Echocardiographic and biochemical evaluation of the development and progression of carcinoid heart disease

OBJECTIVES: To study the applicability of a newly developed echocardiographic scoring system in the assessment of carcinoid valvular heart disease. BACKGROUND: We investigated prospectively the development, progression and regression of carcinoid valvular heart disease in patients with carcinoid syndrome by serial echocardiography, correlating these features with urinary 5-HIAA levels and clinical data collected during therapy with somatostatin analog. METHODS: Twenty-three patients with carcinoid syndrome underwent serial echocardiographic examinations. An echocardiographic carcinoid valvular heart disease (CVHD) % score was determined from points assigned for tricuspid and pulmonary valve structure and function. RESULTS: Fifteen patients had no CVHD at study entry (group 1), while 8 patients had findings of CVHD (group 2). Five patients in group q developed new CVHD (1B), while one demonstrated progression of CVHD (2B). The remaining patients did not develop (1A) or had no progression of CVHD (2B). Despite major declines in 5-HIAA levels during therapy in most patients, CVHD did not regress. There were significantly lower levels of median baseline 5-HIAA (98.8 vs. 256 mg/24 h), posttreatment 5-HIAA (50.3 vs. 324 mg/24 h) and posttreatment 5-HIAA time integral (37.3 vs. 192 g/24 h* days) in group A vs. B (p < 0.05). However, only posttreatment 5-HIAA levels independently predicted the development or progression of CVHD by multiple step-wise regression analysis (p < 0.005), with a threshold observed in the 100 mg/24 h range. CONCLUSIONS: We designed a new echocardiographic scoring system to evaluate CVHD. Correlating echocardiographic scores with biochemical and clinical markers showed that only posttreatment 5-HIAA levels independently predicted the development or progression of CVHD. This study strengthens the association between serotonin secretion and CVHD, as well as introducing a new technique for serial follow-up of these patients.     

Effect of coronary angioplasty on precordial QT dispersion

Dispersion of the QT interval is a measure of inhomogeneity of ventricular repolarization. Because ischemia is associated with regional abnormalities of conduction and repolarization, we hypothesized that the surface electrocardiographic interval dispersion would increase in patients with symptomatic coronary artery disease in the absence of myocardial infarction and that successful revascularization would reduce QT interval dispersion. Thirty-seven consecutive patients with ischemia due to 1-vessel coronary artery disease without prior myocardial infarction who underwent percutaneous transluminal coronary angioplasty (PTCA) were evaluated. Standard 12-lead electrocardiograms were performed 24 hours before, 24 hours after, and late (>2 months) after PTCA. Precordial QT interval dispersions were determined from differences in the maximum and minimum corrected QT intervals. Mean QT interval dispersion before PTCA was 60 +/- 9 ms, immediately after PTCA 23 +/- 14 ms (p <0.001), and late after PTCA 29 +/- 18 ms (p <0.001 vs before PTCA). The shortest precordial QT interval increased immediately after PTCA (367 +/- 40 vs 391 +/- 39 ms; p <0.02) and then remained stable late after PTCA (376 +/- 36 ms, p = NS vs immediately after PTCA). Symptomatic recurrent ischemia in 8 patients with documented restenosis increased QT interval dispersion (56 +/- 15 ms [p <0.01] vs 25 +/- 14 ms immediately after PTCA), which decreased again after successful repeat PTCA (22 +/- 13 ms [p <0.01] vs before the second PTCA). QT interval dispersion decreases after successful coronary artery revascularization and increases with restenosis. Therefore, QT interval dispersion may be a marker of recurrent ischemia due to restenosis after PTCA.     

Unlike other chemicals, etoposide (a topoisomerase-II inhibitor) produces peak mutagenicity in primary spermatocytes of the mouse

The cancer chemotherapy agent, and topoisomerase-II inhibitor, etoposide (VP-16) produced both recessive mutations at specific loci and dominants at other loci with peak frequencies in primary spermatocytes, a cell type in which the topo-II gene has been shown to be activated. Etoposide thus differs from all other chemicals whose germ-cell-stage specificity has been analyzed. No effects of etoposide exposure of spermatogonial stem cells ( approximately 15, 000 offspring scored) were detectable by either mutagenicity or productivity endpoints. The significant mutagenic response that followed exposure of poststem-cell stages ( approximately 25,000 offspring scored) showed a clear peak, with three of four specific-locus mutants, and three of four dominant mutants conceived during weeks 4 or 5 (days 22-35) post-injection, a period that also encompassed the dominant-lethal peak. For this period, the induced specific-locus rate (with 95% confidence limits) at a weighted-average exposure of 75.1 mg etop/kg was 59.5 (14.6, 170. 9)x10-6/locus. At least 3 of the 4 specific-locus mutations were deletions, paralleling findings with etoposide or analogs in other test systems where a recombinational origin of the deletions has been suggested. Because, unlike other chemicals that induce deletions in male germ cells, etoposide is effective in stages normally associated with recombinational events, it will be of interest to determine whether this chemical can affect meiotic recombination.     

