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Biomedical subjects

C M Johnson

Publications and source records attributed to C M Johnson.

At least 109 records · Page 6Linked to original sources
PubMed1994

The A-state of barnase.

The acid-induced denaturation of barnase and its mutants has been analyzed to search for partly-folded intermediates. Differential scanning calorimetry of barnase deviates from two-state behavior below pH 4.0 at low ionic strength, with the maximum discrepancy at pH 2.7. Addition of 200 mM KCl apparently restores the two-state transitions. Thermograms of barnase mutants at pH 2.7 and low ionic strength fall into three classes: alpha, symmetric transitions which fit well to a two-state equilibrium; b, asymmetric transitions indicating deviation from two-state behavior; and c, transitions with an obvious second component. The most distorted thermograms are observed for mutants that had previously been engineered to accumulate at equilibrium the major kinetic folding intermediate state of barnase at neutral pH. Further analysis of these mutants show the existence of complex equilibria on thermal denaturation. Addition of KCl leads to the slow formation of soluble aggregated forms (A-state) which share some of the properties of the "molten globule" state, i.e., significant secondary structure, lack of fixed tertiary structure, and solvent-accessible hydrophobic patches. The far-UV CD spectrum of the A-state can be explained in terms of native-like secondary structure contributions. Kinetic and chemical cross-linking experiments show that dimerization of partly-folded molecules occurs in the transition region, and such dimerization is probably the rate-limiting step in the formation of the A-state in the presence of KCl. As the A-state has been observed clearly so far for only the mutants in which the folding intermediate has been designed to accumulate, we suggest that the A-state would be related to the main folding intermediate state of barnase. The intermediate would be highly stabilized at low pH, and it is prone to self-associate in these conditions.

Bacterial Proteins↗
PubMed1994

The management of patients with advanced carcinoid tumors and islet cell carcinomas.

OBJECTIVE: To determine the effectiveness of hepatic artery occlusion alone and with sequenced chemotherapy for patients with hepatic-dominant metastases of islet cell carcinomas and carcinoid tumors. DESIGN: Nonrandomized, observational study with follow-up from 2.5 to 10 years. PATIENTS: 111 ambulatory patients referred to a multidisciplinary tertiary care center who had histologically proven islet cell carcinoma or carcinoid tumor and symptomatic measurable metastatic lesions in the liver or hormonal abnormalities or both. The patients were ambulatory but were having substantial symptoms because of their endocrine syndromes or their tumors. INTERVENTION: All patients had hepatic artery occlusion done surgically or by catheterization and embolization. After this procedure, 71 patients were selected for chemotherapy with alternating two-drug regimens of doxorubicin plus dacarbazine and streptozocin plus fluorouracil. Main outcome measures of response to therapy were rates of tumor regression, rates of improvement in endocrine abnormalities, symptomatic improvement, and duration of favorable response. RESULTS: Objective regressions were observed in 60% of patients treated with occlusion alone and in 80% with chemotherapy added. Regressions were associated with substantial or complete relief from the endocrine syndromes. With occlusion alone, the median duration of regression was 4.0 months and with chemotherapy added, it was 18.0 months. Any comparative inferences about the two treatment regimens must be guarded, because this was not a randomized trial and marked differences occurred in the distribution of prognostic factors between the patient groups. Side effects of arterial occlusion included fever, nausea, pain, and abnormalities in liver function. Side effects of chemotherapy included nausea, vomiting, leukopenia, and alopecia. CONCLUSIONS: Hepatic arterial occlusion can frequently produce major regression of neuroendocrine tumors with relief from the hormonal syndromes. Sequential chemotherapy may improve the rate and duration of the regression.

Adult↗
PubMed1994

The S-oxidative degradation of a novel corticosteroid tipredane (INN). Part II--Detailed investigations into the primary S-oxidation of tipredane using achiral oxidants.

