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M C Graves

Publications and source records attributed to M C Graves.

At least 37 records · Page 2Linked to original sources
PubMed1996

Suramin in hormone-refractory metastatic prostate cancer: a drug with limited efficacy.

PURPOSE: To confirm the previously reported high response rates and prolonged survival in hormone-refractory prostate cancer treated with suramin. PATIENTS AND METHODS: Thirty-six eligible patients with hormone-refractory prostate cancer with either measurable disease or bone disease only and a prostate-specific antigen (PSA) level greater than 50 ng/mL were enrolled. Treatment consisted of two 8-week courses of outpatient-based therapy with an interposed rest period. A bayesian adaptive control strategy and a three-compartment pharmacokinetic model that accommodates clearance changes was used to guide individual dosing. A rapid infusion of 1,000 mg/m2 suramin was followed by five daily infusions that targeted 285 micrograms/mL peak plasma levels during the first week. All patients received concomitant hydrocortisone. For the next 7 weeks, patients received one to two doses per week that targeted levels in the 150 to 285 micrograms/mL range and integrated weekly averages of 200 ug/mL. RESULTS: Nine patients (28%) had a partial response to suramin based on a > or = 50% decrease in PSA levels coupled with either relief of bone pain or by a 50% decrease in measurable disease. The median overall survival time for all patients is 31 weeks (95% confidence interval [CI], 23 to 51). Treatment was generally well tolerated, with fatigue being the most common significant toxicity, but fatal idiosyncratic myelosuppression (grade V) was observed in one patient. CONCLUSION: Using this dosing schedule, suramin has limited activity against hormone-refractory metastatic prostate cancer. Recent data suggest that hydrocortisone administered with suramin may be partly responsible for the benefit attributed to the drug. Although a small cohort of patients appeared to benefit, we were unable to confirm the previously reported high rate of activity and durability of remission using this agent.

Adenocarcinoma↗
PubMed1994

Factors affecting the fine specificity and sensitivity of serum antiganglioside antibodies in ELISA.

The major problem associated with ELISA of serum antiganglioside antibodies is the high background values (absorbancy of sera added to wells without ganglioside), which interfere with the accurate assessment of the fine specificity and sensitivity of these antibodies. This investigation identifies factors elevating the background values and/or decreasing the fine specificity, and describes strategies to minimize their influence. Using sera of neuropathy and melanoma patients, we found that highest background values were observed with the polystyrene 'tissue culture' microtiter plates; of the various 'non-tissue culture' microtiter plates tested, the lowest background values (> 0.060) were observed with Costar-3590 (H), Immunolon-3, Immunolon-1, Falcon-3915 (in increasing order). Background artifact of polystyrene microtest plates was significantly reduced by gamma irradiation (at 40 kRad) and/or use of detergent Tween-20 (0.1%) in the washing step. Even after controlling the background values, the fine specificity, namely, the ability of the antibody to distinguish between the target epitope of an antigen and epitopes of related antigens (when moles of antigen/well is constant) varied with different microtiter plates. Using sera with high affinity and specificity for GM2, GD3 or GM3, we observed that Immunolon-1, Immunolon-3 and particularly Falcon-3915 were superior for assessing the abilities of the antibodies to distinguish closely related epitopes found on other gangliosides. The reactivity of antiganglioside antibodies was more consistent after detergent treatment. The reactivity of antibodies to GD3 is significantly enhanced after treatment with Tween-20, but that of antibodies reacting to GM1 and GM2 is reduced. Fine specificity of the antiglycolipid antibodies was resolved better by coating glycolipids in mol/well rather than by weight/well. Based on these results, a protocol for a sensitive and reproducible ELISA for serum antiganglioside antibodies is recommended. The protocol takes into consideration the suitability of polystyrene plates, coating based on the number of molecules, pertinency of the solvent for coating, use of human serum albumin for blocking, dilution and washing steps and use of 0.1% Tween-20 to further minimize the background absorbancy.

