Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone,and in combination with Ro15-1788 (flumazenil)

Recent work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine (BDZ) agonist, decreases ethanol (ETOH) self-administration in rodents under fluid deprivation conditions. The present study further examined the effects of Ro15-4513 (2.5 and 5.0 mg/kg) alone and in combination with Ro15-1788, (flumazenil) (8.0 and 16.0 mg/kg), a BDZ receptor antagonist on ETOH self-administration in freely feeding and drinking rats. Animals were trained to consume ETOH (11% v/v) using a limited access procedure. Measurements were taken at 10- and 60-min intervals. Ro15-4513 (2.5 and 5.0 mg/kg) markedly attenuated ETOH consumption at both intervals. The antagonistic actions of Ro15-4513 were completely blocked by the higher dose of flumazenil at both intervals; the lower dose failed to antagonize the Ro15-4513-induced reduction of ETOH intake. When flumazenil was given alone, both doses reduced ETOH self-administration at 60 min; although the magnitude of the antagonism was comparable to that of Ro15-4513 only with the highest does of flumazenil (16.0 mg/kg). Neither Ro15-4513 nor flumazenil alone or in combination significantly altered water intake at any of the tested doses. Rats pretreated with Ro15-4513 showed a substantial reduction in blood ethanol concentration (BEC) compared with the Tween-80 vehicle condition at the 10-min interval. However, the BEC of animals given Ro15-4513 in combination with flumazenil were similar to rats given Tween-80 vehicle. The present study extends our previous research by demonstrating that Ro15-4513 and flumazenil attenuate ETOH self-administration in non-food or water deprived rats. These studies suggest that the suppressant effects of Ro15-4513 and flumazenil on ETOH self-administration are associated with actions at the BDZ site of the GABA_A receptor complex. These data are discussed in relation to the possible mechanism(s) by which Ro-15-4513 and flumazenil exert their antagonism on ETOH self-administration.Portions of this work were presented at the Annual Meeting of the Research Society on Alcoholism under the symposium entitled GABA/BDZ Receptor Update, Marco Island, FL, June 10, 1991.We would like to dedicate this paper to the late Dr. Richard G. Lister, a friend, teacher, colleague and exceptional scientist who contributed substantially to the area of alcohol abuse and alcoholism. Over the past years, Dr. Lister investigated the interactions of alcohol with inverse benzodiazepine agonists and benzodiazepine receptor antagonists. His seminal and more recent papers played an important role in delineating the GABA benzodiazepine systems in the neurobehavioral actions of alcohol. Richard, we will miss you.     

Selective incorporation of111In-labeled PHOTOFRIN™ by glioma tissuein vivo

The use of PHOTOFRIN for photodynamic therapy of human gliomas has been studied by i.v. administration and laser photosensitization. Defining the uptake of PHOTOFRIN in the patient's tumor in comparison with the surrounding normal brain tissue is highly desirable for patient selection and study ofin vivo kinetics. We utilized a non-invasive approach to the detection of PHOTOFRIN uptake in brain tumors with¹¹¹In-oxine radiolabeled PHOTOFRIN and external imaging and quantitation using a gamma camera. Biodistribution of¹¹¹In-labeled PHOTOFRIN in 13 organs was determined in four dogs and 15 mice with gliomas.^99mTc-DTPA was used as a control for nonspecific uptake. The greatest concentration of¹¹¹In-PHOTOFRIN in the brain tumor occurred at 24 hours post i.v. administration. The brain tumor PHOTOFRIN uptake was seven times greater than that of normal brain. The decreased blood background at 72 hours made this the optimum time for imaging. Specific tumor tissue uptake of¹¹¹In-PHOTOFRIN occurred, well beyond that resulting from blood-brain-barrier (BBB) breakdown.     

