Gentamicin and ticarcillin serum levels.

Ticarcillin disodium and gentamicin sulfate serum levels were measured one and five hours after intravenous administration. Patients receiving ticarcillin plus gentamicin had a significantly lower mean gentamicin level one and five hours after antibiotic administration than patients receiving cephalothin sodium plus gentamicin. The serum ticarcillin levels were significantly lower five hours after administration in patients receiving ticarcillin plus gentamicin than in those receiving ticarcillin plus cephalothin. Low antibiotic serum levels in patients with serious infections treated with these antibiotic combinations are of potential clinical significance; therefore, to ensure an optimal antimicrobial therapy, it is advisable to determine the drug serum concentrations (especially aminoglycoside) even in patients with normal renal function when treating with combinations of antimicrobials.     

A third Na+-binding site in the sodium pump

The sodium pump, or Na,K-ATPase, exports three intracellular sodium ions in exchange for two extracellular potassium ions. In the high resolution structure of the related calcium pump, two cation-binding sites have been identified. The two corresponding sites in the sodium pump are expected to be alternatively occupied by sodium and potassium. The position of a third sodium-specific site is still hypothetical. Here, we report the large effects of single residue substitutions on the voltage-dependent kinetics of the release of sodium to the extracellular side of the membrane. These mutations also alter the apparent affinity for intracellular sodium while one of them does not affect the intrinsic affinity for potassium. These results enable us to locate the third sodium-specific site of the sodium pump in a space between the fifth, sixth, and ninth transmembrane helices of the alpha-subunit and provide an experimental validation of the model proposed by Ogawa and Toyoshima [Ogawa, H. & Toyoshima, C. (2002) Proc. Natl. Acad. Sci. USA 99, 15977-15982].     

Maintenance therapy with interferon-alpha 2b, cyclophosphamide, and prednisone in aggressive diffuse large cell lymphoma

Maintenance therapy in patients with aggressive malignant lymphoma using biological modifiers remains uncertain. We conducted a controlled clinical trial to evaluate the efficacy and toxicity of interferon-alpha 2b, cyclophosphamide, and prednisone as maintenance therapy in patients with aggressive diffuse large B cell lymphomas in complete remission after aggressive chemotherapy. In an intent-to-treat analysis, 169 patients were eligible for this study; the end points were event-free survival (EFS) and overall survival (OS). With a median follow-up of 49.3 months, no statistical differences were observed and actuarial curves at 5 years showed that EFS was 71% (95% confidence interval [CI], 63-79%) for patients who received maintenance compared to 63% (95% CI, 59-71%) for patients in control group (p = 0.05). No statistical differences were observed in OS between maintenance arm: 84% (95% CI, 78-89%) and control group 83% (95% CI, 77-88%) in control group (p = 0.2). All patients received the maintenance therapy as planned and in time, thus dose intensity was considered 1.0 in all cases. Acute toxicity was mild, and no delay or suspension of treatment was necessary. Late toxicity was not evident until now. We conclude that use of maintenance therapy combining interferon-alpha 2b, cyclophosphamide, and prednisone is not useful in patients with aggressive lymphoma if they had been treated with aggressive combined chemotherapy.     

Phenylpropanolamine and intracranial hemorrhage risk in a Mexican population

BACKGROUND AND PURPOSE: Phenylpropanolamine (PPA) has been associated with an increased risk of intracranial hemorrhage (ICH). The aim of this study was to assess the association between PPA intake and ICH in a Mexican population. METHODS: We included all patients with ICH aged 18 to 51 years, with no known structural etiology, diagnosed from January 1991 to December 2000. Three to 4 controls per patient matched by sex, age (within 5 years) and place of residence were included. Patients and controls were asked about use of cold medication or appetite suppressant medications within the previous year before the interview. We considered a PPA related hemorrhage when there was a temporal relationship between the use of medication and the development of the hemorrhage, and when other causes could be ruled out. Associated risks for PPA use and other possibly related variables were estimated. RESULTS: 177 patients (mean age 39 +/- 12 years) were included; 58 (33%) were diagnosed with subarachnoid hemorrhage (SAH) and 119 (67%) with ICH. 41.2% (73 of 177) of patients had documented use of PPA within the past year and 10 (5.7%) of them had a temporal relationship between ingestion of PPA and ICH. In control subjects 42.4% (422 of 996) had been exposed to PPA and none of them developed hemorrhage. The time from PPA exposure to the onset of ICH varied from 30 minutes to 24 hours. The risk of PPA exposure for hemorrhage was not significant in cases or controls, OR 0.95 (95% CI, 0.68 to 1.34; p = 0.77). No subjects (cases or controls) reported use of PPA as an appetite suppressant. CONCLUSIONS: We found no association between ingestion of PPA and cerebral hemorrhage with respect to ingestion of PPA in the previous year. When recent use was looked at an apparent risk was evident.     

