Fluconazole therapy in coccidioidal meningitis maintained with intrathecal amphotericin B.

BACKGROUND: Meningitis follows approximately 0.15% to 0.75% of cases of extrapulmonary coccidioidomycosis. Successful treatment of coccidioidal meningitis (CM) has generally required intrathecal therapy with amphotericin B, which often causes significant toxic effects and discomfort to the patient. Prior to fluconazole, azoles had not been efficacious in CM either because of toxicity at elevated doses or because of poor cerebrospinal fluid distribution. Fluconazole however, has been found to have both good cerebrospinal fluid penetration and a favorable side effect profile. METHODS: We studied 11 patients with CM who were maintained with amphotericin B and were then switched to oral fluconazole therapy alone at a dosage of 400 mg/d for a period of up to 19 months. The patients were evaluated clinically for evidence of deterioration measured by need for hospitalization, development of extrameningeal disease during the study period, need to reinstitute intrathecal amphotericin B therapy because of worsening disease, cerebrospinal fluid leukocyte count, protein level, and serologic tests for complement-fixing antibody. RESULTS: Three patients required hospitalization during the study, two patients for reasons unrelated to CM. No patient developed extrameningeal disease or required discontinuation of fluconazole therapy because of deteriorating disease. Patients at exit reported no symptoms related to meningitis or adverse effects related to fluconazole therapy. There was no deterioration in general health or neurologic status. CONCLUSIONS: Our study demonstrates that conversion from amphotericin B to fluconazole was associated with a stable disease course of CM for up to 19 months. Further studies delineating both optimal dosage and characteristics of patients likely to respond to fluconazole therapy alone are needed.

Inclusion of solvation free energy with molecular mechanics energy: alanyl dipeptide as a test case.

A combined force field of molecular mechanics and solvation free energy is tested by carrying out energy minimization and molecular dynamics on several conformations of the alanyl dipeptide. Our results are qualitatively consistent with previous experimental and computational studies, in that the addition of solvation energy stabilizes the C5 conformation of the alanyl dipeptide relative to the C7.

Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnel syndrome.

Clinical evaluation was made of cross-over treatments by pyridoxine and a placebo of patient 22 having the carpal tunnel syndrome. Extraordinary monitoring of the specific activities of the erythrocyte glutamic oxaloacetic transaminase proved a severe vitamin B6 deficiency, which was partially corrected by the Recommended Dietary Allowance of 2 mg, and completely corrected by 100 mg. The severity of the syndrome diminished on the Recommended Dietary Allowances and the patient was asymptomatic at the higher dosage. On placebo, both the vitamin B6 deficiency and syndrome reappeared. Retreatment with 100 mg again corrected both the deficiency and syndrome. Measurements (total n = 19) of flexion of proximal interphalangeal joints of the index fingers by a goniometer, and of pinch by the Preston gauge revealed objective normalization. Scores of 17 symptoms revealed reductions at both the 2- (P less than 0.01) and 100-mg (P less than 0.001) dosages. Conduction through the carpal tunnels had improved by electromyography. These and previous data on a total of 22 patients showed the concomitant presence of a deficiency of vitamin B6 and the carpal tunnel syndrome; a causal relationship is apparent.

Coccidioidomycosis in pregnancy during an epidemic in California.

OBJECTIVE: To determine presentation, clinical course, and outcome of a cohort of pregnant women with coccidioidomycosis and compare findings with common observations reported in the literature. METHODS: Thirty-two women who delivered live infants or aborted fetuses in 1993 and had confirmed diagnoses of coccidioidomycosis were included in the study. Medical records were evaluated retrospectively for clinical characteristics, laboratory results, and disease course. RESULTS: Dissemination occurred in three of 32 cases. The most common management was supportive and symptomatic care. At 1 year, 26 of 32 had recovered. There were no maternal deaths. CONCLUSION: The common depiction of coccidioidomycosis in pregnancy has overstated morbidity and mortality likely because of reporting bias. Many women will have favorable outcomes without drug treatment, and the practice of abortions or early delivery in subjects with active infection should be rare.

Prospective surveillance of antibiotic-associated coagulopathy in 970 patients.

