Harmonization of practices between radiotherapy centres in the Nord and Pas-de-Calais regions (France): A three-year evaluation.

PURPOSE: The delineation of volumes of interest can be a source of significant interobserver variability. The purpose of this study was to improve the homogeneity of delineation between oncologist-radiotherapists in the territorial departments of Nord and Pas-de-Calais (France) through discussions of clinical cases and the adoption of common published reference documents. MATERIALS AND METHODS: All eleven radiotherapy centres in the Nord and Pas-de-Calais departments of France participated. The localizations assessed to date included prostate, head and neck, breast and brain cancers. For each localization, the junior or senior physician(s) in charge of pathology delineated the volumes of interest according to their usual practices. Validated indices, including the Dice similarity coefficient, were used to quantify the delineation differences. The anonymized results were presented at two to three annual meetings. A second delineation of the clinical cases was then carried out to quantify homogenization. An evaluation of dosimetry practices was also conducted for prostate cancer. Wilcoxon assay matched data were used. RESULTS: Our work showed either satisfactory delineation concordance after the initial assessment or improved delineation concordance. For prostate cancer, the Dice similarity coefficient values were greater than 0.6 initially in two of the three clinical cases. For head and neck cancers, a statistically significant improvement was observed for only one of the clinical target volumes. More than half of the Dice similarity coefficient values were greater than 0.6 in the first comparison. The study of clinical cases of breast cancer allowed a homogenization of the delineation of five of the six lymph node clinical target volumes. The dosimetry study of prostate cancer allowed for a homogenization of practices. CONCLUSION: This work makes it possible to harmonize the delineation practices around validated standards. An extension to the entire Hauts-de-France region is planned.

Near-Infrared Spectroscopy and Anharmonic Theory of Protonated Water Clusters: Higher Elevations in the Hydrogen Bonding Landscape.

Near-infrared spectroscopy measurements are presented for protonated water clusters, H+(H2O) n, in the size range of n = 1-8. Clusters are produced in a pulsed-discharge supersonic expansion, mass selected, and studied with infrared laser photodissociation spectroscopy in the regions of 3600-4550 and 4850-7350 cm-1. Although there is some variation with cluster size, the main features of these spectra are a broad absorption near 5300 cm-1, a sharp doublet near 7200 cm-1, as well as a structured absorption near 4100 cm-1 for n ≥ 2. The vibrational patterns measured for the hydronium, Zundel, and Eigen ions are compared to those predicted by different forms of anharmonic theory. Second-order vibrational perturbation theory (VPT2) and a local mode treatment of the OH stretches both capture key aspects of the spectra but suffer understandable deficiencies in the quantitative description of band positions and intensities.

The DNA-bending protein HMG-1 enhances progesterone receptor binding to its target DNA sequences.

Steroid hormone receptors are ligand-dependent transcriptional activators that exert their effects by binding as dimers to cis-acting DNA sequences termed hormone response elements. When human progesterone receptor (PR), expressed as a full-length protein in a baculovirus system, was purified to homogeneity, it retained its ability to bind hormonal ligand and to dimerize but exhibited a dramatic loss in DNA binding activity for specific progesterone response elements (PREs). Addition of nuclear extracts from several cellular sources restored DNA binding activity, suggesting that PR requires a ubiquitous accessory protein for efficient interaction with specific DNA sequences. Here we have demonstrated that the high-mobility-group chromatin protein HMG-1, as a highly purified protein, dramatically enhanced binding of purified PR to PREs in gel mobility shift assays. This effect appeared to be highly selective for HMG-1, since a number of other nonspecific proteins failed to enhance PRE binding. Moreover, HMG-1 was effective when added in stoichiometric amounts with receptor, and it was capable of enhancing the DNA binding of both the A and B amino-terminal variants of PR. The presence of HMG-1 measurably increased the binding affinity of purified PR by 10-fold when a synthetic palindromic PRE was the target DNA. The increase in binding affinity for a partial palindromic PRE present in natural target genes was greater than 10-fold. Coimmunoprecipitation assays using anti-PR or anti-HMG-1 antibodies demonstrated that both PR and HMG-1 are present in the enhanced complex with PRE. HMG-1 protein has two conserved DNA binding domains (A and B), which recognize DNA structure rather than specific sequences. The A- or B-box domain expressed and purified from Escherichia coli independently stimulated the binding of PR to PRE, and the B box was able to functionally substitute for HMG-1 in enhancing PR binding. DNA ligase-mediated ring closure assays demonstrated that both the A and B binding domains mediate DNA flexure. It was also demonstrated in competition binding studies that the intact HMG-1 protein binds to tightly curved covalently closed or relaxed DNA sequences in preference to the same sequence in linear form. The finding that enhanced PRE binding was intrinsic to the HMG-1 box, combined with the demonstration that HMG-1 or its DNA binding boxes can flex DNA, suggests that HMG-1 facilitates the binding of PR by inducing a structural change in the target DNA.

