A Prospective Randomized Evaluation of VV Delay Optimization in CRT-D Recipients: Echocardiographic Observations from the RHYTHM II ICD Study

Background: All current cardiac resynchronization therapy (CRT) devices allow the programming of the atrioventricular (AV/PV) delays and the sequential stimulation of the ventricles via the inter ventricular (VV) delay.
Aim: This post hoc analysis of the RHYTHM II study was conducted to compare the reverse remodeling associated with VV delay optimization in patients randomly assigned to simultaneous (SIM) biventricular stimulation versus patients assigned to optimized VV delay programming (OPT) (1:3 randomization scheme).
Methods: The analysis included 14 patients assigned to the SIM group and 34 patients to the OPT group who completed the 6-month follow-up period with paired echocardiographic recordings.
Results: In both study groups, changes consistent with left ventricular (LV) remodeling were observed between baseline and 6 months, with significant improvements in LV function and decrease in LV dimensions. In the OPT group, there was also a decrease in left atrial diameter and mitral valve closure to opening time. At 6 months, the overall proportion of echocardiographic responders (≥10% decrease in LV end-systolic volume or ≥5% absolute increase in LV ejection fraction) was similar in both groups. The optimal AV/VV delays, evaluated by maximization of LV outflow tract velocity time integral, changed over time.
Conclusions: Ventriculo-ventricular delay optimization was associated with better immediate hemodynamic function than simultaneous biventricular stimulation, though did not promote additional reverse remodeling at 6 months and did not increase the proportion of echocardiographic responders to CRT. Optimization of both the AV and VV intervals was patient-specific and optimal values changed over time.     

EXPRESSION OF CD44 SPLICE VARIANTS IN SQUAMOUS EPITHELIA AND SQUAMOUS CELL CARCINOMAS OF THE HEAD AND NECK

Splice variants of the adhesion molecule CD44 have been described as essential for the lymphatic spread of rat tumour cells and are claimed to be involved in the metastatic spread of several human tumours. Immunohistochemistry has been used to analyse the expression pattern of CD44 standard (CD44s) and variant (CD44v) isoforms in normal and dysplastic squamous epithelia, as well as in primary and metastatic squamous cell carcinomas (SCCs), which spread predominantly by way of the lymphatic system. Frozen sections of squamous epithelia and of squamous cell carcinomas were stained with a panel of monoclonal antibodies recognizing epitopes of CD44s as well as of the variant exons v5, v6, v7, v7–v8, and v10. The stratum basale and stratum suprabasale of squamous epithelia stained with all antibodies; the stratum spinosum stained with anti-CD44v5, anti-CD44v6, anti-CD44v7–8 and anti-CD44v10; the lower layers of the stratum corneum stained with anti-CD44v5. This expression profile was seen in epithelia of the lip, the tongue, the gingiva, the hard palate, the floor of the mouth, the buccal mucosa, and the pharynx. The same pattern of expression was also noted in dysplastic epithelia, but expression of the variant exons v7, v8, and v10 was significantly downregulated in primary squamous cell carcinomas and was not detected at all in the majority of metastasis-derived specimens. Expression of CD44v5 and CD44v6, on the other hand, was mainly unaltered. Thus, epithelial cell layers representing different stages of differentiation express distinct sets of CD44 variant isoforms, where especially exons v8–v10 might be required for the maintenance of the structural integrity of squamous epithelium. Downregulation of these exons on tumour cells could indicate that they are irrelevant for tumour progression or may even hamper infiltration of surrounding tissue or of lymphatics.     

Changes in lymphocyte populations in suckling piglets during primary infections with Isospora suis

Isospora suis, a common intestinal parasite of piglets, causes neonatal porcine coccidiosis, which results in reduced and uneven weaning weights and economic losses in pig production. Nevertheless, there are no detailed studies available on the immune response to I. suis. The aim of this study was to carry out phenotypical characterization of lymphocytes during primary infections on day 3 after birth. Infected and noninfected piglets were investigated between days 7 and 16 after birth. Lymphocytes from the blood, spleen and mesenteric lymph nodes (flow cytometry) and of the jejunal mucosa (immunohistochemistry) were analysed. A decrease in T cells, especially with the phenotype of resting T‐helper cells, T‐cell receptor‐γδ‐T cells, and regulatory T cells in the blood, spleen and mesenteric lymph nodes was noticeable. An increase in cells with the phenotype of natural killer cells in the spleen of infected animals was found, and the subset of TcR‐γδ‐T cells was strongly increased in the gut mucosa. Our findings suggest an accelerated migration of those cells into the gut. This study provides a strong indication for the involvement of adaptive and innate immune response mechanisms in the primary immune response to I. suis, especially of TcR‐γδ‐T cells as a linkage between innate and adaptive immunity.     

