Isolation of a tumor factor responsible for angiogenesis.

Human and animal solid tumors elaborate a factor which is mitogenic to capillary endothelial cells. This factor has been called tumor-angiogenesis factor. The important components of TAF are RNA and protein. It is suggested that blockade of this factor (inhibition of angiogenesis) might arrest solid tumors at a tiny diameter of a few millimeters.

Pyrethroid insecticides: esterase cleavage in relation to selective toxicity.

The ester group of primary alcohol chrysanthemates is cleaved by mouse hepatic microsomal esterases, more rapidly for the (+)-trans than for the (+)-cis isomers. Substrate-specificity and inhibition studies in vivo establish that these pyrethroid-hydrolyzing esterases probably contribute to the low mammalian toxicity of bioresmethrin and other (+)-trans chrysanthemate insecticide chemicals derived from primary alcohols.

Cytotoxic effects of erythromycin estolate and chlorpromazine on hepatocytes isolated from rats of varying ages: a brief note.

Hepatocytes isolated from young (1 month) rats were as sensitive to the cytotoxic effects of erythromycin estolate and chlorpromazine as were liver cells obtained from older (3, 10 and 24 months) rats. The hepatocytes from the 24-month-old rats released aspartate transaminase more slowly than did parenchymal cells isolated from the younger rats.

Modulation of bone resorption by glycosaminoglycans: effects of parathyroid hormone and interleukin-1.

Regulation of calcium release from mouse calvariae by glycosaminoglycans and known modulators of bone resorption has been examined. Anticoagulant and nonanticoagulant fragments of heparin were combined with parathyroid hormone (PTH) and interleukin-1, beta (IL1), and calcium release from radiolabeled bone was determined. Three heparin fragments, dextran and dextran sulfate, when tested alone, released similar amounts of calcium as did native heparin alone. Suboptimal concentrations of PTH combined with heparin fragments of varying amounts of anticoagulant activity released similar amounts of calcium as did native heparin. When dextran or dextran sulfate was combined with PTH, the amount of calcium released was significantly greater than dextran or dextran sulfate alone but not from PTH when tested alone. Heparin, in combination with 0.1 mu/ml IL1, stimulated significant calcium release compared to heparin but not to IL1 tested alone. There was no significant difference in calcium release when hyaluronic acid in combination with 0.1 U/ml IL1 was compared to the amount of calcium released by either agent alone. Two of the heparin fragments combined with 0.1 U/ml IL1 significantly inhibited calcium release compared to IL1 alone. In combination with 1.0 U/ml of IL1, heparin and hyaluronic acid inhibited calcium release compared to IL1 alone but this inhibition was not significant. The heparin fragments, combined with 1.0 U/ml IL1, had decreasing inhibitory activity as the degree of anticoagulant activity decreased. A comparison of glycosaminoglycan-modulated calcium release in mouse calvariae to that release in mouse radii/ulnae revealed consistently greater percentages of calcium release from calvariae.(ABSTRACT TRUNCATED AT 250 WORDS)

Arsenic: health effects, mechanisms of actions, and research issues.

A meeting on the health effects of arsenic (As), its modes of action, and areas in need of future research was held in Hunt Valley, Maryland, on 22-24 September 1997. Exposure to As in drinking water has been associated with the development of skin and internal cancers and noncarcinogenic effects such as diabetes, peripheral neuropathy, and cardiovascular diseases. There is little data on specific mechanism(s) of action for As, but a great deal of information on possible modes of action. Although arsenite [As(III)] can inhibit more than 200 enzymes, events underlying the induction of the noncarcinogenic effects of As are not understood. With respect to carcinogenicity, As can affect DNA repair, methylation of DNA, and increase radical formation and activation of the protooncogene c-myc, but none of these potential pathways have widespread acceptance as the principal etiologic event. In addition, there are no accepted models for the study of As-induced carcinogenesis. At the final meeting session we considered research needs. Among the most important areas cited were a) As metabolism and its interaction with cellular constituents; b) possible bioaccumulation of As; c) interactions with other metals; d) effects of As on genetic material; e) development of animal models and cell systems to study effects of As; and f) a better characterization of human exposures as related to health risks. Some of the barriers to the advancement of As research included an apparent lack of interest in the United States on As research; lack of relevant animal models; difficulty with adoption of uniform methodologies; lack of accepted biomarkers; and the need for a central storage repository for stored specimens.

