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D O'Donnell

Publications and source records attributed to D O'Donnell.

At least 19 recordsLinked to original sources
PubMed2006

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin.

We previously showed that prolonged morphine treatment and chronic inflammation both enhanced delta opioid receptor (deltaOR) cell surface density in lumbar spinal cord neurons. Here, we sought to determine whether administration of morphine to rats with chronic inflammation would further increase the bio-availability of deltaOR, and thereby the analgesic properties of the deltaOR agonist deltorphin, over that produced by inflammation alone. We found that chronic inflammation produced by injection of complete Freund's adjuvant (CFA) into the hind paw resulted in a bilateral increase in the binding and internalization of fluorescent deltorphin in neurons of the lumbar spinal cord as did prolonged morphine treatment [Morinville A, Cahill CM, Aibak H, Rymar VV, Pradhan A, Hoffert C, Mennicken F, Stroh T, Sadikot AF, O'Donnell D, Clarke PB, Collier B, Henry JL, Vincent JP, Beaudet A (2004a) Morphine-induced changes in delta opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord. J Neurosci 24:5549-5559]. This effect was accompanied by an increase in the antinociceptive efficacy of intrathecal deltorphin as measured using the tail-flick test. Treatment of CFA-injected rats with morphine decreased the cell surface availability of deltaOR in neurons of the dorsal horn of the lumbar spinal cord as compared with treatment with CFA alone. Behaviorally, it significantly enhanced the antihyperalgesic effects of deltorphin (plantar test; % maximum possible antihyperalgesic effect (MPAHE)=113.5%+/-32.4% versus 26.1%+/-11.6% in rats injected with CFA alone) but strongly reduced the antinociceptive efficacy of the drug (tail-flick test; % maximum possible antinociceptive effect (MPE)=29.6%+/-3.6% versus 66.6%+/-6.3% in rats injected with CFA alone) suggesting that the latter, but not the former, is linked to the deltaOR trafficking events observed neuroanatomically. These results demonstrate that in chronic inflammation, the antihyperalgesic effects of deltaOR agonists may be enhanced by morphine pre-treatment. They also reveal a dichotomy between mechanisms underlying antihyperalgesic and antinociceptive effects of deltaOR agonists.

Analgesics↗
PubMed2006

Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming.

Fusogenic membrane glycoproteins (FMG) are a family of viral genes that, when expressed in tumour cells, trigger extensive cell to cell fusion and subsequent cell death. Gene therapy approaches using FMG are also potentially immunogenic, since syncitia generated ex vivo can be therapeutic as antitumour vaccines in murine models. This study has addressed the mechanisms responsible for the immunogenicity of FMG-mediated cell death, and its applicability to human immune priming. We show that fusion of human Mel888 melanoma cells following transfection with FMG can reverse the suppressive effects of Mel888 on dendritic cells (DC) phenotype, and potentiate IL-12 production by DC on activation in a cell contact-dependent manner. DC loaded with fusing, but not intact, tumour cells primed a naive, tumour-specific cytotoxic T-cell response, which was MHC class I-restricted and associated with production of high levels of IFNgamma and, later, IL-5. Fusing cells were an effective source of antigen for DC cross-priming and presentation of the melanoma-specific antigen gp100 to a specific T-cell clone. These data show, in a human system, that FMG represent an immunogenic, as well as cytotoxic, gene therapy for cancer, reversing the inhibitory effects of tumour cells on DC to potentiate IL-12 production and naive T-cell priming.

B7-2 Antigen↗
PubMed2006

Kabuki syndrome: oral and general features seen in a 2-year-old Chinese boy.

This report describes the case of a young Chinese boy with Kabuki syndrome (KS). KS is a congenital condition characterized by multiple anomalies, especially of the face, and is usually associated with mild to moderate mental retardation. The patient presented with the characteristic facial features of KS and some skeletal and neurological anomalies including a butterfly vertebrae with scoliosis, cerebral atrophy, and irregular dentition. Dental examination revealed screwdriver-shaped incisors and a high arched maxilla, features typical of patients with KS, as well as very poor oral hygiene and early childhood caries. This report includes discussion of the aetiology of KS as well as discussion of the long-term prognosis for this particular patient, and patients with KS in general, with consideration of associated dental and medical issues.

