Role of prothrombin 19911 A>G polymorphism,blood group and male gender in patients with venous thromboembolism: Results of a German cohort study

Journal of Thrombosis and Thrombolysis - The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism...     

Caspase 8 small interfering RNA prevents acute liver failure in mice

A major concern in therapy of acute liver failure is protection of hepatocytes to prevent apoptosis and maintain liver function. Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL- and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure.     

Role of meal carbohydrate content for the imbalance of plasma amino acids in patients with liver cirrhosis

BACKGROUND AND AIM: Imbalance of circulating branched chain amino acids (BCAA) versus aromatic amino acids (AAA) and hyperinsulinemia are common metabolic alterations in patients with liver cirrhosis. The aim of this study was to characterize the effect of the carbohydrate component of a protein-rich mixed meal on postprandial plasma concentrations of 21 amino acids, insulin and C-peptide in patients with compensated liver cirrhosis. Furthermore, the effect of a dietary intervention on the metabolic alterations in cirrhotic patients was examined. METHODS: Eighteen patients with cirrhosis and 12 healthy volunteers received a protein-rich meal (pork filet 200 g) with or without carbohydrates (bread 50 g, glucose 20 g). A subgroup of four cirrhotic patients received an isoenergetic (117 kJ/kg bw) carbohydrate-enriched (60%) and -restricted (20%) diet for 7 days each. RESULTS: In the cirrhotic patients, basal plasma insulin and C-peptide concentrations were significantly elevated. The ingestion of a protein-rich meal without additional carbohydrates led to a significantly greater increase of insulin and C-peptide in the cirrhotic patients compared to controls. Postprandial increases of leucine and isoleucine were reduced, whereas those of phenylalanine were higher in cirrhotic patients. The addition of carbohydrates led to higher insulin and C-peptide plasma concentrations in cirrhotic patients. Postprandial BCAA increases were more impaired in the cirrhotic group after additional carbohydrate ingestion (46%vs 82%). After the carbohydrate-restricted diet for 7 days BCAA plasma levels increased but the BCAA/AAA ratio remained unaltered. CONCLUSIONS: The carbohydrate content of a meal enhances reduction of BCAA plasma concentrations in clinically stable cirrhotic patients. An imbalanced BCAA/AAA ratio cannot be avoided by a carbohydrate-reduced diet alone, supporting mandatory BCAA supplementation.     

Inhalation of Moli1901 in patients with cystic fibrosis

BACKGROUND: In cystic fibrosis (CF) patients, the absence or dysfunction of the chloride channel CF transmembrane conductance regulator (CFTR) results in reduced chloride ion transport in respiratory epithelial cells. Moli1901 stimulates an alternative chloride channel and may thus compensate for the CFTR deficiency in the airway epithelium of CF patients. METHODS: A phase II, placebo-controlled, double-blinded, single-center, multiple (5 consecutive days), rising-dose (daily dose, 0.5, 1.5, or 2.5 mg of Moli1901) study was conducted to investigate the safety and tolerability of multiple doses of aerosolized inhaled Moli1901 in 24 patients with CF and stable lung disease. RESULTS: Moli1901 was well tolerated in all but one CF patient, in whom a transient significant decrease in FEV(1) developed following inhalation, which resolved spontaneously, and in a second patient in whom transient throat numbness developed during drug inhalation. A significant improvement of FEV(1) was observed in the group receiving treatment with 2.5 mg/d Moli1901 compared to the group receiving placebo (p = 0.01 [Wilcoxon test]). Moli1901 was not detected in the plasma of the highest dose group. CONCLUSIONS: The inhalation of Moli1901 up to a total cumulative dose of 12.5 mg appears to be safe in adult patients with CF. In addition, Moli1901 had a sustained beneficial effect on pulmonary function, which supports further studies of its efficacy in CF patients.     

Antibiotic resistance in <Emphasis Type="Italic">E. coli</Emphasis> isolates from patients with urinary tract infections presenting to the emergency department

Purpose

Escherichia coli urine isolates from patients presenting to the emergency department at a German tertiary care hospital were retrospectively analyzed from January 2015–March 2017 to determine antibiotic resistance patterns and patient risk factors for resistance.

Methods

Uncomplicated urinary tract infection (UTI) was defined as UTI in the otherwise healthy patient without relevant co-morbidities and complications. Patients were assumed to have UTI if diagnosis was made by the attending physician with conclusive dipstick results. For subgroup analysis, only patients with symptoms suggestive for UTI documented in their records were included.

Results

228 patients with a UTI diagnosed by the attending physician with E. coli isolated in urine culture were included. 154/228 patients had documented symptomatic UTI, 57/154 had uncomplicated infection, 76/154 patients had cystitis, and 124/154 were female. Resistance rates of uncomplicated UTI in symptomatic patients were: ciprofloxacin 10.5%, cotrimoxazole 15.8%, amoxicillin/clavulanic acid 5.3%, nitrofurantoin 0% (CLSI MICs). Previous hospitalization in the last 3 months (including patients living in a long-term care facility) was significantly correlated with resistance to ciprofloxacin, cotrimoxazole and amoxicillin/clav. Previous hospitalization was a strong predictor of resistance to ciprofloxacin and cotrimoxazole in multivariate analysis also. Other risk factors correlated with resistance were hematological malignancy (for cotrimoxazole) and renal transplantation (for ciprofloxacin).

