Dual effect of serotonin on the dendritic growth of cultured hippocampal neurons: Involvement of 5-HT1A and 5-HT7 receptors.

Serotonin acts through its receptors (5-HTRs) to shape brain networks during development and modulates essential functions in mature brain. The 5-HT1AR is mainly located at soma of hippocampal neurons early during brain development and its expression gradually shifts to dendrites during postnatal development. The 5-HT7R expressed early during hippocampus development, shows a progressive reduction in its expression postnatally. Considering these changes during development, we evaluated in cultured hippocampal neurons whether the 5-HT1AR and 5-HT7R change their expression, modulate dendritic growth, and activate signaling pathways such as ERK1/2, AKT/GSK3ß and LIMK/cofilin, which may sustain dendrite outgrowth by controlling cytoskeleton dynamics. We show that mRNA levels of both receptors increase between 2 and 7 DIV; however only protein levels of 5-HT7R increase significantly at 7 DIV. The 5-HT1AR is preferentially distributed in the soma, while 5-HT7R displays a somato-dendritic localization at 7 DIV. Through stimulation with 5-HT at 7 DIV during 24h and using specific antagonists, we determined that 5-HT1AR decreases the number of primary and secondary dendrites and restricts the growth of primary dendrites. The activation of 5-HT1AR and 5-HT7R promotes the growth of short secondary dendrites and triggers ERK1/2 and AKT phosphorylation through MEK and PI3K activation respectively; without changes in the phosphorylation of LIMK and cofilin. We conclude that 5-HT1AR restricts dendritogenesis and outgrowth of primary dendrites, but that both 5-HT1AR and 5-HT7R promote secondary dendrite outgrowth. These data support the role of 5-HT in neuronal outgrowth during development and provide insight into cellular basis of neurodevelopmental disorders.

Novel aspects of glucocorticoid actions.

Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to the rhythmic and episodic release of adrenal glucocorticoids (GCs) is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, GCs regulate behaviour, as well as metabolic, cardiovascular, immune and neuroendocrine activities. By contrast to chronic elevated levels, circadian and acute stress-induced increases in GCs are necessary for hippocampal neuronal survival and memory acquisition and consolidation, as a result of the inhibition of apoptosis, the facilitation of glutamatergic neurotransmission and the formation of excitatory synapses, and the induction of immediate early genes and dendritic spine formation. In addition to metabolic actions leading to increased energy availability, GCs have profound effects on feeding behaviour, mainly via the modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that, in addition to the recognised immune suppressive actions of GCs by counteracting adrenergic pro-inflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative-feedback by GCs involves multiple mechanisms leading to limited HPA axis activation and prevention of the deleterious effects of excessive GC production. Adequate GC secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin-releasing hormone (CRH) and vasopressin secretion, which are the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving nongenomic actions of GCs, mediate the immediate inhibition of hypothalamic CRH and ACTH secretion, whereas intermediate and delayed mechanisms mediated by genomic actions involve the modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily conserved, being present in the earliest vertebrates. An understanding of these basic mechanisms may lead to novel approaches for the development of diagnostic and therapeutic tools for disorders related to stress and alterations of GC secretion.

Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones.

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.

Comparison of the antidepressant sertraline on differential depression-like behaviors elicited by restraint stress and repeated corticosterone administration.

Depressive disorder involves emotional, cognitive, autonomic and endocrine alterations and also evidences support the role of stress in the development of this disorder. Because the hypothalamic-pituitary-adrenal axis is involved in the stress response with a concomitant rise in plasma corticoids, the present study compares the antidepressant effects of sertraline (10mg/kg, i.p.) on behavioral changes elicited by (i) restraint stress (2.5h/day for 13days) and (ii) corticosterone injections (30mg/kg, s.c., for 13days). Stressed animals, but not corticosterone-treated animals displayed anxiety behavior and a reduction in the acquisition of a conditioned avoidance response to 25% of control levels (8.0±2.2 vs. 31.7±3.2), being this effect partly sensitive to sertraline. Stressed, but not corticosterone-treated, animals displayed an increased escape failure compared with the control group (24.6%±3.5 vs. 1.6±0.7), an effect partly prevented by sertraline treatment (7.3%±2.0). Both stressed rats and corticosterone-treated rats showed an increase in immobility in the forced swim test, an effect prevented by sertraline. These results suggest that the altered behaviors elicited by stress and corticosterone can be explained by neural modifications that are sensitive to the sertraline antidepressant.

