Effects of chronic antidepressants and electroconvulsive shock on serotonergic neurotransmission in the rat hypothalamus

The hypothalamus may play a critical role in the pathophysiology and treatment of depression. There are two main lines of evidence for this: firstly, many of its functions correspond to those altered in depression; and secondly, many hypothalamic functions are regulated by the serotonergic system, which is a common target of antidepressant treatments. In keeping with observations from other laboratories, we have found that chronic antidepressants and electroconvulsive shock increase serotonergic neurotransmission in the rat hypothalamus by inducing desensitization of presynaptic autoreceptors. We have also found that chronic hypercorticosolemia, which constitutes a model of depression, has an opposite effect. We postulate that presynaptic autoregulation of serotonergic neurotransmission in the hypothalamus may play a critical role in the pathophysiology and treatment of depression.     

Low doses of ipsapirone increase growth hormone but not oxytocin secretion in normal male and female subjects

Objective: The present study investigated whether administration of a 5-HT_1A receptor agonist would increase growth hormone (GH) and oxytocin levels in normal human subjects, and whether the responses would be modified according to the age and gender of the subjects. Methods: Ipsapirone (0.3 mg/kg body weight), or placebo was administered to 30 normal subjects (14 males, 19–74 years and 16 females, 22–69 years) using a randomized, double blind design. Results: Stimulation of GH secretion by ipsapirone was significantly greater in male compared to female subjects, with no apparent effect of age. Oxytocin secretion was not stimulated by ipsapirone compared to placebo in any of the groups. Conclusions: The effects of gender and age on the degree of stimulation of GH secretion by 5-HT_1A agonists in human subjects differ from their effects on secretion of the hormones ACTH and cortisol. A higher dose of ipsapirone is required to stimulate oxytocin secretion in normal human subjects. Received: 10 November 1998/Final version: 7 February 1999     

Adhesion of Candida albicans to epithelial cells - effect of nikkomycin

Summary. This study investigated the effect of the chitin synthetase inhibitors, the nikkomycins (NZ and NZ + NX), on Candida albicans adhesion to buccal epithelial cells (BECs) in vitro. The effect was expressed in reduced chitin synthetase activity and chitin content of fungal cells. In vitro adhesion assays to BECs of Candida exposed to NZ and NZ + NX revealed reduced adhesion values. Light, scanning and transmission electron microscopy (SEM, TEM) of NZ-treated and untreated microorganisms showed changed fungal morphology and reduced adherence of the treated yeasts. Scanning electron microscopy of NZ-treated C. albicans labelled with gold-conjugated wheatgerm agglutinin (WGA) revealed less labelling than in the untreated organisms. A close contact between the fungus and the epithelial cell at a site with intense WGA-gold labelling was noted in TEM experiments. The data point to the involvement of chitin in the adhesion of C. albicans to epithelial cells.
Zusammenfassung. Es wurde die Wirkung des Chitinsynthetase-Hemmers Nikkomycin auf die Adhärenz von Candida albicans an Epithelzellen der Mundschleimhaut in vitro untersucht. Der Einfluß wurde über die Reduktion der Chitinsynthetase-Aktivität und des Chitingehalts der Pilzzellen erfaßt. Lichtmikroskopisch, raster- und transmissions-elektronenmikroskopisch Zeigten die Nikkomycin-behandelten Hefezellen morphologische Veränderungen und reduzierte Adhärenz. Nikkomycin-behandelte C. albicans -Zellen, die mit Gold-konjugiertem Weizenkeimagglutinin (WGA) inkubiert waren, erwiesen sich weniger markiert als nicht mit Nikkomycin-behandelte Hefezellen. Transmissionselektronenmikroskopisch wurde eine intensive WGA-Gold-Markierung am Ort intensiven Kontaktes zwischen Epithelzelle und adhärenter Pilzzelle beobachtet. Die Ergebnisse sprechen für die Beteiligung von Chitin bei der Adhärenz von C. albicans an Epithelzellen.     

An association between clozapine-induced agranulocytosis in schizophrenics and HLA-DQB1*0201

A group of 18 Israeli, clozapine-treated, schizophrenia patients underwent molecular and serological HLA typing in order to determine whether the major histocompatibility complex is associated with the development of clozapine-induced agranulocytosis. While under treatment with clozapine, 2 of the 18 patients developed agranulocytosis (total white blood cell count <3000/mm(3) and absolute polymorphonuclear count <500/mm(3)) and 3 developed granulocytopenia (total white blood cell count <3500/mm(3) and absolute polymorphonuclear count <1000/mm(3)). HLA-DQB1*0201 was present in all five patients who developed agranulocytosis or granulocytopenia (5/5; 100%), but in only 54% (7/13) of the patients who did not develop those complications. These findings indicate that DQB1*0201 or a gene located nearby could be involved in clozapine-induced agranulocytosis.     

