bcl-xs gene therapy induces apoptosis of human mammary tumors in nude mice.

Bcl-xs is a dominant negative repressor of Bcl-2 and Bcl-xL, both of which inhibit apoptosis. We used a replication-deficient adenoviral vector to transiently overexpress Bcl-xs in MCF-7 human breast cancer cells, which overexpress Bcl-xL. Infection with this vector induced apoptosis in vitro. We then determined the effects of intratumoral injection of bcl-xs adenovirus on solid MCF-7 tumors in nude mice. Tumors injected four times with the bcl-xs adenovirus showed a 50% reduction in size. Using terminal transferase-mediated dUTP-digoxigenin nick end labeling, we observed apoptotic cells at sites of bcl-xs adenoviral injection. These experiments demonstrate the feasibility of using bcl-xs gene therapy to induce apoptosis in human breast tumors.

Iron deficiency and sickle cell anemia.

In a patient with sickle cell anemia, iron deficiency was accompanied by hypochromic, microcytic RBCs, absence of bone marrow iron, and a low serum ferritin level. The mean corpuscular hemoglobin concentration (MCHC) was decreased (27.6 g/dL) and was associated with an extreme scarcity of sickled erythrocytes in blood smears. Iron therapy resulted in reticulocytosis and an increase in sickled erythrocytes. In vitro studies demonstrated a decrease in sickling of erythrocytes as a function of oxygen saturation of the blood when the patient was iron deficient. The whole blood oxygen dissociation curve showed a substantial decrease in oxygen pressure necessary to produce 50% saturation of hemoglobin at pH 7.4 and 37 degrees C (P50), indicating an increased oxygen affinity. These data suggest that a reduction of the MCHC induced by iron deficiency may ameliorate sickling.

Evaluation of propylene oxide for mutagenic activity in 3 in vivo test systems.

Propylene oxide (CAS No. 75-56-9) was tested for mutagenic activity following vapor exposure using 3 in vivo test systems. Rat dominant lethal and mouse sperm-head morphology assays were conducted using males exposed to propylene oxide at 300 ppm in a dynamic exposure chamber for 7 h per day on 5 consecutive days. A sex-linked recessive lethal test in Drosophila melanogaster employed a 24-h static exposure to propylene oxide at 645 ppm. Male mice were killed 1, 3, 5, 7, and 9 weeks post-exposure for evaluation of sperm-head morphology. Propylene oxide exposure did not result in an increase in abnormal forms. Male rats were mated with 2 virgin females per week for 6 weeks following exposure. A statistically significant increase in preimplantation losses and a statistically significant reduction in the number of living implants in the first post-exposure week did not appear to be treatment related. A highly significant increase in sex-linked recessive lethal mutations was observed in two germ cell stages (mature sperm and developing spermatocytes). These results warrant continued caution in potential human exposure to propylene oxide.

Case report: bilateral adrenal pheochromocytoma.

Pheochromocytoma remains a clinical challenge to diagnose and manage. In addition, the association of multiple endocrine neoplasia syndromes with pheochromocytoma require the clinician's awareness to evaluate patients with pheochromocytoma (especially when bilateral) for abnormalities in thyroidal C-cell function with serum calcitonin determinations. The authors present a case of a 42-year-old woman initially diagnosed with, and treated for, cranial artery vasculitis because she had a stroke and a history of rheumatoid arthritis and asthma. Subsequent evaluation of episodic blood pressure increases, headache, and tachycardia revealed biochemical evidence of catecholamine overproduction. Bilateral adrenal masses were found on computed tomography scanning, and the functional nature of the adrenal masses was confirmed by a meta-Iodobenzylguanidine scan. Upon further evaluation, an elevated serum calcitonin concentration was demonstrated, which increased greatly with pentagastrin stimulation. C-cell hyperplasia was demonstrated by subsequent thyroidectomy, confirming the diagnosis of multiple endocrine neoplasia 2A. The difficulty in arriving at a correct diagnosis, the subsequent management, including bilateral adrenalectomy and thyroidectomy, and newer insight into the genetic abnormalities of multiple endocrine neoplasia 2A are discussed.

