There are greater tensions than ever before between promoting trade and protecting health. Human health could lose out to trade liberalization unless the health community fights its case Trade is the lifeblood of all commerce. The exchange of goods and services has played a defining role in human history, creating vast empires, encouraging mass migration, and sometimes tipping the balance between peace and conflict. It is thus unsurprising that protecting and encouraging international trade has remained a top priority for governments, businesses and international organisations.Historically, the protection of health has been a permitted reason for restricting trade. Trade brought plague to Athens in 430 BC, killing as much as one third of the population, as well as to fourteenth century Europe after which quarantine practices were introduced. During the nineteenth century, flourishing trade also facilitated the spread of diseases such as cholera. This prompted a series of International Sanitary Conferences among leading trading nations, and the adoption of International Sanitary Conventions . While protecting health was a clear aim, in reality the primary task was to minimise interference by health matters on trade.Today, there are greater tensions than ever before between promoting trade and protecting health because of globalisation. Successive rounds of trade negotiations held since the Second World War, under the General Agreement on Trade and Tariffs and, since 1995, the World Trade Organization (WTO), have substantially reduced tariff levels and standardised trading practices across countries. This process of trade liberalisation has significantly increased trade volumes, bringing more and more countries into the world trading system. For the public health community, trade has raced ahead of corresponding measures to protect health. Efforts to ensure that there is an appropriate balance between the two policy areas has become a difficult challenge.The right to restrict trade to protect the health of humans, animals, and plants is recognised by the General Agreement on Trade and Tariffs (Article XX) under two conditions: (1) the restriction is applied in a nondiscriminatory way; and (2) the restriction is based on recognised scientific evidence. Countries are allowed to restrict trade, for example, of certain goods such as radioactive waste or infected food products.Disputes can arise if the restriction is believed to be discriminatory or there is disagreement about the scientific evidence supporting it (see sidebar). The ban introduced by the European Community in 1989 on hormone-treated beef imported from the US. led to two rulings by the Dispute Settlement Body of the WTO in favour of the American government. The assessment of the evidence primarily by trade experts, rather than public health experts, is a clear problem of the existing dispute settlement process. The process also makes it difficult to regulate inappropriate production methods which do not lead to problems in the end product but may be of public health concern. For example, the practice of using hormones to boost meat production may prove problematic in future research, even if residues in the meat are not judged high enough at present to warrant sufficient proof of health concerns.Moreover, tight regulations on trade that are intended to protect health can come under fire from the trade lobby. Two World Bank studies argue, for instance, that European Union (EU) regulations on pesticides in bananas, as well as aflatoxins, could be interpreted as barriers to trade and market access ,2.The short shrift given to precautionary measures to protect health, where existing scientific evidence is deemed insufficient, reflects a further inbuilt priority given to trade. Growing concerns over the development and use of genetically modified organisms (GMOs), for example, have been dismissed by major companies such as Monsanto and Cargill on the basis of a lack of existing scientific evidence of harm to health. Consumer groups and public health advocates, however, argue that the subject is still in its scientific infancy. Where new causal pathways or systemic impacts of environmental exposures are of concern, such as with GMOs, at best one can say that the jury is still “out”. Hence, allowing GMOs to be spread widely, rather than taking precautionary measures, could prove to have irreversible consequences.The classification of certain goods as a risk to health, and thus subject to trade restrictions, is also a source of dispute. The best example is tobacco products which manufacturers argue should be treated like other traded goods. Public health advocates, however, argue that because tobacco is harmful to health, it should be subject to special restrictions. A battle over tobacco is currently being played out in regional trade negotiations and will be raised at forthcoming multilateral negotiations over agricultural trade. Whether the public health community will be able to argue successfully to protect health, when pitted against the vast resources of a multi-billion dollar industry, remains to be seen.Two new sources of tension have arisen in recent years—intellectual property rights (IPRs) and trade in services. The protection of IPRs is a new feature of international trade law, coming into force under the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) adopted in 1994. The agreement sets out minimum standards for protecting and enforcing patents, trademarks, and copyrights.Since the mid-1990s there has been increasing concern over access to drugs in the developing world, and especially drugs for treating HIV/AIDS. This issue gained international attention when the South African government sought to access cheaper versions of patent protected drugs, but was faced with strong opposition by the pharmaceutical industry. The importance of public health priorities, and the existence of flexibility within TRIPS, was eventually confirmed in the Doha Declaration on the TRIPS Agreement and Public Health signed in 2001 While international debates over TRIPS have so far focused on the developing world, it is clear that there are issues relevant to the public health community as a whole concerning open access to a wide range of health-related knowledge and information. The possible benefits and costs of the TRIPS agreement had not been openly discussed beforehand. Rather, its measures were heavily influenced by industries seeking to exert ownership over intellectual goods such as research, information, and other data sources. Within an increasingly competitive world market, companies are driven to recoup their investment in such resources through IPRs. For the public health community, however, there is a vital need for affordable and open access by all to such resources. Leaving the commercial market to drive research and development (R&D) can lead not only to problems of access in developing countries but it can also lead to the neglect of research and public health priorities in all countries, such as research on antibiotics, which has been deemed insufficiently profitable The General Agreement on Trade in Services (GATS) is another expanded area of trade law. Services are the fastest-growing segment of the world economy, providing more than sixty percent of global output and employment. In the past, most services were not considered to be tradable across borders. Advances in communications technology, including the rise of e-commerce, and regulatory changes have made it easier to deliver services across borders. For trade in health services, the implications are not yet clear.It is generally expected that GATS would not apply to public services due to a general exemption on the matter. However, this exclusion is very narrowly worded, and based on a model of public services which may no longer hold. Health sector reforms have changed the ways in which publicly financed services are provided in many countries, including the extensive use of contracting out and managed competition. In most countries, this includes both medical care and related services such as laboratory or ambulance services. Health services, which are contracted out to the non-profit or for-profit sector, are likely to be no longer considered purely “public” and thus protected by the exclusion. Recent legal reviews of the GATS ,7 confirGiven this, the two reviews warn that there are valid grounds to suggest that negotiations on trade in services, and full commitments in health services in GATS, will have important implications for the ways in which national health systems and policies are implemented. While GATS may not directly limit the aims of national health policies, commitments under GATS can influence the ability of governments to implement health policies and regulate commercial service providers. This could apply especially to efforts to introduce new regulations that restrict market forces. The current GATS negotiations on domestic regulation include requirements of least trade restrictiveness and necessity tests for introducing regulatory measures in committed sectors. These requirements could pose difficulties if a government sought, for example, to oblige hospitals to operate on a non-profit basis. This might be interpreted under the GATS as restricting market forces. In this way, GATS could effectively influence the scope of national health policy, even challenging the capacity of governments to pursue health policies that prioritise universal access, cost containment, and quality control.As world trade continues to expand in scale and scope, the health community faces a number of key challenges. We must be armed with a better understanding of the world trading system, notably the legal framework for international trade. Comprehending the potential health implications of various bilateral, regional, and multilateral agreements regulating trade today is a daunting task. Although the public health community has fewer resources at its disposal than the proponents of trade liberalisation, it is clear that health priorities do have strong support by citizens all over the world.It is critically important for the health community to challenge the value-based assumption that trade liberalisation, rather than human welfare, should be given automatic priority. Indeed, ignoring health can lead to problems in the trade sphere. The outbreaks of bovine spongiform encephalopathy in Europe and North America and severe acute respiratory syndrome in Asia emphasised that trade can be severely disrupted by insufficient measures to protect health. The health community has to press for a much louder voice in the setting of trade policy at the national and international levels. A balance between trade and health policies can only be achieved if the health community is prepared to be far more vocal, and the trade policy community is prepared to listen.In 1998 WTO ruled that a European Community ban of the use of certain growth-promoting hormones was not based on an appropriate risk assessment. Rather than lift the ban, the EU sought new evidence of the risk to human health of hormone residues in meat products. In 1999 Canada and the US imposed trade sanctions worth US$116.8 million and Cdn$11.3 million. In 2003 the EU announced that, based on new scientific evidence, the ban will remain in place and asked the US and Canada to lift sanctions.In 2001 WTO ruled that the European Community was permitted to ban the import of chrysotile asbestos on the grounds of protecting public health, and rejected the Canadian government's claim that the ban was discriminatory and an unnecessary barrier to trade. While the decision shows that WTO panel decisions can prioritise health, the process and grounds of the decision indicates that, even with such a well-established carcinogen, the dispute settlement process required extensive argument by the public health community.


