Wpływ występowania allelu klasy III VNTR genu INS na parametry auksologiczne, stężenie glukozy, insuliny, lipidów i adipocytokin u przeddojrzewaniowych dzieci urodzonych z niską masą ciała

  Introduction: The insulin gene variable number of tandem repeats (INS VNTR) class III allele has been implicated in lower birth weight, obesity, and insulin resistance. We assessed its influence on birth weight in the Polish population and on the current body mass and metabolic profile in prepubertal children born small for gestational age (SGA). Material and methods: DNA for genotyping of INS VNTR was available for 123 subjects born SGA and 132 born appropriate for gestational age (AGA). We identified two alleles: class I and class III. Next, in 112 prepubertal (aged: 6.8 ± 1.38 years) SGA children, the auxological measurements, fasting serum C-peptide, triglycerides, cholesterol, ghrelin, leptin, adiponectin, resistin, cortisol, and insulin-like growth factor type I (IGF-I) concentrations, as well as glucose and insulin during oral glucose tolerance test (OGTT), were assessed and insulin resistance indices were calculated. The results were analysed depending on INS VNTR variants. Results: The occurrence of individual INS VNTR variants were similar in the SGA and AGA groups. In prepubertal SGA children, we did not observe any statistical differences as regards birth weight, body mass, lipids, or adipocytokine concentrations among I/I, I/III, and III/III class groups. The concentration of insulin in 120’ of OGTT was significantly higher in class III homozygous than in class I homozygous individuals. Conclusions: Variant INS VNTR class III was shown not to be associated in any essential way with birth weight in the Polish population. Among prepubertal SGA children, the presence of INS VNTR class III is related to higher insulin secretion during OGTT. (Endokrynol Pol 2016; 67 (6): 585–591)    Wstęp: Sugeruje się, że występowanie allelu klasy III fragmentu różnej liczby tandemowych powtórzeń (VNTR) genu insuliny (INS) przyczynia się do niższej masy urodzeniowej oraz rozwoju otyłości i insulinooporności. Autorzy ocenili wpływ tego wariantu na masę urodzeniową w populacji polskiej oraz na masę ciała i profil metaboliczny u przeddojrzewaniowych dzieci urodzonych ze zbyt niską masą ciała (SGA). Materiały i metody: Oceniono polimorfizm INS VNTR u 123 osób z SGA i 132 urodzonych z prawidłową masą ciała (AGA). Identyfikowano dwa alelle VNTR: klasy I i klasy III. Następnie wyodrębiono grupę 112 przeddojrzewaniowych dzieci z SGA (w wieku 6,8 ± 1,38 lat), u których wykonano pomiary auksologiczne oraz oznaczono stężenie: C-peptydu, triglicerydów, cholesterolu, greliny, leptyny, adiponektyny, rezystyny, kortyzolu i insulinopodobnego czynnika wzrostu typu I (IGF-I), jak również oceniono stężenie glukozy i insuliny podczas doustnego testu tolernacji glukozy (OGTT). Obliczono wskaźniki insulinooporności. Wyniki przeanalizowano w zależności od występowania typu polimorfizmu INS VNTR. Wyniki: Częstość występowania poszczególnych wariantów INS VNTR nie różniła się w grupie AGA i SGA. U przeddojrzewaniowych dzieci z SGA nie obserwowano istotnych różnic w odniesieniu do ich urodzeniowej masy ciała, aktualnej masy ciała, stężenia lipidów i adipocytokin w zależności od występowania klasy I/I, I/III czy III/III. Stężenie insuliny w 120. minucie OGTT było istotnie wyższe u homozygotycznych dzieci z klasą III niż u homozygotycznych dzieci z klasą I. Wnioski: Wariant INS VNTR klasy III nie wydaje się być przyczyną niskiej urodzeniowej masy ciała (SGA) w populacji dzieci polskich. Wśród przeddojrzewaniowych dzieci z SGA, obecność klasy III INS VNTR wiąże się z wyższym wydzielaniem insuliny podczas OGTT. (Endokrynol Pol 2016; 67 (6): 585–591)

