Genetic ablation of the preptin-coding portion of Igf2 impairs pancreatic function in female mice.

Preptin is a 34-amino acid peptide derived from the E-peptide of pro-insulin-like growth factor 2 and is co-secreted with insulin from ß-cells. Little is understood about the effects of endogenous preptin on whole body glucose metabolism. We developed a novel mouse model in which the preptin portion of Igf2 was genetically ablated in all tissues, hereafter referred to as preptin knockout (KO), and tested the hypothesis that the removal of preptin will lead to a decreased insulin response to a metabolic challenge. Preptin KO and wild-type (WT) mice underwent weekly fasting blood glucose measurements, intraperitoneal insulin tolerance tests (ITT) at 9, 29, and 44 wk of age, and an oral glucose tolerance test (GTT) at 45 wk of age. Preptin KO mice of both sexes had similar Igf2 exon 2-3 mRNA expression in the liver and kidney compared with WT mice, but Igf2 exon 3-4 (preptin) expression was not detectable. Western blot analysis of neonatal serum indicated that processing of pro-IGF2 translated from the KO allele may be altered. Preptin KO mice had similar body weight, body composition, ß-cell area, and fasted glucose concentrations compared with WT mice in both sexes up to 47 wk of age. Female KO mice had a diminished ability to mount an insulin response following glucose stimulation in vivo. This effect was absent in male KO mice. Although preptin is not essential for glucose homeostasis, when combined with previous in vitro and ex vivo findings, these data show that preptin positively impacts ß-cell function.NEW & NOTEWORTHY This is the first study to describe a model in which the preptin-coding portion of the Igf2 gene has been genetically ablated in mice. The mice do not show reduced size at birth associated with Igf2 knockout suggesting that IGF2 functionality is maintained, yet we demonstrate a change in the processing of mature Igf2. Female knockout mice have diminished glucose-stimulated insulin secretion, whereas the insulin response in males is not different to wild type.

Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression.

Tumor cells often produce high levels of reactive oxygen species (ROS) and display an increased ROS scavenging system. However, the molecular mechanism that balances antioxidative and oxidative stress in cancer cells is unclear. Here, we determined that oncogenic multiple copies in T-cell malignancy 1 (MCT-1) activity promotes the generation of intracellular ROS and mitochondrial superoxide. Overexpression of MCT-1 suppresses p53 accumulation but elevates the manganese-dependent superoxide dismutase (MnSOD) level via the YY1-EGFR signaling cascade, which protects cells against oxidative damage. Conversely, restricting ROS generation and/or targeting YY1 in lung cancer cells effectively inhibits the EGFR-MnSOD signaling pathway and cell invasiveness induced by MCT-1. Significantly, MCT-1 overexpression in lung cancer cells promotes tumor progression, necrosis and angiogenesis, and increases the number of tumor-promoting M2 macrophages and cancer-associated fibroblasts in the microenvironment. Clinical evidence further confirms that high expression of MCT-1 is associated with an increase in YY1, EGFR and MnSOD expression, accompanied by tumor recurrence, poor overall survival and EGFR mutation status in patients with lung cancers. Together, these data indicate that the MCT-1 oncogenic pathway is implicated in oxidative metabolism and lung carcinogenesis.

Loss of labelling efficiency caused by carotid stent in pseudocontinuous arterial spin labelling perfusion study.

AIM: To elucidate the cause of cerebral hypoperfusion on the stent placement side after carotid artery stent placement (CAS) measured by pseudocontinuous arterial spin labelling (PCASL) perfusion imaging. MATERIALS AND METHODS: Consecutive patients with symptomatic internal carotid artery stenosis receiving CAS were included in the study. Cerebral blood flow (CBF) was measured by PCASL perfusion imaging at 3 T magnetic resonance imaging (MRI) the day before and 3 days after the procedure. Changes in cerebral haemodynamics after CAS were assessed. RESULTS: Twenty-two patients were included; 17 patients had increased or stationary CBF after CAS and five patients had significantly reduced CBF on the stenting side after CAS whereas CBF increased on the contralateral side. High stent position was noticed in the five patients. After labelling plane adjustment to avoid labelling on the stent, no more cerebral hypoperfusion was noticed. CONCLUSION: When using PCASL perfusion imaging to monitor post-stenting CBF, the stent may cause an artefact that leads to a low CBF in the territory of the stented vessel. Routinely adding a fast T2 star gradient-echo echo-planar-imaging covering the upper neck region before PCASL perfusion imaging to identify the stent position and avoid the stent-related artefact is recommended.

