Modulation of high-dose methotrexate toxicity by a non-toxic level of 5-fluorouracil

High-dose methotrexate (MTX) toxicity is reduced by a non-toxic dose of 5-fluorouracil (FU) when these agents are used in combination. Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, hemoglobin, and hematocrit), ileal tissue, body weight, and mean survival were used as parameters to assess toxicity. For all parameters studied, there were no significant differences between the scheduling of MTX (245 mg/kg) after a priming dose of FU (25 mg/kg), simultaneous MTX and FU, FU alone, and control. However, sequential treatment with MTX followed by FU, and MTX alone resulted in: a marked decrease in the hematopoietic parameters; significant morphological changes in ileal tissue; a reduction of body weight; and increased mortality of animals. Hence, this study suggests that FU, a cytotoxic agent, may protect against MTX toxicity and improve its therapeutic index when FU administration precedes MTX or when these agents are given simultaneously.     

Primary non-Hodgkin's lymphomas of the paranasal sinuses and nasal cavity. A report of 18 cases with stage IE disease.

During a 26-year period (1961-1987), a total of 18 patients with primary non-Hodgkin's lymphoma (NHL) of the paranasal sinuses and nasal cavity received radiation therapy at (University of California at Los Angeles) UCLA Medical Center. At the time of diagnosis and using the available diagnostic methods, none of these patients had clinically detectable disease beyond the paranasal sinuses. All 18 patients were staged IE by the Ann-Arbor system. When the patients were staged according to the AJC staging system from epithelial tumors, half presented with advanced T3-4 disease. Diffuse histiocytic lymphoma was the most common histology (eight cases) and maxillary sinus, the most common site of origin (11 cases). All nine T1-2 tumors received radiation therapy alone, while radiation and chemotherapy was used in seven of nine advanced T3-4 staged tumors. The mean follow-up was 71 months. At last follow-up, eight of nine T1-2 patients were rendered disease-free. In contrast, only four of nine T3-4 patients had long-term disease-free survival. Seventy-five percent of the failure occurred within 2 years. Radiation therapy alone achieves high local control in small tumors (T1-2), while large tumors (T3-4) require aggressive combined treatment, i.e., radiation and chemotherapy.     

Sclerosed liver hemangioma mimicking malignant tumor at MR imaging: Pathologic correlation

This case report illustrates atypical magnetic resonance (MR) imaging findings in a liver hemangioma mimicking a malignant lesion—lower signal intensity than cerebrospinal fluid on T2-weighted spin-echo images and lack of early enhancement on dynamic contrast material—enhanced gradient-echo images. Pathologic analysis demonstrated nearly total replacement of the vascular cavities by dense fibrous tissue. In this rare, sclerosed form, this lesion could not be defined as a hemangioma with MR imaging.     

Is there any desensitization of presynaptic alpha 2-adrenergic receptors in hypertension? Experimental and clinical studies]

Several authors have discussed an alteration of adrenergic receptivity in arterial hypertension. De Champlain (Hypertension 1990; 8: S77-S85) suggested that postsynaptic alpha 1-adrenergic functions became dominant while beta-adrenergic functions are attenuated in arterial hypertension. However, the status of presynaptic alpha 2-adrenoceptors remains unknown. The present study investigates presynaptic alpha 2-adrenoceptors in hypertension through the measurement of plasma levels of noradrenaline after administration of yohimbine, an alpha 2-adrenoceptor antagonist, in essential hypertension. Yohimbine (0.2 mg/kg per os) induced a 73% increase of plasma levels of noradrenaline in hypertensive patients (n = 12) and a 178% one in normotensive subjects (n = 6, p < 0.05). A similar significant difference was found in experimental neurogenic hypertension observed in awake dogs 3 weeks after sinoaortic denervation: the increase in plasma concentrations of noradrenaline after yohimbine (0.5 mg/kg i.v.) was +279% in hypertensive versus +642% in normotensive dogs (p < 0.05). The results show that the magnitude of the yohimbine-induced sympathetic activation is lower in hypertensives than in normotensives. They suggest the existence of a presynaptic alpha 2-adrenoceptor desensitization in arterial hypertension. The abnormality of this presynaptic inhibitory mechanism can increase the sympathetic tone and help to develop and maintain arterial hypertension.     

A multicenter evaluation of safety of early extubation in liver transplant recipients.

Small single-institutional studies performed prior to the introduction of organ allocation using the Model for End-Stage Liver Disease (MELD) suggest that early airway extubation of liver transplant recipients is a safe practice. We designed a multicenter study to examine adverse events associated with early extubation in patients selected for liver transplantation using MELD score. A total of 7 institutions extubated all patients meeting study criteria and reported adverse events that occurred within 72 hours following surgery. Adverse events were uncommon: occurring in only 7.7% of 391 patients studied. Most adverse events were pulmonary or surgically related. Pulmonary complications were usually minor, requiring only an increase in ambient oxygen concentration. The majority of surgical adverse events required additional surgery. Analysis of a limited set of perioperative variables suggest that blood transfusions and technical factors were associated with an increased risk of adverse events. In conclusion, while early extubation appears to be safe under specified circumstances, there are performance differences between institutions that remain to be explained.     

Relationship between dynamic balance and self-reported handicap in patients who have unilateral peripheral vestibular loss.

