Cervical cancer: a call for political will.

Cervical cancer kills over a quarter of a million women worldwide on an annual basis, with 80% of these deaths occurring in developing countries. Cytology-based screening programs, widely used in industrialized countries, are difficult to implement in low-resource settings. Non-cytological methods for screening and treatment have been developed and studied over the last decade. Given the barriers to widespread, good quality screening and early treatment, the most promising new prevention strategy will be the introduction of a vaccine to prevent human papillomavirus infection, the cause of cervical cancer. Understanding women's health-seeking behaviors is critical to successful dissemination and uptake of both screening and vaccine prevention strategies.

Preventing cervical cancer in low-resource settings: how far have we come and what does the future hold?

The Alliance for Cervical Cancer Prevention (ACCP) came together in 1999 to answer key research questions and to advocate for greater global and national interest in reducing the heavy burden of morbidity and mortality caused by this preventable disease. Visual inspection with acetic acid (VIA), visual inspection with Lugol's iodine (VILI), and human papillomavirus (HPV) tests have been shown to be viable alternatives to traditional cytology. ACCP experience confirmed that cryotherapy is a safe and effective method that is acceptable to women and can be delivered by a range of health providers, including nonphysicians. Programs can maximize coverage by accommodating local needs and involving community leaders and women in planning and implementation. Advocacy efforts have led to significant policy changes and galvanized support for cervical cancer prevention. Despite the prospect of new HPV vaccines, screening will be needed for at least the next 30-40 years. Our experience has shown that with creativity, flexibility, and well-focused use of resources, the inequitable burden of cervical cancer borne by women in poor countries can be sharply reduced.

Anatomy, physiology, and pharmacology of the basal ganglia.

The basal ganglia consist of five interconnected nuclei in the basal forebrain that influence cortical control of voluntary movement. Synaptic information travels through the basal ganglia using distinct pathways from the input structure, the striatum, to the output nuclei, the substantia nigra pars reticulata and the globus pallidus internal segment. The activity of the striatal output pathways is influenced by glutamatergic input from the cerebral cortex, dopaminergic input from the substantia nigra pars compacta, and cholinergic interneurons. Since the basal ganglia output nuclei tonically inhibit the motor nuclei of the thalamus, the basal ganglia facilitate motor activity by disinhibiting the thalamus.

NMDA glutamate receptor stimulation is required for the expression of D2 dopamine mediated responses in apomorphine primed 6-hydroxydopamine lesioned rats.

Three priming injections with the D1/D2 dopamine agonist apomorphine permits a challenge with the D2 agonist quinpirole to elicit robust contralateral rotation and ipsilateral striatal Fos expression in 6-hydroxydopamine lesioned rats. Pretreatment with NMDA glutamate antagonists MK-801 or CPP dose-dependently attenuates these quinpirole-mediated responses. These findings suggest that concomitant NMDA receptor stimulation is required for the expression of D2-mediated responses in apomorphine primed dopamine-depleted rats.

Efficacy of percutaneous vas occlusion compared with conventional vasectomy.

OBJECTIVES: To determine the efficacy, evaluate the safety and assess side-effects (swelling, haematoma and pain) of percutaneous vas occlusion compared with vasectomy in Dutch men. PATIENTS AND METHODS: Vas occlusion and vasectomy procedures (attempted in 58 and 50 men, respectively) were conducted at the University Hospital Maastricht. The men returned 1 week after the procedure, underwent a clinical examination and completed a questionnaire assessing subjectively any pain, swelling and haematoma. The men were asked to return for semen analysis at 6 and 12 weeks and, if necessary, for additional analyses until they were azoospermic. RESULTS: The vas occlusion procedure was completed on both vasa in 49 of the 58 men (84%) in whom it was attempted. Significantly more (P < 0.001) men were azoospermic after vasectomy (48 of 50) than after vas occlusion (only four). Men undergoing vas occlusion reported significantly less pain (P = 0.02), swelling (P = 0.01) and haematoma (P = 0.04) after the procedure than did men undergoing vasectomy. CONCLUSION: Men undergoing vas occlusion would not have been able to rely on the method for contraception. From this study, vas occlusion, at least in its current form, is an unsuitable method of male contraception. Not only was the efficacy poor, but constraints in delivering the method in its current state would probably limit its utility, especially in situations where resources are limited.

