Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin.

There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia >or=10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was >or=1.5 mg/liter. The 66 patients with vancomycin MICs of >or=1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of or=1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P = 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of >or=1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients.

Black walnut extract-induced laminitis in horses is associated with heterogeneous dysfunction of the laminar microvasculature.

REASONS FOR PERFORMING STUDY: Equine laminitis purportedly involves haemodynamic dysfunction at the level of the laminar vasculature. However, to date, no studies have been performed characterising the function of laminar arteries and veins during the prodromal stages of equine laminitis. HYPOTHESIS: That the prodromal stages of laminitis are associated with contractile dysfunction of the equine laminar vasculature. OBJECTIVE: To assess contractile function of laminar arteries and veins to phenylephrine (PE) and 5-hydroxytryptamine (5-HT). METHODS: Horses were administered black walnut heartwood extract (BWHE) or water (control horses) via nasogastric intubation. After euthanasia, laminar vessels (100-800 microm internal diameter) were isolated and mounted on small vessel myographs to assess contractile function. RESULTS: Contractile responses to PE or 5-HT were identical in laminar arteries isolated from either control horses or those administered BWHE. In contrast, responses to PE or 5-HT were significantly reduced in laminar veins isolated from BWHE-administered horses when compared with laminar veins isolated from control horses. CONCLUSIONS AND POTENTIAL RELEVANCE: These results are consistent with the prodromal stages of laminitis being associated with selective dysfunction of laminar veins. Further studies are required to discern the precise nature of this dysfunction and its potential relevance to the pathogenesis of acute laminitis in the horse and possible therapeutic targets for treatment.

The ancient source of a distinct gene family encoding proteins featuring RING and C(3)H zinc-finger motifs with abundant expression in developing brain and nervous system.

Intronless genes can arise by germline retrotransposition of a cDNA originating as mRNA from an intron-containing source gene. Previously, we described several members of a family of intronless mammalian genes encoding a novel class of zinc-finger proteins, including one that shows imprinted expression and one that escapes X-inactivation. We report here the identification and characterization of the Makorin ring finger protein 1 gene (MKRN1), a highly transcribed, intron-containing source for this family of genes. Phylogenetic analyses clearly indicate that the MKRN1 gene is the ancestral founder of this gene family. We have identified MKRN1 orthologs from human, mouse, wallaby, chicken, fruitfly, and nematode, underscoring the age and conservation of this gene. The MKRN gene family encodes putative ribonucleoproteins with a distinctive array of zinc-finger motifs, including two to four C(3)H zinc-fingers, an unusual Cys/His arrangement that may represent a novel zinc-finger structure, and a highly conserved RING zinc-finger. To date, we have identified nine MKRN family loci distributed throughout the human genome. The human and mouse MKRN1 loci map to a conserved syntenic group near the T-cell receptor beta cluster (TCRB) in chromosome 7q34-q35 and chromosome 6A, respectively. MKRN1 is widely transcribed in mammals, with high levels in murine embryonic nervous system and adult testis. The ancient origin of MKRN1, high degree of conservation, and expression pattern suggest important developmental and functional roles for this gene and its expressed family members.

Regulation of the yeast INO1 gene. The products of the INO2, INO4 and OPI1 regulatory genes are not required for repression in response to inositol.

The ino2Delta, ino4Delta, opi1Delta, and sin3Delta mutations all affect expression of INO1, a structural gene for inositol-1-phosphate synthase. These same mutations affect other genes of phospholipid biosynthesis that, like INO1, contain the repeated element UAS(INO) (consensus 5' CATGTGAAAT 3'). In this study, we evaluated the effects of these four mutations, singly and in all possible combinations, on growth and expression of INO1. All strains carrying an ino2Delta or ino4Delta mutation, or both, failed to grow in medium lacking inositol. However, when grown in liquid culture in medium containing limiting amounts of inositol, the opi1Delta ino4Delta strain exhibited a level of INO1 expression comparable to, or higher than, the wild-type strain growing under the same conditions. Furthermore, INO1 expression in the opi1Delta ino4Delta strain was repressed in cells grown in medium fully supplemented with both inositol and choline. Similar results were obtained using the opi1Delta ino2Delta ino4Delta strain. Regulation of INO1 was also observed in the absence of the SIN3 gene product. Therefore, while Opi1p, Sin3p, and the Ino2p/Ino4p complex all affect the overall level of INO1 expression in an antagonistic manner, they do not appear to be responsible for transmitting the signal that leads to repression of INO1 in response to inositol. Various models for Opi1p function were tested and no evidence for binding of Opi1p to UAS(INO), or to Ino2p or Ino4p, was obtained.

