Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design.

Voltage-gated sodium channels (Navs) are responsible for the initiation of the action potential in excitable cells. Several prokaryotic sodium channels, most notably NavMs from Magnetococcus marinus and NavAb from Arcobacter butzleri, have been shown to be good models for human sodium channels based on their sequence homologies and high levels of functional similarities, including ion flux, and functional consequences of critical mutations. The complete full-length crystal structures of these prokaryotic sodium channels captured in different functional states have now revealed the molecular natures of changes associated with the gating process. These include the structures of the intracellular gate, the selectivity filter, the voltage sensors, the intra-membrane fenestrations, and the transmembrane (TM) pore. Here we have identified for the first time how changes in the fenestrations in the hydrophobic TM region associated with the opening of the intracellular gate could modulate the state-dependent ingress and binding of drugs in the TM cavity, in a way that could be exploited for rational drug design.

The complete structure of an activated open sodium channel.

Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with their activation and opening resulting in the initial phase of the action potential. The cycling of Navs through open, closed and inactivated states, and their closely choreographed relationships with the activities of other ion channels lead to exquisite control of intracellular ion concentrations in both prokaryotes and eukaryotes. Here we present the 2.45 Å resolution crystal structure of the complete NavMs prokaryotic sodium channel in a fully open conformation. A canonical activated conformation of the voltage sensor S4 helix, an open selectivity filter leading to an open activation gate at the intracellular membrane surface and the intracellular C-terminal domain are visible in the structure. It includes a heretofore unseen interaction motif between W77 of S3, the S4-S5 interdomain linker, and the C-terminus, which is associated with regulation of opening and closing of the intracellular gate.

Practice patterns of naturopathic physicians: results from a random survey of licensed practitioners in two US States.

BACKGROUND: Despite the growing use of complementary and alternative medicine (CAM) by consumers in the U.S., little is known about the practice of CAM providers. The objective of this study was to describe and compare the practice patterns of naturopathic physicians in Washington State and Connecticut. METHODS: Telephone interviews were conducted with state-wide random samples of licensed naturopathic physicians and data were collected on consecutive patient visits in 1998 and 1999. The main outcome measures were: Sociodemographic, training and practice characteristics of naturopathic physicians; and demographics, reasons for visit, types of treatments, payment source and visit duration for patients. RESULT: One hundred and seventy practitioners were interviewed and 99 recorded data on a total of 1817 patient visits. Naturopathic physicians in Washington and Connecticut had similar demographic and practice characteristics. Both the practitioners and their patients were primarily White and female. Almost 75% of all naturopathic visits were for chronic complaints, most frequently fatigue, headache, and back symptoms. Complete blood counts, serum chemistries, lipids panels and stool analyses were ordered for 4% to 10% of visits. All other diagnostic tests were ordered less frequently. The most commonly prescribed naturopathic therapeutics were: botanical medicines (51% of visits in Connecticut, 43% in Washington), vitamins (41% and 43%), minerals (35% and 39%), homeopathy (29% and 19%) and allergy treatments (11% and 13%). The mean visit length was about 40 minutes. Approximately half the visits were paid directly by the patient. CONCLUSION: This study provides information that will help other health care providers, patients and policy makers better understand the nature of naturopathic care.

Characteristics of visits to licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians.

BACKGROUND: Despite growing popularity of complementary and alternative medical (CAM) therapies, little is known about the patients seen by CAM practitioners. Our objective was to describe the patients and problems seen by CAM practitioners. METHODS: We collected data on 20 consecutive visits to randomly sampled licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians practicing in Arizona, Connecticut, Massachusetts, and Washington. Data were collected on patient demographics, smoking status, referral source, reasons for visit, concurrent medical care, payment source, and visit duration. Comparative data for conventional physicians were drawn from the National Ambulatory Medical Care Survey. RESULTS: In each profession, at least 99 practitioners collected data on more than 1,800 visits. More than 80% of visits to CAM providers were by young and middle-aged adults, and roughly two thirds were by women. Children comprised 10% of visits to naturopathic physicians but only 1% to 4% of all visits to other CAM providers. At least two thirds of visits resulted from self-referrals, and only 4% to 12% of visits were from conventional physician referrals. Chiropractors and massage therapists primarily saw musculoskeletal problems, while acupuncturists and naturopathic physicians saw a broader range of conditions. Visits to acupuncturists and massage therapists lasted about 60 minutes compared with 40 minutes for naturopathic physicians and less than 20 minutes for chiropractors. Most visits to chiropractors and naturopathic physicians, but less than one third of visits to acupuncturists and massage therapists, were covered by insurance. CONCLUSIONS: This information will help inform discussions of the roles CAM practitioners will play in the health care system of the future.

Characteristics of licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians.

BACKGROUND: Despite the growing popularity of complementary and alternative medical (CAM) therapies, little is known about the professionals who provide them. Our objective was to describe the characteristics of the four largest groups of licensed CAM providers in the United States and to compare them with the characteristics of conventional physicians. METHODS: Random statewide samples of licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians living in Arizona, Connecticut, Massachusetts and Washington were interviewed by telephone. Sociodemographic, training, and practice characteristics of CAM providers were elicited and compared with data on conventional physicians published by the American Medical Association. RESULTS: More than 160 providers in each profession were interviewed. Participation rates ranged between 78% and 94% except for Arizona chiropractors (61%). The proportion of female respondents was highest for massage therapy (85%) and acupuncture and naturopathy (almost 60%) and was lowest for chiropractic (about 25%) and conventional medicine (23%). Except for acupuncturists, only 5% of CAM providers were nonwhite. CAM providers were more likely than conventional physicians to practice solo (51%-74% vs 26%, respectively), and less than 10% practiced with medical physicians. Massage therapists saw the fewest patients per week (about 14), and chiropractors and conventional physicians the most (about 100). Chiropractors and conventional physicians saw about 3 patients per hour compared with roughly 1 patient per hour for the other CAM professions. Interstate differences were small. CONCLUSIONS: This characterization of CAM providers will help inform decisions about the future role of CAM providers in the health care system.