Principles of therapeutics.

Topical administration of drugs is the treatment of choice for diseases of the anterior segment. Drug levels attained by this means are usually of short duration, however, necessitating frequent therapy or continuous perfusion if prolonged drug levels are required. A drug-delivery device (collagen shield or contact lens) or subconjunctival injections can be used to augment topical therapy if frequent treatment is not possible. Subconjunctival injections are recommended for drugs that have low solubility and, hence, low corneal penetration. Retrobulbar injections are seldom indicated, except for regional anesthesia. Systemic administration is useful for anti-inflammatory therapy but it may be difficult to establish therapeutic levels of antibiotic agents in the eye because of the blood-ocular barrier. In severe cases, intraocular injection may be required.


Eyelid and nasolacrimal disease.

An understanding of normal structure and function of the equine eyelid is essential to make an accurate diagnosis and appropriately treat equine eyelid diseases. Entropion, eyelid trauma, neoplasia, and nasolacrimal disorders are reviewed. Methods of diagnosis and treatment are presented.


Ocular trauma.

Horses with ocular trauma frequently present as emergency cases. This article provides a succinct review of various adnexal and globe injury issues. Accurate case assessment, management, prognosis, and follow-up considerations are presented.


Equine ulcerative keratitis.

Ulcerative keratitis is one of the most common vision-threatening diseases of the horse. Successful therapy, however, can be achieved in the majority of cases provided the diagnosis is made early and the treatment is specific for the disease. This article reviews the pathophysiology, clinical signs, and contemporary medical and surgical approaches to bacterial and fungal ulcerative keratitis in the horse.


Equine uveitis.

Uveitis (inflammation of the iris, ciliary body, or choroid) is a potentially blinding condition with a significant economic impact on the horse industry. Variable symptoms are described, as well as a considerable range of structural and functional sequelae. Known causes of initial episodes include bacterial, viral, traumatic, and parasitic insults, with recurrence by immunologic mechanisms. Treatment strategies and management recommendations that may reduce the incidence or severity of episodes are discussed.


Diagnosis and treatment of lens diseases.

The lens represents a unique tissue in light of its embryologic development, retention of old cells and nuclear make-up, transparent nature, immune privileged status, and metabolic restrictions. Disorders of malformation and malposition occur, but cataract development is the most common and significant problem for owners and animals. Technologic and pharmacologic advances have allowed surgical removal of equine cataracts to become an acceptable alternative, capable of returning a visually impaired horse to a functional status. Uveal inflammation represents the greatest threat to successful surgical cataract removal. Veterinarians should consult with those versed in ophthalmology for assistance in diagnosis, prognosis, peroperative treatment, surgical intervention, and follow-up on lens disorders.


Retinal and optic nerve diseases.

Basic knowledge of the normal appearance and variations of the equine fundus coupled with frequent practice in ophthalmology will allow equine practitioners to be confident when assessing the equine fundus during ophthalmic examinations. Once the normal variations are mastered, appreciation of retinal, choroidal, optic nerve, and vitreal abnormalities is possible. Congenital and acquired lesions of the equine retina, optic nerve, and vitreous are discussed and illustrated.


Ocular neoplasia.

Except for two neoplasms, notably SCC and sarcoid, ocular and periocular tumors are uncommon in horses. The practitioner must accurately determine the type of tumor by histopathology so appropriate treatment and a legitimate prognosis can be offered. The first attempt at treatment has the greatest chance to result in a cure; an aggressive treatment regimen therefore should be selected from the start.


Ocular manifestations of systemic diseases.

The diseases included in this article constitute a wide range of maladies that affect the horse. Certainly, the diseases that are known today to produce ocular lesions are just a few of what will be discovered if attending veterinarians always examine the eyes of patients with systemic diseases.


Ocular cosmetic and prosthetic devices.

Specific details on surgical procedures, although not covered here, are available in other references. Factors enhancing the overall cosmetic appearance obtained with procedures are emphasized, providing information that should allow veterinarians to offer clients a good cosmetic appearance and effective treatment for disfiguring ocular problems in their horses. Questions regarding procedures should be addressed to your referral ophthalmologist or, in the case of a corneoscleral prosthesis, the ocularist assisting.


Minimal levels of serum estradiol prevent postmenopausal bone loss.

Biochemical parameters reflecting bone resorption [urinary calcium/creatinine (Ca/Cr) and hydroxyproline/creatinine (OH/Cr)] were related to serum estrogens [estrone (E1) and estradiol (E2)] in 262 healthy women including 158 patients receiving estrogen replacement therapy (ERT) for at least 6 months, 49 eugonadal women, and 55 untreated postmenopausal women. A significant (P < 0.001) correlation exists between serum E2 and Ca/Cr: Ca/Cr (mg/dl) = -0.00044 E2 (pg/ml) + 0.129 (n = 262; r = -0.37), serum E2 and OH/Cr: (OH/Cr (mg/g) = -0.049 E2 (pg/ml) + 18.76 (n = 262; r = -0.36), serum E1 and Ca/Cr: Ca/Cr (mg/dl) = -0.0003 E1 (pg/ml) + 0.127 (n = 261; r = -0.28) but not between serum E1 and OH/Cr. Women with circulating levels of E2 between 60 and 90 pg/ml have a significant (P < 0.01) reduction of Ca/Cr and OH/Cr when compared with those with lower levels of E2. Higher values of E2 do not provide additional benefit. We conclude that in postmenopausal women receiving an estrogen replacement therapy (ERT), a significant reduction of bone resorption is achieved when circulating levels of estradiol reach a value (60 pg/ml) corresponding to the one measured, in eugonadal women, during the last days of the early follicular phase of the menstrual cycle. We suggest that oral or percutaneous ERT should induce a minimal value of 60 pg/ml to prevent postmenopausal bone loss.


Measurement of estrogen and progesterone receptors in abnormal human parathyroid tissue.

Estrogen and/or progestin administration to postmenopausal women with primary hyperparathyroidism lowers serum calcium. We measured cytosolic estrogen receptors (ER) and progesterone receptors (PR) by classical hormone-receptor binding techniques in parathyroid tissue removed from 10 men and 20 women, and ER by immunocytochemistry in tissue from an additional one man and seven women in order to ascertain whether these agents might exert a direct effect upon tissue responsible for hyperparathyroidism. ER were negative (< 3.1 fmol bound estradiol/10 mg tissue) in all 8 adenomas and 4 of 5 secondary hyperplasias removed from men, and from women in 19 of 22 adenomas, 2 of 3 secondary hyperplasias, and 3 of 4 primary hyperplasias. PR were negative (< 10.1 fmol bound progesterone/10 mg tissue) in 7 of 8 adenomas and all 5 secondary hyperplasias removed from men, and from women in 20 of 22 adenomas, all 3 secondary hyperplasias, and all 4 primary hyperplasias. For immunocytochemical studies, quick-frozen specimens were analyzed with a monoclonal antibody (Abbott Laboratory) directed at nuclear ER. All eight samples--five adenoma and three primary hyperplasia--were negative. We conclude that abnormal human parathyroid tissues have nondetectable levels of ER and PR. It is unlikely that estrogen and progesterone exert a direct, ER, or PR-mediated effect upon parathyroid tissue.


Bone marrow plays a role in bone metabolism: histomorphometry of iliac bone in postmenopausal women.

We conducted a histomorphometrical study on the role of the bone marrow in cancellous bone metabolism using iliac bone specimens from 79 postmenopausal women. A gradual decrease in hematopoietic tissue of the bone marrow was proportionate to the decrease in cancellous bone and the ratio of osteoid perimeter/bone perimeter regardless of age. On the other hand, the ratio of eroded perimeter/bone perimeter remained almost steady until hematopoietic tissue decreased significantly. These findings suggest that a change in the bone marrow, that is, a decrease in hematopoietic tissue, causes an imbalance in bone formation and resorption and leads to bone loss.


Comparative assessment of bone mineral density of the forearm using single photon and dual X-ray absorptiometry.

Forearm bone mineral density (BMD) was measured at proximal and distal sites by 125I single photon absorptiometry (SPA) and by dual energy X-ray absorptiometry (DXA) in 67 consecutive subjects, aged 18-75 years. Correlations and regression equations between these two techniques were determined. All forearm measurements were significantly correlated with each other (r = 0.599-0.926; P < or = 0.0001). Although SPA and DXA correct for fat in different ways, we found similar correlation and regression equations in women with body mass index measurements above and below the mean. In addition, forearm measurements by both techniques were moderately correlated with vertebral spine and hip BMD. We conclude that overall, SPA forearm measurements in a population can be calibrated to DXA measurements if necessary, and that DXA forearm measurements are as predictive of the remainder of the skeleton as SPA measurements.


Isolation and characterization of human embryonic osteoblasts.

Human osteoblasts were obtained by migration and proliferation of cells from embryonic membranous bone on glass fragments. Light and electron microscopy analyses revealed a typical osteoblast-like appearance with high protein synthesis activity. The cells showed high alkaline phosphatase activity that was associated with plasma membranes and matrix vesicles and was 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] responsive. In contrast to the adult osteoblasts, embryonic cells could not produce detectable levels of osteocalcin, not even in the presence of 1,25(OH)2D3. Osteoblasts grown in multilayers produced a thick extracellular matrix, mainly composed of type I collagen, that mineralized in the presence of 10 mM beta-glycerophosphate. Because of their intrinsic osteogenic capacity, embryonic osteoblasts represent a valuable model for studying the mineralization process in vitro. In addition, the embryonic origin of these cells renders them a precious experimental system for the elucidation of mechanisms at the basis of differentiation of osteoblastic lineage.


Nacre initiates biomineralization by human osteoblasts maintained in vitro.

When nacreous shell produced by the marine oyster Pinctada maxima, used as a biomaterial in oral surgery, is implanted in human bone, new bone formation occurs, resulting in a tight welding of the bone to the nacre [16]. These findings are consistent with the possibility that nacre adjacent to bone can locally stimulate osteogenic activity. To test this hypothesis, we have evaluated the effect of the simultaneous presence of bone and nacre on human osteoblasts in vitro. Nacre chips (1 mm3) were placed at approximately 1 mm distance from a similarly sized bone chip on a layer of first passage human osteoblasts. None of the chemical inducers generally required to obtain bone mineralization in vitro (in particular, beta-glycerophosphate) was added to the cultures. Mineralized sections of the cultures were evaluated by light and electron microscopy, contact microradiography, and Laser Raman Spectroscopy. The results demonstrated that nacre has strong osteogenic effects on human osteoblasts when placed in proximity to bone in vitro. New bone formation occurred by both appositional growth on the existing bone and by the formation of mineralized nodules within the matrix adjacent to the bone explant. Electron microscopic evaluation of these sites demonstrated findings typical of those described in the course of bone formation in vivo, and no evidence of toxicity was observed. In addition, under the conditions of culture used, nacre can also promote the formation by osteoblasts of a structure with characteristics similar to nacre (e.g., lamellar organic matrix mineralized with aragonite, as demonstrated by Laser Raman Spectroscopy).(ABSTRACT TRUNCATED AT 250 WORDS)


Characteristics of steroid hormone receptors in cultured MC3T3-E1 osteoblastic cells and effect of steroid hormones on cell proliferation.

