Antidepressant response and well-being in pre-, peri- and postmenopausal women with major depressive disorder treated with fluoxetine

BACKGROUND: We assessed the impact of menopausal status on treatment response and well-being in a cohort of outpatient women with major depressive disorder (DSM-III-R criteria), who received treatment with fluoxetine (20 mg/day for 8 weeks). METHODS: Menopausal status was defined based on age, presence of menstrual irregularity or amenorrhea and vasomotor symptoms. Remission and response of depression were defined as a 17-item Hamilton Depression Rating Scale (HAM-D-17) score or=50%, respectively. Well-being was assessed by self-rating with the Symptom Questionnaire. Remitters were followed up for 28 additional weeks. RESULTS: No differences in rates of response and remission as well as in levels of well-being were observed among pre- (n = 121), peri- (n = 28) and postmenopausal (n = 35) women at the endpoint of the acute phase, even after adjustment for baseline depression severity. Residual symptoms, however, were significantly more common in postmenopausal women, except for the continuation phase endpoint. Differences in residual symptoms during the acute phase subsided after adjustment for baseline depression severity. CONCLUSIONS: Overall, menopausal status did not significantly affect the response to fluoxetine treatment and the degree of posttreatment well-being among major depressive disorder patients.     

In Situ Detection of Apoptosis at Sites of Chronic Bacterially Induced Inflammation in Human Gingiva

Apoptosis is a key phenomenon in the regulation of the life span of terminally differentiated leukocytes. Human gingiva represents an established model to study immune responses to bacterial infection. In this investigation, we used the TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) technique to evaluate presence and topographic location of apoptosis-associated DNA damage in human gingival biopsies along with the expression of the p53 and Bcl-2 apoptosis-regulating proteins. Qualitative data analysis showed high densities of cells expressing DNA damage and p53 both within the epithelial attachment to the tooth and in the perivascular infiltrate (infiltrated connective tissue [ICT]) immediately underlying the site of chronic bacterial aggression. Topographic consistency between DNA damage- and p53-positive cells was consistently observed. Quantitative analysis of the ICT showed mean densities of DNA damage- and p53-positive cells of 345 ± 278 and 403 ± 182 cells/mm², respectively. Numerical consistency was confirmed by multivariate regression analysis: densities of DNA damage-positive cells were significantly predicted by densities of p53-positive cells (P = 0.001, r² = 0.84). In the ICT, cells displaying biotinylated DNA nicks were 3.8% ± 2.7% of total cellularity, while p53- and Bcl-2-positive cells represented 4.4% ± 1.7% and 15.4% ± 6.7% of total cells, respectively. It is suggested that p53 expression associated with DNA damage is a prevalent phenomenon in chronically inflamed human gingiva, and that apoptosis may be a relevant process for the maintenance of local immune homeostasis at sites of chronic bacterial challenge in vivo.     

The nociceptin/orphanin FQ/NOP receptor system as a target for treatment of alcohol abuse: a review of recent work in alcohol-preferring rats

The intracerebroventricular administration of the 17 amino acid peptide nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP receptor (previously referred to as ORL-1 or OP4 receptor), reduces voluntary 10% ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Studies aimed at the pharmacological characterization of the receptor, which mediates the effect, have shown that the C-terminal 13 amino acid sequence is crucial for activity and that the selective NOP receptor antagonist [Nphe(1)]N/OFQ(1-13)NH(2) blocks the effect of N/OFQ on ethanol drinking. In place conditioning studies, N/OFQ abolishes the conditioned place preference (CPP) induced by ethanol in msP rats, or by morphine in nonselected Wistar rats; these findings suggest that N/OFQ is able to abolish the rewarding properties of ethanol and morphine. Moreover, N/OFQ inhibits reinstatement of alcohol-seeking behavior induced to electric footshock stress, as well as reinstatement of alcohol-seeking behavior induced by ethanol-paired cues. Together, these findings suggest that N/OFQ and its receptor may represent an interesting target for pharmacological treatment of alcohol abuse.     

Glial fibrillary acidic protein immunoreactive astrocytes in developing rat hippocampus.

