Biologic effects of nonsteroidal anti-inflammatory drugs

Experimental glaucoma was induced in 1 eye of 6 cynomolgus monkeys by laser treatment of the trabecular meshwork. In 5 of the 6 monkeys the increased intraocular pressure (IOP) caused marked glaucomatous damage in the experimental eye. Ocular blood flow was determined with labeled microspheres 4 years after the laser treatment. IOP was regulated with an external reservoir. With the same perfusion pressure in both eyes no statistically significant difference was observed between the 2 eyes for total ocular blood flow or for blood flow through any of the ocular tissues. Total ocular blood flow was 343.5 +/- 61.4 mg/min (mean +/- SEM) in the control eye and 385.3 +/- 107.7 mg/min in the experimental eye.     

17-KS sulfate as a biomarker in health and disease

OBJECTIVE: To attempt to distinguish cases of true malignant histiocytosis from the clinical syndromes of so-called malignant histiocytosis with use of recent methods. DESIGN: We retrospectively studied the laboratory data and clinical course of Mayo patients who had clinical syndromes of so-called malignant histiocytosis and reviewed available paraffin-embedded tissue specimens to identify the nature of the malignant cells. MATERIAL AND METHODS: After elimination of cases of infection-associated hemophagocytic syndrome, we reviewed and studied seven cases of so-called malignant histiocytosis in patients who had undergone assessment at Mayo Clinic Rochester between 1973 and 1993. We identified histiocytes by using current morphologic, cytochemical, and immunohistochemical methods. The clonal nature of the malignant cells was identified with morphologic, cytogenetic, and molecular genetic studies. RESULTS: Only one of the seven cases had a true histiocytic origin. The malignant cells were T cells in three other cases (the cells were also CD30+ in two cases), CD30+ cells only in one case, epithelial cells in one case, and an undetermined cell type (stained positively only with antitrypsin) in one case. CONCLUSION: True malignant histiocytosis is an exceedingly rare disease, and only a few reports have clearly identified the histiocytic origin of the malignant cells. Previously, the lack of monoclonal antibodies specific to histiocytes and the absence of techniques for performing molecular genetic studies on paraffin-embedded tissue prevented the study of such cases. With newer techniques cases of true malignant histiocytosis can now be identified.     

Biologic effects of low-level electromagnetic fields: current issues and controversies

There is uncertainty and controversy about the extent to which low level electromagnetic fields may cause deleterious effects, but even experts who are skeptical about many supposed hazards are willing to agree that electromagnetic fields even weaker than those in the MR environment can have effects under certain conditions. In order that readers can familiarize themselves enough with the subject to make an informed independent assessment, discuss it knowledgeably in public, and have the means with which to evaluate new developments and avoid experimental pitfalls if planning their own research in the area, they are provided with some of the most recent finding of in vitro and in vivo research from outside the MR literature as well as some of the results and controversies coming from recent epidemiological studies.     

Effects of 17 alpha-dihydroequilenin sulfate on atherosclerotic male and female rhesus monkeys

OBJECTIVES: Our purpose was to determine the effects of 17 alpha-dihydroequilenin on plasma lipid and lipoprotein, glucose, and insulin concentrations; coronary artery vasomotor function; and reproductive organ and mammary gland proliferation in atherosclerotic male and female rhesus macaques. STUDY DESIGN: Fifty adult female and 33 adult male rhesus macaques were randomized to treatment by lifetime dietary cholesterol exposure and ratio of total plasma cholesterol to high-density lipoprotein cholesterol. The female treatment groups were intact female controls (n = 9), ovariectomized controls (n = 16), ovariectomized plus 0.3 mg/kg/day 17 alpha-dihydroequilenin (n = 17) and ovariectomized plus subcutaneous estradiol (n = 7). The male treatment groups were control (n = 16) and 1.25 mg/kg/day 17 alpha-dihydroequilenin (n = 17). Treatment lasted 5 weeks. Longitudinal assessments of plasma lipid and lipoprotein and glucose and insulin concentrations were performed. Coronary artery vasomotor function was assessed by quantitative coronary angiography 1 week after initiation of treatment. Morphologic and immunohistochemical assessments of proliferation index values of reproductive organs and mammary glands were done at necropsy. RESULTS: 17 alpha-Dihydroequilenin prevented endothelium-dependent vasoconstriction in males (p < 0.05) and ovariectomized females (p < 0.08). 17 alpha-Dihydroequilenin treatment increased plasma apolipoprotein A-1 concentrations (p < 0.05) and lowered fasting insulin concentrations (p < 0.05) without changing fasting plasma glucose concentrations in males. 17 alpha-Dihydroequilenin had no other effects on plasma lipid and lipoprotein concentrations in either males or females. It had no trophic effects on uterus, endometrium, or breast. There was no effect on either prostatic or testicular weight. CONCLUSION: 17 alpha-Dihydroequilenin may represent a single-agent hormone therapy for reduction of ischemic hear disease risk for both menopausal women and men. It has no apparent trophic effects on reproductive organs or mammary glands of female and male rhesus macaques.     

Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer

BACKGROUND: Interleukin-2 (IL-2) has shown antitumor activity in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is significant, particularly at the cardiorespiratory level. METHODS: To test feasibility, antitumor activity, pulmonary and systemic immunologic effects, and pulmonary function changes of continuous-infusion recombinant IL-2 given to patients with non-small cell lung cancer, eleven subjects with Stage III-IV disease were treated in a standard pulmonary medicine unit with a dose of 18 million IU/m2/day from day 1 to day 13 with 1-day rest on day 7. A second induction course was given after a 3-week rest. In patients with nonprogressive disease, four maintenance courses of 6 days' duration at the same dose were planned. Immunologic tests, including lymphocyte phenotype analysis and assays for the detection of tumor necrosis factor (TNF) and of anti-IL-2 antibodies, were performed before and after treatment in serum and bronchoalveolar lavage fluid (BAL). Cardiopulmonary function tests, including spirometry, arterial blood gas analysis, diffusion capacity, and echocardiography, were obtained before, during, and after treatment. RESULTS: Twenty-one cycles (15 induction courses plus 6 maintenance courses) were administered. No patient was able to complete the six planned courses, and only 3 patients entered the maintenance phase. Reasons for discontinuation included progressive disease in five cases, toxicity in three cases, and patient request in three cases. The most common side effects were fever, hypotension, oliguria, and elevated serum creatinine and liver enzyme levels. No patient required intubation or intensive care. No objective response was seen, and the median survival time was 10 months. Lymphocytosis and eosinophilia were observed in all patients. Surface marker analysis revealed a statistically significant increase in the percentage of CD3+, CD4+, CD25+ and DR+ cells in peripheral blood. Lymphoid cells derived from BAL disclosed an increased natural killer activity after IL-2 treatment, and TNF was increased in BAL fluid. Pulmonary function tests evidenced an increased alveolar-arterial difference for oxygen allied with a decrease of forced expiratory volume in 1 second, forced vital capacity, and carbon monoxide transfer coefficient consistent with a significant, albeit not clinically relevant, interstitial lung defect. CONCLUSION: Continuous-infusion IL-2 is feasible in patients with advanced lung cancer even outside an intensive care unit, but overall compliance is poor. Although clinical pulmonary toxicity is negligible, small but statistically significant alterations of the pulmonary function are evident. In addition, this regimen produces a significant activation of the immune system at the pulmonary level.     

Stress and anticortisols--17-ketosteroid sulfate conjugate as a biomarker in tissue repair and recovery

We attempted to determine compounds in human urine which, differing from cortisol (17-OHCS), show high values in healthy individuals, decrease with failing health, clearly decline with advancing disease and finally reach very low values in severe disease. We have eventually established that 17-ketosteroid sulfate conjugates (17-KS-S) are the compounds we were searching for. Hans Selye regarded stress as the rate of wear and tear and 17-OHCS as its indicator, but we considered that, differing from inanimate objects, living organisms consume energy to cope with stress and "repair" "wear and tear" of the tissue and "recover" its function. This concept led us to determine the organism's requirement for two mechanisms: "Wear and tear" which could be represented by the secretion of 17-OHCS (Selye), and "repair and recovery", which could be determined by the amounts of 17-KS-S derived from dehydroepiandrosterone (DHEA)-sulfate, a product of the adrenal cortex, which enhances neuronal survival, longterm memory, maintains the function of peripheral tissues, and stimulates immune system (17-KS mainly consists of 17-KS-S and 17-KS glucuronides 17-KS-G, the latter derived from cortisol, DHEA and testosterone). We hold that stress response is a series of biological process, beginning from CRH.ACTH and catecholamines, cortisol (17-OHCS), followed by insulin, acting as an anabolic agent and finally DHEA (17-KS-S) leads the tissues to repair by utilizing produced energy. Balanced changes of hormones, such as 17-KS-S, 17-OHCS, cortisol, catecholamines and insulin are seen in healthy individuals under healthy lifestyles and disruption of the balance brings apparent reduction in 17-KS-S. From this standpoint, we wish to develop research in interrelations between biologically antagonistic 17-KS-S and 17-OHCS, focusing particularly at 17-KS-S, which represents a contact point for mind and body, the healthy state of which is kept by appropriate sleeping and exercise programs on the basis of adequate food intake. The above three factors, 17-KS-S, 17-OHCS, and 17-KS-G, are expressed in creatinine ratio (mg/g creatinine).     

Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate

BACKGROUND: A naloxone infusion is effective in reducing epidural and intrathecal opioid-related side effects. The use of naloxone infusion concomitant with intravenous morphine patient-controlled analgesia (PCA) has not been evaluated, probably because of an expected direct antagonism of the systemic opioid effect. The authors compared the incidence of morphine-related side effects and the quality of analgesia from two small doses of naloxone infusion. METHODS: Sixty patients classified as American Society of Anesthesiologists physical status 1, 2, or 3 who were scheduled for total abdominal hysterectomies were enrolled in the study. Patients received a standardized general anesthetic. In the postanesthetic care unit, patients received morphine as a PCA. They were randomized to receive either 0.25 microg x kg(-1) x h(-1) naloxone (low dose), 1 microg x kg(-1) x h(-1) (high dose), or saline (placebo) as a continuous infusion. Verbal rating scores for pain, nausea, vomiting, and pruritus; sedation scores; requests for antiemetic; and morphine use were recorded for 24 h. Blood pressure, respiratory rate, and oxyhemoglobin saturation were also monitored. RESULTS: Sixty patients completed the study. Both naloxone doses were equally effective in reducing the incidence of nausea, vomiting, and pruritus compared with placebo (P < 0.05 by the chi-squared test). There was no difference in the verbal rating scores for pain between the groups. The cumulative morphine use was the lowest in the low-dose group (42.3 +/- 24.1 mg; means +/- SD) compared with the placebo (59.1 +/- 27.4 mg) and high-dose groups (64.7 +/- 33.0 mg) at 24 h (P < 0.05 by analysis of variance). There was no incidence of respiratory depression (<8 breaths/min) and no difference in sedation scores, antiemetic use, respiratory rate, and hemodynamic parameters among the groups. CONCLUSIONS: Naloxone is effective in preventing PCA opioid-related side effects. Naloxone infusion at 0.25 microg x kg(-1) x h(-1) not only attenuates these side effects but appears to reduce postoperative (beyond 4-8 h) opioid requirements. This dosing regimen can be prepared with 400 microg naloxone in 1,000 ml crystalloid given in 24 h to a patient weighing 70 kg.     

Biologic effects of introduction of wild-type p53 cDNA into a human ovarian cancer cell line SKOV-3

OBJECTIVE: To study the effects on biologic behavior in cells obtained from human ovarian cancer cell line SKOV-3 into which the wild-type p53 cDNA was introduced. METHOD: Recombinant eukaryotic expression vector pC53-SN3 containing full-length human wild-type p53 cDNA and vector containing neomycin resistance gene only were introduced by lipofectamine-mediated gene transfection into SKOV-3 cell line which does not express endogenous p53. The clones obtained were observed for their biologic behavior. RESULTS: (1) 2 clones named pC53 and 2 clones named pNeo were obtained after pC53-SN3 and vector transfection respectively; (2) The morphology of cells either from pC53 or from pNeo did not change significantly with respect to their parental SKOV-3; (3) The growth rate of cells from pC53 was much slower than that from SKOV-3, while the cell growth curve of pNeo was similar to that of SKOV-3; (4) The number of colones formed in the soft-agar by pC53 was significantly less than that by SKOV-3 or by pNeo; (5) The percentage of phase G1/G0 of pC53 was much higher than that of SKOV-3 and pNeo. CONCLUSION: Wild-type p53 cDNA may be considered as one of the target genes for the gene therapy of ovarian cancer.     

Biologic characteristics of cultured human vitiligo melanocytes

BACKGROUND: Vitiligo is a pigmentary disorder of unknown cause characterized by depigmented patches due to destruction of melanocytes. Recently, the inherent cellular defect theory has been discussed. To investigate the biologic characteristics of cultured melanocytes from normal and vitiligo subjects, this study had the purpose to examine the functional and ultrastructural characteristics of these melanocytes and to observe the morphologic and functional changes of melanocytes in response to ultraviolet B irradiation. METHODS: Melanocytes were isolated and cultured from foreskin and arm skin of normal and vitiligo subjects. The DNA synthesis, tyrosinase activity assay, transmission and scanning electron microscopic examination, and the effects of ultraviolet B(UVB)-irradiation on cultured melanocytes were studied. RESULTS: Vitiligo melanocytes showed no significant differences in DNA synthesis and tyrosinase activity compared with normal melanocytes, but the vitiligo melanocytes contained dilated and/or circular rough endoplasmic reticulum (RER) on transmission electron microscopic examination. Exposure of the cultured melanocytes to UVB resulted in increased protein synthesis and tyrosinase activity. Morphologic alterations and changes in DNA synthesis were also noted. Compared with normal melanocytes, the responses of vitiligo melanocyte to UVB showed no significant difference. CONCLUSIONS: Normal and vitiligo melanocytes showed similar biologic characteristics except in the changes of RERs in the vitiligo melanocytes. The ultrastructural aberrations in vitiligo subjects do not seem to be directly related to the biologic characteristics and the responses to UVB irradiation in vitiligo melanocytes.     

