Ruxolitinib in patients with polycythemia vera resistant and/or intolerant to hydroxyurea: European observational study.

BACKGROUND: Hydroxyurea (HU) is a commonly used first-line treatment in patients with polycythemia vera (PV). However, approximately 15%-24% of PV patients report intolerance and resistance to HU. METHODS: This phase IV, European, real-world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24-month follow-up. The primary objective was to describe the profile and disease burden of PV patients. RESULTS: In the 350 enrolled patients, 70% were >60 years old. Most patients (59.4%) had received ≥1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit <45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment-related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug-related. CONCLUSION: This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.

Identifying Patients with Polycythemia Vera at Risk of Thrombosis after Hydroxyurea Initiation: The Polycythemia Vera-Advanced Integrated Models (PV-AIM) Project.

Patients with polycythemia vera (PV) are at significant risk of thromboembolic events (TE). The PV-AIM study used the Optum® de-identified Electronic Health Record dataset and machine learning to identify markers of TE in a real-world population. Data for 82,960 patients with PV were extracted: 3852 patients were treated with hydroxyurea (HU) only, while 130 patients were treated with HU and then changed to ruxolitinib (HU-ruxolitinib). For HU-alone patients, the annualized incidence rates (IR; per 100 patients) decreased from 8.7 (before HU) to 5.6 (during HU) but increased markedly to 10.5 (continuing HU). Whereas for HU-ruxolitinib patients, the IR decreased from 10.8 (before HU) to 8.4 (during HU) and was maintained at 8.3 (after switching to ruxolitinib). To better understand markers associated with TE risk, we built a machine-learning model for HU-alone patients and validated it using an independent dataset. The model identified lymphocyte percentage (LYP), neutrophil percentage (NEP), and red cell distribution width (RDW) as key markers of TE risk, and optimal thresholds for these markers were established, from which a decision tree was derived. Using these widely used laboratory markers, the decision tree could be used to identify patients at high risk for TE, facilitate treatment decisions, and optimize patient management.

The Role of miR-29 Family in TGF-ß Driven Fibrosis in Glaucomatous Optic Neuropathy.

Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-ß) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgical treatments targeting the only known modifiable risk factor, raised intraocular pressure, many patients still progress and develop significant visual field loss and eventual blindness. The search for alternative treatment strategies targeting the underlying fibrotic transformation in the optic nerve head and trabecular meshwork in glaucoma is ongoing. MicroRNAs are small non-coding RNAs known to regulate post-transcriptional gene expression. Extensive research has been undertaken to uncover the complex role of miRNAs in gene expression and miRNA dysregulation in fibrotic disease. MiR-29 is a family of miRNAs which are strongly anti-fibrotic in their effects on the TGF-ß signalling pathway and the regulation of extracellular matrix production and deposition. In this review, we discuss the anti-fibrotic effects of miR-29 and the role of miR-29 in ocular pathology and in the development of glaucomatous optic neuropathy. A better understanding of the role of miR-29 in POAG may aid in developing diagnostic and therapeutic strategies in glaucoma.

Tectonic Descemet's stripping automated endothelial keratoplasty for corneal perforation.

We report the use of Descemet stripping automated endothelial keratoplasty (DSAEK) for the treatment of sterile corneal perforation after trauma. In an eye with corneal perforation and cataract due to trauma, cataract surgery and DSAEK were performed. Corneal integrity was promptly restored and the patient avoided tectonic anterior lamellar and penetrating keratoplasty. DSAEK may be performed for the management of corneal perforation.

Ptosis, ophthalmoplegia and corneal endothelial disease - ocular manifestations of mitochondrial disease.

PURPOSE: To describe two patients with bilateral ptosis, ophthalmoplegia, cataracts and corneal endothelial disease requiring corneal transplantation. OBSERVATIONS: Histopathological analysis of muscle biopsy samples from both patients identified features consistent with a mitochondrial cytopathy. A single multigenic mitochondrial deoxyribonucleic acid (DNA) deletion was detected in the first patient. Pathogenic mutations in the POLG gene which codes for mitochondrial DNA polymerase, tasked with replicating the mitochondrial genome were identified in the second patient. CONCLUSION: The collection of clinical features present in both cases described can be explained by a diagnosis of mitochondrial disease. IMPORTANCE: Corneal endothelial disease, in addition to ptosis, ophthalmoplegia, cataract, pigmentary retinopathy and optic atrophy should be recognised as a feature of mitochondrial disease.