We examined the binding characteristics of three kinds of steroid hormones--estrogen, androgen, and glucocorticoid--in cultured MC3T3-E1 mouse osteoblastic cells by whole-cell binding assay. The binding studies revealed the presence of a single class of high-affinity binding sites for [3H]17 beta-estradiol, [3H]mibolerone (a synthetic androgen), and [3H]triamcinolone acetonide (a synthetic glucocorticoid). The numbers of binding sites for these steroid hormones were found to be 4534 +/- 819, 14312 +/- 1884, and 24898 +/- 655 sites/cell; and the Kd values were 8.57 +/- 0.62 x 10(-10) M, 1.12 +/- 0.19 x 10(-9) M, and 6.08 +/- 1.24 x 10(-10) M, respectively. We also examined the effects of steroid hormones on the proliferation of MC3T3-E1 cells. 17 beta-estradiol significantly stimulated the proliferation of the cells (130-150% of control). Dihydrotestosterone also significantly stimulated the proliferation of the cells (115% of control); the effect was, however, much less potent than that of 17 beta-estradiol, although the number of binding sites was approximately three times more than that of 17 beta estradiol. Triamcinolone acetonide and dexamethasone had no effect on cell proliferation. These results suggest that estrogen and androgen act directly on osteoblastic cells through a receptor-mediated mechanism, and that androgen is much less potent than estrogen in stimulating the proliferation of MC3T3-E1 osteoblastic cells.


Interactions of tumor necrosis factor with local and systemic factors in fetal rat limb bones.

In many tissues the actions of tumor necrosis factor-alpha (TNF) are indirectly mediated through the production of autacoids or other cytokines. To determine the role that these factors might have in the action of TNF on bone resorption, we examined the effects of several selective inhibitors on TNF-stimulated resorption. The cyclooxygenase inhibitor indomethacin did not prevent TNF-stimulated resorption in fetal rat limb bones. Stimulation of resorption by TNF was also unaffected by the platelet activating factor antagonist WEB 2086. A 17.5 kD interleukin receptor antagonist protein, at concentrations that completely blocked the bone-resorbing actions of maximally effective concentrations of interleukin (IL)-1 beta, failed to affect the stimulatory actions of TNF. TNF-stimulated resorption was inhibited by both interferon-gamma and dexamethasone. Dexamethasone inhibited TNF-stimulated resorption more effectively than it inhibited parathyroid hormone (PTH)-stimulated resorption. When bones were treated simultaneously with low concentrations of TNF and PTH, potentiation of the bone-resorbing effects was elicited. These results suggest that TNF stimulates resorption through a pathway different from that by which PTH produces its effects. Transforming growth factor-beta (TGF-beta) enhanced responses to TNF; TGF-beta failed to inhibit the effects of TNF, even in long-term culture or when bones were pretreated with TGF-beta. Synergistic interactions between TNF and several other bone-resorbing factors have now been demonstrated. In contrast to the actions of TNF on certain other functions, the bone-resorbing effects of TNF, as determined in the fetal rat limb bone system, do not seem to be mediated by PAF, IL-1, or prostaglandins.


Primary and secondary culture of rat ameloblasts in serum-free medium.

Enamel is the hardest tissue in vertebrates. Ameloblasts are derived from epithelial cells and are responsible for enamel formation. They secrete enamel matrix components in which amelogenins are the major proteins, the biochemical properties of which are well known. However, little is known about the characteristics of ameloblasts themselves or about the functions of amelogenins. In this study, we developed a novel primary and secondary culture system for ameloblasts using a monoclonal antibody which recognized amelogenin (En3). The cell layer on dentine removed from rat mandibular incisors was isolated and cultured in low calcium, serum-free medium. Primary culture was performed on collagen-coated culture plates and typically, two types of cells appeared. One major type changed morphology after the addition of a high concentration of calcium to the medium. Expression of amelogenin was shown as cytoplasmic particles in these cells using En3. In the secondary culture, expression of amelogenins was also observed. In this system, the cells grew and maintained the expression of amelogenin for about 3 weeks.


Factors affecting the future need for dental manpower in Canada and Quebec.

During the past decade, dental faculties in North America have reduced class sizes due to a perceived oversupply of dentists. Several schools have been closed outright, and others have been threatened with closure. These actions may have a negative impact on the future supply of dentists. The current beliefs with regards to the oversupply of dentists have inadequately accounted for the dramatic demographic and epidemiologic changes that are occurring in North America. Major changes in population distribution and disease trends point to an increased need for adult dental services in the future. Therefore, models for dental manpower needs should integrate these data to avoid a potential shortage of dental health care personnel in the future.


[Clinical characteristics affecting the need for relining of class 1 and class 2 removable mandibular prostheses].

This study attempts to identify, from a sample of people wearing a class 1 or 2 removable prosthetic device on the lower jaw, the extent of the relining needs for these prostheses and their determining factors. Epidemiological methods were used to solve this problem. The relining needs increase with the amount of time elapsed since the prosthetic device was put in the mouth (p = 0.014). As for the other factors reviewed, i.e. class of device, type of retainers used, and occlusion, the authors have identified trends instead of real risk factors, since the impact of this study was significantly reduced due to the small number of people we were able to recruit. It was not always possible, therefore, to verify the statistical meaning of the associations observed. In clinical practice, the treatment plan should include a periodical evaluation of the relining needs. As it is now impossible to establish the approximate time when a prosthetic device may need relining, patients wearing one should be examined periodically and regularly.


Does HIV cause AIDS? A review.

It would require a detailed knowledge of virology, molecular biology, epidemiology, clinical medicine and politics, to appropriately compare and contrast the hypotheses on the causes of AIDS. The purpose of this review was not to do that, but to inform colleagues that alternative etiologies for AIDS have been considered. No doubt, this healthy questioning will continue until it has been demonstrated--via controlled studies of high-risk groups (both HIV positive and negative), matched for all other characteristics--that only those individuals with HIV positivity actually develop AIDS. It cannot be denied that a common theme to the hypotheses is the presence of high-risk activities. This has been used against the risk-AIDS hypothesis. How, for example, could it explain babies born with immunodeficiencies, K. Bergalis contacting AIDS from her dentist, the British nurse who died of AIDS after contracting HIV from her husband, or AIDS in the wives of hemophiliacs? It may be that these people died of specific diseases (leukemia, pneumonia, infections), which 20 years ago would have been diagnosed as such. Now, because these individuals are found to be HIV positive, they are viewed as AIDS patients. Alternatively, they may not have been asked about their nutritional status, use of psychoactive drugs, and immunosuppressive sexual practices. Additionally, it is possible that by the time AIDS was diagnosed they may have already received numerous antibiotic (immunosuppressive) drug treatments. In North America, for whatever reason, AIDS is associated with high-risk groups.(ABSTRACT TRUNCATED AT 250 WORDS)


The teaching of geriatric dentistry in Canada.

Very little is known about the current status of geriatric training programs at Canadian universities because of the scarcity of information published on the subject. A study of the geriatric dentistry training programs offered by Canada's 10 dental schools has been completed. Its intent was to determine what type of educational activities in geriatric dentistry have either been offered in the past, are being offered now, will be offered in the next academic year, or are planned for the next five years. The results indicate that the 10 schools are doing very little in this regard. To keep pace with the level of geriatric dentistry training currently being offered in the United States, the dental profession must convince Canadian faculty members that the teaching of geriatric dentistry is crucial to both the undergraduate student and the graduate dentist. Continuing education in geriatric dentistry could be used to meet the oral health needs of our frail and dependent senior citizens. Geriatric dentistry must be taught at all levels of the profession so that this special clientele can receive the necessary treatment either within or outside of the dental office.


Surface disinfection of saliva-contaminated dental X-ray film packets.

A study was undertaken to determine the most effective method for the surface disinfection of saliva-contaminated dental X-ray film packets. Size 2 Kodak Poly-Soft film packets were placed in the oral cavities of patients and "sham" irradiated. After removal from the oral cavity, some of these packets were left untreated before being placed in transfer vials containing transport medium. Other packets were handled in one of three different ways before being placed in the transfer vials: 1) wiped with a piece of sterile tissue paper to remove visible saliva; 2) wiped once with a sterile piece of gauze soaked with disinfectant and then immediately wiped dry with a piece of tissue paper ("one-wipe" surface-disinfection technique); or, 3) wiped twice with a sterile piece of gauze soaked with disinfectant and allowed to air dry ("two-wipe" surface-disinfection technique). The transport medium was serially diluted and microbiological processing completed to obtain bacterial counts corresponding to the levels of bacterial contamination of the film packet surfaces. The two-wipe surface-disinfection method effectively eliminated bacterial contamination of the film packets, with all of the disinfectants tested being equally effective. The one-wipe technique, using disinfectant, appeared to be slightly less effective. Mere physical removal of the saliva from the film packet, without the use of disinfectant, was the least effective method.


[Risks and benefits of removal of impacted third molars: critical review of the literature. 1].

Because of the ever-increasing enthusiasm that new graduates have demonstrated for practising minor oral surgery procedures, the authors believed that it would be useful to translate the results of a research project done in 1990 by Drs. David S. Precious and Paul Mercier, who are well-known oral and maxillofacial surgeons. This paper is about the risks and benefits associated with the removal of impacted third molars.


Some nutritional requirements of a mixed culture transforming Reichstein's compound S into prednisolone.

Reichstein's compound S was successfully converted to prednisolone in a single-step fermentation using a mixed culture of Curvularia lunata and Mycobacterium smegmatis. Introducing additional medium at the time of bacterial inoculation and increasing the M. smegmatis inoculum to 8% were necessary for maximal dehydrogenation of cortisol to prednisolone (86%). However, beef extract, corn-steep solids, and malt extract were inhibitory to the dehydrogenase activity and stimulatory to hydroxylase. Of the vitamins tested, nicotinic acid and riboflavin at 0.2 and 1.13 mg/L, respectively, resulted in maximum transformation of Reichstein's compound S (100%) and optimized prednisolone yields (92%) in the mixed culture. The trace elements present in the medium were sufficient for maximal transformation, and there was no need for an exogenous supply. Addition of ATP, sodium acetate, and NAD inhibited the dehydrogenation reaction.