Plasticity of hippocampus following perinatal asphyxia: effects on postnatal apoptosis and neurogenesis.

Asphyxia during delivery produces long-term deficits in brain development, including hippocampus. We investigated hippocampal plasticity after perinatal asphyxia, measuring postnatal apoptosis and neurogenesis. Asphyxia was performed by immersing rat fetuses with uterine horns removed from ready-to-deliver rats into a water bath for 20 min. Caesarean-delivered pups were used as controls. The animals were euthanized 1 week or 1 month after birth. Apoptotic nuclear morphology and DNA breaks were assessed by Hoechst and TUNEL assays. Neurogenesis was estimated by bromodeoxyuridine/MAP-2 immunocytochemistry, and the levels and expression of proteins related to apoptosis and cell proliferation were measured by Western blots and in situ hybridization, respectively. There was an increase of apoptosis in CA1, CA3, and dentate gyrus (DG) and cell proliferation and neurogenesis in CA1, DG, and hilus regions of hippocampus 1 week after asphyxia. The increase of apoptosis in CA3 and cell proliferation in the suprapyramidal band of DG was still observed 1 month following asphyxia. There was an increase of BAD, BCL-2, ERK2, and bFGF levels in whole hippocampus and bFGF expression in CA1 and CA2 and hilus at P7 and P30. There was a concomitant decrease of phosphorylated-BAD (Ser112) levels. The increase of BAD levels supports the idea of delayed cell death after perinatal asphyxia, whereas the increases of BCL-2, ERK2, and bFGF levels suggest the activation of neuroprotective and repair pathways. In conclusion, perinatal asphyxia induces short- and long-term regionally specific plastic changes, including delayed cell death and neurogenesis, involving pro- and antiapoptotic as well as mitogenic proteins, favoring hippocampal functional recovery.

Early response to venlafaxine antidepressant correlates with lower ACTH levels prior to pharmacological treatment.

A link between stressful life events and development or exacerbation of depression has been established via a large body of evidence. An alteration in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in depression has also been associated with an increase in cortisol secretion. As arginine-vasopressin (AVP) plays an important role in the activation of HPA axis during stress, the present study investigated ACTH and cortisol secretory response induced by an AVP-related peptide desmopressin (ddAVP) in patients with major depression. Prior to antidepressant treatment, endocrinological parameters were evaluated and correlated with the clinical response to venlafaxine treatment, which offers a dual antidepressant action. Depressive patients with no other psychiatric pathology were evaluated with 17-item Hamilton Depression Scale (HAM-D) in order to follow-up the response to venlafaxine. After 1 wk of treatment, 60% of patients reduced their initial HAM-D score to at least 25%; this group was classified as early responders. The other group (40%) started to reduce significantly their HAM-D score after 3 wk of treatment and was classified as late responders. After 6 wk of treatment both groups have reduced HAM-D score to at least 25% of the baseline score. Prior to the pharmacological treatment, both early and late responders showed salivary cortisol rhythm and urinary free cortisol (UFC) in 24-h similar to healthy subjects. However, we did observe differences in basal ACTH secretion, showing that the late responder group had higher basal ACTH than both early responders and controls. The ddAVP challenge promoted a robust secretion of ACTH only in late responders, suggesting a different sensitivity of pituitary vasopressin receptor. The differences in clinical response to venlafaxine among depressive patients seem to be related to endocrinological parameters.

Chronic intermittent cold stress activates ovarian sympathetic nerves and modifies ovarian follicular development in the rat.

