Biomedical subjects

C Silverman

Publications and source records attributed to C Silverman.

At least 19 recordsLinked to original sources

PubMed1998

Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth.

Herpesvirus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor family, mediates herpesvirus entry into cells during infection. Upon overexpression, HVEM activates NF-kappaB and AP-1 through a TNF receptor-associated factor (TRAF)-mediated mechanism. Using an HVEM-Fc fusion protein, we screened soluble forms of novel TNF-related proteins derived from an expressed sequence tag data base. One of these, which we designated HVEM-L, specifically bound to HVEM-Fc with an affinity of 44 nM. This association was confirmed with soluble and membrane forms of both receptor and ligand. HVEM-L mRNA is expressed in spleen, lymph nodes, macrophages, and T cells and encodes a 240-amino acid protein. A soluble, secreted form of the protein stimulates proliferation of T lymphocytes during allogeneic responses, inhibits HT-29 cell growth, and weakly stimulates NF-kappaB-dependent transcription.

Amino Acid Sequence↗

PubMed1998

Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines.

TR2 (TNFR-related 2) is a recently identified member of the TNFR family with homology to TNFRII. We have demonstrated previously that TR2 mRNA is expressed in resting and activated human T cells and that TR2-Ig partially inhibits an allogeneic mixed leukocyte proliferation response. We now characterize TR2 further by the use of specific mAbs. Flow-cytometry analysis using TR2 mAbs confirmed that resting PBL express high levels of cell surface TR2, and that TR2 is widely expressed on all freshly isolated lymphocyte subpopulations. However, stimulation of purified T cells with either PHA or PHA plus PMA resulted in decreased surface expression within 48 h of activation before returning to resting levels at 72 h. TR2 mAbs inhibited CD4+ T cell proliferation in response to stimulation by immobilized CD3 or CD3 plus CD28 mAbs. Assay of culture supernatants by ELISA showed inhibition of TNF-alpha, IFN-gamma, IL-2, and IL-4 production, which, for IL-2 and TNF-alpha was also confirmed by intracellular cytokine staining. Furthermore, expression of activation markers on CD4+ T cells, including CD25, CD30, CD69, CD71, and OX40 (CD134), was inhibited. TR2 mAbs inhibited proliferation in a three-way MLR, and a response to soluble recall Ag, tetanus toxoid. In conclusion, these results suggest that TR2 is involved in the activation cascade of T cell responses and TR2 mAbs prevent optimal T cell proliferation, cytokine production, and expression of activation markers.

Animals↗

PubMed1998

Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL.

TRAIL is a tumor necrosis factor-related ligand that induces apoptosis upon binding to its death domain-containing receptors, DR4 and DR5. Two additional TRAIL receptors, TRID/DcR1 and DcR2, lack functional death domains and function as decoy receptors for TRAIL. We have identified a fifth TRAIL receptor, namely osteoprotegerin (OPG), a secreted tumor necrosis factor receptor homologue that inhibits osteoclastogenesis and increases bone density in vivo. OPG-Fc binds TRAIL with an affinity of 3.0 nM, which is slightly weaker than the interaction of TRID-Fc or DR5-Fc with TRAIL. OPG inhibits TRAIL-induced apoptosis of Jurkat cells. Conversely, TRAIL blocks the anti-osteoclastogenic activity of OPG. These data suggest potential cross-regulatory mechanisms by OPG and TRAIL.

Animals↗

PubMed1997

A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation.

The tumor necrosis factor receptor (TNFR) superfamily consists of approximately 10 characterized members of human proteins. We have identified a new member of the TNFR superfamily, TR2, from a search of an expressed sequence tag data base. cDNA cloning and Northern blot hybridization demonstrated multiple mRNA species, of which a 1.7-kilobase form was most abundant. However, TR2 is encoded by a single gene which, maps to chromosome 1p36.22-36.3, in the same region as several other members of the TNFR superfamily. The most abundant TR2 open reading frame encodes a 283-amino acid single transmembrane protein with a 36-residue signal sequence, two perfect and two imperfect TNFR-like cysteine-rich domains, and a short cytoplasmic tail with some similarity to 4-1BB and CD40. TR2 mRNA is expressed in multiple human tissues and cell lines and shows a constitutive and relatively high expression in peripheral blood T cells, B cells, and monocytes. A TR2-Fc fusion protein inhibited a mixed lymphocyte reaction-mediated proliferation suggesting that the receptor and/or its ligand play a role in T cell stimulation.

Adult↗

PubMed1997

Program environments of self-help agencies for persons with mental disabilities.