Early accumulation of the terminal complement-complex in the ischaemic myocardium after reperfusion

The terminal, membrane-damaging complement complex C5b-9 accumulatesin the infarcted myocardium. In experimental myocardial infarction,we investigated the time course of C5b-9 deposition and theinfluence of reperfusion. In a group of 17 rabbits (group 1),the circumflex coronary artery was occluded for different timeperiods ranging from 0•5 to 29 h without subsequent reperfusion.A second group of 23 rabbits (group 2) underwent coronary arteryocclusion for periods ranging from 0•5 to 6 h followedby reperfusion. C5b-9 was determined in transmural myocardialbiopsies by immunohistochemistry and by ELISA. In group 1, C5b-9accumulation in the ischaemic myocardium was found only after5 to 6 h of coronary artery occlusion. In group 2 (ischaemiaand reperfusion), significant C5b-9 deposition was already observedafter 30 min of myocardial ischaemia. We conclude that in the absence of reperfusion C5b-9 accumulationoccurs as a late event when most of the jeopardized myocardiumhas probably already become necrotic. In the presence of reperfusion,however, the complement system is activated rapidly and thiscould play a role in the pathogenesis of reperfusion injury.     

Is there a positive relationship between molar incisor hypomineralisations and the presence of dental caries?

International Journal of Paediatric Dentistry 2013; 23: 116–124 Objective This epidemiological study aimed to compare the caries experience in 10‐year‐olds with and without molar incisor hypomineralisation (MIH). Methods About 693 children from an ongoing birth cohort study (GINIplus10) were examined for caries lesions to determine the DMF index. Furthermore, enamel hypomineralisation (EH) was scored on all permanent teeth/surfaces, according to the criteria of the European Academy of Paediatric Dentistry. Children with EH were categorised into those with a minimum of one EH in the permanent dentition (MIH/1), with EH on at least one‐first permanent molar (MIH/1A), on at least one‐first permanent molar and permanent incisor (MIH/1B), and on other permanent teeth (MIH/1C). Results The mean caries experience was 0.4 (SD 0.9) DMFT. Existence of MIH/1, MIH/1A, MIH/1B, and MIH/1C was determined in 36.5%, 14.7%, 9.4%, and 21.8% of all children. The corresponding DMFT values were the following: no MIH: 0.3 (SD 0.8); MIH/1: 0.5 (SD 0.9); MIH/1A: 0.5 (SD 0.9); MIH/1B: 0.4 (SD 0.9); and MIH/1C: 0.4 (SD 0.9) DMFT. No significant differences were found between all groups. Conclusions There was no relationship between the presence of EH/MIH and caries in 10‐year‐olds. A ratio of one EH‐associated defect to two caries lesions indicates that both conditions are prevalent and influence the oral health status of 10‐year‐old children from Munich, Germany.     

Chronic Augmentation of the Parasympathetic Tone to the Atrioventricular Node: A Nonthoracotomy Neurostimulation Technique for Ventricular Rate Control During Atrial Fibrillation

