PubMed Health⌕ Search

Biomedical subjects

L Crane

Publications and source records attributed to L Crane.

At least 19 recordsLinked to original sources
PubMed2001

Structural basis for a disfavored elimination reaction in catalytic antibody 1D4.

Murine antibody 1D4 selectively catalyzes a highly disfavored beta-elimination reaction. Crystal structures of unliganded 1D4 and 1D4 in complex with a transition-state analog (TSA) have elucidated a possible general base mode of catalysis. The structures of the unliganded and liganded Fabs were determined to 1.80 and 1.85 A resolution, respectively. The structure of the complex reveals a binding pocket with high shape complementarity to the TSA, which is recruited to coerce the substrate into the sterically demanding, eclipsed conformation that is required for catalysis. A histidine residue and two water molecules are likely involved in the catalysis. The structure supports either a concerted E2 or stepwise E1cB-like mechanism for elimination. Finally, the liganded 1D4 structure shows minor conformational rearrangements in CDR H2, indicative of induced-fit binding of the hapten. 1D4 has pushed the boundaries of antibody-mediated catalysis into the realm of disfavored reactions and, hence, represents an important milestone in the development of this technology.

Animals↗
PubMed2001

Avascular necrosis of bone in patients with human immunodeficiency virus infection: report of 6 cases and review of the literature.

In 1998 and 1999, we diagnosed avascular necrosis of bone in 6 patients in our human immunodeficiency virus clinic practice, an incidence of 0.45%, which is 45 times greater than would be expected in the general population. Antiphospholipid antibodies and hyperlipidemia secondary to protease inhibitor therapy have been implicated as possible etiologies; however, these abnormalities cannot explain all cases of avascular necrosis of bone reported in patients with human immunodeficiency virus infection.

Adult↗
PubMed2001

Pneumocystis carinii cytochrome b mutations are associated with atovaquone exposure in patients with AIDS.

This retrospective cohort study was conducted to determine whether Pneumocystis carinii cytochrome b gene mutations in patients with AIDS and P. carinii pneumonia (PCP) are associated with atovaquone exposure. Portions of the P. carinii cytochrome b genes that were obtained from 60 patients with AIDS and PCP from 6 medical centers between 1995 and 1999 were amplified and sequenced by using polymerase chain reaction. Fifteen patients with previous atovaquone prophylaxis or treatment exposure were matched with 45 patients with no atovaquone exposure. Cytochrome b coenzyme Q binding site mutations were observed in 33% of isolates from patients exposed to atovaquone, compared with 6% from those who were not (P=.018). There was no difference in survival 1 month after treatment between patients with or without cytochrome b mutations (P=.14). Thus, cytochrome b mutations are significantly more common in patients with AIDS and PCP with atovaquone exposure, but the clinical significance of these mutations remains unknown.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands.

Several series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline sites (I1 and I2) and alpha-adrenergic (alpha1 and alpha2) receptor ligands. Their pKi values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases alpha-adrenergic affinity. I1 sites are more accessible by phenyl imidazolines substituted by a methyl or a methoxy group at the ortho or meta position. Indeed, 2-(2'-methoxyphenyl)-imidazoline (17) is one of the best I1 ligands ever reported (pKi = 8.53 and I1/I2 > 3388). On the other hand, I2 selectivity increases in the presence of a methyl group in the para position. The original compound, 2-(3'-fluoro-4'-tolyl)-imidazoline (31) is a new potent ligand for the I2 sites with high selectivity (pKi = 8.53 and I2/I1 > 3388).

Adrenal Glands↗
PubMed2000

Pneumocystis carinii mutations are associated with duration of sulfa or sulfone prophylaxis exposure in AIDS patients.