A survey of 251 patients with acute syphilis treated in the collaborative penicillin study of 1943-1950

The dramatic and apparently curative effect of penicillin for the treatment of acute syphilis led to follow-up studies for only comparatively brief periods, and the acceptance of the long-term benefit of penicillin has rested on uncontrolled clinical impressions. More certainty about the efficacy of penicillin was sought by a follow-up review of 251 patients treated between March 1944 and December 1950 under the Penicillin Study of the Office of Scientific Research and Development (OSRD) and continued under U. S. Public Health Service after World War II. Eighty-eight patients were interviewed and examined. Telephone conversation or correspondence was had with 43 subjects; an additional nine are known to be living but did not respond to letters. Thirty-two patients died greater than or equal to 20 years after treatment, and 21 patients died within less than 20 years of treatment. Fifty-eight patients could not be found. Treatment failures were documented. Syphilis was not shown to be the cause of disability or death, except for a patient with meningovascular syphilis who died soon after initial treatment. Disabilities recorded and deaths documented revealed only diseases common to any middle-aged population. The outcomes of 17 pregnancies of women treated for acute syphilis were documented. Blood samples obtained from the 88 subjects examined were tested at the Center for Disease Control (Atlanta, Ga.); the results are recorded and discussed. Methods for locating the patients are described, and the psychosocial findings for the 88 patients interviewed are presented. The study has confirmed the clinical impressions of the therapeutic effectiveness of penicillin, which have been accepted for greater than 30 years.     

Growth of P511 mastocytoma cells in BALB/c mouse brain elicits CTL response without tumor elimination: a new tumor model for regional central nervous system immunity

We have developed a murine model to explore the tumor-specific CTL response in the immune-privileged central nervous system using P511 mastocytoma cells. Three strains with varying degrees of histocompatibility to P511 cells (CD-1, allogeneic; BALB/c, minor histoincompatible; DBA/2, syngeneic) received tumor cells (10(4)) into the putamen 7 days after cannula implantation, when the blood-brain barrier was functionally intact. Without exception, tumor formed reproducibly by day 7 in all strains. Tumor rejection occurred in CD-1 but not in BALB/c and DBA/2 mice. Using a flank injection site, both CD-1 and BALB/c, but not DBA/2 mice, ultimately rejected flank tumors. Analysis of tumor-specific CTL in BALB/c spleens revealed that P511 administration into brain or flank elicited similar responses: no fully activated CTL were detectable but a significantly expanded population of nonkilling precursors of CTL (pCTL) were present. A P511 cell-specific pCTL population was also identified at the brain tumor site 14 days post-tumor introduction, indicating that pCTL, generated in the periphery, traffic to the tumor site in brain. These data indicate that failure to reject tumor in brain is neither due to lack of afferent stimulation nor to inability of peripheral effectors (P511 cell-specific pCTL) to reach the tumor site. We hypothesize that these effector cells are prevented from developing into fully activated CTL by conditions within the central nervous system microenvironment that down-regulate CTL development.     

The classification of cyclooxygenase inhibitors

In summary, precise classification of COX inhibitors has important clinical implications for efficacy and toxicity. However, classification of these agents clinically is difficult because there are insufficient data to predict correlations between biochemical and pharmacologic properties and the clinical effect of a given agent. In any case, specific COX-2 inhibitors are expected to show antiinflammatory and analgesic activities equivalent to those of NSAID, as well as significant reductions in the incidence of the life threatening side effects (i.e., GI bleeding) associated with COX-1 inhibition. The advantages of preferential COX-2 inhibitors may be more subtle and therefore more difficult to verify in clinical trials.     

