[Mitochondrial A1555G mutation. Molecular genetic diagnosis in sporadic cases of non-syndromic hearing impairment]. / Mitochondriale A1555G-Mutation. Molekulargenetische Diagnostik bei sporadischen Fällen nichtsyndromaler Schwerhörigkeit.

BACKGROUND: The A1555G mutation in mitochondrial DNA is the cause of hearing impairment in about 50% of all carriers. The severity and onset of this impairment is predominantly affected by the use of aminoglycosides. PATIENTS AND METHODS: A total of 391 patients displaying sporadic, non-syndromic, mild to severe hearing impairment were analyzed for the A1555G mutation using molecular genetic methods. RESULTS: We analysed additional family members of the two patients (0.5% of the total) who had the mutation. All maternal relatives carried the mutation, but only three individuals from the two families displayed a variable sensorineural hearing loss. CONCLUSION: The A1555G mutation is infrequently involved as a genetic cause of sporadic, non-syndromic hearing impairment. Nevertheless, based on the variable clinical outcome of hearing impairment and the possibility of preventive steps, a genetic test in this patient subgroup is indicated.

A comparative map of chicken chromosome 24 and human chromosome 11.

To improve the physical and comparative map of chicken chromosome 24 (GGA24; former linkage group E49C20W21) bacterial artificial chromosome (BAC) contigs were constructed around loci previously mapped on this chromosome by linkage analysis. The BAC clones were used for both sample sequencing and BAC end sequencing. Sequence tagged site (STS) markers derived from the BAC end sequences were used for chromosome walking. In total 191 BAC clones were isolated, covering almost 30% of GGA24, and 76 STS were developed (65 STS derived from BAC end sequences and 11 STS derived within genes). The partial sequences of the chicken BAC clones were compared with sequences present in the EMBL/GenBank databases, and revealed matches to 19 genes, expressed sequence tags (ESTs) and genomic clones located on human chromosome 11q22-q24 and mouse chromosome 9. Furthermore, 11 chicken orthologues of human genes located on HSA11q22-q24 were directly mapped within BAC contigs of GGA24. These results provide a better alignment of GGA24 with the corresponding regions in human and mouse and identify several intrachromosomal rearrangements between chicken and mammals.

Kaposi's sarcoma in HIV infection: impact on opportunistic infections and survival.

OBJECTIVE: To determine the effect of Kaposi's sarcoma on survival of HIV-infected patients. METHODS: Retrospective cohort study to compare the survival of 241 HIV-infected homosexual patients with Kaposi's sarcoma (cases) with that of 241 HIV-infected homosexual patients without Kaposi's sarcoma (control subjects) but with a similar level of immunosuppression (measured by the absolute CD4+ lymphocyte count). RESULTS: Cases and control subjects were similar in age, occurrence of previous opportunistic infections, and the use of antiretroviral therapy. The mean CD4+ lymphocyte counts were similar for cases and control subjects (185 x 10(6) versus 184 x 10(6)/l, respectively). Cases had a higher incidence of opportunistic infections (5.95 versus 3.88 infections, respectively, per 100 person-months of observation) and a greater number of infections typical of late-stage HIV infection. Cases had a shorter overall survival than did control subjects (P=0.0025). Kaposi's sarcoma was associated with an increased risk of death (odds ratio, 1.28), even when adjusting for age, previous opportunistic infection, baseline CD4+ lymphocyte count, and antiretroviral therapy. CONCLUSION: Kaposi's sarcoma appears to accelerate the clinical course of HIV infection. Opportunistic infections develop earlier and more often in patients with the disease than in control subjects. Survival was significantly shorter in patients with Kaposi's sarcoma.

Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy.

OBJECTIVE: To determine the incidence of AIDS-defining opportunistic infections and malignancies over a 5-year period from 1992 to 1996. STUDY POPULATION: Subcohort of 1003 homosexual men with HIV infection and CD4 count less than 200 x 10(6) cells/l from the Frankfurt AIDS Cohort Study. METHODS: Data including the earliest date that a CD4 T-lymphocyte count < 200 x 10(6)/l was reached and the dates of AIDS-defining events were compiled from medical records. Incidence analyses for AIDS-defining events and death during the subsequent 5 years (1992-1996) were performed using rates per 100 person-years of exposure. RESULTS: During the observation period, the number of patients per year with CD4 T-lymphocyte counts < 200 x 10(6)/l varied between 402 and 511. In 1992, 56.7% of patients experienced at least one AIDS-defining illness, and 20.7% in 1996. The annual number of AIDS-defining events per 100 patient-years of observation declined from 143.5 in 1992 to 38.3 in 1996, and the number of AIDS-related deaths fell from 25.7 to 12.9. Analysis of the number of events confirmed this trend for malignancies and single opportunistic infections, with the exception of mycobacterial diseases. CONCLUSIONS: The incidence of AIDS-defining events in patients with advanced HIV infection at Frankfurt University Hospital has declined by more than 70% from 1992 to 1996.

Impact of disseminated Mycobacterium avium-complex infection on survival of HIV-infected patients.

