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Biomedical subjects

Patrick Kelly

Publications and source records attributed to Patrick Kelly.

36 records · Page 2Linked to original sources
PubMed2005

Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function.

The passage of leukocytes out of the blood circulation and into tissues is necessary for the normal inflammatory response, but it also occurs inappropriately in many pathological situations. This process is limited by the barrier presented by the junctions between adjacent endothelial cells that line blood vessels. Here we show that activation of the Rap1 GTPase in endothelial cells accelerated de novo assembly of endothelial cell-cell junctions and increased the barrier function of endothelial monolayers. In contrast, depressing Rap1 activity by expressing Rap1GAP led to disassembly of these junctions and increased their permeability. We also demonstrate that endogenous Rap1 was rapidly activated at early stages of junctional assembly, confirming the involvement of Rap1 during junctional assembly. Intriguingly, elevating Rap1 activity selectively within endothelial cells decreased leukocyte transendothelial migration, whereas inhibiting Rap1 activity by expression of Rap1GAP increased leukocyte transendothelial migration, providing physiological relevance to our hypothesis that Rap1 augments barrier function of inter-endothelial cell junctions. Furthermore, these results suggest that Rap1 may be a novel therapeutic target for clinical conditions in which an inappropriate inflammatory response leads to disease.

Cell Movement↗
PubMed2005

Androgen receptor activation by G(s) signaling in prostate cancer cells.

The androgen receptor (AR) is activated in prostate cancer patients undergoing androgen ablative therapy and mediates growth of androgen-insensitive prostate cancer cells, suggesting it is activated by nonandrogenic factors. We demonstrate that activated alpha subunit of heterotrimeric guanine nucleotide-binding G(s) protein activates the AR in prostate cancer cells and also synergizes with low concentration of androgen to more fully activate the AR. The G alpha(s) activates protein kinase A, which is required for the nuclear partition and activation of AR. These data suggest a role for G alpha(s) and PKA in the transactivation of AR in prostate cancer cells under the environment of reduced androgen levels.

Cyclic AMP↗
PubMed2005

Improvement in the visualization of superficial arm veins being evaluated for access and bypass.

OBJECTIVES: Duplex ultrasound mapping of arm veins is being performed with increasing frequency. Unlike ultrasound testing in other areas, this has never been subjected to a gold standard invasive test to determine accuracy. Duplex mapping appears to have a good predictive value whenever large veins are demonstrated preoperatively, but its ability to accurately measure minimum-sized veins is unproven. In this study, we compared diameter measurements obtained under six different conditions and used the maximum diameter as the comparison gold standard. METHODS: A 12-MHz linear probe was used to measure the cephalic and basilic vein cross-sectional diameters at the wrist level in 24 normal volunteers under the following conditions: (1) resting supine with a room temperature of 23 degrees to 24 degrees C, (2) supine with a tourniquet inflated to 65 mm Hg, (3) sitting with the arm dangling, (4) sitting with a tourniquet, (5) sitting after a 2-minute immersion in warm water (44 degrees C), and (6) same with tourniquet. Half the subjects underwent the protocol in a different order. RESULTS: Vein diameters were significantly larger after submersion in warm water compared with supine (P < .05, pair-wise multiple comparison procedure, Student-Newman-Keuls method). Assuming the sitting position (from supine) resulted in a decreased arm vein diameter 58% of the time. In 25% of the normal subjects, the cephalic vein size was <2 mm, which increased to >2 mm after warming. All subjects had either a cephalic or a basilic vein at the wrist that was >3.1 mm after warming. CONCLUSION: Use of warm water immersion before vein diameter measurement in a sitting position, without a tourniquet, will result in significantly larger diameter findings in normal arm veins. These diameters are likely to more closely resemble the venous diameter after distension with arterial pressure. Further studies are needed to see if warming in patients could result in increased utilization of autogenous arm vein for dialysis access and bypass.

Adult↗
PubMed2005

Gene therapy in the treatment of Fanconi anemia, a progressive bone marrow failure syndrome.

Fanconi anemia (FA) is a genetic disease characterized by progressive, fatal bone marrow failure, congenital anomalies and predisposition to cancer. Although stem cell transplantation is therapeutic, human leukocyte antigen-identical sibling donors are available to a minority of patients. In murine models and human cells in vitro, gene transfer corrects the FA cellular phenotype of chromosomal breakage in response to DNA-damaging agents, suggesting therapeutic use of gene transfer is possible. However, disease-specific characteristics make application of viral vector technology difficult. Multiple studies are currently underway to develop a gene therapy approach for treating this disease, including phase I trials.