Recently, there has been an increased use of recombinant activated factor VII (rFVIIa) to promote hemostasis in various hemorrhagic conditions. The objective of this study was to determine the outcome of patients treated with rFVIIa who had intractable bleeding associated with cardiac surgery (CSP) or as a result of other causes (OBP).The medical records of 40 consecutive patients treated with rFVIIa were retrospectively reviewed for blood product use before and after treatment. In all patients, rFVIIa was given only after all other measures to stop bleeding had failed. The number of transfused units of red cells (R), platelets (P), fresh frozen plasma (F), and cryoprecipitate (C) were determined both before and after administration of rFVIIa, and the results compared. Mortality at 4 hours and 30 days was assessed. Patients dying within 4 hours of rFVIIa administration were not evaluable for response. Patient characteristics were also assessed as risk factors for mortality.Twelve of 24 CSP survived for more than 4 hours. These 12 patients required an average of 17 units (U) of R, 18 U of P, 18 U of F and 15 U of C pre-treatment compared to an average of 6 U, 10 U, 9 U and 4 U of R, P, F and C respectively, post-treatment. These differences were statistically significant. For the OBP, 11 of 16 survived more than four hours. These 11 patients required an average of 10 U of R, 11 U of P, 14 U of F and 10 U of C pretreatment compared to an average of 1 U, 2 U, 2 U and 0 U of R, P, F, and C respectively, post-treatment. With the exception of C, there was a statistically significant decrease in blood product use following treatment with rFVIIa. Of the survivors in each group, 6 of 12 CSP and 2 of 11 OBP died between 3 and 30 days post-treatment from causes other than bleeding. Mortality at 30 days for CSP and OBP survivors was 50% and 18% respectively, whereas overall 30 day mortality was 75% for CSP and 44% for OBP.rFVIIa is effective in decreasing blood product use and promoting hemostasis in patients with intractable bleeding associated with cardiac surgery and a variety of other causes. Recombinant factor VIIa (rFVIIa), originally developed for the treatment of acquired inhibitors associated with hemophilia ,2, has bMost critically ill patients with trauma suffer profound coagulopathy. Coagulation abnormalities in these patients have been attributed to multiple factors including disseminated intravascular coagulation (DIC), excessive fibrinolysis due to release of tissue plasminogen activator (tPA), dilutional coagulopathy from fluid replacement and massive blood product transfusion, dysfunctional platelets, and metabolic abnormalities including acidosis and hypothermia -18. In aAlthough the mechanism of action of rFVIIa remains unclear, many investigators have suggested that it binds to the surface of activated platelets and directly activates Factor X, thus bypassing the early steps of the coagulation cascade. Activated Factor X (Xa) then combines with activated Factor V (Va) on the platelet surface, leading to rapid conversion of prothrombin to thrombin ,21. HemoThe present report is a retrospective review of 40 consecutive patients treated with rFVIIa  for intractable hemorrhage. Twenty-four of these patients had bleeding associated with cardiac surgery, and the remaining 16 suffered with bleeding from other causes. The need for transfusion of blood products both before and after treatment and the mortality at 4 hour and 30 day were assessed. Patient characteristics were also assessed as risk factors for mortality.The study was approved by the Institutional Board Review of the Washington Hospital Center, Washington DC, USA. The medical records of 40 consecutive patients treated with rFVIIa between July 2001 and June 2003 at the Washington Hospital Center, a tertiary care teaching hospital and level 1 trauma center, were reviewed. The patients were divided into two groups: 24 patients who had undergone cardiac surgical procedures (CSP), and 16 patients who had bleeding from other causes (OBP). There were more male patients in both groups . The median age in the CSP was higher at 65 years (range 26–85 years) compared to that of OBP . The type of surgery in the CSP group included 15 coronary artery bypass grafts (CABG), 3 aortic arch repairs either elective or for dissection, 2 aorta rupture repair , 3 valve replacements and 1 ventricular rupture. In the OBP group, 5 patients had suffered either stab or gunshot wounds, 2 had traumatic liver lacerations, 2 had undergone joint replacement, 3 had clotting factor abnormalities , and one each had post partum hemorrhage, warfarin overdose, bowel resection, and trauma from a motor vehicle accident.Commercially available rFVIIa,  was used in all patients. There were no predetermined criteria for administration. In most patients, treatment was given after extensive blood product support had failed to control hemorrhage, and the decision to treat was made jointly by the surgeon, hematologist and blood bank pathologist. rFVIIa was administered as a bolus dose of 90 mcg/kg. The first two patients received a second dose of 90 mcg/kg 6 hours after the first.The total number of products given before and up to twenty-four hours after rFVIIa administration, or until death, whichever came first, was quantified. Patients who died within 4 hours of treatment were not evaluable because blood product support was suspended shortly after rFVIIa administration in these hemodynamically unstable patients deemed non-salvageable. Also, given the short half-life of rFVIIa, this time frame did not allow for an accurate determination of efficacy. The number of patients surviving at 4 hours and 30 days after the administration of rFVIIa was compared. Thirty days was chosen as an end point since this is the operative mortality cut off point, as defined by the Society of Thoracic Surgeons, for inpatient and out of hospital death. For patients surviving more than 4 hours, charts were reviewed for thromboembolic complications during hospitalization.In an attempt to determine risk factors for poor outcome, patients were assessed for age, gender, comorbid conditions, left ventricular ejection fraction (LVEF), use of cardiopulmonary bypass (CPB), hemoglobin, platelet count, arterial blood gas results and coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and D-Dimers. Laboratory parameters were not available for some patients.The Paired Student's t-Test was used to compare the number of blood product transfusions before and after treatment with rFVIIa, and, since the number of pair groups was less than 50, this result was confirmed with the Wilcoxon Matched-Pairs Signed-Ranks Test.Twelve of the 24 patients survived for more than 4 hours after the administration of rFVIIa, and the results of their pre- and post-treatment blood product use are listed in Table Six of the 12 patients who survived more than four hours were eventually discharged to home . Due to the limited time frame, it was not possible to determine if bleeding in these patients diminished after rFVIIa treatment. In the urgent setting in which these patients were treated, determining the amount and timing of blood loss and blood transfusion was difficult. Moreover, for patients deemed non-salvageable, blood product transfusion was suspended before response to rFVIIa could be determined.3, prolonged PT and PTT or both (data not given due to wide variations in the results). Seven of the 24 patients did not have a documented arterial blood gas (ABG) around the time of rFVIIa administration; however, among the other 17 patients, pH's of 7.0 in 1, 7.2 in 5, and 7. 