Comparison of loratadine and terfenadine in allergic seasonal rhinoconjunctivitis with emphasis on nasal stuffiness and peak flow.

Non-sedating antihistamines have been used in the treatment of allergic rhinoconjunctivitis. Recommended dosage of loratadine (CAS 79794-75-5) is 10 mg once daily, whereas terfenadine (CAS 50679-08-8) until recently has been recommended as 60 mg twice daily. 105 patients took part in this double-blind 3-week controlled study comparing loratadine 10 mg once daily to terfenadine 120 mg once daily. Patient's daily symptom score and physician's assessment of symptoms, treatment effect and anterior rhinoscopy were evaluated as well as an objective parameter, nasal peak flow. In addition nasal peak flow was compared to patient's symptom score of stuffiness. A significant treatment effect in both treatment groups was found but there was no statistically significant difference between the two groups. Correlation between patient's feeling of stuffiness and nasal peak flow was significant. It is concluded that loratadine 10 mg once daily is as effective as terfenadine 120 mg once daily in controlling allergic rhinoconjunctivitis, and that patients' feeling of stuffiness correlates well to nasal peak flow.


Ocular pharmacokinetics of thiamphenicol in rabbits.

The ocular pharmacokinetics of thiamphenicol (TAP, CAS 15318-45-3) was studied in rabbits by means of the assessment of its ocular and systemic absorption, and urinary excretion after instillation of 0.5% TAP eye drops. TAP concentrations in aqueous humor, plasma and urine were evaluated by a coupled LC/GC method (detection limit = 0.1 ng/ml), because the necessity to have a technique much more sensitive than the traditional chromatographic ones available in order to quantify the very low drug concentrations in biological fluids produced by the ocular treatment, and generally by a topical administration. The intravenous route was chosen as reference and allowed the absolute bioavailability to be estimated. TAP proved to be well absorbed through the cornea with the peak aqueous humor concentration of 110 ng/ml at 45 min following the instillation. The good ocular absorption of TAP was confirmed by the plasma concentrations observed after instillation of 0.5% eye drops. In any case, these concentrations were more than 1000 times lower than those observed after the intravenous treatment at the dose normally used for infectious diseases, allowing to exclude any systemic toxicity of TAP eye drops. The absolute ocular bioavailability was 16.2% when estimated from the AUC values and 34.0% from the cumulative urinary excretion values.


Critical comments on the treatment of leprosy and other mycobacterial infections with clofazimine.

The usefulness of clofazimine (CLO, CAS 2030-63-9) in the treatment of mycobacterial infections with special emphasis on treatment of leprosy is critically discussed. Skin discolouration which decreases compliance, placenta passage, excretion in mother's milk which endanger the embryo or baby respectively, saturation kinetics in absorption and difficulties to determine free drug concentration are severe problems. The observed antagonism in the combination of CLO with other drugs, especially with dapsone, is another argument against its application in the therapy of mycobacterial infections. In Germany CLO has not been approved by the Bundesgesundheitsamt.


Preliminary evaluation of immunoadjuvant activity of an orally administered glucan extracted from Candida albicans.

The immunoadjuvant activity of an orally administered glucan (Glucanil, Gluimmun) was investigated in mice. Glucan was extracted from Candida albicans ATCC 20955 and purified by an alkali-acid and detergent treatment. In this study the chronic intravenous infection with Candida albicans (treated or not with amphotericin B) or Staphylococcus aureus was the experimental model. Moreover the production of interleukin-2 was evaluated in treated animals. Oral treatment with glucan at 1 mg/mouse/day repeated doses, starting from 10 days before the experimental infection, significantly increased polymorphonuclear leukocytes and peripheral monocytes number. A significant increase in number and in vitro candidacidal activity was also observed for alveolar macrophages. The resistance towards systemic infection with Candida albicans or Staphylococcus aureus increased, significantly reducing the growth of microorganisms in the kidneys of infected animals. Glucan significantly increased the candidacidal spleen cells activity and synergized with amphotericin B chemotherapeutic action. Higher doses (eg. 2 or 5 mg/mouse) were not effective. A 10 days oral treatment with 1 mg/mouse/d significantly increased the interleukin-2 production. Toxicological studies showed that glucan is highly tolerated.


Zero interaction response surfaces, interaction functions and difference response surfaces for combinations of biologically active agents.

In the field of combination experiments there is wide-spread confusion over definitions, terminology and methods for the evaluation of interaction between biologically active agents. According to our view the widely used isobole approach is the method of choice. In this contribution it is shown how the combination of the classical isobole approach with response surface modeling and computer graphics leads to powerful new methods for the assessment of interaction of biologically active agents. In particular, zero interaction response surfaces, difference response surfaces and interaction functions are proposed. Zero interaction response surfaces represent surfaces which display zero interaction in the whole dose range. Difference response surfaces display the difference between an actual response surface and the corresponding zero interaction response surface. Interaction functions are a generalization of the index of interaction, which describe the dose dependence of this quantity.


The amount of drug remaining in the body at the time Tmax after simultaneous extravascular and intravenous administration.

When a drug is simultaneously given extravascularly and intravenously, the plasma concentration reaches a maximum at a time Tmax. The purpose of this paper is to get the amount of the drug remaining in the body at this time Tmax. Furthermore, mean residence time of the drug and the area under concentration curve are given.


Dose-dependent effects of recombinant human erythropoietin on the reticulocyte population of rabbits.

The effects of repeated applications of recombinant human erythropoietin (rhEPO, epoetin beta, Recormon, CAS 122312-54-3) on the reticulocyte count and the reticulocyte maturation distribution of rabbits were investigated using the automated reticulocyte analysis system Sysmex R-1000. Therefore, 150, 300, and 600 IU rhEPO per animal were injected 3 times in intervals of 5-6 weeks. The strongest reaction was found on the second day after application of rhEPO with respect to maturation distribution characterized by the distribution quotient (DQ) and on the fourth day with respect to reticulocyte count. At this time these parameters showed a distinct dose dependence (p < 0.001). The effect of rhEPO on the erythropoietic system in the same rabbit population could be repeated. Thus, immunological neutralization of rhEPO did not take place in rabbits in response to a 3-fold application. The results indicate a potential basis for a simple bioassay in order to determine rhEPO activity in normocythemic rabbits.


Issues for academia.

When colleges and universities provide supervised clinical experiences for students, their models of supervision must consider a number of issues related to individuals and program objectives. Although the importance of each issue will vary from one program to another, increased awareness of specific concerns may be helpful to administrators in developing and implementing more appropriate models. Providing high quality in the supervision of new professionals should help the professions achieve continuous improvements in the quality of service to consumers.


1992 Omnibus Survey. Portrait of the professions.

The portrait of our professions has changed in recent years, and the changes are quite positive. For example, the number of speech-language pathologists and audiologists who reported that they are unemployed and seeking employment has decreased while salaries reportedly continue to increase. These findings are especially encouraging given the current economic times. They represent a continuing demand for the valuable contributions that speech-language pathologists and audiologists can make in today's society. Caseload characteristics illustrate a different picture compared with data from previous years. Audiologists and speech-language pathologists both reported an increase in service provision to the birth-5 population. In addition, the severity of caseloads for speech-language pathologists has substantially decreased from that of previous years. The issues of support personnel, the AuD degree, and gender discrimination evoked expression of strong opinion. Based on the responses to these questions and the comments that accompanied them, it is apparent that there are many questions that need to be addressed before these issues reach consensus. We must continue to work together until we create a balanced picture. All in all, the portrait of the ASHA membership is both colorful and attractive--definitely suitable for framing. We should be proud of the progress that we have made over the years and of the image that we are creating for our professions. As we continue to take brush in hand, remember that each one of us can make a difference in the direction of our future. So splash on the colors and keep it bright!


Considerations in screening adults/older persons for handicapping hearing impairments.

Given the present state of the "science," that is, the dearth of data on the "ideal" hearing screening protocol for noninstitutionalized adults and older adults, a definitive recommendation for screening is premature. The controversy and intensity of debate surrounding these issues attests both to the importance of a screening protocol and the acknowledgment of the need for further study by the profession. The ensuing intellectual controversy is not capricious nor whimsical but healthy. The committee has therefore chosen to discuss the issues surrounding selection of a screening protocol and to provide the reader with a series of options for screening. Armed with knowledge of the goal of a particular screening program, it is hoped that clinicians will make educated choices about the screening protocol that best meets their clients' needs. It is also our hope that this report will temporarily assist screening discussions until more comprehensive studies on the reliability, validity and predictive accuracy of selected protocols are available.


Continuous monitoring of jugular venous oxygen saturation in head-injured patients.

The continuous measurement of jugular venous oxygen saturation (SjvO2) with a fiberoptic catheter is evaluated as a method of detecting cerebral ischemia after head injury. Forty-five patients admitted to the hospital in coma after severe head injury had continuous and simultaneous monitoring of SjvO2, intracranial pressure, arterial oxygen saturation, and end-tidal CO2. Cerebral blood flow, cerebral metabolic rates of oxygen and lactate, arterial and jugular venous blood gas levels, and hemoglobin concentration were measured every 8 hours for 1 to 11 days. Whenever SjvO2 dropped to less than 50%, a standardized protocol was followed to confirm the validity of the desaturation and to establish its cause. Correlation of SjvO2 values obtained by catheter and with direct measurement of O2 saturation by a co-oximeter on venous blood withdrawn through the catheter was excellent after in vivo calibration when there was adequate light intensity at the catheter tip (176 measurements: r = 0.87, p less than 0.01). A total of 60 episodes of jugular venous oxygen desaturation occurred in 45 patients. In 20 patients the desaturation value was confirmed by the co-oximeter. There were 33 episodes of desaturation in these 20 patients, due to the following causes: intracranial hypertension in 12 episodes, hypocarbia in 10, arterial hypoxia in six, combinations of the above in three, systemic hypotension in one, and cerebral vasospasm in one. The incidence of jugular venous oxygen desaturations found in this study suggests that continuous monitoring of SjvO2 may be of clinical value in patients with head injury.


Lack of circumcision increases the risk of urinary tract infection in young men.