An innovative course in surgical critical care for second-year medical students.

PURPOSE: To assess students' learning and other aspects of an innovative elective (based on contextual learning) in surgical critical care for second-year medical students. METHOD: In 1990-91, 13 second-year students at the University of Colorado School of Medicine took a 12-week elective in surgical critical care. The elective required the students to be on night call four times in the surgical intensive care units of two university-affiliated hospitals, where they were supervised by second-year surgical residents and collected information about patients. Weekly tutorial sessions were held for case presentations by the students and for lectures by attending surgeons on pertinent clinical entities. At the conclusion of the course, the students took a shelf test from the Society of Critical Care Medicine. RESULTS: All 13 students scored above 70% on the shelf test, a passing grade for the Additional Qualifications in Critical Care. CONCLUSION: That the students passed an examination at the level of the Additional Qualifications in Critical Care without completing a surgical residency, let alone a critical care fellowship, suggests that contextual learning (where the clinical problem is presented initially and is then followed by self-directed study and group discussion) would prove highly effective in medical education. Students would enter clinical clerkships more prepared than presently if clinical skills were introduced contextually into the basic science curriculum.

Prevention of the toxicity of erythromycin estolate in the perfused rat liver by endotoxin.

The possibility that endotoxin pretreatment could prevent the hepatotoxic effects of erythromycin estolate (EE) was investigated using the isolated perfused rat liver. The addition of E. coli endotoxin (25 micrograms/ml) to the perfusate, 30 min prior to EE administration at 150 or 200 microM, significantly ameliorated the decreases in bile and perfusate flow caused by either concentrations of the drug in control liver preparations. This phenomenon was also studied using liver isolated from rats pretreated in vivo with endotoxin for three days. In these preparations, EE at both concentrations did not alter bile flow and caused reductions of perfusate flow which were far less than those observed in untreated control livers. Furthermore, in livers from endotoxin-treated rats EE induced less reduction of bile acid excretion and, at 150 microM, it did not increase the bile to perfusate ratio of sucrose seen in control preparations after the drug, which may be an expression of altered hepatocytic membrane permeability. Since it is known that both endotoxin and EE interact with membranes, it is suggested that the "protective" effects of endotoxin may occur at the membrane level.

Massive air emboli from intravenous infusion pump: etiology and prevention.

A case of massive air embolus secondary to use of an intravenous infusion pump is presented. The pump is unable to detect air entering the intravenous line if the air enters distal to the air detection device. A simple solution is presented.

Are modified radical mastectomies done for T1 breast cancers because of surgeon's advice or patient's choice?

Clinical trials show that T1 breast cancers are equally well treated with breast-conserving surgery as with modified radical mastectomy. However, the Colorado Central Cancer Registry indicates that, for the past 5 years, the majority of women (72%) with T1 breast cancer in Colorado have undergone modified radical mastectomies. A questionnaire was sent to 175 general surgeons to determine the reasons for the high number of modified radical mastectomies still being performed. The results indicate that one group of surgeons (34% of those responding) believes each type of surgery has equal survival rates but unknowingly influences the patient to choose modified radical mastectomy, with a subtly biased presentation. Education of both surgeons and patients is needed to increase the number of patients with T1 breast lesions who can benefit from breast-conserving therapy.

A unified approach to the torn thoracic aorta.

In a 3-year experience treating 12 patients with blunt torn thoracic aorta, the repair technique was "clamp and sew" with an intraluminal graft in the initial six patients and partial left heart bypass using a centrifugal pump in the more recently treated six. Patients in the two groups were similar in regard to age, sex, and injury severity score. In the intraluminal graft group, graft insertion was abandoned for sutured anastomosis in two patients. Two patients sustained spinal cord ischemia, and two developed hypertension due to "pseudo-coarctation" syndrome. Because of these side effects related to the performance of intraluminal graft, partial left heart bypass was adopted as our routine procedure and was successful in all subsequent patients. Based on our experience and on reports in the current literature, we recommend left atrial-femoral bypass with the centrifugal pump for repair of the torn thoracic aorta.