4 in 11 patients were noted. With regards to rFVIIa administration, there was no correlation between pH, PT, PTT, thrombocytopenia, anemia and outcome.Overall, 17 of 24 CSP were over the age of 60. Twenty underwent CPB, and 15 had a LVEF below 25%. Fourteen underwent mediastinal re-exploration for bleeding. Twenty-three patients had a significant coagulopathy defined as thrombocytopenia below 100,000/mmOf the 12 patients who died within 4 hours, all underwent CPB for over 30 minutes (time on CPB for 8 patients was more than 2.5 hours). All 12 had an LVEF of less than 25% and 7 had mediastinal re-exploration for bleeding. In contrast, only 3 of the 12 surviving patients had EF <25%, 8 had surgery with CPB and 7 underwent mediastinal re-exploration. The median age and coagulation parameters were not different between the two groups.Eleven of the 16 patients with bleeding due to other causes survived for more than 4 hours after rFVIIa administration, and the results of their blood product use before and after rFVIIa are summarized in Table Nine of the 11 surviving patients were discharged to home and 2 (Patient # 2 and 23) died between 3 and 30 days from a combination of infection, cardiac arrest and multiorgan failure. Amongst survivors beyond 4 hours, mortality at 30 days was 18% and overall mortality for the entire group was 44%.All five of the 16 patients who died within four hours of rFVIIa treatment had massive injuries either from gunshot or stab wounds. Upon arrival to the emergency room, these patients were hemodynamically unstable, with hemoglobin values ranging between 3–6 g/dL. rFVIIa was given as a last resort, but these patients were not evaluable since transfusions were suspended shortly after infusion of rFVIIa.The median age of this group was 42 years. None underwent CPB, and two of the 7 patients tested had an EF <25%. Only 1 patient had a second exploratory laparotomy for bleeding. The patient suffering with a warfarin overdose had a splenic subcapsular bleed complicating systemic amyloidosis.At the time of rFVIIa administration, a wide variation in laboratory parameters was observed in these patients (data not shown). There was no difference in coagulation parameters between patients who died and those who survived. Eight of the 16 patients did not have an ABG documented. In the 5 patients who died within four hours, the pH was lower (6.9–7.0) than for those who survived (7.3–7.4).Only one of the 23 patients in both the CSP and OBP groups who survived more than 4 hours had a documented thromboembolic complication after receiving rFVIIa. Deep vein thrombosis (DVT) of the left subclavian vein was confirmed by a Doppler ultrasound 2 days after rFVIIa administration. The thrombus was related to a central line placed before rFVIIa treatment. No other clinical or laboratory evidence of thromboembolism was documented in the medical records of the other patients throughout their hospital stays. None of the other 17 patients in both the groups who died within 4 hours were evaluable for thromboembolic complications.This retrospective case series suggests that rFVIIa is effective in promoting hemostasis even when given as a last life-saving measure in poor prognosis patients with massive, transfusion-refractory hemorrhage. A statistically significant decrease in blood product transfusion was evident in 12 CSP and 11 OBP who survived more than 4 hours after rFVIIa infusion. Six of 12 CSP and 2 of 11 OBP died later between 3 and 30 days after rFVIIa infusion, but these deaths were due to causes other than hemorrhage.Despite the obvious limitations of a retrospective analysis, this is the largest series of such patients reported in the literature to date. Al Douri et al , describFactors predictive of inferior outcome after cardiac surgery include age over 60, low LVEF, significant co-morbidity, the use of CPB and re-exploration after initial surgery -24. The Both, the CSP and OBP groups had a significant decrease in blood product use after rFVIIa treatment but the short and long-term survival appeared to be worse in CSP probably due to multiple poor prognostic factors as discussed above. Poor outcome has also been independently associated with peri-operative transfusion of more than 7 units of R . The CSPExcessive hemorrhage requiring massive transfusion can lead to hypothermia, DIC, excessive fibrinolysis, dilutional coagulopathy, and metabolic acidosis, which may further exacerbate bleeding and morbidity. -17 A redin vitro dose-dependent reduction in aPTT in plasma from these patients [The optimal dose and timing of administration of rFVIIa for these patients is unknown. The standard dose (90 mcg/kg) was first used in hemophiliacs and was based on the patients ,29. The patients , used a patients , have shpatients . HoweverPrevious clinical experience with rFVIIa supports a good safety profile in patients with hemophilia and trauma. Less than 1% of patients receiving rFVIIa had thrombosis and thrombosis related complications ,31. In oThis retrospective study suggests that rFVIIa can play a beneficial role as an adjunctive hemostatic agent in patients after cardiac surgery or extensive trauma who experience bleeding that cannot be controlled by conventional therapies. Prospective studies are necessary to determine optimal patient selection, and dose and timing of rFVIIa administration.


Drosophila has been developed recently as a model system to investigate the molecular and neural mechanisms underlying responses to drugs of abuse. Genetic screens for mutants with altered drug-induced behaviors thus provide an unbiased approach to define novel molecules involved in the process. We identified mutations in the Drosophila LIM-only (LMO) gene, encoding a regulator of LIM-homeodomain proteins, in a genetic screen for mutants with altered cocaine sensitivity. Reduced Lmo function increases behavioral responses to cocaine, while Lmo overexpression causes the opposite effect, reduced cocaine responsiveness. Expression of Lmo in the principal Drosophila circadian pacemaker cells, the PDF-expressing ventral lateral neurons (LNvs), is sufficient to confer normal cocaine sensitivity. Consistent with a role for Lmo in LNv function, Lmo mutants also show defects in circadian rhythms of behavior. However, the role for LNvs in modulating cocaine responses is separable from their role as pacemaker neurons: ablation or functional silencing of the LNvs reduces cocaine sensitivity, while loss of the principal circadian neurotransmitter PDF has no effect. Together, these results reveal a novel role for Lmo in modulating acute cocaine sensitivity and circadian locomotor rhythmicity, and add to growing evidence that these behaviors are regulated by shared molecular mechanisms. The finding that the degree of cocaine responsiveness is controlled by the Drosophila pacemaker neurons provides a neuroanatomical basis for this overlap. We propose that Lmo controls the responsiveness of LNvs to cocaine, which in turn regulate the flies' behavioral sensitivity to the drug. Drosophila LIM-only (LMO) gene in circadian pacemaker cells is required for the normal behavioral sensitivity of these animals to cocaineExpression of the  Cocaine, a naturally occurring plant alkaloid, is the prototype addictive psychomotor stimulant. It elicits a variety of acute behavioral changes ranging from mood elevation, disinhibition, and motor activation at low doses to compulsive stereotypies and psychosis at higher doses . Long-teCocaine's primary mechanism of action is to bind and inhibit plasma membrane monoamine transporters, thereby increasing synaptic monoamine neurotransmitter levels and potentiating their actions. Cocaine's direct role in increasing dopamine (DA) in the nucleus accumbens via inhibition of the DA transporter (DAT) has contributed to the prevalent DA hypothesis of drug addiction, which posits that the shared ability of drugs of abuse to increase DA in the nucleus accumbens underlies their reinforcing properties . More reDrosophila melanogaster has been advanced as a useful model system for identifying novel genes that regulate behavioral responses to drugs of abuse including cocaine , isolated due to their increased sensitivity to cocaine-induced loss of negative geotaxis. The products of Drosophila and mammalian Lmo genes modulate the function of LIM-homeodomain (LIM-HD) proteins , which are the primary circadian pacemaker cells in Drosophila , that also showed increased cocaine sensitivity (heldup (hdp) mutant flies, which carry well-characterized loss-of-function mutations in Lmo . Taken together, these data demonstrate that loss-of-function mutations in Lmo result in increased sensitivity to cocaine.Independently, we isolated a P[GAL4] insertion in the sitivity A. Finalls in Lmo , display306 line A. This iiors see . FinallyBeadex (Bx) mutations were first described in 1925 by Morgan, Bridges, and Sturtevant, and named for their characteristic beaded wing margin , decreased slow circling, and