Diabetes care and pregnancy outcomes for women with pregestational diabetes in Ireland.

AIMS: Pre-gestational diabetes mellitus (PGDM) is associated with adverse outcomes. We aimed to examine pregnancies affected by PGDM; report on these pregnancy outcomes and compare outcomes for patients with type 1 versus type 2 diabetes mellitus; compare our findings to published Irish and United Kingdom (UK) data and identify potential areas for improvement. METHODS: Between 2016 and 2018 information on 679 pregnancies from 415 women with type 1 Diabetes Mellitus and 244 women with type 2 diabetes was analysed. Data was collected on maternal characteristics; pregnancy preparation; glycaemic control; pregnancy related complications; foetal and maternal outcomes; unscheduled hospitalisations; congenital anomalies and perinatal deaths. RESULTS: Only 15.9% of women were adequately prepared for pregnancy. Significant deficits were identified in availability and attendance at pre-pregnancy clinic, use of folic acid, attaining appropriate glycaemic targets and appropriate retinal screening. The majority of pregnancies (n = 567, 83.5%) resulted in a live birth but the large number of infants born large for gestational age (LGA) (n = 280, 49.4%), born prematurely <37 weeks and requiring neonatal intensive care unit (NICU) admission continue to be significant issues. CONCLUSIONS: This retrospective cohort study identifies multiple targets for improvements in the provision of care to women with pre-gestational DM which are likely to translate into better pregnancy outcomes.

Nitrogen Reduction to Ammonia on a Biomimetic Mononuclear Iron Centre: Insights into the Nitrogenase Enzyme.

Nitrogenases catalyse nitrogen fixation to ammonia on a multinuclear Fe-Mo centre, but their mechanism and particularly the order of proton and electron transfer processes that happen during the catalytic cycle is still unresolved. Recently, a unique biomimetic mononuclear iron model was developed using tris(phosphine)borate (TPB) ligands that was shown to convert N2 into NH3 . Herein, we present a computational study on the [(TPB)FeN2 ]- complex and describe its conversion into ammonia through the addition of electrons and protons. In particular, we tested the consecutive proton transfer on only the distal nitrogen atom or alternated protonation of the distal/proximal nitrogen. It is found that the lowest energy pathway is consecutive addition of three protons to the same site, which forms ammonia and an iron-nitrido complex. In addition, the proton transfer step of complexes with the metal in various oxidation and spin states were tested and show that the pKa values of biomimetic mononuclear nitrogenase intermediates vary little with iron oxidation states. As such, the model gives several possible NH3 formation pathways depending on the order of electron/proton transfer, and all should be physically accessible in the natural system. These results may have implications for enzymatic nitrogenases and give insight into the catalytic properties of mononuclear iron centres.

A Systematic Account on Aromatic Hydroxylation by a Cytochrome P450 Model Compound I: A Low-Pressure Mass Spectrometry and Computational Study.

Cytochrome P450 enzymes are heme-containing mono-oxygenases that mainly react through oxygen-atom transfer. Specific features of substrate and oxidant that determine the reaction rate constant for oxygen atom transfer are still poorly understood and therefore, we did a systematic gas-phase study on reactions by iron(IV)-oxo porphyrin cation radical structures with arenes. We present herein the first results obtained by using Fourier transform-ion cyclotron resonance mass spectrometry and provide rate constants and product distributions for the assayed reactions. Product distributions and kinetic isotope effect studies implicate a rate-determining aromatic hydroxylation reaction that correlates with the ionization energy of the substrate and no evidence of aliphatic hydroxylation products is observed. To further understand the details of the reaction mechanism, a computational study on a model complex was performed. These studies confirm the experimental hypothesis of dominant aromatic over aliphatic hydroxylation and show that the lack of an axial ligand affects the aliphatic pathways. Moreover, a two-parabola valence bond model is used to rationalize the rate constant and identify key properties of the oxidant and substrate that drive the reaction. In particular, the work shows that aromatic hydroxylation rates correlate with the ionization energy of the substrate as well as with the electron affinity of the oxidant.