Hypoxic events in the surgical intensive care unit.

An oxygen-monitoring protocol was established in the surgical intensive care unit (SICU) at the Denver General Hospital in July 1988. A 3-month surveillance audit ending March 1989 prospectively documented 100 consecutive hypoxic events in 51 of 241 (21%) SICU patients. These episodes occurred during mechanical ventilation in 46 patients, during spontaneous ventilation in 15 patients with artificial airways, and the remaining 39 occurred in nonintubated patients. Hypoxemia was recognized by pulse oximetry in 59, arterial blood gas analysis in 24, mixed venous oximetry in 15, and transcutaneous oxygen monitoring in 2. These events were due to problems with the ventilator or airway in 42, recent interventions in 21, new pulmonary process in 19, progression of underlying disease in 11, and unknown causes in 7. Two thirds resulted from mechanical problems amenable to simple intervention; there were two adverse outcomes. In conclusion, acute hypoxia is a frequent potentially morbid SICU event. Advances in continuous oxygen monitoring permit early identification and thereby may limit adverse outcomes, but should not prompt an expensive diagnostic work-up.

Should vascular surgery be done in the small hospital?

This article presents our successful experience with vascular surgery at the Montrose Memorial Hospital. Before a decision is made to ban vascular operations from all but referral hospitals, hard data from additional small community hospitals concerning their experience must be obtained. Surgeons from small community hospitals should be urged to analyze and objectively report their results with vascular procedures before national guidelines are formed.

Nontraditional education for surgeons.

Some of these programs would not work in every rural (or urban) practice. A partnership practice helps considerably. The ability to step into a medical center position with patient acceptance has been important. We feel that many similar opportunities exist--we have more planned--for other surgeons, and should be utilized. Both our geographic isolation and our small medical community have given us a sense of need for continuing education that is perhaps more acute than that of the urban-based private practicing surgeon. However, one has only to look about at most university surgical grand rounds and to note the paucity of surgeons practicing in those urban communities to realize that the feeling of isolation of the rural surgeon may be a very positive and beneficial force in his continuing education.

Laparoscopy for the general surgeon.

A group of three general surgeons in a small community hospital found laparoscopy and laparascopic tuball ligations to be a valuable addition to their practice. Equipment costs and training costs are not prohibitive for a small hospital. The procedures result in minimal morbidity, and have enhanced treatment of gynecologic problems.

Management of popliteal artery injuries.

In a series of seven popliteal artery injuries including two concomitant popliteal vein injuries and three knee dislocations, only one failure occurred. With appropriate training of emergency medical technicians and adequate supportive services such as blood banking and arteriography, the vascular surgeon in a small hospital setting can manage peripheral vascular trauma with acceptable results.

Effects of endotoxin tolerance on hepatic excretory function: in vivo study.

Induction of endotoxin tolerance in rats led to reductions in bile flow and BSP excretion. BSP serum retention or storage of BSP in the liver was not affected. Although serum alanine aminotransferase (ALT) activity was slightly elevated in endotoxin-tolerant rats, the levels of serum aspartate amino-transferase (AST) and hepatic 5'-nucleotidase were normal. These in vivo data support the validity of in vitro studies demonstrating the cholestatic effect of endotoxin and the viewpoint that endotoxin may be responsible for the cholestatic jaundice associated with Gram-negative bacterial infections.

Development and structure of drinking water biofilms and techniques for their study.

Drinking water systems are known to harbour biofilms, even though these environments are oligotrophic and often contain a disinfectant. Control of these biofilms is important for aesthetic and regulatory reasons. Study of full-scale systems has pointed to several factors controlling biofilm growth, but cause-and-effect relationships can only be established in controlled reactors. Using laboratory and pilot distribution systems, along with a variety of bacterial detection techniques, insights have been gained on the structure and behaviour of biofilms in these environments. Chlorinated biofilms differ in structure from non-chlorinated biofilms, but often the number of cells is similar. The number and level of cellular activity is dependent on the predominant carbon source. There is an interaction between carbon sources, the biofilm and the type of pipe material, which complicates the ability to predict biofilm growth. Humic substances, which are known to sorb to surfaces, appear to be a usable carbon source for biofilms. The finding offers an explanation for many of the puzzling observations in full scale and laboratory studies on oligotrophic biofilm growth. Pathogens can persist in these environments as well. Detection requires methods that do not require culturing.

