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Biomedical subjects

R O'Donnell

Publications and source records attributed to R O'Donnell.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of refractory fludarabine induced autoimmune haemolytic with the anti-CD20 monoclonal antibody rituximab.

A patient with cold-type autoimmune haemolytic anaemia for 8 years developed progressive B cell chronic lymphocytic leukaemia (CLL). Despite the risk of fludarabine induced exacerbation of haemolysis, he was given aggressive anti-CLL therapy with six courses of FCR (fludarabine 25 mg/m2 D1-3, cyclophosphamide 250 mg/m2 D2-4 and rituximab 375 mg/m2 D1) every 4 weeks. This resulted in a marked acute increase in haemolysis shortly after completing each course of fludarabine. However, haemolysis had settled to its baseline level by the time of subsequent courses of FCR. FCR resulted in complete clinical remission of CLL but residual haemolysis persisted. The patient was then given four weekly infusions of single agent rituximab, resulting in ongoing remission of haemolysis. In this patient, rituximab appears to have controlled fludarabine induced exacerbation of autoimmune haemolysis. In addition, subsequent single agent rituximab therapy resulted in prolonged remission of cold-type autoimmune haemolytic anaemia. It remains to be seen if the addition of rituximab will allow other patients with a positive direct Coomb's test and/or autoimmune haemolysis to receive fludarabine containing chemotherapy without undue risk of life-threatening haemolytic anaemia.

Adult↗
PubMed2006

Inflammatory cells in the airways in COPD.

Airway inflammation is central to the pathogenesis of both airway remodelling and parenchymal destruction in chronic obstructive pulmonary disease (COPD). Neutrophils, macrophages, and CD8+ T lymphocytes have been implicated in a number of studies, but a detailed profile of disease-phenotype specific inflammation has yet to emerge. The heterogeneity of the disease has hindered data interpretation while extrapolation of the results of relatively non-invasive studies to the actual pathology found in the distal lung is difficult. Moreover, prominent studies have had frequently conflicting results. Further investigations are needed to marry the different clinical phenotypes of COPD to their respective inflammatory profiles in the airways and thus improve our understanding of the pathogenesis of the disease as a whole.

Bronchitis↗
PubMed2005

CML clonal evolution with resistance to single agent imatinib therapy.

We describe a 58-year-old male diagnosed with chronic myeloid leukaemia (CML) who failed to have a cytogenetic response to interferon-alpha and hydroxyurea. On subsequent therapy with imatinib mesylate he failed to have any cytogenetic response but also developed a complex clonal evolution with an additional Philadelphia (Ph) chromosome and trisomy 8 respectively in two Ph-positive subclones. The addition of cytosine arabinoside to imatinib resulted in reversion to single Ph-chromosome positivity with the disappearance of the previous additional clonal abnormalities. The case demonstrates the efficacy of combined treatment with imatinib and cytarabine in the management of CML resistant to single agent imatinib.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment.

PURPOSE: Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation. MATERIALS AND METHODS: We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician's decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual. RESULTS: There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P =.03; 95% CI, 0.13 to 0.9). CONCLUSION: Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party-payers is warranted.

Adolescent↗
PubMed2001

Intra-amygdala injection of the substance P [NK(1) receptor] antagonist L-760735 inhibits neonatal vocalisations in guinea-pigs.

The involvement of the basolateral amygdala in mediating the inhibition of neonatal vocalisation by substance P (NK(1) receptor) antagonists was examined. These studies determined whether the time course for separation-induced vocalisations in guinea-pig pups coincided with NK(1) receptor internalisation (a marker of substance P release) in the amygdala, and whether vocalisations could be blocked by focal injection of the NK(1) receptor antagonist L-760735 into this brain region. The peak period for neonatal vocalisations occurred 5-10 min following maternal separation. This coincided with the peak increase in the number of cells in the basolateral amygdala exhibiting NK(1) receptor endocytosis, consistent with the proposal that substance P is released in the amygdala as a result of isolation stress. Focal injection of L-760735 (15 nmol per side) but not L-770765 (an analogue of L-760735 which has low NK(1) receptor affinity) into the basolateral amygdala attenuated separation-induced vocalisations. In contrast, injection of L-760735 (15 nmol per side) into the dorsal ventricular nucleus of the thalamus, a region with relatively low density of NK(1) receptors, had no effect on neonatal vocalisations. These findings are consistent with other evidence that the amygdala is one possible site of action for the inhibition of neonatal vocalisations by substance P antagonists.

Amygdala↗
PubMed2001

Water-soluble luminal contents of the gut of the earthworm Lumbricus terrestris L. and their physiological significance.

