Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.

AIMS: To determine the effects of empagliflozin on blood pressure (BP) and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes mellitus (T2DM). METHODS: We conducted a post hoc analysis of data from a phase III trial in patients with T2DM and hypertension receiving 12 weeks' empagliflozin and four phase III trials in patients with T2DM receiving 24 weeks' empagliflozin (cohort 1, n = 823; cohort 2, n = 2477). BP was measured using 24-h BP monitoring (cohort 1) or seated office measurements (cohort 2). RESULTS: Empagliflozin reduced systolic BP (SBP) and diastolic BP in both cohorts (p < 0.001 vs placebo), without increasing heart rate. Empagliflozin reduced pulse pressure (PP; adjusted mean difference vs placebo cohort 1: -2.3 mmHg; cohort 2: -2.3 mmHg), mean arterial pressure (MAP; cohort 1, -2.3 mmHg; cohort 2, -2.1 mmHg) and double product (cohort 1, -385 mmHg × bpm; cohort 2, -369 mmHg × bpm) all p < 0.001 vs placebo. There was a trend towards a reduction in the ambulatory arterial stiffness index (AASI) with empagliflozin in cohort 1 (p = 0.059 vs placebo). AASI was not measured in cohort 2. Subgroup analyses showed that there were greater reductions in PP with increasing baseline SBP in cohort 1 (p = 0.092). In cohort 2, greater reductions in MAP were achieved in patients with higher baseline SBP (p = 0.027) and greater reductions in PP were observed in older patients (p = 0.011). CONCLUSIONS: Empagliflozin reduced BP and had favourable effects on markers of arterial stiffness and vascular resistance.

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1).

AIMS: To investigate the pharmacodynamics, efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes. METHODS: A total of 75 patients with glycated haemoglobin (HbA1c) concentrations of ≥7.5 to ≤10.5% (≥58 to ≤91 mmol/mol) were randomized to receive once-daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as adjunct to insulin for 28 days. Insulin dose was to be kept as stable as possible for 7 days then adjusted, at the investigator's discretion, to achieve optimum glycaemic control. The primary exploratory endpoint was change from baseline in 24-h urinary glucose excretion (UGE) on day 7. RESULTS: Empagliflozin significantly increased 24-h UGE versus placebo on days 7 and 28. On day 28, adjusted mean differences with empagliflozin versus placebo in changes from baseline in: HbA1c were -0.35 to -0.49% (-3.8 to -5.4 mmol/mol; all p < 0.05 vs. placebo); total daily insulin dose -0.07 to -0.09 U/kg (all p<0.05 vs placebo); and weight were -1.5 to -1.9 kg (all p < 0.001 vs. placebo). In the placebo, empagliflozin 2.5, 10 and 25 mg groups, respectively, adverse events were reported in 94.7, 89.5, 78.9 and 100.0% of patients, and the rate of symptomatic hypoglycaemic episodes with glucose ≤3.0 mmol/l not requiring assistance was 1.0, 0.4, 0.5 and 0.8 episodes per 30 days. CONCLUSIONS: In patients with type 1 diabetes, empagliflozin for 28 days as adjunct to insulin increased UGE, improved HbA1c and reduced weight with lower insulin doses compared with placebo and without increasing hypoglycaemia.

Symptomatic and asymptomatic secondary transmission of Cryptosporidium parvum following two related outbreaks in schoolchildren.

Two related outbreaks (in 2009 and 2012) of cryptosporidiosis in Norwegian schoolchildren during a stay at a remote holiday farm provided us with a natural experiment to investigate possible secondary transmission of Cryptosporidium parvum IIa A19G1R1. After the children had returned home, clinical data and stool samples were obtained from their household contacts. Samples were investigated for the presence of Cryptosporidium oocysts by immunofluorescence antibody test. We found both asymptomatic and symptomatic infections, which are likely to have been secondary transmission. Laboratory-confirmed transmission rate was 17% [4/23, 95% confidence interval (CI) 7·0-37·1] in the 2009 outbreak, and 0% (95% CI 0-16·8) in the 2012 outbreak. Using a clinical definition, the probable secondary transmission rate in the 2012 outbreak was 8% (7/83, 95% CI 4·1-16·4). These findings highlight the importance of hygienic and public health measures during outbreaks or individual cases of cryptosporidiosis. We discuss our findings in light of previous studies reporting varying secondary transmission rates of Cryptosporidium spp.