N-methyl-thio-tetrazole (NMTT) has been proposed as a causative factor in antibiotic-associated coagulopathy. To evaluate this hypothesis, a nationwide surveillance program was initiated to determine the relative frequency of antibiotic-associated coagulopathy and the importance of specific risk factors. A total of 970 patients were studied, with 491 being treated for infections and 479 receiving antimicrobial surgical prophylaxis. The NMTT-containing antibiotic cefotetan was compared with non-NMTT-containing antibiotics, for example, cefoxitin and cefazolin (prophylaxis only), and an aminoglycoside-antianaerobic (AG + AA) combination. Prothrombin time (PT) and partial thromboplastin time (PTT) were measured for each patient prior to the start of antibiotics and within 24-96 hours after the conclusion of drug administration. The patient population was relatively young [mean (SD) age 51.0 (20) yrs] with good nutritional status. The overall frequency of hypoprothrombinemia (4.5%) and bleeding (1.7%) was very low, and was highest with the use of AG + AA (p less than 0.05). No statistical differences were observed for the remaining antibiotic regimens in either the prophylaxis or treatment group. Logistic regression analysis identified treatment with the AG + AA combination, presence of liver disease, and renal dysfunction as factors associated with an increased risk of hypoprothrombinemia. In conclusion, this study suggests that the frequency of antibiotic-associated coagulopathy is low, regardless of antibiotic, in patients who are not critically ill and not malnourished.

The effect of methylation of the 6 oxygen of guanine on the structure and stability of double helical DNA.

The effect of methylation of the O-6 position of guanine in short segments of double helical DNA has been investigated by molecular mechanical simulations on the sequences d(CGCGCG)2, d(CGC[OMG]CG)2, d(CGT[OMG]CG)2, d(CGC[OMC]CG/(CGCGCG), d(CGC[OMG]CG/d(CGTGCG), d(CGCGAATTCGCG)2 and d(CGCGAATTC[OMG]CG)2. Guanines methylated at the O-6 position are found to form hydrogen bonds of roughly equal strength to cytosine and thymine. The optimum structure of these modified base pairs are not dramatically different from normal GC pairs, but both involve some bifurcation of the proton donors of cytosine (4NH2) or thymine (3NH) between the guanine N3 and O6 groups.

Do thallium myocardial perfusion scan abnormalities predict survival in sarcoid patients without cardiac symptoms?

Whereas the total mortality rate for sarcoidosis is 0.2 per 100,000, the prognosis, when the heart is involved, is very much worse. The authors used the difference in mortality rate to infer whether thallium 201 myocardial perfusion scan abnormalities correspond to myocardial sarcoid by making the simplifying assumption that if they do, then patients with abnormal scans will be found to have a death rate similar to patients with sarcoid heart disease. The authors therefore analyzed complete survival data on 52 sarcoid patients without cardiac symptoms an average of eighty-nine months after they had been scanned as part of a protocol. By use of survival analysis (the Cox proportional hazards model), the only variable that was significantly associated with survival was age. The patients' scan pattern, treatment status, gender, and race were not significantly related to survival. The authors conclude that thallium myocardial perfusion scans cannot reliably be used to diagnose sarcoid heart disease in sarcoid patients without cardiac symptoms.

Risk factors in alcoholic cardiomyopathy.

Although a relationship has been suggested between abstinence from alcohol and improvement in left ventricular (LV) function, no long-term studies in large groups of patients have been done to confirm this impression or to demonstrate an effect on survival. To address these questions, the authors analyzed the outcome in 105 male patients with alcoholic cardiomyopathy and 64 control male patients with nonalcoholic dilated cardiomyopathy. Survival data were available for all patients. The correlates of survival were assessed via the Cox proportional hazards model. Variables considered were age, race, drinking pattern (current drinker versus former drinker), presence of coronary artery disease (CAD), hypertension, and diabetes, and these echo variables: left atrial (LA) size, posterior wall thickness, LV end diastolic dimension (LVDD), minimal E point septal separation, wall motion, presence of incomplete mitral leaflet closure (IMLC) or low cardiac output, and the ratio of relative wall thickness to LVDD. The two study groups were comparable with respect to all echocardiographic variables. At a mean follow-up of 17.2 months +/- 12.1 months, 42.85% of the alcoholics and 41% of the nonalcoholics had died. Nonsurvival in the alcoholic group was significantly associated with only two factors: an increased LVDD and the presence of IMLC. The drinking pattern was not significantly associated with survival. By contrast, in the nonalcoholics,the variables most closely related to survival were LVDD, low cardiac output, increasing age, and abnormal wall motion. Therefore: (1) the risk factors in alcoholic and nonalcoholic cardiomyopathy are similar although IMLC appears to be a relatively specific prognostic factor for alcoholic cardiomyopathy and (2) abstinence from alcohol does not appear to improve survival.

