Search PubMed⌕ Search

Biomedical subjects

J W Clark

Publications and source records attributed to J W Clark.

At least 127 records · Page 7Linked to original sources
PubMed1989

Randomized trial of recombinant alpha 2b-interferon with or without indomethacin in patients with metastatic malignant melanoma.

alpha-Interferon has antitumor activity in a variety of malignancies but is frequently associated with unacceptable toxic side-effects. The routine use of agents potentially capable of reducing these side-effects has not been recommended out of concern for possible reductions in the therapeutic activity of interferon. We conducted a prospective randomized trial of alpha-interferon given with or without indomethacin to patients with malignant melanoma to determine what effect, if any, indomethacin might have on the toxic, immunomodulatory, and therapeutic properties of interferon in this disease. 53 patients were stratified according to performance status and randomized to receive alpha 2b-interferon, 20 million units per m2 i.v., 5 days per week for 4 weeks followed by 10 million units per m2 s.c. three times per week, either with or without indomethacin, 25 mg orally three times a day. The overall major response rate was 13% (three complete responders and three partial responders among 47 evaluable patients) and was the same on both arms. The mean maximal temperature elevation induced by interferon was significantly reduced (from 102.1 to 100.7, P = 0.0002) by indomethacin, but the incidence and severity of interferon-related fatigue, reduction in performance status, headache, depression, confusion, elevations in liver function tests, and myelosuppression were no different in either arm of the study. Indomethacin did not reduce the frequency of dose reductions for toxic side-effects and did not permit the administration of higher interferon doses. Peripheral blood natural killer activity was significantly enhanced in patients during maintenance therapy whether or not they received indomethacin. Indomethacin appeared to inhibit augmentation of natural killer activity during high dose induction therapy. Immunological changes did not correlate with response status. We conclude that indomethacin can reduce the fever associated with interferon therapy in patients with malignant melanoma without interfering with its therapeutic or chronic immunomodulatory activities. Since fever is rarely the dose-limiting toxicity of interferon, indomethacin is of marginal benefit to patients with malignant melanoma receiving interferon at the doses outlined in this study.

Adult↗
PubMed1989

Comparative study of suture and laser-assisted anastomoses in rat sciatic nerves.

Conventional suture repair of peripheral nerves results in a fibrotic reaction that is detrimental to nerve regeneration. As an alternative procedure known as "laser-assisted" repair, a laser can be used, along with a reduced number of sutures, to reanastomose served peripheral nerves. To explore the long-term implications of this technique, the right sciatic nerves of Sprague-Dawley rats were surgically cut and reanastomosed either by means of four epineurial sutures or two epineurial sutures and CO2 laser welds. Tensile strength, electrophysiology, histology, and functional studies were performed up to 11 months postoperatively. Tensile strength measurements indicate no long-term disadvantage with the laser-assisted technique, although the short-term tensile strength is lower than with conventional suture repair. The conduction velocities of the repaired nerves were similar for both techniques; however, laser-assisted repaired nerves were found to have lower stimulation thresholds and reduced branching compared to the suture repaired nerves. The measured functional recovery was similar for both repair techniques.

Anastomosis, Surgical↗
PubMed1989

The influence of age, race, and gender on peripheral blood mononuclear-cell subsets in healthy nonsmokers.

To investigate the influence of age, race, and gender on the cellular immune system, we determined T-cell, B-cell, monocyte, natural killer (NK)-cell, and HLA-DR+-cell subsets in 266 nonsmokers from a population-based random sample of healthy adults using monoclonal antibodies and flow cytometry. Blacks had a lower total white blood-cell count than whites (P less than or equal to 0.0001), due primarily to a decrease in granulocytes. There was no significant difference in absolute lymphocyte count between blacks and whites. Blacks had a higher proportion of CD19+ cells (Leu 12+ B cells) and a lower proportion of CD3+ cells (OKT3+ T cells) than whites (P less than or equal to 0.01). Female sex and increasing age were independently associated with an increased percentage of CD4+ cells (OKT4A+ helper-inducer T-cell subset), resulting in a higher helper/suppressor ratio among women and older individuals (P less than or equal to 0.05). Black race and increasing age were independently associated with an increased proportion of HLA-DR+ cells (P less than or equal to 0.0001) which was not attributable to B cells or monocytes. No significant age, race, or gender effects were observed for CD14+ cells (Leu M3+ monocytes) or CD16+ cells (Leu 11A+ natural killer cells). These data demonstrate that age, race, and gender are each associated with significant differences in peripheral blood mononuclear-cell subsets. Population-based data such as these provide an important foundation for future design and interpretation of human flow cytometry data.