Opening a door to safe abortion: international perspectives on medical abortifacient use.

International experience compels us to revisit how we define and assess the safety and efficacy of medical abortifacients such as misoprostol. In some countries where safe abortion is neither accessible nor legal, even unsupervised, off-protocol use of misoprostol can provide women with a means to safely terminate pregnancy. This is due primarily to misoprostol-induced uterine contractions that cause bleeding, which in turn provides access to existing reasonable quality health services that would otherwise be unavailable. Several studies have suggested that an increase in the underground use of misoprostol in Brazil has already reduced serious complications from unsafe abortion. Thus, the availability of medical abortifacients combined with strengthened postabortion care services can legitimately be considered a public health success in countries in which safe abortion services do not exist and law reform is unlikely.

Prior D1 dopamine receptor stimulation is required to prime D2-mediated striatal Fos expression in 6-hydroxydopamine-lesioned rats.

Repeated dopamine agonist administration to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway potentiates behavioral and neuronal activation in response to subsequent dopamine agonist treatment. This response sensitization has been termed "priming" or "reverse-tolerance". Our prior work has shown that three pretreatment injections of the mixed D1/D2 agonist apomorphine (0.5 mg/kg) into 6-hydroxydopamine-lesioned rats permits a previously inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to induce robust contralateral rotation and striatal Fos expression in striatoentopeduncular "direct" pathway neurons. These striatal neurons typically express D1 but not D2 receptors. Because apomorphine acts as an agonist at both D1 and D2 receptors, the present study sought to determine whether D1, D2, or concomitant D1/D2 receptor stimulation was required to prime D2-mediated contralateral rotation and striatal Fos expression. Twenty-one days following unilateral stereotaxic injection of 6-hydroxydopamine into the medial forebrain bundle, rats received three pretreatment injections, at three- to six-day intervals, with either: the mixed D1/D2 agonist apomorphine, the D1 agonist SKF38393, the D2 agonist quinpirole, or a combination of SKF38393 + quinpirole. Ten days following the third pretreatment injection, 6-hydroxydopamine-lesioned rats were challenged with the D2 agonist quinpirole (0.25 mg/kg). Pretreatment with SKF38393 (10 mg/kg), quinpirole (1 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to induce robust contralateral rotation which was similar in magnitude to that observed following apomorphine priming. However, only pretreatment with SKF38393 (10 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted the same dose of quinpirole (0.25 mg/kg) to induce striatal Fos expression. These results demonstrate that while prior stimulation of D1, D2 or D1/D2 receptors can effectively prime D2-mediated contralateral rotation, prior stimulation of D1 receptors is required to prime D2-mediated striatal Fos expression. This study demonstrates that priming of 6-hydroxydopamine-lesioned rats with a D1 agonist permits a subsequent challenge with a D2 agonist to produce robust rotational behavior that is accompanied by induction of immediate-early gene expression in neurons that comprise the "direct" striatal output pathway. These responses are equivalent to the changes observed in apomorphine-primed 6-hydroxydopamine-lesioned rats challenged with D2 agonist. In contrast, D2 agonist priming was not associated with D2-mediated induction of striatal immediate-early gene expression even though priming of D2-mediated rotational behavior was not different from that observed following priming with apomorphine or D1 agonist. Therefore, while priming-induced alterations in D2-mediated immediate early gene expression in the "direct" striatal output pathway may contribute to the enhanced motor behavior observed, such changes in striatal gene expression do not appear to be required for this potentiated motor response in dopamine-depleted rats.

Prevalence of visible disruption of cervical epithelium and cervical ectopy in African women using Depo-Provera.