To determine whether lack of circumcision increases the risk of urinary tract infection (UTI) in adult men. Retrospective case-control study (1987-1990) at a sexually transmitted disease clinic in Seattle, Wash. Twenty-six men (median age, 30 years) who had microbiologically confirmed symptomatic UTIs (cases) compared with 52 men (median age, 32 years) who had urinary symptoms but negative urine cultures (controls). Circumcision status among bacteriuric and nonbacteriuric men. The bacteriuric and nonbacteriuric groups were similar in age, race, sexual activity, and sexual preference. Eight (31%) of the 26 bacteriuric men were uncircumcised compared with 6 (12%) of the 52 nonbacteriuric men (P = .037; odds ratio, 3.4; 95% confidence interval, 1.0 to 11.2). Among 19 patients infected with gram-negative bacilli, 8 (42%) of 19 were uncircumcised vs 6 (12%) of 52 nonbacteriuric men (P = .004; odds ratio, 5.6; 95% confidence interval, 1.6 to 19.4). Escherichia coli was the most common urinary isolate (15 of 26 isolates), and the majority of E coli strains possessed urovirulence determinants, including mannose-resistant hemagglutination (10 of 14 isolates), F fimbriae (11 of 14 isolates), P fimbriae (6 of 14 isolates), hemolysin (10 of 14 isolates), and aerobactin (8 of 14 isolates). Although all 26 bacteriuric men had urethral cultures negative for Chlamydia trachomatis and Neisseria gonorrhoeae, Gram-stained urethral smears showed evidence of urethritis in 17 (68%) of 25 men. (1) Lack of circumcision increases the risk of UTI in young adult men. (2) The majority of these infections result from urovirulent strains of E coli. (3) Clinically, these infections often produce urethritis as well as UTI.


Management of children with acute pharyngitis: a decision analysis.

Although the incidence of acute rheumatic fever has declined in the last decades, a few outbreaks have recently been reported. A rapid latex agglutination test for group A streptococci seems reasonably accurate, and early treatment of acute pharyngitis seems to influence the pharyngitis itself. These factors have promoted uncertainty concerning the current best management of patients with sore throat. Clinical decision analysis is used to compare the risks and benefits of symptomatic treatment, and oral and intramuscular penicillin as therapeutic options, and the throat culture and the rapid latex agglutination test as diagnostic strategies. Best estimates of the risk of streptococcal pharyngitis, its complications, the carrier rate, the accuracy of diagnostic tests, the efficacy of antibiotic treatment, allergic reactions, medication compliance, and health outcomes are combined into a management advisory. All results are subjected to a sensitivity analysis in order to check their strength against plausible changes in assumptions. Quality adjusted life days (QALD) lost are used as an outcome measure. The agglutination test combined with oral penicillin yielded the lowest expected loss (.50) of QALD for a typical child with a risk of harboring streptococci of .60. The other strategies, however, yielded losses that were only several hundredths of QALD higher. For children with at least a 40% chance of harboring streptococci and a duration of complaints of less than 2 days before starting treatment, diagnostic testing and prescription of oral penicillin appear to be the best choice of initial management. The rapid latex agglutination test is more effective than the throat culture, because prompt penicillin treatment after a positive test result may shorten the duration of pharyngitis in infected children. High rates of acute rheumatic fever (over 5 X 10(-4] and low medication compliance change the best strategy to agglutination test with intramuscular administration of penicillin.


The arthritis of Christopher Columbus.

Christopher Columbus suffered from an arthritic disorder that began on his First Voyage to the New World. The disease was progressive, punctuated by painful flares in the lower extremities, and, at times, seemed to be associated with fever and ocular symptoms. During his Fourth Voyage and final years of life, Columbus was immobilized by his rheumatologic condition. This article uses contemporary historical accounts of Columbus' illness to trace the clinical features of his disease.


Massive theophylline dosing in a heavy smoker receiving both phenytoin and phenobarbital.

To report unusually high theophylline dosing requirements in a smoker receiving concomitant therapy with phenytoin and phenobarbital. Single case report. 517-bed, university teaching hospital. 29-year-old woman with newly diagnosed asthma, heavy smoking history, and a seizure disorder. The additive influence of smoking, phenytoin, and phenobarbital greatly increased the theophylline dosing requirements. Doses of up to 4 g/d (59 mg/kg/d) were required to achieve adequate symptomatic relief of her asthma as well as to provide therapeutic serum theophylline concentrations. Multiple polymorphisms may additively influence theophylline metabolism and exceptionally large theophylline doses may be required in some patients who smoke and are comedicated with phenytoin and phenobarbital.


Thoracic esophageal perforations at a Virginia hospital 1979-1990.

A study was made of all patients who underwent management for distal esophageal perforation at the Fairfax Hospital from September 1979 to September 1990. The study group consisted of 13 patients. Nine were male, four female. Mean age was 60.8 yrs, ranging from 36 to 83 yrs. In the group of nine patients diagnosed early (less than 24 hrs), hospital mortality was 22.2% versus 75% in the group of four diagnosed late (greater than 24 hrs). Of the six patients treated conservatively, either medically or surgically, only one survived, but all seven patients diagnosed early and aggressively operated upon survived. Thus the authors agree with others in espousing aggressive, definitive surgery for patients diagnosed early.


Drug therapy of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a recently introduced diagnosis. The disorder is quite common, yet often unrecognised, and leads to significant morbidity or mortality. Effective treatment often entails use of psychotropic medication. Only recently has this become apparent, and awareness of the role of drug therapy in PTSD remains limited. A number of studies have indicated efficacy for antidepressant, mood-stabilising, anticonvulsant and antianxiety medications. This review describes the role of pharmacotherapy, by examining issues of diagnosis and recognition of PTSD, the theoretical basis for drug use, goals of drug treatment, dose ranges, and clinical application of psychotropic drugs.


Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis.

The therapeutic options for patients with polymyositis or dermatomyositis that is resistant to corticosteroids are limited, unproved, and often toxic. Uncontrolled trials concluded that both plasma exchange and leukapheresis are beneficial, but despite the considerable use of these approaches, proof of their efficacy is lacking. Thirty-nine patients with definite polymyositis or dermatomyositis were randomly assigned to receive plasma exchange (replacement of one volume of plasma with 5 percent albumin in saline), leukapheresis (removal of 5 x 10(9) to 10 x 10(9) lymphocytes), or sham apheresis in a double-blind manner, with 12 treatments given over a one-month period. Muscle strength, functional capacity, and serum levels of muscle-associated enzymes were measured before and after the 12 procedures. In each group 3 of 13 patients had improvements in strength and functional capacity. The condition of 3 patients treated with leukapheresis and 1 treated with plasma exchange deteriorated, and it was unchanged in the other 26 patients. Adverse effects of apheresis included the need for a central venous catheter (9 patients), major vasovagal episodes (3 patients), and severe citrate reactions (2 patients). Despite the occurrence of significant reductions in the serum levels of muscle enzymes with plasma exchange (P less than 0.001) and significant decreases in lymphocyte counts with leukapheresis (P = 0.002), there were no significant differences among the three treatment groups in the final muscle strength or functional capacity of the patients. As treatments for corticosteroid-resistant polymyositis or dermatomyositis, leukapheresis and plasma exchange are no more effective than sham apheresis.


Adjuvant psychological therapy for patients with cancer: a prospective randomised trial.

To determine the effect of adjuvant psychological therapy on the quality of life of patients with cancer. Prospective randomised controlled trial comparing the quality of life of patients receiving psychological therapy with that of patients receiving no therapy, measured before therapy, at eight weeks, and at four months of follow up. CRC Psychological Medicine Group of Royal Marsden Hospital. 174 patients aged 18-74 attending hospital with a confirmed diagnosis of malignant disease, a life expectancy of at least 12 months, or scores on various measures of psychological morbidity above previously defined cut off points. Adjuvant psychological therapy, a brief, problem focused, cognitive-behavioural treatment programme specifically designed for the needs of individual cancer patients. Hospital anxiety and depression scale, mental adjustment to cancer scale, Rotterdam symptom checklist, psychosocial adjustment to illness scale. 156 (90%) patients completed the eight week trial; follow up data at four months were obtained for 137 patients (79%). At eight weeks, patients receiving therapy had significantly higher scores than control patients on fighting spirit and significantly lower scores on helplessness, anxious preoccupation, and fatalism; anxiety; psychological symptoms; and on orientation towards health care. These differences indicated improvement in each case. At four months, patients receiving therapy had significantly lower scores than controls on anxiety; psychological symptoms; and psychological distress. Clinically, the proportion of severely anxious patients dropped from 46% at baseline to 20% at eight weeks and 20% at four months in the therapy group and from 48% to 41% and to 43% respectively among controls. The proportion of patients with depression was 40% at baseline, 13% at eight weeks, and 18% at four months in the therapy group and 30%, 29%, and 23% respectively in controls. Adjuvant psychological therapy produces significant improvement in various measures of psychological distress among cancer patients. The effect of therapy observed at eight weeks persists in some but not all measures at four month follow up.


Evaluation of nurse triage in a British accident and emergency department.

To compare formal nurse triage with an informal prioritisation process for waiting times and patient satisfaction. Accident and emergency department of a district general hospital in the midlands in 1990. Patients attending between 8:00 am and 9:00 pm over six weeks were grouped for analysis according to whether triage was operating at time of presentation and by their degree of urgency as assessed retrospectively by an accident and emergency consultant. 5954 patients presenting over six weeks. Time waited between first attendance in the department and obtaining medical attention, and patient satisfaction measured by questionnaire. Complete data on waiting time were collected on 5037 patients (85%). Only 1213 of the 2515 (48%) patients presenting during the triage period were seen by a triage nurse. Patients in the triage group waited longer than those in the no triage group in all four retrospective priority categories, though differences were significant for only the two most urgent categories (difference in median waiting time 10.5 (95% confidence interval 3.5 to 14) min for category 1 and 8.5 (3 to 12) min for category 2). Responses to the patient satisfaction questionnaire were similar in the two groups except for the question relating to anxiety relating to pain. This study fails to show the benefits claimed for formal nurse triage. Nurse triage may impose additional delay for patient treatment, particularly among patients needing the most urgent attention.


Screening for pediatric eye disease.

The majority of preschool children in the United States are not screened for visual problems. To avoid permanent visual loss, standardized screening should be incorporated into well-child examinations so that treatment can be initiated promptly. Newborns should be checked for the red reflex, pupillary responses and any constant eye deviation. Infants six months old should be checked for these responses and for "fixation and following" and ocular alignment. Visual acuity should be tested in three- to four-year-old children using the "tumbling E" test, Allen pictures or the HOTV chart.


