Miracle-dz/UniFAR-FTUs huggingface dataset:
Ambient Light Promotes Selective Subcellular Proteotoxicity after Endogenous and Exogenous Porphyrinogenic Stress*

Background: Protoporphyria causes mouse liver damage in association with lamin aggregation. Results: Endogenously and exogenously stimulated protoporphyrin-IX accumulation leads to ambient light-triggered organelle-selective protein aggregation, ultrastructural alterations, ER stress, and proteasome inhibition. Conclusion: External and internal porphyrinogenic stress cause compartment-selective proteotoxic damage and protein aggregation. Significance: Subcellular compartment-specific and porphyrin-selective protein aggregation may be a hallmark injury mechanism in porphyrias. Hepatic accumulation of protoporphyrin-IX (PP-IX) in erythropoietic protoporphyria (EPP) or X-linked-dominant protoporphyria (XLP) cause liver damage. Hepatocyte nuclear lamin aggregation is a sensitive marker for PP-IX-mediated liver injury. We tested the hypothesis that extracellular or intracellular protoporphyria cause damage to different subcellular compartments, in a light-triggered manner. Three hepatoma cell lines (HepG2, Hepa-1, and Huh-7) were treated with exogenous PP-IX (mimicking XLP extrahepatic protoporphyria) or with the iron chelator deferoxamine and the porphyrin precursor 5-aminolevulinic acid (ALA) (mimicking intracellular protoporphyrin accumulation in EPP). Exogenous PP-IX accumulated predominantly in the nuclear fraction and caused nuclear shape deformation and cytoplasmic vacuoles containing electron-dense particles, whereas ALA+deferoxamine treatment resulted in higher PP-IX in the cytoplasmic fraction. Protein aggregation in the nuclear and cytoplasmic fractions paralleled PP-IX levels and, in cell culture, the effects were exclusively ambient light-mediated. PP-IX and ALA caused proteasomal inhibition, whereas endoplasmic reticulum protein aggregation was more prominent in ALA-treated cells. The enhanced ALA-related toxicity is likely due to generation of additional porphyrin intermediates including uroporphyrin and coproporphyrin, based on HPLC analysis of cell lysates and the culture medium, as well as cell-free experiments with uroporphyrin/coproporphyrin. Mouse livers from drug-induced porphyria phenocopied the in vitro findings, and mass spectrometry of liver proteins isolated in light/dark conditions showed diminished (as compared with light-harvested) but detectable aggregation under dark-harvested conditions. Therefore, PP-IX leads to endoplasmic reticulum stress and proteasome inhibition in a manner that depends on the source of porphyrin buildup and light exposure. Porphyrin-mediated selective protein aggregation provides a potential mechanism for porphyria-associated tissue injury.
[Study on risk factors for early postoperative infection after orthotopic liver transplantation in adults].

OBJECTIVE To analyze risk factors related to infection during early postoperative period after orthotopic liver transplantation in adults. METHODS Retrospective study of 400 cases of orthotopic liver transplantation in adults performed between 2003 and 2004. Pre-, intra- and postoperative variables of recipients were analyzed in two groups according to whether or not infection developed. RESULTS Infection developed in 121 patients (30.3%). Bacterial infections were most common, accounting for 62.0% (75/121 cases), followed by fungal infection with the percentage of 20.6% (25/121 cases), and virus infection accounting for 12.4% (15/121 cases). The common infection sites were lung (63 cases, 52.1%), gallbladder (23 cases, 19.0%), peritoneal cavity (22 cases, 18.2%), and venous catheter (13 cases, 10.7%). Significant risk factors for infection as shown by the multivariate analysis were acute renal failure, graft dysfunction, acute lung injury, postoperative bleeding, pulmonary edema, history of diabetes mellitus or new onset diabetes mellitus, Child-Pugh stage>10, age>60. CONCLUSION Early postoperative infection after orthotopic liver transplantation in adults is a common and serious complication that continues to be difficult to control. Certain risk factors can be improved with careful management such as acute kidney failure and graft dysfunction. Appropriate anti-infection remedy is very important to prevent drug resistance. However, immunosuppression agents acts as a real predisposing factor of infection with regard to both its development and its clinical manifestation.
Outcome analysis and rational management of enhancing lesions incidentally detected on contrast-enhanced MRI of the breast.

