Serum levels of matrix metalloproteinase-2 as a marker of intimal hyperplasia.

BACKGROUND: A primary component in the development of intimal hyperplasia (IH) in response to vascular injury is basement membrane remodeling. Matrix metalloproteinases (MMPs) play a major role in this process by degradation of basement membrane proteins, mainly collagen type IV. Vascular injury initiates an inflammatory cascade with the release of tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta), and C-reactive protein (CRP). We hypothesize serum levels of these elements may serve as biomarkers of the development of IH. METHODS AND RESULTS: At baseline, 2, 7, 10, and 14 days post-balloon angioplasty of the carotid artery, rat tissue samples were stained with Masson trichrome elastin to examine IH. Intima:media ratios (I:M) increased significantly over time postinjury. Serum samples were collected at the time of tissue sampling, and levels of MMP-2, MMP-9, collagen type IV, TNFalpha, IL-1beta, and CRP were assayed using sandwich enzyme-linked immunosorbent assay (ELISA). MMP-2 serum levels at 7, 10, and 14 days postinjury were significantly elevated compared with baseline. Other elements were not significantly elevated. CONCLUSION: Early and persistent elevation in the serum levels of MMP-2 may be a useful biomarker of basement membrane remodeling and the presence of IH.

Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma.

The FIP1L1-PDGFRA fusion gene has been described in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD). Here, we report on seven FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. All patients were male, the median age was 58 years (range, 40-66). AML patients were negative for common mutations of FLT3, NRAS, NPM1, KIT, MLL and JAK2; one patient revealed a splice mutation of RUNX1 exon 7. Patients were treated with imatinib (100 mg, n=5; 400 mg, n=2) either as monotherapy (n=2), as maintenance treatment after intensive chemotherapy (n=3) or in overt relapse 43 and 72 months, respectively, after primary diagnosis and treatment of FIP1L1-PDGFRA-positive disease (n=2). All patients are alive, disease-free and in complete hematologic and complete molecular remission after a median time of 20 months (range, 9-36) on imatinib. The median time to achievement of complete molecular remission was 6 months (range, 1-14). We conclude that all eosinophilia-associated hematological malignancies should be screened for the presence of the FIP1L1-PDGFRA fusion gene as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype such as AML.

An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults.

OBJECTIVES: Few investigations have examined the effectiveness of Ginkgo biloba extract for enhancing cognitive abilities in individuals with no history of significant neurocognitive dysfunction. The purpose of this research was to examine the relatively short-term (i.e., 6 weeks) efficacy of Ginkgo biloba extract EGb 761 on the cognitive functioning of cognitively intact persons over the age of 55 years via a diverse battery of neuropsychologic tests and measures. PARTICIPANTS: From the 48 cognitively intact participants between the ages of 55 and 86 years who initially enrolled in this study, 21 males and 19 females successfully completed the study's protocol and provided valid data sets. DESIGN: A 6-week, double-blind, fixed-dose, placebo-controlled, parallel-group experimental design was utilized. Participants were randomly assigned to either a Ginkgo biloba extract EGb 761 (180 mg/d) or placebo control group. To evaluate participants' cognitive and behavioral functioning, series of neuropsychological tests were administered to them prior to the initiation of the Ginkgo biloba extract/placebo therapy (i.e., pretreatment baseline) and again, just prior to the termination of the treatment regimen (i.e., after 6 weeks). RESULTS: Participants who received 180 mg of Ginkgo biloba extract EGb 761 daily for 6 weeks exhibited significantly more improvement on a task assessing speed of processing abilities (i.e., Stroop Color and Word Test color-naming task) by the end of treatment as compared to participants who received placebo. Trends favoring improved performances in the Ginkgo biloba group were also demonstrated in three of the four remaining tasks that involved a timed, speed of processing component, although they did not reach statistical significance. Furthermore, a significant relationship was found between the type of treatment (Ginkgo biloba extract or placebo) and participants' ratings of their overall abilities to remember. Specifically, more participants in the Ginkgo biloba extract group rated their overall abilities to remember by the end of treatment as "improved," as compared to the placebo group. In contrast, no significant differences were found between the Ginkgo biloba and placebo groups by treatment end on any of the four objective memory measures. CONCLUSIONS: Taken together, the findings from standardized neuropsychologic assessment and a subjective, self-report questionnaire suggested that relatively short-term (i.e., 6 weeks) utilization of Ginkgo biloba extract EGb 761 may prove efficacious in enhancing certain neurocognitive functions/processes of cognitively intact older adults.

The metabolic fate of doubly labelled lactose-[13C, 15N]ureide after pre-dosing with different ureides.

