Time-resolved, high-resolution contrast-enhanced MR angiography of dialysis shunts using the CENTRA keyhole technique with parallel imaging

PURPOSE: To evaluate the use of a dynamic keyhole magnetic resonance angiography (MRA) sequence combined with sensitivity encoding (SENSE) for hemodialysis shunts, because surveillance with conventional contrast-enhanced MRA (CE-MRA) is limited by its low temporal resolution, resulting in arteriovenous overlay. MATERIALS AND METHODS: A total of 12 patients with Brescia-Cimino shunts were investigated prospectively using the new technique. During the contrast passage (gadoterate, Gd-DOTA) a series of five to nine dynamic central k-space measurements (10% for upper-arm shunt, 25% for lower-arm shunt) followed by a full reference data set were acquired. The outer k-space data of the single reference scan were used to complete the dynamic data sets. RESULTS: All studies were diagnostic (17 stenoses, three aneurysms) without complications. The acquisition times for a single dynamic scan of the upper- and lower-arm shunts were 2.2 and 3.2 seconds, respectively, while the reference scan needed 13 and 22.4 seconds, respectively. The dynamic angiograms allowed the differentiation of arterial and venous filling despite a mean peak delay time of only 4.2 seconds in the shoulder region. Image quality qualified in consensus by two experienced readers was rated "good" in 19 cases and "intermediate" in five cases with high mean values for signal-to-noise ratios (SNRs) and contrast-to-noise-ratios (CNRs). CONCLUSION: We have successfully implemented a fast, dynamic, CE-MRA technique with CE timing robust angiography (CENTRA) keyhole and SENSE in clinical routine. High spatial and temporal resolution improve the diagnostics of dialysis shunts and allow the assessment of detailed, dynamic, four-dimensional (4D) information.     

Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity

The importance of polymorphisms in the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) for the prediction of severe toxicity in 5-fluorouracil (5-FU) based chemotherapy has been controversially debated. As a key enzyme in the catabolism of 5-FU, DPD is the top candidate for pharmacogenetic studies on 5-FU toxicity, since a reduced DPD activity is thought to result in an increased half-life of the drug, and thus, an increased risk of toxicity. Here, we review the current knowledge on well-known and frequently studied DPYD variants such as the c.1905+1G>A splice site variant, as well as the recent discoveries of important functional variation in the noncoding regions of DPYD. We also outline future directions that are needed to further improve the risk assessment of 5-FU toxicity, in particular with respect to metabolic profiling and in the context of different combination therapeutic regimens, in which 5-FU is used today.     

Prognostic value of transient and sustained increase in in-hospital creatinine on outcomes of patients admitted with acute coronary syndrome

A history of renal insufficiency or increased creatinine level on admission is associated with poor outcomes in patients with acute coronary syndrome (ACS). This study sought to determine whether in-hospital worsening of renal function, either transient or sustained, is an independent risk factor for 6-month mortality in patients admitted with ACS. A total of 1,417 patients admitted with ACS from June 2000 to May 2003 were reviewed. Patients were classified into 3 groups. Group I included patients with an increase in creatinine during hospitalization of 0.5 mg/dl that resolved by discharge. Group III included patients with an increase in creatinine of >0.5 mg/dl that did not resolve. The primary end point was 6-month mortality from any cause. Patients in groups II and III had higher 6-month mortality rates (27% and 23%, respectively; both p<0.001) compared with patients in group I (7.4%). After adjustment for known risk factors, a transient increase in creatinine remained a significant independent predictor of 6-month mortality (odds ratio 2.07, 95% confidence interval 1.14 to 3.76), although a sustained increase in creatinine showed a trend (odds ratio 1.58, 95% confidence interval 0.68 to 3.70). In conclusion, independent of a history of renal insufficiency or increased admission creatinine, in-hospital worsening of renal function is an important risk factor for 6-month mortality in patients admitted with ACS. Furthermore, return to baseline function by discharge does not protect against this risk. These findings have implications for management of these high-risk patients.     

Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes

Inducing an apoptotic response is the goal of most current chemotherapeutic interventions against cancer. However, little is known about the effect of chemotherapeutic agents on the alternative splicing of apoptotic genes. Here, we have tested 20 of the mainstream anticancer drugs for their ability to influence the production of Bcl-x splice isoforms. We find that many drugs shift splicing toward the proapoptotic Bcl-x(S) splice variant in 293 cells. The drugs modulate splicing decisions most likely through signaling events because the splicing switch is not compromised by inhibiting de novo protein synthesis or the activity of caspases. Several drugs also shift Bcl-x splicing in cancer cell lines (MCF-7, HeLa, PC-3, PA-1, and SKOV-3), but the set of active drugs varies between cell lines. We also examined the effect of anticancer agents on the alternative splicing of 95 other human apoptotic genes in different cell lines. Almost every drug can alter a subset of alternative splicing events in each cell line. Although drugs of the same class often influence the alternative splicing of the same units in individual cell lines, these units differ considerably between cell lines, indicating cell line-specific differences in the pathways that control splicing.     

Transgenic ablation of rod photoreceptors alters the circadian phenotype of mice

The impact of photoreceptor loss on the circadian system was examined by utilizing a transgenic mouse model (rdta) in which rod photoreceptors were specifically ablated. These mice were able to phase-shift their circadian locomotor behaviour in response to light, but features of this circadian behaviour were markedly altered. The amplitude of circadian responses to light were approximately 2.5 greater, the circadian period (tau) was reduced (c. 20 min) and the total duration of activity (alpha) was increased (c. 50 min) when compared to wild type (+/+) and rd/rd mice (retinal degeneration, mice which also lack rod photoreceptors) of the same genetic background. The pattern of Fos expression in the suprachiasmatic nuclei (the site of the primary circadian clock in mammals) was indistinguishable between +/+ and rdta mice. However, Fos expression in the retina suggested that rod loss in rdta mice resulted in a functional reorganization of the retina and the constitutive activation of a population of retinal ganglion cells. Although it has been known for several years that the entraining photoreceptors of mammals are ocular, and that rod photoreceptors are not required for light regulation of the clock, these are the first data to show that features of the circadian phenotype (amplitude of the phase response curve, alpha, tau) can be influenced by photoreceptor ablation. These data support the hypothesis that the circadian phenotype of mammals is the product of an interaction between the suprachiasmatic nuclei and the retina. Thus, mammals which show an altered circadian behaviour can no longer be assumed to have defects associated only with specific clock genes; genes that affect photoreceptor survival may also modify circadian behaviour.     

Effect of decreased retinal illumination on simultaneously recorded pattern electroretinograms and visual-evoked potentials

Sixteen normal subjects and three patients with optic neuritis were studied to determine the effect of decreased retinal illumination on simultaneously recorded pattern electroretinograms (PERG) and visual-evoked potentials (VEP). Using neutral-density filters (NDF), it was found that linear modeling is an excellent fit for VEP/PERG amplitudes and latencies as log functions of retinal illumination, both for individual eyes and averages of pooled data. Within narrow statistical limits, regression slopes show that mean PERG B-wave and VEP P100 latencies are affected almost identically by decreased illumination, leaving the mean retinocortical time (RCT) virtually unchanged. However, mean B-wave amplitude was greatly reduced at retinal illuminations at which P100 amplitude was unaffected. Of clinical significance was that these latency and amplitude effects were found in each eye tested, whether normal or pathologic. In particular, the RCT in normal subjects was never found to be statistically abnormal due to decreased retinal illumination, and it faithfully represented the optic nerve lesion in the patients with optic neuritis. This result was applied to a population of eight patients with uncomplicated cataracts. The significance of these results is discussed.     

Interaction between humans and poultry, rural Cambodia

Because avian influenza H5N1 infection risks are associated with exposure to infected poultry, we conducted a knowledge, attitudes, and practices survey of poultry-handling behavior among villagers in rural Cambodia. Despite widespread knowledge of avian influenza and personal protection measures, most rural Cambodians still have a high level of at-risk poultry handling.