Regulation of alpha-aminoadipate reductase from Penicillium chrysogenum in relation to the flux from alpha-aminoadipate into penicillin biosynthesis.

The activity and regulation of alpha-aminoadipate reductase in three Penicillium chrysogenum strains (Q176, D6/1014/A, and P2), producing different amounts of penicillin, were studied. The enzyme exhibited decreasing affinity for alpha-aminoadipate with increasing capacity of the respective strain to produce penicillin. The enzyme from all three strains was inhibited by L-lysine, and the enzyme from the lowest producer, Q176, was least sensitive. Between pH 7.5 and 6.5, inhibition of alpha-aminoadipate reductase by L-lysine was pH dependent, being more pronounced at lower pH. The highest producer strain, P2, displayed the lowest alpha-aminoadipate reductase activity at pH 7.0. In Q176, the addition of 0.5-1 mM of exogenous lysine stimulated penicillin formation, whereas the same concentration was ineffective or inhibitory with strains D6/1014/A and P2. The addition of higher (up to 5 mM) lysine concentrations inhibited penicillin production in all three strains. In mutants of P. chrysogenum D6/1014/A, selected for resistance to 20 mM alpha-aminoadipate, highest penicillin production was observed in those strains whose alpha-aminoadipate reductase was most strongly inhibited by L-lysine. The results support the conclusion that the in vivo activity of alpha-aminoadipate reductase from superior penicillin producer strains of P. chrysogenum is more strongly inhibited by lysine, and that this is related to their ability to accumulate increased amounts of alpha-aminoadipate, and hence penicillin.


Sporulation of Streptomyces antibioticus ETHZ 7451 in submerged culture.

Streptomyces antibioticus ETHZ 7451 formed spores in cultures grown in a liquid medium from either a spore or a mycelium inoculum. The spores formed were similar to those formed on surface-grown cultures, except for reduced heat resistance. Both types of spores were sensitive to lysozyme, which is unusual for Streptomyces spores. Glucose and other carbon sources, which promoted different growth rates, did not affect sporulation efficiency. Nitrogen sources, such as casamino acids, that allowed high growth rates suppressed the sporulation. A remarkable repression was also observed in media with some nitrogen sources that promoted noticeably lower growth rates. In permissive media, with nitrogen sources that permitted relatively high growth rates, sporulation was conditioned to the consumption of ammonium in the medium, but not to that of other nitrogen sources, such as asparagine. Phosphate did not show a repressive effect on sporulation in the assayed conditions.


The nursing case management computerized system: meeting the challenge of health care delivery through technology.

Does nursing case management compute? In this article, the author attempts to explain how computerizing the team plan of care and critical pathways decreases paperwork, makes it easier to develop standardized team care plans, enhances quality improvement trending, and is flexible enough to update the plan of care according to the patient's changing needs. The Nurse Case Management Computerized System puts the patient care team plan into an interactive computer program. The computer does the work of presenting the nurse with care plan options and printing a hard copy ready to implement. Use of the computer program enhances the health care team's ability to individualize the team plan of care while maintaining patient care standards. The system is also used to collect patient care data automatically and to trend for quality improvement.


Prevention of 5-fluorouracil-induced infection with indigenous Escherichia coli in tumor-bearing mice by nonspecific immunostimulation.

We have previously reported that the lethal toxicity of 5-fluorouracil (5-FU) in specific-pathogen-free mice is due to an indigenous infection with Escherichia coli (K. Nomoto, T. Yokokura, Y. Yoshikai, et al. Can. J. Microbiol. 37:244-247, 1991). In the present study, we demonstrate that nonspecific immunostimulation augments host resistance against the lethal toxicity of 5-FU in tumor-bearing mice. Intravenous administration of a preparation of heat-killed Lactobacillus casei (LC 9018), a nonspecific immunostimulant, at a dose of 20 mg/kg to BALB/c mice augmented their resistance against the lethal toxicity of 5-FU if the preparation was injected into the mice 10-40 days before administration of 5-FU. Injection of LC 9018 into BALB/c mice bearing Meth A fibrosarcoma also enhanced their resistance against the lethality of 5-FU. Systemic infection with E. coli was induced in all of the 5-FU-treated tumor-bearing mice 10 days or more after administration of the drug at a lethal dose of 500 mg/kg, and it was accompanied by an overgrowth of the bacteria in the intestine. Treatment of tumor-bearing mice with LC 9018 resulted in decreased rates of occurrence of systemic infection with E. coli and inhibition of overgrowth of the bacteria in the intestine after administration of 5-FU. A single administration of either LC 9018 or 5-FU significantly inhibited the growth of Meth A cells in vivo, and a combined antitumor effect was shown in the mice treated with both 5-FU and LC 9018.


Use of the nursing minimum data set.

The purpose of this study was to obtain information about usage of the Nursing Minimum Data Set (NMDS). Forty-six individuals (44%) who requested the NMDS Data Collection Manual responded to a mailed questionnaire. Most respondents reported actually using the Manual to educate other nurses or to structure nursing documentation. More than one third of the respondents used all of the elements within the NMDS, but the majority used, or intended to use, the elements in the Nursing Care category. The majority of NMDS elements that were being used, or intended to be used, were available from handwritten patient records. The NMDS elements had been recorded on an ongoing basis by 86% of the respondents, but only 31% could retrieve readily all of the elements. Implications for access to comparable, minimum nursing care and resources data are discussed.


Evaluating the appropriateness of a nurse expert system's patient assessment.

The Urological Nursing Information System (UNIS) is an expert-system prototype designed to help nurses perform patient assessments on elderly nursing home residents known to be incontinent of urine. A study was conducted to evaluate the appropriateness of the patient-assessment parameters stored in the knowledge base of UNIS. These parameters were stored as objects--a kind of template for holding related clusters of data, facts, rules, hypotheses, or any knowledge in a single conceptual unit. Each object was rated for its appropriateness by 14 nurse experts. Resulting scores ranged from +14 to -14. The effect of the nurse experts' educational backgrounds and work settings on their ratings were also analyzed. The results indicated that 95.6% of the objects received favorable ratings from the nurse experts. Educational background was not a significant factor chi 2 = 5.2, but work settings did have a significant affect chi 2 = 21.07, p = 0.01.


Pectin decomposition and associated nitrogen fixation by mixed cultures of Azospirillum and Bacillus species.

Cocultures of different Azospirillum species with Bacillus polymyxa or Bacillus subtilis allow the efficient utilization of pectin as carbon and energy sources for nitrogen fixation. The nitrogenase activity obtained with cocultures was as high as 30-80 nmol C2H4 h-1 mL-1, a much higher value than that obtained with pure cultures of either Azospirillum (up to 13 nmol C2H4 h-1 mL-1) or B. polymyxa (up to 2 nmol C2H4 h-1 mL-1) alone. To establish to what extent each partner contributed to nitrogenase activity, acetylene reduction was assayed as a function of time and it was also measured on Azospirillum cultivated in the cultures filtrates of the Bacillus. The results suggested that the nitrogenase activity was mostly produced by Azospirillum. The nitrogenase activity occurred at the expense of the degradation and fermentation products of the pectin. The new pectinolytic species, Azospirillum irakense, utilized both degradation and fermentation products of pectin, whereas the nonpectinolytic strains (Azospirillum brasilense, Azospirillum lipoferum, Azospirillum amazonense) utilized only the fermentation products of pectin, including acetic and succinic acids. These cocultures can be considered as metabolic associations, where the Bacillus produces degradation and fermentation products of pectin, which can be used by Azospirillum species.


Nonspecificity of the Anda A60-tb ELISA test for serodiagnosis of mycobacterial disease.

The conventional methods for the laboratory diagnosis of tuberculosis and other mycobacterial diseases are time consuming and beyond the scope of most of the small and medium-sized hospital facilities. Therefore, there has been considerable interest in the development of a serological method for the detection of antibodies against mycobacteria. We recently evaluated a commercially available ELISA test (Anda Biologicals, Strasbourg, France) that measures antibody levels to A60 antigen, a membrane glycoprotein that is found in most mycobacteria. Of the 123 patients with positive pulmonary cultures for Mycobacterium tuberculosis, 82% had detectable antibodies against the kit antigen. Of the 68 patients with extrapulmonary tuberculosis, 59% yielded positive results. Specimens from 2 of the 12 patients that grew Mycobacterium avium-intracellulare complex, and one each with Mycobacterium fortuitum and Mycobacterium chelonei, were considered significant on the basis of medical history and repeated isolation of the bacterium from clinical specimens, and these patients yielded positive serology. Of the healthy, normal PPD positive and PPD negative controls, 24% gave false positive results.


Interactive effects of salt concentration and temperature on growth and lipid composition in the moderately halophilic bacterium Vibrio costicola.

The interactive effects of NaCl concentration and growth temperature on the growth and lipid composition of the moderately halophilic eubacterium Vibrio costicola have been investigated. Vibrio costicola was shown to be capable of growth over the temperature range 4-37 degrees C. Maximum growth yields were obtained at 30 degrees C when the optimum NaCl concentration was 1.0 M NaCl. In contrast with some previous studies, at higher or lower growth temperatures both the optimum and lower limit of NaCl concentration were higher, but there was no change in the upper limit of NaCl concentration for growth. There were no differences between the lipid compositions of cultures grown in 1 M NaCl at 30 or 37 degrees C, but as the growth temperature was lowered from 30 to 10 or 4 degrees C, the ratio of phosphatidylethanolamine to phosphatidylglycerol increased significantly as a result of the conversion of phosphatidylglycerol to diphosphatidylglycerol; in addition, at the lower growth temperatures the phospholipid fatty acyl composition became more unsaturated and the mean acyl chain length was shorter. It is suggested that the altered salt dependence of V. costicola at temperatures below the optimum for growth is due to a modification in membrane lipid phase behavior and stability brought about by changes in lipid composition, whereas a different mechanism operates above the growth temperature optimum.


Implementing computer simulations as a strategy for evaluating decision-making skills of nursing students.

