Heterogeneity after harmonisation: A retrospective cohort study of bleeding and stroke risk after the introduction of direct oral anticoagulants in four Western European countries.

PURPOSE: Database heterogeneity can impact effect estimates. Harmonisation provided by common protocols and common data models (CDMs) can increase the validity of pharmacoepidemiologic research. In a case study measuring the changes in the safety and effectiveness of stroke prevention therapy after the introduction of direct oral anticoagulants (DOACs), we performed an international comparison. METHODS: Using data from Stockholm, Denmark, Scotland and Norway, harmonised with a common protocol and CDM, two calendar-based cohorts were created: 2012 and 2017. Patients with a diagnosis code of atrial fibrillation 5 years preceding the 1-year cohort window were included. DOAC, vitamin K antagonist and aspirin treatment were assessed in the 6 months prior to the start of each year while strokes and bleeds were assessed during the year. A Poisson regression generated incidence rate ratios (IRRs) to compare outcomes from 2017 to 2012 adjusted for changes in individual-level baseline characteristics. RESULTS: In 280 359 patients in the 2012 cohort and 356 779 in the 2017 cohort, treatment with OACs increased on average from 45% to 65%, while treatment with aspirin decreased from 30% to 10%. In all countries except Scotland, there were decreases in the risk of stroke and no changes in bleeding risk, after adjustment for changes in baseline characteristics. In Scotland, major bleeding (IRR 1.09, 95% confidence interval [CI] [1.00; 1.18]) and intracranial haemorrhage (IRR 1.31, 95% CI [1.13; 1.52]) increased from 2012 to 2017. CONCLUSIONS: Stroke prevention therapy improved from 2012 to 2017 with a corresponding reduction in stroke risk without increasing the risk of bleeding in all countries, except Scotland. The heterogeneity that remains after methodological harmonisation can be informative of the underlying population and database.

Trends in psychiatric diagnoses, medications and psychological therapies in a large Swedish region: a population-based study.

BACKGROUND: Health services utilization for mental health disorders is reported to increase sharply in many countries. The aim of this study was to report trends in all aspects of mental health care utilization in a total population sample. METHODS: Repeated cross-sectional register study of the Stockholm Region (VAL) including both primary and secondary care. Trends in the proportion of adults in the total population of Stockholm Region with a recorded ICD-10 psychiatric diagnosis or psychological therapy during 2007-2017 as well as claims of psychiatric medication from 2011 were calculated. RESULTS: The proportion of adults utilizing any mental health care increased from 13.2% in 2011 to 16.1% in 2017. In 2017, 49.3% were treated in primary care, 32.2% in secondary care and 18.5% were jointly managed. The increase was most pronounced in younger adults. Women were more likely to receive mental health care than men in all ages. Medication decreased from 71.0 to 67.7%, while psychological therapy increased from 33.1 to 37.6%. The use of psychiatric medication increased with age while psychological therapy decreased. All time trends were statistically significant (p < .0001). CONCLUSION: Care for mental health disorders has been increasing mainly in primary care and was delivered to one in seven adult individuals in 2017. Interventions are needed to address the growing burden of mental health disorders while avoiding overtreatment.

Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis--a randomised trial.

In tuberculosis (TB), the production of nitric oxide (NO) is confirmed but its importance in host defense is debated. Our aim was to investigate whether a food supplement rich in arginine could enhance clinical improvement in TB patients by increased NO production. Smear positive TB patients from Gondar, Ethiopia (n = 180) were randomized to a food supplementation rich in arginine (peanuts, equivalent to 1 g of arginine/day) or with a low arginine content (wheat crackers, locally called daboqolo) during four weeks. The primary outcome was cure rate according to the WHO classification and secondary outcomes were sputum smear conversion, weight gain, sedimentation rate, reduction of cough and chest X-ray improvement as well as levels of NO in urine (uNO) or exhaled air (eNO) at two months. There was no effect of the intervention on the primary outcome (OR 1.44, 95% CI: 0.69-3.0, p = 0.39) or secondary outcomes. In the subgroup analysis according to HIV status, peanut supplemented HIV+/TB patients showed increased cure rate (83.8% (31/37) vs 53.1% (17/32), p < 0.01). A low baseline eNO (<10 ppb) in HIV+/TB patients was associated with a decreased cure rate. We conclude that nutritional supplementation with a food supplement rich in arginine did not have any overall clinical effect. In the subgroup of HIV positive TB patients, it significantly increased the cure rate and as an additional finding in this subgroup, low initial levels of NO in exhaled air were associated with a poor clinical outcome but this needs to be confirmed in further studies.