Cellular interactions between n-6 and n-3 fatty acids: a mass analysis of fatty acid elongation/desaturation, distribution among complex lipids, and conversion to eicosanoids.

The biologic effect of eicosanoids depends in large measure upon the relative masses in tissues of eicosanoids derived from the n-6 fatty acids, dihomogammalinolenic acid and arachidonic acid, and the n-3 fatty acid, eicosapentaenoic acid. Generation of this tissue balance is related to the relative cellular masses of these precursor fatty acids, the competition between them for entry into and release from cellular phospholipids, and their competition for the enzymes that catalyze their conversion to eicosanoids. In order to better understand these processes, we studied the cellular interactions of n-6 and n-3 fatty acids using an essential fatty acid-deficient, PGE-producing, mouse fibrosarcoma cell line, EFD-1. Unlike studies using cells with endogenous pools of n-6 and n-3 fatty acids, the use of EFD-1 cells enabled us to examine the metabolic fate of each family of fatty acids both in the presence and in the absence of the second family of fatty acids. Thus, the specific effects of one fatty acid family on the other could be directly assessed. In addition, we were able to replete the cells with dihomogammalinolenic acid (DHLA), arachidonic acid (AA), and eicosapentaenoic acid (EPA) of known specific activities; thus the masses of cellular DHLA, AA, and EPA, and their metabolites, PGE1, PGE2, and PGE3, respectively, could be accurately quantitated. The major findings of this study were: 1) n-6 fatty acids markedly stimulated the elongation of EPA to 22:5 whereas n-3 fatty acids inhibited the delta 5 desaturation of DHLA to AA and the elongation of AA to 22:4; 2) n-6 fatty acids caused a specific redistribution of cellular EPA from phospholipid to triacylglycerol; 3) n-3 fatty acids reduced the mass of DHLA and AA only in phosphatidylinositol whereas n-6 fatty acids reduced the mass of EPA to a similar extent in all cellular phospholipids; and 4) n-3 fatty acids caused an identical (33%) reduction in the bradykinin-induced release of PGE1 and PGE2, whereas n-6 fatty acids stimulated PGE3 release 2.3-fold. Together, these highly quantitative metabolic data increase our understanding of the regulation of both the cellular levels of DHLA, AA, and EPA, and their availability for eicosanoid synthesis. In addition, these findings provide a context for the effective use of these fatty acids in dietary therapies directed at modulation of eicosanoid production.


The effect of cyclosporine administration on the cellular distribution and content of cyclophilin.

Cyclophilin (CYP), an intracellular protein sharing amino acid sequence identity with the enzyme peptidyl-prolyl cis-trans isomerase has become the leading candidate for the receptor responsible for cyclosporine biological effects. Avid binding of CYP to cyclosporine and immunosuppressive cyclosporine metabolites has been demonstrated, while nonimmunosuppressive cyclosporine metabolites have tended not to bind to cyclophilin. A previous immunohistochemical analysis documented that CYP localized principally to the cytoplasmic cellular compartment, but nuclear staining was observed among some cells. This study was undertaken to more precisely define the ultrastructural distribution of CYP, and to determine whether CYP cellular content was affected by CsA therapy. Untreated Wistar rats or those receiving 7 days of CsA (15 mg/kg/day, i.p.) were anesthetized, perfusion-fixed in situ, and sacrificed. Analyses of lymph node, spleen, thymus, kidney, liver, heart, brain, and ileum used an affinity purified, rabbit anticyclophilin IgG. Transmission electron microscopy was performed after staining with anti-CYP using a horseradish peroxidase/biotin/avidin technique. Quantitative immunofluorescence was measured by confocal microscopy using anti-CYP, with a biotin/avidin/phycoerythrin technique. Cyclophilin localized to the cytoplasmic compartment--however, association with mitochondria endoplasmic reticulum, Golgi, and with the nuclear membrane among lymphocytes, as well as cells from kidney, liver and ileum--was documented. Cyclophilin was not identified within the nucleus proper. Tissues obtained from animals receiving CsA exhibited a generalized increase in CYP content compared with tissues from untreated controls, suggesting the possibility that CsA may exert a regulatory influence upon CYP gene activation. Collectively, the data were consistent with the hypothesis that CYP exerts a central role in cellular metabolism, and that CsA-mediated biologic effects result from the CsA/CYP interaction.


Reduced cardiotoxicity and increased cytotoxicity in a novel anthracycline analogue, 4'-amino-3'-hydroxy-doxorubicin.

The acute and chronic cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4'-amino-3'-hydroxy-DXR were compared with those of 4'-deoxy-DXR and DXR. In the acute cardiotoxicity study, the ECG and hemodynamic changes recorded in anesthetized rats that had been treated i.v. with 10 mg/kg 4'-amino-3'-hydroxy-DXR or 8.6 mg/kg 4'-deoxy-DXR were significantly less severe than those caused by 13 mg/kg DXR. In the chronic cardiotoxicity study, rats received 3 weekly i.v. injections of 3 mg/kg DXR, 3 mg/kg 4'-amino-3'-hydroxy-DXR, or 2 mg/kg 4'-deoxy-DXR during the first 14 days of the study and were observed for an additional 35-day period. DXR induced severe cardiomyopathy that was characterized by ECG changes in vivo (S alpha T-segment widening and T-wave flattening) and by impairment of the contractile responses (Fmax, +/- dF/dtmax) to adrenaline of hearts isolated from treated animals. 4'-Deoxy-DXR caused a progressive enlargement of the S alpha T segment in vivo and a significant impairment of the -dF/dtmax value in vitro, which were less severe than those produced by DXR. The least cardiotoxic drug was 4'-amino-3'-hydroxy-DXR, which induced minor ECG changes without causing significant alterations in the contractile responses of isolated hearts to adrenaline. On the basis of the drug concentration required to inhibit 50% of the colony formation (IC50) of cell lines in vitro, 4'-amino-3'-hydroxy-DXR was less active than 4'-deoxy-DXR but at least twice as active as DXR against human cancer and murine transformed cell lines. These data indicate that 4'-amino-3'-hydroxy-DXR is significantly less cardiotoxic and more cytotoxic than DXR.


Characterization of biotinylated repair regions in reversibly permeabilized human fibroblasts.

We have examined the incorporation of biotinyl-11-deoxyuridine triphosphate (BiodUTP) into excision repair patches of UV-irradiated confluent human fibroblasts. Cells were reversibly permeabilized to BiodUTP with lysolecithin, and biotin was detected in DNA on nylon filters using a streptavidin/alkaline phosphatase colorimetric assay. Following a UV dose of 12 J/m2, maximum incorporation of BioUTP occurred at a lysolecithin concentration (80-100 micrograms/mL) similar to that for incorporation of dTTP. Incorporation of BiodUTP into repair patches increased with UV dose up to 4 and 8 J/m2 in two normal human fibroblast strains, while no incorporation of BiodUTP was observed in xeroderma pigmentosum (group A) human fibroblasts. The repair-incorporated biotin was not removed from the DNA over a 48-h period, and only slowly disappeared after longer times (approximately 30% in 72 h), while little of the biotin remained in cells induced to divide. Furthermore, the stability of the biotin in repaired DNA was unaffected by a second dose of UV radiation several hours after the biotin-labeling period to induce a "second round" of excision repair. Exonuclease III digestion and gap-filling with DNA polymerase I indicate that the majority of biotin-labeled repair patches (approximately 80%) are rapidly ligated in confluent human cells. However, the remaining patches were not ligated after a 24-h chase period, in contrast to dTTP-labeled repair patches. The BiodUMP repair label in both chromatin and DNA is preferentially digested by staphylococcal nuclease, preventing the use of this enzyme for nucleosome mapping in these regions.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of losartan potassium and deoxycorticosterone acetate on tail skin temperature response to acute administration of angiotensin II.

The potent vasoconstrictor peptide, angiotensin II (AII) (200 micrograms/kg, SC), increases tail skin temperature (TST) and tail blood flow when acutely administered either peripherally (SC) or centrally (ICV) to rats. Colonic temperature declines with the increase in TST. These responses are apparently mediated by way of AII subtype receptor AT1 because they are blocked by acute administration of the nonpeptide AT1 receptor antagonist, losartan potassium (DuP 753) (10 mg/kg, SC). The responses were also blocked by the peptide AII receptor antagonist, saralasin, at 100 micrograms/kg SC. Chronic administration of the steroid deoxycorticosterone acetate (DOCA, 250-300 micrograms/day for 45 days) sensitized the response of TST to acute administration of AII. The increase in responsiveness resulting from chronic treatment with DOCA is consistent with the increase in dipsogenic responsiveness to AII under similar conditions. The latter was shown to be correlated with the upregulation of AII receptors in the diencephalon. While the location of the AII receptors mediating the increase in TST is not known with certainty, it is reasonable to suggest that they are also upregulated by chronic treatment with DOCA.


The primary structure of neuropeptide F (NPF) from the garden snail, Helix aspersa.

Neuropeptide F (NPF), originally isolated from the sheep tapeworm, Moniezia expansa, consists of 39 amino acid residues terminating in a phenylalaninamide. An analogous neuropeptide has been isolated and sequenced from extracts of circumoesophageal ganglia of the garden snail, Helix aspersa. This neuropeptide exhibits partial primary structural similarity to members of the vertebrate neuropeptide Y (NPY)/pancreatic polypeptide (PP) superfamily. NPF is thus of widespread occurrence in the nervous systems of invertebrates from different phyla and may represent the phylogenetic precursor of the vertebrate NPY/PP superfamily.


Sucking technique and its effect on success of breastfeeding.

We investigated the prognostic value of sucking technique (faulty vs correct) during the first week after birth in relation to the long-term success of breastfeeding. At discharge from the maternity ward, 82 healthy mother-infant pairs were observed for assessment of breastfeeding technique and followed for four months by regular telephone checkups. Correct sucking technique was defined as the infant having a wide-open mouth, with the tongue under the areola, and expressing milk from the breast by slow, deep sucks; faulty technique was defined as superficial nipple sucking. The study population was divided into three groups: one in which faulty sucking technique was corrected when observed (n = 29), one with faulty but uncorrected technique (n = 25), and a control group with a correct technique (n = 28). At the four-month follow-up assessment, the faulty but uncorrected group was characterized by a greater proportion of mothers with breastfeeding problems and early cessation of breastfeeding than the other two groups. Regular use of a pacifier (> 2 hrs/day) was more common among those with breastfeeding problems.


Short-term morbidity associated with cesarean delivery.