almost no akinesia .Lmo display increased sensitivity to the effects of cocaine on locomotor behaviors, while gain-of-function mutations show the converse effect, a reduced response to the drug. This inverse relationship between Lmo gene activity and drug responsiveness suggests that Lmo may regulate the expression of genes that might play a direct role in controlling cocaine responses (see Discussion).In summary, using two different behavioral assays we show that flies carrying loss-of-function mutations in Lmo locus produces at least three transcripts by differential promoter use . Thus, as predicted by the location of the P-element insertion, the EP1306 mutation causes a reduction in Lmo transcript levels, a finding that is consistent with the observation that the cocaine sensitivity of EP1306 flies is similar to that seen with known loss-of-function alleles of Lmo  and opposite to that seen with gain-of-function Bx alleles. In addition, the finding that transcript levels are specifically reduced in the heads of EP1306 flies, and not their bodies, suggests that this mutation affects a nervous-system-enriched (or -specific) Lmo transcript (see below). Finally, none of the P-element insertions in the promoter of the RA transcript leads to a held-up wing phenotype, which is characteristic of loss-of-function hdp alleles  transgene , where Lmo expression has been shown to play an important patterning role . These data demonstrate that the cocaine-sensitivity defect of pdrm flies is due to the loss of Lmo function, and that nervous-system-specific expression of Lmo in cells dictated by the pdrm GAL4 line is sufficient to confer normal cocaine responses.We hypothesized that the expression pattern of the nt flies B. This eLmo function, we attempted to rescue the EP1306 phenotype by expression of Lmo in specific brain regions. EP lines carry a P-element insertion containing multiple UAS sites to which GAL4 can bind to drive expression of adjacent genomic sequences .In order to refine further the spatial requirements for equences . Therefosertions . ConsistLmo expression from the EP1306 insertion. We focused specifically on GAL4 lines that drive expression in the MBs, ALs, pars intercerebralis neurons, LNvs, and glia, sites of expression revealed by the pdrm line (EP1306 (data not shown). Similar negative results were obtained with the glial-specific repo-GAL4 driver  and in a group of neuroendocrine cells located at the very tip of the VNC . This overlap in expression of pdrm and pdf-GAL4 in the LNvs implicates these few neurons as mediators of the altered cocaine sensitivity observed in Lmo mutants.In the adult fly, NC J. H. C. The LNthmicity ; the funrsor PAP C. pdrm dvs is disrupted in Lmo mutants. Projections of the s-LNvs and l-LNvs can be visualized with an antibody that recognizes the PDF precursor PAP . In the EP1306 and pdrm mutants, anti-PAP staining revealed that the number and detailed morphology of LNv neurons were completely normal (data not shown). Thus, Lmo does not appear to play a role in the development of the LNvs, although subtle developmental defects could have been missed.Because of the known role of LMOs as regulators of developmentally important transcription factors , we askersor PAP . L-LNvs al brain C. Both sLmo mutants suggested that these mutations alter LNv function without grossly affecting LNv development. In order to determine whether Lmo mutants have a more general dysfunction in the LNvs, we tested Lmo mutants in locomotor rhythm assays. The LNvs are required for the maintenance of circadian locomotor rhythms in constant darkness, and are thus the pacemaker neurons of the fly  cycles and then tested them for cocaine sensitivity during the light and dark phases at 3-h intervals over 24 h  using pdf-GAL4. This approach was previously used to demonstrate that LNvs are the Drosophila pacemaker neurons responsible for rhythmic locomotor activity .The hypersensitivity of activity . When tecontrols . These rv-ablated animals results from loss of neuronal signaling from these cells, rather than from developmental compensations induced by their ablation, we functionally silenced the LNvs either electrically, by targeted expression of the mammalian inward rectifying K+ channel (Kir2.1), or synaptically, by expression of tetanus toxin light chain (TeTx) TeTx  . These m of LNvs . Expressblations . Importathe LNvs . These ddoes not . In summDrosophila mutants with altered acute responses to cocaine, we isolated multiple mutations in the Lmo locus. Behavioral characterization of gain- and loss-of-function alleles of Lmo demonstrates an inverse correlation between Lmo expression levels and cocaine sensitivity. Through targeted expression of Lmo, we show that these altered cocaine responses are caused by differential Lmo expression in the circadian pacemaker neurons, the LNvs. Consistent with a dysfunction of these pacemaker neurons in Lmo mutants is our finding that the mutant flies also show altered circadian locomotor rhythms. However, using a variety of genetic methods to ablate or functionally silence these neurons, we reveal a novel role for the LNvs in modulating cocaine's acute locomotor responses that is independent of their pacemaker function. These findings add to mounting data in Drosophila and mice supporting a role for circadian genes in cocaine-related behaviors  , the mammalian central pacemaker. Furthermore, microarray analysis revealed that in many tissues, Lmo4 expression varies with circadian time . Expression of PDF, the only known LNv output, is restricted to the LNvs and a few tritocerebral neurons. As PDF expression is a specific marker for the differentiated state of the LNvs, it is unlikely that in Lmo mutants these neurons are grossly abnormal in their terminal differentiation.LMOs are known to act as regulators of LIM-HD protein activity and stability . LIM-HD n detail . The LNvcrickets . An assevs suggests that Lmo may play an active role in regulating cocaine responses. In fact, evidence is mounting that the expression and activity of LMOs are dynamically regulated within the nervous system. For instance, expression of the murine Lmo homologs Lmo1, Lmo2, and Lmo3 is differentially regulated by seizure activity in specific regions of the hippocampus and forebrain of adult mice .We provide evidence that the LN rhythms . pdf nulactivity , we showvs modulate circadian rhythmicity and cocaine sensitivity independently? It is possible that these cells use distinct output mechanisms, PDF to regulate circadian locomotor rhythms and another unknown signal to regulate cocaine sensitivity. Alternatively, these behaviors could be regulated by distinct subsets of LNvs. For example, several recent findings suggest that l-LNvs may play a lesser role in regulating circadian rhythmicity  would result in reduced receptor content and, consequently, in dampened cocaine sensitivity —a neural pathway involved in the acute stimulant and rewarding properties of abused drugs. We posit that LMOs are ideally suited to modulate in a subtle manner the neurochemical identity and sensitivity of the nervous system to various stimuli, including drugs of abuse.LMO-induced changes in receptor expression are not inconceivable given LMO's interaction with LIM-HD proteins. Changes in LIM-HD protein function have been shown to affect aspects of neuronal subtype identity, including neurotransmitter and receptor expression profiles. For instance, mutations in the ynthesis . In addiapterous . The obs mutants  suggestspdrm allele was originally isolated in a genetic screen of P[GAL4] insertions (carrying the GawB element) for altered response to the locomotor-activating effects of ethanol  and consequently tested for cocaine sensitivity. The location of the insertion was determined by inverse PCR (http://www.fruitfly.org/about/methods/inverse.pcr.html). The R590hdp and R26hdp loss-of-function alleles were provided by S. Cohen   . Bx alleles and pdf deficiencies (Df(3R)T1-X and Df(3R)T1-P) were obtained from the Drosophila Stock Center . 