A Comparison Between the Sensitivities of 3-mm and 5-mm Thick Serial Brain MRI for Detecting Lesion Volume Changes in Patients with Multiple Sclerosis

In this longitudinal study the authors evaluated the sensitivity of 3-mm and 5-mm magnetic resonance imaging (MRI) of the brain in the detection of lesion load changes over time in multiple sclerosis (MS). The authors also correlated the changes detected with these two techniques with the changes in disability. Eighteen patients with MS underwent two MRI examinations of the brain-one at entrance into the study and one follow-up examination. At both sessions, images with 24 contiguous slices 5 mm thick and another with 40 contiguous axial slices 3 mm thick were consecutively acquired. On the same occasions, the patients' Expanded Disability Status Scale (EDSS) scores were rated. MR images with slices 3 mm thick showed higher lesion loads than those with slices 5 mm thick at both entrance and follow-up examinations (median, 13.4 vs 12.8 ml and 17.5 vs 17.0 ml, respectively; p < 0.0001). The correlation between MRI and EDSS changes was significant for both MRI acquisition schemes (3 mm, r = 0.64; 5 mm, r = 0.59). The data suggest that acquisition of thinner slices does not significantly increase the sensitivity of MRI of the brain in the detection of lesion load changes in MS.     

Dose-dependent effects of buspirone on behavior and cerebral glucose metabolism in rats

In this study we compared the effects of the anxiolytic buspirone on behavior and regional cerebral metabolic rates for glucose (rCMRglc) with those of the reference serotonin (5-HT)_1A agonist 8-hydroxy-2(di-N-propylamino)tetralin (DPAT). Behavioral effects were assessed by scoring the 5-HT syndrome. rCMRglc was measured in 56 brain regions by using the quantitative autoradiographic [¹⁴C]2-deoxyglucose technique, at 10 min after i.p. injection of DPAT (1 mg/kg) or buspirone (0.4, 4 and 40 mg/kg) in awake male Fischer-344 rats. Whereas DPAT produced an intense 5-HT syndrome, buspirone had no behavioral effect. A low dose (0.4 mg/kg) of buspirone reduced rCMRglc in 18 brain areas (32%), more markedly in limbic areas and raphe nuclei. These were the only rCMRglc effects buspirone had in common with the potent 5-HT_1A agonist DPAT and suggest that low dose buspirone activates preferentially 5-HT_1A receptors. Hence, this receptor subtype may mediate buspirone functional effects on the limbic system and, given the role of these brain areas in mood control, possibly buspirone therapeutic actions. High doses (4 and 40 mg/kg) of buspirone produced widespread rCMRglc decreases in 46 (82%) and 44 (79%) of the areas studied and increased rCMRglc in one brain area, the lateral habenula, that was not affected by DPAT or a low dose of buspirone. The topographic distribution and direction of rCMRglc changes by high doses of buspirone differ from those produced by the 5-HT_1A agonist DPAT. Instead these changes resemble the rCMRglc effects of dopaminergic D₂ antagonists like haloperidol and are consistent with some pharmacological and binding properties of buspirone. In summary, this study suggests that buspirone produces dual, dose-dependent rCMRglc effects: (i) at a low dose rCMRglc reductions in limbic areas and raphe nuclei, probably due to preferential activation of 5-HT_1A receptors, and (ii) at higher doses widespread rCMRglc reductions along with a rCMRglc increase in the lateral habenula resulting from dopamine D₂ receptor blockade.     

Type II cochlear ganglion cells in the chinchilla

In order to ascertain whether Type II cochlear ganglion cells project to the brain, we have studied the retrograde transport of horseradish peroxidase (HRP) from the cochlear nucleus to the spiral ganglion of the chinchilla. In this animal there exist two types of ganglion neurons, which closely correspond to those previously described in guinea pigs, cats and rats. As in the guinea pig, the majority population (Type I) consists of relatively large, myelinated neurons. The minority population (Type II, 10% of the total population) consists of small, mostly unmyelinated cells, with filamentous cytoplasm and finely grained nuclear chromatin. Type II neurons tend to be clustered toward the peripheral side of Rosenthal's canal, often in close proximity to the intraganglionic spiral bundle. By 24 h after injections of HRP into the cochlear nucleus, incubation of the cochlear ganglion in diaminobenzidine/H2O2 reveals abundant HRP label in both Type I and Type II neurons. Type II neurons, however, tend to be labelled less intensely than Type I neurons. Control experiments, consisting of spillage of HRP solution over the cochlear nucleus, were carried out to determine how much HRP might be picked up by neurons after HRP diffusion. Comparison of cochleae from injected animals and from the control animals suggests that most of the label that was found in ganglion neurons after cochlear nucleus injections represents axonally transported HRP. We conclude, at least tentatively, that Type II neurons project to the brain. The fact that less label is found in Type II neurons that in Type I neurons suggests that the former have thinner axons and/or finer terminals in the cochlear nucleus.     

