Risk factors outperform intracranial large artery stenosis predicting unfavorable outcomes in patients with stroke.

BACKGROUND: This study examined how intracranial large artery stenosis (ILAS), symptomatic and asymptomatic ILAS, and risk factors affect unfavorable outcome events after medical treatment in routine clinical practice. METHODS: This was a 24-month prospective observational study of consecutively recruited stroke patients. All participants underwent magnetic resonance angiography, and their clinical characteristics were assessed. Outcome events were vascular outcome, recurrent stroke, and death. Cox regression analyses were performed to identify potential factors associated with an unfavorable outcome, which included demographic and clinical characteristics, the risk factors, and stenosis status. RESULTS: The analysis included 686 patients; among them, 371 were assessed as ILAS negative, 231 as symptomatic ILAS, and 84 as asymptomatic ILAS. Body mass index (p < .05), hypertension (p = .01), and old infarction (p = .047) were factors relating to vascular outcomes. Hypertension was the only factor for recurrent stroke (p = .035). Poor glomerular filtration rate (< 30 mL/min/1.73 m2) (p = .011) and baseline National Institutes of Health Stroke Scale scores (p < .001) were significant predictors of death. CONCLUSIONS: This study extended previous results from clinical trials to a community-based cohort study by concurrently looking at the presence/absence of stenosis and a symptomatic/asymptomatic stenotic artery. Substantiated risk factors rather than the stenosis status were predominant determinants of adverse outcome. Although the degree of stenosis is often an indicator for treatment, we suggest risk factors, such as hypertension and renal dysfunction, should be monitored and intensively treated.

Cutaneous larva migrans induced by swallowing live pond loaches.

Freshwater fish, specifically loaches, are potential hosts of Gnathostoma species. Consumption of uncooked freshwater loaches may result in cutaneous larva migrans. We report the case of a 70-year-old Taiwanese man who presented with a serpiginous skin rash on his abdomen. He had eaten live loaches intermittently (sometimes daily) for 5 months before his presentation. On histopathological examination, a transected parasite body and a headbulb were found in the mid-dermis. The parasite was confirmed as belonging to the genus Gnathostoma, most likely Gnathostoma doloresi. The patient recovered uneventfully without treatment, and had no symptoms at his 12-month follow-up visit.

Ovalbumin sensitizes vagal pulmonary C-fiber afferents in Brown Norway rats.

Sensitization of vagal lung C fibers has been postulated to contribute to the development of asthma, but support for this notion is still lacking. We investigated the characteristics and function of pulmonary C fibers (PCFs) in ovalbumin (OVA)-sensitized Brown Norway rats, an established animal model of asthma. Rats were sensitized with intraperitoneal injection of OVA or were treated with saline (control). In study 1, with the use of open-chest and artificially ventilated rats, inhalation of 5% OVA aerosol evoked an augmented increase in total lung resistance in the OVA-sensitized rats, compared with the control rats. Bilateral vagotomy or subcutaneous pretreatment with a high-dose of capsaicin for blocking of C-fiber function equally attenuated this augmented total lung resistance response, suggesting the involvement of PCFs. In study 2, with the use of anesthetized, spontaneously breathing rats, right atrial injection of capsaicin (1 microg/kg; a PCF stimulant) evoked an augmented apneic response in the OVA-sensitized rats, compared with the control rats. In study 3, with the use of open-chest, paralyzed, and artificially ventilated rats, the afferent PCF responses to right atrial injection of capsaicin (0.5 and 1.0 microg/kg), phenylbiguanide (8 microg/kg; a PCF stimulant), or adenosine (0.2 mg/kg; a PCF stimulant) were enhanced in the OVA-sensitized rats, compared with the control rats. However, the baseline activities of PCFs and their afferent responses to mechanical stimulation by lung hyperinflation in the OVA-sensitized and control rats were comparable. Our results suggested that OVA-sensitized Brown Norway rats possess sensitized vagal PCFs, which may participate in the development of the airway hyperreactivity observed in these animals.