Autoantibodies↗
PubMed1994

Interactions of substrates and inhibitors with a family of tethered HIV-1 and HIV-2 homo- and heterodimeric proteinases.

Genes were constructed to encode single-chain tethered human immunodeficiency virus HIV-1/HIV-1 and HIV-2/HIV-2 homodimeric proteinases and two HIV-1/HIV-2 heterodimers which differed in the nature of the interface strands. All four constructs under the control of a heat-inducible promoter were expressed in E. coli and the resultant proteinases were purified therefrom. Kinetic parameters (Km, kcat and kcat/Km) were derived for the interaction of the tethered homo and heterodimeric proteinases with two distinct substrates at a variety of pH values. All four enzymes were comparably active toward one substrate. With the second substrate at pH 4.7, the kcat/Km value was best for the HIV-1/1 tethered homodimer, 15-fold lower for the two heterodimeric proteinases, and was reduced by an additional 6-fold for the HIV-2/2 homodimer. From the Ki values determined for the interactions of the four tethered dimer proteinases with a systematic series of synthetic inhibitors, a parallel trend was observed. Whereas several inhibitors were equipotent against all four enzymes, two were discriminatory in that they inhibited strongly the HIV-1/1 homodimer and the two heterodimeric proteinases but had little effect on the HIV -2/2 tethered homodimer (or its untethered wild-type counterpart from HIV-2). The significance of these findings for active site interaction with HIV-proteinases is considered.

Amino Acid Sequence↗
PubMed1994

Function of the interarytenoid muscle in a canine laryngeal model.

The interarytenoid (IA) muscle has rarely been studied in the living larynx. In this work, the role of the IA muscle in phonation was studied in three dogs by means of an in vivo phonation model. The isolated action of the IA muscle was studied by sectioning and stimulating its nerve branch. As IA activity increased, subglottic pressure increased significantly until a plateau was reached. In the absence of superior laryngeal nerve stimulation, the fundamental frequency rose with increasing IA activity. In the presence of superior laryngeal nerve stimulation, however, no significant change in fundamental frequency was observed with increasing IA activity. Measurement of adductory force demonstrated that the IA muscle adducts primarily the posterior vocal fold. In this canine model, phonation was not possible without IA stimulation, owing to a large posterior glottic chink.

Analysis of Variance↗
PubMed1993

AIDS dementia complex complicated by cytomegalovirus encephalopathy.

We have studied longitudinally ten patients with AIDS encephalopathy with respect to pathogenetic roles of human immunodeficiency virus (HIV) and cytomegalovirus (CMV). Three patients manifested typical AIDS dementia complex (ADC) (initially without retinitis and with slowly progressive cognitive, motor and behavioral abnormalities which were zidovudine-responsive, and relatively preserved CD4+ T cells), and seven patients presented with AIDS dementia complex complicated by CMV encephalopathy (ACE) (with CMV retinitis, peripheral neuropathy, altered sensorium, and rapidly declining clinical and immunological status). Whereas only HIV antibody was elevated in the spinal fluid of patients with ADC, both virus infections were active in the central nervous system of patients with ACE as shown by HIV p24 antigenemia and antigenrrhachia, elevated HIV and CMV antibody in the spinal fluid, disseminated CMV infection with retinitis, and basilar ventriculoencephalitis with multinucleated cytomegalic cells containing CMV and HIV proteins and CMV DNA. The recognition of ADC and ACE is important, since some patients with ACE may respond to ganciclovir or foscarnet.

AIDS Dementia Complex↗
PubMed1992

Monoclonal IgM antibodies from cytomegalovirus-infected mice recognize the GlcNAc-containing receptor determinant of murine CMV as well as neutralizing anti-CMV IgG antibodies.