This study describes the short-term morbidity associated with cesarean delivery and women's knowledge of the reasons it was performed. It was conducted in a university teaching hospital that delivers approximately 4000 women per year. During 1986, 619 women (16%) were delivered by cesarean, 588 of whom were sent a questionnaire three months after delivery. The response rate was 76 percent. General questions were asked about the women's recovery and health state after the birth, and whether they had experienced more specific types of morbidity, including infection, backache, and depression, and the reasons for the cesarean delivery. Women's answers were then compared with the obstetric case record. In their comprehension of why the cesarean was necessary, 87 percent of women were right or partially right, 35 percent believed they had still not fully recovered, and 28 percent felt less healthy than before the pregnancy. Women experienced a wide variety of postnatal morbidity, most commonly backache (55%), constipation (49%), and depression (38%). The study showed that considerable maternal morbidity is associated with cesarean delivery, and it can persist long after the woman is discharged from hospital. Much more information is necessary about the health of women after delivery, and research is urgently required to determine the comparative rates of morbidity associated with different delivery methods.


Prenatal factors associated with breastfeeding duration: recommendations for prenatal interventions.

This study of 198 urban breastfeeding women examined the psychosocial, demographic, and medical factors identified prenatally that may be associated with longer breastfeeding duration and may serve as suitable areas for prenatal breastfeeding promotion interventions. Of 11 psychosocial and demographic factors examined, 5 were important influences on breastfeeding duration: anticipated length of breastfeeding, normative beliefs, maternal confidence, social learning, and behavioral beliefs about breastfeeding. Methods of multivariate linear regression were used to identify prenatal factors that influenced anticipated length. Of the 10 factors entered into the regression model, parity, plans to return to work or school by six months postpartum, and maternal confidence were the most significant factors affecting anticipated length of breastfeeding. Our data suggest several factors amenable to intervention during the prenatal period that appear to influence breastfeeding duration. Prenatal promotion efforts could easily incorporate strategies that influence factors such as normative and behavioral beliefs and maternal confidence.


College women's expectations about pregnancy, childbirth, and infant care: a prospective study.

A prospective study of 103 women undergraduate students explored expectations and knowledge about pregnancy, childbirth, and newborn care. Participants completed a 35-item questionnaire based on a planned pregnancy. Most women (68%) thought they were extremely likely to become pregnant in their lives and planned to have an average of 2.6 children. Positive emotions about pregnancy were most frequently excited, happy, and proud, and negative emotions were most frequently nervous, scared, and anxious. Women expected that pregnancy and parenting would interfere most with work or education plans. Choices of birthplace were hospital delivery room (54.4%), in-hospital birthing room (35%), out-of-hospital birth center (3.9%), and home (2.9%). One-half of the women planned to breastfeed, 35 percent had not decided, and 10.7 percent would not breastfeed. Positive feelings about pregnancy were correlated with positive feelings about labor and birth (r = 0.48, P < 0.001). Negative feelings about pregnancy were correlated with a low self-assessment of ability to care for an infant (r = -0.27, P < 0.01). Some college women's expectations are similar to those held by pregnant women, and suggest the need for further education of young women in areas such as prenatal health care and breastfeeding.


Sleep disturbances, vitality, and fatigue among a select group of employed childbearing women.

Self-reported sleep disturbances and levels of vitality and fatigue were studied in a secondary analysis of 25 pregnant and 29 postpartum employed women. Results indicate that pregnant women have problems initiating and maintaining sleep, and postpartum women have problems maintaining sleep, but not falling asleep. The primary reason for midsleep awakenings was urinary frequency among the pregnant women, and child care responsibilities among the postpartum women. Chronic sleep disturbance was indicated by a greater percentage of postpartum women who fell asleep easily, very few who felt highly energetic at work, and most who perceived a high level of fatigue during the past week. Even with these sleep disruptions, no differences occurred in the mean scores for perception of fatigue and vitality between the two groups. Clinicians can use these findings to educate women about some changes they may anticipate and how they might manage them during pregnancy and postpartum.


Effects of childhood sexual abuse on childbirth: one woman's story.

Anna Rose is a survivor of childhood emotional, physical, and sexual abuse. Much of the abuse was "submerged" until her mid-thirties, when she was pregnant with her second child, and finally began to remember and deal with the realities of what had happened to her. During her second pregnancy, Anna wrote, "It has taken me more than three years to even begin to deal with the rage I feel about my first birth experience, even though I have been in therapy most of that time. Now that I am pregnant again, the unresolved issues are coming to the surface, and intense fears that this birth will be a repeat of the first." Anna's first child, Elliot, was born in 1987 in a hospital birthing room in the northeastern United States. Her husband Paul, a younger sister, and a close friend were present, and she was attended by an obstetrician named Bernie. She describes that birth as "19 hours of hard labor, absolutely exhausting and unmanageable, which required drugs at some point to let me sleep for a few hours." Labor was induced by Pitocin due to premature rupture of membranes and lack of effective contractions after 12 hours. Continuous electronic fetal monitoring was used throughout labor. Anna breastfed Elliot for three years, and found La Leche League "extremely helpful and supportive" during that time. Tom, Anna's second child, was born at home in 1991. Two midwives attended the birth after she changed caregivers during the pregnancy because she "did not feel safe enough" with the obstetrician and nurse-midwife team she had chosen for this birth. She maintained the team as backup, although they did not know of her plans for a home birth. Her second labor lasted under 6 hours, was noninterventive, and "incredibly intense and painful, partly due to the abuse memories that were coming up and getting in the way and partly due to the baby's position." We thank Anna Rose for sharing her story with Birth. Her reason for doing so is, in her words, because, "I feel strongly that it is important to share this information in an effort to educate health care professionals so that other women may be helped."


Isotypic distribution of HIV-1-specific antibodies in individuals from central Africa.

Individuals infected with human immunodeficiency virus type 1 (HIV-1) develop a humoral immune response to the virus's major structural gene products env, gag, and pol. The distribution of antibodies to env, gag, and pol proteins in Central African populations is of interest as they have a high level of immune system activation compared to non-African populations. Using the Western blot technique, we analyzed the isotypic distribution of anti-HIV antibodies in 45 HIV-1-infected individuals from Central Africa that were either symptomatic or asymptomatic. We observed two basic differences between the isotypic profile of individuals from Central Africa and non-African populations. Central African individuals had a strong polyisotypic response to gag and pol, which has only been observed for gag in American and European populations. In addition, individuals from Central Africa had a high frequency of IgG4 to gag and pol, 75 and 51%, respectively, as compared to 29 and 6% in a non-African population. The elevated IgG4 response may result from the high basal level of immune stimulation seen in Africans due to multiple and frequent exposures to viral, bacterial, and parasitic antigens.


Susceptibility of trout kidney macrophages to viral hemorrhagic septicemia virus.

Viral hemorrhagic septicemia virus (VHSV) lysed the macrophages from rainbow trout kidney cultures either isolated by plastic adherence or stimulated with purified glycoprotein G from VHSV. The trout macrophages supported the replication of VHSV as tested by cell culture and by sandwich ELISA of the supernatants from infected cultures. VHSV-infected macrophages showed a decrease in both acridine-orange fluorescence and average size. Immunofluorescence studies with flow cytometry showed positive membrane staining with monoclonal antibodies (MAbs) anti-N and anti-G VHSV. These findings open the possibility of using trout macrophages as presenting cells to study the possible existence of helper or cytotoxic epitopes relevant to the protection of trout against VHSV.


A method to analyze the interaction between gp120 of human immunodeficiency virus and CD4.

The study presents a new in vitro method to investigate the interaction between the glycoprotein (gp)120 of human immunodeficiency virus (HIV) and its receptor, CD4. The method is based on the binding of soluble recombinant CD4 to a human T cell line, 8E5, which constitutively expresses gp120 at its surface as a result of infection with HIV (LAV) and lacks reverse transcriptase activity. The binding of CD4 to gp120 on the cell surface is revealed by immunofluorescence using a murine monoclonal antibody to CD4. Binding can be inhibited by different substances like dextran sulfate, heparin, pentosan polysulfate, but not Leu3a. The reasons for this discrepancy are discussed. We propose this assay as a simple, reproducible, and rapid new method to screen new, pharmacological inhibitors of the gp120/CD4 interaction.


Endothelial transcytosis of iron-transferrin in the liver does not involve endosomal traffic.

Through a process resembling receptor-mediated internalization, liver endothelium binds and internalizes iron-transferrin (Fe-Tf) complexes, transporting them from the luminal to abluminal side. Since in most systems, the path of receptor-mediated endocytosis leads to the endosomal compartment where the medium is acidified, it is expected that Fe and Tf become dissociated in this acidified medium. However, experiments with double labeling (59Fe, 125I-Tf) indicate that these remain associated. To determine whether the endosomal pathway is used in the course of transendothelial transport of Fe-Tf, experiments were done by incubating purified liver endothelium with radiolabeled Fe-Tf in the presence and absence of endosomal inhibitors, NH4Cl, ethylamine and monensin. The discharge of radiolabeled protein was measured as a function of time. While there was an early phase inhibition in the presence of endosomal inhibitors, the discharge of Tf by endothelium in the presence of inhibitors, reached a plateau comparable to control cells after 4 h, indicating that endosomal inhibition does not inhibit transendothelial transport of Tf and, thus, the transport does not involve endosomal traffic.


Interleukin-6 expression in immunologically elicited murine macrophages.

We report the expression of both interleukin-6 (IL6) messenger RNA and biological activity in complete Freund's adjuvant-elicited peritoneal macrophages (CFA-M phi). IL6 mRNA expression peaked between 4 and 8 h of lipopolysaccharide (LPS) stimulation; biological activity was maximal at approximately 18 h of stimulation. LPS-induced IL6 mRNA was inhibited by treatment with cycloheximide (5 micrograms/ml), implicating the participation of a secondary protein mediator in the induction process, or the dependence upon protein synthesis for receptor ligand interactions. Comparison of CFA-M phi with resident peritoneal macrophages suggests that the elicited cell population makes more IL6 in response to LPS than the resident population on a per cell basis.


Impairment of long-term memory and sparing of short-term memory in monkeys with medial temporal lobe lesions: a response to Ringo.

