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Biomedical subjects

A Fontana

Publications and source records attributed to A Fontana.

At least 163 records · Page 9Linked to original sources
PubMed1997

Social support and psychopathology in the war zone.

Unit cohesion and homecoming support are examined for their protective effects on the development of posttraumatic stress disorder (PTSD) and other psychopathology. Data on 1198 male theater veterans were taken from the National Vietnam Veterans Readjustment Study. Unit cohesion had no significant relationship, as a direct effect, to either PTSD or other psychopathology. In a pattern that was opposite to predictions from the buffering hypothesis of support, however, a high level of unit cohesion in combination with high war zone stress was associated with the highest levels of PTSD and psychopathology. This is consistent with Israeli experiences, suggesting that unit cohesion may have detrimental long-term effects on psychological well-being. In contrast, homecoming support was related negatively as a direct effect to both PTSD and other psychopathology. In addition, interaction results, consistent with the buffering hypothesis, suggest that the protective effects of homecoming support are magnified for veterans with high compared with low levels of exposure.

Adult↗
PubMed1997

Effectiveness and cost of the inpatient treatment of posttraumatic stress disorder: comparison of three models of treatment.

OBJECTIVE: This study compared the outcomes and costs of three models of Department of Veterans Affairs (VA) inpatient treatment for posttraumatic stress disorder (PTSD): 1) long-stay specialized inpatient PTSD units, 2) short-stay specialized evaluation and brief-treatment PTSD units, and 3) nonspecialized general psychiatric units. METHOD: Data were drawn from 785 Vietnam veterans undergoing treatment at 10 programs across the country. The veterans were followed up at 4-month intervals for 1 year after discharge. Successful data collection averaged 66.1% across the three follow-up intervals. RESULTS: All models demonstrated improvement at the time of discharge, but during follow-up symptoms and social functioning rebounded toward admission levels, especially among participants who had been treated in long-stay PTSD units. Veterans in the short-stay PTSD units and in the general psychiatric units showed significantly more improvement during follow-up than veterans in the long-stay PTSD units. Greatest satisfaction with their programs was reported by veterans in the short-stay PTSD units. Finally, the long-stay PTSD units proved to be 82.4% and 53.5% more expensive over 1 year than the short-stay PTSD units and general psychiatric units, respectively. CONCLUSIONS: The paucity of evidence of sustained improvement from costly long-stay specialized inpatient PTSD programs and the indication of high satisfaction and sustained improvement in the far less costly short-stay specialized evaluation and brief-treatment PTSD programs suggest that systematic restructuring of VA inpatient PTSD treatment could result in delivery of effective services to larger numbers of veterans.

Attitude to Health↗
PubMed1997

Posttraumatic stress disorder among female Vietnam veterans: a causal model of etiology.

OBJECTIVES: The Vietnam and Persian Gulf wars have awakened people to the realization that military service can be traumatizing for women as well as men. This study investigated the etiological roles of both war and sexual trauma in the development of chronic posttraumatic stress disorder among female Vietnam veterans. METHODS: Data from the National Vietnam Veterans Readjustment Study for 396 Vietnam theater women and 250 Vietnam era women were analyzed with structural equation modeling. RESULTS: An etiological model with highly satisfactory fit and parsimony was developed. Exposure to war trauma contributed to the probability of posttraumatic stress disorder in theater women, as did sexual trauma in both theater and era women. Lack of social support at the time of homecoming acted as a powerful mediator of trauma for both groups of women. CONCLUSIONS: Within the constraints and assumptions of causal modeling, there is evidence that both war trauma and sexual trauma are powerful contributors to the development of posttraumatic stress disorder among female Vietnam veterans.

Adult↗
PubMed1997

Evidence for intrathecal synthesis of alternative pathway complement activation proteins in experimental meningitis.

Complement has been shown to contribute to intrathecal inflammation in bacterial meningitis. However, the cellular source of complement in the infected central nervous system has not been determined. In this study, we analyzed protein and mRNA expression of two alternative pathway complement activation proteins, C3 and factor B, in the brains of mice with Listeria monocytogenes meningitis. Complement protein levels were found elevated in the cerebrospinal fluid of infected mice, compared with mock-infected animals. In the course of the disease, enhanced C3 and factor B mRNA expression was detected on pyramidal neurons and Purkinje cells within 6 hours, peaking at 12 hours and then gradually decreasing by 72 hours after infection. In addition, leukocytes infiltrating the subarachnoid space, within 12 to 24 hours, expressed mRNA for C3 and factor B. The cellular infiltration increased dramatically up to 72 hours. Intraperitoneal injection of tumor necrosis factor (TNF)-alpha up-regulated C3 and factor B mRNA expression on neurons in normal mice, suggesting that TNF-alpha may represent one cytokine regulating complement expression in this model of bacterial meningitis. However, additional mediators may be involved in regulation of intrathecal complement expression, as infected mice deficient of TNF/lymphotoxin-alpha genes did not demonstrate attenuated complement expression in the brain.

