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Biomedical subjects

M Reddy

Publications and source records attributed to M Reddy.

At least 37 records · Page 2Linked to original sources
PubMed2001

CD4 mAb induced apoptosis of peripheral T cells: multiparameter subpopulation analysis by flow cytometry using Attractors.

Studies describing the induction of apoptosis for CD4 mAbs do not delineate between epitope-dependent and Fc-driven epitope cross-linking induced cell death. Keliximab and clenoliximab are two CD4 mAbs that differ only in their heavy chain isotypes, being an IgG1 and a modified IgG4, respectively. These antibodies suppress CD4 T cell responses in vitro and in vivo and have been in human clinical trials for the treatment of RA and asthma. Here we compared the apoptotic activity of these mAbs to differentiate between the contributions of epitope-dependent vs. Fc-driven epitope cross-linking induced cell death in vitro as a link to differential CD4 cell depletion in vivo. We developed a simple flow cytometry procedure that measures apoptosis within intact and compromised subpopulations of PBMCs within a few hours of culture. Attractors software was used to quantitate the percentage of apoptotic CD4 T cells, which generate reactive oxygen species (ROS), express external phosphatidyl serine (PS) and cleaved fluorescein diacetate (FDA), within the intact and compromised lymphocyte populations. Treatment of freshly isolated PBMCs with keliximab resulted in the appearance of characteristic apoptotic condensed CD4 T cells that contained reactive oxygen species, were annexin V positive and had intact esterase activity. Apoptosis was evident within 3 h and continued throughout the 72-h culture period. In contrast, clenoliximab alone did not induce apoptosis. The use of multiparameter flow cytometry and Attractors to analyze subpopulations based on scatter properties and biochemical processes during apoptosis provides a sensitive assay in which to quantitate and characterize the induction of cell death. Depletion of CD4 T cells in vivo by keliximab may reflect, in part, antibody-mediated apoptosis of these cells that is dependent on Fcgamma receptors.

Annexin A5↗
PubMed2001

Solvation effect on organic compound interactions in soil organic matter.

We examine sorption of pyridine by soil organic matter (SOM) from different organic media including n-hexadecane, acetonitrile, acetone, and n-hexadecane mixtures with either acetonitrile or acetone and compare it with sorption from water. By using an activity-based comparison, we distinguish between solvent-assisted and solvent-competitive sorption behavior. Pyridine was selected because it forms strong complexes with phenolic and carboxylic groups, such that site interactions should dominate interactions in SOM. It is anticipated that pyridine sorption will be illustrative of the importance of disrupting strong interactions in a condensed, shrunken SOM phase for many organic compounds. It was generally found that activity-normalized pyridine uptake was assisted by polar solvent molecules rather than suppressed due to competition. An explanation is tendered on the basis of our earlier hypothesis of water-assisted disruption of polar SOM contacts. Certain polar moieties of dry SOM are unavailable for compound sorption due to strong interactions between them. By penetrating SOM structure, solvent molecules (and water) solvate (hydrate) polar moieties creating new sorption sites. Solvent molecules must solvate both moieties of the polar contact, such that the driving force for solvent-assisted sorption is solvation of the partner of the disrupted contact that does not directly interact with the sorbate.

Adsorption↗
PubMed2001

An integrated physical map of 8q22-q24: use in positional cloning and deletion analysis of Langer-Giedion syndrome.

We have developed an integrated map for a 35-cM area of human chromosome 8 surrounding the Langer-Giedion syndrome deletion region. This map spans from approximately 8q22 to 8q24 and includes 10 hybrid cell intervals, 89 polymorphic STSs, 118 ESTs, and 37 known genes or inferred gene homologies. The map locations of 25 genes including osteoprotegerin, syndecan-2, and autotaxin have been refined from the general locations previously reported. In addition, the map has been used to indicate the location of nine deletions in patients with Langer-Giedion syndrome and trichorhinophalangeal syndrome type I to demonstrate the potential usefulness of the map in the analysis of these complex syndromes. The map will also be of interest to anyone trying to clone positionally disease genes in this region, such as Cohen syndrome (8q22-q23), Klip-Feil syndrome (8q22.2), hereditary spastic paraplegia (8q24), and benign adult familial myoclonic epilepsy (8q23.3-q24.1).

Child↗
PubMed2001

Assessing violence risk in Tarasoff situations: a fact-based model of inquiry.