During the last decade, an animal model of human amnesia was developed in the monkey. Studies using this model have identified structures in the medial temporal lobe that are essential for forming long-term memory (i.e. the hippocampus and the entorhinal, perirhinal and parahippocampal cortices). Recently, an important aspect of these studies was questioned by Ringo (Behav. Brain Res., 42 (1991) 123-134). He suggested that the data from the delayed non-matching-to-sample task, which has been extensively used in these studies, have been analyzed in a potentially misleading way. He reanalyzed the data from several laboratories by transforming percent correct data to a discriminability (d') measure based on signal detection theory. In monkeys with lesions, performance appeared to be equivalently impaired at short and long retention delays. He concluded that the data do not support the idea that medial temporal lobe damage produces an impairment in long-term memory, but not short-term memory. However, most of the studies he analyzed were not designed to address the distinction between short-term and long-term memory. We show here that, in studies designed to compare short-term and long-term memory directly, medial temporal lobe lesions impair long-term memory while leaving short-term memory intact. This result is obtained whether the data are analyzed using a percent correct measure, the d' measure, or an arcsine transform.


A behavioral study of the contributions of cells and fibers of passage in the red nucleus of the rat to postural righting, skilled movements, and learning.

Although the red nucleus consists of cells of origin for the rubro-spinal and rubro-olivary tracts, fibers of passage, including those of the superior cerebellar peduncle, which project from the cerebellum to the ventrolateral thalamus, pass through it. This study examined the relative effect of cell vs. fiber damage in the red nucleus on a number of behaviors thought to involve the red nucleus, including a skilled movement of reaching for food with a forelimb, postural righting on a surface and in the air, and learning a place response in a swimming pool test. Rats received unilateral or bilateral red nucleus lesions, using either the relatively cell-specific neurotoxins, ibotenic and quinolinic acid, or non-specific electrolytic anodal lesions. Both neurotoxic lesions effectively eliminated all red nucleus cell bodies, and in some animals they produced small cavities in the red nucleus and/or loss of cells in adjacent structures. Electrolytic lesions destroyed both cells and fibers, leaving a large cavity. The severity of the behavioral deficits were not related to the loss of red nucleus cells and there was a close relation between fiber damage and behavioral impairments on all of the tasks. The results suggest that for a number of behaviors, which have been thought to involve the red nucleus, impairments are more closely associated with fiber damage or damage to structures outside the red nucleus than they are to damage to cells of the red nucleus.


Lateralization and reaching skill related: results and implications from a large sample of Long-Evans rats.

Limb preference and reaching success were examined in 580 Long-Evans rats. Most rats displayed a strong asymmetry. Although slightly more rats used the left limb than used the right limb, the difference was not significant. Thus, Long-Evans rats do not show dominance with respect to limb use. There was a significant correlation between the degree of lateralization and success of limb use. This relation suggests either that endogenous factors contributing to limb lateralization also contribute to motor skill or else the use of a lateralized reaching strategy facilitates the development of skill in reaching. The results are discussed in terms of their methodological implications for studies of selective breeding and strain differences and also in terms of their significance for understanding the evolutionary basis of lateralization and dominance.


Brief exposure to an enriched environment improves performance on the Morris water task and increases hippocampal cytosolic protein kinase C activity in young rats.

This study was designed to determine whether brief exposure to an enriched environment around the time of weaning would affect learning and memory processes in young rats. In addition, this study sought to determine if experience in an enriched environment would alter hippocampal protein kinase C (PKC) which is thought to be a possible neural substrate that underlies learning and memory processes. Animals were either reared in an enriched environment or standard laboratory cages starting at 15 days old. After 6 (21 days old) or 12 (27 days old) days subjects were either tested in the Morris water task, or had the hippocampus removed for biochemical analysis of PKC activity. Morris water task results showed that compared to laboratory reared controls, the performance of subjects reared in the enriched environment for 12 days, but not 6 days, was improved. In addition, 12 days of exposure to the enriched environment, but not 6 days, produced more cytosolic hippocampal PKC activity. The particulate fraction appeared not to be affected by rearing in the enriched environment. Brief exposure to an enriched environment around weaning, therefore, both improved Morris water task performance and increased hippocampal PKC activity. These outcomes suggest that performance in the Morris water task and hippocampal PKC may be functionally related.


Removal of the hippocampus and transection of the fornix produce comparable deficits on delayed non-matching to position by rats.

Rats with radiofrequency lesions of the fimbria/fornix or with extensive aspiration lesions of the hippocampal region (the hippocampus proper, dentate gyrus, and subicular complex) were tested on their performance of a delayed non-matching to position task which had been learnt before surgery. On a given trial, one of two sample levers was presented in a random manner. Following a response on this lever and a subsequent delay, both levers were presented and reward was now contingent on a response on the lever that was not used as the sample. Both lesions produced equivalent performance deficits on this test of spatial working memory, the pattern of these deficits being consistent with a mnemonic impairment. The lack of difference between these two groups on a variety of performance measures indicates that hippocampal connections passing through the fornix are not only necessary for this test, but that non-fornical hippocampal connections appear unable on their own to maintain accurate responding.


Apomorphine and electrical self-stimulation of rat brain.

The participation of dopamine neurons in reward produced by electrical stimulation of the brain was examined by measuring self-stimulation thresholds after injections of apomorphine, a direct agonist of dopamine receptors. Rats were trained to press a lever to obtain 0.3-s trains of electrical stimulation applied to lateral hypothalamic electrodes in a paradigm where the pulse frequency was decreased every eight stimulations by approximately 20%. The pulse frequency interpolated at 50% of maximum rate was taken as threshold. In a completely within-subject design, five doses of apomorphine from 0.01 to 1.00 mg/kg and the ascorbic acid vehicle were injected in a random order and thresholds were tracked at intervals of 5 min for 2 h postinjection. Low doses from 0.01 to 0.10 mg/kg caused thresholds to increase while the two higher doses, 0.30 and 1.00 mg/kg, caused thresholds to drop; the switch in the direction of the behavioural effect is thought to parallel the shift in apomorphine's action from presynaptic to predominantly postsynaptic activation of dopamine receptors as the concentration of apomorphine increases.


The effects of lesions of area V4 on the visual abilities of macaques: colour categorization.

Monkeys with V4 lesions and unoperated controls were tested behaviourally for their perception of the colour categories red, green, blue and yellow. As expected, the monkeys with V4 lesions took longer to acquire the colour discriminations. However, the pattern of learning was the same in the two groups of animals. Both the lesioned and the control animals made more errors when the stimuli to be discriminated belonged to the same colour category than when they belonged to different categories and thus showed normal colour categorization. The results suggest that monkeys with V4 lesions perceive the colour spectrum according to the same fundamental perceptual categories as normal monkeys and humans, and thus support the view that, in the colour domain, the four basic perceptual categories are constructed by chromatic mechanisms operating earlier than visual area V4.


Short-term memory for the temporal order of events in monkeys.

Two monkeys (Macaca fascicularis) demonstrated short-term memory for the recency of unpredictable visual events in a probe recognition task. On each trial, from two to five 3-dimensional objects were randomly selected from a pool of 200 and presented sequentially. In the test probe that followed, the subjects saw two objects from the preceding list and chose the one that had appeared earlier. Overall accuracy was 73% correct. Like human judgments of recency, accuracy varied inversely with the lag and directly with the temporal separation of the objects in the probe. The data suggest that monkeys encode information about object order as well as object identity, their mnemonic representation of the ordered list contains information about all of its constituent elements, and recency judgments are made at the time the probe is presented and not before. Monkey processing of temporal order information is in these respects similar to human order memory.


Sodium appetite after transection of the chorda tympani nerve in Wistar and Fischer 344 rats.

Acute sodium depletion in rats leads to dramatic increases in intake of hypertonic NaCl solutions, a behavior known as sodium appetite. The importance of signals conveyed by the chorda tympani (CT) nerve to the expression of sodium appetite is unclear. We examined the effects of bilateral CT transection on the short- and long-term response to sodium depletion in Wistar and Fischer 344 (F344) rat strains, because Wistar rats normally display a NaCl preference in the absence of need whereas F344 rats avoid NaCl. In both strains, sodium appetite after CT transection and treatment with the diuretic furosemide was delayed and blunted or eliminated. The results suggest that signals conveyed by the CT nerve are important in the expression of a sodium appetite. Effects on F344 rats are particularly interesting because CT transection surgery appears to have opposite effects on NaCl intake depending on whether F344 rats are sodium replete or deplete.


Posttraining effects of amphetamine, chlorpromazine, ketamine, and scopolamine on the acquisition and extinction of the rabbit's conditioned nictitating membrane response.

Four experiments examined whether posttraining deliveries of drugs modified the performance of the rabbit's conditioned nictitating membrane response (NMR) during acquisition and extinction. The results show that ketamine accelerated, but that amphetamine, chlorpromazine, and scopolamine retarded, conditioning when the drugs were injected immediately after the completion of daily training sessions. However, all conditioning effects of the drugs were lost when their deliveries were delayed by 2 hr after the end of training. During extinction, the only drug that altered conditioned performance was ketamine. Specifically, ketamine retarded the rate of extinction when the drug was given immediately after training. However, delaying ketamine by 2 hr after training neutralized the drug's influence. These findings indicate that the NMR preparation should be useful in examining how the posttraining delivery of drugs influences associative processes in conditioning.


Medial prefrontal cortex lesions and spatial delayed alternation in the developing rat: recovery or sparing?

In Experiment 1, Long-Evans rat pups received medial prefrontal cortex (PFC) aspirations or sham surgery on Postnatal Day 10 (PND10) and were then trained on PND23 to perform one of two T-maze tasks: discrete-trials delayed alternation (DA) or simple position discrimination. Early PFC damage produced a selective failure to learn the DA task. In Experiment 2, pups given the same lesion or sham surgery were trained on DA on PND19, PND27, or PND33. In relation to sham-operated controls, pups with PFC damage were impaired on PND19, somewhat impaired on PND27, and entirely unimpaired when tested on PND33. In Experiment 3, pups given larger lesions of the frontal cortex on PND10 were impaired on DA when tested on PND23 but not when tested on PND33. These findings indicate that early PFC lesions result in a memory deficit around the time of weaning, which then recovers over the next 10-14 days of development. Moreover, the early deficit is selective for a late developing cognitive process (or processes) that is involved in acquisition of DA.


Memory-based learning in preweanling and adult rats after infantile x-irradiation-induced hippocampal granule cell hypoplasia.