OBJECTIVE The purpose of our study was to assess the prevalence, characteristics, and clinical consequence of incidentally detected enhancing lesions on MRI of the breast. SUBJECTS AND METHODS. MRI of the breast (1.0-T scanner, dynamic gadolinium-enhanced T1-weighted three-dimensional gradient-echo sequence, double breast coil) was performed on 1273 women for different indications. Enhancing incidental lesions were defined as enhancing lesions on MRIs that were not expected from findings on the previous conventional imaging. They were classified in five assessment categories using a scoring system based on morphologic and kinetic enhancement characteristics. Detection of enhancing incidental lesions resulted in a review of mammograms and sonograms with the aim of also localizing these lesions on conventional imaging. The lesions were either biopsied or followed up. RESULTS Twenty-five percent (274/1086) of all enhancing lesions detected in the study population were enhancing incidental lesions. Enhancing incidental lesions were found in 16% (210/1273) of all study patients. Forty-one percent (113/274) of the enhancing incidental lesions were histologically confirmed. Forty-eight percent (54/113) of the biopsied and 20% (54/274) of all enhancing incidental lesions were malignant. Eleven percent (54/508) of all malignant lesions occurring in the 1273 women were detected solely through additional MRI. Fifty-seven percent (31/54) of these MRI-detected malignant lesions could be identified on a reevaluation of sonograms and mammograms. CONCLUSION Detection of enhancing incidental lesions should lead to a thorough reevaluation of mammograms and sonograms. If not reidentified, suspicious enhancing incidental lesions should be biopsied, and enhancing incidental lesions that are probably benign should be carefully followed up. Indeterminate enhancing incidental lesions should be histologically examined by minimally invasive techniques or, if they are small, followed up by another MRI 6 months later.
Testing for HIV: concise guidance.

HIV is now a treatable medical condition and the majority of those living with the virus remain fit and well on treatment. Despite this a significant number of people in the UK are unaware of their HIV infection and remain at risk to their own health and of passing their virus unwittingly on to others. Late diagnosis is the most important factor associated with HIV-related morbidity and mortality in the U.K. Testing for HIV infection is often not performed due to misconceptions held by healthcare workers even when it is clinically indicated and this contributes to missed or late diagnosis. This article summarises the recommendations from the U.K. national guidelines for HIV testing 2008. The guidelines provide the information needed to enable any clinician to perform an HIV test within good clinical practice and encourage 'normalisation' of HIV testing. The full version is available at www.bhiva. org/cmsl 222621.asp.
Therapy of pulmonary nocardiosis in immunocompromised mice

We compared the bactericidal efficacies of various antimicrobial agents and combinations thereof in experimentally induced Nocardia asteroides pneumonia in immunocompromised mice. Cortisone acetate treatment, which produced impaired cell-mediated immune function, was followed by nasal inoculation of 5 x 10(4) CFU of N. asteroides into each mouse. Therapy was begun 24 h after inoculation and continued for the next 96 h. Dosages of antimicrobial agents resulted in concentrations approximating levels in human serum. Animals from each of nine treatment groups were sacrificed every 24 h. The pulmonary tissue obtained was homogenized and quantitatively cultured. Results were calculated to indicate the number of CFU per gram of lung tissue. Amikacin and imipenem were the two most effective single agents studied. Sulfadiazine and ciprofloxacin were ineffective, and ceftriaxone reduced bacterial counts modestly. Combination therapy did not enhance the bactericidal activities of the agents tested. We conclude that amikacin and imipenem, as well as select broad-spectrum cephalosporins, represent therapy superior to the sulfonamides in this experimental model and may represent alternative treatment for patients who cannot tolerate sulfa agents (e.g., human immunodeficiency virus-infected patients) or who fail primary treatment.
The influence of epidural anesthesia on the hearing system after normal labor

