Conformational energies are calculated for the glycyl and alanyl dipeptides using four different molecular mechanical models: (1) the Cornell et al. additive force field with phi and psi dihedral parameters V-n/2 set to 0; (2) the standard Cornell et al. additive force field; (3) an alternative version of (2) with phi and psi parameters optimized to fit high level ab initio energies calculated for all-alpha(r) and all-beta alanine tetrapeptides; and 4) a non-additive variation of (1) which includes atom-centered charge polarization. Molecular mechanical energies are calculated with each model for low energy conformations of glycyl and alanyl dipeptides and compared with high level ab initio calculations. In addition, phi-psi maps are calculated and plotted for all four models and compared.

An unprecedented epidemic of coccidioidomycosis began in 1991 in the Southern San Joaquin Valley of California. Data from medical records and patient interviews of 536 cases with laboratory-confirmed diagnosis from the Kern County Health Department were analyzed for hospital days, return clinic visits, drug usage, and employment status. Estimates of work days missed were made from historical and current data from the military. Usual costs for hospital days and return clinic visits, and average wholesale acquisition prices for antifungal medications were utilized for medical costs. Lost wages were estimated from the employment rate in the epidemic population and salary estimates according to race from the 1990 census in Kern County.A total yearly cost per case of $8,096 was calculated from this analysis, with 63 percent attributed to hospitalization, 18 percent to clinic visits, 12 percent to lost wages, and 7 percent to the cost of drug treatment. Nondisseminated cases averaged $5,400 as compared to $48,000 for those with dissemination. Twenty-three percent of total cost was due to disseminated disease, which was present in only 4 percent of the infected population.The total estimated cost for 7,130 cases occurring from 1991 to 1993, utilizing these methods, is more than $56 million. This does not include the cumulative costs of continuing care, beyond 1 year, for those with chronic disease and disability.

Fluconazole, a significant advance in treating disseminated coccidioidomycoses (DC), is frequently required in doses > 400 mg. We retrospectively evaluated 70 consecutive patients receiving fluconazole (F) for adverse effects (AE's). All patients had DC. The mean age of the 47 males and 23 females was 33 years. Fifty-five (percent) had meningitis and fifteen (19 percent) had other sites of dissemination. All patients received F in doses ranging hom 400 mg to 1200 mg/day. Twenty three (32 percent) received 400 mg only, while 47 (68 percent) required higher doses. Adverse events were more common with higher doses. Fifty percent of 57 patients receiving daily F 400 mg had at least one AE, as compared to 60 percent of 47 on greater than or equal to 800 mg. Multiple AE's occurred in 16 percent when receiving 400 mg as compared to 34 percent when doses were greater than or equal to 800 mg (p = 0.05). AE's in order of frequency were: nausea/vomiting (27 percent), weightless (23 percent), arthralgias (16 percent), alopecia (14 percent), skin reactions (14 percent), increased alkaline phosphatase (11 percent), abdominal pain (5.7 percent), and increased transaminases (5 percent). Mean serum levels ranged from 18mcg/ml for skin reactions to 26mcg/ml for alkaline phosphatase elevations. Dose limiting reactions (7 nausea/vomiting, 3 increased transaminases, 5 other) occurred in 15 patients (21 percent). Seventy-five percent of the time, patients had stable or improving disease symptoms at the time AE's were noted. One patient with fatty liver was removed from therapy.Adverse reactions to F are dose related and significantly higher when doses equal or exceed 800 mg in DC. Nausea and vomiting, weight loss, alopecia, and arthralgias are more common than previously appreciated. Nausea/vomiting and liver-function abnormalities can be temporarily dose limiting. Tolerance to AE's improves over time.

Recently published data demonstrating the efficacy of Fluconazole (F) for coccidioidal meningitis (CM) by the NIAID Mycosis Study Group (MSG) prompted a retrospective evaluation of our experience with patients initially treated with (F) since 1991. Fifty patients from the coccidioidomycosis clinic at Kern Medical Center and the private practices of two investigators were identified for review.Two evaluable groups were identified for comparison who received greater than 3 months treatment at a stable dose. Group I (F-400) consisted of 16 patients treated initially with 400 mg/day for a mean duration of 219 days. Group II (F-800) consisted of 18 patients initially treated with 800 to 1600 mg for a mean duration of 276 days. A third non-evaluable group included 16 patients that did not receive stable dosing or a minimum duration of 3 months. There were no differences in the two patient groups in age, sex, race, or skin test. The unevaluable group had a greater co-morbidity of diabetes.The F-400 and F-800 groups were compared using the MSG-scoring system. Initial baseline scores were 7.81 for the F-400 group and 7.00 for the F-800 group. The F-800 group responded with a mean score of 3.6 (mean duration of 276 days). However, the F 400 group only dropped to 6.5 (mean duration 219 days). A mean score of 3.8 in the F-800 group at 180 days was nearly identical to the 276 day score, suggesting that dose was more important than duration of treatment. Patients with a 40 percent decrease from baseline score were considered responders. Five of 16 (31 percent) in the F 400 group responded, compared to 12 of 18 (67 percent) in the F-800 group (p = 0.04 chi-square). There was one death in each evaluable treatment group. Of the 16 patients in the unevaluable group, there were 3 responders, 7 early deaths, and 6 non-responders. Eleven patients were started on 400 mg and five on 800 mg or greater.Compared with 400 mg, initial doses equal to or greater than 800 mg of fluconazole in coccidioidal meningitis are associated with an improved early response. Evaluation at 1 and 2 years of treatment are necessary to assess the long-term efficacy.

