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Biomedical subjects

M P Reddy

Publications and source records attributed to M P Reddy.

At least 19 recordsLinked to original sources
PubMed2001

Modification of the Fc region of a primatized IgG antibody to human CD4 retains its ability to modulate CD4 receptors but does not deplete CD4(+) T cells in chimpanzees.

Keliximab, a Primatized IgG1 CD4 mAb, was reconfigured to an IgG4 antibody. The gamma4 constant region was further modified by substituting glutamic acid for serine at position 235 in the CH2 domain (IgG4-E), to remove residual binding to Fcgamma receptors, and substitution of serine with proline at position 228 in the hinge region (IgG4-PE) for greater stability. Pharmacokinetic analysis in rats gave a t(1/2) of approximately 4 days for IgG4-E and 9 days for IgG4-PE, consistent with a greater stability of the IgG4-PE molecule. The effects on T cell subsets were assessed in chimpanzees given escalating doses of IgG4-PE: 0.05 mg/kg on Day 16, 1.5 mg/kg dose on Day 43, and 15 mg/kg on Day 85. Receptor modulation was observed at the two highest doses, but no depletion of T cells at any dose. The in vitro and in vivo results demonstrate the potential of this IgG4-PE mAb for use in human trials.

Amino Acid Substitution↗
PubMed2000

Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor.

TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines which induces apoptotic cell death in a variety of tumor cell lines. It mediates its apoptotic effects through one of two receptors, DR4 and DR5, which are members of of the TNF receptor family, and whose cytoplasmic regions contain death domains. In addition, TRAIL also binds to 3 "decoy" receptors, DcR2, a receptor with a truncated death domain, DcR1, a glycosylphosphatidylinositol-anchored receptor, and OPG a secreted protein which is also known to bind to another member of the TNF family, RANKL. However, although apoptosis depends on the expression of one or both of the death domain containing receptors DR4 and/or DR5, resistance to TRAIL-induced apoptosis does not correlate with the expression of the "decoy" receptors. Previously, TRAIL has been described to bind to all its receptors with equivalent high affinities. In the present work, we show, by isothermal titration calorimetry and competitive enzyme-linked immunosorbent assay, that the rank order of affinities of TRAIL for the recombinant soluble forms of its receptors is strongly temperature dependent. Although DR4, DR5, DcR1, and OPG show similar affinities for TRAIL at 4 degrees C, their rank-ordered affinities are substantially different at 37 degrees C, with DR5 having the highest affinity (K(D) </= 2 nm) and OPG having the weakest (K(D) = 400 nm). Preferentially enhanced binding of TRAIL to DR5 was also observed at the cell surface. These results reveal that the rank ordering of affinities for protein-protein interactions in general can be a strong function of temperature, and indicate that sizeable, but hitherto unobserved, TRAIL affinity differences exist at physiological temperature, and should be taken into account in order to understand the complex physiological and/or pathological roles of TRAIL.

Animals↗
PubMed2000

Elimination of Fc receptor-dependent effector functions of a modified IgG4 monoclonal antibody to human CD4.

Several CD4 mAbs have entered the clinic for the treatment of autoimmune diseases or transplant rejection. Most of these mAbs caused CD4 cell depletion, and some were murine mAbs which were further hampered by human anti-mouse Ab responses. To obviate these concerns, a primatized CD4 mAb, clenoliximab, was generated by fusing the V domains of a cynomolgus macaque mAb to human constant regions. The heavy chain constant region is a modified IgG4 containing two single residue substitutions designed to ablate residual Fc receptor binding activity and to stabilize heavy chain dimer formation. This study compares and contrasts the in vitro properties of clenoliximab with its matched IgG1 derivative, keliximab, which shares the same variable regions. Both mAbs show potent inhibition of in vitro T cell responses, lack of binding to complement component C1q, and inability to mediate complement-dependent cytotoxicity. However, clenoliximab shows markedly reduced binding to Fc receptors and therefore does not mediate Ab-dependent cell-mediated cytotoxicity or modulation/loss of CD4 from the surface of T cells, except in the presence of rheumatoid factor or activated monocytes. Thus, clenoliximab retains the key immunomodulatory attributes of keliximab without the liability of strong Fcgamma receptor binding. In initial clinical trials, these properties have translated to a reduced incidence of CD4+ T cell depletion.

Animals↗
PubMed1998

Stress signaling through Ca2+/calmodulin-dependent protein phosphatase calcineurin mediates salt adaptation in plants.