Although significant advances in risk assessment research and practice have been made in recent years, there has not been any analysis in the professional literature regarding how and whether the emerging practice recommendations apply in Tarasoff-type situations. We suggest that, when faced with a Tarasoff-type situation, the appraisal of risk should be guided by a method that is primarily fact-based and deductive, rather than by the more inductive risk assessment approach for general violence recidivism, which is guided primarily by base rates and historical risk factors. We review the principles underlying a fact-based, or threat assessment, approach and outline six areas of inquiry that can guide the appraisal of risk: A-attitudes that support or facilitate violence, C-capacity, T-thresholds crossed, I-intent, O-other's reactions, and N-noncompliance with risk reduction interventions.

Duty to Warn↗
PubMed2001

Neonatal repair of truncus arteriosus: continuing improvement in outcomes.

BACKGROUND: Repair of truncus arteriosus in the neonatal and early infant periods has become standard practice at many centers. We reviewed our recent experience with repair of truncus arteriosus in neonates, with a focus on early and intermediate outcomes. METHODS: From July 1992 to December 1999, 65 patients 1 month of age or less underwent primary complete repair of truncus arteriosus. Median age was 10 days, and median weight was 3.2 kg. Major associated anomalies included moderate or severe truncal valve regurgitation in 15 patients (23%), interrupted aortic arch in 8 (12%), coronary artery abnormalities in 12 (18%), and nonconfluence of the pulmonary arteries in 3 (5%). Median durations of cardiopulmonary bypass and cardioplegic arrest were 172 minutes and 90 minutes, respectively. Circulatory arrest was employed only in 7 patients undergoing concomitant repair of interrupted arch. Reconstruction of the right ventricular outflow tract was achieved with an aortic (n = 39) or pulmonary (n = 26) allograft valved conduit (median diameter, 12 mm). Replacement (n = 6) or repair (n = 5) of a regurgitant truncal valve was performed in 11 patients, and interrupted arch was repaired in 8. RESULTS: There were three early deaths (5%). Early reoperations included reexploration for bleeding in 3 patients, emergent replacement of a pulmonary outflow conduit that failed acutely in 1 patient, and placement of a permanent pacemaker in 1. Mechanical circulatory support was required in 1 patient. During the median follow-up of 32 months, there were two deaths. The Kaplan-Meier estimate of survival was 92% at 1 year and beyond. The only demographic, diagnostic, or operative factors significantly associated with poorer survival over time were operative weight of 2.5 kg or less (p = 0.01) and truncal valve replacement (p = 0.009). Actuarial freedom from conduit replacement among early survivors was 57% at 3 years. CONCLUSIONS: Repair of truncus arteriosus in the neonatal period can be performed routinely with excellent survival, even in patients with major associated abnormalities.

Female↗
PubMed2001

Use of erythropoietin before the initiation of dialysis and its impact on mortality.

Erythropoietin (EPO) is recommended in individuals progressing toward end-stage renal disease (ESRD) to correct anemia and its complications, which are common in this disease. This study evaluated the impact of EPO administered before dialysis on mortality in incident ESRD patients. A total of 4,866 patients whose exposure to pre-ESRD EPO was determined from Health Care Financing Administration 2728 forms were analyzed. The median follow-up was 26.2 months, with 1,107 (22.7%) patients given EPO and 1,892 (38.9%) deaths. EPO use was more common in patients who had insurance before dialysis, remained employed, were started on renal replacement therapy outside the hospital, or initiated on peritoneal dialysis, which could be indicative of early intervention or quality care. The risk of death after starting dialysis was lower for patients treated with EPO before dialysis compared with patients who were not treated (adjusted relative risk 0.80, 95% confidence interval 0.70 to 0.91). There was no direct relationship between predialysis hematocrit and mortality; however, the most significant survival benefit with EPO use was in patients with the highest hematocrit values (adjusted relative risk 0.67, 95% confidence interval, 0.51 to 0.89). The most significant effect of pre-ESRD EPO use was observed during the first 19 months after starting dialysis (adjusted relative risk, 0.81; 95% confidence interval, 0.71 to 0.91), but this benefit diminished in patients with longer follow-up on renal replacement therapy. Use of EPO before dialysis confers a survival benefit to ESRD patients, especially in patients with an adequate hematocrit response before initiation of dialysis.

Aged↗
PubMed2001

A lateral mass fracture of C1 associated with left vertebral artery and mid-basilar artery occlusion.