This article describes the implementation of a computer assisted instruction clinical simulation, as an evaluation strategy for determining baccalaureate students' clinical decision-making skills. Students' reactions toward this strategy have been consistently positive. Similarly, faculty were satisfied with this method of assessment. Our experience has convinced us that computer simulation is an objective, efficacious, and pragmatic method for measuring students' clinical decision-making skills.


A filamentous-like mutant of Listeria monocytogenes with reduced expression of a 60-kilodalton extracellular protein invades and grows in 3T6 and Caco-2 cells.

We describe a spontaneous rough mutant of Listeria monocytogenes that produces reduced amounts of a 60-kilodalton major extracellular polypeptide (p60) as shown by sodium dodecyl sulfate--polyacrylamide gel electrophoresis and Western blot analysis. The cells of this mutant are filamentous, do not give rise to smooth wild-type colonies, and produce listeriolysin O in amounts equal to that of the wild-type cells, but they show a reduced virulence in the mouse LD50 model and in the Caco-2 tissue culture virulence assay. Light and electron microscopic studies show that this mutant invades and remains filamentous during in vivo growth in both Caco-2 and 3T6 tissue culture monolayers. The reduced virulence of the rough mutant is not due to the inability of its filamentous forms to invade or to grow in nonprofessional phagocytes since invasion and growth of the smooth wild-type and the rough mutants are comparable in both Caco-2 and 3T6 monolayers.


Identification of Salmonella typhimurium invasiveness loci.

Salmonella typhimurium is capable of entering into (invading) nonphagocytic host cells. To systematically identify the bacterial genes necessary for this process, 15,000 Tn10dCm random transposon mutants of S. typhimurium were individually screened for invasiveness, using the human colonic epithelial Caco-2 cell line. Four hundred and eighty-eight mutants had decreased levels of invasiveness; most were nonmotile. However, five mutants, representing four loci, were completely motile. Further characterization of these five mutants showed that they were also unable to enter the dog kidney epithelial cell line MDCK and the mouse macrophage line J774.A1. In contrast to the parental strain, they were unable to disrupt the transepithelial resistance of polarized epithelial monolayers, nor were they able to penetrate across these epithelial barriers. Three of the four classes of mutants remained virulent in mice. The results confirm several aspects of S. typhimurium invasiveness: (i) intact motility enhances invasiveness of cultured cells; (ii) S. typhimurium invasiveness is multifactorial, and at least six distinct genetic loci are involved; and (iii) invasion loci involved in uptake into epithelial cells are also needed for uptake into cultured phagocytic cells. The results also emphasize that decreased levels of invasiveness eliminate bacterial penetration of polarized epithelial barriers and invasiveness loci mutants are not necessarily avirulent.


DNA sequence heterogeneity in the gene encoding a 60-kilodalton extracellular protein of Listeria monocytogenes and other Listeria species.

Chromosomal DNA sequences from the 60 kilodalton protein gene of Listeria monocytogenes, amplified by the polymerase chain reaction, were used for restriction fragment length polymorphism differentiation of L. monocytogenes serotypes and other Listeria species. All 24 strains of L. monocytogenes examined produced an extracellular protein of molecular weight 60,000 (p60) as determined by Western blot analysis. Four of six other Listeria species had a protein that cross-reacted to antibodies to p60, but all differed in molecular weight, ranging from approximately 50,000 to 65,000. The gene encoding p60 was amplified from chromosomal DNA in all strains using polymerase chain reaction with a single primer pair. Restriction enzyme digestion with HindIII of the amplified product revealed a restriction pattern that was distinct between serotypes 1/2a and either 4b or 1/2b of L. monocytogenes. Of the other Listeria species, four strains that produced a cross-reacting protein likewise produced a polymerase chain reaction amplification product with the primer pair. Listeria innocua alone had a restriction pattern similar to that of Listeria monocytogenes serotype 4b and 1/2b. Genotypic heterogeneity, as revealed by DNA amplification and restriction endonuclease digestion of the p60 open reading frame, correlates with "electrophoretic type" grouping and may be related to differences in virulence mechanisms of Listeria monocytogenes and other Listeria species.


[Changes in culture and biochemical characteristics of Salmonella paratyphi B after incubation in seawater].

After incubation in seawater Salmonella paratyphi B cells rapidly became unable to grow on bacteriological media. Previous adaptation to high osmolarity conditions greatly slowed down this process. Strains isolated from seawater microcosms after varying incubation periods were qualitatively different and showed changes in some of their growth (colony shape and size) and biochemical properties (acidification of some sugars, gelatinase activity, acetoin production, nitrate reduction). Because of these modifications, the bacteria showed atypical profiles and could not be identified as members of the Salmonella genus. The alteration of the phenotype, although reversible, could explain some of the false-negative results obtained upon isolation and identification of these bacteria in seawater samples.


Choledochal cysts: a retrospective review of 28 patients and a review of the literature.

Retained choledochal cysts have been associated with recurrent cholangitis, portal hypertension and malignant lesions of the biliary tract. The authors reviewed the cases of 23 females and 5 males who had congenital cystic dilatation of the biliary tree; 26 were seen primarily and 2 were referred because of complications from previous surgery. Patient age at presentation ranged from 6 weeks to 46 years. The presenting complaints in 25 patients were pain or jaundice, or both; the classic triad of pain, jaundice and an abdominal mass was present in only 3 patients. Primary cyst excision was performed in 11 patients. Internal drainage procedures were performed in 12 patients, external drainage procedures in 3 patients and no direct operative procedure in 2 patients. Follow-up ranged from 1 to 20 years. Nine of 11 patients with primary excision were asymptomatic; 2 had recurrent cholangitis and required treatment for bile duct stricture. Five patients with retained cysts were asymptomatic. Recurrent cholangitis occurred in seven patients. Six patients required at least one reoperation, but only two had secondary cyst excision. The long-term complication rate for patients with retained cysts was 66.7% and for those with primary excision was 18%. The findings of this study support the current recommendation of primary excision of choledochal cysts. Symptomatic patients with retained cysts should have secondary cyst excision. Asymptomatic patients with retained cysts are at risk for malignancy and should undergo lifelong periodic radiologic examinations and liver-function testing.


Primary cutaneous malignant melanoma: experience of the British Columbia Cancer Agency from 1972 to 1981.

A retrospective review of 891 patients with newly diagnosed primary cutaneous malignant melanoma (CMM) registered at the British Columbia Cancer Agency from 1972 to 1981 is presented. Age-standardized incidence rates in British Columbia have increased markedly over that time. The female-to-male ratio was 1.13:1 and the median age overall was 47 years. A change in the size of a mole was the most common presenting sign (in 43% of patients) and the median duration of signs was 5.9 months. Predominant tumour sites were the trunk for males and the lower limbs for females. Dominant growth patterns were superficial spreading melanoma (65%), nodular melanoma (25%), lentigo maligna melanoma (5%) and acral lentiginous melanoma (2%). On staging of the primary tumour, 90% of patients had local disease, 9% of patients had regional disease and 1% of patients had distant disease at presentation. Median depths of tumours were 1.45 mm for males and 1.10 mm for females; no T1 tumours (tumours 0.75 mm or less in depth [TNM classification]) were staged beyond the local area. Disease recurred in 44% of males and 32% of females. The 15-year survival rate was 55.5% for males and 70.3% for females. These findings are compared with those of recent international series. It is apparent that earlier diagnosis improves survival and that more education is needed in view of the increasing incidence and death from CMM.


Elective and therapeutic regional lymph node dissection for cutaneous malignant melanoma: experience of the British Columbia Cancer Agency, 1972 to 1981.

The authors present a 10-year review of patients registered at the British Columbia Cancer Agency (BCCA) who underwent lymph node dissection for malignant melanoma. Pathological findings in the regional lymph nodes were correlated with primary site, growth pattern, depth of invasion and Clark's level. Elective lymph node dissection (ELND) was performed in 223 patients, and the overall positivity rate (pathologically involved nodes) was 16%. Survival rates for patients who had ELND were compared with those for BCCA patients not having had ELND and patients from the University of Sydney, Sydney, Australia. Although patients who underwent ELND had thicker and more frequently ulcerated primary tumours than patients with stage I disease who did not undergo ELND, survival was better in the group who had ELND. However, when all potential prognostic factors were analysed by multivariate analysis, ELND was not a significant factor in prognosis. Therapeutic lymph node dissection (TLND) was performed in 50 patients at the time the primary tumour was diagnosed, and involvement of the lymph nodes was found in 36. Of 525 patients with clinical stage I disease who did not have ELND, disease recurred in the regional lymph nodes in 119; 86 of them had TLND for recurrence (RTLND). Median survival rates from the time of diagnosis of the primary lesion for ELND-positive, TLND-positive and RTLND patients were 4.2, 2.7 and 4.4 years respectively; the differences were not significant. New treatments are required for patients with involved regional lymph nodes.


Clinical performance of the Duromedics bileaflet pyrolite mechanical prosthesis.

The Duromedics (Baxter Healthcare Corp., Edwards CVS Div., Irvine, Calif.) mechanical cardiac valvular prosthesis was implanted in 480 patients between 1984 and 1987 at the Montreal Heart Institute, the Hospital Clinic of Barcelona and the teaching hospitals of the University of British Columbia. The mean age of the patients was 52 years. The early mortality was 7.9% and the late mortality was 4.1% per patient-year. The overall survival at 4 years for aortic valve replacement (AVR) was 87.0% +/- 3.7% and for mitral valve replacement (MVR) was 81.9% +/- 2.9%. There were 16 valve-related reoperations in 14 patients--for prosthetic valve endocarditis in 9 patients, for thromboembolism in 1 patient and for nonstructural dysfunction in 4 patients. The freedom from thromboembolism at 3 and 4 years was 94.3% +/- 3.1% for AVR and 95.1% +/- 1.8% for MVR. The freedom from prosthetic valve endocarditis at 3 and 4 years was 95.3% +/- 2.2% for AVR and 96.2% +/- 1.6% for MVR. The freedom from structural valve deterioration for all positions was 100%. The freedom from reoperation at 4 years was 95.3% +/- 2.1% for AVR and 92.3% +/- 4.3% for MVR and from valve-related death was 98.7% +/- 1.3% for AVR and 96.2% +/- 1.6% for MVR. The freedom from all valve-related complications at 4 years was 87.7% +/- 3.8% for AVR and 85.7% +/- 2.9% for MVR. Long-term evaluation of the Duromedics prosthesis is required to determine the influence of documented structural valve deterioration.


Acute mesenteric ischemia: an aggressive diagnostic and therapeutic approach. 1991 Roussel Lecture.

