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Biomedical subjects

M Brown

Publications and source records attributed to M Brown.

At least 379 records · Page 21Linked to original sources
PubMed1994

A pilot study of anti-CD5 ricin A chain immunoconjugate in systemic lupus erythematosus.

OBJECTIVE: To determine the safety and clinical and biological effects of a murine monoclonal anti-CD5 ricin A chain immunoconjugate (CD5 Plus) in patients with systemic lupus erythematosus (SLE). METHODS: An open label phase I study of CD5 Plus. A dose of 0.1 mg/kg was administered intravenously on 5 consecutive days. A second course of immunoconjugate was given to patients who failed to show any clinical response one to 2 months later. RESULTS: Six patients (4 with glomerulonephritis and 2 with thrombocytopenia) were studied. Improvement was documented in 2 patients with nephritis; no effect on thrombocytopenia was observed. Adverse effects were mild and transient. Relative to pretreatment lymphocyte counts, the mean reduction in CD3+ T cell count was 69% at 2 weeks, 32% at one month, and 34% at 6 months following initial treatment. A comparable decrease in all subpopulations of mature T cells was noted, using a variety of surface markers, including CD4 and CD8. The mean percentage of T cells expressing the activation markers HLA-DR and interleukin 2R (IL-2R) was high before treatment, and remained so. There was a transient decrease in CD5+ B cells, but no persistent depletion of total B cell numbers. There was no consistent change in natural killer cell populations. CONCLUSION: Anti-CD5 ricin A chain immunoconjugate is well tolerated in patients with SLE, causes modest T cell depletion which may persist for months, and may have some clinical efficacy in lupus nephritis.

Antibodies, Monoclonal↗
PubMed1994

Quantitative contrast-enhanced MR imaging of the optic nerve.

During the acute stages of optic neuritis damage to the blood-optic nerve barrier can be detected using i.v. paramagnetic contrast-enhanced MR imaging. Quantification of the enhancement pattern of the optic nerve, intraorbital fat and muscle was determined in 15 normal subjects using 3 fat-suppression MR imaging methods: T1-weighted spin-echo and spoiled gradient-echo sequences preceded by a fat-frequency selective pulse (FATSAT+SE and FATSAT+SPGR, respectively) and a pulse sequence combining CHOPPER fat suppression with a fat-frequency selective preparation pulse (HYBRID). Pre- and postcontrast-enhanced studies were acquired for FATSAT+SE and FATSAT+SPGR. There was no significant enhancement of the optic nerve by either method (mean increase of 0.96% and 5.3%, respectively), while there was significant enhancement in muscle (mean 118.2% and 108.2%, respectively; p < 0.005) and fat (mean increase of 13% and 37%, respectively; p < 0.05). Postcontrast optic nerve/muscle signal intensity ratios (mean, SD) were 0.51 (0.07), 0.58 (0.05) and 0.75 (0.05) for FATSAT+SE, FATSAT+SPGR and HYBRID, respectively. These results suggest a practical methodology and range of values for normal signal intensity increases and ratios of tissue signal that can be used as objective measures of optic neuritis for natural history studies and treatment trials.

Adipose Tissue↗
PubMed1994

Stage IB carcinoma of the cervix: are all staging tests and procedures necessary?

The prognostic value and cost effectiveness of generally recommended ancillary tests and staging procedures in 115 patients with clinical Stage IB carcinoma of the cervix were retrospectively reviewed. All 112 intravenous pyelograms, 108 barium enemas, 102 cystoscopies and 98 sigmoidoscopies were normal. No malignant cells were found in pelvic washings. Of 111 patients who had paraaortic lymph node biopsies, only one had a positive node. This node was grossly enlarged and clinically suspicious. Paraaortic lymph node status was not influenced by tumor grade, prior conization, lymphovascular space involvement, depth of stromal invasion, positive pelvic lymph nodes or number of paraaortic nodes biopsied. The tests evaluated in this study are unnecessary and should no longer be performed in patients with clinical Stage IB carcinoma of the cervix. In addition, paraaortic lymph node biopsies in the absence of clinically suspicious nodes are not warranted. Eliminating these tests and procedures would result in substantial savings in health care cost.