Abnormalities, Multiple↗
PubMed2005

Immunosuppressive effects of radiation on human dendritic cells: reduced IL-12 production on activation and impairment of naive T-cell priming.

Dendritic cells (DC) are professional antigen-presenting cells (APC) of the immune system, uniquely able to prime naive T-cell responses. They are the focus of a range of novel strategies for the immunotherapy of cancer, a proportion of which include treating DC with ionising radiation to high dose. The effects of radiation on DC have not, however, been fully characterised. We therefore cultured human myeloid DC from CD14+ precursors, and studied the effects of ionising radiation on their phenotype and function. Dendritic cells were remarkably resistant against radiation-induced apoptosis, showed limited changes in surface phenotype, and mostly maintained their endocytic, phagocytic and migratory capacity. However, irradiated DC were less effective in a mixed lymphocyte reaction, and on maturation produced significantly less IL-12 than unirradiated controls, while IL-10 secretion was maintained. Furthermore, peptide-pulsed irradiated mature DC were less effective at naive T-cell priming, stimulating fewer effector cells with lower cytotoxicity against antigen-specific targets. Hence irradiation of DC in vitro, and potentially in vivo, has a significant impact on their function, and may shift the balance between T-cell activation and tolerization in DC-mediated immune responses.

Apoptosis↗
PubMed2005

Bifocal right ventricular cardiac resynchronization therapies in patients with unsuccessful percutaneous lateral left ventricular venous access.

Biventricular cardiac resynchronization therapy (CRT) with a lateral left ventricular (LV) lead cannot always be achieved. We report a single center experience of CRT utilizing a protocol that specifically required the implantation of a bifocal right ventricular (RV) lead system when lateral LV pacing could not be achieved. Consecutive candidates for CRT were included in the study. If strict criteria for lateral LV pacing were not met, they underwent implantation of a bifocal RV lead system with two 7F, active fixation leads, one placed septally at the apex, and the other in the high septal outflow tract. All patients were followed for 12 months and the two groups were compared. A biventricular (BiV) stimulation system was implanted in 44 patients, and a bifocal RV system in six. The demographic characteristics of the two groups were similar. Both groups experienced a similar improvement in functional capacity, increase in 6 minutes walking distance, and decreased need for hospitalizations. The mean increase in LV ejection fraction was 11% in the bifocal RV group versus 10% in the BiV group. Though the tissue Doppler indices of LV synchrony improved earlier in the BiV group, (19% vs 10%) the improvement was similar in both groups at 6 months (23% vs 20%). The clinical improvements conferred by CRT can be matched by a bifocal RV system in selected patients. This alternate approach should be considered when implantation of a LV lateral lead was unsuccessful.

Aged↗
PubMed2005

Long-term variations in optimal programming of cardiac resynchronization therapy devices.

The optimal follow-up and long-term programming of cardiac resynchronization therapy (CRT) devices are uncertain. The aim of this study was to quantify the temporal variations in programming parameters to optimize the follow-up of these devices. Before, during, and at specified intervals over 9 months after implant, 40 recipients of CRT devices were studied. At each visit, the patients were tested with a fixed sequence of stimulation parameters during echocardiographic and electrocardiographic (ECG) recordings. The optimal AV delay and inter-ventricular delays (V-V) were determined according to echocardiographic criteria. The echocardiographic data were, in turn, compared with the ECG recordings. Among the 40 patients, the optimal stimulation parameters remained unchanged throughout the follow-up in only three patients. In 18 patients, adjustments were required at each follow-up sessions. There was a trend toward reduction in the left ventricular (LV) predominance of the optimal V-V delay and an increase in the AV delay during follow-up. The mean optimal V-V delay at implant was 22 ms (-12 to +32 ms) with the LV activated first, versus 12 ms (-16 to +32 ms) at 9 months. The mean AV delay at implant was 115 ms versus 137 ms at 9 months. Individual changes could not be accurately predicted. The optimal stimulation parameters for CRT vary over time. Detailed, regular reevaluations, and reprogramming of optimal parameters may be appropriate.

