Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations.

OBJECTIVE: To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: This study used the Medicare 5% sample and MarketScan Commercial (2010-2013) claims data sets to identify men with mCRPC and initial episodes of docetaxel treatment. Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a 24-month look-forward period from initial docetaxel index date. Docetaxel drug claim costs were adjusted for 2011 generic docetaxel introduction, while other costs were adjusted to 2015 values using the national average annual unit cost increase. RESULTS: This study identified 281 Medicare-insured and 155 commercially insured men, with 325 and 172 docetaxel episodes, respectively. The average number of cycles (unique docetaxel infusion days) per episode was 6.9 for Medicare and 6.3 for commercial cohorts. The average cost per episode was $28,792 for Medicare and $67,958 for commercial cohorts, with docetaxel drug costs contributing $2,588 and $13,169 per episode, respectively. The average cost per episode on docetaxel infusion days was $8,577 (30%) for Medicare and $28,412 (42%) for commercial. Non-docetaxel infusion day costs included $7,074 (25%) for infused or injected drugs for Medicare, $10,838 (16%) for commercial cohorts, and $6,875 (24%) and $9,324 (14%) for inpatient admissions, respectively. LIMITATIONS: The applicability is only to the metastatic castration-resistance clinical setting, rather than the metastatic hormone-sensitive setting, and the lack of data on the cost effectiveness of different sequencing strategies of a range of systemic therapies including enzalutamide, abiraterone, radium-223, and taxane chemotherapy. CONCLUSION: The majority of docetaxel episode costs in Medicare and commercial mCRPC populations were non-docetaxel drug costs. Future research should evaluate the total cost of care in mCPRC.

Medication use by athletes during the Athens 2004 Paralympic Games.

OBJECTIVE: To examine the use of food supplements and pharmaceutical preparations by elite Paralympic athletes. DESIGN: Survey study. SETTING: Athens 2004 Paralympic Games. PARTICIPANTS: Data obtained from two sources: (i) athletes' declaration of intake of drugs/supplements recorded on the Doping Control Official Record during sample collection for doping control; (ii) athletes' application forms for granting of a therapeutic use exemption. MAIN OUTCOME MEASURES: Classification of declared food supplements according to the active ingredient and medications according to therapeutic actions and active compounds. RESULTS: 64.2% of the athletes tested for doping control declared use of medications or food supplements, and 81.3% of these athletes declared intake of fewer than four preparations. Non-invasive routes of administration dominated. Food supplements (42.1%) were popular, and drugs used to treat several pathological conditions noted. Non-steroidal anti-inflammatory agents and analgesics were commonly used (9.8% and 5.6%, respectively). The prevalence of inhaled beta2-agonist use (4.8%) was higher than expected and exceeded that at the Athens Olympic Games. CONCLUSIONS: This review, the first to examine elite Paralympic athletes, shows a more rational approach to the use of medication and food supplements, but a similar consumption pattern to that of athletes at the Athens Olympic Games. Because of the dearth of such studies, consumption trends among Paralympic athletes remain unclear. The need to counsel athletes with disabilities on their nutritional needs is confirmed, and close monitoring by healthcare professionals is recommended.

Medicine and science in the fight against doping in sport.

The fight against doping in sports commenced as a result of the death of a Danish cyclist during the Rome Olympic Games in 1960. The International Olympic Committee (IOC) established a Medical Commission (IOC-MC) which had the task of designing a strategy to combat the misuse of drugs in Olympic Sport. Some International Sport Federations (IF) and National Sports Federations followed suit, but progress was modest until the world's best male sprinter was found doped with anabolic steroids at the Olympic Games in Seoul in 1988. Further progress was made following the cessation of the cold war in 1989 and in 1999 public authorities around the world joined the Olympic Movement in a unique partnership by creating WADA--the 'World Anti-Doping Agency'. The troubled history of the anti-doping fight from the 1960s until today is reviewed. In particular, the development of detection methods for an ever increasing number of drugs that can be used to dope is described, as are the measures that have been taken to protect the health of the athletes, including those who may need banned substances for medical reasons.

