Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Interferon Regulatory Factor 3-Mediated Apoptosis in the Establishment and Maintenance of Persistent Infection by Sendai Virus

ABSTRACT Infection of cultured cells by paramyxoviruses causes cell death, mediated by a newly discovered apoptotic pathway activated by virus infection. The key proapoptotic protein in this pathway is interferon regulatory factor 3 (IRF-3), which upon activation by virus infection binds BAX, translocates it to mitochondria, and triggers apoptosis. When IRF-3-knockdown cells were infected with Sendai virus (SeV), persistent infection (PI) was established. The PI cells produced infectious SeV continuously and constitutively expressed many innate immune genes. Interferon signaling was blocked in these cells. The elevated levels of IRF-3-driven genes in the PI cells indicated that the amount of residual IRF-3 activated by endogenous SeV was high enough to drive the transcriptional effects of IRF-3 but too low to trigger its apoptotic activity. We confirmed this IRF-3 threshold idea by generating a tetracycline (Tet)-inducible cell line for IRF-3 expression, which enabled us to express various levels of IRF-3. PI could be established in the Tet-off cell line, and as expected, when doxycycline was withdrawn, the cells underwent apoptosis. Finally, we tested for PI establishment in 12 mouse embryo fibroblasts by natural selection. Eleven lines became persistently infected; although seven out of them had low IRF-3 levels, four did not. When one of the latter four was further analyzed, we observed that it expressed a very low level of caspase 3, the final executor protease of the apoptotic pathway. These results demonstrated that SeV PI can arise from infection of normal wild-type cells, but only if they can find a way to impair the IRF-3-dependent apoptotic pathway.
Colorectal cancer screening with CT colonography, colonoscopy, and double-contrast barium enema examination: prospective assessment of patient perceptions and preferences.

PURPOSE To prospectively assess and compare perceptions of and preferences for computed tomographic (CT) colonography, colonoscopy, and double-contrast barium enema examination (DCBE) by asymptomatic patients undergoing colorectal cancer screening. MATERIALS AND METHODS A total of 696 asymptomatic patients at higher-than-average risk undergoing colorectal cancer screening were consecutively recruited to undergo both CT colonography and colonoscopy (group 1), and a like group of 617 patients was separately recruited to undergo both CT colonography and DCBE (group 2). Standard bowel preparations were different between the groups undergoing colonoscopy and DCBE. Each patient completed a questionnaire that assessed preparation inconvenience and discomfort, examination discomfort, willingness to repeat examinations, and examination preference. Survey results were compared for significance by using the Wilcoxon rank sum or chi2 test. RESULTS The majority of patients considered the preparation to be uncomfortable (group 1, 460 of 515 [89%]; group 2, 482 of 538 [90%]) and inconvenient (group 1, 393 of 502 [78%]; group 2, 427 of 527 [81%]). Reported discomfort was similar at CT colonography and colonoscopy (P =.63) but was less at CT colonography than at DCBE (P <.001). Patients experienced significantly less discomfort than expected at both CT colonography and colonoscopy but not at DCBE. Patients' willingness to undergo frequent rescreening was significantly greater for CT colonography than for either colonoscopy or DCBE. The acceptable time interval between screenings was significantly shorter for all examinations if the bowel preparation could be avoided. Overall, patients preferred CT colonography to colonoscopy (group 1, 72.3% vs 5.1%; P <.001) or to DCBE (group 2, 97.0% vs 0.4%; P <.001). CONCLUSION Patients undergoing colorectal cancer screening prefer CT colonography to both colonoscopy and DCBE. The majority of patients experience discomfort and inconvenience with cathartic bowel preparation.
IL‐1α and IL‐1β have different effects on formation and activity of large osteoclasts

