Serotonergic inhibition of the mossy fibre—granule cell glutamate transmission in rat cerebellar slices

Summary The glutamatergic mossy fibre granule cell pathway has been investigated in rat cerebellar slices. Exposure to 35 mM KCI, a concentration of K⁺ known to elicit Ca²⁺-dependent releases of excitatory amino acids from cerebellar slices, raised cGMP levels. The cGMP response was decreased in a concentration-dependent manner by D-(–)-2-amino-5-phosphonopentanoic acid (D-AP5) and by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) indicating the involvement of ionotropic glutamate receptors of both the N-methyl-D-aspartate (NMDA) and the non-NMDA type. The K⁺-evoked production of cGMP was potently inhibited (EC₅₀ = 1.21 nM) by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT₂ receptor agonist. The effect of DOI (0.01 M) was antagonized by 0.03 M of the 5-HT₂ receptor antagonists ketanserin and methiothepin. At concentrations higher than 0.1 M, both antagonists increased on their own the cGMP response elicited by high-K⁺. This effect was insensitive to tetrodotoxin.It had been previously shown that rat mossy fibre endings release glutamate upon depolarization and that such release can be inhibited by activation of 5-HT₂ receptors sited on the mossy fibre endings. Altogether the available data suggest the following conclusions: (a) the glutamate/aspartate endogenously released in cerebellar slices during K⁺ depolarization increase cGMP synthesis through the activation of both NMDA and non-NMDA receptors; (b) a portion of the cGMP response can be prevented by 5-HT₂ receptor activation and may reflect the activity of the mossy fibre-granule cell pathway. Thus serotonin is likely to exert a potent inhibitory control of the excitatory mossy fibre input to the cerebellum by acting at receptors of the 5-HT₂ type. Correspondence to M. Raiteri at the above address     

Renal tubular acidosis in the Silver-Russell syndrome

Several patients with the Silver-Russell syndrome (SRS) attending our Genetics Clinic were diagnosed as having persistent metabolic acidosis. Since this abnormality has not been reported previously in the SRS, we reexamined 33 SRS patients to evaluate the frequency and type of metabolic acidosis, the clinical and laboratory findings, and the growth pattern in SRS patients with and without metabolic acidosis. Among them, 14 had a consistent decrease in HCO levels. Renal studies in acidotic patients showed urine pH of 5.8 and 24 h urine calcium of <2.4 mg/kg/24 h; serum creatinine, excretion of glucose, and aminoacids were normal, as were renal ultrasound and excretory urography findings. These data supported the diagnosis of renal tubular acidosis, probably type II; the patients were treated with oral bicarbonate and acidosis was corrected successfully. Clinical manifestations were similar in acidotic and non-acidotic patients. The nutritional indices at diagnosis and at last evaluation (at least 8 months after diagnosis) were abnormally low in all patients; however, acidotic patients, treated with bicarbonate, showed an improvement of nutritional status particularly in the weight/height index, although the difference between groups after follow-up did not reach statistical significance. We suggest that metabolic acidosis due to renal tubular acidosis, probably type II, may occur in children with the SRS and should be looked for and treated in all patients. © 1995 Wiley-Liss, Inc.     

A large animal model of bladder exstrophy: observations of bladder smooth muscle and collagen content

PURPOSE: The development of adequate bladder capacity is not ensured in all patients with bladder exstrophy despite successful bladder closure and reconstruction. To determine the factors leading to the development and maturation of the exstrophic bladder we created a large animal model of exstrophy. We compared biopsies obtained from a cohort of experimentally induced exstrophic neonatal sheep bladders to those of normal control bladders and related the findings to a previously reported comparison of human neonatal normal and exstrophic bladders. MATERIALS AND METHODS: Bladder specimens of 7 newborn lambs with experimentally induced exstrophy were compared to specimens of 10 newborn control lamb bladders. All specimens were stained with Masson's trichrome as well as with specific monoclonal antibodies to types I and III collagen. Stained sections were then analyzed using a morphometric image analysis system to quantify the amounts of smooth muscle and collagen present. RESULTS: A significant increase in the ratio of collagen-to-smooth muscle was noted in exstrophic versus normal control bladders (p <0.05). This difference was similar to that in the previous study of neonatal human bladders. There was no significant difference in the ratios of types I and III collagen in the 2 groups of sheep bladders. This finding is different from that reported in the previous human studies. CONCLUSIONS: Overall changes in the ratio of smooth muscle-to-collagen in the sheep exstrophy model are similar to those in humans. However, the differences in collagen types I and III do not seem to be present.     