This study examines monoclonal antibodies derived from mice at different time points after infection with attenuated murine cytomegalovirus (MCMV). The antibodies obtained from mice at 3 weeks p.i. were of IgG type (designated V-antibodies) and several could neutralize the virus. Those obtained at 5 weeks p.i. were of the IgM class (designated R-antibodies), bound to uninfected (MEF, mouse embryo fibroblast) cells, and thereby blocked MCMV plaque formation. In ELISA, the IgM monoclonals (R-antibodies) bound to GalB1-3GlcNAc and GalB1-4GlcNAc, the receptor determinants for MCMV. Similarly, these GlcNAc-containing residues blocked the binding of purified IgM monoclonal antibodies (MAbs) to MEF. The R- and V-series of antibodies showed mutual binding activities; for example, IgM MAb R-2D8 bound specifically to four (V-8C4, V-1C7, V-8C7, V-9C5) of six neutralizing IgG MAbs in ELISA. The same neutralizing IgG MAbs bound to antireceptor IgM antibodies in an immunoblot assay. This suggests that the IgM monoclonals directed against the known cell surface receptor determinant are anti-idiotypic antibodies against neutralizing antiviral IgG antibodies. The neutralizing antiviral IgG MAbs bound to 60- and 66-kDa MCMV polypeptides on Western blots, suggesting that these viral polypeptides may be important in MCMV binding to this receptor. The R-series might represent anti-idiotype antibodies capable of down-regulating antiviral V-antibodies and may also represent a mechanism for the induction of IgM autoantibodies directed at cell surface glycolipids present in autoimmune CMV-associated neuropathies.

Acetylglucosamine↗
PubMed1992

Bilateral thyroarytenoid denervation: a new treatment for laryngeal hyperadduction disorders studied in the canine.

Adductor spasmodic dysphonia is a vocal disorder of uncertain etiology with no satisfactory long-term treatment. Recently, injection of botulinum toxin (Botax) into the thyroarytenoid (TA) muscle has been used as an effective temporary treatment. A surgical counterpart to bilateral TA Botox injection is described in this article. Bilateral thyroarytenoid denervation was performed through a window in the thyroid cartilage in seven canines, including four that were studied 3 months after the procedure. No serious complications occurred in the animals, each maintaining full vocal fold abduction and adduction. In all cases, anticipated physiologic changes in laryngeal function were observed, including the inability to generate high subglottic pressures during high levels of laryngeal nerve (RLN) stimulation. In two of the surviving animals, the ansa cervicalis was used to reinnervate the TA muscle, thereby preventing the possibility of reinnervation from the proximal RLN stump while limiting TA atrophy and fibrosis. Bilateral TA denervation represents a hopeful new long-term approach to spasmodic dysphonia treatment.

Animals↗
PubMed1992

Physiologic motion after vocal cord reinnervation: a preliminary study.

This study attempted to reestablish physiologic vocal cord motion, rather than synkinesis, to a reinnervated vocal cord. One mongrel dog underwent a division and reanastomosis of the anterior branch of the right recurrent laryngeal nerve and simultaneous separation and reimplantation of a posterior division nerve-muscle pedicle into the posterior cricoarytenoid muscle. After 21 weeks, spontaneous physiologic vocal cord movement and electromyographic (EMG) activity were recorded during respiratory obstruction and laryngeal mechanical stimulation. Acoustic measures and histologic data are also presented from the reinnervated and normal vocalis muscle and from the recurrent laryngeal nerve. This study demonstrated that physiologic vocal cord motion can be achieved after laryngeal reinnervation using this technique.

Anastomosis, Surgical↗
PubMed1992

Autoimmune disease and the nervous system. Biochemical, molecular, and clinical update.

