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Biomedical subjects

A Rosen

Publications and source records attributed to A Rosen.

At least 109 records · Page 6Linked to original sources
PubMed1998

Sindbis virus induces apoptosis through a caspase-dependent, CrmA-sensitive pathway.

Sindbis virus infection of cultured cells and of neurons in mouse brains leads to programmed cell death exhibiting the classical characteristics of apoptosis. Although the mechanism by which Sindbis virus activates the cell suicide program is not known, we demonstrate here that Sindbis virus activates caspases, a family of death-inducing proteases, resulting in cleavage of several cellular substrates. To study the role of caspases in virus-induced apoptosis, we determined the effects of specific caspase inhibitors on Sindbis virus-induced cell death. CrmA (a serpin from cowpox virus) and zVAD-FMK (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) inhibited Sindbis virus-induced cell death, suggesting that cellular caspases facilitate apoptosis induced by Sindbis virus. Furthermore, CrmA significantly increased the rate of survival of infected mice. These inhibitors appear to protect cells by inhibiting the cellular death pathway rather than impairing virus replication or by inhibiting the nsP2 and capsid viral proteases. The specificity of CrmA indicates that the Sindbis virus-induced death pathway is similar to that induced by Fas or tumor necrosis factor alpha rather than being like the death pathway induced by DNA damage. Taken together, these data suggest a central role for caspases in Sindbis virus-induced apoptosis.

Alphavirus Infections↗
PubMed1998

African-American race and antibodies to topoisomerase I are associated with increased severity of scleroderma lung disease.

STUDY OBJECTIVES: To determine whether African-American race is independently associated with lung disease in scleroderma. DESIGN: Retrospective review. SETTING: University medical center in Baltimore. PATIENTS: One hundred one patients with diffuse cutaneous scleroderma with available serum samples. MEASUREMENTS: Patients underwent lung function testing as part of their routine clinical care. Percent predicted values adjusted for race were calculated for FVC, single-breath carbon monoxide diffusing capacity (Dco), and FEV1. Serum samples were assayed for the presence of antibodies to topoisomerase I and RNA polymerase II. RESULTS: Scleroderma patients of African-American race had lower percent predicted values than white patients for FVC (p<0.002), Dco (p<0.0001), and FEV1 (p<0.0001). Antibodies to topoisomerase I but not antibodies to RNA polymerase II were also associated with lung function. African-American scleroderma patients were distinct from white patients in having younger age of onset and higher prevalence of antibodies to topoisomerase I. In multivariate analyses accounting for sex, age, smoking history, years of scleroderma symptoms, and RNA polymerase II antibody status, African-American race and topoisomerase I antibody status independently predicted lower lung function. CONCLUSION: African-American race and antibodies to topoisomerase I are independent risk factors for scleroderma lung disease.

Autoantibodies↗
PubMed1997

The Family Attitude Scale: reliability and validity of a new scale for measuring the emotional climate of families.

Research on outcomes from psychiatric disorders has highlighted the importance of expressed emotion (EE), but its cost-effective measurement remains a challenge. This article describes development of the Family Attitude Scale (FAS), a 30-item instrument that can be completed by any informant. Its psychometric characteristics are reported in parents of undergraduate students and in 70 families with a schizophrenic member. The total FAS had high internal consistency in all samples, and reports of angry behaviour in FAS items showed acceptable inter-rater agreement. The FAS was associated with the reported anger, anger expression and anxiety of respondents. Substantial associations between the parents' FAS and the anger and anger expression of students was also observed. Parents of schizophrenic patients had higher FAS scores than parents of students, and the FAS was higher if disorder duration was longer or patient functioning was poorer. Hostility, high criticism and low warmth on the Camberwell Family Interview (CFI) were associated with a more negative FAS. The highest FAS in the family was a good predictor of a highly critical environment on the CFI. The FAS is a reliable and valid indicator of relationship stress and expressed anger that has wide applicability.

Adolescent↗
PubMed1997

The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients.