Infantile exposure to x-irradiation induced severe hippocampal granule cell hypoplasia in preweanling and young adult rats. Hippocampally damaged pups, tested at 16 days of age, showed deficits in a memory-based discrimination based on single alternations of reward and nonreward when training was conducted at a 60-s intertrial interval (ITI) but not when conducted at a 30-s ITI. This deficit was still present at the 60-s ITI in animals x-irradiated in infancy and tested at 60-65 days of age. These data provide further support for the role of the hippocampus in intermediate-term memory and demonstrate, in a developmental context, the importance of an intact hippocampus in learning that depends on nonspatial memory.


Laterality, alternation, and perseveration relationships on the T-maze test.

The T-maze test has been used to study several entirely different issues: spontaneous alternation behavior (SAB), perseveration behavior (PB), and behavioral lateralization. Despite the fact that in this test the behavior studied is always the same one (i.e., side choice), the possible relationships among SAB, PB, and lateralization have not been previously evaluated. The present study investigated the relationships among these functions. The results demonstrated that (a) shock increases PB and lateralization but decreases SAB, (b) practice increases lateralization and decreases SAB but does not modify PB, and (c) there are sex differences for alternation and SAB. Because these functions are expressed by the same behavioral pattern, they must be quantified simultaneously to avoid mistaken conclusions when the T-maze test is used.


Dorsal diencephalic self-stimulation: a movable electrode mapping study.

The function relating electrical self-stimulation (ESS) bar-pressing rate to the frequency of cathodal pulses (0.2 mA and 0.1 ms) was obtained for several positions of a movable electrode in the dorsal diencephalon of the rat. The rate-frequency functions were fitted to a sigmoid model to obtain the asymptotic rate and threshold frequency. ESS was found along the epithalamic route (stria medullaris, habenula, and fasciculus retroflexus) and in the following thalamic nuclei: mediodorsal, paratenial, interanteromedial, centromedial, reuniens, and rhomboid. The lowest threshold (approximately 5 pulses/train), which was found in the stria medullaris and the junction of the paratenial and centromedial nuclei, was comparable to that usually obtained for the brain areas where the ESS is most effectively rewarding (medial forebrain bundle, dorsal raphe, and amygdala). However, most of threshold estimates were 4 to 8 times higher. In most brain sites, ESS was accompanied by epileptiform, motor, or aversive reactions (or a combination of these). These reactions may explain the fact that the maximum rates were generally very low. Nevertheless, no correlation was found between maximum rates and threshold frequencies.


Influences of hypothyroidism on the taste detection performance of rats: a signal detection analysis.

The influences of hypothyroidism on behavioral measures of the taste function in male and female Long-Evans rats were determined. Experimental rats' preferences for and ability to detect NaCl, HCl, sucrose, and quinine sulfate were examined before, during, and after 9 weeks of maintenance on 0.1% propylthiouracil (PTU), an agent that produces marked hypothyroidism, with similar determinations made for control animals. Despite significant decreases in PTU-treated rats' serum triiodothyronine (T3) and thyroxin (T4), there were no changes in sensitivity or responsivity to the target tastants. However, altered preferences for NaCl, HCl, and quinine sulfate were observed for PTU-treated rats; elevated consumption of HCl and quinine sulfate was present at the end of the study when serum T3 and T4 had returned to near-baseline levels. The data confirm observations that PTU-induced hypothyroidism alters rats' taste preference behavior.


Ethanol and cytokine secretion.

Cytokines are regulatory polypeptides secreted during the generation of an immune or inflammatory response by lymphocytes, cells of the monocyte/macrophage series, and a variety of other cell types. Alterations in the production, site of action, or metabolism of cytokines by exogenous factors, such as ethanol (EtOH), may have deleterious effects on the immune system as a whole. EtOH has been implicated in the onset of a variety of immune defects in vivo including effects on the production of cytokines critically involved in inflammatory responses (tumor necrosis factor, interleukin 1 and interleukin 6). In this review, we examine current knowledge regarding the effects of EtOH on the release of cytokines in humans and in animal models, in vitro and in vivo, which may help to elucidate the adverse actions of EtOH on mammalian immune systems.


Effects of ethanol on parameters of cellular immunity and host defense mechanisms to infectious agents.

Results of several studies have associated ethanol abuse with an increased incidence of infections, including opportunistic infections and those caused by microorganisms, as well as of certain types of cancer. Research findings from several laboratories clearly indicate that one possible mechanism in this association is an effect of ethanol on the immune system. We have developed an animal model fo ethanol ingestion in a liquid diet to study the effects of ethanol on immune responses. In most of the studies, we have used a pair-feeding design in which control animals are given a liquid diet that is isocaloric to the ethanol diet by the addition of either sucrose or dextran-maltose. Here, we discuss data obtained from in vivo studies of cellular function. We have studied the effects of ethanol on activation of T lymphocytes in vivo after intravenous injection of monoclonal antibody to CD3. The stimulation of cells in the spleen was assessed by measuring levels of cytokine RNA. We have also assessed the ability of animals to respond to a sublethal dose of Listeria monocytogenes to determine whether ethanol alters host defense mechanisms. Our findings indicate that ethanol ingestion reduced the ability of mice to respond to anti-CD3 and to resist infection with a bacterium that predominantly infects the liver.


Fetal alcohol exposure and adult tumorigenesis.

Adult rats exposed to prenatal alcohol were evaluated for their susceptibility to either hormone- or chemical-inducing tumors. In the first study, rats exposed to prenatal alcohol displayed an increased propensity to beta-estradiol (E2)-induced adenohypophyseal prolactinoma. The susceptibility was manifest as a potentiated increase in anterior pituitary weight as well as in serum prolactin levels after 1 and 3 weeks but not 5 weeks of hormone treatment. Two weeks after withdrawing the E2-implant, the prolactinoma underwent involution and serum prolactin reversed to baseline levels. The high concentrations of serum corticosterone were also reduced but did not return to baseline levels after E2 removal. In the second study, nitrosomethylbenzylamine (NMBA) was utilized to induce esophageal cancer in adult rats. There were no significant differences in tumor incidence or size between the prenatal alcohol-exposed and the pair-fed cohorts. However, the NMBA-treated prenatal alcohol-exposed rats displayed a marked decrease in thymus: body wt ratio as well as adrenal gland hyperplasia. The results suggest that no single mechanism can account for the variable susceptibility displayed by the prenatal alcohol-exposed rats to chemical carcinogens. Some of the observed changes, however, may be attributable to the long-lasting adverse effects of prenatal alcohol exposure on the well-being of the adult host.


Alcohol, hepatic sinusoidal microcirculation, and chronic liver disease.

According to the "intact cell hypothesis," ethanol (EtOH) primarily targets nonparenchymal hepatic sinusoidal and perisinusoidal cells, thereby promoting sinusoidal capillarization, which impairs microcirculatory exchange of nutrients and wastes, promotes tissue fibrosis, and only indirectly damages hepatic parenchyma. To test this hypothesis, sinusoidal ultrastructure and hepatic lymph flow and protein composition were examined in rats up to 16 weeks after intragastric EtOH (36% calories)-high fat infusion (Tsukamoto-French model) (TF). The findings were compared to dietary controls and interpreted in light of restricted transsinusoidal protein movement observed in patients with alcoholic cirrhosis. In vitro, alterations in rat hepatic sinusoidal endothelial cell (RSE) morphology, proliferative index, and transendothelial macromolecular permeability (Evans blue-albumin uptake into microcarrier beads) were determined after acute and more chronic exposure to 0.1%-5 vol% EtOH. TF displayed 75% increased liver size, perisinusoidal collagenosis, and basal lamina deposition, ascitic fluid, and doubling of hepatic lymph liquid and protein flux. In vitro, 1% EtOH retracted RSE cell margins, enhanced transendothelial Evans blue-albumin flux and suppressed proliferative index. Thus, high EtOH concentration, clinically attainable in the portal blood during an alcoholic binge, both in vivo and in vitro, promotes early structural and functional alterations in sinusoidal endothelium, which over time may be responsible for progressive restriction of free intrahepatic exchange of liquid, macromolecules, and migrating immune cells.


Selective effects of fetal alcohol exposure on rat thymocyte development.

The thymoproliferative response to concanavalin A (ConA) following fetal alcohol exposure (FAE) is higher than control (149%) on day 44, is lower than control (64%) by day 51, and normalizes by day 69 (88% of controls). The ontogeny of HLA-Dr and transferrin receptor (CD71) expression in response to anti-CD3 stimulation is similar among the groups, but is distinct from that of ConA proliferation. The ontogeny of glucocorticoid cytoplasmic receptor (GCCR) sites per thymocyte is also different from the ontogeny of the ConA response. The number of GCCR sites rises sharply (2.5-fold) in control rat thymocytes between days 30 and 44, and remains at that level at later time points. By contrast, the number of GCCR sites per FAE thymocytes rises nearly linearly and normalizes by day 72. Our data support the notion that prenatal alcohol exposure significantly alters thymic development and indicates that the relationship between the development of thymocyte functional responses and that of GCCR is more complex than initially hypothesized.


Ethanol enhances immunosuppression induced by cocaine.

Use of cocaine concurrently with alcohol is prevalent among cocaine addicts. Cocaine has been shown to inhibit phytohemagglutinin- and ConA-induced proliferation of T-lymphocytes, NK cell cytotoxicity, and phagocytic activity of peritoneal macrophages. In some studies no effects of cocaine on the immune response have been observed, although on the contrary, others show it increased the NK cell activity and serum antibody response to T-dependent antigen. Effects of cocaine on the immune system may be mediated by its neurostimulatory action on the hypothalamo-pituitary-adrenal axis. ACTH, beta-endorphine, and corticosterone released under the action of cocaine exert various inhibitory effects on the immune function. We studied the immunotoxic effect of cocaine, combination of cocaine with ethanol, and cocaethylene, a derivative formed from cocaine and ethanol in the body, on the mitogen-stimulated production of cytokines by splenocytes. C57BL mice were injected twice daily with 20 mg/kg cocaine or equivalent dose of cocaethylene and received a liquid Lieber-DeCarli diet containing ethanol (26% of total calories) or isocaloric amount of maltose-dextrin. After 3 weeks of treatment, cocaine and cocaethylene caused a significant decrease of the spleen weight and total number of splenocytes. In splenocytes isolated from the cocaine- or cocaethylene-treated mice, mitogen-stimulated production of gamma-interferon, tumor necrosis factor, and interleukin-2 was suppressed, in all cases more severely when cocaethylene was used. Thus, formation of cocaethylene during simultaneous consumption of cocaine and ethanol may enhance the immunotoxicity of cocaine.