The decision to treat patients with primary coccidioidomycosis sis (CM) is fraught with uncertainty. An ongoing epidemic in Kern County California provided opportunity to evaluate treatment in a community based retrospective analysis. Forty eight percent of patients received drug treatment. Response analysis of treated cases revealed a worse outcome compared to nontreated cases. To evaluate a treatment effect in a comparable population, the following patients were excluded: those cases with early death, given amphotericin B in < 30 days, or with dissemination < 30 days from symptom onset. Fifty-four such cases were removed from study. Determination of dissemination and disease onset were made by two physician-authors blinded to treatment and out come.Two groups were created from the remaining cases based on treatment timing. The ''EarlyRx'' group included those receiving azole treatment in less than 30 days from symptom onset. The ''LateRx'' group included those receiving any antifungal treatment after 30 days.The EarlyRx group had 124 cases and the LateRx group 80. There were no significant differences between patient groups in age, sex, race, or treatment with azoles or amphotericin. The EarlyRx group had a higher rate of skin test negativity (64 percent vs. 47 percent p = 0.08). Patients were evaluated up to 1 year or until recovered. There were five with unknown outcomes in the EarlyRx group and one in the LateRx group. The EarlyRx group had a significantly decreased incidence of peak complement fixation (CF) titer greater than or equal to 1:32 (27 percent vs. 45 percent, p = 0.009), dissemination (2 percent vs. 9 percent, p = 0.05), and chronic disease requiring treatment at 1 year (1.6 percent vs. 10 percent, p = 0.015), Comparing serious disease outcome (dissemination + death + chronic disease) revealed a 6 percent rate for the EarlyRX group and a 16 percent rate for the LateRx group. (p = 0.01).Conclusion: Treatment of moderate eases of CM with azoles initiated less than 30 days from symptom onset appears associated with a significant reduction in peak CF titer > 1:32, dissemination, and chronic disease. Combined serious disease endpoints were reduced by 68 percent.

Contrary to simple expectations about increasing hydrophobicity, successive methylation of ammonia (NH3) does not yield a monotonic increase in the observed solvation free energies; in fact, NH2CH3 is found to be more soluble than NH3. Previous free energy calculations have not reproduced the trend in experimental values. Here, we perform the perturbations NH3 → NH2CH3 and NH3 → N(CH3)3 with explicitly polarizable water and solute. Although the increases in solvation energy with methyl substitution are smaller than with a pairwise-additive model, the methylamines are still calculated to be hydrophobic compared to ammonia. The computed relative solvation energies and solute dipole moments, however, agree remarkably well with previous results obtained with a different implementation of polarizability.

The incidence of coccidioidomycosis has increased dramatically in the Southern San Joaquin Valley of California. Between September 1991 and January 1994 there have been over 7,000 seropositive cases. An average of the 10 years preceding 1991 would have predicted only 1,000 cases during this interval. Cases from September 1, 1991 to January 1, 1992, were selected for review, from which extensive data with 1 year of followup were obtained on 536 patients.Presenting symptoms included fever (76 percent), cough (73 percent), chest pain (44 percent), fatigue (38 percent), chills (28 percent), erythema nodosum (26 percent), shortness of breath (22 percent), and headache (18 percent). Pulmonary disease was most frequently lower lobe in distribution but found in all lobes. Among those with abnormal chest x-rays, infiltrate occurred only in 68 percent, infiltrate with effusion in 10 percent, and infiltrate plus adenopathy in 9.8 percent. Twenty-five cases (4.7 percent) developed disseminated disease, 44 percent of which were meningitis.Disease outcome was evaluated after 1 year of follow-up. Sixty-three percent recovered, 11 percent probably recovered, and 8.2 percent developed serious disease (continued treatment at 1 year, disease dissemination, or death) In 17 percent the outcome was unknown. There were 17 deaths (3.2 percent), thirteen of which were without evidence of dissemination and four where disseminated disease was confirmed.Evaluation of outcome compared individuals with serious disease to those who recovered and those who probably recovered. Stepwise multivariate regression analysis revealed significant associations to serious disease with age, African-American race, negative skin test, and maximum complement fixation titer.

