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Biomedical subjects

J V Torres

Publications and source records attributed to J V Torres.

At least 19 recordsLinked to original sources
PubMed2006

Risk factors for suicidality in Europe: results from the ESEMED study.

BACKGROUND: Precise knowledge of the epidemiology of suicidality provides necessary information for designing prevention programs. The aims of the present study were to investigate the prevalence and correlates of suicidal ideas and attempts in the general population of Europe. METHODS: The European Study on the Epidemiology of Mental Disorders (ESEMED) is a cross-sectional household survey carried out in a probability representative sample of non-institutionalised adults (aged 18 years or older) of six European countries (Belgium, France, Germany, Italy, the Netherlands and Spain). The Composite International Diagnostic Interview (CIDI 3.0) was administered to 21,425 individuals. RESULTS: Lifetime prevalence of suicidal ideation was 7.8% and of suicidal attempts 1.3%. Being women, younger and divorced or widowed were associated with a higher prevalence of suicide ideation and attempts. Psychiatric diagnoses were strongly related to suicidality. Among them, major depressive episode (Rate ratio 2.9 for lifetime ideas and 4.8 for lifetime attempts), dysthymia (RR 2.0 and 1.6), GAD (RR 1.8 and 2.3 for lifetime), PTSD (RR 1.9 and 2.0) and alcohol dependence (RR 1.7 and 2.5) were the most important. Population attributable risks for lifetime suicidal attempt was 28% for major depression. LIMITATIONS: Information about suicidal ideas and attempts was self reported, psychiatric diagnoses were made using fully structured lay interviews rather than clinician-administered interviews. CONCLUSIONS: In spite of meaningful country variation in prevalence, risk factors for suicidality are consistent in the European countries. Population prevention programmes should focus on early diagnosis and treatment of major depression and alcohol abuse and in those individuals with recent appearance of suicidal ideas.

Adolescent↗
PubMed2001

Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase.

Elevated levels of urokinase plasminogen activator-1 (uPA) and the insulin-like growth factor-I receptor (IGF-IR) are associated with breast cancer recurrence and decreased survival. It is possible that activation of IGF-IR and elevations in uPA are mechanistically linked. Our laboratory recently showed that insulin-like growth factor-I (IGF-I) induces uPA protein and mRNA in the breast cancer cell line MDA-MB-231. We also found that IGF-IR and uPA were commonly overexpressed in primary breast cancers. In this study, we investigated the signal transduction pathway through which IGF-I regulates uPA. Phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p70 kinase were inhibited with LY294002, PD98059, and rapamycin, respectively. Induction of uPA protein by IGF-I was partially inhibited by LY294002 (60% inhibition) or PD98059 (30% inhibition) but not by rapamycin. The production of uPA protein induced by IGF-I was blocked up to 90% by the tyrosine kinase inhibitor herbimycin A. Furthermore, herbimycin A suppressed the phosphorylation of AKT and Erk1/2. Next, we tested the impact of the signal transduction inhibitors on uPA gene expression. Both LY294002 and PD98059 were required to completely inhibit uPA mRNA expression, whereas each drug alone resulted in approximately 50% reduction in uPA expression. Next, using a minimal uPA-luciferase promoter construct containing the binding sites for the AP-1 and Ets transcription factors, we observed that IGF-I stimulated the uPA promoter via these sites. Furthermore, both Ly294002 and PD98059 were necessary to block IGF-I-stimulated uPA-Luc activity. In summary, we conclude that IGF-I requires both phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase-dependent pathways to optimally induce uPA expression. These findings suggest that the development of drugs targeting these pathways may benefit breast cancer patients at a high risk of recurrence, such as those who have primary tumors overexpressing IGF-IR and uPA.

Benzoquinones↗
PubMed2001

Overcoming original (antigenic) sin.

Original antigenic sin describes a phenomenon in which the antibody response elicited in an individual after a secondary viral infection reacts more strongly to the viral variant that originally infected the individual. As T helper cells play critical roles in promoting antibody responses, a similar phenomenon may hold true for T helper cell responses. This concept is particularly relevant to the development of vaccines against viruses such as human immunodeficiency virus and hepatitis C virus, in which myriad viral variants are present throughout the human population. We have compared the effects of priming the immune system with a single peptide epitope or with a cocktail of related peptides based on the epitope. Our data demonstrate that immunization with multiple peptide variants expands a more broadly reactive and durable T helper cell response than does immunization with a single peptide. This vaccine strategy may circumvent original antigenic sin.