01w33, pdf and pdf-GAL4 flies were obtained from P. Taghert    . All lines used for behavioral experiments, unless noted below, were out-crossed for five generations to a 1118w stock isogenic for Chromosomes II and III. Because 01pdf and its background control strain (w33) are unmarked, only Chromosomes I and II were replaced via crosses to balancer stocks in the 1118w genetic background.All flies were maintained on standard cornmeal molasses agar at 25 °C and 70% humidity under constant weak light. The Rørth EP collection was obtained from G. M. Rubin  . The pdrGermany) . UAS-Lmo States) . The hdp States) . UAS-Kir States) . UAS-TeTescribed . UAS-hid States) . UAS-tauw, X^X/Y tester strain in the crackometer as described below (n = 6–9). These lines distributed normally, and 30 lines with phenotypes greater than 1.5 standard deviation from the mean were out-crossed into our 1118w background and retested. An additional 70 lines were selected to be out-crossed in order to provide a population distribution from which to select control lines. These 100 out-crossed lines were rescreened for acute responses to cocaine. A group of five control EP lines were chosen based on having a normal acute response (near the mode of the distribution). In all behavioral experiments involving EP lines, at least three of these control lines were tested to ensure that the control shown was representative of the EP population. The specific control EP line shown for each experiment is noted in the figure legends. As a control for the pdrm line we used a P[GAL4] insertion (line 8.142) that shows a normal response to multiple drugs, including cocaine . For data shown in w, X^X/Y tester strain to reduce possible effects of recessive autosomal modifiers. In addition to the genotypes shown, we tested three P-element lines in the Lmo locus that did not produce cocaine phenotypes: MS1096, which lies 20 bp downstream of the first RA transcript exon, and two additional EP lines, EP0443 and EP1394, inserted 5′ to EP1383; the EP lines have normal wings. MS1096 has been shown to have a very weak wing venation phenotype, but has otherwise not been phenotypically or molecularly characterized , and tested 2–3 d later. Flies were equilibrated to room temperature for at least 1 h before being exposed to cocaine. Cocaine exposures were performed as described previously . Error bars in all experiments represent the standard error of the mean. To maintain an experiment-wide error rate of α = 0.05, the adjusted error rates were p = 0.05/n for the n subsequent planned pairwise comparisons in each experiment. To observe cocaine locomotor activity patterns, ten flies were exposed to volatilized cocaine for 1 min, transferred to a 7.5 cm × 10 cm × 0.5 cm acrylic box, and images were captured on an Apple G4 computer  using Adobe Premiere  at 10 frames/s for 5 min. Fly locomotion was tracked using the dynamic image analysis system software . All genotypes were tested at each dose multiple times (n ≥ 3), and representative data were selected for the figures. Baseline negative geotaxis was measured by mock exposures of flies and subsequent assay in the crackometer as above; all genotypes displayed behavioral scores of less than 10%, with no significant differences between genotypes (n > 8).For cocaine-sensitivity assays, for all behavioral experiments, 15 male flies were collected under COeviously , and staeviously . A drug 2 anesthesia during the light phase 1–2 d after eclosion, and placed back in LD for 2–3 d. At the indicated Zeitgeber times, flies were tested in the crackometer, under lights, within 5 min of being removed from LD conditions.For circadian experiments, locomotor activity of individual flies was measured using the TriKinetics  infrared beam-crossing system recording total crosses in 10-min bins. Raw activity histograms were analyzed for circadian rhythms using Actimetrics  Clocklab software. Chi-square periodograms were constructed according to pdrm P[GAL4] insertion was examined by crossing to UAS-GFPT2 and UAS-mCD8GFP. All adult and larval preparations were dissected in PBS, fixed in 4% formaldehyde/PEM for 40 min, washed in PBS, and dehydrated in 50% glycerol/PBS for 1 h. Tissue was mounted in Vectashield mounting medium  and analyzed with a Bio-Rad confocal microscope with Bio-Rad Lasersharp 2000 software . PAP antibody staining (provided by P. Taghert) was performed on CNS preparations that were dissected, fixed, and washed as above. Specimens were incubated in 1:2,000 dilution of anti-PAP in PBT, and with a Texas Red–coupled goat anti–guinea pig secondary antibody, diluted 1:200 .Expression pattern of the LmoRA-For, GAAGAGAAACAACAGCAGCAACA; LmoRA-Rev, ATTTGCATATTTCGCACTTGTTTAGCT; and LmoRA-Probe, CTGCTGCCGTTGCTG. rp49 probe and primers (CT 6405) were obtained from Applied Biosystems. TaqMan PCR reactions consisted of 50 ng of cDNA, 0.9 μM each diagnostic primer, 0.25 μM diagnostic probe, and 1x final of TaqMan Universal PCR Mastermix (Applied Biosystems) in a reaction volume of 25 μl. The TaqMan PCR conditions used were as described in TaqMan guidelines. Each sample was analyzed in triplicate. As negative controls, we used both no-template and DNase-treated non-reverse-transcribed mRNA samples; no significant amplification was observed in these samples. rp49 transcript levels were used as an endogenous normalization control for RNA samples, and relative mRNA abundance was calculated using the comparative delta-Ct method. Reference mRNA is noted in figure legends. Quantitative RT-PCR analysis was performed on at least two independent RNA preparations, with similar results.Flies 2- to 4-d-old were collected and frozen immediately at −80 °C. Heads were removed from bodies by vortexing, and separated in a sieve. RNA was extracted from heads and bodies by homogenizing the flies in hot phenol and NTES. Complementary DNA (cDNA) was prepared using TaqMan Reverse Transcription Reagents  according to the manufacturer's specifications, with the addition of random sequence hexamers to 2.5 μM. cDNA was analyzed by quantitative, real-time PCR using the ABI PRISM 7700 Sequence Detection System (Applied Biosystems). The following probes and primers were designed using ABI PrimerExpress software:


Background to the debate: A variety of biomedical technologies are being developed that can be used for purposes other than treating disease. Such “enhancement technologies” can be used to improve our appearance and regulate our emotions, with the goal of feeling “better than well.” While these technologies can help people adapt to their rapidly changing lifestyles, their use raises important ethical issues. Biomedical "enhancement technologies" are being developed that can be used for purposes other than treating disease, such as improving our appearance and regulating our emotions Perfection has come in for a lot of bad press recently. A torrent of books and articles has recently appeared ,6,7,8,9,Biomedical scientists and physicians might be inclined to ignore this literature as just so much abstract philosophical handwringing. After all, it is almost impossible to find mainstream scientists arrogant enough to proclaim their interest in perfecting anything, much less themselves or their fellow human beings.Beating up on the pursuit of perfection is silly. As Salvadore Dali famously pointed out, “Have no fear of perfection—you'll never reach it.” Critics of those who allegedly seek to perfect human beings know this. While often couching their critiques in language that assails the pursuit of perfection, what they really are attacking is the far more oft-expressed—albeit far less lofty—desire to improve or enhance a particular behavior or trait by the application of emerging biomedical knowledge in genetics, neuroscience, pharmacology, and physiology. Those who might accurately be termed “anti-meliorists” wonder how we will ever resist the obvious temptation to put this knowledge to use to alter ourselves. They are quick to note that we have already given in to such temptation—we augment our breasts, smooth our wrinkles, and pump ourselves full of antidepressants.Putting the brakes on biologically driven human betterment would have real consequences for science. Some lines of research would be slowed or restricted ,5,8. TheWhy is the drive to improve ourselves so disturbing to the anti-meliorists? Their arguments cluster around three key worries: that the pursuit of perfection by biomedical means is vain, selfish, and unrewarding ,2,3,6,7,It cannot simply be the pursuit of improvement that is making anti-meliorists