Carotenoid, tocopherol, and retinol concentrations in elderly human brain.

BACKGROUND: Antioxidants, such as tocopherols and carotenoids, have been implicated in the prevention of degenerative diseases. Although correlations have been made between diseases and tissue levels of antioxidants, to date there are no reports of individual carotenoid concentrations in human brain. OBJECTIVE: To measure the major carotenoids, tocopherols, and retinol in frontal and occipital regions of human brain. DESIGN: Ten samples of brain tissue from frontal lobe cortex and occipital cortex of five cadavers were examined. Sections were dissected into gray and white matter, extracted with organic solvents, and analyzed by HPLC. RESULTS: At least 16 carotenoids, 3 tocopherols, and retinol were present in human brain. Major carotenoids were identified as lutein, zeaxanthin, anhydrolutein, alpha- cryptoxanthin, beta- cryptoxanthin, alpha-carotene, cis- and trans-betacarotene, and cis- and trans-lycopene. Xanthophylls (oxygenated carotenoids) accounted for 66-77% of total carotenoids in all brain regions examined. Similar to neural retina, the ratio of zeaxanthin to lutein was high and these two xanthophylls were significantly correlated (p <0.0001). The tocopherol isomers occurred in the brain over a wider range of mean concentrations (0.11-17.9 nmol/g) than either retinol (87.8 - 163.3 pmol/g) or the identified carotenoids (1.8-23.0 pmol/g). CONCLUSIONS: The frontal cortex, generally vulnerable in Alzheimer's disease, had higher concentrations of all analytes than the occipital cortex which is generally unaffected. Moreover, frontal lobes, but not occipital lobes, exhibited an age-related decline in retinol, total tocopherols, total xanthophylls and total carotenoids. The importance of these differences and the role(s) of these antioxidants in the brain remain to be determined.

Gender differences in clinical status at time of coronary revascularisation in Spain.

OBJECTIVE: To study gender differences in clinical status at the time of coronary revascularisation. DESIGN: Retrospective study of clinical records. Two stage stratified cluster sampling was used to select a nationally representative sample of patients receiving a coronary revascularisation procedure in 1997. SETTING: All of Spain. MAIN OUTCOME MEASURES: Odds ratios (OR) in men and women for different clinical and diagnostic variables related with coronary disease. A logistic regression model was developed to estimate the association between coronary symptoms and gender. RESULTS: In the univariate analysis the prevalence of the following risk factors for coronary heart disease was higher in women than in men: obesity (OR=1.8), hypertension (OR=2.9) and diabetes (OR=2.1). High surgical risk was also more prevalent among women (OR=2.6). In the logistic regression analysis women's risk of being symptomatic at the time of revascularisation was more than double that of men (OR=2.4). CONCLUSIONS: Women have more severe coronary symptoms at the time of coronary revascularisation than do men. These results suggest that women receive revascularisation at a more advanced stage of coronary disease. Further research is needed to clarify what social, cultural or biological factors may be implicated in the gender differences observed.

Medida del uso apropiado de revascularización coronaria en el ámbito de una compañía aseguradora privada / Appropriateness of use of coronary revascularization in a private medical insurance company