Leaders of self-help agencies (SHAs) aspire to develop program environments that are different from community mental health agencies (CMHAs). This article addresses two questions. Do consumers' perceptions of SHAs approximate the characteristics leaders think ought to typify such agencies? Do SHA and CMHA consumers differ in their program perceptions? Using the Community-Oriented Program Environment Scale, leader expectations of ideal SHA environments were obtained from a national survey of 189 consumer-run agency heads, perceptions of actual environments from interviews with 310 SHA consumers, and perceptions of CMHAs from questionnaire responses of 779 consumers in 54 programs. SHA reality conforms to ideology in offering opportunities for consumers to experience involvement, support, and autonomy in the receipt of needed service. While showing only modest differences from CMHAs on relationship and treatment characteristics, SHA consumers differ in their perceived control over program rules, a fact previously found significant in promoting positive outcomes.

Adult↗

PubMed1997

Social networks and psychological disability among housed and homeless users of self-help agencies.

We look at the effects of psychological disability on social networks and support of homeless and non-homeless individuals. We analyze a survey of 310 long-term users of client-run mental health agencies. Psychological disability is negatively associated with network characteristics for housed individuals, but not for the homeless. There is a positive relationship between psychological distress and network size for the homeless who receive SSI while homeless individuals who do not receive SSI show a negative, non-significant association. We suggest the financial resources of SSI enable network members to become expressively involved with homeless individuals with relatively more psychological disturbance.

Adult↗

PubMed1996

Isolation of a neutralizing human RSV antibody from a dominant, non-neutralizing immune repertoire by epitope-blocked panning.

We isolated a large panel of human Abs directed against the respiratory syncytial virus (RSV) Ag from combinatorial phage display libraries. Following initial differentiation of the Fabs by BstNI restriction patterns, DNA sequence analysis revealed 10 different classes of VH paired with more than 35 different VL genes. All the Fabs bound with high affinity to the F Ag. However, most Fabs competed with the binding of a representative member of this group, suggesting that the Fabs recognized a common epitope on the F Ag, and none of them neutralized virus in vitro. To suppress repetitive isolation of these non-neutralizing Abs, a representative Fab was included during panning to block this common epitope on the F Ag. By this "epitope-blocked panning" approach, two novel Fabs, encoded by unique VH and VL genes, were isolated from a previously screened library. Competition binding analysis confirmed that the Fabs recognized epitopes distinct from that of the previously isolated Fabs. One of these Fabs, 516, neutralized RSV in cell culture. These activities of Fab-516 were retained upon its genetic conversion to a mAb (IgG1) and expression in mammalian cells. Our results suggest that the RSV F glycoprotein presents a dominant, non-neutralizing epitope to the human immune system, which may serve in evasion of host defenses. However, less prevalent, fusion-inhibiting Abs were revealed by blockade of this epitope during the panning process.

Amino Acid Sequence↗

PubMed1995

Heavy chain dimers as well as complete antibodies are efficiently formed and secreted from Drosophila via a BiP-mediated pathway.

We have constructed a stable Drosophila cell line co-expressing heavy chain (HC) and light chain (LC) immunoglobulins of a humanized monoclonal antibody (mAb) that recognizes the F antigen of respiratory syncytial virus (Tempest, P. R., Bremmer, P., Lambert, M., Taylor, G., Furze, J. M., Carr, F. J., and Harris, W. J. (1991) Bio/Technology 9, 266-271. These cells efficiently secrete antibody with substrate binding activity indistinguishable from that produced from vertebrate cell lines. Significantly, the Drosophila homologue of the immunoglobulin binding chaperone protein (BiP), hsc72, was found to interact specifically with the immunoglobulin HC in an ATP-dependent fashion, similar to the BiP-HC interaction known to occur in vertebrate cells. This is, in fact, the first substrate ever shown to interact specifically with Drosophila hsc72. Most surprisingly, expression of heavy chains in the absence of LC led to the efficient secretion of heavy chain dimers. Moreover, this secretion occurred in association with hsc72. This dramatically contrasts with what is seen in vertebrate cells where in the absence of LC, HC remains sequestered inside the cell in stable association with BiP. Our results clearly suggest that Drosophila BiP can substitute for its mammalian counterpart and chaperone the secretion of active IgG. However, the finding that Drosophila BiP can also uniquely chaperone heavy chain dimers indicates mechanistic differences that may relate to the evolved need for retaining immature IgGs in vertebrates.

Animals↗

PubMed1995

Current trends in molecular recognition and bioseparation.