The incidence of acute mesenteric ischemia (AMI) has increased substantially over the last few decades. Death rates of 70% to 90% have been reported for traditional methods of diagnosis and therapy. Use of an aggressive radiologic, pharmacologic and surgical approach has decreased the mortality and morbidity associated with AMI. The cornerstones of management are prompt diagnosis by the earlier and more liberal use of angiography and the incorporation of intra-arterial papaverine in the treatment of both occlusive and nonocclusive AMI. Widespread adoption of this protocol in patients at risk might improve the overall results of treatment of AMI.


Routine omission of nasogastric intubation after gastrointestinal surgery.

The need for routine nasogastric-tube decompression after gastrointestinal surgery has been challenged repeatedly for several years. To determine whether nasogastric intubation can be omitted routinely, 101 consecutive patients who underwent gastrointestinal surgery were managed prospectively without nasogastric tubes. Excluded were patients with complete bowel obstruction and those who required prolonged endotracheal intubation. These patients were compared with 101 retrospective controls who had nasogastric decompression routinely. There were four protocol violations in the prospective group (nasogastric tubes were left in place postoperatively) and one in the retrospective group (no nasogastric tube postoperatively), leaving 97 and 100 patients, respectively, for follow-up. The mean duration of hospitalization in comparable patients was 10.6 days in patients without decompression and 11.9 days in those with routine decompression. Subsequent nasogastric-tube insertion was required in nine patients who did not undergo routine decompression, compared with two patients who had routine decompression. There were no statistically significant differences in the rates of anastomotic leaks, wound disruptions and pulmonary or other complications between the two groups. The authors conclude that nasogastric decompression can be safely omitted as a routine part of postoperative care after gastrointestinal surgery.


A prospective randomized trial of routine postoperative nasogastric decompression in patients with bowel anastomosis.

Until relatively recently, the nasogastric (NG) tube has been used routinely for decompression in the patient with small- or large-bowel anastomosis. To determine if routine postoperative NG decompression benefited such patients, 102 patients were randomized prospectively to either NG decompression or no-NG tube. Excluded were patients with chronic bowel obstruction, peritonitis, gross fecal contamination or spillage, and previous abdominal or pelvic irradiation. There were 52 patients in the no-NG group and 50 in the NG group. Patients in the no-NG group had earlier bowel sounds, return of flatus, oral intake and first bowel movement. Four patients (8%) in the no-NG group, compared with one patient (2%) in the NG group, required subsequent decompression. Length of hospital stay was significantly (p < 0.001) shorter in the no-NG group. There were no significant differences in the presence of atelectasis, postoperative fever, wound infections and anastomotic leaks between the two groups. The authors conclude that routine nasogastric decompression is not warranted after elective surgery involving small- or large-bowel anastomosis.


Renal perfusion with the Biomedicus pump during resection of an abdominal aortic aneurysm.

Renal artery perfusion is usually unnecessary during resection of an abdominal aortic aneurysm, because most of these aneurysms are situated below the renal arteries. The authors report the interesting case of a patient with a solitary functioning kidney, who had undergone previous bypass grafting from the right iliac artery to the right renal artery and in whom the kidney was perfused with the Biomedicus pump during the repair of an abdominal aortic aneurysm. This technique may be useful in special situations in which any period of renal ischemia might be hazardous to renal function.


Reconstruction of avulsed scalp after go-cart injury.

Scalp avulsion is a rare injury that has significant physical and psychological consequences. It may require emergency replantation or late, challenging surgical reconstruction, or both. The authors describe two patients who had scalp avulsion. Each patient got long hair entangled in the uncovered engine of a go-cart. One underwent unsuccessful replantation without vascular repair; the other had a large segment of scalp successfully replanted with microvascular repair. Both patients required late reconstruction with tissue expansion. The final results were good. When feasible, microvascular replantation is the treatment of choice. If replantation is not possible, temporary cover by skin grafts followed by later reconstruction with tissue expansion can be effective.


Injuries to the nervous system and spine in downhill skiing.

The authors describe injuries to the nervous system and spine from downhill skiing accidents through a review of the charts of downhill skiers admitted over 5 years to the three teaching hospitals of the University of Calgary. The office of the chief medical examiner provided details about accidental deaths from downhill skiing in which nervous system trauma occurred. During the study period, 145 downhill skiers suffered injury to the nervous system or spine. There were five deaths from nervous system trauma. The mean age of the injured skiers was 23.8 years, and these injuries were three times more common in men than in women. Eighty-eight skiers sustained a head injury, 25 had spinal fractures alone, 20 had spinal cord or nerve root injury and 12 had peripheral nerve injury. A simple fall on the hill was the commonest method of injury, followed in frequency by collision with a tree, which caused the most severe injuries. Reckless skiing, design of ski runs and man-made snow were contributing factors. The serious nature and number of these injuries must be recognized, and further study is needed on causal factors and preventive measures.


Splenic vein thrombosis as a cause of variceal bleeding.

Splenic vein thrombosis as a cause of variceal bleeding is underdiagnosed. Newer, noninvasive techniques of diagnosis that have been introduced recently appear to be accurate. Isolated gastric varices in the presence of normal liver function and especially in the presence of pancreatic disease should prompt a search for splenic vein thrombosis. Splenectomy is the treatment of choice.


Major vessel excision in retroperitoneal lymph node dissection.

Retroperitoneal malignant tumours, both primary and metastatic, may involve surrounding structures such as the aorta and vena cava, making complete tumour excision difficult. En bloc resection of major blood vessels should be considered in such cases. The authors describe three patients who underwent excision of major blood vessels with retroperitoneal lymph node dissection. Two patients had aortic resection with placement of a Dacron tube graft, and one had excision of the vena cava from above the renal vessels to the level of the common iliac veins with distal venous ligation. The low complication rate confirms the feasibility of excising major blood vessels to accomplish complete retroperitoneal lymphadenectomy.


Blunt traumatic avulsion of an intercostal artery: an unusual case of thoracic aortic injury.

The aortic isthmus is the most commonly injured part of the thoracic aorta in patients who survive blunt deceleration injury to that vessel long enough to reach a hospital. Occasionally, avulsion of the brachiocephalic arteries from the aortic arch is seen. The authors describe an unusual form of intrathoracic vascular injury in which mediastinal hemorrhage occurred secondary to avulsion of an intercostal artery from the descending thoracic aorta as a result of a vertical deceleration injury.


Treatment for nonunion of the shaft of the humerus: comparison of plates and Seidel interlocking nails.

From July 1986 to November 1989, fractures of the humeral shaft in 35 adults who had nonunion of the fracture were managed by plate fixation (19 patients) or antegrade nailing of the fracture fragments with the Seidel interlocking nail (16 patients) together with cancellous bone grafting. The follow-up period ranged from 12 to 52 months. Of the patients who had plate fixation, 89.5% had fracture union within 4.5 +/- 1.7 months; of the patients whose fracture was managed with the Seidel interlocking nail, 87.5% had fracture union within 4.4 +/- 1.8 months. The range of shoulder motion was improved with both techniques. Patients who had plate fixation had more complications than those whose fracture was managed by interlocking nailing (21% v. 12%). The authors prefer interlocking nailing because it is a relatively simpler technique, resulting in fewer complications. It may replace plating in the treatment of nonunion of humeral shaft fractures. However, rotatory instability with interlocking nailing cannot be disregarded, and if this is evident plate fixation should be done.


Guidelines for transfusion of erythrocytes to neonates and premature infants. Fetus and Newborn Committee, Canadian Paediatric Society.

The transfusion of erythrocytes to neonates and premature infants is common and should be minimized through a reduction in the number of blood samples taken for laboratory tests. The risks to patients have been minimized with current blood-banking techniques, although neonates and premature infants may require special consideration. The indications for transfusion of erythrocytes to neonates include the presence of shock, a loss of 10% or more of the blood volume within 72 hours when further blood sampling is expected, a hemoglobin level of less than 130 g/L in neonates with cardio-respiratory disease who require increased oxygen-carrying capacity, and a hemoglobin level of less than 80 to 100 g/L in neonates with tachypnea, tachycardia, recurrent apnea, poor feeding or failure to gain weight. The attending physician should consider these indications along with clinical judgement to ensure safe and effective erythrocyte transfusion.


Rate of death from cervical cancer among native Indian women in British Columbia.

To compare the rates of death from cervical cancer among native Indian women and non-native women in British Columbia from 1953 to 1984. Retrospective analysis of data retrieved from the British Columbia Division of Vital Statistics. Age-standardized death rate and relative rate. The rate of death from cervical cancer was significantly higher among the native women than among the non-native women throughout the study period. No deaths from cervical cancer were recorded in women under 20 years of age. Among those 20 to 64 the relative rate increased from 3.83 in 1953-62 to 6.53 in 1973-84; among those 65 or more it decreased slightly. For the entire study period the relative rate for women 20 to 64 years old was 5.95 and for those 65 or older 2.98. The rate of death from cervical cancer among native women in British Columbia is unacceptably high, probably because the provincial screening program does not reach as many native women as it does non-native women.


Underrecognition of chylomicronemia as a cause of acute pancreatitis.

To determine how often chylomicronemia is considered by admitting physicians as a possible cause of acute pancreatitis. Retrospective hospital chart review. Tertiary care teaching hospital in an urban centre with a referral population of 1 million. All patients admitted with acute pancreatitis from Jan. 1, 1985, to Dec. 31, 1987. Episodes of pancreatitis were divided into two groups: those for which a cause was known after history taking, physical examination and laboratory investigation at the time of admission (group 1) and those for which a cause was unknown after full examination (group 2). There were 319 episodes of chylomicronemia in 162 patients. The cause of the pancreatitis was known after examination at the time of admission in 239 (75%) of the episodes; there was hypertriglyceridemia in 7 (3%). No cause was identified after examination in the other 80 episodes (25%); chylomicronemia was considered in 18 cases (29%) and was found in 6 (33%) of them (mean serum triglyceride level 34.4 mmol/L). Of the remaining 62 episodes in group 2, 10 (16%) were later found to be caused by chylomicronemia (mean serum triglyceride level 22.6 mmol/L). Among the 80 episodes in group 2 at least one medical condition associated with chylomicronemia was present in 24. In only 7 (29%) of the 24 was chylomicronemia considered; in 6 the mean serum triglyceride level was 19.7 mmol/L. Although the overall detection rate of chylomicronemia was low, its presence in patients without other etiologic factors after examination may have been much higher. Consideration of chylomicronemia in this subgroup at the time of presentation may increase diagnostic yield and help prevent further occurrences of pancreatitis.


