On the epidemiology of 'mysterious' phenomena.

In the field of epidemiology, research topics are favored or dismissed depending on whether respective variables under investigation are believed to exist according to current scientific theories. Unconventional independent variables or exposures, such as religiousness and spirituality, and controversial dependent variables or outcomes, such as chronic fatigue syndrome, may be considered unacceptable topics for researchers because they do not fit comfortably into the consensus clinical perspectives of mainstream medical scientists or physicians. Disapproval of research in these and other taboo areas is generally masked by claims that such studies are "pseudoscientific," despite hundreds or thousands of peer-reviewed publications on these topics. In reality, seemingly "mysterious" variables are equally as amenable to epidemiologic research as any other exposure or disease. Similarly, alternative therapies are able to be investigated using existing methods, despite claims to the contrary. Such research is vital for scientific understanding to be expanded into new areas of inquiry.

Quantitative methods in research on complementary and alternative medicine. A methodological manifesto. NIH Office of Alternative Medicine.

OBJECTIVES: This article summarizes the deliberations of the Quantitative Methods Working Group convened by the National Institutes of Health (NIH) in support of the NIH Office of Alternative Medicine. METHODS: The working group was charged with identifying methods of study design and data analysis that can be applied to empirical research on complementary and alternative medicine. This charge was broad and inclusive and addressed the evaluation of alternative therapies, the investigation of the basic science of complementary medical systems, studies of health promotion and disease prevention, and health services research. RESULTS: The working group produced a "methodological manifesto," a summary list of seven recommended methodological guidelines for research on alternative medicine. These recommendations emphasize the robustness of existing research methods and analytic procedures despite the substantive unconventionality of alternative medicine. CONCLUSIONS: Contrary to the assertions of many researchers and alternative practitioners, established methodologies (eg, experimental trials, observational epidemiology, social survey research) and data-analytic procedures (eg, analysis of variance, logistic regression, multivariate modeling techniques) are quite satisfactory for addressing the majority of study questions related to alternative medicine, from clinical research on therapeutic efficacy to basic science research on mechanisms of pathogenesis and recovery.

Acquired resistance of Nocardia brasiliensis to clavulanic acid related to a change in beta-lactamase following therapy with amoxicillin-clavulanic acid.

Previous studies have demonstrated that Nocardia brasiliensis is susceptible to amoxicillin-clavulanic acid and that its beta-lactamases are inhibited in vitro by clavulanic acid. A cardiac transplant patient with disseminated infection caused by N. brasiliensis was treated with this drug combination with good response, but relapsed while still on therapy. The relapse isolate was found to be identical to the initial isolate by using genomic DNA restriction fragment patterns obtained by pulsed field gel electrophoresis, but it was resistant to amoxicillin-clavulanic acid. On isoelectric focusing, the beta-lactamase from the relapse isolate exhibited a shift in the isoelectric point (pI) of its major band from 5.10 to 5.04 compared with the enzyme from the pretreatment isolate. As determined by using values of the amount of beta-lactamase inhibitor necessary to give 50 +/- 5% inhibition of beta-lactamase-mediated hydrolysis of 50 microM nitrocefin, the beta-lactamase of the relapse isolate was also 200-fold more resistant than the enzyme from the pretreatment isolate to clavulanic acid and was more resistant to sulbactam, tazobactam, cloxacillin, and imipenem. The beta-lactamase of the relapse isolate exhibited a 10-fold decrease in hydrolytic activity for cephaloridine and other hydrolyzable cephalosporins compared with that for nitrocefin. Acquired resistance to amoxicillin-clavulanic acid in this isolate of N. brasiliensis appears to have resulted from a mutational change affecting the inhibitor and active site(s) in the beta-lactamase.

Activities of ciprofloxacin and ofloxacin against rapidly growing mycobacteria with demonstration of acquired resistance following single-drug therapy.