An analysis of the outcome of microsurgical and laparoscopic adhesiolysis for infertility

We evaluated 81 women with adnexal adhesions and no male factorwho underwent microsurgical (n = 59) and laparoscopic (n = 22)adhesiolysis for infertility. The cumulative conception ratesfor all 81 patients at 12 and 24 months were 41 and 44% respectively.The impact of the following variables on cumulative conceptionrates for all patients was examined: age, duration of infertility,type of infertility, ovulatory status, presence and stage ofendometriosis, adhesion grade, adnexal status (bilateral orunilateral disease, unilateral tubal absence), history of previoussurgery, history of pelvic inflammatory disease and treatmentmodality (microsurgical versus laparoscopic). The results ofindependent comparisons of subgroups within each of these variablesmay be biased because of the interrelationships between thevariables. To overcome this problem, a stepwise Cox's proportionalhazards regression analysis was employed. Our analysis showedthat the single most significant variable influencing the cumulativeconception rates was the duration of infertility (P < 0.005).For every additional year of infertility, the probability ofpregnancy after adhesiolysis (microsurgical or laparoscopic)was reduced by 20%. Cumulative conception rates at 12 and 24months after microsurgical adhesiolysis were 36 and 40% respectively,while after laparoscopic adhesiolysis they were 57% at 12 and24 months. When imbalances were adjusted between the two treatmentgroups, there was no statistically significant difference betweenthe cumulative conception rates for microsurgical and laparoscopicadhesiolysis.     

A better incision for pectus excavatum repair: avoiding the keloid triangle

The most common approach to the pepair of pectus excavatum and pectus carinatum deformities is via a central transverse submammary incision. The subsequent suprasternal scar is conspicuous and prone to hypertrophic and keloid scarring. To avoid the keloid triangle and to produce a less noticeable scar, we have utilized bilateral inframammary incisions for repairs of five female and two male patients with pectus defects. This approach provides excellent access for cartilage resection, sternotomy, and sternal tupport without increasing opearative time or compromising operative exposure. On follow-up for up to 25 months, all patients have had excellent cosmetic and functional results. Chest wall configuration and stability, wound healing, and scar formation have all been without complication. No keloid or hypertrophic scars have developed. To date, there has been no recurrence of pectus defects. We believe bilateral inframammary incisions are a superior approach for pectus repairs by enchancing cosmesis with less noticeable scars and fewer hypertropic and keloid scars, all without compromising operative exposure or increasing operative time.     

A series of articles on the usefulness and uselessness of physical diagnostics; comment

The sensitivity, specificity and reproducibility (especially the interassessor variation) of many physical diagnostic tests taught in the medical curricula appear not to have been established. Nevertheless, many of these tests are mentioned as end terms in the General plan 1994 medical education. A series of articles in this journal will be concerned with tests from physical diagnostics, with reference to usefulness and uselessness: sensitivity, specificity and reproducibility.     

Iris crystals in chronic uveitis.

AIMS: To analyse the unusual physical sign of iris crystals occurring in patients with uveitis. METHODS: Demographic details and clinical features were documented in 24 patients with chronic uveitis and iris crystals. Plasma immunoglobulin subclasses were measured, and a histopathological review of iridectomy specimens from 33 patients with chronic uveitis was also undertaken. RESULTS: The mean age of patients was 38 years, with a slight preponderance of females. 17 patients had Fuchs' heterochromic cyclitis although a number of other uveitis entities were represented. There was no correlation between severity of clinical signs and presence of iris crystals. Over a mean follow up period of 15 months no significant change in the number, size, or position of the crystals was seen except in four patients who underwent intraocular surgery. Only three patients had raised plasma IgG1. The review of the histology of iridectomy specimens failed to show evidence of Russell body formation in any patient. CONCLUSIONS: Iris crystals appear to be rare but may be underreported as they are small and can easily be missed. They are likely to be associated with disease processes in which there is active immunoglobulin production within the anterior chamber, such as Fuchs' heterochromic cyclitis.     

Prevalence of known diabetes in different ethnic groups in inner urban South Auckland.

