Construction of endophenotypes for complex diseases in the presence of heterogeneity

Endophenotypes such as behavior disorders have been increasingly adopted in genetic studies for complex traits. For efficient gene mapping, it is essential that an endophenotype is associated with the disease of interest and is inheritable or co-segregating within families. In this study, we proposed a strategy to construct endophenotypes to analyze the Genetic Analysis Workshop 14 simulated dataset. Initially, generalized estimating equation models were employed to identify phenotypes that were correlated to the disease (affected status) in combination with the family structures in data. Endophenotypes were then constructed with consideration of heterogeneity as functions of the identified phenotypes. Genome scans on the constructed endophenotypes were carried out using family-based association analysis. For comparison, genome scans were also performed with the original affected status. The family-based association analysis using the endophenotypes correctly identified the same susceptible gene in about 80 of the 100 replicates

Large aortic aneurysm mimicking a cardiac tumor

<p>Abstract</p> <p>Introduction</p> <p>Extrinsic left atrial compression caused by a displaced, crooked descending thoracic aorta is rare. This anomaly may mimic primary cardiac tumors or metastatic neoplasms from the first look.</p> <p>Case presentation</p> <p>We reported a 78-year-old woman presented to our emergency room with back pain, increased exercise intolerance and intermittent angina. She also had one syncopal event 1 month ago and gastric cancer post gastrectomy history. Subsequent chest plain film showed no mediastinum widening.</p> <p>Two-dimensional echocardiography was performed and revealed a heterogeneous mass as large as 2.3 × 2.4 cm occupying the left atrium (LA). Three-dimensional echocardiography vividly demonstrated that LA was constrained between the aortic valve (AV) and a luminal structure with pulsatile character suggestive of the aorta.</p> <p>Conclusions</p> <p>We successfully demonstrated the detailed structure and location of an anomalous descending aorta on the oblique imaging plane of RT-3DE, which may not be readily available by traditional 2D method.</p

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Abscess formation of a spherical-shape duplication in the splenic flexure of the colon: case report and review of the literature

Gastrointestinal tract duplications are rare congenital malformations that may occur anywhere in the alimentary tract from the mouth to the anus, and vary greatly in presentation, size, location, and especially in symptoms. We present a case of an infected spherical colonic duplication, in a 20-day-old baby, located at the splenic flexure of the colon. The prominent symptom was acute abdomen, accompanied by bilious vomiting, intestinal obstruction, and high fever. We present this case, due to atypical clinical presentation and the inability of the imaging modality to establish the diagnosis preoperatively

Polycythemia vera as a presentation of renal angiomyolipoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Angiomyolipoma is a common benign renal tumor composed of thick-walled blood vessels, smooth muscle, and adipose tissue. It may be found incidentally during workup for suspected renal disease. Although angiomyolipoma may present as a palpable, tender renal mass with flank pain and gross or microscopic hematuria, many patients are asymptomatic. Erythrocytosis is an unusual presentation, and malignant transformation may be suspected. This report describes a rare case of a woman diagnosed with renal angiomyolipoma and polycythemia vera. The report discusses the differential diagnosis using erythropoietin, erythropoietin-receptor and Janus kinase 2.</p> <p>Case presentation</p> <p>A 79-year-old Chinese woman was diagnosed with erythrocytosis according to World Health Organization criteria. An upper left renal pole angiomyolipoma was successfully ablated after multiple phlebotomy treatments. Red cell count immediately returned to normal, but gradually increased after 4 months. Polycythemia vera was finally diagnosed by positive mutation of Janus kinase 2 and negative erythropoietin protein expression. Her clinical symptoms improved with regular phlebotomy and hydroxyurea treatment.</p> <p>Conclusion</p> <p>Concurrent occurence of angiomyolipoma and polycythemia vera is rare. Polycythemia vera can be easily missed. Polycythemia vera can be confirmed with high specificity and sensitivity by the acquired somatic mutation. Surgical intervention for this renal tumor should be avoided unless malignancy or renal cell carcinoma is suspected or to prevent spontaneous rupture of larger tumors.</p

An outcome analysis of self-expandable metallic stents in central airway obstruction: a cohort study

<p>Abstract</p> <p>Background</p> <p>Self-expandable metallic stents (SEMSs) have provided satisfactory management of central airway obstruction. However, the long-term benefits and complications of this management modality in patients with benign and malignant obstructing lesions after SEMS placement are unclear. We performed this cohort study to analyze the outcomes of Ultraflex SEMSs in patients with tracheobronchial diseases.</p> <p>Methods</p> <p>Of 149 patients, 72 with benign and 77 with malignant tracheobronchial disease received 211 SEMSs (benign, 116; malignant, 95) and were retrospectively reviewed in a tertiary hospital.</p> <p>Results</p> <p>The baseline characteristics of patients who received SEMS implantation for benign conditions and those who underwent implantation for malignant conditions were significantly different. These characteristics included age (mean, 63.9 vs. 58; <it>p </it>< 0.01), gender (male, 62% vs. 90%; <it>p </it>< 0.0001), smoking (47% vs. 85%; <it>p </it>< 0.0001), forced expiratory volume in 1 second (mean, 0.9 vs. 1.47 L/s; <it>p </it>< 0.0001), follow-up days after SEMS implantation (median; 429 vs. 57; <it>p </it>< 0.0001), and use of covered SEMS (36.2% vs. 94.7%; <it>p </it>< 0.0001). Symptoms improved more after SEMS implantation in patients with benign conditions than in those with malignant conditions (76.7% vs. 51.6%; <it>p </it>< 0.0001). The overall complication rate after SEMS implantation in patients with benign conditions was higher than that in patients with malignancy (42.2% vs. 21.1%; <it>p </it>= 0.001). Successful management of SEMS migration, granulation tissue formation, and SEMS fracture occurred in 100%, 81.25%, and 85% of patients, respectively.</p> <p>Conclusions</p> <p>Patients who received SEMS implantation owing to benign conditions had worse lung function and were older than those who received SEMS for malignancies. There was higher complication rate in patients with benign conditions after a longer follow-up period owing to the nature of the underlying diseases.</p

