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Biomedical subjects

James R Wright

Publications and source records attributed to James R Wright.

At least 19 recordsLinked to original sources
PubMed2007

Insulin expression in the brain and pituitary cells of tilapia (Oreochromis niloticus).

While the presence of immunoreactive insulin in the central nervous system of many vertebrate species is well known, the origin of brain insulin is still debated. In this study, we applied RT-PCR, quantitative RT-PCR (qRT-PCR), and Northern hybridization to examine expression of the insulin gene in different tissues of an adult teleost fish, the Nile Tilapia (Oreochromis niloticus). We found that the insulin gene is transcribed at a high level in Brockmann bodies (pancreatic islet organs) and at a low level in the brain and pituitary gland. In the brain, insulin transcripts were detected in all areas by qRT-PCR and in situ hybridization. The highest level of insulin mRNA was found in the hypothalamus. The level of insulin transcription in the pituitary gland was 6-fold higher than that in the brain and 4.6-fold higher than that in the hypothalamus. Furthermore, insulin mRNA and immunoreactive insulin-like protein was detected in the pituitary gland using in situ hybridization, immunohistochemistry, and Western blot analysis. Our results indicate that in adult tilapia insulin expression is not restricted to the endocrine pancreatic cells, but also occurs in endocrine cells of the pituitary gland and in the neuronal cells of the brain, suggesting that the brain/pituitary gland might represent extrapancreatic origin of insulin production.

Animals↗
PubMed2006

Phase III Trial of an emulsion containing trolamine for the prevention of radiation dermatitis in patients with advanced squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Trial 99-13.

PURPOSE: This multicentered phase III trial was designed to compare an emulsion containing trolamine against the usual supportive care within each participating institution for patients with head and neck cancer undergoing radiation therapy. PATIENTS AND METHODS: Patients with biopsy-proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to one of the following treatments: prophylactic trolamine emulsion, interventional trolamine emulsion, or declared institutional preference. The primary outcome was the reduction in grade 2 or higher skin toxicity, as per National Cancer Institute Common Toxicity Criteria version 2.0. Secondary outcomes included patient-reported quality of life (QOL). RESULTS: From October 2000 to April 2002, 547 patients from 51 institutions were entered onto the trial. The average age was 59 years. Patients were predominately male (79%) and most continued to use tobacco products (52%). The rates of grade 2 or higher radiation dermatitis were 79%, 77%, and 79% in the prophylactic, interventional, and institutional preference arms of the study, respectively. No significant differences in QOL were found. CONCLUSION: The results of this trial demonstrate no advantage for the use of trolamine in reducing the incidence of grade 2 or higher radiation dermatitis or improving patient-reported QOL. The use of 15 different local standards of care highlights the need to continue research that will result in evidence-based recommendations to reduce the burden of radiation dermatitis.

Carcinoma, Squamous Cell↗
PubMed2006

Things we have learned from tilapia islet xenotransplantation.

An islet xenotransplantation model has been developed using tilapia (Oreochromis niloticus) as the donors. Studies using this model for the treatment of experimental type 1 diabetes in mice have produced promising results including the maintenance of long-term normoglycemia and mammalian-like glucose tolerance profiles in islet graft recipients. Islet encapsulation has also provided a promising method for the prevention of graft rejection, and strains of transgenic tilapia expressing a [desThrB30] human insulin molecule have been produced. In addition to studying islet transplantation for the treatment of type 1 diabetes, these studies have also produced insights into piscine glucose homeostasis. Studies demonstrating the glucose responsiveness of tilapia islets are described. In addition, work performed by our group and by others pertaining to presence and nature of piscine glucose transporters is reviewed. Finally, studies addressing some of the broader challenges of islet xenotransplantation are discussed with particular attention paid to the post-transplantation fate of the various islet cell populations and the proteins they produce.

Animals↗
PubMed2006

Barriers to participation in clinical trials of cancer: a meta-analysis and systematic review of patient-reported factors.

