Miracle-dz/UniFAR-FTUs huggingface dataset:
Potential Roles of Large Mafs in Cell Lineages and Developing Pancreas

Objectives: Maf is a family of transcription factor proteins characterized by a typical bZip structure, and mafA, a member of the large-maf family, is a strong transactivator of insulin in cell lines. The present study investigated the expression profiles of the large-maf family proteins in porcine pancreatic tissue and in primary culture cells. Methods: Immunohistochemical staining was performed to localize each maf protein. Messenger RNA expression was quantitated by real-time polymerase chain reaction, and protein expression was assessed by Western blotting. Results: Islet formation was not as clear in newborn pancreatic tissue as in adult pancreatic tissue. MafA- and c-maf-positive cells were more diffusely localized in pancreatic tissue with fewer mafB-positive cell clusters scattered throughout. By contrast, islet formation was clearer, and positive staining for mafA and c-maf tended to be more prominent in the islets of adult pancreatic tissue. Messenger RNA and protein expressions were consistent with the immunohistochemical findings. MafA, mafB, and c-maf coexpressed with insulin-positive cells, and c-maf coexpressed with glucagon-positive cells in adult porcine pancreas based on the results of a double-staining study. Conclusions: Large mafs were identified in normal porcine and human pancreas, and the expression levels and localizations of the large mafs in newborn and adult pancreatic tissues differed. Mafs may play important roles in establishing endocrine function during pancreatic cell differentiation.
Comparative Biodistribution and Radiation Dosimetry of 68Ga-DOTATOC and 68Ga-DOTATATE in Patients with Neuroendocrine Tumors

68Ga-DOTATOC and 68Ga-DOTATATE are 2 radiolabeled somatostatin analogs for in vivo diagnosis of neuroendocrine tumors with PET. The aim of the present work was to measure their comparative biodistribution and radiation dosimetry. Methods: Ten patients diagnosed with neuroendocrine tumors were included. Each patient underwent a 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 3 h after injection of each tracer on consecutive days. Absorbed doses were calculated using OLINDA/EXM 1.1. Results: Data from 9 patients could be included in the analysis. Of the major organs, the highest uptake at 1, 2, and 3 h after injection was observed in the spleen, followed by kidneys and liver. For both tracers, the highest absorbed organ doses were seen in the spleen and urinary bladder wall, followed by kidney, adrenals, and liver. The absorbed doses to the liver and gallbladder wall were slightly but significantly higher for 68Ga-DOTATATE. The total effective dose was 0.021 ± 0.003 mSv/MBq for both tracers. Conclusion: The effective dose for a typical 100-MBq administration of 68Ga-DOTATATE and 68Ga-DOTATOC is 2.1 mSv for both tracers. Therefore, from a radiation dosimetry point of view, there is no preference for either tracer for PET/CT evaluation of somatostatin receptor–expressing tumors.
The relationship between alcohol screening questionnaires and mortality among male veteran outpatients.

OBJECTIVE This study evaluated whether responses to alcohol screening questionnaires predicted mortality in a Department of Veterans Affairs (VA) primary care population. METHOD This study involved 5,703 male outpatients (mean age = 64) who were enrolled in General Internal Medicine clinics at three Veterans Affairs (VA) medical centers and returned mailed questionnaires in 1993-94. The two questionnaires included the CAGE and Alcohol Use Disorders Identification Test (AUDIT) alcohol screening tests. Mortality was ascertained using the VA Beneficiary Identification and Record Locator System. Five-year crude and adjusted mortality rates were calculated for patients who screened positive and patients who screened negative on each alcohol screening test. RESULTS The risk of mortality was increased among drinkers who scored > or = 8 on the full AUDIT (hazard ratio: 1.47; 95% confidence interval [CI]: 1.08-2.00) or the three AUDIT consumption questions (1.58; 1.11-2.27), after adjusting for age, smoking, sociodemographic characteristics and chronic illnesses. The risk of mortality was also increased among drinkers who reported drinking > or = 3 drinks daily (1.69; 1.28-2.22) or prior alcohol treatment (1.66; 1.27-2.17), in "fully adjusted" models. A positive CAGE score (> or = 2) was associated with significantly increased risk of mortality among drinkers in a model adjusted only for age and smoking (1.27; 1.02-1.58). Among nondrinkers, neither a positive CAGE score (> or = 2) nor report of prior alcohol treatment was associated with increased risk of mortality. CONCLUSIONS VA outpatients who reported drinking during the previous year and who had a positive result on an alcohol screening test experienced higher mortality over the subsequent 5 years than did patients who screened negative.
Kainic Acid‐Induced Neurotrophic Activities in Developing Cortical Neurons

