DNA adducts, mutant frequencies and mutation spectra in lambda lacZ transgenic mice treated with N-nitrosodimethylamine

Groups of lambda lacZ transgenic mice were treated i.p. with N- nitrosodimethylamine (NDMA) as single doses of 5 mg/kg or 10 mg/kg or as 10 daily doses of 1 mg/kg and changes in DNA N7- or O6-methylguanine or the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) were followed for up to 14 days in various tissues. Adduct induction in the liver exceeded by at least one order of magnitude than observed in the next nearest target tissue (lung), and was approximately linearly related to dose, except for O6-methylguanine after the first dose of 1 mg/kg which was lower than expected. Substantial induction of lambda lacZ mutagenesis was observed only in the liver, where the mutant frequency was already maximal within 7 days after 5 mg/kg NDMA and remained unchanged thereafter up to 49 days. Small but marginally significant increases in mutant frequency were consistently observed in the spleen after all three modes of treatment. A lack of proportionality between mutation induction and the administered dose or the corresponding adduct levels was observed, probably reflecting the importance of toxicity-related cell proliferation caused by NDMA at higher doses. Twenty eight days after a dose of 10 mg/kg (causing a 3.6- fold increase in mutant frequency), NDMA was found to increase the frequency of GC-->AT mutations (with a concomitant shift of their preferential location from CpG sites to GpG sites), which made up approximately 60% of the induced mutations. Surprisingly, NDMA also caused a significant increase in deletions of a few (up to 11) base- pairs (22%).      

Sequential changes in hepatitis A virus genotype distribution in Estonia during 1994 to 2001

Hepatitis A virus (HAV) isolates from a large outbreak and from non-outbreak cases in Estonia were characterized by sequencing the aminoterminal VP1 region. From January 1998 to December 1999, a total of 1084 cases of hepatitis A were reported to the Harjumaa-Tallinn and Ida-Virumaa Health Protection Services in Estonia. The attack rate was highest among males aged 15-29. Initial cases were noted to be associated with injecting drug use. IgM anti-HAV positive sera were available from 107 hospitalized outbreak cases and from 68 patients sampled during 1994 to 2001. HAV RNA was detected in 42% of sera from 1994-1996 and in 88% of sera from 1998-2001. It was possible to obtain HAV sequences from 83 outbreak and 29 background cases. The outbreak strain was represented by five different sequences, all belonging to subtype IIIA. During the outbreak, this IIIA strain also spread into the general population. All available non-outbreak isolates from 1994 to 2001 but one belonged to genotype IA and formed distinct clusters as compared to isolates from other parts of the world. One subtype IIIA isolate from 1995 was unrelated to the outbreak strain. Subtype IA had been dominating in Estonia during 1994-2001, but the outbreak strain from 1998 to 1999 was IIIA. This subtype was encountered previously in addicts in Sweden during the 1980s and in Norway at the end of the 1990s. This study supports the use of limited sequencing within the aminoterminal VP1 region for studying the molecular epidemiology of hepatitis A.     

Posttransplant T-cell lymphoproliferative disorders--an aggressive, late complication of solid-organ transplantation

T-cell non-Hodgkin's lymphomas are an uncommon occurrence after solid- organ transplantation. We describe a morphologically and immunophenotypically distinct group of T-cell lymphoproliferative disorders that occurred late in the course of six patients with solid- organ transplants. The patients ranged in age from 31 to 56 years (median, 43). Three were male; all were splenectomized. The interval from transplant to the diagnosis of lymphoma ranged from 4 to 26 years (median, 15). Symptoms at presentation were related to sites of involvement. Pulmonary, marrow, and CNS involvement were present in five, four, and one case, respectively. No patient had lymphadenopathy. Five patients had an elevated lactate dehydrogenase level (range, 226 to 4,880 IU/L; median, 1,220 IU/L). Five of six patients had a leukoerythroblastic reaction. All cases had large-cell histology and frequently contained cytoplasmic granules. Those cases tested expressed CD2, CD3, and CD8 and were negative for B-cell antigens. T-cell receptor beta- and gamma-chain genes were clonally rearranged in three of three and one of three cases, respectively. All T-cell posttransplant lymphoproliferative disorders (T-PTLDs) studied were negative for Epstein-Barr virus (EBV), human T-cell leukemia/lymphoma virus type 1 (HTLV-1), human T-cell leukemia/lymphoma virus type 2 (HTLV-2), and human herpes virus type 8 (HHV-8) genomes. Treatment with acyclovir (three patients) or chemotherapy (three patients) resulted in two responses. All patients had an aggressive course, with a median survival duration of 5 weeks. In conclusion, a clinically aggressive T- PTLD may be a late complication of solid-organ transplantation and does not appear to be related to EBV, HTLV-1, HTLV-2, or HHV-8 infection.     

