Long-term imipramine effects are prevented by NMDA receptor blockade.

Long-term exposure to different antidepressant treatments induces increased motor response to central stimulants, due to a selective supersensitivity of dopamine D2 receptors in the limbic areas. Such an effect is accompanied by down-regulation of dopamine D1 receptor number, and by a decreased response of adenylyl cyclase to dopamine stimulation in the limbic system. Moreover, the number of beta-adrenergic receptors and the response of adenylyl cyclase to beta-adrenergic stimulation in the cortex result to be reduced. The present data confirms that imipramine (10 mg/kg twice a day for 3 weeks) produces such effects, and shows that the co-administration of imipramine with MK-801 (administered by a subcutaneously implanted osmotic minipump delivering 0.05 mg/kg/day of the compound) prevented the occurrence of both the behavioral supersensitivity to quinpirole, and the decrease of dopamine D1 and beta-adrenergic receptor function.

Choroid plexus calcification as a possible clue of serotonin implication in schizophrenia.

Choroid plexus calcification (CPC) was measured on computed tomography (CT) scans of 87 schizophrenics and 46 controls divided into age subgroups. We studied the relationship between presence and size of CPC and age in both groups, whilst in the schizophrenic group we also investigated the possible correlation between CPC size and age of onset and duration of illness, duration of formal education, psychopathological features of the illness as well as some neuroradiological brain measures. CPC size correlated with age in healthy controls but not in schizophrenics. In the schizophrenic group, left choroid plexus calcification size correlated with the Scale for the Assessment of Positive Symptoms (SAPS) subscales scores of 'formal thought disorder' whilst right choroid plexus calcification size correlated with the ventricular brain ratio at frontal horns (VBRFH). The data are not conclusive, but a possible correlation with a dysgenetic or functional 5-HT alteration can be hypothesized.

Imipramine and fluoxetine prevent the stress-induced escape deficits in rats through a distinct mechanism of action.

A large body of evidence indicates that brain monoamines are involved in the pathogenesis of mental depression, as well as in the mechanism of action of most antidepressant treatments. The present report shows that long-term exposure to imipramine (IMI) or fluoxetine (FLX) was equally potent in preventing the escape deficits produced in rats by repeated unavoidable shocks. The acute administration of SCH 23390, a selective D1 dopamine receptor blocker, shortly before the inescapable shock session, entirely prevented IMI effect on escape performance, but only partially prevented that of FLX. Moreover, pindolol (an antagonist of beta-adrenoceptors and of serotonin 5-HT(1A) and 5-HT(1B) receptors) completely antagonized the efficacy of FLX in preventing escape deficits, whereas it did not effect the activity of IMI. The acute administration of propranolol failed to alter the effect of either antidepressant. It was concluded that in rats, the efficacy of IMI in counteracting the stress-induced behavioral sequelae is mainly mediated by the activation of D1 dopamine receptors, whereas that of FLX is largely dependent upon the stimulation of post-synaptic 5-HT(1A) receptors. Finally, the effects of the two drugs appear to be totally unrelated to activation of beta-adrenoceptors.

Molecular detection of microsatellite instability in basal cell carcinoma.

Several studies have shown that the presence of genetic instability can be associated to carcinogenesis process. The detection of microsatellite instability (MI) that consists of an expansion and/or deletion of DNA within repeat sequences, may constitute a sensitive marker for the presence of gene mutations. A series of 18 basal cell carcinoma (BCC) consecutive patients was examined for the presence of alteration in 12 DNA microsatellite markers, in order to better understand the molecular significance of MI in the genesis and progression of BCC. Molecular alterations were detected in 6 out of 12 analyzed microsatellite loci. Five out of 18 BCC samples showed loss of heterozygosity at chromosome loci localized in the vicinity of the tumor suppressor genes, whereas six out of 18 BCC patients presented at least one altered microsatellite (instability). We demonstrated molecular genetic alterations at 2p16 locus, in the proximity of MSH2 gene and 17p21, in the proximity of the p53 gene. These data validate and confirm a role of MI in genesis and progression of BCC, by analysis of markers localized at specific chromosome region in proximity of oncogenes and tumor suppressor genes.

