Human liver mitochondrial carnitine palmitoyltransferase I: characterization of its cDNA and chromosomal localization and partial analysis of the gene.

Using the cDNA for rat liver mitochondrial carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21) as a probe, we isolated its counterpart as three overlapping clones from a human liver cDNA library. Both the nucleotide sequence of the human cDNA and the predicted primary structure of the protein (773 aa) proved to be very similar to those of the rat enzyme (82% and 88% identity, respectively). The CPT I mRNA size was also found to be the same (approximately 4.7 kb) in both species. Screening of a human genomic library with the newly obtained cDNA yielded a positive clone of approximately 6.5 kb which, upon partial analysis, was found to contain at least two complete exons linked by a 2.3-kb intron. Oligonucleotide primers specific to upstream and downstream regions of one of the exon/intron junctions were tested in PCRs with DNA from a panel of somatic cell hybrids, each containing a single human chromosome. The results allowed unambiguous assignment of the human liver CPT I gene to the q (long) arm of chromosome 11. Additional experiments established that liver and fibroblasts express the same isoform of mitochondrial CPT I, legitimizing the use of fibroblast assays in the differential diagnosis of the "muscle" and "hepatic" forms of CPT deficiency. The data provide insights into the structure of a human CPT I isoform and its corresponding gene and establish unequivocally that CPT I and CPT II are distinct gene products. Availability of the human CPT I cDNA should open the way to an understanding of the genetic basis of inherited CPT I deficiency syndromes, how the liver CPT I gene is regulated, and which tissues other than liver express this particular variant of the enzyme.     

Social environment and longevity in schizophrenia

OBJECTIVE: The role of social support as a predictor of long-term survival among patients with schizophrenia was examined. METHODS: Social histories were abstracted from the medical records of a cohort of 133 deceased schizophrenic patients admitted for inpatient treatment between 1934 and 1944. Two independent raters assessed the quantity and quality of support available in each patient's social environment. RESULTS: Cox regression analysis revealed that higher quantity of social support was significantly related to survival time (p<.05) after controlling for marital status and quality of support. The Cox model indicated that a 1-point increase in the support quantity rating was associated with a proportional 25% decrease in the hazard rate. CONCLUSIONS: The present findings suggest that social environment, specifically the quantity of social support available to the patient, may impact longevity in psychiatric populations.     

Relationship between clinical and radiological diagnostic criteria for Alzheimer's disease and the extent of neuropathology as reflected by 'stages': a prospective study

The distribution of pathology related to Alzheimer's disease (AD) is not uniform throughout the brain. Sites which have a predilection for the development of Alzheimer-type pathology are the limbic regions and neocortical association areas. The changes in these areas of the brain develop gradually, following a well-determined sequence that allows a pathological staging of the disease process. According to the staging hypothesis, the first pathological alterations develop in the transentorhinal and entorhinal regions. The neurofibrillary pathology then spreads into the hippocampus, but not until the final stages does it affect the neocortex. In this study we analyse the relationship between the pathological stages of AD, according ot the staging hypothesis, and the clinical diagnosis in a prospectively assessed patient group. Prediction of any given pathological stage from the clinical diagnosis was found to be poor. This may be partly due to the fact that additional pathologies can alter the clinical picture and severity of dementia in patients who are only in the initial stages of AD. Nevertheless, the NINCDS-ADRDA clinical criteria had a high sensitivity for detection of AD-related pathology: the 'probable AD' category included 22/38 (57.9%) of those in the late isocortical stage, while the 'possible AD' category included 19/23 (82.6%) of those in the limbic stage. Using proposed neuro-imaging protocols for improved identification of patients with AD-related pathology, we largely identified subjects in whom the extent of pathology had spread to the neocortex.     

Radiation burden to paediatric patients due to micturating cystourethrography examinations in a Dutch children's hospital

Micturating cystourethrography (MCU) examinations of paediatric patients in a major Dutch children's hospital (JKZ) were evaluated to generate quantitative information on effective dose (E). A standard examination involves three radiographs plus fluoroscopy. Observed total dose-area product (DAP) for 84 children increased, on average, with increasing age class from 0.2 to 2.2 Gy cm2. In 11 cases, separate DAP per view was measured; enabling determination, per view, of organ (CF) and effective (CE) dose conversion factors, i.e. dose per unit of DAP. Monte Carlo simulation of photon transport in male and female mathematical phantoms was applied for newborn, 1 year, 5 year, 10 year and 15-year-old patients, and interpolated for other ages. CE per view decreases with increasing age class, yielding about a factor of 10 difference between the extremes of the range. Female values are usually some 20-30% above male ones. CE for one of the views appeared to be representative for the complete examination and was used to estimate total E for each patient. Averaged per age class, E remains approximately constant at 0.3-0.4 mSv, although a tendency to increase with increasing age exists, for females in particular. Within an age class, individual patients may differ in E by a factor of two up to six. Stomach, lower large intestine, bladder wall, liver and ovaries receive relatively high doses. Compared with published data and DAP measured in a few other Dutch hospitals, the radiation burden of MCU is low at the JKZ. This indicates a good degree of optimization with respect to radiation protection (e.g. modern equipment, increased tube voltage, fast film-screen combination).     