Children with screening-detected coeliac disease show increased levels of nitric oxide products in urine.

AIM: Increased concentration of nitric oxide (NO) metabolites, nitrite and nitrate, in the urine is a strong indication of ongoing small intestinal inflammation, which is a hallmark of the enteropathy of coeliac disease (CD). It has previously been shown that children with symptomatic, untreated CD have increased levels of NO oxidation products in their urine. The aim of this study was to investigate whether screening-detected, asymptomatic coeliac children display the same urinary nitrite/nitrate pattern. METHODS: In a multicenter screening study, serum samples were collected from 7208 12-year-old children without previously diagnosed CD. Sera were analysed for anti-human tissue transglutaminase (tTG) of isotype IgA. Small bowel biopsy was performed in antibody-positive children, yielding 153 new cases of CD. In the screening-detected individuals, the sum of nitrite and nitrate concentrations in the urine was analysed and used as an indicator of NO production. For comparison, 73 children with untreated, symptomatic CD were studied. RESULTS: The nitrite/nitrate levels in children with screening-detected CD and those with untreated symptomatic CD did not differ significantly. Both groups had significantly increased urinary nitrite/nitrate concentrations compared to the children with normal small bowel biopsy (p < 0.001). CONCLUSION: Children with screening-detected CD have increased production of NO just as children with untreated symptomatic CD. High NO metabolite levels in the urine may indicate a pathogenetic feature of CD and be a marker of major clinical importance.

Remission of membranous glomerulonephritis after pancreatectomy for pancreatic neuroendocrine neoplasm - a rare coincidence.

The concomitant existence of a non-malignant neuroendocrine tumor (NET) and membranous glomerulonephritis (MGN) is rare. We report a subject with kidney biopsy proven MGN and nephrotic syndrome in which a computerized scan tomography (CT) examination was performed revealing a pancreatic tumor. A pancreatectomy was performed and the tumor was shown to be a non-malignant NET with a malignant potential. Although treatment with corticosteroids was initiated remission of MGN was observed within the next month after pancreatectomy. The rapid remission observed shortly after pancreatectomy pointed to that tumor removal contributed to, and that neither spontaneous nor corticosteroid treatment alone did induce the rapid remission of the MGN. The coexistence of the two disorders NET and MGN is very rare, however. This is the first report on remission of MGN after pancreatectomy for a NET.

De novo seropositive rheumatoid arthritis during immunosuppressive treatment after kidney transplantation.

We detected de novo seropositive erosive rheumatoid arthritis (RA) in a patient seven years after successful cadaveric kidney transplantation (RTx). RA developed in spite of treatment with cyclosporine A (CyA), methylprednisolon (MP) and azathioprine (Aza), compounds often also used for treatment of active RA. Renal failure was due to diabetes mellitus (DM) nephropathy. Besides a slight increase in C-reactive protein (CRP) concentration two years after RTx, the clinical symptoms of RA were observed seven years after RTx. RA was confirmed by X-ray examination, isotopic skeletal scan and positive serum RA factor. After switching Aza to methotrexate (Mtx) treatment, his symptoms disappeared and CRP concentration returned to normal. Our patient had HLA DRB1 *0101, *0401 alleles and DQB1 *0501, *0302 alleles which have strong genetic association with both DM and RA. To our best knowledge, this is the first case in which de novo seropositive erosive RA developed while on treatment with triple immunosuppression after RTx. The immunosuppressive treatment probably masked the inflammation and symptoms of RA.

