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M A Goldsmith

Publications and source records attributed to M A Goldsmith.

At least 73 records · Page 4Linked to original sources
PubMed1987

Isolation and characterization of a T-lymphocyte somatic mutant with altered signal transduction by the antigen receptor.

We have developed an approach for deriving and characterizing antigen-receptor (CD3/Ti) signal-transduction mutants. This strategy combines receptor-mediated growth inhibition and fluorescence-activated cell sorting with the Ca2+-indicator indo-1. Despite the expression of structurally normal CD3/Ti complexes, one such mutant (J.CaM1) fails to exhibit inositolphospholipid metabolism or Ca2+ mobilization in response to anti-CD3 or anti-Ti monoclonal antibodies and fails to produce lymphokines in response to these antibodies. Surprisingly, anti-Ti antibody retains its effectiveness as a stimulus for the down-regulation of CD3/Ti surface expression. These cells remain responsive to AIF-4, at least one anti-CD3 antibody, and some combinations of nonagonist anti-Ti and anti-CD3 antibodies. The mutation in J.CaM1 appears to lie in a proximal component of the signal-transduction apparatus.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Alterations in protein transport events in rat liver after estrogen treatment.

The effects of 17 alpha-ethynylestradiol (EE) treatment on the hepatic processing of rat polymeric immunoglobulin A (IgA) and human asialoorosomucoid (ASOr) were studied. After 5 days of treatment with EE (5 mg/kg) or solvent alone, male rats were anesthetized and injected with tracer doses of the test proteins. Bile flow rates had been reduced by greater than 60% in the EE-treated animals. A previously reported radiolabeling strategy was used to monitor both the transport of intact protein to bile and the degradation of protein in lysosomes. Transport of intact IgA to bile was reduced by 43%, with transport peaking 27 min later in EE-treated animals compared with controls. There was a corresponding impairment of uptake of labeled IgA from blood. EE induced no kinetic change in the uptake or processing of ASOr. However, there was an increase in the proportion of ASOr reaching bile intact from 3% to 15-23% of the injected dose. The data indicate that EE disables the transport pathway for IgA and causes a partial change in the routing of ASOr after endocytosis in favor of direct transport to the bile canaliculus. These findings may have implications for the importance of membrane composition in protein transport events.

Animals↗
PubMed1987

The activation of T lymphocytes.

The events involved in T cell activation are initiated at the cell surface by the interaction of ligands with specific cell surface receptors on the T cell. Central to antigen-induced activation is the CD3/Ti complex, a complex multi-chain receptor responsible for antigen/MHC recognition and signal transduction. Triggering the CD3/Ti complex results in the generation of intracellular second messengers, IP3 and DG, which are derived from PI metabolism. The second messengers lead to increases in [Ca2+]i and activation of pkC, events causally linked to various cellular responses, including the production of IL-2 through as yet poorly defined pathways. Little is known about how other cell surface molecules that may provide an accessory function participate in such events. However, future genetic and biochemical studies are likely to shed light upon the mechanisms of signal transduction by the CD3/Ti complex and accessory molecules and the details of the intracellular events involved in the activation of a host of cellular genes associated with activation.

Animals↗
PubMed1984

Phase I study of mitoxantrone on a daily X 5 schedule.

Mitoxantrone (NSC-301739) is a synthetic amino anthraquinone DNA intercalater active in several experimental tumor systems. Thirty-three patients with advanced cancer received the drug on a daily X 5 schedule. Myelosuppression, especially leukopenia, was the dose-limiting toxicity and was reversible. Nausea and vomiting occurred sporadically. No definite hepatic, renal, or cardiac toxicities were noted. The recommended dose for phase II evaluation in solid tumor patients with little or no prior therapy is 4.2 mg/m2/day X 5. Patients with prior myelosuppressive therapy but adequate bone marrow reserve may be started at 2.6 mg/m2/day X 5.

Adult↗
PubMed1983

Phase I study of L-alanosine (NSC 15353).

L-alanosine (NSC 15353) is a newly developed antitumor antibiotic which acts as an inhibitor of purine intermediary metabolism. Experimental antitumor activity was demonstrated in a variety of murine neoplasms. A Phase I trial was undertaken on a daily x 5 (d x 5) schedule in 22 evaluable patients. Dose limiting toxicity was an oral mucositis characterized by beefy red oral, lingual and pharyngeal erythema. The maximum tolerated dose is 320 mg/m2/d x 5 every three weeks. The recommended dose for Phase II evaluation is 160 mg/m2/d x 5 every three weeks.

Adult↗
PubMed1983

Kaposi's sarcoma in a young homosexual man. Association with angiofollicular lymphoid hyperplasia and a malignant lymphoproliferative disorder.