Objetivos: Identificar la proporción de uso apropiado en los procedimientos de revascularización coronaria (RC), angioplastia transluminal percutánea (ACTP) y cirugía de by-pass (CRC) en el ámbito de una aseguradora sanitaria: Sanitas S.A. en Madrid. Metodología: El grado de uso apropiado se determinó usando los estándares españoles de uso apropiado, basados en RAND/UCLA Appropriateness Method. El estudio consistió en una revisión retrospectiva de 179 historias clínicas de pacientes revascularizados durante 1996 y 1997 provenientes de tres hospitales privados de Madrid. Los criterios de grado de uso apropiado se han hecho conforme a un análisis de sensibilidad con dos aproximaciones: menos favorable y más favorable al uso apropiado. Resultados: Según el análisis de sensibilidad, la proporción de uso inapropiado para ACTP podría oscilar entre el 29 per cent en la aproximación menos favorable y el 13 per cent en la más favorable. La proporción de uso inapropiado de CRC variaría desde el 16 per cent en la menos favorable al 10 per cent en la más favorable. Los factores asociados con el uso inapropiado fueron enfermedad vascular de un solo vaso no DAP y estar siguiendo un tratamiento médico sub-óptimo sin agotar todas las alternativas farmacológicas. Conclusiones: Una parte sustancial de las revascularizaciones realizadas en Sanitas durante 1996 y 1997 lo fue por razones inapropiadas. La estrategia diseñada en este estudio servirá para estimular el uso apropiado de los procedimientos de RC en el ámbito privado, a disminuir el uso inapropiado, a evitar decisiones dirigidas a reducir indiscriminadamente el número de procedimientos y a ayudar al médico a tomar decisiones con un menor grado de incertidumbre (AU)

Quantification of terbutaline in urine by enzyme-linked immunosorbent assay and capillary electrophoresis after oral and inhaled administrations.

The International Olympic Committee and World AntiDoping Agency restricts the use of beta2-agonists and only the inhaled administration of terbutaline, salbutamol, formoterol and salmeterol is permitted for therapeutic reasons. The aim of this study was to develop a test for the quantitation of terbutaline in urine and evaluate different parameters to distinguish between oral and inhaled administration of the drug. Urine samples were collected from asthmatic and non-asthmatic recreational swimmers who had received repeated doses of oral (3x2.5 mg plus 1x5 mg during 24 h) and inhaled (12x0.5 mg in 24 h with half of it being in the last 4 h) racemic terbutaline, and single oral (5 mg) or single inhaled doses (1 mg). Total terbutaline concentrations (free+conjugated) were determined by enzyme-linked immunosorbent assay. Results showed that after oral administrations urinary terbutaline concentrations were higher than those detected after inhalation. For confirmation purposes, a chiral capillary electrophoretic procedure was established and validated. A solid-phase extraction with Bond-Elut Certify cartridges was undertaken, separation performed using a 50 mM phosphate buffer (pH 2.5) containing 10 mM of (2-hydroxypropyl)-beta-cyclodextrin as running buffer and diode-array UV detection set at 204 nm. The proposed procedure is rapid, selective and sensitive allowing quantitation of free terbutaline enantiomers in urine. No statistical differences were found between total free terbutaline concentrations [S-(+)+R-(-)] in urine collected after oral and inhaled administrations of the drug. After oral doses enantiomeric [S-(+)]/[R-(-)] ratios lower than those obtained after inhalation were observed probably due to an enantioselective metabolism that take place in the intestine, but differences between both routes of administration were not statistically significant. Although different trends were observed after oral and inhaled doses in total terbutaline, total free terbutaline concentrations and in ratios between its enantiomers, differences observed were not sufficiently significant to establish cut-off values to clearly distinguish between both routes of administration.

Laboratory protocol for exercise asthma to evaluate salbutamol given by two devices.