We studied the effects of a chronic intermittent cold stress regime on sympathetic nerve activation and ovarian physiology. This paradigm (4 degrees C for 3 h/day, Monday-Friday, for 3 or 4 wk) does not affect basal plasma levels of corticosterone. After 3 wk of stress, we detected a decrease in noradrenaline (NA) in the ovary, but after 4 wk, this ovarian neurotransmitter concentration increased over that of unstressed control rats. To analyze whether this effect on NA is preceded by an activation of the neurotrophic factor system responsible for growth and survival of sympathetic neurons, we measured both nerve growth factor (NGF) (by enzyme immunoassay) and the intraovarian levels of its low affinity receptor mRNA (by reverse transcription-polymerase chain reaction). The activation of sympathetic nerves was followed by an increase in NGF concentration without affecting the ovarian levels of either NGF or the mRNA of its receptor. Interestingly, follicular development changed during the stress procedure; after 3 or 4 wk of stress, we found a decrease in preantral healthy follicles without a compensatory increase in atresia. Concomitantly with the increase in NA and NGF in the ovary, we observed that a new population of follicles with hypertrophied thecal cell layers appeared after 4 wk of stress. These results suggest that chronic stress, through an intraovarian neurotrophin-mediated sympathetic activation, produces changes in follicular development that could lead to an impairment of reproductive function.

Corticosterone differentially regulates bax, bcl-2 and bcl-x mRNA levels in the rat hippocampus.

It has previously been shown that adrenalectomy (ADX) produces apoptosis in the granule cell of the dentate gyrus (DG), and that this effect is prevented by corticosterone replacement. Thus, we have investigated how this phenomenon takes place in rat hippocampus using in situ hybridization. The expression of the pro-apoptotic gene bax was measured in the pyramidal cell fields and in the DG. After 5 days of ADX, there was a significant increase in bax mRNA levels in the suprapyramidal layer of the DG, an effect prevented by corticosterone replacement. The mRNA of the anti-apoptotic bcl-2 gene was expressed in CA3 and DG. ADX increased bcl-2 mRNA levels, but only in the suprapyramidal layer of the DG, an effect that was prevented by corticosterone administration. It is concluded that the up-regulation of bax may explain the apoptosis observed in DG after ADX, while the bcl-2 induction may correspond to a compensatory mechanism protecting the cells from death.

Adrenalectomy regulates apoptotic-associated genes in rat hippocampus.

Morphological studies of granular neurons of the hippocampus have shown that adrenalectomy (ADX) induces the cell death of granular neurons, an effect prevented by corticosterone replacement. We addressed the hypothesis that corticosterone regulates the expression of the apoptotic bcl-2 gene family. Five days after adrenalectomy, we observed morphological changes related to hippocampal granule cell apoptosis that was accompanied by terminal dUTP nick and labeling (TUNEL) labeling in nuclei located in the hilus region. Corticosterone replacement prevented the cell death induced by ADX. Using RT-PCR we found a reduction in mRNA levels of the antiapoptotic gene bcl-2 in whole hippocampus, an effect which was prevented by corticosterone administration to ADX rats. However, Bcl-2 protein levels were not altered by this treatment. We did not observe modifications in the level of bcl-X(L) mRNA however, we did find a 40% reduction in Bcl-X(L) protein levels, an effect not reversed by corticosterone. In contrast, we found a reduction in the mRNA of the antiapoptotic gene bax and Bax levels after ADX; both effects were prevented by corticosterone. The reduction in proapoptotic bax and in antiapoptotic bcl-2 mRNA levels in the whole hippocampus, suggests that local variations in these molecules could account for both neuronal viability of the CA1-CA3 and granular cell death detected by morphological means and observed after ADX.

The Nepal National Vitamin A Program: prototype to emulate or donor enclave?

More than 250 million of the world's children suffer from vitamin A deficiency. Nepal is one of 60 countries in which this deficiency constitutes a significant public health problem. Each year in Nepal, vitamin A deficiency is responsible for the deaths of 9000 children and for 2500 children becoming permanently blind. The Nepal National Vitamin A Program (NVAP) was begun in 1993 in eight of the country's 75 districts. By the end of 1997, the programme covered 32 districts, and by 2003 its coverage will be nationwide. The Nepal NVAP is considered by many to be a highly successful, model programme. It consists primarily of distributing high-dose vitamin A capsules to all children 6 to 60 months of age during twice-yearly campaigns. The capsule distribution is carried out by a previously existing network of Female Community Health Volunteers (FCHVs) that has been reinvigorated by the highly visible and universally acclaimed success of the NVAP. An important strategy of the programme has been the empowerment of the FCHVs, which has been accomplished by organizing, training and motivating community workers and other representatives from education, agriculture and other sectors, as well as political representatives, to support the FCHVs. The annual cost of the NVAP is US$1.7 million. It costs $1.25 to deliver two vitamin A capsules to each participant. The cost per averted death is $327. The NVAP reduces the incidence and severity of diarrhoeal disease and measles, which in turn reduces the need for Ministry of Health services, thereby annually saving the Government of Nepal $1.5 million. Factoring in these cost savings, the net annual cost of the current NVAP is $167,000, and the net annual cost of the permanent, nationwide programme is estimated at $1.1 million. The NVAP is a highly cost-effective programme. The article concludes with a discussion of the sustainability and replicability of the programme.