Inducible nitric oxide synthase is expressed in synovial fluid granulocytes.

The objective of the study was to evaluate the NO-producing potential of synovial fluid (SF) cells. SF from 15 patients with arthritis was compared with blood from the same individuals and with blood from 10 healthy controls. Cellular expression of inducible nitric oxide synthase (iNOS) was analysed by flow cytometry. High-performance liquid chromatography was used to measure l-arginine and l-citrulline. Nitrite and nitrate were measured colourimetrically utilizing the Griess' reaction. Compared to whole blood granulocytes in patients with chronic arthritis, a prominent iNOS expression was observed in SF granulocytes (P < 0.001). A slight, but statistically significant, increase in iNOS expression was also recorded in lymphocytes and monocytes from SF. l-arginine was elevated in SF compared to serum (257 +/- 78 versus 176 +/- 65 micro mol/l, P = 0.008), whereas a slight increase in l-citrulline (33 +/- 11 versus 26 +/- 9 micro mol/l), did not reach statistical significance. Great variations but no significant differences were observed comparing serum and SF levels of nitrite and nitrate, respectively, although the sum of nitrite and nitrate tended to be elevated in SF (19.2 +/- 20.7 versus 8.6 +/- 6.5 micro mol/l, P = 0.054). Synovial fluid leucocytes, in particular granulocytes, express iNOS and may thus contribute to intra-articular NO production in arthritis.

Interstitial nephritis, acute renal failure in a patient with non-fulminant hepatitis A infection.

This is the first report from Norway of a patient with interstitial nephritis and renal failure due to non-fulminant hepatitis A virus (HAV) infection. HAV infection was confirmed by positive anti-HAV IgM serology. All tests for other virus infections were negative. At admittance serum creatinine (s-Creat) and blood urea nitrogen (BUN) concentration were 539 microlmol/l and 32.6 mmol/l increasing the following days to 890 micromol/l and 39.9 mmol/l, respectively. Nine courses of hemodialysis had to be given. Kidney biopsy specimen showed interstitial edema, lymphocytic cell infiltration and acute tubular injury with normal glomeruli. Examination with immunohistochemistry was negative. In contrast to the findings associated with HBV and HCV infection in which glomerular disease is predominantly found, the HAV infection in our patient was associated with interstitial nephritis and acute tubular necrosis. The prognosis of the renal failure due to HAV infection was good although the recovery was substantially delayed.

The use of pretransplant erythropoietin to normalize hemoglobin levels has no deleterious effects on renal transplantation outcome.

BACKGROUND: The aim of this study was to establish the outcome of renal transplantation in patients given pretransplant erythropoietin (EPO) treatment targeted at reaching a normal hemoglobin concentration (Hb), compared to those given EPO-treatment aimed at maintaining subnormal Hb. METHODS: A total of 416 patients from Scandinavian countries and with renal anaemia were enrolled to examine the effects of increasing Hb from a subnormal level (90-120 g/liter) to a normal level (135-160 g/liter) by EPO treatment. Half of the patients were randomized to have their Hb increased, with the other half randomized to maintain a subnormal Hb. Thirty-two patients from the normal Hb group and 24 patients from the subnormal group received a renal graft during the study period. The outcomes of these transplantations were examined prospectively for 6 months. RESULTS: Preoperative Hb levels were 143+/-17 and 121+/-14 g/liter in the two groups, respectively (P<0.0001). The Hb remained higher in the normal Hb group during the first 2 weeks after transplantation. The percentage of patients requiring postoperative blood transfusions in the normal Hb group was 16%, compared with 50% in the subnormal group (P<0.01). No statistically significant difference in the proportion of functioning grafts or in the serum creatinine levels could be detected. No correlation between EPO treatment and creatinine levels after transplantation was found. The frequency of adverse events was similar in the two groups. CONCLUSIONS: EPO treatment aimed at reaching a normal Hb in renal transplant recipients reduces the postoperative requirement for blood transfusions and has no deleterious effects on kidney graft function.