The susceptibility to ciprofloxacin of 548 clinical isolates of rapidly growing mycobacteria belonging to eight subgroups or species was determined. The 170 isolates of Mycobacterium fortuitum biovar.fortuitum were most susceptible; the MIC for 90% of the organisms was 0.125 micrograms/ml. The other biovariants of M. fortuitum, M. smegmatis, and the M. chelonae-like organisms were less susceptible; the modal MIC was 0.5 micrograms/ml, and the MIC for 90% of organisms was 1.0 micrograms/ml. The two subspecies of M. chelonae were generally resistant, with only 8% of 206 isolates falling in the moderately susceptible category (MIC, 2 micrograms/ml) and only 2% falling in the susceptible category (MIC, less than or equal to 1 micrograms/ml). MICs of ofloxacin averaged 1 to 2 dilutions higher than those of ciprofloxacin for all subgroups tested. Three patients with M. fortuitum cutaneous disease relapsed after an initial response to therapy with ciprofloxacin, and their isolate was shown to have acquired drug resistance. Mutational frequencies for M. fortuitum with ciprofloxacin were relatively high (10(-5) to 10(-7), and MICs for single-step mutants were similar to those for the clinically resistant strains. Thus, despite the excellent activity of ciprofloxacin against rapidly growing mycobacterial groups other than M. chelonae, single-drug therapy should be used with caution because of the risk of development of mutational resistance.

Sulfonamide-containing regimens for disease caused by rifampin-resistant Mycobacterium kansasii.

Fourteen wild strains and 14 relapse or treatment failure isolates of Mycobacterium kansasii were tested and found to be highly susceptible to sulfamethoxazole (SMX), with 26 of 28 isolates having minimal inhibitory concentrations (MIC) of less than or equal to 4 micrograms/ml), using a broth microdilution method. Treatment failure isolates frequently exhibited resistance to rifampin (RMP) (greater than 2 micrograms/ml), isoniazid (INH) (greater than 4 micrograms/ml), and ethambutol (EMB) (greater than 4 micrograms/ml) not seen among the wild strain isolates. Eight patients with cavitary disease caused by RMP-resistant M. kansasii were treated with SMX-containing regimens that also included high dose INH (900 mg), EMB (25 mg/kg), and an aminoglycoside (either streptomycin or amikacin). Patients were treated initially in the hospital for 4 to 10 wk. In 7 of the 8 patients, sputum cultures became negative in a mean of 10 wk (range, 7 to 14 wk). Acquired drug resistance to INH, RMP, and EMB can be demonstrated in M. kansasii, and SMX in combination with other agents chosen on the basis of MIC determinations are effective in the treatment of disease caused by RMP-resistant M. kansasii.

Relationships between behavioral rhythms, plasma corticosterone and hypothalamic circadian rhythms.

Circadian rhythms in physiological processes and behaviors were compared with hypothalamic circadian rhythms in norepinephrine (NE) metabolites, adrenergic transmitter receptors, cAMP, cGMP and suprachiasmatic nucleus (SCN) arginine vasopressin (AVP) in a single population of rats under D:D conditions. Eating, drinking and locomotor activity were high during the subjective night (the time when lights were out in L:D) and low during the subjective day (the time when lights were on in L:D). Plasma corticosterone concentration rose at subjective dusk and remained high until subjective dawn. Binding to hypothalamic alpha 1- and beta-adrenergic receptors also peaked during the subjective night. Cyclic cGMP concentration was elevated throughout the 24-hr period except for a trough at dusk, whereas DHPG concentration peaked at dawn. Arginine vasopressin levels in the suprachiasmatic nucleus peaked in the middle of the day. No rhythm was found either in binding to the alpha 2-adrenergic receptor, or in MHPG or cAMP concentration. Behavioral and corticosterone rhythms, therefore, are parallel to rhythms in hypothalamic alpha 1- and beta-receptor binding and NE-release. Cyclic GMP falls only at dusk, suggesting the possibility that cGMP inhibits activity much of the day and that at dusk the inhibition of nocturnal activity is removed. SCN AVP, on the other hand, peaking at 1400 hr, may play a role in the pacemaking function of the SCN that drives these other rhythms.