Adult↗
PubMed1989

Biochemical epidemiology in community-based studies: practical lessons from a study of T-cell subsets.

Elaborate laboratory tests are increasingly being incorporated into traditional epidemiologic research designs, a concept commonly termed biochemical epidemiology. Some of the issues encountered are illustrated by a recent population-based survey of healthy individuals in the Washington, D.C. area designed to examine the effects of demographic characteristics, lifestyle, and medical conditions on peripheral blood T-cell subsets. The study was conducted in three phases: selection of households by random digit dialing (Phase I); telephone interviews (Phase II), and self-administered questionnaires and phlebotomy (Phase III). Although this design facilitated the selection of the final study population, it influenced the participation rates by offering opportunities for nonresponse at each phase. Race was the strongest determinant of response rate despite the use of highly-trained, racially-matched telephone interviewers and repeated attempts at refusal conversion. Also discussed are issues of confidentiality, and logistics of biologic specimen collection and handling. The difficulties encountered in this survey are examined, with suggestions for future population-based investigations involving biochemical epidemiology.

Adult↗
PubMed1989

Association of cigarette smoking with decreased numbers of circulating natural killer cells.

To investigate the relationship between cigarette smoking and the level of circulating natural killer (NK) cells, we studied 282 subjects from a population-based, stratified random sample of healthy persons. NK cells were enumerated by flow cytometry using the monoclonal antibody anti-Leu 11A. Cigarette smokers had a significantly lower proportion of NK cells than did subjects who had never smoked (5.5 +/- 0.3% versus 7.4 +/- 0.4% of lymphoid cells; p = 0.0002). NK cells were also decreased among ex-smokers (5.6 +/- 0.4%; p = 0.002), including subjects who had not smoked for more than 20 yr. The white blood cell and lymphocyte counts were increased in smokers compared with those in never smokers (p less than 0.0001). In contrast to NK cells, the smoking-related changes in leukocyte count were not present in ex-smokers, even those who had stopped smoking within the past year. Multivariate analysis confirmed that both current and past smokers had significant decreases in both the number and proportion of NK cells after controlling for age, sex, and lymphocyte count. These data indicate that cigarette smoking is associated with a decrease in the number and proportion of circulating NK cells, and that this effect is present many years after smoking cessation. This quantitative NK cell deficit may contribute to the elevated risk of malignancy in this population.

Adult↗
PubMed1989

The effects of cigarette smoking on T cell subsets. A population-based survey of healthy caucasians.

To investigate the influence of cigarette smoking on mononuclear cell subsets, we determined T cell, B cell, monocyte, and HLA-DR+ subsets in a population-based, stratified, random sample of healthy Caucasians using monoclonal antibodies and flow cytometry. The study population consisted of 282 subjects 20 to 69 yr of age, including 108 smokers and 174 nonsmokers. Multivariate analysis techniques were used to assess the influence of cigarette smoking status after controlling for the effects of age and gender. Cigarette smoking was associated with a nonspecific increase in the leukocyte count involving all major cell types (smokers: 8.50 +/- 0.15 versus nonsmokers: 7.33 +/- 0.12 cells/mm3; p less than or equal to 0.0001). In addition, cigarette smokers had a selective increase in CD4+ cells (helper-inducer T cells) compared with nonsmokers (55.3 +/- 0.8 versus 52.2 +/- 0.6% of lymphoid cells; p = 0.002), resulting in a statistically significant increase in the CD4+/CD8+ (helper/suppressor) ratio (2.42 +/- 0.1 versus 2.13 +/- 0.16; p = 0.02). There was no significant difference between smokers and nonsmokers in the level of CD3+ cells (total T cells: 76.8 +/- 0.7 versus 76.1 +/- 0.5; p = 0.5), CD8+ cells (suppressor-cytotoxic T cells: 25.7 +/- 0.8 versus 27.0 +/- 0.5%; p = 0.1), CD19+ cells (B cells) (10.7 +/- 0.4 versus 10.0 +/- 0.3%; p = 0.2), CD14+ cells (monocytes) (18.0 +/- 0.6 versus 17.0 +/- 0.4%; p = 0.2), or HLA-DR+ cells (14.5 +/- 0.5 versus 14.0 +/- 0.4%; p = 0.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Deoxycoformycin-induced immunosuppression in patients with hairy cell leukemia.

