The Pathogenesis and Treatment of Gout

In the past, the etiology of gout was simplistically believed to be based in the generous indulgence of rich foods and alcohol. However, research has revealed that gout has complex environmental and genetic origins. Specifically, researchers have begun to focus attention on the molecular basis of gout and its related features. These features include hyperuricemia, the stages of gout, and the decreased solubility of uric acid. Furthermore, with epidemiologic evidence indicating that the prevalence of gout is consistently rising, it is imperative that medical providers understand the research-based guidelines for treatment. This includes what medications to administer, monitoring for drug-induced adverse effects, and modifying the treatment plan in elderly or unresponsive patients. Medical providers must also be aware of the importance of diet as a contributing factor to gout and which foods increase or decrease the risk of gout. This review will, therefore, attempt to present the current understanding of the pathophysiology of gout and guidelines for treatment and dietary modifications. Because gout is a disease related to metabolic dysfunction and produces arthritic symptoms, the information presented in this review was extracted from textbooks and journals chiefly relating to biochemistry, rheumatology, and pharmacology. The results of the research conducted revealed that there are three features that are genetically induced that independently contribute to the onset of gout: phosphoribosyl pyrophosphate (PRPP) synthetase hyperactivity, partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPT), and hyperactivity of the uric acid transporter in the renal tubule. In addition, diets rich in meat and seafood and devoid of dairy products substantially increase the risk of developing gout. Finally, research has indicated that the preferred treatment plan for gout includes using NSAIDs to alleviate the pain and inflammation of an acute gout attack, using colchicine for prophylactic therapy, and using either uricosurics or xanthine oxidase inhibitors for the long-term management of uric acid levels. Based on the results presented, medical providers will be better informed of methods to treat gout by knowing how to skillfully manage drug therapy, thereby reducing dangerous adverse effects and improving patient adherence to the drug regimen. In addition, by understanding the role of diet in the onset of gout, providers will better be able to advise patients on what foods to include or limit in their diet. From a research perspective, the elucidation of the pathophysiology of gout can lead to the development of even more effective therapeutic options

Key stages in mammary gland development: The mammary end bud as a motile organ

In the rodent, epithelial end buds define the tips of elongating mammary ducts. These highly motile structures undergo repeated dichotomous branching as they aggressively advance through fatty stroma and, turning to avoid other ducts, they finally cease growth leaving behind the open, tree-like framework on which secretory alveoli develop during pregnancy. This review identifies the motility of end buds as a unique developmental marker that represents the successful integration of systemic and local mammotrophic influences, and covers relevant advances in ductal growth regulation, extracellular matrix (ECM) remodeling, and cell adhesion in the inner end bud. An unexpected growth-promoting synergy between insulin-like growth factor-1 and progesterone, in which ducts elongate without forming new end buds, is described as well as evidence strongly supporting self-inhibition of ductal elongation by end-bud-secreted transforming growth factor-β acting on stromal targets. The influence of the matrix metalloproteinase ECM-remodeling enzymes, notably matrix metalloproteinase-2, on end bud growth is discussed in the broader context of enzymes that regulate the polysaccharide-rich glycosaminoglycan elements of the ECM. Finally, a critical, motility-enabling role for the cellular architecture of the end bud is identified and the contribution of cadherins, the netrin/neogenin system, and ErbB2 to the structure and motility of end buds is discussed

Erenumab in chronic migraine: Patient-reported outcomes in a randomized double-blind study.