[Water channels of the cell--aquaporins]. / Cellenes vannporer--akvaporinene.

BACKGROUND: Several mechanisms in the body regulate the water transport within the cells up and down during physiological and pathological conditions. The discovery of aquaporins, water channel proteins, has brought more insight into and understanding of how water crosses plasma membranes within cells in body tissue. MATERIAL AND METHODS: The functions of aquaporins are not fully understood; this paper summarise current knowledge of various aquaporins. RESULTS: Known aquaporins are discussed in relation to some physiological, pathological and clinical conditions. INTERPRETATION: In the future, measurements of aquaporin concentrations in urine and possibly in other samples will give us a broader picture of water exchange and a better understanding of the mechanisms underlying water production in clinical states like renal and heart failure and liver insufficiency. Moreover, by manipulating water channel proteins by compounds developed for this purpose, one may have a tool for treating some clinical disorders in which water depletion or water overload is an important factor.

Nitric oxide regulates the aggregation of stimulated human neutrophils.

Neutrophil aggregation is mediated by both CD18 integrin and L-selectin. Nitric oxide attenuates the integrin-mediated adhesion of neutrophils to collagen and to endothelium and may therefore affect aggregation as well. FMLP-stimulated neutrophils exposed to l-arginine showed increased and prolonged aggregation, whereas cells pretreated with L-NAME did not differ from FMLP-stimulated controls. Nitric oxide is known to induce ADP ribosylation of G-actin, which inhibits polymerization. We detected equivalent levels of total F-actin in cells pretreated with l-arginine or L-NAME and non-pretreated controls. However, neutrophils pretreated with l-arginine and stimulated by CD18 integrin cross-linking exhibited a more limited increase in total F-actin, compared to control and L-NAME-pretreated cells. Thus at least two signaling pathways may be involved FMLP-stimulated aggregation, mediated by CD18 integrins. More specifically, it is plausible that FMLP-receptor signaling upregulates CD18 integrins and endogenous NO subsequently modulates CD18-mediated signaling to prolong aggregation, possibly through ADP-ribosylation of actin.

Nitric oxide-releasing particles inhibit phagocytosis in human neutrophils.

We have constructed a yeast (Saccharomyces cerevisiae) particle capable of releasing NO, by loading heat-killed yeast particles with a hydrophobic NO-generating substance, GEA-5171. This particle decreased phagocytosis in solution, as measured with flow cytometry, to about 80% of control values. Phagocytosis on a surface, as counted under the microscope, was also decreased by about 20%. The nitric oxide furthermore counteracted the production of oxygen metabolites by neutrophils to about 20% of control values. The inhibitory effect was most pronounced for the intracellular production, as could be seen when neutrophils preincubated with NO-releasing particles were stimulated with chemotactic agent (FMLP) or phorbol ester (PMA). In conclusion, NO has inhibitory effects on both phagocytosis and the respiratory burst of neutrophils. Since nitric oxide is a hydrophobic gas and an air pollutant, there is a possibility that it accumulates in particles which then become more resistant to elimination.

Fosinopril versus enalapril in the treatment of hypertension: a double-blind study in 195 patients.

