Tacrolimus Pharmacokinetics and Dose Monitoring After Lung Transplantation for Cystic Fibrosis and Other Conditions

In cystic fibrosis (CF), absorption of tacrolimus through the gastrointestinal tract may be impaired due to fat malabsorption. The aim of this pilot study was to compare tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure in stable lung transplant recipients with and without CF, and to determine the best single-time predictors of exposure. The study included 11 lung transplant recipients with CF and 11 without CF who received tacrolimus twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h postdose on 3 separate days within 1 week. Tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure were similar in the two groups, though exposure-per-milligram-dose was approximately 50% lower in CF patients. Tacrolimus trough concentration did not accurately predict the area under the concentration curve (AUC(0-12)), but the concentration measured 3 h postdose (C(3)) was tightly correlated with the AUC(0-12) in both CF (r(2)= 0.86) and non-CF (r(2)= 0.92) patients. In summary, patients with CF have a higher tacrolimus oral clearance, but nonsignificant differences in short-term inter- and intrasubject variability of exposure compared to patients without CF. C(3) is tightly correlated with AUC(0-12) in lung transplant recipients with and without CF.     

Increased Radiosensitivity as an Indicator of Genes Conferring Breast Cancer Susceptibility

PURPOSE: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity. MATERIAL AND METHODS: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17. RESULTS: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045). CONCLUSION: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness.     

Ewing's sarcoma of the femur: Prognosis in 69 patients treated by the CESS group

We reviewed the treatment outcome of 69 patients with Ewing's sarcoma of the femur. The patients received chemotherapy according to the CESS 81 (n 14), CESS 86 (n 43), and CESS 91P (n 12) protocols. The 10-year relapse-free survival rates were 36%, 65%, and 65% (p = 0.01). 68 patients received local treatment. The primary tumor was treated by surgery without radiotherapy in 28 patients; 1 developed a local recurrence and 7 metastases. 10 patients received radiotherapy alone; 4 developed metastases and 4 local recurrences and metastases. 30 cases had a combination of surgery and radiotherapy; 7 developed metastases and 1 a local recurrence and metastasis. The survival of patients after radiotherapy alone was worse than that of patients after surgery with/without radiotherapy (p = 0.005). Pathological fractures (n 16) did not influence the prognosis.     

Sensitivity of laser-evoked potentials versus somatosensory evoked potentials in patients with multiple sclerosis.

OBJECTIVE: Somatosensory evoked potentials (SEPs) play a less important role in the diagnosis of multiple sclerosis (MS) than visually evoked potentials. Since standard SEPs only reflect the dorsal column function, we now investigated spinothalamic tract function in patients with MS using laser-evoked potentials (LEPs). METHODS: LEPs to thulium laser stimuli (3ms, 540 mJ, 5mm diameter) were recorded from 3 midline positions (Fz, Cz, Pz) in 20 patients with MS, and 6 patients with possible but unconfirmed MS. Peak latencies and peak-to-peak amplitude of the vertex potential negativity (N2) and positivity (P2) were evaluated and compared with normative values from 22 healthy control subjects. Median and tibial nerve SEPs were recorded with standard methods. Depending on the results of sensory testing, two skin areas (both hands, both feet, or one hand and foot of the same body side) were assessed in each patient. RESULTS: In group comparisons, LEPs in patients with MS were significantly delayed and reduced in amplitude compared with healthy subjects (P<0.001) or patients with suspected but unconfirmed MS (P<0.05). In intraindividual comparisons within the patients with MS, LEP amplitude was significantly lower (P<0.01) and latencies were significantly longer (N2: P<0.01; P2: P<0.05) for a clinically hypoalgesic skin area than an unaffected control area. On a single case basis, LEPs were abnormal in 12 (60%) and SEPs in 8 (40%) of the patients with MS; combined analysis of LEPs and SEPs raised sensitivity to 75% (15 patients). LEPs were also abnormal for 7 skin areas with clinically normal nociception and thermal sensitivity, indicating subclinical lesions. Standard SEPs detected subclinical lesions in 5 areas with normal tactile sensitivity. CONCLUSIONS: In patients with multiple sclerosis, spinothalamic tract function and LEPs were impaired more often than dorsal column function and SEPs. LEPs also detected subclinical lesions. Combined assessment of LEPs and SEPs can help to document dissemination of demyelinating CNS lesions and thus contribute to the diagnosis of multiple sclerosis.     