Humanitarianism in surgery.

PURPOSE: Humanitarianism is by definition a moral of kindness, benevolence and sympathy extended to all human beings. In our view as surgeons working in underserved countries, humanitarianism means performing the best operation in the best possible circumstances with high income country (HIC) results and training in-country surgeons to do the same. Hernia Repair for the Underserved (HRFU), a not for profit organization, is developing a long term public health initiative for hernia surgery in Western Hemisphere countries. We report the progress of HRFUs methods to render humanitarian care. METHODS: In a collaborative effort, Creighton University and the Institute for Latin American Concern developed an outpatient surgery site for hernia surgery in Santiago, Dominican Republic. Based on this experience, we developed a sustainable care model by recruiting American and European Hernia Society expert surgeons, staff members they recommended, building relationships with local and industry partners, and selecting local surgeons to be trained in mesh hernioplasty. HRFU then extended the care model to other Western Hemisphere countries. RESULTS: Between 2004 and 2015, the HRFU elective hernia morbidity and mortality rates for 2052 hernia operations were 0.7 and 0%, respectively. This is consistent with outcomes from HICs and confirms the feasibility of a public health initiative based on the principles of the Preferential Option for the Poor. CONCLUSIONS: HRFU has recorded HIC morbidity and mortality rates for hernia surgery in low and middle income countries and has initiated a new surgical training model for sustainability of effect.

Effects of single cyclophosphamide doses on the kinetics of thoracic duct lymph and blood leukocytes in calves.

After 5 or 20 mg cyclophosphamide per kg body weight, given once i.v., the output in thoracic duct lymph of small and large lymphoid cells, cells incorporating [3H]lymidine in vitro, mitotic cells, pyknotic cells, and/or the number of lymphocytes and neutrophils in peripheral blood were measured in six calves. The median grain count of labeled cells and the DNA content of pyknotic nucleic were determined. After both doses there was an exponential decrease and subsequent recovery of the median grain count. The larger dose caused a temporary cessation of lymphoid cell division, reduced the output of nondividing small lymphoid cells, and probably imparied proliferation of neutrophil precursors. The results suggest that increased cell production during recovery was due to changes in the growth fraction and that feedback mechanisms acting on G0-G1 cells controled the proliferation of lymphoid cells.

Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor.

Mounting evidence indicates that extracellular factors exert proliferative effects on neurogenetic precursors in vivo. Recently we found that systemic levels of basic fibroblast growth factor (bFGF) regulate neurogenesis in the brain of newborn rats, with factors apparently crossing the blood-brain barrier (BBB) to stimulate mitosis. To determine whether peripheral bFGF affects proliferation during adulthood, we focused on regions in which neurogenesis persists into maturity, the hippocampus and the forebrain subventricular zone (SVZ). In postnatal day 1 (P1) rats, 8 hr after subcutaneous injection (5 ng/gm body weight), bFGF increased [(3)H]thymidine incorporation 70% in hippocampal and SVZ homogenates and elicited twofold increases in mitotic nuclei in the dentate gyrus and the dorsolateral SVZ, detected by bromodeoxyuridine immunohistochemistry. Because approximately 25% of proliferating hippocampal cells stimulated in vivo expressed neuronal traits in culture, bFGF-induced mitosis may reflect increased neurogenesis. bFGF effects were not restricted to the perinatal period; hippocampal DNA synthesis was stimulated by peripheral factor in older animals (P7-P21), indicating the persistence of bFGF-responsive cells and activity of peripheral bFGF into late development. To begin defining underlying mechanisms, pharmacokinetic studies were performed in P28 rats; bFGF transferred from plasma to CSF rapidly, levels rising in both compartments in parallel, indicating that peripheral factor crosses the BBB during maturity. Consequently, we tested bFGF in adults; peripheral bFGF increased the number of mitotic nuclei threefold in the SVZ and olfactory tract, regions exhibiting persistent neurogenesis. Our observations suggest that bFGF regulates ongoing neurogenesis via a unique, endocrine-like pathway, potentially coordinating neuron number and body growth, and potentially providing new approaches for treating damaged brain during development and adulthood.

