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Biomedical subjects

D R Kelly

Publications and source records attributed to D R Kelly.

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

Radiation-induced glioma of the spinal cord.

We report a case of a radiation-induced spinal cord glioma. A 20-year-old girl presented with neck pain and new significant neurological deficits 17 years after resection of a posterior fossa medullomyoblastoma and subsequent craniospinal irradiation. She was found to have a cervical intramedullary tumor that was resected using a standard microsurgical technique. The permanent histopathological diagnosis was anaplastic astrocytoma. Her neurological status was worse immediately following the operation. She improved to her pre-operative status, but then had a relentless neurological decline resulting in death 16 weeks following surgery. Because of the high incidence of malignancy in the few radiation-induced spinal cord gliomas reported in the literature, and the poor outcome independent of therapy in patients with malignant spinal cord gliomas, an initial strategy of biopsy only may be more appropriate than attempted resection for the patient with a suspected radiation-induced intramedullary spinal cord tumor.

Adult↗
PubMed1996

Stage-specific expression of integrin alphaVbeta3 in neuroblastic tumors.

The ligand specificity of the integrin cell adhesion receptors probably determines the ability of specific integrins to promote tumor cell proliferation and metastasis. Therefore, we compared the expression of integrin alphaVbeta3, a promiscuous receptor that binds with high affinity to numerous cell matrix proteins, with the expression of integrin alphaVbeta5 and the integrin beta 1 subunit (which pairs with multiple alpha subunits) in neuroblastic tumors at various stages of differentiation. Undifferentiated neuroblastoma tumors rapidly invade and metastasize, whereas ganglioneuroblastomas rarely metastasize. Differentiating neuroblastomas are associated with an intermediate prognosis. Paraffin sections of neuroblastic tumors at various stages of differentiation obtained at biopsy from 17 patients were hybridized with antisense integrin subunit-specific alphaV, beta3, beta1, and beta5 riboprobes. All neuroblastic tumors and seven adrenal glands obtained at autopsy were analyzed immunohistochemically with antibodies directed toward the alphaV, beta3, beta1, and beta5 subunits. The alphaV subunit was expressed in neuroblastic tumors independent of the stage of differentiation, although mRNA and protein expression were generally weak in ganglioneuroblastomas, and was also detected in adrenal gland medullae. The beta1 subunit was detected in most neuroblastic tumors independent of the stage of differentiation as well as in adrenal gland medullae. In contrast, the beta3 subunit, which was not expressed in adrenal gland medullae, was expressed at the protein and mRNA levels in undifferentiated neuroblastomas (six of seven and seven of seven, respectively) but was not expressed in neuroblasts or ganglion cells in ganglioneuroblastomas (one case weakly positive out of five). The beta 5 subunit was expressed at the protein (five of five) and mRNA (four of five) levels in the ganglion cells of ganglioneuroblastomas and, although mRNA for this subunit was detectable in undifferentiated tumors, the protein was not detectable. The expression of integrin alphaVbeta3 in undifferentiated neuroblastomas may contribute to the rapid growth of these tumors and their tendency to metastasize.

Adolescent↗
PubMed1996

GTP synthases. Proton pumping and phosphorylation in ligand-receptor-G alpha-protein complexes.

A structural model for a ligand-receptor-Gs alpha-protein complex to function as a GTP synthase is presented. The mechanism which is dependent on the movement and rotation of the G alpha-protein alpha 2-helix is seen to involve the delivery of, at least, one proton to the phosphorylation site in the rotation of this helix. The cycle is driven by a ligand-mediated proton pump through the alpha-helices of the receptor, attachment of the conserved Tyr-Arg-Tyr receptor proton shuttle being made to an aspartate group on the Gs alpha-protein terminal sidechain, which is itself linked to the Asn-Gln interaction known to control movement and rotation of the alpha 2-helix between .GDP and .GTP structures. The energetics of proton transfer through the shuttle mechanism and delivery of a proton to the aspartate group are shown to be sufficient to rupture this controlling interaction and its associated backbone bond. The complex leads to full spatial and energetic definition of the receptor proton shuttle mechanism, while there is a striking association of further Tyrosine and Arginine residues in the vicinity of the Gs alpha-protein Asn-Gln interaction. Calculations at the HF 6-31G** level confirm that a critical balance between ion pair and neutral forms of Tyr-Arg interactions under multiply hydrogen bonded conditions in a hydrophobic environment controls proton transfer and recovery mechanisms. The intrinsic preference of the neutral Tyr-Arg form over the ion-pair is 14.0 kcal/mol. Activation of the Tyrosine oxygen atom in the neutral form by single-NH or -OH groups reduces this difference by some 6.4-8.6 kcal/mol but the dominance of the neutral form is maintained. The expected slight overestimates are consistent with the maximum activation enthalpy of 11.0-12.0 kcal/ mol required to initiate proton transfer through the shuttle. The extended form of the shuttle with the Arginine acting competitively between the two Tyrosine residues allows interpretation of observed enthalpic differences in ligand binding with and without the presence of GTP. The uniqueness of Gs proteins among the G alpha-proteins is seen as their inability to transfer a proton directly through the alpha 2-helix switch Asn-Gln residues. A possible proton pathway to the mid-point of the Gs alpha-protein alpha 2 helix is outlined.