Thrombospondin promotes platelet aggregation

Thrombospondin (TSP), isolated from human platelets, promotes aggregation of both nonstimulated platelets and platelets stimulated with thrombin or ADP. The TSP-promoted aggregation is specific since a monoclonal antibody against TSP inhibits the effect of exogenously added TSP and inhibits thrombin-induced platelet aggregation in the absence of added TSP. Several lines of evidence suggest that TSP mediates its effect on aggregation of nonstimulated and stimulated platelets through different platelet-surface receptor systems. The TSP- promoted aggregation of nonstimulated platelets was inhibited by a monoclonal antibody to platelet glycoprotein IV (GPIV), but not by a monoclonal antibody to the fibrinogen receptor, GPIIb-IIIa. In contrast, the antibody to GPIIb-IIIa totally inhibited the TSP- potentiated aggregation of thrombin-stimulated platelets, whereas the antibody to GPIV has no effect. Thus, these studies suggest that TSP promotes platelet aggregation by at least two mechanisms--one dependent on and one independent of the platelet fibrinogen receptor system.     

Assessing the quality of medical death certification: a case study of concordance between national statistics and results from a medical record review in a regional hospital in the Philippines

Background

Medical certificates of cause of death (MCCOD) issued by hospital physicians are a key input to vital registration systems. Deaths certified by hospital physicians have been implicitly considered to be of high quality, but recent evidence suggests otherwise. We conducted a medical record review (MRR) of hospital MCCOD in the Philippines and compared the cause of death concordance with certificates coded by the Philippines Statistics Authority (PSA).

Methods

MCCOD for adult deaths in Bohol Regional Hospital (BRH) in 2007–2008 and 2011 were collected and reviewed by a team of study physicians. Corresponding MCCOD coded by the PSA were linked by a hospital identifier. The study physicians wrote a new MCCOD using the patient medical record, noted the quality of the medical record to produce a cause of death, and indicated whether it was necessary to change the underlying cause of death (UCOD). Chance-corrected concordance, cause-specific mortality fraction (CSMF) accuracy, and chance-corrected CSMF were used to examine the concordance between the MRR and PSA.

Results

A total of 1052 adult deaths were linked between the MRR and PSA. Median chance-corrected concordance was 0.73, CSMF accuracy was 0.85, and chance-corrected CSMF accuracy was 0.58. 74.8% of medical records were deemed to be of high enough quality to assign a cause of death, yet study physicians indicated that it was necessary to change the UCOD in 41% of deaths, 82% of which required addition of a new UCOD.

Conclusions

Medical records were generally of sufficient quality to assign a cause of death and concordance between the PSA and MRR was reasonably high, suggesting that routine mortality statistics data are reasonably accurate for describing population level causes of death in Bohol. While overall agreement between the PSA and MRR in major cause groups was sufficient for public health purposes, improvements in death certification practices are recommended to help physicians differentiate between treatable (immediate) COD and COD that are important for public health surveillance.

     

PGD12 Cost of Prescription Drugs and Cost of Treatment Failure for Sinusitis

A self-administered, disease-specific form of health status instrument for patients with COPD is not available in America. The St. George's Respiratory Questionnaire (SGRQ) is a successful measure in Great Britain and Europe that meets these requirements, but syntax and colloquial differences make an American version necessary.
OBJECTIVE: To test the validity and reliability of an American translation (ATSGRQ) of the SGRQ.
METHODS: Two bilingual health professionals independently translated the SGRQ based on summarized input from panels of American COPD patients and American respiratory professionals. Consensus was reached on the translated version and then back-translated by two other bilingual health professionals. To establish reliability, the ATSGRQ was given to COPD patients at the beginning of a pulmonary rehabilitation program (PRP) and repeated 1 week later. To establish validity, the ATSGRQ was used with pulmonary function tests, the Medical Research Council's dyspnea scale (DYS), 6-minute walk (6MW), and Short Form Health Status Profile-36 (SF-36) at the beginning and end of PRP for 24 COPD patients.
RESULTS: The patients were mean age 70 yr, 40% male, mean FEV1 = 0.95. The ATSGRQ Cronbach's alpha for overall scale and symptom, activity, and impact components was respectively .87, .65, .79, .80. Test-retest correlations were .70, .60, .72, .64, respectively. Baseline correlations between total ATSGRQ and FEV1, DYS, 6MW, and SF-36 physical and mental health component scores were −.43, 54, .56, −.76, −.62. From initial to post-PRP, the symptom ATSGRQ decreased 12.6% (p = .004); DYS decreased 10.6% (p = .043).
CONCLUSION: Based on these preliminary data, the ATSGRQ appears to be a valid, reliable health status instrument for use in an American COPD population.