The new angiotensin-converting enzyme (ACE) inhibitor fosinopril was compared with the ACE inhibitor enalapril in a multicenter (n = 11), multinational (Denmark, Finland, Iceland, Norway, and Sweden), double-blind, randomized, parallel-group 24-week study in 195 patients with mild to moderate essential hypertension [supine diastolic blood pressure, (SDBP) > or = 95 to < or = 110 mm Hg]. After discontinuing all previous antihypertensive medication, patients were entered into a placebo lead-in period of 4-6 weeks, followed by 24 weeks of randomized treatment with the active compounds administered with a double-dummy technique. The dose of fosinopril was 20 mg, which could be increased to 40 mg after 8 weeks (average 25.6 mg); that of enalapril was 10 mg, which could be increased to 20 mg after 8 weeks (average 12.9 mg). Hydrochlorothiazide 12.5 mg could be added after 16 weeks and was administered to 27% of the patients in the fosinopril group and to 30% in the enalapril group. All drugs were administered once daily. Supine systolic BP (SSBP) decreased from 157 to 143 mm Hg in the fosinopril group (p < 0.01), and from 159 to 147 mm Hg in the enalapril group (p < 0.01). SSDP decreased from 100 to 89 mm Hg in the fosinopril group (p < 0.01) and from 100 to 92 mm Hg in the enalapril group (p < 0.01). Throughout the study period, fosinopril reduced SSBP and SDBP numerically more than did enalapril, by 0-3 mm Hg. Adverse events (AE) caused withdrawal of study medication in 8 patients in the fosinopril group and in 14 patients in the enalapril group (NS). The number of reported AE was not statistically different in the two groups. Inhibition of the ACE was assessed in a subgroup of patients (n = 26, 13 in each group). Fosinopril caused a greater inhibition of ACE at the doses used in the present study, which was statistically significant. Both fosinopril and enalapril caused statistically significant reductions in BP of a similar magnitude, and both agents were well tolerated. However, fosinopril was consistently numerically slightly more effective than enalapril in reducing BP. There were fewer withdrawals due to AE (NS) in the fosinopril group, and the overall recorded AE were fewer in the fosinopril group (NS).

Nitric oxide regulates the chemiluminescence from stimulated human neutrophils.

Nitric oxide produced from L-arginine by a variety of cells, is a biologically active compound that can react with iron and thiols. The objective of this study was to investigate the effects of nitric oxide on the respiratory burst from human neutrophils. Treatment with nitroprusside increased the chemiluminescence from neutrophils stimulated with PMA or collagen, but not from cells stimulated with FMLP. Addition of L-arginine increased the chemiluminescence after stimulation with any of the three stimuli, while N omega-nitro-L-arginine methyl ester decreased it. Low doses of nitric oxide, either endogenously or exogenously produced, probably inhibited catalase or glutathione, leading to an increase in hydrogen peroxide available for chemiluminescence detection. This indicates that nitric oxide may reduce the protection against hydrogen peroxide in tissue and in invading catalase-positive bacteria.

Angio-oedema induced by enalapril.

We report the case of a patient who, 9 months after initiation of enalapril and hydrochlorothiazide combination treatment for hypertension, developed angio-oedema with near fatal outcome. Our patient was successfully intubated using a flexible bronchofiberoscope. This case demonstrates that patients given an angiotensin-converting enzyme (ACE) inhibitor may develop serious facial and laryngeal swelling even several months after the initiation of treatment. The occurrence of even mild swelling should lead to prompt cessation of the drug. Patients with incipient ACE inhibitor-related angio-oedema should, without any delay, be referred to hospital for emergency treatment.

Hypertension in cyclosporin A-treated patients is independent of circulating endothelin levels.

