Effect of pancreatic and leukocyte elastase on hydraulic conductivity in lung interstitial segments.

Elastase-induced changes in flow were used to quantify the degradation of lung interstitial elastin. Degassed rabbit lungs were inflated with silicon rubber via airways and vessels. The lungs were cut into 1-cm-thick sections. Two chambers were bonded to each section to enclose the interstitium surrounding an arterial segment. Flow of albumin solution (0-5 g/dl) between the chambers was followed by that of the albumin solution with 0.25 g/dl pancreatic elastase solution. Driving pressure was 5 cmH(2)0, and mean interstitial pressure was either 0 or 10 cmH(2)O. Elastase caused an increase in flow in approximately 70% of the interstitial segments and a reduction in flow in the remaining segments. The elastase-induced response in flow was independent of both albumin concentration and mean interstitial pressure. Leukocyte elastase (5 units/dl) produced flow responses similar to those of 0.25 g/dl pancreatic elastase. The increased flow of leukocyte elastase was reduced by a subsequent flow with 0.25 g/dl pancreatic elastase but enhanced by a subsequent flow with a 10-fold lower concentration. A change in the order of the elastase flows reversed the concentration-dependent responses. This behavior suggests a complex interaction among the interstitial fibers after degradation by pancreatic and leukocyte elastase. Endogenous elastase-induced increases in interstitial permeability might affect blood-lymph barrier permeability, whereas elastase-induced cessation of flow might be related to the alveolar septal wall destruction observed in emphysema.

Effect of concentration and hyaluronidase on restriction of hetastarch flux through lung interstitial segments.

The transport properties of lung interstitium were studied by measuring the flow of hetastarch solution (2 and 6%) through 1-cm perivascular interstitial segments of rabbit lungs. Hetastarch (10(4)-10(7) Da) solution has a colloid osmotic pressure similar to that of albumin solution. Driving pressure was 5 cm H(2)O and mean interstitial pressure was 0 cm H(2)O. The flows of 2 and 6% hetastarch solutions were measured before (Q(1)) and after (Q(2)) the addition of 0.02% hyaluronidase. Hetastarch molecular distributions in effluent samples were measured by high-performance size-exclusion chromatography (HPSEC) to determine sieving ratio (C(out)/C(in), downstream-to-upstream concentration ratio). Hyaluronidase significantly (P < 0.0004) increased flow sixfold, but the increase in flow (Q(2)/Q(1)) was reduced through the interstitium around smaller vessels. A similar behavior was observed with the flow of albumin solution without and with hyaluronidase. C(out)/C(in) decreased monotonically with molecular weight, was greater with 6% than with 2% (low colloid osmotic pressure) hetastarch, and increased with hyaluronidase. Modeling the transport through uniform pores, equivalent pore radius was 10 and 15 nm with 2 and 6% hetastarch, respectively, and doubled with hyaluronidase. In conclusion, interstitial pores expand in response to an increase in colloid osmotic pressure both before and after tissue degradation by hyaluronidase.

Erythropoietin: a paradigm for the development of practice guidelines.

Erythropoietin (EPO) is an endogenous hormone produced in the kidney that regulates red blood cell production within the body. Since the cloning and first clinical introduction of recombinant erythropoietin (epoetin) in the late 1980s indications and usage of epoetin have expanded significantly. It is estimated that as many as one third of patients with substantial anemia (hemoglobin less than 10.0 g/dL) resulting from chemotherapy for cancer are treated with epoetin. Though use of epoetin may avoid the inconvenience and infectious risk of blood transfusions, it is expensive and its benefit in some clinical scenarios has been modest. Like many new technologies, strong evidence suggesting situations where the benefit is high has lagged behind its adoption by patients and practitioners. As well, epoetin is expensive and third party payers do not always reimburse it. Research suggests there is considerable variation in epoetin usage in practice. To provide guidance to hematology/oncology specialists regarding use of epoetin, the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) proposed that the Agency for Healthcare Research and Quality (AHRQ) fund an evidence review by one of the Evidence-based Practice Centers (EPC) that would be used to develop evidence-based guidelines for members of the society. This review highlights principles of evidence-based medicine, distills and appraises the evidence in the published literature that supports the use of epoetin, and presents evidence-based recommendations for use of epoetin in situations where benefit is substantiated by high-quality studies. As well, this review addresses some of the difficulties of performing clinical research in this area, provocative research findings that will require further study, and suggestions regarding epoetin in those areas where further strong evidence has yet to be developed.

