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Biomedical subjects

M R Clark

Publications and source records attributed to M R Clark.

At least 55 records · Page 3Linked to original sources
PubMed1996

A successful university-school-district partnership to help San Francisco's K-12 students learn about science and medicine.

The Science and Health Education Partnership (SEP) is a program at the University of California, San Francisco, established in 1987 to support the San Francisco School District ("the District") in its efforts to improve science education in grades K-12. A large cadre of active biomedical scientists and health professionals and a core program staff provide support to 90-95% of the District's schools. The District's students are from a variety of racial and ethnic groups, including a large percentage from underrepresented minorities (URMs). The SEP program has numerous components, some designed to help teachers (e.g., a clinician or scientist forms an ongoing partnership with a teacher to enrich classroom instruction) and some involving direct work with students (e.g., a contest where teams of students design and present lessons on science or health to their peers; activities related specifically to the encouragement of URM students). The SEP's perspective has evolved from an emphasis on assisting individual teachers and students to one of supporting systemic change throughout the District (e.g., supporting full implementation of hands-on, inquiry-based science instruction throughout the District via professional development). During this evolution, the kinds of issues facing program staff have changed and a great deal has been learned about fostering successful partnership activities. For example, (1) having a coordinator is crucial to make such a program work well; (2) it is easier to find start-up funding than to find continuing funding for ongoing activities that are working; and (3) it is important to work with the volunteering scientists and the teachers to help them understand what each has to offer the partnership and to encourage explicit dialogue about roles and expectations. The author concludes with advice for starting a new partnership: think big but start small, and work toward a long-term association based on communication and trust.

Adolescent↗
PubMed1995

Interaction of human monocyte Fc gamma receptors with rat IgG2b. A new indicator for the Fc gamma RIIa (R-H131) polymorphism.

Rat mAbs receive considerable interest for immunologic intervention in man. The rat IgG2b isotype has previously been found to be optimally active both in vivo and in vitro. We found that both a rat IgG2b CD3 mAb and a monovalent hybrid rat IgG2b-mouse IgG1 bispecific Ab triggered T cell activation in PBMC. Inhibition analyses with mAb blocking different human IgG Fc receptors (Fc gamma R) showed a dimorphic pattern. In donors expressing an Fc gamma RIIa-R/R131 allotype (previously defined on the basis of interaction with mouse (m) IgG1 as "high responder") anti-Fc gamma RI mAb 197 inhibited rat IgG2b induced T cell mitogenesis almost completely. In Fc gamma RIIa-H/H131 ("low responder" allotype) donors, however, both anti-Fc gamma RI mAb 197 and anti-Fc gamma RII mAb IV.3 were essential for optimal inhibition of mitogenesis. T cell proliferation experiments performed with the use of Fc gamma R-transfected fibroblasts as accessory cells showed the high affinity Fc gamma RIa (CD64) to interact with both rat IgG2b and rat IgG2b-mlgG1 hybrid CD3 mAb. The use of the two types of Fc gamma RIIa (CD32)-transfectants instead showed rat IgG2b CD3 mAb to interact solely with the IIa-H/H131 allotype. Interestingly, rat IgG2b-mlgG1 hybrid mAb did not interact effectively with this low affinity Fc gamma R. This suggests a requirement for only one rat IgG2b H chain for Fc gamma RIa-mediated binding, whereas two identical H chains seem to be necessary for proper interaction with Fc gamma RIIa. Ab-sensitized RBC-rosette experiments performed with the use of a rat IgG2b anti-NIP mAb confirmed the interaction pattern observed with rat CD3 mAb, supporting the phenomena to be isotype-, and not mAb-, dependent. These analyses point to a unique reactivity pattern for rat IgG2b Abs, interacting both with the high affinity Fc gamma RIa in all donors and Fc gamma RIIa of individuals expressing the IIa-H131 allotype.

Animals↗
PubMed1995

CD8 T cell activation after intravenous administration of CD3 x CD19 bispecific antibody in patients with non-Hodgkin lymphoma.

