Nitric oxide mediates intestinal hyperaemic responses to intraluminal bile-oleate

It has long been recognized that intestinal blood flow increases at mealtimes. Mesenteric hyperaemia is also evoked by activation of sensory peptidergic nerves. Our studies explored the possible role of endogenous nitric oxide (NO) in the rat intestinal vasodilator response to luminal instillation of an oleic acid plus bile mixture before and after acute intrajejunal instillation of capsaicin and after chronic pretreatment with capsaicin. In anaesthetized rats we measured jejunal blood flow (BF) with an ultrasonic Doppler flowmeter and systemic arterial pressure (AP) with a pressure transducer. Intestinal perfusion with 80 mM oleic acid in bile increased BF by 98±12%. Instillation of 4 mg of capsaicin into the jejunal lumen initially increased BF by 42±9% but was followed by vasoconstriction. Inhibition of NO synthase with 25 mg/kg i.v. N-nitro-L-arginine (L-NNA) decreased BF by 27±5% and increased AP by 37±11%. After treatment with L-NNA and after acute and chronic administration of capsaicin, the bile-oleate-induced maximal increases in BF above control levels were 42±7%, 65±12%, and 58±8%, respectively. The observed inhibitory effect of L-NNA on the intestinal hyperaemic response to the bile-oleate mixture was reversed by pretreatment with L-arginine (100 mg/kg i.V.). In capsaicin pretreated rats the subsequent bile-oleate-induced hyperaemia was reduced in magnitude but the inhibitory effects of L-NNA were proportionately the same as in animals not receiving capsaicin. These findings support the hypothesis that NO is involved with bile-oleate-induced mesenteric hyperaemia.     

The activity of erythrocyte enzymes in rats subjected to running exercises

Summary The studies were carried out on male Wistar rats subjected to running within an electric rotating drum. The animals were divided into four experimental groups, differing one from another as to the duration of training. Each training session lasted 30 days. In the first group the daily run lasted 3 min, in the second group 5 min; in the third group, a 1 min run on the first day, and one min longer on each successive day; in the fourth group a 2 min run on the first day and for two min longer on each successive day.The determinations made prior to and after training included the peripheral blood erythrocyte (Er) and reticulocyte (Ret.) count, the hemoglobin concentration (Hb) and packed cell volume (PCV) and, determined by spectrophotometric methods, the activity of pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase (GR). Training induced an improvement of all enzymatic activities. The heavier the physical exertion, the more intensive was the enzymatic activity of red blood cells, due to the intensification of bone marrow erythropoetic activity under physical exertion and the appearance of young red cells in peripheral blood. All the experimental groups revealed a drop in erythrocyte count (Er), hemoglobin concentration (Hb), and hematocrit values (PCV), as well as an increase in the reticulocytes count (Ret) and in the activity of all the enzymes investigated. In the fourth group anemia was detected: prolonged endurance training decreased the RBC by 24.2%, Hb by 31.1%, PCV by 26.2% and increased the reticulocyte count by 881.6%. Pronounced loading with physical effort leads to shifts in the glucose utilization ratio along particular erythrocyte metabolic pathways. This change in enzymatic activities may prove to be one of the causes of faster elimination of old RBCs.     

The impact of location and patency of the arteriovenous fistula on quality of life of kidney transplant recipients

BackgroundArteriovenous fistulae (AVFs) may remain patent after kidney transplantation (KTx), contributing to maladaptive cardiac remodeling. The flow in AVFs is associated with the diameter of its vessels and thus with the AVF location. The main objective of this study is to assess the influence of AVF location and its patency on the self-reported quality of life (QOL) of kidney transplant recipients (KTRs) with past history of hemodialysis.MethodsTo gain clinical data, during a scheduled visit, 353 KTRs were asked to fill out an anonymous questionnaire. From this group, 284 respondents were found eligible for analysis. The outcome was defined as prevalence of symptoms and health status, measured with the Left Ventricular Dysfunction-36 (LVD-36) Questionnaire in symptomatic patients.ResultsThe hemodialysis patients (n = 243) were divided into two groups according to AVF location, i.e., DAVF – distally located AVF – (n = 174) and PAVF – proximally located AVF – (n = 69). The proportion of patients with heart failure (HF) was higher in PAVF group (24% vs. 12%, p = 0.0482). In the multivariable regression, PAVF, serum creatinine levels, and the presence of HF or coronary artery disease (CAD) remained independent predictors of lower functional capacity. Among patients with heart disease, the presence of active AVF was independently associated with worse functional outcome (higher LVD-36 scores).ConclusionsThe influence of persistent PAVF in KTRs seems to be unfavorable, especially when coexisting with CAD or HF. Abbreviations: AVF arteriovenous fistula; BMI body mass index; CAD coronary artery disease; D-AVF distally-located arteriovenous fistula; EC exercise capacity; HD hemodialysis; HF heart failure; KTx kidney transplantation; KTR kidney transplant recipient; LVD-36 Left Ventricle Disfunction – 36; LVEF left ventricle ejection fraction; LVH left ventricle hypertrophy; NYHA New York Heart Association; P-AVF proximally located arteriovenous fistula; PD peritoneal dialysis; PRO patient-reported outcomes; QOL quality of life.     