Molecular alterations of E-cadherin gene: possible role in human bladder carcinogenesis.

E-cadherin is a transmembrane glycoprotein which mediates a calcium dependent homophilic interaction among epithelial cells. The altered expression and gene mutations of E-cadherin adhesion molecule have been frequently observed in various tumors. Several invasive carcinomas showed cell-cell adhesion loss although the tumor cells expressed considerable amounts of E-cadherin protein. The purpose of this study was to evaluate the role of E-cadherin gene alterations in genesis and progression of bladder carcinoma by mutation analysis of coding region, expression analysis and microsatellite instability at E-cadherin chromosome locus. We analyzed 30 bladder carcinoma (28 transitional and 2 squamous cell carcinoma) at different stage and grade. The mutation analysis showed that in one case there was a presence of a point mutation at codon 846 that consisted of a G (AGC) to C (ACC) transversion resulting in the replacement of R to T. In another sample the sequence analysis revealed a same-sense mutation at the codon 785 (AAC - AAT). The study of E-cadherin mRNA by Northern blot analysis showed that there were no differences of mRNA levels between tumor and normal mucosa samples. We noted that invasive and anaplastic tumors showed a trend to loss of expression, even if we did not find any statistically significant differences. The microsatellite analysis showed the presence of genomic instability in proximity of the E-cadherin gene. Nine out of 30 (30%) specimens presented molecular alterations in at least one out of 2 loci (D16S260 and D16S301) analyzed. The comparison between microsatellite mutations and clinical-histopathological parameters revealed a higher number of alterations in invasive respect to superficial tumors (p=0.014). On the other hand, there were no statistical differences regarding the correlation with pathological grade. These observations, which, nevertheless, need to be confirmed in a larger number of patients, suggest that alterations of E-cadherin gene may be related to pathobiology of bladder cancer development and clinical progression.

Dizocilpine antagonizes the effect of chronic imipramine on learned helplessness in rats.

Dizocilpine coadministered with imipramine (IMI) through an SC-implanted osmotic minipump completely prevents the occurrence of behavioral supersensitivity to quinpirole, as well as the decrease of dopamine D1 and beta-adrenergic receptor function. The present report shows that, in the same experimental conditions, dizocilpine completely antagonized the capacity of IMI to prevent the development of the learned helplessness behavior in rats. Thus suggesting that the blockade of NMDA receptors also antagonizes the antidepressant effect of IMI. Interestingly, rats acutely treated with dizocilpine 30 min before the inescapable shock session behaved similarly to naive animals during the escape test session.

Severity of obstetric complications and risk of adult schizophrenia in male patients: a case-control study.

OBJECTIVE: Obstetric complications may be an etiologically important factor in the development of schizophrenia. The aim of this study was to evaluate whether the risk for developing schizophrenia in adult life is increased in individuals with more severe obstetric complications at birth. METHODS: To this end, mothers were interviewed to gather data about obstetric complications. The 'midwife protocol' of Parnas and colleagues was used to quantify the presence and entity of obstetric complications. We studied the frequency distribution and the severity of obstetric complications in 64 male DSM IV schizophrenic patients. The genetic load was reduced by using 81 brothers who were not psychiatric patients as controls. Odds ratios for the effects of obstetric complications, maternal age, birth order and birth weight were calculated using conditional logistic regression. RESULTS: The only factor found to have a significant effect on the risk of schizophrenia was the overall measure of obstetric complications at birth. The history of obstetric complications was higher in schizophrenic patients than in their siblings. CONCLUSION: The results seem to confirm the hypothesis that obstetric complications may contribute to increased vulnerability to the disease, in addition to genetic risk factors.

Computed tomography study of pineal calcification in schizophrenia.

