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1.
Alex N. Bullock Julia Henckel Brian S. DeDecker Christopher M. Johnson Penka V. Nikolova Mark R. Proctor David P. Lane Alan R. Fersht 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(26):14338-14342
Some 50% of human cancers are associated with mutations in the core domain of the tumor suppressor p53. Many mutations are thought just to destabilize the protein. To assess this and the possibility of rescue, we have set up a system to analyze the stability of the core domain and its mutants. The use of differential scanning calorimetry or spectroscopy to measure its melting temperature leads to irreversible denaturation and aggregation and so is useful as only a qualitative guide to stability. There are excellent two-state denaturation curves on the addition of urea that may be analyzed quantitatively. One Zn2+ ion remains tightly bound in the holo-form of p53 throughout the denaturation curve. The stability of wild type is 6.0 kcal (1 kcal = 4.18 kJ)/mol at 25°C and 9.8 kcal/mol at 10°C. The oncogenic mutants R175H, C242S, R248Q, R249S, and R273H are destabilized by 3.0, 2.9, 1.9, 1.9, and 0.4 kcal/mol, respectively. Under certain denaturing conditions, the wild-type domain forms an aggregate that is relatively highly fluorescent at 340 nm on excitation at 280 nm. The destabilized mutants give this fluorescence under milder denaturation conditions. 相似文献
2.
To date, despite very encouraging preclinical results, almost all phase II/III clinical neuroprotection trials in traumatic
brain injury (TBI) have failed to show any consistent improvement in outcome for TBI patients. To understand the reasons behind
such developments we need to review and evaluate the evolution of trial design as a result of our changing understanding of
the pathophysiology of brain cell death and progress of translational research from the laboratory bench to the bedside. This
paper attempts to critically appraise these neuroprotection trials, rationalize the paucity of effectiveness, review any recent
developments in the field, and try to draw some conclusions on how to move forward. 相似文献
3.
L Bullock J F Fitzgerald M R Glick R B Parks J G Schnabel B G Hancock 《American journal of hospital pharmacy》1989,46(11):2321-2325
The stability of famotidine in total parenteral nutrient (TPN) solutions and the concentrations of amino acids in the presence of famotidine were determined. Two famotidine concentrations (20 mg/L and 40 mg/L) and two amino acid concentrations (20 g/L and 42.5 g/L) were studied under the following storage conditions: refrigerated for 24 hours and then kept at room temperature (20-22 degrees C) for 24 hours, at room temperature for 48 hours, or refrigerated for seven days. Control TPN solutions were studied under the same storage conditions. TPN solutions also contained dextrose 25%, electrolytes, trace elements, and vitamins. Famotidine concentration was determined at 0, 24, and 48 hours and at seven days by high-performance liquid chromatography. Amino acid concentration was determined in the TPN solutions containing 42.5 g/L of amino acids without famotidine and with famotidine 40 mg/L under both 48-hour storage conditions. At 24 hours, all solutions retained at least 95% of the initial famotidine concentration. Seven of the eight famotidine solutions retained more than 95% of the initial famotidine concentration at 48 hours. All samples refrigerated for seven days retained more than 95% of the initial famotidine concentration. The concentration of amino acids in TPN solutions containing 42.5 g/L of amino acids was not affected by the addition of famotidine 40 mg/L under either 48-hour storage condition. Famotidine in concentrations of 20 mg/L and 40 mg/L is stable under the studied 48-hour storage conditions in TPN solutions containing amino acid concentrations of either 20 g/L or 42.5 g/L.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
4.
A 57-year-old woman who had been treated with an indwelling ureteral stent for over a year was admitted with massive gross hematuria caused by a fistula between the left ureter and hypogastric artery. Despite intensive radiographic evaluation, the definitive diagnosis was made only at the time of surgical exploration. Because of radiation-induced retroperitoneal fibrosis, midureteral obstruction, and prior pelvic and abdominal surgery, primary ureteral repair was not possible, and renal autotransplantation was performed. This case illustrates the need to consider the diagnosis of ureteroarterial fistula in patients with massive hematuria who have chronic indwelling stents, and the feasibility of autotransplantation when primary ureteral repair is not feasible. 相似文献
5.
