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Background Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions We established a mouse model in which CaMKII’s activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.

Background Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)δC mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo. Methods and Results Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10−8 M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca]i rose clearly on ISO in TG but not in wild-type cells (+20±5% versus +3±4% at 10−6 M ISO, P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9±0.5 versus 2.0±0.4 sparks per 100 μm−1·s−1, P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKIIδ-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%, P<0.05) and late (86% versus 43%, P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05). Conclusions We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIδC mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.

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Recurrent laryngeal papillomatosis is a benign disease of the larynx often leading to organic and functional restrictions. The therapeutic treatment of choice in larynx-obstructing papillomatosis is at present surgical laser ablation. The effectiveness of adjuvant intralesional injection of the virustaticum Cidofovir has been investigated recently in a variety of therapeutic models. The present case study deals with the treatment of recurrent laryngeal papillomatosis by means of surgical laser ablation of the laryngeal papillomas with adjuvant local injection of the virustaticum Cidofovir (dose of 5 mg/1 ml). Within the period from October 2001 to August 2004, ten patients aged between 5- and 70 years were treated with intralesional injections of Cidofovir. Papillomatosis was confirmed histologically in all cases, and the virus types were defined in part. Each of the patients underwent clinical-phoniatric examinations and was photographed for documentation. After 2-7 treatments with surgical laser papilloma ablation and intralesional Cidofovir injections, all patients showed a definite papilloma reduction, while in six cases complete remission was achieved. During the follow-up period of 8-30 months, not a single recurrence of the laryngeal papillomatosis occurred. In the majority of patients, a clear improvement in the voice was achieved. There were no local or systemic side effects caused by the virustaticum. Intralesional injection of Cidofovir is an adjuvant, but not a curative therapeutic option in recurrent laryngeal papillomatosis. Remission of previously frequently recurrent laryngeal papillomas can be achieved, but recurrence after longer treatment-free intervals is also possible.

Use of real-time ultrasonography in meat animal improvement programs has increased largely as a result of the perceived accuracy of such instruments in measuring longissimus muscle area (LMA) and fat depth (BF). The objective of this study was to examine operator effects for ultrasonic determination of BF and LMA in market-weight cattle, sheep and pigs. The day prior to slaughter, five persons scanned 45 pigs, 32 sheep and 18 cattle at the last rib using an A-mode Ithaco Model 731AM101 body composition meter (ABF) and a Johnson and Johnson Ultrasound 210DX B-mode scanner fitted with a 3.0 MHz probe. All operators measured their own B-mode recordings (OBF, OLMA); an independent, experienced technician also obtained measurements from all recordings (TBF, TLMA). Species x machine x operator interaction effects were detected (P less than .001) for ultrasonic BF. Within-species analyses also revealed that the machine x operator interaction was important (P less than .001) for all species. Analyses of ABF, OBF, TBF, OLMA and TLMA detected species x operator interactions (P less than .001) for all traits except TLMA (P less than .20). Assuming a random model with animal, operator and residual effects, variance components were estimated by maximum likelihood for each species. Repeatabilities, calculated as the intraclass correlation among animals for BF and LMA scanned and interpreted by different operators, were .13, .21 and .51 (OBF) and .28, .15 and .29 (OLMA) for cattle, sheep and pigs, respectively, indicating the importance of operator effects. Repeatabilities of TBF were .90, .42 and .68 and of TLMA were .19, .55 and .65 for cattle, sheep and pigs, respectively, indicating the importance of image interpretation in determining operator effects associated with use of the 210DX B-mode scanner. Technical training standards must, therefore, be established for operators of such equipment.

Surgical plume resulting from routine LEEPs for HSIL of the cervix uteri has the risk of contamination with high-risk HPV. Further investigations of infectiousness of surgical plume are necessary for evaluation of potential hazards to involved healthcare professionals.