High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series.

PURPOSE: The impact of treatment options on survival and late neurologic toxicity was investigated in a series of patients with primary cerebral lymphoma (PCL) and no known cause of immunosuppression. PATIENTS AND METHODS: Prognostic factors for survival and treatment-induced late neurotoxicity were investigated in a retrospective series of 226 patients with PCL. RESULTS: With a median follow-up of 76 months, the median overall survival was 16 months and 5-year survival was 19%. In a univariate analysis, age greater than 60 years, performance status, CSF protein level greater than 0.6 g/L, involvement of corpus callosum or subcortical grey structures, detectable lymphoma cells in CSF, increased serum lactate dehydrogenase (LDH), but not histological subtype, were significantly correlated with a poor survival. Treatment with chemotherapy versus radiotherapy alone (P = .05), high-dose methotrexate (HDMTX; P = .0007), and cytarabine (P = .04) correlated with a better survival in univariate analysis. Using the Cox model, age, performance status, and CSF protein were independently correlated with survival. After adjustment of these factors, treatment with an HDMTX-containing regimen remained the only treatment-related factor independently correlated with survival (P = .01). The projected incidence of treatment-induced late neurotoxicity was 26% at 6 years in this series, with a median survival from the diagnosis of late neurotoxicity of 12 months. Treatment with radiotherapy followed by chemotherapy was the only parameter correlated with late neurotoxicity in multivariate analysis (relative risk, 11.5; P = .0007). CONCLUSION: Patients with PCL treated with regimens that included HDMTX followed by radiotherapy have an improved survival, but not a higher risk of late neurotoxicity as compared with other treatment modalities in this series.

Radiation therapy in the conservative treatment of carcinoma of the anal canal.

PURPOSE: Radiotherapy is the standard treatment of anal canal carcinoma. We retrospectively analyzed our experience with 108 patients. Special attention was given in evaluating 51 patients who received concomitant chemotherapy with 5-FU-CDDP. METHODS AND MATERIALS: From January 1980 to December 1989, 108 patients with anal canal carcinoma were treated with exclusive radiotherapy at the Centre Hospitalier Lyon Sud. There were 11 men and 97 women, mean age was 65 years (30-86). Histologic types were 94 epidermoid carcinomas, 13 basaloid carcinomas, and one adenocarcinoma. The TNM classification (UICC 87) was: 16 T1 (14.8%), 53 T2 (49%), 33 T3 (39.5%), six T4 (5.5%), 77 N0 (71.3%), 20 N1 (18.5%), nine N2 (8.3%) and two N3 (1.8%). Papillon's radiotherapy technique with a Cobalt direct perineal field was used in 82 patients. Ninety-six patients were treated with an interstitial 192Ir implant with a mean delay of 55 days after the end of the radiotherapy. In 59 patients at least one course of either 5-FU-mitomycin (8) or 5-FU-CDDP was added with at least one course concomitantly to the radiotherapy in 53 patients. RESULTS: A complete response in 104/108 patients (96%) was obtained 2 months after the brachytherapy. A locoregional relapse (local and/or pelvic failure) was seen in 18 patients (16.6%) and inguinal node relapse in nine (8.3%). Eight patients with locoregional recurrence and five with inguinal relapse were salvaged. A systemic failure occurred in six (5.5%) patients. Twenty-nine patients died, 16 of progressive disease. One patient died of treatment related toxicity. The overall 5-year survival was 64% +/- 6 and specific survival 72% +/- 8. None of the patient parameters was found to be statistically significant but there was a trend toward longer 5-year survival in T1-T2 patients and in those with well or moderately differentiated tumors. Noteworthy are the same survival rates for N0 and N1-N3 patients (65 vs. 62%). The objective response and the locoregional failure rates were similar in the patients treated with or without chemotherapy. The difference did not reach statistical significance though it was important for the following parameters: overall survival rates for T1-T2 with and without chemotherapy (94 vs. 61%) and for N1-3 patients (73% vs. 27%). The main prognostic factors in this series were differentiation (5-year overall survival with chemotherapy 95% vs. 27% without chemotherapy p = 0.02) and the response at 3 months after treatment initiation, before brachytherapy implant (5-year overall survival for complete responders and "very good responders" 71% vs. 34% in partial responders p = 0.002). The complications rate was acceptable (Grade III 9%, Grade II 14%). Anal preservation was possible in 85% of the patients (92/108). Nine abdominoperineal resection were performed for recurrence and seven for severe necrosis. The T3-T4 group abdomino perineal resection was 23% while it was 9.2% of the T1-T2 group. CONCLUSION: We confirm that exclusive radiotherapy is the treatment of choice for epidermoid carcinomas of the anal canal. The role of chemotherapy is still unclear.