Islet cell autoantigen 69 kD (ICA69). Molecular cloning and characterization of a novel diabetes-associated autoantigen.

We have identified a novel 69-kD peptide autoantigen (ICA69) associated with insulin-dependent diabetes mellitus (IDDM) by screening a human islet lambda gt11 cDNA expression library with cytoplasmic islet cell antibody positive sera from relatives of IDDM patients who progressed to the overt disease. The deduced open reading frame of the ICA69 cDNA predicts a 483-amino acid protein. ICA69 shows no nucleotide or amino acid sequence relation to any known sequence in GenBank, except for two short regions of similarity with BSA. The ICA69 cDNA probe hybridizes with a 2-kb mRNA in poly(A+) RNA from human pancreas, brain, heart, thyroid, and kidney, but not with skeletal muscle, placenta, spleen, or ovary. Expression of ICA69 was also detected in beta cells and cell lines, as well as in tumoral tissue of islet cell origin. The native ICA69 molecule migrates to 69 kD in SDS-PAGE as detected with specific antibodies. Serum samples from relatives of IDDM patients specifically reacted with affinity-purified recombinant ICA69 on Western blotting. The structural gene for ICA69 was designated ICA1. A homologue in the mouse, designated Ica-1 was mapped to the proximal end of chromosome 6 (within 6 cM of the Met protooncogene). ICA69 adds a novel autoantigen to the family of identified islet target molecules, and by the manner of its identification and characterization large amounts of antigen are available for development of quantitative, convenient predictive assays for autoantibodies and analysis of the role of this molecule in diabetes autoimmunity, as well as its physiologic function.

Degradation of di-butyl-phthalate by soil bacteria.

Twelve Gram-positive phthalate ester degraders were isolated from soil. Using Biolog GP2 plates, eight of them were identified as belonging to the Corynebacterium-Mycobacterium-Nocardia group, while the remaining four were unidentifiable. When cultured in the presence of di-butyl-phthalate (DBP) in basal salts solution, five of these isolates accomplished more than 90% of DBP degradation within 48 h (fast group), three were placed in the medium group, and the remaining four were placed in the slow group which caused less than 30% of DBP degradation within the same period of time. A 420 bp DNA fragment was amplified from six isolates and none of them fell within the slow group. When compared with the large subunit of phthalate dioxygenase gene (phtA) of Arthrobacter keyseri, 83% and 91% similarities were evident in the nucleotide and amino acid sequences, respectively. However, no correlation between cell surface hydrophobicity and phthalate degradation ability was evident. Six surfactants (Brij 30, Brij 35, Tergitoltype NP-10, Triton N-101, Triton X-100 and SDS) were tested for their abilities to increase degradation rate. When added at the critical micellar concentration (CMC), they all displayed strong growth inhibition against the three bacteria tested, with Brij 30 been the least toxic to isolates G2 and G11, and Brij 35 had the least inhibitory effect for G1. When half the CMC of Brij 30 was incorporated into the basal salts, the inhibitory effect on DBP degradation remained. Soil helped to minimize surfactant toxicity of surfactant and increase the degradation potential of some of the test bacteria. When DBP-amended soil had been aged for three months, decreases in bioavailability were observed but the effect varied tremendously between different organisms. For isolates G1, G2, G5, G7 and G17 the aging effects were almost non-exist. The present study indicates that selection of a suitable degrader may minimize the undesired effect of aging on bioremediation process.

Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data.