Adenocarcinoma↗
PubMed1994

The effects of spiritual/religious practices on psychological well-being among inner city homeless women.

As part of a larger, retrospective investigation of homeless women's wholistic family planning needs, we examined spiritual/religious practices in relationship to mental health status and substance use. Ninety-two percent of our sample reported one or more spiritual/religious practices, such as praying, attending worship services, or reading religious materials. Forty-eight percent of the women reported the use of prayer as significantly related to less use of alcohol and/or street drugs, fewer perceived worries, and fewer depressive symptoms.

Adolescent↗
PubMed1994

Estrogen receptor molecular biology.

A greater understanding of the molecular biology of estrogen receptor (ER) will allow the extension of its utility as a target in therapy to an increased number of patients. The treatment of ER-positive breast cancer with antiestrogens involves a very sophisticated decision. Patients are treated with tamoxifen based on the direct measurement of the level of ER expression in the tumor and an indirect assessment of its activity through the measurement of an important target gene, progesterone receptor (PR). An understanding of the mixed agonist-antagonist nature of tamoxifen has led to the development of pure antagonists with clinical potential. Thus, the hormonal therapy of breast cancer can serve as the paradigm for the rational treatment of cancer based on the presence of the specific target of the therapy in the tumor and an understanding at the molecular level of the function of that target.

Animals↗
PubMed1993

Single point D-substituted corticotropin-releasing factor analogues: effects on potency and physicochemical characteristics.

In an attempt to determine which conformational parameters are important for the biological activity of ovine corticotropin-releasing factor (oCRF), we have synthesized in significant amounts (50-200 mg) and characterized chemically, structurally (CD), and biologically, oCRF analogues with substitution of each amino acid by its corresponding D-isomer. Out of 37 of these analogues, three were found to be equipotent to, or twice as potent as, oCRF, 13 had potencies in the range from 10 to 60%, 17 had potencies ranging from 1 to 10%, and the four others had potencies less than 0.5%. None of the analogues antagonized oCRF-induced release of ACTH in vitro at concentrations > or = 1000 oCRF. Since antagonists to CRF action can be generated by deletion of the first 8-14 residues, a series of CRF antagonists which exhibit significantly higher in vitro and in vivo biological potency than [Met18,Lys23,Glu27,29,40,Ala32,41,-Leu33,3 6,38] h/rCRF, [alpha-helical-CRF9-41], is also described. [D-Phe12,Nle21,38,Arg36]h/rCRF, in particular, was found to be ca. 15 times more potent than alpha-helical-CRF9-41 in vitro. In the rat, however, this analogue was about as effective as alpha-helical-CRF9-41 in blocking CRF-induced decrease in mean arterial blood pressure and increase in heart rate. Its potency in blocking epinephrine release by CRF was not significantly different from that of alpha-helical-CRF9-41. In the adrenalectomized rat, [Lys36]alpha-helical-CRF(9-41) (1.7 mg/kg) blunted the effect of endogenous CRF over a 90-min period; by comparison, a similar dose of alpha-helical-CRF9-41 was effective for less than 1 h.

Adrenocorticotropic Hormone↗
PubMed1993

Depression in stroke rehabilitation.

Despite recent advances in understanding the pathophysiology of poststroke depression, major questions remain. They include the relative importance of lesion location and size and the confounding effects of time since stroke, age, prior history of depression, and cerebral atrophy. To evaluate these issues, we systematically assessed depressive features, functional status, and brain structure with computer tomography scans in 91 men undergoing stroke rehabilitation. Forty percent met DSM-III criteria for major depressive disorder. Mood disturbance was more severe for patients with right than with left hemisphere lesions, correlated with functional disability and lesion size, and was associated with previous history of depression. Age, time since stroke, and atrophy did not correlate with mood. Depression is common in delayed stroke recovery, regardless of lesion location. Because there are no demographic or anatomic features that predict the absence of depression, depression screening should be part of the assessment of all patients undergoing stroke rehabilitation.

Activities of Daily Living↗
PubMed1993

Application of an algorithm for staging small-cell lung cancer can save one third of the initial evaluation costs.