Recent reports have described an unexpected number of cases of a virulent form of a Kaposi's sarcoma (KS) as well as acquired immunodeficiency in young homosexual men. A 31-year-old man initially had a benign disorder, angiofollicular lymphoid hyperplasia. Kaposi's sarcoma then developed, and he died of a malignant lymphoproliferative disorder. We believe that this is unique among the recently described cases of KS in homosexual men because of the occurrence of this second malignancy. It may be that similar cases will be recognized in this population.

Adult↗
PubMed1983

Hepatic handling of bile salts and protein in the rat during intrahepatic cholestasis.

17 alpha-Ethynyl estradiol-induced cholestasis was used to study the relationship of protein to bile salt transport in liver. The biliary secretion of horseradish peroxidase was unaltered in treated animals despite a 56% reduction in bile flow. Cytochemistry confirmed that estradiol caused no alteration in the handling of tracer. In a second study, the peak biliary secretion of [14C]taurocholate was reduced by approximately 46% in treated animals. The kinetics of 125I-cholyglycylhistamine, a bile salt derivative, were identical to those of taurocholate in control and cholestatic animals. Taurocholate and cholylglycylhistamine secretion were markedly reduced in control animals during competition with unlabeled taurocholate. Quantitative electron microscopic autoradiography with 125I-cholylglycylhistamine revealed a high concentration of grains over the endoplasmic reticulum and the Golgi complex including associated lysosomes and vesicles. These data demonstrate that estradiol markedly inhibits bile salt transport, but not vesicular transport of horseradish peroxidase. Furthermore, estradiol may alter the movement of bile salts through these organelles.

Animals↗
PubMed1981

Gluconate calcium therapy and neonatal hypercalciuria.

Nephrolithiasis was present in a 2-month-old premature infant with bronchopulmonary dysplasia who had been receiving furosemide and intravenous (IV) gluconate calcium therapy. This infant was found to be hypercalciuric. Furosemide therapy is known to increase calcium excretion. In the present study, we examined sick infants who were receiving gluconate calcium without furosemide to evaluate the effect of gluconate calcium therapy on urinary calcium excretion. The sick infants receiving gluconate calcium had higher values of urinary calcium than did the well infants taking regular formula feedings. Moreover, the calciuria appeared to increase progressively with continued gluconate calcium therapy. It appears that prolonged use of either furosemide or IV gluconate calcium leads to hypercalciuria, which, in turn, may predispose the premature infant to nephrolithiasis.

Calcium↗
PubMed1981

A method of screening for growth hormone deficiency using anthropometrics.

Among children less than 3rd percentile in height, less than 1% are deficient in endogenous growth hormone, while 80% have no recognizable organic cause for short stature, and are termed normal variants. This study investigated whether anthropometric evaluation can distinguish growth hormone-deficient from normal variant children. Height, weight, midarm circumference and 10 skinfold thicknesses were measured in 24 growth hormone-deficient and 26 normal variant children; indices of linear growth, adiposity, and lean body mass were derived from these. All these variables were analyzed statistically by discriminant analysis. This led to a screening formula, here called a "Z-function," based only on height and five skinfolds (abdomen, back, chest, knee, and calf). The Z-function classified correctly all but two growth hormone-deficients and two normal variants. Because of the small and possibly inhomogeneous sample, the particular formula developed here is not recommended for general use, but these preliminary findings show that a simple anthropometric screening test is indeed feasible, and could be useful in pediatric practice.

Adipose Tissue↗
PubMed1980

Abnormal polyamine metabolism in hereditary muscular dystrophies: effect of human growth hormone.

Previous studies showed hyperre-sponsiveness to human growth hormone (hGH) in men with myotonic or limb girdle dystrophies (MMD or LGD). Because polyamines may mediate some actions of hGH, we have now investigated polyamine metabolism in these and other dystrophies. Under metabolic balance study conditions, serum and urine levels of putrescine (Pu), spermidine (Sd), spermine (Sm), and cadaverine (Cd) were measured in six normal men (36-44 yr), four men with MMD (38-44 yr), and three men with LGD (30-36 yr), before and during treatment with 0.532 U/kg body wt ((3/4)/d) of hGH. Daily balances of N, P, and K were also monitored. In the normal subjects, hGH did not influence elemental balances or serum and urine polyamines. In MMD, hGH caused significant retention of N, P, and K (P < 0.005). Basal levels of Sm and Cd were significantly elevated above normal (P < 0.005), and Pu, Sm, and Cd increased two- to fourfold above basal during hGH treatment (P < 0.005). In LGD, hGH also caused retention of N, P, and K. Basal levels of nearly all the polyamines (not serum Pu) were significantly above normal in serum and urine (P < 0.05). During hGH treatment, all four polyamines rose significantly above basal (P < 0.005). Serum and urine polyamine levels in five boys with Duchenne muscular dystrophy, age 8-13, did not differ from those in five age-matched normal boys. Skeletal muscle polyamines were measured in five men (31-40 yr) without muscle disease and in three men with LGD (30-38 yr). Average concentrations of Pu, Sd, Sm, and Cd were 46, 306, 548, and 61 nmol/g wet wt in LGD and 1, 121, 245, and 14 in the normal subjects, respectively (P < 0.05 in each instance). Polyamines were determined in skeletal muscle, liver, kidney, and brain of male mice with hereditary muscular dystrophy and in age- and sex-matched normal controls. Pu, Sd, Sm, and Cd levels were two to three times higher than normal in muscle, but did not differ in liver, kidney, and brain. Similar findings were made in male hamsters with hereditary dystrophy and in their controls. The abnormality in hamster muscle polyamines appeared between 1 and 6 wk of age and persisted or intensified until 30 wk. These data reveal abnormalities of polyamine metabolism in men with MMD, in men with LGD, and in mice or hamsters with hereditary muscular dystrophy. The polyamine disorder could be related to dystrophic patients' hyperresponsiveness to hGH.

