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Biomedical subjects

John P Dowling

Publications and source records attributed to John P Dowling.

11 recordsLinked to original sources
PubMed2006

Distinct clinical and pathological features are associated with the BRAF(T1799A(V600E)) mutation in primary melanoma.

The BRAF(T1799A) mutation encodes BRAF(V600E) that leads to activation of the mitogen-activated protein kinase pathway. This study aimed to assess the clinico-pathological features of primary invasive melanomas containing the BRAF(T1799A) mutation. Patients (n=251) with invasive primary melanomas from Australia were interviewed and examined with respect to their melanoma characteristics and risk factors. Independent review of pathology, allele-specific PCR for the BRAF(T1799A) mutation, immunohistochemical staining with Ki67, and phospho-histone-H3 (PH3) were performed. The BRAF(T1799A) mutation was found in 112 (45%) of the primary melanomas. Associations with the BRAF(T1799A) mutation (P<0.05) were as follows: low tumor thickness (odds ratio (OR)=3.3); low mitotic rate (OR=2.0); low Ki67 score (OR=5.0); low PH3 score (OR=3.3); superficial spreading melanoma (OR=10.0); pigmented melanoma (OR=3.7); a lack of history of solar keratoses (OR=2.7); a location on the trunk (OR=3.4) or extremity (OR=2.0); a high level of self-reported childhood sun exposure (OR=2.0); < or =50 years of age (OR=2.5); and fewer freckles (OR=2.5). We conclude that the BRAF(T1799A) mutation has associations with host phenotype, tumor location, and pigmentation. Although implicated in the control of the cell cycle, the BRAF(T1799A) mutation is associated with a lower rate of tumor proliferation.

Adolescent↗
PubMed2006

Rate of growth in melanomas: characteristics and associations of rapidly growing melanomas.

OBJECTIVES: To investigate the spectrum of growth rates in melanomas and to identify clinical associations of rapidly growing melanomas. DESIGN: Clinical interview, skin examination, and pathology review. SETTING: Three tertiary melanoma referral centers and 2 private dermatology practices. PATIENTS: A total of 404 consecutive patients with invasive primary cutaneous melanomas. MAIN OUTCOME MEASURE: A surrogate for rate of growth in primary invasive melanoma was calculated as the ratio of Breslow thickness to time to melanoma development based on a previously reported assessment tool. RESULTS: One third of the melanomas grew 0.5 mm per month or more. The median monthly growth rate was 0.12 mm for superficial spreading melanomas, 0.13 mm for lentigo maligna melanomas, and 0.49 mm for nodular melanomas. Rapid tumor growth was associated with tumor thickness ( 4 mm, GMR = 12.1) and mitotic rate (<1/mm(2), GMR = 1.0; 1-4/mm(2), GMR = 2.9; 5-10/mm(2), GMR = 6.1; and >10/mm(2), GMR = 9.7). Rapid tumor growth occurred more often in males (GMR = 1.7), elderly individuals (>or=70 years old, GMR = 2.8), and patients with fewer melanocytic nevi (n<50, GMR = 2.0) and fewer freckles (GMR = 2.5). Rapidly growing melanomas were more often symmetrical (GMR = 2.5), elevated (GMR = 1.4), amelanotic (GMR = 1.7), regular in border (GMR = 2.5), and symptomatic (GMR = 1.7). CONCLUSIONS: Rapid growth of primary cutaneous melanomas is associated with aggressive histologic features and atypical clinical features. It occurs more frequently in elderly men and individuals with fewer nevi and fewer freckles.

Adolescent↗
PubMed2006

Renal graft rejection after allogeneic peripheral-blood stem cell transplantation.

A 28-year-old woman underwent peripheral-blood stem cell transplantation from her HLA-identical sister for cytogenetic progression of Fanconi anemia. She had received a living-related renal allograft from her father 2 years previously. Nine days after peripheral-blood stem cell transplantation, she developed acute renal failure secondary to acute rejection. Severe microangiopathic hemolysis developed, and cyclosporine therapy was discontinued. Renal biopsy showed humoral rejection and thrombotic microangiopathy. Despite daily plasmapheresis and immunosuppression, she remained dialysis dependent. The renal graft was removed, with rapid resolution of microangiopathic hemolysis. At no stage was there evidence of acute graft-versus-host disease. We speculate that the engrafting third-party hematopoiesis produced acute renal allograft rejection with secondary microangiopathic hemolysis through a graft-versus-graft mechanism.