AIDS Vaccines↗
PubMed2001

RNAIII inhibiting peptide (RIP), a global inhibitor of Staphylococcus aureus pathogenesis: structure and function analysis.

Staphylococcus aureus are gram-positive bacteria that can cause serious diseases in humans and animals. S. aureus infections can be prevented by the heptapeptide RNAIII inhibiting peptide (RIP). RIP was originally isolated from culture supernatants of coagulase negative staphylococci presumed to be S. xylosus. The sequence of RIP was identified as YSPXTNF. Native RIP and its synthetic analogue YSPWTNF have been shown to be effective inhibitors of diseases caused by various strains of S. aureus, including, cellulitis, keratitis, septic arthritis, osteomylitis and mastitis. RIP is therefore considered to be a global inhibitor of S. aureus. We show here that: 1) the amide form of RIP (YSPWTNF-NH2) is highly stable and is therefore the one recommended for use. 2) RIP inhibits S. aureus pathogenesis by inhibiting the synthesis of both agr transcripts RNAII and RNAIII. 3) Although RIP inhibits agr, it also reduces bacterial adherence to mammalian cells and to plastic (tested on HEp2 cells and on polystyrene by fluorescence and atomic force microscopy), suggesting that RIP can be used safely as a therapeutic molecule. 4) RIP derivatives were designed and tested for their ability to inhibit RNAIII in vitro and cellulitis in vivo. Not all peptides that inhibited RNAIII also inhibited an infection in vivo, indicating that studies must be carried out in vivo before considering a peptide to be of therapeutic potential. 5) The RIP derivative containing Lysine and Isoleucine at positions 2 and 4, respectively, inhibited S. aureus infections in vivo (tested on cellulitis), suggesting that both RIP YSPWTNF and its derivative YKPITNF are effective inhibitors of infections caused by S. aureus.

Bacterial Proteins↗
PubMed2001

A retroviral DNA vaccine vector.

A versatile DNA vaccine (pdIV3) was constructed by replacing the integrase, vif, vpx, and vpr genes of a pathogenic simian immunodeficiency virus (SIV) molecular clone with a linker containing unique cloning sites. The 5' long terminal repeat (LTR) is truncated and transcription is controlled by a cytomegalovirus (CMV) promoter. The construct expresses Gag and Env in vitro and noninfectious virus particles are produced from transfected cells. The ability of pdIV3 to promote cellular and humoral immune responses, along with the flexibility of the linker design to allow insertion of immunostimulatory genes in future constructs, makes this a useful base vector for immunization against primate lentiviruses. We present the construction of a retroviral plasmid designed to serve as a template for the development of safe and effective vaccines against primate immunodeficiency retroviruses. This vaccine component should facilitate the simultaneous induction of cellular and humoral immune responses that protect primates against infection with SIV and human immunodeficiency virus (HIV) and the development of acquired immune deficiency syndrome (AIDS). This plasmid could induce the appropriate immune response required to attack both cell-free and cell-associated viruses. The lack of infectivity, the inability to integrate, and the SIV origin make this construct a safe alternative to attenuated vaccines based on HIV. In addition, we intend to develop this construct as an immunotherapeutic approach to lower the viremia in AIDS patients.

Animals↗
PubMed2001

Impairment of Gag-specific CD8(+) T-cell function in mucosal and systemic compartments of simian immunodeficiency virus mac251- and simian-human immunodeficiency virus KU2-infected macaques.

The identification of several simian immunodeficiency virus mac251 (SIV(mac251)) cytotoxic T-lymphocyte epitopes recognized by CD8(+) T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8(+) T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8(+) and CD4(+) T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIV(mac251) and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4(+) T cells. The frequency of the Gag 181 (p11C, C-->M) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8(+) T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIV(mac251) that were progressing to disease. Overall, the functionality of CD8(+) tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIV(mac251)-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8(+) T-cell function.

Animals↗
PubMed2000

Morphine induces gene expression of CCR5 in human CEMx174 lymphocytes.

