Outpatient Worsening Heart Failure in Patients With Transthyretin Amyloidosis With Cardiomyopathy in the HELIOS-B Trial.

Background: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a fatal disease, caused by misfolded transthyretin depositing as amyloid fibrils in the heart. Because disease progression is common, practical and sensitive methods are needed to monitor patients and optimize treatment decisions. Outpatient worsening heart failure (HF) (oral loop diuretic intensification or initiation) is simple to assess and has been shown to be prognostic of mortality in patients with ATTR-CM.

A pediatric quantitative systems pharmacology model of neurofilament trafficking in spinal muscular atrophy treated with the antisense oligonucleotide nusinersen.

Phosphorylated neurofilament heavy subunit (pNfH) has been recently identified as a promising biomarker of disease onset and treatment efficacy in spinal muscular atrophy (SMA). This study introduces a quantitative systems pharmacology model representing the SMA pediatric scenario in the age range of 0-20 years with and without treatment with the antisense oligonucleotide nusinersen. Physiological changes typical of the pediatric age and the contribution of SMA and its treatment to the peripheral pNfH levels were included in the model by extending the equations of a previously developed mathematical model describing the neurofilament trafficking in healthy adults.

Complexities of cooccurrence of catatonia and autoimmune thyroiditis in bipolar disorder: A case series and selective review.

In recent years the neurobiological underpinnings of catatonia have been an emerging area of interest. Catatonia is frequently encountered in mood disorders, neurological disorders and systemic illnesses. Furthermore, the manifestation of catatonia in autoimmune disorders such as NMDA receptor antibody encephalitis and thyroiditis reinforces its neuropsychiatric nature.

An age-dependent mathematical model of neurofilament trafficking in healthy conditions.

Neurofilaments (Nfs) are the major structural component of neurons. Their role as a potential biomarker of several neurodegenerative diseases has been investigated in past years with promising results. However, even under physiological conditions, little is known about the leaking of Nfs from the neuronal system and their detection in the cerebrospinal fluid (CSF) and blood.

Evaluation of salivary parameters and dental status in adult hemodialysis patients in an indian population.

Background: Renal failure is a process that expresses a loss of functional capacity of the nephrons, independently of its etiology. The most widely used technique to combat renal failure is hemodialysis. Renal failure causes various systemic alterations including oral complications such as variations in the flow and composition of the saliva.

Safety and Efficacy of Delayed-Release Dimethyl Fumarate in Pediatric Patients With Relapsing Multiple Sclerosis (FOCUS).

Background: No therapies have been formally approved by the Food and Drug Administration for use in pediatric multiple sclerosis, a rare disease.

Objective: We evaluated the safety, efficacy, and pharmacokinetics of dimethyl fumarate in pediatric patients with multiple sclerosis.

Methods: FOCUS, a phase 2, multicenter study of patients aged 10 to 17 years with relapsing-remitting multiple sclerosis, comprised an eight-week baseline and 24-week treatment period; during treatment, patients received dimethyl fumarate (120 mg twice daily on days one to seven; 240 mg twice a day thereafter).

Telehealth Versus In-Person Acceptance and Commitment Therapy for Chronic Pain: A Randomized Noninferiority Trial.

Unlabelled: The purpose of this randomized noninferiority trial was to compare video teleconferencing (VTC) versus in-person (IP) delivery of an 8-week acceptance and commitment therapy (ACT) intervention among veterans with chronic pain (N = 128) at post-treatment and at 6-month follow-up. The primary outcome was the pain interference subscale of the Brief Pain Inventory. Secondary outcomes included measures of pain severity, mental and physical health-related quality of life, pain acceptance, activity level, depression, pain-related anxiety, and sleep quality.

An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network.

There has been a recent interest in the broader physiological importance of multispecific "drug" transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wet-lab assays, together with re-evaluation of existing transport and knock-out metabolomics data, generated an experimentally validated, confidence ranked set of OAT1-interacting endogenous compounds enabling construction of an "OAT1-centered metabolic interaction network.

Transcriptome-based reconstructions from the murine knockout suggest involvement of the urate transporter, URAT1 (slc22a12), in novel metabolic pathways.

URAT1 (slc22a12) was identified as the transporter responsible for renal reabsorption of the medically important compound, uric acid. However, subsequent studies have indicated that other transporters make contributions to this process, and that URAT1 transports other organic anions besides urate (including several in common with the closely related multi-specific renal organic anion transporters, OAT1 (slc22a6) and OAT3 (slc22a8)). These findings raise the possibility that urate transport is not the sole physiological function of URAT1.

Striking differences between knockout and wild-type mice in global gene expression variability.

Microarray analyses of gene knockouts have traditionally focused on the identification of genes whose mean expression is different in knockout and wild-type mice. However, recent work suggests that changes in the variability of gene expression can have important phenotypic consequences as well. Here, in an unbiased sample of publicly available microarray data on gene expression in various knockouts, highly significant differences from wild-type (either increases or decreases) are noted in the gene expression coefficients of variation (CVs) of virtually every knockout considered.

Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk.