Glioblastoma (GBM) is a common and malignant tumor with a poor prognosis. Glioblastoma stem cells (GSCs) have been reported to be involved in tumorigenesis, tumor maintenance and therapeutic resistance. Thus, to discover novel candidate therapeutic drugs for anti-GBM and anti-GSCs is an urgent need. We hypothesized that if treatment with a drug could reverse, at least in part, the gene expression signature of GBM and GSCs, this drug may have the potential to inhibit pathways essential in the formation of GBM and thereby treat GBM. Here, we collected 356 GBM gene signatures from public databases and queried the Connectivity Map. We systematically evaluated the in vitro antitumor effects of 79 drugs in GBM cell lines. Of the drugs screened, thioridazine was selected for further characterization because it has potent anti-GBM and anti-GSCs properties. When investigating the mechanisms underlying the cytocidal effects of thioridazine, we found that thioridazine induces autophagy in GBM cell lines, and upregulates AMPK activity. Moreover, LC3-II was upregulated in U87MG sphere cells treated with thioridazine. In addition, thioridazine suppressed GBM tumorigenesis and induced autophagy in vivo. We not only repurposed the antipsychotic drug thioridazine as a potent anti-GBM and anti-GSCs agent, but also provided a new strategy to search for drugs with anticancer and anticancer stem cell properties.

The diagnostic and prognostic value of renal allograft biopsy.

We prospectively studied 89 patients to assess the diagnostic use of renal allograft biopsy in the first three months after transplantation. These biopsies were done in patients in whom diagnosis was not clear or clinical rejection was deemed to be severe. Clinical diagnosis at initial biopsy was compared with the morphological diagnosis. To determine if morphological data improved the prognostic usefulness of the clinical data, we performed multiple logistic regression relating clinical variables at initial biopsy and histological changes in the transplant to the outcome of 120 patients one year after biopsy. The clinical and morphological diagnosis differed in 41 of 89 patients (46%). Of 120 patients in the prognostic study, 35 returned to dialysis during the first year following transplantation. Using multiple logistic regression, a categorical variable that took into account both the serum creatinine and its rate of change before biopsy was the best clinical predictor of return to dialysis. Further increase in chi 2 occurred with type of donor, number of transfusions, and age. Using the clinical variables we produced an index, from 0 to 1 to predict outcome. Only 8 had index less than 0.2, of whom 7 returned to dialysis. The best morphological predictor of outcome was interstitial hemorrhage. Further increase in chi 2 was obtained with vascular endothelial proliferation, glomerular endothelial swelling, and glomerular necrosis. With an index derived from the morphological variables only 11 had index less than 0.2, of whom 9 returned to dialysis. Combining both clinical and morphological data, the best predictor of return to dialysis was interstitial hemorrhage, followed by creatinine, glomerular endothelial swelling, and type of donor. Using both clinical and morphological variables we produced another index to predict outcome. A group of 65 patients had index greater than 0.8, of whom 63 (94%) did not return to dialysis, and 18 patients had index less than 0.2, 17 of whom returned to dialysis. The remaining 12 patients in the dialysis group and 15 in the nondialysis group had indices greater than 0.2 less than 0.8. We conclude that a transplant biopsy yields important diagnostic and prognostic information. Unexpected diagnoses were made in 46% of cases. The addition of morphological data to the clinical data available at time of biopsy greatly improved the prediction of return to dialysis.

Kinase-inducible domain-like region of HTLV type 1 tax is important for NF-kappaB activation.

Partial proteolysis of HTLV-1 Tax protein has revealed the region surrounding amino acid residues (88)KVL(90) to be highly exposed. The protein sequence surrounding this region ((81)QRTSKTLKVLTPPIT(95)) bears resemblance to the kinase-inducible domain (KID, (129)SRRPSYRKILNE(140)) of CREB and is involved in recruiting transcriptional coactivators, p300 and CBP, for trans-activating the viral long terminal repeat (LTR). Data have also revealed the KID-like region to be important for Tax binding to DNA. Here we report that single (K88A, V89A, L90A) and double alanine substitutions (V89A-L90A) in the (88)KVL(90) motif attenuate the ability of Tax to activate NF-kappaB. Deletions near or spanning this motif also had the same effect. The alanine substitutions affect HTLV-1 LTR activation and NF-kappaB activation differently, with K88A and V89A mutants showing much reduced activities for HTLV LTR activation while retaining attenuated but significant NF-kappaB-activating function. In contrast, although the L90A mutant is similarly attenuated for NF-kappaB activation, it showed significant activity in LTR trans-activation. Incorporation of both V89A and L90A substitutions in a V89A-L90A double mutant further reduced NF-kappaB activation and completely abrogated LTR trans-activation. In aggregate, these results demonstrate the importance of the KID-like domain of Tax and implicate its interaction with cellular factors other than p300/CBP in NF-kappaB activation.