Cardiac Pacing, Artificial↗
PubMed2005

Pulmonary vein ablation for idiopathic atrial fibrillation: six month outcome of first procedure in 100 consecutive patients.

OBJECTIVES: To report six month outcome in patients undergoing their first pulmonary vein ablation procedure for idiopathic atrial fibrillation (AF) at a "non-pioneering" hospital. DESIGN: Prospective observational study. SETTING: Specialist electrophysiology unit at a university hospital. PATIENTS: The first 100 consecutive patients undergoing their first pulmonary vein catheter ablation procedure for highly symptomatic, drug resistant AF in the period 1999-2002. MAIN OUTCOME MEASURES: Incidence of symptomatic or asymptomatic, Holter documented AF six months after ablation. RESULTS: Mean patient age was 52 years (range 23-73 years), mean length of AF history 53 months (range 6-180 months), mean number of antiarrhythmic drug failures was 3 (range 1-5), and 81 were men. At the time of the ablation procedure, 64 had progressed to persistent AF and 23 had increased transverse left atrial diameter. The number of pulmonary veins ablated in each patient was one in 11, two in 45, three in 36, and four in 8. Six months after ablation, 55 patients were consistently in sinus rhythm, asymptomatic, and without any Holter evidence of AF. The chance of being in sinus rhythm was 73% (29 of 64) in those with paroxysmal as compared with only 45% (26 of 36) in those with persistent AF at the time of ablation (p = 0.01). Outcome was not influenced by patient age, length of AF history, or duration of persistent AF before ablation or to left atrial dimension. Follow up was complete and no patient has died or experienced a stroke during or after ablation; nor have any developed symptoms of late pulmonary vein stenosis. However, other complications occurred during or shortly after the procedure in 12 patients, including cardiac tamponade in six. CONCLUSIONS: In selected patients with drug resistant AF, focal pulmonary vein catheter ablation offers a realistic prospect of achieving stable sinus rhythm compared with alternatives. However, it is a complex form of ablation with a significant risk of serious complications. Although a new milestone in arrhythmia management, the optimum ablation technique is still evolving and any impact on the natural history of AF remains to be determined.

Adult↗
PubMed2003

Clinical and electrophysiological differences between patients with arrhythmogenic right ventricular dysplasia and right ventricular outflow tract tachycardia.

AIMS: Radiofrequency catheter ablation is considered first line treatment for symptomatic patients with right ventricular outflow tract tachycardia (RVOT). The role of ablation in arrhythmogenic right ventricular dysplasia (ARVD) is more limited. As such, differentiating between the two conditions is essential. METHODS AND RESULTS: This study compared non-invasive findings, magnetic resonance images (MRI), invasive electrophysiological characteristics, results of ablation and long-term outcome in 50 consecutive patients with RVOT (33) or ARVD (17). Structural abnormalities were uniform in the ARVD group; in addition 18 (54%) of the RVOT tachycardia group had MRI abnormalities. At electrophysiological study the tachycardia in the ARVD group displayed features of re-entry in over 80%, but behaved with a triggered automatic basis in 97% with RVOT. Ablation was complete or partial success in 12 (71%) patients with ARVD and ventricular tachycardia (VT) recurred in eight (48%). In the RVOT patients, ablation was a complete success in 97% with recurrent VT in 6%. Long-term success in the RVOT patients was 95% in both patients with and without MRI abnormalities. CONCLUSIONS: Electrophysiological characterization can differentiate ARVD from RVOT. The finding of abnormalities on MRI does not have any bearing on arrhythmia mechanism, acute or long-term success of RFA.

Adolescent↗
PubMed2003

Up-regulation and trafficking of delta opioid receptor in a model of chronic inflammation: implications for pain control.