BACKGROUND: Enrolling participants onto clinical trials of cancer presents an important challenge. We aimed to identify the concerns of patients with cancer about, and the barriers to, participation in clinical trials. METHODS: We did a systematic review to assess studies of barriers to participation in experimental trials and randomised trials for validity and content. We estimated the frequency with which patients identified particular issues by pooling across studies that presented data for barriers to participation in clinical trials as proportions. FINDINGS: We analysed 12 qualitative studies (n=722) and 21 quantitative studies (n=5452). Two qualitative studies inquired of patients who were currently enrolled onto clinical trials, and ten inquired of patients who were eligible for enrolment onto various clinical trials. Barriers to participation in clinical trials were protocol-related, patient-related, or physician-related. The most common reasons cited as barriers included: concerns with the trial setting; a dislike of randomisation; general discomfort with the research process; complexity and stringency of the protocol; presence of a placebo or no-treatment group; potential side-effects; being unaware of trial opportunities; the idea that clinical trials are not appropriate for serious diseases; fear that trial involvement would have a negative effect on the relationship with their physician; and their physician's attitudes towards the trial. Meta-analysis confirmed the findings of our systematic review. INTERPRETATION: The identification of such barriers to the participation in clinical trials should help trialists to develop strategies that will keep to a maximum participation and cooperation in cancer trials, while informing and protecting prospective participants adequately.

Clinical Trials as Topic↗
PubMed2005

Rapid destruction of encapsulated islet xenografts by NOD mice is CD4-dependent and facilitated by B-cells: innate immunity and autoimmunity do not play significant roles.

BACKGROUND: Spontaneously diabetic NOD mice rapidly reject microencapsulated islet xenografts via an intense pericapsular inflammatory response. METHODS: Tilapia (fish) islets were encapsulated in 1.5% alginate gel microspheres. Recipients in series 1 were spontaneously diabetic NOD mice and streptozotocin-diabetic nude, euthymic Balb/c, prediabetic NOD, and NOR (a recombinant congenic strain not prone to autoimmune diabetes) mice. Recipients in Series 2 were STZ-diabetic NOD, NOD-scid, NOD CD4 T-cell KO, NOD CD8 T-cell KO, and NOD B-cell KO mice. RESULTS: In Series 1, encapsulated fish islet grafts uniformly survived long-term in nude mice but were rejected in Balb/c and, at a markedly accelerated rate, in spontaneously diabetic NOD, streptozotocin-diabetic NOD and NOR recipients. Histologically, intense inflammation (macrophages and eosinophils) surrounding the microcapsules was seen only in NOD and NOR recipients. In Series 2, encapsulated fish islets uniformly survived long-term in NOD-scid and NOD CD4 KO mice; graft survival was markedly prolonged in B-cell KO (P<0.001) but not CD8 KO mice. CONCLUSIONS: The rapid rejection of alginate encapsulated islet xenografts by NOD mice is not solely a consequence of beta-cell directed autoimmunity nor is it merely a vigorous innate immune response. Graft rejection requires CD4 T-cells, is facilitated by B-cells, and does not require CD8 T-cells.

Animals↗
PubMed2005

Prenatal infantile cortical hyperostosis (Caffey's disease): a 'hepatic myeloid hyperplasia-pulmonary hypoplasia sequence' can explain the lethality of early onset cases.