Calcineurin (CaN) is a Ca2+- and calmodulin-dependent protein phosphatase (PP2B) that, in yeast, is an integral intermediate of a salt-stress signal transduction pathway that effects NaCl tolerance through the regulation of Na+ influx and efflux. A truncated form of the catalytic subunit and the regulatory subunit of yeast CaN were coexpressed in transgenic tobacco plants to reconstitute a constitutively activated phosphatase in vivo. Several different transgenic lines that expressed activated CaN also exhibited substantial NaCl tolerance, and this trait was linked to the genetic inheritance of the CaN transgenes. Enhanced capacity of plants expressing CaN to survive NaCl shock was similar when evaluation was conducted on seedlings in tissue culture raft vessels or plants in hydroponic culture that were transpiring actively. Root growth was less perturbed than shoot growth by NaCl in plants expressing CaN. Also, NaCl stress survival of control shoots was enhanced substantially when grafted onto roots of plants expressing CaN, further implicating a significant function of the phosphatase in the preservation of root integrity during salt shock. Together, these results indicate that in plants, like in yeast, a Ca2+- and calmodulin-dependent CaN signal pathway regulates determinants of salt tolerance required for stress adaptation. Furthermore, modulation of this pathway by expression of an activated regulatory intermediate substantially enhanced salt tolerance.

Adaptation, Physiological↗
PubMed1997

Stroke rehabilitation.

Stroke is the leading cause of brain damage and resultant disability. Rehabilitation measures help to restore lost abilities, improve quality of life and decrease the long-term economic cost of stroke. Proper patient selection, realistic goal setting, the active participation of both the patient and family, and the use of an interdisciplinary team approach are important for the success of stroke rehabilitation. Functional demand and intensive training are believed to trigger central nervous system reorganization, which is responsible for late functional recovery after stroke. The outcome following a stroke is most likely to be positive when patients have bladder and bowel continence, are able to feed themselves and have a healthy and caring spouse. Stroke rehabilitation must include the prevention or early diagnosis of medical complications as well as patient and family education concerning the prevention of recurrent stroke.

Cerebrovascular Disorders↗
PubMed1997

After a stroke: strategies to restore function and prevent complications.

Mortality and morbidity are high in elderly stroke patients. Early mobilization and prevention of stroke-related complications improve their ability to participate in a more intense and comprehensive rehabilitation program. An interdisciplinary approach to stroke rehabilitation restores functional loss, improves quality of life, and decreases long-term economic costs. Important parts of stroke rehabilitation include patient and family education, treatment of stroke-related complications, and prevention of recurrent stroke. A healthy and caring spouse, continence of bladder and bowel, and ability to feed oneself are the most positive predictors of stroke outcome.

Aged↗
PubMed1994

Pyridinyl imidazoles inhibit the inflammatory phase of delayed type hypersensitivity reactions without affecting T-dependent immune responses.

The effects of pyridinyl imidazoles, specifically SK&F 105809 and its metabolite, on normal T-cell and B-cell mediated immune responses were examined and compared to the fungal macrolide immunosuppressives, cyclosporin A, FK506 and rapamycin and to the corticosteroid, dexamethasone. The orally active prodrug SK&F 105809 [2-(4-methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo [1,2-a] imidazole[ and its metabolite, SK&F 105561 [2-(4-methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2 -a] imidazole] are dual 5-lipoxygenase (5-LO) and cycloxygenase (CO) inhibitors with potent anti-inflammatory and cytokine (IL-1/TNF) suppressive activities. The anti-inflammatory activity of SK&F 105809 and its metabolite were evaluated in an antigen-specific murine model of delayed type hypersensitivity (DTH) response, where they were found to affect only the inflammatory and not the induction phase of this response. In contrast, these compounds and other pyridinyl imidazoles (SK&F 86002 and its analog, SK&F 104351) exhibited no immunosuppressive activity under conditions where the macrolide rapamycin and the corticosteroid dexamethasone abrogated both the cellular and humoral immune responses. Thus, the ability of pyridinyl imidazoles to attenuate independently the inflammatory components of the disease without causing generalized immunosuppression enhances their profile as candidates for therapy of chronic inflammatory diseases, specifically those mediated by cytokines (e.g. IL-1, TNF) and eicosanoids.

Animals↗
PubMed1986

Inhibition of vesicular stomatitis virus protein synthesis and infection by sequence-specific oligodeoxyribonucleoside methylphosphonates.

