KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer\u27s disease-related pathology

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer\u27s disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2-/- mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes

X-ray structural and spectroscopic investigation of 1-piperidine-2,4-dinitrobenzene

The crystal structure of the title compound (C11H13N3O4) has been determined by single-crystal X-ray diffraction. The compound is monoclinic, space group P21/n, witha=9.968(2),b=9.156(2),c=13.249(2)A, β=102.05(2)°, andDx=1.563 gcm−3 forZ=4. The aromatic ring shows a slight boat deformation. Theo- andp-NO2 groups are twisted out of the plane of the phenyl ring by 39.0(2)° and 4.4(1)°, respectively. The piperidine ring exhibits a slightly deformed chair conformation. Short C−H...O intermolecular contacts stabilize the three dimensional structure. UV and NMR data indicate that the molecule in solution presents a conformation similar to that of the the solid state.Facultad de Ciencias Exacta

Acute left ventricular dysfunction secondary to right ventricular septal pacing in a woman with initial preserved contractility: a case report

<p>Abstract</p> <p>Introduction</p> <p>Right ventricular apical pacing-related heart failure is reported in some patients after long-term pacing. The exact mechanism is not yet clear but may be related to left ventricular dyssynchrony induced by right ventricular apical pacing. Right ventricular septal pacing is thought to deteriorate left ventricular function less frequently because of a more normal left ventricular activation pattern.</p> <p>Case presentation</p> <p>We report the case of a 55-year-old Tunisian woman with preserved ventricular function, implanted with a dual-chamber pacemaker for complete atrioventricular block. Right ventricular septal pacing induced a major ventricular dyssynchrony, severe left ventricular ejection fraction deterioration and symptoms of congestive heart failure. Upgrading to a biventricular device was associated with a decrease in the symptoms and the ventricular dyssynchrony, and an increase of left ventricular ejection fraction.</p> <p>Conclusion</p> <p>Right ventricular septal pacing can induce reversible left ventricular dysfunction and heart failure secondary to left ventricular dyssynchrony. This complication remains an unpredictable complication of right ventricular septal pacing.</p

Genetički polimorfizmi u dijabetesu: Utjecaj na terapiju oralnim antidijabeticima