nervous. Many religious traditions and spiritual movements seek perfection ,11,12,13Anti-meliorism rests, however, on a very shaky foundation. To support their position, the anti-meliorists must state what human nature is. They do not. They must also be very clear about why they see human nature as static. They are not. And they must advance an argument about why human nature, which has presumably evolved in response to an enormous array of random forces, tells us anything about what is good or desirable in terms of the traits humans should possess. They cannot.The fight over whether there is any such thing as human nature is a long-standing one Worse still for anti-meliorists, we are clearly creatures who have long tinkered with ourselves, using all manner of technologies from clothing to telescopes to computers to airplanes. Our view of our “nature” is closely linked to the technologies that we have invented and to which we have adapted Nor is there any normative guidance offered by our evolutionary history that shows why we should not try to improve upon the biological design with which we are endowed. Augmenting breasts or prolonging erections may be vain and even a waste of scarce resources, but seeking to use our knowledge to enhance our vision, memory, learning skills, immunity, or metabolism is not obviously either.Ultimately, anti-meliorism posits a static vision of human nature to which the anti-meliorists mandate we reconcile ourselves. If anything is clear about human nature, it is that this is not an accurate view of who we have been or what we are now, or a view that should determine what we become.Those of us who worry about medical enhancement are usually less worried about the technologies themselves than about the larger social effects of embracing them too enthusiastically. Just as you do not need to object to cars to worry about urban sprawl, you do not need to object to enhancement technologies to question where these technologies may be taking us. It is not just technophobes who wonder whether a society that consumes 90% of the world's supply of methylphenidate , where the most profitable class of drugs is antidepressants, and where cosmetic surgeons perform liposuction on prime-time television is a society that has somehow lost its way.Let's look at three of the most commercially successful medical enhancements of recent years: selective serotonin reuptake inhibitors, hormone replacement therapy, and the diet drug fenfluramine-phentermine (Fen-Phen). What can we learn from these interventions?First, the manufacturers of enhancement technologies will usually exploit the blurry line between enhancement and treatment in order to sell drugs. Because enhancement technologies must be prescribed by physicians, drug manufacturers typically market the technologies not as enhancements, but as treatments for newly discovered or under-recognized disorders. Selective serotonin reuptake inhibitors were marketed not as personality enhancers, or even only as treatments for clinical depression, but as treatments for questionable illnesses like “premenstrual dysphoric disorder” Second, an alarming number of supposedly risk-free enhancements have later been associated with unanticipated side effects, some of them deadly. Wyeth has set aside over $16 billion to compensate the thousands of patients who have developed valvular heart disease and pulmonary hypertension after taking Fen-Phen Feminine ForeverThird, the most successful enhancement technologies have been backed by tremendously influential public relations campaigns. These campaigns have included ghostwritten journal articles, industry-funded front groups, and lucrative payments to academics, professional societies, and university centers The traditional worry about enhancement technologies is that users of the technologies are buying individual well-being at the expense of some larger social good. I may improve my own athletic ability by taking steroids, but I set off a steroid arms race that destroys my sport. I may get cosmetic surgery for my “Asian eyes” or use skin lighteners for my dark skin, but I reinforce the implicitly racist social norms that say that Asian eyes or dark skin are traits to be ashamed of. The worry is that some aspect of the way we live together, collectively, is going to be damaged by actions that we take individually A market-driven health-care system brings this worry much closer to home. The pharmaceutical industry is now the most profitable and politically powerful industry in the United States Elliott professes to be unhappy about enhancement. What arguments does he present to support his unhappiness? Not many, and the arguments that he does offer miss the point completely.If people want to feel better, sleep less, have fewer hot flashes, better vision, or fewer wrinkles, then they may want to use enhancement technologies to achieve these things. Technology in itself isn't driving us in any particular direction—I believe that we decide where it should go. Elliott, however, gravely warns us that you and I do not really decide a direction when it comes to matters of enhancement. It is—listen carefully for the Darth Vader–esque hissing—drug companies!The rest of Elliott's viewpoint amounts to what is his increasingly familiar harangue against the pharmaceutical industry. The drug companies sucker us into buying enhancement by getting us hooked on pseudotherapies. The drug companies rob us of our will to fend off their siren-like messages of better living through their chemistry. And the drug companies get us feeling so bad about ourselves that we empty our wallets on their latest overpriced geegaws.Pharmaceutical companies may be evil incarnate. And we may be putty in their pecuniary little hands. But that has nothing at all to do with the question of whether there is anything wrong with pursuing enhancement. When Elliott eagerly dons his hair shirt to bemoan Big Pharma, he finds so much sin to revel in that he forgets to give a reason, any reason, why enhancement is, in itself, immoral.At most he presents an argument for keeping the pharmaceutical industry out of enhancement. Okay, so let's take Big Pharma out of the picture. If we left the encouragement of enhancement to the government, the military, schools, foundations, doctors, or parents, would this now be morally acceptable? I think sometimes it would be. And nothing that Elliott says provides any reason to think otherwise.Caplan does not defend medical enhancement so much as attack its critics. Or rather, he attacks a small group of conservative critics who want to preserve “human nature.” He dispatches those critics with admirable precision, but I am not sure why he believes that group of critics includes me. My worry about enhancement technologies has little to do with human nature. My worry is that we will ignore important human needs at the expense of frivolous human desires; that dominant social norms will crowd out those of the minority; that the self-improvement agenda will be set not by individuals, but by powerful corporate interests; and that in the pursuit of betterment, we will actually make ourselves worse off.It's no secret that many Americans are deeply ashamed of their personal shortcomings and inadequacies. Nor is it any secret that these shortcomings and inadequacies can be exploited for commercial profit. But do we really want to submit our health-care system to the same forces that have made millionaires out of motivational speakers and diet book authors?Extreme Makeover.Skepticism about enhancement technologies is not equivalent to a wish to set back medical research and declare some applications off-limits. This is a debate about enhancing human traits, not curing human illness. To say that our medical research agenda will be set back if we restrict enhancement technologies makes no more sense than saying that cancer surgery will be set back if the American Broadcasting Corporation cancels its cosmetic surgery reality TV show We live in a country where 46 million uninsured people cannot get basic medical care, while the rest of us spend a billion dollars a year on baldness remedies. It is not just the inequity here that is so impressive. It is the fact that we have gotten so accustomed to the inequity that we do not see it as obscene.