Oligodeoxyribonucleoside methylphosphonates which have sequences complementary to the initiation codon regions of N, NS, and G vesicular stomatitis virus (VSV) mRNAs were tested for their ability to inhibit translation of VSV mRNA in a cell-free system and in VSV-infected mouse L cells. In a rabbit reticulocyte lysate cell-free system, the oligomers complementary to N (oligomer I) and NS (oligomer II) mRNAs inhibited translation of VSV N and NS mRNAs whereas oligomer III had only a slight inhibitory effect on N protein synthesis. At 100 and 150 microM, oligomer I specifically inhibited N protein synthesis in the lysate. In contrast, at 150 microM, oligomer II inhibited both N and NS protein synthesis. This reduced specificity of inhibition may be due to the formation of partial duplexes between oligomer II and VSV N mRNA. The oligomers had little or no inhibitory effects on the synthesis of globin mRNA in the same lysate system. Oligomers I-III specifically inhibited the synthesis of all five viral proteins in VSV-infected cells in a concentration-dependent manner. The oligomers had no effects on cellular protein synthesis in uninfected cells nor on cell growth. An oligothymidylate which forms only weak duplexes with poly(rA) had just a slight effect on VSV protein synthesis and yield of virus. Oligomers I-III have extensive partial complementarity with the coding regions of L mRNA. The nonspecific inhibition of viral protein synthesis in infected cells may reflect the role of N, NS, and/or L proteins in the replication and transcription of viral RNA or result from duplex formation between the oligomers and complementary, plus-strand viral RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Solid-phase syntheses of oligodeoxyribonucleoside methylphosphonates.

Oligodeoxyribonucleoside methylphosphonates of defined sequence of the type d-Np(NP)nN, where n is 6-13, are readily prepared on insoluble polystyrene supports by use of protected 5'-(dimethoxytrityl)deoxyribonucleoside 3'-(methylphosphonic imidazolides) as synthetic intermediates. The imidazolides are prepared in situ by reaction of protected 5'-(dimethoxytrityl)deoxyribonucleoside with methylphosphonic bis(imidazolide) and can be stores in the reaction solution for up to 2 weeks at 4 degrees C with no loss in activity. The condensation reaction is accelerated by the presence of tetrazole, which appears to act as an acid catalyst. The half-life for dimer formation on the polystyrene support is 5 min, and the reaction is 95% complete after 60 min. Although similar kinetics are observed when controlled pore glass is used as the support, the extent of the reaction does not go beyond 78%, even after prolonged incubation. In order to simplify purification and sequence analysis of the oligomer, the 5'-terminal nucleoside unit is linked via a phosphodiester bond. This linkage may be introduced by either an o-chlorophenyl phosphotriester method or a cyanoethyl phosphoramidite method. The latter procedure simplifies the deprotection step, since the cyanoethyl group is readily cleaved by ethylenediamine, which also removes the base protecting groups and cleaves the oligomer from the support. The singly charged oligomers are easily purified by affinity chromatography on DEAE-cellulose. The chain lengths of the oligomers were confirmed after 5'-end labeling with polynucleotide kinase by partial hydrolysis of the methylphosphonate linkages with 1 M aqueous piperidine followed by polyacrylamide gel electrophoresis of the hydrolysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1986

Antiviral effect of an oligo(nucleoside methylphosphonate) complementary to the splice junction of herpes simplex virus type 1 immediate early pre-mRNAs 4 and 5.

Selective inhibition of regulatory immediate early (IE) genes of herpes simplex virus type 1 (HSV-1) should inhibit virus growth. Treatment of HSV-1-infected cells with the oligo(nucleoside methylphosphonate) d(TpCCTCCTG) (deoxynucleoside methylphosphonate residues in italic), which is complementary to the acceptor splice junction of HSV-1 IE pre-mRNA 4 and 5, before (1-24 hr) or at the time of infection caused a dose-dependent inhibition in virus replication. Virus titers were decreased 50% and 90% in cells treated with 25 microM and 75 microM oligomer, respectively; at 300 microM, a 99% reduction in virus production was observed. Viral DNA synthesis was reduced 70-75% and there was a 90% reduction in synthesis of viral proteins, including other IE species and viral functional (130-kDa major DNA-binding) and structural (glycoprotein gB) proteins. In the same concentration range, d(TpCCTCCTG) caused a minimal reduction (0-30%) in protein synthesis and growth rates (less than 40%) of uninfected cells. The data suggest that oligo(nucleoside methylphosphonate)s may be effective in antiviral chemotherapy.

Animals↗
PubMed1986

A guide to early mobilization of bedridden elderly.

A vigorous, functionally oriented program should be started as early as the patient's medical or surgical condition permits. This comprehensive approach requires the efforts of a team of health professionals coordinated by the patient's primary care physician. Restoration of strength, flexibility, coordination, and balance are the goals of successful ambulation. When an elderly person has difficulty in walking, the physician and therapist must search for the cause and take corrective measures.

Activities of Daily Living↗
PubMed1986

Management of common 'pinched nerves' in the elderly.

