A Novel von Hippel Lindau Gene Intronic Variant and Its Reclassification from VUS to Pathogenic: the Impact on a Large Family.

We present a case where a variant of uncertain significance in the von Hippel Lindau syndrome gene (VHL) was identified in a proband with haemangioblastoma, and in a second degree relative with phaeochromocytoma. Initial uncertainty due to the unclear nature of the variant created psychosocial challenges for this family, in which four other genetic conditions were also present. Subsequent RNA studies confirmed this as a novel pathogenic mutation affecting splicing of exon 2. A third relative has since been diagnosed with haemangioblastoma. We suggest that this mutation possibly has reduced penetrance as there was no history of haemangioblastoma, renal tumours (apart from small cysts) or other VHL tumours among five mutation positive and seven untested adult relatives at 50 % risk of the VHL mutation (average age 46 years, range 18-70 years). This case presents a novel VHL splicing mutation and highlights the psychosocial and medical value of additional laboratory studies on uncertain variants for individuals, their families and for the health professionals providing advice and counseling.

Predictive genetic testing of a bone marrow recipient-ethical issues involving unexpected results, gender issues, test accuracy, and implications for the donor.

We present a case where an apparently straightforward Lynch syndrome predictive genetic test of DNA from a blood sample from a woman yielded an unexpected result of X/Y chromosome imbalance. Furthermore, it demonstrates the complexities of genetic testing in people who have had bone marrow transplants. This highlights the potential for multiple ethical and counselling challenges, including the inadvertent testing of the donor. Good communication between clinics and laboratories is essential to overcome such challenges and to minimise the provision of false results.

Treatment of myelodysplasia with oral cyclosporin.

Recent studies have shown a good response to immunosuppressive treatment with cyclosporin A (CSA) in patients with the myelodysplastic syndrome (MDS). We have treated six transfusion-dependent MDS patients with CSA for a minimum of 3 months. None of these patients showed a significant response, while the drug was withdrawn in 3/6 patients because of intolerable side-effects. Two reasons for the failure of this treatment in our patients can be advanced. Firstly, the hypoplastic variant of MDS predominated in previous studies in contrast to ours. Secondly, the concomitant use of other immunosuppressive agents in previous studies might have enhanced the effect of CSA. We suggest further therapeutic trials of CSA in MDS, selecting patients on the basis of in vitro studies that predict an immunological basis for their disease, to assess its efficacy in prolonging survival.

Novel phosphonium salts display in vitro and in vivo cytotoxic activity against human ovarian cancer cell lines.

Phosphonium salts are part of a class of lipophilic cationic molecules that accumulate preferentially in mitochondria and inhibit the growth of human and rodent carcinoma cells in vitro and in animal models. The delocalized cations tested previously such as dequalinium have exhibited considerable cross resistance against multiple drug-resistant cells expressing gp 170. In order to overcome this cross resistance, we have developed two novel phosphonium salts which contain haloalkyl moieties with potential protein alkylating capabilities. 3-Chloropropyltris(4-dimethylaminophenyl)phosphonium chloride (APPCL) and 3-iodopropyltris(4-dimethylaminophenyl)phosphonium iodide (APPI) are more lipophilic than other phosphonium salts described to date. By comparing the 50% inhibitory concentration (IC50) values for the A2780 human ovarian carcinoma parental line to a multiple drug-resistant variant (A2780-DR), the degree of cross resistance (IC50 for A2780-DR/IC50 for A2780 Parental) were found to be 494 for doxorubicin, but only 2.7 for APPCL. Similarly, the degree of cross resistance using a cisplatin-resistant variant (IC50 for A2780-CR/IC50 for A2780 Parental) was 30 for cisplatin, but only 2.2 for APPCL. APPCL is also active in vitro against UCI 101 (IC50 = 80 nM), an ovarian carcinoma line isolated from a patient who had failed chemotherapy with taxol, doxorubicin, and high-dose cisplatin. The cytotoxicity of APPI was comparable to that of APPCL with an IC50 ranging from 16.7 to 83.0 nM for a panel of seven cell lines. When administered intraperitoneally at a total dose of 46 mg/kg over 15 days, APPCL increased the median lifespan of nude mice bearing UCI 101, from a control value of 48.0 to 92.5 days (P < 0.0061). The median survival of the APPI-treated mice was 55 days. A total of 37.5% of the APPCL-treated group and 12.5% of the APPI-treated group were long-term survivors: sacrifice of these mice on Day 180 and subsequent histology showed no evidence of disease. Exposure to APPCL and APPI caused mitochondrial damage to UCI 101 cells at sublethal doses in vitro, as shown by morphological damage observed with transmission electron microscopy. APPCL appears to decrease the uptake of rhodamine 123 by mitochondria, suggesting that mitochondria may be significant targets or initial reservoirs for this agent. In conclusion, APPI and APPCL show promising anticancer activity against a variety of human ovarian carcinoma cell lines warranting further investigation.

Segmental ulcerative colitis: a case report and review of the literature.

Ulceractive colitis, a chronic diffuse inflammatory disease affecting the mucosa of the colon and rectum, is characterized by ulcerations with bleeding, mucosal crypt abscesses, and inflammatory pseudopolyps. Classically, it begins in the rectosigmoid but often extends to involve the entire colon. It is uncommon to find segmental involvement sparing the rectosigmoid.A case of segmental ulcerative colitis is presented with a brief comparison of segmental ulcerative colitis and segmental Crohn's colitis.