Importance: Posttraumatic stress disorder (PTSD) has been associated in cross-sectional studies with peripheral inflammation. It is not known whether this observed association is the result of PTSD predisposing to inflammation (as sometimes postulated) or to inflammation predisposing to PTSD.

Objective: To determine whether plasma concentration of the inflammatory marker C-reactive protein (CRP) helps predict PTSD symptoms.

Multispecific drug transporter Slc22a8 (Oat3) regulates multiple metabolic and signaling pathways.

Multispecific drug transporters of the solute carrier and ATP-binding cassette families are highly conserved through evolution, but their true physiologic role remains unclear. Analyses of the organic anion transporter 3 (OAT3; encoded by Slc22a8/Oat3, originally Roct) knockout mouse have confirmed its critical role in the renal handling of common drugs (e.g.

Organic anion transport pathways in antiviral handling in choroid plexus in Oat1 (Slc22a6) and Oat3 (Slc22a8) deficient tissue.

Transporters in the choroid plexus (CP) regulate transport of numerous compounds of physiological and therapeutic interest between blood and CSF and thus likely play a key role in determining CNS levels of drugs, toxins and metabolites. Here, high CP expression was noted for the organic anion transporters, Oat1 (SLC22A6 or NKT) and Oat3 (SLC22A8) which are also the principal Oats in the renal proximal tubule, as well as SLC22A17, hypothesized to be involved in iron transport. Because Oat1 and Oat3 have overlapping substrate specificity, ex vivo preparations of CP from Oat1((-/-)) and Oat3((-/-)) mice were used to isolate the individual transport function of each, respectively.

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice.

Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.

Syndrome of inappropriate antidiuretic hormone associated with moxifloxacin.

Purpose: A possible case of moxifloxacin-induced syndrome of inappropriate antidiuretic hormone (SIADH) is reported.

Summary: A 66-year-old Caucasian woman with stage II chronic obstructive pulmonary disease (COPD) arrived at the emergency department from an outpatient clinic complaining of worsening shortness of breath, headache, body aches, and dizziness. Five days before her arrival at the hospital, the patient was seen in an outpatient clinic with symptoms of COPD exacerbation and was given a corticosteroid taper of prednisone 40 mg daily and moxifloxacin 400 mg daily.

Linkage of organic anion transporter-1 to metabolic pathways through integrated "omics"-driven network and functional analysis.

The main kidney transporter of many commonly prescribed drugs (e.g. penicillins, diuretics, antivirals, methotrexate, and non-steroidal anti-inflammatory drugs) is organic anion transporter-1 (OAT1), originally identified as NKT (Lopez-Nieto, C.

Analysis of three-dimensional systems for developing and mature kidneys clarifies the role of OAT1 and OAT3 in antiviral handling.

The organic anion transporters OAT1 (SLC22A6, originally identified by us as NKT) and OAT3 (SLC22A8) are critical for handling many toxins, metabolites, and drugs, including antivirals (Truong, D. M., Kaler, G.

Interaction of organic cations with organic anion transporters.

Studies of the organic anion transporters (Oats) have focused mainly on their interactions with organic anionic substrates. However, as suggested when Oat1 was originally identified as NKT (Lopez-Nieto, C. E.

Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members.

When the organic anion transporter Oat1 was first identified as NKT (Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, Nigam SK. J Biol Chem 272: 6471-6478, 1997), it was argued that it, together with Oct1, may be part of a larger subfamily (now known as SLC22) involved in organic ion and xenobiotic transport. The least studied among SLC22 transporters are the so-called unknown substrate transporters (USTs).

Implications of the alternating access model for organic anion transporter kinetics.

Many transport proteins, including the clinically important organic anion transporters (OATs), appear to function via an "alternating access" mechanism. In analyzing the kinetics of these transporters, the terms K(m) and V(max) are often treated in the field as denoting, respectively, the affinity of the substrate for the transporter and the turnover (conformational switch) rate of the substrate-transporter complex. In fact, the expressions for both these parameters have very complex forms comprising multiple rate constants from conformational switch as well as association/dissociation steps in the cycling of the transporter and, therefore, do not have straightforward physical meanings.

Organic anion transporter 3 inhibitors as potential novel antihypertensives.

Hypertension is an exceedingly common disease with potentially devastating complications. Unfortunately, existing treatments are often only partially effective, indicating the utility of the development of novel therapeutics. It has recently been discovered that loss of renal organic anion transporter 3 (Oat3) results in decreased blood pressure.

Organic anion transporter 3 contributes to the regulation of blood pressure.

Renal organic anion transporters (OAT) are known to mediate the excretion of many drugs, but their function in normal physiology is not well understood. In this study, mice lacking organic anion transporter 3 (Oat3) had a 10 to 15% lower BP than wild-type mice, raising the possibility that Oat3 transports an endogenous regulator of BP. The aldosterone response to a low-salt diet was blunted in Oat3-null mice, but baseline aldosterone concentration was higher in these mice, suggesting that aldosterone dysregulation does not fully explain the lower BP in the basal state; therefore, both targeted and global metabolomic analyses of plasma and urine were performed, and several potential endogenous substrates of Oat3 were found to accumulate in the plasma of Oat3-null mice.