Ultrastructural localization of HIV-1 RNA and core proteins. Simultaneous visualization using double immunogold labelling after in situ hybridization and immunocytochemistry.

The analysis of human immunodeficiency virus type 1 (HIV-1) RNA sequences in CEM and Jurkat lymphoid cells infected with the virus has been performed at the subcellular level. Using a biotinylated DNA probe specific for HIV-1, virus RNA sequences were detected on Lowicryl thin sections after immunogold cytochemistry. The labelling observed on the cytoplasm was localized near the plasma membrane connected with extracellular cluster of virions. On free immature and nascent form of the virus the detection of HIV-1 RNA was associated with the peripheral electron-dense structure, whereas on mature form the labelling was concentrated on the central nucleoid known to be the site of the HIV-1 genomic RNA. The identification of virus RNA was also performed simultaneously with the detection of HIV-1 core protein p24 or p17 using a double immunogold labelling. Whereas the HIV-1 RNA showed again a cytoplasmic and virions localization, the structural protein was only observed on viral formations. The cytoplasmic localization of virus RNA, at the time of virus production, suggests that they are of genomic origin destined to be packaged in virions once the assembly of virus structural proteins has taken place in the plasma membrane at the viral budding site. The present molecular investigation conducted at the subcellular level provides insight into the cell periphery distribution of HIV-1 RNA observed at the light microscope as corresponding to the detection of HIV-1 infected lymphoid cells actually releasing virions.


A study of peritoneal cells from healthy and Schistosoma mansoni-infected mice with special reference to myofibroblasts arising in culture.

Adherent, trypsin-resistant, peritoneal cells from mice with chronic schistosomiasis mansoni, and from control mice, were cultivated in vitro up to 20 days. Fibroblasts regularly appeared, about 6 days after seeding, in cultures of the manyfold more numerous cells from infected mice, concomitantly with a dramatic increase, detected by autoradiography, in the percentage of DNA-replicating cells of the monocyte-macrophage lineage. Peritoneal cells from healthy and from infected mice were fractionated on discontinuous Percoll gradients. Eight cell subsets were harvested in both cases, quantitated, and studied by electron microscopy. Two fractions (2 and 3: 1.041 < densities < 1.060 g/ml) from infected mice were greatly enriched in monoblasts and promonocytes. The cells of the different subsets were seeded separately, trypsin-treated and cultivated in vitro. Cultures of cell fractions 2 and 3 from infected mice contained the majority of the DNA-synthesizing cells and gave regularly rise to fibroblasts. Cultures of the different fractions were used for sequential morphological observations (2-11 days) at the electron microscope level. Early cultures were also used for the ultrastructural detection of the Mac-1 (CD 18/CD 11b) surface antigen by gold immunocytochemistry. A few fibroblasts were rarely observed in cultures of fractions 2 and 3 from control mice, while cells with ultrastructural features of myofibroblasts were regularly observed in cultures of the same fractions harvested from mice with chronic schistosomiasis. Fractions 2 and 3 from infected mice contained a large number of Mac-1 positive monoblasts. The correlations between the presence of monoblasts, DNA replication in cells of the monocyte-macrophage lineage and the appearance of myofibroblasts in cultures of the same fractions derived from infected mice are discussed.


A mouse repeat sequence conserved in eukaryotic genomes.

To study the biological role of simple repetitive DNA sequences, we analysed a clone isolated from a mouse macrophage cDNA library called T2. This clone contains two simple repetitive sequences: a new sequence, 'CAGAGAGG', and a sequence previously described, 'GATA'. By sequencing analysis, an open reading frame, coding for 225 amino acids, is detected in the T2 clone. The new simple sequence is present thousands of time in the mouse genome, associated or not with the sequence 'GATA'. The sequence 'CAGAGAGG' is transcribed in messenger RNAs. Northern blots of RNAs extracted from adult tissues and from differentiated or non differentiated cell lines show a large number of transcripts that quantitatively decrease when in vitro differentiation occurs. Moreover, Southern blots of DNA extracted from different organisms, hybridize with a fragment containing only the 'CAGAGAGG' sequence, demonstrating that this sequence is represented in the genome of phylogenetically distant eukaryotes, and is highly conserved during eukaryotic evolution.


Ultrastructure of cilia in horses.

This paper presents some ultrastructural details of cilia from the ciliated tracheal epithelium of healthy horses. By using a new fixation method, the Authors were able to describe minute details, some of which have been only rarely observed in other species and mostly by means of the freeze-etch technique (i.e. electron dense particles of ciliary necklace). The Authors justify the need to investigate the ultrastructural details of cilia in various species since the minute morphological differences might be functionally significant.


Reorganization of the Golgi complex in association with mitosis: redistribution of mannosidase II to the endoplasmic reticulum and effects of brefeldin A.

Previous studies have shown that the Golgi complex is broken down into dispersed clusters of vesiculotubular elements as mammalian cells enter mitosis and is reformed in each daughter cell in telophase/cytokinesis. In the present investigation, mannosidase II (a membrane-bound enzyme involved in oligosaccharide processing) was used as a marker to explore the fate of the Golgi complex in dividing L929 and CHO cells in some additional detail. Immunofluorescence microscopy demonstrated a juxta- or perinuclear staining for mannosidase II (man II) in interphase and immunoelectron microscopy revealed that it was restricted to the stacked Golgi cisternae at this stage. As the cells entered mitosis, the staining for man II assumed a pattern of dispersed elements in prophase and then turned into a diffuse pattern during metaphase and anaphase. At the electron microscopic level, this corresponded to a successive disorganization of the Golgi complex, first into structurally modified stacks scattered throughout the cytoplasm, and thereafter into small clusters of vesicles and tubules. In parallel, most of the immunoreactivity for man II was shifted into partially fragmented cisternae of endoplasmic reticulum, and only small amounts were found in the clusters just mentioned. During telophase/cytokinesis a circumscribed staining for man II reappeared in each daughter cell. At the electron microscopic level, cisternal stacks positive for man II were found to reform at the same time as immunoreactivity disappeared from the endoplasmic reticulum. Typically, the Golgi region was first located on the proximal side of the nucleus as related to the intercellular bridge, and then moved to the distal side of the nucleus before the cells were about to separate. Treatment of synchronized mitotic cells with brefeldin A, a fungal metabolite that inhibits endoplasmic reticulum to Golgi transport, prevented reformation of the Golgi complex in telophase/cytokinesis. Nevertheless, the separation of the daughter cells was completed at a similar rate as in the controls. On the basis of these findings, an extended model of the disorganization and reorganization of the Golgi complex in association with mitosis is presented. According to this model the disorganization of the Golgi complex at the onset of mitosis is a two-step process: the Golgi stacks are first separated from each other and spread out in the cytoplasm; thereafter the Golgi stacks disintegrate, at least in part by return of Golgi components to the endoplasmic reticulum. In interphase cells, similar changes in the organization of the Golgi complex are produced by microtubule-disruptive drugs (dispersion of the stacks) and brefeldin A (redistribution of Golgi proteins into the endoplasmic reticulum), respectively.


Ultrastructural analysis of differentiation of rat endoderm in vitro. Adipose vascular-stromal cells induce endoderm differentiation, which in turn induces differentiation of the vascular-stromal cells into chondrocytes.

Isolated definitive endoderm from 9-day-old rat embryos was cultivated up to 24 days in plastic and glass petri dishes and on developing vascular-stromal cells (mesenchymal cells) from epididymal white and interscapular brown adipose tissue of 4-week-old male rats. Explants were analyzed histologically and ultrastructurally. Endoderm attached to the bottom of the glass or petri dishes degenerated under one week of cultivation. Endoderm free floating in the culture medium developed into unilaminar vesicles whose flat epithelium did not differentiate. However, endoderm inoculated on developing mesenchymal cells differentiated into glandular explants or into ciliated pseudostratified columnar respiratory epithelium. The glandular explants were made up of at least four different kinds of cells whose cytoplasm showed predominantly: a) polyribosomes, b) lysosomes, c) mitochondria or d) cytoskeletal filaments. Endodermal cells differentiated only if, during cultivation, they were in contact with or in close proximity to developing mesenchymal cells. Endoderm differentiating into the respiratory epithelium in turn directed differentiation of the underlying vascular-stromal cells into lamina propria cells and chondrocytes. Cultivated vascular-stromal cells in the upper layers became thicker, ellipsoid in shape and with enlarged intercellular space. They appeared to be lamina propria cells and, together with the respiratory epithelium, built folds of respiratory mucosa. The vascular-stromal cells in the layers close to the bottom developed into chondrocytes; i.e., the cells became oval and agglomerated in nest like structures with a defined extracellular matrix. Their cytoplasm contained abundant cisternae of rough endoplasmic reticulum and numerous vacuoles with PAS positive substance. These observations showed that even developing vascular-stromal cells from adipose tissue from postlactating rats can trigger the process of definitive endoderm differentiation. Once triggered, differentiating endoderm influenced differentiation of the vascular-stromal cells into the cells and tissues of a wall of the respiratory tract.


The effect of thyrotropic hormone (TSH) on the thyroid gland of the newborn rat. An electron microscopic study.

The activity of the thyroid gland of the newborn rat is influenced by the treatment of TSH. Shortly after hormone injection, its effects can be detected in the synthesis and storage of the colloid. In a longer term (30 min and 60 min) the morphological signs of resorption and secretion are evident. At this early age the cellular compartments involved in the secretory pathway of the cells are still not complete in maturation (less developed Golgi complex, missing secretory vesicles and micropinocytotic vesicles). According to our results, even TSH administration cannot influence this picture in the short term. Our work supports the intracellular way of folliculogenesis, and the TSH action as a promoter in this way.


Increased adhesion of human diabetic platelets to cultured valvular endothelial cells.