Evaluation of a conceptual model for the subsurface transport of plutonium involving surface mediated reduction of PuV to PuIV.

A conceptual model is proposed to explain the transport behavior of plutonium in laboratory columns packed with a sandy coastal soil from the U.S. Department of Energy (DOE)'s Savannah River Site. The column transport experiments involved the introduction of a finite step input of plutonium, predominately in the +5 oxidation state, into the columns followed by elution with a low-carbonate solution of 0.02 M NaClO4 at pH 3, 5, and 8. Total plutonium concentrations were measured in the effluent as a function of time. These elution profiles suggest at least two distinct physical/chemical forms of plutonium, each with a different mobility. To explain the observed behavior, the following conceptual model was evaluated: [1] equilibrium partitioning of plutonium (V) and plutonium (IV) between the aqueous and sorbed phases as defined by pH-dependent, oxidation-state specific distribution coefficients and [2] kinetic reduction of plutonium (V) to plutonium (IV) in the sorbed phase. The conceptual model was applied to the column experiments through a one-dimensional advective/dispersive mathematical model, and predictions of the mathematical model were compared with the experimental data. Overall, the model was successful in predicting some of the major features observed in the experiments. It also yielded quantitative estimates of the rate constant for surface mediated reduction of plutonium (V) to plutonium (IV) that were of the same order (10(-4) to 10(-5) s(-1)) as those calculated from batch data both for this soil and for goethite.

The re-emergence of space medicine as a distinct discipline.

Space Medicine is a discipline whose scope will encompass primary and advanced medical care amidst the environmental constraints of space. At one time, there was a Department of Space Medicine associated with the U.S. Air Force School of Aviation Medicine. Until 1993, an academic, university-based training program dedicated to space medicine did not exist. This paper reviews the history of space medicine in the United States. It presents the current conceptions of space medicine, and postulates the need for space medicine to mature as a distinct discipline.

The future of occupational health nursing in space.

Space offers the occupational health nurse a unique occupational environment and many challenges. Zero gravity and severe limitations on working space will require many changes in methods of operation. The health maintenance facility within the space station will not be equipped to deal with all conceivable emergencies, but personnel will be able to diagnose and treat injuries and illnesses which are most likely to occur and are easily treated. Occupational health nurses are uniquely qualified to meet NASA's health maintenance facility objectives.

Biological considerations for combining carcinogenicity data for quantitative risk assessment.

Quantitative risk assessments for carcinogens conducted by the U.S. EPA have most frequently been based on results of a bioassay from a single sex/strain/species of animal. In some cases, more than one data set derived from different sexes, strains, or species of animals is suitable for quantitative risk assessment. When there is no apparent difference among the data sets in sensitivity to the carcinogen, use of more of the available data should result in a higher level of confidence in the risk estimate. Several biological factors must be considered before combining data from different animal sexes, strains, species, or tumor sites. The relevance of the animal models, study design and execution, dose selection, and route of administration are factors which influence whether data from separate studies should be combined. The decision to combine data sets is also based on what is known of the mechanism of action of the agent, its pharmacokinetics, any species/sex specificity of the effect, and considerations regarding tumor site specificity. Statistical analysis also indicates whether the data sets may be described by the same multistage model. The evaluation of these factors in the decision to combine or not combine data sets is discussed.

Special considerations for monitoring vancomycin concentrations in pediatric patients.