The C-17 dithioketal moiety of the corticosteroid tipredane (INN,I) has been shown to undergo site and stereoselective S-oxidations with a range of achiral oxidants. S-Oxidation was favoured on the methylthio substitutent (beta-plane) in preference to the ethylthio substituent (alpha-plane) in a ratio of 1.8-3.5:1. S-Oxidation on both substituents appeared to be stereoselective yielding an approximate ratio of 4:1 and 1:3.5-6 for the S-:R-methyl and ethylsulphoxide diastereoisomers, (II and VI) respectively. The preferred sites for S-oxidation have been explained in terms of the preferred rotamers of the C-17 substituents and the steric factors imposed on the attack of the oxidant on the lone pair of electrons at each sulphur atom. Optimized HPLC conditions using a Hypersil ODS column and an acetonitrile-0.025 M NH4OAc pH 7.2 gradient at 26 degrees C were developed to prevent degradation of the ethylsulphoxide diastereoisomers (VI) occurring during chromatographic analysis, via elimination of ethylsulphenic acid to yield the corresponding C-17 vinylmethylthio derivative (VII).

Administration, Topical↗
PubMed1994

Effect of sodium chloride, enalapril, and losartan on the development of polycystic kidney disease in Han:SPRD rats.

We found that the administration of an angiotensin I-converting enzyme inhibitor and sodium chloride loading lessen the development of renal cystic disease induced by 2-amino-4-5-diphenylthiazole in rats. To determine whether similar effects could be observed in an autosomal dominant model of polycystic kidney disease, heterozygous cystic (Cy/+) and homozygous normal (+/+) Han:SPRD rats were divided into experimental groups at 3 weeks of age. The first study included four groups receiving enalapril (50 mg/L), losartan (400 mg/L), hydralazine (80 mg/L), or no drug in their drinking water. The second study included four groups fed a sodium-deficient diet or the same diet supplemented with 0.25%, 0.6%, or 3.3% sodium chloride. The Cy/+ rats receiving enalapril had lower kidney weights and histologic scores than those in the control group, and lower kidney weights, plasma creatinines, and histologic scores than those in the hydralazine group. The Cy/+ rats receiving losartan had lower plasma creatinines and histologic scores than those in the control and hydralazine treatment groups. A sodium-deficient diet markedly blunted the growth of the animals and the development of cystic disease. Increases in the sodium content of the diet in the other three groups were accompanied by higher relative kidney weights and histology scores, while the levels of plasma creatinine were not significantly different. Regression of the cystic disease was observed between 3 and 4 months of age. These results indicate that the development of autosomal dominant polycystic kidney disease in the rat can be modulated by pharmacologic and nutritional factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1994

Mesenteric venous thrombosis: still a lethal disease in the 1990s.

PURPOSE: This study was designed to evaluate progress in diagnosis, management, and clinical outcome of mesenteric venous thrombosis (MVT). METHODS: We retrospectively reviewed the clinical course of 72 patients treated for mesenteric venous thrombosis between 1972 and 1993. RESULTS: Fifty-three patients had acute and 19 had chronic mesenteric venous thrombosis. Fifty-seven patients had secondary mesenteric venous thrombosis; previous abdominal surgical procedure and hypercoagulable states were the most prevalent associated conditions. Computed tomography was abnormal in all patients who underwent this test for acute mesenteric venous thrombosis and in 93% of those who had chronic disease. Angiography diagnosed acute mesenteric venous thrombosis in five (72%) of seven patients. Acute mesenteric venous thrombosis presented most frequently as abdominal pain (83%), anorexia (53%), and diarrhea (43%). Thirty-three (75%) had symptoms longer than 48 hours. Thirty-four (64%) patients with acute mesenteric venous thrombosis underwent a surgical procedure. Bowel resection was necessary in 31 patients. One patient had unsuccessful mesenteric venous thrombectomy. Seven patients with acute mesenteric venous thrombosis underwent anticoagulation without a surgical procedure, and 12 were observed. All patients with chronic mesenteric venous thrombosis were observed; nine of the 19 underwent anticoagulation. The median delay in diagnosis for patients with acute mesenteric venous thrombosis was 48 hours and did not decrease during the last decade. Mesenteric venous thrombosis recurred in 19 (36%) patients. The 30-day mortality was 27%. Long-term survival of patients with acute mesenteric venous thrombosis was significantly worse than that of those with chronic disease (36% vs 83% survival at 3 years). The patients with acute mesenteric venous thrombosis who underwent anticoagulation with and without surgical procedure had improved survival when compared with the observed group. CONCLUSION: Acute mesenteric venous thrombosis remains a lethal disease. Mortality has not improved in the last 22 years. Computed tomography is the most sensitive diagnostic test. Anticoagulation and surgical procedure enhanced survival in the acute subgroup. The underlying disease determined survival in chronic disease.