Age dependent development of ethanol drinking in rats after inhibition of aldehyde dehydrogenase.

The purpose of this experiment was to determine the temporal characteristics associated with the age-related development of volitional consumption of ethanol induced by the pharmacological inhibition of aldehyde dehydrogenase (AlDH). To induce preference for ethanol, the AlDH inhibitor, cyanamide, was administered to male Sprague-Dawley rats which were 30 days of age. Cyanamide (n = 8) was injected subcutaneously twice daily in a dose of 10 mg/kg over a period of 3 days while the control group (n = 6) received the saline vehicle solution according to the same schedule. Then at 50, 70, 90, and 110 days of age, both groups of rats were given a standard 11-day test of preference for water versus ethanol offered in concentrations ranging from 3% through 30%. The results showed that at 70 days of age the preference for ethanol increased above the level of the 50-day test in terms of absolute g/kg intakes and proportion of ethanol to water consumed over the lower range of 3% through 15% concentrations. During the tests at 90 and 110 days of age, the cyanamide-treated rats further increased their preference for ethanol significantly over the levels at the 70-day test in terms of both g/kg and proportional intakes. The pattern of drinking of ethanol offered in the higher concentrations of 25% and 30% was unrelated to the age of the rats and the overall intakes were significantly higher than those of the lower concentrations. These findings demonstrate that the enzymatic inhibition of AlDH systematically acts in a delayed fashion to shift the pattern of preference for ethanol which is contingent on the maturation of the animal. In this instance, the volitional intake of ethanol in the cyanamide-treated rats reached its maximal level by 90-110 days of age. It is proposed that an endocrine mechanism involved in gonadal maturation may function in the intense shift in alcohol drinking.


Ultrastructural changes in the rat kidney following fetal exposure to ethanol.

Previous studies have implicated renal ultrastructural abnormalities in the pathogenesis of tubular dysfunction in fetal alcohol syndrome. Scanning electron microscopic studies were performed to examine the role of glomerular and tubular structural changes in this syndrome. Pregnant Sprague-Dawley rats were fed a liquid diet in which ethanol constituted 35% of the total caloric content or pair-fed an isocaloric control diet from gestational day 8 to the day of birth. After delivery, offspring were housed with the dam and left undisturbed until 18 days of age when they were weaned and given free access to standard chow diet and water. At random, kidneys from 11 offspring of ethanol-fed (E) rats and 7 pair-fed control (C) rats were fixed by in vivo retrograde perfusion at 90 days of age for ultrastructural studies. The E rats showed cytoplasmic mitochondrial atrophy and vacuolar structures of the epithelial cells of the distal tubules and collecting ducts not seen in C rats. No obvious difference was found in the glomerular, proximal tubule, or loop of Henle architecture between the two groups. These findings suggest that rats prenatally exposed to ethanol have renal ultrastructural abnormalities that may be important in the genesis of functional disturbances.


Opposite effects of dimethyl sulfoxide and ethanol on synaptic membrane fluidity.

Dimethyl sulfoxide (DMSO) is an organic solvent with myriad biological actions, including actions on synaptic membrane transport processes. In this study, fluorescence polarizations of the probes diphenylhexatriene (DPH: a probe of the hydrophobic membrane core), trimethylammonium-diphenylhexatriene (a probe of the superficial domain of the cytofacial synaptic membrane leaflet) and diphenylhexatriene propionic acid (a probe of the superficial domain of the exofacial synaptic plasma membrane leaflet) were measured in isolated rat cerebral synaptic plasma membranes. DMSO, added in vitro, increased fluorescence polarization of all of these intramembranous probes, an effect opposite that observed with the addition of ethanol. The fluorescence polarization increase appeared at lower concentrations of DMSO for the superficial membrane region probes (6% vol/vol DMSO) than for the membrane core probe (10% vol/vol DMSO). This is again in contrast to the effects of ethanol, which required lesser concentrations to decrease fluorescence polarization of DPH (50 mM ethanol) than that of the derivative probes (200 mM ethanol). The enhancement of DPH fluorescence polarization produced by DMSO was antagonized by the concomitant addition of ethanol. These results suggest an ordering effect of DMSO on synaptic plasma membranes, with greater effects in superficial membrane domains.


Pyridoxine acts in the brain to reduce ethanol toxicity in rats.

Although for many years it has been proposed that megadoses of pyridoxine protect from ethanol toxicity, this issue remains unclear. In the present report the interaction between ethanol and pyridoxine was tested. Pyridoxine was administered intramuscularly or intracerebroventricularly to rats. Intramuscular administration of 187.2 mg/kg of pyridoxine displaced the ethanol-lethality dose curve significantly toward the right (p < 0.005) and increased the LD50 of ethanol from 4.46 to 5.19 g/kg (p < 0.005). Intracerebroventricular administration of pyridoxine (1.1 mg) completely suppressed the mortality due to a LD100 of ethanol and the effect was dose dependent. We conclude that pyridoxine is an effective treatment for ethanol intoxication. The results are discussed in terms of an interaction of ethanol and pyridoxine on the GABAergic system.


Acute ethanol intoxication during pregnancy: postnatal effects on the behavioral response to serotonin agents.

Pregnant wistar rats were treated on the eighth day of gestation (GD 8) with two IP injections, spaced by 4 h, of either ethanol (2.9 g/kg in 24% v/v saline solution, EG) or saline (SG). Other pregnant females did not received any type of IP injections (absolute control group, ACG). Offspring were tested at 45 or 90 days of age. At 45 days of age, EG showed an increased behavioral response (forepaw treading and hindlimb abduction) to the 5-HT1 agonist, 5-methoxy-N,N-dymethyltryptamine. In addition, an enhanced "wet-dog" shakes behavioral response to 5-HT2 agonist, 5-hydroxy-L-tryptophan, was also observed in EG as compared to ACG and SG. On the contrary, at 90 days, EG exhibited a diminished behavioral reactivity to 5-HT1 and 5-HT2 agonists as compared to SG. These results demonstrated that acute administration of ethanol on GD 8 induced long-lasting changes in the functioning of central serotonergic systems.


Specific and nonspecific effects of ethanol vapor on plasma corticosterone in mice.

The intent of this study was to determine whether chronic ethanol (EtOH) vapor inhalation, with or without adjunct pyrazole (PYR) administration, was stressful in mice, as defined by increases in plasma corticosterone (CORT) concentration. Mice were randomly assigned to groups differentiated both on the basis of EtOH vapor exposure and the presence or absence of PYR administration. Blood samples for blood EtOH concentration (BEC) and plasma CORT concentration were obtained from mice after 72-96 hours of treatment. Mice were sacrificed after 96 hours of treatment and body and adrenal weight determined. BEC was significantly higher in PYR-treated animals and animals treated with the higher EtOH vapor concentration. Plasma CORT was elevated in proportion to BEC; however, other nonspecific stresses, in particular that of PYR administration, also elevated plasma CORT. Nonspecific stresses associated with this protocol may reduce the generality of these observations. Nevertheless, the high correlation between BEC and plasma CORT concentration in the PYR groups indicates that, with suitable control groups, the PYR-EtOH vapor inhalation approach is viable for studies concerned with EtOH effects on hypothalamic-anterior pituitary-adrenocortical function.


Actions of ethanol and acetate on rat cortical neurons: ethanol/adenosine interactions.

Recent studies have suggested that ethanol may exert some of its central depressant actions by increasing the extracellular levels of adenosine in the brain. Ethanol can inhibit the cellular uptake of adenosine, thus increasing its extracellular concentration. After ethanol metabolism by the liver, blood acetate levels are elevated and acetate metabolism in the brain could also lead to the production of adenosine. Rat cerebral cortical cup release experiments failed to reveal any elevation in the extracellular levels of either adenosine or inosine following the intraperitoneal (IP) administration of ethanol (1.5 g/kg) or acetate (2 g/kg). IP-administered ethanol (0.5 and 1.0 g/kg) enhanced the magnitude and duration of the inhibition by iontophoretically applied adenosine of the spontaneous firing of rat cerebrocortical neurons; an action which would be consistent with the block of adenosine uptake. Acetate, applied iontophoretically, depressed the spontaneous firing of 63% of the cerebrocortical neurons tested. 8-p-Sulphophenyltheophylline, an adenosine antagonist, was ineffective at blocking these inhibitions, indicating that adenosine generation is unlikely to have played a major role in the acetate-evoked depression of cerebral cortical neurons.


Ethanol-reinforced responding of naive rhesus monkeys: acquisition without induction procedures.

Rodents will typically consume greater amounts of low concentration ethanol (1-6%) than water. However, few primate oral self-administration studies have examined low ethanol concentrations. Additionally, there is a scarcity of data showing ethanol-maintained behavior without using induction procedures in either rats or primates. In this study, 14, free-feeding, naive, adult, male rhesus monkeys were given access to a 2% (w/v) ethanol solution and vehicle (tap water) during daily 3-hour sessions. Water was freely available between sessions. Liquids were available under a concurrent fixed-ratio four reinforcement schedule; thus, four responses (mouth-spout contacts) on either spout were immediately followed by the delivery of approximately 0.65 ml of liquid. In phase 1, tap water was available from both spouts. In phase 2, vehicle and a 2% ethanol solution were concurrently available. The 2% ethanol solution maintained considerably higher response rates than vehicle for 12 of 14 monkeys. In phase 3, food intake was limited. During this phase, the 2% ethanol solution maintained significantly higher response rates than vehicle for all monkeys. Additionally, during phase 3, ethanol intakes were greater than those in phase 2 for all monkeys. Central drug effects and taste factors are discussed. These results demonstrate that ethanol will serve as a reinforcer for naive rhesus monkeys in the absence of induction procedures.


A review of the management of 15 cases of aneurysms of the posterior cerebral artery.

The presenting features of 15 cases of posterior cerebral artery aneurysm are discussed. The use of the axial radiographic view in determining the anatomy of these aneurysms is highlighted. Ten out of 15 patients underwent surgery. In three patients the aneurysm was approached by the transzygomatic route, in six via the subtemporal route and in one using the pterional approach. There was no operative mortality. Nine out of 10 patients made good long-term recoveries following surgery, one patient remains moderately disabled. Three out of five patients in the non-surgical group made a good recovery. The advantages and disadvantages of the various operative approaches are discussed with particular reference to ease of access, brain retraction and adequate exposure of the aneurysm. It was possible to clip the aneurysm and spare the parent vessel in all three cases using the transzygomatic approach, but this was possible in only one of the remaining cases.


