The pharmacokinetics and protein-binding of fusidic acid in patients with severe renal failure requiring either haemodialysis or continuous ambulatory peritoneal dialysis

Antibiotic treatment options for Burkholderia cepacia infection are limited because of high intrinsic resistance. The problem is complicated by development of cross-resistance between antibiotics of different classes. We isolated antibiotic-resistant mutants by stepwise exposure to chloramphenicol (Chlor) and to trimethoprim/sulphamethoxazole (T/S) for four B. cepacia strains: ATCC13945, Per (clinical isolate), Cas and D4 (environmental isolates). Chlor(r) mutants did not produce chloramphenicol acetyl-transferase. Cross-resistance, defined as greater than four-fold increase in MIC by microtitre dilution method, was consistently seen in both types of mutants. For chloramphenicol-resistant (Chlor[r]) and trimethoprim/sulphamethoxazole-resistant (Tr/Sr) mutants of B. cepacia ATCC13945 and Cas, no MIC change was seen for piperacillin, ceftazidime, rifampicin, gentamicin, tobramycin, polymyxin B or azithromycin. B. cepacia-Per and -D4 mutants showed cross-resistance to ceftazidime and to piperacillin. Comparison of outer membrane protein (OMP) profiles of B. cepacia and their mutants by SDS-PAGE revealed Tr/Sr) mutants to be deficient in a major OMP (molecular weight 39-47 kDa). Tr/Sr mutants also expressed additional OMPs not found in wild type strains at 75-77 kDa for B. cepacia-ATCC13945 and -Cas, and 20-21 kDa in B. cepacia-D4 and -Per. No OMP changes occurred in Chlor(r) mutants. Lipopolysaccharide (LPS) profiles of each type of mutant showed new high and low molecular weight LPS bands. Cross-resistance seems to be mediated by alterations in porin and LPS for Tr/Sr mutants, but only by LPS in Chlor(r) mutants.     

The rationale for cementless total hip replacement

Current cementing techniques of distal plugging, pulsatile water cleaning of the canal, and retrograde filling with PMMA in a low-viscous state prepared using porosity reduction techniques and then pressurized have been shown to give excellent results at 10 or more years after operation. However, physical and aging characteristics of PMMA do not guarantee that those results will hold up in the 20- to 30-year time frame. Fifteen-year experience with bony ingrowth systems indicate the development of a durable interface without PMMA, although the interface does appear more vulnerable to attack by the biologic reaction to HMWPE debris. Bone remodeling appears more favorable around proximally fixed bone ingrowth prostheses than around distally fixed prostheses. Softening of the physical characteristics of the stem tip may reduce the incidence of thigh pain. Patients with high activity potential and a life expectancy of greater than 25 years should be strongly considered for a proximally fixed bone ingrowth or ongrowth prosthesis.     

Arterial reactivity is enhanced in genetic males taking high dose estrogens

OBJECTIVES: We sought to assess whether high dose estrogen treatment is associated with enhanced arterial reactivity in genetic males. BACKGROUND: Although estrogens have been shown to enhance arterial reactivity in women, and are thereby thought to confer cardiovascular benefit, the vascular effects of long-term estrogen therapy in genetic males is unknown. METHODS: We studied the arterial physiology of 30 genetic males--15 male to female transsexuals receiving long-term high dose estrogen therapy and 15 healthy male control subjects matched for age, smoking history and vessel size. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilation [EDD]) and after nitroglycerin (GTN), an endothelium-independent dilator. Blood pressure, cholesterol and testosterone levels were also measured in each subject. RESULTS: Total testosterone and free testosterone index levels were lower in the transsexuals compared with the control subjects (p < 0.001). In contrast, EDD was significantly higher in the transsexuals than in the control males (mean [+/-SD] 7.1 +/- 3.1% vs. 3.2 +/- 2.8%, p = 0.001), as was the GTN response (21.2 +/- 6.7% vs. 14.6 +/- 3.3%, p = 0.002). Total and high density lipoprotein cholesterol, blood pressure levels and baseline vessel size were similar in the two groups. On multivariate analysis, enhanced EDD was associated independently with estrogen therapy (p = 0.02) and with low total cholesterol (p = 0.04). An enhanced GTN response was also significantly associated with estrogen therapy (p = 0.03). CONCLUSIONS: Long-term treatment with high dose estrogens is associated with enhanced arterial reactivity in genetic males, which may be due to the effects of estrogen excess or androgen deprivation, or both.     

Potentiation of a three drug chemotherapy regimen by radiation

The combination of N-(phosphonacetyl)-L-aspartate, 6-methylmercaptopurine, and 6-aminonicotinamide has been shown to be an effective antineoplastic regimen and also to enhance the effects of other chemotherapeutic agents. The mechanism of action of this combination of drugs is not known definitively, but one possible mechanism is biochemical modulation of energy metabolism and inhibition of production of tumor ATP. Tumor-bearing mice were treated with N-(phosphonacetyl)-L-aspartate, followed 17 h later by 6-methylmercaptopurine and 6-aminonicotinamide. 31P nuclear magnetic resonance spectroscopic studies demonstrated a significant depletion of high energy phosphates at 10 h post-6-methylmercaptopurine and 6-aminonicotinamide. The addition of radiation at this time was shown to induce a significantly longer tumor growth delay and a greater number of regressions (including durable complete regressions) than either chemotherapy or radiation alone. The combination of chemotherapy and radiation was found to be supra-additive compared to the antineoplastic effects of either modality administered separately, without a measurable increase in host toxicity.     

