Kappa Delta Award paper. Osteoregulatory nature of mechanical stimuli: function as a determinant for adaptive remodeling in bone

The capacity for functional adaptation within the skeleton was studied using the functionally isolated turkey ulna preparation. The results of this study would suggest that adaptive bone remodeling is extremely sensitive to alterations in both the magnitude and distribution of the strain generated within the bone tissue. At present, it appears that a loading regime can only influence bone remodeling when it is dynamic in nature. The full osteogenic potential of its influence is then achieved after only an extremely short exposure to this stimulus. The potency of the stimulus appears to be proportional to the magnitude of the strain engendered. As strain levels that are acceptable in one location induce adaptive remodeling in others, it would appear that each region of each bone is "genetically programmed" to accept a particular amount and pattern of intermittent strain as "normal." Deviation from this "optimal strain environment" will stimulate changes in the bone's remodeling balance, resulting in adaptive increases or decreases in its mass.     

The Mexican asthma cure. Systemic steroids for gullible gringos

Asthmatic patients from western Canada and the United States have reported that after visits to an asthma clinic in Mexicali, Mexico, they return home substantially improved or cured having received "a bronchodilator medication unavailable in the United States or Canada because of the big drug companies." Analysis of these medications reveals that the most commonly prescribed combination is the glucocorticoid triamcinolone (unscored white tablets) and the antihistamine chlorpheniramine (coated biconvex orange or red tablets). Occasionally benzodiazepines are added to these medications. The patients are assured that the medications which they have been given are free of side effects and specifically, that corticosteroids are not used. Such therapy is dangerous to the patient who not only is unaware of the medications that he or she is taking, but is unlikely to mention this therapy to his or her physician. These patients risk drug interactions, medication side effects, and the possibility of adrenal failure either with a stress to their system or on withdrawal of drug treatment. Patients are also at risk of abandoning safer forms of asthma therapy for the miracle cure. We, too, are partially responsible for these unethical practices by avoiding the use of steroids and undertreating our patients at times, leaving them unnecessarily restricted and eager for any form of relief.     

Analysis of cis-acting requirements of the Rh3 and Rh4 genes reveals a bipartite organization to rhodopsin promoters in Drosophila melanogaster

The rhodopsin genes of Drosophila melanogaster are expressed in nonoverlapping subsets of photoreceptor cells within the insect visual system. Two of these genes, Rh3 and Rh4, are known to display complementary expression patterns in the UV-sensitive R7 photoreceptor cell population of the compound eye. In addition, we find that Rh3 is expressed in a small group of paired R7 and R8 photoreceptor cells at the dorsal eye margin that are apparently specialized for the detection of polarized light. In this paper we present a detailed characterization of the cis-acting requirements of both Rh3 and Rh4. Promoter deletion series demonstrate that small regulatory regions (less than 300 bp) of both R7 opsin genes contain DNA sequences sufficient to generate their respective expression patterns. Individual cis-acting elements were further identified by oligonucleotide-directed mutagenesis guided by interspecific sequence comparisons. Our results suggest that the Drosophila rhodopsin genes share a simple bipartite promoter structure, whereby the proximal region constitutes a functionally equivalent promoter "core" and the distal region determines cell-type specificity. The expression patterns of several hybrid rhodopsin promoters, in which all or part of the putative core regions have been replaced with the analogous regions of different rhodopsin promoters, provide additional evidence in support of this model.     

Original article: Effects of Raised Extracellular Magnesium on Platelet Reactivity

The inhibitory effects on platelet reactivity of increased extracellular magnesium were investigated. Wherever possible, experiments were performed in hirudinized whole blood. Concentration dependent inhibition of platelet aggregation and dense granule release were observed with MgSO(4). Antiaggregatory effects were identical with MgCl(2), indicating that the effects are due to the Mg(2+) ion. Antiaggregatory effects of CaCl(2), differed from those of MgCl(2), indicating that this is not a non-specific divalent cation effect. MgSO(4) also caused concentration-dependent inhibition of platelet thromboxane production. Experiments in the presence of apyrase and indomethacin showed that complex formation with ADP and inhibition of cyclo-oxygenase do not entirely account for the inhibitory effect of magnesium on platelet activation. Studies with an anti-GPIIb/IIIa antibody showed that the inhibitory effects on the release reaction and thromboxane synthesis are independent of those on aggregation. The results are consistent with magnesium modifying an intracellular signal transduction pathway common to several agonists, rather than the effects of magnesium being specific for one agonist. This study also shows that MgSO(4) inhibits agonist-induced increases in intracellular free calcium. Increasing the extracellular concentration of magnesium up to 10 mM had no effect on agonist-induced increments in intraplatelet free Mg(2+) concentration.     

emm typing and validation of provisional M types for group A streptococci

This report discusses the following issues related to typing of group A streptococci (GAS): The development and use of the 5' emm variable region sequencing (emm typing) in relation to the existing serologic typing system; the designation of emm types in relation to M types; a system for validation of new emm types; criteria for validation of provisional M types to new M-types; a list of reference type cultures for each of the M-type or emm-type strains of GAS; the results of the first culture exchange program for a quality control testing system among the national and World Health Organization collaborating centers for streptococci; and dissemination of new approaches to typing of GAS to the international streptococcal community.     