Clinical Trials as Topic↗
PubMed2004

Infantile subdural haematoma in Auckland, New Zealand: 1988-1998.

AIM: To review the Auckland experience of traumatic subdural haematoma (SDH) in infants under 2 years of age, with particular regard to features which might help to differentiate accidental from non-accidental injury (NAI). METHODS: Retrospective review of the medical records of children under 2 years of age, coded for subdural haematoma (SDH) and retinal haemorrhage (RH) over a 10-year period. RESULTS: Sixty-four cases of SDH were identified. Forty-one of these were due to non-accidental trauma, and 23 cases were accidental. Differences between these two groups related to the age of presentation, ethnicity, the type of explanation for the injury, and differences in aspects of the clinical presentation (apnoea, seizures, fractures, retinal haemorrhage). Mortality in the non-accidental group was far higher. CONCLUSIONS: Subdural haemorrhage is a significant cause of death and disability in infants presenting to hospital in Auckland. In the majority of cases, it is caused by child abuse, and there are certain features that are helpful in establishing this diagnosis. The long-term outcome in this group is unknown, but there is reason to believe that, in many cases, it is poor. There is considerable scope for further research.

Hematoma, Subdural↗
PubMed2004

Identification of a role for beta-catenin in the establishment of a bipolar mitotic spindle.

beta-Catenin is a multifunctional protein that is known to participate in two well defined cellular processes, cell-cell adhesion and Wnt-stimulated transcriptional activation. Here we report that beta-catenin participates in a third cellular process, the establishment of a bipolar mitotic spindle. During mitosis, beta-catenin relocalizes to mitotic spindle poles and to the midbody. Furthermore, biochemical fractionation demonstrates the presence of beta-catenin in purified centrosome preparations. Reduction of cellular beta-catenin by RNA interference leads to the failure of centrosomes to fully separate, resulting in a marked increase in the frequency of monoastral mitotic spindles. Our results define a new and important function for beta-catenin in mitosis and demonstrate that beta-catenin is involved in vital biological processes beyond cell adhesion and Wnt signaling.

Animals↗
PubMed2004

Cytological diagnosis of cystic brain tumors: a retrospective study of 88 cases.

The stereotaxic aspiration of cystic brain tumors is performed to provide cyst decompression and/or to facilitate surgical resection. The purpose of our study was to determine the diagnostic value of brain cyst fluid cytology, especially in clinically suspected recurrent tumors with no histological follow-up (HF), when a diagnosis is most needed. We reviewed the cytological diagnoses of 88 aspirates from 70 patients with cystic brain tumors between 1995 and 2001, of which 31 had a prior known malignancy including 18 primary brain tumors (PBTs) and 13 adenocarcinomas (ACAs). Sixty-nine of 88 aspirates were obtained intraoperatively. Nineteen of 88 aspirates were obtained from 10 patients with recurrent or persistent cystic brain tumors (8 patients with PBT and 2 patients with ACA), with available clinicoradiological correlation (magnetic resonance imaging/computed tomography [MRI/CT] scans) in 13 of them. The 88 aspirates were classified in three categories: 28 positive (32%), 15 atypical (17%), and 45 negative (51%). Eight of 28 positive cases (5 case of PBT, 2 cases of ACA, and 1 case of melanoma) were given a nonspecific diagnosis of malignant neoplasm (9% of all cases). Fifteen of 28 positive cases (6 cases of PBT, 8 cases of ACA, and 1 case of melanoma) were diagnosed correctly and confirmed by HF (17% of all cases). Four of 28 cases were ACA diagnosed solely by cytology (<4% of all cases). One neurocytoma (1/28) case was mistaken for an oligodendroglioma despite cell blocks (CBs) and immunophenotyping (IPT) (<1% of all cases). Eleven of 15 atypical cases were 8 cases of PBT, 2 cases of ACA, and 1 case of postoperative change (PC). Four of 15 atypical cases (from three patients with suspected PBT recurrence) could not be further characterized by CB/IPT and had no HF. Twenty-seven of 45 negative cases were falsely negative (23 cases of PBT, 3 cases of ACA, and 1 case of malignant neoplasm); 11/45 cases were PC, and 7/45 (from five patients with clinically suspected tumor recurrence) cases had no HF. Cytological evaluation of brain cyst fluid is not a reliable means of diagnosing cystic brain neoplasms (including recurrences) due to a high false negative rate and a low sensitivity. Most of the negative or atypical cases (68% of all cases) were recurrent PBT of glial origin that may not be prone to exfoliate. These cytological specimens consisted of lysed blood, obscuring inflammatory cells, and degenerated diagnostic cells if any, yielding inconclusive results.