Molecular recognition guides the selective interaction of macromolecules with each other in essentially all biological processes. Perhaps the most impactful use of biomolecular recognition in separation science has been in affinity chromatography. The results of the last 26 years, since Cuatrecases, Wilchek and Anfinsen first reported the purification of staphylococcal nuclease, have validated the power of biomolecular specificity for purification. This power has stimulated an explosion of solid-phase ligand designs and affinity chromatographic applications. An ongoing case in point is the purification of recombinant proteins, which has been aided by engineering the proteins to contain Affinity-Tag sequences, such as hexa-histidine for metal-chelate separation and epitope sequence for separation by an immobilized monoclonal antibody. Tag technology can be adapted for plate assays and other solid-phase techniques. The advance of affinity chromatography also has stimulated immobilized ligand-based methods to characterize macromolecular recognition, including both chromatographic and optical biosensor methods. And, new methods such as phage display and other diversity library approaches continue to emerge to identify new recognition molecules of potential use as affinity ligands. Overall, it is tantalizing to envision a continued evolution of new affinity technologies which use the selectivity built into biomolecular recognition as a vehicle for purification, analysis, screening and other applications in separation sciences.

Chromatography, Affinity↗

PubMed1995

Measuring empowerment in client-run self-help agencies.

"Empowerment" connotes a process of gaining control over one's life and influencing the organizational and societal structures in which one lives. This study defines and validates three measures: the Personal Empowerment Scale, the Organizational Empowerment Scale, and the Extra-Organizational Empowerment Scale. Measurement efforts are based on observational work, baseline interviews (N = 310), and six month follow-ups (N = 241) in four client-run self-help agencies (SHAs) for persons with severe mental disabilities. All three study scales demonstrated strong internal consistency and stability. They were sensitive to user changes over time and have construct validity.

Activities of Daily Living↗

PubMed1995

Characteristics and service use of long-term members of self-help agencies for mental health clients.

OBJECTIVE: This study examined the characteristics of long-term members of self-help agencies managed and staffed by mental health clients, why they sought help from the agencies, and how they differed from clients of community mental health agencies. METHODS: A survey and assessment instruments were used to obtain information on the service utilization of 310 long-term agency members as well as on their resources, history of disability, functional status, psychological disability, health problems, and DSM-III-R diagnosis. Data from management information systems of the self-help and community mental health agencies were used to compare service populations. RESULTS: The self-help agencies served a primarily African-American population (64 percent), many of whom were homeless (46 percent). Eighty-seven percent had confirmed DSM-III-R diagnoses, and 50 percent had dual diagnoses with moderate to severe substance or alcohol abuse or dependence. They had sought help from the self-help agencies primarily for resources such as food or clothing, for "a place to be," or because they were homeless. Obtaining counseling or help for substance or alcohol abuse was a less important reason for coming to the self-help agencies. CONCLUSIONS: A high proportion of the persons served by the self-help agencies in the study were homeless and had a dual diagnosis of mental disorder and substance abuse. The self-help agencies provided their clients with material resources while community mental health agencies provided psychotherapeutic and medical care.

Activities of Daily Living↗

PubMed1994

The outcome and techniques of primary and secondary tracheoesophageal puncture.

OBJECTIVES: To evaluate the outcome of primary vs secondary tracheoesophageal puncture (TEP), in particular the effects of preoperative and postoperative radiotherapy on success and complication rates in primary TEPs, and to highlight modified surgical and management techniques. DESIGN: Retrospective study of case series. SETTING: Chevalier Jackson-Norris Center-Department of Otorhinolaryngology and Bronchoesophagology at Temple University Health Sciences Center Hospital, Philadelphia, Pa. PATIENTS: One hundred six consecutive patients underwent primary TEPs and 30 underwent secondary TEPs for voice restoration after laryngectomy for cancer over a period of 8 years with follow-ups ranging from 6 months to 8.5 years. The group given primary TEP also includes 19 patients who received radiation for cure and salvage laryngectomy and 75 who received full-course postoperative radiotherapy. INTERVENTION: Tracheoesophageal puncture and Blom-Singer prosthesis. MAIN OUTCOME MEASURES: Speech measures including (1) voice intensity, (2) pitch of speech, (3) duration of sustained phonation, and (4) rate of speech. RESULTS: A success rate of 93% was achieved in the group of patients given primary TEP regardless of radiotherapy. An 83% success rate was achieved with patients given secondary TEP. There were no major complications related to TEPs. CONCLUSIONS: Primary TEP for patients requiring total laryngectomy is highly recommended since a second operative procedure can be avoided and speech obtained rapidly. Postoperative radiotherapy does not increase the complication rate from TEP.