Pharmacological and physiological evidence supports a role for delta (delta) opioid receptors in the nociceptive mechanisms of inflammation. However, few data exist regarding delta opioid receptor expression and localization in such conditions. In this study, we have assessed the distribution and function of delta opioid receptors in the rat spinal cord following induction of chronic inflammation by intraplantar injection of complete Freund's adjuvant (CFA). Intrathecal administration of the selective delta opioid receptor agonist, D-[Ala(2), Glu(4)] deltorphin, dose-dependently reversed thermal hyperalgesia induced by CFA. In situ hybridization and Western blotting experiments revealed an increase in delta opioid receptor mRNA and protein levels, respectively, in the dorsal lumbar spinal cord ipsilateral to the CFA injection site compared to the contralateral side and sham-injected controls. By electron microscopy, immunopositive delta opioid receptors were evident in neuronal perikarya, dendrites, unmyelinated axons and axon terminals. Quantification of immunopositive signal in dendrites revealed a twofold increase in the number of immunogold particles in the ipsilateral dorsal spinal cord of CFA-injected rats compared to the contralateral side and to sham-injected rats. Moreover, the relative frequency of immunogold particles associated with or in close proximity to the plasma membrane was increased in the ipsilateral dorsal spinal cord, indicating a more efficient targeting of delta opioid receptors to neuronal plasma membranes. These data demonstrate that CFA induces an up-regulation and increased membrane targeting of delta opioid receptors in the dorsal spinal cord which may account for the enhanced antinociceptive effects of delta opioid receptor agonists in chronic inflammatory pain models.

Animals↗
PubMed2003

Pro-nociceptive effects of neuromedin U in rat.

The neuropeptide neuromedin U (NMU) has been shown to have significant effects on cardiovascular, gastrointestinal and CNS functions. The peptide was first isolated from the porcine spinal cord and later shown to be present in spinal cords of other species. Little is known about the distribution of neuromedin U receptors (NMURs) in the spinal cord and the spinal action of the peptide. Here we report on the expression of NMURs and a potential role in nociception in the rat spinal cord using a combination of behavioral and electrophysiological studies. Receptor autoradiography showed that NMU-23 binding was restricted to the superficial layers of spinal cord, a region known to be involved in the control of nociception. In situ hybridization analysis indicated the mRNA of NMUR2 was located in the same region (laminae I and IIo) as NMU-23 binding, while the mRNA for NMU receptor 1 was observed in a subpopulation of small diameter neurons of dorsal root ganglia. Intrathecal (i.t.) administration of neuromedin U-23 (0.4-4.0 nmol/10 microl) dose-dependently decreased both the mechanical threshold to von Frey hair stimulation and the withdrawal latency to a noxious thermal stimulus. Mechanical allodynia was observed between 10 and 120 min, peaking at 30 min and heat hyperalgesia was observed 10-30 min after i.t. administration of NMU-23. A similar mechanical allodynia was also observed following i.t. administration of NMU-8 (0.4-4 nmol/10 microl). A significant enhancement of the excitability of flexor reflex was induced by intrathecal administration of NMU-23 (4 nmol/10 microl). Evoked responses to touch and pinch stimuli were increased by 439+/-94% and 188+/-36% (P<0.01, n=6) respectively. The behavioral and electrophysiological data demonstrate, for the first time, a pro-nociceptive action of NMU. The restricted distribution of NMU receptors to a region of the spinal cord involved in nociception suggests that this peptide receptor system may play a role in nociception.

Animals↗
PubMed2003

Severe gingival hyperplasia in a child with I-cell disease.

I-cell disease (mucolipidosis II) is a rare metabolic disorder resulting from the deficiency of a specific lysosomal enzyme, N-acetylglucosamine-1-phosphotransferease. The disease presents as a mental and motor developmental delay with oral manifestations that include severe gingival hyperplasia usually seen before one year of age. The life expectancy of children with this condition is poor, with death usually occurring around the fifth year. A case report of a 3-year-old Pakistani male, with I-cell disease, is presented. The chief dental concerns of the parents were his swollen gums and delayed tooth eruption. Supportive treatment only was initiated. Differential diagnosis for severe gingival overgrowth in young patients should take account of this rare metabolic disorder in addition to hereditary and idiopathic fibromatosis and drug associated gingival overgrowth.

Child, Preschool↗
PubMed2003

Effect of nasal or oral breathing route on upper airway resistance during sleep.