In the post-gizzard gut of the earthworm Lumbricus terrestris, distinguishing the functions of the luminal epithelium from those of the chloragogenous tissue has been hindered by the close apposition of these two tissues. Moreover, both tissues may have different functions from the anterior to the posterior of the animal. We analyzed the gut luminal contents of L. terrestris so as to gain a better understanding of the function of the luminal epithelium. The intestine was divided into four regions from anterior to posterior, and the water-soluble portion of the luminal contents of these four regions was analyzed for protease and amylase activity, calcium and ammonium ions, and protein. The same four regions of the gut wall were analyzed for glutamate dehydrogenase (GDH) and serine dehydratase (SDH) to determine their location with reference to the site of ammonia production. We observed high levels of proteases, amylase, protein and calcium ions in the gut luminal contents of the first two regions, and a significant decline of all four variables in region III. Conversely, ammonia was low in the gut contents of regions I and II but rose sharply in region III, which was also the region to which the tissue enzymes GDH and SDH were localized. The ammonia content of earthworm casts was observed to be much higher than that of the surrounding soil. These data are presented as partial evidence for the proposal that the excretory ammonia produced by feeding earthworms is a product of the luminal epithelium of region III of the gut. It is also proposed that ammonia and calcium may function as ion-exchangers in the absorptive function of the earthworm gut.

Animals↗
PubMed2001

MR Imaging of sports-related pseudotumor in children: mid femoral diaphyseal periostitis at insertion site of adductor musculature.

OBJECTIVE: The objective of this study was to review the imaging appearance of the femurs of five patients who had been referred from outside institutions after presenting with thigh pain and being given a preliminary diagnosis of primary malignant bone tumor. Typically, when making a diagnosis, physicians place emphasis on the characteristic appearances of diseases on MR imaging, but such appearances may be misleading. An awareness of the specific MR imaging pattern of stress-related partial muscle avulsion can lead to the correct diagnosis. CONCLUSION: Femoral diaphyseal periostitis after a sports injury to the adductor musculature in children has a characteristic imaging appearance. This condition can initially appear to be misleadingly aggressive. Knowledge of the findings-particularly of the findings on MR imaging-in the proper clinical setting can help physicians make the correct diagnosis and eliminate unnecessary biopsy or inappropriate treatment.

Adolescent↗
PubMed2000

Prevalence of Müllerian duct anomalies detected at ultrasound.

The true prevalence of müllerian duct abnormalities is not well established. We used standard ultrasound examinations to establish the prevalence of müllerian duct abnormalities in girls and women who were evaluated for reasons unrelated to the presence of uterine anomalies. Prospective ultrasound examinations for nonobstetric indications in 2,065 consecutive girls and women (aged 8-93) showed that 8 had anomalies, including bicornuate uterus, septate uterus, and double uterus. In this first attempt to determine the prevalence of uterine anomalies in the general population, using noninvasive methodology, the rate of anomalies was 3.87 per 1,000 women (exact 95% confidence interval: 1.67-7.62), or approximately 1 in 250 women. This prevalence estimate may be greater than the true rate if selection biases are strong, or less than the true prevalence if ultrasound detection rates are low. As a first attempt to establish the prevalence by pelvic ultrasound in a consecutive series, these data may serve as a baseline estimate.

Adolescent↗
PubMed2000

Transcranial Doppler (TCD) screening for stroke prevention in sickle cell anemia: pitfalls in technique variation.

BACKGROUND: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) identified children as being at high stroke risk if the time-averaged maximum mean velocity (TAMMV) of the middle cerebral or intracranial internal carotid arteries measured > or = 200 cm/s. These values were obtained utilizing a 2-mHz dedicated nonimaging pulsed Doppler technique (TCD) and manual measurements. Questions have been raised as to the comparability of results obtained with different ultrasound machines and measurement techniques. OBJECTIVE: The purpose of this study was to compare nonimaging (TCD) and transcranial duplex imaging (TCDI) findings in children potentially at risk for stroke with sickle cell disease. MATERIALS AND METHODS: Twenty-two children with sickle cell disease and no history of stroke were evaluated by both TCD and TCDI. Examinations were performed on the same day without knowledge of the other modality results and read independently using manually obtained measurements. Mean velocities, peak systolic velocities, and end diastolic velocities obtained by the two techniques were compared. In a subgroup, manual measurements were compared to electronically obtained measurements. RESULTS: TCDI values were lower than TCD measurements for all vessels. TCDI TAMMV values were most similar to the TCD values in the middle cerebral artery (-9.0%) and distal internal cerebral artery (-10.8%), with greater variability in the anterior cerebral artery (-19.3%), bifurcation (-16.3%), and basilar arteries (-23.1%). Risk group placement based on middle cerebral artery TAMMV values did not change when comparing the two techniques. Measurements obtained electronically were lower than those obtained manually. CONCLUSION: Velocities obtained by TCDI may be lower than TCD measurements, and these differences should be taken into consideration when performing screening for stroke risk and selection for prophylactic transfusion based on the STOP protocol.