Amino Acid Sequence↗
PubMed1995

Isolated CNS metastasis as the first site of recurrence in a child with germ cell tumor of the mediastinum.

We describe a 2-year-old black female who was previously in complete remission from a stage 4 mediastinal germ cell tumor (stage 4 because of a single pulmonary parenchymal lesion). She presented with headaches, obtundation, and brain herniation, and suffered sudden death 12 months after completing high-dose chemotherapy. Autopsy revealed a large intraventricular lesion with mixed germ cell tumor elements, but no other evidence of malignancy was found. This case represents the first report of isolated CNS metastasis of malignant germ cell tumor in a child in apparent remission without evidence of advanced or recurrent disease in other sites. It is possible that the aggressive chemotherapy used resulted in a change in the natural history of this disorder.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Evidence for in vivo peroxynitrite production in human acute lung injury.

Oxidant-mediated toxicity resulting from acute pulmonary inflammation has been demonstrated in acute lung injury. A potent biological oxidant, peroxynitrite, is formed by the near diffusion-limited reaction of nitric oxide with superoxide. In addition to having hydroxyl radical-like oxidative reactivity, peroxynitrite is capable of nitrating phenolic rings, including protein-associated tyrosine residues. Nitric oxide does not directly nitrate tyrosine residues, therefore, demonstration of tissue nitrotyrosine residues infers the action of peroxynitrite or related nitrogen-centered oxidants. Lung tissue was obtained from formalin-fixed, paraffin-embedded autopsy specimens, and specific polyclonal and monoclonal antibodies to nitrotyrosine were visualized by diaminobenzidene-peroxidase staining. Acute lung injury resulted in intense staining throughout the lung, including lung interstitium, alveolar epithelium, proteinaceous alveolar exudate, and inflammatory cells. In addition, staining of the vascular endothelium and subendothelial tissues was present in those patients with sepsis-induced acute lung injury. Antibody binding was blocked by coincubation with nitrotyrosine or nitrated bovine serum albumin but not by aminotyrosine, phosphotyrosine, or bovine serum albumin. Reduction of tissue nitrotyrosine to aminotyrosine by sodium hydrosulfite also blocked antibody binding. In control specimens with no overt pulmonary disease, there was only slight staining of the alveolar septum. These results demonstrate that nitrogen-derived oxidants are formed in human acute lung injury and suggest that peroxynitrite may be an important oxidant in inflammatory lung disease.

Cadaver↗
PubMed1995

Short bowel syndrome.

Improvements in parenteral nutrition and supportive therapy have led to a growing population of patients who survive for prolonged periods with short bowel syndrome. Definitive treatment for these patients requires innovative therapy based on a sound knowledge of small intestinal physiology and adaptation. Current understanding of short bowel pathophysiology and of intestinal adaptation are reviewed. Medical and surgical therapeutic options are described, highlighting the promotion of small bowel adaptation and methods to increase the small intestinal mucosal mass.

Adaptation, Physiological↗
PubMed1994

Effects of cholinergic blockade on hemodynamic disturbances and intestinal lesions in endotoxic shock in newborn piglets.