Abstract Objective: The purpose of our study was to evaluate the influence of epidural anesthesia on the hearing system in women undergoing normal labor. Design: We examined two groups of patients: women with epidural anesthesia underwent four tests of distortion product otoacoustic emissions(DPOAEs): on admission, and fifteen minutes, one hour, and three hours after the last epidural bolus of local anesthetic. Auditory brainstem response (ABR) tests were performed on admission, and one hour, and three hours after the last epidural bolus. Women who gave birth without epidural anesthesia underwent DPOAEs tests on admission, during a uterine contraction, during active delivery, and three hours after labor. ABR tests were performed on admission, during a uterine contraction, and three hours after labor Study sample: twenty patients participated in the study. Twelve gave birth with epidural anesthesia and eight without anesthesia. Results: No significant changes in DPOAEs and ABR recordings were found between the two groups. Conclusions: Epidural anesthesia does not impair the sensory or the neural elements of the hearing system and therefore does not influence hearing. Sumario Objetivo: El propósito de este studio fue evaluar la influencia de la anestesia epidural en el sistema auditivo de mujeres en trabajo de parto normal. Diseño: examinamos dos grupos de pacientes: uno de mujeres con anestesia epidural, realizaron cuatro pruebas con emisiones otoacústicas por productos de distorsión (DPOAE): al ingreso y a los 15 minutos, una hora y tres horas después del último bolo de anestesia local epidural. También se obtuvieron Respuestas Auditivas de Tallo Cerebral (ABR) al ingreso y una y tres horas después del último bolo epidural. Al grupo de mujeres que dieron a luz sin anestesia epidural se les practicaron pruebas de DPOAE al ingreso, durante una contracción uterina durante el parto activo y tres horas después del mismo. También se hicieron pruebas de ABR al ingreso, durante una contracción uterina y tres horas después del parto. Muestra de estudio: veinte pacientes participaron en el estudio. Doce dieron a luz con anestesia epidural y ocho sin anestesia. Resultados: No se encontraron cambios significativos en los registros de las DPOAE y de las ABR entre los dos grupos. Conclusiones: La anestesia epidural no afecta los elementos sensoriales y neurales del sistema auditivo y consecuentemente, no influencia la audición
Effects of misclassification on estimates of relative risk in family history studies

Two types of misclassification that commonly occur in family‐genetic studies are distinguished: 1) nondifferential misclassification, in which the probability of error as to phenotype (presence or absence of psychiatric disorder) does not depend on exposure status (being kin to a case or control proband) and 2) differential misclassification, in which it does. Nondifferential misclassification of phenotype reduces the observed relative risk towards the null value, sometimes quite dramatically. Differential misclassification can bias the observed relative risk in either direction, depending on the different values of sensitivity and specificity among relatives of cases and controls. The impact of these biases on genetic‐epidemiologic studies is reviewed and discussed. In particular, the ability to detect major gene effects from the pattern of relative risks in first‐, second‐, and third‐degree relatives can be severely compromised. Although there are some methods available to correct the effects of nondifferential misclassification, a major priority for family history studies is to minimize differential misclassification. Genet. Epidemiol. 16:368–381, 1999. © 1999 Wiley‐Liss, Inc.
The Risk of Colon Cancer in Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD) involves chronic inflammation in the patient’s digestive track, leading to the development of ulcerative colitis and Crohn’s disease. IBD is painful and debilitating disease that develops into life threatening risk in the long run, particularly colorectal carcinoma (CRC). As per the studies, there are 18% of chances for the IBD to develop into colorectal carcinoma after 30 years. Although IBD is contributing to only 1% of overall Colorectal Cancer cases, the mortality rate is pretty high among the colorectal cancer developed due to IBD. The present article prescribes guidelines for screening and surveillance that minimizes the risks of CRC.
Antimitochondrial and antinuclear antibodies in primary biliary cirrhosis** Przeciwciała antymitochondrialne i antyjądrowe w pierwotnej żółciowej marskości wątroby