Adolescent↗
PubMed2004

Dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms and their association with 5-fluorouracil/leucovorin chemotherapy in colorectal cancer.

The causes of interpatient variation in severe toxicity resulting from treatment with weekly 5-fluorouracil (5-FU)/ leucovorin (LV) are poorly understood. This study was undertaken to examine the contribution of commonly occurring polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene to interpatient variability in 5-FU pharmacokinetics and toxicity. Patients with stage III/IV colorectal cancer were treated by bolus intravenous (I.V.) injection with 500 mg/m2 doses of 5-FU and LV once every week. The pharmacokinetics of 5-FU was determined on weeks 1 and 4. Genotyping assays were developed for 8 polymorphisms in the DPYD gene. A well-characterized functional polymorphism in the 5' untranslated region of the thymidylate synthase (TS) gene was also analyzed. A cohort of 22 patients (15 male, 7 female) with a median age of 61 years was evaluated. Although there was no relationship between the area under the plasma concentration time curve (AUC) for the first dose of 5-FU and worst-grade toxicity during the first cycle of therapy, 3 of the 4 patients in whom the AUC on week 4 was more than equal to 5 microgram/h/mL greater than the value for the first dose experienced grade 3/4 toxicity during subsequent treatment. Among the 8 polymorphisms in the DPYD gene, 7 were found to vary in the study population but none were significantly associated with the AUC of 5-FU. There was no relationship between the DPYD and TS genotypes examined and 5-FU toxicity. Extensive polymorphism in the DPYD gene was observed; however, no conclusive correlations existed between the DPYD and TS genotype and 5-FU pharmacokinetics or toxicity. Decreases in 5-FU clearance in certain patients may provide insight into the increased toxicity following repetitive cycles of treatment with weekly I.V. bolus 5-FU. The present study offers useful themes for undertaking larger prospective pharmacogenetic studies in the future.

Adult↗
PubMed2003

Tissue (muscle) oxygen saturation (StO2): a new measure of symptomatic lower-extremity arterial disease.

OBJECTIVES: Near-infrared spectroscopy provides a noninvasive method of measuring tissue oxygen saturation and has been used to monitor extremity compartment syndrome. Tissue O(2) saturation (StO(2)) is potentially useful in assessing patients with peripheral arterial disease (PAD). The purposes of this feasibility study are to (1) explore the diagnostic sensitivity of StO(2) in subjects with PAD and symptoms of intermittent claudication (IC) compared with normal subjects, and (2) correlate the change in StO(2) during and after exercise with the ankle brachial index (ABI) in patients with IC. Material and methods Forty-nine subjects, 35 normal and 14 PAD, from two centers were evaluated in a prospective cross-sectional analysis comparing StO(2) by using the InSpectra tissue spectrometer and ABI at rest (baseline) and after treadmill exercise. Measurements were obtained at baseline and peak exercise (normal subjects) and at baseline, initial claudication distance (ICD) and absolute claudication distance (ACD) in PAD subjects. Endpoint values were the mean of 15 data points. Times to 50% of StO(2) recovery to baseline (T(50)) and complete recovery to baseline (T(100)) were measured. Receiver-operator characteristic curves were constructed to assess the sensitivity/specificity values associated with various StO(2) cut-points. RESULTS: The PAD patients were older (P =.0002) and 57% were male, compared with 37% males in the normal group. The ABI was 0.68 +/- 0.14 in PAD patients versus 1.14 +/- 0.08 in normal subjects (P <.0001). The baseline StO(2) was 65% in both groups. The peak exercise StO(2) was significantly lower and the absolute change in StO(2) and the percent change in StO(2) were significantly greater in PAD patients (P < 0.45). The T(50) and T(100) were longer in the PAD patients compared to normal subjects (P =.0001 and.002, respectively). A T(50) of >70 seconds yielded a sensitivity of 89% and a specificity of 85% for PAD. CONCLUSIONS: StO(2) is a new and potentially useful technique to evaluate patients with PAD. Resting StO(2) was similar in PAD-IC subjects and normals. There was a significantly greater drop in StO(2) and longer recovery times in PAD-IC subjects. Interestingly, StO(2) at the ICD and ACD was similar. StO(2) offers a different and perhaps more appropriate end point for diagnosis and monitoring of the management of patients with PAD, and may offer additional insight into the pathophysiology of exercise-induced muscle ischemia and its recovery.

Adult↗
PubMed2003

African tick bite fever.