The developmental pattern of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes was investigated in the hippocampus (subfields CA1, CA3 and CA4) and in the dentate gyrus of male and female rats aged 11, 16, 30, 90 and 150 days by immunohistochemistry associated with image analysis. Analysis was centred on stratum radiatum, a hippocampal area rich in GFAP-immunoreactive astrocytes. The volume of different portions of hippocampus, the number and the size of astrocytes, the intensity of cell body GFAP immunostaining as well as the extension of astrocyte were assessed. A maturation pattern consisting in higher cellular expression of GFAP, an increase in overall cell size and expanding arborisation from the 11th to the 30th postnatal day, followed by stabilisation of these parameters until the 90th day of life, and a subsequent decrease in the oldest age group studied was found. A sex-related different temporal pattern of astrocytes maturation in size and GFAP content was observed in the CA1 subfield only. The increase of GFAP content during pre-weaning ages was less pronounced in females than in males as well as the decrease between the 90th and the 150th day of age. Moreover, the size of astrocytes was larger in females than in males at the 11th and 150th days of life. These findings suggest that hippocampal astrocytes undergo rapid maturation in the 1st month of postnatal life, followed by a slow consolidation of this process until the 3rd month of life. At 5 months of age, there are still dynamic changes in the mature astrocytes, which become slender and thinner probably as a response to the increased volume of hippocampus noticeable at this age.     

Identification and Subcellular Localization of Neuronal Calcium Sensor-1 (NCS-1) in Human Neutrophils and HL-60 Cells

Secretion in neutrophils is thought to be regulated in different ways for the different granule types. Specific granules are endowed with proteins which are related to docking and fusion events and are absent on azurophilic granules. Furthermore, even if secretion of content from all neutrophil granules is a Ca(2+)-dependent process, a higher concentration of cytosolic calcium is required for azurophilic than for specific granule secretion. In this paper we show that human neutrophils and promyelocitic cells express neuronal calcium sensor-1 (NCS-1), a calcium binding protein involved in exocytosis in various cell types. Both mRNA and protein were found in mature cells and precursors. NCS-1 is shown to be mainly associated with azurophilic granules and, therefore could play an instrumental role in the calcium-dependent secretion of azurophilic granules.     

Molecular identification of Wolbachia from the filarial nematode Mansonella ozzardi

Mansonella ozzardi, a filarial parasite of humans in Latin America, has been shown to harbour intracellular bacteria not yet identified. Here we show that these bacteria, like those of other filarial nematodes, belong to the genus Wolbachia (alpha 2 Proteobacteria; Rickettsiales). Their unambiguous placement in the Wolbachia group was shown by 16S rDNA sequence analysis. However, the exact position of the Wolbachia from M. ozzardi relative to the other wolbachiae is not clear. Indeed, 16S rDNA sequence analysis places this bacterium at a deep branch in Wolbachia evolution. It is interesting that analysis of the 5S rDNA gene spacer of the nematode host also suggests that the genus Mansonella, together with the genus Loa, could represent a deep-branching lineage in filarial evolution.     

Indications for peripheral light-chain revision and somatic hypermutation without a functional B-cell receptor in precursors of a composite diffuse large B-cell and Hodgkin's lymphoma

Composite lymphomas are rare combinations of Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma in the same patient, where clonal relatedness has been observed in most of the few cases analyzed. Here, we report a composite classical HL and diffuse large B-cell lymphoma (DLBCL) with interesting molecular features. Micromanipulation of single cells and analysis of V gene rearrangements revealed clonal relatedness with shared and distinct mutations, indicative of derivation from a common germinal center (GC) B-cell precursor and also of further development of both lymphomas in a GC. In the DLBCL, a very high mutation load, including inactivating mutations, and two copies of the same clonal rearrangement with different mutations in single cells were observed. Intriguingly, in the DLBCL precursor somatic hypermutation activity continued after acquisition of destructive V gene mutations, a feature previously found only in Epstein-Barr virus (EBV) infected B-cell expansions. Furthermore, we found evidence of light-chain receptor revision in the lymphoma precursor during a GC reaction. Re-expression of the V(D)J recombination machinery may enhance genomic instability in GC B cells and contribute to lymphomagenesis.     

