High throughput crystallography of TB drug targets.

Tuberculosis (TB) infects one-third of the world population. Despite 50 years of available drug treatments, TB continues to increase at a significant rate. The failure to control TB stems in part from the expense of delivering treatment to infected individuals and from complex treatment regimens. Incomplete treatment has fueled the emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis (Mtb). Reducing non-compliance by reducing the duration of chemotherapy will have a great impact on TB control. The development of new drugs that either kill persisting organisms, inhibit bacilli from entering the persistent phase, or convert the persistent bacilli into actively growing cells susceptible to our current drugs will have a positive effect. We are taking a multidisciplinary approach that will identify and characterize new drug targets that are essential for persistent Mtb. Targets are exposed to a battery of analyses including microarray experiments, bioinformatics, and genetic techniques to prioritize potential drug targets from Mtb for structural analysis. Our core structural genomics pipeline works with the individual laboratories to produce diffraction quality crystals of targeted proteins, and structural analysis will be completed by the individual laboratories. We also have capabilities for functional analysis and the virtual ligand screening to identify novel inhibitors for target validation. Our overarching goals are to increase the knowledge of Mtb pathogenesis using the TB research community to drive structural genomics, particularly related to persistence, develop a central repository for TB research reagents, and discover chemical inhibitors of drug targets for future development of lead compounds.

Perceptions about complementary therapies relative to conventional therapies among adults who use both: results from a national survey.

BACKGROUND: Little is known about perceptions of complementary and alternative medical (CAM) therapy relative to conventional therapy among patients who use both. OBJECTIVE: To document perceptions about CAM therapies among persons who use CAM and conventional therapies. DESIGN: Nationally representative, random-household telephone survey. SETTING: The 48 contiguous U.S. states. PARTICIPANTS: 831 adults who saw a medical doctor and used CAM therapies in 1997. MEASUREMENTS: Perceptions about helpfulness and patterns of CAM therapy use relative to conventional therapy use and reasons for nondisclosure of CAM therapies. RESULTS: Of 831 respondents who saw a medical doctor and used CAM therapies in the previous 12 months, 79% perceived the combination to be superior to either one alone. Of 411 respondents who reported seeing both a medical doctor and a CAM provider, 70% typically saw a medical doctor before or concurrent with their visits to a CAM provider; 15% typically saw a CAM provider before seeing a medical doctor. Perceived confidence in CAM providers was not substantially different from confidence in medical doctors. Among the 831 respondents who in the past year had used a CAM therapy and seen a medical doctor, 63% to 72% did not disclose at least one type of CAM therapy to the medical doctor. Among 507 respondents who reported their reasons for nondisclosure of use of 726 alternative therapies, common reasons for nondisclosure were "It wasn't important for the doctor to know" (61%), "The doctor never asked" (60%), "It was none of the doctor's business" (31%), and "The doctor would not understand" (20%). Fewer respondents (14%) thought their doctor would disapprove of or discourage CAM use, and 2% thought their doctor might not continue as their provider. Respondents judged CAM therapies to be more helpful than conventional care for the treatment of headache and neck and back conditions but considered conventional care to be more helpful than CAM therapy for treatment of hypertension. CONCLUSIONS: National survey data do not support the view that use of CAM therapy in the United States primarily reflects dissatisfaction with conventional care. Adults who use both appear to value both and tend to be less concerned about their medical doctor's disapproval than about their doctor's inability to understand or incorporate CAM therapy use within the context of their medical management.

Varieties of healing. 1: medical pluralism in the United States.

Medicine has become interested in unconventional healing practices, ostensibly because of recent demographic research that reveals a thriving medical market of multiple options. This essay presents a historical overview of medical pluralism in the United States. Consistent evidence is examined suggesting that unconventional medicine has been a persistent presence in U.S. health care. Despite parallels with the past, the recent widespread interest in alternative medicine also represents a dramatic reconfiguration of medical pluralism-from historical antagonism to what might arguably be described as a topical acknowledgment of postmodern medical diversity. This recent shift may have less to do with acknowledging "new" survey data than with representing shifts in medicine's institutional authority in a consumer-driven health care environment. This essay is an introduction to a discussion of a taxonomy of contemporary U.S. medical pluralism, which also appears in this issue.

Varieties of healing. 2: a taxonomy of unconventional healing practices.