Sepsis continues to be a leading cause of death in the United States. Rarely, Coccidioides immitis has been reported to cause sepsis. In this report we describe the clinical characteristics and cytokine response in a group of eight patients admitted to Kern Medical Center between August 1991 and December 1993 with septic shock secondary to C. immitis. The three females and five males had a mean age of 59.8 years; one was African-American, two were Filipino and five were Hispanic. All presented with fever, chills, shortness of breath, and a productive: cough. Physical findings included tachycardia, tachypnea, and bilateral crackles. Chest x-rays showed diffuse lung infiltrates. All had negative skin reaction to spherulin. The diagnosis was made by demonstration of C. immitis spherules in the sputum. Cocci serology was positive in 75 percent of the patients. All developed adult respiratory distress syndrome that required mechanical ventilation, and subsequently developed septic shock syndrome multisystem failure. All patients showed leukocytosis with shift to the left and developed lactic acidosis. Fifty percent showed peripheral eosinophilia and 25 percent had hypercalcemia. All the patients died despite initiation of rapid sequence amphotericin B therapy within 24-48 hours of admission. Four patients were analyzed for cytotokines, specifically for IL-1, IL-2, IL-6, and tumor necrosis factor (TNF). All four had undetectable IL-I and IL-2 and elevated TNF and IL-6.CONCLUSION: 1. Septics shock secondary to C. immitis cannot be differentiated from bacterial sepsis clinically. 2. IL-1 is undetectable but IL-6 and TNF are elevated in patients with coccidioidal sepsis. 3. The prognosis of coccidioidal sepsis is much more grave than bacterial sepsis. Cytokine Response in Septic Shock Secondary to Coccidioidomycosis. E. Arsura, Y. Ismail, J. Abraham, P. Bellinghausen, J. Caldwell and R. Johnson. Depart ment of Medicine, Kern Medical Center/UCLA.

Molecular dynamics and free energy perturbation have been applied to study the complexation and the selectivity of a host molecule hexaanisole spherand (1) with its metal ion ligands, Two different potential function force fields were tested: a two-body interactive potential with the TIP3P water model and a recently derived polarizable and three-body interactive potential including a polarizable water model. Our results show that the two-body additive potential is able to provide useful information on the relative binding affinities of alkali metal ions, although for the Na+ --> Li+ case the agreement with experiment is only qualitative. The relative binding free energy of Li+ and Na with the hexaanisole spherand is calculated to be -2.7 kcal/mol, compared to the experimental value of < -3.8 kcal/mol. The agreement improved when the mole sophisticated polarizable and three-body interactive potential force field was employed, resulting in a relative binding free energy of Li+ and Na+ of -3.7 kcal/mol. We have also tested different electrostatic charge fitting protocols and models, and the results showed that the choice of protocol is of critical importance for obtaining quantitative agreement with experiment.

We present the derivation of a new molecular mechanical force field for simulating the structures, conformational energies, and interaction energies of proteins, nucleic acids, and many related organic molecules in condensed phases. This effective two-body force field is the successor to the Weiner et al. force field and was developed with some of the same philosophies, such as the use of a simple diagonal potential function and electrostatic potential fit atom centered charges. The need for a 10-12 function for representing hydrogen bonds is no longer necessary due to the improved performance of the new charge model and new van der Waals parameters. These new charges are determined using a 6-31G* basis set and restrained electrostatic potential (RESP) fitting and have been shown to reproduce interaction energies, free energies of solvation, and conformational energies of simple small molecules to a good degree of accuracy. Furthermore, the new RESP charges exhibit less variability as a function of the molecular conformation used in the charge determination. The new van der Waals parameters have been derived from liquid simulations and include hydrogen parameters which take into account the effects of any geminal electronegative atoms. The bonded parameters developed by Weiner et al. were modified as necessary to reproduce experimental vibrational frequencies and structures. Most of the simple dihedral parameters have been retained from Weiner et al., but a complex set of 4 and yj parameters which do a good job of reproducing the energies of the low-energy conformations of glycyl and alanyl dipeptides has been developed for the peptide backbone.