Adolescent↗
PubMed2000

Urinary interleukin-6 and interleukin-8 in children with urinary tract infection.

Urinary interleukin-6 (UIL-6) and urinary interleukin-8 (UIL-8) concentrations were measured by immunoassay in 39 and 34 patients respectively, hospitalized with febrile urinary tract infection (UTI), and in 37 and 32 age-, race- and sex-matched febrile control children respectively, with negative urine cultures. UIL-6 and UIL-8 concentrations, measured in picograms per milliliter and corrected for creatinine, were compared with clinical and laboratory indicators of inflammation and bacterial virulence factors of Escherichia coli. Median UIL-6 concentrations at the time of admission were 397 pg/ml (range 0-65,789 pg/ml) in the 37 patients compared to 0 pg/ml (range 0-473.8 pg/ml) in the 37 controls (P < 0.0001). Median UIL-8 concentrations at the time of admission were 5809 pg/ml (range 0-347,368 pg/ml) in the 32 patients compared to 0 pg/ml (range 0-2231 pg/ml) in the 32 controls (P < 0.0001). UIL-6 and UIL-8 concentrations were lower (P < 0.0001 for UIL-6 and P = 0.0005 for UIL-8) in follow-up urine samples from UTI patients, obtained 48 h after the initiation of antibiotic therapy. UIL-6 and UIL-8 concentrations were statistically significantly correlated with urine white blood cells (WBC). UIL-8 concentrations were elevated in patients with E. coli organisms producing hemolysin. UIL-6 and UIL-8 are elevated in children with febrile UTI and decrease in response to antibiotic therapy. Magnitude of UIL-8 response is associated with hemolysin production, a bacterial virulence factor of E. coli. UIL-6 and UIL-8 concentrations are statistically correlated with urine WBC. UIL-6 and UIL-8 may be mediators of inflammation in children with febrile UTI.

Child↗
PubMed2000

Changes in inpatient psychiatric utilization and quality of care performance measures in a capitated HMO population, 1989-1999.

Managed behavioral health care approaches have significantly reduced inpatient utilization and related cost of care, but the relationship between decreased utilization and cost of care to changes in quality of care performance over time remains in question. The trends in utilization and quality of care performance measures over the course of 10 years of the Tufts Health Plan Designated Facility Program, a model health maintenance organization capitated program for inpatient behavioral health care, are presented. The results indicate that substantial decreases in inpatient utilization were sustained while quality of care measures improved over time. The data support the Tufts Health Plan Designated Facility Program as a successful means of balancing cost containment with quality of care.

Adult↗
PubMed2000

Scanning techniques for three-dimensional forward-viewing intravascular ultrasound imaging.

Intravascular ultrasound (US) imaging is a useful tool for assessing arterial disease and aiding treatment procedures. Forward-viewing intravascular US imaging could be of particular use in severely stenosed or totally occluded arteries, where the current side-viewing intravascular US systems are limited by their inability to access the site of interest. In this study, five 3-D forward-viewing intravascular scanning patterns were investigated. The work was carried out using scaled-up vessel phantoms constructed from tissue-mimicking material and a PC-controlled scanning and acquisition system. The scanning patterns were examined and evaluated with regard to the image quality of dense and sparse data sets, the accuracy of quantitative measurements of lumen dimensions and the potential for clinical use. The relative merits and drawbacks of the different patterns are discussed and a preferred scanning pattern is recommended.

Arterial Occlusive Diseases↗
PubMed1999

Structure and function of residue 104 and water molecules in the xenobiotic substrate-binding site in human glutathione S-transferase P1-1.