The objectives of this study were to estimate the prevalence of low or excessive vancomycin dosing after initiation of treatment in pediatric patients and to determine the factors that are most predictive of optimized vancomycin dosage in this group. Among 74 patients who underwent vancomycin concentration monitoring, low trough (< 4.0 micrograms/ml) and/or peak (< 15.0 micrograms/ml) concentrations were noted in 28 (38%) patients after the initiation of therapy but in only four of the 28 (14%) patients (p = 0.29) after optimization of the initial dosage. There were not toxic peak concentrations (> 60 micrograms/ml) reported during the study. In patients older than 1 month old, 11 low peaks were associated with troughs less than 7.5 micrograms/ml, whereas no low peaks were associated with troughs more than 7.5 micrograms/ml. The significant predictive variables of optimized vancomycin dosage in the reduced regression model (p < 0.00001; adjusted r2 =0.85; n = 36) were (log) initial dose (p < 0.0001), initial trough (p < 0.0001), and age (p = 0.009). Initial peak concentrations were not associated with the optimized dosage (p = 0.50). The results of this study indicate that approximately 40% of all pediatric patients will be at risk of significant underdosing if standard vancomycin dosing guidelines are followed and that patients older than 1 month old with initial trough concentrations less than 7.5 micrograms/ml are at a greater risk of low peak concentrations than individuals with trough concentrations more than 7.5 micrograms/ml. Monitoring vancomycin concentrations appears to be essential to prevent the underdosing of many pediatric patients; however, only initial trough vancomycin concentrations may be needed to optimize dosages.

Simultaneous measurement of tyrosine, tryptophan and related monoamines for determination of neurotransmitter turnover in discrete rat brain regions by liquid chromatography with electrochemical detection.

Concomitant measurement of monoamine neurotransmitter turnover in discrete rat brain areas with the use of radiolabeled amino acid precursors permits simultaneous evaluation of interacting transmitter systems. [3H]Tyrosine and [3H]tryptophan were administered via indwelling catheters to unrestrained rats. Content and specific activity of norepinephrine, dopamine, 5-hydroxytryptamine, and the metabolites dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid in addition to tyrosine and tryptophan were quantified by liquid chromatography with electrochemical detection and liquid scintillation counting. The method employs a simple extraction procedure without prior cleanup for chromatography. Neurotransmitter turnover rates that incorporated tyrosine- or tryptophan-specific activities were found to be two to four times greater than those that did not include them.

Hormonal and behavioral response of male chimpanzees to a long-acting analogue of gonadotropin-releasing hormone.

A long-acting preparation of gonadotropin-releasing hormone (GnRH) was administered to three adult male chimpanzees living in a socially integrated group. Hormonal changes and behavioral responses were monitored for 8 days. Blood serum levels of luteinizing hormone peaked at about 8 hr and returned to baseline at 48 hr. Total serum testosterone reached the highest levels of 140% above baseline at 24 hr and returned to baseline after 48 hr. Out of a wide variety of behaviors observed in detail, only one cluster of three related behaviors showed even a suggestion of response: The two measures of activity, lone travel (p < 0.05) and distance traveled (p < 0.1), decreased on the day of hormone administration followed by an increase on the 2 subsequent days, and idle time (p < 0.1) revealed the reciprocal pattern. In view of various reports of behavioral effects of GnRH in other species, it is particularly noteworthly that parameters of sexual and agonistic behavior of male chimpanzees definitely did not change.

Iron stores in adults with sickle cell anemia.

Iron status was investigated in 60 adults with sickle cell anemia as determined by stainable iron in bone marrow aspirates, serum ferritin, serum iron, and the total iron-binding capacity. Seventeen patients (28%) were found to have absent bone marrow iron. There was an excellent inverse correlation between serum ferritin and the serum transferrin (p less than 0.001), and a significant positive correlation between serum ferritin and transferrin saturation (p less than 0.005), bone marrow iron (p less than (p less than 0.001), and history of prior blood transfusion (p = 0.005). Results of complete radiologic examination of the gastrointestinal tract and proctoscopy were negative in the 17 patients in the iron-deficient group. The high incidence of iron deficiency may be related to excessive urinary losses of iron. Our data indicate that serum ferritin values of less than 30 ng/ml are diagnostic of iron deficiency in patients with sickle cell anemia, with a high degree of specificity (98.7%). However the sensitivity of the test at a serum ferritin level of 30 ng/ml is only 32%. The diagnostic evaluation and the management of sickle cell anemia in iron-deficient patients needs to be better defined.

Male reproductive toxicity and recovery associated with acute ethoxyethanol exposure in rats.