Transmission of methicillin-resistant Staphylococcus aureus in the neonatal intensive care unit from a patient with community-acquired disease.

Methicillin-resistant Staphylococcus aureus (MRSA) has traditionally been a nosocomial pathogen. However, several recent studies have noted community-acquired MRSA among young, healthy patients with no risk factors or healthcare system exposure. We report the transmission of a strain of community-acquired MRSA in our neonatal intensive care unit.     

Mitochondrial DNA variability detected in a single wheat regenerant involves a rare recombination event across a short repeat

The mitochondrial genome of the selfed progeny of a plant regenerated from long-term somatic tissue culture displays specific structural rearrangements characterized by the appearance of novel restriction fragments. A mitochondrial DNA library was constructed from this selfed progeny in the SalI site of cosmid pHC79 and the novel fragments were subsequently studied. They were shown to arise from reciprocal recombination events involving DNA sequences present in the parental plant. The regions of recombination were sequenced and the nucleotide sequences were aligned with those of the presumptive parental fragments. We characterized an imperfect short repeated DNA sequence, 242 bp long, within which a 7-bb DNA repeat could act as a region of recombination. The use of PCR technology allowed us to show that these fragments were present in both parental plants and tissue cultures as low-abundance sequence arrangements.     

Should harm minimization as an approach to adolescent substance use be embraced by junior and senior high schools?: Empirical evidence from An integrated school- and community-based demonstration intervention addressing drug use among adolescents

The objective of this demonstration project was to determine if school-based harm minimization drug education was potentially acceptable and effective for junior and senior high school students in Nova Scotia. We conducted a four-year quasi-experimental intervention using mixed quantitative and qualitative methodologies. The intervention was a co-operative participatory research project with various activities determined by the participants. The project involved a partnership of four schools, two school boards, two regional addiction services, the provincial department of health, and a university. The outcomes evaluation was based on a sample of 1117 and 849 students in the intervention schools, compared with 3755 and 4247 students in the rest of the province, in 1998 and 2002, respectively. The evaluation of acceptability was based on an analysis of 491 documents generated from 1998 to 2002. The outcomes of effectiveness were specific risks and harmful consequences associated with substance use. We found that harm minimization was an acceptable approach to drug education targeting the senior high school population, and there was also some evidence of effectiveness in that age group in that the prevalence of several risks and negative consequences of substance use decreased significantly in the intervention schools relative to the rest of the province. In junior high school, harm minimization was found to not be an acceptable approach to drug education. This demonstration project provides evidence that school-based harm minimization may be acceptable and effective in senior high schools but may not be acceptable in junior high schools.     

Coronary-like revascularization for atherosclerotic renal artery stenosis

AIMS: The aim of this study was to document the early outcome of coronary-like revascularization for atherosclerotic renal artery stenosis (ARAS). METHODS AND RESULTS: A total of 181 consecutive patient, 102 men, mean age 66.1 (+/- 9.2) years and 79 females, mean age 68.4 (+/- 9.2) years and 198 lesions were treated between February 1999 and May 2004 for ARAS and retrospectively analyzed. At least one major cardiovascular risk factor was present in 179 (98.9%) patients. Pre-dilatation ARAS was 81.3+/-9.6%, 27 ARAS were 50-70% and no ARAS was <50%. 135 (68.2%) of the ARAS lesions were ostial and 63 (31.8%) were non-ostial. In 17 (9.4%) patients bilateral ARAS were present. Technical success defined as residual stenosis < or =30% was achieved in 178 (98.3%) of patients and 195 (98.5%) of lesions. In one patient (0.5%) the target ARAS could not be crossed, in two (1.1%) patients residual stenosis was >30%. No major adverse cardiac or cerebral effects were observed. In 3.9% of patients minor local complications of the access site occurred; 4 (2.2%) inguinal hematoma, 3 (1.7%) pseudoaneurysm were documented. Serum creatinine concentrations and systolic and diastolic blood pressure before and after the intervention were not statistically different. CONCLUSIONS: Coronary-like approach to ARAS revascularization is technically feasible and associated with a very low complication rate.