Differential regulation of major surface promoter in hepatitis B virus.

The major surface promoter of human hepatitis B virus can produce three distinct groups of S transcripts. The initiation sites of these transcripts are in close proximity. Encompassing the ATG for the middle surface protein, the largest S transcript (+1) encodes the middle surface protein whereas the other two (+20 and +31) can only code for small surface protein. Sequence analysis does not reveal any TATA element. In this study, we employ deletion, linker scanning, and linker insertion analyses to study systematically the sequence requirements for the initiations of all three transcripts and their upstream regulatory sequences. Our study reveals that the sequence downstream of -16 is sufficient for precise initiation of all three groups of S transcripts. The 3' boundary of minimal promoter element is +15 for the +1 transcript, whereas it is +39 for both +20 and +31 transcripts. Furthermore, there are distinct sequence requirements for the initiations of three groups of S transcripts. The sequences from -17 to -10 and from -1 to +7 are required for the initiation of +1 transcript, the sequence from +16 to +39 is essential for the +20 transcript, and the sequences from -17 to -10 and from +24 to +39 are required for the + 31 transcript. Our results also suggest that the transcription initiations of major surface promoter may be mediated in part by initiators. The initiations of these three groups of S transcripts are under differential regulation. The region from -39 to -16 containing both negative and positive regulatory elements selectively regulates the transcription levels of the two major S transcripts. Most notably, mutation of the sequence from -17 to -10, which contains a Sp1 site, leads to an increase in the imprecise initiation at +1 site and depresses the initiation of +20 and, to a greater extent, +31 transcript. The relevance of differential regulation of major surface promoter to the varied production of different surface protein isoforms in viral life cycle is discussed.

Superior sagittal sinus thrombosis induced by thyrotoxicosis. Case report.

There is a wide variety of disorders associated with thrombosis of the superior sagittal sinus (SSS), including infectious disease. noninfectious conditions such as vasculitis and hypercoagulable states, and complications arising from pregnancy or use of oral contraceptive medications. Despite these well-defined associations, approximately 25% of the cases remain idiopathic. In this article the authors describe a patient who was found to have SSS thrombosis while experiencing a thyrotoxic phase of Graves disease. The patient presented with intracerebral hemorrhage, subarachnoid hemorrhage, seizure, coma, a raised fibrinogen concentration, low protein C activity, and atrial fibrillations. Thrombolysis was successfully performed despite the coexistence of thrombosis and intracranial hemorrhage. Patients with thyrotoxicosis and a diffuse goiter may be predisposed to the development of SSS thrombosis, as a result of hypercoagulation and stasis of local venous blood flow. In the present case, a patient in whom thrombosis coexisted with intracranial hemorrhage was successfully treated using thrombolytic therapy.

Superior rectal artery injury following lumbar disc surgery. Case report.

Traumatic injury of the aorta, inferior vena cava, and iliac vessels due to penetration of the anterior anulus fibrosus and anterior longitudinal ligament is a recognized complication of lumbar disc surgery. The authors report, to the best of their knowledge, the first case of discectomy-related superior rectal artery injury treated by endovascular intervention.

Percutaneous puncture and pre-operative cyanoacrylate obliteration of a traumatic false aneurysm of an angular artery branch.