Caffeic Acid Phenethyl Ester Causes p21Cip1 Induction, Akt Signaling Reduction, and Growth Inhibition in PC-3 Human Prostate Cancer Cells

Caffeic acid phenethyl ester (CAPE) treatment suppressed proliferation, colony formation, and cell cycle progression in PC-3 human prostate cancer cells. CAPE decreased protein expression of cyclin D1, cyclin E, SKP2, c-Myc, Akt1, Akt2, Akt3, total Akt, mTOR, Bcl-2, Rb, as well as phosphorylation of Rb, ERK1/2, Akt, mTOR, GSK3α, GSK3β, PDK1; but increased protein expression of KLF6 and p21Cip1. Microarray analysis indicated that pathways involved in cellular movement, cell death, proliferation, and cell cycle were affected by CAPE. Co-treatment of CAPE with chemotherapeutic drugs vinblastine, paclitaxol, and estramustine indicated synergistic suppression effect. CAPE administration may serve as a potential adjuvant therapy for prostate cancer

Do Neutrophils Play a Role in Establishing Liver Abscesses and Distant Metastases Caused by Klebsiella pneumoniae?

Serotype K1 Klebsiella pneumoniae is a major cause of liver abscesses and endophthalmitis. This study was designed to identify the role of neutrophils in the development of distant metastatic complications that were caused by serotype K1 K. pneumoniae. An in vitro cellular model was used to assess serum resistance and neutrophil-mediated killing. BALB/c mice were injected with neutrophils containing phagocytosed K. pneumoniae. Serotype K1 K. pneumoniae was significantly more resistant to serum killing, neutrophil-mediated phagocytosis and intra-cellular killing than non-K1 isolates (p<0.01). Electron microscopic examination had similar findings as in the bioassay findings. Intraperitoneal injection of neutrophils containing phagocytosed serotype K1 K. pneumoniae led to abscess formation in multiple sites including the subcutaneous tissue, lung, and liver, whereas no abscess formation was observed in mice injected with non-K1 isolates. The resistance of serotype K1 K. pneumoniae to complement- and neutrophil-mediated intracellular killing results in the dissemination of K. pneumoniae via the bloodstream. Escape from neutrophil intracellular killing may contribute to the dissemination and establishment of distant metastases. Thus, neutrophils play a role as a vehicle for helping K. pneumoniae and contributing to the establishment of liver abscess and distant metastatic complications

Temperature effects on an InGaP (GaInP) (55)Fe X-ray photovoltaic cell.

This paper investigates the effects of temperature on an InGaP (GaInP) (55)Fe X-ray photovoltaic cell prototype for a radioisotope microbattery (also called a nuclear microbattery). An In0.5Ga0.5P p-i-n (5 μm i-layer) mesa photodiode was illuminated by a standard 206 MBq (55)Fe radioisotope X-ray source and characterised over the temperature range -20 °C to 100 °C. The electrical power output of the device reached its maximum value of 1.5 pW at a temperature of -20 °C. An open circuit voltage and a short circuit current of 0.82 V and 2.5 pA, respectively, were obtained at -20 °C. While the electrical power output and the open circuit voltage decreased with increasing temperature, an almost flat trend was found for the short circuit current. The cell conversion efficiency decreased from 2.1% at -20 °C to 0.7% at 100 °C

S100A6 (Calcyclin) is a prostate basal cell marker absent in prostate cancer and its precursors

S100A6 (Calcyclin) is a calcium-binding protein that has been implicated in a variety of biological functions as well as tumorigenesis. The aim of our study was to investigate the involvement of S100A6 during prostate cancer development and progression. Using immunohistochemistry, the expression of S100A6 was examined in benign (n ¼ 66), premalignant (n ¼ 10), malignant (n ¼ 66) and metastatic prostate (n ¼ 5) tissues arranged in a tissue-microarray or whole sections as well as in prostate cancer cell lines. The S100A6 immunostaining pattern in tissues was compared with that of cytokeratin 5 (a basal cell marker) and 18 (a benign luminal cell marker). In all cases of benign epithelium, intense S100A6 expression was seen in the basal cell layer with absent staining in luminal cells. In all cases of prostatic adenocarcinoma (matched), metastatic lesions and 3/10 high-grade prostatic intraepithelial neoplasia lesions, an absence of S100A6 was seen. Western blotting and RT–PCR analysis of cell lines showed S100A6 expression to be absent in LNCaP, LNCaP-LN3 and LNCaP-Pro5 but present in Du145, PC3, PC-3M and PC-3M-LN4. LNCaP cells treated with 5- Azacytidine, caused re-expression of S100A6 mRNA. Sequencing of bisulphite modified DNA showed CpG methylation within the S100A6 promoter region and exon 1 of LNCaP, LNCaP-LN3 and LNCaP-Pro5 cell lines but not in Du145 cells. Our data suggest that loss of S100A6 protein expression is common in prostate cancer development and may occur at an early stage. The mechanism of loss of expression may involve hypermethylation of CpG sites. The finding of intense S100A6 expression in the basal cells of benign glands but loss of expression in cancer could be useful as a novel diagnostic marker for prostate cancer