Management strategies in tuberculous atlanto-axial dislocation.

Tuberculous atlanto-axial dislocation is an uncommon disease. Five of six patients with tuberculous atlanto-axial dislocation were successfully managed using different strategies. The advantages and disadvantages of these different protocols and their appropriateness in a particular clinical situation are discussed.


Epileptogenic anaplastic astrocytoma imaged only by T2-weighted magnetic resonance studies: clinical and surgical implications.

The case of a 28-year-old woman who presented with focal sensory seizures and later developed mild sensory loss in the face and hand is described. An EEG, two contrast-enhanced CT and non-enhanced T1-weighted magnetic resonance (MR) scans were normal, but T2-weighted MR scans revealed a lesion measuring 3 x 2 cm in the mid-rolandic region. This lesion did not enlarge over a 6-month period. Resection of the abnormal gyrus was guided by electrocorticography and histology revealed an anaplastic astrocytoma. Although there was resolution of the facio-digital sensory loss postoperatively the frequency and pattern of the partial sensory seizures was unchanged. The neuroradiological and histological findings in this case highlight the difficulties concerning the indications for surgical intervention in adult patients who present with epilepsy and have lesions visualized only on magnetic resonance imagery.


The formation of stable acetaldehyde-hemoglobin adducts in a red blood cell model.

The formation of stable hemoglobin adducts was examined (in the absence of an added reducing agent) in metabolizing red blood cells (RBCs) exposed to micromolar concentrations of acetaldehyde for up to 48 hours in vitro. The rapid disappearance of acetaldehyde due to oxidation by RBC aldehyde dehydrogenase was prevented by pretreating the cells with the inhibitor cyanamide. The RBCs remained viable for 48 hours (37 degrees C) as determined by cell hemolysis and glycolytic activity. [14C]acetaldehyde-modified hemoglobin was assessed in untreated and in cyanamide-pretreated cells. In untreated cells, after 3 hours of exposure to 50 and 200 nmol/ml of [14C]acetaldehyde, the molar ratios of acetaldehyde to hemoglobin were 0.00069 and 0.0038, respectively; [14C]acetaldehyde concentrations decreased to less than 4% of the initial levels within 3 hours. In cyanamide-pretreated RBCs, the molar ratios of acetaldehyde bound to hemoglobin ranged from 0.0013 after 3 hours of exposure to 20 nmol/ml [14C]acetaldehyde up to 0.039 after 48 hours of exposure to 200 nmol/ml [14C]acetaldehyde. Following tryptic digestion of [14C]acetaldehyde-hemoglobin and separation of peptides by high-performance liquid chromatography, significant incorporation of [14C]acetaldehyde was observed in nine peptides. Modifications of the labeled peptides remain to be characterized.


Stereotactic brachytherapy for malignant glioma using a relocatable frame.

Interstitial brachytherapy for recurrent gliomas normally necessitates the invasive application of a stereotactic frame by screw-fixation which must be kept on for several hours. The use of a relocatable stereotactic frame offers many advantages over conventional systems. We present our experience in 18 patients and verify that the frame used is accurate, comfortable, well tolerated and associated with no major disadvantages.


Outcome prediction in early management of severe head injury: an experience in Malaysia.

The outcome of 109 patients with severe head injury was studied in relation to clinical and computed tomographic (CT) criteria on admission, after resuscitation. Age, Glasgow Coma Score (GCS) and state of pupils strongly correlated with outcome. The presence of hypothalamic disturbances, hypoxia and hypotension were associated with an adverse outcome. The CT indicators associated with poor outcome were perimesencephalic cistern (PMC) obliteration, subarachnoid haemorrhage, diffuse axonal injury and acute subdural haematoma. The prognostic value of midline shift and mass effect were influenced by concomitant presence of diffuse brain injury. For the subset of patients aged < 20 years, with GCS 6-8 and patent PMC (n = 21), 71.4% correct predictions were made for a good outcome. For the subset of patients aged > 20 years, with GCS 3-5 and partial or complete obliteration of PMC (n = 28), 89.3% correct predictions were made for a poor outcome.


Alcohol inhibition of NMDA-stimulated catecholamine efflux in aging brain.

The influence of aging on the ability of ethanol to inhibit N-methyl-D-aspartate-stimulated catecholamine overflow in rat brain was examined. Alcohol effects on N-methyl-D-aspartate stimulated [3H]norepinephrine or [3H]dopamine overflow from the cortex, hippocampus, and striatum of aged (24-28 months) middle aged (12-14 months), and young (3-5 months) rats were examined. N-methyl-D-aspartate (500 microM) stimulated catecholamine overflow in all brain regions, with aged rats showing declines in overflow of 33% in the hippocampus and 41% in the striatum. Alcohol (30-200 mM) produced a concentration-dependent inhibition of overflow at all ages and brain regions tested. The IC50 for alcohol inhibition of NMDA-stimulated catecholamine release was not significantly different in aged brain or across brain regions. These results indicate that alcohol's ability to inhibit NMDA-stimulated catecholamine release is not significantly altered with aging.


The use of a computer-based image link system to assist inter-hospital referrals.

Early CT scanning leads to the early diagnosis and referral of intracranial lesions, particularly in head injuries. Such early scanning is more feasible with the advent of CT scanners in most peripheral hospitals. However, the neurosurgical service in most countries remains regional with limited bed capacity and involves a potentially hazardous inter-hospital transfer of critically ill patients. We investigated the value and reliability of new information technology in the management of emergency neurosurgical referrals in the Mersey region. One hundred and ninety-nine emergency referrals were studied. In 147 referrals the patient was scanned in the referring hospital and the images were transmitted immediately to the neurosurgical unit. Of these, 51 (34.7%) patients were transferred immediately, 14 (9.5%) the following day and 11 (7.5%) electively. Of those patients who were transferred immediately, 48 (94.1%) underwent emergency surgery. Seventy-one (48.3%) patients were not transferred due to diffuse head injury (40), a cerebral infarct (15), poor grade subarachnoid haemorrhage (10) and normal scans (6). Another 52 patients were transferred to the unit without image transfer, of whom 12 (23.1%) underwent emergency surgery, 17 (32.7%) went back to the referring hospital within 24 h, 17 (32.7%) were electively operated and six (11.5%) died. Comparison of 100 original CT scan films with the corresponding transmitted images showed no significant difference in the quality of the image, diagnosis or clinical decision. Image transfer together with the clinical history has reduced potentially hazardous inter-hospital transfer of patients (p < 0.001). It is reliable, fast, cheap and leads to considerable economic savings.


Effect of dexfenfluramine on alcohol intake in alcohol-preferring "P" rats.

The intake of alcohol, in 2-h daily sessions, by the preferring (P) line of rats was reduced in a dose-related manner by acute subcutaneous (SC) administration of dexfenfluramine (DFEN). Ad lib intake of alcohol was reduced by chronic SC administration of DFEN. The effective doses and magnitude of effects of DFEN on alcohol intake are comparable to those previously reported for DFEN anorexia. Because DFEN anorexia is related to increased brain serotonin (5HT) activity, its effect on alcohol consumption may also be via 5HT.


Primary cerebral lymphoma: report of 24 patients and review of the literature.

A retrospective study of 24 patients with primary non-Hodgkin's cerebral lymphoma (non-immunocompromised) is presented. All patients were seen at the Royal Preston Hospital, Lancashire between 1976 and 1991. Fifteen patients were over the age of 50 years (range 27-84). The commonest clinical presentation, seen in 16 patients was of an expanding space-occupying lesion. The diagnosis was suspected from the radiological findings but confirmation in every case was by histological examination of biopsy or necropsy material. The tumours were treated either by surgical excision or by biopsy and radiotherapy. Chemotherapy was given in two patients. Despite these measures the mean survival time was 3.6 months. The clinical radiological and pathological features of these tumours are highlighted with particular emphasis on the use of stereotactic biopsy, immunohistochemistry and chemotherapy in diagnosis and treatment.


Solitary cervical lymphoma presenting as a neurofibroma.

A patient is described who presented with cervical cord compression. The imaging and operative findings were typical of a neurofibroma of the right third cervical root. However, histological studies confirmed that the tumour was a B-cell lymphoma. Isolated spinal lymphomas can therefore occur and may present as nerve sheath tumours.


Recurrent craniopharyngioma in the posterior fossa.

Craniopharyngioma situated in the posterior fossa is rare. It has been unclear whether such lesions arise primarily in this site or represent direct spread from a suprasellar focus. We report a patient with recurrent craniopharyngioma which had extended into the posterior fossa as far as the cerebellopontine angle through the tentorial hiatus with evidence that it had done so directly. A further separate lesion of similar signal characteristics on MRI scan, lying in the prepontine area, probably represented a seeding from the suprasellar area.


Brain abscess caused by Cladosporium trichoides.

Brain abscess caused by the fungus Cladosporium trichoides is rare. Only 20 cases of brain abscess caused by this fungus are reported in the literature. We report a case of brain abscess caused by Cladosporium trichoides in a healthy adult male. The relevant literature on this subject is reviewed.


Death from chronic tonsillar herniation in a patient with lumboperitoneal shunt and Crouzon's disease.

A 2.5-year-old girl with Crouzon's disease, hydrocephalus, and a lumboperitoneal shunt died as a result of chronic tonsillar herniation (acquired Chiari 'malformation'). The possible synergistic role of the cranial dysmorphism and the lumboperitoneal shunt in the development of this anomaly is discussed. The literature is reviewed and it is argued that if hydrocephalus occurs in infants in whom cephalocranial disproportion is likely to develop, then it is inadvisable to insert a lumboperitoneal shunt.


Cranioectodermal dysplasia with sagittal craniosynostosis (Sensenbrenner's syndrome): case report and review of the literature.

We report the clinical features and neurosurgical management of a 9-month-old girl with cranioectodermal dysplasia and scaphocephaly. The technique of surgical correction is discussed together with details of the pre-operative investigations. The importance of early referral to an experienced geneticist is emphasized.


Osteoptysis: a complication of cervical spine surgery.

The case is described of a lady who developed dysphagia and dysphonia misdiagnosed first as hysteria, then as myasthenia gravis, one year after a Cloward's operation for cervical disc disease. After a bout of coughing the bony dowel was expelled and the correct diagnosis was made.