OBJECTIVE: To determine the effect of erenumab, a human monoclonal antibody targeting the calcitonin gene-related peptide receptor, on health-related quality of life (HRQoL), headache impact, and disability in patients with chronic migraine (CM). METHODS: In this double-blind, placebo-controlled study, 667 adults with CM were randomized (3:2:2) to placebo or erenumab (70 or 140 mg monthly). Exploratory endpoints included migraine-specific HRQoL (Migraine-Specific Quality-of-Life Questionnaire [MSQ]), headache impact (Headache Impact Test-6 [HIT-6]), migraine-related disability (Migraine Disability Assessment [MIDAS] test), and pain interference (Patient-Reported Outcomes Measurement Information System [PROMIS] Pain Interference Scale short form 6b). RESULTS: Improvements were observed for all endpoints in both erenumab groups at month 3, with greater changes relative to placebo observed at month 1 for many outcomes. All 3 MSQ domains were improved from baseline with treatment differences for both doses exceeding minimally important differences established for MSQ-role function-restrictive (≥3.2) and MSQ-emotional functioning (≥7.5) and for MSQ-role function-preventive (≥4.5) for erenumab 140 mg. Changes from baseline in HIT-6 scores at month 3 were -5.6 for both doses vs -3.1 for placebo. MIDAS scores at month 3 improved by -19.4 days for 70 mg and -19.8 days for 140 mg vs -7.5 days for placebo. Individual-level minimally important difference was achieved by larger proportions of erenumab-treated participants than placebo for all MSQ domains and HIT-6. Lower proportions of erenumab-treated participants had MIDAS scores of severe (≥21) or very severe (≥41) or PROMIS scores ≥60 at month 3. CONCLUSIONS: Erenumab-treated patients with CM experienced clinically relevant improvements across a broad range of patient-reported outcomes. CLINICALTRIALSGOV IDENTIFIER: NCT02066415. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with CM, erenumab treatment improves HRQoL, headache impact, and disability

The alpha subunit of the Saccharomyces cerevisiae oligosaccharyltransferase complex is essential for vegetative growth of yeast and is homologous to mammalian ribophorin I

Oligosaccharyltransferase mediates the transfer of a preassembled high mannose oligosaccharide from a lipid-linked oligosaccharide donor to consensus glycosylation acceptor sites in newly synthesized proteins in the lumen of the rough endoplasmic reticulum. The Saccharomyces cerevisiae oligosaccharyltransferase is an oligomeric complex composed of six nonidentical subunits (alpha-zeta), two of which are glycoproteins (alpha and beta). The beta and delta subunits of the oligosaccharyltransferase are encoded by the WBP1 and SWP1 genes. Here we describe the functional characterization of the OST1 gene that encodes the alpha subunit of the oligosaccharyltransferase. Protein sequence analysis revealed a significant sequence identity between the Saccharomyces cerevisiae Ost1 protein and ribophorin I, a previously identified subunit of the mammalian oligosaccharyltransferase. A disruption of the OST1 locus was not tolerated in haploid yeast showing that expression of the Ost1 protein is essential for vegetative growth of yeast. An analysis of a series of conditional ost1 mutants demonstrated that defects in the Ost1 protein cause pleiotropic underglycosylation of soluble and membrane-bound glycoproteins at both the permissive and restrictive growth temperatures. Microsomal membranes isolated from ost1 mutant yeast showed marked reductions in the in vitro transfer of high mannose oligosaccharide from exogenous lipid-linked oligosaccharide to a glycosylation site acceptor tripeptide. Microsomal membranes isolated from the ost1 mutants contained elevated amounts of the Kar2 stress-response protein

Is the reputation of Eucalyptus plantations for using more water than Pinus plantations justified?

The effect of Eucalyptus plantations on water balance is thought to be more severe than for commercial alternatives such as Pinus species. Although this perception is firmly entrenched, even in the scientific community, only four direct comparisons of the effect on the water balance of a Eucalyptus species and a commercial alternative have been published. One of these, from South Africa, showed that Eucalyptus grandis caused a larger and more rapid reduction in streamflow than Pinus patula. The other three, one in South Australia and two in Chile, did not find any significant difference between the annual evapotranspiration of E. globulus and P. radiata after canopy closure. While direct comparisons are few, there are at least 57 published estimates of annual evapotranspiration of either a Eucalyptus or Pinus species. This paper presents a meta-analysis of these published data. Zhang et al. (2004) fitted a relationship between the crop factor and the climate wetness index to published data from catchment studies and proposed this approach for comparing land uses. We fitted the same model to the published data for Eucalyptus and Pinus and found that the single parameter of this model did not differ significantly between the two genera (p=0.48). This implies that for a given climate wetness index the two genera have similar annual water use. The residuals compared to this model were significantly correlated with soil depth for Eucalyptus, but this was not the case for Pinus. For Eucalyptus the model overestimates the crop factor on deep soils and underestimates the crop factor on shallow soils.</p

Is the reputation of Eucalyptus plantations for using more water than Pinus plantations justified?

