The graph shows the cumulative number of preparations administered to patients, with the amount of IVIG received during 5 days resulting in a mean of 1571 mg total (active and latent) TGF-beta (52% TGF-beta 1, 48% TGF-beta 2). The presence of TGF-beta in substantial amounts in commercially available IVIG preparations suggests that immunoglobulin acts as a carrier for TGF-beta. Although our experiments did not show adherence of TGF-beta to IgG, the methods for manufacturing and long-term storage of IVIG may facilitate dissociation of TGF-beta non-specifically bound to IgG. Animal studies have shown that the administration of TGF-beta led to increased immunosuppression similar to that seen under IVIG therapy, supporting the inference that TGF-beta contributes to the therapeutic effects of IVIG therapy in autoimmune diseases. However, the value of TGF-beta-containing IVIG preparations in treating other disorders is unknown and needs further clinical trials comparing IVIG preparations with and without TGF-beta or applying TGF-beta alone.

In examining the hypothesis that mtDNA mutations contribute to longevity, we sequenced the entire coding regions of mtDNA from Japanese centenarians and identified several nucleotide substitutions more frequent in these centenarians than in controls. Among these variations, we focused on Mt5178A and screened for its presence in centenarians and healthy blood donors. The frequency of Mt5178A was significantly higher in centenarians than in blood donors, suggesting its relation to longevity. In analysing the frequencies of Mt5178A and Mt5178C in patients at Nagoya University Hospital, we found that patients with Mt5178C are more susceptible to adult-onset diseases than those with Mt5178A. This suggests that individuals with Mt5178C are more susceptible to degenerative diseases and shorter life spans.Maternally transmitted mitochondrial genotypes influence oxidative damage to mtDNA, the accumulation rate of mtDNA mutations, and susceptibility to degenerative diseases. Cann et al reported, in their study on human evolution, that among 147 samples from the world, only five Asians and one European carried Mt5178A. This observation indicates that Mt5178A is relatively rare among the global population. The high frequency of Mt5178A among the Japanese population (45%) may be relevant to the fact that life expectancy at birth in Japan is among the highest on Earth, with females living up to 83 years and males up to 77 years. Our findings support the concept that carrying an mtDNA genotype predisposing resistance to adult-onset diseases is one of the genetic factors for longevity. Further studies are needed to clarify the functional differences between these mtDNA variations. It will also be interesting to identify those adult-onset diseases to which individuals with Mt5178C are susceptible. Supported in part by the programme Grants-in-Aid for Priority Areas of the Ministry of Education and Science and Culture of Japan, and a grant from Ministry of Health and Welfare to MT. We thank Ko Sahashi, Hiroaki Miyajima, Tadashi Kamiya, and Kazunobu Yamauchi.

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Brand F, Kiely D, Kannel W, Myers R. Family patterns of coronary heart disease mortality: the Framingham longevity study. J Clin Epidemiol; :
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Edetic acid 10-2 mol/L, clavulanate 10-3 mol/L, 1=metallo-enzyme from Stenotrophomonas maltophilia, TEM-1=class A enzyme. Experiments with ethidium bromide were used to determine if imipenem resistance was plasmid-mediated. Susceptibility tests and IEF were carried out on cured colonies.

Department of Gene Therapy (M Tanaka), Gifu International Institute of Biotechnology, Yagi Memorial Park, Mitake, Gifu 505-0116, Japan. Strain 1622 was resistant to all antibiotics tested, including imipenem (MIC 16 mg/L). The addition of enzyme inhibitors, including sulbactam which is usually intrinsically active against Acinetobacter spp., did not reduce carbapenem MIC values. IEF detected the presence of a novel β-lactamase designated ARI-2 (main band of pI 6.5). Enzyme activity was inhibited by clavulanate and BRL 42715 but not edetic acid (shown by IEF inhibitor overlays), indicating that ARI-2 was a class A β-lactamase rather than a metallo-enzyme (figure). Strain 1622 inactivated imipenem as detected by the microbiological assay. Slow imipenem hydrolysis was calculated by the modified microbiological assay (0.75 nmol min-1 mL-1). After plasmid curing, the ARI-2 enzyme was lost from strain 1622, detected by IEF. There was also more than a tenfold decrease in the rate of imipenem hydrolysis (0.067 nmol min-1 mL-1), as well as a reduction in carbapenem MIC values to susceptible levels, which strongly linked ARI-2 with plasmid-encoded carbapenemase activity.