Comparative effectiveness of incident oral antidiabetic drugs on kidney function

Diabetes is a major cause of chronic kidney disease, and oral antidiabetic drugs are the mainstay of therapy for most patients with Type 2 diabetes. Here we evaluated their role on renal outcomes by using a national Veterans Administration database to assemble a retrospective cohort of 93,577 diabetic patients who filled an incident oral antidiabetic drug prescription for metformin, sulfonylurea, or rosiglitazone, and had an estimated glomerular filtration rate (eGFR) of 60 ml/min or better. The primary composite outcome was a persistent decline in eGFR from baseline of 25% or more (eGFR event) or a diagnosis of end-stage renal disease (ESRD). The secondary outcome was an eGFR event, ESRD, or death. Sensitivity analyses included using a more stringent definition of the eGFR event requiring an eGFR <60 ml/min per 1.73 m2 in addition to the 25% or more decline; controlling for baseline proteinuria thereby restricting data to 15,065 patients; and not requiring persistent treatment with the initial oral antidiabetic drug. Compared to patients using metformin, sulfonylurea users had an increased risk for both the primary and the secondary outcome, each with an adjusted hazard ratio of 1.20. Results of sensitivity analyses were consistent with the main findings. The risk associated with rosiglitazone was similar to metformin for both outcomes. Thus, compared to metformin, oral antidiabetic drug treatment with sulfonylureas increased the risk of a decline in eGFR, ESRD, or death

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

The Role of Adenosine Signaling in Headache: A Review

Migraine is the third most prevalent disease on the planet, yet our understanding of its mechanisms and pathophysiology is surprisingly incomplete. Recent studies have built upon decades of evidence that adenosine, a purine nucleoside that can act as a neuromodulator, is involved in pain transmission and sensitization. Clinical evidence and rodent studies have suggested that adenosine signaling also plays a critical role in migraine headache. This is further supported by the widespread use of caffeine, an adenosine receptor antagonist, in several headache treatments. In this review, we highlight evidence that supports the involvement of adenosine signaling in different forms of headache, headache triggers, and basic headache physiology. This evidence supports adenosine A2A receptors as a critical adenosine receptor subtype involved in headache pain. Adenosine A2A receptor signaling may contribute to headache via the modulation of intracellular Cyclic adenosine monophosphate (cAMP) production or 5' AMP-activated protein kinase (AMPK) activity in neurons and glia to affect glutamatergic synaptic transmission within the brainstem. This evidence supports the further study of adenosine signaling in headache and potentially illuminates it as a novel therapeutic target for migraine

The (R)- isomer of isometheptene decreases trigeminal sensitivity in a rat model of primary headache

Introduction Isometheptene is thought to be the active ingredient of the commonly known headache medication, Midrin. Previously, we found only the (R) enantiomer to be effective in alleviating headache behavior in two models of headache compared to the (S) enantiomer. Experiments using electrical and mechanical stimulation of the dura in animals with no history of head pain have been used to elucidate the mechanisms of the trigeminovascular system at the level of the trigeminal ganglion, trigeminal nucleus caudalis, periaqueductal gray, and the thalamus. The limitation of these acute models is that electrical and mechanical stimulation of the dural blood vessels does not cause long lasting pain similar to recurrent headache pain in humans. Two animal models for the investigation of headache pathophysiology that include aspects of the chronic nature of headache were included in this study. These models provide a new approach to study the pathophysiology of recurrent headache and support validation of novel treatments. Using behavior methods of monitoring trigeminal allodynia in rats, our group discovered a rat with spontaneous episodic trigeminal allodynia (STA) (Oshinsky et al, 2012). The model was established through 18 generations of inbreeding for testing analgesics and the further understanding of mechanisms of migraine. STA rats experience similar symptoms to human migraine patients, such as episodic trigeminal sensitivity, phonophobia, responsiveness to abortive and prophylactic headache treatments, and sensitivity to migraine triggers. A second well-characterized model of repeated dural inflammatory stimulation (IS), in which an inflammatory stimulant is infused over the dura, also results in persistent headache behavior that has been accepted as a valid model for drug testing. Although the pathological mechanisms between the two models are different, one being considered idiopathic or a spontaneous model and the other inflammatory in nature, the precise mechanism(s) remain elusive. The aim of this study is to determine the dose response of the (R)-isomer of isometheptene on trigeminal sensitivity in the STA and IS rat models and study the mechanism of action of isometheptene. Poster presented at: American Headache Society 58th Annual Scientific Meeting in San Diego CA.https://jdc.jefferson.edu/neurosurgeryposters/1005/thumbnail.jp