Associations between Depo-Provera (injectable, progesterone-only contraceptive) use and visible disruption of cervical epithelium and cervical ectopy were investigated using data collected as part of a cervical cancer screening study in periurban Cape Town, South Africa. Women were interviewed about their contraceptive use, and underwent a gynecologic examination that included two 35-mm photographs of the cervix after application of 5% acetic acid. Photographs of 723 subjects were reviewed (blind to clinical information and using systematic criteria developed before review) for evidence of atrophy and epithelial disruption, including inflammation and ulceration. The percentage of the cervix covered with columnar epithelium (ectopy) was also estimated from the photographs. A random sample of 85 photographs was reviewed again for reliability. A total of 121 current users of Depo-Provera were no more likely to have evidence of epithelial disruption (38%) than 574 nonusers (39%), odds ratio (OR) = 1.37, 95% CI: 0.89-2.11 adjusting for age and parity. The prevalence of significant ectopy (columnar epithelium covering > 10% of the cervix) was also no different among current Depo-Provera users (OR = 1.22, 95% CI: 0.80-1.86 adjusting for age and parity). Reliability of visual scoring of epithelial disruption and ectopy was excellent (kappa = 0.8). Although the underlying prevalence of visible disruption of cervical epithelium was very high, current use of Depo-Provera was not associated with increased prevalence of visible disruption of the cervical epithelium or with ectopy in this sample of African women.

PIP: The relationship between cervical epithelium disorders and cervical ectopy and Depo-Provera use was investigated among African women. The women, aged 35-65 years, had gynecologic examinations, which included various cervical cancer screening tests including two 35-mm colored photographs of the cervix. Cervical photographs from 723 participants were reexamined for the signs of disruption. Results showed that among 121 current Depo-Provera users, 38% showed no steady increase in epithelial disruption compared with 34% of past users and 49% of nonusers. There was no difference in the odds ratio (OR = 1.37; 95% CI: 0.89-2.11). The percentage of women with significant ectopy was higher in current and past users of Depo-Provera, but no trends remain after age adjustment and parity (OR = 1.22; 95% CI: 0.80-1.86). The credibility of the diagnosis of cervical disruption combined (either ulceration, inflammation, or athropy) was excellent (K = 0.8). However, the results were doubtful in light of the concept that simple epithelial thinning may account for putative effects of Depo-Provera. The validity of this method needs further investigations.

Time dependence and role of N-methyl-D-aspartate glutamate receptors in the priming of D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats.

Administration of dopamine agonists to 6-hydroxydopamine (6-OHDA) lesioned rats enhances the rotational response to subsequent administration of dopamine agonist, an effect called 'priming'. Previously, we have shown that 6-OHDA rats primed with three injections of the D1/D2 dopamine agonist apomorphine (0.5 mg/kg) permitted a challenge with an otherwise inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to elicit robust rotational behavior and to induce Fos expression in striatoentopeduncular neurons. In this study, the time-course and role of N-methyl-d-aspartate (NMDA) glutamate receptors on apomorphine-priming of these D2 responses were investigated. The enhanced rotational behavior and striatal Fos expression observed following challenge with quinpirole (0.25 mg/kg) peaked 1 day following the third apomorphine priming injection and persisted, in reduced form, for at least 4 months. Pretreatment with the NMDA antagonists MK-801 or 3-[(+)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) dose-dependently attenuated apomorphine-priming of quinpirole-mediated rotational behavior and striatal Fos induction compared to 6-OHDA rats primed with apomorphine alone. Taken together, these data suggest that priming of these D2-mediated responses in 6-OHDA rats develops rapidly, persists for several months, and is dependent on concomitant NMDA receptor stimulation. Since this priming effect resembles response fluctuations observed in patients with Parkinson's disease receiving long-term l-dihydroxyphenylalanine therapy, the results of the present study suggest that interventions that prevent the development of this enhanced response, such as NMDA antagonists, could prove useful in reducing the incidence these response fluctuations.

Role of NMDA glutamate receptors in regulating D2 dopamine-dependent Fos induction in the rat striatopallidal pathway.