Diabetes is accompanied by impaired platelet function and accelerated vascular disease. To find out whether a correlation exists between these two complications, and if modifications occurring in diabetic platelets influence their relationship with endothelium, we have studied the interaction between platelets isolated from plasma of diabetic patients and bovine valvular endothelial cells (VEC), in culture. For quantitative analysis, normal and diabetic [3H]-adenine-labeled platelets were incubated with confluent VEC grown in Dulbecco's modified Eagle medium, containing 4.5 g/l glucose, for 30 min at 37 degrees C. After extensive washing and solubilization of the monolayer, the calculated adhesion index showed a two-fold increased adherence of diabetic platelets to VEC as compared to normal platelets. Statistical analysis (by Pitman randomization test) indicated that the adhesion was significantly higher (p = 0.0003) than that of normal platelets to VEC. To partially identify the membrane components implicated in the adhesion process, either platelets or VEC were treated with neuraminidase, trypsin or heparinase prior to the adhesion assay. Trypsin or neuraminidase treatment of platelets significantly diminished their adherence to VEC, suggesting a role of platelets sialylated glycoproteins in the adhesion process. Neuraminidase or heparinase treatment of VEC increased the adhesion of both normal and diabetic platelets, indicating that the cell membrane sialyl residues and heparan sulfate participate in the normal thromboresistant properties of VEC. Transmission and scanning electron microscopy revealed a close apposition between platelets and VEC with the formation of an adhesion plaque, characterized by fine fibrillar bridges between the plasma membranes of the two cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Conventional and high resolution scanning electron microscopy of outer and inner surface features of cerebellar nerve cells.

This paper provides an exploration into the inner and outer surfaces of vertebrate cerebellar neurons utilizing secondary electron (SE-I and SE-II) topographic contrasts. SE-I enriched chromium coated, cryofractured Rhesus monkey cerebellum staged within the condenser/objective stage of SEMs equipped with high brightness LaB6 and field emission emitters generated quality images of intact and fractured nerve cells studied at intermediate and high magnifications. These images were compared with conventional SE-III images of gold-palladium teleost fish cerebellar neurons and transmission electron micrographs of mouse cerebellar nerve cells obtained either by thin-sections or freeze-etch replicas. Chromium coated Rhesus monkey granule and Golgi cell surfaces revealed smooth, accurately delineated profiles of true cell surface features, which lacked the SE-III dominated brilliance of conventional teleost fish gold or gold-palladium, decorated neurons. Chromium coated fractured nerve processes showed the outer smooth surface of interconnected anastomotic networks or ER tubules, vesicles and cisterns. Cross fractured presynaptic endings of parallel fibers in the molecular layer exhibited spheroidal synaptic vesicles and SE-I edge brightness contrast delineated their limiting plasma membranes. Fractured synaptic endings showed a homogeneous extravesicular material surrounding the synaptic vesicles. The presynaptic dense projections appeared as columnar shaped structures. The postsynaptic membrane and associated postsynaptic density showed a discontinuous surface formed by round subunits 25-35 nm in diameter. The neuroglial cytoplasm ensheathing nerve process exhibited a smooth discontinuous surface. The surface of the myelin sheath showed a mixed population of globular structures 10-30 nm in diameter, apparently corresponding, according to freeze-etch images, to protein and phospholipid microdomains.


Ultrastructure of Brunner's glands in the horse.

Investigation of the duodenal submucosal glands of Brunner in the horse for the first time at the ultrastructural level has clarified some of the unique features of these equine glands. The horse is one of the very few mammals in which Brunner's glands are comprised of both mucous and serous tubuloacinar glands. Although the ultrastructural differences between the serous and mucous cell types are marked, particularly with respect to secretory granules and rough endoplasmic reticula, these cell types closely correspond to serous and mucous cells in the upper digestive system of other mammals. A minor and distinct population of goblet cell-like mucous cells, and endocrine-like cells were also observed in equine Brunner's glands. Both the serous and mucous cells appear to empty into common ducts which enter the base of the duodenal crypts. These submicroscopic cytologic data taken together with other physiologic data would suggest that, in the horse, Brunner's glands function both to provide mucosal protection in the proximal duodenum as well as to release digestive enzymes, such as lipase or other unidentified materials.


Cytogenetic studies in 112 cases of untreated myelodysplastic syndromes.

Cytogenetic studies were performed in 112 untreated cases of myelodysplastic syndrome (MDS) between 1985 and 1990. Among 112 patients who were examined at the time of diagnosis, 54 had an abnormal karyotype (48%). The highest frequency of chromosome abnormalities was observed in refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-t) and the lowest in refractory anemia with ring sideroblasts (RARS) and chronic myelomonocytic leukemia (CMMoL). Numerical changes were observed in 19 cases and structural in 17; chromosome 8 was most frequently gained (11 cases), whereas chromosome 7 was most frequently lost (6 cases), 5q- in 14 (4 as a sole anomaly); involvement of 7q22 was seen in 3 cases, 11p in 2 patients, 11q in 3 (one patient as a sole anomaly), 12p in 4 (2 patients as a sole anomaly), i(17q) in 4 (3 patients as a sole anomaly), and complex chromosomal defects in 10 patients. If one takes into account the prognosis value, a complex karyotype and the presence of ring chromosomes were correlated with the worst prognosis, followed by -7/7q-; an intermediate prognosis corresponds to i(17q), 12p as a sole anomaly, +8 (as a sole anomaly or plus other anomalies), and involvement of 12p. Patients with a 5q- as a sole anomaly or with a normal karyotype, had the best prognosis.


Chromosome 12 in human testicular cancer: dosage changes and their parental origin.

Cytogenetically, a marker chromosome interpreted as i(12p) is present in most testicular tumors of germ cell origin. In this study, 22 patients with testicular germ-cell tumors were investigated by Southern blot hybridization to characterize changes in chromosome 12. In comparison with normal DNA, tumor DNA of 18 patients showed increased dosages of 12p accompanied by a comparable or smaller increase or no change in the dosage of centromeric sequences of chromosome 12. A likely interpretation was that most testicular tumors had one or several isochromosomes for 12p that were formed by somatic division of the centromere and that the points of breakage and reunion in the centromeric region were different in different tumors. Allelic 12p fragments showing increased intensity were paternal in four and maternal in three of seven informative cases. Thus, there was no evidence of sex-limited parental imprinting. Furthermore, the observed patterns of allelic fragments suggested that the marker was an i(12p) formed by sister chromatids of one homolog number 12 rather than the result of interchange of genetic material between different homologues.


Translocation (12;17)(p11-12;q11-12): a recurrent primary rearrangement in acute leukemia.

We identified two patients with acute leukemia in relapse (one lymphoblastic and the other with evidence of mixed lymphoid-myeloid differentiation) with t(12;17)(p12;q11) as the primary karyotypic abnormality. There are six previously reported cases of acute leukemia with an identical or similar translocation. To our knowledge, t(12;17) has not been reported in other forms of neoplasia. A review of these cases suggests that t(12;17) carries a poor prognosis.


Variant complex translocation t(8;15;21) in acute myeloblastic leukemia (M2) associated with bilateral chloroma.

Complex translocation t(8;15;21)(q22;q21;q22) in a 9-year-old female with acute myeloblastic leukemia (M2) with bilateral chloroma is described. This particular variant type of translocation in M2 type is rare. The importance of variant translocation in defining the critical segment on the chromosomes responsible for phenotypic expression of the disease is emphasized.


A t(2;3)(q12-13;p24-25) in follicular thyroid adenomas.

We report the cytogenetic analysis of five cases of follicular thyroid adenoma. In two of them, we observed an identical t(2;3)(q12-13;p24-25) as a unique chromosome change. A third case showed a hyperdiploid karyotype with trisomies of chromosomes 7 and 12. Two cases had a normal diploid karyotype. These changes could define subgroups of follicular adenomas endowed with different malignant potential.


Cellular proliferation and genetic events involved in the genesis of Burkitt lymphoma (BL) in immune compromised patients.

A mathematical model simulating lymphomagenesis based on the two-hit theory of carcinogenesis is presented by contrasting the biologic variables responsible for a high risk of developing Burkitt lymphoma (BL) in three immunosuppressed groups with that of nonendemic BL. In this model, the pro-B lymphocyte is considered to be the target for BL-specific translocations such as t(8;14). With repeated mitosis, the target cell pool expands in the high-risk individual, and, thereby, the opportunities for a spontaneous translocation to arise are increased. The chromosomal translocation endows the target cell with survival advantages, and, hence, lymphoma develops. Modeling results demonstrate that this increased cell proliferation is sufficient in accounting entirely for the increase in tumor prevalence. Preventing enhanced cellular proliferation by obviating immune deficiency and treating patients with agents that restore immunity or have antiviral and antiproliferative properties prior to conversion from polyclonal B-cell proliferation to monoclonal malignancy could obviate the development of BL.


Prognostic significance of karyotype in a twelve-year follow-up in childhood acute lymphoblastic leukemia.

We report a follow-up of 49 children with acute lymphoblastic leukemia (ALL) diagnosed between 1972 and 1978 (follow-up 12-18 years). This series allowed us to analyze the predictive value of karyotype in a long-term follow-up. Karyotypes were abnormal in 33 cases (67.3%): pseudodiploidy in 11 (22.4%), hyperdiploidy > 50 chromosomes in 8 (16.3%), hyperdiploidy 47-50 chromosomes in 11 (22.4%), and hypodiploidy in 3 cases (6.1%). Event-free survival (EFS) and survival studies showed that the outcome of patients was determined only by treatment and karyotype. Eleven patients have survived, nine in first remission (6 years 5 months to 15 years 2 months), and two are in second remission (3 years 8 months and 8 years 2 months). All ploidy groups are represented in these patients. Late relapses can occur in the hyperdiploid > 50 group, thus accounting for shorter EFS than expected, but because of the unusually long second remission of one patient, the rate of surviving patients was higher for this ploidy group than for all other ploidy groups together. Conversely, patients with only numerical abnormalities (no matter which ploidy group they belonged to), had a better outcome than did patients with structural changes or normal karyotypes and no discrepancy between EFS and survival curves was observed in this chromosomal group. Thus, our results suggest that numerical changes only should be considered an indicator of low risk factor, but our results, based on partially banded karyotypes, need to be verified by a current method and therapy.


A new nonrandom chromosomal abnormality, t(2;16)(p11.2;p11.2), possibly associated with poor outcome in childhood acute lymphoblastic leukemia.

We report a new, nonrandom t(2;16)(p11.2;p11.2) in childhood acute lymphoblastic leukemia (ALL). Three of 292 patients with childhood ALL studied at Indiana University Medical Center had this translocation. All three had additional chromosomal abnormalities at diagnosis and were classified as having low hyperdiploidy (47-49 chromosomes) with structural abnormalities. The patients, two boys and one girl, ranged in age from 3 to 13 years. Peripheral white blood cells (WBC) counts ranged from 1.8 to 107.4 x 10(9)/L, all were classified as French-American-British (FAB) type L1, and all had B-lineage ALL. Because all three patients have relapsed after first remissions of 2 years 8 months to 6 years, the t(2;16) may indicate a poor prognosis and more aggressive treatment may be indicated for such patients. Because this translocation was the sole abnormality in one clone of patient 2 at relapse, it may be considered the primary abnormality. Therefore, it may also be the primary abnormality in the other two patients, and the genes involved in the breakpoints may be important in leukemogenesis.


