Mechanism for Species-Specific Induction of Leydig Cell Tumors in Rats by Lansoprazole

Lansoprazole is a substituted benzimidazole which inhibits gastricacid secretion by inhibiting the hydrogen-potassium ATPase (protonpump) in the parietal cell. The finding of Leydig cell hyperplasiaand Leydig cell tumors in 2-year oral studies in Sprague-Dawleyrats but not in CD-1 mice prompted investigative studies todetermine the mechanism for the Leydig cell changes. hCG challengestudies in Sprague-Dawley rats revealed decreased testosteroneresponsiveness in rats treated orally for 1 or 2 weeks withlansoprazole. After 4 weeks of daily oral treatment increasesin serum LH and decreases in serum testosterone were detectedwithin a few hours after dosing. In a study where 9-month-oldmale F344 rats were given testosterone supplementation via Silasticimplants and then treated with lansoprazole for 6 months, ahigh incidence of Leydig cell tumors was seen in lansoprazoletreated,unsupplemented rats, whereas no Leydig cell tumors were seenin testosterone supplemented rats. This implied that reductionof the normal feedback inhibition at the level of the hypothalaumsand/or pituitary due to reduced testosterone levels, thus givingrise to elevated levels of LH, was involved in the inductionof Leydig cell tumors by lansoprazole. In vitro studies withLeydig cells from rats using various stimulators and precursorsof testosterone biosynthesis demonstrated that the most sensitivesite for inhibition of testosterone synthesis by lansoprazoleis the transport of cholesterol to the cholesterol side chaincleavage enzyme. The IC50s for inhibition of LH or hCG-stimulatedtestosterone synthesis in Leydig cells from rats, mice, andmonkeys were 11–12, 8, and 27.4 µg/ml, respectively.In vitro studies with metabolites of lansoprazole revealed thatthree metabolites were more potent inhibitors of testosteronesynthesis than the parent drug, two of them being at least 10times more potent. These metabolites are present in rats atsubstantial levels but are undetectable in humans. The lackof induction of Leydig cell tumors in mice, lower sensitivityof primate Leydig cells, and the absence of testosterone synthesisinhibitingmetabolites in man suggest that Leydig cell tumors found inrats represent a species-specific sensitivity and does not implya risk for clinical use in man.     

A case of obstructive sleep apnoea with anterior cervical osteophytes

Summary  Osteophytes of the cervical spine are usually seen in elderly adults. When prominent, they have been blamed for dysphagia, cough, dysphonia and dyspnoea. This paper reports on an obstructive sleep apnoea (OSA) patient with cervical spinal osteophytes, one cause of airway obstruction. A 75-year-old male complained of pronounced snoring. The diagnosis was mild OSA, apnoea hypopnoea index was 9·4. Patient reported no restrictions in neck movements, experiences of neck pain or neck trauma. Previously, patient underwent a tonsillectomy due to discomfort in the pharyngeal region. A lateral cephalometric image was taken to observe airway before oral appliance therapy. The image revealed the presence of large osteophytes or sclerotic enthesopathy, lying on anterior surfaces from the fourth to seventh cervical vertebrae. A computed tomography (CT) image revealed the relationship of airway position to the spine. In the reconstructed three-dimensional (3D) image, the airway appeared displaced to the right of the craniomandiblar bone, with the hyoid bone similarly displaced in a manner to that of the airway. The spine also appeared displaced to the left side ofcraniomandiblar bone. Additionally, the 3D image revealed calcification of the stylohyoideum ligament and ligamentum nuchae. This present case highlights the necessity of CT examination for OSA patients. There were several ligament calcifications in the head and neck region. Cervical spine osteophytes, as a component of Forestier's or cervical spine disease, have been associated with dysphagia and dysphonia. It was reported that bilateral vocal cord paralysis was caused by osteophytes compressing the post-cricoid area of larynx.     

Efficacy of Additional Ablation of Complex Fractionated Atrial Electrograms for Catheter Ablation of Nonparoxysmal Atrial Fibrillation

Background: The efficacy of ablation of complex fractionated atrial electrograms (CFEs) in the single ablation procedure for nonparoxysmal atrial fibrillation (AF) patients is not well demonstrated. The aim of this study was to compare the ablation strategies of pulmonary vein isolation (PVI) plus linear ablation with and without additional ablation of CFEs in these patients.
Methods: Consecutive 60 patients (49 ± 11 years old, 50 male, 10 female) with nonparoxysmal AF underwent catheter ablation guided by a NavX mapping system. A stepwise approach included a circumferential PVI and left atrial (LA) linear ablation followed by either the additional ablation of continuous CFEs in the LA/coronary sinus (the first 30 patients) or not (the second 30 patients), detected by an automatic algorithm.
Results: There was no difference in the baseline characteristics between the two groups. Complete PVI eliminated some continuous CFEs and altered the distribution of CFEs. Following PVI and linear ablation, the remaining continuous CFEs were identified in 7.9 ± 10% mapping sites of the LA and CS, and were ablated successfully with a procedural AF termination rate of 53%. With a follow-up of 19 ± 11 months, a Kaplan–Meier analysis showed that the patients with additional ablation of the CFEs had a higher rate of sinus rhythm maintenance. Multivariate analysis showed the single procedure success could be predicted by the procedural AF termination and the additional ablation of continuous CFEs in the LA/CS.
Conclusions: Ablation of continuous CFEs after PVI and LA linear ablation had a better long-term efficacy based on the results of single-ablation procedure.     