Healthy subjects with normal nasal resistance breathe almost exclusively through the nose during sleep. This study tested the hypothesis that a mechanical advantage might explain this preponderance of nasal over oral breathing during sleep. A randomised, single-blind, crossover design was used to compare upper airway resistance during sleep in the nasal and oral breathing conditions in 12 (seven male) healthy subjects with normal nasal resistance, aged 30+/-4 (mean+/-SEM) yrs, and with a body mass index of 23+/-1 kg x m2. During wakefulness, upper airway resistance was similar between the oral and nasal breathing routes. However, during sleep (supine, stage two) upper airway resistance was much higher while breathing orally (median 12.4 cmH2O x L(-1) x s(-1), range 4.5-40.2) than nasally (5.2 cmH2O x L(-1) x s(-1), 1.7-10.8). In addition, obstructive (but not central) apnoeas and hypopnoeas were profoundly more frequent when breathing orally (apnoea-hypopnoea index 43+/-6) than nasally (1.5+/-0.5). Upper airway resistance during sleep and the propensity to obstructive sleep apnoea are significantly lower while breathing nasally rather than orally. This mechanical advantage may explain the preponderance of nasal breathing during sleep in normal subjects.

Adult↗
PubMed2002

Differentiation enhances aminolevulinic acid-dependent photodynamic treatment of LNCaP prostate cancer cells.

Photodynamic therapy using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) may be applied to the treatment of neoplasms in a variety of organs. In order to enhance existing regimens of photodynamic therapy, we investigated the effects of adding differentiation therapy to photodynamic therapy in human prostate cancer cells in vitro. The objective of differentiation therapy per se is to reverse the lack of differentiation in cancer cells using pharmacological agents. The motivation for this study was to exploit the differentiation-dependent expression of some heme enzymes to enhance tumour cell toxicity of ALA-photodynamic therapy. A short course of differentiation therapy was applied to increase PpIX formation during subsequent ALA exposure. Using the synthetic androgen R1881, isomers of retinoic acid, and analogues of vitamin D for 3 to 4 days, exogenous ALA-dependent PpIX formation in LNCaP cells was increased, along with markers for growth arrest and for differentiation. As a consequence of higher PpIX levels, cytotoxic effects of visible light exposure were also enhanced. Short-term differentiation therapy increased not only the overall PpIX production but also reduced that fraction of cells that contained low PpIX levels as demonstrated by flow cytometry and fluorescence microscopy. This study suggests that it will be feasible to develop protocols combining short-term differentiation therapy with photodynamic therapy for enhanced photosensitisation.

Aminolevulinic Acid↗
PubMed2002

Radiofrequency ablation for post infarction ventricular tachycardia. Report of a single centre experience of 112 cases.

OBJECTIVES: This report presents the largest consecutive series to date of radiofrequency ablation in the treatment of post infarction ventricular tachycardia. METHODS: One hundred and twelve consecutive patients were studied, with an average of 12 documented episodes of ventricular tachycardia in the month preceding the radiofrequency ablation. Seventy-four percent of the subjects had an ejection fraction of less than 35%; 84% had more than one morphology of ventricular tachycardia and 30% had haemodynamically unstable ventricular tachycardia. The mean follow-up period was 61 months. RESULTS: Complete success defined as no inducible sustained monomorphic ventricular tachycardia was achieved in 38%. Modified result, defined as ventricular tachycardia only inducible by two stimuli more aggressive than at baseline was achieved in 34%. During follow-up, ventricular tachycardia recurred in 25 patients: 22 after a failed procedure, two following a modified result and one following a complete success. Twenty-five patients died: 13 of progressive cardiac failure and four of presumed arrhythmic causes, three after a failed procedure and one following a modified result. There were no procedure-related deaths. Procedural complications occurred in seven patients. CONCLUSIONS: In this report, radiofrequency ablation of post infarction ventricular tachycardia is a successful procedure with a low complication rate. Acute procedural success accurately predicts long-term freedom from recurrent ventricular tachycardia.

Adult↗
PubMed2001

Assessment of the use of problem-orientated, small-group discussion for learning of a fixed prosthodontic, simulation laboratory course.