African tick bite fever is an acute febrile illness that is frequently accompanied by headache, prominent neck muscle myalgia, inoculation eschars, and regional lymphadenitis. The disease is caused by Rickettsia africae, a recently identified spotted fever group rickettsia, which is transmitted by ungulate ticks of the Amblyomma genus in rural sub-Saharan Africa and the French West Indies. Whereas reports on African tick bite fever in indigenous populations are scarce, the number of reported cases in travellers from Europe and elsewhere has recently increased significantly. Treatment with doxycycline is associated with rapid recovery in most patients. An immunofluorescence assay is recommended for the diagnosis but seroconversion is commonly delayed and this limits the usefulness of the test. Travellers to endemic areas should be informed of the risk of contracting African tick bite fever and be encouraged to take personal protective measures against tick bites.

Adult↗
PubMed2003

Direct comparison of RD114-pseudotyped versus amphotropic-pseudotyped retroviral vectors for transduction of rhesus macaque long-term repopulating cells.

Recently, RD114 (feline endogenous retrovirus envelope protein)-pseudotyped retroviral particles have been shown to transduce human NOD/SCID repopulating cells efficiently. In this study, we compared directly transduction of repopulating cells with RD114-pseudotyped vector to that with standard amphotropic vector in the rhesus macaque model. G-CSF/SCF-mobilized CD34(+) rhesus peripheral blood cells were cultured in the presence of SCF, Flt-3 ligand, and MGDF on Retronectin-coated flasks. To assess directly the ability of the two pseudotypes to transduce primitive cells, both vectors were added simultaneously to the target cells every 24 h, for a total of four exposures in 96 h. The cells were reinfused after the animals received 1000 cGy total body irradiation. At the end of transduction, gene marking efficiency of CFU was higher with amphotropic LNL6 vector (mean 88.4%) vs RD114-G1Na vector (mean 18.5%). After long-term engraftment in three animals, total neo gene marking levels were 4-5% in PBMNCs and 1.5-4% in granulocytes. The RD114-G1Na marking levels were consistently higher in granulocytes than in mononuclear cells, while amphotropic LNL6 marking levels were higher in PBMNCs than in granulocytes. The differential gene marking patterns suggest that RD114 and amphotropic vectors may target distinct progenitor or stem cell populations. There was no clear advantage for RD114-pseudotyped vectors in this predictive preclinical model in terms of overall long-term marking levels; however, optimization of transduction conditions by increasing m.o.i. or inducing the receptor could potentially improve results with this novel vector system.

Amino Acid Transport System ASC↗
PubMed2002

Childhood gonorrhoea in Auckland.

AIM: To review the Auckland experience of childhood gonorrhoea, with particular regard to inter-agency management and medicolegal outcome. METHODS: Retrospective review of medical records at a specialist child abuse assessment unit, and follow up with other agencies involved. RESULTS: Twelve cases of genital gonorrhoea in pre-pubertal children in five years, in contrast to two cases in the preceding six years. Major problems in inter-agency coordination, and an inability to identify the source of the infection in most cases. CONCLUSIONS: Gonorrhoea in the pre-pubertal child is an increasing problem, and is often poorly handled. Proposals for an inter-agency guideline are discussed.

Child↗
PubMed2002

An unusual etiology of hypertension in a 5-year-old boy.

Ganglioneuromas are rare benign tumors of neural crest origin, arising from ganglia of the sympathetic nervous system and adrenal medulla. These masses are usually detected during the first 2 decades of life and are generally discovered incidentally. We present a 5-year-old boy with sickle beta-thalassemia whose hypertension is caused by a perihilar ganglioneuroma encasing the right renal artery and distorting the right renal vein. The tumor was resected and the child's blood pressure subsequently normalized.

Anemia, Sickle Cell↗
PubMed2002

Treatment of children with Langerhans cell histiocytosis with 2-chlorodeoxyadenosine.

Langerhans cell histiocytosis (LCH) is a disorder characterized by proliferation of activated Langerhans cells. Immune dysregulation is believed to be part of the pathogenesis. Although current therapies are very effective at inducing remission, multiple recurrences and long-term sequelae are common for patients with low-risk disease, and a significant proportion of young patients die of their disease. More effective therapies based on the pathogenesis of LCH are needed. We investigated the use of 2-chloro-deoxyadenosine (2-CdA), a purine analogue with an antiproliferative effect on histiocytes and lymphocytes, in patients with recurrent or high-risk LCH. Six patients with recurrent LCH received 2-CdA (5-7 mg/m(2)/day for 5 days, repeated every 21-28 days). All patients achieved remission. With a median follow-up of 15 months (range, 3-25 months), 5 patients remain in remission. A patient with multisystem disease who recurred after 13 months, achieved a second remission with 2-CdA. Hematologic toxicity was minimal, and no infectious complications were documented. 2-CdA is among the most effective drugs for the treatment of LCH, and this is probably due to both its anti-proliferative and immunomodulatory effects. 2-CdA needs to be considered for the treatment of recurrent LCH. However, its incorporation into front-line treatment of patients with multi-system LCH needs further study.

