Consensus guidelines on the management of methotrexate-induced nephrotoxicity using glucarpidase (Voraxaze) may be relatively unfamiliar to the nephrology community.A 61-year-old man with intravascular large B-cell lymphoma was admitted for cycle #1 of high-dose methotrexate (HDMTX) following 2 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. On admission, he was clinically euvolemic and had a creatinine clearance of 98 mL/min. He received standard HDMTX toxicity prophylaxis with volume expansion, urinary alkalinization, and leucovorin rescue.Despite prophylactic efforts, he developed a severe acute kidney injury, creatinine 63 to 226 µmol/L (2.56 mg/dL), following HDMTX, impaired methotrexate clearance, and neurotoxicity manifested by status epilepticus.He was given glucarpidase to convert extracellular methotrexate into its inactive metabolites, glutamate and DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) at 52 hours post-HDMTX. Cross-reactivity between commercial methotrexate immunoassays with DAMPA led to falsely elevated methotrexate concentrations for much longer than expected based on the current guideline (5 days instead of <48 hours). This required ongoing monitoring of methotrexate concentration by mass spectrometry.The patient remained nonoliguric and did not develop acute indications for dialysis. Serum creatinine peaked at 608 µmol/L (6.88 mg/dL) 6 days after HDMTX. He ultimately had a full renal and neurologic recovery.Glucarpidase is an effective option for nonrenal elimination of methotrexate-induced nephrotoxicity. Timing of methotrexate concentration monitoring to assess for toxicity, how to access the drug, and the need for ongoing monitoring by mass spectrometry beyond the guideline recommendation are highlighted for centers where HDMTX therapy may be used.Les lignes directrices consensuelles sur la prise en charge de la néphrotoxicité induite par le méthotrexate par l’administration de glucarpidase (VoraxazeMD) sont possiblement mal connues en néphrologie.Nous présentons le cas d’un patient de 61 ans atteint d’un lymphome intravasculaire à grandes cellules B qui avait été admis pour un cycle de traitement à dose élevée de méthotrexate (HDMTX) après deux cycles de chimiothérapie par R-CHOP. À l’admission, le patient était cliniquement euvolémique et présentait une clairance de la créatinine à 98 mL/min. Le patient a reçu la prophylaxie standard pour une toxicité à HDMTX avec expansion volumique, alcalinisation urinaire et sauvetage par leucovorine.Malgré les mesures prophylactiques, l’état du patient a évolué vers une grave insuffisance rénale aigüe (créatinine initiale de 63 à 226 µmol/L [2,56 mg/dL]) après le traitement au HDMTX, de même qu’une altération de la clairance du méthotrexate et une neurotoxicité manifestée par un status epilepticus.Le patient a reçu du glucarpidase pour convertir le méthotrexate extracellulaire en ses métabolites inactifs, le glutamate et le DAMPA (acide 4-déoxy-4-amino-N10-méthylptéroïque) 52 heures après le traitement au HDMTX. La réactivité croisée entre les immunoessais commerciaux au méthotrexate et le DAMPA a entraîné des concentrations faussement élevées de méthotrexate pour beaucoup plus longtemps que prévu selon la recommandation actuelle (5 jours plutôt que < 48 heures). Cette situation a nécessité une surveillance continue de la concentration du méthotrexate par spectrométrie de masse.Le patient est demeuré non oligurique et n’a pas nécessité de dialyse. Le taux de créatinine sérique a culminé à 608 µmol/L (6,88 mg/dL) six jours après l’administration de HDMTX. Les fonctions rénale et neurologique du patient se sont finalement rétablies complètement.La glucarpidase est une option efficace pour éliminer de façon non rénale la néphrotoxicité induite par le méthotrexate. Le moment de mesurer la concentration de méthotrexate pour évaluer la toxicité, la façon d’accéder au médicament et la nécessité d’une surveillance continue par spectrométrie de masse au-delà de la recommandation actuelle sont clarifiés pour les centres où un traitement par HDMTX pourrait être administré.