Feline hyperthyroidism bears a strong clinical and pathologic resemblance to toxic nodular goiter in humans. To evaluate whether the observed thyroid growth might be due to circulating thyroid antibodies, as has been postulated in humans, we studied the effect of purified immunoglobulin (Ig) G preparations on a rat thyroid follicular (FRTL-5) cell line. When compared with control, hyperthyroid cat IgG caused significantly increased [3H]-thymidine (Tdr) incorporation into DNA (p less than 0.02) and stimulated cellular proliferation 15-fold. Stimulation of 3H-Tdr incorporation tended to be biphasic and could be inhibited completely by a potent, specific TSH receptor blocking antibody. Hyperthyroid cat IgG also significantly inhibited 125I-bTSH binding to porcine thyroid membranes, an effect that could be reproduced using electrophoretically pure IgG and normal cat thyroid membranes. Unlike its effect on growth, hyperthyroid cat IgG did not stimulate intracellular cAMP, and there was no correlation between thyroid function in vivo and IgG growth-promoting activity in vitro. These data suggest that elevated titers of thyroid growth IgGs, probably acting through the TSH receptor, are present in feline hyperthyroidism and may play a role in goiter formation. Unlike growth, the thyroid hyperfunction observed is not IgG dependent. Further study of feline hyperthyroidism may contribute important insights into human nodular goiter and into the mediation of thyroid growth in general. 相似文献
6.
7.
Respiratory muscle weakness is an uncommon cause of chronic respiratory failure and a rare cause of cor pulmonale. The problem may not be apparent unless specific physical signs are sought or appropriate investigations performed. We present three patients who presented diagnostic difficulty for prolonged periods until the presence of respiratory muscle weakness was considered. Once the diagnosis was established treatment with nocturnal nasal intermittent positive pressure ventilation produced a dramatic improvement in symptoms and allowed a return to a near normal lifestyle. 相似文献
8.
Inhibition of intracellular growth of Histoplasma capsulatum yeast cells by cytokine-activated human monocytes and macrophages. 总被引:7,自引:4,他引:3
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Human monocytes/macrophages (M psi) were infected with Histoplasma capsulatum yeast cells, and intracellular growth was quantified after 24 h of incubation in medium alone or in medium containing cytokines. Yeast cells multiplied within freshly isolated monocytes, cultured M psi, and alveolar M psi with intracellular generation times of 14.2 +/- 1.4, 18.5 +/- 2.1, and 19.9 +/- 1.9 h (mean +/- standard error of the mean), respectively. Monocytes and M psi inhibited the intracellular growth of yeast cells in response to cytokine supernatant; maximum inhibition was obtained when cytokines were added to cell monolayers immediately after infection. Opsonization of yeast cells in normal serum or in H. capsulatum-immune serum did not affect the intracellular generation time of yeast cells in either control M psi or cytokine-activated M psi. 相似文献
9.
Despite the dramatic success of inhaled steroids in controlling asthma symptoms there remains a small number of patients in whom asthma can only be treated with continuous oral steroids. Eighteen such patients, aged 19-62 years (seven males, 11 females) were followed in an open trial of nebulized budesonide over 12-18 months. All had required at least 7.5 mg or more daily prednisolone to control their symptoms over the preceeding 2 or more years and were taking 1200 micrograms beclomethasone dipropionate or 1600 micrograms budesonide daily. With a daily dose ranging between 4 and 8 mg nebulized budesonide, 14 patients successfully stopped oral steroids while in three the dose was reduced; only one patient failed to benefit. There was an increase in the mean FEV1 from 1.9 (+/- 0.9) to 2.2 (+/- 0.9) l, and in the mean morning PEFR, from 238 (+/- 119) to 286 (+/- 130) l min-1. There was also a significant decrease in the mean number of hospital admissions for acute severe asthma, from 1.5 (+/- 1.8) to 0.9 (+/- 1.1) per year. These findings should encourage a careful and controlled evaluation of nebulized steroids as a substitute for oral steroids in this difficult group of asthmatics. 相似文献
10.
J D Bullock 《Journal of clinical neuro-ophthalmology》1990,10(1):45-51
A relative afferent pupillary defect usually occurs in an eye with unilateral or asymmetric optic nerve or extensive retinal disease. In general, the eye with poorer visual acuity has the afferent pupillary defect. Twenty-five patients are reported, however, in whom an afferent pupillary defect occurred in the eye with better visual acuity. These eyes had optic nerve or retinal dysfunction. The eyes with worse visual acuity but no afferent pupillary defect had an abnormality of the ocular media (corneal opacity, hyphema, anterior segment membrane, cataract, or vitreous opacity), amblyopia, refractive error, age-related macular degeneration, or cystoid macular edema. An afferent pupillary defect does not necessarily occur in the eye with poorer visual acuity. 相似文献