EXTRADIGESTIVE MANIFESTATIONS OF GASTROESOPHAGEAL REFLUX DISEASE: DEMOGRAPHIC, CLINICAL, BIOLOGICAL AND ENDOSCOPIC FEATURES.

UNLABELLED: Gastroesophageal reflux disease (GERD) with extradigestive manifestations is a disorder increasingly recognized both by gastroenterologists, pneumologists, otolaryngologists and cardiologists. AIM: To evaluate the demographical, clinical, biological and endoscopic features of the patients with gastroesophageal reflux disease and extradigestive manifestations (chronic laryngitis, asthma, pseudoangina). MATERIAL AND METHODS: Prospective case-control study, including 137 patients selected from patients referred to the Iasi Institute of Gastroenterology and Hepatology between July 2014-September 2015. In the presence of typical GERD symptoms (heartburn or regurgitation), the patients were assessed by upper digestive endoscopy for the detection or exclusion of esophagitis. Despite the absence of esophageal lesions, the patients were further assessed by impedance-pHmetry. RESULTS: Depending on the dominant extradigestive manifestation, the patients were assigned into 3 groups: 94 chronic laryngitis patients, 24 asthma patients and 19 pseudoangina patients. Females were more frequent among pseudoangina patients (68.4%). Mean age of the male patients with dysphonia or asthma was lower (p=0.002), the majority (78.1%) living in urban areas. Obesity was predominant in pseudoangina group (52.6%), as compared to dysphonia group (16%) the differences being statistically significant (p=0.002). A share of 57.9% of pseudoangina patients were dyslipidemic, in contrast to dysphonia (24.5%) or asthma group (37.5%) (p=0.013). Esophagitis was also more frequent at pseudoangina group (84.2%), but with no significant statistical difference between the study groups (79.8% and 75%, respectively) (p=0.115). It seems that Helicobacterpylori infection tends to be protective in patients with GERD and pseudoangina (RR=0.61), but it can not be extrapolated to the general population (p=0.459). CONCLUSION: GERD with extradigestive manifestations is a prevalent and heterogeneous disease. There are demographic, clinical, biological and endoscopic differences between patiens with extradigestive GERD.

THE TRIBES AND TRIBULATIONS OF LARYNGOPHARYNGEAL REFLUX: A REVIEW OF RECENT STUDIES WITH IMPLICATIONS FOR INTERDISCIPLINARY COLLABORATIONS BETWEEN OTOLARYNGOLOGISTS AND GASTROENTEROLOGISTS.

Laryngopharyngeal reflux has been recognized since 2006 (Montreal Consensus) as an extradigestive manifestation of gastroesophageal reflux disease. However, despite numerous research studies, the relationship between these two pathologies is yet to be fully understood. The aim of this paper is to review the literature of the last five years available via the PubMed database, looking at the controversies about the prevalence, pathophysiology and diagnosis of laryngopharyngeal reflux.

Different profile of peripheral antioxidant enzymes and lipid peroxidation in active and non-active inflammatory bowel disease patients.

BACKGROUND: The role of oxidative stress in inflammatory bowel diseases (IBD) has been extended lately from a simple consequence of inflammation to a potential etiological factor, but the data are still controversial. Active disease has been characterized before by an enhanced production of reactive oxygen species and the increased peroxidation of lipids, but patients in remission were generally not considered different from healthy people in terms of oxidative stress. AIMS: We evaluated the antioxidant defense capacity and lipid peroxidation status in the serum of patients with active and non-active disease compared with healthy matched control subjects. METHODS: The study included 20 patients with confirmed IBD in clinical and biological remission, 21 patients with active disease, and 18 controls. We determined the serum levels of two antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GPX), and a lipid peroxidation marker, malondialdehyde (MDA). RESULTS: Active disease patients had an increased activity of both SOD and GPX, as well as significant high values of MDA versus controls. Furthermore, patients being in remission had significantly lower values of antioxidant enzymes (SOD and GPX) and increased lipid peroxidation measured by MDA serum levels, as compared with healthy control subjects. CONCLUSIONS: Our study confirmed the presence of high oxidative stress in active IBD. More importantly, we have demonstrated a lower antioxidant capacity of patients in remission versus control group. This may represent a risk factor for the disease and can be an additional argument for the direct implication of oxidative stress in the pathogenesis of IBD.