Metabolism of N-[4-hydroxyphenyl]retinamide (4-HPR) to N-[4-methoxyphenyl]retinamide (4-MPR) may serve as a biomarker for its efficacy against human breast cancer and melanoma cells.

A clinical trial of N-[4-hydroxyphenyl]retinamide (4-HPR) has been in progress for the past 4 years to evaluate its role in chemoprevention of breast cancer. However, it is currently not known whether the effect of 4-HPR in breast cells is mediated by 4-HPR directly or through one of its metabolites. In this report, we investigated in vivo and in vitro effects of 4-HPR on three different breast carcinoma cells and two different melanoma cell lines. In vitro, the growth of all three breast carcinoma cell lines was inhibited by 4-HPR. Only one of two melanoma cell lines (UISO-Mel-1) showed growth inhibition to 4-HPR. The cell lines sensitive to 4-HPR in vitro also showed inhibition to 4-HPR in a xenograft model. Dietary 4-HPR (0.5 mmol/kg diet) reduced the growth of UISO-BCA-1 xenografts in female athymic mice, but had no effect on UISO-Mel-6 xenografts. Metabolism investigations of the 4-HPR-sensitive and insensitive cell lines indicated that N-[4-methoxyphenyl]retinamide (4-MPR), the major metabolite of 4-HPR, was detected only in cells sensitive to 4-HPR. Further in vitro studies with 4-MPR suggested that it is not an active metabolite of 4-HPR as it failed to inhibit growth of 4-HPR-resistant UISO-Mel-6 cells, and showed no dose-dependent inhibition of 4-HPR-sensitive breast carcinoma and melanoma cell lines. Our results in the present study indicate that, although 4-MPR is not an active metabolite of 4-HPR, detection of this metabolite in the malignant cells may serve as an indirect biomarker to predict response of cells to 4-HPR.

Pleiotropic effects of the opi1 regulatory mutation of yeast: its effects on growth and on phospholipid and inositol metabolism.

Key factors which impact on the biosynthesis and subsequent fate of the phospholipid precursor inositol were studied as a function of growth phase in the yeast Saccharomyces cerevisiae. Both wild-type and strains disrupted for the OPI1 gene, the principal negative regulator of the phospholipid biosynthetic genes, were examined. Overexpression of the INO1 gene and overproduction of both inositol and the major inositol-containing phospholipid, phosphatidylinositol, varied as a function of growth phase. In opi1 cells, INO1 expression was constitutive at a high level throughout growth, although the level of transcript was reduced at stationary phase when the cells were grown in defined medium. In the wild-type strain, INO1 expression was limited to a peak in the exponential phase of growth in cells grown in the absence of inositol. Interestingly, the pattern of OPI1 expression in the wild-type strain resembled that of its putative target, INO1. Intracellular inositol contents of the opi1 strain were higher than those of the wild-type strain, with peak levels occurring in the stationary phase. Membrane phosphatidylinositol content paralleled intracellular inositol content, with opi1 strains having a higher phosphatidylinositol content in stationary phase. The proportion of the predominant phospholipid, phosphatidylcholine, exhibited a profile that was the inverse of the phosphatidylinositol content: phosphatidylcholine content was lowest in opi1 cells in stationary phase. The opi1 mutation was also found to have effects beyond phospholipid biosynthesis. opi1 cells were smaller, and opi1 cultures achieved a cell density twice as high as comparable wild-type cultures. opi1 cells were also more salt tolerant than wild-type cells: they were partly resistant to shrinking, more rapidly resumed growth, and attained a higher culture density after upshift to medium supplemented with 8% NaCl.

Controlled trial of nimodipine in amyotrophic lateral sclerosis.

Calcium channel blocking drugs antagonize excitatory amino acid receptor activation, decrease calcium entry into damaged neurons, and might help to slow or reverse amyotrophic lateral sclerosis (ALS). We enrolled 87 patients with ALS in a randomized, placebo-controlled, prospective, double-blind crossover study of nimodipine therapy. Monthly measures of isometric muscle strength and respiratory function compared the effects of drug and placebo. No difference in adverse events occurred in placebo vs drug-treated patients, but diarrhoea, nausea, and lightheadedness were more common with nimodipine. There was no significant difference in the rate of decline of pulmonary function or limb strength during treatment with drug or placebo. Nimodipine was ineffective in slowing the progress of ALS.

The changing health care delivery structure: opportunities for nursing practice and administration.