The estimated costs and savings of medical nutrition therapy: the Medicare population

OBJECTIVES: To measure the potential savings from medical nutrition therapy (MNT) and to estimate the net cost to Medicare of covering these services for Medicare enrollees. This includes developing an estimate of the cost of providing medical nutrition services to the Medicare population and estimating the savings in hospital and other spending resulting from the use of these services. DESIGN: Analysis of longitudinal data from the Group Health Cooperative of Puget Sound (Seattle, Wash) for persons aged 55 years and older who have coverage for MNT services. SUBJECTS/SETTING: Persons aged 55 years and older who had diabetes (n = 12,308), cardiovascular disease (n = 10,895), or renal disease (n = 3,328) and who were covered under the Group Health Cooperative of Puget Sound, including Medicare beneficiaries enrolled in the plan's Medicare risk contract program. Extrapolation to the US Medicare population is based on data for persons served by the Group Health Cooperative of Puget Sound. INTERVENTION: The use of MNT. MAIN OUTCOMES MEASURE: Differences in health care utilization levels of persons with diabetes, cardiovascular disease, and renal disease who do and do not receive MNT. Differences in utilization were estimated for hospital discharges per calendar quarter, physician visits per quarter, and other outpatient visits per quarter. STATISTICAL ANALYSES PERFORMED: Multivariate regression models of changes in utilization for persons after they receive MNT services. RESULTS: Our analysis showed that MNT was associated with a reduction in utilization of hospital services of 9.5% for patients with diabetes and 8.6% for patients with cardiovascular disease. Also, utilization of physician services declined by 23.5% for MNT users with diabetes and 16.9% for MNT users with cardiovascular disease. The net cost of covering MNT under Medicare is estimated to be $369.7 million over the 1998 through 2004 period. The total cost of benefits is estimated to be $2.7 billion over this period. This would be partially offset by estimated savings of $2.3 billion resulting in net costs of $369.7 million. The program would actually yield net savings after the third year of the program, which would continue through 2004 and beyond. CONCLUSION: After an initial period of implementation, coverage for MNT can result in a net reduction in health services utilization and costs for at least some populations. In the case of persons aged 55 years and older, the savings in utilization of hospital and other services will actually exceed the cost of providing the MNT benefit. These results suggest that Medicare coverage of MNT has the potential to pay for itself with savings in utilization for other services.     

Hypermanganesemia in patients receiving total parenteral nutrition

BACKGROUND: Manganese is one of the trace elements that is routinely administered to total parenteral nutrition (TPN) patients. The recommended daily IV dosage ranges from 100 to 800 MICROg. We have used 500 microg daily. Recent reports have suggested neurologic symptoms seen in some patients receiving home parenteral nutrition (HPN) may be due to hypermanganesemia. Therefore, HPN patients and some short-term inpatients receiving TPN were studied to ascertain the relationship between dose and blood levels. METHODS: Red blood cell manganese levels were obtained by atomic absorptiometry. RESULTS: The levels in 36 hospitalized, short-term patients obtained within 48 hours of initiating TPN were all normal. The 30 patients receiving TPN from 3 to 30 days had levels that ranged from 4.8 to 28 microg/L (normal, 11 to 23 microg/L). Two patients had abnormal levels, at days 14 and 18. Fifteen of the 21 patients receiving inpatient TPN or HPN for 36 to 5075 days had elevated Mn levels. Only one patient with hypermanganesemia, an inpatient, had abnormal biochemical liver tests (bilirubin and alkaline phosphatase). One of the patients with a high level had some vestibular symptoms attributed to aminoglycoside use and had increased signal density in the globus pallidus on T1-weighted images on magnetic resonance imaging (MRI). A second patient with Mn levels twice normal had no neurologic symptoms, but had similar MRI findings. A third had some basal ganglia symptoms, confirmed by a neurologic evaluation, seizures, and very high Mn levels. The MRI showed no signal enhancement, but motion artifacts limited the study technically. CONCLUSIONS: Hypermanganesemia is seen in HPN patients receiving 500 microg manganese daily and may have resulted in some neurologic damage in three patients. Hypermanganesemia is sometimes seen after a short course of TPN in inpatients, as early as 14 days. Patients should be monitored for hypermanganesemia if they receive Mn in their TPN for >30 days. A 500 microg/d dose of Mn is probably excessive, and 100 microg/d should probably never be exceeded. Mn should be eliminated from the solution if the Mn level is elevated and should not be readministered unless the level returns to normal or subnormal. Mn should not be supplemented if the patient has liver disease with an elevated bilirubin.