Second outbreak of infection with a rare Cryptosporidium parvum genotype in schoolchildren associated with contact with lambs/goat kids at a holiday farm in Norway.

In March 2012, a second outbreak of Cryptosporidium parvum affected children following a stay at a holiday farm in Norway; the first outbreak occurred in 2009. We studied a cohort of 145 schoolchildren who had visited the farm, of which 40 (28%) were cases. Cryptosporidium oocysts were detected in faecal samples from humans, goat kids and lambs. Molecular studies revealed C. parvum subtype IIa A19G1R1 in all samples including human samples from the 2009 outbreak. A dose-response relationship was found between the number of optional sessions with animals and illness, increasing from two sessions [risk ratio (RR) 2·7, 95% confidence interval (CI) 0·6-11·5] to six sessions (RR 8·0, 95% CI 1·7-37·7). The occurrence of two outbreaks 3 years apart, with the same subtype of C. parvum, suggests that the parasite is established in the farm's environment. We recommend greater emphasis on hand hygiene and routines related to animal contact.

A Shigella sonnei outbreak traced to imported basil--the importance of good typing tools and produce traceability systems, Norway, 2011.

On 9 October 2011, the University Hospital of North Norway alerted the Norwegian Institute of Public Health (NIPH) about an increase in Shigella sonnei infections in Tromsø. The isolates had an identical 'multilocus variable-number tandem repeat analysis' (MLVA) profile. Most cases had consumed food provided by delicatessen X. On 14 October, new S. sonnei cases with the same MLVA-profile were reported from Sarpsborg, south-eastern Norway. An outbreak investigation was started to identify the source and prevent further cases. All laboratory-confirmed cases from both clusters were attempted to be interviewed. In addition, a cohort study was performed among the attendees of a banquet in Tromsø where food from delicatessen X had been served and where some people had reported being ill. A trace-back investigation was initiated. In total, 46 cases were confirmed (Tromsø= 42; Sarpsborg= 4). Having eaten basil pesto sauce or fish soup at the banquet in Tromsø were independent risk factors for disease. Basil pesto was the only common food item that had been consumed by confirmed cases occurring in Tromsø and Sarpsborg. The basil had been imported and delivered to both municipalities by the same supplier. No basil from the specific batch was left on the Norwegian market when it was identified as the likely source. As a result of the multidisciplinary investigation, which helped to identify the source, the Norwegian Food Safety Authority, together with NIPH, planned to develop recommendations for food providers on how to handle fresh plant produce prior to consumption.

Could tendinosis be involved in osteoarthritis?

Ten patients, age 60 (48-75 years), with osteoarthritis (OA) of the hip and 10 patients, age 82.5 (60-90 years), with fracture of the collum femoris (FCF; minimum Garden stage III) underwent an open biopsy procedure from the internal obturator tendon in conjunction with a total hip replacement. The histological evaluation revealed that all tendon samples in the OA group revealed scar tissue; the corresponding was found in 50% of patients in the FCF group (P=0.02). There were also more GAGs (P=0.023) and calcium deposits (P=0.001) in the samples from the OA group. The ultrastructural evaluation revealed fewer small and medium-sized fibrils (P=0.001) and more non-collagenous extracellular matrix (ECM) (P=0.003) in the OA group. Taken together, the samples from the internal obturator tendon in the OA group revealed a more degenerative appearance with more scar tissue, change in fibril diameter distribution and more non-collagenous ECM. Our findings suggest that OA and periarticular tendinopathy are closely linked. Further research is needed to determine whether musculotendinous changes in the deep rotators are sequelae of joint pathology, or a contributing factor in the development of degenerative joint change.

Outbreak of Shigella sonnei infection in Norway linked to consumption of fresh basil, October 2011.

We report a Shigella sonnei outbreak of 46 cases that occurred in Norway during October 2011. Two municipalities were involved. A large cluster (42 cases)was concentrated in north Norway, while a smallcluster (4 cases) occurred in the south-east region.Epidemiological evidence and trace back investigations have linked the outbreak to the consumption of imported fresh basil. The product has been withdrawn from the market. No further cases have been reported since 25 October.