PURPOSE: As new delivery devices and formulations are being introduced for drugs given by inhalation, there is a need to evaluate their equivalence with old preparations. One way to do this is to investigate their equivalence in protecting from exercise-induced asthma (EIA). METHODS: We used a protocol for EIA to compare the protective effect of salbutamol delivered by the pressurised metered dose inhaler (pMDI) and the new Diskus dry powder device. Twenty-seven asthmatic subjects with moderately severe EIA completed an exercise test on four separate days at two study centers. Exercise was performed by cycling for 8 min while inhaling dry air (0% RH, 20-24 degrees C). The target workload in W was predicted as (53.76 x predicted FEV1) - 11.07 and 95% of this target was achieved at 4 min of exercise. This target was chosen in order to achieve ventilation between 50 and 60% of predicted maximum in the last 4 min. RESULTS: There was no significant difference in the workload, ventilation, or heart rate achieved on the study days. The severity of EIA was measured as the % fall in FEV1. EIA severity was similar on the placebo and control day and the coefficient of variation was 19.4%. The mean +/- SD % fall on the control, placebo, salbutamol by Diskus, and pMDI were 42.0% +/- 15, 39.4% +/-17.6, 13.4% +/- 13.2, and 8.5% +/- 13.8, respectively. Salbutamol significantly inhibited the % fall in FEV1 after exercise, and there was no difference between the preparations. CONCLUSION: The protocol described here is suitable for evaluating equivalence of salbutamol preparations in protecting against EIA and could be used to evaluate the protective effect of other medications.

The appropriateness of use of percutaneous transluminal coronary angioplasty in Spain.

BACKGROUND: The rapid increase in the number of percutaneous transluminal coronary angioplasty (PTCA) procedures performed in Spain in recent years raises questions about how appropriately this procedure is being used. To examine this issue, we studied the appropriateness of use of PTCA in Spanish patients and factors associated with inappropriate use. METHODS: We applied criteria for the appropriate use of PTCA developed by an expert panel of Spanish cardiologists and cardiovascular surgeons to a random sample of 1913 patients undergoing PTCA in Spain in 1997. The patients were selected through a two-step sampling process, stratifying by hospital type (public/private) and volume of procedures (low/medium/high). We examined the association between inappropriate use of PTCA and different clinical and sociodemographic factors. RESULTS: Overall, 46% of the PTCA procedures were appropriate, 31% were uncertain and 22% were inappropriate. Two factors contributing to inappropriate use were patients' receipt of less than optimal medical therapy and their failure to undergo stress testing. Institutional type and volume of procedures were not significantly related with inappropriate use. CONCLUSIONS: One of every five PTCA procedures in Spain is done for inappropriate reasons. Assuring that patients receive optimal medical therapy and undergo stress testing when indicated could contribute to more appropriate use of PTCA.

Effect of specialty and nationality on panel judgments of the appropriateness of coronary revascularization: a pilot study.

BACKGROUND: Appropriateness criteria are frequently used to assess quality of care. However, assessing care in one country with criteria developed in another may be misleading. One approach to measuring care across countries would be to develop common standards using physicians from different countries and specialties. OBJECTIVE: To identify the degree to which appropriateness ratings for coronary revascularization developed by a multinational panel differ by panelist specialty and nationality. METHODS: A 13-member panel of cardiothoracic surgeons and cardiologists from the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom was convened to rate the appropriateness of 842 indications for percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG) on a 1 (extremely inappropriate) to 9 (extremely appropriate) scale. MEASURES: Mean appropriateness ratings by panelist specialty and nationality. RESULTS: Surgeons' mean ratings for PTCA indications ranged from 0.64 points lower than the corresponding ratings of the cardiologists for acute myocardial infarction indications to 1.22 points lower for chronic stable angina indications. Conversely, their ratings for bypass surgery indications ranged from 0.59 points higher for chronic stable angina indications to 0.69 points higher for unstable angina indications. Although Spanish panelists' ratings were significantly higher than the mean for 3 of the 4 clinical conditions treated by PTCA, their ratings were similar for bypass surgery indications. No specific patterns were observed in the ratings of the panelists from the other countries. CONCLUSIONS: These findings support the use of physicians from multiple specialties on appropriateness panels because they represent more divergent views than physicians from a single specialty. Finding no systematic difference in beliefs regarding the appropriateness of PTCA and CABG among physicians from different countries will require confirmation before multinational panels supplant single country panels in future studies.

European criteria for the appropriateness and necessity of coronary revascularization procedures.