Immune function in patients with hairy cell leukemia (HCL) was examined serially during treatment with alternating monthly cycles of recombinant interferon alpha-2a and 2'-deoxycoformycin (dCF). At presentation, most patients had normal numbers of T lymphocytes and their cells had normal proliferative responses to mitogens [phytohemagglutinin (PHA) and concanavalin A (Con A)] and alloantigens. Patients had severe monocytopenia, decreased delayed-type hypersensitivity (DTH) reactions, and decreased peripheral blood natural killer (NK) activity. Treatment caused a profound decrease in all lymphocyte subpopulations. T cells were more affected than B cells or NK cells. Numbers of CD4+ and CD8+ lymphocytes decreased to levels less than 200 cells/microliters in all patients during treatment. This decrease in T cell number was associated with a marked decrease in proliferative responsiveness to PHA, Con A, and alloantigens. These abnormalities persisted throughout the 14 months of treatment and have continued for up to 6 months beyond discontinuation of treatment. NK cell activity increased during treatment, but cycled depending on the phase of treatment; highest activities were observed after interferon (IFN)-alpha and lower levels of activity were observed after dCF. DTH responses generally did not improve during therapy. Levels of IgM, IgG, IgA, and IgD did not change during treatment, but IgE levels rose in most patients. All immunosuppressive effects were attributable to dCF since patients receiving IFN-alpha 2a alone did not exhibit these same immunosuppressive effects, and patients receiving dCF alone after IFN failure exhibited similar abnormalities. Despite this severe immunosuppression from dCF, life-threatening opportunistic infections have not been observed in our patient population. Six patients developed localized Herpes zoster infection among 21 patients who had received dCF. Pending the results of long-term follow-up, we recommend that dCF be reserved for patients who have failed splenectomy and IFN therapy.

Coformycin↗
PubMed1988

Resistance to recombinant interferon alfa-2a in hairy-cell leukemia associated with neutralizing anti-interferon antibodies.

To explain the hematologic deterioration occasionally observed during interferon therapy, we assayed serum specimens from 51 patients with hairy-cell leukemia receiving treatment with recombinant interferon alfa-2a for the presence of anti-interferon antibodies. After a median of seven months of therapy, anti-interferon antibodies were found in 31 patients. Fifteen of these patients had only non-neutralizing antibodies, but antibody from the other 16 neutralized the antiviral effects of recombinant interferon alfa-2a in vitro. In no case, however, did neutralizing antibody inhibit the antiviral effects of purified natural interferon alfa. Clinical resistance to interferon of various degrees was present in 6 of 16 patients with neutralizing antibodies; the remaining 10 patients and all 20 patients without antibody continue to respond after a minimum of two years of therapy. In all the patients with interferon resistance, antibody was present when it developed. These data suggest that the development of clinical resistance to interferon alfa-2a in hairy-cell leukemia is not necessarily related to an altered cellular response to interferon. Treatment with other interferons, such as purified natural interferon alfa, may be useful in patients with clinically important neutralizing antibodies against interferon alfa-2a.

Antibodies↗
PubMed1988

Adult T-cell leukemia/lymphoma in Brooklyn.

Fifteen patients with adult T-cell leukemia/lymphoma (ATLL) were identified in less than a two-year period in the Crown Heights-Bedford Stuyvesant section of Brooklyn, NY. All patients were black; nine patients originated from the Caribbean islands and six from the southern United States. Two of the patients were father and daughter, the first evidence of familial occurrence in the United States. Their clinical course was similar to that of previously described patients with this disorder. To our knowledge, these 15 patients represent the largest series of ATLL reported in the United States. We recommend that ATLL be seriously considered in the differential diagnosis of patients with non-Hodgkin's lymphoma, mycosis fungoides, lymphatic leukemia, or hypercalcemia.

Adult↗
PubMed1988

Molecular epidemiology of HTLV-I-associated non-Hodgkin's lymphomas in Jamaica.

