Role of ligand exchange processes in the reaction kinetics of the antitumor drug cis-diamminedichloroplatinum(II) with its targets

The kinetics of a model reaction between the antitumor drug cis-diamminedichloroplatinum(II)(cis-DDP) and the signal nucleotide diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A) has been investigated by spectrophotometry. The formation of the reactive platinum aquated species was first analyzed by potentiometry using a chloride-specific electrode. Both equilibrium and rate constants were measured. The rate constants for the release of the first and second chloride were found 1.1 +/- 0.5 (S.D.) X 10(-4) and 4.2 +/- 0.2 X 10(-5) sec-1, respectively, at 37 degrees. It was shown that anions such as acetate, phosphate, and pyrophosphate were able, in some conditions, to exchange with chloride to form acetato, phosphato, or pyrophosphato complexes. The reaction of cis-DDP with Ap4A or other targets involves at least four steps, which have been analyzed separately. The values of rate constants deduced from the analysis of the overall reaction are in agreement with those determined independently from the separated steps. The second-order rate constants for the reaction of acetato, phosphato, and pyrophosphato complexes with Ap4A (0.2 +/- 0.02, 0.20 +/- 0.02, and 0.16 +/- 0.03 M-1 sec-1, respectively) are close to that of monoaqua-monochloro (0.16 +/- 0.1 M-1 sec-1) and lower than that of the diaqua species (0.94 +/- 0.06 M-1 sec-1). At a high concentration of Ap4A, the reaction kinetics is slowed down. The formation of a complex of cis-platinum with the Ap4A phosphate groups is suggested. The intracellular concentration of phosphates, pyrophosphates, and carboxylates is large enough to displace chloride from cis-DDP. Inside cells, therefore, ligand exchange processes have to be taken into account to analyze the in vivo reactivity of cis-DDP with its potential targets.     

Synovial cysts of unusual localization. 2 cases and review of the literature

Two patients with true synovial cysts in atypical sites (internal compartment of knee and inguinal hollow) were investigated by radioarthrography, ultrasound and computed tomography imaging. The cyst in the hip region originated from a dilated serous bursa of the iliopsoas muscle that did not communicate or was no longer in communication with the joint. In contrast, the cyst of the knee appeared to be a lateral synovial capsule hernia. Positive diagnosis in both cases was dependent on combined ultrasound-CT scan imaging, this eliminating a tumor (sarcoma) of soft tissues. However, affirmation of the synovial origin (mesothelial covering of the wall) of the lesion was obtained by histology only, this allowing differentiation from a "capsular" (fibrous wall) cyst, which probably provokes similar ultrasound and CT scan images.     

Changes in serum CPK, LDH, and their isoenzymes in the perioperative period in patients undergoing craniotomy

The perioperative changes in the serum concentration of creatine phosphokinase (CPK) and its isoenzymes MM, MB, and BB and of lactic dehydrogenase (LDH) and its isoenzymes LDH1 to LDH5 were determined during craniotomy in order to distinguish operation-induced changes in these enzymes from those due to acute myocardial infarction and malignant hyperthermia. Twenty-eight male patients, 29 to 76 years of age (mean +/- SD = 58 +/- 13.2 years), undergoing craniotomy for tumor reseaction (n = 26) or cerebral artery aneurysm clipping (n = 2) were included in this study. Ten serial blood samples were obtained from each patient: one sample before and another after induction of anesthesia, and eight samples after the incision, over a period of 70 h. The preinduction serum CPK level of 97 +/- 32 U/L (mean +/- SD) increased gradually and significantly and reached the peak level of 542 +/- 116 U/L 34 h after incision (p <0.05). Whereas all of the CPK isoenzymes increased in terms of U/L after incision, only the MM fraction (expressed as percent of total CPK) increased, and the MB and BB fractions (expressed as percent of total CPK) decreased. The preinduction serum LDH level of 150 +/- 42 U/L (mean +/- SD) increased gradually after incision and reached the peak level of 210 +/- 32 U/L 58 h after incision (p <0.05). LDH2 as a percent of total LDH decreased significantly, but the LDH1/LDH2 ratio did not change. LDH4 and LDH5, as percents of total LDH, increased significantly. The large increases in total serum CPK and the concomitant decrease in MB percent after craniotomy may minimize and/or mask the percentage increase in the MB level following acute myocardial infarction. The perioperative serum CPK level as a marker in the diagnosis of malignant hyperthermia should be interpreted in light of the present results and in conjunction with clinical symptomatology.     