Circulating E-Selectin Levels in Chronic Hepatitis C Patients with Normal or Elevated Transaminase Before and After Alpha-Interferon Treatment

E-selectin, an adhesion molecule of the selectin family, is involved in leukocyte adhesion to the endothelium and in the cellular immunological reactions. Expression of this molecule, in fact, is physiologically absent, but it becomes evident on sinusoidal lining cells during inflammatory liver disease. The aim of this study was to evaluate the behavior of E-selectin in chronic hepatitis C (CH-C) patients with persistently normal transaminase in comparison to patients with CH-C and elevated transaminase, and its changes during alpha-interferon therapy. Immunohistochemical localization of E-selectin was also performed on liver tissue specimens of both groups. Fifty-eight subjects were divided into 3 groups: group A included 18 patients with CH-C and persistently normal transaminase; group B 20 patients with CH-C and persistently elevated transaminase levels and group C included 20 healthy subjects, representing the control group. The first two groups were treated with r-IFN at a dose of 6 MU 3 times a week for 3 months and followed-up with 3 MU 3 times a week for another 3 months. Serum baseline values of E-selectin in groups A and B were significantly higher than those in group C (P < 0.04), but there was no difference between groups A and B. Furthermore, there was a trend toward higher E-selectin values as histological severity increased (r = 0.69; P < 0.0001). Post-treatment E-selectin serum values showed a moderate decrease in both groups, but only among responder patients; while E-selectin levels were unchanged in non responders. Immunohistochemical localization showed no staining for E-selectin in normal liver specimens, while there was a quite similar staining for E-selectin in the two groups of patients. In conclusion, this study shows that serum E-selectin levels in patients with CH-C and persistently normal transaminase are higher than in controls and they are associated with severity of liver disease. Liver of these patients express E-selectin molecules, suggesting an activation of the immune system almost identical to that of patients with CH-C and elevated transaminase. In both groups only responder patients showed a moderate decrease below baseline serum values.     

Identification of cerebral networks by classification of the shape of BOLD responses

Changes in regional blood oxygen level dependent (BOLD) signals in response to brief visual stimuli can exhibit a variety of time-courses. To demonstrate the anatomical distribution of BOLD response shapes during a match to sample task, a formal analysis of their time-courses is presented. An event-related design was used to estimate regional BOLD responses evoked by a cue word, which instructed the subject to attend to the motion or color of an upcoming target, and those evoked by a briefly presented moving target consisting of colored dots. Regional BOLD time-courses were adequately represented by the linear combination of three orthogonal waveforms. BOLD response shapes were then classified using a fuzzy clustering scheme. Three classes (sustained, phasic, and negative) best characterized cue responses. Four classes (sustained, sustained-phasic, phasic, and bi-phasic) best characterized target responses. In certain regions, the shape of the BOLD responses was modulated by the instruction to attend to the target's motion or color. A left frontal and a posterior parietal region showed sustained activity when motion was cued and transient activity when color was cued. A right thalamic and a left lateral occipital region showed sustained activity when color was cued and transient activity when motion was cued. Following the target several regions showed more sustained activity during motion than color trials. In summary, the effect of the task variable was focal following the cue and widespread following the target. We conclude that the temporal patterns of neural activity affected the shape of the BOLD signal.     

Enzymatic activities induced by interferon in human fibroblast cell lines differing in their sensitivity to the anticellular activity of interferon

IF^r, a subline of transformed human fibroblast cells, which is sensitive to the antiviral but resistant to the anticellular activity of interferon, was found to be equally well inducible as its parental cell line RSa for the two major interferon-mediated double-stranded RNA-dependent enzymatic activities, 2–5A synthetase and 73K phosphoprotein kinase. The induction of 2-5A synthetase as a function of interferon dose, the specific activity of the 2-5A synthetase, the nature of the 2-5A oligonucleotide products, and the activity of the 2-5A-activated endonuclease were essentially the same for both cell lines. The 73K phosphoprotein kinase was induced at a similar rate of activity, whether detected in solution or after immobilization on poly(I)·poly(C)-Sepharose. Our observations thus suggest that the induction of these two enzymatic activities are not sufficient for the anticellular activity of interferon.