As part of epidemiologic studies of human T-lymphotropic virus (HTLV)-I-associated malignancies in Jamaica, the authors evaluated 26 patients with non-Hodgkin's lymphoma for the presence of integrated HTLV-I provirus in their malignant cells. Fifteen of 26 patients had integrated provirus. All 15 also were HTLV-I antibody positive. Eleven patients did not have integrated provirus, and all 11 were antibody negative. All of the antibody-positive cases had onset of their disease in adulthood (age range, 21-57 years) as opposed to the broad age range of negative cases (4-66 years). Clinical features which were more common in provirus positive than negative patients included leukemic phase, skin involvement, and hypercalcemia, which are all features frequently seen in HTLV-I-associated adult T-cell leukemia/lymphoma (ATLL). The presence of skin involvement, circulating malignant cells, abnormal liver function tests, or the presence of two or more of these four features were statistically significantly different between virus-positive and virus-negative cases. Although the survival of positive cases (6 months) was shorter than that of negative cases (9 months), this was not statistically significant. The only significant determinant of survival was hypercalcemia, with those who developed hypercalcemia at some point in their disease course, independent of their HTLV-I status, surviving a mean of 5 months as compared to a mean of 17.5 months in those who never became hypercalcemic. The six HTLV-I-positive lymphomas that underwent cell typing were all primarily OKT4 positive, whereas two HTLV-I antibody-negative cases that were typed were B-cell lymphomas.

Antibodies, Viral↗
PubMed1988

Human T-cell lymphotropic virus type I (HTLV-I) seroepidemiology and risk factors in metropolitan Panamá.

Human T-cell lymphotropic virus type I (HTLV-I) infection and associated hematologic malignancies cluster in Japan, the Caribbean basin, and Central Africa. The authors believe that this study of HTLV-I seroepidemiology in the Republic of Panamá is the first detailed analytic study of environmental factors pertaining to HTLV-I infection in representative tropical populations. The study analyzed observational data concerning housing conditions, family composition, and demographic and behavioral attributes as risk factors for HTLV-I infection (HTLV-I antibody). The 745 study subjects were residents of representative households in Panamá City and Colón. Overall, 5% of sera had antibody against HTLV-I, detected by enzyme-linked immunosorbent assay and confirmed by competitive binding. Housing conditions, race, and socioeconomic factors were not associated with infection nor did infection cluster in families. Interview of 706 women enrolled in cervical cancer studies documented that female sexual experience (number of marriages or sexual partners) was associated with HTLV-I infection. These findings support the hypothesis that HTLV-I is not transmitted by casual contact but requires exposures involving exchange of bodily fluids.

Adolescent↗
PubMed1988

Adoptive therapies: quo vadis?

The success of adoptive immunotherapy using interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells in treating a percentage of patients with melanoma and renal cell carcinoma has provided impetus to research into both how to optimize this treatment as well as approaches into making immunotherapy in general more successful. As the question on how to optimize IL-2 dose, schedule, cell culture conditions, and other specifics of IL-2 plus LAK therapy are addressed in clinical trials, other approaches suggested by data from in vitro, animal, and the clinical studies using IL-2 are emerging into clinical trials. (table; see text) These include two major areas of focus at the present time: (1) the use of IL-2 +/- LAK in combination with a variety of agents which have been shown to be synergistic with it, including other biological response modifiers (such as interferons), agents which may act both as interferon inducers as well as by other mechanisms (poly-IC:LC and flavone-8-acetic acid), and chemotherapeutic agents (especially cyclophosphamide, doxorubicin and agents which have some activity against the disease being treated such as DTIC for melanoma), and (2) various approaches aimed at inducing and expanding tumor-specific immune cells which appear to have greater antitumor activity than LAK cells and which may be major contributors to the antitumor efficacy of IL-2 therapy. These approaches also have the potential benefit of inducing memory cells with a resultant long-term immune antitumor response. Approaches aimed at activating specific antitumor immune cells include the use of IL-2-expanded infiltrating lymphocytes from tumors, exposure of peripheral blood cells cultured in IL-2 to tumor cells to hopefully expand those with a specific antitumor response, and the use of tumor cell vaccines in conjunction with IL-2. In addition to approaches using activated and expanded LAK effectors or specific T cells, the potential role of activated (e.g. by gamma interferon) and expanded (e.g. by macrophage colony stimulating factor) macrophages in the adoptive immunotherapy of cancer remains an area of ongoing exploration both in preclinical studies and clinical trials. As a greater understanding of the antitumor mechanisms of IL-2 and LAK therapy and other forms of adoptive immunotherapy is achieved, therapeutic approaches can be defined which will maximize the ability to mediate the immune destruction of tumor cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Comparison of the effects of two topical fluoride regimens on demineralized enamel in vivo.