Value of clinical features for distinguishing myxedema ascites from other forms of ascites.

The diagnosis of myxedema ascites is often difficult and delayed, from our experience and the reports of other investigators. To address this situation, previous reports on the diagnosis of ascites were pooled in order to distinguish the features of myxedema ascites from other forms of ascites. These features were confined to variables that would be obtained routinely from patients with ascites requiring paracentesis. The data of 26 patients with myxedema ascites, and 61 patients with ascites from another cause were analyzed. Discriminant analysis was used to select the variables that best separated patients into myxedema and non-myxedema groups. The variables selected were if the ascites was straw-colored or with a protein content less than 2.5 g/dl, if the patient was over age 40, and if there was periorbital edema or hepatomegaly. These variables correctly classified 90.8% of patients. However, considering the roughly 1% prevalence of myxedema ascites among patients with ascites, the predictive value of these variables, in combination, is only 8.7%. With this low rate, these variables should probably not be used to screen for myxedema ascites.

Quarterly U.S. patent review: first quarter, 1999.

The following are among the U.S. patents, issued in the first quarter of 1999, directed to combinatorial chemistry and related technologies. Patent issuances in the field are growing in number. Additionally, patents claiming libraries themselves, as opposed to synthetic methodologies, are becoming more common. It is impossible to be comprehensive. The author would be pleased to recognize additional patents and invites the use of his e-mail address for this purpose.

Relationship between body weight and mortality in men aged 75 years and older.

As our population ages, recommendations about weight control in the elderly will assume increasing importance. But such recommendations are not supported by the literature, in that there is little information about the independent effect of obesity on survival in subjects who are more than 70 years old. We studied body weight, as assessed by Quetelet's index (weight in kilograms divided by the square of the height in meters), in 162 men aged 75 to 98 years (mean age = 81 +/- 5.3). Length of follow-up averaged 28.6 months. Early deaths (those occurring within the first year of the study) were attributed to preexisting morbid conditions. Cox regression was determined for the entire group, and then for the same group with early deaths excluded. Covariates were Quetelet's index, age, race, history of cigarette smoking, glucose intolerance, and hypertension. Two variables, a low Quetelet's index and glucose intolerance, were significantly associated with decreased survival for the entire group. When early deaths were excluded, however, the only variable significantly related to survival was age. These data suggest that the inverse relationship of body weight to mortality in aged men is due to preexisting morbid conditions and that when these morbid conditions are accounted for, body weight is not significantly related to survival. Hence, the relationship between body weight and mortality risk in aged men differs substantially from that in younger adults.

Investigation of the substrate binding and phosphate transfer in adenylate kinase by molecular mechanics.

Molecular mechanics calculations of adenylate kinase (ADK) complexed with ATP, AMP, and Mg2+ have been carried out with three different model-built geometries. The lowest energy structure is that inferred from the X-ray structure, but such a geometry is not as consistent with the inference of an NOE contact between His36 and the ATP C2-H proton as the model of the second lowest energy. We have used the latter structure as a basis for modeling the reaction AMP + ATP----2ADP in the presence of Mg2+ and ADK. The key residues in the enzyme that stabilize the intermediate points in the above reaction are Arg44 and Arg97. This is the first clear picture of how an enzyme can catalyse a reaction which is electrostatically unfavorable.

A classifier system for the diagnosis of disease from routine laboratory values.

LAB VALUES is an expert system that diagnoses the likelihood of various diseases, given the results of routine blood tests. Its knowledge structure employs bit maps. The similarity between a new case and a bit map in the knowledge base is calculated via a similarity score. The system was tested against published cases with definite diagnostic endpoints, and was found to perform well when compared to these published cases. System performance was not improved by incorporating disease frequency into the results.

Free energy calculations on binding and catalysis by alpha-lytic protease: the role of substrate size in the P1 pocket.

