Proteomic associations with forced expiratory volume - a Mendelian randomisation study.

A decline in forced expiratory volume (FEV1) is a hallmark of obstructive respiratory diseases, an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. Data from the general population-based AGES-Reykjavik study were used. Proteomic measurements were done using 4,782 DNA aptamers (SOMAmers). Data from 1,648 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5,368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). In observational analyses, 473 SOMAmers were associated with FEV1 after multiple testing adjustment. The most significant were R-Spondin 4, Alkaline Phosphatase, Placental Like 2 and Retinoic Acid Receptor Responder 2. Of the 235 SOMAmers with genetic data, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta and Apolipoprotein M. THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments. In summary, this large scale proteogenomic analyses of FEV1 reveals protein markers of FEV1, as well as several proteins with potential causality to lung function.

Rebamipide attenuates pain severity and cartilage degeneration in a rat model of osteoarthritis by downregulating oxidative damage and catabolic activity in chondrocytes.

OBJECTIVE: The objectives were to investigate the in vivo effects of treatment with rebamipide on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA) and to explore its mode of action. MATERIALS AND METHODS: OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA). Oral administration of rebamipide was initiated on the day of MIA injection, 3 or 7 days after. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. We analyzed the samples macroscopically and histomorphologically, and used immunohistochemistry to investigate the expression of matrix metalloproteinase-13 (MMP-13), interleukin-1ß (IL-1ß), hypoxia-inducible factor-2α (HIF-2α), inducible nitric oxide synthase (iNOS), and nitrotyrosine in knee joints. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify the mRNA for catabolic and anticatabolic factors in human OA chondrocytes. RESULTS: Rebamipide showed an antinociceptive property and attenuated cartilage degeneration. Rebamipide reduced the expression of MMP-13, IL-1ß, HIF-2α, iNOS, and nitrotyrosine in OA cartilage in a dose-dependent manner. Nitrotyrosine expression in the subchondral bone region was decreased in the rebamipide-treated joints. mRNA expression of MMP-1, -3, and -13, and ADAMTS5 was attenuated in IL-1ß-stimulated human OA chondrocytes. By contrast, rebamipide induced the mRNA expression of tissue inhibitor of metalloproteinase-1 and -3. CONCLUSION: The results show the inhibitory effects of rebamipide on pain production and cartilage degeneration in experimentally induced OA. The suppression of oxidative damage and the restoration of extracellular matrix homeostasis of articular chondrocyte suggest that rebamipide is a potential therapeutic strategy for OA.

Author Correction: 3D-printed vascular networks direct therapeutic angiogenesis in ischaemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Successful Heart-Lung Transplant for a Patient on Continuous-Flow Left Ventricular Assist Device Support Complicated With Amiodarone-Induced Pulmonary Fibrosis.

In this case report, we present a successful case of en bloc heart-lung transplant in a patient with advanced cardiopulmonary respiratory failure from amiodarone-associated pulmonary fibrosis that occurred post-left ventricular assist device implantation.

Successful Outcome Following Orthotopic Heart Transplantation With a Donor Half Way Across The Country.

Orthotopic heart transplantation is the criterion standard treatment for end-stage heart failure and the number of recipient candidates has been increasing. Despite this increasing demand, there is limited donor organ supply. In order to surmount this challenge, we propose harvesting donor hearts from more distant locations and accepting longer cold ischemic times. The usual accepted total ischemic time limit for the transplanted human heart is up to 4 hours. Here, we report the successful use of a donor heart from 1268 miles away with a total allograft ischemic time greater than 6 hours.

Preoperative clinical features of reactivated of Graves' orbitopathy after orbital decompression.

PurposeTo investigate the incidence and preoperative clinical features of reactivated Graves' orbitopathy (GO) after orbital decompression.MethodsThis study included patients with GO who underwent orbital decompression for disfiguring proptosis and not compressive optic neuropathy and received postoperative follow-up care for more than 12 months. Patients who experienced active inflammatory signs within 6 months of decompression were excluded from analysis. The demographic characteristics, ophthalmic manifestations, and biochemical parameters of the patients were analyzed for association with reactivation of GO by logistic regression analysis.ResultsOut of the 92 patients included in this study, seven (7.6%) experienced reactivation of GO after orbital decompression. The mean time interval between surgery and reactivation of GO was 36.3±14.3 weeks. Univariate logistic regression analysis identified age, existing smoking habits, and modified NOSPECS and Gorman scores as significant factors for the reactivation of GO. The results of multivariate logistic regression analysis revealed that smoking and modified NOSPECS and Gorman scores were associated with the reactivation of GO.ConclusionsQuitting smoking is important for the prevention of reactivation of GO after orbital decompression. Patients with severe symptoms, especially those with restrictive myopathy, should be carefully monitored for reactivation of GO after orbital decompression.