Animals↗
PubMed1996

Systemically (but not intrathecally) administered IL-10 attenuates pathophysiologic alterations in experimental pneumococcal meningitis.

IL-10, a potent immunosuppressive cytokine, leads to macrophage/monocyte deactivation, inhibiting the production of cytokines and the release of reactive oxygen species and reactive nitrogen intermediates, which are known to be involved in the pathophysiology of bacterial meningitis. We investigated the effect of IL-10 on regional cerebral blood flow, intracranial pressure, cerebrospinal fluid (CSF) white blood cell count, and brain water content within 6 h after intracisternal (i.c.) pneumococcal challenge in a rat model of meningitis. Compared with IL-10 vehicle-injected infected rats, i.p. administration of 5 microg of IL-10 significantly attenuated the increase in regional cerebral blood flow, brain water content, intracranial pressure, and CSF white blood cell count, whereas a lower dosage of IL-10 (0.5 microg) was ineffective. The inhibitory effect of IL-10 (5 microg) was observed irrespective of time of IL-10 administration: just before, 1 h after, or 4 h after pneumococcal challenge. In contrast, i.c. application of IL-10 (5 microg) did not modulate these pathophysiologic parameters, and even augmented CSF pleocytosis. Moreover, i.c. injection of IL-10 alone induced meningeal inflammation in uninfected rats. IL-10 injected i.p., but not i.c., markedly inhibited the increase in IL-6 levels, as determined in CSF of infected animals. IL-10 suppressed the increase of nitrite concentration in cell culture supernatant of primary rat cerebral endothelial cells when stimulated with heat-killed pneumococci. The possible modes of action of IL-10 in pneumococcal meningitis may involve its interference with the production of nitric oxide or IL-6.

Animals↗
PubMed1996

Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape.

Malignant melanoma accounts for most of the increasing mortality from skin cancer. Melanoma cells were found to express Fas (also called Apo-1 or CD95) ligand (FasL). In metastatic lesions, Fas-expressing T cell infiltrates were proximal to FasL+ tumor cells. In vitro, apoptosis of Fas-sensitive target cells occurred upon incubation with melanoma tumor cells; and in vivo, injection of FasL+ mouse melanoma cells in mice led to rapid tumor formation. In contrast, tumorigenesis was delayed in Fas-deficient lpr mutant mice in which immune effector cells cannot be killed by FasL. Thus, FasL may contribute to the immune privilege of tumors.

Animals↗
PubMed1996

Identification, sequencing and mutagenesis of the gene for a D-carbamoylase from Agrobacterium radiobacter.

A clone positive for D-carbamoylase activity (2.7 kb HindIII-BamHI DNA fragment) was obtained by screening a genomic library of Agrobacterium radiobacter in Escherichia coli. This DNA fragment contains an open reading frame of 912 bp which is predicted to encode a peptide of 304 amino acids with a calculated molecular mass of 34247 Da. The D-carbamoylase gene, named cauA, was placed under the control of T7 RNA-dependent promoter and expressed in E. coli BL21(DE3). After induction with isopropyl-thio-beta-D-galactopyranoside, the synthesis of D-carbamoylase in E. coli reached about 40% of the total protein. The expressed protein was shown to possess a molecular mass, on SDS-PAGE, of 36 kDa and showed an enhanced stability with respect to that of the wild-type enzyme derived from A. radiobacter. Site-directed mutagenesis experiments allowed us to establish that a Pro14-->Leu14 exchange leads to an inactive enzyme species, while a Cys279-->Ser279 exchange did not impair the functional properties of the enzyme.

Amidohydrolases↗
PubMed1996

Evidence for the molten globule state of human apo-ceruloplasmin.

The conformational features of copper-free ceruloplasmin (CP), as compared to the holo-protein, were evaluated utilizing far- and near-UV circular dichroism and fluorescence spectroscopy. The results obtained indicate that apo-CP maintains the secondary structure of the holo-protein, while the tertiary interactions are much weaker. In addition, the removal of copper from the holo-protein leads to the exposure of hydrophobic patches to solvent, as shown by the fact that apo-CP, at variance from the holo-protein, binds the hydrophobic probe ANS. It is proposed that the CP molecule, upon copper removal, acquires the conformational features typical of a molten globule, which might be the conformational state of CP during its biosynthesis before metal incorporation.

Anilino Naphthalenesulfonates↗
PubMed1996

Incidence rates of leukemias, lymphomas and myelomas in Italy: geographic distribution and NHL histotypes.