Computed tomography studies concerning pineal calcification (PC) in schizophrenia have been conducted mainly by one author who correlated this calcification with several aspects of the illness. On the basis of these findings the aim of the present study was to analyze size and incidence of pineal gland calcification by CT in schizophrenics and healthy controls, and to verify the relationship between pineal calcification and age, and the possible correlation with psychopathologic variables. Pineal calcification was measured on CT scans of 87 schizophrenics and 46 controls divided into seven age subgroups of five years each. No significant differences in PC incidence and mean size between patients and controls were observed as far as the entire group was considered. PC size correlated with age both in schizophrenics and controls. We found a higher incidence of PC in schizophrenics in the age subgroup of 21-25 years, and a negative correlation with positive symptoms of schizophrenia in the overall group. These findings could suggest a premature calcific process in schizophrenics and a probable association with 'non-paranoid' aspects of the illness. Nevertheless the potential role of this process possibly related to some aspects of the altered neurodevelopment in schizophrenia is still unclear.

Usefulness of the TRH test in the management of patients with differentiated thyroid cancer.

Thirty patients thyroidectomized for differentiated thyroid cancer were studied. Serum TSH was assayed in basal conditions and after TRH stimulation, while patients were in suppressive therapy with thyroid hormones. The basal TSH was normal in all the patients and less than 2 microU/ml in 20 patients. The TRH test was negative (no TSH response) in 27 patients and in all the cases with the basal TSH lower than 2 microU/ml.

[Essential tremor: a follow-up study]. / Der essentielle Tremor: eine katamnestische Untersuchung.

41 patients who had been diagnosed as having essential tremor at least two years previously have been controlled. In 39 cases this diagnosis was confirmed. One patient was completely symptom-free after bilateral thalamotomy and another patient was now considered to have Parkinson's disease which had been discussed already four years before. 61% of the patients gave a positive family history for essential tremor, only two had non-first degree relatives suffering from Parkinson's disease. The present study does not provide any evidence for a correlation between essential tremor and Parkinson's disease. However, it should be noted that discrete other "extrapyramidal" signs may occasionally be found in patients having essential tremor.

Effects of Smilax macrophylla Vers. in normal or hyperuricemic and hyperuricosuric rats.

Smilax macrophylla Vers., administered per os at the doses of 1 or 2 g/kg in normal rats or in rats made hyperuricemic and hyperuricosuric by potassium oxonate (250 mg/Kg p.o.) or fructose (4 g/Kg p.o.) does not modify diuresis, but increases the excretion of uric acid and allantoin in normal rats and in those pretreated with fructose, whereas it is inactive in oxonate pretreated rats. Allantoinemia is not modified by fructose or oxonate, whereas uricemia is modified.

Modulation of presynaptic cholinergic receptors by adrenergic drugs.

Some adrenergic drugs were tested for their ability to interact with the stimulatory activity of scopolamine on Ach output from brain cortex. The noradrenergic neurotoxin DSP4 was the most potent in depressing the effect of the anticholinergic drug and behaved like a potent alpha 2-agonist and alpha 1-antagonist on nervous peripheral structures. This finding supports the view of a connection between presynaptic adrenergic and muscarinic receptors.

[Familial occurrence and obstetric complications in siblings discordant for schizophrenia]. / Familiarità e complicanze ostetriche nello studio di fratelli discordanti per schizofrenia.

Obstetric complications seem to play a relevant role in the development of schizophrenia. This study aimed to assess whether not only frequency but also severity of obstetric complications was different in schizophrenic patients when compared with their healthy siblings. Furthermore, we examined whether a family history positive for schizophrenia was related to an increased frequency or severity of obstetric complications in healthy siblings. Frequency and severity of obstetric complications were evaluated in 76 subjects (30 schizophrenics and 46 siblings). The diagnosis of schizophrenia were made according to DSM III-R. Mothers were interviewed to gather data about obstetric complications and the "midwife protocol" by Parnas et al. (1982) was used to quantify presence and entity of obstetric complications. Information regarding family history were collected from mothers. We used the method of segregation analysis to test the mode of inheritance. Complicated births were more frequently found in schizophrenics independently from a family history positive for schizophrenia or schizophrenia related personality disorders and obstetric complications were more severe in schizophrenics with respect to siblings. Obstetric complications occurred more frequently among schizophrenics without genetic risk; the same result was not found in healthy sibs. Our findings show that obstetric complications would play a major role in patients especially if they show a negative family history for schizophrenia. Moreover, a family history positive for schizophrenia or schizophrenia related personality disorder seems not to augment the frequency or severity of obstetric complications in healthy sibs.