3D-printed vascular networks direct therapeutic angiogenesis in ischaemia.

Arterial bypass grafts remain the gold standard for the treatment of end-stage ischaemic disease. Yet patients unable to tolerate the cardiovascular stress of arterial surgery or those with unreconstructable disease would benefit from grafts that are able to induce therapeutic angiogenesis. Here, we introduce an approach whereby implantation of 3D-printed grafts containing endothelial-cell-lined lumens induces spontaneous, geometrically guided generation of collateral circulation in ischaemic settings. In rodent models of hind-limb ischaemia and myocardial infarction, we demonstrate that the vascular patches rescue perfusion of distal tissues, preventing capillary loss, muscle atrophy and loss of function. Inhibiting anastomoses between the construct and the host's local capillary beds, or implanting constructs with unpatterned endothelial cells, abrogates reperfusion. Our 3D-printed grafts constitute an efficient and scalable approach to engineer vascular patches able to guide rapid therapeutic angiogenesis and perfusion for the treatment of ischaemic diseases.

Creatine phosphate administration preserves myocardial function in a model of off-pump coronary revascularization.

AIM: Off pump coronary artery bypass grafting (OPCAB) involves, and is occasionally impaired by obligatory regional myocardial ischemia, particularly with the use of proximal coronary in-flow occlusion techniques. Intracoronary shunts do not guarantee absence of distal ischemia given their small inner diameter and the presence of proximal coronary stenosis. Additional adjunctive measures to provide short-term myocardial protection may facilitate OPCAB. High-energy phosphate supplementation with creatine phosphate prior to ischemia may attenuate ischemic dysfunction. METHODS: In a rodent model of a transient coronary occlusion and myocardial ischemia, 36 animals underwent preischemic intravenous infusion of either creatine phosphate or saline, 10 minutes of proximal left anterior descending (LAD) occlusion, and 10 minutes of reperfusion. Rats underwent continuous intracavitary pressure monitoring and cellular ATP levels were quantified using a luciferin/luciferase bioluminescence assay. RESULTS: Within 2 minutes of ischemia onset, creatine phosphate animals exhibited statistically significant greater preservation of myocardial function compared to controls, an augmentation which persisted throughout the duration of ischemia and subsequent reperfusion. Furthermore, significantly greater cellular ATP levels were observed among creatine phosphate treated animals (344+/-55 nMol/g tissue, n=5) compared to control animals (160+/-9 nMol/g tissue, n=5)(p=0.014). CONCLUSIONS: A strategy of intravenous high-energy phosphate administration successfully prevented ischemic ventricular dysfunction in a rodent model of OPCAB.

Pathogenic significance of neuronal migration disorders in temporal lobe epilepsy.

To assess the epileptogenic lesions, a series of 202 cases with temporal lobectomy were analyzed histopathologically. The severity of hippocampal neuronal loss in patients with temporal lobe epilepsy was quantitatively analyzed and compared against autopsy controls of patients who died of nonneurologic disorders. For the histopathologic diagnosis of neuronal migration disorder (NMD), immunohistochemical stains for neurofilament protein (NF-M/H) and microtubule-associated protein 2 (MAP2) and Bielschowsky silver stains were routinely performed. Histopathology of NMD was classified by the 4-grade system. MAP2 immunoreactivity was useful in the identification of loss of normal polarization of dendrites in the abnormal neurons. NF-M/H immunohistochemistry and silver stains effectively labeled microscopic or occult lesions of NMD (grade II and III). Ammon hom sclerosis (AHS) was identified in 73.3% and NMD in 57.9%. There was more than 50% neuronal cell loss in 82.8% of AHS, and variable degrees of cell loss were observed in the dual-pathology groups. The frequency of dual pathology (both AHS and NMD) was 65.0% and showed relatively equal distributions in grades I, II, III, whereas the pure NMD group were classified predominantly as grades II and III. NMD might be a basic pathogenic substrate causing temporal lobe epilepsy. The dual pathology may indicate the presence of epileptogenic lesions in the neocortical and temporolimbic areas.