The purpose of this investigation was to study the intra-oral remineralization of acid-softened enamel by a NaF dentifrice compared with that from a combination of topical F agents. Bovine enamel slabs were demineralized with 0.1 mol/L lactic acid at pH 4.0 for 14 hr and then mounted in a removable mandibular appliance. Control slabs were worn for 96 hr by seven adult males who brushed daily with a F-free dentifrice. Test slabs were brushed with a NaF dentifrice 4 x/day or with the same dentifrice 4 x/day and a 0.02% APF mouthrinse and a 0.4% SnF2 gel which were applied once/day for three days. The natural dentition was also brushed with the NaF dentifrice during both test periods. Microhardness testing was performed on sound enamel, and after acid-softening, intra-oral exposure (IOE), and acid resistance testing (ART) in 0.01 mol/L lactic acid at pH 4.0 for 24 hr. Control and test slabs were etched with 0.5 mol/L HC1O4 for from 15 to 60 sec. The F content was measured with a F electrode and PO4 by spectrophotometry. Contact microradiography and image analyses were performed on control and test slabs so that changes in mineral content resulting from treatment could be assessed. Both test groups were significantly harder after both IOE and ART than were controls, but no differences appeared between the effects of the two test groups. The F content of control slabs was significantly less than that of both test groups, and the combination-treated slabs showed greater F than did the dentifrice-treated slabs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Rearrangement of both immunoglobulin and T-cell receptor genes in a prolymphocytic variant of hairy cell leukemia patient resistant to interferon-alpha.

We describe a patient with the so-called "prolymphocytic variant" form of hairy cell leukemia (HCL) resistant to treatment with interferon-alpha (IFN-alpha). Analysis of immunoglobulin (Ig) and T-cell receptor-beta (TCR beta) gene rearrangements from serial peripheral blood mononuclear cell specimens (MNCs) confirmed not only the B-cell nature of the disease, but also the subsequent emergence of a morphologically indistinguishable population of cells with a clonal TCR beta rearrangement in addition to the original Ig gene rearrangement. With the exception of a transient increase in peripheral blood T cells during treatment with deoxycoformycin (DCF), the MNCs remained essentially constant throughout therapy with no evidence of a co-existing T-cell clone to account for the TCR beta rearrangement. Although MNCs from this patient bound significantly less IFN-alpha than did MNCs from other HCL patients, the binding was of high affinity with a kd similar to that of control cells. The number of IFN-gamma receptors on our patient's MNCs was four times higher than the number of IFN-alpha receptors and was similar to the number of IFN-alpha receptors on MNCs from HCL patients responsive to IFN-alpha. While various treatments including IFN-alpha, DCF, chlorambucil, splenectomy, leukopheresis, and IFN-gamma were not able to change the clinical progression of the disease, they may have provided an opportunity for the divergent TCR beta rearranged clone to expand and displace the initially dominant clone.

Aged↗
PubMed1988

Lack of relation between human T-lymphotropic virus type I infection and systemic lupus erythematosus in Jamaica, West Indies.

To determine whether systemic lupus erythematosus (SLE) is associated with human T-lymphotropic virus, type I (HTLV-I) infection in Jamaica, an endemic area for the virus, we studied 63 patients with SLE at the University Hospital of the West Indies in Kingston. Antibodies to HTLV-I were measured by an enzyme-linked immunosorbent assay (ELISA) technique using purified disrupted whole virus as antigen, with confirmation by p24 protein RIA or competitive binding. Four of 63 SLE patients were HTLV-I seropositive (6.3%). There was no evidence for excess HTLV-I infection in SLE patients when their age- and sex-standardized HTLV-I seroprevalence rate was compared to that of a large group of healthy food service employees. None of 13 patients with rheumatoid arthritis were seropositive for HTLV-I. We conclude that HTLV-I infection does not appear to be linked with SLE in Jamaica.

Adolescent↗
PubMed1987

Clinical and laboratory observations in a lymphoma-prone family.

Three sisters developed non-Hodgkin's lymphoma (NHL). Thirteen maternal relatives had adenocarcinomas of various types, predominantly breast and large bowel. Detailed laboratory assessment of this family revealed a variety of immunologic abnormalities. Two lymphoma patients had elevated anti-early antigens (EA) Epstein-Barr virus (EBV) titers. One of the two also had a markedly elevated anti-viral capsid antigen (VCA) EBV titer. The two lymphoma patients were human leukocyte antigen (HLA)-identical, but two unaffected siblings shared the same HLA haplotypes. One of the lymphoma patients and four unaffected family members were anergic; and three unaffected family members had a decreased percentage of T-cells. These data suggest that a subtle disturbance in cellular immune functions may play a causal role in some familial aggregations of malignant lymphoma.

Aged↗