The effects of "unwanted" signals and d-amphetamine sulfate on observer responses.

The effects of unwanted signals and d-amphetamine sulfate on observer responses (OR) in a 2-hour vigilance task were studied. Scope observation was contingent on a lever press (OR). 8 different schedule of frequency and regularity of unwanted conditions were used involving 8 independent groups of 4 Ss each. The effects of oral ingestion of placebo and drug were also tested. Increasing the frequency and irregulants of unwanted signals without drugs markedly increased frequency and rate of OR. This effect was enhanced under placebo and drug. Variance due to individual differences lessened as reinforcement from unwanted signals and drugs increased. Hypotheses based on activation theory emphasizing arousal aspects of vigilance behavior were verified. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The transcriptional effects and DNA-binding specificities of 17beta-estradiol after dimethyldioxirane activation

We investigated the spatio-temporal brain activity on the time scale of several milliseconds related to the mental rotation task requiring judgements of hand orientation, using a whole-cortex MEG (magnetoencephalography) system. Neuronal activity in the visual cortex was observed approximately 100-200 ms from stimulus onset, and that in inferior parietal lobe followed (after 200 ms). Both of these activities showed a contralateral dominance to visual stimulus hemifield. Premotor activity started later than the inferior parietal lobe activity, and these activities partially overlapped. Activity in primary motor and/or motosensory areas was observed in some subjects. The whole-cortex neuromagnetic measurements provided the time course of activity in the human brain associated with the implicit motor imagery: visual cortex-->inferior parietal lobe<-->premotor cortex. This process is considered to be the transformation process of retinotopic locations into a body-centered reference frame necessary for the mental rotation task.     

Heparan sulfate: its kinetic effects on fibrinolytic-coagulative parameters after oral administration]

The effects of the oral administration of 100 or 200 mg of heparan sulphate or placebo over time were assessed in nine healthy volunteers. Blood samples were collected at 1, 2, 4, 6, 8 and 12 hours after administration to assay prothrombin activity, partially activated thromboplastin time, and the activation to tPA and PAI-1. A significant increase (P < 0.001) of tPA activity and a reduced inhibition of fibrinolytic systems by PAI-1 were observed. These effects, which were clearly dose-dependent, appeared 2 hours after administration and persisted for 6-8 hours. On the contrary, no changes were recorded in coagulative tests at the doses used.     

The effects of sodium lauryl sulfate on the phrenic nerve diaphragm preparation from the rat

Noncytotoxic CD8+ T cells may play a critical role in preventing progression to disease following human immunodeficiency virus (HIV) infection. This antiviral response, mediated by a novel CD8+ T-cell antiviral factor (CAF), occurs soon after infection and is maintained in asymptomatic individuals. Here, Jay Levy and colleagues propose that this antiviral activity represents a natural cellular immune reaction that controls HIV production and protects the host from potential harmful effects of cytotoxic T lymphocytes.     

Temperature and seeding effects on the precipitation of scorodite from sulfate solutions under atmospheric-pressure conditions

Arsenic is a major contaminant in the nonferrous extractive metallurgy. In the past 20 years, many studies have shown that it can be precipitated as relatively stable crystalline scorodite (FeAsO₄·2H₂O) by precipitation under ambient or elevated pressures. In the present study, an extensive program of scorodite precipitation tests under ambient pressure has shown that the rate of scorodite formation increases dramatically by a small increase in temperature from 85 °C to 100 °C. The beneficial effects of temperature are attributed to the higher thermodynamic stability of scorodite at elevated temperatures, but also to higher rates of secondary nuclei formation and crystal growth. In any case, irrespective of the precipitation temperature, the leachability of all scorodite precipitates observed in toxicity characterization leaching procedure (TCLP) tests is below 5 mg/L As. Another parameter examined in this study was seeding. It was observed that the higher the initial concentration of seed, the faster the precipitation. Precipitation of well-crystallized scorodite can be effected equally well on heterogeneous seed such as hematite (Fe₂O₃) or gypsum (CaSO₄·2H₂O) added externally or formed in situ.