Understanding forgiveness: minding and mining the gaps between pharmacokinetics and therapeutics.

The usual objective during long-term pharmacotherapy is, in large part, to maintain continuity of action of the prescribed drug(s). Continuity of action arises from the continuity of execution of a prescribed dosing regimen that is pharmacologically sound in dose quantity and interval between successive doses. Interruptions in dosing can interrupt drug action, but the consequences vary according to length of interruption, drug, drug formulation, length of the patient's prior exposure to the drug, and the disease being treated.

High-resolution genomic profiling of carboplatin resistance in early-stage epithelial ovarian carcinoma.

Chemotherapy resistance remains a major obstacle to successful treatment of ovarian cancer patients. Therefore, increased knowledge of underlying mechanisms and identification of predictive factors are of great importance. Standard treatment for ovarian carcinoma is surgery followed by platinum-based chemotherapy. In this study, we aimed to search for genes or genomic regions involved in platinum resistance in ovarian carcinoma. Array-based comparative genomic hybridization (CGH) was used to identify genetic alterations in 32 early-stage epithelial ovarian carcinomas homogeneously treated with single-agent carboplatin. The arrays contain 33,370 bacterial artificial chromosome (BAC) clones and form a contiguous and tiling coverage of the human genome with an average resolution of approximately 100 kb. We found certain genetic changes associated with carboplatin response. Gains in 1q25.1-q41 were significantly more frequent in carboplatin-resistant tumours. In this region, we further detected two smallest regions of overlap (SRO) at 1q25.2 and 1q32.2 (approximately 690 and approximately 830 kb in size, respectively). Interestingly, we found some regions that were lost exclusively in the sensitive tumours 17q24.1, Xq21.33-q22.1, and 6 regions in 15q. We also detected genetic differences with regard to histologic subtype. Gain in 8q was found highly associated with serous and clear cell subtypes, and an SRO was identified at 8q24.22-q24.23. The genomic regions found altered in this study confirm some of our previous metaphase CGH results. The alteration found in chromosome arm 1q was verified and specified, and is therefore of great interest as a candidate for predictive markers. Identifying predictive markers of chemosensitive and chemoresistant disease would greatly help in the choice of chemotherapy in the clinic, and thus improve treatment of women with ovarian cancer.

Chromosomal alterations in 98 endometrioid adenocarcinomas analyzed with comparative genomic hybridization.

The aim of the present study was to investigate chromosomal alterations in a large set of homogeneous tumors, 98 endometrioid adenocarcinomas. We also wanted to evaluate differences in chromosomal alterations in the different groups of tumors in relation to stage, survival and invasive or metastatic properties of the tumors. Comparative genomic hybridization (CGH) was used to detect chromosomal alterations in tissue samples from 98 endometrioid adenocarcinomas. All chromosomes were involved in DNA copy number variations at least once in the tumor material, but certain changes were recurrent and rather specific. Among the specific changes, it was possible to identify 39 chromosomal regions displaying frequent DNA copy number alterations. The most frequent alteration was detected at 1q25-->q42, in which gains were found in 30 cases (30%). Gains at 19pter-->p13.1 were detected in 26 tumors (26%) and at 19q13.1-->q13.3 in 19 tumors (19%). Increased copy numbers were also detected at 8q (8q21-->q22 and 8q22-->qter), at a relatively high rate, in 17 cases (17%). Furthermore, gains at 10q21-->q23 and 10p were found in 14 (14%) and 13 cases (13%), respectively. The most common losses were found in the three regions 4q22-->qter, 16q21-->qter and 18q21-->qter, all of which were detected in eight of the 98 tumors (8%). We also detected differences between the tumors from deceased patients and from survivors. Gain at 1q25-->q42 was more commonly detected in the tumors from patients who died of cancer. We noted that the regions most affected differed in the different surgical stages (I-IV). The results of the CGH analysis identify specific chromosomal regions affected by copy number changes, appropriate objects for further genetic studies.

Comparison of exercise test scores and physician estimation in determining disease probability.

