Four factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices

Continuous flow left ventricular assist devices (CF-LVAD) require therapeutic anticoagulation which is often interrupted for procedures or bleeding. Prior to the availability of four factor prothrombin complex concentrate (4F-PCC) in the United States, warfarin was held and its effects reversed by vitamin K or fresh frozen plasma. We evaluated the use of 4F-PCC for temporary warfarin reversal in patients with CF-LVADs and assessed outcomes. This analysis is a retrospective study of CF-LVAD patients who received 4F-PCC for warfarin reversal in the setting of bleeding or need for urgent or elective procedures. Primary outcome assessments included feasibility of administration in elective versus emergent situations, safety measured as incidence of thrombotic events, and change in INR after administration. In total, 37 CF-LVAD patients received 49 4F-PCC administrations. The average 4F-PCC dose was 1842 units (range 518–4292 units), or 22 units/kg (range 5.8–58 units/kg). 4F-PCC significantly decreased the mean INR from 2.9 to 1.7 (p?<?0.0001) in 47 of 49 administrations; two patients did not have post infusion INR testing. No cases of new confirmed or suspected pump thrombosis, stroke, venous thromboembolism, arterial thrombosis, or myocardial infarction were observed within 30 days of administration of 4F-PCC. 4F-PCC administration for temporary warfarin reversal was demonstrated to be feasible, effective, and, safe in CF-LVAD patients and judged to be 96% effective in patients for whom data were available. We observed no thrombotic events attributed to use of 4F-PCC.     

Production of heparin binding epidermal growth factor-like growth factor in the early phase of regeneration after acute renal injury. Isolation and localization of bioactive molecules.

We have recently reported that heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA is induced in the rat kidney after acute ischemic injury. The present studies were designed to investigate whether bioactive HB-EGF protein is also produced in response to renal injury induced by either ischemia/reperfusion or aminoglycosides. Heparin-binding proteins were purified from kidney homogenates by heparin affinity column chromatography using elution with a 0.2-2.0 M gradient of NaCl. A single peak of proteins that eluted at 1.0-1.2 M NaCl was detected in the postischemic kidney within 6 h of injury. This eluate fraction stimulated DNA synthesis in quiescent Balb/c3T3, RIE, and NRK-52E cell lines, all of which are responsive to the epidermal growth factor family of mitogenic proteins. The EGF receptor of A431 cells was also tyrosine phosphorylated by this eluate peak. Furthermore, immunoblotting with a polyclonal antibody against rat HB-EGF indicated that the eluate peak contained immunoreactive proteins of 22 and 29 kD mol wt, consistent with the reported sizes of the secreted form and membrane anchored form of HB-EGF, respectively. Immunohistochemical studies revealed that HB-EGF was produced predominantly in distal tubules in kidneys injured either by ischemia/reperfusion or aminoglycoside administration. We also found that during metanephric development immunoreactive HB-EGF was detected in the ureteric bud as early as E14.5 and persisted in structures arising from the ureteric bud throughout embryogenesis. These results suggest that in response to acute injury, HB-EGF is produced predominantly in distal tubules and that endogenous HB-EGF may be an important growth factor involved in renal epithelial cell repair, proliferation, and regeneration in the early stages of recovery after acute renal injury, as well as in nephrogenesis.     

Iron distribution in Belgrade rat reticulocytes after inhibition of heme synthesis with succinylacetone

We have used succinylacetone (4,6-dioxoheptanoic acid), a specific inhibitor of delta-aminolevulinic acid dehydrase, to gain insight into the defect in iron metabolism in the Belgrade anemia. The Belgrade rat has an inherited microcytic, hypochromic anemia associated with poor iron uptake into developing erythroid cells. Succinylacetone inhibits heme synthesis, leading to nonheme iron accumulation in mitochondria and cytosol of normal reticulocytes. When succinylacetone is used to inhibit Belgrade heme synthesis, iron from diferric transferrin does not accumulate in the stromal fraction that contains mitochondria, nor does 59Fe accumulate in the nonheme cytosolic fraction. Hence, the defect in the Belgrade rat reticulocyte occurs in the endocytic vesicle or in a step subsequent to iron transit from the vesicle but before the nonheme cytosolic or mitochondrial iron fractions. Therefore, the mutation affects either the release of iron from transferrin or iron transport from the vesicle to the mitochondrion.     