Extreme acceleration and deceleration forces as well as axial loading are exerted at the occipito-cervical junction of drivers involved in high-velocity motor vehicle accidents, especially with fastened seatbelts. Injury at this level, usually lethal, can go unrecognized despite modern emergency management of the unconscious patient. A precise neurologic and radiographic workup of damage to this area is often not possible or overlooked in the initial phase of such severe trauma. We describe a patient with multiple injuries who sustained a left vertebral artery occlusion associated with a left-sided lateral mass fracture of C1 and a basilar artery occlusion resulting in a locked-in syndrome after an automobile accident.

Arterial Occlusive Diseases↗
PubMed2001

IS186 insertion at a hot spot in the lon promoter as a basis for lon protease deficiency of Escherichia coli B: identification of a consensus target sequence for IS186 transposition.

The radiation sensitivity of Escherichia coli B was first described more than 50 years ago, and the genetic locus responsible for the trait was subsequently identified as lon (encoding Lon protease). We now show that both E. coli B and the first reported E. coli K-12 lon mutant, AB1899, carry IS186 insertions in opposite orientations at a single site in the lon promoter region and that this site represents a natural hot spot for transposition of the insertion sequence (IS) element. Our analysis of deposited sequence data for a number of other IS186 insertion sites permitted the deductions that (i) the consensus target site sequence for IS186 transposition is 5'-(G)(> or =4)(N)(3-6)(C)(> or =4)-3', (ii) the associated host sequence duplication varies within the range of 6 to 12 bp and encompasses the N(3-6) sequence, and (iii) in a majority of instances, at least one end of the duplication is at the G-N (or N-C) junction. IS186-related sequences were absent in closely related bacterium Salmonella enterica serovar Typhimurium, indicating that this IS element is a recent acquisition in the evolutionary history of E. coli.

ATP-Dependent Proteases↗
PubMed2001

Implants in regenerated bone in a primate model.

BACKGROUND: Earlier publications from our laboratory described the use of guided bone regeneration to fill large bone voids in the mandible created through en bloc resection in primates. The present report describes placement of implants into the regenerated bone with subsequent prostheses construction and loading. METHODS: Lesions were created in the mandibles of 9 monkeys in a standardized mandibular defect of 8 x 19 mm. Reinforced expanded polytetrafluoroethylene membranes were placed in the animals and held in place with mini screws and sutures for anywhere from 1 to 12 months. No material was added to the defect. In each animal a root-form implant was placed 12 mm distal to the abutment teeth into the regenerated bone and was loaded with a prosthesis for 12 months. These implants were compared to original implants placed in the same monkeys years earlier in the same location in non-regenerated bone. Digital radiology and histomorphometry are described. RESULTS: The results show that root-form implants placed in regenerated bone show the same radiological and histomorphometric characteristics as in normal bone when loaded. In addition, the percentage of bone contact with implants seen in regenerated bone versus non-regenerated bone is the same when both are loaded (65 +/- 13% SD in regenerated bone versus 59 +/- 15% SD in non-regenerated bone). CONCLUSIONS: In a primate model root-form implants placed in regenerated bone and prosthetically loaded show no difference when compared to root-form implants placed in non-regenerated bone and prosthetically loaded.

Alveolar Bone Loss↗
PubMed2001

Transmission of penile cuff pressure to the penile urethra.

PURPOSE: We developed a noninvasive method to measure voiding bladder pressure by inflating a penile cuff to interrupt flow. We tested the underlying assumption that cuff pressure is transmitted to the penile urethra. MATERIALS AND METHODS: In 35 men we simultaneously recorded penile cuff and urethral pressure during 2 experimental protocols for 6 cuffs of various widths and manufactures. Initially a urethral pressure transducer was placed at the mid point of the cuff and urethral pressure was continuously recorded during cuff inflation. In experiment 2 cuff pressure was set at 120 cm. water and the urethral pressure profile was measured by withdrawing the urethral transducer through the cuff width. RESULTS: There was excellent agreement of cuff with urethral pressure over the range of 0 to 200 cm. water for cuffs 37 to 54 mm. wide. Narrower cuffs showed wider variation with less efficient transmission of cuff pressure to the urethral lumen. Similarly maximum pressure in the urethral pressure profile showed best agreement for cuffs 38 and 46 mm. wide. Wider cuffs produced higher and narrower cuffs produced lower transmitted pressure within the urethra. Cuff performance was also related to penile size. Results had good within-subject repeatability. CONCLUSIONS: We demonstrated that pressure transmission from cuff to urethra is optimal at a cuff width of 40 to 50 mm. and recommended this width for other investigations of noninvasive bladder pressure measurement.