OBJECTIVE: Design of a cost-effective algorithm for staging disease in patients with small-cell lung cancer. DESIGN: An algorithm was constructed by analyzing all permutations of a sequence of procedures required to stage disease in patients with small-cell lung cancer. Procedural costs were determined, and the model was applied to the small-cell lung cancer patient population treated at the National Cancer Institute, Bethesda, Md, from 1973 to 1989. The final algorithm was derived from the permutation with the lowest cost per accurately staged patient. SETTING: A single government institute, the National Cancer Institute. PATIENTS: Four hundred fifty-one patients with previously untreated, consecutive histologically documented small-cell lung cancer entered into therapeutic protocols at the National Cancer Institute from April 1973 through July 1989. Data were obtained from small-cell lung cancer protocol databases and patients' medical records. MAIN OUTCOME MEASURE: The cost per patient of each sequence of staging procedures when applied to the patient population. RESULTS: The least expensive sequence of procedures saved $1418 per patient when compared with application of a standard set of staging procedures to all patients. The major factor in reducing costs was the concept of stopping the staging procedures after a site of distant metastatic disease had been identified. CONCLUSIONS: An algorithm consisting of a set of sequential staging procedures can accurately stage disease in patients with small-cell lung cancer and save more than one third of the costs of an inclusive standard set of staging procedures.

Algorithms↗
PubMed1993

Immunosuppression by glucocorticoids: inhibition of production of multiple lymphokines by in vivo administration of dexamethasone.

Glucocorticoids are extremely potent immunosuppressive agents, capable of directly affecting the function of lymphocytes. We studied the effect of in vivo dexamethasone (DEX) administration on anti-CD3-induced lymphocyte proliferation and lymphokine production in mice. To characterize the kinetics and dose responsiveness of lymphocytes to DEX, splenocytes from BALB/c mice that had received a single dose of DEX in vivo were cultured in vitro with suboptimal and optimal concentrations of anti-CD3 monoclonal antibody. Cell proliferation in response to suboptimal concentrations of anti-CD3 was decreased by DEX doses of > or = 30 mg/kg; much higher doses (> or = 200 mg/kg) were required to inhibit cell proliferation in response to optimal anti-CD3 stimulation. Inhibition of suboptimal anti-CD3-stimulated proliferation was evident within 4 hr after DEX administration, was maintained for at least 24 hr, and was no longer evident at 7 and 14 days. Lymphokine secretion induced by optimal doses of anti-CD3 in vitro was differentially affected by in vivo DEX treatment. IL-1 alpha, IL-4, IL-6, IL-10, and IFN-gamma levels were decreased by treatment with low doses of DEX (30 mg/kg), whereas higher doses were required to inhibit production of IL-2, IL-3, and TNF. GM-CSF (granulocyte-macrophage-colony stimulating factor) was least susceptible to DEX inhibition. Low-dose (30 mg/kg) DEX treatment significantly reduced anti-CD3-stimulated production of most lymphokines tested at 4 and 12 hr; by 24 hr the levels of most lymphokines had begun to return to control values. Hence, our data indicate that administration of a single dose of DEX (30 mg/kg for 4 hr) results in significant suppression of lymphokine production and cell proliferation that precedes any significant cell loss and can be used as a reversible model of immunosuppression.

Animals↗
PubMed1993

The role of the reduced-folate carrier and metabolism to intracellular polyglutamates for the activity of ICI D1694.