Effects of 2-ethoxyethanol (EE) on semen parameters in male rats were investigated employing an animal model that allowed assessment of toxicity and recovery in the same animal. Prior to exposure, 70-d-old Long-Evans hooded males were placed with ovariectomized, hormonally primed females on several occasions and their copulatory behaviors were monitored and scored. At 100 d of age, these males were mated with females that were sacrificed 15 min postejaculation. The semen sample was recovered from the female reproductive tract and scored for sperm motility, sperm count, and abnormal sperm morphology. Following this preexposure baseline assessment, the males were intubated with 0, 936, 1872, or 2808 mg EE/kg for 5 consecutive days. The males were mated weekly for the next 14 wk. Copulatory behaviors were monitored and ejaculated semen samples analyzed on wk 1, 4, 7, 10, and 14. The males were sacrificed at wk 16 and the testes and epididymides were processed for histological evaluation. Data analyses indicated that EE produced a rapid decline in sperm counts in the two highest groups, with most of the males becoming azoospermic by wk 7. The males in the low dose group also exhibited a significant decrease in sperm counts at this week. Additionally, there was a significant increase in abnormal sperm morphology at wk 7 in the low-dose males. Partial or complete recovery was apparent in the sperm parameters by wk 14, as evidenced by an increase in sperm counts and a decrease in abnormal morphology and further supported by epididymal and testicular histological assessment at wk 16. At sacrifice, there were no significant differences between groups on body weights, organ weights, or epididymal sperm counts, except for a significant depression of epididymal weight in the middle dose group. While high doses of EE produced a decline in sperm counts starting after the first week of exposure, the early spermatid-late spermatocyte stages, represented by mature spermatozoa in the wk 7 ejaculates, appeared to be particularly sensitive to this compound. Moreover, most of the males exhibited recovery following this acute dosing regimen.

Health characteristics of elderly personal care home residents.

The purpose of this descriptive study was to explore the health characteristics of elderly personal care home residents. Personal care homes are community-based facilities that provide living arrangements, assistance with basic needs and protective oversight. Personal care home providers were interviewed regarding the health status of 80 elderly residents. The most frequent ADL needs were bathing, personal hygiene and dressing. Thirty-seven per cent of the residents had some bladder incontinence. Eighty-two per cent of residents needed some help with medication management. Over half of the residents had some cognitive impairment. These findings support the proposition of increased prevalence of cognitive impairment in personal care home residents as compared to the first studies a decade ago. The combination of functional deficits and cognitive impairment indicates that these elderly residents may have unmet health needs. The role of the registered nurse in this environment is discussed.

Ileocecal intussusception of small-bowel lymphoma: diagnosis by colonoscopy.

Intussusception is rare in adults. There is little information on the role of colonoscopy in colonic intussusception. We report, to our knowledge, the first adult case of small-bowel lymphoma causing ileocecal intussusception in which the diagnosis was made by colonoscopy. Colonoscopy has a useful role in the diagnosis and management of ileocecal intussusception.

Combination of cancer data in quantitative risk assessments: case study using bromodichloromethane.

There are often several data sets that may be used in developing a quantitative risk estimate for a carcinogen. These estimates are usually based, however, on the dose-response data for tumor incidences from a single sex/strain/species of animal. When appropriate, the use of more data should result in a higher level of confidence in the risk estimate. The decision to use more than one data set (e.g., representing different animal sexes, strains, species, or tumor sites) can be made following biological and statistical analyses of the compatibility of the these data sets. Biological analysis involves consideration of factors such as the relevance of the animal models, study design and execution, dose selection and route of administration, the mechanism of action of the agent, its pharmacokinetics, any species- and/or sex-specific effects, and tumor site specificity. If the biological analysis does not prohibit combining data sets, statistical compatibility of the data sets is then investigated. A generalized likelihood ratio test is proposed for determining the compatibility of different data sets with respect to a common dose-response model, such as the linearized multistage model. The biological and statistical factors influencing the decision to combine data sets are described, followed by a case study of bromodichloromethane.