We present the derivation of a new molecular mechanical force field for simulating the structures, conformational energies, and interaction energies of proteins, nucleic acids, and many related organic molecules in condensed phases. This effective two-body force field is the successor to the Weiner et al, force field and was developed with some of the same philosophies, such as the use of a simple diagonal potential function and electrostatic potential fit atom centered charges. The need for a 10-12 function for representing hydrogen bonds is no longer necessary due to the improved performance of the new charge model and new van der Waals parameters. These new charges are determined using a 6-31G basis set and restrained electrostatic potential (RESP) fitting and have been shown to reproduce interaction energies, free energies of solvation, and conformational energies of simple small molecules to a good degree of accuracy. Furthermore, the new RESP charges exhibit less variability as a function of the molecular conformation used in the charge determination. The new van der Waals parameters have been derived from liquid simulations and include hydrogen parameters which take into account the effects of any geminal electronegative atoms. The bonded parameters developed by Weiner et al. were modified as necessary to reproduce experimental vibrational frequencies and structures. Most of the simple dihedral parameters have been retained from Weiner et. al., but a complex set of phi and psi parameters which do a good job of reproducing the energies of the low-energy conformations of glycyl and alanyl dipeptides has been developed for the peptide backbone.

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.

We present the first nonadditive molecular dynamics simulation of organic liquids, studying the structure and energetics of methanol and N-methylacetamide. Beginning with an additive potential that reproduces the structure and energetics of these liquids quite well, we have shown that one can simply reduce the atomic charges by a scale factor in the range of 0.88-0.90 and add isotropic atomic polarizabilities to create nonadditive models that also quite accurately reproduce the structures and energies of these liquids. Thus, we have a clear pathway for the general inclusion of nonadditive effects for organic and biological molecules.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCation-.pi. Interactions: Nonadditive Effects Are Critical in Their Accurate RepresentationJames W. Caldwell and Peter A. KollmanCite this: J. Am. Chem. Soc. 1995, 117, 14, 4177–4178Publication Date (Print):April 1, 1995Publication History Published online1 May 2002Published inissue 1 April 1995https://pubs.acs.org/doi/10.1021/ja00119a037https://doi.org/10.1021/ja00119a037research-articleACS PublicationsRequest reuse permissionsArticle Views1310Altmetric-Citations282LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAccurate Solvation Free Energies of Acetate and Methylammonium Ions Calculated with a Polarizable Water ModelElaine C. Meng, Piotr Cieplak, James W. Caldwell, and Peter A. KollmanCite this: J. Am. Chem. Soc. 1994, 116, 26, 12061–12062Publication Date (Print):December 1, 1994Publication History Published online1 May 2002Published inissue 1 December 1994https://pubs.acs.org/doi/10.1021/ja00105a060https://doi.org/10.1021/ja00105a060research-articleACS PublicationsRequest reuse permissionsArticle Views544Altmetric-Citations40LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

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.

Models of protein structure are frequently used to determine the physical characteristics of a protein when the crystal structure is not available. We developed a procedure to optimize such models, by use of a combined solvation free energy and molecular mechanics force field. Appropriately chosen atomic solvation parameters were defined using the criterion that the resulting protein model should deviate least from the crystal structure upon a forty picosecond molecular dynamics simulation carried out using the combined force field. Several tests were performed to refine the set of atomic solvation parameters which best complement the molecular mechanics forces. Four sets of parameters from the literature were tested and an empirically optimized set is proposed. The parameters are defined on a well characterized small molecule (alanyl dipeptide) and on the highly refined crystal structure of rat trypsin, and then tested on a second highly refined crystal structure of alpha-lytic protease. The new set of atomic solvation parameters provides a significant improvement over molecular mechanics alone in energy minimization of protein structures. This combined force field also has advantages over the use of explicit solvent as it is possible to take solvent effects into account during energetic conformational searching when modeling a homologous protein structure from a known crystal structure.

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.

Recently, Perera and Berkowitz have presented molecular dynamics simulations on Cl-(H2O)14 using two models, one additive (TIP4P) and the other nonadditive (POL1). Rather different structures emerged from then simulations, with the POL1 model predicting "Cl- outside" structures to be more favorable, and TIP4P predicting "Cl- inside to be more favorable. We have carried out ab initio quantum mechanical calculations at the STO-3G, STO-4G(d), 6-31G, 6-31G(d), and 6-31G(d)/MP2 levels on two low energy geometries resulting from each of the molecular dynamics models. At all levels of ab initio theory, the "Cl- outside' model created by POL1 is the lowest in energy with DELTAE0 of -166.4 and -223.7 kcal/mol at 6-31G(d) and 6-31G(d)/MP2. respectively, compared to the average potential energy of -151 kcal/mol found by Perera and Berkowitz.