Time-course of the electrophysiological maturation and integration of transplanted cardiomyocytes

Electrophysiological maturation and integration of transplanted cardiomyocytes are essential to enhance safety and efficiency of cell replacement therapy. Yet, little is known about these important processes. The aim of our study was to perform a detailed analysis of electrophysiological maturation and integration of transplanted cardiomyocytes. Fetal cardiomyocytes expressing enhanced green fluorescent protein were transplanted into cryoinjured mouse hearts. At 6, 9 and 12days after transplantation, viable slices of recipient hearts were prepared and action potentials of transplanted and host cardiomyocytes within the slices were recorded by microelectrodes. In transplanted cells embedded in healthy host myocardium, action potential duration at 50% repolarization (APD50) decreased from 32.2±3.3ms at day 6 to 27.9±2.6ms at day 9 and 19.6±1.6ms at day 12. The latter value matched the APD50 of host cells (20.5±3.2ms, P=0.78). Integration improved in the course of time: 26% of cells at day 6 and 53% at day 12 revealed no conduction blocks up to a stimulation frequency of 10Hz. APD50 was inversely correlated to the quality of electrical integration. In transplanted cells embedded into the cryoinjury, which showed no electrical integration, APD50 was 49.2±4.3ms at day 12. Fetal cardiomyocytes transplanted into healthy myocardium integrate electrically and mature after transplantation, their action potential properties after 12days are comparable to those of host cardiomyocytes. Quality of electrical integration improves over time, but conduction blocks still occur at day 12 after transplantation. The pace of maturation correlates with the quality of electrical integration. Transplanted cells embedded in cryoinjured tissue still possess immature electrophysiological properties after 12days.     

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.     

Accuracy of cone beam computed tomography in assessing peri-implant bone defect regeneration: a histologically controlled study in dogs

Objective: To assess the accuracy of cone‐beam computed tomography (CBCT) in terms of buccal bone‐wall configuration and peri‐implant bone defect regeneration after guided bone regeneration (GBR). Material and methods: Titanium implants were inserted into standardized box‐shaped defects in the mandible of 12 foxhounds. Defects of one side were augmented following the principle of GBR, while the other side was left untreated. Radiological evaluation was performed using CBCT and compared with histomorphometrical measurements of the respective site serving as a validation method. Results: Non‐augmented control sites providing a horizontal bone width (BW) of<0.5 mm revealed a significantly lower accuracy between the radiological and the histological evaluation of the buccal defect depth (1.93 ± 1.59 mm) compared with the group providing a BW of >0.5 mm (0.7 ± 0.7 mm) (P<0.05, Mann–Whitney U‐test). In GBR‐treated defects, the subgroup <0.5 mm (1.49 ± 1.29 mm) revealed a significantly higher difference between CBCT and histology compared with >0.5 mm (0.82 ± 1.07) (P>0.05, Mann–Whitney U‐test). However, a radiological discrimination between original bone, integrated and non‐integrated bone substitute material was not reliable. Additionally, it was found that a minimum buccal BW of 0.5 mm was necessary for the detection of bone in radiology. Conclusion: The evaluation of peri‐implant bone defect regeneration by means of CBCT is not accurate for sites providing a BW of <0.5 mm. Moreover, a safe assessment of the success of the GBR technique is not possible after the application of a radiopaque bone substitute material. To cite this article:
Fienitz T, Schwarz F, Ritter L, Dreiseidler T, Becker J, Rothamel D. Accuracy of cone beam computed tomography in assessing peri‐implant bone defect regeneration: a histologically controlled study in dogs.
Clin. Oral Impl. Res. 23 , 2012; 882–887.
doi: 10.1111/j.1600‐0501.2011.02232.x     

Condylar metastasis from prostatic carcinoma mimicking temporomandibular disorder: a case report

Background

Although metastatic carcinoma is the most common malignant tumor of the bone, less than 1% of all metastatic bone lesions are presented in the maxillofacial area. As the mandibular body is the most frequent localization, metastasis to the mandibular condyle is extremely rare.

Case report

This report describes a rare case of prostate carcinoma metastatic to the mandibular condyle in a 75-year old man, who was referred because of persistent pain in the temporomandibular joint (TMJ) region and a limitation of opening, initially misdiagnosed and treated as temporomandibular disorder (TMD). Histopathological examination confirmed the suspected metastasis of prostate carcinoma and local radiation therapy was performed.

Discussion

TMD represent a diagnostic challenge and sometimes an interdisciplinary approach is required to prevent a delay of the correct treatment. Metastatic cancer should be included in the differential diagnosis of TMD, especially in patients with a malignant disease.     

The development of the Tuebingen Cushing's disease quality of life inventory (Tuebingen CD-25). Part I: construction and psychometric properties

Objective To develop a disease‐specific questionnaire for Cushing’s disease (CD), the Tuebingen Cushing’s disease quality of life inventory (Tuebingen CD‐25). Methods Sources for item generation consisted of technical literature, interviews with patients and the rating of neurosurgeons, endocrinologists and a neuropsychologist. A preliminary inventory with 64 items was handed out to 63 CD patients. Twenty‐eight patients filled out the questionnaire preoperative, the remaining 35 patients evaluated their health‐related quality of life (HRQoL) retrospectively. Item reduction and scale generation followed the principles of classical test theory. Validation was performed with the WHOQoL‐BREF. Results The final version of the Tuebingen CD‐25 contained 25 items, showed high reliability (Cronbach’s alpha = 0·93) and validity (r = ?0·65) and includes the subdomains Depression, Sexual Activity, Environment, Eating Behaviour, Bodily Restrictions and Cognition. The retrospective rating of the Tuebingen CD‐25 showed similar results compared to the pretreatment group. We found a non‐linear correlation between the Tuebingen CD‐25 scores and patients’ age, younger (21–30 years) and middle‐aged (51–60 years) patients having inferior HRQoL than patients between 31 and 50 years and older than 61 years. Preoperative 24 h urinary free cortisol (UFC) levels correlated significantly with the subscale Cognition and only marginally failed significance level for the subscale Eating Behaviour, while preoperative cortisol and ACTH levels did not correlate with any scale. Conclusion The Tuebingen CD‐25 is a valid and reliable instrument to evaluate HRQoL in CD. Based on impairment of HRQoL for the different subdimensions, specific support can be offered to the patients.     

Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: proceedings from the 6th International Post-ASH Symposium

Immediately after the annual scientific meeting of the American Society of Hematology (ASH), a select group of clinical and laboratory investigators in myeloproliferative neoplasms (MPN) is summoned to a post-ASH conference on chronic myeloid leukemia and the BCR-ABL1-negative MPN. The 6th such meeting occurred on December 13–14,2011, in La Jolla, California, USA, under the direction of its founder,Dr. Tariq Mughal. The current document is the first of two reports on this post-ASH event and summarizes the most recent preclinical and clinical advances in polycythemia vera, essential thrombocythemia,and primary myelofibrosis.