Abstract: Using primary cultured cortical neurons from embryonic rat brains, we elucidated an α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA)/kainic acid (KA) receptor‐mediated neuroprotective mechanism through actions of nerve growth factor (NGF) in developing neurons. Neurotoxicity of KA in early days in vitro neurons was quite low compared with the mature neurons. However, pretreatment with anti‐NGF antibody or TrkA inhibitor AG‐879 profoundly raised KA toxicity. Furthermore, KA stimulation resulted in an increase of TrkA expression and phosphorylation, which was blocked not only by the AMPA/KA receptor antagonist 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione and AG‐879, but also by the phospholipase C inhibitor U73122 and the intracellular calcium chelator BAPTA. A study of polyphosphoinositide turnover showed that KA‐stimulated phospholipase C (PLC) activity was directly triggered by the AMPA/KA receptor activity, but not by the activity of TrkA or other excitatory amino acid receptor subtypes. Sources of KA‐increased intracellular calcium levels were contributed by both extracellular calcium influx and intracellular calcium release and were partially sensitive to guanosine 5′‐O‐(2‐thiodiphosphate). These results indicate that in developing cortical neurons, activation of AMPA/KA receptors by KA may induce expression, followed by activation of TrkA via PLC signaling and intracellular calcium elevation and hence increase reception of NGF on KA‐challenged neurons. A G protein‐coupled AMPA/KA receptor may be involved in these metabotropic events for neuronal protection.
Chromosome aberrations in vitro related to cytotoxicity of nonmutagenic chemicals and metabolic poisons

Chromosome aberrations can occur by secondary mechanism(s) associated with cytotoxicity, induced by chemicals that do not attack DNA. Aberrations are formed from DNA double‐strand breaks, and DSBs are known to be induced by nonmutagenic (Ames test negative) noncarcinogens at toxic levels [Storer et al. (1996): Mutat Res 368:59–101]. Here, 8 of 12 of these chemicals caused aberrations in CHO cells at cytotoxic doses, and often only when cell counts (survival) at 20 hr approached ≤50% of controls. Five of eight noncarcinogens (2,4,‐dichlorophenol, dithiocarb, menthol, phthalic anhydride, and ethionamide) and one of two equivocal carcinogens (bisphenol A) caused aberrations, usually over a narrow dose range with steeply increasing cytotoxicity. Phthalic anhydride and ethionamide were positive only at doses with precipitate. Phenformin was negative even at toxic doses and ephedrine and phenylephrine were negative and gave little toxicity. Aberrations were also induced by metabolic poisons, 2,4‐dinitrophenol, (uncouples oxidative phosphorylation), and sodium iodoacetate, (NaI; blocks ATP production). Five of the chemicals that induced aberrations in CHO cells were tested in human TK6 cells and four were positive, the fifth being equivocal. Stable aberrations (translocations) were induced in human cells by NaI. Clearly, chemicals can give “false‐positive” results in the chromosome aberration assay at cytotoxic levels, though cytotoxicity does not always produce aberrations, so that further information (e.g., DNA reactivity) is needed to determine whether a result is a “false‐positive. ” Primary DNA‐damaging chemicals such as alkylators are also cytotoxic, but give strong increases in aberrations without marked initial toxicity by the measures used here, although the aberrations they induce do reduce long‐term survival in colony‐forming assays. Environ. Mol. Mutagen. 31:316–326, 1998 © 1998 Wiley‐Liss, Inc.
Phagocytosis in Macrophages Lacking Cbl Reveals an Unsuspected Role for Fcγ Receptor Signaling and Actin Assembly in Target Binding1