Retrograde cerebral and distal aortic perfusion during ascending and thoracoabdominal aortic operations.

BACKGROUND: Several alternative circulatory management techniques during thoracic aortic reconstruction have been implemented at this institution. This study was performed to assess whether retrograde cerebral perfusion during proximal aortic operations and distal aortic perfusion during thoracoabdominal aortic operations have improved outcomes. METHODS: A retrospective review of 156 patients undergoing elective and emergent operations of the thoracic aorta over the past 7 years was performed. Seventy-five patients underwent proximal aortic procedures: 22 with ascending aneurysms, 45 with type A dissections, and 8 with arch reconstructions. Eighty-one patients underwent descending thoracic or thoracoabdominal procedures: 26 with Crawford type I aneurysms, 18 with type II, 8 with type III, 8 with type IV, 11 with traumatic transections, and 10 with type B dissections. Outcomes measured were neurologic injury, renal failure, and mortality. RESULTS: For proximal aortic procedures, the stroke rate was 12% using cardiopulmonary bypass and 48% using hypothermic circulatory arrest. The addition of retrograde cerebral perfusion decreased the stroke rate to 0% (p < 0.01) and the mortality rate to 7.1% compared with 37% for hypothermic circulatory arrest (p < 0.05). For thoracic and thoracoabdominal aortic operations, straight cross-clamping resulted in a 27% rate of spinal cord injury and a 24% rate of renal failure, whereas the addition of distal aortic bypass resulted in a statistically significant reduction (p < 0.01) in neurologic injury to 7% and a notable, but not statistically significant, decrease in renal failure to 13%. Distal aortic bypass also reduced the mortality rate from 22% to 7% (p < 0.05). CONCLUSIONS: Retrograde cerebral perfusion decreases the stroke rate and mortality rate in proximal aortic operations and distal aortic perfusion decreases the rates of neurologic injury, renal failure, and mortality in thoracoabdominal aortic operations.

Weighted centroid neural network for edge preserving image compression.

An edge preserving image compression algorithm based on an unsupervised competitive neural network is proposed. The proposed neural network, the called weighted centroid neural network (WCNN), utilizes the characteristics of image blocks from edge areas. The mean/residual vector quantization (M/RVQ) scheme is utilized in this proposed approach as the framework of the proposed algorithm. The edge strength of image block data is utilized as a tool to allocate the proper code vectors in the proposed WCNN. The WCNN successfully allocates more code vectors to the image block data from edge area while it allocates less code vectors to the image black data from shade or non-edge area when compared to conventional neural networks based on VQ algorithm. As a result, a simple application of WCNN to an image compression problem gives improved edge characteristics in reconstructed images over conventional neural network based on VQ algorithms such as self-organizing map (SOM) and adaptive SOM.

[Magnetic resonance imaging of skeletal muscle in patients with Duchenne muscular dystrophy--serial axial and sagittal section studies].

Magnetic resonance imaging of skeletal muscles in thirteen patients with Duchenne muscular dystrophy was performed to estimate pathological changes. Serial axial and sagittal sections of the right lower extremity were recorded. In the early stage, the T1 values of gastrocnemius and soleus muscles were slightly lower than the control values, and in the late stage, the values were much lower in all muscles examined. In sagittal sections, the gastrocnemius muscles in the early stage showed a high density area at the distal region adjacent to soleus muscle, and the soleus muscle showed a high density area adjacent to the gestrocnemius muscle. In serial axial sections, high density areas of the anterior and posterior tibialis muscles appeared first at their proximal and peripheral regions. It was concluded that the sequence of appearance of pathological changes was different not only among individual muscles but also among various regions of each muscle; the high density changes appeared first at myotendon junctions.

Comparison of Coapsys annuloplasty and internal reduction mitral annuloplasty in the randomized treatment of functional ischemic mitral regurgitation: impact on the left ventricle.