Long-term results of coronary artery bypass grafting in patients with dialysis-dependent renal failure.

AIM: Coronary artery disease is the main cause of mortality and morbidity in dialysis-dependent renal failure patients. Both the prevalence and incidence of renal failure are high in Taiwan. However, there were few reports exploring the outcome of coronary aortic bypass grafting (CABG) in these patients. The aim of this study was to determine the survival outcome and risk factors for mortality from CABG in this population. METHODS: The operative, early postoperative and late results of 170 dialysis patients undergoing isolated coronary artery bypass grafting from January, 2000 to January, 2012 were retrospectively reviewed. Operative mortality, long-term survival, and risk factors were analyzed. RESULTS: One hundred and seventeen patients (68.8%) were male, and the mean age was 61.5±10.3 years (range, 34-86 years). Follow-up was 40.3±32.1 months. Operative mortality was 8.2%. Actuarial survival, including operative mortality, was 81±3% at 1 year, 68±4% at 3 years, 58±5% at 5 years and 49±6% at 10 years, better than the natural course of dialysis-dependent renal failure patients. Age, emergent operation, postoperative ventricular tachycardia or fibrillation, postoperative intra-aortic balloon pump insertion, gastrointestinal bleeding, and left internal mammary artery graft were significant predictors of operative or long term mortality. Most causes of late death were due to infection or cardiac events. CONCLUSION: CABG in dialysis patients is associated with a higher incidence of complications, but has acceptable mortality. CABG is beneficial in this population. Internal mammary artery grafting may provide more favorable long term outcomes.

MCT-1 expression and PTEN deficiency synergistically promote neoplastic multinucleation through the Src/p190B signaling activation.

Multinucleation is associated with malignant neoplasms; however, the molecular mechanism underlying the nuclear abnormality remains unclear. Loss or mutation of PTEN promotes the development of malignant tumors. We now demonstrate that increased expression of the oncogene MCT-1 (multiple copies in T-cell malignancy 1) antagonizes PTEN gene presentation, PTEN protein stability and PTEN functional activity, thereby further promoting phosphoinositide 3 kinase/AKT signaling, survival rate and malignancies of the PTEN-deficient cells. In the PTEN-null cancer cells, MCT-1 interacts with p190B and Src in vivo, supporting that they are in proximity of the signaling complexes. MCT-1 overexpression and PTEN loss synergistically augments the Src/p190B signaling function that leads to inhibition of RhoA activity. Under such a condition, the incidence of mitotic catastrophes including spindle multipolarity and cytokinesis failure is enhanced, driving an Src/p190B/RhoA-dependent neoplastic multinucleation. Targeting MCT-1 by the short hairpin RNA markedly represses the Src/p190B function, improves nuclear structures and suppresses xenograft tumorigenicity of the PTEN-null breast cancer cells. Consistent with the oncogenic effects in vitro, clinical evidence has confirmed that MCT-1 gene stimulation is correlated with p190B gene promotion and PTEN gene suppression in human breast cancer. Accordingly, MCT-1 gene induction is recognized as a potential biomarker of breast tumor development. Abrogating MCT-1 function may be a promising stratagem for management of breast cancer involving Src hyperactivation and/or PTEN dysfunction.

Jahn-Teller effect in VCl4.

A theoretical study is made of the Jahn-Teller and other properties of vanadium tetrachloride. Relativistic effective core potentials and corresponding valence spin-orbit operators are used with Gaussian atomic orbitals to compute self-consistent-field and spin-orbit configuration-interaction wave functions. Energy-surface parameters, electronic excitation energies, vibronic energy levels, and g factors are computed. Electron correlation is shown to have a substantial effect on the Jahn-Teller properties. As have others, we find the Jahn-Teller effect in VCl4 to be of the dynamic form.