Due to new genetic insights, etiologic classification of diabetes is under constant scrutiny. Hundreds, or even thousands, of genes are linked with type 2 diabetes. Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to be predisposed to type 2 diabetes mellitus across many large studies. Individually, each of these polymorphisms is only moderately predisposed to type 2 diabetes. On the other hand, monogenic forms of diabetes such as MODY and neonatal diabetes are characterized by unique clinical features and the possibility of applying a tailored treatment. Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of a number of medications. Mutations in genes important in drug absorption, distribution, metabolism and excretion (ADME) play a critical role in pharmacogenetics of diabetes. There are currently five major classes of oral pharmacological agents available to treat type 2 diabetes: sulfonylureas, meglitinides, metformin (a biguanide), thiazolidinediones, and α-glucosidase inhibitors. Other classes are also mentioned in literature. In this work, different types of genetic mutations (mutations of the gene for glucokinase, HNF 1, HNF1ß and Kir6.2 and SUR1 subunit of KATP channel, PPAR-γ, OCT1 and OCT2, cytochromes, direct drug-receptor (KCNJ11), as well as the factors that influence the development of the disease (TCF7L2) and variants of genes that lead to hepatosteatosis caused by thiazolidinediones) and their influence on the response to therapy with oral antidiabetics will be reviewed.Dijabetes tipa 2 dosegao je proporcije epidemije u SAD (> 18 milijuna) i cijelom svijetu (170 milijuna oboljelih osoba) te ima tendenciju daljnjeg dramatičnog rasta. Stoga se u posljednje vrijeme ulažu napori da se otkriju i razviju novi farmakološki agensi za liječenje ove bolesti. Klasifikacija šećerne bolesti proširena je uspjesima istraživača na području genetike. Da bismo razumjeli farmakogenetiku antidijabetika neophodno je razumjeti genetiku samog dijabetesa. Kao što će biti prikazano u ovom radu veliki broj gena koji su povezani s razvojem dijabetesa takođe utječu i na odgovor na terapiju antidijabeticima. S druge strane, mutacije gena koji utječu na ADME (apsorpcija, distribucija, metabolizam i ekskrecija) lijeka imaju značajan utjecaj na farmakogenetiku oralnih antidijabetika. Utvrđeno je da je dijabetes genetički heterogena bolest. Uobičajeni oblici dijabetesa su gotovo uvijek poligenski i za razvoj same bolesti vrlo su značajne snažne interakcije među različitim genima kao i između gena i okoliša. Zbog toga mutacije ili polimorfizmi koji u manjoj mjeri utječu na funkciju gena mogu postati klinički značajni samo u slučaju kada se kombiniraju s drugim faktorima odnosno genima. Smatra se da u razvoju dijabetesa mogu sudjelovati stotine pa čak i tisuće gena. Do 2006. identificirano je nekoliko uobičajenih alela koji povećavaju rizik za razvoj dijabetesa, od kojih su najznačajniji PPARG (Pro12), KCNJ11 (Lys23) i TCF7L2 (T na rs7903146). Do danas je najveći uspjeh postignut u identifikaciji gena odgovornih za razmjerno rijetke oblike ove bolesti poput ”Maturity-onset diabetes of the young” (MODY) i neonatalnog dijabetesa. Monogenske oblike dijabetesa odlikuju jedinstvene kliničke karakteristike i mogućnost primjene individualnog tretmana. Genetički polimorfizmi enzima koji utječu na metabolizam lijekova, transportera, receptora i drugih ciljeva djelovanja lijekova povezani su s interindividualnim razlikama u efikasnosti i toksičnosti mnogih lijekova. Vrlo je važno da se na temelju farmakogenetičkih istraživanja mogu predvidjeti neki neželjeni efekti lijekova. Trenutačno postoji pet glavnih klasa oralnih antidijabetika: sulfoniluree, meglitinidi, metformin (bigvanid), tiazolidindioni i inhibitori α-glukozidaze. U literaturi se također spominju inhibitori dipeptidil peptidaze IV (DPP-IV), selektivni antagonisti kanabinoidnog receptora 1 (CB-1), glukagonu slični peptid 1 mimetici i amilin mimetici. Razumijevanje mehanizama koji rezultiraju disfunkcijom β stanica na fiziološkom i molekularnom nivou neophodno je za napredak u razumijevanju tretmana dijabetesa. U ovom radu dat je pregled različitih genetičkih mutacija (mutacije gena za glukokinazu, HNF 1, HNF1ß, Kir6.2 i SUR 1 podjedinicu KATP kanala ß stanica, PPAR-γ, OCT1 i OCT2, citohrome, KCNJ11, faktore koji utječu na razvoj bolesti (TCF7L2) i varijante gena koji dovode do hepatosteatoze uzrokovane tiazolidindionima) te njihov utjecaj na odgovor na terapiju oralnim antidijabeticima

Tamoxifen-Induced Cre-loxP Recombination Is Prolonged in Pancreatic Islets of Adult Mice

Tamoxifen (Tm)-inducible Cre recombinases are widely used to perform gene inactivation and lineage tracing studies in mice. Although the efficiency of inducible Cre-loxP recombination can be easily evaluated with reporter strains, the precise length of time that Tm induces nuclear translocation of CreERTm and subsequent recombination of a target allele is not well defined, and difficult to assess. To better understand the timeline of Tm activity in vivo, we developed a bioassay in which pancreatic islets with a Tm-inducible reporter (from Pdx1PB-CreERTm;R26RlacZ mice) were transplanted beneath the renal capsule of adult mice previously treated with three doses of 1 mg Tm, 8 mg Tm, or corn oil vehicle. Surprisingly, recombination in islet grafts, as assessed by expression of the β-galactosidase (β-gal) reporter, was observed days or weeks after Tm treatment, in a dose-dependent manner. Substantial recombination occurred in islet grafts long after administration of 3×8 mg Tm: in grafts transplanted 48 hours after the last Tm injection, 77.9±0.4% of β-cells were β-gal+; in β-cells placed after 1 week, 46.2±5.0% were β-gal+; after 2 weeks, 26.3±7.0% were β-gal+; and after 4 weeks, 1.9±0.9% were β-gal+. Islet grafts from mice given 3×1 mg Tm showed lower, but notable, recombination 48 hours (4.9±1.7%) and 1 week (4.5±1.9%) after Tm administration. These results show that Tm doses commonly used to induce Cre-loxP recombination may continue to label significant numbers of cells for weeks after Tm treatment, possibly confounding the interpretation of time-sensitive studies using Tm-dependent models. Therefore, investigators developing experimental approaches using Tm-inducible systems should consider both maximal recombination efficiency and the length of time that Tm-induced Cre-loxP recombination occurs