Autoimmunity in the central and peripheral nervous system can manifest as the result of cellular or humoral immune responses to autoantigens. There is evidence that multiple sclerosis is a cell-mediated autoimmune disease of the central nervous system in which both myelin and the cell that produces the myelin are destroyed. Diseases such as acute inflammatory demyelinating polyneuropathy (also called Guillain-Barré syndrome) and myasthenia gravis are considered antibody-mediated diseases of the peripheral nervous system and neuromuscular junctions, respectively. We review these diseases and explore mechanisms of immune-mediated destruction of these nervous system components. We specifically focus on one effective therapy aimed at countering the immune attack, that of thymectomy in patients with myasthenia gravis.

Autoimmune Diseases↗
PubMed1991

A functional evaluation of ansa cervicalis nerve transfer for unilateral vocal cord paralysis: future directions for laryngeal reinnervation.

There are a variety of methods for treating unilateral vocal cord paralysis, but to date there are few objective studies that evaluate the functional results of nerve transfer from the ansa cervicalis. Six dogs underwent unilateral recurrent laryngeal nerve section with immediate reanastamosis to the sternothyroid branch of the ansa cervicalis. After 5 to 6 months, measurements of vocal efficiency and acoustic parameters, videolaryngoscopy, videostroboscopy, and evoked electromyography were performed. Identical measurements were made in eight control dogs during normal electrically induced phonation and a simulated unilateral recurrent laryngeal nerve paralysis. Histologic analysis of both vocalis muscles, recurrent laryngeal nerves, ansa cervicalis, and the ansa-recurrent laryngeal nerve anastamosis site was performed. Evidence of reinnervation was found in all of the animals that underwent nerve transfer. The vocal efficiency and acoustic quality after ansa cervicalis nerve transfer were dependent on the degree of electrical stimulation from the transferred nerve to the reinnervated cord during phonation. In the absence of electrical stimulation to the nerve transfer, physiologic vocal cord motion could not be elicited from the reinnervated cord.

Anastomosis, Surgical↗
PubMed1990

Identification of a human immunodeficiency virus-1 protease cleavage site within the 66,000 Dalton subunit of reverse transcriptase.

The human immunodeficiency virus-1 reverse transcriptase is a heterodimer of related 51 and 66 kDa subunits. The smaller subunit arises by viral protease-catalyzed cleavage of the carboxy-terminal domain of the 66 kDa species. Comparison of the amino acid composition analyses of the isolated 51 kDa and 66 kDa subunits indicates that the carboxyl terminus of 51 kDa is Phe440. This site was confirmed in vitro using purified recombinant protease and a peptide spanning the postulated cleavage area. The sequence surrounding this site does not show significant homology to other protease cleavage sites in the viral gag and pol precursors; thus, this new information may contribute to our understanding of the sequence specificity of the viral protease.

Amino Acid Sequence↗
PubMed1990

Human immunodeficiency virus type 1 protease cleaves the intermediate filament proteins vimentin, desmin, and glial fibrillary acidic protein.

The intermediate filament proteins vimentin, desmin, and glial fibrillary acidic protein are cleaved in vitro by human immunodeficiency virus type 1 protease (HIV-1 PR). Microsequencing showed that HIV-1 PR cleaved both human and murine vimentin between leucine-422 and arginine-423 within the sequence between positions 418 and 427, Ser-Ser-Leu-Asn-Leu/Arg-Glu-Thr-Asn-Leu (SSLNL/RETNL). Minor cleavages at other sites were also observed. Heat-denatured vimentin was cleaved by HIV-1 PR less efficiently than native vimentin. A decapeptide containing the sequence SSLN-LRETNL was also cleaved in vitro by HIV-1 PR as predicted. The presence of a charged residue (arginine) at the primary cleavage site distinguishes this from other known naturally occurring cleavage sites. Microinjection of HIV-1 PR into cultured human fibroblasts resulted in a 9-fold increase in the percentage of cells with an altered and abnormal distribution of vimentin intermediate filaments. Most commonly, the intermediate filaments collapsed into a clump with a juxtanuclear localization. These results support the possibility that intermediate filament proteins may serve as substrates within HIV-1-infected cells.

Amino Acid Sequence↗