The first of two essays in this issue demonstrated that the United States has had a rich history of medical pluralism. This essay seeks to present an overview of contemporary unconventional medical practices in the United States. No clear definition of "alternative medicine" is offered because it is a residual category composed of heterogeneous healing methods. A descriptive taxonomy of contemporary unconventional healing could be more helpful. Two broad categories of unconventional medicine are described here: a more prominent, "mainstream" complementary and alternative medicine (CAM) and a more culture-bound, "parochial" unconventional medicine. The CAM component can be divided into professional groups, layperson-initiated popular health reform movements, New Age healing, alternative psychological therapies, and non-normative scientific enterprises. The parochial category can be divided into ethno-medicine, religious healing, and folk medicine. A topologic examination of U.S. health care can provide an important conceptual framework through which health care providers can understand the current situation in U.S. medical pluralism.

Long-term trends in the use of complementary and alternative medical therapies in the United States.

BACKGROUND: Although recent research has shown that many people in the United States use complementary and alternative medical (CAM) therapies, little is known about time trends in use. OBJECTIVE: To present data on time trends in CAM therapy use in the United States over the past half-century. DESIGN: Nationally representative telephone survey of 2055 respondents that obtained information on current use, lifetime use, and age at first use for 20 CAM therapies. SETTING: The 48 contiguous U.S. states. PARTICIPANTS: Household residents 18 years of age and older. MEASUREMENT: Retrospective self-reports of age at first use for each of 20 CAM therapies. RESULTS: Previously reported analyses of these data showed that more than one third of the U.S. population was currently using CAM therapy in the year of the interview (1997). Subsequent analyses of lifetime use and age at onset showed that 67.6% of respondents had used at least one CAM therapy in their lifetime. Lifetime use steadily increased with age across three age cohorts: Approximately 3 of every 10 respondents in the pre-baby boom cohort, 5 of 10 in the baby boom cohort, and 7 of 10 in the post-baby boom cohort reported using some type of CAM therapy by age 33 years. Of respondents who ever used a CAM therapy, nearly half continued to use many years later. A wide range of individual CAM therapies increased in use over time, and the growth was similar across all major sociodemographic sectors of the study sample. CONCLUSIONS: Use of CAM therapies by a large proportion of the study sample is the result of a secular trend that began at least a half century ago. This trend suggests a continuing demand for CAM therapies that will affect health care delivery for the foreseeable future.

The crystal structure of phosphinothricin in the active site of glutamine synthetase illuminates the mechanism of enzymatic inhibition.

Phosphinothricin is a potent inhibitor of the enzyme glutamine synthetase (GS). The resolution of the native structure of GS from Salmonella typhimurium has been extended to 2.5 A resolution, and the improved model is used to determine the structure of phosphinothricin complexed to GS by difference Fourier methods. The structure suggests a noncovalent, dead-end mechanism of inhibition. Phosphinothricin occupies the glutamate substrate pocket and stabilizes the Glu327 flap in a position which blocks the glutamate entrance to the active site, trapping the inhibitor on the enzyme. One oxygen of the phosphinyl group of phosphinothricin appears to be protonated, because of its proximity to the carboxylate group of Glu327. The other phosphinyl oxygen protrudes into the negatively charged binding pocket for the substrate ammonium, disrupting that pocket. The distribution of charges in the glutamate binding pocket is complementary to those of phosphinothricin. The presence of a second ammonium binding site within the active site is confirmed by its analogue thallous ion, marking the ammonium site and its protein ligands. The inhibition of GS by methionine sulfoximine can be explained by the same mechanism. These models of inhibited GS further illuminate its catalytic mechanism.

Randomized trial comparing traditional Chinese medical acupuncture, therapeutic massage, and self-care education for chronic low back pain.

BACKGROUND: Because the value of popular forms of alternative care for chronic back pain remains uncertain, we compared the effectiveness of acupuncture, therapeutic massage, and self-care education for persistent back pain. METHODS: We randomized 262 patients aged 20 to 70 years who had persistent back pain to receive Traditional Chinese Medical acupuncture (n = 94), therapeutic massage (n = 78), or self-care educational materials (n = 90). Up to 10 massage or acupuncture visits were permitted over 10 weeks. Symptoms (0-10 scale) and dysfunction (0-23 scale) were assessed by telephone interviewers masked to treatment group. Follow-up was available for 95% of patients after 4, 10, and 52 weeks, and none withdrew for adverse effects. RESULTS: Treatment groups were compared after adjustment for prerandomization covariates using an intent-to-treat analysis. At 10 weeks, massage was superior to self-care on the symptom scale (3.41 vs 4.71, respectively; P =.01) and the disability scale (5.88 vs 8.92, respectively; P<.001). Massage was also superior to acupuncture on the disability scale (5.89 vs 8.25, respectively; P =.01). After 1 year, massage was not better than self-care but was better than acupuncture (symptom scale: 3.08 vs 4.74, respectively; P =.002; dysfunction scale: 6.29 vs 8.21, respectively; P =.05). The massage group used the least medications (P<.05) and had the lowest costs of subsequent care. CONCLUSIONS: Therapeutic massage was effective for persistent low back pain, apparently providing long-lasting benefits. Traditional Chinese Medical acupuncture was relatively ineffective. Massage might be an effective alternative to conventional medical care for persistent back pain.