Adult↗

PubMed1994

Safety, immunogenicity, and efficacy of a malaria sporozoite vaccine administered with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane as adjuvant.

A Plasmodium falciparum circumsporozoite protein (PfCSP) recombinant fusion protein, R32NS1(81), formulated with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane (Detox) was administered to 12 volunteers. One volunteer had malaise and self-limited painful induration at the injection site after the second dose and declined further immunization. The other 11 volunteers tolerated the three doses of 1,230 micrograms of vaccine, but most complained of sore arms; in five cases the pain or malaise was severe enough to interfere with work or sleep. Two weeks after the third dose of vaccine, four of the 11 immunized volunteers had > or = 14 micrograms/ml of antibodies to the repeat region of the PfCSP in their serum. Two of these four volunteers did not develop P. falciparum parasitemia when challenged by the bite of five mosquitoes carrying P. falciparum sporozoites. The seven volunteers with lower levels of antibodies and 11 of 11 controls developed parasitemia. These data are consistent with other studies, and indicate that vaccine-induced antibodies against the repeat region of PfCSP can prevent effective sporozoite infection of hepatocytes in humans. The challenge is to improve the immunogenicity of PfCSP-based vaccines, and to develop methods for including PfCSP peptides as components of multitarget malaria vaccines.

Adjuvants, Immunologic↗

PubMed1994

Baby boomers in retirement: what are their prospects?

This Issue Brief examines the baby boomers' retirement income prospects by analyzing trends in the elderly's income and pension participation among workers; examining saving behavior and critically evaluating studies of the adequacy of the boomers' saving; and looking at tenure trends, lump-sum distribution preservation, and changes in Social Security benefits. Since the mid 1970s, the real median income of individuals aged 65 and over has increased 18 percent. Sources of income have shifted, with employment-based pensions increasing and earnings and asset income decreasing as a proportion of income. The boomers' prospects are partly dependent on participation in employment-based retirement plans. After decreases in the sponsorship rates, participation rates, and vesting rates of workers during the 1980s, all three percentages increased during the early 1990s. Data do not support the perception that the U.S. work force is becoming increasingly mobile. Tenure levels for prime age workers in the 1980s and beginning of the 1990s were higher than those of previous decades. Still, in response to competitive pressures, employers may not offer the security of paternalistic benefit packages as in the past. Various studies have reached different conclusions regarding the adequacy of the boomers' financial preparation for retirement. Evidence indicates that boomers, in general, will enjoy a retirement standard of living exceeding that of their parents. It is less clear whether they will maintain a standard of living in retirement comparable to that of their working years. To the extent they are willing to tap housing wealth, they would appear at this early stage to be in good shape. Federal fiscal policy decisions will impact boomers by affecting their disposable income today, and thus their ability to save, as well as the benefits they will receive in retirement through Social Security and Medicare. The boomers are 17 to 35 years away from age 65. Given heterogeneity of the boomers, research is needed to identify what specific groups within the generation are at risk and the magnitude of that risk. Groups that would now appear to be at risk to some degree include non-homeowners, the less educated, the single, and the youngest boomers.

Aged↗

PubMed1993

Induction of cytolytic and antibody responses using Plasmodium falciparum repeatless circumsporozoite protein encapsulated in liposomes.

Plasmodium circumsporozoite (CS) protein-induced antibody and T-cell responses are considered to be important in protective immunity. Since the key repeat determinant of the CS protein may actually restrict the recognition of other potential T- and B-cell sites, a modified Plasmodium falciparum CS protein lacking the central repeat region, RLF, was expressed in Escherichia coli. On purification, RLF was encapsulated into liposomes [L(RLF)] and used for the in vivo induction of cytolytic T lymphocytes (CTL) and antibodies. Immunization of B10.Br (H-2k) mice with L(RLF), but not with RLF, induced CD8+ CTL specific for the P. falciparum CS protein CTL epitope, amino acid residues 368-390. Anti-L(RLF) serum reacted with antigens on intact sporozoites and inhibited sporozoite invasion of hepatoma cells. Antibody specificity studies in New Zealand White rabbits revealed new B-cell sites localized in amino acid residues 84-94, 91-99, 97-106 and 367-375. Although the mechanisms by which liposomes enhance cellular and humoral immune responses remain unknown, liposome-formulated vaccines have been well tolerated in humans; hence, their use in vaccines, when efficacy depends on antibody and CTL responses, may be broadly applicable.