OBJECTIVES: Large variations in the use of coronary revascularization procedures have led many countries to apply the RAND appropriateness method to develop specific criteria describing patients who should be offered these procedures. The method is based on the work of a multidisciplinary expert panel that reviews a synthesis of the scientific evidence and rates the appropriateness of a comprehensive list of indications for the procedure being studied. Previous studies, however, have all involved single-country panels. We tested the feasibility of carrying out a multinational panel to rate the appropriateness and necessity of coronary revascularization, thereby producing recommendations for common European criteria. METHODS: Using the RAND methodology, a multispecialty (interventional cardiologists, non-interventional cardiologists and cardiovascular surgeons), multinational (The Netherlands, Spain, Sweden, Switzerland and the United Kingdom) panel rated the appropriateness and necessity of indications for percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG). A synthesis of the evidence and list of indications for PTCA and CABG were sent to 15 panelists, three from each country, who performed their ratings in three rounds. RESULTS: For PTCA, 24% of the indications were appropriate and necessary, 16% were appropriate, 43% were uncertain and 17% were inappropriate. The corresponding values for CABG were 33% appropriate and necessary, 7% appropriate, 40% uncertain and 20% inappropriate. The proportion of indications rated with disagreement was 4% for PTCA and 7% for CABG. CONCLUSION: Multinational panels appear to be a feasible method of addressing issues concerning the appropriateness and necessity of medical procedures in western European countries. The criteria produced provide a common tool that can be used to measure the overuse and underuse of medical procedures and to guide decision-making.

Discrimination of prohibited oral use of salbutamol from authorized inhaled asthma treatment.

BACKGROUND: The administration of salbutamol is permitted only by inhalation by the International Olympic Committee (IOC) for the management of asthma and exercise-induced asthma in athletes. The establishment of criteria to distinguish between the (IOC) authorized use (inhaled) and the (IOC) prohibited use (oral) of salbutamol appeared possible using simultaneous evaluation of variables based on the concentration of nonconjugated enantiomers of salbutamol excreted in urine. METHODS: Urine was collected from asthmatic and nonasthmatic swimmers who had received various preexercise doses of oral (five doses of 4 mg) or inhaled (two doses of 100 microgram) salbutamol. Urine was also obtained from subjects who had received the maximum dosage of inhaled salbutamol advisable for competing athletes to provide protection from exercise-induced asthma and treatment of asthma (1600 microgram in 24 h, 800 microgram being in the last 4 h). All samples were analyzed to determine the total amount of unchanged salbutamol excreted in urine and the ratio between the S: and R: enantiomers. RESULTS: The discriminant function D = -3.776 + 1.46 x 10(-3) ([S:(+)] + [R:(-)]) + 1.012 ([S:(+)]/[R(-)]) can be used to classify data into two groups, inhaled and oral. The confirmatory criterion suggested (cutoff at D = 1.06, 4 SD from the mean D value of the inhaled distribution) has been verified in different sets of samples showing suspicious concentrations by conventional screening procedures in doping control. An 11.8% false-negative (oral classified as inhaled) rate is assumed with the confirmatory criterion proposed, but virtually no false positives (inhaled classified as oral) are obtained (<1 in 33 000). CONCLUSIONS: The overall procedure recommended is to screen all samples and to apply the confirmation criterion proposed to samples showing free racemic salbutamol concentrations >500 microgram/L by gas chromatography-mass spectrometry or free + conjugated racemic salbutamol concentrations >1400 microgram/L by ELISA.

Distinction of inhaled and oral salbutamol by urine analysis using conventional screening procedures for doping control.