Adolescent↗
PubMed1980

Phase I study of m-AMSA in patients with solid tumors and leukemias.

m-AMSA is a synthetic aminoacridine DNA intercalator found to have experimental murine antitumor activity. A phase I investigation was undertaken in 71 patients with solid tumors and acute leukemia. Using an intermittent every 3-week schedule in solid tumors, toxicity encountered was primarily hematologic, predominantly leukopenia with relative platelet sparing. The recommended dose for phase II evaluation in patients with solid tumors is 90 mg/m2 every 3 weeks; patients with minimal prior therapy could be treated at 120 mg/m2 and patients with hepatic dysfunction or marginal bone marrow reserve should have an initial dose reduction to 70 mg/m2. Therapeutic activity was seen in Hodgkin's disease, hepatoma, and epidermoid carcinoma of the esophagus. Various dose schedules were studied in leukemia. The recommended dose for phase II evaluation is 120 mg/m2 daily for 5 days as a daily 30-minute infusion. At this dose, nausea, vomiting, mucositis, alopecia, and hepatic toxicity were noted. Therapeutic activity was seen in AML, blastic CML, and CLL. Further clinical trials with this agent are warranted.

Acute Disease↗
PubMed1979

Serum and urine polyamines in normal and in short children.

The serum and urine polyamines putrescine, spermidine, and spermine were measured in 112 normal subjects from 0 to 70 yr of age, and in three groups of short children from 7 to 20 yr: 21 growth hormone (GH) deficient patients, 20 normal variant short stature children, and 9 girls with 45, X Turner's syndrome. Urine polyamines were expressed as micromoles per gram of creatinine or per kilogram body weight, and serum polyamines were expressed as nanomoles per milliliter. In normals, the three polyamines were highest in urine and serum at birth. The mean levels declined progressively with age, the rate of change decreasing with age. The mean for the normal subjects, and its 95% confidence and prediction intervals, were estimated from birth to age 70 for each serum and urine polyamine. In GH-deficient children, serum and urine values were significantly lower (P < 0.05) than the age-specific normal values (with the exception of serum spermidine and spermine), averaging 25-55% below normal. This abnormality was corrected during 1 wk of treatment with human GH. In Turner's syndrome, serum and urine values were significantly reduced (P < 0.05), averaging 35-80% below age-specific normals. GH treatment had no corrective effect. In 6 of 20 normal variant short stature children, polyamine levels were significantly (P < 0.01) subnormal, averaging 50-80% below age-specific normals in both serum and urine. Treatment with GH had no corrective effect. These data show that levels of polyamines in serum and urine are correlated with linear growth primarily during the first decade of life. Subnormal polyamine levels are generally associated with growth retardation.

Adolescent↗
PubMed1979

Predicting the response of growth hormone-deficient children to long term treatment with human growth hormone.

A previous study showed that when GH-deficient children below the third percentile in height are treated with 0.168 U human GH (hGH)/kg BW3/4 for 10 days, their height increases by 0.3--1.9 cm during the next 8 weeks. The present study determined whether this acute response would predict the child's long term response to 1 yr of treatment with the same dose of hGH given three times a week. Eighteen GH-deficient children and adolescents, aged 8--16 yr, were measured every 2 weeks over 108 weeks. After a control period of 12 weeks (period 1), the patient received hGH for 10 days. During the remainder of the 12 weeks of period 2 and during the next 12 weeks (period 3), hGH was not given. Patients recieved hGH three times a week during periods 4 and 5 (24 weeks each). Periods 6 and 7 (12 weeks each) were posttreatment control periods. During periods 1, 3, 6, and 7, rate of growth was less than 0.2 cm/month. During period 2, the rate ranged between 0.1--0.8 cm/month. During periods 4 and 5, the growth rate ranged from 0.2--1.0 cm/month. Rate of growth during periods 4 and 5 (y) was related to rate during period 2 (x) by the equation y = 0.027 + 1.17 x. The correlation coefficient between y and x was 0.91 (P less than 0.001). The increment in height which will occur during 48 weeks of treatment can be predicted from the response to 10 days of treatment by this equation. The SE of the prediction averages +/- 1.2 cm/yr.

Adolescent↗