Inability of an "energy transfer diagnostician" to distinguish between fertile and infertile women.

CONTEXT: Various forms of "energy healing" have become popular in the United States. OBJECTIVE: To test the assertion that an energy healer can, without physical contact, distinguish the presence or absence of internal organ pathology in individuals who lack overt physical findings. DESIGN: Observational randomized study, in which we tested the assertion by a well-recognized alternative healer that he had particular skill in using energy transfer to detect the presence or absence of fertility disorders in women. PATIENTS: Convenience sample of 37 women, 28 of whom had documented pathology resulting in infertility, and 9 of whom were fertile. OUTCOMES: The healer was provided with no medical history and performed diagnostic evaluations without physical contact with the blindfolded, clothed, and silent subjects. We compared to random chance the ability of the healer to establish a diagnosis of fertility or fertility disorder. SETTING: Teaching hospital. MAIN RESULTS: The healer was unable to distinguish the presence or absence of fertility disorders in the study subjects. CONCLUSION: This study points to further need for fair yet rigorous assessment of claims that energy transfer can lead to accurate clinical diagnoses.

The use of complementary and alternative therapies to treat anxiety and depression in the United States.

OBJECTIVE: This study presents data on the use of complementary and alternative therapies to treat anxiety and depression in the United States. METHOD: The data came from a nationally representative survey of 2,055 respondents (1997-1998) that obtained information on the use of 24 complementary and alternative therapies for the treatment of specific chronic conditions. RESULTS: A total of 9.4% of the respondents reported suffering from "anxiety attacks" in the past 12 months; 7.2% reported "severe depression." A total of 56.7% of those with anxiety attacks and 53.6% of those with severe depression reported using complementary and alternative therapies to treat these conditions during the past 12 months. Only 20.0% of those with anxiety attacks and 19.3% of those with severe depression visited a complementary or alternative therapist. A total of 65.9% of the respondents seen by a conventional provider for anxiety attacks and 66.7% of those seen by a conventional provider for severe depression also used complementary and alternative therapies to treat these conditions. The perceived helpfulness of these therapies in treating anxiety and depression was similar to that of conventional therapies. CONCLUSIONS: Complementary and alternative therapies are used more than conventional therapies by people with self-defined anxiety attacks and severe depression. Most patients visiting conventional mental health providers for these problems also use complementary and alternative therapies. Use of these therapies will likely increase as insurance coverage expands. Asking patients about their use could prevent adverse effects and maximize the usefulness of therapies subsequently proven to be effective.

Alternative medicine use in older Americans.

OBJECTIVES: Because there are few data describing alternative medicine use in older populations, we analyzed a nationally representative survey to quantify and characterize the use of alternative medicine in people aged 65 and older. DESIGN: We utilized data collected in a nationally representative, random, telephone survey of adults, measuring use of conventional medical services and use of 20 alternative medicine therapies in the last 12 months. PARTICIPANTS: A total of 2,055 adults, 311 of whom were aged 65 and older and who constituted our sample of older Americans. RESULTS: Overall, 30% of people aged 65 and older used at least one alternative medicine modality in the last year compared with 46% of those less than age 65 (P < .001), and 19% of older people saw a provider of alternative medicine within the past year compared with 26% of those less than age 65. The alternative medicine modalities used most commonly by those aged 65 and older were chiropractic (11%), herbal remedies (8%), relaxation techniques (5%), high dose or mega-vitamins (5%), and religious or spiritual healing by others (4%). Older persons with a primary care provider used alternative medicine more frequently (34% vs 7% P < .05) than those with no primary care provider. Patients who saw their physician more frequently were more likely to use alternative medicine (0 visits 7%, 1-2 visits 22%, 3-6 visits 35%, 7 or more visits 44% P < .05). Six percent of older patients were taking both herbs and prescription drugs. Of older patients who used alternative medicine, 57% made no mention of their use of any alternative modality to their doctor. CONCLUSIONS: Thirty percent of Americans aged 65 and older reported using alternative medicine (amounting to 10 million Americans based on extrapolations to census data) and 19% visited an alternative medicine provider (making 63 million visits based on extrapolations to census data) within the past year. The two modalities used most commonly were chiropractic and herbs, both of which may be problematic in older patients. Physicians should ask all patients, including those aged 65 and older, about their use of alternative medicine, and in those aged 65 and older, physicians should ask specific questions about the user of chiropractic and herbal medicine.

