Studies on the biochemical mechanism of the novel antitumor agent,CI-920

Summary Biochemical studies on a new antitumor antibiotic, CI-920, have been directed toward understanding its mode of action. The most striking effect brought on by CI-920 was a marked inhibition of macromolecular synthesis. L1210 leukemia cells exposed to 10 M CI-920 exhibited a decreased rate of DNA, RNA, and protein synthesis within 45 min, and maximal inhibition occurred within 60 min. The reduction in nucleic acid synthesis was not due to precursor depletion, since ribonucleoside and deoxyribonucleoside triphosphate levels in cells exposed to 10 M CI-920 for 2 h either remained unchanged relative to control cells or were elevated, suggesting a block more directly at the level of nucleotide incorporation. Nevertheless, CI-920 (50 M) had no effect on DNA or RNA polymerase activity as assessed in permeabilized L1210 cells. However, if viable cells were exposed to 20 M CI-920 for 1 h prior to permeabilization and then the polymerases assayed in the absence of drug, there was a 60% depression in enzyme activity. The inhibition of RNA polymerase appears to result from an effect on the enzyme rather than the template, since inhibition of RNA polymerase activity in cell-free systems from drug-treated cells could not be restored by addition of excess DNA template. DNA polymerase, however, was at least partially restored by addition of template and therefore was inconclusive in this respect. The data, then, suggest that CI-920 inhibits nucleic acid synthesis directly at the level of nucleotide incorporation, either by direct inhibition of DNA or RNA polymerase or by inactivation of an essential component of these enzyme systems. Since the drug in its parent form did not inhibit nucleic acid synthesis in cell-free systems the effects may possibly be mediated through conversion of this agent to another chemical form within viable cells.     

Sociodemographic Patterns of Exclusive,Dual, and Polytobacco Use Among U.S. High School Students: A Comparison of Three Nationally Representative Surveys

PurposeThis study examines sociodemographic patterns of exclusive/dual/polytobacco use among U.S. high school students using multiple national surveys.MethodsUsing three national youth surveys (Population Assessment of Tobacco and Health [PATH] Wave 4 [2016–2017], 2017 Youth Risk Behavior Survey, and 2017 National Youth Tobacco Survey), we classified tobacco products into four groups: (1) electronic nicotine delivery systems (ENDS), (2) conventional cigarettes (CCs), (3) other combustible tobacco products, and (4) smokeless tobacco products. We created 16 categories of non/exclusive/dual/polytobacco use within the past 30 days using the four product groups and calculated weighted population prevalence by sex and race/ethnicity (all surveys) and parental education and income (PATH), based on variable availability.ResultsThe results from 9,331, 12,407, and 9,699 high school students in PATH, Youth Risk Behavior Survey, and National Youth Tobacco Survey, respectively, largely agreed and pointed to similar conclusions. ENDS was the most prevalent exclusive use product (3.8%–5.2% across surveys), with CCs falling to second or third (1.2%–2.0% across surveys). By sex, exclusive, dual, and poly smokeless tobacco product use were more common for males, whereas exclusive CC use was more common for females. By race/ethnicity, non-Hispanic Whites had a higher prevalence of exclusive ENDS use and ENDS/CC dual use than non-Hispanic Blacks. As income and parental education levels increased from low to high, the prevalence of exclusive CC use decreased, whereas the prevalence of exclusive ENDS use increased.ConclusionUnderstanding sociodemographic patterns of tobacco use can help identify groups who may be at greater risk for tobacco-related health outcomes.     

Fatal case of endocarditis due to Weissella confusa

This is the first reported case of endocarditis due to the Lactobacillus-like vancomycin-resistant gram-positive bacillus Weissella confusa. Full identification and susceptibility testing of Lactobacillus-like organisms recovered in blood culture should be performed for patients with clinical presentations that suggest endocarditis.     

A critical review of chemical lymph node clearance and staging of colon and rectal cancer at Ferguson Hospital, 1977 to 1982

A unique opportunity to evaluate the method of chemical lymph node clearance for colorectal cancer exists at Ferguson Hospital. Lymph node clearance has been used at the institution since 1977, and this retrospective analysis was undertaken to ascertain its validity there. Furthermore, the node positive group was evaluated to ascertain if the current staging system (Turnbull, 1967) is prognostically accurate for the Dukes' C group. Specifically evaluated for possible prognostic variance was the survival of those patients whose tumors demonstrated partial bowel wall penetration and only one to four positive nodes, a C1 subset, previously reported to have favorable prognosis. Eight hundred sixty-four cases of colon and rectal cancer treated surgically from 1977 to 1982 were analyzed. There was a mean of 27 lymph nodes retrieved per specimen and a mean of 4.5 positive nodes per Dukes' C specimen. There were 43 C1 and 201 C2 cases with five-year survival rates of 73 and 38 percent, respectively. The results of chemical clearance at Ferguson Hospital were found to be comparable with that of other centers using chemical clearance and superior to hand dissection. The C1 subset clearly is noted to have prognostic advantage and should occupy a separate designation in any staging system.Read at the meeting of the American Society of Colon and Rectal Surgeons, Toronto, Canada, June 11 to 16, 1989.Presented at Gramec Research Day, Grand Rapids, Michigan, May 10, 1988.     

