Mutation in the vasopressin gene eliminates the sex difference in social reinforcement in adolescent rats.

The neuropeptide, arginine vasopressin (AVP), is thought to contribute to sex differences in normative and pathological social development by regulating social motivation. Recent studies using Brattleboro rats that have a mutation in the Avp gene, however, have suggested that AVP impacts adolescent social behaviors of males and females in a similar manner through actions on behavioral state (i.e., arousal). In the present study, we made use of a recently developed operant conditioning paradigm to test whether the chronic, lifelong AVP deficiency caused by the Brattleboro mutation impacts the reinforcement value of social stimuli during adolescence. Operant responding for access to a familiar conspecific was assessed in male and female adolescent wild type (WT; normal AVP), heterozygous Brattleboro (HET), and homozygous Brattleboro (HOM) rats. Following the social reinforcement test, rats were tested in the same operant paradigm except that the social reinforcer was replaced with a light reinforcer to determine whether effects of the Brattleboro mutation were specific to social stimuli or a general characteristic of operant conditioning. WT males directed a greater proportion of their responding toward the social and light stimuli than WT females; only males exhibited a preference for these reinforcers over unreinforced ports. The sex difference in social reinforcement was absent in HOM rats, whereas the sex difference in light reinforcement was present in all genotypes. These data indicate that adolescent males are more sensitive to the reinforcing properties of social and light stimuli, and that the sex difference in social, but not light, reinforcement depends upon normal levels of AVP. These findings support the hypothesis that AVP plays a critical role in sex differences in social development by acting on factors that influence social motivation.

Quetiapine (Seroquel) shows a pattern of behavioral effects similar to the atypical antipsychotics clozapine and olanzapine: studies with tremulous jaw movements in rats.

RATIONALE: Previous studies demonstrated that clozapine and olanzapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. OBJECTIVE: The present studies were undertaken to evaluate the novel atypical antipsychotic quetiapine using the jaw movement model. METHODS: The effect of acute quetiapine on the suppression of tacrine-induced tremulous jaw movements was examined. To determine the relative potency of this effect compared with other behavioral effects of quetiapine, suppression of lever pressing also was studied. In other studies, rats received quetiapine for 14 consecutive days to study the effects of repeated injections of this drug. RESULTS: Acute quetiapine injections decreased tacrine-induced jaw movements and lever pressing. The ratio of the ED50 for suppression of jaw movements divided by the ED50 for suppression of lever pressing was used as an index of liability to produce motor side effects, and the present results demonstrate that quetiapine has a ratio similar to that previously shown for clozapine and olanzapine. In the repeated-administration studies, quetiapine failed to induce jaw movements. On day 14, quetiapine reduced tacrine-induced tremulous jaw movements, and in a parallel experiment quetiapine significantly suppressed lever pressing on days 1-14. Repeated injections of quetiapine reduced tacrine-induced jaw movements over a dose range lower than that required for suppression of lever pressing. CONCLUSIONS: On tests of jaw movement activity and lever pressing after both acute and repeated drug administration, quetiapine showed a profile somewhat similar to clozapine and olanzapine. A theoretical model is offered suggesting that atypical antipsychotics that act on 5-HT or muscarinic receptors have intrinsic antiparkinsonian actions that work in opposition to the motor effects produced by dopamine antagonism.

The cannabinoid CB1 antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats.

Cannabinoid CB1 receptor agonists, including delta-9-tetrahydrocannabinol (Delta 9-THC) (the main psychoactive ingredient in marijuana) have been shown to increase feeding in rats and humans. Conversely, it has been reported that acute administration of the CB1 receptor antagonist SR 141716A reduces food intake in rats. Based upon this observation, it has been suggested that CB1 antagonists could be useful as appetite suppressant drugs. The present studies were designed to provide a detailed examination of the effects of CB1 antagonists on food intake across a range of paradigms. Two CB1 antagonists (SR 141716A and AM 251) were administered to rats trained on fixed-ratio schedules with two different ratio requirements (fixed-ratio 1 and fixed-ratio 5). Both drugs produced a dose-dependent decrease in lever pressing, and had a relatively long duration of action (T1/2: SR 141716A, 15.1 h; AM 251, 22.0 h). Furthermore, intake of three diets with differing macronutrient composition (lab chow, high fat, high carbohydrate) was studied. Both drugs significantly suppressed intake of all three foods, and there were no significant interactions between drug dose and diet type. These findings support the hypothesis that CB1 receptor antagonists could be useful pharmacological tools for the suppression of appetite.

Spontaneous improvement in a case of C1q nephropathy.