We report a case of traumatic false aneurysm developed in the right glabella in a 5-year-old boy 3 weeks after an innocuous fall. Ultrasound, CT and facial arteriography did not reveal the feeding artery. After direct puncture of the glabellar bulge and rapid aspiration of blood, percutaneous contrast agent infusion revealed that the false aneurysm was supplied by the contralateral angular artery. Intralesional obliteration with cyanoacrylate was subsequently performed smoothly. Succeeding excision was easy and the cosmetic outcome was excellent.

Efficacy and safety of ribavirin plus pegylated interferon alfa in geriatric patients with chronic hepatitis C.

BACKGROUND: Limited data are available on the efficacy and safety of antiviral therapy in geriatric patients with chronic hepatitis C virus (HCV) infection. AIM: To evaluate the efficacy and safety of pegylated interferon (pegIFN) plus ribavirin (RBV) therapy in geriatric HCV-infected patients. METHODS: Ninety-one geriatric patients (age ≥65 years; the elderly group) with HCV infection and 91 gender- and HCV genotype-matched middle-aged patients (age 50-64 years; the younger group) were assigned to receive weekly pegIFN injection plus weight-based oral RBV for 24 weeks. The on- and off-treatment virological responses were evaluated for treatment efficacy. RESULTS: In intention-to-treat analysis, the sustained virological response (SVR) rate was substantially decreased in the elderly patients (elderly group vs. younger group, 40.7% vs. 61.5%, respectively; P = 0.005). The SVR rate was significantly lower in geriatric patients than in middle-aged patients with HCV genotype non-1 (54.3% vs. 82.9%; P = 0.01), but the difference was not significant with HCV genotype 1 (32.1% vs. 48.2%; P = 0.083). Furthermore, the older patients infected with HCV genotype non-1 who achieved a rapid virological response had a similar SVR rate to that of the younger patients. The withdrawal rate was 13.2% in the elderly group and 7.7% in the younger group. CONCLUSIONS: Compared with middle-aged patients, the therapeutic efficacy of pegylated interferon plus ribavirin therapy is lower in hepatitis C virus-infected geriatric patients with an acceptable withdrawal rate. Considering prolonged lifespan in geriatric patients, we recommend treating geriatric hepatitis C virus-infected patients who have significant hepatic fibrosis and no other health problems.

Thaliporphine preserves cardiac function of endotoxemic rabbits by both directly and indirectly attenuating NFκB signaling pathway.

Cardiac depression in sepsis is associated with the increased morbidity and mortality. Although myofilaments damage, autonomic dysfunction, and apoptosis play roles in sepsis-induced myocardial dysfunction, the underlying mechanism is not clear. All of these possible factors are related to NFκB signaling, which plays the main role in sepsis signaling. Thaliporphine was determined to possess anti-inflammatory and cardioprotective activity by suppressing NFκB signaling in rodents. The purpose of this study is to further prove this protective effect in larger septic animals, and try to find the underlying mechanisms. The systolic and diastolic functions were evaluated in vivo by pressure-volume analysis at different preloads. Both preload-dependent and -independent hemodynamic parameters were performed. Inflammatory factors of whole blood and serum samples were analyzed. Several sepsis-related signaling pathways were also determined at protein level. Changes detected by conductance catheter showed Thaliporphine could recover impaired left ventricular systolic function after 4 hours LPS injection. It could also reverse the LPS induced steeper EDPVR and gentler ESPVR, thus improve Ees, Ea, and PRSW. Thaliporphine may exert this protective effect by decreasing TNFα and caspase3 dependent cell apoptosis, which was consistent with the decreased serum cTnI and LDH concentration. Thaliporphine could protect sepsis-associated myocardial dysfunction in both preload-dependent and -independent ways. It may exert these protective effects by both increase of "good"-PI3K/Akt/mTOR and decrease of "bad"-p38/NFκB pathways, which followed by diminishing TNFα and caspase3 dependent cell apoptosis.

Invasive infections caused by non-Aspergillus moulds identified by sequencing analysis at a tertiary care hospital in Taiwan, 2000-2008.