The increase in national health care expenditures has placed great stress on the economy and has contributed to a widespread consensus that reform of the health care delivery system is necessary. Three interrelated strategies are frequently used to cope with the turbulent environment in the health care industry today: managed care, hospital merger and acquisition to form integrated health care delivery systems, and redefined roles for nurses and other health care workers. These strategies have profound implications and will offer great opportunities for nursing administrators to foster nursing practice in new and improved systems of care delivery.

Effect of bufalin and pregnanes on vasoreactivity of human resistance arteries.

Endogenous Na/K ATPase inhibitory activity has been implicated in salt and water homeostasis in mammals and amphibians. Recent interest has focused on endogenous cardiac glycosides, some progesterone derivatives (pregnanes) and the amphibian bufodienolides. This study has examined the effects of non-planar and planar pregnanes and the bufodienolide bufalin on vasoreactivity of human resistance arteries. Bufalin and a non-planar pregnane caused concentration-dependent potentiation of the tone of submaximally pre-contracted arteries and inhibited endothelium-dependent relaxation, whereas a planar pregnane affected neither response. The relative potency of the compounds studied suggest the results do not simply reflect degrees of Na/K ATPase inhibition. The active compounds may be important in the regulation of vascular tone.

Plasma uptake of manganese as affected by oral loads of manganese, calcium, milk, phosphorus, copper, and zinc.

Six adult subjects were administered a series of manganese (Mn) tolerance tests to investigate the influence of various minerals on Mn plasma uptake. Oral loads given to all six subjects included 40 mg manganese alone, or with 800 mg calcium (Ca) as either calcium carbonate (CaCO3) or 545 ml 2% milk. Four of the subjects also received loads of 800 mg phosphorus (P), 2 mg copper (Cu), and 50 mg zinc (Zn) with the 40 mg Mn. Baseline Mn tolerance tests for all subjects produced a rapid increase in plasma Mn, followed by return to baseline. The addition of Ca as either CaCO3 or 2% milk to the oral Mn essentially blocked the plasma uptake of Mn. No significant differences were found between the source of Ca in its inhibitory effect. Plasma Ca uptake was lower when Mn was simultaneously administered, but the results were not significantly different. Ionized levels of plasma Ca did not change significantly. The addition of Cu to the Mn load decreased the area under the curve for plasma Mn by about half, but it was not significantly different in the four subjects. In contrast, the addition of Zn to the Mn produced a significant increase in plasma Mn. Phosphorus has no influence on plasma uptake of Mn. These results indicate that the plasma uptake of Mn is greatly reduced by concomitant ingestion of Ca but may be increased by an oral load of Zn.

Safety and efficacy of amlodipine added to hydrochlorothiazide therapy in essential hypertension.

We compared amlodipine, a dihydropyridine calcium antagonist, to placebo as add-on therapy to hydrochlorothiazide in 91 hypertensive patients inadequately controlled on hydrochlorothiazide (50 mg/d for four weeks). This was a double-blind, randomized, multicenter, parallel group-trial; 45 patients received placebo and 46 received amlodipine in doses of 2.5 to 10 mg qd (mean 9 mg/d). Supine blood pressure systolic/diastolic, mean +/- SE mm Hg) 24-hour postdose was significantly reduced by 14.2 +/- 2.3/11.7 +/- 1, compared to placebo, 4.5 +/- 2.7/5 +/- 1.2. Standing blood pressure was similarly reduced: amlodipine by 14 +/- 2.7/12.5 +/- 1.2; placebo by 3 +/- 2.1/5.8 +/- 1.2. This reduction in blood pressure was attained without any significant changes in pulse rate, EKG, and serum lipids (triglycerides were reduced in the amlodipine group by 42.9 mg/dL, P = .023). Only two patients had side effects requiring discontinuation from the study (both in the amlodipine group). Side effects occurred in 27 amlodipine-treated patients (11 with peripheral edema) and 18 patients in the placebo (three with peripheral edema) group. Investigator's assessment of therapeutic effect and tolerability, and the percent of responders v nonresponders was also in favor of amlodipine. Thus amlodipine administered once daily is an effective and safe agent for second-step therapy in mild to moderate essential hypertension.

Mineral adequacy of vegetarian diets.

The bioavailability of a number of minerals may be altered by the special characteristics of vegetarian diets. Concern has centered on both inadequate and high dietary levels of specific minerals as well as reduced bioavailability because of a variety of dietary components. The possibility that plant-based diets may compromise mineral status is briefly reviewed for the following minerals: zinc, calcium, iron, manganese, selenium, and copper.

Vitamin and mineral status of trained athletes including the effects of supplementation.