The uptake of ICI D1694 into L1210 cells is very rapid and evidence strongly suggests that transport is via the reduced-folate/MTX cell membrane carrier (RFC); for example a cell line with a greatly impaired RFC is highly resistant to ICI D1694. Polyglutamates can be found intracellularly within a few minutes, so that experiments initially designed to measure transport were actually measuring transport and polyglutamation. After 30mins, in normal serum-containing tissue culture medium, the concentration of polyglutamates (di, tri and tetra) exceeded that of the parent drug 6-fold. Studies where cells were resuspended in drug-free medium demonstrated that the parent drug and its diglutamate could readily leave the cell. Folinic acid could markedly decrease the polyglutamation of ICI D1694, but had to be given simultaneously with the drug as a 4hr delayed rescue was less effective because substantial polyglutamation had already occurred. This effect was translated into considerable antagonism for cell growth inhibition by simultaneous folinic acid. The importance of the metabolism of ICI D1694 to polyglutamates to its potent cytotoxic activity is demonstrated by compounds related in structure to ICI D1694 but with different properties for the RFC and FPGS. For example, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolate (ICI 198583) owes its less potent cytotoxic activity to its poorer FPGS substrate activity (Km 40 microM compared with 1.3 microM for ICI D1694). Replacing the 2-methyl of either compound with amino, which appears to prevent use of the RFC, has a deleterious effect on growth inhibitory activity presumably by limiting the transport of the parent compounds into the cells, thereby slowing the rate of polyglutamate formation. Again a single change to another part of the molecule, that is methylation of the 7-position can have serious consequences on cytotoxic potency, particularly for the ICI D1694 molecule. The 7-methylated compounds are apparently poor or non-substrates for FPGS and therefore retain activity against a cell line unable to polyglutamate antifolates. These same compounds are only slightly affected by coincubation with folinic acid in L1210 tissue culture, consistent with the failure of these compounds to form intracellular polyglutamates. The results of short-exposure assays and in situ TS assays confirms that 7-methylation largely prevents the formation of a retained drug-form (polyglutamates), continuous exposure being necessary to maintain TS inhibition and cause a cytotoxic effect after removal of extracellular drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Assessment of proinsulin's effects on intermediary metabolism using the forearm technique in normal man.

We have compared the effects of human proinsulin and insulin on forearm metabolism. Seven normal, non-obese subjects were infused with 386 pmol/kg per hour of proinsulin and 180 pmol/kg per hour of insulin using the euglycaemic clamp technique. Glucose appearance and utilization rates were quantified using a primed continuous infusion of [6',6'-2H2]glucose. Mean blood glucose was 4.1 +/- 0.1 and 4.1 +/- 0.2 mmol/l during proinsulin and insulin infusions respectively. Basal insulin concentrations increased from 0.02 +/- 0.01 to 0.25 +/- 0.03 nmol/l. The proinsulin infusion was chosen to give steady-state levels approximately 20-fold higher on a molar basis than those of insulin, based on previous findings that proinsulin has only 5% the biological potency of insulin. Basal proinsulin concentrations increased from 0.003 to 5.4 +/- 0.3 nmol/l. Hepatic glucose production was suppressed similarly during the last hour of each hormone infusion: 0.07 +/- 0.16 (proinsulin, P), and 0.01 +/- 0.13 (insulin, I) mg/kg per minute. Glucose disposal, however, was significantly increased during the final hour of the insulin infusion: 4.7 +/- 0.4 (I) and 3.4 +/- 0.2 (P) mg/kg per minute (P = 0.025). Net forearm glucose uptake (FGU) increased by a greater amount during insulin compared with proinsulin infusion: 1.44 +/- 0.02 (I) and 0.71 +/- 0.01 (P) mumol/100 ml forearm per minute (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Effects of walking, jogging and cycling on strength, flexibility, speed and balance in 60- to 72-year olds.

The effects of a moderate intensity endurance training program on strength, speed of muscle contraction, balance, gait and flexibility were assessed in fifty 60- to 72-year-old men and women who had just completed a 3-month program of flexibility and strengthening exercise. Subjects trained for approximately 45 minutes/day, 4.1 days a week, for one year. Before and after the endurance exercise program, exercise participants underwent isometric and dynamic strength testing (Cybex II), standing balance tests, a gait examination, lower extremity flexibility testing, and a fatigue test for the quadriceps femoris muscle group. Fifteen control subjects who did not exercise were tested at the same time periods as exercise subjects. Gains made during the low intensity strengthening and flexibility program in strength, range of motion and quadriceps endurance were maintained throughout the year of endurance exercise training. Additional significant improvements in speed of muscular contraction, walking velocity and standing balance occurred with the program of moderate intensity endurance training which produced a 24% increase in VO2max for men and a 21% increase for women. These results provide additional evidence that older adults are able to improve their functional capacity in response to exercise training.