Clinical and microbiological characteristics of urine culture-confirmed genitourinary tuberculosis at medical centers in Taiwan from 1995 to 2007.

All patients with urine culture-confirmed genitourinary tuberculosis (GUTB) diagnosed between 1995 and 2007 at two medical centers in northern Taiwan were included in this retrospective study. Genotypes of 48 preserved Mycobacterium tuberculosis (MTB) isolates from these patients were determined by spoligotyping and double repetitive element PCR (DRE-PCR) analysis. Among the 64 patients, 38 (59.4%) were male with a mean ±SD age of 60.3 ± 16.1 years old. The overall mortality rate was 26.2%. Poor prognostic factors included age over 65 years (HR = 4.03; 95%; CI: 1.27-12.76), cardiovascular disease (HR = 5.96; 95% CI: 1.98-17.92), receiving steroids (HR = 10.16; 95% CI: 2.27-45.47), not being treated (HR 4.81; 95% CI 1.12-20.67). Spoligotyping and DRE-PCR of the 48 MTB isolates revealed that 20 (41.7%) belonged to the Beijing family and 40 (83.3%) had a clustering pattern. Identification of a Beijing family isolate was not correlated with drug resistance or mortality. Clustering strains were likely to be resistant to isoniazid (OR = 4.71; 95% CI: 1.10 to 23.53). In this study of patients with urine culture-confirmed GUTB, age and coexisting diseases were independently associated with an unfavorable outcome. The Beijing family was the dominant genotype of GUTB isolates, but did not correlate with drug resistance or outcome.

Mixed infection with Beijing and non-Beijing strains in pulmonary tuberculosis in Taiwan: prevalence, risk factors, and dominant strain.

Patients with pulmonary tuberculosis (TB) can be simultaneously infected with different strains of Mycobacterium tuberculosis (mixed infection). We investigated the prevalence and risk factors of mixed infection by Beijing and non-Beijing strains in pulmonary TB patients in Taiwan. We developed a quantitative PCR method to simultaneously detect the presence of Beijing and non-Beijing strains. A total of 868 pretreatment samples (from 868 patients), including 563 sputum samples smear-positive for acid-fast bacilli and 305 liquid medium samples culture-positive for mycobacteria, were tested. Medical records of patients with culture-confirmed pulmonary TB were reviewed. The detection limit of our quantitative PCR method was five copies of target sequences. With mycobacterial culture result as the reference standard, the sensitivity and specificity of our quantitative PCR method were 95% and 98%, respectively. M. tuberculosis strains were isolated in 466 samples, of which 231 (49.6%) were infected with a Beijing strain. Another 14 patients (3.0%) had mixed infection, with the Beijing strain being the dominant strain in 13 (93%). Age <25 years with pulmonary cavities was associated with mixed infection. In patients infected with non-Beijing strains, the bacterial load of non-Beijing strains was lower among those with mixed infection than among those without. Our quantitative PCR method was accurate in detecting Beijing and non-Beijing strains in smear-positive sputum and culture-positive liquid medium samples. Mixed infection was present in pulmonary TB patients (3.0%), especially in those aged <25 years with pulmonary cavities. Beijing strains seem to be more dominant than non-Beijing strains in patients with mixed infection.

Hospital-acquired pneumonia and bacteremia caused by Legionella pneumophila in an immunocompromised patient.

The Legionella species is an important cause of communityand hospital-acquired pneumonia. Bacteremic pneumonia caused by L. pneumophila is rarely reported. We describe the first reported case of hospital-acquired pneumonia and bacteremia caused by L. pneumophila from Taiwan in a patient with idiopathic thrombocytopenic purpura who received steroid treatment. The patient was successfully treated with ceftazidime and clindamycin initially, followed by ciprofloxacin for 14 days. The blood isolate was further confirmed by 16S rDNA sequence analysis.

Clinical and genotypic characteristics of extensively drug-resistant and multidrug-resistant tuberculosis.