Salbutamol administration in athletes is permitted only by inhalation, for the management of asthma. The authors discuss different criteria for suspecting oral use of salbutamol, taking into account the data obtained by application of two conventional screening procedures for doping control: gas chromatography/mass spectrometry (GC/MS) and enzyme-linked immunosorbent assay (ELISA). Urine samples obtained after administration of oral and inhaled salbutamol to asthmatic and nonasthmatic swimmers were analyzed using both analytical approaches. As expected, concentrations obtained by the ELISA test (detection of total salbutamol) were higher than those obtained using the GC/MS procedure (detection of nonsulfated salbutamol). After oral administration, the ELISA test detected significantly higher salbutamol concentrations than those detected after inhalation, reflecting the greater doses administered orally. Urine samples with total salbutamol greater than 1400 ng/mL were obtained after oral doses, but no sample reached this value after inhaled doses. Higher concentrations of nonsulfated salbutamol have also been detected after oral intake, although there is an overlap between the distributions of concentrations after oral and inhaled doses. A cut-off concentration of 500 ng/mL can be used for nonsulfated salbutamol to select suspicious samples, giving 11.8% false negative results and 4.3% false positive results. An additional criterion evaluated was the androsterone-salbutamol peak height ratio, which was lower after oral doses because of the higher concentrations of salbutamol in urine. This ratio was lower than 2 for all the samples collected after oral administration, although 6.8% false positive samples resulted because of low concentrations of androsterone in female urine. Several possibilities for detecting suspicious samples from athletes who have taken prohibited oral salbutamol are available with conventional screening procedures in doping control.

Use of mammography among women residing in Spanish provinces with breast cancer screening programmes.

The objective of this study was to measure use of mammography and associated factors among women living in Spanish provinces with breast cancer screening programmes. From a cross-sectional population survey in a representative sample of Spanish women aged 40-70 years, we selected all women aged 45-65 living in provinces with breast cancer screening programmes (336 women). The programmes invited women in this age group to have a mammogram every 2 years. Data were collected by oral interviews in 1994. Use of mammography was defined as having received at least one test in the previous 2 years. Factors associated with mammography were studied using a logistic regression model. In the three autonomous communities (totalling 11 provinces) with programmes, the percentage of women receiving the test was 41.1% in Castille-Leon, 41.7% in Castille-La Mancha and 87.6% in Navarre (mean: 55.4%). The programmes began in 1990 in Navarre and between 1992 and 1993 in the other two communities. The most important factors affecting mammography use in the multivariate analysis were: intention to have a mammogram [odds ratio (OR) = 5.52; 95% confidence interval (CI) = 3.17-9.63]; not rejecting the test for fear of cancer diagnosis (OR = 4.23; 95% CI = 1.64-10.9); and physician recommendation of the test (OR = 3.43; 95% CI = 1.88-6.24). In conclusion, although the more established screening programmes have higher mammography use than those more recently implemented, programmes alone may not guarantee that women receive the test. Women's attitudes about mammography, and the role of the physician, are fundamental factors in the use of mammography.

[Standards for the appropriate use of percutaneous transluminal coronary angioplasty and aortocoronary surgery]. / Estándares para el uso apropiado de la angioplastia coronaria transluminal percutánea y cirugía aortocoronaria.

INTRODUCTION AND OBJECTIVES: The large differences in rates of use of clinical procedures among regions, hospitals and physicians raise questions as to whether some population groups are receiving inappropriate procedures or others are not receiving necessary ones. The objective of this study is to develop criteria for the appropriate use of coronary revascularization procedures in Spain. METHODS: Following the RAND appropriateness method, criteria were developed for the appropriate use of coronary revascularization (percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery) in Spain. A literature review was produced as well as a comprehensive and mutually exclusive list of 1,826 indications for coronary revascularization. A panel of 12 experts (4 interventional cardiologists, 4 non-interventional cardiologists and 4 cardiovascular surgeons) rated the appropriateness of each indication on a scale from 1 (highly inappropriate) to 9 (highly appropriate). The ratings were made twice; anonymously in the first round, and during a 2-day meeting in the second round. In accordance with the panelists' mean rating and level of agreement, each indication was classified as appropriate, uncertain or inappropriate for revascularization, angioplasty and bypass surgery. RESULTS: Criteria have been developed for the appropriate use of angioplasty and bypass surgery which can be applied to patients with coronary artery disease. The combination of clinical characteristics makes it possible to classify patients with a high degree of specificity. CONCLUSIONS: These criteria can be used retrospectively, to measure the proportions of appropriate use, or prospectively, as an aid to decision making in order to promote the appropriate use of coronary revascularization.