The parasympathetic nervous system actively participates in the regulation of pathophysiologic responses in circulatory shock. To determine the effects of cholinergic blockade in endotoxic shock in newborn piglets, 16 chronically instrumented newborn piglets were infused with 10 mg/kg of endotoxin over 10 min. Eight animals were injected intravenously with 10 mg/kg of anisodamine, an anticholinergic drug, 10 min before endotoxin and then with escalating doses of 2, 5, 10, and 20 mg/kg every 10 min, beginning 60 min after endotoxin. The other eight animals were given saline as a control. Endotoxin infusion caused elevations in mean pulmonary artery pressure and vascular resistance index and an initial increase in systemic artery pressure followed by hypotension. Heart rate was stable for 45 min and then increased. Cardiac index fell from a baseline of 173 +/- 20 (mean +/- S.E.) to 136 +/- 23 mL.min-1.kg-1 60 min after endotoxin. Pretreatment with anisodamine increased heart rate from 163 +/- 15 to 289 +/- 10 beats.min-1 and cardiac index from 195 +/- 15 to 238 +/- 14 mL.min-1.kg-1 before endotoxin infusion. These variables remained at higher levels than in the control group until 60 min after endotoxin infusion; thereafter, the two groups were similar. The changes in pulmonary and systemic artery pressures were not significantly altered by anisodamine. After 60 min, additional doses of anisodamine caused no significant hemodynamic responses, and the differences between the two groups were not significant. Arterial plasma thromboxane B2 levels rose immediately and tumor necrosis factor-alpha levels increased 60 min after endotoxin infusion; no significant differences were noted between groups at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Successful medical treatment of a spinal histoplasmoma.

A woman with previously treated disseminated histoplasmosis was admitted with progressive paraparesis. Magnetic resonance imaging showed multifocal cerebritis and spinal histoplasmoma. She recovered following a second treatment with amphotericin B. This is the fourth reported patient with intramedullary spinal histoplasmoma, and the first demonstrating successful treatment of the lesion with medical therapy alone.

Adult↗
PubMed1994

Ligand-activated trans-membrane proton transfer in beta 1-adrenergic and m2-muscarinic receptors.

An alignment of beta 1-adrenoceptor alpha-helices on the bacteriorhodopsin model is compared with an equivalent alignment to m2-muscarinic alpha-helices. A proposed mechanism of ligand-activated trans-membrane proton transfer within alpha-helices III, IV, V, VI and VII of the beta 1-adrenoceptor involving activation of a Tyr377-Arg156-Tyr157 proton shuttle by two hydrogen bond proton donor interactions of the natural ligand, nor-adrenaline is found to have an equivalent representation in the m2-muscarinic receptor. Activation of Tyr377 in the beta 1-adrenoceptor is achieved by a direct hydrogen bond interaction of the para-hydroxy moiety and by an indirect action of the beta-hydroxyl group involving reversal of a hydrogen bond relay. Activation of Tyr440 in the m2-muscarinic receptor is achieved directly by Tyr403 and indirectly by reversal of the equivalent hydrogen bond relay Asn432-Ser433-Ser110-Asn436. The necessity for the beta-hydroxyl group in adrenoceptor ligands is attributed to the presence of Val142 and equivalent residues which function to isolate reversal of the hydrogen bond relay by the protonated amine moiety. A simple modification to the mechanism of the previously proposed hydrogen-bond relay brings all hydrogen bonds to within accepted tolerances (+/ 0.2 A) and the energetics of proton shuttle activation are theoretically evaluated.

Amino Acid Sequence↗
PubMed1993

Treatment of IgA nephropathy in children: efficacy of alternate-day oral prednisone.

We have previously reported our experience with the use of alternate-day prednisone in the treatment of 6 patients with IgA nephropathy who have clinical or pathological risk factors for disease progression. We have now treated a total of 13 patients and followed them from 4 to 10 years. Patients received an alternate-morning dose of prednisone for 2-4 years. Dosage began at 60 mg/m2 for 3 month, was reduced to 30 mg/m2 by 1 year and 15 mg/m2 by 2 years. At last observation, urinary protein excretion was normal in 12 patients and no patient had hematuria. Twelve patients had normal estimated glomerular filtration rate (GFR) and one had renal insufficiency (GFR = 38 ml/min per 1.73 m2). A renal biopsy was performed in 11 patients after 2 years of treatment. Activity score decreased from 5.2 to 4.3 (P = 0.03) and chronicity score increased from 2.2 to 2.8 (P = 0.12). There were no complications of treatment. When compared with a historical group, the treated patients had a significant improvement in urinalysis (P < 0.00001) and preservation of normal GFR (P = 0.03). We conclude that alternate-day prednisone therapy may benefit patients with IgA nephropathy. A large prospective controlled trial is needed.