Abstract Background The clinical use of common cardiac biomarkers, such as brain natriuretic peptides and troponins, has traditionally been limited to adult populations in the assessment of heart failure and acute coronary syndrome, respectively. While many have discounted the value of these markers in pediatric populations, emerging evidence suggests they may be useful in the diagnosis and prognostication of many cardiac and noncardiac pathologies in neonates, children, and adolescents, and an increasing number of pediatric hospitals are routinely measuring cardiac markers in their clinical practice. Content This review summarizes and critically evaluates the current literature regarding the application of cardiac biomarkers for clinical decision-making in the pediatric population. Main potential clinical indications discussed herein include primary cardiac disease, immune-related conditions, and noncardiac disease. Important diagnostic and interpretative challenges are also described in relation to each potential indication. Summary Despite a general lack of clinical awareness regarding the value of cardiac biomarkers in pediatrics, there is increasing literature to support their application in various contexts. Cardiac biomarkers should be considered an undervalued resource in the pediatric population with potential value in the diagnosis and prognosis of myocarditis, congenital heart disease, and heart failure, as well as in the assessment of severity and cardiac involvement in immune-related and other systemic conditions. While interpretation remains challenging in pediatrics due to the age- and sex-specific dynamics occurring throughout growth and development, this should not prevent their application. Future research should focus on defining evidence-based cut-offs for specific indications using the most up-to-date assays.
Nucleotide de novo synthesis is highly conserved among organisms and represents an essential biochemical pathway. In plants, the two initial enzymatic reactions of de novo pyrimidine synthesis occur in the plastids. By use of green fluorescent protein fusions, clear support is provided for a localization of the remaining reactions in the cytosol and mitochondria. This implies that carbamoyl aspartate, an intermediate of this pathway, must be exported and precursors of pyrimidine salvage (i.e., nucleobases or nucleosides) are imported into plastids. A corresponding uracil transport activity could be measured in intact plastids isolated from cauliflower (Brassica oleracea) buds. PLUTO (for plastidic nucleobase transporter) was identified as a member of the Nucleobase:Cation-Symporter1 protein family from Arabidopsis thaliana, capable of transporting purine and pyrimidine nucleobases. A PLUTO green fluorescent protein fusion was shown to reside in the plastid envelope after expression in Arabidopsis protoplasts. Heterologous expression of PLUTO in an Escherichia coli mutant lacking the bacterial uracil permease uraA allowed a detailed biochemical characterization. PLUTO transports uracil, adenine, and guanine with apparent affinities of 16.4, 0.4, and 6.3 μM, respectively. Transport was markedly inhibited by low concentrations of a proton uncoupler, indicating that PLUTO functions as a proton-substrate symporter. Thus, a protein for the absolutely required import of pyrimidine nucleobases into plastids was identified.
The implementation of standardized dosing units for six i.v. medications at an academic medical center is described.During the implementation of an electronic health record system at an academic medical center, it was noticed that providers could order some i.v. medications in multiple dosing units, including epinephrine, isoproterenol, midazolam, nitroglycerin, norepinephrine, and phenylephrine. Possible options to standardize i.v. medications along with their pros and cons were presented for discussion to key providers in all of the intensive care units. Once the providers agreed on a solution, the information was presented to the pharmacy and therapeutics committee for final approval. A nursing education plan was created and administered before the standardization of dosing units was implemented. A nursing survey was conducted before and after implementation of dosing-unit standardization to determine the effectiveness of nursing education on compliance with the standardization of the dosing units for the listed medications. The survey was designed to evaluate, when given a choice, what dosing units nurses would use to administer epinephrine, isoproterenol, midazolam, nitroglycerin, norepinephrine, and phenylephrine. The decision was made by the key providers to use weight-based dosing-micrograms per kilograms per minute-to allow for consistency of use of these medications for pediatric and adult patients. Nursing education was completed to ensure that nurses were aware of how to safely administer these medications using the new dosing units.Dosing-unit standardization for dose-adjustable i.v. infusions can provide improved consistency and decrease the potential for dosing errors when administering epinephrine, isoproterenol, midazolam, nitroglycerin, norepinephrine, and phenylephrine.
We examined how transient cerebral ischemia affects the mRNA expression, and the immunoreactive distribution, of the somatostatin type 2 (sst2) receptor in the adult rat hippocampus. Following reperfusion, sst2 mRNA levels increased significantly in the CA1 region by 3 h, and were also increased in the CA3 and CA4/hilus subfields at 6 and 12 h. At 24 h, however, sst2 receptor mRNA levels returned to baseline throughout the hippocampus. At the protein level, we found the regional immunoreactivity of the sst2a receptor was maintained, or slightly elevated, throughout the hippocampus at 6 h, but not different from control at 24 h. These results suggest that sst2 receptors maintain their normal distribution and prevalence in the post-ischemic hippocampus before the deterioration of the vulnerable CA1 neurons. Thus, they represent attractive targets for neuroprotective interventions.
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