The aims of this study were to compare the clinical features of patients with extensively drug-resistant tuberculosis (XDRTB) and multidrug-resistant tuberculosis (MDRTB) and the genotypic characteristics of these Mycobacterium tuberculosis isolates. A total of 90 non-HIV-infected patients having MDRTB (n = 80, not including XDRTB, 88.9%) and XDRTB (n = 10, 11.1%) were identified from 2000 to 2007. Genotypes of the 39 available isolates were evaluated by spoligotyping and the 24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) scheme. Patients with XDRTB were more likely to have previous history of TB and cavitary lung lesions than patients with MDRTB (P < 0.05). Among the 39 isolates for spoligotyping analysis, the Beijing genotype was the most common (n = 21, 53.8%). Four (44.4%) isolates of XDRTB and 17 (56.7%) isolates of MDRTB belonged to Beijing family genotypes. There was no significant difference in the anti-tuberculosis drug resistance rates between Beijing and non-Beijing genotype isolates or in the clinical features of infected patients. In conclusion, significant differences in clinical manifestations existed among patients with XDRTB and MDRTB. The clinical features of patients infected with the Beijing genotype and the drug resistance profile of the Beijing genotype isolates were similar to those for the non-Beijing family genotype.

Mycobacterial bacteraemia in patients infected and not infected with human immunodeficiency virus, Taiwan.

The clinical characteristics and outcomes of 71 patients with mycobacterial bacteraemia, infected with human immunodeficiency virus (HIV) (n = 47) and not infected with HIV (n = 24) are described. Mycobacterium avium complex (MAC) (54.9%) constituted the most frequently isolated mycobacterium, followed by Mycobacterium tuberculosis (MTB) (38.0%), Mycobacterium kansasii (4.2%), and Mycobacterium abscessus (2.8%). The Beijing family genotype was the most common type in MTB, and Mycobacterium intracellulare was the most common species in MAC. The overall mortality rate was 33.8%; it was lower in HIV-infected than in non-HIV-infected patients. HIV-infected patients were younger, had fewer underlying diseases and better nutritional status, and were more likely to have MAC bacteraemia than MTB bacteraemia.

Clinical and microbiological characteristics of Nocardiosis including those caused by emerging Nocardia species in Taiwan, 1998-2008.

The genus of Nocardia is rapidly expanding and the species distribution varies with different geographical locations. We retrospectively reviewed the laboratory records of the bacteriology laboratory at National Taiwan University Hospital from January 1998 to June 2008 to identify patients with nocardiosis. During the study period, 164 isolates of Nocardia spp. were identified from 134 patients but only 113 patients had Nocardia infection. Nocardia brasiliensis (n = 54) was the most common pathogen, followed by N. asteroides (n = 36), N. farcinica (n = 7), N. flavorosea (n = 4), N. otitidiscaviarum (n = 3), N. nova (n = 3), N. beijingensis (n = 2) and one each of N. puris, N. jinanensis and N. takedensis. The major types of infection were cutaneous infection (56.6%), pulmonary infection (33.6%) and disseminated infection (7.1%). Eighty-eight patients received sulfonamide-containing antibiotic and eight of 100 patients with available data on outcomes died during the episode of nocardiosis. In conclusion, the clinical and microbiological manifestations of Nocardiosis vary with the different Nocardia species. Accurate identification of the species is crucial to make the diagnosis.

Diagnostic performance of an enzyme-linked immunospot assay for interferon-gamma in extrapulmonary tuberculosis varies between different sites of disease.

OBJECTIVES: To evaluate diagnostic performance of an enzyme-linked immunospot assay for interferon-gamma (T SPOT-TB) in patients with suspected extrapulmonary tuberculosis (TB). METHODS: From January 2007 to December 2008, patients with suspected extrapulmonary TB were prospectively enrolled from 2 tertiary care hospitals. RESULTS: A total of 138 patients with suspected extrapulmonary TB were enrolled; 50 patients had positive culture for Mycobacterium tuberculosis and 39 patients had probable TB. The sites of infection were lymph node (n = 20), pleura (n = 19), bone/joint (n = 15), urinary tract (n = 7), peritoneum (n = 7), meninges (n = 6), disseminated (n = 5), intestine (n = 3), pericardium (n = 2), skin (n = 2), throat (n = 1), neck (n = 1), and genitalia (n = 1). The overall sensitivity and specificity were 79.8% (71/89) and 81.6% (40/49). The sensitivity ranged from 100% for tuberculous meningitis, tuberculous pericarditis, and intestinal TB, 95% for lymphadenitis, to 42.9% for tuberculous peritonitis. The sensitivity of the T SPOT-TB assay was 70.6% in immunocompromised patients and 85.5% in immunocompetent patients (p = 0.09). CONCLUSIONS: The T SPOT-TB assay can be a useful tool for diagnosing extra-pulmonary TB in immunocompetent and immunocompromised patients, particularly for tuberculous meningitis, pericarditis, lymphadenitis, and intestinal TB.