Child↗
PubMed2002

Minimally invasive Le Fort III distraction.

Recent applications of distraction osteogenesis to the Le Fort III osteotomy in patients with craniofacial dysostosis have proven promising (1-3). Distraction has allowed the midfacial segment to be brought further forward and maintained in position with greater stability when compared with the standard technique of intraoperative advancement. Because no bone grafts or plates must be placed, access incisions are necessary only for performance of the osteotomy. In an effort to minimize the morbidity of the procedure, we have begun performing the Le Fort III osteotomy without the coronal incision. Instead, the nasofrontal junction is approached using the medial aspect of an upper blepharoplasty incision. A lower eyelid and gingivobuccal sulcus incision are also used to complete the osteotomy. This technique has resulted in a shorter operative time and decreased blood loss when compared with the Le Fort III distraction procedure using the standard coronal incision.

Adolescent↗
PubMed2002

Review: metabolism of immunosuppressant drugs.

Pharmacokinetic concepts provide a basis for individualization of drug therapy to optimize outcomes of the critical-dose drugs cyclosporine (CsA), tacrolimus (TRL), sirolimus (SRL), and mycophenolate mofetil (MMF). The therapeutic range of a drug-defined as the concentrations at which the desired pharmacologic effect is produced without adverse effects in most patients-is difficult to achieve given the significant inter-and intrapatient variability of the effects of a given concentration of therapeutic agents. Because of the highly variable rates of absorption of immunosuppressive agents and clinical responses to given concentrations in transplant recipients, individualization of drug regimens by using therapeutic drug monitoring (TDM) is essential to optimize pharmacotherapy Assessing proclivity for acute rejection episodes in transplant recipients currently is attempted by estimating drug exposure using the area under the time-concentration curve (AUC) for MMF and the average concentration (Cav, the quotient of the AUC and the dosing interval) for CsA. These studies have revealed that low oral bioavailability was a more important predictor of rejection than was a rapid clearance rate. In addition, the degree of intra-individual variability of AUC values correlated with the development of chronic rejection in renal transplant recipients. Similarly, TDM of MMF requires AUC determinations. Low mycophenolic acid (MPA) exposure, as estimated by the AUC, demonstrates a significant association with an increased risk of an acute renal transplant rejection episode. The AUC0-2 estimate of MPA shows good agreement with the 12-hr AUC estimate from samples obtained during the entire dosing interval. In contrast, trough levels are utilized during treatment with TRL or SRL, potent new immunosuppressive agents that display a pleiotropic array of side effects. Standard body measures, including weight and body mass index, poorly predict the concentration of SRL in whole blood. Large inter- and intra-individual differences displayed in patients also could not be predicted by demographic features or by laboratory parameters. When SRL is given with other immunosuppressive agents such as CsA, which shares with SRL mutual microsomal metabolism by the cytochrome P450 3A system, pharmacokinetic interactions occur, especially when the agents are administered concomitantly. Because of the critical-dose nature of most of the recent generation of immunosuppressive agents, therapeutic drug monitoring is becoming increasingly important in the selection of doses and treatment regimens.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Sexually transmitted infections in alleged sexual abuse of children and adolescents.

AIM: To describe the prevalence of sexually transmitted infections (STI) in children and young people aged 0-17 years seen for suspected sexual abuse in Auckland, New Zealand. METHODS: Retrospective review of consecutive medical records over a 7-year period from December 1991 to December 1998. RESULTS: A total of 2162 children and young people had a genital examination related to concerns about possible sexual abuse, of whom 1909 (88.3%) had some form of screening test for STI. Sixty children and young people (2.8%) had STI, diagnosed either by examination, laboratory investigation, or both. The rate was 5.6% (43/770) in those aged 10 years or older and 1.2% (17/1392) in those aged under 10 years. CONCLUSION: The prevalence of STI in children and young people referred for suspected sexual abuse is low but significant. Chlamydia and pelvic inflammatory disease were the most common infections. No STI was found in an asymptomatic pre-pubertal child.

Adolescent↗