Summary Primary biliary cirrhosis (PBC) is a chronic liver disease of unknown etiology. It starts with inflammatory changes in the small biliary ducts and slowly develops pathological changes in the tissue, leading to complete liver cirrhosis. Serum autoantibodies are crucial tools for diagnosis of PBC. Antimitochondrial autoantibodies (AMA), directed against the 2-oxoaciddehydrogenase complex of the inner mitochondrial membrane, are the most sensitive and specific immunologic markers of PBC. Additionally 50% of PBC patients have antinuclear antibodies (ANA). The nuclear envelope proteins have been identified as target of ANA reactivity. A part of PBC patients develops antibodies against constituents of the nuclear pore complex – gp210 protein, p62 nucleoporin and lamin B receptor (LBR). Antibodies to these antigens such as gp210 protein and p62 nucleoporin are highly specific for PBC and can aid in the serologic diagnosis, especially in cases in which antimitochondrial antibodies are not detectable. A review of several studies performed in various regions of the world showed wide differences in prevalence (9-45%) of antibodies against gp210 protein in PBC. There are reports indicating an association of positivity for antibodies against the nuclear pore complex with poor outcome of PBC. During the last years a number of another nuclear structures have been recognized as a specific targets of ANAs in PBC. These include Sp100 and promyelocytic leukemia proteins. Specific antinuclear antibodies will provide an important, novel clinical tool in diagnostic process of patients with PBC.
Examining the Impending Gap in Clinical Nursing Expertise

Much has been written about current and future nursing shortages and the numerical gap between nurses available and projected nursing needs. Very little analysis has focused on the implications of the pending expertise gap within the nursing workforce. A graying and retiring registered nurse workforce will greatly increase the proportion of novice nurses with minimal experience in bedside practice. The expertise gap will also affect nursing education. This article explores the implications of these phenomena. Without careful planning, efforts to address the numerical shortage may inadvertently worsen the expertise gap, contributing to unsafe care and affecting nursing retention.
Competitive Two-Agent Scheduling and Its Applications

We consider a scheduling environment with m (m ≥ 1) identical machines in parallel and two agents. Agent A is responsible for n1 jobs and has a given objective function with regard to these jobs; agent B is responsible for n2 jobs and has an objective function that may be either the same or different from the one of agent A. The problem is to find a schedule for the n1 + n2 jobs that minimizes the objective of agent A (with regard to his n1 jobs) while keeping the objective of agent B (with regard to his n2 jobs) below or at a fixed level Q. The special case with a single machine has recently been considered in the literature, and a variety of results have been obtained for two-agent models with objectives such as fmax, Σ wjCj, and Σ Uj. In this paper, we generalize these results and solve one of the problems that had remained open. Furthermore, we enlarge the framework for the two-agent scheduling problem by including the total tardiness objective, allowing for preemptions, and considering jobs with different release dates; we consider also identical machines in parallel. We furthermore establish the relationships between two-agent scheduling problems and other areas within the scheduling field, namely rescheduling and scheduling subject to availability constraints.
Phosphorylation mechanism and structure of serine‐arginine protein kinases

The splicing of mRNA requires a group of essential factors known as SR proteins, which participate in the maturation of the spliceosome. These proteins contain one or two RNA recognition motifs and a C‐terminal domain rich in Arg‐Ser repeats (RS domain). SR proteins are phosphorylated at numerous serines in the RS domain by the SR‐specific protein kinase (SRPK) family of protein kinases. RS domain phosphorylation is necessary for entry of SR proteins into the nucleus, and may also play important roles in alternative splicing, mRNA export, and other processing events. Although SR proteins are polyphosphorylated in vivo, the mechanism underlying this complex reaction has only been recently elucidated. Human alternative splicing factor [serine/arginine‐rich splicing factor 1 (SRSF1)], a prototype for the SR protein family, is regiospecifically phosphorylated by SRPK1, a post‐translational modification that controls cytoplasmic–nuclear localization. SRPK1 binds SRSF1 with unusually high affinity, and rapidly modifies about 10–12 serines in the N‐terminal region of the RS domain (RS1), using a mechanism that incorporates sequential, C‐terminal to N‐terminal phosphorylation and several processive steps. SRPK1 employs a highly dynamic feeding mechanism for RS domain phosphorylation in which the N‐terminal portion of RS1 is initially bound to a docking groove in the large lobe of the kinase domain. Upon subsequent rounds of phosphorylation, this N‐terminal segment translocates into the active site, and a β‐strand in RNA recognition motif 2 unfolds and occupies the docking groove. These studies indicate that efficient regiospecific phosphorylation of SRSF1 is the result of a contoured binding cavity in SRPK1, a lengthy Arg‐Ser repetitive segment in the RS domain, and a highly directional processing mechanism.
Study on the Automobile Safe Speed at Rapid Steering