Women aged ≥ 65 years are high utilizers of prescription and over-the-counter medications, and many of these women are also taking dietary supplements. Dietary supplement use by older women is a concern because of possible side effects and drug-supplement interactions. The primary aim of this study was to provide a comprehensive picture of dietary supplement use among older women in a large health plan in Northern California, USA, to raise awareness among health care providers and pharmacists about the need for implementing structural and educational interventions to minimize adverse consequences of self-directed supplement use. A secondary aim was to raise awareness about how the focus on use of herbals and megavitamins that has occurred in most surveys of complementary and alternative therapy use results in a significant underestimate of the proportion of older women who are using all types of dietary supplements for the same purposes.We used data about use of different vitamin/mineral (VM) supplements and nonvitamin, nonmineral (NVNM) supplements, including herbals, from a 1999 general health survey mailed to a random sample of adult members of a large Northern California health plan to estimate prevalence of and characteristics associated with supplement use among women aged 65–84 .Based on weighted data, 84% had in the past 12 months used >1 dietary supplement, 82% a VM, 59% a supplement other than just multivitamin or calcium, 32% an NVNM, and 25% an herbal. Compared to white, nonHispanic women, African-Americans and Latinas were significantly less likely to use VM and NVNM supplements and Asian/Pacific Islanders were less likely to use NVNM supplements. Higher education was strongly associated with use of an NVNM supplement. Prevalence did not differ by number of prescription medications taken. Among white, nonHispanic women, multiple logistic regression models showed that college education, good health, belief that health practices have at least a moderate effect on health, and having arthritis or depression significantly increased likelihood of NVNM use, while having diabetes decreased likelihood.An extremely high proportion of older women are using dietary supplements other than multivitamins and calcium, many in combination with multiple prescription medications. Increased resources should be devoted to helping clinicians, pharmacists, supplement vendors, and consumers become more aware of the safety, effectiveness, and potential side effects of dietary supplements. A recent national survey of medication use patterns found the highest prevalence of medication use over a one-week period was among women aged ≥ 65 years . Over 80In a previous study, we used data from a 1999 general health survey of adult members of the Kaiser Permanente Medical Care Program of Northern California (KPCMP) to characterize use of nonvitamin, nonmineral (NVNM) supplements, including herbals, among the adult membership of this large health plan . The resDuring Spring 1999, a confidential general health survey  was mailed to a stratified random sample of 40,000 adults aged ≥ 25 who were members of the Kaiser-Permanente Medical Care Program in Northern California. Up to three attempts were made to obtain a mailed response from each person in the sample unless the individuals refused or were deemed ineligible due to curtailment of membership, death, language barrier, or incorrect address. The survey questionnaire used in the first two mailing attempts included questions about use of complementary and alternative medicine (CAM) modalities and dietary supplement use, in addition to questions covering demographic and health-related characteristics and medication use. (A shortened form of the questionnaire sent to non-respondents to the first two mailings did not contain the CAM and dietary supplement questions.) Completed non-abridged questionnaires were received from 72%  of women aged 65–84 in the survey sample. We restricted our estimates to women under age 85 because both the response rate and numbers of respondents aged ≥ 85 were too low to generalize about the "oldest old" cohort.ginkgo biloba, Echinacea, kava kava, glucosamine, St. John's Wort, and a space to write in other supplements, which were then individually coded and categorized as herbal supplements, other nonvitamin/nonmineral (NVNM) supplements, or vitamin/mineral (VM) supplements. Respondents were classified as VM users if they reported use of one or more vitamins/minerals, although we further subdivided this group into multivitamin and/or calcium users only and those who reported using other VMs such as vitamins C and E or minerals such as zinc and magnesium, with or without a daily multivitamin and/or calcium . Respondents were classified as herbal users if they had indicated herbal use on the CAM modality checklist or indicated use of one or more herbals in the dietary supplement checklist. Respondents were classified as NVNM supplement users if they had indicated use of any of the herbals, glucosamine, or melatonin on the dietary supplement checklist or wrote in a supplement subsequently categorized as an herbal/botanical, amino acid, enzyme, protein, hormone or other non-herbal NVNM dietary supplement [Use of dietary supplements during the previous 12 months was ascertained through two questions. First, a question covering use of 19 different CAM modalities: "Have you used the following methods to help treat or prevent health problems?" included items for "Any herbal medicine or supplement" and "Megavitamins/high dose vitamin therapy (not including daily multiple vitamin)." A separate question asked about use of selected dietary supplements: "In the past 12 months, did you use any nutritional supplements?" This question had a response checklist that included daily multiple vitamin with or without minerals , calcium with or without vitamin D, vitamin C, vitamin E, melatonin, pplement .The estimated percentages of women who regular took one or more prescription medications were based on response to the question "How many prescription medicines do you regularly take," while estimated use of prescription medication with a narrow therapeutic index was based on health plan pharmacy data for the sample. The decision to use self-report rather than pharmacy data to estimate the numbers of prescription medications regularly was made because nearly 17% of the women had reported filling prescriptions outside of the health plan during the 12 months preceding the survey, and also because it was going to be extremely labor-intensive to determine from pharmacy data the numbers of different types of prescription medications each respondent "regularly" used.The respondent sample was assigned post-stratification weights so that analyses with weighted data would reflect the actual age , gender and geographic distribution of the adult membership from which the sample was drawn. All percentages reported in the text and tables are based on weighted data. However, the tables include the actual (unweighted) subgroup denominators used in the analyses. All analyses were performed using PC-SAS version 8.2 . CalculaPrevalence ratios (PR) were calculated to compare supplement use rates for subgroups of interest against rates for a reference group . Confidence intervals around the PRs were used to assess the range of PR's compatible with the data at a level of 95% confidence. In the text and tables, a PR confidence interval that includes 1.0 indicates that rates are not statistically significantly different from each other at the p < .05 level. Logistic regression models run with unweighted data were used to test whether African-American/Black (AA/B), Hispanic/Latina (H/L), and Asian/Pacific Islander (A/PI) women differed significantly from white nonHispanic (whiteNH) women in use of different supplements after controlling for age and also after controlling for age, education, and health status.Logistic regression models were used to identify statistically significant independent predictors of four types of use: (a) any dietary supplement, (b) any dietary supplement other than a multivitamin and/or calcium supplement only, (c) any NVNM supplement, and (d) any herbal supplement. The results we present are restricted to whiteNH women because we found that the predictor variables did not operate the same way in separately run models for the other race/ethnic groups in the sample. Indicator variables included in the logistic models were 3 age groups , 4 education levels , overall health status , arthritis (yes vs. no), diabetes (yes vs. no), depression for at least two weeks during the past 12 months, and belief that "lifestyle/habits  affect health" moderately to extremely vs. not at all/a little bit. Rates of supplement use were not substantially different for ages 65–69 and 70–74, so these age groups were collapsed. All four logistic models included the same set of predictor variables and were run using data from the 96% (n=2378) whiteNH women who had complete data for all variables. In the text and tables, adjusted odds ratios (Adj. OR) with 95% confidence intervals that cross 1.0 are not statistically significant at the p < .05 level.Table Table 2 See   shows eAA/B = 0.32, CI: 0.13–0.82; ORH/L = 0.19, CI: 0.06–0.61; ORA/P = 0.56, CI: 0.28–1.11). Similarly, women of color who had experienced depression for at least two weeks during the 12-month interval were substantially less likely than whiteNHs to report using St. John's Wort to treat depression. Rates of ginkgo biloba use did not significantly differ by race/ethnicity.After adjusting for age, African-American/Black seniors were significantly less likely than whiteNH seniors to use daily multivitamins and calcium, as well as all the other categories of dietary supplements. This difference remained statistically significant after also adjusting for education, health status, and the three chronic health conditions. Hispanic/Latina seniors were also significantly less likely than whiteNH seniors to use VM supplements (with the exception of vitamin E) and NVNM supplements, but did