Distinguishing ankle and knee articular cartilage

Degenerative changes in the tall and femoral distal cartilages of more than 2,000 tissue donors were graded based on the appearance of articular cartilage and osteophytes. In the ankle and the knee the degenerative changes increased with age; however, the rate of degeneration in the ankle was slower than in the knee. The degenerative changes in the ankle were more severe in men than in women, were predominantly bilateral, and seemed to be correlated with weight. The slower rate of change in the ankle may be caused, in part, by the biochemical and biomechanical tissue properties that distinguish ankle cartilage from that of the knee.     

Problematic variation in local institutional review of a multicenter genetic epidemiology study

Context  Sequencing of the human genome provides an immense resource for studies correlating DNA variation and epidemiology. However, appropriately powered genetic epidemiology studies often require recruitment from multiple sites. Objectives  To document the burden imposed by review of multicenter studies and to determine the variability among local institutional review boards (IRBs) in the approval of a multicenter genetic epidemiology study. Design  A PubMed search was performed to determine the frequency of citations of multicenter studies by 5-year intervals from 1974 through 2002. A 7-question survey was sent to all participating study centers to obtain information on frequency of IRB meetings, dates for submission and approval, use/nonuse of a specific consent form, type of review performed, types of consent forms required, preparation time, and number of changes requested by the IRB at each center. Centers also provided a copy of all consent forms they generated and IRB correspondence regarding the study. Setting and Participants  Thirty-one of 42 cystic fibrosis care centers in this single US multicenter genetic epidemiology study of cystic fibrosis replied, yielding a 74% response rate. Main Outcome Measures  Frequency of published research studies and consistency among IRBs. Results  The number of all published single-center studies has increased 1.3-fold since 1985, while the number of published epidemiology and genetic epidemiology multicenter studies increased by 8- and 9-fold, respectively, during this same period. Evaluation of the risk of the same genetic epidemiology study by 31 IRBs ranged from minimal to high, resulting in 7 expedited reviews (23%) and 24 full reviews (77%). The number of consents required by the IRBs ranged from 1 to 4; 15 IRBs (48%) required 2 or more consents, while 10 (32%) did not require assent for children. The most common concern (52%) of IRBs pertained to the genetic aspects of the study. Conclusions  Review of a protocol for a multicenter genetic epidemiology study by local IRBs was highly variable. Lack of uniformity in the review process creates uneven human subjects protection and incurs considerable inefficiency. The need for reform, such as the proposed centralized review, is underscored by the ever increasing rate of genetic discoveries facilitated by the Human Genome Project and the unprecedented opportunity to assess the relevance of genetic variation to public health.      

Sequence specificity of adriamycin-DNA adducts in human tumor cells

The anticancer anthracycline compound Adriamycin is a known topoisomerase II inhibitor but is also capable of exerting other cellular consequences. After intercalation, Adriamycin can form covalent adducts with DNA, and the magnitude of these adducts appears to be limited by the cellular availability of formaldehyde. Adducts produced by Adriamycin in the presence of formaldehyde have been well characterized in cell-free systems but not in cells. In this study, we show that when Adriamycin is used in conjunction with the formaldehyde-releasing prodrug AN-9 in IMR-32 tumor cells, this allows the formation of sufficiently high levels of adducts in genomic DNA to enable detection of their DNA sequence specificity for the first time. The 340-bp alpha-satellite EcoRI repeat sequence was isolated from drug-treated cells and digested with lambda-exonuclease to determine adduct sites at which exonuclease digestion was blocked. The Adriamycin adducts were formed predominantly at 5'-GC and GG sequences and unstable with respect to elevated temperatures and extended times at 37 degrees C. The use of three anthracycline derivatives lacking a 3'amino group demonstrated that this amino portion is critical for the formation of anthracycline adducts in cells. The structure of these drug-DNA adducts can therefore be considered to be identical to the Adriamycin adducts, which have been characterized rigorously in cell-free systems by X-ray crystallography, two-dimensional nuclear magnetic resonance, and mass spectrometry.     