Acute administration of reserpine induces Fos expression in striatopallidal neurons, an effect blocked by pretreatment with the D2 dopamine agonist quinpirole. Pretreatment with the NMDA antagonists (+)MK-801 or CPP attenuated reserpine-mediated striatal Fos induction whereas pretreatment with ketamine or the inactive isomer (-)MK-801 did not. These results support a role of NMDA glutamate receptors in regulating the activity of the striatopallidal pathway.

Vasectomy in the United States, 1991 and 1995.

OBJECTIVES: This study sought to assess whether the controversy surrounding publications linking vasectomy and prostate cancer has had an effect on vasectomy acceptance and practice in the United States. METHODS: National probability surveys of urology, general surgery, and family practices were undertaken in 1992 and 1996. RESULTS: Estimates of the total number of vasectomies performed, population rate, and proportion of practices performing vasectomy were not significantly different in 1991 and 1995. CONCLUSIONS: This study provides no solid evidence that the recent controversy over prostate cancer has influenced vasectomy acceptance or practice in the United States. However, the use of vasectomy appears to have leveled off in the 1990s.

Clinical aspects of vasectomies performed in the United States in 1995.

OBJECTIVES: Currently, no surveillance system collects data on the numbers and characteristics of vasectomies performed annually in the United States. This study provides nationwide data on the numbers of vasectomies and the use of no-scalpel vasectomy, various occlusion methods, fascial interposition, and protocols for analyzing semen after vasectomy. METHODS: A retrospective mail survey (with telephone follow-up) was conducted of 1800 urology, family practice, and general surgery practices drawn from the American Medical Association's Physician Master File and stratified by specialty and census region. Mail survey and telephone follow-up yielded an 88% response rate. RESULTS: In 1995, approximately 494,000 vasectomies are estimated to have been performed by 15,800 physicians in the United States. Urologists performed 76% of all vasectomies, and nearly all (93%) urology practices performed vasectomies in 1995. Nearly one third (29%) of vasectomies in 1995 were no-scalpel vasectomies, and 37% of physicians performing no-scalpel vasectomies taught themselves the procedure. The most common occlusion method in 1995 (used for 38% of all vasectomies) was concurrent use of ligation and cautery. In 1995, slightly less than half (48%) of all physicians surveyed interposed the fascial sheath over one end of the vas when performing a vasectomy. Protocols for ensuring azoospermia varied: 56% of physicians required one postvasectomy semen specimen; 39% required two, and 5%, three or more. CONCLUSIONS: No-scalpel vasectomy, used by nearly one third of U.S. physicians, has become an accepted part of urologic care. Physicians' variations in occlusion methods, use of fascial interposition, and postvasectomy protocols underscore the need for large scale, controlled, and statistically valid studies to determine the efficacy of occlusion methods and fascial interposition, as well as whether azoospermia is the only determination of a successful vasectomy.

Results of a pilot study of the time to azoospermia after vasectomy in Mexico City.

In a joint pilot study by Family Health International (FHI), AVSC International, and the Instituto Mexicano del Seguro Social (IMSS), information was gathered on the determinants of azoospermia following vasectomy on 38 healthy men who chose vasectomy for contraception. The time and number of ejaculations associated with loss of sperm motility and loss of sperm eosin vital staining were also evaluated. "Azoospermia" was defined on the basis of two consecutive azoospermic semen samples collected at least 3 days apart. The single decrement life table method was used to calculate weekly gross cumulative life table rates for the time to azoospermia, zero motility, and zero viability. The Kaplan-Meier method was used to calculate the product-limit estimates of the cumulative rates for the total number of ejaculations to azoospermia, 0% motility and 0% viability. The median time to azoospermia was 10 weeks and at the end of week 20, the life table rate (+/- standard error) was 93.0 (+/- 6.30) weeks/100 men. The median number of ejaculations to azoospermia was between 25 and 30, and the cumulative rate (+/- standard error) at 60 ejaculations reached 94.5 (+/- 5.16)/100 men.