The worst symptom as defined by patients during heart failure hospitalization: implications for response to therapy

BackgroundPatients perceive different symptoms of heart failure decompensation. It is not known whether the nature of the worst symptom relates to hemodynamic profile, response to therapy, or improvement in clinical trials.Methods and ResultsPatients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial were hospitalized with advanced heart failure, ejection fraction ≤30%, and at least 1 sign and 1 symptom of elevated filling pressures. Visual analog scales (VAS) for symptoms were completed by 371 patients, who selected their worst symptom as difficulty breathing, fatigue, abdominal discomfort, or body swelling and also scored breathing and global condition at baseline and discharge. The dominant symptom identified was difficulty breathing by 193 (52%) patients, fatigue by 118 (32%), and abdominal discomfort and swelling each by 30 (8%) patients, combined as right-sided congestion for analysis. Clinical and hemodynamic assessments were not different between groups except that right-sided congestion was associated with more hepatomegaly, ascites, third heart sounds, and jugular venous distention. This group also had greater reduction in jugular venous distention and trend toward higher blood urea nitrogen after therapy. By discharge, average improvements in worst symptom and global score were 28 points and 24 points. For those with ≥10 points in improvement in worst symptom, 84% also improved global assessment ≥10 points. Initial fatigue was associated with less improvement (P = .002) during and after hospitalization, but improvements in symptom scores were sustained when re-measured during 6 months after discharge.ConclusionIn most patients hospitalized with clinical congestion, therapy will improve symptoms regardless of the worst symptom perceived, with more evidence of baseline fluid retention and reduction during therapy for worst symptoms of abdominal discomfort or edema. Improvement in trials should be similar when tracking worst symptom, dyspnea, or global assessment.     

Effect of calorie restriction and refeeding on skin wound healing in the rat

Calorie restriction (CR) is a reliable anti-aging intervention that attenuates the onset of a number of age-related diseases, reduces oxidative damage, and maintains function during aging. In the current study, we assessed the effects of CR and other feeding regimens on wound healing in 7-month-old Fischer-344 rats from a larger cohort of rats that had been fed either ad libitum (AL) or 40% calorie restricted based on AL consumption. Rats were assigned to one of three diet groups that received three skin punch wounds along the dorsal interscapular region (12-mm diameter near the front limbs) of the back as follows: (1) CR (n = 8) were wounded and maintained on CR until they healed, (2) AL (n = 5) were wounded and maintained on AL until wound closure was completed, and (3) CR rats were refed (RF, n = 9) AL for 48 h prior to wounding and maintained on AL until they healed. We observed that young rats on CR healed more slowly while CR rats refed for 48 h prior to wounding healed as fast as AL fed rats, similar to a study reported in aged CR and RF mice (Reed et al. 1996). Our data suggest that CR subjects, regardless of age, fail to heal well and that provision of increased nutrition to CR subjects prior to wounding enhances the healing process.     

The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins

Frataxin deficiency in Friedreich’s ataxia (FRDA) causes cardiac, endocrine, and nervous system manifestations. Frataxin is a mitochondrial protein, and adequate amounts are essential for cellular iron homeostasis. The main histological lesion in the brain of FRDA patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed grumose degeneration. This cerebellar nucleus may be especially susceptible to FRDA because it contains abundant iron. We examined total iron and selected iron-responsive proteins in the dentate nucleus of nine patients with FRDA and nine normal controls by biochemical and microscopic techniques. Total iron (1.53 ± 0.53 μmol/g wet weight) and ferritin (206.9 ± 46.6 μg/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 ± 0.88 μmol/g; ferritin: 210.9 ± 9.0 μg/g) but Western blots exhibited a shift to light ferritin subunits. Immunocytochemistry of the dentate nucleus revealed loss of juxtaneuronal ferritin-containing oligodendroglia and prominent ferritin immunoreactivity in microglia and astrocytes. Mitochondrial ferritin was not detectable by immunocytochemistry. Stains for the divalent metal transporter 1 confirmed neuronal loss while endothelial cells reacting with antibodies to transferrin receptor 1 protein showed crowding of blood vessels due to collapse of the normal neuropil. Regions of grumose degeneration were strongly reactive for ferroportin. Purkinje cell bodies, their dendrites and axons, were also ferroportin-positive, and it is likely that grumose degeneration is the morphological manifestation of mitochondrial iron dysmetabolism in the terminals of corticonuclear fibers. Neuronal loss in the dentate nucleus is the likely result of trans-synaptic degeneration.     