Expression studies of delta-globin gene alleles associated with reduced hemoglobin A2 levels in Greek Cypriots

We previously identified five delta-globin gene alleles associated with reduced hemoglobin (Hb) A2 (Trifillis, P., Ioannou, P., Schwartz, E., and Surrey, S. (1991) Blood 78, 3298-3305). We have now evaluated functional consequences of the changes after expression in COS-1 cells to monitor effects on RNA splicing. In addition, variant Hb A2 tetramers were expressed in yeast to assess effects of amino acid changes on oxygen binding and stability to heat and mechanical agitation. The G --> T change at codon 27 and the A --> G change in IVS-2 both affect RNA splicing, whereas the C --> T change at codon 97 and the AT deletion in IVS-2 have no effect. Oxygen equilibrium curves of the Hb A2 variants expressed in yeast were similar to that of wild type Hb A2. None of the three variant Hb A2 tetramers (Thr --> Ile at codon 4 (Hb deltaT4I), Ala --> Ser at codon 27 (Hb deltaA27S), and Arg --> Cys at codon 116 (Hb deltaR116C)) showed decreased heat stability compared with Hb A2, whereas the Hb deltaT4I variant showed highest instability to mechanical agitation. Co-expression in yeast of alpha-globin chain and the delta-chain variant containing a Leu --> Pro change at codon 141 yielded no identifiable tetramers, suggesting lack of assembly or severe tetramer instability. These studies show the probable cause for decreased Hb A2 for two alleles is due to defective splicing, whereas decreased protein stability, increased tetramer association with red cell membranes, increased interdisulfide bond formation of delta-chains, which inhibits assembly with alpha-chains, and/or reduced assembly is suggested for the other three alleles.     

Development of the bi-directional ultrasound system for base of tongue imaging

The use of conventional ultrasound systems to image the upper airway has been limited because ultrasound energy is attenuated by the air column. In an attempt to study upper airway geometry, we developed a computer controlled bi-directional ultrasound system which combines two conventional ultrasound devices with computer image processing to yield images of upper airway structures. Human studies and cadaver studies were performed to evaluate the system. Images acquired by the bi-directional ultrasound system were comparable to images from 3D volume rendered CT scans. This system may provide valuable data in the study of upper airway physiology and pathology.     

Adverse environmental conditions in the respiratory and medical ICU settings

Sleep deprivation and fragmentation occurring in the hospital setting may have a negative impact on the respiratory system by decreasing respiratory muscle function and ventilatory response to CO2. Sleep deprivation in a patient with respiratory failure may, therefore, impair recovery and weaning from mechanical ventilation. We postulate that light, sound, and interruption levels in a weaning unit are major factors resulting in sleep disorders and possibly circadian rhythm disruption. As an initial test of this hypothesis, we sampled interruption levels and continuously monitored light and sound levels for a minimum of seven consecutive days in a medical ICU, a multiple bed respiratory care unit (RCU) room, a single-bed RCU room, and a private room. Light levels in all areas maintained a day-night rhythm, with peak levels dependent on window orientation and shading. Peak sound levels were extremely high in all areas representing values significantly higher than those recommended by the Environmental Protection Agency as acceptable for a hospital environment. The number of sound peaks greater than 80 decibels, which may result in sleep arousals, was especially high in the intensive and respiratory care areas, but did show a day-night rhythm in all settings. Patient interruptions tended to be erratic, leaving little time for condensed sleep. We conclude that the potential for environmentally induced sleep disruption is high in all areas, but especially high in the intensive and respiratory care areas where the negative consequences may be the most severe.     

Cyromazine toxicity in different laboratory strains of the tobacco hornworm (Lepidoptera:Sphingidae)

Three different strains of tobacco hornworm, Manduca sexta (L.), were treated with cyromazine ingestion of cyromazine-treated artificial diet or by intrahemocoelic injection. The effect of cyromazine on larval growth and the onset and severity of poisoning symptoms were similar in the wild-type green-pigmented strain and the white-pigmented mutant. Feeding times of 4 h or greater and injected doses of 22.6 micrograms/g larva or more resulted in lower weight gains than were observed with controls. Elongation caused by exposure was evident within 12-24 h. The incidence of cuticular rupture was 55 and 67% in the dietary exposure tests and 24 and 22% in the injection tests for the green and white strains, respectively. The response of the black strain to cyromazine differed by the route of administration. Like the other strains, dietary exposure times of 4 h or greater led to smaller weight gains than in the controls. Injected doses of 2.8 micrograms/g larva or more caused a decrease in the weight gain of the treated versus controls. A smaller proportion (21%) of black larvae consuming treated diet developed cuticular ruptures, whereas injected treatments had a higher incidence (87%). The differences in the pigmentation of the white and black strains had been linked to high and low juvenile hormone titers, respectively. The greater susceptibility of the juvenile hormone-deficient black strain raises the possibility that the mode of action of cyromazine involves a hormonal component. In a separate series of experiments, the poisoning symptoms of cyromazine were attenuated or eliminated by periods of starvation of 1-3 d following exposure to the chemical. Starvation for 3 d preceding treatment attenuated but did not eliminate signs of poisoning.