All HIV-1 strains studied to date use CCR5, CXCR4, or both receptors to enter cells. Simian immunodeficiency virus (SIV) infection of non-human primates has served as a useful model for understanding AIDS pathogenesis in humans. Research on several genetically divergent SIV isolates has revealed that SIV uses CCR5, and not CXCR4, for entry. CEM x174, a human lymphoid cell line, has been routinely used to cultivate and maintain various SIV strains. However, questions have arisen about how CEM x174, which reportedly was unable to express detectable amounts of CCR5 transcripts, efficiently supports the growth of SIV. In searching for an answer, we resorted to a sensitive competitive reverse transcriptase-polymerase chain reaction procedure in an attempt to detect as well as quantify the amount of CCR5 expression. Here we present our findings, which indicate that CEM x174 indeed expresses CCR5 and that the amount of CCR5 is increased in cells pretreated with morphine. These results correlate well with our previous observations that morphine treatment causes CEM x174 cells to be more susceptible to SIV infection. Similar morphine effect was not observed on CEM x174 cells infected with simian retroviruses, which do not depend on CCR5 for entry. These findings suggest a plausible mechanism whereby opiate drug users render themselves more susceptible to HIV infection, thereby explaining the vast prevalence of HIV infection among endemic drug use populations.

B-Lymphocytes↗
PubMed2000

The kinetics of specific immune responses in rhesus monkeys inoculated with live recombinant BCG expressing SIV Gag, Pol, Env, and Nef proteins.

Development of an effective preventive or therapeutic vaccine against HIV-1 is an important goal in the fight against AIDS. Effective virus clearance and inhibition of spread to target organs depends principally on the cellular immune response. Therefore, a vaccine against HIV-1 should elicit virus-specific cytotoxic lymphocyte (CTL) responses to eliminate the virus during the cell-associated stages of its life cycle. The vaccine should also be capable of inducing immunity at the mucosal surfaces, the primary route of transmission. Recombinant Bacille Calmette-Guérin (BCG) expressing viral proteins offers an excellent candidate vaccine in view of its safety and ability to persist intracellularly, resulting in the induction of long-lasting immunity and stimulation of the cellular immune response. BCG can be administered orally to induce HIV-specific immunity at the mucosal surfaces. The immunogenicity of four recombinant BCG constructs expressing simian immunodeficiency virus (SIV) Gag, Pol, Env, and Nef proteins was tested in rhesus macaques. A single simultaneous inoculation of all four recombinants elicited SIV-specific IgA and IgG antibody, and cellular immune responses, including CTL and helper T cell proliferation. Our results demonstrate that BCG recombinant vectors can induce concomitant humoral and cellular immune responses to the major proteins of SIV.

Animals↗
PubMed2000

Immunogenicity of a vaccine preparation representing the variable regions of the HIV type 1 envelope glycoprotein.

Variability of the major antigenic sites of the envelope glycoprotein of HIV-1 constitutes a major problem in the formulation of effective vaccines. We have prepared a synthetic peptide vaccine that represents the major hypervariable epitopes (V1 through V5) of the clade B HIV-1 envelope glycoprotein (gp120). We refer to this preparation as variable epitope immunogen or VEI vaccine. This construct takes into consideration the type and frequency of amino acid substitutions found at each epitope during the evolution of the virus in individual patients and in the target population. Immunization of mice, rabbits, and rhesus macaques with the VEI vaccine resulted in the induction of long-lasting, high-titered HIV-1 antibodies, including antibodies that neutralize primary isolates. We also documented lymphocyte proliferative responses to the VEI vaccine, its individual components, analogs, and subtype-specific peptides representing the major hypervariable regions of HIV-1 gp120. Delayed-type hypersensitivity responses to these antigens were also demonstrated in mice. Our results show that this vaccine is highly immunogenic and safe in animals. Our data suggest that this formulation could become an important component of combination vaccine approaches against HIV-1 and other antigenically variable pathogens.

AIDS Vaccines↗
PubMed2000

The insulin-like growth factor-1 elevates urokinase-type plasminogen activator-1 in human breast cancer cells: a new avenue for breast cancer therapy.