Medulloblastoma in adults: survival and prognostic factors.

The authors report a series of 30 adults with medulloblastoma treated after surgery between 1975 and 1990. Half the patients presented a classical medulloblastoma and the other half presented desmoplastic medulloblastoma. Brainstem infiltration was noted in 3 patients, cerebellar peduncle infiltration in 6 cases and 4 patients had cerebrospinal fluid (CSF) involvement. Tumor resection was achieved in all patients except 1, and in 5 surgery was incomplete. All patients but 2 received postoperative cerebral radiotherapy. Six patients did not receive chemotherapy before radiotherapy, 7 patients received CCNU-Vincristine concomitantly with and after irradiation, 1 patient was given a CHOP regimen, and the remaining 16 patients received the 8 drugs in a 1-day (8/1) regimen before irradiation. The median follow-up time was 104 months. The 5- and 10-year overall survival rates were 58.5% and 41%, respectively. Two toxic deaths occurred under the 8/1 regimen, and no better survival was observed for this group of patients in comparison with those receiving other regimens. Persistence of malignant cells in the CSF, brainstem involvement, cerebellar peduncle infiltration, non-radical surgery and a postoperative performance status (PS) of more than 2 were significantly correlated with an adverse outcome for overall survival in adult patients with medulloblastoma.

Epididymal cystadenomas in von Hippel-Lindau disease.

OBJECTIVES: Epididymal cystadenomas (ECs) are frequently found in association with von Hippel-Lindau disease (VHL), but little has been reported about their sonographic appearance. We review the sonographic appearance of ECs, the relationship of ECs to other manifestations of VHL, and the specific genetic mutations associated with ECs. METHODS: Fifty-six male patients with VHL were examined with scrotal sonography and physical examination as part of a larger screening program for VHL. The head of the epididymis was measured in two planes on sonography and compared with age-matched normal controls. All VHL patients with palpable epididymal abnormalities or enlargement (more than two standard deviations) of the head of the epididymis on ultrasound were considered positive for EC. RESULTS: Thirty of 56 (54%) male patients with VHL demonstrated a unilateral (n = 10; 33%) or bilateral (n = 20; 67%) solid abnormality in the head of the epididymis suggestive of EC. Sonographic appearances ranged from a solid mass with multiple tiny cysts to an almost completely solid mass. The most common appearance was a 15- to 20-mm solid mass with small cystic components. Dilated efferent ductules were seen within the testicle in 7 men, evidently a result of chronic obstruction. There was no association between the clinical subtype of VHL and the presence of ECs (P > 0.10, chi square). Mutations resulting in a truncated gene product were associated with the development of ECs but the association did not reach statistical significance (P = 0.06). CONCLUSIONS: ECs are a common manifestation of VHL in men and exhibit a range of appearances on ultrasound. Sonography can be used to identify ECs and determine the extent of cystic dilation of the rete testes. The benign course of ECs and the usual absence of clinical symptoms favor a conservative approach to their management.

Cerebellar granule cells elaborate neurites before mitosis.

Neuronal birth and neurite outgrowth have been regarded as discrete, sequential stages of development. However, we recently found that sympathetic neuroblasts often elaborate axons before mitosis, in culture [E. Wolf, I.B. Black, E. DiCicco-Bloom, Mitotic neuroblasts determine neuritic patterning of progeny, J. Comp. Neurol. 367 (1996) 623-635] and in vivo [E. Wolf, I.B. Black, E. DiCicco-Bloom, Central and peripheral neuroblasts elaborate neurites prior to division in vivo and in vitro, Soc. Neurosci. Abstr. 21 (1995) 785; E. Wolf, I.B. Black, E. DiCicco-Bloom, Mitotic neuroblasts engage in axonal outgrowth and pathfinding in vivo, Soc. Neurosci. Abstr. 22 (1996) 525]. Here, we report that cerebellar granule cells often divide with heritable neurites in vitro. Therefore, mitotic CNS precursors, in addition to peripheral neuroblasts, simultaneously undergo proliferation and process formation. Potentially, neurites on dividing precursors may allow target fields to influence directly the course of neurogenesis.