A comparison between medial meniscus repair, partial meniscectomy, and normal meniscus in anterior cruciate ligament reconstructed knees.

A clinical, radiographic, and scintigraphic comparative study was performed on 57 consecutive successful patellar tendon anterior cruciate ligament reconstructions for chronic laxity. Patients were divided into 3 matched groups according to the medial meniscal treatment. Group A included 18 patients with medial meniscal repairs; Group B, 19 patients with partial medial meniscectomies; and Group C, 20 patients with normal menisci (controls). The average followup was 55 months. At clinical examination, patients in Group B had more activity-related pain than those in Group C (p = 0.04). The anteroposterior weight-bearing views in extension showed more degenerative changes in the medial compartment in Group B than in the other 2 groups (Group A versus B, p = 0.01; Group C versus B, p < 0.001). Scintigraphy showed an increased uptake in the operated knee as compared with the normal side (11%), but no differences among the 3 study groups. The patients with partial meniscectomies had more pain and degenerative radiographically evident changes than the control group. Medial meniscal repair offers a better chance than partial meniscectomy to preserve the articular cartilage of the medial compartment. Bone homeostasis, as detected by bone scanning, remains slightly altered in successful reconstructions as compared with the opposite normal side.

Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/del22q11 syndromes.

The del22q11 syndrome is associated with a highly variable phenotype despite the uniformity of the chromosomal deletion that causes the disease in most patients. Df1/+ mice, which model del22q11, present with reduced penetrance of cardiovascular defects similar to those seen in deleted patients but not with other del22q11-like findings. The reduced penetrance of cardiovascular defects is caused by the ability of mutant embryos to recover from a fourth pharyngeal arch artery growth abnormality that is fully penetrant in early embryos. Here we show that genetic background has a major effect on penetrance of cardiovascular defects by affecting this embryonic recovery process. This effect could not be explained by allelic variation at the haploid locus, and it is likely to be caused by genetic modifiers elsewhere in the genome. We also show that genetic factors control extension of the Df1/+ phenotype to include thymic and parathyroid anomalies, establishing the Df1 mouse as a model for the genetic analysis of three major features of human del22q11 syndrome. We found that in Df1/+ mice, as in human patients, expression of the heart and thymic phenotypes are essentially independent from each other, suggesting that they may be controlled by different genetic modifiers. These data provide a framework for our understanding of phenotypic variability in patients with del22q11 syndrome and the tools for its genetic dissection.

Circadian rhythm in prostatic acid phosphatase (PAP): a potential tumor marker rhythm in prostatic cancer (PCa).

In order to define circadian states for an earlier diagnosis and for optimal response to treatment, the possibility of a circadian rhythm in serum PAP was investigated in subjects with and without prostatic cancer. Two groups of subjects were investigated: a. 12 patients affected by PCa, further subdivided in two subgroups: 1. without metastasis (6 patients) and 2. with metastatic disease (6 patients); b. 9 age-matched healthy control subjects. Controls and PCa patients were synchronized before starting the study with standardized meal times and nocturnal rest (22(00) to 06(00) ). Venous blood samples were drawn at prearranged hours (00(00), 04(00), 08(00), 12(00), 16(00), 20(00) ) for 24 consecutive hours. Each serum sample was assayed for PAP. Data on each group and subgroup were evaluated by conventional statistical analysis and by 'single' and 'population mean cosinor' to define rhythm parameters. PCa patients, as a single group, did not show a significant circadian PAP rhythm. A statistically significant circadian PAP rhythm was however detected in the subgroup without metastasis, on the contrary no rhythm was detected in the subgroup with metastatic disease. The potential of these rhythms as marker of cancer is noted.