Rapid identification of the Mycobacterium tuberculosis complex by an enzyme-linked immunosorbent assay.

SETTING: A medical centre in Taipei, Taiwan. OBJECTIVE: To investigate the performance of an enzyme-linked immunosorbent assay (ELISA) using anti-early secreted antigenic target 6 and culture filtrate protein 10 antibodies (MeDiPro Mycobacterium tuberculosis Antigen ELISA) for the detection of M. tuberculosis in positive signals of Mycobacterium Growth Indicator Tubes (MGIT; BACTEC MGIT 960 system). DESIGN: A total of 208 consecutive clinical samples, including 185 respiratory specimens and 23 non-respiratory specimens, with positive signals in MGIT were analysed. The assay was performed on Days 1 and 7. The ELISA and conventional culture results were compared. RESULTS: Among the tubes with positive signals, 86 (41.3%) were M. tuberculosis, 55 (26.4%) were non-tuberculous mycobacteria and 67 (32.2%) were negative for mycobacteria. The sensitivity of the ELISA for tubes with positive signals (initial smear with positive acid-fast bacilli) on Days 1 and 7 was respectively 75.6% (70.5%) and 96.5% (97.7%), and the specificity was respectively 98.4% (100%) and 100% (100%). CONCLUSION: Our results show that the MeDiPro M.tuberculosis Antigen ELISA is a simple, rapid assay (<3 h) for M. tuberculosis antigen detection, especially on Day 7 of incubation with positive signals in the BACTEC MGIT 960 system.

Enzyme-linked immunospot assay for interferon-gamma in the diagnosis of tuberculous pleurisy.

Patients presenting with pleural effusion of undetermined aetiology were prospectively enrolled, and an enzyme-linked immunospot (ELISPOT) assay on pleural fluid and peripheral blood was performed. Forty patients were studied, including 19 with culture- or biopsy-confirmed (n = 15) or clinically compatible (n = 4) tuberculous pleurisy, and 21 with pleural effusions due to non-tuberculous causes. The sensitivity, specificity and positive and negative predictive values of the assay were 94.7%, 85.7%, 85.7% and 94.7%, respectively, on pleural fluid, and 77.8%, 90.5%, 87.5% and 82.6%, respectively, on blood. Antigen-specific, interferon-gamma-secreting T-cells were concentrated eight to ten times in pleural fluid as compared with blood. Among the seven patients not suitable for pleural biopsy and three patients whose biopsy results were non-diagnostic, nine had positive ELISPOT result with pleural fluid. The ELISPOT assay for interferon-gamma can accurately diagnose tuberculous pleurisy and is helpful for patients not suitable for pleural biopsy and those whose biopsy results are non-diagnostic.

Extensive cerebrospinal fluid enhancement following gadolinium chelate administration: possible pathogenesis.

Diffuse cerebrospinal fluid (CSF) enhancement following gadolinium administration is a rarely recognized phenomenon, and its mechanism is not fully understood. We report two cases of diffuse CSF enhancement following gadolinium administration and review the literature. We conclude that the contributing factors of this phenomenon include blood-CSF barrier disruption, increased dosage, impair renal clearance, delayed imaging after contrast administration, and use of different pulse sequences.

Primary intracranial myxopapillary ependymomas: report of two cases and review of the literature.

Myxopapillary ependymoma is a variant of ependymoma occurring almost exclusively in the conus medullaris or filum terminale. Myxopapillary ependymoma found primarily in the brain is extremely rare. Two such cases appearing at the 4th ventricle and cerebral falx are reported. The imaging features of such tumors are a primary cystic mass with strong enhancement at its solid part. Myxopapillary ependymoma should be a possible differential diagnosis when an intracranial cystic tumor is found.