Sedentary elderly persons and elderly patients with dementia, depression, stroke, hip fracture, and restricted mobility are at high risk for developing entrapment neuropathies. Although several causes of peroneal nerve entrapment have been described, the most common in the elderly are leg-crossing and prolonged squatting or kneeling.

Aged↗
PubMed1985

Hybridization arrest of globin synthesis in rabbit reticulocyte lysates and cells by oligodeoxyribonucleoside methylphosphonates.

Oligodeoxyribonucleoside methylphosphonates which are complementary to the 5' end, the initiation codon regions, or the coding regions of rabbit globin mRNA were synthesized. These oligomers were shown to interact with their complementary mRNA binding sites by their ability to serve as primers for reverse transcriptase. In several cases, the priming efficiency of the oligomers was enhanced when the oligomer was preannealed with the mRNA. This behavior correlates with the predicted secondary structure of the mRNA and suggests that some oligomer binding sites occur in hydrogen-bonded stem regions of the mRNA. Methylphosphonate oligomers inhibit translation of globin mRNA in reticulocyte lysates. Inhibition is due to the interaction of the oligomers with mRNA. The extent of inhibition is affected by the sequence and chain length of the oligomer, the location of the oligomer binding site on the mRNA, and the secondary structure of the binding site. Oligomers which bind to the 5' end and initiation codon regions of beta-globin mRNA inhibit both alpha- and beta-globin synthesis whereas oligomers which bind to the coding region of alpha-globin mRNA or the coding region of beta-globin mRNA inhibit translation of their target mRNA in a specific manner. Oligodeoxyribonucleoside methylphosphonates inhibit globin synthesis in rabbit reticulocytes. The effects of various oligomers on cellular globin synthesis are similar to those in the lysate system and suggest that the conformation of globin mRNA is the same in both systems during translation.

Animals↗
PubMed1984

Electrodiagnosis of motor unit disorders.

Electromyography and nerve stimulation studies evaluate the function of lower motor neurons, nerve roots, plexus, peripheral nerves, neuromuscular junctions and muscles. Electrodiagnostic studies differentiate myopathic and neuropathic muscle weakness. No single abnormality is diagnostic for a particular disease. The combination of certain abnormal findings and their pattern of presentation in specific muscle groups, when correlated with the patient's history and clinical findings, will help to identify and localize a lesion in the motor unit pathway.

Amyotrophic Lateral Sclerosis↗
PubMed1984

Nerve entrapment syndromes in the upper extremity contralateral to amputation.

Five cases are reported of upper extremity amputation with no metabolic disease. Patients experienced pain, paresthesia and weakness in the intact extremity associated with electrophysiologic evidence of entrapment neuropathies. All patients did heavy manual work, and all had carpal tunnel syndrome. One patient also had cubital tunnel syndrome and compression of the medial cord of the brachial plexus in the axilla, and another patient had cubital tunnel syndrome and axillary neuropathy. Surgery did not relieve symptoms of carpal tunnel and cubital tunnel syndromes for prosthesis users until the figure-8 harness was changed. Patients who did not use a prosthesis felt relief of symptoms following surgical release. Possible mechanisms which produce nerve entrapment syndromes in patients with upper extremity amputations are use of one limb for heavy manual work over prolonged periods, direct compression of neural structures from the axilla loop of a figure-8 harness, and compression of neural structures in the axilla resulting in entrapment at a distal site. Changing the figure-8 harness should be considered prior to surgical decompression for patients who have upper extremity amputations with entrapment syndromes.

Adult↗
PubMed1983

Conduction studies of the medial cutaneous nerve of the forearm.

The forearm medial cutaneous nerve is a pure sensory branch from the medial cord of the brachial plexus. Its fibers are derived from the eighth cervical and first thoracic nerves. A simple, easily reproducible antidromic technique for studying conduction of the forearm medial cutaneous nerve is described with the knowledge (obtained from cadaver dissections) of its exact topography. Sixty nerves were studied in 30 able-bodied adults, 15 women and 15 men. Surface stimulation was done over the medial aspect of the middle of the arm at a level where the nerve pierces the deep fascia. Surface recordings were made 18cm distally over the course of its volar branch. Action potentials were obtained in 100% of the subjects without electronic averaging. Mean values obtained were as follows: latency to onset 2.73 +/- 0.17 msec; latency to peak 3.31 +/- 0.19 msec; conduction velocity of the fastest fibers 65.9 +/- 4.3 m/s; amplitude 15.4 +/- 4.1 microvolts, and the mean difference in latency between the right and left nerves in the same subject was 0.1 msec. Conduction studies of this nerve should be useful in electrodiagnostic evaluation of peripheral neuropathy (particularly in below amputees), local neuropathic conditions, and entrapment syndromes involving the medial cord of the brachial plexus.

Adult↗