Acute Kidney Injury↗
PubMed2005

Incidence of new and changed nevi and melanomas detected using baseline images and dermoscopy in patients at high risk for melanoma.

OBJECTIVE: To determine the incidence of new, changed, and regressed nevi and melanomas in a cohort of patients at high risk for melanoma using baseline total body photography and dermatoscopy. DESIGN: Cohort study of patients at high risk for melanoma who underwent baseline cutaneous photography between January 1, 1992, and December 31, 1997, and had at least 1 follow-up visit by December 31, 1998. SETTING: Private practice rooms of 1 dermatologist in conjunction with a public hospital-based, multidisciplinary melanoma clinic in Victoria, Australia. PATIENTS: A total of 309 patients who had at least 1 of the following risk factors for melanoma: personal history, family history, 100 or more nevi, or 4 or more dysplastic nevi. MAIN OUTCOME MEASURES: Number of new, changed, and regressed nevi and melanomas detected and excised during the study interval. RESULTS: The incidence of new, changed, and regressed nevi decreased with increasing age (P<.001), whereas the incidence of melanomas increased (P = .05). The number of dysplastic nevi at baseline was positively associated with the incidence of changed nevi (P<.001) and melanomas (P = .03). The use of baseline photography and dermatoscopy was associated with low biopsy rates and early detection of melanomas. The development of melanoma in association with a preexisting nevus was not directly correlated with a change in a preexisting lesion monitored by baseline photography. CONCLUSIONS: Nevi are dynamic, and only a small percentage of all new and changed melanocytic lesions are melanomas. Patients younger than 50 years had a lower incidence of melanomas and a higher rate of new, changed, and regressed nevi when compared with patients older than 50 years. A new or changed pigmented lesion is more likely to be a melanoma in patients older than 50 years.

Adolescent↗
PubMed2004

Action myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder.

Action myoclonus-renal failure syndrome (AMRF) is a distinctive form of progressive myoclonus epilepsy associated with renal dysfunction. The syndrome was not recognized prior to the advent of dialysis and renal transplantation because of its rapidly fatal course if renal failure is untreated. The first and only description of AMRF was in four French Canadian patients in three families (Andermann et al., 1986). We now describe 15 individuals with AMRF from five countries, including a follow-up of the four French Canadian patients, allowing a more complete characterization of this disease. Our 15 patients with AMRF belong to nine different families. Segregation analyses were compatible with autosomal recessive inheritance. In addition, our findings show that AMRF can present with either renal or neurological features. Tremor (onset 17-26 years, mean 19.8 years, median 19 years) and progressively disabling action myoclonus (onset 14-29 years, mean 21.7 years, median 21 years), with infrequent generalized seizures (onset 20-28 years, mean 22.7 years, median 22 years) and cerebellar features are characteristic. Proteinuria, detected between ages 9 and 30 years in all cases, progressed to renal failure in 12 out of 15 patients within 0-8 years after proteinuria detection. Brain autopsy in two patients revealed extraneuronal pigment accumulation. Renal biopsies showed collapsing glomerulopathy, a severe variant of focal glomerulosclerosis. This study extends the AMRF phenotype, and demonstrates a more extensive ethnic and geographic distribution of a syndrome originally believed to be confined to individuals of French Canadian ancestry. The independent progression of neurological and renal disorders in AMRF suggests a unitary molecular lesion with pleiotropic effects. Our results demonstrate that the renal lesion in AMRF is a recessive form of collapsing glomerulopathy. Genes identified for focal segmental glomerulosclerosis and involved with the function of the glomerular basement membrane and related proteins are thus good candidates. Treatment can improve quality of life and extend the lifespan of these patients. Dialysis and renal transplantation are effective for the renal but not the neurological features, which continue to progress even in the presence of normalized renal function; the latter can be managed with anti-myoclonic and anti-epileptic drugs.

Adolescent↗
PubMed2004

Hepatic failure due to fibrosing cholestatic hepatitis in a patient with pre-surface mutant hepatitis B virus and mixed connective tissue disease treated with prednisolone and chloroquine.