Rapid diagnosis of leishmaniasis by fluorogenic polymerase chain reaction.

A fluorescent DNA probe (LEIS.P1) specific for a conserved region of the small-subunit ribosomal RNA gene of Leishmania and a pair of flanking primers (LEIS.U1 and LEIS.L1) were designed for use in a fluorogenic polymerase chain reaction. Optimal assay conditions with zero background were established to detect low levels of Leishmania from clinical samples. By use of this assay, we amplified DNA from 27 strains of cultured Leishmania (both Old and New World strains) and selectively amplified Leishmania DNA from 12 paraffin-embedded human biopsy samples and 3 fresh human skin biopsy specimens. For the fresh human tissue biopsies, the turnaround time from biopsy to test result was < 24 hr. No amplification was detected in negative control samples (including the kinetoplastid protozoa Trypanosoma rangelli and Crithidia fasiculata). This assay provides a specific and rapid diagnostic modality to detect infection with Leishmania.

Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials.

Epoetin treatment offers an attractive but costly alternative to red blood cell transfusion for managing anemia associated with cancer therapy. The goal of this review is to facilitate more efficient use of epoetin by 1) quantifying the effects of epoetin on the likelihood of transfusion and on quality of life in patients with cancer treatment-related anemia and 2) evaluating whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds. Two independent reviewers followed a prospective protocol for identifying studies. Outcomes data were combined with the use of a random-effects meta-analysis model. Double-blind, randomized, controlled trials that minimized patient exclusions were defined as higher quality for sensitivity analysis; randomized but unblinded trials and trials with excessive exclusions were included in the meta-analysis but were defined as lower quality. Twenty-two trials (n = 1927) met inclusion criteria, and 12 (n = 1390) could be combined for estimation of odds of transfusion. Epoetin decreased the percentage of patients transfused by 9%-45% in adults with mean baseline hemoglobin concentrations of 10 g/dL or less (seven trials; n = 1080), by 7%-47% in those with hemoglobin concentrations greater than 10 g/dL but less than 12 g/dL (seven trials; n = 431), and by 7%-39% in those with hemoglobin concentrations of 12 g/dL or higher (five trials; n = 308). In sensitivity analysis, the combined odds ratio for transfusion in epoetin-treated patients as compared with controls was 0.45 (95% confidence interval [CI] = 0.33 to 0.62) in higher quality studies and 0.14 (95% CI = 0.06 to 0.31) in lower quality studies. The number of patients needed to treat to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with mean baseline hemoglobin concentrations of 10 g/dL or less reported statistically significant effects of epoetin treatment on quality of life; quality-of-life data were insufficient for meta-analysis. No studies addressed epoetin's effects on anemia-related symptoms. We conclude that epoetin reduces the odds of transfusion for cancer patients undergoing therapy. Evidence is insufficient to determine whether initiating epoetin earlier spares more patients from transfusion or results in better quality of life than waiting until hemoglobin concentrations decline to nearly 10 g/dL.

Biliary giardiasis in a patient with human immunodeficiency virus.

A 41-year-old man with human immunodeficiency virus (HIV) (CD4 count, 446/mm3) developed a protracted course of abdominal pain, weight loss, and increasing liver function tests after undergoing a metronidazole treatment regimen for Giardia enteritis. Three months later, endoscopic retrograde cholangiography (ERCP) showed dilated common and intrahepatic bile ducts and luminal irregularities of the common bile duct. Seven months after the onset of his acute diarrhea, a repeat ERCP with aspiration demonstrated many Giardia trophozoites and cysts in the bile and continued structural abnormalities consistent with cholangiopathy. A 10-day course of high-dose intravenous metronidazole did not resolve these signs or symptoms. A gallbladder ultrasound showed a thickened wall. Laparoscopic cholecystectomy led to resolution of abdominal pain and normalization of serum alkaline phosphatase over an 8-month period. Gallbladder histopathology revealed chronic cholecystitis, but no parasites were seen on hematoxylin and eosin staining or with Giardia antigen enzyme immunoassay testing of the gallbladder. The patient refused to undergo a follow-up ERCP, but a right upper quadrant ultrasound and computed tomography of the abdomen were normal.

Selective serotonin reuptake inhibitors and isoniazid: evidence of a potential adverse interaction.