Metronidazole-sensitive organisms in children with severe acute malnutrition: an evaluation of the indication for empiric metronidazole treatment.

OBJECTIVES: Children with severe acute malnutrition (SAM) are treated with empiric amoxicillin or penicillin and gentamicin because of the high risk of severe infections. Experts have suggested, based on available evidence, adding metronidazole to cover anaerobic bacteraemia and diarrhoea caused by Giardia duodenalis or Clostridium difficile. The objective of this study was to assess the importance of these infections in children with SAM. METHODS: Children from 6 months to 15 years with SAM were enrolled and followed clinically. Aerobic and, when patient weight permitted, anaerobic blood cultures were done using Bactec® system, and isolates identified with matrix-assisted laser desorption ionization-time of flight mass spectrometry. Stool samples were tested for C. difficile, G. duodenalis and Entamoeba histolytica by PCR. RESULTS: A total of 334 children were enrolled and 174 out of 331 (53%) for which data on this was available had diarrhoea. Of 273 patients tested by blood culture, 11 had bacteraemia (4.0%, 95% CI 2.3-7.1%) but none with strict anaerobic bacteria (0/153, 95% CI 0-2.4%). There was no difference in the prevalence of C. difficile between children with (5/128, 4%) and without (7/87, 8%) diarrhoea (OR 0.47, 95% CI 0.14-1.53), and no difference in the prevalence of Giardia between these groups (78/138, 60% vs. 46/87, 53%; OR 1.34, 95% CI 0.77-2.32). Children with C. difficile had higher mortality than those without this infection (3/11, 27%, vs. 7/186, 4%; OR 43, 95% CI 3.9-483). CONCLUSION: Our results do not provide support for empiric metronidazole to cover for anaerobic bacteraemia. Trials evaluating the effect of empiric treatment and its effect on G. duodenalis and C. difficile are warranted.

Prenatal ultrasound detection of facial clefts: a prospective study of 49,314 deliveries in a non-selected population in Norway.

OBJECTIVES: To evaluate prenatal detection of facial clefts by ultrasound examination in a large non-selected population, and to study trends in detection rates over 18 years, as well as the prevalence of isolated cases and those with associated anomalies. METHODS: This prospective follow-up study from January 1987 to December 2004 was divided into two 9-year periods. The study included all registered cases of prenatally or postnatally diagnosed facial clefts in a non-selected population in Norway. RESULTS: A total of 101 fetuses or newborns with facial clefts in a population of 49 314 deliveries were registered. The distribution of clefts was: 25 (25%) cleft lip, 52 (51%) cleft lip and palate, and 24 (24%) cleft palate (CP). No CP was detected prenatally. Cleft lip with or without cleft palate (CL(P)) was detected prenatally in 35/77 (45%) cases, with a significant increase in the detection rate from 34% to 58% between the two 9-year periods (P = 0.03). Over the whole study period CL(P) was detected at a median of 19 + 2 gestational weeks, with no change over time; altogether 24/35 (69%) cases were detected at the routine second-trimester ultrasound examination. Thirty-three of 77 (43%) cases of CL(P) and 14/24 (58%) cases of CP had associated anomalies; 12/101 (12%) had chromosomal aberrations. In 18/101 (18%) the clefts were part of a syndrome or sequence. CONCLUSIONS: The detection rate for CL(P) improved significantly over time. Detection of CL(P) is important because nearly half the cases have associated anomalies.

Latitude of the study place and age of the patient are associated with incidence of mediastinitis and microbiology in open-heart surgery: a systematic review and meta-analysis.