BACKGROUND: The recent American College of Cardiology/American Heart Association exercise testing guidelines provided equations to calculate treadmill scores and recommended their use to improve the predictive accuracy of the standard exercise test. However, if physicians can estimate the probability of coronary artery disease as well as the scores can, there would be no reason to add this complexity to test interpretation. To compare the exercise test scores with physician's estimation of disease probability, we used clinical, exercise test, and coronary angiographic data to compute the recommended scores and print patient summaries and treadmill reports. OBJECTIVE: To determine whether exercise test scores can be as effective as expert cardiologists in diagnosing coronary disease. METHODS: Five hundred ninety-nine consecutive male patients without previous myocardial infarction with a mean +/- SD age of 59 +/- 11 years were considered for this analysis. With angiographic disease defined as any coronary lumen occlusion of 50% or more, 58% had disease. The clinical/treadmill test reports were sent to expert cardiologists and to 2 other groups, including randomly selected cardiologists and internists, who classified the patients as having high, low, or intermediate probability of disease and estimated a numerical probability from 0% to 100%. RESULTS: Forty-five expert cardiologists returned estimates on 336 patients, 37 randomly chosen practicing cardiologists returned estimates on 129 patients, 29 randomly chosen practicing internists returned estimates on 106 patients, 13 academic cardiologists returned estimates on 102 patients, and 27 academic internists returned estimates on 174 patients. When probability estimates were compared, the scores were superior to all physician groups (0.76 area under the receiver operating characteristic curve to 0.70 for experts [P=.046], 0.73 to 0.58 for cardiologists [P=.003], and 0.76 to 0.61 for internists [P=.006]). Using a probability cut point of greater than 70% for abnormal, predictive accuracy was 69% for scores compared with 64% for experts, 63% to 62% for cardiologists, and 70% to 57% for internists. CONCLUSION: Although most similar to the disease estimates of the presence of clinically significant angiographic coronary artery disease provided by the expert cardiologists, the scores outperformed the nonexpert physicians.

Pulmonary melioidosis.

Melioidosis is the name given to all diseases caused by the bacterium Pseudomonas pseudomallei. Melioidosis is a tropical disease and prevails in parts of Southeast Asia, northern Australia, and Central and South America. However, in recent years, cases of melioidosis have been reported in the United States and other areas. The organism can infect any organ system, although the lung is the most common organ affected. Pulmonary melioidosis presents either as an acute fulminant pneumonia or as an indolent cavitary disease. In northeastern Thailand, the incidence of P pseudomallei infection is extremely high with significant mortality. One of the key problems with treating melioidosis is its recalcitrance to therapy and high relapse rate. In addition, this Gram-negative rod is resistant to aminoglycosides. In nonendemic regions, patients with melioidosis more typically present with reactivation disease occurring months to years after initial exposure to the organism. The pulmonary disease is mainly in the apices and resembles tuberculosis. With the increasing mobility of people throughout the world and the influx of immigrants from endemic to nonendemic areas, it is important that clinicians be aware of this disease. This article will review the epidemiology, clinical presentations, diagnosis, and treatment of pulmonary melioidosis.

[Rotavirus diarrhea in a health center and a hospital of Managua, Nicaragua]. / Diarrea por rotavirus en un centro de salud y un hospital de Managua, Nicaragua.

Diarrhoea has been considered by WHO as a major problem of morbidity and mortality in children under 5 years. Rotavirus has been reported as one of the main causal agents, although its frequency as causal agent of diarrhoea in Nicaragua is not known. A study was carried out on 206 samples from an equal number of children under 5 years, who presented at a health center and a pediatric hospital in Managua during 9 months in 1987. In order to detect the presence of Rotavirus in faeces, the ELISA technique was used. It was proved that Rotavirus is not a significant cause of diarrhoea in children under 5 years in the places studied.

Purification of a protein histidine kinase from the yeast Saccharomyces cerevisiae. The first member of this class of protein kinases.

An enzyme of molecular weight 32,000 comprising a single subunit has been isolated from whole cell extracts of the yeast Saccharomyces cerevisiae. In vitro, the enzyme transfers the gamma phosphate of ATP to a protein substrate, histone H4, to produce an alkali-stable phosphorylation. Modification of the substrate histidine with diethylpyrocarbonate prevented phosphorylation. Phosphoamino acid analysis of the phosphorylated substrate showed the presence of 1-phosphohistidine. Hence, the isolated enzyme is a protein histidine kinase. A novel assay for acid-labile alkali-stable protein phosphorylation was used in the purification of the kinase activity to a final specific activity of 2,700 nmol/15 min/mg. The purified enzyme phosphorylates specifically histidine 75 in histone H4 and does not phosphorylate histidine 18 nor histidine residues in any other core histone. Steady state kinetic data are consistent with an ordered sequential reaction with Km values for Mg-ATP and histone H4 of 60 and 17 microM, respectively. The protein histidine kinase requires a divalent cation such as Mg2+, Co2+, or Mn2+ but will not use Ca2+, Zn2+, Cu2+, Fe2+, spermine, or spermidine. This is the first purification of an enzyme that catalyzes N-linked phosphorylation in proteins.