Effective removal of methotrexate by high-flux hemodialysis

The purpose of the present study was to examine the clearance of methotrexate (MTX) by high-flux hemodialysis (HD) in pediatric oncology patients. We present three patients who experienced nephrotoxicity and prolonged exposure to toxic MTX concentrations following high-dose infusions during treatment for osteogenic sarcomas. Each patient was successfully treated with high-flux HD, followed by carboxypeptidase G2 (CPDG2) in two cases. Minimal systemic toxicity occurred. We review the literature and discuss guidelines for early and aggressive treatment for this complication of high-dose MTX therapy. Clinically important removal of MTX depends upon prompt initiation of HD after detection of nephrotoxicity and delayed clearance of MTX. Therapy is indicated in cases where compassionate use of CPDG(2) may not be available, or while awaiting its delivery.     

Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension

PURPOSE: Retinal ganglion cell (RGC) death in glaucoma involves apoptosis. Activation of caspases and abnormal processing of amyloid precursor protein (APP) are important events in other chronic neurodegenerations, such as Alzheimer's disease (AD). The retinal expression and activation of caspases and the patterns of caspase-3-mediated APP processing in ocular hypertensive models of rat glaucoma were investigated. METHODS: RGC death was produced in one eye by chronic exposure to increased intraocular pressure (IOP) or by optic nerve transection. Elevated IOP was produced by obstruction of aqueous humor outflow with laser coagulation or limbal hypertonic saline injection. Caspase activity and APP processing in the retina were examined by RNase protection assay (RPA), immunocytochemistry, immunoblot assay, and colorimetric assay. RESULTS: RPA revealed elevations of caspase-3 mRNA, as well as other apoptosis-related mRNAs. Immunocytochemistry showed caspase-3 activation in RGCs damaged by ocular hypertension. The generation of the caspase-3-mediated APP cleavage product (DeltaC-APP) was also increased in ocular hypertensive RGCs. Western immunoblot assay and colorimetry revealed significantly more activated caspase-3 in ocular hypertensive retinas than in control retinas. The activated form of caspase-8, an initiator caspase, and amyloid-beta, a product of APP proteolysis and a component of senile plaques in AD, were detected in RGCs by immunohistochemistry significantly more often in ocular hypertensive than in control retinas. The amounts of full-length APP were reduced and amyloid-beta-containing fragments were increased in ocular hypertensive retinas by Western immunoblot assay. CONCLUSIONS: Rat RGCs subjected to chronic ocular hypertension demonstrate caspase activation and abnormal processing of APP, which may contribute to the pathophysiology of glaucoma.     

Effect of technique on intraocular pressure after combined cataract and glaucoma surgery: An evidence-based review

TOPIC: To analyze the literature pertaining to the techniques used in combined cataract and glaucoma surgery, including the technique of cataract extraction, the timing of the surgery (staged procedure versus combined procedure), the anatomic location of the operation, and the use of antifibrosis agents. CLINICAL RELEVANCE: Cataract and glaucoma are both common conditions and are often present in the same patient. There is no agreement concerning the optimal surgical management of these disorders when they coexist. METHODS/LITERATURE REVIEWED: Electronic searches of English language articles published since 1964 were conducted in Pub MED and CENTRAL, the Cochrane Collaboration's database. These were augmented by a hand search of six ophthalmology journals and the reference lists of a sample of studies included in the literature review. Evidence grades (A, strong; B, moderate; C, weak; I, insufficient) were assigned to the evidence that involved a direct comparison of alternative techniques. RESULTS: The preponderance of evidence from the literature suggests a small (2-4 mmHg) benefit from the use of mitomycin-C (MMC), but not 5-fluorouracil (5-FU), in combined cataract and glaucoma surgery (evidence grade B). Two-site surgery provides slightly lower (1-3 mmHg) intraocular pressure (IOP) than one-site surgery (evidence grade C), and IOP is lowered more (1-3 mmHg) by phacoemulsification than by nuclear expression in combined procedures (evidence grade C). There is insufficient evidence to conclude either that staged or combined procedures give better results or that alternative glaucoma procedures are superior to trabeculectomy in combined procedures. CONCLUSIONS: In the literature on surgical techniques and adjuvants used in the management of coexisting cataract and glaucoma, the strongest evidence of efficacy exists for using MMC, separating the incisions for cataract and glaucoma surgery, and removing the nucleus by phacoemulsification.     

Aging and intestinal motility: a review of factors that affect intestinal motility in the aged

Normal aging is associated with significant changes in the function of most organs and tissues. In this regard, the gastrointestinal tract is no exception. The purpose of this review is to detail the important age-related changes in motor function of the various parts of the gastrointestinal tract and to highlight some of the important motility changes that may occur, either in relation to common age-related disorders, or as a result of certain drugs commonly prescribed in the aged. A major confounding factor in the interpretation of motor phenomena throughout the gastrointestinal tract in this age group is the frequent coexistence of neurological, endocrinological and other disease states, which may be independently associated with dysmotility. Overall, current data are insufficient to implicate normal aging as a cause of dysmotility in the elderly. Normal aging is associated with various changes in gastrointestinal motility, but the clinical significance of such changes remains unclear. More important is the impact of various age-related diseases on gastrointestinal motility in the elderly: for example, long-standing diabetes mellitus may reduce gastric emptying in up to 50% of patients; depression significantly prolongs whole-gut transit time; hypothyroidism may prolong oro-caecal transit time; and chronic renal failure is associated with impaired gastric emptying. In addition, various, frequently used drugs in the elderly cause disordered gastrointestinal motility. These drugs include anticholinergics, especially antidepressants with an anticholinergic effect, opioid analgesics and calcium antagonists.     