The effects of amiflamine on cerebrospinal fluid amine metabolites in the rhesus monkey

Amiflamine, a drug reported to be a reversible inhibitor of monoamine oxidase type A (MAO-A) selective for serotonergic neurons in rodents, was administered to rhesus monkeys over a 12-fold dosage range (0.5-6 mg/kg). Amiflamine produced small, essentially equivalent reductions in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA, 1-28%), 3-methoxy-4-hydroxyphenylglycol (MHPG, 4-26%), and homovanillic acid (HVA, 7-29%), suggesting that the effects of amiflamine are approximately equal on serotonin, norepinephrine and dopamine metabolism in nonhuman primates. Concentrations of amiflamine were very low in CSF 3-6 h after drug administration (less than 7 nmol/l), while those of its two major, biologically active metabolites were higher (22-150 nmol/l) and varied in relative proportions among the monkeys. Further investigation is required of some preliminary observations of a possible association between drug metabolite variations and the substantial individual differences in the amine metabolite changes following amiflamine treatment. MAO-B in platelets was not inhibited by 6 mg/kg amiflamine, indicating that MAO-A selectivity was maintained. At low amiflamine doses, early and transient increases in CSF 5-HIAA and HVA concentrations were observed, suggesting an amine-releasing effect of the drug within brain serotonergic and dopaminergic neurons.     

Serotonin depletion potentiates gastric secretory and motor responses to vagal but not peripheral gastric stimulants

Vagal stimulation is known to release gastrointestinal serotonin. The effect of depletion of serotonin stores on vagally stimulated gastric acid secretion and motility was studied in rats. Pretreatment of rats with parachlorophenylalanine (p-CPA) did not alter basal gastric acid and serotonin secretion but produced a 57% reduction in the intraluminal gastric release of serotonin and a 43 to 100% potentiation of the gastric acid secretory response elicited by intracisternal injection of the stable thyrotropin-releasing hormone analog, RX 77368, in conscious pylorus-ligated rats or urethane-anesthetized rats with an acute gastric fistula. Dose-response studies revealed that the gastric acid secretion induced by submaximal but not high doses of RX 77368 was elevated significantly by p-CPA pretreatment. p-CPA also enhanced the gastric acid output produced by submaximal, but not high doses of the vagal stimulant baclofen, [beta-(p-chlorophenyl)-gamma-aminobutyric acid]. In contrast, p-CPA pretreatment had no effect on gastric acid secretion stimulated by bethanechol, histamine or pentagastrin. Selective depletion of central serotonin stores by pretreatment with the neurotoxin 5,7-dihydroxytryptamine given alone, or combined with parachloroamphetamine did not alter RX 77368-stimulated gastric acid secretion. In addition, gastric contractility stimulated by intracisternal injection of RX 77368 was significantly enhanced by p-CPA but not by 5,7-dihydroxytryptamine pretreatment, whereas the contractile response to carbachol was not altered by p-CPA pretreatment. These results suggest that depletion of peripheral but not central serotonergic stores potentiate gastric acid secretion and contractility induced by vagally, but not peripherally acting gastric stimulants. Thus, peripheral serotonin may exert an inhibitory tone on vagally stimulated gastric acid secretion and motility in the rat.     

Multifocal visual evoked potential latency analysis: predicting progression to multiple sclerosis

OBJECTIVE: To monitor the difference in conversion rates to multiple sclerosis (MS) in 46 patients with optic neuritis between patients with multifocal visual evoked potential latency delay and those with normal latency. DESIGN: Prospective case series. SETTING: Metropolitan neuro-ophthalmology clinic. PARTICIPANTS: Forty-six patients with optic neuritis who did not have a diagnosis of MS on enrollment in the study. MAIN OUTCOME MEASURES: Conversion to MS according to the McDonald criteria. RESULTS: Analysis revealed that only 22 subjects had multifocal visual evoked potential latency delay. Over 1 year, 36.4% of patients with optic neuritis with latency delays progressed clinically to MS compared with 0% of those with normal latencies (P = .03, chi2). CONCLUSION: This may indicate that multifocal visual evoked potential latency delay can assist in predicting progression to future MS.