The annual incidence of non-Hodgkin's lymphomas is increasing by 3 to 4% in different parts of the developed world, while rates for Hodgkin's disease, myelomas and leukemias are more stable. In the case of this group of malignancies, hypothesis generation on risk factors has been limited by the use of the ICD classification in mortality and incidence statistics. We have computed incidence rates in different Italian areas after careful re-classification of diagnoses, and considering specific histotypes (Working Formulation for NHL, Rye's classification for HD). While no particularly interesting pattern is suggested for Hodgkin's disease (even after considering specific Rye subgroups), multiple myeloma and leukemias, for non-Hodgkin's lymphomas the high rate in one agricultural area (Forli) was mainly due to the A sub-group in the Working Formulation (low-grade). In a heavily industrialized area (Varese), the high incidence rate was at least partly explained by a higher proportion of cases classified in the G sub-group (intermediate grade). Excesses of non-Hodgkin's lymphomas have been observed in populations exposed to phenoxy-acetic-acid herbicides, to insecticides and to organic solvents. One can hypothesize that different risk factors act on different stem cells and induce lymphoid malignancies belonging to different histologic sub-types.

Adult↗
PubMed1996

Acid-induced molten globule state of a fully active mutant of human interleukin-6.

Interleukin-6 (IL-6), a four-helix bundle protein, is a multifunctional cytokine which plays an important role in the regulation of the immune system, hematopoiesis, and inflammatory response, as well as in the pathogenesis of multiple myeloma. We have previously shown that a single-disulfide variant of human IL-6, lacking 22 N-terminal amino acids and the disulfide bond connecting Cys-45 and Cys-51 in the 185-residue chain of the wild-type protein, fully retains the conformational, stability, and functional properties of the full-length human IL-6 [Breton et al. (1995) Eur. J. Biochem. 227, 573-581]. In this study, we have investigated the conformational and stability properties of mutant IL-6 at acidic pH (A-state). Using far- and near-ultraviolet (UV) circular dichroism (CD), fluorescence emission, and second-derivative absorption spectroscopy, we have established that mutant IL-6 at pH 2.0 fully retains the helical secondary structure of the native protein at pH 7.5, while the tertiary interactions are much weaker. At variance from the native species, mutant IL-6 in the A-state binds 1-anilinonaphthalene-8-sulfonic acid (ANS), a property considered most typical of a protein in the molten globule state. The pH-induced conformational change from the native to the A-state, monitored either by near-UV CD or by ANS-binding measurements, shows a transition midpoint at pH approximately 4.5, thus indicating that the partial unfolding of the protein is mediated by the titration of glutamic and/or aspartic acid residues. At pH 2.0, the thermal denaturation of mutant IL-6 occurs as a broad process of low cooperativity with a transition at 50-60 degrees C, whereas at pH 7.5 the thermal unfolding is cooperative and characterized by a transition midpoint at 65 degrees C. Of interest, the unfolding of the A-state is not complete even up to approximately 85 degrees C. The urea-mediated unfolding profile of mutant IL-6, measured by far-UV CD, is essentially identical at both pH 7.5 and 2.0, with a midpoint of the cooperative unfolding transition at 5.5 +/- 0.1 M denaturant. Both thermal and urea denaturations of the A-state are complex and cannot fit to a two-state model for unfolding. The unusual stability of mutant IL-6 in acid is also reflected by the resistance to proteolysis at pH 3.6-4.0 by Staphylococcus aureus V8 protease or cathepsin D, an acid protease released by machrophages upon inflammatory stimulation. It is suggested that the molten globule state of IL-6 at acidic pH can play a role in the biological activity of this cytokine, which can exert its activity also at mildly acidic pH, as in inflammation sites.

Amino Acid Sequence↗
PubMed1996

Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice.

Allogeneic transplantation of islets of Langerhans was facilitated by the cotransplantation of syngeneic myoblasts genetically engineered to express the Fas ligand (FasL). Composite grafting of allogeneic islets with syngeneic myoblasts expressing FasL protected the islet graft from immune rejection and maintained normoglycemia for more than 80 days in mice with streptozotocin-induced diabetes. Graft survival was not prolonged with composite grafts of unmodified myoblasts or Fas-expressing myoblasts. Islet allografts transplanted separately from FasL-expressing myoblasts into the contralateral kidney were rejected, as were similarly transplanted third-party thyroid allografts. Thus, the FasL signal provided site- and immune-specific protection of islet allografts.

Animals↗
PubMed1996

TGF-beta-induced apoptosis of cerebellar granule neurons is prevented by depolarization.