Interleukin 1 (IL‐1) is a proinflammatory cytokine upregulated in conditions such as rheumatoid arthritis and periodontal disease. Both isoforms, IL‐1α and IL‐1β, have been shown to activate osteoclasts (OCs), the cells responsible for resorbing bone. Inflammatory conditions are also characterized by increased bone loss and by the presence of large OCs (10+ nuclei). We and others have previously shown that large OCs are more likely to be resorbing compared to small OCs (2–5 nuclei). Moreover, large OCs express higher levels of the IL‐1 activating receptor IL‐1RI, integrins αv and β3, RANK, and TNFR1, while small OCs have higher levels of the decoy receptor IL‐1RII. We hypothesized that IL‐1 would have different effects on large and small OCs due to these distinct receptor expression patterns. To test this hypothesis, RAW 264.7 cells were differentiated into populations of small and large OCs and treated with IL‐1α or IL‐1β (1 and 10 ng/ml). In the presence of sRANKL, both IL‐1α and IL‐1β increased total OC number and resorptive activity of large OCs. IL‐1α stimulated formation of large OCs and increased the number of resorption pits, while IL‐1β changed the morphology of large OCs and integrin‐β3 phosphorylation. No effects were seen in small OCs in response to either IL‐1 isoform. These results demonstrate that IL‐1 predominantly affects large OCs. The dissimilarity of responses to IL‐1α and IL‐1β suggests that these isoforms activate different signaling pathways within the two OC populations. J. Cell. Biochem. 109: 975–982, 2010. © 2010 Wiley‐Liss, Inc.
Novel α2β1 Integrin Inhibitors Reveal That Integrin Binding to Collagen under Shear Stress Conditions Does Not Require Receptor Preactivation*

Background: Integrin α2β1 is a platelet collagen receptor. Results: Novel sulfonamide derivatives are conformation-selective inhibitors of α2β1, especially when tested under shear stress conditions. Only inhibitors that block non-activated integrins inhibit platelet binding to collagen. Conclusion: Non-activated α2β1 integrin plays an important role in platelet binding to collagen. Significance: We propose an alternative model for α2β1 activation during thrombosis. The interaction between α2β1 integrin (GPIa/IIa, VLA-2) and vascular collagen is one of the initiating events in thrombus formation. Here, we describe two structurally similar sulfonamide derivatives, BTT-3033 and BTT-3034, and show that, under static conditions, they have an almost identical effect on α2-expressing CHO cell adhesion to collagen I, but only BTT-3033 blocks platelet attachment under flow (90 dynes/cm2). Differential scanning fluorimetry showed that both molecules bind to the α2I domain of the recombinant α2 subunit. To further study integrin binding mechanism(s) of the two sulfonamides, we created an α2 Y285F mutant containing a substitution near the metal ion-dependent adhesion site motif in the α2I domain. The action of BTT-3033, unlike that of BTT-3034, was dependent on Tyr-285. In static conditions BTT-3034, but not BTT-3033, inhibited collagen binding by an α2 variant carrying a conformationally activating E318W mutation. Conversely, in under flow conditions (90 dynes/cm2) BTT-3033, but not BTT-3034, inhibited collagen binding by an α2 variant expressing E336A loss-of-function mutation. Thus, the binding sites for BTT-3033 and BTT-3034 are differentially available in distinct integrin conformations. Therefore, these sulfonamides can be used to study the biological role of different functional stages of α2β1. Furthermore, only the inhibitor that recognized the non-activated conformation of α2β1 integrin under shear stress conditions effectively blocked platelet adhesion, suggesting that the initial interaction between integrin and collagen takes place prior to receptor activation.
Gametocytogenesis of Plasmodium falciparum in vitro: an electron microscopic study

SUMMARY Plasmodium falciparum was grown in vitro in blood taken from naturally infected Gambian patients, and the development of the cultured sexual parasites was studied by light and electron microscopy. The young (Stage II and III) female gametocytes undergo a single cryptomitotic nuclear division. This division immediately follows the S phase which Sinden & Smalley (1979) have demonstrated in the Stage I and II gametocytes of both sexes. The male gametocytes, by contrast, do not undergo mitosis during their maturation period in the erythrocyte and thus remain polyploid. Hence the cell cycles of the male and female gametocytes differ significantly. The ultrastructural basis of the characteristic changes in shape of the developing gametocyte are shown to be due to the assembly and subsequent loss of components of the sub-pellicular membranous and microtubular cytoskeleton. Stage I–III gametocytes synthesize numerous ribosomes and endoplasmic reticulum. This correlates with the active synthesis of RNA and protein in these young parasites (Sinden & Smalley, 1979). The marked reduction in macromolecular synthesis in the mature parasites is paralleled by a reduction in cytoplasmic ribosome density in the male gametocyte only. In the female, however, this reduction in activity is correlated with the appearance of a nucleolus. These changes suggest that different mechanisms are being used to control RNA synthesis in the two sexes of gametocyte.
The IL-1–Dependent Sterile Inflammatory Response Has a Substantial Caspase-1–Independent Component That Requires Cathepsin C