The clinical and microbiological characteristics of 103 patients with cultures positive for non-Aspergillus moulds in the period 2000 to 2008 were described. Among these patients, 27 had proven or probable invasive infections caused by Fusarium (n = 12), Paecilomyces (n = 7), Zygomycetes (n = 5) and Scedopsorium species (n = 3). The incidence of invasive infections caused by these moulds has not increased during the study period. Lung was the most common infection site and disseminated disease was observed in three leukaemic patients. The overall mortality rate was 40.7%, and was highest in cases zygomycosis. Antifungal susceptibility varied considerably among species. Amphotericin B and posaconazole demonstrated greatest activity against these moulds.

Rapid identification of fungal pathogens in positive blood cultures using oligonucleotide array hybridization.

Identification of fungal species in positive blood cultures using conventional methods can be time-consuming, particularly for non-albicans Candida species, non-Candida yeasts, and moulds. An oligonucleotide array system targeting the internal transcribe spacer (ITS) 1 or 2 region of the rRNA genes was used to analyse prospectively 116 fungus-positive blood cultures [BACTEC Myco/F Lytic bottles (Becton-Dickinson Microbiology Systems, Sparks, MD, USA)] from 105 patients, and the results were compared with those obtained using conventional methods. A total of 124 yeast isolates and two mould isolates were identified; these microorganisms (isolate no.) included C. albicans (50), C. tropicalis (26), C. glabrata (18), C. parapsilosis (14), Cryptococcus neoformans (9), Trichosporon asahii (2), Rhodotorula mucilaginosa (2), Penicillium marneffei (2) and three other species. Multiple species fungaemia (MSF) was detected in ten samples as opposed to six detected using conventional methods. In two discrepant samples, antifungal susceptibility testing revealed that the additionally detected isolate had higher MICs of fluconazole. An isolate reported as Rhodotorula glutinis by the Vitek Yeast Biochemical Card (bioMérieux Vitek, Marcy l'Etoile, France) was identified as R. mucilaginosa by the array and the identification by array hybridization was confirmed by sequence analysis of the ITS region. A test sensitivity of 100% was obtained. The test specificity was 100% according to examination of 57 blood samples containing non-target fungal species or bacterium only. From the time at which growth was detected in blood cultures, the entire identification procedure could be completed within 16-24 h.

Necrotizing fasciitis caused by Vibrio vulnificus: epidemiology, clinical findings, treatment and prevention.

Necrotizing fasciitis is a soft-tissue infection with a high risk of fatality. Infection with Vibrio vulnificus can lead to development of necrotizing fasciitis and primary septicemia, and occurs mostly in immunocompromised host-associated diseases such as hepatic disease, diabetes mellitus, chronic renal insufficiency, and adrenal insufficiency. Early recognition and treatment of the infection, which are unclear, are vital to patient welfare. We studied the disease epidemiology and reviewed the prognosis and clinical features of patients treated using our developed protocol. Clinical manifestations and outcomes were retrospectively analyzed for 67 patients with V. vulnificus-mediated necrotizing fasciitis and sepsis. All patients who had contacted seawater or raw seafood with positive culture for vibrio were included. Patients were divided into two groups based on the timing of first fasciotomy and injury; within 24 h (group A) and beyond 24 h (group B). Twenty-three of the 67 patients (40%) had hepatic disease, 17 (25.4%) had chronic renal insufficiency, and 12 (17.9%) exhibited adrenal insufficiency. The most common site of infection was the upper extremity (74.7%). Group B presented with more clinical symptoms including fever (p = 0.02), hemorrhagic bullae (p < 0.0001), and shock (p = 0.007). Group A patients exhibited enhanced survival compared to group B (in hospital mortality: 4.9% vs. 23%; p = 0.005). We conclude that early and appropriate diagnosis for V. vulnificus infection should be made, especially in patients presenting with atypical clinical findings. Early fasciotomy within 24 h remains the highest priority and decreases the mortality rate.