A patient with Prader-Willi syndrome and a supernumerary marker chromosome r(15)(q11.1-13p11.1)pat and maternal heterodisomy

We report on a Prader-Willi patient with a de novo supernumerary marker chromosome (SMC) in 16% of the cells. The SMC was a ring chromosome and it included the PWS/AS critical region as was demonstrated by FISH. Segregation analysis indicated that the SMC originated from a paternal chromosome 15 and the two normal chromosomes 15 of the patients were of the maternal homologues. Namely, the patient had maternal heterodisomy in 85% of the cells and triplication of the PWS/AS region in 15% of the cells. The Prader-Willi features were the result of the low mosaicism of the SMC. The evolution of the maternal heterodisomy and the SMC were two unrelated events, the occurrence of both events in the same embryo rescued it from lethality.     

A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem

Glycine encephalopathy (GE) (non-ketotic hyperglycinemia) is an autosomal recessive neurometabolic disease caused by defective activity of the glycine cleavage system. Clinically, patients present usually in the neonatal period with hypotonia, encephalopathy, hiccups and breath arrests with or without overt seizures. GE is considered rare, but its incidence is relatively high in several geographical areas around the world. We report a novel mutation causing GE in six extended Arab families, all from a small suburban village (population 5,000). A methionine to threonine change in the initiation codon of the glycine decarboxylase gene led to markedly reduced glycine decarboxylase mRNA levels and abolished glycine cleavage system activity.     

Why do young women smoke? IV. Role of genetic variation in the dopamine transporter and lifetime traumatic experience.

Cigarette smoking is a complex behavior to which environmental, psychological, and genetic factors contribute. Applying a multifactorial model, we examined the role of genetic variation in the dopamine transporter (DAT1) in smoking initiation (SI) and nicotine dependence. The participants were female college students who had never smoked (n = 148) or had smoked daily for at least a year (n = 242). All participants provided extensive background information and completed a series of psychological instruments. Five SNPs were genotyped in the 3' and 5' regions of DAT1. Data were analyzed by logistic regression. The best fitting model for SI (P = 1.9 x 10(-17), Nagelkerke R2 = 0.33) revealed novelty seeking (OR = 1.14, P = 0.000004) and lifetime traumatic experience (OR = 2.3, P = 0.001) as risk factors and a DAT1_E15 + 274-DAT1_VNTR G-9 haplotype as protective (OR = 0.57, P = 0.03). In the model for nicotine dependence (P = 1.4 x 10(-8), Nagelkerke R2 = 0.27) novelty seeking was a risk factor (OR = 1.07, P = 0.03); the DAT1_E15+274-DAT1_VNTR G-9 haplotype (OR = 0.37, P = 0.001) and the interaction between trauma and a DAT1_E15 + 274-DAT1_VNTR C-9 haplotype (OR = 0.15, P = 0.01) were protective. Lifetime experience of trauma was associated with high nicotine dependence among non-carriers of the C-9 haplotype but not among carriers of this haplotype. These findings indicate that in the context of a multifactorial model, haplotypes in the 3' region of DAT1 influence the propensity of young women to initiate smoking as well as the severity of nicotine dependence once the habit is established. A haplotype in the 3' untranslated region of DAT1 modifies the effect of lifetime traumatic experience on the severity of nicotine dependence.     

Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders

Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.     

Age-Dependent Effects of Electroconvulsive Therapy on Memory

We examined the relation between age and recovery of memory functions after electroconvulsive therapy (ECT). In a group of patients 20-65 years of age, older depressed patients treated with ECT experienced more severe and longer lasting memory deficits than did younger patients. Testing conducted 24-72 h after a course of ECT showed more severe deficits in older patients for verbal and visuospatial anterograde memory, and for retrograde memory. The difference between younger and older subjects was marginal at 1 month follow-up, seen only in differences in verbal anterograde memory. At 6 months follow-up, no difference in memory test scores between older and younger patients was observed. Older patients are more vulnerable to cognitive effects of ECT, and these effects last longer.     

Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening

We have tested 144 unrelated Jewish patients suffering from the classical form of cystic fibrosis. The patients were screened for a panel of 12 mutations including the six Ashkenazi founder mutations (DeltaF508, W1282X, N1303K, G542X, 3849 + 10 kb C-->T, 1717-1G > A) and six mutations that were found in non-Ashkenazi Jewish patients (S549R (T-->G), G85E, 405 + 1G-->A, W1089X, Y1092, and D1152H). Patients of Georgian origin were tested also for the Q359K/T360K mutation. In addition, all the patients were tested for the IVS-8 variant (9T/7T/5T). Of all the cystic fibrosis (CF)-bearing chromosomes, 94% (264/281) were accounted for by one of the known mutations, and none of the patients had the 5T allele of the IVS-8 variant. Single strand conformation polymorphism (SSCP) analysis of the coding sequence of the CFTR gene followed by sequencing showed eight mutations on ten CF chromosomes, leaving seven chromosomes (2.5%) with unknown mutations. We identified three mutations in two or more CF chromosomes, 2571 + 1insT in Jews from Iraq, 3121-1G > A in patients from Kurdistan and I1234V in Yemenite Jewish patients. The other five mutations appeared on a single allele and are considered "private mutations." In this study we have identified 99% of CF alleles in Ashkenazi Jewish patients, 91% in Jews of North African origin and 75% in Jewish patients from Iraq. The significance of these findings to the population screening in Israel is discussed.