Immunization with a cannabinoid receptor type 1 peptide results in experimental allergic meningocerebellitis in the Lewis rat: a model for cell-mediated autoimmune neuropathology

Sky (also known as "Tyro3" and "Rse") is a member of the Axl/Sky/Mer receptor tyrosine kinase family and has two immunoglobulin-like repeats and two fibronectin type III-like repeats in the extracellular domain. Gas6 is a ligand for all members of the Axl family, each of which (Axl, Sky, and c-Mer) has different affinities to Gas6. Physiological functions of Sky and Gas6 in the nervous system are not well understood, despite their importance, which is suggested by Sky structural features and its predominant expression in the brain. We found in the RNase protection assays that gas6 and sky mRNAs are expressed in the adult rat hippocampus and are similarly regulated during development. Expression levels were low during embryonic stages but gradually increased during development and reached the highest level in adulthood. Sky, but not Axl, immunoreactivity was observed in the adult hippocampus. Recombinant rat Gas6 attenuated hippocampal neuronal cell death that was caused by serum starvation in vitro, indicating that Gas6 is a novel neurotrophic factor for hippocampal neurons. Gas6 showed regulated expression in the sciatic nerve after nerve transection. Therefore, Sky and Gas6 have neurotrophic roles in the nervous system.     

Mapping functionally related regions of brain with functional connectivity MR imaging

BACKGROUND AND PURPOSE: In subjects who are performing no prescribed cognitive task, functional connectivity mapped with MR imaging (fcMRI) shows regions with synchronous fluctuations of cerebral blood flow. When specific tasks are performed, functional MR imaging (fMRI) can map locations in which regional cerebral blood flow increases synchronously with the performance of the task. We tested the hypothesis that fcMRI maps, based on the synchrony of low-frequency blood flow fluctuations, identify brain regions that show activation on fMRI maps of sensorimotor, visual, language, and auditory tasks. METHODS: In four volunteers, task-activation fMRI and functional connectivity (resting-state) fcMRI data were acquired. A small region of interest (in an area that showed maximal task activation) was chosen, and the correlation coefficient of the corresponding resting-state signal with the signal of all other voxels in the resting data set was calculated. The correlation coefficient was decomposed into frequency components and its distribution determined for each fcMRI map. The fcMRI maps were compared with the fMRI maps. RESULTS: For each task, fcMRI maps based on one to four seed voxel(s) produced clusters of voxels in regions of eloquent cortex. For each fMRI map a closely corresponding fcMRI map was obtained. The frequencies that predominated in the cross-correlation coefficients for the functionally related regions were below 0.1 Hz. CONCLUSION: Functionally related brain regions can be identified by means of their synchronous slow fluctuations in signal intensity. Such blood flow synchrony can be detected in sensorimotor areas, expressive and receptive language regions, and the visual cortex by fcMRI. Regions identified by the slow synchronous fluctuations are similar to those activated by motor, language, or visual tasks.     

Creative arterial bypass grafting can be performed on the beating heart

BACKGROUND: To demonstrate that compromise is unnecessary in either the design or performance of beating heart surgery, we report our experience, over 1 year, of total arterial revascularization where composite or creative grafting was utilized. METHODS: We performed 321 off-pump coronary artery bypass operations, of which, 290 (90%) were done with only arterial conduits. The mean number of distal anastomoses was 2.48, with a range of 1 to 5. There were no aortic anastomoses. One hundred eighty-nine patients (65%) were male, and 101 (35%) were female, with a mean age of 67 years. Comorbidities included chronic renal failure (CRF), 21 (7%); diabetes, 92 (32%); obesity, 68 (23%); hypertension, 212 (73%); chronic obstructive pulmonary disease, 189 (65%); cerebral vascular accident (CVA), 39 (13%); smoking, 164 (56%); and hypercholesterolemia, 151 (52%). The mean ejection fraction was 56%, with a range of 21% to 71%. All procedures were performed with external stabilizers with or without vacuum assist. The complete arterial revascularizations included a T-graft (internal thoracic [ITA]/radial arteries [RA]), 130 (45%); a sequential graft (ITA +/- RA), 118 (41%); a U-graft (coronary-coronary graft perfused by the ITA or right gastroepiploic artery), 5 (2%); an I-graft (ITA/RA), 4 (1%); an X-graft (ITA/RA), 2 (12); and a Y-graft (ITA/RA), 31 (10%). RESULTS: The postoperative incidence of atrial fibrillation was 80 of 290 (27%); CVA, 5 of 290 (2%); bleeding resulting in take-back, 5 of 290 (2%); CRF, 8 of 290 (3%); deep sternal infection, 4 of 290 (1%); and readmission (30-day) for angina, 4 of 290 (1%). The observed perioperative (30-day) mortality was 9 of 290 (3.1%), with the STS predicted rate of 3.82%. CONCLUSIONS: Our experience indicates that once the operating surgeon has learned to safely expose the lateral and inferior walls of the heart, the type of conduit and the method of revascularization should be no different than that used with cardiopulmonary bypass. However, we still recommend conventional methods of revascularization (on-pump with saphenous vein conduits) for the ischemic patient.