OBJECTIVE: We aimed to summarize the pooled frequency of mediastinitis following open-heart surgery caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Gram-negative bacteria. DESIGN: This study was a systematic review and a meta-analysis of prospective and retrospective cohort studies. MATERIALS AND METHODS: We searched the literature, and a total of 97 cohort studies were identified. Random-effect model was used to synthesize the results. Heterogeneity between studies was examined by subgroup and meta-regression analyses, considering study and patient-level variables. Small-study effect was evaluated. RESULTS: Substantial heterogeneity was present. The estimated incidence of mediastinitis evaluated from 97 studies was 1.58% (95% confidence intervals [CI] 1.42, 1.75) and that of Gram-positive bacteria, Gram-negative bacteria, and MRSA bacteria evaluated from 63 studies was 0.90% (95% CI 0.81, 1.21), 0.24% (95% CI 0.18, 0.32), and 0.08% (95% CI 0.05, 0.12), respectively. A meta-regression pinpointed negative association between the frequency of mediastinitis and latitude of study place and positive association between the frequency of mediastinitis and the age of the patient at operation. Multivariate meta-regression showed that prospective cohort design and age of the patients and latitude of study place together or in combination accounted for 17% of heterogeneity for end point frequency of mediastinitis, 16.3% for Gram-positive bacteria, 14.7% for Gram-negative bacteria, and 23.3% for MRSA bacteria. CONCLUSION: Evidence from this study suggests the importance of latitude of study place and advanced age as risk factors of mediastinitis. Latitude is a marker of thermally regulated bacterial virulence and other local surgical practice. There is concern of increasing risk of mediastinitis and of MRSA in elderly patients undergoing sternotomy.

N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial.

OBJECTIVES: The aim of the study was to investigate whether omega-3 fatty acids (n-3 FA) reduce the occurrence of restenosis after percutaneous transluminal coronary angioplasty. BACKGROUND: Meta-analyses have shown significant reduction of restenosis after coronary angioplasty upon supplementation with n-3 FA. METHODS: In a prospective, placebo-controlled, double-blind study, 500 patients were randomly allocated to treatment with n-3 FA (Omacor, Pronova AS, Oslo, Norway) 5.1 g/day or corn oil (placebo) starting at least two weeks prior to elective coronary angioplasty. The treatment was continued until restenosis evaluation by quantitative coronary angiography after six months. Stenosis was defined as a minimal luminal diameter (MLD) < 40% of the reference diameter. Successful coronary angioplasty was defined as > or = 20% acute gain in MLD and a residual stenosis < 50%. Restenosis was defined as > or = 20% late loss of diameter and stenosis > 50% or an increase in stenosis of > or = 0.7 mm. Three-hundred ninety-two patients fulfilled the criteria for initial stenosis and successful coronary angioplasty, and, except four patients who died, none were lost for follow-up. RESULTS: Restenosis occurred in 108/266 (40.6%) of the treated stenoses in the Omacor group and in 93/263 (35.4%) in the placebo group (odds ratio [OR] 1.25, 95% confidence interval [CI] [0.87-1.80] p = 0.21). In the Omacor group one or more restenoses occurred in 90/196 (45.9%) patients as compared with 86/192 (44.8%) in the placebo group (OR 1.05, 95% CI [0.69-1.59] p = 0.82). CONCLUSIONS: Supplementation with 5.1 g n-3 FA/day for six months, initiated at least two weeks prior to coronary angioplasty did not reduce the incidence of restenosis.

Procoagulant activity and cytokine expression in whole blood cultures from patients with atherosclerosis supplemented with omega-3 fatty acids.

Omega-3 fatty acids (n-3 FA) may reduce atherogenesis and thrombosis. We investigated the effects of n-3 FAs on procoagulant activity and cytokine expression in whole blood cultures from patients with atherosclerosis. Eleven of the 23 included patients had received 5.1 g n-3 FA daily for 6 months (group I) whereas 12 patients had been on placebo (group II). All patients were then given 5. g n-3 FA daily for another 4 weeks. At baseline significantly lower levels of LPS-induced prothrombin fragment1+2 were found in group I (p = 0.010), this difference being eliminated after 4 weeks. Il-6 and TNFalpha were significantly higher at baseline in group I and the differences in changes from baseline between the groups were statistically highly significant with increasing values in group II(Il-6 p = 0.001, TNF alpha p = 0.002). The present results indicate a reduction in pro-thrombotic potential in patients receiving highly concentrated n-3 FA, whereas some proinflammatory responses might be adverse.

Effects of insulin on mononuclear leukocyte beta-adrenoceptor density and adenylate cyclase coupling.