BACKGROUND: To date, the measurement of the orocaecal transit time (OCTT) with lactose-[(13)C]ureide usually requires a pre-dosing with the analogous substrate in its unlabelled form. OBJECTIVE: In this study, the enzyme induction provoked by different unlabelled sugar ureides in OCTT measurements when using doubly labelled lactose-[(13)C, (15)N]ureide (DLLU) was evaluated. METHODS: Thirteen healthy adults (age: 22-58 years) received 500 mg DLLU together with a standardized breakfast. Expired air, urine and faeces were collected over a period of 14, 48 and 72 h, respectively. After 1 and 2 weeks, the test was repeated after pre-dosing of 3 x 120 mg glucose ureide (GU) and 3 x 200 mg cellobiose ureide (CU), respectively, on the day before study begin. The (13)C- and (15)N-enrichments were measured by isotope ratio mass spectrometry. The OCTT was calculated by the detection of a significant (13)CO(2) increase. RESULTS: In comparison with the period without pre-dosing (7.8+/-2.2 h), the measured OCTT was significantly lowered either after GU pre-dosing (5.8+/-1.9 h, P=0.033) or CU pre-dosing (6.0+/-2.2 h, P=0.039). The respective renal (13)C- and (15)N-excretions amounted to 24.5 and 45.6, 24.7 and 54.0, and 22.5 and 50.1%, respectively, whereas the faecal (13)C- and (15)N-excretions amounted to 12.1 and 45.8, 4.8 and 21.5, and 9.6 and 39.8%, respectively. CONCLUSIONS: Pre-dosing with unlabelled GU and CU before the administration of DLLU led to an unequivocal induction of the enzyme activity and resulted in a definitive estimation of the OCTT, clearly demonstrating that glucose-[(13)C]ureide is the matrix of the bacterial degradation in the caecum.

The molecular anatomy of the FIP1L1-PDGFRA fusion gene.

The FIP1L1-PDGFRA fusion gene is a recurrent molecular abnormality in patients with eosinophilia-associated myeloproliferative neoplasms. We characterized FIP1L1-PDGFRA junction sequences from 113 patients at the mRNA (n=113) and genomic DNA (n=85) levels. Transcript types could be assigned in 109 patients as type A (n=50, 46%) or B (n=47, 43%), which were created by cryptic acceptor splice sites in different introns of FIP1L1 (type A) or within PDGFRA exon 12 (type B). We also characterized a new transcript type C (n=12, 11%) in which both genomic breakpoints fell within coding sequences creating a hybrid exon without use of a cryptic acceptor splice site. The location of genomic breakpoints within PDGFRA and the availability of AG splice sites determine the transcript type and restrict the FIP1L1 exons used for the creation of the fusion. Stretches of overlapping sequences were identified at the genomic junction site, suggesting that the FIP1L1-PDGFRA fusion is created by illegitimate non-homologous end-joining. Statistical analyses provided evidence for clustering of breakpoints within FIP1L1 that may be related to DNA- or chromatin-related structural features. The variability in the anatomy of the FIP1L1-PDGFRA fusion has important implications for strategies to detect the fusion at diagnosis or for monitoring response to treatment.

Removal of the OptEase retrievable vena cava filter is not feasible after extended time periods because of filter protrusion through the vena cava.

BACKGROUND: Therapeutic and prophylactic vena cava filters (VCFs) are used to prevent pulmonary embolism. Concerns exist over placing a permanent filter in a young trauma patient. Recently, retrievable VCFs have become available. One such filter is the OptEase, which has a recommended time of removal of up to 23 days after insertion. Data supporting this recommendation are sparse. Many trauma patients will need filters for more than 2 weeks, and there are no data evaluating the safety of removal after extended time periods. The purpose of this study was to determine the safety, feasibility, and reaction of the vena cava when removing the OptEase retrievable VCF at different time intervals. METHODS: Twenty Yorkshire cross pigs (80-113 kg) underwent general anesthesia with tiletamine and zolazepam. Filters were placed in the infrarenal vena cava (VC) through the femoral vein under fluoroscopic guidance. Animals were then divided into four groups. In group 1, filters were removed at 14 days; in group 2, at 30 days; in group 3, at 60 days; and in group 4, at 90 days. Removal was attempted using a snare-and-sheath technique through the femoral vein. Animals with successful filter removal were allowed to recover; then, the animals underwent autopsy (gross and microscopic VC examination) 2 months later. Animals with unsuccessful filter removal underwent autopsy immediately after attempted removal. Venacavograms were taken at filter insertion, at removal, and before autopsy to evaluate any VC abnormalities. RESULTS: Successful removal of the filter in all five pigs (100%) was reliably performed only in the 14-day group. In this group, the initial VC transverse diameter was 19.4 +/- 0.8 mm and was significantly reduced to 9.8 +/- 1.1 mm (p < 0.05) immediately after removal. Sixty days later, before autopsy, VC diameter had increased to 15.3 +/- 1.9 mm, which was significantly larger than at removal (p < 0.05) but not different from the initial value. In the 30-day group, removal was successful in only one of five animals. Although removal was successful in the one pig, autopsy at 2 months postremoval revealed total occlusion of the VC. Filters could not be removed from 60- and 90-day groups. At autopsy, the VCF struts were embedded or protruded through the VC wall. Microscopic examination of the VC revealed significant scarring underneath and between the struts. CONCLUSION: Removal of the retrievable OptEase VCF may be successfully performed up to 14 days after insertion. Strut protrusion through the VC wall prohibited successful and safe removal at extended time intervals.