Use of complementary medicine by adult patients participating in HIV/AIDS clinical trials.

OBJECTIVE: To identify and characterize patterns of use of complementary and alternative (CAM) therapies by human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients participating in clinical trials in a research setting. DESIGN: A descriptive survey using a nonrandom sample of 100 patients was conducted over 17 months, using a 99-item interview schedule adapted from a previous study. SETTING: National Institutes of Health (NIH) Warren G. Magnuson Clinical Center. SUBJECTS: Patients diagnosed with HIV/AIDS, participating in clinical research protocols at the National Institute of Allergy and Infectious Diseases and the National Cancer institute (NCI) at the NIH. RESULTS: Ninety-one percent (91%) had used at least one CAM therapy, as defined by a 1993 study by Eisenberg et al., sometime in their lives. Postdiagnosis, 84% used at least one CAM therapy with an average of just fewer than 5. The increase in frequency of use from 64% prediagnosis was significant (P2 = 0.019). Therapies that became significantly more popular postdiagnosis were, imagery (P2 = 0.00012), high-dose vitamins, (P2 = 0.000019), weight gain (p2 = 0.000244), massage (p2 = 0.00091), relaxation (p2 = 0.0033), herbals (p2 = 0.013), spiritual (p2 = 0.024), and acupuncture (p2 = 0.035). They were primarily used for HIV/AIDS-related problems: dermatological, nausea, depression, insomnia, and weakness. There was a high level of agreement that benefits of CAM use were: feeling better, 51 (98.1%), increased coping, 52 (100%), feeling in control, 44 (88.5%), and enhanced treatment outcome, 49 (94.2%) with 32 (61%) stating CAM was as, or more effective than conventional treatment. Fifty-three percent (53%) were specifically asked by physicians whether they were using adjunct therapies. CONCLUSIONS: Subjects used a variety of CAM therapies to cope with their diseases and rigors of treatment and clinical trials. Further research is needed to identify CAM therapies that may be used as adjunct treatments during clinical trials.

Use of complementary medicine by adult patients participating in cancer clinical trials.

PURPOSE/OBJECTIVES: To document the prevalence, demographic correlates, patterns of use, and beliefs about complementary and alternative medicine (CAM) therapies of adult patients enrolled in National Cancer Institute (NCI) clinical trials. DESIGN: Prospective, cross-sectional, descriptive survey. SETTING: W.G. Magnuson Clinical Center of the National Institutes of Health in Bethesda, MD. SAMPLE: Convenience sample of 100 English-speaking, adult patients with cancer admitted to intramural clinical trials. METHODS: A standardized, 99-item questionnaire assessing use of CAM therapies pre- and postcancer diagnosis was administered by face-to-face interview. MAIN RESEARCH VARIABLES: Use of CAM therapies, beliefs, communication with physician. FINDINGS: 63% used at least one CAM therapy, with an average use of two therapies per patient. Men were significantly less likely to use a therapy than women; women were more likely to use numerous therapies. Cancer diagnosis seems to have had no influence overall on the frequency of use of CAM therapies. The major reasons stated for CAM use were for treatment-related medical conditions as well as depression, anxiety, and insomnia. The most frequently reported therapies were spiritual, relaxation, imagery, exercise, lifestyle diet (e.g., macrobiotic, vegetarian), and nutritional supplementation. Patients unanimously believed that these complementary therapies helped to improve their quality of life through more effective coping with stress, decreasing the discomforts of treatment and illness, and giving them a sense of control. CONCLUSIONS: Patients with cancer use various complementary therapies to cope with their disease and the rigors of clinical trials. Women and those with higher educational backgrounds were more frequent users. IMPLICATIONS FOR NURSING PRACTICE: Nurses who provide care to subjects of biomedical research have an opportunity and responsibility regarding their patients' use of CAM therapies. Nurses may use in-house resources to help evaluate subjects' use of a CAM modality or to provide quality-of-life therapies such as relaxation, imagery, or healing touch. Discussing these health practices in a nonjudgmental manner adds to the assessment of patients' coping skills and ability to make decisions about their health care.