40 recipients of first cadaver kidney transplants were given perioperative donor vertebral bone marrow infusions (DBMC), compared with 100 controls who did not receive donor bone marrow. The immunosuppressive regimen included OKT3, Tacrolimus, and steroid maintenance therapy, and, in some patients, newly introduced mycophenolate mofetil. This report describes the 24-mo actuarial follow-up and several immunological monitoring studies including sequential measurements of donor bone marrow lineage subset chimerism by the recently reported PCR-flow assay. This is a sensitive in situ PCR detection system for donor versus recipient histocompatibility genes as well as cell surface CD epitope markers using flow cytometry. The results indicate (a) the stabilization of the donor CD3+ and CD34+ cells in recipient peripheral blood at levels below 1% between 6 mo and 1 yr postoperatively, with a 10-fold higher level of donor cell chimerism of these lineages in recipient iliac crest marrow; (b) significantly lower levels of chimerism in peripheral blood up to 6 mo postoperatively in patients who had early acute (reversible) rejection episodes compared with those who did not; (c) a higher degree of chimerism seen in patients who were class II MHC HLA DR identical with their donors; (d) the identification of a high proportion of the donor bone marrow derived CD3 dimly staining subset of T cells (to which regulatory functions have been ascribed) in recipient peripheral blood and especially in recipient bone marrow; and (e) an unexpectedly increased susceptibility to clinically significant infections (primarily viral), and even death in the DBMC-infused group, compared with controls, but no graft losses because of rejection in the DBMC-infused group. Mixed lymphocyte culture assays showed a trend toward a greater number of nonspecifically low reactors in the DBMC group, as well as a greater number of nonspecifically high reactors in the controls (P = 0.058). The autologous mixed lymphocyte reaction also indicated a trend towards nonspecific immune activation in the DBMC group. Finally, anti-cytomegaloviral IgG antibody reactivity was significantly inhibited in the DBMC group 4-6 mo postoperatively (P = < 0.05). In the controls, there were no donor cell lineages detected by PCR-flow in the peripheral blood. These rather unexpected findings, indicating a more depressed cellular and humoral immune capacity in the DBMC cadaver kidney transplant recipients in this relatively early follow-up period, are discussed relevant to chimerism, MHC restriction, and suppressor activity brought about by specialized DBMC subsets, which still need to be defined.

Adolescent↗
PubMed1997

Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis.

The observation that revelation of immunocryptic epitopes in self antigens may initiate the autoimmune response has prompted the search for processes which induce novel fragmentation of autoantigens as potential initiators of autoimmunity. The reversible ischemia reperfusion which characterizes scleroderma has focused attention on reactive oxygen species as molecules which might induce autoantigen fragmentation. We demonstrate that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by reactive oxygen species, in a metal-dependent manner. Multiple features of the fragmentation reaction and its inhibition indicate that these autoantigens possess metal-binding sites, which focus metal-catalyzed oxidation reactions (and consequent fragmentation) to specific regions of the antigens. These data suggest that the autoantibody response in scleroderma is the immune marker of unique protein fragmentation, induced by ischemia reperfusion in the presence of appropriate metals, and focus attention on abnormal metal status as a potential pathogenic principle in this disease.

Autoantigens↗
PubMed1997

Macromolecular substrates for the ICE-like proteases during apoptosis.

The interleukin-1 beta-converting enzyme (ICE) family of proteases is an important component of the mechanism of the apoptotic process, but the physiologic roles of the different homologs during apoptosis remain unclear. Significant information about the roles of proteolysis in apoptosis will be gained through identification of the distal substrates through which these proteases achieve their pro-apoptotic effects. Identification of these substrates therefore remains an important challenge. A subset of autoantibodies from patients with systemic lupus erythematosus (SLE) recognize molecules that are specifically cleaved early during apoptosis. Several of the identified autoantigens are nuclear proteins (PARP, U1-70 kDa, and DNA-PKcs) that are substrates for CPP32 in vitro and in apoptotic cells. Of note, these substrates are catalytic proteins involved in homeostatic pathways, suggesting that abolition of homeostasis is one fundamental feature ensuring the rapid irreversibility of the apoptotic process. Identification of the other substrates for this protease family will provide the tools to assess the roles of the different proteases in apoptotic death.

Animals↗
PubMed1997

Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings.

Mycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been approved for clinical use (CellCept) in renal transplant patients in combination with cyclosporine (CsA). With the expanded use of tacrolimus (Prograf) as well in renal transplant patients, there is a lack of pharmacokinetic studies clarifying drug interactions between the three agents. A pharmacokinetic study was performed on 18 stable renal transplant patients receiving MMF and tacrolimus together, and four control groups, one receiving tacrolimus alone, two receiving CsA, in combination with MMF (1.0 or 1.5 g bid), and one receiving CsA microemulsion (Neoral). Area-under-the-curve values were calculated for each drug to assess if there was a reciprocal effect on the respective bioavailability of each. In vitro, the immunosuppressive effect of trough level plasma from each patient group was studied using mixed lymphocyte culture (MLC), as well as MLC reactions spiked with various combinations of each drug. There was a minimal effect of MMF on tacrolimus pharmacokinetics. However, patients receiving tacrolimus and MMF displayed significantly higher levels (Cmin and area under the curve) of mycophenolic acid (MPA) than those receiving CsA (Sandimmune or Neoral) and the same dose of MMF (50.2 +/- 16.5 vs 32.1 +/- 16.7 micrograms h/ml AUC, p < 0.02). Equivalent MPA levels could be attained in patients receiving CsA if the MMF dose was increased by 50% (1.5 g bid). There were also significantly lower levels of the glucuronide metabolite of MPA (MPAG) (755 +/- 280 vs 1230 +/- 250 micrograms h/ml AUC, p = 0.02), suggesting a specific inhibition (either direct or indirect) of the conversion of MPA to MPAG in tacrolimus patients, as opposed to those receiving CsA. For each drug combination, there was a positive correlation between the plasma immunosuppressive effect seen in MLC assays and the MMF dose. In addition, trough plasma from patients receiving tacrolimus and MMF was significantly more MLC inhibitory than from those receiving CsA or CsA microemulsion and equivalent-dose MMF. Culture media containing MPA and tacrolimus equal to clinical therapeutic trough concentrations (10 ng/ml) were significantly more MLC inhibitory than CsA at equivalent clinical therapeutic trough concentrations (200 ng/ml) with equivalent MPA levels. These studies in renal transplant patients suggest that tacrolimus in combination with MMF may result in a greater degree of immunosuppression than may be anticipated.

Adult↗
PubMed1997

Role of metal-catalyzed oxidation reactions in the early pathogenesis of scleroderma.

The observation that revelation of immunocryptic epitopes in self-antigens may initiate the autoimmune response has prompted the search for processes that induce novel autoantigen structure as potential initiators of autoimmunity. Recent studies have demonstrated that the autoantigens targeted in diffuse scleroderma are unified by their enrichment in nucleolini and by their susceptibility to fragmentation in a novel metal-dependent reaction that requires the generation of reactive oxygen species. Several other studies highlight the importance of reactive oxygen species as mediators of damage during ischemia-reperfusion and present evidence for increased generation of these radicals in patients with scleroderma. Together, these studies suggest a model for the pathogenesis of scleroderma in which metals and free radicals play a central, autoamplifying role.

Autoantibodies↗
PubMed1997

Nonseptic lateral sinus thrombosis: the otolaryngologic perspective.

Nonseptic lateral sinus thrombosis (NSLST) differs from septic lateral thrombosis (SLST) in that it is not associated with ear or sinus infection, it usually occurs in the adult population, and it has an ambiguous clinical presentation. The otolaryngologist is often consulted about diagnostic findings associated with lateral sinus thrombosis. We report three cases of NSLST that required otolaryngologic assessment. The patients were women, ages 23 to 31 years. Presenting symptoms were headaches in all three patients; one also had concomitant ear pain. Two patients had negative head computed tomography scans; only magnetic resonance imaging was diagnostic. Treatment of NSLST consists of anticoagulation and elimination of predisposing factors. Familiarity with this condition is fundamental for early diagnosis and initiation of appropriate therapy. We discuss the origins and causes of NSLST, clinical presentation, preferred diagnostic strategy, and treatment alternatives.

Adult↗
PubMed1997

Surgical closure of persisting failed tracheoesophageal voice fistula.