Clinical, biological and epidemiological aspects of inflammatory bowel diseases in North-East Romania.

AIM: Inflammatory bowel diseases (IBD) are chronic conditions of unknown etiology with increasing incidence in South-East Europe. The epidemiological characteristics, clinical, biological and endoscopic profiles are very different worldwide, with little data existing from Moldova region. This study aims to characterize IBD in North-East Romania from the mentioned points of view. MATERIAL AND METHODS: All patients with Crohn's disease or ulcerative colitis (UC) admitted to a tertiary hospital during a three year interval were retrospectively analyzed in terms of epidemiological characteristics. All IBD patients hospitalized during 2010 were complexly analyzed by noting the type and form of disease, the biological picture, the clinical and endoscopic scores. RESULTS: UC represents 77% of all cases (one of the highest values of the recent studies). Age at onset is higher in the studied region, with the average over 40 years. In UC the forms of severity and extension are uniformly distributed, but in Crohn's disease there is a predominance of colonic forms and the number of complicated cases is high - over 50%. The parameters with the best correlation with endoscopic scores were the clinical Mayo score for UC, serum C-reactive protein and fibrinogen. CONCLUSIONS: There is a definite predominance of UC in North-East Romania, but Crohn's disease tends to present an increased number of complications. The age of onset of the two diseases is high. There is a good correlation between the clinical and biological scores with endoscopic activity, but without this assessment inflammation may be underestimated. Systematic exploration of the small bowel may increase detection of ileal manifestations.

[Some aspects of viral hepatitis B and C. Observations on patients treated in Bacau County, between 2007 and 2010]. / Unele aspecte privind hepatitele virale B si C. observatii pe un lot de pacienti tratati în judetul Bacau, în perioada 2007-2010.

UNLABELLED: The study aim was to assess some features of samples of patients assisted for viral hepatitis B and C, as well as cirrhosis, and included in a national antiviral treatment protocol. MATERIAL AND METHODS: The study considered patients assisted in the medical assurance system in the Bacau County, Romania, during 2007 and 2010. RESULTS: A sample of 1127 patients with chronic viral hepatitides B and C was assisted, from which 154 cases with B virus (13.7%) with a male predominance and 973 with C virus (86.3%) and a female predominance. An increase trend for both hepatitides prevalence was highlighted and a number of non-responders every year (18.1% of total cases). CONCLUSIONS: A correct diagnosis and treatment of\cases with chronic viral hepatitis B and C and to have a smaller number ofnon-responders represent major purposes of specialists in the Bacau County also.

Evaluation of tumor response to systemic therapy in hepatocellular carcinoma.

Evaluation of tumor response (the change in tumor volume) represents the basis for assessing therapeutic efficacy. Furthermore, objective response and progression are endpoints in clinical trials. Response Evaluation Criteria in Solid Tumors (RECIST) is an assessment tool derived from the conversion of quantitative imaging observations. Version 1.1 has been validated and its criteria are useful in all studies intended to assess objective response, disease stabilization and tumor progression, or time to progression analysis. In addition to changes regarding the disease assessment criteria of measurable and non-measurable lesions, the new system integrates volumetric assessment and functional imaging. The REC1ST's utility system follows from the applicability in clinical trials and the possible use in clinical practice. However, adapting it to assess liver tumors requires evaluation in prospective trials.

[Colorectal cancer--clinical course, epidemiologic and pathologic aspects]. / Cancerul colorectal--consideratii asupra tendintelor evolutive ale profilului epidemiologic si anatomoclinic.