BACKGROUND: Recognizing a potential interaction between isoniazid (INH), a weak monoamine oxidase inhibitor, and serotonin reuptake inhibitors (SSRIs), we assessed medication discontinuation rates in human immunodeficiency virus-infected individuals taking an SSRI, INH, or both. METHOD: We retrospectively reviewed treatment records to determine if patients on an SSRI, INH, or both completed drug therapy in accordance with a treatment plan (e.g., 12 months of INH therapy). Patients on both medications constituted the study group; patients taking either an SSRI or INH alone constituted comparison groups. RESULTS: There were no significant differences between the groups based on age, gender, CD4%, or CD4 count. Seven of the 10 patients (70%) in the study group discontinued therapy, which was significantly greater than the 2 of 14 (14%) in the SSRI group (P = 0.01) and the 4 of 18 (22%) in the INH group (p = 0.02) who discontinued therapy. CONCLUSION: Medication discontinuation rates for patients prescribed an SSRI coincident with INH were significantly higher than for individuals prescribed these medications separately. These differences cannot be accounted for on the basis of age, gender, or CD4%, but they may be attributable to increased side effects caused by interactions between these medications.

Infected endovascular stents managed with medical therapy alone.

More than 400,000 endovascular stents are put in place in the United States annually. Infectious complications have been reported in fewer than one in 10,000 cases. It remains unclear whether the optimal management strategy for these patients is with medicine alone or surgery. We report two cases of endovascular stent infections that were treated successfully with antibiotics alone.

Clinical implications of identifying non-B subtypes of human immunodeficiency virus type 1 infection.

Although human immunodeficiency virus type 1 (HIV-1) infection in the United States has predominantly involved subtype B, increasing global travel is leading to wider dissemination of genetically heterogeneous subtypes. While physicians depend on HIV-1 viral load measurements to guide antiretroviral therapy, commonly used molecular assays may underestimate the viral load of patients with non-B subtypes. Nine patients with non-B subtypes of HIV-1 were identified by physicians who suspected a non-B subtype on the basis of a low or undetectable HIV-1 viral load, by the Amplicor HIV-1 Monitor test, version 1.0, in conjunction with either a declining CD4 cell count or history of travel outside the United States. Use of version 1.5 of the Amplicor HIV-1 Monitor test detected a median HIV-1 viral load that was 2.0 log(10) RNA copies/mL higher than was determined with version 1.0. Clinical management was altered in all cases after diagnosis of a non-B-subtype infection. These cases demonstrate that it is critical for physicians to suspect and diagnose non-B subtypes of HIV-1 so that an assay with reliable subtype performance can be used to guide antiretroviral therapy.

Inferior vena cava compression due to massive hydronephrosis from bladder outlet obstruction.

A 71-year-old man presented with acute urinary retention due to benign prostatic hyperplasia and was found to have computed tomography-documented mechanical obstruction of the inferior vena cava (IVC) due to massive hydronephrosis. Obstruction of IVC flow promptly resolved after bladder decompression.

Cutaneous leishmaniasis following local trauma: a clinical pearl.

Cutaneous leishmaniasis is acquired from the bite of an infected sand fly and can result in chronic skin lesions that develop within weeks to months after a bite. Local trauma has been implicated as a precipitating event in the development of skin lesions in patients who have been infected with Leishmania species. Here we report a case series and review the literature on patients who developed cutaneous leishmaniasis after local trauma, which may familiarize clinicians with this presentation.

Prevalence of genotypic and phenotypic resistance to anti-retroviral drugs in a cohort of therapy-naïve HIV-1 infected US military personnel.

OBJECTIVE: While transmission of drug-resistant HIV-1 has been reported, estimates of prevalence of resistance in drug-naïve populations are incomplete. We investigated the prevalence of genotypic mutations and phenotypic antiretroviral resistance in a cohort of HIV-1 infected U.S. military personnel prior to the institution of antiretroviral therapy. DESIGN: Cross-sectional cohort study. METHODS: Plasma was obtained from 114 recently HIV-1 infected subjects enrolled in an epidemiological study. Genotypic resistance was determined by consensus sequencing of a PCR product from the HIV-1 pol gene. Sequences were interpreted by a phenotypic-genotypic correlative database. Resistance phenotypes were determined by a recombinant virus cell culture assay. RESULTS: Genotypic mutations and phenotypic resistance were found at a higher than expected frequency. Resistance to non-nucleoside reverse transcriptase inhibitors was most common, with a prevalence of 15% of 95 subjects by genotype and 26% of 91 subjects by phenotype. Genotypic and phenotypic resistance respectively were found in 4% and 8% of subjects for nucleoside reverse transcriptase inhibitors and in 10% and 1% for protease inhibitors. One subject harbored virus with resistance to all three drug classes. CONCLUSIONS: A substantial frequency of resistance to antiretroviral drugs was identified in a therapy-naïve U.S. cohort. In most cases, the genotypic and phenotypic assays yielded similar results, although the genotypic assay could detect some protease inhibitor resistance-associated mutations in the absence of phenotypic resistance. These data suggest the need for optimization of treatment guidelines based on current estimates of the prevalence of drug resistance in HIV-1 seroconverters.

Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy.

OBJECTIVES: To systematically review and synthesize the available evidence on the efficacy of the ketogenic diet in reducing seizure frequency for children with refractory epilepsy. DATA SOURCES: Medline searches were performed using the keywords epilepsy/therapy, dietary therapy, and epilepsy, and the text word ketogenic diet. The Cochrane Library of clinical trials was searched using the term ketogenic diet. Bibliographies of recent review articles and relevant primary research reports, as well as Current Contents were reviewed for additional relevant citations. STUDY SELECTION: Studies were selected for inclusion in the review that reported the reduction of seizure frequency following treatment with the ketogenic diet in children with refractory epilepsy. The outcome measures used were the percentage of patients with: 1) complete elimination of seizures, 2) >90% reduction in seizures, and 3) >50% reduction in seizures. RESULTS: The evidence consists entirely of uncontrolled studies. Of 11 studies identified for this review, 9 are retrospective series of patients from a single institution. Two studies are prospective, 1 of which is a multicenter trial. The results of these studies are consistent in showing that some children benefit from the ketogenic diet, demonstrated by a significant reduction in seizure frequency. Estimates of the rates of improvement by combined analysis (confidence profile method) are complete cessation of all seizures in 16% of children (95% confidence interval [CI]: 11.0-21.7); a greater than 90% reduction in seizures in 32% (95% CI: 25.3-39.8); and a greater than 50% reduction in seizures in 56% (95% CI: 41.2-69.7). It is unlikely that this degree of benefit can result from a placebo response and/or spontaneous remission. CONCLUSIONS: Although controlled trials are lacking, the evidence is sufficient to determine that the ketogenic diet is efficacious in reducing seizure frequency in children with refractory epilepsy.

Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis.

PURPOSE: To compare luteinizing hormone-releasing hormone (LHRH) agonists with orchiectomy or diethylstilbestrol, and to compare antiandrogens with any of these three alternatives. DATA SOURCES: A search of the MEDLINE, Cancerlit, EMBASE, and Cochrane Library databases from 1966 to March 1998 and Current Contents to 24 August 1998 for articles comparing the outcomes of the specified treatments. The search was limited to studies on prostatic neoplasms in humans. Total yield was 1477 studies. STUDY SELECTION: Reports of efficacy outcomes were limited to randomized, controlled trials. Twenty-four trials involving more than 6600 patients, phase II studies that reported on withdrawals from therapy (the most reliable indicator of adverse effects), and all studies reporting on quality of life were abstracted. DATA EXTRACTION: Two independent reviewers abstracted each article by following a prospectively designed protocol. The meta-analysis combined data on 2-year overall survival by using a random-effects model and; reported results as a hazard ratio relative to orchiectomy. DATA SYNTHESIS: Ten trials of LHRH agonists involving 1908 patients reported no significant difference in overall survival. The hazard ratio showed LHRH agonists to be essentially equivalent to orchiectomy (hazard ratio, 1.1262 [corrected] [95% CI, 0.915 to 1.386]). There was no evidence of difference in overall survival among the LHRH agonists, although CIs were wider for leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835]) and buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404]) than for goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]). Evidence from 8 trials involving 2717 patients suggests that nonsteroidal antiandrogens were associated with lower overall survival. The CI for the hazard ratio approached statistical significance (hazard ratio, 1.2158 [CI, 0.988 to 1.496]). Treatment withdrawals were less frequent with LHRH agonists (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%). CONCLUSIONS: Survival after therapy with an LHRH agonist was equivalent to that after orchiectomy. No evidence shows a difference in effectiveness among the LHRH agonists. Survival rates may be somewhat lower if a nonsteroidal antiandrogen is used as monotherapy.