A 17-year-old girl showed mild proteinuria accompanied by hematuria and mild hypocomplementemia. A light microscopic study of the first renal biopsy specimen showed diffuse mild to moderate mesangial proliferation and thickening of the glomerular basement membrane (GBM). An immunofluorescence study showed dominant positive staining (3+) of IgG and C1q in the glomerular mesangium and capillary loop. Staining for C3 and fibrinogen was weak or 1+. Staining for IgA and IgM was negative. Electron-dense deposits were present in the mesangial area and also in the subepithelial, subendothelial, and intramembranous space. Urinary findings improved after dipyridamole treatment. The second renal biopsy, which was performed 5 years later, showed histological improvements, and various pictures of washing-out of deposits were also noted in an electron microscopic study. However, dominant positive staining for IgG and C1q was persistent in an immunofluorescence study. The glomerulopathy of this case belongs in the criteria of neither membranoproliferative glomerulonephritis nor lupus nephritis but could be designated as C1q nephropathy. This is the first report of a histological improvement in C1q nephropathy.

Effect of epidermal growth factor on sodium-dependent L-alanine transport in LLC-PK1 cells.

We evaluated the role of epidermal growth factor (EGF) in the regulation of L-alanine transport in LLC-PK1 renal epithelia. After 2 h of incubation, EGF had no significant effect on L-alanine uptake by LLC-PK1 cells. However, prolonged (16 h) incubation with 2 and 20 ng/ml of EGF resulted in significant increases in sodium-dependent L-alanine uptake as compared with controls. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA; 20 ng/ ml) caused a marked increase in sodium-dependent L-alanine uptake after both 2 and 16 h of incubation, and the treatment with TPA (20 ng/ml) EGF (20 ng/ml) for 16 h resulted in significant acceleration of the TPA-stimulated increase in L-alanine uptake by LLC-PK1 cells. Coincubation with H-7 (20 microM) inhibited both EGF- and TPA-stimulated increases in L-alanine uptake, and genistein (20 microg/ml) blocked the stimulatory effect of EGF in L-alanine transport to the control level. Furthermore, coincubation with cycloheximide (20 microg/ml) for 16 h inhibited both EGF- and TPA-stimulated increases in L-alanine transport to a great extent. The sodium- independent L-alanine uptake was not affected by treatment with either EGF or TPA. These results suggest that the activation of protein kinase C through tyrosine kinase activation plays a role in the EGF effect of stimulating L-alanine transport in LLC-PK1 cells and that the effect is mainly due to increased protein de novo synthesis which occurs after protein kinase C activation.

Serum hepatocyte growth factor levels in Henoch-Schönlein purpura.

BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common form of vasculitis in children. The potential role of hepatocyte growth factor (HGF) in acute immune-mediated vasculitis has not been elucidated. METHODS: Serum HGF levels were determined in patients with HSP. RESULTS: In patients with acute-phase HSP, mean (+/- SD) serum HGF levels were 0.32 +/- 0.14 ng/mL and were significantly higher than those in the control group (0.11 +/- 0.10 ng/mL). This elevation of serum HGF levels recovered to control levels in parallel with improvement of the clinical symptoms. CONCLUSIONS: It is suggested that elevation of serum HGF levels in patients with acute-phase HSP may reflect endothelial cell damage or dysfunction in HSP.

Serum hepatocyte growth factor levels in patients with renal diseases.

The serum levels of hepatocyte growth factor (HGF) were determined in patients with various renal diseases. In patients with acute-phase acute renal failure (ARF) and chronic tubulointerstitial nephritis (chronic TIN), the serum HGF levels were 0.55 +/- 0.24 and 0.44 +/- 0.37 ng/ml (mean +/- SD), respectively, and were significantly higher than that in the control group (0.12 +/- 0.12 ng/ml). The serum HGF level tended to be high also in patients with active-phase steroid-sensitive nephrotic syndrome (SSNS). The serum levels of HGF were not elevated in patients with IgA nephropathy (IgAN), Henoch-Schönlein purpura nephritis (HSPN), membranoproliferative glomerulonephritis (MPGN), poststreptococcal acute glomerulonephritis (PSAGN), unilateral renal atrophy, unilateral nephrectomy, or proximal tubular dysfunction. These observations suggest that glomerular disorders cause no apparent elevation of the serum HGF level, and that elevation of the serum HGF level may be associated with tubulointerstitial damage in renal diseases.

Values for urinary beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase in normal healthy infants.

BACKGROUND: Measuring urinary beta 2 microglobin (B2M) and N-acetyl-beta-D-glucosaminidase (NAG) excretion is widely used as a valuable clinical tool in assessing renal tubular lesions. However, few data are available on normal values for urinary excretion of B2M and NAG in infancy. METHODS: Urinary B2M and NAG were measured in healthy infants. The logarithmic values of urinary B2M, NAG, B2M/creatinine ratio and NAG/creatinine ratio were distributed almost normally and reference ranges were calculated from the logarithms of the observed values. RESULTS: The levels of urinary B2M and B2M/creatinine ratio were highest in the 1-month-old group, followed by a decrease during the first 3 months. Urinary B2M excretions in the 3-month-old group showed rather lower levels than those of the 12-month-old and 36-month-old groups. Although urinary NAG excretions were almost constant throughout all groups, urinary NAG/creatinine ratio decreased gradually until 3 years of age. CONCLUSIONS: We suggest that these reference ranges are of importance in evaluating tubular damage due to a variety of renal diseases in infancy.