Atypowe cechy fenotypowe u nosicieli nowej mutacji nonsens Q248X w genie HNF1B

Introduction: Hepatocyte transforming factor 1B-maturity onset diabetes mellitus of the young (HNF1B-MODY) is an autosomal dominant type of monogenic diabetes caused by a mutation in the gene encoding hepatocyte nuclear factor 1beta (HNF-1beta). The aim of this study was to determine if a HNF1B gene mutation was responsible for a dominantly inherited form of diabetes mellitus among the members of a three-generation Polish family. Material and methods: The index subject was a 13-year-old boy with metabolic syndrome, spina bifida occulta, posterior urethral valves, congenital ureteropelvic junction obstruction, and a family history of diabetes of autosomal dominant trait of inheritance. We performed clinical and laboratory examinations of his family and sequenced the HNF1B gene. Results: A novel Q248X mutation (nucleotide C to T transition at position 742 of the exon 3 of HNF1B gene, resulting in stop codon formation) was identified. Phenotypes of family members sharing this mutation are highly variable, and include previously known abnormalities of the urinary system and pancreas, diabetes mellitus of variable onset and severity, hyperinsulinaemia, insulin resistance, metabolic syndrome, elevated aminotransferases, hyperbilirubinemia, hyperamylasemia, short stature and cataracts. To the best of our knowledge, spina bifida occulta, pectus carinatum, and splenomegaly have not been previously reported. Conclusions: Our results broaden the spectrum of HNF1B gene mutations and HNF1B-MODY-related phenotypes. Wstęp: Cukrzyca HNF1B-MODY dziedziczona w sposób autosomalnie dominujący jest rodzajem cukrzycy monogenowej, którą powoduje mutacja w genie HNF1B (hepatocyte transforming factor 1B). Celem pracy było zbadanie czy mutacja w HNF1B jest przyczyną występowania cukrzycy w trzech pokoleniach polskiej rodziny. Materiał i metody: Przeprowadzono ocenę kliniczną i laboratoryjną oraz sekwencjonowanie genu HNF1B trzynastoletniego chłopca z zespołem metabolicznym, rozszczepem kręgosłupa, zastawkami cewki tylnej i wrodzonym zwężeniem moczowodu oraz obciążonym wywiadem rodzinnym w kierunku cukrzycy. Ze względu na wywiad rodzinny o autosomalnie dominującym sposobie dziedziczenia cukrzycy zbadano również członków jego rodziny. Wyniki: Stwierdzono obecność nowej mutacji Q248X będącej skutkiem przeniesienia nukleotydu C na miejsce T w pozycji 742 eksonu 3 genu HNF1B i powstaniem kodonu stop. Cechy fenotypowe członków rodziny będących nosicielami tej mutacji okazały być się bardzo zróżnicowane, a niektóre z nich takie jak spina bifida occulta, pectus carinatum i splenomegalia nie były dotychczas opisywane. Wnioski: Wyniki poszerzają spectrum mutacji genu HNF1B oraz związanych z nimi cech fenotypowych cukrzycy HNF1B-MODY

Phenotype variability and neonatal diabetes in a large family with heterozygous mutation of the glucokinase gene

Monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY) is usually characterized by a mild clinical phenotype. The clinical course of diabetes may be, however, highly variable. The authors present a child with diabetes manifesting with ketoacidosis during the neonatal period, born in a large family with ten members bearing a heterozygous p.Gly223Ser mutation in GCK. DNA sequencing and multiplex ligation-dependent probe amplification were used to confirm GCK mutation and exclude other de novo mutations in other known genes associated with monogenic diabetes. Continuous glucose monitoring (CGM) was used to assess daily glycemic profiles. At the onset of diabetes the child had hyperglycemia 765 mg/dl with pH 7.09. Her glycated hemoglobin level was 8.6% (70.5 mmol/mol). The C-peptide level was below normal range (<0.5 pmol/ml) at onset, and the three- and 6-month follow-up examinations. Current evaluation at age 3 still showed unsatisfactory metabolic control with HbA1c level equal to 8.1% (65.0 mmol/mol). CGM data showed glucose concentrations profile similar to poorly controlled type 1 diabetes. The patient was confirmed to be heterozygous for the p.Gly223Ser mutation and did not show any point mutations or deletions within other monogenic diabetes genes. Other family members with p.Gly223Ser mutation had retained C-peptide levels and mild diabetes manageable with diet (five individuals), oral hypoglycemizing agents (five patients), or insulin (one patient). This mutation was absent within all healthy family members. Heterozygous mutations of the GCK gene may result in neonatal diabetes similar to type 1 diabetes, the cause of such phenotype variety is still unknown. The possibility of other additional, unknown mutations seems to be the most likely explanation for the unusual presentation of GCK-MODY

Molecular disorder of bicalutamide : amorphous solid dispersions obtained by solvent methods