Animal models of traumatic brain injury: a critical evaluation.

Animal models are necessary to elucidate changes occurring after brain injury and to establish new therapeutic strategies towards a stage where drug efficacy in brain injured patients (against all classes of symptoms) can be predicted. In this review, six established animal models of head trauma, namely fluid percussion, rigid indentation, inertial acceleration, impact acceleration, weight-drop and dynamic cortical deformation are evaluated. While no single animal model is entirely successful in reproducing the complete spectrum of pathological changes observed after injury, the validity of these animal models including face, construct, etiological and construct validity and how the models constitute theories about brain injury is addressed. The various types of injury including contact (direct impact) and non-contact (acceleration/deceleration) and their associated pathologies are described. The neuropathologic classifications of brain injury including primary and secondary, focal and diffuse are discussed. Animal models and their compatibility with microdialysis studies are summarised particularly regarding the role of excitatory and inhibitory amino acid neurotransmitters. This review concludes that the study of neurotransmitter interactions within and between brain regions can facilitate the development of novel compounds targeted to treat those cognitive deficits not limited to a single pharmacological class and may be useful in the investigation of new therapeutic strategies and pharmacological testing for improved treatment for traumatic head injury.

Increased intestinal permeability in rats subjected to traumatic frontal lobe percussion brain injury.

BACKGROUND: Dysfunction of the gastrointestinal tract is a common occurrence after traumatic brain injury (TBI). We hypothesized that increased intestinal permeability may result from a precisely controlled percussion injury to the exposed brains of anesthetized rats and that such an effect could be assessed in vitro using excised intestinal mucosae mounted in Ussing chambers. METHODS: After craniotomy over the left medial prefrontal cortex on anesthetized rats, neurotrauma was produced using a pneumatically driven impactor on the exposed brain. Control rats were subjected to identical procedures but did not receive an impact. Muscle-stripped rat intestinal ileal and colonic segments were mounted in Ussing chambers within 30 minutes of death. Transepithelial electrical resistance (TEER) and the apparent permeability coefficient (Papp) of [C]-mannitol were recorded from intestinal tissue for 120 minutes. Histopathologic analysis was also performed to determine any gross morphologic changes in the intestine. RESULTS: Ileal and colonic mucosae showed no differences in TEER in ileum or colon of TBI rats compared with controls. The Papp of mannitol was significantly increased in ilea from rats previously exposed to TBI compared with controls. Histologic analysis showed gross changes to 50% of the ileal but not the colonic sections from TBI rats. CONCLUSION: TBI results in significantly reduced ileal barrier function, most likely mediated by open tight junctions. For patients with acute head injury, this may have implications for subsequent oral absorption of nutrients. Systemic delivery of luminal endotoxins may contribute to multiple organ failure.

NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat.

Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate that induces excitotoxic brain cell death. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress neurotransmitter release through selective activation of presynaptic group II metabotropic glutamate receptors. Therefore, strategies to elevate levels of NAAG following brain injury could reduce excessive glutamate release associated with TBI. We hypothesized that the NAAG peptidase inhibitor, ZJ-43 would elevate extracellular NAAG levels and reduce extracellular levels of amino acid neurotransmitters following TBI by a group II metabotropic glutamate receptor (mGluR)-mediated mechanism. Dialysate levels of NAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by in vivo microdialysis. Dialysate levels of NAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared with control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GABA levels. Co-administration of the group II mGluR antagonist, LY341495 (1 mg/kg, i.p.) partially blocked the effects of ZJ-43 on dialysate glutamate and GABA, suggesting that NAAG effects are mediated through mGluR activation. The results are consistent with the hypothesis that inhibition of NAAG peptidase may reduce excitotoxic events associated with TBI.