Tracheoesophageal puncture (TEP) is a highly successful procedure for voice restoration. Occasionally, however, patients fail to achieve satisfactory voice or develop salivary leakage through the fistula into the trachea. Closure of the TEP is then necessary. In most cases, spontaneous closure occurs once the prosthesis has been removed. When the fistula does not close spontaneously, surgical closure is indicated to prevent aspiration and pulmonary complications. We describe a three-layer technique that employs interposition of dermal graft. The technique was used on 14 patients over a 7-year period. Most patients received irradiation to the neck. Complete closure was achieved in 13 of 14 cases; 1 patient developed partial breakdown of the closure. Our technique is relatively easy to perform and has a high success rate (92%). Irradiation did not adversely affect the closure rate.

Aged↗
PubMed1997

Ultraviolet light-induced keratinocyte apoptosis: a potential mechanism for the induction of skin lesions and autoantibody production in LE.

Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease which is characterized clinically by pleiotropy and periodicity. The immune features which accompany the characteristic flares of the disease have strongly suggested that the autoimmune response is driven by self antigen, and is T cell-dependent. These features have prompted the search for potential initiating process(es) which induce the release of self-antigens in a form which causes T cell tolerance to those self molecules to be broken. We review here several recent observations which implicate apoptotic cells as an important potential source of clustered and concentrated autoantigens in SLE, and present our current model whereby the novel autoantigen fragments generated in apoptotic surface blebs initiate and drive the autoimmune response in this disease.

Apoptosis↗
PubMed1997

Pressure at residual volume: a useful adjunct to standard fill cystometry.

PURPOSE: Determining the role of the bladder in incontinence and/or upper urinary tract deterioration involves the cystometrographic evaluation of detrusor compliance. Management decisions based on information provided by standard fill water cystometry assume that data reflect the physiological state of the patient but this is not always true. We report the use of pressure at residual volume as a physiological measurement to aid in the interpretation of data obtained during standard fill urodynamics. MATERIALS AND METHODS: All patients presenting to our urodynamic suite for standard cystometry between June 1994 and December 1995 underwent measurement of bladder pressure at insertion of the urodynamic catheter. Residual volume and pressure measured before draining this urine, that is pressure at residual volume, were recorded. The bladder was then filled at a rate equal to or less than 10% per minute of known or predicted capacity. When a volume equal to the residual volume had been instilled, filling pressure was recorded and the remainder of the standard urodynamic evaluation was completed. Uncooperative patients as well as those with an active infection or residual volume less than 10 ml. were excluded from further analysis. RESULTS: In 152 children pressure at residual volume was compared to filling pressure and the difference was analyzed. Filling pressure was higher than pressure at residual volume in the majority of cases. In 59 children there was a positive change (filling pressure greater than pressure at residual volume) of 5 cm. water or greater and in 13 there was a negative change (pressure at residual volume greater than filling pressure) of 5 cm. water or less. When only cases in which pressure at residual volume was greater than 5 cm. water were analyzed, 46 and 33% had a difference between filling pressure and pressure at residual volume of 5 cm. water or greater and 10 cm. water or greater, respectively. CONCLUSIONS: Pressure at residual volume is physiological, simple to determine and may provide additional information regarding storage characteristics of the bladder. In the context of the clinical history differences between pressure at residual volume and filling pressure may help to interpret standard fill cystometry data.

Adolescent↗
PubMed1997

Human monoclonal antibodies to viral peptides.

A new approach to the developing of human monoclonal antibodies to viral peptides is described. The method is based on the positive selection of B cells specific to viral peptides from normal human tissues. To isolate B cells bearing immunoglobulin receptors specific to viral epitopes magnetic beads coated by viral peptides were used. Human B lymphocytes specific to the neutralizing epitope of gp120 of human immunodeficiency virus and to the major epitope of Epstein-Barr nuclear antigen-I were isolated from freshly removed human tonsils. Preselected cells were transformed by Epstein-Barr virus and cultivated on irradiated human embryonic lung fibroblasts in RPMI 1640-OptiMEM medium with 10% fetal calf serum and all necessary supplements. The cultures of B cells producing antibodies to viral epitopes used for selection were obtained. Two cultures secreting IgM antibodies to the peptide MN-24 (neutralizing epitope of immunodeficiency virus) and to the peptide p107 of Epstein-Barr nuclear antigen-1 were expanded, and the specificity of the antibodies and antibody-producing cells was analyzed. The method of positive selection of B cells specific to viral peptides may be used for the preparation of human monoclonal antibodies to viral antigens.

Amino Acid Sequence↗