins of peripartum complications, are intimately linked to the religious beliefs and values; other aspects such as the relationship of nutrition and pregnancy are not so linked. An understanding of the traditional concepts of pregnancy, delivery and child care is invaluable if not essential for the upgrading of pregnancy and delivery care, the elimination of harmful practices and the building of supportive links between the traditional and the formal health system.

Female

Negative cross-match selection of HLA-DR compatible kidneys for highly sensitised patients.

Patients who have developed alloantibodies against almost all foreign HLA antigens are very difficult to transplant, because the cross-match with potential donors is often positive. The ideal donor for such patients is an HLA identical or compatible donor, but due to the enormous polymorphism of the HLA complex, the chance of finding such a donor is very small. The acceptable mismatch program, which takes advantage of the HLA-A and B antigens toward which the patient has not developed antibodies, and HLA-DR matching in the computerised selection of kidney donors, has significantly decreased the waiting time for these highly sensitised patients. Furthermore, graft survival is similar to that of non-highly sensitised patients.

Graft Survival

Osteoporosis: impact on the elderly societal concerns, and the role of radiology.

Osteoporosis has recently become a concern in both the medical and lay communities. Osteoporosis may be defined as a decrease in bone mass with maintenance of normal bone composition. The increase in bone fragility results in an increased incidence of fractures. The disease most commonly affects postmenopausal women, particularly Caucasians. It is estimated that 1.2 million fractures per year can be attributed to osteoporosis. These fractures cost the health care system approximately $18.1 billion per year. Given the magnitude of the health and attendant financial problems, osteoporosis deserves the attention of clinicians and researchers. This article will deal with the pathophysiologic processes, techniques for bone mineral determination, therapeutic regimens and the advisability of mass screening. The relationship between bone mineral content and fracture risk has not been clearly defined. If every American woman between the ages of 40 and 54 years were given a single bone mineral screening examination, the cost would be approximately $187.5 million/year. At this price and in the absence of accepted treatment programs, it does not seem prudent for radiologists or other physicians to recommend expensive mass screening.

Aged

Prerequisites for successful human sperm cryobanking: sperm quality and prefreezing holding time.

Frozen-thawed donor semen was used in artificial inseminations and in vitro fertilization programs. Semen accepted for donation was characterized (mean +/- SE) by sperm concentration of 150 +/- 18.6 x 10(6)/mL, normal morphology of 57% +/- 1.4%, good progressive motility at 1 hour of 57% +/- 1.0%, and post-thaw motility of 45% +/- 1.0%. Delay of the freezing process for greater than 1 hour after semen delivery caused a deleterious effect to the freezability of sperm. The average monthly fecundability for the 1st 6 months after inseminations was 13.6%. This value decreased dramatically to 2.6% from the 7th month onward. In 74 IVF/embryo transfer (ET) cycles, the fertilization rate was 55.3% +/- 3.8%, pregnancy rate (PR) per ET was 39.6%, and the PR per woman was 42.8%.

Cryopreservation

Worldwide patterns of infertility: is Africa different?

The World Health Organisation sponsored a multicentre, collaborative investigation of a standard approach to evaluating infertile couples. The study was conducted between 1979 and 1984 in thirty-three medical centres in twenty-five countries throughout the developed and developing world. Over 5800 couples completed the investigation. African centres had a pattern of infertility different from those in other developing regions or the developed countries. African couples were more likely than those from elsewhere to have secondary infertility or longer duration, a history of sexually transmitted diseases or pregnancy complications, and infertility diagnoses (such as bilateral tubal occlusion or pelvic adhesions) suggestive of previous genital infections.

Adult

The optimism of policy choices in child welfare.

That the desire for sure answers to problems in child welfare has led to acceptance of programs on the basis of faith rather than realism is illustrated by examination of some current programs. The need for rational choices in policy, program, and practice that respond to the basic human requirements of vulnerable families is highlighted.

Adolescent