Isolated cytochrome c oxidase deficiency as a cause of MELAS.

Deletion of a single nucleotide (7630delT) within MT-CO2, the gene of subunit II of cytochrome c oxidase (COX), was identified in a clinically typical MELAS case. The deletion-induced frameshift results in a stop codon close to the 5' end of the reading frame. The lack of subunit II (COII) precludes the assembly of COX and leads to the degradation of unassembled subunits, even those not directly affected by the mutation. Despite mitochondrial proliferation and transcriptional upregulation of nuclear and mtDNA-encoded COX genes (including MT-CO2), a severe COX deficiency was found with all investigations of the muscle biopsy (histochemistry, biochemistry, immunoblotting). The 7630delT mutation in MT-CO2 leads to a lack of COII with subsequent misassembly and degradation of respiratory complex IV despite transcriptional upregulation of its subunits. The genetic and pathobiochemical heterogeneity of MELAS appears to be greater than previously appreciated.

Anal human papillomavirus testing with Digene's hybrid capture 2 using two different sampling methods.

PURPOSE: The incidence of human papillomavirus detection in the anal canal is rising. Efficient anal screening by cytology is hampered because of poor specificity. Human papillomavirus (HPV) testing is proposed in addition to Papanicolaou (Pap) testing for the detection of cervical neoplasia. The purpose of this study was to determine the usefulness of a human papillomavirus-DNA detection test to detect human papillomavirus-associated disease and to compare two different methods of sample collection. METHODS: In 555 patients, anal samples were obtained by using a cervical brush and a Dacron swab to test for high-risk and low-risk human papillomavirus-DNA. Patients positive for human papillomavirus-DNA underwent anoscopy. Biopsies were taken from visible lesions. RESULTS: Low-risk human papillomavirus-DNA was found in 325 of 555 patients (58.6 percent) and high-risk human papillomavirus-DNA in 285 of 555 patients (51.4 percent). Positive results confined to one single test method were higher for Dacron swab sampling (2.3 vs. 4.3 percent for low-risk human papillomavirus, P < 0.0001; 3.1 vs. 4.9 percent for high-risk human papillomavirus, P < 0.001). A positive correlation of relative light units was found for both sampling methods in the total cohort (P < 0.0001) as well as for patients who tested human papillomavirus-positive by both sampling techniques (P < 0.0001). Sampling with Dacron swabs yielded higher relative light units values compared with sampling with cervical brush for low-risk human papillomavirus-DNA and high-risk human papillomavirus-DNA. CONCLUSIONS: Anal screening for human papillomavirus-DNA by hybrid capture 2 is a useful method for detection of human papillomavirus-associated disease. Sample collection using Dacron swabs identifies more human papillomavirus-positive patients, and yields higher relative light unit values than using the cervical brush. Further studies are needed to determine the exact value of hybrid capture 2 in the screening for (pre)cancerous lesions of the anal canal.

Prevalence of anal HPV infection in solid-organ transplant patients prior to immunosuppression.

Patients that undergo organ transplantation have a high risk of developing various malignancies, depending on the duration and magnitude of immunosuppressive therapy. Among others, a 10-fold increased relative risk has been reported for the development of anal cancer. There is a strong association between persistent infection with high-risk mucosal types of human papillomavirus (HPV) and anogenital neoplasia. In this study we analysed the prevalence of anal HPV infection in organ transplant patients before starting immunosuppressive therapy. In a university transplant unit, patients ( n=60, 40 male, 20 female) that were undergoing solid-organ transplantation (kidney, liver) for the first time were routinely screened for anal HPV infection. Anal swabs were obtained within 24 h after transplantation and analysed for the presence of mucosal-type HPV DNA by liquid DNA/RNA hybridization [hybrid capture (HC) 2 test]. Overall, some type of HPV DNA was detected in 14/60 (23.3%) patients; 9/60 (15%) were positive for high-risk HPV and 8/60 (13.4%) were positive for low-risk HPV, and 3/60 (5%) were positive for both types. Prevalence of HPV infection tended to be higher in patients that were receiving liver transplants than in those receiving kidney transplants (29.4% vs. 20.9%), but the difference did not reach statistical significance. In our series of organ transplant patients the prevalence of previous HPV infection (23.3%) before immunosuppressive therapy was started was higher than that found in previous epidemiological studies or in a control group. In particular, there was a high rate (15%) of infection with oncogenic HPV types. These findings have important implications on screening and surveillance policies in this patient group at risk of developing neoplasias, including anal cancer.

The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNALys gene.

In a case of childhood-onset myoclonus epilepsy with "ragged-red fibers" (MERRF), a hitherto unreported mutation within the mitochondrial tRNA(Lys) gene was identified as the cause of the disease. Substitution G8361A was maternally inherited, heteroplasmic in all tissues tested, and correlated with mitochondrial dysfunction in individual muscle fibers. The growing number of MERRF-associated mutations within the tRNA(Lys) gene affirms the specific role of this mitochondrial tRNA in the pathogenesis of the disease.