Equipment Design↗
PubMed2000

Utility of the tandem Pauson-Khand reaction in the construction of tetracycles

The scope of the tandem Pauson-Khand reaction has been explored for the regiospecific construction of [5.5.5.5]- and [5.6.6.5]tetracyclic systems via the photolytic method of Livinghouse. The rapid regiospecific entry into the two dicyclopentapentanoid systems 17 and 29 was accomplished from the key diene-diynes 11 and 19b. A photochemically mediated catalytic tandem Pauson-Khand cyclization was employed to prepare the parent ring systems of dicyclopenta[a,e]pentalene (from 19b) and dicyclopenta[a,f]pentalene (from 11) in regiospecific fashion in a one-pot process. Under these conditions, conversion of acyclic diene-diyne 16 into tetracyclic system 17 was achieved in 74% yield, while a similar process was employed to convert 28 into tetracycle 29 in 90% yield. This is much improved over the previous conditions that employed NMO. Six carbon-carbon bonds were generated in this process constituting up to 98% yield for each carbon-carbon bond so formed. Furthermore, tetracyclic [5.6.6.5] systems such as dicyclopenta[b,g]decalins 37, 38, and 40 were prepared from similar diene-diyne precursors via the tandem Pauson-Khand cyclization. Importantly, acetal 36 provided the desired cis-fused [5.6.6.5] system 38a (via 40a/b) in stereospecific fashion. This reaction is unique in that it provides a cis-decalin ring system; moreover, the yield of each of the six carbon-carbon bonds formed in this process was at least 89%. The structure of cis diol 38a was confirmed by X-ray crystallography.

Journal Article↗
PubMed2000

Defining the role of stereotactic radiosurgery versus microsurgery in the treatment of single brain metastases.

Stereotactic radiosurgery (RS) and surgery have proved to be effective treatment modalities for brain metastasis. We followed 133 patients whose treatment for intracranial disease was either RS or a single surgical resection at the University of Vienna from August 1992 through October 1996. All patients who received additional Whole Brain Radiotherapy were included. This was a retrospective, case-control study comparing these treatment modalities. Sixty-seven patients were treated by RS and 66 patients were treated by microsurgery. The median size of the treated lesions for RS patients was 7800 mm3, and 12500 mm3 for microsurgery patients, respectively. The median dose delivered to the tumour margin for RS patients was 17 gray. The median survival for patients after RS was 12 months, and 9 months for patients after microsurgery. This difference was not statistically significant (p = 0.19). Comparison of local tumour control, defined as absence of regrowth of a treated lesion, showed that tumours following RS had a preferred local control rate (p < 0.05). Univariate and multivariate analysis showed that this fact was due to a greater response rate of "radioresistant" metastasis to RS (p < 0.005). Postradiosurgical complications included the onset of peritumoural oedema (n = 5) and radiation necrosis (n = 1). Two patients after microsurgery experienced local wound infection. One postoperative death occurred due to pulmonary embolism in this group. On the basis of our data we conclude that RS and microsurgery combined with Whole Brain Radiotherapy are comparable modalities in treating single brain metastasis. Concerning morbidity and local tumour control, in particular in cases of "radioresistant" primary tumours, RS is superior. Therefore we advocate RS except for cases of large tumours (> 3 cm in maximum diameter) and for those with mass effect.

Brain Neoplasms↗
PubMed2000

Inhibition of contact sensitivity in human CD4+ transgenic mice by human CD4-specific monoclonal antibodies: CD4+ T-cell depletion is not required.

Clenoliximab and keliximab are monkey/human chimeric monoclonal antibodies (mAbs) of the immunoglobulin G4 (IgG4) and IgG1 isotypes, respectively, that recognize the same epitope on human CD4. The two mAbs possess identical idiotypes and exhibit equal affinities for CD4. Upon administration of these mAbs to mice that express a human CD4 transgene, but not mouse CD4 (HuCD4/Tg mice), clenoliximab and keliximab exhibited similar kinetics of binding to CD4, and induced the same degree of CD4 modulation from the cell surface, although only keliximab mediated CD4+ T-cell depletion. Epicutaneous sensitization and challenge of HuCD4/Tg mice with the hapten oxazolone resulted in a contact sensitivity response characterized by tissue swelling, and the presence of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in the local tissue. Administration of a single 2-mg dose of either clenoliximab or keliximab to HuCD4/Tg mice prior to sensitization significantly reduced post-challenge tissue swelling, and levels of IFN-gamma and IL-4, indicating that CD4+ T-cell depletion is not required for anti-CD4 mAb-mediated inhibition of contact sensitivity. Administration of either mAb prior to challenge failed to inhibit the contact sensitivity response, indicating differential sensitivity of the afferent and efferent phases of the response to inhibition by CD4-specific mAbs. Collectively, these data indicate that CD4 functions as a positive regulatory molecule in the contact sensitivity response.

