Antihypertensive Medication Effect on Cerebral Blood Flow

Introduction: Data on the cerebral effects of antihypertensive agents are limited but potentially important in patients requiring blood pressure reduction in neurological emergencies. Our objective was to measure the effect of rapid-acting antihypertensive agents on cerebral blood flow (CBF) in patients with acute hypertension. Methods: We conducted a prospective, quasi-experimental study of patients with a SBP \u3e 180 mmHg and planned rapid-acting antihypertensive treatment in the emergency department. Patients \u3c 18 years or pregnant were excluded. Non-invasive hemodynamic and transcranial Doppler measurements of the middle cerebral artery mean flow velocity (MFV) were obtained prior to and post treatment. Analysis included descriptive statistics and generalized linear modeling to test the effect of four categories of antihypertensive agents on MFV. Categories included clonidine, IV labetalol, IV hydralazine and combination therapy. Results: We enrolled 35 patients (37% female) with a mean age of 49 ± 13 years. Eight (23%) patients received clonidine, 6 (17%) IV labetalol, 5 (14%) IV hydralazine and 16 (46%) combined therapy. The mean baseline SBP was 214 ± 24 mmHg and MFV 49 ± 13 cm/sec. The mean percentage fall in SBP by medication was: clonidine -12 ±7%, labetalol -13 ±12%, hydralazine -23 ±11%, and combination -23 ±16%. The overall change in MFV was -9 ±15%, and by medication was: clonidine -10% (95%CI -2 to - 21%), labetalol -11% (95%CI -5 to -27%), hydralazine +1% (95%CI -18 to +21%), and combination -11% (95%CI -2 to -19%). Adjusting for baseline BP, hydralazine caused less change in MFV compared to other medications (difference between means +12%, 95%CI -3 to +26%, p=0.1). Conclusions: In this study with modest BP reductions, rapid-acting antihypertensive medications had comparable effects on cerebral blood flow. These results hint that cerebral blood flow may be more stable with hydralazine administration, but further testing of hydralazine and infusions such as nicardipine is required

The Utility of Liquid Biopsy in Central Nervous System Malignancies

PURPOSE OF REVIEW: Liquid biopsy is a sampling of tumor cells or tumor nucleotides from biofluids. This review explores the roles of liquid biopsy for evaluation and management of patients with primary and metastatic CNS malignancies. RECENT FINDINGS: Circulating tumor cell (CTC) detection has emerged as a relatively sensitive and specific tool for diagnosing leptomeningeal metastases. Circulating tumor DNA (ctDNA) detection can effectively demonstrate genetic markup of CNS tumors in the cerebrospinal fluid, though its role in managing CNS malignancies is less well-defined. The value of micro RNA (miRNA) detection in CNS malignancies is unclear at this time. Current standard clinical tools for the diagnosis and monitoring of CNS malignancies have limitations, and liquid biopsy may help address clinical practice and knowledge gaps. Liquid biopsy offers exciting potential for the diagnosis, prognosis, and treatment of CNS malignancies, but each modality needs to be studied in large prospective trials to better define their use

Hyperglycemia‐ and neuropathy‐induced changes in mitochondria within sensory nerves

Objective This study focused on altered mitochondrial dynamics as a potential mechanism for diabetic peripheral neuropathy ( DPN ). We employed both an in vitro sensory neuron model and an in situ analysis of human intraepidermal nerve fibers ( IENF s) from cutaneous biopsies to measure alterations in the size distribution of mitochondria as a result of hyperglycemia and diabetes, respectively. Methods Neurite‐ and nerve‐specific mitochondrial signals within cultured rodent sensory neurons and human IENF s were measured by employing a three‐dimensional visualization and quantification technique. Skin biopsies from distal thigh (DT) and distal leg (DL) were analyzed from three groups of patients; patients with diabetes and no DPN , patients with diabetes and confirmed DPN , and healthy controls. Results This analysis demonstrated an increase in mitochondria distributed within the neurites of cultured sensory neurons exposed to hyperglycemic conditions. Similar changes were observed within IENF s of the DT in DPN patients compared to controls. This change was represented by a significant shift in the size frequency distribution of mitochondria toward larger mitochondria volumes within DT nerves of DPN patients. There was a length‐dependent difference in mitochondria within IENF s. Distal leg IENF s from control patients had a significant shift toward larger volumes of mitochondrial signal compared to DT IENF s. Interpretation The results of this study support the hypothesis that altered mitochondrial dynamics may contribute to DPN pathogenesis. Future studies will examine the potential mechanisms that are responsible for mitochondrial changes within IENF s and its effect on DPN pathogenesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109326/1/acn3119.pd

A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance

Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemias (CMLs). However, a significant proportion of patients chronically treated with imatinib develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Mutations occur at residues directly implicated in imatinib binding or, more commonly, at residues important for the ability of the kinase to adopt the specific closed (inactive) conformation to which imatinib binds. In our quest to develop new BCR-ABL inhibitors, we chose to target regions outside the ATP-binding site of this enzyme because these compounds offer the potential to be unaffected by mutations that make CML cells resistant to imatinib. Here we describe the activity of one compound, ON012380, that can specifically inhibit BCR-ABL and induce cell death of Ph(+) CML cells at a concentration of <10 nM. Kinetic studies demonstrate that this compound is not ATP-competitive but is substrate-competitive and works synergistically with imatinib in wild-type BCR-ABL inhibition. More importantly, ON012380 was found to induce apoptosis of all of the known imatinib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection of 32Dcl3 cells expressing the imatinib-resistant BCR-ABL isoform T315I. Daily i.v. dosing for up to 3 weeks with a >100 mg/kg concentration of this agent is well tolerated in rodents, without any hematotoxicity