Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe non-missile traumatic brain injury without macroscopically detectable lesions: a T1 weighted MRI study

OBJECTIVE: The gross morphology and morphometry of the hippocampus, fornix, and corpus callosum in patients with severe non-missile traumatic brain injury (nmTBI) without obvious neuroradiological lesions was examined and the volumes of these structures were correlated with performance on memory tests. In addition, the predictability of the length of coma from the selected anatomical volumes was examined. METHOD: High spatial resolution T1 weighted MRI scans of the brain (1 mm3) and neuropsychological evaluations with standardised tests were performed at least 3 months after trauma in 19 patients. RESULTS: In comparison with control subjects matched in terms of gender and age, volume reduction in the hippocampus, fornix, and corpus callosum of the nmTBI patients was quantitatively significant. The length of coma correlated with the volume reduction in the corpus callosum. Immediate free recall of word lists correlated with the volume of the fornix and the corpus callosum. Delayed recall of word lists and immediate recall of the Rey figure both correlated with the volume of the fornix. Delayed recall of the Rey figure correlated with the volume of the fornix and the right hippocampus. CONCLUSION: These findings demonstrate that in severe nmTBI without obvious neuroradiological lesions there is a clear hippocampal, fornix, and callosal volume reduction. The length of coma predicts the callosal volume reduction, which could be considered a marker of the severity of axonal loss. A few memory test scores correlated with the volumes of the selected anatomical structures. This relationship with memory performance may reflect the diffuse nature of the damage, leading to the disruption of neural circuits at multiple levels and the progressive neural degeneration occurring in TBI.     

Diffuse, micronodular lung disease. The high-resolution CT approach. A pictorial essay

Careful HRCT evaluation of the preferential distribution of micronodular lesions within the secondary lobule provides a fundamental contribution in the correct interpretation of the different associated patterns. This paper suggests a modern diagnostic algorithm that, together with clinical-anamnestic data and additional imaging features, is able to provide a definitive diagnosis or to reduce the possible differential diagnoses.     

Biosensors for determination of total antioxidant capacity of phytotherapeutic integrators: comparison with other spectrophotometric, fluorimetric and voltammetric methods

Enzymatic electrodes based on superoxide dismutase (SOD) biosensors, working both in aqueous and non-aqueous solutions, recently developed by the present authors, were used to experimentally evaluate the antioxidant capacity of several phytotherapeutic diet integrators. The precision of this method of analysis was found to be reasonable (R. S. D. < or = 10%). The results were also compared with those obtained using a traditional spectrophotometric method as well as a spectrofluorimetric method described in literature. Lastly, the comparison was extended to another method based on cyclic voltammetry currently being trialled by the present authors.     

Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response

The influence of dosage, age, and co-medication on plasma topiramate (TPM) concentrations at steady state was investigated in 51 patients aged 3 to 30 years. All patients had chronic active epilepsy, and most were receiving concomitant medication with enzyme-inducing anticonvulsants (carbamazepine and phenobarbital). Plasma TPM concentrations were determined by a specific immunoassay in samples obtained before the morning dose. Thirty-five patients could be evaluated prospectively at different dose levels, and the relationship between plasma TPM concentration and dosage was linear over the assessed dose range (1.8 to 10.0 mg/kg) both in adults and in children. The influence of age on pharmacokinetic parameters could be assessed only for the 42 patients co-medicated with enzyme inducers. In these patients dose-normalized plasma TPM concentrations correlated positively with age (r = 0.59, P < 0.0001), where apparent oral clearance values (CL/F) were inversely related to age (r = 0.73, P < 0.0001). In particular, CL/F values in children aged less than 10 years (112 +/- 82 mL/kg/h, mean +/- SD, n = 14) were almost three times as high as those observed in patients aged >15 to 30 years (42 +/- 16 mL/kg/h, n = 17), whereas the CL/F value in children aged 10 to 15 years (66 +/- 22 mL/kg/h, n = 11) was intermediate between those found in the two other age groups. Patients not receiving enzyme-inducing AEDs showed lower CL/F values than did age- and gender-matched patients on enzyme-inducing co-medication. A preliminary evaluation of the relationship between plasma TPM concentration and therapeutic response could be made in 41 patients. No significant difference in drug concentration was detected between patients showing a greater than 50% reduction in seizure frequency compared with baseline (5.9 +/- 2.2 micrograms/mL, n = 30) and those having no clinical improvement (5.2 +/- 2.2 micrograms/mL, n = 11). Likewise, there was no consistent relationship between plasma TPM concentration and appearance of adverse effects. These results indicate that plasma TPM concentrations are linearly related to dosage both in adults and in children and that children aged <10 years require much greater body weight-adjusted dosage to achieve drug levels comparable to those observed in young adults. The marked increase in TPM clearance caused by enzyme-inducing co-medication was confirmed.     

Glucose-6-phosphate dehydrogenase expression associated with NADPH-dependent reactions in cerebellar neurons

This review describes the variation of glucose-6-phosphate dehydrogenase (G6PD) activity in the main neurons of the molecular and granular layers as well as in the deep nuclei of the cerebellum as observed so far by optical and electron microscopy studies. Light microscopy and semiquantitative microphotometry of histochemical staining showed that the highest G6PD activity was expressed by Purkinje cells and neurons of the deep cerebellar nuclei; the elements of the molecular layer showed a diffuse G6PD staining, while the granular layer displayed only scattered G6PD activity. Electron microscopy analysis showed that the basket and stellate cells, as well as the Golgi cells, have a remarkable G6PD activity, while in the granule cells the enzyme was barely detectable. The results show that cerebellar G6PD activity changes with different neuron types as a function of its role in sustaining NADPH dependent pathways in these cells.     