A species-specific nucleotide sequence of Mycobacterium tuberculosis encodes a protein that exhibits hemolytic activity when expressed in Escherichia coli.

Species-specific proteins may be implicated in the unique pathogenic mechanisms characteristic of Mycobacterium tuberculosis. In previous studies, a 3.0-kb species-specific DNA fragment of M. tuberculosis was identified (C. A. Parra, L. P. Londoño, P. del Portillo, and M. E. Patarroyo, Immun. 59:3411-3417, 1991). The nucleotide sequence of this 3.0-kb fragment has been obtained. This sequence was shown to contain two open reading frames (ORFs) whose putative gene products share 68.9% identity between each other. The major ORF shows 57.8% similarity with PLC-N and 53.2% similarity with PLC-H, two phospholipase C enzymes from Pseudomonas aeruginosa. The major ORF was amplified by PCR and cloned into the pGEX-5T expression vector. Cell extracts of Escherichia coli overexpressing this glutathione S-transferase fusion protein were shown to produce beta-hemolysis suggestive of phospholipase activity. Since phospholipase C enzymes have been reported as virulence factors of P. aeruginosa and also of the intracellular pathogen Listeria monocytogenes, it is possible that the proteins identified in this study could also play a role in sustaining tuberculosis infection in humans.     

Mammographic density and risk of breast cancer according to tumor characteristics and mode of detection: a Spanish population-based case-control study

Introduction

It is not clear whether high mammographic density (MD) is equally associated with all subtypes of breast cancer (BC). We investigated the association between MD and subsequent BC, considering invasiveness, means of detection, pathologic subtype, and the time elapsed since mammographic exploration and BC diagnosis.

Methods

BC cases occurring in the population of women who attended screening from 1997 through 2004 in Navarre, a Spanish region with a fully consolidated screening program, were identified via record linkage with the Navarre Cancer Registry (n = 1,172). Information was extracted from the records of their first attendance at screening in that period. For each case, we randomly selected four controls, matched by screening round, year of birth, and place of residence. Cases were classified according to invasiveness (ductal carcinoma in situ (DCIS) versus invasive tumors), pathologic subtype (considering hormonal receptors and HER2), and type of diagnosis (screen-detected versus interval cases). MD was evaluated by a single, experienced radiologist by using a semiquantitative scale. Data on BC risk factors were obtained by the screening program in the corresponding round. The association between MD and tumor subtype was assessed by using conditional logistic regression.

Results

MD was clearly associated with subsequent BC. The odds ratio (OR) for the highest MD category (MD >75%) compared with the reference category (MD <10%) was similar for DCIS (OR = 3.47; 95% CI = 1.46 to 8.27) and invasive tumors (OR = 2.95; 95% CI = 2.01 to 4.35). The excess risk was particularly high for interval cases (OR = 7.72; 95% CI = 4.02 to 14.81) in comparison with screened detected tumors (OR = 2.17; 95% CI = 1.40 to 3.36). Sensitivity analyses excluding interval cases diagnosed in the first year after MD assessment or immediately after an early recall to screening yielded similar results. No differences were seen regarding pathologic subtypes. The excess risk associated with MD persisted for at least 7 to 8 years after mammographic exploration.

Conclusions

Our results confirm that MD is an important risk factor for all types of breast cancer. High breast density strongly increases the risk of developing an interval tumor, and this excess risk is not completely explained by a possible masking effect.