The effect of solvent removal techniques on phase transition, physical stability and dissolution of bicalutamide from solid dispersions containing polyvinylpyrrolidone (PVP) as a carrier was investigated. A spray dryer and a rotavapor were applied to obtain binary systems containing either 50% or 66% of the drug. Applied techniques led to the formation of amorphous solid dispersions as confirmed by X-ray powder diffractometry and differential scanning calorimetry. Moreover, solid–solid transition from polymorphic form I to form II was observed for bicalutamide spray dried without a carrier. The presence of intermolecular interactions between the drug and polymer molecules, which provides the stabilization of molecularly disordered bicalutamide, was analyzed using infrared spectroscopy. Spectral changes within the region characteristic for amide vibrations suggested that the amide form of crystalline bicalutamide was replaced by a less stable imidic one, characteristic of an amorphous drug. Applied processes also resulted in changes of particle geometry and size as confirmed by scanning electron microscopy and laser diffraction measurements, however they did not affect the dissolution significantly as confirmed by intrinsic dissolution study. The enhancement of apparent solubility and dissolution were assigned mostly to the loss of molecular arrangement by drug molecules. Performed statistical analysis indicated that the presence of PVP reduces the mean dissolution time and improve the dissolution efficiency. Although the dissolution was equally affected by both applied methods of solid dispersion manufacturing, spray drying provides better control of particle size and morphology as well as a lower tendency for recrystallization of amorphous solid dispersions

How does the CO2 in supercritical state affect the properties of drug-polymer systems, dissolution performance and characteristics of tablets containing bicalutamide?

The increasing demand for novel drug formulations has caused the introduction of the supercritical fluid technology, CO2 in particular, into pharmaceutical technology as a method enabling the reduction of particle size and the formation of inclusion complexes and solid dispersions. In this paper, we describe the application of scCO2 in the preparation of binary systems containing poorly soluble antiandrogenic drug bicalutamide and polymeric excipients, either Macrogol 6000 or Poloxamer®407. The changes in the particle size and morphology were followed using scanning electron microscopy and laser di raction measurements. Di erential scanning calorimetry was applied to assess thermal properties, while X-ray powder di ractometry was used to determine the changes in the crystal structure of the systems. The dissolution of bicalutamide was also considered. Binary solid dispersions were further compressed, and the attributes of tablets were assessed. Tablets were analyzed directly after manufacturing and storage in climate chambers. The obtained results indicate that the use of supercritical CO2 led to the morphological changes of particles and the improvement of drug dissolution. The flowability of blends containing processed binary systems was poor; however, they were successfully compressed into tablets exhibiting enhanced drug release

Less but better : cardioprotective lipid profile of patients with GCK-MODY despite lower HDL cholesterol level

Patients with diabetes caused by single-gene mutations generally exhibit an altered course of diabetes. Those with mutations of the glucokinase gene (GCK-MODY) show good metabolic control and low risk of cardiovascular complications despite paradoxically lowered high-density lipoprotein (HDL) cholesterol levels. In order to investigate the matter, we analyzed the composition of low-density lipoprotein (LDL) and HDL subpopulations in such individuals. The LipoPrint(©) system (Quantimetrix, USA) based on non-denaturing, linear polyacrylamide gel electrophoresis was used to separate and measure LDL and HDL subclasses in fresh-frozen serum samples from patients with mutations of glucokinase or HNF1A, type 1 diabetes (T1DM) and healthy controls. Fresh serum samples from a total of 37 monogenic diabetes patients (21 from GCK-MODY and 16 from HNF1A-MODY), 22 T1DM patients and 15 healthy individuals were measured in this study. Concentrations of the small, highly atherogenic LDL subpopulation were similar among the compared groups. Large HDL percentage was significantly higher in GCK-MODY than in control (p = 0.0003), T1DM (p = 0.0006) and HNF1A-MODY groups (p = 0.0246). Patients with GCK-MODY were characterized by significantly lower intermediate HDL levels than controls (p = 0.0003) and T1DM (p = 0.0005). Small, potentially atherogenic HDL content differed significantly with the GCK-MODY group showing concentrations of that subfraction from control (p = 0.0096), T1DM (p = 0.0193) and HNF1A-MODY (p = 0.0057) groups. Within-group heterogeneity suggested the existence of potential gene–gene or gene–environment interactions. GCK-MODY is characterized by a strongly protective profile of HDL cholesterol subpopulations. A degree of heterogeneity within the groups suggests the existence of interactions with other genetic or clinical factors