Fcγ receptor (FcγR)-mediated phagocytosis is known to require tyrosine kinases (TKs). We identified c-Cbl and Cbl-b as proteins that undergo tyrosine phosphorylation during phagocytosis. Cbl-deficient macrophages displayed enhanced FcγR-mediated signaling and phagocytosis. Surprisingly, binding of IgG-coated targets (EIgG) was also enhanced. c-Cbl-deficient macrophages expressed less FcγRIIb, the inhibitory Fcγ receptor; however, this did not account for enhanced target binding. We isolated the function of one Fc receptor isoform, FcγRI, using IgG2a-coated targets (EIgG2a). Cbl-deficient macrophages demonstrated a disproportionate increase in binding EIgG2a, suggesting that signal strength regulates binding efficiency toward opsonized targets. In resting cells, FcγRI colocalized with the Src family TK Hck in F-actin-rich structures, which was enhanced in Cbl-deficient macrophages. Target binding was sensitive to TK inhibitors, profoundly inhibited following depletion of cholesterol, and ablated at 4°C or in the presence of inhibitors of actin polymerization. Sensitivity of EIgG binding to cytoskeletal disruption was inversely proportional to opsonin density. These findings challenge the view that FcγR-mediated binding is a passive event. They suggest that dynamic engagement of TKs and the cytoskeleton enables macrophages to serve as cellular “Venus fly traps”, with the capacity to capture phagocytic targets under conditions of limiting opsonin density.
Parkinson’s disease and sleepiness: An integral part of PD

ObjectiveTo investigate the potential causes of excessive daytime sleepiness in patients with PD—poor sleep quality, abnormal sleep–wakefulness control, and treatment with dopaminergic agents. MethodsThe authors performed night-time polysomnography and daytime multiple sleep latency tests in 54 consecutive levodopa-treated patients with PD referred for sleepiness, 27 of whom were also receiving dopaminergic agonists. ResultsSleep latency was 6.3 ± 0.6 minutes (normal >8 minutes), and the Epworth Sleepiness score was 14.3 ± 4.1 (normal <10). A narcolepsy-like phenotype (≥2 sleep-onset REM periods) was found in 39% of the patients, who were sleepier (4.6 ± 0.9 minutes) than the other 61% of patients (7.4 ± 0.7 minutes). Periodic leg movement syndromes were rare (15%, range 16 to 43/h), but obstructive sleep apnea–hypopnea syndromes were frequent (20% of patients had an apnea–hypopnea index >15/h; range 15.1 to 50.0). Severity of sleepiness was weakly correlated with Epworth Sleepiness score (r = −0.34) and daily dose of levodopa (r = 0.30) but not with dopamine-agonist treatment, age, disease duration, parkinsonian motor disability, total sleep time, periodic leg movement, apnea–hypopnea, or arousal indices. ConclusionsIn patients with PD preselected for sleepiness, severity of sleepiness was not dependent on nocturnal sleep abnormalities, motor and cognitive impairment, or antiparkinsonian treatment. The results suggest that sleepiness—sudden onset of sleep—does not result from pharmacotherapy but is related to the pathology of PD.
Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse.

Dopaminergic (DA) and serotonergic (5-HT) projections to striatum and cortex have been implicated as the primary targets of substituted amphetamine (AMP)-induced neurotoxicity, largely on the basis of the propensity of these compounds to cause protracted decrements in DA and 5-HT rather than on the basis of AMP-induced alterations of indices linked to neural damage. Moreover, most studies of AMP-induced neurotoxicity, regardless of the endpoints assessed, have been conducted using a rat model; relatively little attention has been focused on the effects of these compounds in the mouse. Here, we evaluated the potential neurotoxic effects of d-methamphetamine (d-METH), d-methylenedioxyamphetamine (d-MDA), d-methylene-dioxymethamphetamine (d-MDMA) and d-fenfluramine (d-FEN) in the C57BL6/J mouse. Astrogliosis, assessed by quantification of glial fibrillary acidic protein (GFAP), was taken as the main index of AMP-induced neural damage. A silver degeneration stain also was used to obtain direct evidence of AMP-induced neuronal damage. Assays of tyrosine hydroxylase (TH), DA and 5-HT were used to assess effects on DA and 5-HT systems. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg), d-MDMA (20 mg/kg) or d-FEN (25 mg/kg) every 2 hr for a total of four s.c. injections. d-METH, d-MDA and d-MDMA caused a large (300%) increase in striatal GFAP that resolved by 3 weeks and a 50 to 75% decrease in TH and DA that did not resolve. d-METH, d-MDA and d-MDMA also caused fiber and terminal degeneration in striatum as revealed by silver staining. d-FEN did not affect any parameters in striatum. d-METH, d-MDA and d-MDMA also increased GFAP in cortex, effects that were associated with small (10-25%) and transient decrements in cortical 5-HT. d-FEN caused prolonged (weeks) decrements (20%) in cortical 5-HT but did not affect cortical GFAP. The effects of d-METH, d-MDA and d-MDMA were stereoselective and were blocked by pretreatment with MK-801. Core temperature was slightly elevated by d-METH, d-MDA and d-MDMA but was dramatically lowered by d-FEN. The data suggest that d-METH, d-MDA and d-MDMA, but not d-FEN, produce damage to neural elements of mouse striatum and cortex.
Backup channel and cooperative channel switching on-demand routing protocol for multi-hop cognitive radio ad hoc networks (BCCCS)