Abnormalities of chromosome 22 in meningiomas and confirmation of the origin of a dicentric 22 by in situ hybridization.

We report three cases of meningioma. Case 1 had a dicentric chromosome number 22 resulting in partial monosomy for a portion of the q-arm, i.e., 46,XX,idic(22)(pter-->q11.2::q11.2-->pter) and 46,XX,psu dic(22)(pter-->q11.2::q11.2-->pter), which was the sole clonal abnormality. The origin of the dicentric chromosome from 22 was confirmed by in situ hybridization studies, using biotin-labeled alpha centromeric DNA probes for the acrocentric chromosomes. Case 2 had two distinct clonal abnormalities: deletion of 22q and monosomy of 22. Case 3 also had a deleted 22q.


DNA sequence analysis of mutations induced by melphalan in the CHO aprt locus.

In previous work, we established that treatment with melphalan (L-phenylalanine mustard) produced a predominance of A.T-->T.A transversions in the Simian virus 40 (SV40)-based shuttle vector pZ189 during replication in human 293 cells. Mutations were induced with varying doses (4-12 microM) melphalan in the aprt gene of the hemizygous Chinese hamster ovary (CHO) cell line D422 to determine whether a similar mutation spectrum would be observed in an endogenous gene. DNA sequence alterations were determined for 39 spontaneous and 41 melphalan-induced independent mutant clones. Other than a predominance of transversions in both systems, the spectrum of melphalan-induced aprt mutations bears little resemblance to the spectrum observed in the supF gene of the shuttle plasmid pZ189. In aprt, mutations at G.C base pairs (bp) predominated (29 of 41 base substitutions). Significantly enhanced mutagenesis was observed at 5' G-G-C 3' and 5' G-G-C-C 3' sites in the aprt gene. Almost half of the melphalan-induced base substitutions occurred at 5' G-N-C 3' sequences, which are believed to be potential interstrand crosslink sites.


Acute leukemia with t(1;3)(p36;q21), evolution to t(1;3)(p36;q21), t(14;17)(q32;q21), and loss of red cell A and Le(b) antigens.

At transformation of refractory anemia with ring sideroblasts to acute nonlymphocytic leukemia (ANLL) the bone marrow cells of a 75-year-old woman showed three different karyotypes, i.e., 46,XX,46,XX,t(1;3)(p36;q21) and 46,XX,t(1;3)(p36;q21),t(14;17)(q32;q21). She received no antileukemic therapy, and 1 year later, all her bone marrow cells were t(1;3)(p36;q21),t(14;17)(q32;q21). In association with the onset and first 11 months of ANLL, the platelet count increased 10-fold to a peak of 750 x 10(9)/L, providing further evidence that the t(1;3)(p36;q21) translocation causes stimulation of thrombopoiesis. Six months after transformation, her red cells showed reduced expression of A and Leb antigens. Serum alpha-n-3-acetylgalactosaminyl transferase (blood group A transferase) and red cell adenylate kinase were both reduced. The genes for both these substances are at 9q34, which suggests an abnormality here, although cytogenetically chromosome 9 appeared normal. This is the first case with t(1;3)(p36;q21) to show concurrent loss of red cell antigens and the first report detailing the course of untreated ANLL with t(1;3)(p36;q21).


Myelodysplastic syndrome and trisomy 14q.

Trisomy 14 as a sole karyotypic abnormality in neoplasia is extremely rare. In hematologic disorders, 18 cases have been reported so far, 17 of which involved disorders of the myeloid lineage. Five were cases of myelodysplastic syndrome (MDS), and a further four involved Philadelphia-negative atypical chronic myeloid leukemia. The case presented here is the second case of trisomy 14q in MDS involving the chronic myelomonocytic leukemia subtype. There were certain features in common with some of the previously reported cases. We raise the possibility that this represents a specific entity.


Concomitant presence of trisomy 21 and del(9q) in acute myeloid leukemia.

We report two cases of acute myeloid leukemia with deletion of the long arm of chromosome 9 [del(9q)] and trisomy 21. del(9q) and +21 do not often occur as a sole karyotypic abnormality in acute myeloid leukemia (AML). Their concomitant presence is rare; the significance of the findings in leukemia is discussed.


Cytogenetics of sacral chordoma.

Only four cases of chordoma have been described cytogenetically. We report the cytogenetic findings of a fifth case. Chromosome analysis of a primary sacral chordoma from a 69-year-old man showed the following chromosome complement: 43,XY,-2,-3,del(4)(q32),-6,+7,-11,der(12)t(9;12)(q12;p11),add(16)(q23),- 20,add(22)(q13),+mar.


Isochromosome 14q and leukemia with dysplastic features.

We report a case of chronic myelomonocytic leukemia (CMMoL) with unusual features and an isochromosome 14q as the sole abnormality. A review of the literature suggests that isochromosome 14q (or trisomy 14) is a marker of leukemia with dysplastic features.


Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention.

Evidence from pathology and epidemiology studies has been provided for a human model of gastric carcinogenesis with the following sequential stages: chronic gastritis; atrophy; intestinal metaplasia; and dysplasia. The initial stages of gastritis and atrophy have been linked to excessive salt intake and infection with Helicobacter pylori. The intermediate stages have been associated with the ingestion of ascorbic acid and nitrate, determinants of intragastric nitrosation. The final stages have been linked with the supply of beta-carotene and with excessive salt intake. Nitrosating agents are candidate carcinogens and could originate in the gastric cavity or in the inflammatory infiltrate.


Down-regulation of c-MYC antigen expression in lymphocytes of Emu-c-myc transgenic mice treated with anti-c-myc DNA methylphosphonates.

In transgenic mice bearing a murine immunoglobulin enhancer/c-myc fusion transgene (Emu-myc), it was found that antisense DNA methylphosphonates targeted against c-myc mRNA inhibited production of c-MYC protein in peripheral lymphocytes. The decrease in protein was measured 3-4 h after i.v. administration of a 300-nmol dose. c-MYC was detected by immunofluorescence of fixed cells stained with an anti-c-MYC antiserum. In addition, DNA methylphosphonates did not induce acute toxicity following i.v. administration of a 300-nmol dose. An identically administered scrambled sequence oligomer did not decrease c-MYC protein or induce toxicity. Finally, recovery of DNA methylphosphonates from the blood plasma of treated mice indicated that the oligomers remained intact up to 3 h, while their concentrations decreased rapidly for the first h, then slowly decreased over the next 2 h. This is the first demonstration of sequence-specific antisense DNA methylphosphonate inhibition of gene expression in the bloodstream of an animal model.


Phase I and pharmacokinetic study of the novel platinum analogue CI-973 on a 5-daily dose schedule.

CI-973, a platinum(II) derivative with a 2-methyl-1,4-butanediamine carrier ligand, has activity in cisplatin-resistant tumor models in vitro and in vivo. In a Phase I pharmacokinetic study, 31 patients were treated with CI-973 (24 to 50 mg/m2/day for 5 days; 28-day cycles) given i.v. over 30 min without routine antiemetic prophylaxis or hydration. Of the 29 patients evaluable for maximum tolerated dose determination, most had a performance status of 0 or 1, and most had received prior chemotherapy. Neutropenia was dose limiting at 40 and 50 mg/m2/day. Recovery from neutropenia was generally rapid with nadir counts and recovery usually occurring by Days 15 and 22, respectively. Drug-associated thrombocytopenia was uncommon and never severe, even in patients with Grade 4 neutropenia. Anemia was common, but did not appear dose related. Drug-related nausea and vomiting and changes in renal function were relatively infrequent and mild. No clinically evident ototoxicity was reported, although changes in audiograms were noted in several patients. CI-973 concentrations were measured in plasma ultrafiltrate and urine by high-pressure liquid chromatography. The harmonic mean terminal half-life was 2.0 h. The mean CI-973 renal and nonrenal clearance values were 42.3 and 37.4 ml/min/m2, respectively. The mean recovery of CI-973 in urine was 53% of the administered dose. The mean ratio of CI-973 renal clearance to creatinine clearance was 0.92. Total clearance correlated with creatinine clearance (r2 = 0.63). A relationship between toxicity, expressed as the percentage of reduction in absolute granulocyte count, and area under the CI-973 plasma concentration-time curve was found in a subgroup of "good-risk" patients. This relationship, described well by a sigmoidal Emax pharmacodynamic model, did not hold for patients with extensive prior therapy or poor performance status. A model for toxicity prediction based on dose and creatinine clearance has been derived and will be validated in future studies. The recommended Phase II dose of CI-973 is 30 mg/m2/day for 5 days.


Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies.

Human-mouse chimeric immunoglobulins G1 and G3 (IgG1 and IgG3) (ChG1, ChG3) and "complementarity-determining region"-grafted, humanized IgG1 and IgG3 (HuG1, HuG3) constructs of the mouse monoclonal antibody (mAb) M195 were characterized. M195 is a murine immunoglobulin G2a (IgG2a), anti-CD33 mAb, specifically reactive with acute myelogenous leukemia cells, that is active as an antileukemia agent in humans. The new mAb constructs maintained specificity and biological function, including rapid internalization after binding to the cell surface, which has been important for delivery of therapeutic isotopes in patients. Although previously reported complementarity-determining region-grafted mAbs had reduced avidities, the HuG1 and HuG3 M195 showed up to an 8.6- and 4-fold higher binding avidity, respectively, than the original murine mAb. All constructs were effective at mediating rabbit complement-mediated cytotoxicity against HL60 targets. Fibroblasts transfected with CD33 genes and expressing high levels of CD33 antigen were also lysed in the presence of human complement, but HL60 cells or fibroblasts with lower CD33 levels were not killed. Thus, the inability of M195 and constructs to kill HL60 targets with human complement is due to the much lower antigen density on HL60 cells compared to CD33+ fibroblasts. Unlike the murine M195, the chimeric and humanized M195 demonstrated antibody-dependent cell-mediated cytotoxicity using human peripheral blood mononuclear cells as effectors. Because the chimeric and humanized M195 have improved avidities as compared to the original M195 and have, in addition, the potential to avoid human anti-mouse antibody responses and to recruit human effector functions, these new constructs may be useful therapeutically, either alone or conjugated to toxins or isotopes, in the treatment of acute myelogenous leukemia.