Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response

Congenital nephrogenic diabetes insipidus (NDI) is a rare disease caused most often by mutations in the vasopressin V2 receptor (AVPR2). We studied a family which included a female patient with NDI with symptoms dating from infancy. The patient responded to large doses of desmopressin (dDAVP) which decreased urine volume from 10 to 4 I/day. Neither the parents nor the three sisters were polyuric. The patient was found to be a compound heterozygote for two novel recessive point mutations in the aquaporin-2 (AQP2) gene: L22V in exon 1 and C181W in exon 3. Residue Cys181 in AQP2 is the site for inhibition of water permeation by mercurial compounds and is located near to the NPA motif conserved in all aquaporins. Osmotic water permeability (Pf) in Xenopus oocytes injected with cRNA encoding C181W-AQP2 was not increased over water control, while expression of L22V cRNA increased the Pf to approximately 60% of that for wild-type AQP2. Co-injection of the mutant cRNAs with the wild-type cRNA did not affect the function of the wild-type AQP2. Immunolocalization of AQP2-transfected CHO cells showed that the C181W mutant had an endoplasmic reticulum-like intracellular distribution, whereas L22V and wild-type AQP2 showed endosome and plasma membrane staining. Water permeability assays showed a high Pf in cells expressing wild-type and L22V AQP2. This study indicates that AQP2 mutations can confer partially responsive NDI.      

The need for an adapted initiation nomogram during Fiix prothrombin time monitoring of warfarin

Journal of Thrombosis and Thrombolysis - The new Fiix prothrombin time (Fiix-PT) and its derived Fiix-normalized ratio (Fiix-NR) is affected only by reductions in coagulation factors (F) II and X,...     

Declining Coronary Heart Disease Mortality in Iceland: Contribution by Incidence,Recurrence and Case Fatality Rate

Objective : To analyse to what extent the recent decline in coronary heart disease mortality in Iceland is due to changes in incidence, recurrence and case fatality rates. Design : A countrywide registration of myocardial infarction (MI) in people aged 25-74 was performed in Iceland during 1981-1999 according to the MONICA protocol. Possible cases were found by review of all hospital discharge records, autopsy records and death certificates. Results : MI death rate declined by 63% in males and 51% in females, most in the youngest age groups in men (86%) and least in the oldest (49%). In women there was not a significant difference in age groups. Overall the age-adjusted reduction in MI death rate was 55.4% in both sexes combined; of this 23.1% was due to incidence reduction, 22.8% to recurrence reduction and 11.6% to case fatality reduction. In the youngest age groups the decline in incidence contributed most to the decline in MI death rate (62% in men and 71% in women), but thereafter the decline in case fatality in men. In the older age groups decline in recurrence rate has greater weight. Conclusion : The recent decline in MI mortality under the age of 75 years in Iceland is due to reduction in incidence and recurrence rate by about 40% each and to reduction in case fatality by 20%.     

Controlling systolic blood pressure is difficult in patients with diabetic kidney disease exhibiting moderate-to-severe reductions in renal function

This study compared the use of antihypertensive treatment and blood pressure (BP) controls between patients with diabetic kidney disease (DK+) and patients with non-diabetic kidney disease (DK-) exhibiting moderate-to-severe chronic renal failure who did not need renal replacement therapy. A cross-sectional survey included all renal patients with s-creatinine at ?200 micromol/l attending regular control sessions at six renal units in Norway. Of the 351 patients included, 73 (20.8%) were DK+. The proportion reaching a BP goal of <130/80 mmHg was similar in DK+ and DK- (14.1% vs 13.6%, p = 0.92), while 38% and 39% achieved a BP of <140/90 mmHg, respectively. The systolic BP goal was more difficult to achieve than the diastolic BP goal in DK+ patients (35% vs 15%) despite a mean of three different types of drugs being used. Loop diuretics and beta-adrenergic-receptor antagonists were the most frequently prescribed drugs, and the use of angiotensin-converting enzyme inhibitors or angiotensin-II-receptor antagonists declined when renal function deteriorated, from 80% to 0% and from 66% to 20% in the DK+ and DK- groups, respectively (p = 0.001). Thus, despite the use of multiple antihypertensive drugs, controlling BP - especially the systolic BP - is difficult in high-risk patients with chronic renal failure caused by diabetic kidney disease.     

Gastroenteropancreatic neuroendocrine tumors in Iceland: a population-based study

Objective: To determine the incidence, distribution, and prognosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) over the last 30 years and analyze changes over time.

Methods: All patients diagnosed with GEP-NETs in Iceland from 1985 to 2014 were identified through the Icelandic Cancer Registry and pathology laboratory records. Relevant clinical information was obtained from medical records. In order to assess trends, the study period was divided into two periods, 1985–1999 and 2000–2014.

Results: A total of 364 patients with GEP-NETs were identified. Overall, 18 patients diagnosed at autopsy or with primary tumors of an unknown site were excluded, leaving 346 patients with 351 primary tumors for final analysis. The overall mean annual incidence 1985–2014 was 3.65/100,000, 3.39/100,000 during 1985–1999 and 3.85/100,000 during 2000–2014 (p?=?NS). The most common primary tumor site was the appendix (32%), followed by the jejunum/ileum (24%) and stomach (17%). In all, 18% of patients presented with distant metastases at the time of diagnosis, most noticeably patients with primary tumors of the colon (47%), pancreas (46%) and jejunum/ileum (39%). The most favorable 5-year survival was observed for tumors of the appendix (94%) and rectum (88%) and the least favorable for tumors of the pancreas (31%), colon (47%) and jejunum/ileum (66%). There were no statistically significant changes in incidence, staging or survival between the two time periods.

Conclusions: In this population-based study, the incidence of GEP-NETs has not changed significantly over the last decades. The incidence of metastatic disease has remained stable and overall prognosis has not improved in recent years.     

ATG16L1 and NOD2 polymorphisms enhance phagocytosis in monocytes of Crohn’s disease patients

AIM:To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn’s disease(CD).METHODS:In this study,we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls.As both autophagy related like 1(ATG16L1)and immunityrelated guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleo-tide-binding ligomerization domain-containing protein2(NOD2)has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction.The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo?Escherichia coli Bioparticles Phagocytosis kit for flowcytometry.RESULTS:In this study,we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity(ratio of mean fluorescence intensity)between the patient groups and the healthy controls.CD patients show a significantly higher phagocytic capacity(ratio mean percentage of phagocytic cells)compared to healthy controls(51.91%±2.85%vs 37.67%±7.06%,P=0.05).The extend of disease was not of influence.However,variants of ATG16L1(WT:2.03±0.19 vs homozygoot variant:4.38±0.37,P<0.009)as well as NOD2(C-ins)(heterozygous variant:42.08±2.94 vs homozygous variant:75.58±4.34(P=0.05)are associated with the phagocytic activity in patients with CD.CONCLUSION:Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants.This could be part of the pathophysiological mechanism resulting in the disease.