Adjuvants, Immunologic↗
PubMed2000

Bacteria-mucin interaction in the upper aerodigestive tract shows striking heterogeneity: implications in otitis media, rhinosinusitis, and pneumonia.

The mucociliary system of the upper and lower respiratory tracts is a critical nonspecific pathway for the elimination of bacteria and other particulate matter. The interaction between bacteria and purified mucin of the upper and lower respiratory tracts has been a major focus of our laboratory for the past decade. We have previously demonstrated that nontypable Haemophilus influenzae and Moraxella catarrhalis adhere to human purified nasopharyngeal mucin and human middle ear mucin by a very limited number of specific outer membrane proteins. There have been no previous studies on the interaction of Streptococcus pneumoniae and purified mucin. Such information would be of extreme importance in identifying specific mechanisms of preventing colonization of this important pathogen to nasopharyngeal mucin. Using an overlay technique of purified radiolabeled mucins of the upper and lower respiratory tracts in a solid phase assay with 4 predominant pathogens of the upper and lower respiratory tracts, we found a striking heterogeneity of bacteria-mucin interaction. The implications of these interactions in the development of otitis media, rhinosinusitis, and lower respiratory infections are briefly discussed.

Bacterial Adhesion↗
PubMed2000

lon incompatibility associated with mutations causing SOS induction: null uvrD alleles induce an SOS response in Escherichia coli.

The uvrD gene in Escherichia coli encodes a 720-amino-acid 3'-5' DNA helicase which, although nonessential for viability, is required for methyl-directed mismatch repair and nucleotide excision repair and furthermore is believed to participate in recombination and DNA replication. We have shown in this study that null mutations in uvrD are incompatible with lon, the incompatibility being a consequence of the chronic induction of SOS in uvrD strains and the resultant accumulation of the cell septation inhibitor SulA (which is a normal target for degradation by Lon protease). uvrD-lon incompatibility was suppressed by sulA, lexA3(Ind(-)), or recA (Def) mutations. Other mutations, such as priA, dam, polA, and dnaQ (mutD) mutations, which lead to persistent SOS induction, were also lon incompatible. SOS induction was not observed in uvrC and mutH (or mutS) mutants defective, respectively, in excision repair and mismatch repair. Nor was uvrD-mediated SOS induction abolished by mutations in genes that affect mismatch repair (mutH), excision repair (uvrC), or recombination (recB and recF). These data suggest that SOS induction in uvrD mutants is not a consequence of defects in these three pathways. We propose that the UvrD helicase participates in DNA replication to unwind secondary structures on the lagging strand immediately behind the progressing replication fork, and that it is the absence of this function which contributes to SOS induction in uvrD strains.

ATP-Dependent Proteases↗
PubMed2000

Characterization of the uup locus and its role in transposon excisions and tandem repeat deletions in Escherichia coli.

Null mutations in the Escherichia coli uup locus (at 21.8 min) serve to increase the frequency of RecA-independent precise excision of transposable elements such as Tn10 and to reduce the plaque size of bacteriophage Mu (Uup(-) phenotype). By the combined approaches of physical mapping of the mutations, complementation analyses, and protein overexpression from cloned gene fragments, we have demonstrated in this study that the Uup(-) phenotype is the consequence of the absence of expression of the downstream gene (uup) of a two-gene operon, caused either directly by insertions in uup or indirectly by the polar effect of insertions in the upstream gene (ycbY). The promoter for uup was mapped upstream of ycbY by primer extension analysis on cellular RNA, and assays of reporter gene expression indicated that it is a moderately active, constitutive promoter. The uup mutations were also shown to increase, in a RecA-independent manner, the frequencies of nearly precise excision of Tn10 derivatives and of the deletion of one copy of a chromosomal tandem repeat, suggesting the existence of a shared step or intermediate in the pathways of these latter events and that of precise excision. Finally, we found that mutations that increase the frequency of precise excision of Tn10 are divisible into two categories, depending upon whether they did (uup, ssb, polA, and topA) or did not (mutHLS, dam, and uvrD) also increase precise excision frequency of the mini-Tn10 derivatives. It is suggested that the differential response of mini-Tn10 and Tn10 to the second category of mutations is related to the presence, respectively, of perfect and of imperfect terminal inverted repeats in them.

ATP-Binding Cassette Transporters↗