PIP: The time and number of ejaculations to azoospermia after vasectomy were investigated in a prospective pilot study of 38 vasectomy acceptors conducted by Family Health International and the Instituto Mexicano del Seguro Social. Two consecutive azoospermic semen samples collected at least 3 days apart were required for azoospermia to be declared. 25 men (65.8%) demonstrated azoospermia during the 24-week follow-up period; however, 9 (23.7%) discontinued prior to the study's end or before achieving azoospermia. The median time to azoospermia was 10 weeks. At the end of week 20, the single decrement life table rate was 93.0 +or- 6.30 weeks per 100 men. The median number of ejaculations to azoospermia was 25-30 and the cumulative rate of azoospermia at 60 ejaculations was 94.5 +or- 5.16 per 100 men. It took approximately 5 weeks longer for men with fewer than three ejaculations per week to reach azoospermia than their counterparts with a higher number of ejaculations. The median time to sperm motility was 3 weeks, while that to 0% viability was 9 weeks. There were two pregnancies, one of which involved a man who had been declared azoospermic. An expanded study based on this pilot study is underway.

Apomorphine priming alters the response of striatal outflow pathways to D2 agonist stimulation in 6-hydroxydopamine-lesioned rats.

Chronic treatment with dopaminergic agonists is associated with response fluctuations to L-dihydroxyphenylalanine in Parkinson's disease and enhanced motor activity to D1 and D2 dopamine agonists in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. In dopamine-depleted rodents this phenomenon has been referred to as "priming" or reverse tolerance. The neurochemical changes that underlie "priming" of dopaminergic agonist responses are poorly understood. Some aspects of priming of D1 agonist-mediated rotation in the 6-hydroxydopamine-lesioned rat have been characterized, but priming of D2-agonist-dependent motor responses has been less thoroughly studied. In this study, examination of rotational behaviour and induction of Fos-like immunoreactivity were used to investigate changes in the striatal outflow systems in response to treatment with the D2 agonist quinpirole in 6-hydroxydopamine-lesioned rats that had been primed with apomorphine. Administration of apomorphine (0.5 mg/kg; three injections at three to six day intervals) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to produce robust contralateral rotation and to induce the expression of Fos in striatal neurons belonging to the striato-nigro-entopeduncular ("direct") pathway. The increase in contralateral rotation and ipsilateral striatal Fos expression following administration of quinpirole to apomorphine-primed rats was mediated by a D2-like receptor and did not appear to be due to a change in sensitivity of D2 receptors. Apomorphine priming also enhanced the ability of quinpirole to induce Fos expression in the globus pallidus, a target of the striatopallidal ("indirect") pathway. Western blot analysis confirmed that treatment with quinpirole induced the expression of c-Fos protein with no change in the expression of 35-37,000 mol. wt Fos-related antigens in apomorphine-primed rats treated with water or quinpirole. Induction of Fos expression in the striatum generally results from blockade of D2 receptors and the striato-nigro-entopeduncular pathway preferentially expresses D1 receptors. Thus, the quinpirole-dependent induction of striatal Fos in apomorphine-primed 6-hydroxydopamine-lesioned rats represents a qualitative alteration in striatal outflow. These studies demonstrate that pretreatment of 6-hydroxydopamine-lesioned rats with apomorphine increases the activity of the "direct" and "indirect" striatal outflow pathways in response to D2 receptor stimulation. These changes have the net result of enhancing thalamocortical activity and likely underlie the enhanced contralateral rotation produced by quinpirole in apomorphine-primed rats. Changes in striatal outflow, particularly in the striato-nigro-entopeduncular pathway, may contribute to alterations in D2-dependent motor responses observed after chronic dopaminergic stimulation in the dopamine-depleted striatum.

Increasing the availability of vasectomy in public-sector clinics.