Acrylamide: its metabolism, developmental and reproductive effects, genotoxicity, and carcinogenicity.

Monomeric acrylamide is an important industrial chemical primarily used in the production of polymers and copolymers. It is also used for producing grouts and soil stabilizers. Acrylamide's neurotoxic properties have been well documented. This review will focus on pertinent information concerning other, non-neurotoxic, effects observed after exposure to acrylamide, including: its genotoxic, carcinogenic, reproductive, and developmental effects. It will also cover its absorption, metabolism, and distribution. The data show that acrylamide is capable of inducing genotoxic, carcinogenic, developmental, and reproductive effects in tested organisms. Thus, acrylamide may pose more than a neurotoxic health hazard to exposed humans. Acrylamide is a small organic molecule with very high water solubility. These properties probably facilitate its rapid absorption and distribution throughout the body. After absorption, acrylamide is rapidly metabolized, primarily by glutathione conjugation, and the majority of applied material is excreted within 24 h. Preferential bioconcentration of acrylamide and/or its metabolites is not observed although it appears to persist in tests and skin. Acrylamide can bind to DNA, presumably via a Michael addition-type reaction, which has implications for its genotoxic and carcinogenic potential. The available evidence suggests that acrylamide does not produce detectable gene mutations, but that the major concern for its genotoxicity is its clastogenic activity. This clastogenic activity has been observed in germinal tissues which suggest the possible heritability of acrylamide-induced DNA alterations. Since there is 'sufficient evidence' of carcinogenicity in experimental animals as outlined under the U.S. EPA proposed guidelines for carcinogen risk assessment, acrylamide should be categorized as a 'B2' carcinogen and therefore be considered a 'probable human carcinogen.' The very limited human epidemiological data do not provide sufficient evidence to enable one to judge the actual carcinogenic risk to humans. Acrylamide is able to cross the placenta, reach significant concentrations in the conceptus and produce direct developmental and post-natal effects in rodent offspring. It appears that acrylamide may produce neurotoxic effects in neonates from exposures not overtly toxic to the mothers. Acrylamide has an adverse effect on reproduction as evidenced by dominant lethal effects, degeneration of testicular epithelial tissue, and sperm-head abnormalities.

The effect of naproxen on acute mountain sickness and vascular responses to hypoxia.

The role of prostaglandins in the pathogenesis of acute mountain sickness and two hypoxia-induced vascular responses was evaluated using the cyclooxygenase inhibitor naproxen. Eleven men spent 24 hours at sea level, followed by 34 hours of decompression to 428 mm Hg while receiving naproxen (N), 250 mg twice daily or placebo (P) in a double-blind crossover trial. Serum naproxen levels measured by high pressure liquid chromatography were not changed by hypoxia. The severity of acute mountain sickness (AMS) by the Environmental Symptom Questionnaire scores and observer assessment were unaffected by drug treatment. Retinal artery diameter measured from projected fundus photographs was increased after 27 hours at altitude (11.4 +/- .5 mm) vs. sea level (9.4 +/- .5 mm, p less than 0.05) during both trials. Upright mean arterial pressure fell after 6 hours at altitude (79 +/- 3 mm Hg during N and P vs. 92 +/- 3 at sea level, p less than 0.01). Minute ventilation, end expiratory alveolar PO2 and PCO2 did not differ between drug trials. This study suggests vasodilating prostaglandins do not have a major role in the genesis of AMS, hypoxia-induced retinal vasodilatation, or postural blood pressure responses in man.

Nanoscale magnetic regions formed in GaN implanted with Mn.

Platelet structures with diameters less than 250 A and hexagonal symmetry were formed in GaN by high dose Mn+ ion implantation and annealing at 700-1000 degrees C. Selected-area diffraction pattern analysis indicates that these regions are GaxMn1-xN with a different lattice constant to the host GaN. The presence of the GaMnN corresponds to ferromagnetic behavior of the samples with a Curie temperature of approximately 250 K.