Efficacy, safety and tolerability of aleglitazar in patients with type 2 diabetes: pooled findings from three randomized phase III trials.

AIMS: To evaluate the potential efficacy, safety and tolerability of aleglitazar as monotherapy or add-on therapy to metformin or to a sulphonylurea (either alone or in combination with metformin). METHODS: We conducted a pooled analysis of data from three randomized phase III clinical trials of aleglitazar in patients with type 2 diabetes (n = 591). The three studies focused on: (i) aleglitazar alone; (ii) aleglitazar and metformin; and (iii) aleglitazar and sulphonylurea with or without metformin. Patients were randomized to 26 weeks' treatment with aleglitazar 150 µg/day or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) concentration from baseline to week 26. Secondary endpoints included changes in lipids, fasting plasma glucose and homeostatic model assessment of insulin resistance (HOMA-IR) at week 26. RESULTS: Reductions in HbA1c concentration from baseline to week 26 were statistically significantly greater with aleglitazar than with placebo. Aleglitazar treatment was associated with more beneficial changes in lipid profiles and HOMA-IR values than was placebo. Aleglitazar was generally well tolerated, with no reports of congestive heart failure. The incidence of peripheral oedema was similar in both groups. Change in body weight was +1.37 kg with aleglitazar and -0.53 kg with placebo. Hypoglycaemia was more frequently reported with aleglitazar (7.8%) than with placebo (1.7%), a result probably driven by the type of background medication. CONCLUSIONS: Development of aleglitazar was halted because of a lack of cardiovascular efficacy and peroxisome proliferator-activated receptor-related side effects in patients with type 2 diabetes post-acute coronary syndrome; however, in the present studies, aleglitazar was well tolerated and effective in improving HbA1c, insulin resistance and lipid variables.

Plasma levels of NT-pro-BNP in patients with atrial fibrillation before and after electrical cardioversion.

OBJECTIVE: Plasma levels of brain natriuretic peptide (BNP) have been examined in studies on patients with persistent atrial fibrillation, both before and after electrical cardioversion. Studied patients often showed a comorbidity with congestive heart failure, which complicates interpretation of measured BNP values as a natriuretic peptide. The aim of this study was to examine plasma levels of N-terminal fragment pro-brain natriuretic peptide (NT-pro-BNP), which is the more stable but inactive cleavage product of pro-BNP in patients with atrial fibrillation, but normal left ventricular ejection fraction, before and after electrical cardioversion. PATIENTS AND METHODS: NT-pro-BNP plasma levels of 34 consecutive patients were measured before, shortly after and 11 days after electrical cardioversion. All patients showed a normal ejection fraction after echocardiographic or laevocardiographic criteria. RESULTS: At baseline, all patients showed elevated NT-pro-BNP compared to a healthy control group (1086 vs. 66.9 pg/ml, p<0.001). After a mean follow-up time of 11 days in patients with persistent restored sinusrhythm, NT-pro-BNP decreased from 1071 pg/ml at baseline to 300 pg/ml (p<0.001). In contrast, patients with recurrence of atrial fibrillation showed increased levels from 1570.5 pg/ml at baseline to 1991 pg/ml (p=0.13; n.s.). Recurrence of atrial fibrillation was independent from height of NT-pro-BNP levels at baseline (p=0.23). CONCLUSIONS: Atrial fibrillation in patients with a normal left ventricular ejection fraction is associated with elevated NT-pro-BNP plasma levels, which decrease when a persistent sinus-rhythm can be restored by electrical cardioversion. On the other hand, NT-pro-BNP seems to increase (n.s.) when recurrence of atrial fibrillation occurs. Finally, NT-pro-BNP is no valid predictor for long-term success of sinus-rhythm restoration by electrical cardioversion.

[The freiburg incision for cochlear implantation -- initial results]. / Die Freiburger Inzision zum Cochlear Implant -- Erste Ergebnisse.

BACKGROUND: Cochlear implant surgery is a well standardized therapy for rehabilitation of congenital or acquired deafness at all ages. Mastoidectomy, posterior tympanotomy, cochleostomy and electrode insertion are performed consistently worldwide. Recently newly developed types of incision are taken into account. In our experience over more than 15 years the extended endaural incision has proven to be reliable with a low complication rate. OBJECTIVE: To evaluate a modified retroauricular incision for clinical use and complication rate in cochlear implant surgery with devices of different manufacturers. MATERIAL AND METHODS: We performed a prospective analysis of cochlear implant surgeries between 03/2003 and 03/2004. In all cases a modified retroauricular incision was used. Necessary adaptations of incision, depending on the device used, and postoperative complications were evaluated. RESULTS: In 76 ears a retroauricular incision was performed. Depending on the shape and size of receiver/stimulator an extension of the incision was necessary. The mean observation time was 6.3 months. Intra- or postoperative complications were not observed. In one case a skin dehiscence following trauma 28 days after surgery was reported without dehiscence of fascia or implant failure with uneventful healing after secondary suture. CONCLUSIONS: With regard to the results with the extended endaural incision the modified retroauricular incision allows a safe access for cochlear implant surgery. Observation of long term results and outcomes in revision surgery is mandatory.