Tumor recurrence is a common problem in the treatment of breast cancer. In breast cancer, the expression of high protein levels of the insulin-like growth factor-1 receptor (IGF-1R) and urokinase-type plasminogen activator-1 (uPA) is strongly associated with breast cancer recurrence and decreased survival. The expression of uPA by tumors is thought to not only stimulate tumor invasion but also facilitate angiogenesis. In this study, our goal was to address whether IGF-1R could influence the expression of the extracell ular matrix proteases, matrix metalloproteinase (MMP), or uPA thus allowing a selective advantage for tumor invasion and concomitant neovascularization. Initially, we determined whether or not insulin-like growth factor (IGF)-1 regulated the production MMP or uPA in the human breast cancer MDA-MB-231 cells. There was no increase in MMP activity when the cells were treated with IGF-1 (10 ng/mL) for 24 h. In contrast, uPA mRNA and protein were induced in a time-dependent manner. Furthermore, clones expressi ng a dominant negative inhibitor of IGF-1R termed 486stop had less uPA mRNA, and the clones were less invasive through Matrigel. Taken together, these data illustrate that IGF-1R stimulates uPA production. Hence, these two prognostic indicators may be interrelated, suggesting they may function in a synergistic manner to facilitate local tumor invasion as well as angiogenesis. Our data suggest that disruption of IGF-1 signaling in breast cancer may lead to breast cancer prevention and intervention by decreasing uPA expression.

Blotting, Northern↗
PubMed2000

Prevention of diseases caused by Staphylococcus aureus using the peptide RIP.

Staphylococcus aureus causes many diseases including cellulitis, keratitis, osteomyelitis, septic arthritis and mastitis. The heptapeptide RIP has been shown to prevent cellulitis in mice, which was induced by S. aureus strain Smith diffuse. Here we show that RIP can also significantly reduce the overall pathology and delay the onset of disease symptoms in several other models of S. aureus infections, including: keratitis (tested in rabbits against S. aureus 8325-4), osteomyelitis (tested in rabbits against S. aureus MS), mastitis (tested in cows against S. aureus Newbould 305, AE-1, and environmental infections) and septic arthritis (tested in mice against S. aureus LS-1). These findings substantiate that RIP is not strain specific in its inhibitory activity and that RIP is an effective inhibitor of bacterial pathology at multiple body sites following diverse routes and doses of administration. These findings strongly evidence the potential value of RIP as a chemotherapeutic agent.

Animals↗
PubMed2000

Preparation and induction of immune responses by a DNA AIDS vaccine.

In an effort to evaluate the feasibility of developing a safe DNA vaccine for acquired immunodeficiency syndrome (AIDS), we have prepared a plasmid-based immunogen modeled after a naturally occurring noninfectious mutant of the simian immunodeficiency virus (SIV). The mutant SIV genome produces defective virus particles that are noninfectious in vitro and nonpathogenic in vivo in rhesus macaques. Analysis of the mutant genome revealed a 1.6 kb deletion that is in frame and spans integrase, vif, vpx, and most of vpr and results in a pol/vpr gene fusion. This deletion was introduced into the parental pathogenic molecular clone and the U3 region of the 5' LTR was replaced with a cytomegalovirus promoter to produce a candidate DNA vaccine, pIV. After transfection with this plasmid, SIV gag and envelope proteins are expressed and properly processed in vitro. When injected into rabbits, pIV elicited an antibody response to SIV gp130 envelope glycoprotein with titers reaching 1:2048, and a strong lymphoproliferative response to SIV gp130 and whole SIV. The potential to produce defective virus particles in vivo without integrating into the host genome should result in both a strong humoral and cellular immune response in rhesus macaques. In addition, this approach offers a safe alternative to live attenuated vaccines and DNA vaccines that are capable of integration.

Animals↗
PubMed2000

Unappreciated agenesis of cerebellum in an adult: case report of a 38-year-old man.

An unexpected finding at autopsy of almost complete agenesis of the cerebellum in an apparently functional, mentally subnormal 38-year-old man who died as the result of an accidental electrocution is reported. The posterior fossa was normal in appearance despite nearly complete absence of the cerebellum. A number of syndromes of cerebellar atrophy or dysgenesis have been reported, but congenital agenesis is considered a very rare condition. It does not resemble most common cerebellar malformations or acquired conditions, especially in an adult, who apparently had reasonable motor and coordinative function. The relevant literature is reviewed.

Adult↗
PubMed1999

Antibodies from HIV-positive and AIDS patients bind to an HIV envelope multivalent vaccine.