Nuclear Pedigree Criteria for the Identification of Individuals Suspected to Be at Risk of an Inherited Predisposition to Gastric Cancer

Gastric cancer is the second most frequently diagnosed malignancy worldwide and therefore represents a significant healthcare burden. Environmental and genetic factors are involved in the development of gastric cancer. To date only one clear genetic predisposition has been identified involving mutations in the E-cadherin gene. The disease phenotype in patients harbouring E-cadherin mutations appears to be specifically related to diffuse gastric cancer. Little is known genetically about the other forms of gastric cancer. Since there is a growing awareness about the necessity of early intervention criteria have been developed that aid the identification of hereditary forms of gastric cancer. The aim of the current study was to identify minimal inclusion criteria so that nuclear pedigree families can be provided with risk assessment and/or genetic testing.The results reveal that inclusion features described herein such as (a) gastric cancer diagnosed before 46 years of age; (b) two gastric cancers among first degree relatives diagnosed over the age of 50 are useful in identifying suspected hereditary gastric cancer patients.     

Using the Smith-Watson-Topper Parameter and Its Modifications to Calculate the Fatigue Life of Metals: The State-of-the-Art

The Smith-Watson-Topper parameter (SWT) in its original form was designed to estimate the fatigue life of metal materials in a uniaxial load state (tension–compression) in the range up to fatigue crack initiation, with non-zero mean values. This parameter is based on the analysis of both stress and strain. Therefore, the stress–strain criterion is the focus, rather than the energy criterion. This paper presents the original SWT model and its numerous modifications. The first part presents different versions of this parameter defined by the normal parameters. Then, it presents versions defined through the tangent parameter and the most promising parameter defined through the tangent and normal parameters. It was noted that the final form of the equivalent value is defined either by stress or by an energy parameter. Therefore, the possible characteristics from which the fatigue life can be determined are also presented.     

Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues

Novel tiazofurin adenine dinucleotide (TAD) analogues 25-33 containing a substituent at C2 of the adenine ring have been synthesized as inhibitors of the two isoforms of human IMP-dehydrogenase. The 2-ethyl TAD analogue 33 [Ki = 1 nM (type I), Ki = 14 nM (type II)] was found to be the most potent. It did not inhibit three other cellular dehydrogenases up to 50 microM. Mycophenolic adenine bis(phosphonate)s containing a 2-phenyl (37) or 2-ethyl group (38), were prepared as metabolically stable compounds, both nanomolar inhibitors. Compound 38 [Ki = 16 nM (type I), Ki = 38 nM (type II)] inhibited proliferation of leukemic K562 cells (IC50 = 1.1 microM) more potently than tiazofurin (IC50 = 12.4 microM) or mycophenolic acid (IC50 = 7.7 microM).     

Oxazoline scaffold in synthesis of benzosiloxaboroles and related ring-expanded heterocycles: diverse reactivity,structural peculiarities and antimicrobial activity

Two isomeric benzosiloxaborole derivatives 3a and 5a bearing fluorine and 4,4-dimethyl-2-oxazolin-2-yl substituents attached to the aromatic rings were obtained. Both compounds were prone to hydrolytic cleavage of the oxazoline ring after initial protonation or methylation of the nitrogen atom. The derivative 3c featuring N-methylammoniumalkyl ester functionality was successfully subjected to N-sulfonylation and N-acylation reactions to give respective derivatives which demonstrates its potential for modular synthesis of structurally extended benzosiloxaboroles. Compound 5c bearing N-ammoniumalkyl ester underwent conversion to a unique macrocyclic dimer due to siloxaborole ring opening. Furthermore, an unexpected 4-electron reduction of the oxazoline ring occurred during an attempted synthesis of 5a. The reaction gave rise to an unprecedented 7-membered heterocyclic system 4a comprising a relatively stable B–O–B–O–Si linkage and stabilized by an intramolecular N–B coordination. It could be cleaved to derivative 4c bearing BOH and SiMe₂OH groups which acts as a pseudo-diol as demonstrated by formation of an adduct with Tavaborole. Apart from the multinuclear NMR spectroscopy characterization, crystal structures of the obtained products were determined in many cases by X-ray diffraction. Investigation of biological activity of the obtained compounds revealed that derivatives 3e and 3f with pendant N-methyl arylsulfonamide groups exhibit high activity against Gram-positive cocci such as methicillin-sensitive Staphylococcus aureus ATCC 6538P, methicillin-resistant S. aureus (MRSA) ATCC 43300 as well as the MRSA clinical strains, with MIC values in the range of 3.12–6.25 mg L⁻¹. These two compounds also showed activity against Enterococcus faecalis ATCC 29212 and Enterococcus faecium ATCC 6057 (with MICs of 25–50 mg L⁻¹). The results of the antimicrobial activity and cytotoxicity studies indicate that 3e and 3f can be considered as potential antibacterial agents, especially against S. aureus MRSA.

