Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes

The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.     

Impact of Empiric Antimicrobial Therapy on Outcomes in Patients with <Emphasis Type="Italic">Escherichia coli</Emphasis> and <Emphasis Type="Italic">Klebsiella pneumoniae</Emphasis> Bacteremia: A Cohort Study

Background  

It is unclear whether appropriate empiric antimicrobial therapy improves outcomes in patients with bacteremia due to Escherichia coli or Klebsiella. The objective of this study is to assess the impact of appropriate empiric antimicrobial therapy on in-hospital mortality and post-infection length of stay in patients with Escherichia coli or Klebsiella bacteremia while adjusting for important confounding variables.     

Gene-mediated inhibition of the b-adrenergic receptor kinase: a new therapeutic strategy for heart failure.

Molecular changes that take place during the evolution of heart failure (HF), especially the well characterized beta-adrenergic receptor (betaAR) signaling abnormalities, represent attractive targets for myocardial gene therapy. The beta-adrenergic receptor kinase (betaARK1 or GRK2) is a cytosolic enzyme that phosphorylates only agonist-occupied betaARs as well as other G protein-coupled receptors (GPCRs), leading to desensitization and functional uncoupling. betaARK1 levels and activity are elevated in the failing heart and therefore, it has recently been evaluated as a potential target for novel HF treatment. This review summarizes recent results obtained in transgenic mouse models as well as in animals where a betaARK1 inhibitor peptide (betaARKct) was delivered via the coronary arteries by exogenous gene transfer. These results strongly suggest that betaARK1 inhibition may represent a significant improvement in HF therapy.     

Increased Risk for Group B Streptococcus Sepsis in Young Infants Exposed to HIV,Soweto, South Africa, 2004–2008

Although group B Streptococcus (GBS) is a leading cause of severe invasive disease in young infants worldwide, epidemiologic data and knowledge about risk factors for the disease are lacking from low- to middle-income countries. To determine the epidemiology of invasive GBS disease among young infants in a setting with high maternal HIV infection, we conducted hospital-based surveillance during 2004–2008 in Soweto, South Africa. Overall GBS incidence was 2.72 cases/1,000 live births (1.50 and 1.22, respectively, among infants with early-onset disease [EOD] and late-onset [LOD] disease). Risk for EOD and LOD was higher for HIV-exposed than HIV-unexposed infants. GBS serotypes Ia and III accounted for 84.0% of cases, and 16.9% of infected infants died. We estimate that use of trivalent GBS vaccine (serotypes Ia, Ib, and III) could prevent 2,105 invasive GBS cases and 278 deaths annually among infants in South Africa; therefore, vaccination of all pregnant women in this country should be explored.     

DRG-based cost analysis of inpatient conservative treatment of stage III/IV peripheral arterial occlusive disease

DRG-based cost analysis of inpatient conservative treatment of PAD stage III/IV BACKGROUND: In a prospective study carried out by the German Society of Angiology and the DRG Competence Center, Munich, the question was investigated whether the costs of conservative treatment of patients with PAOD stage III/IV (DRG F65) are adequately represented within the current G-DRG system. METHODS UND PATIENTS: Between September 1 and December 16, 2002, a total of 704 patients with DRG F65 (peripheral vascular diseases) were evaluated at 8 angiologic centers in Germany. Apart from the length of hospital stay, the total costs (cost equivalents) were calculated using a method developed by the DRG Research Group at the University of Münster. Moreover, the study population was compared with a German calculation sample for the DRGs F65A/B, as published by InEK. RESULTS: As it turned out, conservatively treated patients with PAOD stage III or IV (DRGs F65A/B) cause significantly (p < 0.001) higher costs and have significantly (p < 0.001) greater lengths of hospital stay than patients who were also assigned to DRG F65 because of other vascular diseases. At the same time it became clear that angiologic centers treat twice as many patients with critical limb ischemia in comparison with the German average. The reimbursement hitherto estimated by InEK covers not even half the cost actually produced by conservative treatment of PAD stage III/IV. CONCLUSION: To ensure a performance-related reimbursement, a new basis DRG for patients with PAD stage III/IV has to be created, as has ben proposed by the German Society of Angiology. Otherwise, adequate conservative therapy in accordance with existing guidelines, of patients who cannot be treated surgically or interventionally will not be possible any more in the future.     

Novel approach to discriminate left bundle branch block from nonspecific intraventricular conduction delay using pacing-induced functional left bundle branch block

Purpose

Left bundle branch block (LBBB) has a predictive value for response to cardiac resynchronization therapy as reported by Zareba et al. (Circulation 123(10):1061–1072, 2011). However, based on ECG criteria, the discrimination between complete LBBB and nonspecific intraventricular conduction delay is challenging. We tested the hypothesis that discrimination can be performed using standard electrophysiological catheters and a simple stimulation protocol.

Methods

Fifty-nine patients were analyzed retrospectively. Patients were divided into groups of narrow QRS (n?=?20), wide QRS of right bundle branch block (RBBB) morphology (n?=?14), and wide QRS of LBBB morphology (n?=?25). Using a diagnostic catheter placed in the coronary sinus, left ventricular activation was assessed during intrinsic conduction as well as during right ventricular (RV) stimulation.