not significantly differ on herbal use. Asian/Pacific Islander seniors did not significantly differ from whiteNH seniors on use of any type of dietary supplement, use of VMs, or use of dietary supplements other than just a multivitamin and/or calcium. However, they were significantly less likely than whiteNH women to use NVNM supplements. Among women using any supplement, mean use of all supplements and supplements excluding multivitamins and calcium were both significantly higher among whiteNH women than among women of color (not shown). Table 2 also shows that use of glucosamine by women with arthritis was significantly lower among African-American/Black, Hispanic/Latina, and Asian/PI women as compared to whiteNH women  or Hispanic/Latina  race/ethnicity significantly decreased the likelihood of glucosamine use as compared to whiteNH women, while having education beyond high school  and the belief that health practices have a moderate-large effect on health  were associated with significantly greater likelihood of glucosamine use.ginkgo biloba or garlic supplements, even though there is evidence that this combination of blood thinners can lead to adverse consequences.The prevalence of use of NVNM supplements and dietary supplements other than a multivitamin and/or calcium did not differ by number of prescription medications taken  nor by whether a prescription medication with a narrow therapeutic index was being taken. Approximately 10% of women seniors who were taking an anticoagulant were also using Figure Finally, Figure ginkgo biloba (15% vs. 5%), glucosamine (12% vs. 4%), and Echinacea (8% vs. < 1%) [et al's 1997 national survey of alternative medicine use over a 12-month interval [The 84% prevalence of use of any vitamin/mineral (VM) or nonvitamin/nonmineral (NVNM) supplements, 32% prevalence of NVNM supplement use, and 25% prevalence of herbal supplement use by women aged 65–84 in this Northern California health plan membership are substantially higher than prevalences previously reported for women ≥ 65 years of age. Compared to the results of the national Slone Survey of medication use among adults, this population was significantly more likely to report use of any vitamin/mineral (82% vs. 59%), daily multivitamin (57% vs. 33%), calcium , any herbal or other NVNM supplement 32% vs. 14%), and specific NVNM supplements, including 4%, and sinterval . FurtherOur findings that supplement use was significantly higher among women who had higher levels of education, were white, nonHispanic (vs. African-American/Black or Hispanic/Latino), and were in good health are consistent with findings reported by other studies -22. Howeet al. national survey samples are not substantially different from ours. Our observed usage rates may also be higher because of the social environment. Previous national surveys have shown that rates of NVNM and any alternative therapy use among people in the Western United States are higher than rates for the entire country [The higher rates we observed in our study may be a result of differences in the demographic composition of the survey populations. Our sample was predominantly (80%) white, nonHispanic and education beyond high school (35% some college and 20% college graduates), and in this and other surveys, being whiteNH and better educated was significantly associated with supplement use. However, while the usage rates among African-American/Black and Hispanic/Latina women and those without post-high school education are substantially lower, the demographics of the 1998–1999 Slone survey and 1997 Eisenberg  country ,24. Howeet al. and Radimer et al. also may be related to the timing of the surveys. Eisenberg et al. reported highly significant increases in use of herbal medicine (2.5% to 12.1%) and megavitamin use (2.4% to 5.5%) for the adult population overall in1990 vs. 1997 [The higher herbal and NVNM usage rates observed in this study compared to those reported by Foster vs. 1997 . In an evs. 1997 .Finally, the wording of the questions to ascertain herbal use and NVNM use were not totally comparable across surveys. The estimates of VM and NVNM use reported in the Slone study are based on an open-ended question about use of any medication during the preceding 7 days, with a prompt for both VM and herbal supplement use, but not use of other types of NVNM supplements. Foster's estimate is based on response to a question about use of herbals as one of several different types of therapies. In contrast, our results are based on a question that provided a response checklist of some specific VM, herbal, and other NVNM supplements along with the opportunity for individuals to add additional supplements used, which were later coded and categorized. In an earlier study of alternative therapy use, we examined the difference in estimates of herbal use by the health plan membership based on indication of herbal use in a checklist of 17 different methods  used to treat or prevent health problems and indication of herbal use based on that item and response to the dietary supplement use question. We found that basing the estimate on the combined questions versus the single item nearly doubled the rate of herbal use among women ≥ 65 years (17.6% vs. 9.6%) .Our finding that much larger percentages of adult women are taking NVNMs and VMs other than multivitamins and calcium suggests that for purposes of surveying populations about complementary and alternative therapy use and for medical interviews, the focus should be on use of all types of dietary supplements and medicinal teas, not just herbal supplements. There are several reasons for this. First, VMs and NVNMs other than herbals have the potential for causing adverse reactions, such as high doses of Vitamin C or zinc resulting in gastric upset, that can lead to further self-medication and/or medical visits. Second, certain VMs and NVNMs other than herbals also have the potential to interact with prescription medications, resulting in decreased effectiveness or affecting physiological indicators of how the medication is affecting the individual. Third, a focus on herbals alone excludes other NVNMs that are commonly used by patients with certain health conditions. For example, we estimate that nearly 3% of women used melatonin and 15% of whiteNH women (24% of those with arthritis) use glucosamine, neither of which is an herbal supplement. Finally, surveys of Mexican-American and Central American older women have shown a high prevalence of use herbal and other types of medicinal teas, which may not be picked up by questions asking about dietary supplement use . HoweverSeveral surveys have found that patients do not tend to report use of herbals and other dietary supplements to their health care providers in clinical encounters ,9,11,27.Our finding that nearly 60% of older women in this population were using dietary supplements other than multivitamins and calcium underscores the importance of clinicians querying patients about use of all types of dietary supplements when assessing health problems and prescribing medications, and as a back up, pharmacists inquiring about use of dietary supplements that may interact with prescription and over-the-counter medicines that are being purchased. Initiation of the communication by clinicians and pharmacists is likely to result in increased patient awareness that these dietary supplements may affect their health and treatment outcomes, which should then lead to higher rates of patient-initiated communication about dietary supplements they are using or considering using. Greater clinician and pharmacist awareness of all the different prescribed and self-directed regimens patients are using may lead to more proactive interventions to decrease adverse effects of supplement use. However, in order for clinicians and pharmacists to be able to respond to patient questions about dietary supplements, as well as to identify individuals at high risk for adverse effects, better information about the safety, effectiveness, and side-effects of dietary supplements need to be available and easily accessible, such as through the Natural Standard and National Medicines Databases.In conclusion, our study indicates that use of dietary supplements to treat or prevent health problems is very prevalent among older insured women, and that based on current use in younger age groups, the prevalence can be expected to increase over the next few decades. It will be important for federal agencies, professional associations, manufacturers, and consumer groups to promote research into the safety and effectiveness of commonly used dietary supplements, to develop standards for product quality, and to develop guidelines for recommended dosages based on age, weight, and health history that can be disseminated to both health care professionals and stores or clinics which sell these products. At the same time, it is important to begin to educate patients and the broader public about the importance of more thoroughly researching the safety, effectiveness, and potential negative effects of particular dietary supplements before beginning to use them.The author(s) declare that they have no competing interests.NG designed the study, conducted the survey, analyzed the data, and drafted the manuscript. DS developed the scheme for coding the dietary supplement data, consulted on data analysis, and participated in manuscript development. Both authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Table 2 - Estimated percentages of female health plan members aged 65–84 using specific types of dietary supplements, overall and by race/ethnicityClick here for fileTable 3 - Estimated use of dietary supplements by women aged 65–84 by selected personal characteristics other than race/ethnicityClick here for fileTable 4 - Association of selected personal characteristics with dietary supplement use by white, nonHispanic women aged 65–84Click here for fileTable 5 - Results of multiple logistic regression models predicting dietary supplement use by white, nonHispanic women aged 65–84Click here for file