Conclusions

Cotrimoxazole is still an alternative for treating uncomplicated cystitis. Previous hospitalization in the last 3 months was a strong predictor of resistance to cotrimoxazole and ciprofloxacin. Other risk factors which might help guide empirical therapy are hematological malignancy and renal transplantation.

     

Oncological outcomes of IBD-associated versus sporadic colorectal cancer in modern era: a matched case-control study

Aim

Inflammatory bowel diseases (IBD) are associated with an increased risk for colorectal cancer (CRC). However and despite significant advances in the management of IBD and CRC, the prognosis of IBD-related CRC (IBD-CRC) remains controversial. The aim of the present case-control study was to compare the prognosis of IBD-CRC to sporadic CRC.

Methods

Consecutive patients operated for IBD-CRC from 2004 to 2014 were recruited and matched with sporadic CRC (ratio 3:1) from the same center. Matching was performed on gender, tumor stage, and location and period of surgery. Endpoints were postoperative morbidity (Dindo-Clavien III-V), quality of surgery, and long-term oncological outcomes.

Results

Among 1498 CRC patients operated during the study period, 21 patients were identified with IBD-CRC and matched to 63 patients with sporadic CRC (S-CRC). Patients with IBD-CRC were significantly younger (p?<?0.001), had multifocal lesions more frequently (p?=?0.04), and undergone abdominoperineal excision and coloproctectomy more often (p?=?0.001). Postoperative morbidity was not significantly different between the two groups (25 vs. 14%; p?=?0.309), as well as the rate of R0 resection (86 vs. 95%; p?=?0.162). Five-year disease-free and overall survival were 71 and 81% in patients with IBD-CRC and 69% (p?=?0.801) and 78% (p?=?0.845) in those with S-CRC, respectively.

Conclusion

In a case-control study of patients operated for CRC within the last decade, the prognosis of cancer associated with IBD is similar to sporadic cancer.

     

Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases

Purpose

Interleukin-6 (IL-6) production and signalling are increased in the inflamed mucosa in inflammatory bowel diseases (IBD). As published serum levels of IL-6 and its soluble receptors sIL-6R and sgp130 in IBD are from small cohorts and partly contradictory, we systematically evaluated IL-6, sIL-6R and sgp130 levels as markers of disease activity in Crohn’s disease (CD) and ulcerative colitis (UC).

Methods

Consecutive adult outpatients with confirmed CD or UC were included, and their disease activity and medication were monitored. Serum from 212 CD patients (815 measurements) and 166 UC patients (514 measurements) was analysed, and 100 age-matched healthy blood donors were used as controls.

Results

IL-6 serum levels were significantly elevated in active versus inactive CD and UC, also compared with healthy controls. However, only a fraction of IBD patients showed increased serum IL-6. IL-6 levels ranged up to 32.7 ng/mL in active CD (>?5000-fold higher than in controls), but also up to 6.9 ng/mL in inactive CD. Increases in active UC (up to 195 pg/mL) and inactive UC (up to 27 pg/mL) were less pronounced. Associations between IL-6 serum levels and C-reactive protein concentrations as well as leukocyte and thrombocyte counts were observed. Median sIL-6R and sgp130 levels were only increased by up to 15%, which was considered of no diagnostic significance.

Conclusions

Only a minority of IBD patients shows elevated IL-6 serum levels. However, in these patients, IL-6 is strongly associated with disease activity. Its soluble receptors sIL-6R and sgp130 do not appear useful as biomarkers in IBD.

     

9‐month results of polymer‐free sirolimus eluting stents in young patients compared to a septuagenarian and octogenarian all‐comer population

Objectives

To evaluate the 9‐month safety and efficacy of polymer‐free sirolimus eluting drug eluting stents in septuagenarians and octogenarians.

Methods

An all‐comer, worldwide single armed trial ( ClinicalTrials.gov Identifier NCT02629575) was conducted to demonstrate the safety and efficacy of an ultra‐thin strut, polymer‐free sirolimus eluting stent (PF‐SES). The primary endpoint was the 9‐month target revascularization rate (TLR). Secondary endpoints included the rates of major adverse cardiac events (MACE), stent thrombosis (ST) and bleeding (BARC) in septuagenarians (≥70 years, <80 years), and in octogenarians (≥80 years) to be compared to the younger patient group (<70 years).