Long‐Term Cardiac Neurostimulation. Introduction: The right inferior ganglionated plexus (RIGP) selectively innervates the atrioventricular node. Temporary electrical stimulation of this plexus reduces the ventricular rate during atrial fibrillation (AF). We sought to assess the feasibility of chronic parasympathetic stimulation for ventricular rate control during AF with a nonthoracotomy intracardiac neurostimulation approach. Methods and Results: In 9 mongrel dogs, the small endocardial area inside the right atrium, which overlies the RIGP, was identified by 20 Hz stimulation over a guiding catheter with integrated electrodes. Once identified, an active‐fixation lead was implanted. The lead was connected to a subcutaneous neurostimulator. An additional dual‐chamber pacemaker was implanted for AF induction by rapid atrial pacing and ventricular rate monitoring. Continuous neurostimulation was delivered for 1–2 years to decrease the ventricular rate during AF to a range of 100–140 bpm. Implantation of a neurostimulation lead was achieved within 37 ± 12 min. The latency of the negative dromotropic response after on/offset or modulation of neurostimulation was <1 s. Continuous neurostimulation was effective and well tolerated during a 1–2 year follow‐up with a stimulation voltage <5 V. The neurostimulation effect displayed a chronaxie‐rheobase behavior (chronaxie time of 0.07 ± 0.02 ms for a 50% decrease of the ventricular rate during AF). Conclusion: Chronic parasympathetic stimulation can be achieved via a cardiac neurostimulator. The approach is safe, effective, and well tolerated in the long term. The atrioventricular nodal selectivity and the opportunity to adjust the negative dromotropic effect within seconds may represent an advantage over pharmacological rate control. (J Cardiovasc Electrophysiol, Vol. 21, pp. 193‐199, February 2010)     

PROGNOSTIC VALUE OF MIB-1 IN NEUROENDOCRINE TUMOURS OF THE LUNG

The spectrum of neuroendocrine lung tumours ranges from highly aggressive small cell carcinomas (SCLC) to carcinoid tumours (CD) of low malignant potential. Between these two extremes, the ‘well-differentiated neuroendocrine carcinomas’ (WDNEC) form a transitional group with uncertain biological behaviour. This study investigated the prognostic value of the proliferation marker MIB-1 (paraffin Ki-67) in 59 neuroendocrine lung tumours (32 SCLC, 13 WDNEC, 14 CD) by immunostaining of routinely processed paraffin sections. Morphometric evaluation was done by semi-automatic image analysis. The results were compared with survival data (mean follow-up: 42 months). The proliferation rates of the tumours as determined by MIB-1 immunoreactivity (MIB-1-PR) were significantly different between the tumour types (SCLC>WDNEC>CD) and showed a strong inverse correlation with survival time. In CD, the percentage of MIB-1-labelled nuclei never exceeded 1·1 per cent; higher values would therefore favour the diagnosis of WDNEC over that of CD. Among WDNEC, MIB-1 was able to differentiate a subgroup with excellent prognosis (MIB-1-PR: 0·3–3·4 per cent) from another subgroup with a death rate of 50 per cent (MIB-1-PR: 7·3–20·3 per cent). Within each tumour type, all patients without distant metastases at diagnosis survived when MIB-1-PR was ⩽9·4 per cent, suggesting a potential threshold for prognosis. Although the status of metastases was the dominant prognostic factor in these neoplasms, MIB-1 was able to provide additional prognostic information allowing the definition of prognostically different subgroups of patients. In conclusion, MIB-1 and the status of metastases are complementary prognostic indicators and are best used in combination to characterize the biological behaviour of neuroendocrine lung tumours.     

COMPARATIVE GENOMIC HYBRIDIZATION (CGH) ANALYSIS OF NEUROBLASTOMAS—AN IMPORTANT METHODOLOGICAL APPROACH IN PAEDIATRIC TUMOUR PATHOLOGY

Comparative genomic hybridization (CGH) was applied to 35 neuroblastomas to obtain a global view of genetic imbalances. Results were validated by means of Southern blot hybridization (detection of N-myc amplification), loss of heterozygosity (LOH) studies (detection of deletion 1p), and interphase cytogenetics [dual labelling fluorescence in situ hybridization (FISH) of centromeric 17 and erbB-2]. CGH allowed sensitive detection of N-myc amplification and chromosome 1p deletion, representing the most established prognostic markers of neuroblastoma. In addition, a high rate of chromosome 17 aberrations (63 per cent) with possible prognostic relevance was observed. Previously unreported high level copy number increases indicating oncogene amplification were mapped to chromosome subbands 2p13–14 and 3q24–26. Other recurrent regional chromosomal aberrations were localized on 11q, 12q, 13q, 14q, and 15q. CGH results were fully consistent with data of Southern blot analysis and LOH study, as well as interphase cytogenetics. These results show that CGH is a sensitive method for the detection of all prognostically relevant genetic alterations in neuroblastomas; that CGH considerably simplifies the detection of these alterations, resulting in a single methodological approach; and that CGH is a powerful tool to elucidate previously unknown genetic changes in neuroblastomas. © 1997 by John Wiley & Sons, Ltd.