Processing and metabolism of beta-amyloid precursor protein (APP) and generation of a variety of beta-amyloid (Abeta) peptides in the human brain is essentially associated with pathophysiology of Alzheimer's disease (AD). APP degradation activity of the 68 kDa serine protease, which was originally prepared from familial AD lymphoblastoid cells and harbors beta-secretase-like activity, was analyzed by Western blot using anti Abeta 1/40 antibody and anti APP cytoplasmic domain (CT) antibody. Native lymphocyte APP (LAPP) prepared from normal or AD-derived lymphoblastoid cells was degraded by the protease, generating a 16 kDa Abeta-bearing C-terminal fragment of APP. N-terminal amino acid sequencing of the fragment indicated that the protease cleaves LAPP at the Abeta-N-terminus. When the LAPP was treated with chondroitinase ABC prior to proteolysis, the activity to generate the fragment was inhibited, but pretreatment with heparitinase resulted in no effect. Native hippocampal APP prepared from normal brain, however, did not generate the 16 kDa peptide by the protease treatment. These results suggest that the process of APP degradation and Abeta-peptides generation, including beta-secretase activity, is associated with tissue specificity of both APP substrate and proteases. They also indicate that sulfated glycoconjugates attached to a portion of APP isoforms may play a role as a molecular determinant in the proteolysis.
Americium-241 (²4¹Am) is the second most significant radiation hazard after ²³?Pu at some of the Mayak Production Association facilities. This study summarizes current data on the accumulation, distribution, and excretion of americium compared with plutonium in different organs from former Mayak PA workers. Americium and plutonium were measured in autopsy and bioassay samples and correlated with the presence or absence of chronic disease and with biological transportability of the aerosols encountered at different workplaces. The relative accumulation of ²4¹Am was found to be increasing in the workers over time. This is likely from ²4¹Pu that increases with time in reprocessed fuel and from the increased concentrations of ²4¹Am and ²4¹Pu in inhaled alpha-active aerosols. While differences were observed in lung retention with exposures to different industrial compounds with different transportabilities (i.e., dioxide and nitrates), there were no significant differences in lung retention between americium and plutonium within each transportability group. In the non-pulmonary organs, the highest ratios of ²4¹Am/²4¹Am + SPu were observed in the skeleton. The relative ratios of americium in the skeleton versus liver were significantly greater than for plutonium. The relative amounts of americium and plutonium found in the skeleton compared with the liver were even greater in workers with documented chronic liver diseases. Excretion rates of ²4¹Am in ‘‘healthy’’ workers were estimated using bioassay and autopsy data. The data suggest that impaired liver function leads to reduced hepatic ²4¹Am retention, leading to increased ²4¹Am excretion.
The occurrence of acute leukaemia and other secondary neoplasms in 432 patients treated with conventional chemotherapy for multiple myeloma was analysed after a follow-up period of 11-19 yr (mean 16 yr). The number and organ-specific distribution of observed solid neoplasms was close to that expected in the general population. Non-Hodgkin's lymphoma developed in three patients (expected 0.7, p = 0.19). Acute leukaemia was diagnosed in 14 patients with an actuarial risk of 9.8% at 9 yr. No further cases were diagnosed thereafter. The average numbers of courses (26.2 vs. 25.5) and cumulative doses of melphalan (1440 and 1400 mg) were similar in patients with or without acute leukaemia. It seems possible that the advanced stage of multiple myeloma is more vulnerable to the leukaemogenic effect of melphalan compared with the earlier stages.