A bispecific antibody directed to T and B cells (CD3 x CD19 bsAb) was daily infused intravenously in escalating doses from 10 micrograms up to 5 mg in three patients with chemotherapy-resistant non-Hodgkin lymphoma; in this way we aimed to activate T cells to kill the malignant B cells. Only limited toxicity was observed, consisting of moderate fever preceded by chills or shivers and mild thrombocytopenia. No human anti-(mouse Ig) antibodies were found. Pharmacokinetics showed a t1/2 of 10.5 h with peak levels of 200-300 ng/ml after infusion of 2.5 mg bsAb. bsAb in serum was functionally active in vitro. After bsAb infusion a rise in serum tumour necrosis factor alpha was observed, accompanied by an increase in soluble CD8 and to some extent in soluble interleukin-2 receptor (IL-2R), but not in interferon gamma. IL-4 or soluble CD4. No evidence was found for monocyte activation (no increases in IL-6, IL-8 or IL-1 beta in serum). No gross changes in histology or number of IL-2R+, CD4+ or CD8+ cells were found in the lymph nodes after therapy, but one patient showed activated CD8+ T cells within the tumour nodules. In conclusion, after intravenously administered CD3 x CD19 bsAb only moderate toxicity was found, probably due to CD8+ T cell activation and cytokine release, without CD4+ T cell activation.

Adult↗
PubMed1995

Comparison of tetracaine-adrenaline-cocaine (TAC) with topical lidocaine-epinephrine (TLE): efficacy and cost.

Topical anesthesia in the form of TAC (tetracaine, adrenaline, cocaine) solution has been used for wound repair. This pilot study was designed to determine if the topical anesthesia achieved using a mixture of lidocaine (5%) and epinephrine (1:2000) (TLE) is equivalent to the topical anesthesia obtained using a solution of tetracaine (0.5%), epinephrine (1: 2000), and cocaine (10.4%) (TAC). A prospective, randomized, double-blind trial was carried out from May 1992 to August 1992 at a community-based teaching hospital Emergency Department (ED) that receives 50,000 annual visits. Patients with facial or scalp lacerations suitable for topical anesthesia presenting to the ED were included when study physicians were in attendance. Exclusion criteria included the presence of a sensory altering substance (eg, ethanol), age younger than two years, hypertension, pregnancy, allergy to any of the study's pharmacological agents, wounds greater than six hours old, grossly contaminated wounds, and wounds longer than six centimeters. Either a TAC or TLE solution was applied to lacerations before suturing. The laceration was repaired and the patient or physician evaluated the degree of pain from the procedure by using a standardized visual pain scale. A total of 35 patients were studied. Seventeen patients were in the TLE group; 18 in the TAC group. The mean ages were compared and found to be similar (P = .40) between the two test groups. The pain scale values, the diameter of tissue blanch around laceration (halo size), and the time to laceration repair from the onset of application of anesthetic were compared and no difference was shown between the TAC and TLE groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Chronic fatigue: risk factors for symptom persistence in a 2 1/2-year follow-up study.

BACKGROUND: The prolonged disability of patients suffering from chronic fatigue may be due to sustaining factors that are independent of the cause and subject to intervention. This study reexamined a cohort of patients with chronic fatigue to define medical and psychiatric predictors of persistent symptoms. METHODS: Seventy-eight patients with chronic fatigue present for 6 months or more (not required to meet the Centers for Disease Control case definition for chronic fatigue syndrome [CFS]) completed a self-report, follow-up questionnaire to measure the overall improvement or worsening of their condition at a mean of 2.5 years after their initial examination. At the time of initial evaluation, patients underwent a structured psychiatric examination, physical examination, laboratory studies, and self-report measures of psychological distress and functional disability. The psychiatric examination queried the patient about 28 somatic symptoms that are separate from those associated with CFS. Discriminant analysis was used to determine which variables present at the initial examination were significant predictors of persistent symptoms and disability at 2.5 years. RESULTS: The factors most important at the time of initial presentation in predicting persistent illness were: (1) more than eight medically unexplained physical symptoms separate from those associated with CFS case definition; (2) lifetime history of dysthymia; (3) duration of chronic fatigue symptoms greater than 1.5 years; (4) less than 16 years of formal education; and (5) age older than 38 years. None of the results of the initial physical examination, or immunologic, general laboratory, or viral antibody measurements were significant in predicting persistence of symptoms. Recovery rates for those who met the criteria for CFS by either of two case definitions were lower than the rate of noncases, but the differences were not statistically significant. The five aforementioned variables formed a significant discriminative function, correctly classifying 78% of those who recovered and 74% of those with persistent symptoms. CONCLUSIONS: At initial examination, patients with chronic fatigue, more than eight medically unexplained physical symptoms (excluding symptoms in the case criteria for CFS), a lifetime history of dysthymic disorder, longer than 1.5 years of chronic fatigue, less than 16 years of formal education, and who were older than 38 years were the most likely to have persistence of symptoms of chronic fatigue at the 2.5-year follow-up.