Reduced hemodynamic load and cardiac hypotrophy in patients with anorexia nervosa

BACKGROUND: Anorexia nervosa is associated with lower left ventricular mass (LVM) and systolic dysfunction. Whether these abnormalities reflect chronic protein-energy malnutrition or are primarily related to lower cardiac workload is unclear. OBJECTIVE: The objective of the study was to verify whether low LVM in anorexia nervosa is explained by low hemodynamic load. DESIGN: Ninety-one women with anorexia nervosa [macro x +/- SD age: 20.5 +/- 6.1 y; body mass index (in kg/m(2)): 15.6 +/- 1.9; group 1] and 62 normal-weight female control subjects (age: 22.5 +/- 5.5 y; body mass index: 20.9 +/- 1.2; group 2) underwent Doppler echocardiography. LVM was evaluated as the percentage predicted by body height, sex, and stroke work (systolic blood pressure x stroke volume). RESULTS: The left ventricular chamber dimension was smaller and the chamber walls were thinner in group 1 than in group 2, which resulted in significantly lower LVM and LVM indexes (P < 0.0001). Ejection fraction, heart rate, stroke volume, and cardiac output were significantly (P < 0.007) lower in group 1, but peripheral resistance was substantially higher (P < 0.0001). The deviation of LVM from predicted values was lower and the proportion of subjects with inadequate LVM was significantly higher in group 1 than in group 2 (P < 0.0001). This difference was attenuated after adjustment for body weight and heart rate. There were no relations between LVM and laboratory tests in group 1. CONCLUSIONS: Anorexia nervosa is a condition of low hemodynamic load that leads to low LVM. Even with adjustment for stroke work, however, LVM is lower than would be predicted by height, because of the effect of body weight reduction (ie, wasting of lean body mass).     

The significance of isolated elevation of serum aminotransferases in infants and young children.

INTRODUCTION: The aim of this study was to assess the clinical significance and prognosis of a prolonged isolated elevation of serum aminotransferases without cholestasis (>3 months) in infants and young children, investigated for a variety of conditions, and to determine a protocol for their follow-up and investigation. METHODS: A combined prospective-retrospective analysis of apparently healthy babies and young children with isolated elevation of serum aminotransferases of at least 1.5 times above the norm for age which persisted for at least 3 months and whose creatine phosphokinase (CK), gamma glutamyltransferase (GGT), alkaline phosphatase and bilirubin levels remained normal throughout the study duration. The children underwent the following investigations: abdominal ultrasound and infectious, metabolic and/or immunological investigation depending on the duration of the abnormality. RESULTS: Six children were eliminated following the finding of positive cytomegalovirus (CMV) antigen in the urine. 72 children were investigated (47 males and 25 females). The duration of serum aminotransferases elevation was 3-36 months (average 12.4, median 11.5 months). The initial, maximal and final alanine aminotransferase (ALT) values were 85.5, 140.5 and 39.8 IU/l, respectively. Of seven children who had liver biopsies performed, three (42.8%) were suspected of having a glycogen storage disease which was not confirmed enzymatically. Four biopsies revealed non-specific histological changes. CONCLUSIONS: Isolated elevation of serum aminotransferases in healthy looking young children is mostly a benign condition that usually resolves within a year. If no pathology is found during routine investigation, these children can be followed conservatively. Liver biopsy does not contribute much to the diagnosis and is probably unnecessary.     

Xanthine Oxidase Status in Ethanol-Intoxicated Rat Liver

The status of xanthine oxidase in ethanol-induced liver injury has been investigated in the rat, by acute and chronic ethanol treatments. A 38% increase of the enzyme O-form was observed after repeated ethanol administration. Chronic intoxication caused a significant decrease of total xanthine oxidase activity after both prolonged ethanol feeding and life span ethanol ingestion. The intermediate D/O-form of xanthine oxidase (that can act either as an oxidase or as a dehydrogenase, being able to react with O2 as well as with NAD+ as electron acceptor) increased 5.5-fold after prolonged ethanol feeding.