OBJECTIVE: The purpose of this study was to investigate whether Dizziness Handicap Inventory (DHI) score is related to postural performance as assessed by dynamic posturography. STUDY DESIGN: Retrospective study. SETTING: Outpatient in a tertiary referral center. PATIENTS: Ninety-two complete unilateral vestibular loss patients, categorized into 3 groups according to the postlesion stage: 1 to 2 months (n = 32; age, 47.6 +/- 10.7 yr), 4 to 7 months (n= 23; 47.1 +/- 8.37 yr), and 1 year and older (n = 37; 49.2 +/- 9.5 yr). MAIN OUTCOME MEASURES: Dizziness Handicap Inventory and dynamic balance measured with a seesaw platform moving either in the anterior-posterior or in the mediolateral direction. RESULTS: The mean DHI score was 25.8 +/- 18.7 and the range was 0 to 68. Dizziness Handicap Inventory scores did not differ significantly between the different unilateral vestibular loss groups studied. No difference was detected between the groups for the 3 subscores (emotional, functional, and physical), except that the older-than-1-year group had a significantly higher physical score than the 2 others. No correlation was found between DHI scores and postural indicators for either direction of the platform. However, patients unable to maintain balance when the seesaw platform moved in the mediolateral direction had significantly higher DHI scores than those who did not fall. CONCLUSION: Even if they are not directly related, we suggest that DHI and dynamic posturography are complementary approaches for appreciating the vestibular compensation process and are thus useful for postoperative counseling for vestibular loss patients.     

Keloid fibroblast responsiveness to epidermal growth factor and activation of downstream intracellular signaling pathways.

Keloids, which overgrow the boundaries of the original injury, represent aberrations in the fundamental process of wound healing that include over-abundant cell in-migration, cell proliferation, and inflammation, as well as increased extracellular matrix synthesis and defective remodeling. To understand the key events that result in the formation of these abnormal scars would open new avenues for better understanding of excessive repair, and might provide new therapeutic options. We examined epidermal growth factor receptor (EGFR)-induced cell motility in keloid fibroblasts, as this receptor initiates cell migration during normal wound repair. We show that keloid fibroblasts respond to EGF-induced cell migration but the response is somewhat diminished compared to normal adult fibroblasts (approximately 30% reduced); the mitogenic response was similarly blunted (approximately 5% reduced). Keloid fibroblasts express near normal levels of EGFR (82%), but show a much more attenuated activation of EGFR itself and the motility-associated phospholipase C-gamma. This was reflected in part by rapid loss of EGFR upon exposure to EGF. Interestingly, while extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) activation was relatively robust in keloid fibroblasts, the downstream triggering of the motility-associated calpain activity was blunted. This was reflected by high cell-substratum adhesiveness in the keloid fibroblasts. Thus, the blunted migratory response to EGF noted in keloid fibroblasts appears due to limited activation of two important biochemical switches for cell motility.     

Protection Against Chemically-Induced Oxidative Gastrointestinal Tissue Injury in Rats by Bismuth Salts

Oxygen free radicals (OFR) are implicated in thepathogenesis of stress, chemically induced gastriclesions, and gastrointestinal injury. Theconcentration-dependent scavenging abilities of bismuthsubsalicylate (SBS), colloidal bismuth subcitrate (CBS), andselected OFR scavengers, including superoxide dismutase(SOD), catalase, mannitol, and allopurinol were examinedagainst biochemically or chemically generated superoxide anion, hydroxyl radical, andhypochlorite radical plus hypochlorous acid based on achemiluminescence assay. Furthermore, both gastric (GM)and intestinal mucosa (IM) were individually exposed in vitro to these free radical generatingsystems, and the concentration-dependent protectiveabilities of SBS and CBS against lipid peroxidation (LP)were compared with selected OFR scavengers. In addition, 24-hr fasted rats were orally treated with thenecrotizing agents 0.6 M HCl, 0.2 M NaOH, 80% ethanol,and aspirin (200 mg/kg). The extent of tissue injury inthe GM and IM was determined by assessing LP, DNA fragmentation, and membrane microviscosity.Dose- and time-dependent in vivo protective abilities ofCBS (100 mg/kg) and SBS (15 mg/kg) were also assessed.Following incubations with superoxide anion and hydroxyl radical generating systems in thepresence of 125 mg SBS/liter, approximately 47% and 61%inhibitions were observed in the chemiluminescenceresponse, respectively, while 48% and 46% inhibitions were observed with 125 mg CBS/liter. SBS andCBS exerted similar abilities towards hypochloriteradical plus hypochlorous acid. Approx. 3.1- and3.7-fold increases in LP were observed in the GM and IMof rats following oral administration of 0.6 MHCl. Pretreatment of the rats with SBS and CBS decreased0.6 M HCl-induced LP in the GM by approx. 39% and 27%,respectively, with similar decreases in LP in the IM. SBS exhibited better protectiveabilities towards 0.6 M HCl and 0.2 m NaOH-induced GMand IM injury as compared to CBS. SBS and CBS providedsimilar protection towards 80% ethanol-induced gastric injury, while CBS exerted a superior protectiveability towards aspirin-induced gastric injury. Theresults demonstrate that both SBS and CBS can scavengereactive oxygen species and prevent tissue damage produced by OFR.     

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.