Cognitive radio technology solves the problem of spectrum underutilization by allowing the unlicensed users to opportunistically access available spectrum without affecting the activity of licensed user. Channel assignment and routing in cognitive radio networks is especially challenging in networks where nodes are equipped with only a single transceiver (as is the case in commodity wireless networks that run IEEE 802.11 DCF MAC). We propose a combined framework of routing and channel assignment that exploits channel diversity in cognitive radio networks to optimize routing performance and increase the network capacity. Specifically, we propose a joint cross-layer routing/ channel assignment protocol based on AODV that works without any central control channel and accounts for the state of the links. In this paper, we propose to keep a backup channel to cater for channel heterogeneity thereby avoiding end to end re-route procedures. We also propose cooperative channel switching in which various nodes exchange routing and control information in a coordinated way. Simulation results show that our proposed backup channel approach ensures higher connectivity as compared to the single channel approach as the number of channels interfered with increases.
MiR-145 mediates zebrafish hepatic outgrowth through progranulin A signaling

MicroRNAs (miRs) are mRNA-regulatory molecules that fine-tune gene expression and modulate both processes of development and tumorigenesis. Our previous studies identified progranulin A (GrnA) as a growth factor which induces zebrafish hepatic outgrowth through MET signaling. We also found that miR-145 is one of potential fine-tuning regulators of GrnA involved in embryonic hepatic outgrowth. The low level of miR-145 seen in hepatocarinogenesis has been shown to promote pathological liver growth. However, little is known about the regulatory mechanism of miR-145 in embryonic liver development. In this study, we demonstrate a significant decrease in miR-145 expression during hepatogenesis. We modulate miR-145 expression in zebrafish embryos by injection with a miR-145 mimic or a miR-145 hairpin inhibitor. Altered embryonic liver outgrowth is observed in response to miR-145 expression modulation. We also confirm a critical role of miR-145 in hepatic outgrowth by using whole-mount in situ hybridization. Loss of miR-145 expression in embryos results in hepatic cell proliferation, and vice versa. Furthermore, we demonstrate that GrnA is a target of miR-145 and GrnA-induced MET signaling is also regulated by miR-145 as determined by luciferase reporter assay and gene expression analysis, respectively. In addition, co-injection of GrnA mRNA with miR-145 mimic or MO-GrnA with miR-145 inhibitor restores the liver defects caused by dysregulation of miR-145 expression. In conclusion, our findings suggest an important role of miR-145 in regulating GrnA-dependent hepatic outgrowth in zebrafish embryonic development.
Resistance to activated protein C as a basis for venous thrombosis.

BACKGROUND In three families with various forms of venous thrombosis, we observed an apparently inherited poor response to the anticoagulant activated protein C (APC). The condition was due to a deficiency in a previously unrecognized anticoagulant factor that functioned as a cofactor to activated protein C. METHODS We conducted the present study to determine the prevalence of resistance to APC in patients with venous thrombosis. We compared 104 consecutive patients with venous thrombosis confirmed by objective tests with 130 controls. In addition, 211 members of 34 families of persons with resistance to APC were studied. The anticoagulant response to APC was measured with a modified version of the activated partial-thromboplastin time test; the results were expressed as APC ratios. RESULTS Forty-five percent of patients had a family history of thrombosis. A significant (P < 0.001) difference in APC ratios was observed between the controls and the patients with thrombosis. For 33 percent of patients, the APC ratio was below the 5th percentile of the control values, although the results of the family studies suggested that the prevalence of APC resistance may be even higher (approximately 40 percent) in the patients with thrombosis. The inherited nature of the defect was confirmed in a majority of cases, and the family studies suggested the mode of inheritance to be autosomal dominant. The thrombosis-free survival of APC-resistant family members was significantly less than that of non-APC-resistant family members. CONCLUSIONS There was a high prevalence of APC resistance among young persons with a history of venous thrombosis, and this resistance appeared to be inherited as an autosomal dominant trait.
Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience.