Two variants of human class pi glutathione (GSH) S-transferase 1-1 with either isoleucine or valine in position 104 (hGSTP1-1[I104] and hGSTP1-1[V104]) have distinct activity toward (+)-anti-7, 8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE]. To elucidate their structure-function relationship, we determined the crystal structures of the two variants in complex with GSBpd, the GSH conjugate of (+)-anti-BPDE, at 2.1 and 2.0 A resolution, respectively. The crystal structures reveal that residue 104 in the xenobiotic substrate-binding site (H-site) dictates the binding modes of the product molecule GSBpd with the following three consequences. First, the distance between the hydroxyl group of Y7 and the sulfur atom of GSBpd is 5.9 A in the hGSTP1-1[I104].GSBpd complex versus 3.2 A in the V104 variant. Second, one of the hydroxyl groups of GSBpd forms a direct hydrogen bond with R13 in hGSTP1-1[V104].GSBpd; in contrast, this hydrogen bond is not observed in the I104 complex. Third, in the hydrophilic portion of the H-site of the I104 complex, five H-site water molecules [Ji, X., et al. (1997) Biochemistry 36, 9690-9702] are observed, whereas in the V104 complex, two of the five have been displaced by the Bpd moiety of GSBpd. Although there is no direct hydrogen bond between Y108 (OH) and the hydroxyl groups of GSBpd, indirect hydrogen bonds mediated by water molecules are observed in both complexes, supporting the previously suggested role of the hydroxyl group of Y108 as an electrophilic participant in the addition of GSH to epoxides.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1999

Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn.

The present study investigated the regional distribution of the N-methyl-D-aspartate (NMDA) receptor containing the NR2B subunit protein in rat lumbar spinal cord and examined whether selective NR2B antagonists would exhibit antinociception with reduced side-effect liability than subtype non-selective NMDA antagonists and anticonvulsants. Immunocytochemical studies showed the NR2B subunit had a restricted distribution, with moderate labelling of fibres in laminas I and II of the dorsal horn suggesting a presynaptic location on primary afferent fibers and possible involvement in pain transmission. In the in vivo studies, the NMDA/glycine antagonists (MK-801, 0.02-1 mg/kg i.p., L-687,414 10-300 mg/kg i.p., and L-701,324 1-10 mg/kg i.p.) and the anticonvulsant, gabapentin (10-500 mg/kg p.o.), induced rotarod deficits at antinociceptive doses. In contrast, the selective NR2B antagonists, (+/-)-CP-101,606 (1-100 mg/kg p.o.) and (+/-)-Ro 25-6981 (3-100 mg/kg i.p.) showed a significant dose window. (+/-)-CP-101,606 caused no motor impairment or stimulation in rats at doses up to 100 mg/kg p.o., which is far in excess of those inhibiting allodynia in neuropathic rats (ID50 4.1 mg/kg, p.o.). (+/-)-Ro 25-6981 also showed a significant separation (ID50 allodynia 3.8 mg/kg, i.p.), however, some disruption of rotarod performance was observed at 100 mg/kg. The anticonvulsant lamotrigine (3-500 mg/kg p.o.) also showed a good dose window. These findings demonstrate that NR2B antagonists may have clinical utility for the treatment of neuropathic and other pain conditions in man with a reduced side-effect profile than existing NMDA antagonists.

Acetates↗
PubMed1999

Analysis of the neurotrophic effects of GPI-1046 on neuron survival and regeneration in culture and in vivo.

The putative neurotrophic effects of the immunophilin ligand GPI-1046 were evaluated in established experimental systems of neuron survival and axon growth in vitro and in vivo. GPI-1046 marginally increased neurite outgrowth of chick dorsal root ganglia in culture under conditions where a very robust effect of nerve growth factor was seen. GPI-1046 failed to protect dopaminergic neurons from 1-methyl-4-phenylpyridinium in culture or to protect cultured cortical neurons from experimentally induced apoptosis in vitro. In adult rats in vivo, daily administration of GPI-1046 (10 mg/kg, s.c.) for three days enhanced the maximal regeneration distance of both motor and large myelinated sensory axons measured using an electrophysiological assay. However, detailed morphometric analysis of these animals failed to provide evidence for an increase in axon numbers in GPI-1046-treated animals. The ability of GPI-1046 to promote the recovery of dopaminergic function following unilateral 6-hydroxydopamine lesions of the substantia nigra was also tested in rats. In the first study, the duration of amphetamine (3 mg/kg, s.c.)-induced circling, but not the maximal number of rotations, was significantly reduced in animals treated with GPI-1046 for five days (10 mg/kg/day). In a second study, testing the effects of delayed GPI-1046 administration, chronic treatment with GPI-1046 (10 mg/kg/day) for two weeks, beginning one month after surgery, did not alter circling responses. Morphometric analysis failed to reveal any changes in either the density of tyrosine hyroxylase-positive fibres in dopaminergic target areas or in cell numbers in the substantia nigra in both experiments. Thus, while GPI-1046 produced marginal effects on neurite outgrowth in dorsal root ganglia cultures and on functional paramaters of nerve regeneration in vivo, we failed to obtain evidence in support of the notion of a general neuroprotective effect of the compound or for an effect on morphologic nerve regeneration in vivo.

1-Methyl-4-phenylpyridinium↗