Presynaptic input regulates development of beta-adrenergic control of rat brain ornithine decarboxylase: effects of 6-hydroxydopamine or propranolol.

beta-Adrenergic control of ornithine decarboxylase (ODC) activity is exerted only during a critical period in central nervous system development, playing an important role in neurotransmitter modulation of cell replication and differentiation. The current study examines the effects of lesions caused by 6-hydroxydopamine administration to neonatal rats, or of gestational exposure to propranolol, on the subsequent development of the ODC response to beta-adrenergic stimulation elicited by an acute intracisternal challenge with isoproterenol. 6-Hydroxydopamine treatment severely attenuated the ability of isoproterenol to stimulate ODC in the cerebellum, a tissue that shows a postnatal peak of ODC reactivity. In contrast, much smaller effects were seen in the cerebral cortex, which has an earlier (pre/perinatal) peak of ODC, despite the fact that norepinephrine depletion was more persistent in the cortex. On the other hand, blockade of fetal beta-receptors by maternal propranolol infusions resulted in immediate postnatal attenuation of the ODC response in cerebral cortex, but not cerebellum. These data suggest that early exposure of beta-receptors to norepinephrine "programs" the subsequent efficiency of the receptor linkage to ODC during a critical ontogenetic period that occurs prenatally in the cerebral cortex and postnatally in the cerebellum.

[Evaluation of the consequences of signing a written consent on physician-patient relations. Apropos of Huriet's legislation]. / Evaluation des conséquences de la signature d'un consentement écrit sur la relation médecin-malade. A propos de la loi Huriet.

Whenever an innovative treatment or a research protocol is proposed to a patient, the "loi Huriet" requires a written consent from the patient. This is an important change in the field of the interrelation between the doctor and his patient. To evaluate the impact of this written consent we asked 215 patients who have signed a consent form to answer a questionnaire at the end of their radiation treatment. The signature appears as an important event. The majority of the patients (70%) is not shocked by this procedure. In 97% of cases, in spite of this written relation, the patients keep intact their confidence in their doctor. Sometimes this consent form may improve the information given to the patient and it should not be seen as an obstacle for the development of research trials. There are still many problems to be solved as regards the information of the patient and the application of the "loi Huriet".

Alanine-ESR in vivo dosimetry: a feasibility study and possible applications.

A new alanine-ESR dosimeter has been developed at AERIAL in order to study its potential use in radiotherapy. Alanine-ESR results are compared with ion chamber for depth-dose measurements. A good concordance has been found between provisional dosimetry and absorbed dose during high dose rate and intra operative treatments. The results of the experiments indicate that alanine-ESR dosimetry is suited to check dose optimisation routines and seems to be a promising in vivo dosimetry technique.

[Iodine 125 curietherapy of choroidal melanomas. Values of the technique and initial results]. / Curiethérapie à l'iode 125 des mélanomes choroïdiens. Intérêts de la technique et premiers résultats.

PURPOSE: Among conservative treatment of the choroidal melanoma, improved functional capacities can be provided with Iodine 125 and with a treatment planning system for optimized dosimetry. METHODS: Forty patients were treated with Iodine 125 with a minimal follow-up period of 6 months and a mean follow up of 25 months. RESULTS: Response to the treatment based on tumor regression or stabilization was 97%. Complication rate was 32%. Retinopathy was the major cause of loss of vision and was linked to the proximity of the tumor to the macula. Two patients developed metastasis and one required enucleation for tumor regrowth. CONCLUSION: Brachytherapy with Iodine 125 was found to be effective on tumor growth within the limits of the follow-up. High doses (100 Gy) given to the apex of the tumor did not increase complications rate. Many years will be necessary to assess efficiency of such a procedure in terms of preventing complications.

Impaired social cognition 30 years after hemispherectomy for intractable epilepsy: the importance of the right hemisphere in complex social functioning.