Arginine vasopressin stimulates phospholipid methylation in cultured rat mesangial cells: possible role for PGE2 production.

Incorporation of [3H-methyl] groups into phospholipids and prostaglandin E2 (PGE2) production in cultured rat mesangial cells were examined in the presence and absence of arginine vasopressin (AVP). In cells stimulated with AVP, a rapid increase in the incorporation of [3H-methyl] group into phospholipids was observed within 1 min after stimulation. The [3H-methyl] group present in the phospholipids began to decline 2.5 min after stimulation. The production of PGE2 increased with AVP treatment, and the decline in methylated phospholipids paralleled the release of PGE2 in AVP-stimulated cells. The inhibition of phospholipid methylation by treatment with adenosyl-S-isobutyl mercaptan (SIBA) resulted in a marked decrease in AVP-stimulated PGE2 production. In order to determine the identity of the methylated phospholipids, [3H-methyl] incorporation into phosphatidylethanolamine derivatives was examined. In AVP-stimulated cells, an increase of [3H-methyl] labeled phosphatidylcholine and lysophosphatidylcholine was observed after stimulation with AVP, followed by an apparent increase of [3H-methyl] labeled lysophosphatidylcholine. These findings indicate that AVP stimulates phospholipid methylation in cultured rat mesangial cells and phosphatidylcholine, synthesized by a transmethylation pathway, may be a source for PGE2 production.

Platelet-activating factor induces cell growth through tyrosine phosphorylation pathway in cultured rat mesangial cells.

Accumulating evidence suggests that platelet-activating factor (PAF) may play a role in renal pathophysiology. Therefore, in order to investigate this notion further, the effects of PAF on cell growth and tyrosine phosphorylation were analyzed in cultured rat mesangial cells. PAF was found to enhance a time and concentration-dependent increase in phosphotyrosine in several proteins and stimulate 3H-thymidine incorporation. Tyrosine phosphorylation was also enhanced by PAF in protein kinase C (PKC) depleted cells, whereas a tyrosine kinase inhibitor, genistein, inhibited tyrosine phosphorylation of these proteins at the concentration of 1 microgram/ml. PAF stimulated 3H-thymidine incorporation at concentrations below 10(-6) M, but exerted progressive inhibition at concentrations above 10(-6) M. Pre-treatment with phorbol 12-myristate 13-acetate (PMA) did not affect PAF-enhanced incorporation at lower concentrations of PAF, and reversed the inhibitory effects of PAF at higher concentrations. Finally, genistein pre-treatment completely inhibited PAF-induced cell growth at the concentration of 1 microgram/ml. Both tyrosine phosphorylation and 3H-thymidine incorporation induced by PAF were completely inhibited by pre-treatment with the PAF-receptor antagonist, CV-6209, at the concentration of 10(-5)M. These results suggest that PAF enhancement of tyrosine phosphorylation occurred in a PKC-independent manner and that a tyrosine kinase was associated with PAF-induced tyrosine phosphorylation. Moreover, they indicate that the phosphoinositide hydrolysis-PKC pathway is not essential for PAF-induced cell proliferation, and that PKC activation may play an inhibitory rather than a stimulatory role in mitogenesis in response to PAF. Our results indicate that the tyrosine phosphorylation pathway induced by PAF may participate critically in downstream mitogenic signaling through the PAF receptor.

[Neuroblastoma].

Neuroblastoma is the most common and highly malignant tumor. The 2-year survival rate for NB patients for 1970s was 32% in US and 29% in Japan. But, improvement of prognosis was observed by recent advances in surgery, chemotherapy and numerous other supportive therapies. We introduce the some treatment regimens to patients with neuroblastoma which should be selected by the age and the stage at diagnosis and other prognostic factors such as N-myc amplification, trk overexpression, chromosome anomalies (lp-. double minutes, homogeneous staining region) of neuroblastoma cells and histological pathology. As a general rules, patients under 1 year of age without unfavorable prognostic factors should be treated less intensive regimen, even their tumors are progressive stages. Conversely, patients with progressive stages over 1 year of age without unfavorable factors, it is necessary to treat with intensive protocol. Furthermore, to patients of all age group with unfavorable factors, they are given a very strong intensive treatment through advances in supportive therapies such as the new antiemetics, G-CSF, antibiotics, or IVH etc.. Recent treatment regimens to the patients with neuroblastoma are presented.

[Relationship between molecular structure of halogenated methane compounds and their hypotensive effect in rats].

In this study gases of twelve halogenated methane compounds were administered by inspiration to Wistar rats in order to elucidate the relationship between molecular structure of the compounds and their hypotensive effect, and to develop new inhalational circulatory control agents. The correlation between the hypotensive effect of the compounds evaluated from the experimental data and computed van der Waals volume as well as surface area following molecular mechanics calculations of structure and energy, was investigated. The results showed that the compounds with van der Waals volume and surface area more than 73 A3 and 100 A2, respectively, had the hypotensive effect. In conclusion, our data suggest that the hypotensive effect of inhalational agents requires greater molecular sizes than regular ones.