When an automobile works on rapid steering condition, it tends to occur side slip and side tumbling under centrifugal force, the threshold condition at the different steering speed, steering radius, and the different road conditions are derived based on the rapid steering automobile’s stress analyzes. In this paper, the maximum allowable speed of automobile rapid steering without occurring side slip and side tumbling is present. It provides a theory foundation for studying safety and the automobile rapid steering control.
Expression cloning and humoral immune response to the nucleocapsid and membrane proteins of equine arteritis virus

To provide a convenient and sensitive method for the detection of equine arteritis virus (EAV)-specific serum antibodies, we developed an immunoblot assay employing the EAV nucleocapsid (N) and membrane (M) proteins expressed in a procaryotic expression vector (pMAL-c2) for the production of recombinant maltose-binding (MBP) fusion proteins (MBP-N and MBP-M). The antigenic reactivity of the recombinant fusion proteins and their Xa factor cleavage EAV products was confirmed by immunoblot using horse antisera to EAV. Some horse sera, however, showed immune reactivity to the MBP fusion partner protein. Based on a total of 32 horse sera analyzed for the presence of EAV antibodies by immunoblot, using the MBP-N or -M fusion proteins and the Xa factor cleavage EAV products, and in the serum neutralization test, there was 100% concordance between the assays. Sera from horses experimentally infected with EAV were reactive in the immunoblot test with both the MBP-N and the MBP-M fusion proteins by day 14 after EAV exposure. The reactivity continued to the end of the experiment at day 145 after infection. This immune reactivity correlated with the detection of neutralizing antibodies in the serum samples. Based on these findings, the recombinant N and M proteins might be useful for serodetection of EAV-infected animals.
Outpatient Worsening Heart Failure as a Target for Therapy: A Review

Importance Hospitalizations for worsening heart failure (WHF) represent an enormous public health and financial burden, with physicians, health systems, and payers placing increasing emphasis on hospitalization prevention. In addition, maximizing time out of the hospital is an important patient-centered outcome. In this review, we discuss the concept of outpatient WHF, highlight the rationale and data for the outpatient treatment of WHF as an alternative to hospitalization, and examine opportunities and strategies for developing outpatient “interceptive” therapies for treatment of worsening symptoms and prevention of hospitalization. Observations Worsening heart failure has traditionally been synonymous with an episode of in-hospital care for worsening symptoms. While WHF often leads to hospitalization, many patients experience WHF in the outpatient setting and carry a similarly poor prognosis. These findings support WHF as a distinct condition, independent of location of care. For those that are hospitalized, most patients have an uncomplicated clinical course, with diuretics as the only intravenous therapy. Although complicated scenarios exist, it is conceivable that improved tools for outpatient management of clinical congestion would allow a greater proportion of hospitalized patients to receive comparable care outside the hospital. Most patients with WHF have a gradual onset of congestive signs and symptoms, offering a potential window in which effective therapy may abort continued worsening and obviate the need for hospitalization. To date, outpatient WHF has received minimal attention in randomized clinical trials, but this high-risk group possesses key features that favor effective clinical trial investigation. Conclusions and Relevance As the public health and economic burdens of heart failure continue to grow, recognizing the entity of outpatient WHF is critical. Efforts to reduce heart failure hospitalization should include developing effective therapies and care strategies for outpatient WHF. The outpatient WHF population represents a major opportunity for therapeutic advancements that could fundamentally change heart failure care delivery.