Aged↗
PubMed1993

Hydrocortisone and exercise effects on articular cartilage in rats.

The combined effects of hydrocortisone and running exercise on articular cartilage were assessed in female Sprague-Dawley rats. Animals were divided into three groups: 12 control (C), 12 who received an injection of 0.1 mL hydrocortisone once a week for three weeks (HC), and 12 rats who received three weekly injections of hydrocortisone and ran twice daily for six weeks (HC + run). Previous study revealed that rats that ran on a treadmill for three to 12 months did not have articular cartilage that was different from controls and thus a fourth group of rats, runners only, was not included in this analysis. At sacrifice, both knees were examined, photographed, and subsequently decalcified, then sectioned at 6 mu and stained. HC + run rats had significant more surface degeneration on femoral cartilage than HC or C rats. Eight of 12 HC + run rats displayed fibrotic invasion and/or subchondral bone replacement of degenerated articular cartilage, a feature not seen in HC or C rats. Cross-sections from HC + run rats displayed areas of cell death, and loss of matrix staining. Results suggest that, in rats, running exercise combined with intraarticular injections of hydrocortisone is more detrimental to articular cartilage than hydrocortisone or running alone.

Animals↗
PubMed1993

Appraisal and response to pain may be a function of its bodily location.

This study explored the hypothesis that appraisals of and responses to pain may in part be a function of where the pain is located. Results revealed that appraising pain as life-threatening, seeking help, disclosing pain to others and emotional distress in response to pain were contingent on the pain's bodily location. Significant ethnic differences in appraisal of pain, and significant gender differences in disclosure of and emotional response to pain also were found.

Adolescent↗
PubMed1993

The effects of subcutaneous human proinsulin on the production of 64/65 split proinsulin, glucose turnover and intermediary metabolism in non-insulin-dependent diabetic man.

We have compared the effects of subcutaneously injected human proinsulin, insulin zinc suspension and inactive diluent (control) on glucose turnover, intermediary carbohydrate and lipid metabolism in non-insulin-dependent diabetic man. Six weight-matched (24.8 +/- 1.6 kg M-2) non-insulin-dependent diabetic subjects underwent 3 separate, randomized, 10 h isoglycemic clamps. Glucose turnover was measured using a primed continuous infusion of [6'6'2H2] glucose. Each subject received 0.35 U/kg of hormone or control made up to isovolumetric amounts. The mean blood glucose level of 7.3 +/- 0.8 mmol/l was similar at the start of each isoglycemic clamp. Incremental area under the curve proinsulin levels (1195 +/- 146 nmol/l) were about 21-fold higher, on a molar basis, than insulin (62.4 +/- 10 nmol/l). Des 64/65 split proinsulin increased in a parallel manner to intact proinsulin (r = 0.99, P < 0.0001) and comprised approximately 13% of the intact proinsulin concentration. Hepatic glucose production was suppressed similarly following proinsulin and insulin zinc injection. However, both proinsulin and insulin zinc had a significantly greater effect on suppression of hepatic glucose production compared to control (P = 0.01, P = 0.009, respectively). Metabolic clearance rate of glucose fell significantly during the control studies compared to insulin zinc or proinsulin injections (P < 0.05). Blood lactate, pyruvate and alanine concentrations were similar following control or hormone injections. However blood glycerol, 3-hydroxybutyrate and plasma-non-esterified fatty acids were suppressed significantly by proinsulin and insulin zinc compared to control injections. The conclusions were: (1) In overnight fasted hyperglycemic non-insulin-dependent subjects s.c. injections of proinsulin and insulin zinc can produce similar effects on glucose turnover, intermediary lipid and carbohydrate metabolism. (2) Similar carbohydrate intermediary metabolism profiles can be obtained following insulin zinc, proinsulin or control injections. (3) However lipolysis and ketogenesis were significantly suppressed by both hormones compared to control. (4) Subcutaneous proinsulin injection resulted in approximately 13% conversion to des 64/65 split proinsulin.

Alanine↗