The effects of insulin on human beta-adrenoceptor density and isoproterenol-induced cyclic AMP (cAMP) accumulation were characterized in mononuclear leukocytes from healthy subjects. In cells equilibrated with theophylline (4 mM) at 37 degrees C, insulin (4 microU/ml) was present in periods from 1 to 35 min prior to stimulation. The basal cAMP levels were not influenced. After 1 min pretreatment with insulin, the (-)-isoproterenol concentration necessary to cause half-maximal stimulation (EC50) decreased from 260 to 170 nM (P less than 0.025) and the maximal (-)-isoproterenol response above basal increased from 44 to 63 pmol/10(6) cells (P less than 0.01). The short exposure to insulin caused an increase in the number of functional beta-adrenoceptors from 1420 to 2160 receptors/cell (P less than 0.01). The increased (-)-isoproterenol responsiveness showed a time-dependent decline. When insulin had been present for 35 min before stimulation, the EC50 value had increased to 600 nM (P less than 0.01 vs. control) and the maximal (-)-isoproterenol response above basal was reduced to 29 pmol/10(6) cells (P less than 0.01 vs. control). The receptor density decreased to the pretreatment value (1480 receptors/cell) after 35 min exposure to insulin. The present study shows that insulin modifies the beta-adrenoceptor density as well as the beta-adrenoceptor coupling to adenylate cyclase, dependent on the duration of exposure.

The effects of 'in-use' surgical handwashing on the pre- and postoperative fingertip flora during cardiothoracic and orthopaedic surgery.

Two operating teams (25 persons) were followed for two months with fingerprint samples taken preoperatively; before and after 'in-use' surgical handwashing; and immediately postoperatively, with and without surgical gloves. The mean time for handwashing for the cardiothoracic team (CT) was 2 min and for the orthopaedic team (OT) was 3.5 min. A closer observation of 10 persons revealed a great individual variation in washing techniques, in spite of standard guidelines. The CT team performed eight, and the OT team nine sterile operations with an average duration of 3 h and 20 min and 2 h and 40 min, respectively. Surgical handwashing resulted in fingertip sterility in 111/118 (94.1%) cases; in 61/66 (92.4%) samples from the surgeons and in 50/52 (96.2%) samples from the assistants. Postoperative fingerprinting with gloves on showed sterile conditions in 85/91 (93.4%) samples; 57/59 (96.6%) from the surgeons and 28/32 (87.5%) from the assistants. Immediately after removal of the gloves, 43/67 (64.2%) of fingerprint samples from the surgeons and 13/48 (27.1%) from the assistants were still sterile. Coagulase-negative staphylococci (CNS) and Bacillus species predominated in fingerprint samples. Of the 105 CNS strains tested, 11.4% were methicillin resistant. Only five strains of Staphylococcus aureus were isolated; in 4/5 cases from the OT. This study illustrates that in spite of standard guidelines, there is great individual variation in surgical handwashing. However, in most instances, the bacteria are eradicated from the fingertips. Even after surgery for 2-3 h, there may still be a residual effect of the hand disinfecting agent in half of the cases.

Cyanidin 3-[6-(p-coumaroyl)-2-(xylosyl)-glucoside]-5-glucoside and other anthocyanins from fruits of Sambucus canadensis.

From the fruits of Sambucus canadensis four anthocyanin glycosides have been isolated by successive application of an ion-exchange resin, droplet-counter chromatography and gel filtration. The structure of the novel, major (69.8%) pigment, cyanidin 3-O-[6-O-(E-p-coumaroyl-2-O-(beta-D-xylopyranosyl)-beta-D- glucopyranoside]-5-O-beta-D-glucopyranoside, was determined by means of chemical degradation, chromatography and spectroscopy, especially homo- and heteronuclear two-dimensional NMR techniques. The other anthocyanins were identified as cyanidin 3-sambubioside-5-glucoside (22.7%), cyanidin 3-sambubioside (2.3%) and cyanidin 3-glucoside (2.1%).

Comparison of the modifying effects of somatostatin and propranolol on morphine-induced changes in glucose, glucagon and insulin levels in fed rats.