Alternative therapies used by women with breast cancer in four ethnic populations.

BACKGROUND: Interest in alternative therapies is growing rapidly in the United States. We studied the types and prevalence of conventional and alternative therapies used by women in four ethnic groups (Latino, white, black, and Chinese) diagnosed with breast cancer from 1990 through 1992 in San Francisco, CA, and explored factors influencing the choices of their therapies. METHODS: Subjects (n = 379) completed a 30-minute telephone interview in their preferred language. Logistic regression models assessed factors associated with the use of alternative therapies after a diagnosis of breast cancer. RESULTS: About one half of the women used at least one type of alternative therapy, and about one third used two types; most therapies were used for a duration of less than 6 months. Both the alternative therapies used and factors influencing the choice of therapy varied by ethnicity. Blacks most often used spiritual healing (36%), Chinese most often used herbal remedies (22%), and Latino women most often used dietary therapies (30%) and spiritual healing (26%). Among whites, 35% used dietary methods and 21% used physical methods, such as massage and acupuncture. In general, women who had a higher educational level or income, were of younger age, had private insurance, and exercised or attended support groups were more likely to use alternative therapies. About half of the women using alternative therapies reported discussing this use with their physicians. More than 90% of the subjects found the therapies helpful and would recommend them to their friends. CONCLUSIONS: Given the high prevalence of alternative therapies used in San Francisco by the four ethnic groups and the relatively poor communication between patients and doctors, physicians who treat patients with breast cancer should initiate dialogues on this topic to better understand patients' choices with regard to treatment options.

Talking with patients about alternative and complementary medicine.

The growing use of alternative and complementary therapies in the United States as well as other parts of the world is a trend that the responsible rheumatologist cannot ignore. With chronic musculoskeletal conditions being the leading indication for the use of alternative and complementary therapies, rheumatologists must become experts on talking to patients and advising them about the use or avoidance of such therapies. Currently, there is a growing body of literature on the safety and efficacy of the multiple alternative and complementary therapies available. Much of this information is reliable and of high methologic quality; however, much of it is not. With an increase in the budget of the Office of Alternative Medicine from $20 to $50 million in 1999 and the status of the office changing to an independent center, an important step has been taken to try to assure improved research in the near future to validate or disprove many of the current alternative and complementary therapies. In the meantime, our patients are using these therapies and are likely to continue to do so, with or without our guidance. We must get beyond the "don't ask, don't tell" approach that characterizes many physicians' attitudes toward the subject of alternative and complementary therapies. Although all discussions need not end in agreement, they are still opportunities for shared decision making and "relationship-centered care." Ultimately, we should not be concerned with practicing what is perceived to be traditional versus alternative and complementary medicine or biomedicine versus naturalistic medicine but only with what is truly "good" medicine.

Physician-patient communication about complementary and alternative medical therapies: a survey of physicians caring for patients with human immunodeficiency virus infection.

OBJECTIVE: To examine frequency and correlates of physicians' reports of discussions with patients with human immunodeficiency virus (HIV) about complementary and alternative medical (CAM) therapies. DESIGN: Mailed physician survey. SETTING: The setting was Eastern Massachusetts. PARTICIPANTS: Participants included 89 physicians caring for patients with HIV. MEASUREMENTS AND MAIN RESULTS: Physicians were asked how common the use of CAM therapies was among their patients, how useful these therapies were, how often they discussed the use of CAM therapies with new and follow-up patients, and whether they had used a CAM therapy themselves in the last year. We also collected information on physicians' sociodemographic and practice characteristics. Sixty-eight percent (89/130) of physicians responded, and 26% and 5% reported discussing CAM therapies with HIV-infected patients at most new and follow-up visits, respectively. Respondents' attitudes toward the use of CAM therapies were generally positive, and they believed their HIV-infected patients used CAM therapies more than their non-HIV infected patients. The majority (63%) believed that CAM therapies may be helpful for HIV-infected patients. Thirty-six percent (36%) had used a CAM therapy themselves in the last year. In multivariate analyses, only the belief that CAM therapies are helpful was correlated with discussion of CAM therapies (p = 0.006). Respondents' demographic characteristics, training, personal use of CAM therapies, reported visit length, and satisfaction with visit length were not associated with discussion of CAM therapies. CONCLUSIONS: Despite awareness that their HIV-infected patients commonly use CAM therapies and positive attitudes towards such therapies, most of these physicians did not routinely discuss CAM therapies with them. Barriers to physician-patient communication about CAM therapies merit further investigation.