Results

In patients with narrow QRS and RBBB, the Q-LV/QRS ratio was 0.43?±?0.013 (n?=?20) and 0.41?±?0.026 (n?=?14), respectively. In patients with LBBB morphology, the Q-LV/QRS split up into a group of patients with normal (0.43?±?0.022, n?=?7) and a group with delayed left ventricular activation (0.75?±?0.016, n?=?18). By direct comparison of the Q-LV/QRS ratio during intrinsic conduction with the Q-LV/QRS ratio during RV pacing leading to a functional LBBB, a clear distinction between a group of “true LBBB” and another group of “apparent LBBB”/nonspecific intraventricular conduction delay (NICD) could be generated.

Conclusions

We present a novel and practical method that might facilitate discrimination between patients with apparent LBBB and true LBBB by comparing Q-LV/QRS ratios during intrinsic activation and during RV stimulation. Although this method can already be directly applied, validation by 3D electrical mapping and prospective correlation to cardiac resynchronization therapy (CRT) response will be required for further translation into clinical practice.

     

Pharmacodynamic studies in suicidal digoxin poisoning (author's transl)

In two patients with suicidal digoxin poisoning the correlations between serum digoxin concentration and changes in the duration of QTc and the flattening of the T-waves were studied. The digoxin serum half-life following suicidal digoxin poisoning was in the first patient (10 mg beta-acetyl derivative of digoxin) 77 h, prolonged cause of renal insufficiency, and in the second patient 39.6 h. (20 mg beta-acetyl derivative of digoxin). In both patients the digoxin induced flattening of the T-wave reached a plateau of maximum efficacy at a serum level of 2-3 ng/ml with no further change up to a serum level of 13.2 ng/ml and 9.6 ng/ml respectively. A linear correlation, however, was found between the digoxin serum concentration and the digoxin induced shortening of QTc, r = 0.88 and r = 0.92 respectively. A plateau maximum efficacy was not found. The regression equations were y = -12.0 chi + 430.8 and y = -8.0 chi + 391.9 respectively. The shortening of QTc is therefore an important parameter for the diagnosis of digoxin poisoning. It can be determined very quick with no methodical problems.     

Non-compliance in surveillance for patients with previous resection of large (≥1 cm) colorectal adenomas

AIM: To assess the extent and reasons of noncompliance in surveillance for patients undergoing polypectomy of large (≥ 1 cm) colorectal adenomas.METHODS: Between 1995 and 2002, colorectal adenomas ≥ 1 cm were diagnosed in 210 patients and subsequently documented at the Erlangen Registry of Colorectal Polyps. One hundred and fifty-eight patients (75.2%) could be contacted by telephone and agreed to be interviewed. Additionally, records were obtained from the treating physicians.RESULTS: Fifty-four out of 158 patients (34.2%)neglected any surveillance. Reasons for non-compliance included lack of knowledge concerning surveillance intervals (45.8%), no symptoms (29.2%), fear of examination (18.8%) or old age/severe illness (6.3%).In a multivariate analysis, the factors including female gender (P = 0.036) and age ≥ 62 years (P = 0.016)proved to be significantly associated with non-compliance in surveillance.CONCLUSION: Efforts to increase compliance in surveillance are of utmost importance, This applies particularly to women's compliance. Effective strategies for avoiding metachronous colorectal adenoma and cancer should focus on both the improvement in awareness and knowledge of patients and information about physicians for surveillance.     

Existence of nitric oxide synthase in rat hippocampal pyramidal cells.

It has been proposed that nitric oxide (NO) serves as a key retrograde messenger during long-term potentiation at hippocampal synapses, linking induction of long-term potentiation in postsynaptic CA1 pyramidal cells to expression of long-term potentiation in presynaptic nerve terminals. However, nitric oxide synthase (NOS), the proposed NO-generating enzyme, has not yet been detected in the appropriate postsynaptic cells. We here demonstrate specific NOS immunoreactivity in the CA1 region of hippocampal sections by using an antibody specific for NOS type I and relatively gentle methods of fixation. NOS immunoreactivity was found in dendrites and cell bodies of CA1 pyramidal neurons. Cultured hippocampal pyramidal cells also displayed specific immunostaining. Control experiments showed no staining with preimmune serum or immune serum that was blocked with purified NOS. These results demonstrate that CA1 pyramidal cells contain NOS, as required were NO involved in retrograde signaling during hippocampal synaptic plasticity.     

Evidence for haploidy in metacyclic forms of Trypanosoma brucei.

The parasitic flagellate Trypanosoma brucei undergoes a series of morphologic and metabolic changes during its passage in the digestive organs of its insect vector, a Glossina or tsetse fly. This morphogenesis ends by the differentiation, in the salivary gland of the fly, of the metacyclic form, which will be transmitted in the bloodstream of the mammalian host. On the basis of DNA microfluorometric measurements, we propose that these metacyclic trypanosomes have a haploid amount of DNA, compared to that of bloodstream forms and also of the proventricular forms, which initiate the invasion of the salivary glands. It can be inferred that trypanosomes undergo meiosis during their developmental cycle in the tsetse fly's salivary glands and syngamy shortly after cyclic transmission.