OBJECTIVES: To measure blood pressure (BP), plasma endothelin-1 (ET-1), atrial natriuretic peptide (ANP), antidiuretic hormone (ADH) and aldosterone (ALDO) concentration, and plasma renin activity (PRA) in patients treated with a low-dose cyclosporin A (CyA). DESIGN: An open study of patients with rheumatoid arthritis (RA) or palmoplantar pustulosis (PPP). SETTING: Out-patient clinics at the Central Hospital of Jyväskylä and Helsinki University Central Hospital. SUBJECTS: CyA was given to 25 patients with RA and to 10 patients with PPP. INTERVENTION: RA patients were given CyA at a dose of 2.5 +/- 0.13 mg kg-1 body weight (BW) to 3.47 +/- 0.79 mg kg-1 BW (mean values +/- SD) at the start of the study and after 6 months, respectively, and the CyA dose was 2.67 +/- 0.13 mg kg-1 BW decreasing to 2.07 +/- 0.96 mg kg-1 (P < 0.001) after 4 months in PPP subjects. RESULTS: Systolic (sBP) and diastolic blood pressure (dBP) increased from 127.8 +/- 13.6/79.7 +/- 8.4 mmHg to 140.0 +/- 19.8/83.8 +/- 9.7 mmHg during the study (P < 0.03). Plasma ET-1, ANP, ALDO and ADH concentration and PRA did not change during 4 to 6 months of CyA treatment. The plasma ANP concentration was constantly higher in CyA-treated RA patients (112 +/- 87 ng 1-1 to 118 +/- 78 ng 1-1) than in PPP patients (37.3 +/- 26 ng 1-1 to 47.7 +/- 39.9 ng 1-1; P < 0.02). The serum creatinine concentration remained within the normal range, but increased from baseline (76.7 +/- 11.9 mumol 1-1), to 90 +/- 15.4 mumol 1-1 (p < 0.001). The serum magnesium concentration decreased significantly (P < 0.005) after 6 months of CyA treatment in RA patients. No correlation was found between serum creatinine and plasma ET-1 concentration. CONCLUSIONS: Increased blood pressure during CyA treatment was independent of circulating ET-1 levels. A low dose of CyA did not induce increased ET-1 synthesis as judged from plasma samples. The high plasma ANP level observed in RA patients could be due to fluid retention caused by concomitant treatment with non-steroid anti-inflammatory drugs. Fluid retention and decreased magnesium levels could also be involved in the development of hypertension in CyA-treated subjects.

Nitric oxide reduces hydrogen peroxide production from human polymorphonuclear neutrophils.

Nitric oxide has been reported to affect both adhesion and respiratory burst of neutrophils. This indicates a possible role of nitric oxide in regulation of acute inflammatory responses. Release of oxygen metabolites from neutrophils can be measured using luminol-enhanced chemiluminescence and this method can detect both extracellularly and intracellularly released oxygen metabolites. Neutrophils treated with nitroprusside and activated with FMLP, type I collagen or PMA decreased their extracellular release of oxygen metabolites, while their intracellular release was almost unaffected. The effect of nitroprusside was mediated by nitric oxide since treatment with cyanide had the opposite effect. N-ethylmalemide treatment decreased both extra- and intracellular release of oxygen metabolites. This indicates that nitric oxide affects membrane-bound NADPH-oxidase either indirectly or directly, and not a cytosol factor of the oxidase as earlier shown for N-ethylmaleimide. In conclusion, extracellular nitric oxide attenuates extracellularly released oxygen metabolites from activated neutrophils in an inflammatory response.

S-nitroso-N-acetylpenicillamine reduces leukocyte adhesion to type I collagen.

The initial step in the migration of neutrophils to the extravascular space is adhesion to the endothelium. We examined the effect of nitric oxide on this process by treating human neutrophils with S-nitroso-N-acetylpenicillamine (SNAP), a NO-producing compound. Since NO has been shown to increase the level of cGMP in other cell types, we used 8-Br-cGMP in order to mimic the effects of NO. Indeed, both these treatments resulted in a reduced adhesion of neutrophils to type I collagen coated surfaces. After a prolonged incubation with SNAP, the adhesion was the same as for untreated cells. SNAP incubation reduced the F-actin content in the cells whereas 8-Br-cGMP increased it, demonstrating different mechanisms of action on F-actin. These data suggest that endothelium-derived nitric oxide is an important endogenous modulator of neutrophil adhesion, but the effect is not mediated by a cGMP-dependent regulation of F-actin levels.