A program designed to improve the availability of vasectomy in public-sector clinics trained physicians at 43 facilities in no-scalpel vasectomy between 1993 and 1995. Among the 38 clinics that responded to a follow-up survey in 1996, the number of clinics providing vasectomies rose from 23 to 32, an increase of almost 40%, while the number of vasectomies performed rose by 18%. Seventeen of the 32 clinics performed more vasectomies after the training; 10 of the 17 had not previously provided the procedure. In-depth interviews with staff from seven sites that experienced large caseload increases and from seven that experienced decreases identified three elements for the successful establishment or expansion of vasectomy services-sufficient numbers of trained providers, funds to subsidize vasectomies for men who cannot afford them and activities to raise awareness about the availability of low-cost or free vasectomy.

PIP: The low utilization of vasectomy in the US by low-income, minority men reflects, in part, the lack of availability of this contraceptive method through the public sector. Nationally, only 23% of family planning agencies offer this option. To improve the availability and quality of vasectomy services for low-income men, physicians at 43 public-sector clinics in 17 states were trained in the no-scalpel vasectomy technique during 1993-95. 37% of the physicians trained had never performed a vasectomy before. Among the 38 clinics that responded to a follow-up survey, the number providing vasectomy services increased from 23 before the training to 32 in 1996. At the time of the follow-up survey, these 32 clinics were providing 1650 vasectomies annually. Thus, the training program increased the number of clinics performing vasectomies by 37% and the number of men obtaining them by 18%. In-depth interviews with physicians from 7 clinics that reported sharp increases in their vasectomy caseloads after the training and 7 clinics that experienced sharp decreases identified 3 key components of a successful vasectomy service: 1) a sufficient number of providers committed to serving men and providing a quality service, 2) marketing activities to raise awareness among women and men about the availability of vasectomy services, and 3) the commitment of funds to subsidize vasectomies for men who cannot afford them. Midlevel clinic staff (e.g., nurse practitioners and physician assistants) could be trained to perform no-scalpel vasectomy, thereby easing the burden on physicians, reducing costs, and increasing access.

A comparison of "U" and standard techniques for Norplant removal.

OBJECTIVE: To evaluate the "U" technique versus the manufacturer-recommended technique for Norplant removal. METHODS: We conducted a randomized comparison of the manufacturer-recommended method of removal and the "U" technique. The latter involves an incision between and parallel to the third and fourth implants and uses a modified vasectomy clamp to remove the implants by pulling perpendicular to the implant's axis. RESULTS: Twenty-one physicians (three experienced, 18 inexperienced) performed 200 Norplant removals. Inexperienced physicians took significantly less time for removal using the "U" technique than the standard technique (7.9 versus 10.5 minutes), even after controlling for other factors. Experienced physicians also required less time for removal using the "U" technique (3.1 versus 3.7 minutes), but the difference was not statistically significant after controlling for other factors. Both experienced and inexperienced physicians broke implants more frequently using the standard technique, although the difference was significant only for experienced physicians (relative risk 3.6, 95% confidence interval 1.2, 10.8). No differences were noted between the techniques with respect to tissue damage or patient reports of pain during or after removal. CONCLUSIONS: These results suggest that the "U" technique is an improvement over the standard technique, particularly for personnel who are not highly experienced in Norplant removal.

Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization.

Expression in striatum of c-Fos, a 35 kDa Fos-related antigen (FRA) and the phosphorylated form of cyclic AMP response element binding protein (phosphoCREB) was assessed using Western blots in rats that developed behavioral sensitization following repeated amphetamine administration. Treatment with d-amphetamine (5 mg/kg) for 5 consecutive days produced behavioral sensitization. Similar to previous observations using chronic cocaine administration, amphetamine sensitized animals had decreased c-Fos and increased FRA proteins in striatum. Supershift analysis with antisera to c-Fos and FRA proteins demonstrated that 4-Fos and the 35 kDa FRA are components of the striatal AP-1 binding complex from sensitized rats. Thus, amphetamine sensitization is accompanied by alterations in the composition of the AP-1 DNA binding complex. An increased amount of phosphoCREB protein was also present in the striatum of amphetamine sensitized rats. These results suggest that alterations in Fos, FRA and CREB transcription factors are common neuronal responses to chronic psychostimulant administration and may contribute to regulation of genes important to the neuroplastic changes underlying psychostimulant sensitization.