AIM: To describe the prevalence of known diabetes in different ethnic groups in inner urban South Auckland. METHOD: Cross-sectional household survey of 27,419 residences in the multi-ethnic community of inner urban South Auckland 1992-1995. RESULTS: Responses from 91.3% of households included 90,477 residents, 1862 (2.1%) of whom had diabetes. The all-age adjusted prevalence of known diabetes was 1.9 (1.7-2.0)% in Europeans, 5.2 (4.9-5.5)% among Maori, 4.0 (3.8-4.2)% among Pacific Islands people and 4.3 (3.8-4.9) 2% among other ethnic groups. There was heterogeneity within the Pacific Islands and "other" groups with the highest prevalence present in South Asians, Niueans and those from the Middle East. A non-significantly lower prevalence of diabetes was found among Chinese respondents. These data predicted 85,581 people with known diabetes in New Zealand in 1996. The greatest growth, due to demographic changes alone (i.e. without taking account of the known increased incidence of diabetes), was predicted among non-European, non-Polynesian groups, with a 181% increase in numbers with diabetes since 1991. CONCLUSION: Demographic pressures have been sufficient to increase the number with known diabetes by 13.9% in five years. This would have underestimated the epidemic in view of the observed growth in the age-adjusted incidence of diabetes in overseas studies.     

In vivo modulation of vincristine-induced neurotoxicity in Lymnaea stagnalis, by the ACTH(4–9)analogue Org 2766

Summary The use of the cytostatic agent vincristine (VCR) is limited by the occurrence of peripheral neuropathy. This side-effect is probably caused by interference with axonal microtubules. VCR depolymerizes microtubules and reacts with tubulin to form paracrystals. The potential of a neurotrophic ACTH_(4–9) analogue, Org 2766, to counteract peripheral neuropathy caused by cytostatic agents is being investigated. In the present ultrastructural study, modulatory effects of Org 2766 on VCR-induced neurotoxicity were studied in vivo in neurons of the pond snail Lymnaea stagnalis, which has been shown previously to be a suitable test system to investigate neurotoxic side-effects of cytostatic agents. 24 h after treatment with VCR (25 M), 68.4 ± 34.7 paracrystals were counted per cross-section of the cerebral commissure and the number of microtubules in the axons had been lowered to 46% of the control level. After a survival period of two weeks all paracrystals had disappeared. By that time, no recovery of the axonal microtubular system could be observed. However, post-treatment with Org 2766 (10^–6 M) on day 6 after VCR treatment had induced a significant increase in the number of microtubules (+ 55%) on day 7. This beneficial effect lasted for the rest of the experimental period (14 days). These results suggest that post-treatment with Org 2766, i.e. after VCR clearance, can induce long-lasting beneficial effects on VCR-induced neurotoxicity in vivo.     

A high-yield and simplified procedure for the synthesis of α-[C]Methyl-l-tryptophan

Alpha-[¹¹C]methyl-l-tryptophan (AMT) has been synthesized by stereoselective methylation with [¹¹C]methyl iodide of the lithium-enolate generated by treating dimethyl 2(S),3a(R),8a(S)-(+)-hexahydro-8(phenylsulfonyl) pyrrolo[2,3-b]indole-1,2-dicarboxylate (2) with lithium diisopropyl amide (LDA) at −55 °C, followed by ring opening using trifluoroacetic acid and alkaline hydrolysis of the protecting groups. The crude product was purified by a simple reverse-phase C-18 Sep-Pak procedure. The purified product was isolated with an average radiochemical yield of 53 ± 12% (decay corrected) in 30–35 min from [¹¹C]methyl iodide. At end of synthesis (EOS), 138 ± 35 mCi (n = 24) of product was collected with a specific activity of ca. 1–1.3 Ci/μmol (EOS) (4–5 Ci/μmol @ EOB) starting from 1.5 Ci (EOB) of [¹¹C]CO₂.