Acetabular fractures. Clinical outcome of surgical treatment

Sixty patients with acetabular fractures were treated surgically. All fractures were a result of high energy trauma, most with significant associated injuries. Fifty-three of the patients were followed up for at least 2 years. Clinical outcome was analyzed clinically using the Harris hip score and radiographically. In 41 (77.4%) of the patients, the surgical procedure was judged successful (Harris hip score greater than 80 points). Three factors were found to be statistically significant predictors of such an outcome: patient age younger than 40 years; simple fractures based on the classification of Letournel and Judet; and absence of damage to the femoral head. Possible influential factors that were not found to be statistically significant in this population included additional injuries, immediate complications, quality of reduction, heterotopic ossification, ipsilateral femoral fracture, and sciatic nerve damage. Open reduction and internal fixation of the displaced acetabular fracture, although a demanding procedure, can result in a satisfactory clinical outcome given a consistent approach with a dedicated team.     

Individualized feedback of volatile agent use reduces fresh gas flow rate, but fails to favorably affect agent choice

BACKGROUND: Cost reduction has become an important fiscal aim of many hospitals and anesthetic departments, despite its inherent limitations. Volatile anesthetic agents are some of the few drugs that are amenable to such treatment because fresh gas flow rate (FGFR) can be independent of patient volatile anesthetic agent requirement. METHODS: FGFR and drug use were recorded at the temporal midpoint of 2,031 general anesthetics during a 2-month preintervention period. Staff and residents were provided with their preintervention individual mean FGFR, their peer group mean, and educational material regarding volatile agent costs and low-flow anesthesia. FGFR and drug use were remeasured over a 2-month period (postintervention) immediately after this information (N = 2,242) and again 5 months later (delayed follow-up), for a further 2-month period (N = 2,056). RESULTS: For all cases, FGFR decreased from 2.4+/-1.1 to 1.8+/-1.0 l/min (26% reduction) after the intervention and increased to 1.9+/-1.1 l/min (5% increase of preintervention FGFR) at the time of delayed follow-up. Use of more expensive volatile agents (desflurane and sevoflurane) increased during the study period (P < 0.01). In a subgroup of 44 staff members with more than five cases in all study periods, 42 members decreased their mean FGFR after intervention. At delayed follow-up, 30 members had increased their FGFR above postintervention FGFR but below their initial FGFR. After accounting for other predictors of FGFR, the effectiveness of the intervention was significantly reduced at follow-up (28% reduction), but retained a significant effect compared to preintervention FGFR (19% reduction). CONCLUSIONS: Although individual feedback and education regarding volatile agent use was effective at reducing FGFR, effectiveness was reduced without continued feedback. Use of more expensive volatile agents was not reduced by education regarding drug cost, and actually increased.     

Duodenal ulcer and working-class mobility in an African population in South Africa

The number of Africans in Johannesburg presenting with duodenal ulcers has steadily increased over the past 50 years. The characteristics of 105 patients with duodenal ulcer who presented a Baragwanath Hospital were compared with those of matched and unmatched samples of patients without gastrointestinal conditions in the same hospital. Men with duodenal ulcers were found to be significantly better educated than their controls, most had been born in the town, and more of them were employed at higher, though not the highest, educational levels. These data were used to test Susser's proposition that duodenal ulcers are associated with "early urbanisation." Johannesburg blacks with duodenal ulcer did seem to fit the pattern, but the relation between stress and duodenal ulcer remains unclear.     

Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling.

PURPOSE: To develop a genome-based classification scheme for clear-cell sarcoma (CCS), also known as melanoma of soft parts (MSP), which would have implications for diagnosis and treatment. This tumor displays characteristic features of soft tissue sarcoma (STS), including deep soft tissue primary location and a characteristic translocation, t(12;22)(q13;q12), involving EWS and ATF1 genes. CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression, and a propensity for regional lymph node metastases. MATERIALS AND METHODS: RNA samples from 21 cell lines and 60 pathologically confirmed cases of STS, melanoma, and CCS/MSP were examined using the U95A GeneChip (Affymetrix, Santa Clara, CA). Hierarchical cluster analysis, principal component analysis, and support vector machine (SVM) analysis exploited genomic correlations within the data to classify CCS/MSP. RESULTS: Unsupervised analyses demonstrated a clear distinction between STS and melanoma and, furthermore, showed that CCS/MSP cluster with the melanomas as a distinct group. A supervised SVM learning approach further validated this finding and provided a user-independent approach to diagnosis. Genes of interest that discriminate CCS/MSP included those encoding melanocyte differentiation antigens, MITF, SOX10, ERBB3, and FGFR1. CONCLUSION: Gene expression profiles support the classification of CCS/MSP as a distinct genomic subtype of melanoma. Analysis of these gene profiles using the SVM may be an important diagnostic tool. Genomic analysis identified potential targets for the development of therapeutic strategies in the treatment of this disease.     

Pulmonary thrombo-embolism in nephrotic syndrome treated with tissue plasminogen activator

We describe the case of a boy with steroid sensitive nephrotic syndrome and left pulmonary artery thrombo-embolism. Clinical presentation initially suggested sepsis and respiratory signs were minor. Treatment with tissue plasminogen activator infused into the pulmonary artery was successful. Conclusion Pulmonary thrombo-embolism should be considered in unwell children with nephrotic syndrome. Received: 6 September 1996 / Accepted: 17 December 1996