Clinical research with individuals following hemispherectomy typically quantifies the success of surgical outcomes by focusing primarily on the achievement of seizure control and the preservation of general brain functions, such as movement, sensation, language, and memory. In addition to these outcomes, careful study of individuals following hemispherectomy also has the potential to contribute to our understanding of functional brain asymmetries involving other complex cognitive behaviors. In this study, we report preliminary evidence for the lateralization of social perception. We administered a series of neuropsychological tests that were developed to assess emotional recognition and the formation of social inferences and advanced social cognitive judgments, as they occur in everyday situations, to two adult participants who underwent complete anatomic left- or right-sided hemispherectomy. Our results show that despite a 30-year postsurgical period of recovery and consistent and high levels of family support and social engagement, distinct cognitive profiles are still evident between our right- and left-sided participants. In particular, participant S.M., who underwent an anatomic right hemispherectomy, showed the most severe impairments in identifying negative emotional expressions and conversational exchanges involving lies and sarcasm and in "mentalizing" the intent of others. In contrast, participant J.H., who underwent an anatomic left hemispherectomy was highly skilled interpersonally, despite evident language-related limitations, and showed only mild difficulties when asked to identify emotional expressions involving disgust and anger. These results suggest that the right hemisphere plays a particularly important role in social cognitive functioning and reasoning. Further examination of the extent of social perceptual difficulties prior to and following surgical intervention for epilepsy may guide the development of effective social skills training programs that can improve quality of life beyond seizure control.

Human adult bone marrow-derived somatic cell therapy results in functional recovery and axonal plasticity following stroke in the rat.

Stroke is the leading cause of adult disability in the United States. To date there is no satisfactory treatment for stroke once neuronal damage has occurred. Human adult bone marrow-derived somatic cells (hABM-SC) represent a homogenous population of CD49c/CD90 co-positive, non-hematopoietic cells that have been shown to secrete therapeutically relevant trophic factors and to support axonal growth in a rodent model of spinal cord injury. Here we demonstrate that treatment with hABM-SC after ischemic stroke in adult rats results in recovery of forelimb function on a skilled motor test, and that this recovery is positively correlated with increased axonal outgrowth of the intact, uninjured corticorubral tract. While the complete mechanism of repair is still unclear, we conclude that enhancement of structural neuroplasticity from uninjured brain areas is one mechanism by which hABM-SC treatment after stroke leads to functional recovery.

Increased DNA-bending activity and higher affinity DNA binding of high mobility group protein HMG-1 prepared without acids.

Recently, DNA ring closure assays showed that high mobility group protein HMG-1 and its close homolog HMG-2 mediate sequence-independent DNA flexion. This DNA-bending activity appears to be central to at least some of the recently elucidated functions of HMG-1/2, such as the enhancement of progesterone receptor DNA binding. Here we show that standard purification procedures utilizing perchloric and trichloroacetic acid can produce HMG-1 significantly deficient in its abilities to bind and bend double-stranded DNA, while acid-independent methods purify HMG-1 that is superior in these respects. Significant losses of DNA ring closure activity were seen upon limited 2-5-h exposures of nonacid-purified HMG-1/2 to perchloric acid and/or trichloroacetic acid. Measurements of the apparent DNA dissociation binding constant (Kd(app)) of acid-extracted preparations of HMG-1 gave a wide range of values, and only those preparations demonstrating little DNA ring closure activity had Kd values near the previously published value (approximately 10(-6) M). The highest ring closure activities and lowest Kd(app) (< 3 x 10(-9) M) were obtained for HMG-1 purified without acids. These combined results support the use of alternative, non-acid purification procedures for preserving the DNA-bending activity of HMG-1/2 and suggest that past procedures utilizing acids have led to an underestimation of the affinity of HMG-1 for DNA.

Early developmental exposure to benzodiazepine ligands alters brain levels of thiobarbituric acid-reactive products in young adult rats.

Levels of thiobarbituric acid (TBA)-reactive material were measured in brain regions of 3-4 month-old rats following prenatal exposure to several benzodiazepine (BDZ) receptor ligands over gestational days 14-20. Prenatal exposure to diazepam (DZ) at 1.0 mg/kg/day markedly elevated levels of brain TBA-reactive material while exposure to a higher dose (2.5 mg/kg) induced a significant increase only in the hippocampus. Early exposure to the central-type BDZ agonist clonazepam as well as to the central-type antagonist Ro 15-1788 also increased brain levels of TBA-reactive material. Concurrent exposure to the higher dose of DZ partially attenuated the effect of Ro 15-1788. Prenatal exposure to the peripheral-type BDZ ligand PK11195 produced a profound increase in TBA-reactive products in all regions, and concurrent DZ exposure did not attenuate this effect, except in the basal ganglia. Measurement of TBA-reactive material from birth to 3 months indicated that the effect of prenatal exposure to DZ was not apparent until after 8 weeks of age. Acute in vitro exposure of adult and fetal tissue to DZ had no effect on TBA-reactive material. The results suggest an interference in the organization of cellular metabolism in the brain by developmental exposure to BDZ ligands.