Acute Disease↗
PubMed1994

Development of clinical disease in cats experimentally infected with feline immunodeficiency virus.

Cats naturally infected with feline immunodeficiency virus (FIV) develop an AIDS-like syndrome whereas experimentally infected cats do not. To investigate the role of cofactors in the development of this disease in cats, 7 specific pathogen-free (SPF) and 12 random-source (RS) cats were infected with FIV. Over 4 years, infected cats developed similar phenotypic and functional immune abnormalities characterized by early and chronic inversion of CD4+:CD8+ cell ratios and significantly decreased mitogen responses compared with controls. Beginning 18-24 months after infection, 10 RS cats developed chronic clinical disease typical of feline AIDS, including stomatitis and recurrent upper respiratory disease; 4 SPF cats also developed chronic clinical disease, 2 with neurologic disease and 2 with B cell lymphomas. Thus, immunologic background is important in the type of disease that develops in cats infected with FIV, and FIV represents a promising animal model for studying the immunopathogenesis of AIDS in humans.

Animals↗
PubMed1994

Contribution of a proline residue and a salt bridge to the stability of a type I reverse turn in chymotrypsin inhibitor-2.

The contributions of the components of a type I reverse turn to the stability of chymotrypsin inhibitor-2 (Lys43-Pro44-Gly45) have been determined by protein engineering methods. A double-mutant cycle was used to determine the interaction between Lys43 and Glu45 by replacing them with alanine. We also mutated Pro44, which gives the geometry of the turn, to alanine and analysed the stability of the resulting mutants compared with wild-type chymotrypsin inhibitor-2, using equilibrium denaturation induced by guanidinium chloride. There are decreases in stability (in kcal/mol) of 0.64 +/- 0.06 for Lys43-->Ala, 0.57 +/- 0.15 for Glu45-->Ala, 0.95 +/- 0.06 for Lys43-->Ala/Glu45-->Ala and 1.93 +/- 0.09 for Pro44-->Ala. The free energy of interaction between Lys43 and Glu45 is calculated to be only 0.25 +/- 0.09 kcal/mol. From the changes in denaturation midpoint, Tm measured by circular dichroism, we estimate the energy of interaction between Lys43 and Glu45 to be 0.36 +/- 0.07 kcal/mol whereas the contribution of Pro44 is approximately 2.0 kcal/mol. The contribution of the salt bridge to the stability of the protein is very small and the residue Pro44 plays the key role in stabilizing the turn.

Amino Acid Sequence↗
PubMed1994

Extrapolation to water of kinetic and equilibrium data for the unfolding of barnase in urea solutions.

Assumptions about the dependence of protein unfolding on the concentration of urea have been examined by an extensive survey of the equilibrium unfolding of barnase and many of its mutants measured by urea denaturation and differential scanning calorimetry. The free energy of equilibrium unfolding and the activation energy for the kinetics of unfolding of proteins are generally assumed to change linearly with [urea]. A slight downward curvature is detected, however, in plots of highly precise measurements of logku versus [urea] (where ku is the observed rate constant for the unfolding of barnase). The data fit the equation logku = logkuH2O* + mku*.[urea] - 0.014[urea]2, where mku* is a variable which depends on the mutation. The constant 0.014 was measured directly on four destabilized mutants and wild-type, and was also determined from a global analysis of data from > 60 mutants of barnase. Any equivalent deviations from linearity in the equilibrium unfolding are small and in the same region, as determined from measurements on 166 mutants. The free energy of unfolding of barnase, delta GU-F, appears significantly larger by 1.6 kcal mol-1 when measured by calorimetry than when determined by urea denaturation. However, the changes in delta GU-F on mutation, delta delta GU-F, determined by calorimetry and by urea denaturation are identical. We show analytically how, in general, the curvature in plots of activation or equilibrium energies against [denaturant] should not affect the changes of these values on mutation provided measurements are made over the same concentration ranges of denaturant and the curvature is independent of mutation.