This study was conducted to determine whether Pneumocystis carinii dyhydropteroate synthase (DHPS) gene mutations in AIDS patients with P. carinii pneumonia (PCP) are affected by duration of sulfa or sulfone prophylaxis and influence response to sulfa or sulfone therapy. The P. carinii DHPS genes from 97 AIDS patients with PCP between 1991 and 1999 from 4 medical centers were amplified, using polymerase chain reaction (PCR), and sequenced. Mutations were observed in 76% of isolates from patients exposed to sulfa or sulfone prophylaxis compared with 23% of isolates from patients not exposed (P=.001). Duration of prophylaxis increased the risk of mutations (relative risk [RR] for each exposure month, 1.06; P=.02). Twenty-eight percent of patients with mutations failed sulfa or sulfone treatment; mutations increased the risk of sulfa or sulfone treatment failure (RR, 2.1; P=0.01). Thus, an increased duration of sulfa or sulfone prophylaxis increases the chance of developing a P. carinii mutation. The majority of patients with mutations respond to sulfa or sulfone therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Discontinuation of prophylaxis against Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS: We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS: A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS: Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed1999

A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA)

We enrolled 2,625 human immunodeficiency virus-infected patients into a randomized trial to assess the efficacy and tolerability of daily vs. thrice-weekly trimethoprim-sulfamethoxazole (160 mg/800 mg) for prophylaxis of Pneumocystis carinii pneumonia (PCP). The rate of PCP was 3.5 and 4.1 per 100 person-years in the daily and thrice-weekly groups, respectively, with a relative risk (RR) of 0.82 (95% confidence interval [CI], 0.61-1.09; P = .16) (RR of <1.0 favors daily trimethoprim-sulfamethoxazole). The RR for PCP determined by on-treatment analysis was 0.59 (P = .03). The RR for death was 0.91 (P = .12); for bacterial pneumonia, 0.82 (P = .06); and for combined PCP and bacterial pneumonia, 0.84 (P = .04). Discontinuation due to adverse events occurred more commonly in the daily trimethoprim-sulfamethoxazole group (RR, 2.14; 95% CI, 1.73-2.66; P < .001). Overall estimates for efficacy end points favored daily trimethoprim-sulfamethoxazole, although rates of intolerance were higher among patients receiving that dose. Daily trimethoprim-sulfamethoxazole may offer advantages as a first choice for PCP prophylaxis; thrice-weekly dosing is an appropriate option for patients intolerant of the daily dose.

AIDS-Related Opportunistic Infections↗
PubMed1998

Statistical issues for HIV surrogate endpoints: point/counterpoint. An NIAID workshop.

This paper summarizes the proceedings of an NIAID-sponsored workshop on statistical issues for HIV surrogate endpoints. The workshop brought together statisticians and clinicians in an attempt to shed light on some unresolved issues in the use of HIV laboratory markers (such as HIV RNA and CD4+ cell counts) in the design and analysis of clinical studies and in patient management. Utilizing a debate format, the workshop explored a series of specific questions dealing with the relationship between markers and clinical endpoints, and the choice of endpoints and methods of analysis in clinical studies. This paper provides the position statements from the two debaters on each issue. Consensus conclusions, based on the presentations and discussion, are outlined. While not providing final answers, we hope that these discussions have helped clarify a number of issues, and will stimulate further consideration of some of the highlighted problems. These issues will be critical in the proper assessment and use of future therapies for HIV disease.

Biomarkers↗
PubMed1998

Management of elevated intracranial pressure in patients with Cryptococcal meningitis.