Administration, Oral↗
PubMed1993

Partial liquid breathing with perflubron improves arterial oxygenation in acute canine lung injury.

Tidal liquid breathing with perfluorocarbon liquid improves lung mechanics and gas exchange in surfactant-deficient lambs. We asked whether an intratracheal dose of perflubron equal to liquid functional residual capacity (FRC) or less (partial liquid breathing) would alter gas exchange in gas-ventilated, anesthetized, and oleic acid (OA)-injured dogs. We gave eight dogs perflubron in six aliquots, each equal to one-sixth of liquid FRC [sequential dose (SEQ) group], starting 90 min after OA. Two other groups of eight dogs each received a liquid FRC dose of perflubron (60-70 ml/kg) either just before (P-Pre) or 90 min after (P-Post) OA, and eight control (CON) dogs received OA but no perflubron. In CON, SEQ, and P-Post dogs, OA caused a significant decrease in static respiratory system compliance (Crs) (1.50 +/- 0.05 to 1.15 +/- 0.06 ml.cmH2O-1.kg-1) and arterial PO2 (508 +/- 10 to 113 +/- 16 Torr) by minute 90. In P-Pre, P-Post, and after the third dose of perflubron (50% FRC) in SEQ dogs, arterial PO2 was significantly higher than that in the CON dogs but was similar to that in the CON dogs after perflubron removal. Perflubron doses less than two-thirds of liquid FRC were associated with increased Crs compared with CON dogs, but further lung filling caused a decrease in Crs. Lung histology showed widespread edema and hemorrhage and was similar in perflubron and CON dogs. O2 delivery and uptake were well maintained in all four groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Desmin positivity in primitive neuroectodermal tumors of childhood.

In this report, we describe two rosette-forming primitive neuroectodermal tumors that were found to contain desmin by both immunohistochemistry and Western blotting. Electron microscopy on both cases was consistent with primitive neuroectodermal tumors and revealed that the tumor cells contained cytoplasmic bundles of intermediate filaments. In both cases, studies for MyoD1 protein using immunohistochemistry and Western blotting were negative. Thus, the detection of desmin in a pediatric neoplasm does not absolutely exclude the diagnosis of primitive neuroectodermal tumor and should not be considered as prima facie evidence that a small-cell tumor is a rhabdomyosarcoma.

Abdominal Neoplasms↗
PubMed1992

An assessment of vocational training.

A retrospective analysis of the opinions of vocationally trained doctors was obtained from a postal questionnaire. Ninety-eight doctors who had trained in the West of Scotland before the introduction of new criteria in 1985 for the appointment and reappointment of training practices were compared with 107 doctors who had trained following the introduction of the criteria, looking at their rating of training, the frequency of tutorials, value of teaching and research encouragement. There was a significant improvement in the rating of training, frequency of tutorials, research encouragement and enjoyment of training in the group who trained after the new criteria were adopted. The study demonstrates the benefits of vocational training for general practice when criteria are set and followed. This training model may be applicable in other branches of medicine.

Education, Medical, Undergraduate↗
PubMed1992

Peripheral primitive neuroectodermal tumors. A flow cytometric analysis with immunohistochemical and ultrastructural observations.

Flow cytometry of classical neuroblastoma has provided provocative evidence that cell cycle and ploidy analysis generate prognostically useful information. To determine whether such analyses of peripheral primitive neuroectodermal tumors might yield similar results, formalin-fixed, paraffin-embedded tissue specimens from 19 peripheral primitive neuroectodermal tumors, each previously characterized by immunohistochemical or ultrastructural study, were assessed. An acceptable histogram was obtained in 16 cases. Of these, nine neoplasms were diploid and seven contained aneuploid DNA. Among patients with diploid lesions, four were free of disease, whereas three had persistent or recurrent disease, and two had died of tumor. Among patients with aneuploid neoplasms, four were free of disease, one had recurrence, and two had died. There was no apparent correlation between immunophenotype and proliferative activity with the clinical outcome. Among aneuploid peripheral primitive neuroectodermal tumors, DNA index did not predict survival. Hence, cell cycle and DNA ploidy analyses do not appear to contribute to the prognostic assessment of peripheral primitive neuroectodermal tumors, as they do to presumably related neoplasms of the central and peripheral nervous system.

Aneuploidy↗