Cost analysis as a vitamin A program design and evaluation tool: a case study of the Philippines.

Vitamin A deficiency (VAD) is a serious and widespread public health problem in the Philippines. Initiated in 1993, the Philippines National Vitamin A Supplementation Program (NVASP) is one of the oldest, most mature and comprehensive of its kind. This paper presents a cost-effectiveness and efficiency analysis of the NVASP and of a hypothetical program of vitamin A fortification of wheat flour that was conducted to inform policymakers as to how to modify the program. Employing a proxy effectiveness indicator of VAD--the intake of < 70% of the recommended daily allowance of vitamin A--in a series of simulations using individual child consumption data, the analysis finds that fortification is more efficient in reducing inadequate vitamin A intake (IVAI) compared to the NVASP. Due to the nature of food consumption patterns, however, fortification alone, is not enough. At what is regarded as the maximum politically acceptable fortification level, there will still be 2.2 million (29%) Filipino children aged 12-59 months who will have IVAI. An investigation of the cost and efficiency of geographically targeted supplementation programs reveals that maintaining a universal supplementation program in urban areas and, in rural areas, introducing a targeted program to only the poorest municipalities (where the prevalence of VAD is the highest) will provide a more acceptable public health policy response than fortification alone. Such a policy will reduce incremental direct Government expenditures on vitamin A programs by nearly 20% and will reduce the number of children with IVAI to 900,000 (12%) Filipino children. The paper describes the fortification and supplementation programs, and how their costs were estimated. Lessons for program designers and policymakers in other countries in which vitamin A deficiency constitutes a public health problem are also discussed.

An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat.

A form of polycystic ovary (PCO) resembling some aspects of the human PCO syndrome can be induced in rats by a single injection of estradiol valerate (EV). An increase in sympathetic outflow to the ovary precedes, by several weeks, the appearance of cysts, suggesting the involvement of a neurogenic component in the pathology of this ovarian dysfunction. The present study was carried out to test the hypotheses that this change in sympathetic tone is related to an augmented production of ovarian nerve growth factor (NGF), and that this abnormally elevated production of NGF contributes to the formation of ovarian cysts induced by EV. Injection of the steroid resulted in increased intraovarian synthesis of NGF and its low affinity receptor, p75 NGFR. The increase was maximal 30 days after EV, coinciding with the elevation in sympathetic tone to the ovary and preceding the appearance of follicular cysts. Intraovarian injections of the retrograde tracer fluorogold combined with in situ hybridization to detect tyrosine hydroxylase (TH) messenger RNA-containing neurons in the celiac ganglion revealed that these changes in NGF/p75 NGFR synthesis are accompanied by selective activation of noradrenergic neurons projecting to the ovary. The levels of RBT2 messenger RNA, which encodes a beta-tubulin presumably involved in slow axonal transport, were markedly elevated, indicating that EV-induced formation of ovarian cysts is preceded by functional activation ofceliac ganglion neurons, including those innervating the ovary. Intraovarian administration of a neutralizing antiserum to NGF in conjunction with an antisense oligodeoxynucleotide to p75 NGFR, via Alzet osmotic minipumps, restored estrous cyclicity and ovulatory capacity in a majority of EV-treated rats. These functional changes were accompanied by restoration of the number of antral follicles per ovary that had been depleted by EV and a significant reduction in the number of both precystic follicles and follicular cysts. The results indicate that the hyperactivation of ovarian sympathetic nerves seen in EV-induced PCO is related to an overproduction of NGF and its low affinity receptor in the gland. They also suggest that activation of this neurotrophic-neurogenic regulatory loop is a component of the pathological process by which EV induces cyst formation and anovulation in rodents. The possibility exists that a similar alteration in neurotrophic input to the ovary contributes to the etiology and/or maintenance of the PCO syndrome in humans.