Rapid broth macrodilution method for determination of MICs for Mycobacterium avium isolates

A multicenter study was done to investigate the accuracy and reproducibility of a method for determining the MICs of antimicrobial agents against the Mycobacterium avium complex in 7H12 broth with the BACTEC system. In phase I, with eight drugs and 10 strains, intralaboratory reproducibility was 95.7 to 100%, allowing a 1-dilution difference upon repeat testing. The results of phase II testing with 41 additional strains were consistent with those obtained in phase I, with good interlaboratory reproducibility. The radiometric method was validated by sampling and plating of the same broth cultures and determining, by the number of CFU per milliliter, the lowest drug concentration that inhibited more than 99% of the initial bacterial population. Three test concentrations of each drug and the tentative interpretation of results are proposed. Radiometric MIC determination has the potential to become the method of choice for clinical microbiology laboratories and evaluation of new agents for the treatment of M. avium infections, both pulmonary and disseminated.     

Oral involvement of recessive dystrophic epidermolysis bullosa inversa

The inversa subtype of autosomal recessive dystrophic epidermolysis bullosa (EBDR-I) is a rare variant characterized by lesions involving primarily the flexural areas of the body. The purpose of this investigation was to characterize the oral manifestations of this unusual dermatologic condition. Ten individuals having EBDR-I were evaluated and compared with an age and sex-matched population of unaffected individuals that served as controls. The diagnosis of EBDR-I was confirmed by skin biopsy that demonstrated tissue separation below the lamina densa and the clinical presentation of blister formation that typically localized to flexural areas. There was clinical variability in the severity and distribution of skin involvement; however, none of the affected individuals demonstrated pronounced digital webbing, severe generalized blistering or growth retardation characteristic of the Hallopeau-Siemens form of EBDR. Oral involvement was seen in all cases with ankyloglossia, loss of tongue papillae and obliteration of the oral vestibule between the lips and gingiva being typical. The oral opening was significantly reduced in older EBDR-I individuals compared with matched controls, confirming that acquired microstomia is a characteristic of EBDR-I. The teeth were not clinically abnormal or malformed and showed no evidence of generalized enamel hypoplasia. Despite this, the prevalence of dental caries in EBDR-I individuals was significantly higher than the control group. The inversa form of EBDR presents with oral findings that are similar but generally milder than those seen in the Hallopeau-Siemens variant of EBDR.     

Case-mix adjustment using objective measures of severity: the case for laboratory data

OBJECTIVE: We evaluate the use of routinely gathered laboratory data to subclassify surgical and nonsurgical major diagnostic categories into groups homogeneous with respect to length of stay (LOS). DATA SOURCES AND STUDY SETTING: The source of data is the Combined Patient Experience database (COPE), created by merging data from computerized sources at the University of California San Francisco (UCSF) Medical Center and Stanford University Medical Center for a total sample size of 73,117 patient admissions. STUDY DESIGN: The study is cross-sectional and retrospective. All data were extracted from COPE consecutive admissions; the unit of analysis is an admission. The outcome variable LOS proxies hospital resource utilization for an inpatient stay. Nine (candidate) predictor variables were derived from seven lab tests (WBC, Na, K, C02, BUN, ALB, HCT) by recording the whole-stay minimum or maximum test result. DATA COLLECTION/EXTRACTION METHODS: Patient groups were formed by first assigning to major diagnostic categories (MDCs) all 73,117 admissions. Each MDC was then partitioned into medical and surgical subgroups (sub-MDCs). The 13 sub-MDCs selected for study define a study population of 32,599 patients that represents approximately 45 percent of inpatients. Within each of the 13 sub-MDCs, patients were randomly assigned to one of two data sets in a ratio of 2:1. The first set was used to create, the second to validate, three different LOS predictors. Predictive accuracies of individual DRG classes were compared with those of two alternative classification schemes, one formed by recursive partitioning (the sub-MDC) using only lab test results, the other by partitioning with both lab test results and individual DRGs. PRINCIPAL FINDINGS: For the eight largest sub-MDCs (81 percent of study population), individual DRGs explained 23 percent of the within sub-MDC variance in LOS, laboratory data classes explained 31 percent, and classes derived by considering individual DRGs and laboratory data explained 37 percent. (Each result is a weighted average R2. The average number of LOS classes into which the eight largest sub-MDCs were partitioned were 20, 10, and 10, respectively. Within six of the eight, partitioning on the basis of laboratory data alone explained more within sub-MDC variance than did partitioning into individual DRGs. CONCLUSIONS: Routine lab test data improve the accuracy of LOS prediction over that possible using DRG classes. We note that the improvements do not result from overfitting the data, since the numbers of LOS classes we use to predict LOS are considerably fewer than the numbers of individual DRGs.