Twenty-eight rats in four different groups were used. Catheters were implanted in the carotid artery and jugular vein one week before the experiments were performed. The rats were trained to the experimental situation daily, and allowed food and water ad libitum. One group of rats was used to establish control values; a second was injected with morphine (10 mg/ml, 1 ml/kg); a third group got morphine injection (10 mg/ml, 1 ml/kg) combined with somatostatin infusion (0.01 mg/ml, 1 ml/h); and the fourth group was injected with morphine (10 mg/ml, 1 ml/kg) combined with propranolol (0.4 ml, 1 mg/ml). Blood samples for venous glucose and arterial insulin and glucagon were drawn 15 min after start of stimulation. Glucose, insulin and glucagon levels were significantly higher in morphine treated than in control rats. When morphine was combined with somatostatin, the increase in glucose, insulin and glucagon was significantly reduced. However, after the morphine and propranolol stimulation the increase in glucose and glucagon was significantly reduced, whereas the insulin levels were as high as when morphine was given alone. The combined reduction of both glucagon and glucose after somatostatin or propranolol treatment in morphine exposed rats, points to glucagon as a potential link between opioid stimulation and hyperglycemia. Beta-receptor stimulation seems to contribute to the glucagon but not to the insulin release after morphine.

Increments in glucose, glucagon and insulin after morphine in rats, and naloxone blocking of this effect.

In awake rats adapted to experimental conditions and allowed food ad libitum, hyperglycemia was induced by the administration of morphine 10 mg/kg through indwelling catheters in the external jugular vein. High glucose values were measured at 5, 15 and 25 min. Glucagon values were high at 5 and 15 min, and again at basal level at 25 min. Insulin was increased after morphine both at 5, 15 and 25 min, whereas somatostatin levels did not change after morphine. When morphine was administered together with naloxone after an initial 10 min period of naloxone administration, there was no increment in glucose, insulin or somatostatin values; neither at 5, 15 or 25 min. There was a remarkable glucagon decrease after naloxone and morphine remaining from 5 to 25 min. Then, one of the possible mechanisms for the hyperglycemic response after morphine may be an opioid effect on pancreas, stimulating glucagon and thereby causing hepatic glucose output.

Determination of indium in standard rocks by neutron activation analysis.

A rapid neutron activation method for the determination of indium in rocks, based on 54 min (116m)In, is described. The method has been applied to a series of geochemical standards including granite G-1 and diabase W-1. The precision is better than +/- 5% for samples containing more than 5 x 10(-10)g indium. Good agreement with previously published values for G-1 and W-1 has been obtained.

Determination of Co, Cu, Fe, Ga, W, and Zn in rocks by neutron activation and anion-exchange separation.

A neutron-activation method for the simultaneous determination of cobalt, copper, gallium, iron, tungsten and zinc in rocks is described. The method is based on anion-excbange separation in hydrochloric acid media. Chemical yield is higher than 97% for all elements, except for tungsten, where the recovery of the carrier is established by re-activation. The precision is about 1-3% for the iron determination and about 3% for cobalt, copper, gallium and zinc.

Amplifications of phleomycin and bleomycin-induced antibiotic activity in Escherichia coli by aromatic cationic compounds.

A wide range of aromatic compounds has been shown to amplify phleomycin-induced cell killing in Escherichia coli. They include acridines, acridinium chlorides, dihydroanthracenes, anthracenes, dianthracenes, phenanthridinium salts, phenazinium chlorides, phenoxazones, triphenyl methane dyes, benzoquinolizinium chloride, diphenylmethane derivatives, stilbene and diphenyl derivatives. Low concentrations of these amplifiers also amplified the DNA breakage and degradation effects of phleomycin. The minimum structural specification for activity as an amplifying agent is suggested. A representative sample of compounds effective as amplifiers of phleomycin also amplified the antibiotic effects of bleomycins B4 and B6. The amplifiers described are known to vary in their ability to penetrate and accumulate in different organisms or tissues. This suggests the possibility of developing a series of antibiotic regimes using these amplifiers (or the large number of derivative compounds also likely to be active) where the therapeutic index is determined by the properties of the amplifier chosen rather than of the phleomycin or the bleomycin.