[Results with the Contour cochlear implant in patients with cochlear otosclerosis]. / Ergebnisse mit dem Contour-Cochlear-Implant bei Kapselotosklerose.

BACKGROUND: Results after cochlear implant surgery may be complicated by postoperative facial nerve stimulation. Aim of the study presented was to evaluate postoperative results in implanting the straight Nucleus electrode array and the preformed Contour array in patients with deafness due to cochlear otosclerosis. METHODS: A retrospective analysis of intra- and postoperative reports of all patients with cochlear otosclerosis was carried out. Results with the Nucleus straight electrode array and the Contour array were compared with regard to postoperative facial nerve stimulation. RESULTS AND CONCLUSION: None of the Contour patients (n = 7) presented with postoperative facial nerve stimulation. This is in contrast to the majority (4 of 6) of patients being implanted with the straight electrode array. Our results indicate that the use of the Contour array is advantageous in patients being at risk for facial nerve stimulation. In addition intraoperative reports suggest a more reliable insertion of the Contour electrode array in cochlear otosclerosis with partial obliteration.

Cochlear structures after implantation of a perimodiolar electrode array.

OBJECTIVE: A perimodiolar prototype electrode array has been evaluated on 12 human temporal bone specimens. To achieve modiolar proximity, a fine Teflon positioner is attached to the tip and base of a conventional Nucleus 22 electrode array. METHODS: Intracochlear electrode position was examined by macroscopic preparation and confirmed by a cochlear view x-ray after insertion into human temporal bones. The temporal bones were examined with light microscopy for intracochlear trauma after insertion, explantation, and re-implantation of the perimodiolar array. RESULTS: Macroscopic preparation and x-ray confirmed close proximity of the intracochlear electrodes to the modiolar wall. In some bones, electrode insertion and positioning was performed without significant damage to intracochlear structures, but explantation caused varying degrees of trauma depending on the explantation technique used. Re-implantation and repeat explantation appeared to destroy most of the intracochlear architecture. CONCLUSIONS: The perimodiolar electrode array prototype with Teflon positioner cannot be recommended for clinical use, especially in children in whom the possibility for re-implantation is high.

[Squamous epithelial carcinoma in a Zenker diverticulum]. / Plattenepithelcarcinom in einem Zenker-Divertikel.

Zenker's diverticulum is a common anomaly in the elderly patient. Carcinoma in such a diverticulum is a rare but recognized complication of a posterior pharyngeal pulsion diverticulum. We present a case of a 67-year-old patient with a long-standing symptomatic Zenker's diverticulum. The diagnosis of the neoplasm was only achieved intraoperatively. The patient underwent a proximal esophageal resection with lymphadenectomy. Reconstruction was done with a microvascular free jejunal transplant. The postoperative course was uneventful. Wide oncologic surgical resection is the therapy of choice in cases of carcinoma in a Zenker's diverticulum.

UV-responsive genes of arabidopsis revealed by similarity to the Gcn4-mediated UV response in yeast.

A UV response that involves the Ras proteins and AP-1 transcription factors has recently been described in mammals and yeast. To test whether an equivalent response exists in plants, we monitored the expression of Arabidopsis histidinol dehydrogenase gene (HDH), a homologue of the yeast HIS4 gene, which is strongly induced by UV light and is a target of the transcriptional activator Gcn4. We show that HDH mRNA levels increase specifically in response to UV-B light. Only small increases were detected upon exposure to other wavelengths. To isolate plant genes involved in this UV response, a gcn4 mutant was transfected with an Arabidopsis thaliana cDNA library. A new type of nucleotide diphosphate kinase (NDPK Ia) with a significant homology to the human tumor suppressor protein Nm23 rescued the gcn4 phenotype. NDPK Ia specifically binds to the HIS4 promoter in vitro and induces HIS4 transcription in yeast. In Arabidopsis, the NDPK Ia protein is located in the nucleus and cytosol. Expression studies in seedlings revealed that the level of NDPK Ia mRNA, like that of HDH, increases in response to UV-B light. It appears that NDPK Ia and HDH are components of a novel UV-responsive pathway in A. thaliana.