The effect of Eucalyptus plantations on water balance is thought to be more severe than for commercial alternatives such as Pinus species. Although this perception is firmly entrenched, even in the scientific community, only four direct comparisons of the effect on the water balance of a Eucalyptus species and a commercial alternative have been published. One of these, from South Africa, showed that Eucalyptus grandis caused a larger and more rapid reduction in streamflow than Pinus patula. The other three, one in South Australia and two in Chile, did not find any significant difference between the annual evapotranspiration of E. globulus and P. radiata after canopy closure. While direct comparisons are few, there are at least 57 published estimates of annual evapotranspiration of either the Eucalyptus or Pinus species. This paper presents a meta-analysis of these published data. Zhang et al. (2004) fitted a relationship between the vegetation evaporation efficiency and the climate wetness index to published data from catchment studies and proposed this approach for comparing land uses. We fitted this model to the published data for Eucalyptus and Pinus and found that the single parameter of this model did not differ significantly between the two genera (p = 0.48). This was also the case for all parameters of an exponential relationship between evapotranspiration and rainfall (p = 0.589) and a linear relationship between the vegetation evaporation index and rainfall (p = 0.155). These results provide strong evidence that, for a given climate wetness index, the two genera have similar annual water use. The residuals compared to the model of Zhang et al. (2004) were significantly correlated with soil depth for Eucalyptus, but this was not the case for Pinus. For Eucalyptus, the model overestimates the vegetation evaporation efficiency on deep soils and underestimates the vegetation evaporation efficiency on shallow soils

A fluorescence nanoscopy marker for corticotropin-releasing hormone type 1 receptor: Computer design, synthesis, signaling effects, super-resolved fluorescence imaging, and: In situ affinity constant in cells

Class B G protein-coupled receptors (GPCRs) are involved in a variety of human pathophysiological states. These groups of membrane receptors are less studied than class A GPCRs due to the lack of structural information, delayed small molecule drug discovery, and scarce fluorescence detection tools available. The class B corticotropin-releasing hormone type 1 receptor (CRHR1) is a key player in the stress response whose dysregulation is critically involved in stress-related disorders: psychiatric conditions (i.e. depression, anxiety, and addictions), neuroendocrinological alterations, and neurodegenerative diseases. Here, we present a strategy to label GPCRs with a small fluorescent antagonist that permits the observation of the receptor in live cells through stochastic optical reconstruction microscopy (STORM) with 23 nm resolution. The marker, an aza-BODIPY derivative, was designed based on computational docking studies, then synthesized, and finally tested in biological cells. Experiments on hippocampal neurons demonstrate antagonist effects in similar concentrations as the well-established antagonist CP-376395. A quantitative analysis of two color STORM images enabled the determination of the binding affinity of the new marker in the cellular environment.Fil: Szalai, Alan Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Armando, Natalia Giannina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Barabas, Federico Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Stefani, Fernando Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Giordano, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Bari, Sara Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Cavasotto, Claudio Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Silberstein Cuña, Susana Iris. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Aramendia, Pedro Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentin

Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.

A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions

Implications of hepatitis C virus subtype 1a migration patterns for virus genetic sequencing policies in Italy

Background: In-depth phylogeographic analysis can reveal migration patterns relevant for public health planning. Here, as a model, we focused on the provenance, in the current Italian HCV subtype 1a epidemic, of the NS3 resistance-associated variant (RAV) Q80K, known to interfere with the action of NS3/4A protease inhibitor simeprevir. HCV1a migration patterns were analysed using Bayesian phylodynamic tools, capitalising on newly generated and publicly available time and geo-referenced NS3 encoding virus genetic sequence data. Results: Our results showed that both immigration and local circulation fuel the current Italian HCV1a epidemic. The United States and European continental lineages dominate import into Italy, with the latter taking the lead from the 1970s onwards. Since similar migration patterns were found for Q80K and other lineages, no clear differentiation of the risk for failing simeprevir can be made between patients based on their migration and travel history. Importantly, since HCV only occasionally recombines, these results are readily transferable to the genetic sequencing policy concerning NS5A RAVs. Conclusions: The patient migration and travel history cannot be used to target only part of the HCV1a infected population for drug resistance testing before start of antiviral therapy. Consequently, it may be cost-effective to expand genotyping efforts to all HCV1a infected patients eligible for simeprevir-based therapies. © 2017 The Author(s)