Immigrants from South Asia to Western countries have a high prevalence of type 2 diabetes mellitus (T2DM) associated with obesity. We investigated the relationship between diabetes and adipose tissue distribution in a group of younger T2DM subjects from Norway and Pakistan. Eighteen immigrant Pakistani and 21 Norwegian T2DM subjects (age 29-45, 49% men) were included. They underwent anthropometrical measurements including bioelectrical impedance analysis, CT scans measuring fatty infiltration in liver and adipose and muscle tissue compartments in mid-abdomen and thigh, a euglycemic clamp, and blood samples for serum insulin and plasma glucose, adipokines and inflammation markers. Adipose tissue distribution was similar in Norwegians and Pakistanis. Pakistanis, but not Norwegians, showed a negative correlation between insulin sensitivity and visceral adipose tissue (VAT, rs = - 0.704, p = 0.003). Subcutaneous adipose tissue (SAT) correlated to leptin in both Pakistanis and Norwegians (rs = 0.88, p
Age peculiarities of cadmium cumulation in the organs of rats under different conditions of antioxidants administration. Considerable hepato- and nefrotoxic effect of the given xenobiotic under different conditions of its supply into the organism was revealed. The strongly pronounced differences between the age distribution of cadmium in the organisms have been marked. It is proved that the most antioxidantal activity is shown by sodium selenite when administered into the organism before poisoning with cadmium. It is stated that the indices showing the acid-alkaline state are subject to the greatest changes in the bodies of young animals. In this case they have more expressed toxic effects under the influence of ions of heavy metals as well as the receptivity to the positive influence of antioxidants.
Since the report of a double mutation at codons 670 and 671 of the amyloid precursor protein (APP) gene identified in two Swedish families with clinically diagnosed Alzheimer's disease (AD), a carrier with dementia has died. Neuropathology confirmed the clinical diagnosis of AD. Genealogical investigations have confirmed that the two families are related to common founders. Two-point linkage analysis of the mutation versus the disease in the revised pedigree now gives a lod score of 7.62.
An experimental rat model to study acute cytomegalovirus infections is described. Eight-week old male Brown Norway rats, immunosuppressed by total body irradiation, were infected with rat cytomegalovirus (RCMV). The effects of infection were determined by survival rates and the presence of virus or viral components in different organs was assayed by plaque test, immunoperoxidase staining, dot-blot DNA hybridization and in situ DNA hybridization. At days 10-post infection nearly 90% of the animals had died. Spleen, liver and bone marrow were heavily infected. Interstitial pneumonia was observed. Pathological findings strongly resembled the full scale of lesions in human CMV infections. Anti-RCMV hyperimmune serum was effective against mortality from RCMV infection and viral spread to lungs and liver was prevented. This model is appropriate for studies on the pathogenesis and antiviral therapy of CMV infections in the immunocompromised host.
An unknown focus of infection is associated with an increased risk of death in patients with bacteraemia. However, the implications for patient management remain uncertain, and to our knowledge, the validity of an unknown focus has not been evaluated. Therefore, we conducted a retrospective record review of bacteraemias with an unknown focus recorded in a regional bacteraemia database. The study cohort comprised 645 cases of bacteraemia diagnosed in 537 hospitalized patients at Aalborg Hospital, Denmark, in 2003. The focus was unknown in 184 (29%) bacteraemia episodes (162 patients). The record review pointed conclusively to a focus in 39 episodes. The positive predictive value of an unknown focus was 79% and the proportion of bacteraemias with a focus increased from 71% to 78%. Among the 145 cases of bacteraemia with a de facto unknown focus, there were 36 incidents of febrile neutropenia and 20 additional incidents of early death which precluded a search for a focus. The study confirmed the focus to be de facto absent in most patients classified with an unknown focus. The distribution of foci changed only marginally by the disclosure of a focus in one of five patients in the 'unknown' group.
Tissues from healthy subadult and moribund newborn northern fur seals (Callorhinus ursinus) on St. Paul Island, Pribilof Islands, Alaska, and from healthy pups and yearlings on San Miguel Island, California, were sampled for bacteria and fungi. Corynebacterium spp. and Staphylococcus spp. were more frequently present in tissues from animals on St. Paul Island whereas Pseudomonas spp. were frequently isolated on San Miguel Island. Approximately half of the blood samples were positive for bacteria. Salmonella spp. were isolated from rectal swabs of animals only on San Miguel Island. Fungi were isolated from the hair and skin of subadult males.