Compression-Induced Phase Transitions of Bicalutamide

The formation of solid dispersions with the amorphous drug dispersed in the polymeric matrix improves the dissolution characteristics of poorly soluble drugs. Although they provide an improved absorption after oral administration, the recrystallization, which can occur upon absorption of moisture or during solidification and other formulation stages, serves as a major challenge. This work aims at understanding the amorphization-recrystallization changes of bicalutamide. Amorphous solid dispersions with poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA) were obtained by either ball milling or spray drying. The applied processes led to drug amorphization as confirmed using X-ray diffraction and differential scanning calorimetry. Due to a high propensity towards mechanical activation, the changes of the crystal structure of physical blends of active pharmaceutical ingredient (API) and polymer upon pressure were also examined. The compression led to drug amorphization or transition from form I to form II polymorph, depending on the composition and applied force. The formation of hydrogen bonds confirmed using infrared spectroscopy and high miscibility of drug and polymer determined using non-isothermal dielectric measurements contributed to the high stability of amorphous solid dispersions. They exhibited improved wettability and dissolution enhanced by 2.5- to 11-fold in comparison with the crystalline drug. The drug remained amorphous upon compression when the content of PVP/VA in solid dispersions exceeded 20% or 33%, in the case of spray-dried and milled systems, respectively.Polish National Science Centre 2015/16/W/NZ7/0040

The Implementation of European Market Infrastructure Regulation and Its Influence on Derivatives Market in Poland in 2010–2014

The article presents the analysis of the changes of derivates market structure in Poland before and after the implementation of regulations on OTC derivatives market, which was imposed in EU by EMIR (European Market Infrastructure Regulations). That was implemented by EU Parliament and EU Council ordinance No. 648/2012 dated on the 4th of July 2012, on the derivatives being the subjects of trade outside of the regulated market, central counterparties and transactions repository. The article describes the origin of the world financial crisis in 2008 as well as regulations which were published 2010-2012 in USA and EU aiming to reduce the possibility of critical situations occurrence in following years. Furthermore, Poland’s most popular OTC derivatives and local derivatives regulations have been characterized in the paper. The assessment of introducing in 2012 regulations on OTC and its value structure has been performed

The legal nature of the SWAP contract as one of the derivatives

Przedmiotem niniejszej pracy jest przedstawienie instrumentów pochodnych w ujęciu prawnym. Zostało to zaprezentowane na przykładzie kontraktu swap, który jest umową wymiany przyszłych płatności, związanych zwykle z instrumentami dłużnymi lub walutami obcymi, zawartą według wcześniej określonych zasad pomiędzy dwoma lub więcej stronami transakcji. Rozdział pierwszy poświecony został ogólnej charakterystyce rynku transakcji terminowych oraz omówieniu jego instrumentów. Omówiono rynek instrumentów finansowych w ujęciu giełdowym i pozagiełdowym w świetle polskich uregulowań prawnych w tym zakresie. Zaprezentowano kluczowe rodzaje instrumentów pochodnych w powiązaniu z celowością ich stosowania. Omówiono regulacje prawne, którym podlegają umowy dotyczące transakcji finasowych na instrumenty pochodne. W rozdziale drugim przedstawiono polskie uregulowania prawne instrumentów pochodnych w aspekcie zmian ustrojowych mających miejsce w Polsce po 1989 roku, jak również w aspekcie zmian światowego rynku instrumentów pochodnych wymuszonych przez światowy kryzys w 2008 roku. W rozdziale trzeciem omówiono istotę kontraktu swap jako umowy zawartej pomiędzy stronami oraz odniesiono ją do przepisów ustawy Kodeks Cywilny. W rozdziale czwartym przedstawiono kontrakt swap w ujęciu publiczno – prawnym. Scharakteryzowano swap jako instrument finansowy, instrument pochodny, terminową transakcję finansową oraz czynność maklerską.The subject of this paper is to present derivatives from a legal perspective. It is done on an example of a swap contract. Swap is defined as a contract where parties exchange future payments, usually associated with debt instruments or foreign currencies. It is signed upon predetermined set of rules between two or more parties to the transaction. The first chapter of this paper is dedicated to a general description of the futures market and its instruments. Derivatives market is presented in terms of the exchange and over the counter transactions under Polish legislation in this regard. There is a description of the most common usage of different types of derivatives. The paper goes through regulations governing contracts for the derivatives. The second chapter presents the Polish legal regulations of derivatives in terms of political changes taking place in Poland after 1989, as well as in terms of changes in the global derivatives market caused by the global financial crisis in 2008. The third chapter discusses the nature of a swap contract as the contract between the parties and with the reference to the provisions of the Civil Code. The fourth chapter presents the swap contract in terms of public law. The paper is ended with conclusions