Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome

By using comparative genomic hybridization (CGH), we characterized the genetic profiles of 36 VHL-related pheochromocytomas. We then compared the results with those of sporadic and MEN 2-related pheochromocytomas. In 36 VHL-related tumors, loss of chromosome 3 and chromosome 11 were found in 34 tumors (94%) and 31 tumors (86%), respectively. There was significant concordance of deletions in chromosomes 3 and 11 (Kappa=0.64, P=0.0095), suggesting that they are involved in two different but necessary and complementary genetic pathways. The loss of chromosome 11 appeared to be specific for VHL-related pheochromocytoma as it was not present in any of the 10 VHL-related CNS hemangioblastomas studied and was significantly less common when compared with (a) sporadic pheochromocytomas from previously published results (13%; P=<0.0001), and (b) MEN 2-related pheochromocytomas from this and previously published studies (30%; P=0.0012). In summary, this is the first report of a novel consistent genetic alteration that is selected and specific for VHL-related pheochromocytoma, besides the two hits of the VHL gene.     

Local instillation of Staphylococcus aureus peptidoglycan at operation prevents wound healing impairment after trauma

BACKGROUND: Considerable experimental evidence and limited clinical evidence indicate that wound healing is impaired after trauma. Because Staphylococcus aureus peptidoglycan (SaPG) accelerates healing in normal rats and prevents wound healing impairment induced by glucocorticoids, cyclophosphamide, and streptozotocin-diabetes, we hypothesized that SaPG would prevent the impaired wound healing after trauma. METHODS: In each of two experiments, 18 Sprague-Dawley male rats were divided into two groups, nine rats each, paired by weight; one group received unilateral comminuted femoral fracture and wounding (two dorsal skin incisions and six subcutaneous polyvinyl alcohol [PVA] sponges), and the other group was only wounded. The incision and PVA sponges on one side were inoculated at operation with saline (200 microL/incision, 50 microL/sponge) and on the other side with SaPG in saline (860 microg of SaPG per centimeter of incision, 0.5 mg of SaPG per sponge). Rats ate chow and drank tap water ad libitum and were killed 7 days postoperatively. RESULTS: In both experiments, the wound breaking strength (WBS) of saline-inoculated incisions was significantly lower in rats with femoral fracture; histologically, reparative granulation tissue was looser and less prominent. WBS of SaPG-inoculated incisions in rats with and without femoral fracture was significantly higher than that of saline-inoculated incisions and, histologically, reparative tissue was more prevalent, more closely packed, and more mature. WBS of SaPG-inoculated incisions in rats with femoral fracture was similar to that of saline-inoculated incisions in rats without femoral fracture. Reparative tissue hydroxyproline and histologic findings of saline-inoculated PVA sponge reparative tissue were similar in all rats, as were the increases induced by SaPG inoculation. CONCLUSION: Wound breaking strength and histologic findings of skin incisions (impaired in rats with unilateral femoral fracture) are more sensitive to the adverse effects of trauma than accumulation of PVA sponge reparative tissue. A single inoculation of SaPG at operation increased wound incision healing in rats both without and with femoral fracture and notably prevented the impaired healing in rats with femoral fracture.     

Altered expression of members of the IGF-axis in clear cell renal cell carcinoma

Renal cell carcinoma (RCC) is a heterogeneous disease and its biology is poorly understood. The commonest subtype identified is clear cell RCC. The insulin-like growth factor axis is intimately involved with many cellular roles including that of renal development. Dysregulation of this axis has frequently been demonstrated in cancer. In this study, we examine the expression of several IGF-axis components, including receptors, ligands, and binding proteins in clear cell renal cell carcinoma. A series of clear cell RCCs with matched normal kidney from the same individuals were obtained. Total RNA was extracted and expression levels of genes examined using RNase protection analysis. We confirm the dysregulation of the IGF-axis within clear cell renal cell carcinoma including the upregulation of IGFBP-3, which is further validated by immunohistochemical staining on a tissue array containing 50 RCC: positive staining in 29/30 clear cell; 1/10 papillary and 0/10 chromophobe. In addition, we demonstrate that the expression of the A isoform of the insulin receptor is significantly upregulated, while that of IGFBP-5 are significantly downregulated in this tumour subtype.     

Development and preliminary validation of a systemic lupus erythematosus-specific quality-of-life instrument (SLEQOL)

OBJECTIVES: Systemic lupus erythematosus (SLE), a chronic illness with an unpredictable and variable course, profoundly affects the quality of life (QOL). General health questionnaires are used to assess QOL in SLE, but a disease-specific instrument could offer enhanced responsiveness and content validity. We detail the steps we took to develop and validate a new SLE-specific QOL instrument, SLEQOL. METHODS: Rheumatology professionals nominated items that they felt were important determinants of QOL of SLE patients. One hundred SLE patients were asked to assess the importance and frequency of occurrence of these items and to suggest those that had not been listed. Item reduction was performed using Rasch model and factor analyses to create a new questionnaire in English. This final questionnaire was administered to a cohort of 275 patients to study its psychometric properties. RESULTS: Fifty-one items covering a wide range of QOL concerns were identified. The patients' responses led to the elimination of 11. The new questionnaire of 40 items was found to have Cronbach's alpha of 0.95 and to consist of eight domains covering physical, mental and social QOL issues. It has good test-retest reliability, poor to fair cross-sectional correlation with the SF-36, with poor correlation with lupus activity or damage indices. The SLEQOL was more responsive to change than the SF-36. CONCLUSIONS: We have developed a new 40-item SLEQOL in English and showed that it is valid for use in SLE patients in Singapore. It offers better content validity and responsiveness to change than the SF-36.     

A novel T cell receptor transgenic animal model of seborrheic dermatitis-like skin disease

We have characterized a novel animal model of the common inflammatory skin disease seborrheic dermatitis (SD) that involves the expression of the self-specific 2C transgenic T cell receptor on the DBA/2 genetic background. Opportunistic fungal pathogens are present in the primary histological lesions and severe disease can be mitigated by the administration of fluconazole, demonstrating a role for infection in disease pathogenesis. Spontaneous disease convalescence occurs at 70-90 d of age and is preceded by an expansion of CD4+ T cells that partially restores the T cell lymphopenia that occurs in these animals. The adoptive transfer of syngeneic CD4+ T cells into pre-diseased DBA/2 2C mice completely abrogates the development of cutaneous disease. The pattern of disease inheritance in DBA/2 backcrosses suggests that one, or a closely linked group of genes, may control disease penetrance. Bone marrow reconstitution experiments demonstrated that the DBA/2 susceptibility factor(s) governing disease penetrance is likely non-hematopoietic since bone marrow from disease-resistant 2C mice can adoptively transfer the full disease phenotype to non-transgenic DBA/2 animals. This model implicates fungal organisms and CD4+ T cell lymphopenia in the development of a SD-like condition and, as such, may mimic the development of SD in acquired immunodeficiency syndrome.     

Genetic influences in the aetiology of tears of the rotator cuff. Sibling risk of a full-thickness tear

From a retrospective, cohort study of 205 patients diagnosed with full-thickness tears of the rotator cuff, we determined, using ultrasound, the prevalence of such tears in their 129 siblings. Using 150 spouses as controls, the relative risk of full-thickness tears in siblings versus controls was 2.42 (95% CI 1.77 to 3.31). The relative risk of symptomatic full-thickness tears in siblings versus controls was 4.65 (95% CI 2.42 to 8.63). The significantly increased risk for tears in siblings implies that genetic factors play a major role in the development of full-thickness tears of the rotator cuff.