Intradermal vaccination with hollow microneedles: A comparative study of various protein antigen and adjuvant encapsulated nanoparticles

Drug Delivery TechnologySupramolecular & Biomaterials Chemistr

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

Reduced responsiveness is an essential feature of chronic fatigue syndrome: A fMRI study

BACKGROUND: Although the neural mechanism of chronic fatigue syndrome has been investigated by a number of researchers, it remains poorly understood. METHODS: Using functional magnetic resonance imaging, we studied brain responsiveness in 6 male chronic fatigue syndrome patients and in 7 age-matched male healthy volunteers. Responsiveness of auditory cortices to transient, short-lived, noise reduction was measured while subjects performed a fatigue-inducing continual visual search task. RESULTS: Responsiveness of the task-dependent brain regions was decreased after the fatigue-inducing task in the normal and chronic fatigue syndrome subjects and the decrement of the responsiveness was equivalent between the 2 groups. In contrast, during the fatigue-inducing period, although responsiveness of auditory cortices remained constant in the normal subjects, it was attenuated in the chronic fatigue syndrome patients. In addition, the rate of this attenuation was positively correlated with the subjective sensation of fatigue as measured using a fatigue visual analogue scale, immediately before the magnetic resonance imaging session. CONCLUSION: Chronic fatigue syndrome may be characterised by attenuation of the responsiveness to stimuli not directly related to the fatigue-inducing task

Necrotrophism Is a Quorum-Sensing-Regulated Lifestyle in Bacillus thuringiensis

How pathogenic bacteria infect and kill their host is currently widely investigated. In comparison, the fate of pathogens after the death of their host receives less attention. We studied Bacillus thuringiensis (Bt) infection of an insect host, and show that NprR, a quorum sensor, is active after death of the insect and allows Bt to survive in the cadavers as vegetative cells. Transcriptomic analysis revealed that NprR regulates at least 41 genes, including many encoding degradative enzymes or proteins involved in the synthesis of a nonribosomal peptide named kurstakin. These degradative enzymes are essential in vitro to degrade several substrates and are specifically expressed after host death suggesting that Bt has an active necrotrophic lifestyle in the cadaver. We show that kurstakin is essential for Bt survival during necrotrophic development. It is required for swarming mobility and biofilm formation, presumably through a pore forming activity. A nprR deficient mutant does not develop necrotrophically and does not sporulate efficiently in the cadaver. We report that necrotrophism is a highly regulated mechanism essential for the Bt infectious cycle, contributing to spore spreading

Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient

Monogenic diabetes results from one or more mutations in a single gene which might hence be rare but has great impact leading to diabetes at a very young age. It has resulted in great challenges for researchers elucidating the aetiology of diabetes and related features in other organ systems, for clinicians specifying a diagnosis that leads to improved genetic counselling, predicting of clinical course and changes in treatment, and for patients to altered treatment that has lead to coming off insulin and injections with no alternative (Glucokinase mutations), insulin injections being replaced by tablets (e.g. low dose in HNFα or high dose in potassium channel defects -Kir6.2 and SUR1) or with tablets in addition to insulin (e.g. metformin in insulin resistant syndromes). Genetic testing requires guidance to test for what gene especially given limited resources. Monogenic diabetes should be considered in any diabetic patient who has features inconsistent with their current diagnosis (unspecified neonatal diabetes, type 1 or type 2 diabetes) and clinical features of a specific subtype of monogenic diabetes (neonatal diabetes, familial diabetes, mild hyperglycaemia, syndromes). Guidance is given by clinical and physiological features in patient and family and the likelihood of the proposed mutation altering clinical care. In this article, I aimed to provide insight in the genes and mutations involved in insulin synthesis, secretion, and resistance, and to provide guidance for genetic testing by showing the clinical and physiological features and tests for each specified diagnosis as well as the opportunities for treatment

Interstitial fluid: the overlooked component of the tumor microenvironment?

Background: The interstitium, situated between the blood and lymph vessels and the cells, consists of a solid or matrix phase and a fluid phase, together constituting the tissue microenvironment. Here we focus on the interstitial fluid phase of tumors, i.e., the fluid bathing the tumor and stromal cells. Novel knowledge on this compartment may provide important insight into how tumors develop and how they respond to therapy. Results: We discuss available techniques for interstitial fluid isolation and implications of recent findings with respect to transcapillary fluid balance and uptake of macromolecular therapeutic agents. By the development of new methods it is emerging that local gradients exist in signaling substances from neoplastic tissue to plasma. Such gradients may provide new insight into the biology of tumors and mechanistic aspects linked to therapy. The emergence of sensitive proteomic technologies has made the interstitial fluid compartment in general and that of tumors in particular a highly valuable source for tissue-specific proteins that may serve as biomarker candidates. Potential biomarkers will appear locally at high concentrations in the tissue of interest and will eventually appear in the plasma, where they are diluted. Conclusions: Access to fluid that reliably reflects the local microenvironment enables us to identify substances that can be used in early detection and monitoring of disease