UNLABELLED: In the past 3 years colorectal cancer became the second cause death (after the broncho-pulmonary cancer) exceeding gastric cancer by 4150 deaths in 2002 (19,05 per hundred thousand inhabitants) and 4860 deaths in 2006. MATERIAL AND METHODS: 644 of the 18,978 patients coloscopically investigated at the lasi Gastroenterology and Hepatology Institute in the interval 2000-2007 in which pathology results revealed colorectal cancer, and 279 patients operated at the First Clinic Surgery of the Iasi "Sf. Spiridon" Hospital during 2008-2010 were selected for this study. RESULTS: Colorectal carcinoma has a high incidence in the patients over 60 years. Sex distribution of the tumors showed that this disease most commonly affects males. The male/female ratio was 1.3. In less than 3% of the cases the disease occurred at ages under 40 years. The most frequent clinical manifestations were intestinal transit disorder (97%), pain syndrome on the left side of the abdomen (82.82%), and progressive severe constipation (67.89%). 24.07% of the colorectal cancer cases were located at the level of the proximal colon (cecum, ascending colon, hepatic flexure, transverse colon and splenic flexure), while 75.9% were located at the distal level. The most frequent macroscopic form was the vegetative one (89.91%).

[Budd-Chiari syndrome--case presentation]. / Sindrom Budd-Chiari--prezentare de caz.

The Budd-Chiari syndrome represents the obstruction of hepatic veins usually due to a hepatocarcinoma. We present the case of a 68 year old patient, in medical evidence for ten years with a Child A ethanolic liver cirrhosis, who was admitted in emergency for hematemesis and melena. Clinical examination and the laboratory findings at the admittance revealed signs of decompensated cirrhosis and severe anemia. Ultrasound examination showed a cirrhotic liver with portal hypertension signs and a multinodular mass in the right lobe of the liver with portal, biliary and right hepatic vein invasions extended to inferior caval vein. In upper digestive endoscopy stage IV esophageal varices were evidenced with signs of recent bleeding (sclerotherapy was performed) along with gastric varices and portal gastropathy. The particularity of the case consists in the invasive complications of the hepatocarcinoma regarding hepatic and inferior caval veins wich defines the Budd-Chiari syndrome (posthepatic portal hypertension added to the intrahepatic and prehepatic ones), the invasions of the biliary tract and portal vein being more frequent.

[The role of upper gastrointestinal endoscopy in evaluation of portal hypertension]. / Rolul endoscopiei digestive superioare în evaluarea hipertensiunii portale.

UNLABELLED: Portal hypertension is the main cause of complications of hepatic diseases determining portosystemic collateral circulation, ascites and gastroesophageal varices. Aim of the study is to review current opinions and to correlate clinical and endoscopic signs determined by portal hypertension. MATERIAL AND METHODS: We performed a retrospective study on 150 patients diagnosed and treated for diseases associated with portal hypertension at the Institute of Hepatology and Gastroenterology from Iasi between 2007 and 2009. RESULTS AND DISCUSSION: Most of the patients presented with cirrhosis (112 cases) mainly of toxic (63 cases) and viral (31 cases) etiology. In order to appreciate bleeding from esophageal varices we applied Forrest criteria and identified type Ia bleeding in 26,6% of cases and type Ib bleeding at 73,4% of patients. In 15% of cases, variceal bleeding represented the first symptom of slowly progressing hepatic cirrhosis. CONCLUSIONS: The objective of subsequent evaluation of small varices is detecting size increase, an important prognostic and therapeutic index.

[Radiofrequency ablation in the multimodal treatment of liver metastases--preliminary report]. / Utilizarea termoablatiei prin radiofrecventa in tratamentul multimodal al metastazelor hepatice.

UNLABELLED: Although the "gold standard" in the multimodal treatment of liver primary and secondary tumors is the surgical ablation, the rate of resection, despite the last decades advances, remains still low (10 - 20%). In addition, the interest for non-surgical ablation therapies is increasing. Among them, regional or systemic chemotherapy, intra-arterial radiotherapy as well as locally targeted therapies--cryotherapy, alcohol instillation and radiofrequency (RF) are the most valuable options as alternative to the surgical approach. MATERIAL AND METHOD: Between February 2005 - January 2007, 9 patients with liver metastases underwent open RF ablation of their secondaries in the III-rd Surgical Unit, "St. Spiridon" Hospital. An Elektrotom 106 HiTT Berchtold device with a 60W power generator and a 15 mm monopolar active electrode was used. RESULTS: Destruction of the tumors was certified with intraoperative ultrasound examination. Pre- and postoperative CarcinoEmbryonic Antigen (CEA) together with imaging follow-up was carried out, in order to determine local or systemic recurrencies. Six patients died between 6 month - 4 years after the RF ablation. Median survival is 29.2 months. CONCLUSION: RF ablation is a challenge alternative in non-resectable liver tumors.