The regulation of programmed cell death in the developing nervous system involves target-derived survival factors, afferent synaptic activity, and hormone- and cytokine-dependent signaling. Cultured immature cerebellar granule neurons die by apoptosis within several days in vitro unless maintained in depolarizing (high) concentrations of potassium (25 mM K+). Here we report that transforming growth factors (TGF)-beta1, -beta2, and -beta3 accelerate apoptosis of these neurons when maintained in physiological (low) K+ medium (5mM K+) as assessed by measures of viability, quantitative DNA fragmentation, and nuclear morphology. TGF-beta-induced apoptosis of these neurons is not blocked by CNTF and LIF, cytokines that enhance neuronal survival when applied alone, or by IGF-I, which prevents apoptosis upon potassium withdrawal. In contrast, neurons that differentiate in high K+ medium for several days in vitro acquire resistance to TGF-beta-mediated cell death. Granule neurons maintained in either low or high K+ medium produce latent, but not bioactive, TGF-beta1 and -beta2. Because neutralizing TGF-beta antibodies fail to augment survival of low K+ neurons, the cerebellar neurons are apparently unable to activate latent TGF-beta. Thus, apoptosis of low K+ neurons is not attributable to endogenous production of TGF-beta. Taken together, our data suggest that TGF-beta may limit the expansion of postmitotic neuronal precursor populations by promoting their apoptosis but may support survival of those neurons that have maturated, differentiated, and established supportive synaptic connectivity.

Animals↗
PubMed1996

Identification and characterization of an extracellular protease activity produced by the marine Vibrio sp. 60.

The marine fish pathogen Vibrio sp. 60 has been used as a host for heterologous expression of the Escherichia coli heat-labile enterotoxin B-subunit and derivatives carrying a C-terminal extension. In this study, a chimeric enterotoxin B-subunit with an extension corresponding to the carboxy-terminal nine amino acids -Tyr-Ala-Gly-Ala-Val-Val-Asn-Asp-Leu-COOH from the small subunit of herpes simplex virus type 1-encoded ribonucleotide reductase, is shown to be proteolytically cleaved in the extracellular medium by a single virus type 1-encoded ribonucleotide reductase, is shown to be proteolytically cleaved in the extracellular medium by a single protease that is secreted by the host strain. Such protease behaves as a typical metalloprotease, being inhibited by EDTA but not by a serine protease inhibitor. Purification and amino acid composition analysis of the two proteolysis products revealed a specific cleavage of the peptide bond between amino acids glycine and alanine of the nine amino acid extension with loss of activity. The above observation is relevant for the biotechnological exploitation of Vibrio sp. 60.

Amino Acid Sequence↗
PubMed1996

Neurons induced to express major histocompatibility complex class I antigen are killed via the perforin and not the Fas (APO-1/CD95) pathway.

Cytotoxic T lymphocytes (CTL) kill target cells by perforin-mediated pore formation, induction of apoptosis by the Fas ligand, or both. It has been demonstrated that depolarized neurons can be induced to express major histocompatibility complex (MHC) class I antigens by interferon-gamma. Evidence for antigen-dependent CTL-mediated killing was obtained by transfecting neurons with MHC class I cDNA. The present study was designed to investigate the mechanisms of killing of cerebellar granule neurons depolarized by high K+ concentrations and thereby inducible for MHC class I antigen expression. We found that neurons express only low levels of Fas (APO-1/CD95) and are resistant to Fas ligand-mediated killing even when pretreated with cytokines. However, granules extracted from CTL as well as purified perforin induce almost complete lysis of neurons. These data suggest that CTL-mediated elimination of neurons involves the perforin, but not the Fas pathway of target cell killing.

Animals↗
PubMed1996

Race and outcome of treatment for veterans suffering from PTSD.

This study examines the relationship between racial group membership and psychometrically measured outcomes 4, 8 and 12 months after program entry in a program for veterans seeking treatment for war-related posttraumatic stress disorder (PTSD). Longitudinal assessment data were gathered and used to compare service use, clinicians' improvement ratings and psychometrically assessed clinical change among Black (n = 122) and White (n = 403) veterans treated at six geographically diverse sites. There were no significant differences between Blacks and Whites on any of the clinicians' improvement ratings, or on 13 of the 17 outcome measures. In this prospective study of veterans suffering from long-standing, severe PTSD, no consistent or sustained differences were observed between racial groups, in improvement whether measured as psychometric change or by clinicians' ratings.

Black or African American↗
PubMed1996

Posterior skin flap numbness after total hip arthroplasty.

The results of a study into posterior skin flap numbness in 25 scars following primary hip arthroplasty using a straight lateral incision are reported. Nineteen scars (76%) examined were found to have some degree of skin flap numbness. In none of these patients, however, was it considered to be a significant problem. This is believed to be the first description of this neurologic problem following this approach to total hip arthroplasty and that patients should be advised of it before surgery.

Aged↗