Amino Acid Sequence↗

PubMed1993

Empowerment and self-help agency practice for people with mental disabilities.

During the past 15 years, there has been tremendous growth in the number of self-help groups and agencies for mental health clients. This article examines the self-help perspective in relation to problems with traditional mental health services and the need for client-run services. Self-help agencies see their goal as empowerment on an individual, organizational, and societal level. They strive to accomplish this by helping members obtain needed resources and develop coping skills; providing means of enhancing members' self-concept and lessening the stigma of perceived mental disability; giving members control in the agencies' governance, administration, and service delivery; and furthering member involvement in social policy-making. The goal of this article is not to endorse the self-help perspective but to use it as the basis for raising research questions that will further the mental health practitioner's understanding of this service modality.

Adaptation, Psychological↗

PubMed1992

Liposomal malaria vaccine in humans: a safe and potent adjuvant strategy.

This study describes the safety and immunogenicity of a liposome-based vaccine injected into human subjects. Thirty healthy adult male volunteers were immunized with a liposome-encapsulated recombinant protein (R32NS181) containing epitopes from the repeat region of the circumsporozoite protein of Plasmodium falciparum. This antigen had previously been found to be poorly immunogenic in humans when it was adsorbed with Al(OH)3. In the present study, R32NS181 was encapsulated in liposomes containing monophosphoryl lipid A that were subsequently adsorbed to Al(OH)3. Increasing doses of liposomes containing antigen and monophosphoryl lipid A were used, but the liposomes were always adsorbed to the same dose of Al(OH)3. R32-specific serum IgG antibody responses to liposome-encapsulated R32NS181 were much higher than levels attained previously in humans with R32NS181 adsorbed to Al(OH)3. Geometric mean specific IgG levels after three doses ranged from 14 to 33 micrograms/ml. Sera from volunteers receiving the two highest doses inhibited P. falciparum sporozoite invasion of cultured hepatoma cells by an average of 92%, a result that was again superior to previously reported vaccines. Moderate but acceptable transient local reactogenicity was noted at high doses of the vaccine formulation, but little or no systemic toxicity was seen despite liposomal monophosphoryl lipid A doses up to 2200 micrograms. We conclude that encapsulation of poorly immunogenic circumsporozoite protein repeat peptides in monophosphoryl lipid A-containing liposomes is a successful adjuvant strategy in humans for inducing high levels of specific antibody production.

Adjuvants, Immunologic↗

PubMed1992

Immunogenicity and efficacy trials in Aotus nancymai monkeys with model compounds representing parts of a 75-kD merozoite surface antigen of Plasmodium falciparum.

We tested the ability of a recombinant DNA-encoded fragment (C7Ag) of a Plasmodium falciparum merozoite protein (p75) and of two carrier-free peptide models (28-mer and 76-mer) to stimulate boostable antibody responses in Aotus nancymai monkeys. In addition, we evaluated protection against challenge with the Uganda Palo Alto (FUP) strain of this parasite. The data indicate that C7Ag elicited a strong and boostable IgG antibody response in all the monkeys immunized. However, studies with the peptide models demonstrated that various animals produce antibodies to different portions of this structure. When the post-boost sera from monkeys immunized with C7Ag were analyzed for reactivity against two major portions of C7Ag, most of the antibody response was observed against the disulfide-bonded 76-residue region that forms a conformational immunogenic epitope. In the same sera, antibody levels against the charged helical region modeled with a 28-mer were generally low. Immunization with synthetic peptides revealed that the 76-mer stimulated an antibody response almost as strong as C7Ag, with substantial cross-reactivity against the parasite antigen. The 28-mer evoked a response that was not efficient or uniform, and showed little reactivity with the authentic parasite antigen. Aotus nancymai was shown to be susceptible to infection with the Uganda Palo Alto strain of P. falciparum; however, maximum parasitemia varied markedly in both immunized and control monkeys. Statistical analysis failed to recognize differences in maximum parasitemia between the vaccine and control groups. The variation in maximum parasitemia suggests that the FUP strain in this species of Aotus is a poor model for the detection of differences in efficacy based on maximum parasitemia. This initial study with structures based on parts of the 75-kD merozoite surface antigen of P. falciparum indicated that both the recombinant-produced protein C7 and the 76-mer synthetic peptide, when combined with a Syntex adjuvant formulation, were safe and immunogenic in A. nancymai monkeys. However, the data emphasize the problems of using animal models to evaluate the potential effects of immunogens in humans.

Adjuvants, Immunologic↗