Rational selection of structurally diverse natural product scaffolds with favorable ADME properties for drug discovery.

Natural product analogs are significant sources for therapeutic agents. To capitalize efficiently on the effective features of naturally occurring substances, a natural product-based library production platform has been devised at Aurigene for drug lead discovery. This approach combines the attractive biological and physicochemical properties of natural product scaffolds, provided by eons of natural selection, with the chemical diversity available from parallel synthetic methods. Virtual property analysis, using computational methods described here, guides the selection of a set of natural product scaffolds that are both structurally diverse and likely to have favorable pharmacokinetic properties. The experimental characterization of several in vitro ADME properties of twenty of these scaffolds, and of a small set of designed congeners based upon one scaffold, is also described. These data confirm that most of the scaffolds and the designed library members have properties favorable to their utilization for creating libraries of lead-like molecules.

[Sequential esophageal scintigraphy contribution on cardia achalasia diagnosis]. / Contributia scintigrafiei esofagiene secventiale în diagnosticul acalaziei cardiei.

Achalasia is a mortality disorder described in 1674 by Willis. It has a small incidence in the general population. The main symptom is dysphagia. The golden standard for diagnosis is esophageal manometry. Esophageal scintigraphy is a non-invasive method of exploration: the technique is simple, it lasts five minutes and is more sensitive than the radiologic exam. The esophageal scintigraphy was made in the Nuclear Medicine Laboratory of the Sf. Spiridon Hospital using a gamma scann Diacam--Siemens. The parameters measured with esophageal scintigraphy are: esophageal transit time, residuary radioactivity. Our study included a number of 37 patients with achalasia with ages between 16 and 80 years (the average--47, 3 years). Our conclusions are the same with the data from literature.

[The scintigraphic assessment of the patients suffering from cardia achalasia, treated by pneumatic dilatation]. / Evaluarea scintigrafica a bolnavilor cu acalazia cardiei tratati prin dilatare cu balonas.

The esophageal scintigraphy is a technique used to evaluate the motility and the clearance of the esophagus. The patients with achalasia of the cardia were evaluated, before treating them with pneumatic dilatation and after. The reason is to evaluate the efficiency of the pneumatic dilatation technique in the treatment of esophageal achalasia. The pneumatic dilatation with an instrument type Rigiflex is a well/handled and used technique in our clinic. In the study 22 patients were included and we had in view the esophageal transit time and the residuary radioactivity before and after the pneumatic dilatation. We established an important statistical improvement of the data obtained after the dilatation comparative with the data before the treatment (p < 0.01).

In vitro-in vivo correlation (IVIVC) models for metformin after administration of modified-release (MR) oral dosage forms to healthy human volunteers.

The objective of the current study was to develop and evaluate the internal predictability for level C and A in vitro-in vivo correlation (IVIVC) models for prototype modified-release (MR) dosage forms of metformin. In vitro dissolution data for metformin were collected for 22 h using a USP II (paddle) method. In vivo plasma concentration data were obtained from 8 healthy volunteers after administration of immediate-release (IR) and MR dosage forms of metformin. Linear level C IVIVC models were developed using dissolution data at 2.0 and 4.0 h and in vitro mean dissolution time (MDT). A deconvolution-based level A model was attempted through a correlation of percent in vivo input obtained through deconvolution and percent in vitro dissolution obtained experimentally. Further, basic and extended convolution level A IVIVC models were attempted for metformin. Internal predictability for the IVIVC models was assessed by comparing observed and predicted values for C(max) and AUC(INF). The results suggest that highly predictive level C models with prediction errors (%PE) of <5% could be developed. Mean percent in vivo input for metformin was incomplete from all formulations and did not exceed 35% of dose. The deconvolution-based level A models for all MR formulations were curvilinear. However, a unique IVIVC model applicable to all MR formulations could not be developed using the deconvolution approach. The basic convolution level A model, which used in vitro dissolution as the in vivo input, had %PE values as high as 103%. Using an extended convolution approach, which modeled the absorption of metformin using a Hill function, a level A IVIVC model with %PE as low as 11% was developed. In conclusion, the current work indicates that level C and A IVIVC models with good internal predictability may be developed for a permeability- and absorption window-limited drug such as metformin.