Results

A total of 1607 patients were treated with PF‐SES in the sub‐70‐year‐old age group, 694 in septuagenarians, and 371 in the octogenarian patient group. At 9 months, the MACE rates were 7.2% in octogenarians, 5.3% in septuagenarians, and 3.0% in the younger patient group (P = 0.001). These were mostly driven by all‐cause mortality (4.4% vs 1.9% vs 0.6%, P < 0.001) while the TLR rates were only numerically lower in the younger age group (P = 0.080). BARC 1‐5 bleeding events were more frequent in the older age group (1.9% vs 2.7% vs 4.6%, P = 0.012) whereas the rates for ST were not different (0.7% vs 0.6% vs 0.6%, P = 0.970).

Conclusions

In octogenarians treated with PF‐SES, the rates for MACE, overall mortality, and bleeding are higher as compared to the younger age groups. However, the rates for TLR and ST were not significantly different across the investigated age groups. PF‐SES are safe and effective in octogenarians.

     

Mechanisms of 5-hydroxytryptamine(2A) receptor activation of the mitogen-activated protein kinase pathway in vascular smooth muscle

5-Hydroxytryptamine (5-HT) activates the extracellular signal-regulated kinase (Erk) mitogen-activated protein kinases (MAPKs) in the vasculature, resulting in contraction. The mechanisms by which this occurs are unclear. G protein-coupled receptors can activate Erk MAPK pathways through a variety of mechanisms, including stimulation of Src, phosphoinositide-3 kinase (PI-3-K), protein kinase C (PKC), or the epidermal growth factor (EGF) receptor tyrosine kinase. We hypothesize that 5-HT uses one or more of these pathways. In isolated strips of rat aorta, the MAPK/Erk kinase inhibitor U0126 (50 microM), Src inhibitor PP1 (0.5 microM), PKC inhibitors calphostin C (1 microM) and chelerythrine (10 microM), and the PI-3-K inhibitor LY294002 (1-20 microM) reduced 5-HT-induced contraction. The EGF receptor tyrosine kinase inhibitor AG1478 (0.25-1 microM) was without effect. Thus, 5-HT activates PKC, Src, and possibly PI-3-K to result in contraction. In rat aortic myocytes, 5-HT (1 microM) activated Erk MAPK proteins 2- to 3-fold over basal values; activation was reduced by U0126, PP1, and LY294002 and unaffected by calphostin C or chelerythrine, wortmannin, or AG1478. The lack of effect of EGF receptor tyrosine kinase and PI-3-K inhibitors was confirmed in that the EGF receptor immunoprecipitated from 5-HT-exposed cells did not display an increase in autophosphorylation, nor did 5-HT significantly increase activation of Akt/protein kinase B, a downstream substrate for PI-3-K. These data suggest that the rat aortic 5-HT(2A) receptor uses Src but not PKC, PI-3-K, or the EGF receptor tyrosine kinase in stimulating Erk MAPK activation.     

Screening and detection of delirium in older ED patients: performance of the modified Confusion Assessment Method for the Emergency Department (mCAM-ED). A two-step tool

Delirium is frequent in older Emergency Department (ED) patients, but detection rates for delirium in the ED are low. To aid in identifying delirium, we developed and implemented a two-step systematic delirium screening and assessment tool in our ED: the modified Confusion Assessment Method for the Emergency Department (mCAM-ED). Components of the mCAM-ED include: (1) screening for inattention, the main feature of delirium, which was performed with the Months Backwards Test (MBT); (2) delirium assessment based on a structured interview with questions from the Mental Status Questionnaire by Kahn et al. and the Comprehension Test by Hart et al. The aims of our study are (1) to investigate the performance criteria of the mCAM-ED tool in a consecutive sample of older ED patients, (2) to evaluate the performance of the mCAM-ED in patients with and without dementia and (3) to test whether this tool is efficient in keeping evaluation time to a minimum and reducing screening and assessment burden on the patient. For this prospective validation study, we recruited a consecutive sample of ED patients aged 65 and older during an 11-day period in November 2015. Trained nurses assessed patients with the mCAM-ED. Results were compared to the reference standard [i.e. the geriatricians’ delirium diagnosis based on the criteria of the Text Revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR)]. Performance criteria were computed. We included 286 consecutive ED patients aged 65 and older. The median age was 80.02 (Q₁ = 72.15; Q₃ = 86.76), 58.7% of included patients were female, 14.3% had dementia. We found a delirium prevalence of 7.0%. In patients with dementia, specificity and positive likelihood ratio were lower. When compared to the reference standard, delirium assessment with the mCAM-ED has a 0.98 specificity and a 39.9 positive likelihood ratio. In 80.0% of all cases, the first step of the mCAM-ED, i.e. screening for inattention with the MBT, took less than 30 s. On average, the complete mCAM-ED assessment required 3.2 (SD 2.0), 5.6 (SD 3.2), and 6.2 (SD 2.3) minutes in cognitively unimpaired patients, patients with dementia and patients with dementia or delirium, respectively. The mCAM-ED is able to efficiently rule out delirium as well as confirm the diagnosis of delirium in elderly patients with and without dementia and applies minimal screening and assessment burden on the patient.