BACKGROUND: Infantile cortical hyperostosis (ICH) is benign and self-limiting when it presents near or after birth but is usually lethal when it presents earlier. METHODS: We present the clinical, ultrasonic, radiographic and pathologic findings in an instructive case of early onset prenatal ICH. RESULTS: A 40-year-old G2P1 woman delivered spontaneously at 22 weeks' gestation. Prenatal ultrasounds showed rib and mandibular abnormalities as well as short humeri. Post-mortem radiographs showed asymmetric hyperostosis in long bones, mandible, scapulae and pelvis with sparing of spine, hands, feet and skull. The affected skeleton showed marked bony sclerosis and ballooning of the diaphyses of the long bones with periosteal sclerosis. A complete autopsy showed characteristic histologic findings in affected bones. Previous reports at 20+ weeks have described anasarca, fetal hydrops, hepatomegaly, and pulmonary hypoplasia. In our case, there was no hydrops/anasarca; hepatomegaly, due to massive extramedullary hematopoiesis with marked myeloid hyperplasia, combined with ribcage abnormalities, caused mild pulmonary hypoplasia. CONCLUSION: We hypothesize that early onset fetal ICH is usually lethal because massive hepatic myeloid hyperplasia sequentially causes: (1) hepatomegaly and, in conjunction with rib abnormalities, mild pulmonary hypoplasia, (2) sinusoidal and pre-sinusoidal portal hypertension followed by ascites/hydrops, and (3) ascites/hydrops-induced severe pulmonary hypoplasia.

Adult↗
PubMed2005

C-Kit-positive metastatic malignant pigmented clear-cell epithelioid tumor arising from the kidney in a child without tuberous sclerosis.

We report the first pediatric case of malignant pigmented epithelioid clear-cell tumor arising from kidney; the lesion occurred in a 12-year-old girl without tuberous sclerosis. The tumor was widely metastatic to the retroperitoneum and chest, and the patient died of the disease 9 months after diagnosis, despite active chemotherapy. Pigmented epithelioid clear-cell tumor of the kidney is a rare variant of epithelioid angiomyolipoma and a member of the family of perivascular epithelioid cell tumors (PEComas). The tumor demonstrated overlapping features between clear-cell sugar tumor and epithelioid variant of angiomyolipoma. Tumor cells were positive for HMB-45 expression, negative for any evidence of muscular differentiation, and contained melanin pigment and premelanosomes in the cytoplasm. Diffuse C-Kit (CD117) positivity was identified throughout the tumor. This is the first report of C-Kit-positive malignant PEComas.

Angiomyolipoma↗
PubMed2005

Estimating per patient funding for cancer clinical trials: an Ontario based survey.

The financial implications of conducting clinical trials in oncology have not been well researched from a perspective that would facilitate the negotiation of appropriate reimbursement. A better understanding of the resources required to conduct clinical trials is central to this process. Summaries of two hypothetical clinical trials were circulated to the clinical trials departments of the nine regional cancer centres of Cancer Care Ontario (CCO), in the Province of Ontario, Canada. The centres were asked to produce itemized budgets with per patient charges detailed for each trial. Additionally, each trial was to be separately considered as if sponsored by a federally funded cooperative group, and then as if sponsored by industry. Six of the centres reported experience generating clinical trial budgets. Specific charges by the local Institutional Review or Research Ethics Boards (REB) were not included. The total of all per patient charges for the first trial ranged from 1352 dollars to 3082 dollars when considered as a cooperative group trial, and from 1700 dollars to 7217 dollars when considered as an industry sponsored trial. Similar charges for the second trial ranged from 2251 dollars to 5826 dollars and from 2251 dollars to 11,304 dollars respectively. Despite the similarities of the regional cancer centres across the province of Ontario, there were surprisingly large differences in the submitted budgets. No centre consistently produced the highest or lowest estimates. The majority of the differences appeared to be based on the range in estimates for professional support (nurse and physician), and the required radiology investigations. For centres that negotiate specific per patient funding amounts with industry, this data would suggest a need to better understand the budgeting process and its link to appropriate resource identification to ensure appropriate funding is obtained. These issues are likely not unique to oncology.

Budgets↗
PubMed2005

Effect of glucose toxicity on intraportal tilapia islet xenotransplantation in nude mice.