Case Report - Cardiomyopathie hypertrophique néonatale de diagnostic étiologique difficile

La cardiomyopathie hypertrophique n&#233;onatale est une entit&#233; rare, h&#233;t&#233;rog&#232;ne regroupant plusieurs formes cliniques et donc de diagnostic &#233;tiologique difficile. Nous rapportons l&#8217;observation d&#8217;un nouveau n&#233; issu d&#8217;une grossesse g&#233;mellaire, ayant pr&#233;sent&#233; &#224; la naissance un tableau d&#8217;insuffisance cardiaque, l&#8217;&#233;chocardiographie avait conclut &#224; une cardiomyopathie hypertrophique obstructive. Le bilan &#233;tiologique &#233;tait n&#233;gatif notamment une m&#232;re non diab&#233;tique. L&#8217;&#233;volution &#233;tait favorable avec r&#233;gression de l&#8217;hypertrophie 2 semaines apr&#232;s la naissance. L&#8217;&#233;tiologie finalement sugg&#233;r&#233;e &#233;tait une cardiomyopathie secondaire &#224; l&#8217;injection ant&#233;natale de cortico&#239;des dans le but d&#8217;acc&#233;l&#233;rer la maturation pulmonaire. L&#8217;&#233;tablissement par les soci&#233;t&#233;s savantes d&#8217;un consensus de bilan &#233;tiologique minimal standard selon une chronologie bien d&#233;termin&#233;e serait d&#8217;un grand apport dans la prise en charge de cette anomalie

Prevalence of Brugada-type ECG pattern and early ventricular repolarization pattern in Tunisian athletes

Sana Ouali1, Helmi Ben Salem1, Sami Hammas1, Elyes Neffeti1, Fahmi Remedi1, Abdallah Mahdhaoui2, Essia Boughzela1, Rafik Mankai31Department of Cardiology, Sahloul Hospital, Sousse, Tunisia; 2Department of Cardiology, Farhat Hached, Sousse, Tunisia; 3Central Sports Medicine Centre of El Menzah, TunisiaIntroduction: No data regarding the prevalence of the Brugada-type electrocardiogram (ECG) pattern and the early ventricular repolarization pattern (ERP) in the North African population were available. The aims of this study were to determine the frequency of Brugada-type ECG pattern and ERP in Tunisia and to evaluate ECG descriptors of ventricular repolarization in a population of athletes.Methods: Over a 2-year period, resting 12-lead ECG recordings were analyzed from athletes (n = 540; 348 males; age 18.3 &amp;plusmn; 2.4 years). Brugada-type ECG pattern was defined as Type 1, 2, or 3, and ERP was characterized by an elevation of the J point in the inferior and/or lateral leads. The population was divided into three groups of athletes: ERP group; Brugada-type ECG pattern group; and control group, with neither ERP nor Brugada ECG pattern. Clinical and electrocardiographic parameters were compared among the study groups.Results: Nine subjects (1.66%) had a Brugada-type ECG pattern. None of them had the coved-type, 3 (0.6%) had the Type 2, and 6 (1.1%) had the Type 3. All subjects were asymptomatic. A Brugada-type ECG pattern was observed in seven males. No female had the Type 2 Brugada ECG pattern. ECG parameters were similar among Brugada-type ECG pattern and control athletes. ERP (119 subjects, 22%) was obtained in 98 males. Heart rate was lower, the QRS duration shorter and QT and Tpeak&amp;ndash;Tend intervals were longer in ERP than control groups.Conclusion: The results indicate that the frequency of the Brugada-type ECG pattern and ERP were respectively 1.66% and 22.00% in athletes, being more prevalent in males. The ERP group experienced shorter QRS duration and longer Tpeak&amp;ndash;Tend interval than in the control population.Keywords: J wave, ERP athletes, T wav