PURPOSE To report the results of a prospective, nonrandomized European study on infants with neuroblastoma and MYCN gene amplification. PATIENTS AND METHODS Infants with neuroblastoma (stage 2, 3, 4, and 4s) and MYCN gene amplification who were diagnosed between 1999 and 2004 were eligible for enrollment onto the study. After diagnosis, staging, and mandatory biologic studies, induction chemotherapy (IC) with conventional drugs was administered, followed by delayed surgery, megatherapy (busulfan-melphalan as a conditioning regimen), and local radiotherapy. RESULTS Of the 46 infants enrolled onto the study, 35 infants were eligible; of these 35 infants, 97% had metastatic spread (24 infants had stage 4, and 10 infants had stage 4s). Two-year overall survival (OS) was 30% (SE, 0.08), with median survival time of 12 months, and 23 deaths due to disease. Two-year, event-free survival (EFS) was 29% (SE, 0.07). The treatment was well tolerated with no deaths as a result of toxicity or severe toxicity. Despite protocol adherence, 30% of the patients who were assessable for response to IC experienced disease progression or did not respond. Stage and high lactate dehydrogenase reached significance in the univariate analysis (P = .028 and .039, respectively for OS; and P = .05 and .031 respectively, for EFS). Ten of 16 patients who received megatherapy are still alive. CONCLUSION Although treatment was well tolerated, survival was poor and our IC failed to achieve a satisfactory response in 30% of our patients. New therapeutic approaches and more intense world-wide collaboration are needed to achieve a cure in this population.
Epidemiologic Background of Hand Hygiene and Evaluation of the Most Important Agents for Scrubs and Rubs

SUMMARY The etiology of nosocomial infections, the frequency of contaminated hands with the different nosocomial pathogens, and the role of health care workers' hands during outbreaks suggest that a hand hygiene preparation should at least have activity against bacteria, yeasts, and coated viruses. The importance of efficacy in choosing the right hand hygiene product is reflected in the new Centers for Disease Control and Prevention guideline on hand hygiene (J. M. Boyce and D. Pittet, Morb. Mortal. Wkly. Rep. 51:1-45, 2002). The best antimicrobial efficacy can be achieved with ethanol (60 to 85%), isopropanol (60 to 80%), and n-propanol (60 to 80%). The activity is broad and immediate. Ethanol at high concentrations (e.g., 95%) is the most effective treatment against naked viruses, whereas n-propanol seems to be more effective against the resident bacterial flora. The combination of alcohols may have a synergistic effect. The antimicrobial efficacy of chlorhexidine (2 to 4%) and triclosan (1 to 2%) is both lower and slower. Additionally, both agents have a risk of bacterial resistance, which is higher for chlorhexidine than triclosan. Their activity is often supported by the mechanical removal of pathogens during hand washing. Taking the antimicrobial efficacy and the mechanical removal together, they are still less effective than the alcohols. Plain soap and water has the lowest efficacy of all. In the new Centers for Disease Control and Prevention guideline, promotion of alcohol-based hand rubs containing various emollients instead of irritating soaps and detergents is one strategy to reduce skin damage, dryness, and irritation. Irritant contact dermatitis is highest with preparations containing 4% chlorhexidine gluconate, less frequent with nonantimicrobial soaps and preparations containing lower concentrations of chlorhexidine gluconate, and lowest with well-formulated alcohol-based hand rubs containing emollients and other skin conditioners. Too few published data from comparative trials are available to reliably rank triclosan. Personnel should be reminded that it is neither necessary nor recommended to routinely wash hands after each application of an alcohol-based hand rub. Long-lasting improvement of compliance with hand hygiene protocols can be successful if an effective and accessible alcohol-based hand rub with a proven dermal tolerance and an excellent user acceptability is supplied, accompanied by education of health care workers and promotion of the use of the product.