Financing health care at the local level: the community drug funds of Honduras.

In response to UNICEF's Bamako Initiative, hundreds of privately run Community Drug Funds were established in Honduras during the 1990s, generally under the auspices of a non-government organization and usually with the financial assistance of international agencies. Honduras' Community Drug Funds (CDF) are rotating drug funds intended to: (1) serve as a means of increasing access to care in isolated rural populations, (2) promote the more rational use of medicines and (3) promote community participation in the financing and oversight of primary health care activities. This study is the first to analyse empirically the impact and efficiency of these institutions, relying upon primary data obtained from a survey of 51 of the 450 active CDFs in Honduras. Archival data from Ministry of Health and other sources were also analysed. The structure, operations, and impact of CDFs are detailed, with special attention given to access and quality of care issues. The study found that CDFs are rapidly becoming under-capitalized because of basic management problems, principally in pricing and in medicine purchasing practices. These shortcomings, and more generally, increasing financial pressures on NGO sponsors, are negatively affecting quality and access to care. Given the rate of erosion in CDF assets, unless they are recapitalized, the current average estimated lifespan of a CDF is 5.5 years. If these funds are to be sustainable, changes in their financing, training and supervision will be required. In addressing these issues, Honduran health policy-makers must decide how best to balance the competing goals of holding down costs, while maintaining adequate quality and improving access to care.

Effects of adrenalectomy on the stress-induced changes in ovarian sympathetic tone in the rat.

A 3-wk period of stress promotes the development of ovarian cysts in rats apparently mediated by increased sympathetic nerve activity and ovarian steroid secretion. After 11 wk of stress, these parameters are indistinguishable from nonstressed control rats. To study adrenal contribution, we adrenalectomized rats and studied the effect of 3-wk of cold/restraint stress (1.5 h/d) on them compared to intact animals. Adrenalectomy (ADX) increased ovarian norepinephrine (NE) release, the content of beta-adrenergic receptors (betaAR) and basal, but not isoproterenol (Iso)-induced, androgen secretion. Stress to intact animals increased NE release, decreased betaAR content, and Iso-induced, but not basal, androgen secretion from the ovary. ADX did not modify the response to stress. We propose a tonic inhibition by the adrenal gland on nerve activity of ovarian nerves. Stress overrides this inhibitory effect, and nerve activity downregulates betaAR, decreasing ovarian steroid secretion.

Risk adjustment and hospital cost-based resource allocation, with an application to El Salvador.

Ignorance about the costs, case loads and case mixes of different hospitals within the public health system constitutes an important obstacle to reforming health care spending in many developing countries. National (tertiary) hospitals generally receive significantly larger budgets, per patient, than lower-level (district) hospitals. One reason for these differential allocations is the widely held belief that national hospitals treat persons with more difficult illnesses and persons who are more severely ill than do other, non-national, hospitals. This belief is but a presumption and one that warrants investigation. This paper analyzes expenditures among public hospitals in El Salvador over a 12-year period to address this question. While controlling for patient morbidity, outputs and other characteristics, district hospitals are found to be substantially underfunded relative to national hospitals. Four policy options to redress this situation are examined.

Stress promotes development of ovarian cysts in rats: the possible role of sympathetic nerve activation.

Activation of the sympathetic innervation precedes the induction of polycystic ovaries in rats given estradiol valerate (EV). The mechanism of induction by EV may thus involve both direct and neurogenic components. We tested this hypothesis using a combined cold and restraint stress to induce an increase in sympathetic tone, including that of the ovarian sympathetic nerves. Three weeks after the start of stress we found: 1. An increase in the content of norepinephrine (NE) in the celiac ganglion. 2. An increase in the release of NE from the ovary. 3. An unchanged NE uptake by the ovary. 4. An unchanged content of NE in the ovary. The ovarian content of neuropeptide Y (NPY) (colocalized with NE) was significantly decreased. These results suggest that NE synthesis and its secretion are increased during this period and correlate with the increase in secretion of androgens and estradiol, the development of precystic follicles, and a decrease in the ovulatory rate. After 11 wk, NE release had returned to control values, whereas the ovarian NE content had risen significantly, suggesting a maintained high rate of NE synthesis. In the ovary, NPY contents, steroid secretion, morphology, and ovulation had returned to the control state. These results suggest the participation of an extraovarian factor that might act locally to control the release of NE from the ovary, and further support the hypothesis that increased sympathetic activity plays a role in the development and maintenance of ovarian cysts.