BACKGROUND: Discordant xenogeneic islets transplanted intraportally into athymic nude rats experience primary non-function and are rapidly destroyed. Recently, it has been reported that adult porcine islets transplanted intraportally into nude mice are also rapidly destroyed and that this constitutes a new model for instant blood-mediated inflammatory reaction (IBMIR). METHODS: Tilapia (fish) islets were harvested, mechanically broken into mammalian islet-sized fragments, cultured for 48 h, and transplanted via the portal vein into athymic or euthymic mice. RESULTS: There were several groups of recipient mice. Streptozotocin-diabetic nude mice received 400 islets via the portal vein (n = 12). Recipients were killed when hyperglycemic (>200 mg/dl); livers and native pancreases were examined histologically. Mean graft survival time, based on function, was 5.4 +/- 1.2 days; at autopsy, histology showed occasional viable islets. We also performed a group of transplants in non-diabetic nude mice (n = 6) and then killed the recipients 2 or 4 weeks later; all had abundant viable, well-granulated islet grafts based on histology. Therefore, the intraportal environs in nude mice are not incompatible with discordant fish islets; rather, it appears as if hyperglycemia adversely affects the intraportal islet grafts (i.e. ''glucose toxicity''). To test this hypothesis, transplants were performed into non-diabetic nude mice and allowed to engraft for either 3 days (n = 6) or 10 days (n = 8) prior to injection of streptozotocin (200 to 220 mg/kg i.v.) to destroy the beta-cells in the recipients' native islets (n.b. tilapia islets are exceedingly resistant to streptozotocin); these recipients were followed for 28 days post-transplantation (or until hyperglycemic) and then killed for histology. Mean graft function exceeded 25 days for both groups and viable well-granulated, tilapia islets grafts were readily identified in all recipients; in all but one, the native pancreases were markedly beta-cell depleted -- confirming that normoglycemia was due to functional fish islet xenografts. CONCLUSIONS: Our results suggest that ''glucose toxicity'' plays a role in the immediate demise of intraportal tilapia islet xenografts.

Animals↗
PubMed2004

Why cancer patients enter randomized clinical trials: exploring the factors that influence their decision.

PURPOSE: Few interventions have been designed and tested to improve recruitment to clinical trials in oncology. The multiple factors influencing patients' decisions have made the prioritization of specific interventions challenging. The present study was undertaken to identify the independent predictors of a cancer patient's decision to enter a randomized clinical trial. METHODS: A list of factors from the medical literature was augmented with a series of focus groups involving cancer patients, physicians, and clinical research associates (CRAs). A series of questionnaires was developed with items based on these factors and were administered concurrently to 189 cancer patients, their physicians, and CRAs following the patient's decision regarding trial entry. Forward logistic regression modeling was performed using the items significantly correlated (by univariate analysis) with the decision to enter a clinical trial. RESULTS: A number of items were significantly correlated with the patient's decision. In the multivariate logistic regression model, the patient's perception of personal benefit was the most important, with an odds ratio (OR) of 3.08 (P < .05). CRA-related items involving supportive aspects of the decision-making process were also important. These included whether the CRA helped with the decision (OR = 1.71; P < .05), and whether the decision was hard for the patient to make (OR = 0.52; P < .05). CONCLUSION: Strategies that better address the potential benefits of trial entry may result in improved accrual. Interventions or aids that focus on the supportive aspects of the decision-making process while respecting the need for information and patient autonomy may also lead to meaningful improvements in accrual.

Adult↗
PubMed2004

Public consultation on xenotransplantation.

Although xenotransplantation could potentially benefit individuals with organ failure, this new technology is both controversial and potentially risky not only to recipients and their close contacts but also to society as a whole. The Canadian government wanted the public to have input into the decision of whether to pursue this new treatment. Therefore, Health Canada hired the Canadian Public Health Association to design and perform an arm's length public consultation; this program resulted in some high-profile negative recommendations. I offer an alternative analysis of the data collected during the consultation, which results in different conclusions.

Animals↗
PubMed2004

Development of the islets, exocrine pancreas, and related ducts in the Nile tilapia, Oreochromis niloticus (Pisces: Cichlidae).