Expansion of tumor-specific CD8+ T cell clones in patients with relapsed myeloma after donor lymphocyte infusion

Donor lymphocyte infusions (DLI) provide effective therapy for patients with multiple myeloma who have relapsed after allogeneic bone marrow transplantation. However, the immunological mechanisms of the graft-versus-myeloma (GVM) effect have not been defined, and the target antigens of this response have not been identified. Molecular analysis of CDR3 Vbeta repertoire after CD4+ DLI demonstrated previously that the development of GVM and graft-versus-host-disease (GVHD) were associated with the clonal expansion of distinct T-cell populations in patient peripheral blood. In the current study, we undertook a molecular and functional characterization of GVM- and GVHD-associated T-cell clones. T-cell clones associated with GVM were detectable by clone-specific PCR at a low level in peripheral blood before DLI and expanded approximately 10-fold after DLI. In contrast, T-cell clones associated with GVHD were not detectable before DLI or before the development of clinical GVHD. Two T-cell clones associated with GVM were isolated and expanded in vitro, allowing their phenotypic and functional characterization. Both GVM clones were derived from donor cells and had a CD3+CD8+CD4- phenotype. One GVM clone specifically recognized patient myeloma cells in an HLA class I-restricted manner, but was not reactive with patient normal bone marrow cells or patient EBV transformed B cells. Taken together, these findings suggest that the GVM response is mediated by donor-derived CD8+ T-cell clones with antimyeloma specificity that may be present before DLI. In contrast, T-cell clones associated with GVHD are expanded de novo after DLI.     

Predictive variables for malignant transformation in 452 patients with asymptomatic IgM monoclonal gammopathy

The natural history of asymptomatic IgM monoclonal gammopathies (MG) and variables predicting evolution to symptomatic lymphoproliferative disorders were investigated in 452 patients diagnosed from 1975 to 2001. Univariate and multivariate Cox models were used to identify possible predictors of disease progression. At a median follow-up of 49 months (range, 12 to 233), 41 cases (9.1%) evolved to symptomatic Waldenstrom's macroglobulinemia (n = 36), non-Hodgkin's lymphoma (n = 2), B-cell chronic lymphocytic leukemia (n = 1), IgM multiple myeloma (n = 1), and primary amyloidosis (n = 1); the median interval from diagnosis was 53 months (range, 12 to 154). The cumulative probabilities of transformation into a symptomatic lymphoproliferative disease at 5 and 10 years were 8% (95% confidence interval [CI], 6% to 12%) and 21% (95% CI, 16% to 29%), respectively. At univariate analysis, monoclonal component size and hemoglobin level as continuous parameters, lymphocytosis (>4 x 10(9)/L), bone marrow lymphoplasmacytoid infiltration (>10%), erythrocyte sedimentation rate (>40 mm/h), and detectable Bence Jones proteinuria were significantly related with evolution probability. At multivariate analysis, paraprotein level (P <.0001), hemoglobin level (P <.05), and lymphocytosis (P <.0001) independently predicted malignant evolution (P <.0001). In conclusion, patients with asymptomatic IgM-MG showing hematological features predictive of progression should be carefully monitored in view of an early treatment of the disease.     

Effects of cannabinoids on non-adrenergic non-cholinergic-mediated relaxation in guinea-pig trachea

The effects of cannabinoid receptor agonists on the non-adrenergic non-cholinergic (NANC) inhibitory responses to electrical field stimulation in guinea-pig trachea were assessed. R-(+)-[2,3-dihydro-5-methyl-3-[(morpholilinyl) methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2; 10(-5) M) significantly enhanced the frequency-dependent response to electrical stimulation. The same concentration of R-(N)-(2-hydroxy-1-methylethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (R(+)methanandamide) and 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015) did not affect significantly the electrically induced inhibitory NANC responses. The effect of WIN 55,212-2 was not modified by the cannabinoid CB1 and CB2 receptor-selective antagonists, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 10(-5) M) and N-(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR 144528; 10(-5) M), respectively. Moreover, the nitric oxide synthase inhibitor, L-NG-nitro-arginine methyl ester (L-NAME; 10(-4) M), but not the peptidase, alpha-chymotrypsin (2 U/ml), blocked the effect of WIN 55,212-2. Postsynaptically, WIN 55,212-2 did not produce any change of tracheal smooth muscle tone, either basal or histamine-induced, and did not interfere with the relaxant activity of the nitric oxide donor, sodium nitroprusside (10(-8)-10(-4) M). In conclusion, our results suggest that (a) cannabinoid CB1 and CB2 receptor stimulation does not alter the inhibitory NANC transmission in guinea-pig trachea, and (b) WIN 55,212-2 potentiates the NO-mediated component of the NANC relaxant response to electrical stimulation through a cannabinoid receptor-independent mechanism.     

Synthesis and pharmacological evaluation of new N-methyl-arylpyrrolidinols with analgesic activity

In the present paper, we report on the synthesis and antinociceptive activity of a new series of N-methyl-arylpyrrolidinols that we designed for a rational structure-activity relationship (SAR) study. The antinociceptive properties were investigated in vivo by the hot plate and formalin tests in mice and control on the locomotory activity was also monitored by the rota rod test. With this aim, the evaluation of the lipophilicity of all compounds was performed by the Daylight computational method in order to better understand the SAR. Interesting properties were proven for the compounds of the entire series.