[Compounds with psychotropic activity. VIII. Synthesis and sedative activity of various 9-substituted derivatives of 5-phenylpyrrolo[2,1-d][1,5] benzothiazepine and cis-4,5-dihydro-4-hydroxy-5-phenylpyrrolo[2,1-d][1,5]benzothiazepine]. / Ricerche su composti ad attività psicotropa. Nota VIII - Sintesi ed attività sedativa di alcuni derivati 9-sostituiti della 5-fenilpirrolo [2,1-d] [1,5]benzotiazepina e della cis-4,5-diidro-4-idrossi-5-fenilpirrolo [2,1-d] [1,5]benzotiazepina.

Syntheses of 9-chloro-, 9-trifluoromethyl- and 9-methoxy-5- phenylpyrrolo [2,1-d] [1,5] benzothiazepine [II a-c] and of cis-9-chloro- and cis-9-trifluoromethyl-4,5-dihydro-4-hydroxy-5- phenylpyrrolo [2,1-d] [1,5] benzothiazepine with the respective acetyl derivatives (III a-d), according to previously restated routes, are described. The sedative activity was tested against the anti-amphetamine activity in the rat. The 1-[5-trifluoromethyl-2-(alpha- hydroxycarbonylbenzyl ) thiophenyl + ++]-pyrrole ( NF34 ) and the pyrrolo [2,1-d] [1,5] benzothiazepine -5-carboxamide ( NF44 ) showed sedative activity similar to that of diazepam.

[Research on a compound with psychotropic activity. V - a new derivative of pyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide: synthesis and sedative activity]. / Ricerche su composti ad attività psicotropa. Nota V - nuovi derivati del pirrolo[2,1-d][1,5]benzotiazepin-6,6-diossido: sintesi ed attività sedativa.

The following compounds have been synthesized according to a previously tested route, of the 9-chloro-, 9-trifluoromethyl- and 9-methoxy-5-phenylpyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (II a-c), 9-chloro- and 9-trifluoromethyl-5-p-nitrophenylpyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (II d, e), 5-(4-pyridyl)pyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (III) and 5-(3-pyridyl)pyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (IVa) with the 9-chloro- and 9-trifluoromethyl- derivatives (IV b, c) are reported. The sedative action in the rat was tested against the motor activity induced by amphetamine. The 9-chloro-5(3-pyridyl)pyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide was particularly active and showed sedative action superior to that of diazepam. Marked sedative activity was observed with 9-methoxy-5-phenylpyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (NF19) and 9-chloro-5-p-nitrophenylpyrrolo[2,1-d][1,5]benzothiazepin-6,6-dioxide (NF20).

Vesical-renal reflex: diuresis and natriuresis activated by intravesical capsaicin.

In the last years the role of capsaicin sensitive innervation, in the activation of the micturition reflex, has been reported in many papers. In our experience, upon the intravesical administration of capsaicin in humans, we noticed an increase of diuresis. No interaction is known about the sensory innervation of the bladder and renal function, so we studied the possibility of the existence of a vesical-renal reflex arc. Twenty-one patients (9 men and 12 women) were randomised to receive intravesical infusion of saline solution containing 10 microM capsaicin. Urine output, glomerular renal filtrate (GRF) and effective plasma renal flow (EPRF), measured by Technetium-99m diethylenetetramine-penta-acetic acid (DTPA) renal scintigraphy, were recorded over twenty minutes before and after the intravesical administration of capsaicin. Urine density, [Na+] and [K+] concentration, and prostaglandin E2 excretion were also determined before and after intravesical administration of capsaicin or vehicle. Installation of saline solution containing 10 microM capsaicin produced a significant increase of mean urine output, an increase of GRF, of EPRF and of [Na+] and [K+] urine concentration. An increase, not statistically significant, was observed of PgE2 excretion. None of the patients treated with vehicle showed any modification of parameters examined. The present findings demonstrate a hitherto unrecognized effect: increased diuresis following selective chemical stimulation of bladder efferents with capsaicin. The renal diuretic response to intravesical capsaicin represents a working hypothesis about the possible involvement of a vesical-renal reflex arc organized at spinal or supraspinal level.