Pancreatic development and the relationship of the islets with the pancreatic, hepatic, and bile ducts were studied in the Nile tilapia, Oreochromis niloticus, from hatching to the onset of maturity at 7 months. The number of islets formed during development was counted, using either serial sections or dithizone staining of isolated islets. There was a general increase in islet number with both age and size. Tilapia housed in individual tanks grew more quickly and had more islets than siblings of the same age left in crowded conditions. The pancreas is a compact organ in early development, and at 1 day posthatch (dph) a single principal islet, positive for all hormones tested (insulin, SST-14, SST-28, glucagon, and PYY), is partially surrounded by exocrine pancreas. However, the exocrine pancreas becomes more disseminated in older fish, following blood vessels along the mesenteries and entering the liver to form a hepatopancreas. The epithelium of the pancreatic duct system from the intercalated ducts to the main duct entering the duodenum was positive for glucagon and SST-14 in 8 and 16 dph tilapia. Individual insulin-immunopositive cells were found in one specimen. At this early stage in development, therefore, the pancreatic duct epithelial cells appear to be pluripotent and may give rise to the small islets found near the pancreatic ducts in 16-37 dph tilapia. Glucagon, SST-14, and some PPY-positive enteroendocrine cells were present in the intestine of the 8 dph larva and in the first part of the intestine of the 16 dph juvenile. Glucagon and SST-14-positive inclusions were found in the apical cytoplasm of the mid-gut epithelium of the 16 dph tilapia. These hormones may have been absorbed from the gut lumen, since they are produced in both the pancreatic ducts and the enteroendocrine cells. At least three hepatic ducts join the cystic duct to form the bile duct, which runs alongside the pancreatic duct to the duodenum.

Animals↗
PubMed2004

Protective anti-donor IgM production after crossmatch positive liver-kidney transplantation.

The mechanism by which a liver transplantation might protect a simultaneous kidney transplant in a crossmatch-positive recipient is unknown. Flow cytometry crossmatch (FCXM) has increased the sensitivity of donor-specific antibody (DSA) detection compared with complement-dependant cytotoxicity (CDC). Here we compare the outcome of a liver-kidney transplantation (LKT), which was CDC and FCXM positive, to the mate-isolated kidney transplantation (KT), which was CDC negative but FCXM positive, from the same donor. Immunoglobulin G (IgG) and immunoglobulin M (IgM) DSAs were measured by FCXM using splenocytes and purified T cells. The KT graft was hyperacutely rejected and removed, but the LKT graft survived without episodes of rejection. Both the KT and the LKT recipients had high levels of circulating antidonor IgG, but not IgM, before transplantation. By day 3, antidonor IgG and IgM in the LKT recipient increased 2 and 7 fold respectively, whereas the KT recipient maintained the high IgG level but did not increase IgM. Histology of the KT graft showed IgG and complement (C1q) deposition, but in the LKT grafts, IgM was deposited without IgG or C1q. Circulating IgG and IgM DSAs returned to background by day 10 and were still at background on day 100. We report a crossmatch-positive LKT where posttransplantation production of IgM DSA, which failed to fix complement, appeared to protect the grafts.

Adult↗
PubMed2004

Immunoglobulin-G subclass antidonor reactivity in transplant recipients.

Outcomes may differ after kidney transplantation compared to combined liver-kidney transplantation. In animal models, distinct patterns of antidonor immunoglobulin (Ig) G subclasses are associated with either rejection or transplant tolerance. Flow cytometry has increased the sensitivity of antidonor immunoglobulin detection. We compared antidonor IgG subclass responses in kidney transplant recipients to those in recipients of liver or multiorgan grafts. In this study of 19 organ (kidney, liver, pancreas) transplantations, recipient serum incubated with donor splenocytes was tested by flow cytometry for the presence of IgM, IgG, or IgG subclass 1-4. Sera before transplantation and 10 days and 100 days after transplantation were used. No differences were seen in antidonor IgM, IgG, or IgG subclass antibodies among recipients of kidney transplants and liver grafts or combination grafts, either before or after transplantation. IgG4 gradually but significantly increased after transplantation in all groups. High levels of antidonor IgG3 either before transplantation or produced after it were found in 3 kidney recipients who experienced acute rejection. No other patients experienced rejection, and no other increase in IgG3 was seen. In conclusion, antidonor IgG subclass profiles may be useful to distinguish populations at risk of rejection but they do not differentiate the immunological response after kidney transplantation from that after liver or combined transplantation. A late rise in antidonor IgG4 is consistent with decreased antidonor reactivity thought to occur late after transplantation.