We present free energy calculations using molecular dynamics on different substrates of alpha-lytic protease in the gas phase, in solution, while forming a noncovalent Michaelis complex with the enzyme, and in a tetrahedral structure representing a transition state/intermediate for acylation by the enzyme. Various P1 substrates were studied, with P1 = Gly, Ala, Val, and Leu. In qualitative agreement with experiment, the enzyme was calculated to bind and catalyze most effectively substrates with P1 = Ala over those with P1 = Gly, Val or Leu. Also, the calculated relative solvation free energies of Gly----Ala and Ala----Val were in qualitative agreement with experimental values in corresponding model systems. However, the level of quantitative agreement with experiment achieved in our earlier study of relative binding and catalysis of native subtilisin and an Asn-155----Ala mutant was not achieved. We surmise that this is due to the greater difficulty in quantitatively simulating effects that are predominantly van der Waals and hydrophobic compared to those that are hydrogen bonding/electrostatic.

The calcium-phosphorus metabolism expert system module: a program developed in the ALEX Smalltalk/V shell.

The object-oriented computing model of Smalltalk/V proved to be very well suited for the creation of a medical expert system on the diagnosis of calcium-phosphorus metabolism abnormalities. A major reason for this was that a disease could be viewed as a self-contained, active, entity. The expert system is implemented in ALEX, an expert system shell that is written in Smalltalk/V. The shell consists of classes and methods that can be modified, as needed, by the developer. The expert system is, at present, 140,000 bytes in size, and includes 43 diseases, arranged in 7 contexts. Sixty case reports were used to test the expert system. In 30 cases, there was complete agreement between clinician and expert system; in 12 cases, the expert system responded appropriately when presented with diseases that were not known to the system; and in 18 cases, the system gave plausible results.

Clinical and economic evaluation of subsequent infection following intravenous ciprofloxacin or imipenem therapy in hospitalized patients with severe pneumonia.

A recent multicentre clinical study evaluated the safety and efficacy of i.v. ciprofloxacin therapy compared with imipenem-cilastatin in hospitalized patients with severe pneumonia. Monotherapy with i.v. ciprofloxacin was at least equivalent to imipenem in terms of bacteriological eradication and clinical response. In a single-centre, retrospective, post-therapy evaluation of persistent and subsequent infection, the incidence of gram-negative infections and associated costs were compared. The main elements of the economic analysis included costs of additional antimicrobial therapy and hospitalization. Thirty-two patients were randomized into the study, of whom 27 were efficacy-valid. The 13 patients randomized into the ciprofloxacin group were not significantly different from the 14 patients in the imipenem group in terms of clinical parameters. Clinical cure occurred in ten of 13 patients (77%) in the ciprofloxacin group and in seven of 14 (50%) in the imipenem group. Bacteriological eradication was achieved in 11 of 13 (85%) ciprofloxacin-treated and eight of 14 (57%) imipenem-treated patients. Five of 13 (38%) patients in the ciprofloxacin group and nine of 14 (64%) in the imipenem group experienced persistent or subsequent infection requiring post-treatment antimicrobials. In these five ciprofloxacin patients, three had cultures with gram-positive organisms only and two had cultures with both gram-positive and gram-negative organisms. In the nine imipenem-treated patients requiring post-study antimicrobials, all had gram-negative bacteria and three also had gram-positive organisms. The incidence of subsequent gram-negative infection in the two groups (15% vs 64%) was significantly different (P < 0.05). Pseudomonas aeruginosa was isolated from seven patients in the imipenem group but only one in the ciprofloxacin group (P < 0.05). Subsequent costs for post-therapy antimicrobials and hospital stay while receiving study and post-study drug therapy were evaluated; the cost per patient cure was US$29,000 for ciprofloxacin and US$76,000 for imipenem. Initial treatment of severe pneumonia with ciprofloxacin resulted in significantly less subsequent gram-negative infection and was associated with substantially lower curative costs.

Prediction of homologous protein structures based on conformational searches and energetics.

A "knowledge-based" method of predicting the unknown structure of a protein from a homologous known structure using energetics to determine a sidechain conformation is proposed. The method consists of exchanging the residues in the known structure for the sequence of the unknown protein. Then a conformational search with molecular mechanics energy minimization is done on the exchanged residues. The lowest energy conformer is the one picked to be the predicted structure. In the structure of bovine trypsin, the importance of including a solvation energy term in the search is demonstrated for solvent accessible residues, while molecular mechanics alone is enough to correctly predict the conformation of internal residues. The correctness of the model is assessed by a volume error overlap of the predicted structure compared to the crystal structure. Finally, the structure of rat trypsin is predicted from the crystal structure of bovine trypsin. The sequences of these two proteins are 74% identical and all of the significant changes between them are on external residues. Thus, the inclusion of solvation energy in the conformational search is necessary to accurately predict the structure of the exchanged residues.