Adult↗
PubMed1994

Killing of autologous B-lineage malignancy using CD3 x CD19 bispecific monoclonal antibody in end stage leukemia and lymphoma.

To develop an effective tumor immunotherapy for B-lineage non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL), a bispecific monoclonal antibody (BsAb) has been generated with the first specificity for the CD3 epsilon-chain and the second for the CD19 antigen. Peripheral blood mononuclear cells (PBMCs) isolated from patients with NHL or ALL during remission or relapse rapidly proliferated (up to 179-fold increase) on in vitro activation combining phytohemagglutinin or CD3 monoclonal antibody with interleukin-2. After 3 weeks of stimulation, more than 90% of the PBMCs was CD3+ and CD8+, even when cultures were started with only 5% CD3+ cells. Cytotoxic activity against autologous malignant B cells was markedly enhanced (from 5% baseline to 70% lysis) by the addition of the CD3 x CD19 BsAb in all samples tested. Immunophenotypic examination of a series of tumor target cells showed that all samples examined showed CD54 (intercellular adhesion molecule-1) and HLA class I, but showed no B7 expression. CD11a (lymphocyte function-associated antigen-1) expression was heterogeneous. Various types of experiments showed that efficient CD3 x CD19 BsAb-mediated cytolytic capacity was not dependent on expression of either of these surface proteins. This contrasts with normal major histocompatibility complex-restricted antigen-specific cytotoxicity and may be essential for effective in vivo application of this BsAb.

Antibodies, Bispecific↗
PubMed1994

Analysis of Ig-alpha-tyrosine kinase interaction reveals two levels of binding specificity and tyrosine phosphorylated Ig-alpha stimulation of Fyn activity.

The B cell antigen receptor complex (BCR) is composed of membrane Ig and heterodimers of Ig-alpha and Ig-beta/gamma. Recent findings indicate that Ig-alpha associates with Src-family kinases, including Fyn and Lyn, via an approximately 26 amino acid motif termed ARH1. Studies reported here (i) define two mechanisms whereby this motif binds Fyn and (ii) reveal an important functional consequence of binding, i.e. kinase activation. Mutational analysis indicates that specific low-affinity binding is determined by a short sequence, -DCSM-, in the motif and is not dependent on motif tyrosine residues. In contrast, the doubly tyrosine phosphorylated motif binds independently of DCSM and with high affinity. Importantly, this binding leads to Fyn activation. Taken together with studies which map low-affinity binding of Fyn or Lyn to the kinase's N-terminal unique region and high-affinity binding to the kinase's SH2 domain, these results suggest a mechanism of BCR activation in which the non-phosphorylated resting receptor is associated with Src-family kinases and, upon stimulation, tyrosine phosphorylation of Ig-alpha leads to reorientation and activation of receptor-associated kinases.

3T3 Cells↗
PubMed1994

Unprimed CD4+ and CD8+ T cells can be rapidly activated by a CD3 x CD19 bispecific antibody to proliferate and become cytotoxic.