A major problem impeding development of an effective HIV vaccine is the rapid antigenic variability that is characteristic of several envelope glycoprotein epitopes. Frequent mutations alter the composition of the most immunogenic regions of the envelope glycoprotein. We have prepared a synthetic immunogen representing the evolution of the major hypervariable epitopes on the envelope glycoprotein (gp120) of HIV-1. Five synthetic constructs, representing each of the HIV-1 gp120 hypervariable epitopes were tested for recognition by antibodies from patients infected with HIV-1 from different geographic regions worldwide. An HIV-1 human plasma panel provided a representation of the antibodies recognizing subtype-specific epitope sequences prevalent at different parts of the world. The vaccine construct was recognized by antibodies from HIV-1-positive individuals infected with subtypes A, B, C, D, E, and F. Antibodies in pooled HIV-1 patient sera from San Francisco also recognized all five constructs. This complex immunogen was recognized by antibodies in sera from individual HIV-1-positive and AIDS patients from Puerto Rico and Canada, with a strong binding to the complete vaccine and the V3 component. Altogether, our results demonstrate that antibodies from seropositive patients infected with different HIV-1 clades recognize and bind to the HIV hypervariable epitope construct vaccine preparation and its individual components.

AIDS Vaccines↗
PubMed1999

Hypervariable epitope construct: a synthetic immunogen that overcomes MHC restriction of antigen presentation.

Vaccines are not universal in their ability to induce favorable immune responses in all individuals because the major histocompatibility complex (MHC) molecules needed for presentation of vaccine components to T cells are limited in the peptides they recognize and bind. A heterogeneous cocktail of related peptides synthesized simultaneously and representing amino acids 414-434 of the SIV envelope protein was used to induce immune responses stronger than those induced by a single T cell peptide synthesized conventionally and representing the same region of the viral envelope. The heterogeneous peptide mixture called a hypervariable epitope construct (HEC) was capable of overcoming MHC restriction in peptide presentation in four different inbred mouse strains, including a strain that was a poor responder to the AA 414-434 single sequence peptide (SSP). HEC induced proliferation responses 15 times better than those induced by SSP. Antibodies elicited by HEC but not SSP immunization effectively bind viral antigen. The 414-434 HEC and the 414-434 SSP were also tested for their ability to upregulate the expression of MHC class I molecules on the surface of the mutant RMA-S murine cell line. Surface display of MHC molecules was measured by confocal microscopy followed by calculation of fluorescence intensity of images. HECs upregulated expression of MHC molecules 30% more than SSP peptides. Our findings suggest that HEC cocktails could be effective components of subunit vaccines to help overcome the unresponsiveness observed in outbred animals and in humans as a result of MHC-restricted antigen presentation.

Animals↗
PubMed1999

Effect of human immunodeficiency virus type 1 on intracellular activation and superoxide production by neutrophils.

The immunopathogenesis of AIDS is associated with the development of opportunistic infections by intracellular pathogens that can invade and reproduce freely because of impaired cellular functions. Neutrophils from asymptomatic human immunodeficiency virus (HIV) type 1-infected persons and from symptomatic patients with AIDS were found to retain normal phagocytosis activity while producing significantly less superoxide than neutrophils from HIV-1-negative subjects, when stimulated through Fc receptors or protein kinase C. After priming with a synthetic HIV-1 envelope peptide and stimulation via the Fc receptor, the neutrophils from HIV-1-negative controls had suppressed superoxide production, reduced phosphorylation of two unidentified cellular proteins, and increased expression of a third phosphoprotein. These results suggest that HIV-1 can produce direct functional damage of neutrophils through binding of envelope components to the cell membrane.

Adolescent↗
PubMed1999

Induction of cytotoxic and helper T cell responses by modified simian immunodeficiency virus hypervariable epitope constructs.

We previously reported the broad humoral immunogenicity of peptides synthesized according to the cumulative variability of an epitope (1,16). These peptides, hypervariable epitope constructs (HECs), are designed to represent the envelope glycoproteins of several isolates of the simian immunodeficiency virus (SIV). When HEC peptides were conjugated to palmitic acid and palmitic acid ester (lipoHECs), they promoted the induction of cellular immune responses. SIV envelope lipoHEC immunization of BALB/c and ICR mice resulted in up to 80% cytotoxic T lymphocyte (CTL) lysis of SIV envelope-expressing target cells and SIV envelope-specific delayed type hypersensitivity (DTH). This DTH response was significantly higher than that of single peptide controls, and the response peaked at 24 hours. Strong SIV envelope-specific T-cell proliferative responses were also induced in mice with stimulation indexes higher than 20 for spleen cells and higher than 10 for lymph node cells. Overall, our results demonstrate that conjugation of these variable synthetic peptides to a lipid moiety results in an immunogen capable of inducing strong and cross-reactive cellular immune responses.

Amino Acid Sequence↗