We measured serum concentrations of thiamin, riboflavin, nicotinic acid, pyridoxine, folate, cyanocobalamin, ascorbic acid, retinol, tocopherol, zinc, magnesium, copper, iron, and ferritin as well as hemoglobin, hematocrit, percentage transferrin saturation, and total iron-binding capacity in athletes who ingested a multivitamin and mineral supplement for 3 mo. All blood variables were normal and except for pyridoxine and riboflavin there were no significant changes in the blood concentrations of any other vitamins or minerals measured. This may have been due to variable interactions between the vitamins and minerals in the supplement that prevented their being adequately absorbed. There were no signs or symptoms of serious toxic side effects. We conclude that multivitamin and mineral supplementation was without any measurable ergogenic effect and that such supplementation is unnecessary in athletes ingesting a normal diet.

Effects of furosemide versus isolated ultrafiltration on extravascular lung water in oleic acid-induced pulmonary edema.

We studied the effects of no treatment, furosemide treatment, and isolated ultrafiltration on extravascular lung water (ETVL) in mongrel dogs in whom pulmonary edema was induced with oleic acid. In all treatment groups, ETVL was significantly elevated 90 min after oleic acid infusion. At 270 min, we found no difference between nontreatment and furosemide. There was, however, a significant difference between no treatment and ultrafiltration but not between furosemide and ultrafiltration. In spite of observations which suggest that ultrafiltration is of benefit in reducing ETVL, we could not demonstrate superiority of one therapy over another.

Zinc tolerance tests in zinc deficient and zinc supplemented diets.

Seven men consumed a low-zinc (3.3 mg/day) diet for 8 wk, followed by zinc-repletion (+15 mg/day) for 12 days. Zinc tolerance tests (50 mg) were administered initially and following depletion and repletion periods. Plasma zinc after 2 h in the zinc tolerance test was marginally higher after both the depletion (p less than 0.06) and repletion (p less than 0.001) periods as compared to the initial test. No changes were seen in parotid zinc tolerance tests or fasting levels of zinc in plasma or parotid saliva. In a subsequent study, zinc tolerance tests were given to normal subjects before and after 12 days of zinc supplementation (15 mg/day). Again, zinc levels in plasma were increased following zinc supplementation at the 2nd h post-zinc dose, but levels in saliva did not change. The elevation of plasma zinc curves with both zinc deficiency and supplementation suggests that this test is not a reliable indicator of zinc status.

Effect of zinc supplementation on plasma high-density lipoprotein cholesterol and zinc.

The recent report by Hooper PL, et al. (JAMA 1980;244:1960-1) that pharmacological doses (160 mg) of zinc lowered high-density lipoprotein (HDL)-cholesterol in men and that zinc might be an atherogenic agent prompted this report of the effect of zinc supplementation on HDL-cholesterol in women. Four levels of zinc supplements (0, 15, 50, or 100 mg/day) were given to 32 women for 8 wk. Fasting plasma HDL-cholesterol and zinc were measured at biweekly intervals. Plasma zinc increased in the supplemented groups, peaked at wk 4, then decreased toward initial values. The decline in plasma zinc regardless of continuing zinc administration may reflect a homeostatic response. No significant differences were seen in HDL-cholesterol over the 8 wk except in the 100 mg group at wk 4 when a transient decrease, -8.4% (57 to 48 mg/dl, p less than 0.04) was observed. Thus we conclude that in women the reduction in HDL-cholesterol in response to the pharmacological doses of zinc used in this study was transient and not dose-related.

Zinc and copper content of foods used in vegetarian diets.

The zinc and copper content of seventy-four foods was determined by atomic absorption spectrophotometry. Each of these foods was reported to have been consumed by practicing vegetarians. Legumes, seeds, nuts, whole grains, hard cheeses, and some nutritional supplements were found to be excellent sources of both zinc and copper. Vegetables, fruits, and their products were generally poor sources of trace minerals, with the exception of seed and bean sprouts. Milk and milk products, including rennetless cheeses, contain small quantities of these minerals. Although many of the foods consumed by vegetarians do contain adequate amounts of zinc and copper, their bioavailability may be limited.

A review of the current status of oil adjuvants in foot--and--mouth disease vaccines.

Review of lipovaccines since 1916, including oil adjuvants (1935-1943) and the two Freund's adjuvants. The first oil-adjuvanted vaccines appeared in 1961. Criticism of the water-in-oil and oil-in-water vaccines and description of the mineral oil adjuvants which are available today. The authors set forth the advantages of oil adjuvants and secondary reactions which might occur; they are particularly interested in the foot-and-mouth disease vaccine intended for use in swine and express their regret that no method of standardization has yet been adopted for oil-adjuvanted vaccines which are promising but which necessitate still further study.