A demographic and health survey of Spanish female sex workers: HIV prevalence and associated risk factors.

In order to examine the prevalence of HIV infection and associated risk factors amongst Spanish female prostitutes a multicentre (n = 22) cross-sectional study was conducted between November 1989 and January 1991. Data collected included socioeconomic characteristics, sexual behavior and health status together with blood samples. A total of 1633 prostitutes were recruited into the study. Of these, 1433 (87.8%) consented to blood samples being taken and 180 (12.6%) were HIV positive. HIV seroprevalence was 54.7% for intravenous drug users (IVDUs) versus 3.7% for non-IVDUs. Previous imprisonment, hepatitis B and a partner who was an IVDU were significant predictors of HIV infection according to multivariate logistic regression models.

The paternal effect gene ms(3)sneaky is required for sperm activation and the initiation of embryogenesis in Drosophila melanogaster.

Although a large number of maternal factors are known to be essential for fertilization or the earliest stages of embryogenesis in Drosophila melanogaster, the role of paternally supplied products is not clearly understood. Paternal effect mutations provide a means to identify factors specifically required by the sperm after its entry into the egg. Here we describe the third strict paternal effect gene to be identified in Drosophila ms(3)sneaky(snky), which defines the earliest developmental arrest phenotype so far described. Characterization of two independently isolated snky mutations showed that they affected male fertility, but not viability or female fertility. Cytological analyses showed that spermatogenesis proceeded normally in snky males. However, the snky defect was evident after sperm entry into the egg; snky sperm did not undergo nuclear decondensation, form a functional male pronucleus, or initiate mitotic divisions in the egg. Immunolocalization of tubulin and Drosophila Centrosomin, a known centrosomal component, showed that snky-inseminated eggs failed to reconstitute a microtubule-organizing center. In addition, snky sperm chromatin retained the histochemical properties of mature sperm chromatin for several hours after sperm entry, showed reduced staining with membrane-impermeant nuclear dyes, and failed to replicate. We conclude that the snky+ product is required for the initial response of the sperm to cytoplasmic cues in the egg and for the subsequent initiation of embryogenesis in Drosophila. We suggest that all of the snky defects can be explained by the failure of the sperm plasma membrane to break down after entry into the egg.

Paternal effects in Drosophila: implications for mechanisms of early development.

The study of paternal effects on development provides a means to identify sperm-supplied products required for fertilization and the initiation of embryogenesis. This review describes paternal effects on animal development and discusses their implications for the role of the sperm in egg activation, centrosome activity, and biparental inheritance in different animal species. Paternal effects observed in Caenorhabditis elegans and in mammals are briefly reviewed. Emphasis is placed on paternal effects in Drosophila melanogaster. Genetic and cytologic evidence for paternal imprinting on chromosome behavior and gene expression in Drosophila are summarized. These effects are compared to chromosome imprinting that leads to paternal chromosome loss in sciarid and coccid insects and mammalian gametic imprinting that results in differential expression of paternal and maternal loci. The phenotypes caused by several early-acting maternal effect mutations identify specific maternal factors that affect the behavior of paternal components during fertilization and the early embryonic mitotic divisions. In addition, maternal effect defects suggest that two types of regulatory mechanisms coordinate parental components and synchronize their progression through mitosis. Some activities are coordinated by independent responses of parental components to shared regulatory factors, while others require communication between paternal and maternal components. Analyses of the paternal effects mutations sneaky, K81, paternal loss, and Horka have identified paternal products that play a role in mediating the initial response of the sperm to the egg cytoplasm, participation of the male pronucleus in the first mitosis, and stable inheritance of the paternal chromosomes in the early embryo.