Incomplete intertrochanteric fractures: imaging features and clinical management

PURPOSE: To present the imaging findings and treatment options for incomplete intertrochanteric fractures. MATERIALS AND METHODS: Among 31 patients with the magnetic resonance (MR) imaging diagnosis of incomplete intertrochanteric fracture, 30 also underwent radiography. MR and radiographic findings were compared. Note was made of fracture length and extent as depicted on the coronal and axial MR images, treatment (surgical vs conservative), and follow-up. RESULTS: Correlation between radiographic and MR findings was poor. Incomplete intertrochanteric fracture was the prospective radiographic diagnosis in only one case. Fracture in 18 patients was treated surgically and in 13 was managed conservatively. In both groups, the average age of the patients and length of the fractures and the percentage of separate fractures involving the greater trochanter and crossing the midline of the femur in the axial plane were the same. Fractures crossed the midline in the coronal plane in 50% of the surgical group but in only 23% of the nonsurgical group. Average time from injury to ambulation was 2 days less in the surgical group, but no difference in functional status was found subjectively between the two groups at clinical follow-up. CONCLUSION: Incomplete intertrochanteric fractures are a previously unrecognized subset of intertrochanteric fractures that are diagnosed unequivocally only with MR imaging.     

Resting metabolic rate, body composition and aerobic fitness comparisons between active and sedentary 54-71 year old males.

OBJECTIVE: To test the hypothesis that 55-70 y old male longterm exercisers (LE) have higher resting metabolic rates (RMR) than longterm nonexercisers (LNE). DESIGN: A power analysis demonstrated that this cross-sectional study required 12 subjects per group to detect a 10% RMR difference (kJ x kg FFM(-1) x d(-1)) between the LE and LNE (power = 0.8;alpha = 0.05). SUBJECTS: Twelve LE (X +/- s.d.; 63.5+/-3.4 y; 1.75+/-0.06 m; 69.01+/-8.24 kg; 20.4+/-4.9 %BF) and 12 LNE (63.6+/-5.6 y; 1.72+/-0.07 m; 79.44 12.4 kg; 29.6 4.4 %BF) were recruited from advertisements placed in a newspaper and on university and community noticeboards. INTERVENTIONS: Measurements were conducted for: RMR using the Douglas bag technique; body composition via a four compartment model which is based on determination of body density, total body water and bone mineral mass; and aerobic fitness using a submaximal work test on a cycle ergometer. RESULTS: The LE (93.00+/-7.16 kJ x kg(-1) x d(-1)) registered a significantly greater (P = 0.04) RMR than the LNE (84.70+/-11.23 kJ x kg(-1) x d(-1)) when energy expenditure was expressed relative to body mass, but this difference disappeared (P = 0.55) when the data were corrected for the non-zero intercept of the graph of RMR (MJ/d) against body mass. ANCOVA with FFM as the covariate also indicated that the RMR (MJ/d) difference between the groups was not statistically significant (P = 0.28). The adjusted means for the LE and LNE were 6.39 and 6.62 MJ/d, respectively. CONCLUSIONS: There are no RMR (MJ/d) differences between LE and LNE 54-71 y old males when statistical control is exerted for the effect of FFM and the higher value of the former group for RMR normalised to body mass disappears when this ratio is corrected for statistical bias.     

Improved uptake and retention of lipophilic prodrug to improve treatment of HIV

Dideoxynucleosides currently in use for anti-HIV therapy have been found to be inefficient in passing through the blood-brain barrier to enter and maintain therapeutic drug levels in brain, a very significant reservoir of HIV. The low bioavailability of these drugs combined with the bone marrow toxicity of AZT (3'-azido, 3'-deoxythymidine, Zidovudine), resulting in anemia and leukopenia, pancreatitis with ddI (2',3'-dideoxyinosine, Didanosine) and painful peripheral neuropathy in case of ddC (2',3-dideoxycytosine, Zalcitabine) are the limiting factors in their use. In addition, the emergence of strains of HIV resistant to AZT, the most commonly used drug, further restricts its use. Thus the control of AIDS and its complications, needs special therapeutic approaches to combat the disease. In order to overcome these limitations, AZT and ddI have been synthesized as ester-linked ceramide- and phosphatidylcholine-linked prodrugs possessing therapeutic attributes lacking in the parent compounds. There is greater uptake and longer retention of these prodrugs in NIH/3T3 cells in vitro. Pretreatment with our prodrugs blocked infection of these cells by Moloney murine leukemia virus (M-MuLV) for an extended period, which the parent drugs failed to do. When human CD4+ HeLa cells were continuously exposed to the AZT prodrug, subsequent infection of these cells by HIV was blocked. Similar results were obtained with NIH/3T3 cells exposed to M-MuLV. AE(6)C, a prodrug of AZT linked to ceramide via a cleavable ester bond and a six carbon linker, was less toxic to both mouse and human bone marrow progenitor cells than free AZT. Most significantly, the prodrugs concentration was greater and the retention longer, in well known sanctuaries for HIV, such as the brain, testes and thymus.