The sterile inflammatory response to cell death and irritant crystals is medically important because it causes disease. Although these stimuli are structurally distinct, they cause inflammation through a common pathway that requires the cytokine IL-1. In vitro, the inflammasome, and in particular its generation of active caspase-1, is absolutely required to produce bioactive IL-1β. However, in this study, we report that caspase-1 is not required in vivo for much of the IL-1β–dependent sterile inflammatory response. Furthermore, we find that cathepsin C, which controls the activity of a number of leukocyte serine proteases capable of processing IL-1β, plays a major role in this caspase-1–independent pathway. Mice that are deficient in cathepsin C have reduced inflammatory responses to dying cells and silica crystals. In the absence of cathepsin C, caspase-1 becomes rate limiting such that mice doubly deficient in both of these proteases make little IL-1β in vivo and have markedly attenuated inflammatory responses to the sterile stimuli. In contrast, these mutant mice generate normal inflammation in response to exogenous IL-1β, indicating that cathepsin C and caspase-1 function upstream of IL-1β, and, in their absence, all components of the pathway downstream of mature IL-1β are intact.
Perennial rhinitis in the under 4s: A difficult problem to treat safely and effectively? A comparison of intranasal fluticasone propionate and ketotifen in the treatment of 2–4‐year‐old children with perennial rhinitis

To compare the safety and efficacy of fluticasone propionate aqueous nasal spray (FPANS) and oral ketotifen in children aged 2–4 years with perennial rhinitis. A randomized, multicentre, double‐blind, double dummy, placebo‐controlled study. Paediatric patients between the ages of 2–4 years with perennial rhinitis. Rhinitis symptoms score (parent‐rated), clinical evaluation of symptoms (investigator‐rated) and adverse event profiles during the treatment period. Patients treated with FPANS had a significant reduction in both the total night‐time rhinitis symptom assessment for weeks 4–6 (p‐value 0.036), and the total daytime rhinitis symptom score over the same period (p‐value 0.049). Generally, except for nasal itching/rubbing over weeks 1–3, the patients taking FPANS had lower recorded symptom scores for all individual symptoms measured. Nasal blockage, in particular, was significantly reduced over the 4–6 week period (p‐value 0.027). The overall investigator‐rated clinical evaluation showed substantial improvement or improvement in nine of 12 of the children taking FPANS compared with four of 14 taking ketotifen. Finally, there were no reports of serious adverse events, the incidence of drug‐related adverse events was low and there was no statistical difference between the groups. FPANS may be an appropriate treatment to control the symptoms of rhinitis in children between 2 and 4 years old.
Duration of antihypertensive drug use and risk of dementia

Background: The evidence from prospective observational research for a protective effect of antihypertensive drug use on the risk of dementia is far from uniform. Duration of follow-up was limited and relied mainly on baseline drug exposure data without information on duration of use. We investigated the association between the duration of antihypertensive use and risk of dementia. Methods: We followed 6,249 participants (mean 68.4 years, 60% women) of a prospective, population-based cohort from baseline (1990–1993) until 2005 for incident dementia. Continuous data on filled prescriptions came from pharmacy records. Total cumulative duration of antihypertensive use was expressed in years. We subtracted a latent 4-year period before the date of dementia diagnosis in the quantification of exposure duration to avoid potential bias in antihypertensive prescription due to prodromal changes in blood pressure or cognition. With Cox regression models, we calculated crude and adjusted hazard ratios (HRs) of all dementia and Alzheimer disease (AD) with antihypertensive use vs never used. Results: Compared to never used, antihypertensive use was associated with a reduced risk of all dementia (adjusted HR per year of use 0.95; 95% confidence interval [CI] 0.91–0.99). We observed an 8% (95% CI −15% to −1%) risk reduction per year of use for persons ≤75 years, whereas for persons >75 years this was 4% (95% CI −11% to 4%). Equivalent estimates were observed for AD. No apparent differences were observed among different types of antihypertensive drugs. Conclusions: Antihypertensive drug use was associated with 8% risk reduction of dementia per year of use for persons ≤75 years.
Systematic Review and Meta-analysis of Outcomes After Hip Arthroscopy in Femoroacetabular Impingement