Pancreatic enzymes replacement therapy in chronic pancreatitis: an update.

Chronic pancreatitis is the major cause of exocrine pancreatic insufficiency which should be compensated by pancreatic enzyme replacement therapy. There are now available a great number of pancreatic enzyme preparations, but encapsulated enteric-coated microspheres and minimicrospheres are considered the enzyme treatment of choice. However, full compensation of pancreatic exocrine insufficiency with enzyme replacement therapy cannot be obtained in all patients with chronic pancreatitis.

In-vitro in-vivo correlation models for glibenclamide after administration of metformin/glibenclamide tablets to healthy human volunteers.

In this study, level C and A in-vitro in-vivo correlation (IVIVC) models were developed for glibenclamide. In-vitro dissolution data were collected for the glibenclamide component of three metformin/glibenclamide tablets using a USP Type II apparatus. In-vivo plasma concentration data were obtained after administration of the prototype formulations to 24 healthy volunteers and subject to deconvolution analysis to obtain percentage in-vivo absorbed profiles. Multiple linear level C models were developed for CMAX and AUC(0-48) using percentage in-vitro dissolved data at 10, 45 and 120 min. Initially, the level A model was constructed for the first 2 h only, based on availability of in-vitro data. Another level A model was attempted using a time-scaled approach, with percentage in-vivo absorbed at time t and percentage in-vitro dissolved at time t/I as the correlating data. Internal predictability was evaluated for the level C and time-scaled level A models. For all level C approaches, linear regression models with r2 > 0.99 were determined. The prediction errors (% PE) for Cmax and AUC(0-48) were less than 1% for all formulations at all three chosen time points. The deconvolution analysis indicated biphasic absorption for glibenclamide, with one phase occurring at 2-3h and another at 6-12h after dose administration. The level A model using 2-h data was not unique for all formulations and was therefore not developed. The time-scaling factor I correlated highly (r2 = 0.99) with in vitro mean dissolution time (MDT). A linear regression time scaled model (r2 = 0.97) was successfully developed using in-vitro and in-vivo data from all 3 formulations. However, the internal predictability of the time-scaled model was poor, with % PE values for Cmax and AUC(0-48) being as much as 30.5% and 18.7%, respectively. The results indicate that level C models have good internal predictability. Though a time-scaled level A IVIVC model was successfully developed, the model was found to have poor internal predictability.

[Klatskin's tumor]. / Tumora Klatskin.

During the period 1989-1998, 27 patients with primary proximal bile duct cancer were treated (17 females and 10 males with a mean age of 61 years). The main presenting symptoms were: jaundice (96.2%), itching (92.5%), weight loss (74%) and atypical pain (33.3%). All the patients underwent ultrasound (US) examination, 7 patients endoscopic retrograde cholangiopancreatography (ERCP) and 4 patients computed tomography (CT) examination. US examination revealed the tumor in 51% cases; most frequently a dilatation of the intrahepatic bile ducts was diagnosed with all methods. 8 patients underwent resection of the tumor and one a biliary-enteric anastomosis, in 15 cases a stent was inserted. In 3 cases the extension of the malignancy did not allowed any procedure. Three patients died during immediate postoperative period (mortality 11.2%). The mean survival was 13 months after stenting and 22 months after resection of the tumor. The authors recommended an aggressive surgical therapy for Klatskin tumors.