OBJECTIVE: To determine the frequency of disseminated Mycobacterium avium-complex infections (MAC) and the impact of MAC disease on overall survival in patients with HIV disease and AIDS. METHODS: Prospective study of HIV infected patients with a CD4 lymphocyte count < 150/microliter or patients with AIDS over a 7-year period. Blood cultures of all patients presenting symptoms and signs suggestive of disseminated MAC infection were grown. Only patients who deceased at our clinic (n = 427) were included in the final analysis in order to calculate MAC disease-free survival and overall survival after first CD4 lymphocyte count < 100/microliter. RESULTS: 101 out of 427 patients (24%) developed disseminated MAC disease: The median time between first CD4 lymphocyte count < 100/microliter and MAC disease was 441 days (range 16 to 1560). The actuarial risk of MAC disease for the entire patient population was 12%, 28%, and 42% after 1, 2, and 3 years, respectively. When comparing overall survival after first CD4 lymphocyte count < 100/microliter, there was no statistically significant difference between patients who subsequently developed disseminated MAC infection and those who did not. CONCLUSION: MAC disease is a very frequent opportunistic infection in advanced AIDS, mostly in patients with less than 50 CD4 cells/microliter. In contrast to reports from the US, only 24% of our patients developed MAC disease. Survival time between patients with and without MAC infection did not differ.

The influence of immobilization versus exercise on scar formation in the rabbit patellar tendon after excision of the central third.

There is much discussion about the appropriate timing and intensity of rehabilitation after reconstruction of the anterior cruciate ligament with a patellar tendon autograft. The purpose of this study was to look at two extremes (complete immobilization and vigorous, forced exercise) on the extent of scar formation and mechanical properties of the host tendon. Three groups of six Flemish Giant rabbits had the central third patellar tendon removed in one limb. Group I was sacrificed immediately after surgery. Group II was exercised on a treadmill for 12 weeks. In Group III the limb was immobilized for 12 weeks. After 3 months, average length and cross-sectional area from Group II were greater than those of the controls and Group III tendons. Structural properties of all tests limbs were similar to each other but different from controls. Tensile modulus of Group III tendons did not decrease as much that of Group II tendons. Histology revealed a clear demarcation between the central defect and host tendon in Group III, whereas Group II tendons remodeled throughout their cross-sections. We propose that early joint mobility produces large multiaxial stresses in original tendon leading to microdamages and repair processes within the entire host tissue. Less aggressive exercise or delay in joint mobility may help control tissue remodeling.

AIDS-free survival and overall survival in HIV infection: the new CDC classification system (1993) for HIV disease and AIDS.

The clinical history of 1538 HIV positive patients was analyzed on the basis of the new CDC classification system of HIV disease and AIDS. This classification system combines three CD4 cell categories (1, 2, and 3) with three clinical categories (A, B, and C) into nine subgroups A1-C3. We examined the overall survival for all subgroups and the AIDS-free survival for subgroups A1-B3. AIDS-free survival for patients in subgroups A1, A2, and B1 was considerably longer than survival in patients from subgroups A3, B2, and B3 (P < 0.0001). According to these findings, the new CDC classification system could be simplified into three stages, stage I and II comprising the above mentioned six subgroups, and stage III comprising clinical AIDS defining categories C1, C2, and C3. These three stages correspond to different periods in the management of HIV positive patients, i.e., period of observation, period of prophylaxis, and period of treatment.

Heterosexual transmission of HIV in hemophiliacs.

Of 686 hemophiliacs who are being treated at our institution, 402 (59%) are HIV-sero-positive. One hundred seventy-eight heterosexual partners of HIV-infected hemophiliacs have been serologically examined; 19 (11%) are HIV-positive. So far none of the seropositive partners suffers from ARC or AIDS. The rate of heterosexual transmission of HIV is statistically significantly correlated with the CD4+ count of the HIV-infected index patient. No such correlation was found with the index patient's clinical stage or the isolation of HIV from the index patient's blood. Of 39 seronegative female partners who were investigated clinically and immunologically, 17 showed pathologically increased numbers of CD8+ counts. In one case, HIV was transmitted from a female patient with von Willebrand's disease to her husband. As compared to other groups at risk for AIDS, the rate of heterosexual HIV transmission is comparatively low in hemophiliacs. The exact reason for this difference is not yet known. The relevance of the immunopathological findings in seronegative sexual partners of hemophiliacs also remains to be determined.

Natural history of HIV-infection in hemophiliacs: clinical, immunological, and virological findings.

At our institution 686 hemophiliacs are being treated. Of them 402 (59%) are anti-HIV-seropositive. The general use of heat-treated clotting factor products was begun in July 1983, and from May 1984 all patients exclusively used heat-treated clotting factors. Thus, one can assume that infection occurred no later than early 1984 in our patients. Since December 1985 HIV-positive hemophiliacs have regularly been clinically and immunologically examined. Most of the 306 patients who could be investigated were clinically symptom-free at the time of their first visit. However, 45 patients have developed AIDS from 1982 through August 1988. The mean survival time of hemophiliacs with AIDS is less than 6 months. In 36% of those 274 patients who have been followed for a mean period of 14 months the clinical stage of the disease worsened by at least one stage according to the classification system proposed by the Centers for Disease Control. We did not find a correlation between clotting-factor consumption during the years 1984-1986 and the actual clinical stage of the patients. Virus isolation from peripheral blood lymphocytes (PBIs) answered the question whether anti-HIV seropositive hemophiliacs are not only immunized but really infected in many more cases than those revealed by detection of p24 antigen or decline of p24 antibody. Positive viral culture correlated strongly with a drop in CD4+ lymphocytes under the level of 400/microliters. However, HIV could not be cultured regularly in advanced cases, suggesting that virus replication in PBLs is not necessarily the cause of depletion of T-helper cells.(ABSTRACT TRUNCATED AT 250 WORDS)