SUPPRESSION OF BLOOD GROUP AGGLUTINABILITY OF HUMAN ERYTHROCYTES BY CERTAIN BACTERIAL POLYSACCHARIDES

Erythrocytes coated with bacterial capsular polysaccharides, notably the Vi antigen, were no longer agglutinated by antibodies directed against the various antigens native to the red cell surface. These effects could not be attributed to prevention of antibody uptake even though in some systems the uptake of antibody was diminished. In fact, agglutination by Rh-incomplete antibody was brought back to the original titer only after the sensitized Vi-coated cells had been subjected to ten alternating exposures to globulin and antiglobulin. Hemagglutination by Newcastle, mumps, and influenza viruses was also suppressed. Erythrocytes coated with Vi polysaccharide assumed the distinctive physicochemical attributes of this acidic polymer which results in a stabilization of the erythrocyte suspension as manifested by increased electrophoretic mobility and a striking decrease in the rate of sedimentation. Among the possible models for explaining the nature of the Vi effect on immune agglutination, the data favor interference with lattice formation.     

Adult Acute Lymphoblastic Leukaemia: Study of 32 Patients and Analysis of Prognostic Factors

The clinical and haematological characters and the response to therapy of 32 consecutive patients with acute lymphoblastic leukaemia, aged more than 12 years, were reviewed. All patients were given vincristine (V) and (6-methyl) prednisolone (P) for 6 weeks; daunomycin (D) was added in 9 cases, and cyclophosphamide (C) + D in another 10 cases. 3 patients died during induction. 4 patients failed to achieve remission. 25 patients (78 %) achieved complete remission (CR). All of them but one received ‘prophylactic’ central nervous system (CNS) therapy with cranial irradiation and i.t. methotrexate (MTX) and arabinosyl cytosine. CR was maintained with daily 6-mercaptopurine and weekly MTX. Median duration of CR was of 22 months. 2 patients are currently disease-free and off-therapy, 78 and 53 months after diagnosis, respectively. Blast cell membrane markers were studied in 21 consecutive cases: 3 patients had T-cell leukaemia and 2 patients B-cell leukaemia. Prognostic factors were evaluated basing on the present series of 32 patients, and on further 106 cases reported by others. Age (under and above 40) influenced significantly both the CR rate and the length of survival. In patients aged under 40, a circulating blast cell count higher than 25,000/μl, or a platelet count lower than 50,000/μl, negatively affected the survival.     

Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha

Recurrent chromosomal translocations involving the RAR alpha locus on chromosome 17 are the hallmark of acute promyelocytic leukemia (APL). The RAR alpha gene fuses to variable partners (PML, PLZF, NPM, NuMA and STAT5B: X genes) leading to the expression of APL-specific fusion proteins with identical RAR alpha moieties. To analyse whether the variable X moiety could affect the activity of the fusion protein in vivo, we generated and characterized, on a comparative basis, NPM/RAR alpha transgenic mice (TM) in which the fusion gene is expressed under the control of a human Cathepsin G (hCG) minigene. We compared the features of the leukemia observed in these TM with those in hCG-PML/RAR alpha and hCG-PLZF/RAR alpha TM. In all three transgenic models, leukemia developed after a variably long latency, with variable penetrance. However, the three leukemias displayed distinct cytomorphological features. hCG-NPM/RAR alpha leukemic cells resembled monoblasts. This phenotype contrasts with what was observed in the hCG-PML/RAR alpha TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts. Similarly, hCG-PLZF/RAR alpha TM displayed a different phenotype where terminally differentiated myeloid cells predominated. Importantly, the NPM/RAR alpha oncoprotein was found to localize in the nucleolus, unlike PML/RAR alpha and PLZF/RAR alpha, thus possibly interfering with the normal function of NPM. Similarly to what was observed in human APL patients, we found that NPM/RAR alpha and PML/RAR alpha, but not PLZF/RAR alpha leukemia, was responsive to all-trans retinoic acid (ATRA) or As2O3 treatments. Taken together, our results underscore the critical relevance of the X moiety in dictating the biology of the disease and the activity of the APL fusion oncoprotein.     

Primary microparticles and agglomerates of morphine for nasal insufflation

The aim of this work was to study the characteristics of powders of morphine HCl suitable for nasal administration to be employed for pain treatment as alternative to injection. Primary microparticles of morphine were prepared by spray drying of aqueous drug solutions using sugars or sugar derivatives as drying protectors and particle shapers. The spray drying procedure modified morphine crystallinity making the substance amorphous and affecting its stability in dependence on the excipient employed. A tendency of the spray-dried powders to turn to varying degrees of yellow was observed. Tumbling the powder in a rotating pan allowed the agglomeration of the primary microparticles. Agglomerates were also obtained by tumbling a mixture of morphine crystals and spray-dried microparticles of excipients, with advantages for the stability of the preparation. A nasal device quantitatively insufflated all the morphine agglomerates. The in vitro transport of morphine through rabbit nasal mucosa was faster using nasal powders than with the saturated solution of morphine. Lactose was the most effective excipient for agglomerate manufacturing and delivery of spray-dried morphine. The agglomerates of morphine crystals mixed with mannitol/lecithin microparticles showed superior stability. However, the drug permeation through rabbit mucosa was slower than with spray-dried morphine microparticle agglomerates.     

Effect of chronic administration of dimethylnitrosamine on the excision of 0-methylguanine from rat liver DNA

Rats were exposed chronically to unlabelled N,N-dimethylnitrosamine (25 ppm in the drinking water) then given a single dose of N-[³H]methyl-N-nitrosourea (10 mg/kg body weight). The rates of loss of tritium-labeled 7-methylguanine, 0⁶-methylguanine and 3-methyladenine from the liver DNA in control and dimethylnitrosamine-treated rats were found not to be significantly different. Thus, under the conditions used, inhibition of the 0⁶-methylguanine excision repair system does not seem to be a factor in the induction of liver tumours by chronic DMN application.