The Disparities in the Electrogram Voltage Measurement During Atrial Fibrillation and Sinus Rhythm

Unipolar Electrogram Voltage in Patients with Atrial Fibrillation . Introduction: The peak electrogram voltage is a typical metric applied at each site for voltage mapping. However, the peak amplitude depends on the direction and complexity of the wavefront propagation. The root‐mean‐square (RMS) measure of the amplitude is a temporal integral that represents the steady‐state value. The objective of this study was to investigate the disparities between the electrogram voltage during SR and AF by using 2 recording modalities: the conventional peak voltage and an RMS measurement. Methods and Results: This study enrolled 20 patients (age = 59 ± 13) with paroxysmal AF undergoing catheter ablation guided by Ensite array. The unipolar electrogram voltage during SR and AF (7 seconds in duration) was obtained from the same sites, and labeled by the 3‐dimensional (3D) geometry. Overall 1,200 electrograms were analyzed from equally distributed mapping sites in the left atrium. A point‐by‐point comparison of the unipolar peak negative voltage (PNV) showed less agreement (Bland and Altman test: 10.4% outside 2 standard deviations, and intraclass correlation coefficient [ICC]= 0.64). The RMS voltage demonstrated agreement between SR and AF for all sites (BA test: 5.9% of the sites, and the ICC = 0.81). The probability of predicting a low‐voltage during AF using the voltage during SR was significantly lower when using the PNV measurement compared to that when using the RMS voltage (15% vs 61%, P < 0.05). Conclusion: The peak electrogram unipolar voltage during AF did not represent the voltage during SR. The RMS amplitude may be an alternative metric for voltage mapping to characterize the myocardial substrate. (J Cardiovasc Electrophysiol, Vol. 21, pp. 393–398, April 2010)     

东北红豆杉愈伤组织中紫杉烷类化合物的分离与鉴定

目的明确东北红豆杉(Taxus cuspidata)愈伤组织中的化学成分,为开发可持续利用的红豆杉资源提供理论依据。方法采用硅胶柱色谱、制备型高效液相色谱等手段对愈伤组织的正己烷和乙酸乙酯提取物进行分离和纯化;根据化合物的理化性质和波谱数据并结合相关文献对化合物结构进行鉴定。结果从东北红豆杉愈伤组织中分离得到11个紫杉烷类化合物,分别鉴定为tax-uyunnanine C(1)、2α,5α,10β-triacetoxy-14β-propionyloxy-4(20),11-taxadiene(2)、2α,5α,10β-tri-acetoxy-14β-isobutyryloxy-4(20),11-taxadiene(3)、2α,5α,10β-triacetoxy-14β-(2′-methyl)butyrylo-xy-4(20),11-taxadiene(4)、云南红豆杉甲素(yunnanxane,5)、紫杉醇(paclitaxel,6)、taxol C(7)、baccatin VI(8)、1β-deoxybaccatin VI(9)、taxayuntin C(10)、baccatin I(11)。结论化合物9、11为首次从东北红豆杉愈伤组织中分离得到,化合物1-4、8-10尚未在东北红豆杉中发现。     

The Influence of Morphological Changes in Amplatzer Device on the Atrial and Aortic Walls Following Transcatheter Closure of Atrial Septal Defects

Objective: This study prospectively investigated morphological changes in Amplatzer Septal Occluder (ASO) over time and the influences of these changes on the atrial and aortic walls after atrial septal defect (ASD) closure.
Methods: Between August 2005 and December 2007, 78 patients with ASD were treated with ASO devices and changes in the device shape, the device thickness, and relations of the discs to the atrial and aortic walls over time were evaluated by transesophageal echocardiography immediately and 3–12 months after deployment.
Results: The maximum unstretched ASD diameter was 16.2 ± 4.8 mm and the device diameter selected was 20.6 ± 5.5 mm. At the time of last follow-up, the device thickness decreased by 17–33%, 6 of 26 devices with a flare shape on the aortic side developed a closed shape, and the relations of the discs to the anterior atrial and aortic walls changed from touching to intermittent compression in 14 of the 78 cases. In these 14 cases, the aortic rim was significantly smaller, the number of flared device shapes on the aortic side/the number of closed shapes immediately after deployment was significantly larger, and the maximum device thickness at the middle part was significantly more decreased than those in other cases.
Conclusion: As the device becomes thinner, loses its flexibility, and often changes from a flare-to-closed shape on the aortic side over time, the edges of ASO can start to compress the atrial and aortic walls. However, erosion was not recognized in these cases.     

Churg–Strauss syndrome: a retrospective study of 11 cases from a single center in Japan

Objective: To investigate the clinical characteristics of patients with Churg–Strauss syndrome (CSS), including symptoms, blood chemistry and immunological findings. Patients and methods: We retrospectively investigated the records of 11 patients (six female and five male) with CSS admitted to our hospital from September 2003 to October 2009. Results: Eight patients had preceding symptoms including bronchial asthma and allergic rhinitis. Seven patients showed eosinophilia. Nine patients had mononeuritis multiplex. Positive findings of myeloperoxidase‐antineutrophil cytoplasmic antibody (MPO‐ANCA) were found in five patients. Neither clinical manifestations nor laboratory findings were correlated with positivity for MPO‐ANCA. However, the MPO‐ANCA‐positive group showed a higher level of blood urea nitrogen and proteinuria than those negative for MPO‐ANCA. Ten patients recovered after starting steroid or immunosuppressive therapy, although one patient died of unknown etiology. Conclusion: Although general assessments based on various factors such as medical history, clinical manifestation and laboratory studies are indispensable in CSS, MPO‐ANCA might be useful as a predictor of renal dysfunction in patients with CSS.