AIM: To evaluate a simulation laboratory course that used student-centred small-group problem-orientated discussion activities as the main medium of instruction. METHODS: A structured questionnaire using a six-point Likert scale with 30 statements relating to a fixed prosthodontics course was distributed to 4th-year and 5th-year students who had completed the course. RESULTS: A 93% response rate was achieved for both years with a mean score for the 4th-year being 94.2 (+/- 13.7) and the 5th-year 107.5 (+/-16.9). The differences between the scores of both years are highly significant (P = 0.0006) indicating that the 5th-year were more favourable about the course and learning approach used. Consistency and reliability of the questionnaire was judged reliable according to Cronbach's alpha (4th-year = 0.7, 5th-year = 0.83). Many aspects of the small-group student-centred activities were highly valued by students however, students expressed a preference for learning and interacting with teachers than colleagues. CONCLUSION: Small-group student-centred learning activities were reported as creating an active, safe learning environment with beneficial opportunities for peer-peer interaction such as questioning, teaching and learning from students. However, students expressed a preference for teacher-centred information dissemination and activities. An understanding of the rationale of student dependence to teacher-centred learning may allow improved modifications in a student-centred learning environment.

Denture, Partial, Fixed↗
PubMed2001

Immunohistochemical distribution of delta opioid receptors in the rat central nervous system: evidence for somatodendritic labeling and antigen-specific cellular compartmentalization.

Many studies have reported on the distribution of delta opioid receptors (delta OR) in the mammalian central nervous system (CNS) by using a variety of techniques. However, no general consensus has emerged with regards to the localization of this receptor due to inconsistencies in the immunohistochemical literature. In the present study, we analyzed the cellular and subcellular distribution of immunoreactive delta OR in the rat CNS using two different antibodies (directed against a sequence in the C-terminus or N-terminus of the rat delta OR). By using Western blotting, these two antibodies recognized similar forms of the delta OR in COS-7 cells transfected with this receptor, but distinct forms in membranes from the rat spinal cord. By using light microscopic immunohistochemistry, both antibodies recognized identical populations of nerve cell bodies throughout the CNS; the distribution of these cell bodies conformed to that of delta OR mRNA-expressing cells detected by in situ hybridization. However, whereas the C-terminus-directed antibody recognized predominantly perikarya and proximal dendrites, the N-terminus-directed antibody also labeled extensively dendritic and terminal arbors. Furthermore, by using electron microscopy, the two antibodies were found not only to label differentially somatodendritic versus axonal compartments, but also plasma membrane versus cytoplasmic ones, suggesting that distinct immunological forms of the receptor are being targeted preferentially to different cellular and subcellular domains.

Animals↗
PubMed2001

Lessons from a proficiency testing event for acid-fast microscopy.

OBJECTIVES: To evaluate the routine performance and the technical parameters of different acid-fast staining methods: Kinyoun, Ziehl-Neelsen (ZN), auramine, and auramine-rhodamine. DESIGN AND PARTICIPANTS: The performance of 167 laboratories was analyzed using prestained and unstained slides. SETTING: Laboratories holding New York State permits. RESULTS: The results revealed that Kinyoun's cold carbol fuchsin method is inferior to both the ZN and fluorochrome (auramine and/or auramine-rhodamine) methods. Even though 91% of the participants used commercial staining kits, the study identified unexpected errors concerning the concentration of carbol fuchsin, time for staining and counterstaining, and the concentration of acid alcohol for decolorization, which may significantly influence the sensitivity. Besides these findings, the present study showed that the examination of < 300 view fields may also decrease the sensitivity of acid-fast microscopy. In addition, we found that the sensitivity and specificity of the ZN and fluorochrome methods are comparable if the procedural standards are followed. CONCLUSIONS: The strict and ongoing quality control of the "simple to perform" acid-fast microscopy and the immediate review of commercially available staining kits are necessary. Because of the rapidity of the fluorochrome method, laboratories with large specimen numbers should use this technique. In all other cases, the ZN method should be used. Moreover, all clinicians should be aware of the method of acid-fast microscopy used and the proficiency of the laboratory in performing the assay.

Benzophenoneidum↗