BACKGROUND: The most important predictor of early mortality in patients with HIV-associated cryptococcal meningitis is mental status at presentation; patients who present with altered mental status have up to 25% mortality. Historically, cerebrospinal fluid (CSF) diversion in HIV-negative patients with cryptococcal meningitis and signs of elevated intracranial pressure (ICP) has improved survival. In an effort to affect survival and morbidity rates in patients with HIV-associated cryptococcal meningitis, we have initiated aggressive management of elevated ICP in patients with focal neurologic deficits, mental obtundation, or both. METHODS: We identified 10 patients with HIV-associated cryptococcal meningitis who presented with symptoms consistent with elevated ICP, including headache, mental obtundation, papilledema, and cranial nerve palsies. Elevated opening pressure was defined as > 20 cm CSF during lumbar puncture. In patients with elevated opening pressures who had focal neurologic deficits or mental status changes refractory to serial lumbar puncture, management consisted of immediate placement of lumbar drains for continuous drainage of CSF to maintain normal ICP (10 cm CSF). Patients with persistent elevations of spinal neuraxis pressure following lumbar drainage underwent placement of lumbar peritoneal shunts. RESULTS: All patients returned to their baseline level of consciousness following normalization of ICP. Two patients were weaned from lumbar drainage. Eight patients eventually required placement of lumbar peritoneal shunts for persistently elevated ICP despite successful antifungal therapy. Follow-up ranged from 1 to 15 months. One shunt infection occurred, one lumbar peritoneal shunt was converted to a ventriculoperitoneal shunt, and one shunt was removed. CONCLUSIONS: Elevated ICP in patients with HIV-associated cryptococcal meningitis is a significant source of morbidity and mortality. The use of lumbar drainage and selective placement of lumbar peritoneal shunts in the management of elevated ICP in patients with HIV-associated cryptococcal meningitis can ameliorate the sequelae of elevated ICP.

Adult↗
PubMed1996

Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. Investigators for the Terry Beirn Community Programs for Clinical Research on AIDS.

BACKGROUND: We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection. METHODS: A total of 1102 patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter were randomly assigned to receive zidovudine alone or zidovudine combined with either didanosine or zalcitabine. Disease progression, survival, toxic effects, and the CD4 cell response were assessed. RESULTS: After a median follow-up of 35 months, disease progression or death occurred in 62 percent of the 363 patients assigned to zidovudine plus didanosine, 63 percent of the 367 assigned to zidovudine plus zalcitabine, and 66 percent of the 372 assigned to zidovudine only (P=0.24). As compared with zidovudine therapy, treatment with zidovudine plus didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03), and treatment with zidovudine plus zalcitabine was associated with a relative risk of 0.92 (95 percent confidence interval, 0.76 to 1.10). Survival was similar in the three groups. In a subgroup analysis, combination therapy delayed disease progression or death in patients who had previously received zidovudine for 12 months or less. Therapy with zidovudine plus didanosine resulted in more gastrointestinal adverse effects, and treatment with zidovudine plus zalcitabine, more neuropathy. The mean increases in CD4 cell counts at two months were higher with combination therapy than with zidovudine alone. CONCLUSIONS: In patients with advanced HIV infection, combination therapy with zidovudine and either didanosine or zalcitabine is not superior to zidovudine therapy alone. However, these combinations may be more effective than zidovudine monotherapy in patients with little or no previous zidovudine treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Cytomegalovirus sinusitis. A new manifestation of AIDS.

Cytomegalovirus is a common pathogen in patients infected with the human immunodeficiency virus. In this article, cytomegalovirus sinusitis is described and documented for the first time, to our knowledge. Cytomegalovirus was cultured from the sinuses of four patients who were positive for the human immunodeficiency virus and who had antibiotic-resistant infections. In one patient who underwent surgery, cytomegalovirus inclusions were documented consistent with invasive infection. Optimal treatment has yet to be determined, but in this case surgery did provide temporary relief of sinus symptoms.

AIDS-Related Opportunistic Infections↗
PubMed1996

Adrenal insufficiency, recurrent bacteremia, and disseminated abscesses caused by Nocardia asteroides in a patient with acquired immunodeficiency syndrome.

Nocardia asteroides is an opportunistic pathogen of increasing incidence in human immunodeficiency virus (HIV)-infected persons. The lungs are the most common site of infection, followed by the brain; involvement of other extrapulmonary sites is less common. We describe a patient with acquired immunodeficiency syndrome who presented with a number of unique manifestations of nocardial infection: the first reported case of bilateral adrenal abscesses with adrenal insufficiency, the first case of a renal abscess due to N. asteroides alone, and the first case of recurrent, symptomatic bacteremia. A review of the literature on nocardial infections in HIV-positive individuals is presented.

AIDS-Related Opportunistic Infections↗
PubMed1994

Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. A randomized, double-blind clinical trial. The Bristol-Myers Squibb AI454-010 Study Group.