Clinical aspects of breast cancer in the aged woman]

In Italy breast cancer mortality is constantly increasing in women over 70 years of age. The retrospective analysis of the cases observed at the "Senology Center" of the II Institute of Obstetrics and Gynecology (University "La Sapienza" of Rome) shows when compared to the group of women under age of 40 a higher number of advanced cases. This delayed diagnosis needs a most radical treatment and adjuvant therapies (i.e. chemotherapy) that cannot often be carried out because of general problems. Therefore, elderly women should be sensibilized to undergo periodical and regular sanitary inspection.     

Lomest psychiatric case register: Old and new long-stay patients

Summary Data derived from a psychiatric case-register are presented on the attrition of the cohort of theold long-stay in-patients, and the accumulation of thenew long-stay cases in Lomest, a town in northern Italy, from 1975 to 1980. The characteristics of high user groups of out-patients attending the non-residential services are also described. The analysis seeks to provide some information on who has been left behind by the massive deinstitutionalization programme that has been carried out in Italy since 1970.     

Increased beta-carboline 9N-methyltransferase activity in the frontal cortex in Parkinson's disease

Enzymatic beta-carboline N-methyltransferase activities generate N-methylated beta-carbolinium cations that are analogs of the parkinsonian-producing neurotoxin MPP+. We measured beta-carboline-2N-methyltransferase and beta-carboline-9N-methyltransferase activities in the supernatant and particulate fractions from postmortem human brains. These N-methyltransferase activities were assessed in the substantia nigra, putamen, and frontal cortex from control and Parkinson's disease cases. No significant differences were measured in any brain region in particulate and supernatant fraction beta-carboline 2N-methyltransferase activity or particulate fraction beta-carboline 9N-methyltransferase activity. Likewise, supernatant fraction beta-carboline 9N-methyltransferase activity was similar in the putamen and substantia nigra from Parkinson's disease and control cases. Unexpectedly, supernatant fraction beta-carboline 9N-methyltransferase activity was increased fourfold in Parkinson's disease frontal cortex (P < 0.05), suggesting that beta-carboline N-methylation may play a role in Parkinson's disease.     

Effect of aluminum adjuvants on safety and immunogenicity of Haemophilus influenzae type b-CRM197 conjugate vaccine

OBJECTIVE: The present study was carried out to evaluate the safety and immunogenicity of the Haemophilus influenzae type b-CRM197 (Hib-CRM197) conjugate vaccine in relation to the change of adjuvant from aluminum hydroxide to aluminum phosphate (AlPO4). METHODS: The present study was a clinical phase II, observer-blind, randomized, multicenter, controlled study. Subjects were healthy infants aged 6-12 weeks, eligible for expanded program of immunization (EPI) routine vaccination and admitted to Hacettepe University Department of Social Pediatrics and Gülveren Health Center, Ankara. A total of 520 healthy infants were randomized in a 2:2:1 ratio to receive at either Chiron Hib/AlPO4 vaccine or VaxemHib (aluminum hydroxide adjuvant) vaccine or HibTiter (no adjuvant). Vaccines were administered simultaneously with routine diphtheria, tetanus and pertussis (DTaP) and oral polio vaccine (OPV) vaccines at 2, 4 and 6 months of age. Blood samples for anti-plain polysaccharide (PRP) antibody measurement were collected before the first vaccination and 1 month after the last vaccination. After each vaccination parents filled out a diary for 7 days. RESULTS: Out of 520 subjects enrolled, 514 received three doses and were included for safety analysis. Local and systemic reactions occurred with low and similar frequencies in all groups. Only erythema was more common in Chiron Hib/AlPO4 vaccine (19, 10, 11% in Chiron Hib/AlPO4, VaxemHib and HibTiter, respectively, P < 0.05). Nine serious adverse events were reported in seven cases of which none were related to vaccines. A total of 504 subjects were included in the immunogenicity analysis. The three vaccines were highly immunogenic and equivalent in terms of percentage of acquisition of long-term protective levels. The anti-PRP geometric mean titers were 9.9, 8.3 and 5.14 micro g/mL, respectively (P < 0.05). CONCLUSIONS: The use of aluminum compounds adjuvants in Hib-CRM197 conjugate vaccines does not impact the safety profile, while it does increase the magnitude of anti-PRP antibody titers.