Public hospital resource allocations in El Salvador: accounting for the case mix of patients.

National hospitals in developing countries command a disproportionate share of medical care budgets, justified on the grounds that they have a more difficult patient case mix and higher occupancy rates than decentralized district hospitals or clinics. This paper empirically tests the hypothesis by developing direct measures of the severity of patient illness, hospital case-mix and a resource intensity index for each of El Salvador's public hospitals. Based on an analysis of inpatient care staffing requirements, national hospitals are found to receive funding far in excess of what case-mix and case-load considerations would warrant. The findings suggest that significant system-wide efficiency gains can be realized by allocating hospital budgets on the bases of performance-related criteria which incorporate the case-mix approach developed here.

Health financing policy formulation in the Eastern Caribbean.

Stakeholders formulating policies on national health insurance (NHI) in the Eastern Caribbean have circled the abstract concept called NHI like the proverbial blind men explaining the elephant. Definitions of NHI have shifted depending on their perspectives and philosophical leanings, their understanding of the issues, and their degree of influence on the process. Based on NHI feasibility studies, market research, and stakeholder analysis conducted in five countries, this article analyses the policy formulation stage of NHI development in these tiny countries. Given the level of economic development and the existing administrative capacity of the governments, this 'phase one' NHI could be a pragmatic first step in introducing a health insurance component into the social security systems of the countries, and gradually reforming other aspects of the health sector. The article is structured around key questions which help to define the positions and relationships of key stakeholders, and then evaluate NHI plans in terms of economic viability, equity, administrative feasibility and efficiency, cost containment incentives, and political palatability. These are the elements that--in combination with economic and political context--will determine the success or failure of NHI in the Eastern Caribbean.

A cost analysis of family planning in Bangladesh.

This article presents a step-down cost analysis using secondary data sources from 26 Bangladesh non-government organizations (NGOs) providing family planning services under a US Agency for International Development-funded umbrella organization. The unit costs of the NGOs' Maternal-Child Health (MCH) clinics and community-based distribution (CBD) systems were calculated and found to be minimally different. Several simulations were conducted to investigate the impact of alternative cost-reduction measures. The more general financial analysis proved more insightful than the unit cost analysis in terms of identifying means by which to improve the efficiency of the family planning operations of these NGOs. The analysis revealed that 56 per cent of total expenditures in the two-tiered umbrella's organizational structure are incurred in management operations and overheads. Of the remaining 44 per cent of project expenditures, 39 per cent is spent on the CBD program and 5 per cent on the MCH clinics. Within the CBD program, most resources are spent providing 4 million contacts (two-thirds of the annual total) which do not involve contraceptive re-supply. The clinics devote more resources to providing MCH services than to providing family planning services. The findings suggest that significant savings could be generated by containing administrative costs, improving operational efficiency, and reducing unnecessary or redundant fieldworker contacts. The magnitude of the potential savings raises a fundamental question about the continued viability and sustainability of this supply-driven CBD strategy.

PIP: A successful supply-side approach has governed the delivery of family planning in Bangladesh for the past 20 years. The heart of the current system is an extensive community-based distribution (CBD) system which provides free door-to-door services and visits almost every eligible couple in the country 6 times per year. However, considerable program overlap and duplication waste resources. The current system is also inefficient because of its reliance upon relatively more expensive re-supply methods and its failure to consider contraceptive demand. With US Agency for International Development (USAID) funding likely to be reduced in the coming years, an impending need exists to improve system efficiency. Findings are presented from a step-down cost analysis using secondary data sources from 26 Bangladeshi nongovernmental organizations (NGOs) which provide family planning services through a USAID-funded umbrella organization. 56% of total expenditures in this 2-tiered umbrella's organizational structure are incurred in management operations and overhead expenses. 88% of the remaining program funds are spent upon the CBD program and 12% are spent upon maternal-child health (MCH) clinic activities. Most CBD program resources are spent providing 4 million contacts which do not involve contraceptive re-supply, with the clinics devoting more resources to providing MCH services than to providing family planning services. Significant savings could be generated through containing administrative costs, improving operational efficiency, and reducing unnecessary or redundant field worker contacts.