We previously reported that a CD3 x CD19 bispecific antibody (bsAb) can induce efficient killing of tumour cells by preactivated T cells isolated from patients with B cell malignancy. For future intravenous application we investigated whether resting T cells from peripheral blood can be stimulated to proliferate and become cytotoxic with the CD3 x CD19 bsAb alone. Indeed peripheral blood mononuclear cells, isolated from healthy donors or patients with B cell malignancy, started to proliferate within 1 day in response to CD3 x CD19 bsAb. Within the same time span cytotoxic activity against CD19-positive tumour cells was already detectable. Maintenance of cytotoxic activity was seen during 3 days of culture but optimal lysis of the target cells then required fresh CD3 x CD19 bsAb in the cytotoxicity assay. Essentially the same results for proliferation and cytotoxicity were found when separated CD4-positive and CD8-positive T cells were activated by the bsAb in the presence of autologous monocytes. These results may be relevant for the in vivo application of the bsAb when used as immunotherapy in patients with B cell malignancy.

Antibodies, Bispecific↗
PubMed1994

The B cell antigen receptor complex: mechanisms and implications of tyrosine kinase activation.

The B cell receptor is a multimeric receptor complex whose constituent chains appear to mediate distinct and possibly interrelated functions. In this review we have focused on how one chain, immunoglobulin (Ig)-alpha, may function to activate tyrosine kinases and the consequences of that activation. The cytoplasmic domain of Ig-alpha contains a consensus sequence, the antigen recognition homology 1 (ARH 1) motif, which is found in Ig-beta and other antigen recognition receptor associated chains. We argue that this conserved structure reflects an underlying conserved mechanism of secondary effector activation. Our data also indicates that the specificity of each motif (i.e., the elements which restrict secondary effector binding to particular motifs) is encoded within divergent sequences found in each ARH 1 motif. In the particular case of kinase activation by Ig-alpha, the subsequent phosphorylation of multiple tyrosines on Ig-alpha, Ig-beta, CD19, CD22 and possibly other functionally related chains form recruitment sites for a myriad of secondary signal transducers. In this model, proximal tyrosine kinases and phosphatases do not function so much to mediate the linear transfer of information as to establish and modulate an interrelated network of signal transducers capable of driving complicated cellular responses.

Amino Acid Sequence↗
PubMed1994

Symptoms as a clue to otologic and psychiatric diagnosis in patients with dizziness.

Dizziness is a common symptom that often remains unexplained despite extensive medical evaluation. Psychiatric disorders are usually considered only after all medical causes of dizziness have been ruled out. Sixty-five patients referred to an otolaryngology practice received a structured psychiatric interview, an otologic evaluation, and a dizziness questionnaire modified to assess psychiatric symptoms. They were divided into four diagnostic groups: psychiatric diagnosis only, otologic diagnosis only, both diagnoses, or neither diagnosis. Eleven questionnaire items were significantly associated with diagnostic groupings. Stepwise discriminant function analysis utilizing age, gender, rapid/irregular heartbeat, extremity weakness, nausea/vomiting, and difficulty with speech resulted in correct group classification for 70% of subjects. The presence of dizziness symptoms like vertigo or lightheadedness was not significantly different between groups. This study suggests that assessment of psychiatric and autonomic symptoms should accompany, not follow, otologic evaluation of dizziness. These symptoms may be more important diagnostically than dizziness quality.

Adult↗
PubMed1994

Signal transduction by the B cell antigen receptor and its coreceptors.

B lymphocyte antigen receptors, membrane immunoglobulins (mIg), function in focusing and internalization of antigen for subsequent presentation to T cells and in transmembrane transduction of signals leading to cell activation, anergy, or deletion. Until quite recently, the ability of this receptor to transduce signals in spite of a virtual lack of cytoplasmic structure, left a significant gap in our understanding of how it is coupled to cytoplasmic signal propagators. Studies conducted during the past five years have defined a mIg-associated protein complex homologous to the CD3 complex associated with the T cell antigen receptor. Components of this disulfide linked heterodimeric complex, Ig-alpha and Ig-beta, contain an approximately 26 residue sequence motif termed ARH1, also known as TAM, which binds to cytoplasmic effectors, including src-family tyrosine kinases, and contains all structural information needed for signal transduction. Receptor associated src-family kinases which are activated following receptor cross-linking, also associate with downstream effectors, including phospholipase C gamma (PLC gamma), p21ras. GTPase activating protein (GAP), phosphatidylinositol 3-kinase (PI3-k) and microtubule associate protein kinase (MAPk2). In some cases, these associations are induced by receptor cross-linking and lead directly to effector activation. The current literature indicates that these interactions may occur in sequence and culminate in the activation of three major pathways of signal propagation including those mediated by PLC gamma, p21ras and PI3-k. This chapter reviews various molecular aspects of the B cell antigen receptor complex, including extended structure of the complex, and receptor-effector interactions and their biologic consequences. Finally, an integrated model of antigen receptor signaling is presented.