Load testing of geometric and polycentric total knee replacements.

Static loading of implanted geometric and polycentric knee replacements was conducted in order to define fixation characteristics and load capabilities of the prostheses and the bone prostheses interface. Failures occurred in some specimens at load levels normally encountered across the knee joint during ambulation. Disruption of the tibial bone-cement interface and crushing of the tibial plateau were the modes of failure. There was no failure on the femoral side of the joint. The major determinants of stress failure suggested by this study were: (1) the tibial bone strength, (2) the design of the geometric and polycentric tibial component, and (3) method of component implantation.

Association between facial cutaneous coccidioidomycosis and meningitis.

The skin is frequently a site of extrapulmonary dissemination in patients with coccidioidomycosis. Clinical experience in an endemic area suggests an association between facial cutaneous coccidioidomycosis and meningitis. Awareness of this association is important because coccidioidal meningitis is the most ominous site of spread in coccidioidomycosis. In this study, we assess whether cutaneous dissemination involving the face is associated with meningitis to a greater degree than that limited to the body. We retrospectively reviewed the medical records of 201 patients from 1987 to 1996 with disseminated coccidioidomycosis and found 30 patients with cutaneous involvement. Their mean age was 29.5 +/- 11.6 years; 20 patients were male; 14 were African American, 12 were Hispanic, 3 were white, and 1 was Asian. Nineteen patients had facial involvement, and 11 had isolated body involvement. Meningitis developed in 11 patients, 10 with facial involvement and 1 with only body involvement. Patients with facial lesions were more likely to have meningitis (odds ratio, 11.1; 95% confidence interval, 1.1 to 529, P = .023). The identification of a subgroup of patients at significant risk of developing meningitis may allow earlier detection and perhaps improved management of patients with meningeal disease.

Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group.

Intravenously administered ciprofloxacin was compared with imipenem for the treatment of severe pneumonia. In this prospective, randomized, double-blind, multicenter trial, which included an intent-to-treat analysis, a total of 405 patients with severe pneumonia were enrolled. The mean APACHE II score was 17.6, 79% of the patients required mechanical ventilation, and 78% had nosocomial pneumonia. A subgroup of 205 patients (98 ciprofloxacin-treated patients and 107 imipenem-treated patients) were evaluable for the major efficacy endpoints. Patients were randomized to receive intravenous treatment with either ciprofloxacin (400 mg every 8 h) or imipenem (1,000 mg every 8 h), and doses were adjusted for renal function. The primary and secondary efficacy endpoints were bacteriological and clinical responses at 3 to 7 days after completion of therapy. Ciprofloxacin-treated patients had a higher bacteriological eradication rate than did imipenem-treated patients (69 versus 59%; 95% confidence interval of -0.6%, 26.2%; P = 0.069) and also a significantly higher clinical response rate (69 versus 56%; 95% confidence interval of 3.5%, 28.5%; P = 0.021). The greatest difference between ciprofloxacin and imipenem was in eradication of members of the family Enterobacteriaceae (93 versus 65%; P = 0.009). Stepwise logistic regression analysis demonstrated the following factors to be associated with bacteriological eradication: absence of Pseudomonas aeruginosa (P < 0.01), higher weight (P < 0.01), a low APACHE II score (P = 0.03), and treatment with ciprofloxacin (P = 0.04). When P. aeruginosa was recovered from initial respiratory tract cultures, failure to achieve bacteriological eradication and development of resistance during therapy were common in both treatment groups (67 and 33% for ciprofloxacin and 59 and 53% for imipenem, respectively). Seizures were observed more frequently with imipenem than with ciprofloxacin (6 versus 1%; P = 0.028). These results demonstrate that in patients with severe pneumonia, monotherapy with ciprofloxacin is at least equivalent to monotherapy with imipenem in terms of bacteriological eradication and clinical response. For both treatment groups, the presence of P. aeruginosa had a negative impact on treatment success. Seizures were more common with imipenem than with ciprofloxacin. Monotherapy for severe pneumonia is a safe and effective initial strategy but may need to be modified if P. aeruginosa is suspected or recovered from patients.