OBJECTIVE: To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. DESIGN: Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. SETTING: Outpatient clinics at 19 tertiary care medical centers. PATIENTS: 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. INTERVENTION: Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). MEASUREMENTS: Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)--defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. RESULTS: Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% Cl, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; Cl, 1.1 to 4.4). CONCLUSIONS: This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.

AIDS-Related Complex↗
PubMed1994

The effect of exercise training on pulmonary function in persons with quadriplegia.

The purpose of this study is to determine if measures of pulmonary function are different between endurance trained and nontrained groups of persons with quadriplegia. After minimum criteria were met, 57 subjects with spinal cord injuries ranging from C5-T1 were surveyed to determine type, duration and intensity of exercise training for the previous 6 months. Subjects were assigned to the trained or untrained groups based on the operational definitions of 'trained' vs 'untrained'. A computerized spirometer was used to test forced vital capacity (FVC), forced mid-expiratory flow (FEF25-75%) and maximum voluntary ventilation (MVV) as indicators of respiratory muscle strength, airway patency and respiratory muscle endurance, respectively. Independent t tests and Wilcoxon-Mann-Whitney nonparametric tests revealed no significant differences between the 'trained' and 'untrained' groups for the pulmonary functions. Correlation analysis revealed a moderate relationship (r = 0.498; p < or = 0.0001) between a derived continuous variable called the weighted training equivalent (WTE) and FVC. Regression analysis revealed that WTE and level of injury accounted for approximately 30% of the variance of FVC with WTE contributing 25%. Exercise training may positively affect FVC in persons with quadriplegia.

Adult↗
PubMed1992

Diagnosis of acute diffuse pulmonary infiltrates in immunosuppressed patients by open biopsy of the lung.

Herein is a review of the results of open biopsies of the lung performed upon immunosuppressed patients between the years 1982 and 1988. The goal was to assess the safety and value of the procedure on a group of patients who are many times in extremis because of multiorgan failure. Obtaining the correct diagnosis and establishing treatment poses a challenge. The study includes 74 patients. Fifty-four had malignant tumors; 20 had various diseases associated with immunosuppression. The biopsy was obtained from the left side in 65 instances. An adequate thoracotomy was done to permit exploration of the thoracic cavity and obtain a representative sample of tissue. The mortality rate related to the operation was 1.4 percent and the complication rate was 11.0 percent. Forty-six percent of the infiltrates were the result of infection. In 42 percent, a change in treatment was made. Thirty-two percent survived and were discharged from the hospital. Patients with adverse drug reaction, with nonspecific pneumonitis and with bacterial infection had a favorable prognosis and benefited most from open biopsy of the lung.

Acute Disease↗
PubMed1991

The role of infection in the morbidity and mortality of patients with head and neck cancer undergoing multimodality therapy.

Cancer of the head and neck is a common cancer worldwide. The majority of patients present with locally advanced disease. Recently a great deal of improvement has been made in multimodality therapy of this disease, warranting more careful consideration of factors affecting quality of life, disease course, and treatment. Infection is clearly a factor. Analysis of 662 hospital admissions of 169 head and neck cancer patients was performed. A definite infection was documented in 86 febrile episodes, pneumonia contributed to 40%, bacteremia to 13%, skin and soft tissue infection to 12%, and tracheobronchitis to 10%. Among the evaluated risk factors, foreign bodies, specifically intravenous (IV) cannulae and gastrostomy tubes, race, performance status, alcohol intake, and nutritional status were statistically significant variables that predicted for or were associated with infection. Infection contributed to 44% of the deaths.

Adult↗
PubMed1986

Successful treatment of disseminated Trichosporon beigelii (cutaneum) infection with associated splenic involvement.

Fungemia caused by Trichosporon beigelii (cutaneum) has been recently recognized as a fatal infection afflicting immunocompromised patients. The authors report the case of a leukemic patient who developed splenic infection from disseminated T. beigelii. Treatment with amphotericin B, 5-fluorocytosine, and splenectomy proved successful. The etiology of disseminated T. beigelii infection, visceral seeding, and combination antifungal therapy also are discussed.

Adult↗