BACKGROUND: Functional mitral regurgitation is associated with both annular and ventricular distortion. Aggressive reduction annuloplasty for functional mitral regurgitation acts primarily at the annulus, with variable impact on the left ventricle. The Coapsys device externally reshapes the left ventricle to correct functional mitral regurgitation. Left ventricular reshaping was analyzed in a randomized study. METHODS: The RESTOR-MV study randomizes patients with coronary artery disease and functional mitral regurgitation to either reduction annuloplasty and coronary artery bypass grafting (the RA group) or Coapsys annuloplasty and bypass grafting (the CO group). The Coapsys device consists of epicardial pads connected by a cord. It was placed without cardiopulmonary bypass under echocardiographic guidance and sized to reduce annular dimension and improve leaflet coaptation. Internal reduction annuloplasty was performed by device placement. Intraoperative transesophageal echocardiograms were analyzed in 7 patients having reduction annuloplasty and 7 having Coapsys annuloplasty. RESULTS: Baseline mitral regurgitation (0-4 scale) was similar for the RA (3.0 +/- 0.6) and the CO groups (3.0 +/- 0.6). Intraoperative mitral regurgitation was reduced from 2.86 +/- 0.7 to 0.5 +/- 0.7 (P < .01 pre vs post) for the RA group and from 2.64 +/- 0.9 to 05 +/- 0.7 (P < .01 pre vs post) for the CO group. Annular anteroposterior diameter was reduced with both techniques: RA, 3.45 +/- 0.39 to 2.34 +/- 0.37 cm (P < .01 pre vs post); CO, 3.40 +/- 0.27 to 2.85 +/- 0.34 cm (P < .05 pre vs post). Long-axis dimensions were unchanged with both techniques. Short-axis dimensions measured at three levels were significantly reduced only in the CO patients: basal diameter 4.77 +/- 0.58 to 3.58 +/- 0.38 cm (P < .01 pre vs post); mid diameter 4.88 +/- 0.55 to 3.57 +/- 0.43 cm (P < .01 pre vs post); and apical diameter 4.39 +/- 0.46 to 3.38 +/- 0.34 cm (P < .01 pre vs post). CONCLUSIONS: Coapsys and reduction annuloplasty techniques both acutely reduce functional mitral regurgitation and annular dimension. The Coapsys device provided significantly greater left ventricular reshaping than did reduction annuloplasty. Further evaluation will assess the long-term valvular function and ventricular geometric stability associated with both techniques.

In situ hybridization study on human papillomavirus DNA expression in benign and malignant squamous lesions of the esophagus.

Histologic changes suggesting HPV infection are occasionally found adjacent to squamous cell carcinoma or in squamous papilloma of the esophagus, but the relationship between HPV infection and benign and malignant squamous lesions of the esophagus is not yet dear. The aim of this study was to examine the role of HPV in squamous lesions of the esophagus. Microscopic examination with emphasis on HPV infection was done on 15 cases of squamous cell carcinoma and 26 cases of squamous papilloma. In situ hybridization technique for wide-spectrum HPV probe was performed on 35 endoscopically biopsied esophageal tissues. Among the histologic parameters suggesting HPV infection, acanthosis was the most frequent finding: 100.0% in benign and malignant esophageal lesions, and koilocytosis and intraepithelial capillary loops were the second (92.7%).: Dyskeratosis, basal cell hyperplasia and bi- or multinucleation were 52.3%, 44.0% and 34.1% in frequency, respectively. On in situ hybridization study, the HPV DNA expression rates of 10 squamous cell carcinomas with evidence of HPV infection and 15 carcinomas without evidence of HPV infection were 60.0% and 33.3%, respectively. In contrast to the carcinoma cases, only one (10.0%) of 10 squamous papillomas revealed positive signal. In conclusion, HPV infection is strongly associated with squamous cell carcinoma, but the causal relation of HPV to squamous papilloma is inconspicous.

[A photoelastic study of the stress distribution in the surrounding tissues of the abutments of a fixed partial denture with tilted molar abutments].

The purpose of this study was to evaluate the stress distributions to the abutments of a fixed partial denture with tilted molar abutments. In cases of the lower 1st molar being missing four 2-dimensional photoelastic models with 3- unit fixed partial dentures of which the 2nd molars were tilted 0 degrees, 10 degrees, 20 degrees and 30 degrees toward the 2nd premolar were made. A vertical load of 50 lbs was applied to the 1st and 2nd molar in each case. Two-dimensional photoelastic stress analysis was used, and the stress areas were recorded photographically. The results were as follows; 1. When the vertical load was applied to pontic and 2nd molar on the central fossae, the magnitude of stress distribution of the surrounding tissues of the root of the 2nd premolar was increased incrementally with increasing inclination. 2. Under two loading conditions, the stress distributions were directed to the long axis of the abutments. 3. In this experiment, no stress distributions were observed on the mesial area of the mesial root of the second molar.