Amino Acid Sequence↗
PubMed1993

Mood variability in normal subjects on lithium.

To investigate the effect of lithium carbonate on normal volunteers' moods, we randomly assigned 30 subjects to 5 weeks each of placebo and lithium treatment with crossover at midstudy. Lithium levels were maintained during the treatment period at a mean serum level of 0.54 mEq/L. All subjects completed visual analogue mood scales (VAMS) daily throughout the study period; segmented visual analogue scales (SVAS) measuring mood, anxiety, and energy and the Profile of Mood States (POMS) were completed weekly at testing sessions. Neither mean mood nor mood variability as assessed by the delta square (mean square successive difference) differed between placebo and lithium conditions. Segmented visual analogue scale mood ratings were highly correlated with the VAMS and similarly showed no difference between conditions. The self-rated mood variability, however, declined significantly in both experimental conditions as a function of time on study. None of the POMS factors differed between placebo and lithium conditions. These data suggest that lithium, in modest doses administered over 5 weeks, does not have a substantial mood-stabilizing effect in normal subjects.

Adult↗
PubMed1993

Psychiatric and otologic diagnoses in patients complaining of dizziness.

BACKGROUND: Dizziness is a common and disabling symptom in primary care practice, especially among the elderly. Though there are many organic causes of dizziness, the results of medical workups are negative in the majority of patients. METHODS: A total of 75 patients with dizziness who were referred to a community otolaryngology practice received a structured psychiatric diagnostic interview (National Institute of Mental Health Diagnostic Interview Schedule) and questionnaires that assessed psychological distress as well as a complete otologic evaluation, including electronystagmogram. Patients with evidence of a peripheral vestibular disorder were compared with those without such evidence. RESULTS: While psychiatric diagnoses were present in both those with and without evidence of a peripheral vestibular disorder, those without such evidence had a greater mean number of lifetime psychiatric diagnoses as defined by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, and specifically, a greater lifetime prevalence of major depression and panic disorder. This group also more frequently met criteria for somatization disorder, had more current and lifetime unexplained medical symptoms, and had more severe current depressive, anxiety, and somatic symptoms. CONCLUSIONS: Psychiatric diagnoses are common among patients with dizziness referred for otologic evaluation who do not show evidence of a peripheral vestibular disorder. Specific psychiatric disorders should be part of the differential diagnosis of patients who present with dizziness.

Adult↗
PubMed1993

Hereditary hemolytic disease with increased red blood cell phosphatidylcholine and dehydration: one, two, or many disorders?

We have compared characteristics of red cells from patients who were originally diagnosed as having two different disorders, high phosphatidyl choline hemolytic anemia (HPCHA) and hereditary xerocytosis (HX). Both types of cells had reduced intracellular potassium, with attendant cell dehydration and an increase in the relative amount of membrane phosphatidyl choline. Neither these observations nor a review of previous studies of HX and HPCHA revealed any means of distinguishing between the two disorders. Measurements of chloride-dependent potassium transport revealed flux characteristics in both HX and HPCHA red cells that were different from those in simultaneously run control samples. HX and HPCHA red cells did not show the same kinds of deviations from the normal pattern. However, extensive characterization of transport behavior under a variety of controlled conditions will be required to determine whether these differences represent intrinsic differences in chloride-dependent transport properties. It appears likely that HX and HPCHA both represent a spectrum of disorders resulting from a variety of defects that produce the same general pattern of abnormalities in cation content and membrane phospholipid composition.

Adult↗
PubMed1993

Connective tissue activation. XXXVI. The origin, variety, distribution, and biologic fate of connective tissue activating peptide-III isoforms: characteristics in patients with rheumatic, renal, and arterial disease.