Fibrosing cholestatic hepatitis (FCH) is a severe variant of hepatitis B infection that has until recently been described almost exclusively in the setting of organ transplantation and HIV infection. This case report describes a patient with pre-surface (pre-S) mutant hepatitis B virus (HBV) infection who developed a fatal form of FCH after high dose prednisolone for mixed connective tissue disease (MCTD). The role of corticosteroids and pre-S viral mutation in the pathogenesis of the disease is discussed, and the importance of early diagnosis is emphasised. This report alerts the physician to the need for close monitoring of LFTs and HBV DNA of hepatitis B carriers during immunosuppressive therapy regardless of the indication. As in the transplantation setting, viral DNA levels should be kept to undetectable if viral replication or recurrence is to be prevented.

Adult↗
PubMed2003

Over-expression of platelet-derived growth factor in human diabetic nephropathy.

BACKGROUND: The pathogenetic mechanisms responsible for progressive renal impairment of diabetic nephropathy are still poorly understood, despite its growing incidence. Increasing evidence suggests that growth factors may contribute to the initiation and progressive fibrosis of diabetic nephropathy. In this study, the gene expression and protein distribution of platelet-derived growth factor-A and -B (PDGF-A and PDGF-B) in human diabetic nephropathy were examined. METHODS: PDGF-A and PDGF-B mRNA levels in surplus renal biopsy tissue from seven patients with overt diabetic nephropathy and six nephrectomy samples were examined using quantitative reverse transcription-polymerase chain reaction (RT-PCR). In addition, each sample was also examined immunohistochemically to quantify and localize peptide expression of each PDGF isoform. RESULTS: Gene expression of PDGF-A and PDGF-B mRNA were increased 22- and 6-fold, respectively, in biopsies from patients with diabetic nephropathy compared with control tissue. Immunostaining also demonstrated increased peptide expression of both PDGF-A and PDGF-B in diabetic nephropathy, with each isoform showing a specific pattern of tissue distribution. CONCLUSIONS: The findings of increased gene and protein expression of PDGF in renal biopsies from patients with diabetic nephropathy imply a potential role for this prosclerotic growth factor in the development of the progressive fibrosis that characterizes human diabetic kidney disease.

Diabetes Mellitus, Type 2↗
PubMed2002

Nodular type and older age as the most significant associations of thick melanoma in Victoria, Australia.

OBJECTIVES: To explore the clinical associations of thick melanoma and to compare the clinicopathological variables of nodular and superficial spreading types. DESIGN: Cross-sectional study of all invasive primary melanomas recorded by the Victorian Cancer Registry for 1998 and those reviewed by the Victorian Melanoma Service between October 1, 1994, and April 31, 1999. SETTING: Population-based cancer registry and public hospital-based multidisciplinary melanoma clinic. PATIENTS: This study included 1422 patients recorded by the Victorian Cancer Registry and 674 patients who had attended the Victorian Melanoma Service; unclassifiable tumor types were excluded, leaving 1144 and 645 patients, respectively, eligible for analysis. MAIN OUTCOME MEASURES: Melanomas were categorized by thickness into thin (< or =1 mm), intermediate (>1-3 mm), and thick (>3 mm) and compared according to patient age, sex, and tumor type and site. Superficial spreading and nodular types were also compared in this manner. Use of the Victorian Melanoma Service database enabled a more comprehensive analysis of historical and phenotypic characteristics. RESULTS: Thick melanoma was predominantly nodular, occurring in older men, mostly on the head and neck and associated with fewer nevi. Nodular melanoma was thicker and found mostly on the lower limbs or head and neck; it had a greater association with a history of solar keratoses than did superficial spreading melanoma. CONCLUSION: Nodular type and older age are the most significant associations of thick melanoma.

Age Factors↗
PubMed2002

Idiopathic calciphylaxis.

A 68-year-old woman presented with a painful necrotic ulcer on her right calf and necrotic breakdown of a left below-knee amputation stump as a result of calciphylaxis. No cause could be identified and corrected. Treatment comprised wound care, substituting low molecular weight heparin for warfarin, hyperbaric oxygenation and etidronate disodium, none of which were helpful and major limb amputations were considered the best option for this patient.

Aged↗