Preliminary evaluation of a fixed dose of zwitterionic piperazine (TVZ-7) in clinical cancer

One of the zwitterion buffers that has shown significant therapeutic value in the treatment of pain due to cancer, immunologically mediated diseases, and the pain associated with these conditions is in the class of N-substituted amino-sulfonic acids known as "Good Buffers." Zwitterion molecules have neither a negative nor a positive charge; thus, they are neutral. 4-(2 Hydroxyethyl)-1-piperazine ethane sulfonic acid has been used for several decades in artificial biological systems (tissue culture) as a buffer. We have been exploring the therapeutic value of these zwitterionic buffers. Pilot animal studies have demonstrated that zwitterionic piperazine increases bone marrow hypercellularity and induces extramedullary hematopoiesis. We report the initial human use to explore dose toxic and physiologic effects of a fixed dose of the zwitterionic piperazine molecule. There appears to be potential therapeutic value in the treatment of pain due to cancer, and there are preliminary indications that tumor activity and tumor size are reduced. Immunologically mediated diseases may also be affected. Toxicity is low and there appear to be minimal side effects.     

Pilot ascending dose tolerance study of parenterally administered 4-(2 hydroxyethyl)-1-piperazine ethane sulfonic acid (TVZ-7) in dogs

We report a pilot toxicity study in healthy beagle dogs which revealed no significant adverse events for TVZ-7 given at i.v. doses up to 520 mg/kg/day. All treated dogs displayed calm behavior and maintained normal clinical laboratory values throughout the study. Increased bone marrow hypercellularity and extramedullary hematopoiesis was also noted in these dogs. Three other dogs with advanced spontaneously occurring tumors have also been dosed. No serious adverse events were reported in any of the dogs. This pilot study suggests that 4-(2 Hydroxyethyl)-1-piperazine ethane sulfonic acid may be used safely in planned human clinical trials.     

Four-contrast defecography: Pelvic “floor-oscopy”

PURPOSE: This study was designed to determine the accuracy of physical examination (as judged by four-contrast defecography) for women with pelvic floor relaxation disorders. METHODS: Sixty-two women (mean age, 59 years) who had obstructed defecation or constipation, vaginal prolapse, urinary difficulty, or pelvic pain underwent four-contrast defecography. Oral, vaginal, bladder, and rectal contrast were administered selectively and fluoroscopy was performed. Radiographic findings were compared with physical examination diagnosis. RESULTS: Four-contrast defecography changed the diagnosis in 46 patients (75 percent); 26 percent of presumed cystoceles, 36 percent of enteroceles, and 25 percent of rectoceles were not present on defecography. Defecography also revealed unsuspected coexisting defects in addition to known abnormalities detected on physical examination. In contrast, when physical examination was negative for these defects, 63 percent of patients were found to have cystoceles, 46 percent to have enteroceles, and 73 percent to have rectoceles on four-contrast defecography. The discovery of Grade 2 or 3 unsuspected abnormalities was significant, especially so for enteroceles. For posterior vaginal eversions extending to or past the introitus, physical examination was accurate in only 61 percent. Physical examination of large anterior defects was more accurate, with 74 percent of patients being correctly diagnosed. CONCLUSIONS: Physical examination diagnosis of pelvic floor relaxation disorders is frequently inaccurate, especially for large vaginal eversions. Four-contrast defecography improves diagnostic accuracy, helps to identify all pelvic floor defects before surgery, and can assist with planning the correct operative approach.     

Intracisternal injection of TRH antibody blocks gastric emptying stimulated by 2-deoxy-d-glucose in rats

We evaluated the effect of 2-deoxy-d-glucose (2-DG) on gastric emptying of a non nutrient solution in conscious rats using a Phenol red method. Intravenous injection of 2-deoxy-d-glucose dose-dependently increased the rate of gastric emptying. This stimulatory action of 2-DG was abolished by subdiaphragmatic vagotomy. Intracisternal injection of thyrotropin-releasing hormone (TRH) antibody blocked intracisternal TRH and intravenous 2-DG-induced enhancement of gastric empyting but not the stimulation of gastric emptying induced by intracisternal pancreatic polypeptide. The TRH antibody injected intraperitoneally had no effect. These results suggest that endogenous TRH in the brain is involved in vagal-dependent stimulation of gastric emptying by 2-DG.     

Comparison of ambulatory and inpatient experiences in five specialties

This study compared medical student evaluations of ambulatory and inpatient components of third-year clerkships in internal medicine, obstetrics/gynaecology, paediatrics, psychiatry, and surgery. Seventy-two students completed evaluation questionnaires at the conclusion of each of five clerkships over 12 months. Although ambulatory and inpatient evaluations were comparable across all five specialties in several areas, ambulatory education was rated more favorably in scheduling, clear definition of student roles and responsibilities, appropriate supervision, timely and constructive feedback, being welcomed, and working in a non-threatening environment.Student feedback thus implied that ambulatory experiences were comparable to, or better than, inpatient experiences and suggests areas for improving clinical education in inpatient settings.