Bacillus↗
PubMed1994

Percutaneous adrenal biopsy: review of a 10-year experience.

PURPOSE: To evaluate the indications for and complications, accuracy, and techniques of percutaneous adrenal biopsy performed from 1982 through 1991 at the authors' institution. MATERIALS AND METHODS: Two hundred seventy-seven percutaneous adrenal biopsies were performed in 270 patients (175 male and 102 female patients, aged 31-84 years). Imaging studies and histories were reviewed, and each patient's case was followed up for at least 1 year after the biopsy. A patient was excluded from the study only if follow-up data could not be obtained. RESULTS: The accuracy of percutaneous adrenal biopsy was 90% (249 of 277 biopsies). In the first 5 years of the study, the accuracy was 85% (87 of 102 biopsies); in the latter 5 years it was 93% (163 of 175 biopsies). The sensitivity was 81%, and the specificity was 99%. The positive predictive value was 99%, and the negative predictive value was 80%. The complication rate was 2.8%. CONCLUSION: Percutaneous biopsy is a safe, accurate procedure for the diagnosis of pathologic conditions of the adrenal glands. The most common indication for a biopsy is the presence of an adrenal mass in a patient with lung cancer.

Adrenal Gland Neoplasms↗
PubMed1994

Postoperative apnoea in infants.

Past studies concerning postoperative apnoea in infants were identified and reviewed. A total of only 200 former preterm infants having minor surgery under general anaesthesia have been prospectively studied. The incidence of apnoea after general anaesthesia is approximately 30%, and is inversely related to postconceptual age. A large number of term infants have been studied, and the incidence of postoperative apnoea is very low. The initial apnoea is always within 12 hours of surgery, though only one study has collected data beyond this length of time. Past history of apnoea episodes, bronchopulmonary dysplasia, anaemia or neurological disease may be associated with an increased risk, though current evidence is not strong. No patient characteristic apart from postconceptual age has enough sensitivity and specificity to identify a high-risk group. The use of spinal anaesthesia or methylxanthines may reduce the incidence of postoperative apnoea, but again the evidence is not strong. Recommendations concerning the timing of elective surgery and the use of postoperative respiratory monitoring in the former preterm infant can only be made cautiously in view of the paucity of data on which to base them.

Age Factors↗
PubMed1994

Rectal indomethacin for analgesia after appendicectomy in children.

A prospective randomised controlled trial comparing rectal indomethacin with placebo was performed in children. Thirty children aged seven years and over undergoing open appendicectomy were given suppositories of either indomethacin 2 mg/kg or placebo. Suppositories were given at the conclusion of surgery and again 12 and 24 hours later. All children were given morphine by a patient-controlled analgesia pump. After 36 hours, children given indomethacin had used 0.51 (SD 0.34) mg/kg, and children given placebo 0.91 (SD 0.46) mg/kg (P < 0.02). Pain scores measured with a visual analogue scale, sedation scores and the incidence of vomiting were similar in both groups. Children given indomethacin suppositories used 44% less morphine than children given placebo, and at the same time obtained similar postoperative analgesia.

Administration, Rectal↗
PubMed1994

Trained motor imitation by bottlenose dolphins (Tursiops truncatus).

Each of two bottlenose dolphins, Tursiops truncatus, was trained to mimic a set of behaviors on command. They were tested on transfer of the mimic command to a set of familiar behaviors which they had not previously been commended to mimic. They were similarly tested on two novel behaviors. One dolphin demonstrated complete mimicry of 5 of 11 familiar behaviors; the other dolphin mimicked 1 of 9 behaviors. None of the mimicked behaviors was exhibited to an inappropriate model, suggesting that performance was not due to chance. Neither dolphin imitated the novel behaviors.

Animals↗