Transformations of oxazoline–benzosiloxaborole conjugates gave rise to novel boracyclic systems as well as functionalized derivatives featuring antibacterial activity.     

Thrombotic thrombocytopenic purpura in pregnancy. A case report

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and thrombocytopenia, accompanied by microvascular thrombosis that causes variable degrees of tissue ischemia and infarction. About 10-20% of TTP cases are associated with the pregnancy. Preterm delivery and intrauterine fetal death are frequent pregnancy complications of TTP. The following paper presents the case of a 32-year-old woman with TTP relapse at 10 weeks of her second pregnancy. Despite regular fresh frozen plasma transfusions, intrauterine fetal death occurred at 21 weeks of gestation. Current views on TTP management during pregnancy have been presented in the article as well.     

The 3020insC NOD2 gene mutation in patients with ovarian cancer

OBJECTIVE: There is an increasing evidence that genetic factors play a role in the etiology of malignant tumors. Mutations of BRCA1 and BRCA2 genes are responsible for an increased risk of ovarian cancer. The role of mutations in NOD2 gene in this type of neoplasm is still under investigation. THE AIM: The aim of this study was to determine: 1. incidence of NOD 2 3020insC constitutional mutation in a group of consecutive women with ovarian cancer, 2. risk of developing ovarian cancer in patients with NOD2 gene mutation, 3. clinical and pathological features of ovarian cancer in NOD2 gene mutation carriers. PATIENTS AND METHODS: Clinical and pathological data were collected from 257 non-selected patients with primary epithelial ovarian cancer. The researches identified NOD2 3020insC gene mutation. On the basis of patient source documentation we obtained the data concerning the age of patients at diagnosis, histopathological recognition, FIGO stage and morphological grade G. RESULTS: 19 out of 257 women were identified with germ-line 3020insC mutation of NOD2 gene (7.39%). An increased risk of ovarian cancer in NOD2 mutation carriers was not revealed (OR=1.01; p=0.928; 95% Cl=0.61-1.66). The mean age at diagnosis of patients with NOD2 mutation was 54.8 (SD=9.9), while for non-carriers it was 53.2 (SD=10.2). The difference between these frequencies was statistically irrelevant (p=0.550). Clinical and pathological profile of ovarian cancer was made. We assessed the following features: age at disease onset, histopathology, FIGO stage and morphological grade G. For NOD2 mutation carriers no statistically significant features of ovarian cancer were revealed. CONCLUSION: 1. Despite high frequency of constitutional mutations occurrence in NOD2 gene in women with ovarian cancer, genetic testing seem not to be justified in all women diagnosed with this disease. 2. Due to a lack of increased risk of ovarian cancer in NOD2 gene mutation carriers, proceedings for them may not differ from recommendations for general population. 3. It is difficult to determine characteristic clinical and pathological features of ovarian cancer for NOD2 gene mutation carriers.     

The course of pregnancy and delivery in women after genetic amniocentesis before and after 35 years of age

OBJECTIVES: The demand for genetic amniocentesis in case of young pregnant women has significantly increased due to various new indications. Moreover, nowadays a growing number of women aged > or =35, who required genetic amniocentesis, get pregnant The aim of the following study has been to compare the course of the pregnancy, the delivery and the condition of the newborn in two groups of patients: 18-34 years old and > or =35 years old. MATERIAL AND METHODS: 783 women underwent the procedure of amniocentesis at the Department of Obstetrics of Medical University of Gdansk in 1996-2003. A group of 540 women, who answered the questionnaire about the course of the pregnancy and the delivery after the procedure, has been isolated. RESULTS: Fetal loss occurred in 2 cases (1.6%) in the group of the younger women and in 8 cases (0.8%) in the group of > or =35 year-olds (p=0.84). There was no statistically significant difference between younger and older patients when comparing complications after the procedure in the first three weeks following amniocentesis: spotting, bleeding, leakage of amniotic fluid. Frequency of late complications such as gestational diabetes mellitus, pregnancy induced hypertension and urinary tract infections were comparable in both age groups women. Cesarean section has been more frequently performed in case of the older women than in the group of younger patients, with statistical difference p=0.003. In most cases (33.9%) it has been an elective cesarean section, performed due to advanced maternal age rather than any obstetric cause. Frequency of pneumonia and the number of respiratory infections in the newborns have been comparable in both groups. CONCLUSIONS: Prenatal invasive diagnosis has no influence on frequency of complications during pregnancy and delivery in the group of women less than 35 years old and more than 35 years old.