Adult↗
PubMed2004

Pilot study of the quality initiative in rectal cancer strategy.

INTRODUCTION: Total mesorectal excision vs. traditional surgical techniques may lead to improved rates of permanent colostomy, local tumor recurrence, and survival for patients undergoing major rectal cancer operations. We developed the surgeon-directed, multipronged Quality Initiative in Rectal Cancer strategy to encourage surgeons to use total mesorectal excision techniques. METHODS: The Quality Initiative in Rectal Cancer strategy interventions included a workshop, an operative demonstration of total mesorectal excision, and a postoperative questionnaire. The design of the strategy was informed by the industrial theory principles of continuous quality improvement. We assessed the logistics of implementing the strategy and the attitudes of surgeons toward the strategy through a pilot study at three community hospitals in the Central-West region of Ontario. RESULTS: Seventeen of 19 surgeons participated in a workshop, and 12 of 17 workshop participants received at least one operative demonstration of total mesorectal excision. Ten of 11 surgeons who completed a postoperative questionnaire indicated their traditional approach to rectal cancer surgery varied with that of the operative demonstration. The attitudes of surgeons toward the Quality Initiative in Rectal Cancer strategy were positive. For the time periods before and after the pilot study, there was a trend toward a lower rate of permanent colostomy among patients treated by surgeons who participated in both the workshop and an operative demonstration of total mesorectal excision. CONCLUSION: The Quality Initiative in Rectal Cancer strategy may be an effective method of introducing optimal rectal cancer surgery techniques to a large group of practicing surgeons.

Aged↗
PubMed2004

Tilapia islet grafts are highly alloxan-resistant.

We have previously shown that dose-response studies performed in streptozotocin (STZ)-diabetic nude mouse recipients bearing established, functioning islet xenografts can be used to directly compare in vivo STZ-sensitivity between donor species and that tilapia (fish) islet grafts are exceedingly STZ-resistant. Using this method, we tested whether tilapia islets are sensitive to alloxan. Tilapia or rat islets were transplanted under the renal capsules of STZ-diabetic nude mice. Recipients with normal glucose tolerance tests (GTTs) on day 30-35 were injected with increasing i.v. doses of alloxan and blood glucose levels were followed for 5-7 days and then GTTs were repeated. Next, mice were killed and their grafts/native pancreata examined histologically (including insulin stains). Control nude mice were also injected with increasing i.v. doses of alloxan. Based upon non-fasting blood glucose levels, GTT, and graft histology, the following observations were made: (1) Tilapia islet xenografts were uniformly resistant to i.v. doses of 75 mg/kg (n=3), 150 mg/kg (n=4), and 300 mg/kg (n=3). (2) Rat islet recipients became uniformly severely diabetic after alloxan i.v. doses of 50-70 mg/kg (n=6) (i.e., equivalent to the dosage needed to induce diabetes in rats). (3) Control nude mice were severely diabetic at doses of 75 mg/kg (4/5) and 150 mg/kg (n=3/3). Alloxan dose-response studies were also performed in tilapia. Interestingly, tilapia appeared more sensitive than tilapia islet grafts. Although 75 mg/kg i.v. had little effect in tilapia, higher doses caused severe beta cell necrosis, diabetes, and systemic damage; however, this seeming discrepancy can be explained as tilapia have about one-quarter of the blood volume of mice (i.e., as a percentage of body weight) and so the actual concentration in the blood was about 4-fold higher at each dose. We conclude that tilapia beta cells are highly resistant to the beta cell toxin alloxan.

Alloxan↗