Calcium/calmodulin kinase II activity of hippocampus in kainate-induced epilepsy.

This study investigated calcium/calmodulin kinase II (CaMKII) activity related to long-standing neuronal injury of the hippocampus in kainate (KA)-induced experimental temporal lobe epilepsy. Epileptic seizure was induced by injection of KA (1 microg/microL) dissolved in phosphate buffer (0.1 M, pH 7.4) into the left amygdala. Clinical seizures, histopathologic changes and CaMKII activity of the hippocampus were evaluated. Characteristic early limbic and late seizures were developed. Hippocampal CaMKII activity increased significantly 4 and 8 weeks after intra-amygdaloid injection of KA, when late seizures developed. The histopathologic changes of the hippocampus included swelling of neuronal cytoplasm with nuclear pyknosis and loss of neurons in CA3 during this period. The increased activity of CaMKII may correlate with appearance of distant damage in the hippocampus. The above results indicate that intra-amygdaloid injection of KA produces excitatory signals for ipsilateral CA3 neurons in the hippocampus and that subsequently increased levels of CaMKII in postsynaptic neurons induce neuronal injury via phosphorylation of N-methyl-D-aspartate type glutamate receptor.

Circulatory management with retrograde cerebral perfusion for acute type A aortic dissection.

BACKGROUND: Cerebral circulation during urgent repair of acute type A aortic dissection has traditionally been managed with cardiopulmonary bypass and aortic cross clamping proximal to the innominate artery or by the use of hypothermic circulatory arrest (HCA). The more recently introduced retrograde cerebral perfusion (RCP) may confer additional cerebral protection during elective aortic arch reconstruction. The purpose of this study was to demonstrate the efficacy of RCP in the urgent repair of acute type A aortic dissection. METHODS AND RESULTS: We evaluated 60 consecutive patients who underwent repair of acute type A aortic dissection over a 6-year period. Patients were grouped according to intraoperative circulatory management strategies. Group 1 consisted of 41 patients operated on early in the series who were managed by cardiopulmonary bypass and standard aortic cross clamping (n = 21) with conversion to HCA (n = 20) if the intimal tear extended into the aortic arch. Since 1993, 19 patients, who make up group 2, were managed with routine open distal anastomosis and HCA with RCP. Data were analyzed for clinically evident, radiographically confirmed cerebrovascular accidents and 60-day mortality and evaluated by chi 2 analysis. Stroke and mortality rates of patients managed with either cardiopulmonary bypass or HCA were 26.3% and 29.3%, respectively. Patients undergoing RCP experienced statistically significant reductions in rates of confirmed cerebrovascular accidents (0%, P = .015) and mortality (5.3%, P = .04). CONCLUSIONS: We conclude that the introduction of circulatory management using RCP with HCA during urgent operative repair of acute type A aortic dissection has significantly improved both stroke and mortality rates.

Efficient transmural cardiac gene transfer by intrapericardial injection in neonatal mice.

An efficient cardiac gene transfer technique in murine models would greatly facilitate the elucidation of the pathophysiology of cardiomyopathies and the development of genetic therapies. Direct myocardial injection or catheter-based intracoronary infusion is not easily achievable in mice and resultant transgene expression is often limited in distribution. A replication-defective, recombinant adenovirus encoding luciferase (5x10(9)pfu) or lacZ (4-5x10(10)particles/animal) was injected percutaneously into the pericardial cavity of 4-5 day old mice. Chemiluminescence assay for luciferase activity at 3 days post-injection revealed the highest activity in the heart (heart=288+/-110, lungs=19+/-5, liver=11+/-5 ng/gm tissue, n=11). X-gal staining of cryostat sections demonstrated widespread transmural lacZ expression in the left ventricle, interventricular septum, right ventricle, and atrial appendages, and the average fractional area of X-gal staining in a left ventricle was 66+/-16% (range 40-92%, n=21 sections). However, the long-term survival of these mice was compromised. Reduction in the injectate volume by 50% significantly improved survival but concurrently reduced lacZ expression. Significant lacZ expression was observed in the right ventricle and interventricular septum but left ventricular expression was predominantly epicardial, with variable myocardial penetration. At 2 months post-injection, lacZ expression persisted only in atrial tissues, pulmonary veins, and great vessels. Despite lack of persistent transgene expression in ventricular tissues, the high degree of transgene expression achieved may be sufficient to allow evaluation of short-term effects of specific genetic manipulations in the heart.