OBJECTIVE: To determine the origin, distribution, and biologic fate of platelet-derived connective tissue activating peptide-III (CTAP-III), to define the relative amounts of the antigen forms (CTAP-III, beta-thromboglobulin [beta-TG], neutrophil activating peptide-2 [NAP-2]) in plasma of normal persons and those with rheumatic or end-stage renal disease, and to define the isoforms of CTAP-III in platelets, plasma, transudates, and tissue deposits. METHODS: CTAP-III in plasma was measured by enzyme-linked immunosorbent assay, and growth promoting activity of CTAP-III isoforms was tested in synovial and peritoneal cell cultures by measuring increased synthesis of 14C-glycosaminoglycan (14C-GAG) and 3H-DNA. Isolated CTAP-III was characterized by Western blotting, microsequencing, and mass spectrometry. RESULTS: CTAP-III was the primary isoform of this antigen family in normal platelets and platelet-rich plasma; beta-TG and NAP-2 accounted for < 1% of CTAP-III isoforms. Previously undescribed isoforms, i.e., CTAP-III des 1, des 1-2, des 1-3, and a phosphate adduct of CTAP-III, were observed in varying amounts. Elevated plasma levels of CTAP-III antigen were found in a substantial fraction of rheumatic disease patients: 24% of those with rheumatoid arthritis, 36% of those with systemic sclerosis, and 15% of those with systemic lupus erythematosus. All 10 patients with end-stage kidney disease had marked elevations of plasma CTAP-III levels, which stimulated DNA and GAG synthesis by peritoneal cells in culture. Only large isoforms (such as CTAP-III) were detected in venous plasma of normal subjects, rheumatic disease patients, and patients receiving long-term dialysis. Normal human spleen and kidney contained substantial (micrograms/gm) amounts of CTAP-III and traces of an isoform with the electrophoretic mobility of CTAP-III des 1-15/NAP-2. Liver, lung, and urine contained lesser (ng/gm) amounts of CTAP-III. CONCLUSION: These data show that, among the 10 known isoforms, intact CTAP-III itself was the major circulating isoform (> 90%), and beta-TG was the most rare (0-1%). Deposition of CTAP-III in tissues, such as synovium, spleen, and kidney, is associated with partial processing to NAP-2-like isoforms and the potential to induce neutrophil and fibroblast activation in patients with rheumatic or end-stage renal disease.

Adult↗
PubMed1993

Role of protein synthesis, prostaglandins, and estrogen in rat ovarian metalloproteinase inhibitor production.

Matrix metalloproteinases and their inhibitors regulate follicular connective tissue remodeling associated with ovulation. We examined the control of metalloproteinase inhibitor activity and gene expression by various treatments in cultured rat granulosa cells and intact whole ovaries. Cells were isolated from preovulatory follicles of immature eCG-primed rats and cultured with various treatments for 24 h. Metalloproteinase inhibitor activity was measured in the media. The addition of LH or the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) increased inhibitor activity 2.5- and 2.6-fold above that in control cultures, respectively. Cycloheximide treatment blocked basal and LH- and TPA-stimulated inhibitor activity, suggesting that the increase in granulosa cell inhibitor activity resulted from de novo protein synthesis. Indomethacin, a prostaglandin synthase inhibitor, had no effect on basal or LH-induced granulosa cell inhibitor activity. Addition of the antiestrogen tamoxifen citrate or an aromatase inhibitor, 10-propargylestr-4-ene-3,17-dione, did not affect basal or LH-stimulated inhibitor activity, implying that estrogen is not involved in the signal transduction pathway leading to increased inhibitor activity. Northern analysis demonstrated the presence of mRNA for a tissue-derived metalloproteinase inhibitor, TIMP-1, which increased with LH stimulation, in rat granulosa cells. Similarly, an hCG stimulus increased TIMP-1 mRNA in periovulatory ovaries to the highest levels prior to ovulation. Neither cycloheximide nor indomethacin altered hCG-stimulated TIMP mRNA levels in periovulatory ovaries. The present study demonstrates that the LH- and TPA-induced increase in inhibitor activity resulted from de novo protein synthesis; however, de novo protein synthesis does not appear necessary for the increase in TIMP mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