Background: Femoroacetabular impingement (FAI) has become a more commonly recognized cause of limited hip range of motion and hip pain among young adults and athletes. Hip arthroscopy is recommended for the surgical treatment of this disorder, unless specific contraindications exist. Despite the increasing rate of published studies in this area, there remains no aggregate data for outcomes after this approach. Purpose: To evaluate risk factors and outcomes after arthroscopic management of FAI, including return to play, revision rate, surgical and nonsurgical complications, change in α-angle, intraoperative bone resection, and patient-reported outcomes. Study Design: Meta-analysis and systematic review. Methods: A review of the current literature was performed with the terms “femoroacetabular impingement,” “hip arthroscopy,” and numerous variations thereof in PubMed, EMBASE, BioMed Central, Cochrane, Science Direct, and Scopus, yielding 1723 abstracts. After screening by eligibility criteria, 31 articles were included. The incidence of bilateral FAI was determined by enrollment data, and pooled estimates were calculated for postoperative patient-reported outcome measures, α-angles, return to sport, postoperative complications, and reoperation risk. Results: A total of 1981 hips among 1911 patients were identified, with a mean ± SD age of 29.9 ± 1.9 years and 29.5 ± 14.0 months of follow-up. The incidence of bilateral FAI in these studies that required operative intervention was 3.6%. The pooled risk of reoperation after hip arthroscopy, including revision surgery or subsequent total hip arthroplasty, was 5.5% (95% CI, 3.6%-7.5%). The risk of clinical complications was 1.7% (95% CI, 0.9%-2.5%). In total, 87.7% of patients demonstrated return to sport after surgery (95% CI, 82.4%-92.9%, P < .001), and all patient-reported outcomes improved postoperatively, with the highest increase observed in the Hip Outcome Score sports scale (41.7 points; 95% CI, 34.1-49.4; P < .001). The α-angle decreased by an average of 23.6° (95% CI, 18.2°-29.0°; P < .001). We identified 11 factors associated with the success of hip arthroscopy in FAI and 16 factors associated with failure or negative outcomes. Conclusion: A high percentage of patients return to sport activities after hip arthroscopy for FAI, with a low rate of complications and reoperation. All patient-reported outcome measures, except for mental health, significantly improved after surgery.
Serum cholesterol in young men and subsequent cardiovascular disease.

BACKGROUND The increased risk of cardiovascular disease associated with higher serum cholesterol levels in middle-aged persons has been clearly established, but there have been few opportunities to examine a potential link between serum cholesterol levels measured in young men and clinically evident premature cardiovascular disease later in life. METHODS We performed a prospective study of 1017 young men (mean age, 22 years) followed for 27 to 42 years to quantify the risk of cardiovascular disease and total mortality associated with serum cholesterol levels during early adult life. The mean serum cholesterol level at entry was 192 mg per deciliter (5.0 mmol per liter). RESULTS During a median follow-up of 30.5 years, there were 125 cardiovascular-disease events, 97 of which were due to coronary heart disease. The serum cholesterol level at base line was strongly associated with the incidence of events related to coronary heart disease and cardiovascular disease, as well as to total mortality and mortality due to cardiovascular disease. The risks were similar whether the events occurred before or after the age of 50. In a proportional-hazards analysis adjusted for age, body-mass index (the weight in kilograms divided by the square of the height in meters), the level of physical activity, coffee intake, change in smoking status, and the incidence of diabetes and hypertension during follow-up, a difference in the serum cholesterol level at base line of 36 mg per deciliter (0.9 mmol per liter)--the difference between the 25th and 75th percentiles of cholesterol level in the study population at base line--was associated with an increased risk of cardiovascular disease (relative risk, 1.72; 95 percent confidence interval, 1.39 to 2.14), coronary heart disease (relative risk, 2.01; 95 percent confidence interval, 1.59 to 2.53), and mortality due to cardiovascular disease (relative risk, 2.02; 95 percent confidence interval, 1.23 to 3.32). A difference in the base-line serum cholesterol level of 36 mg per deciliter was significantly associated with an increased risk of death before the age of 50 (relative risk, 1.64; 95 percent confidence interval, 1.03 to 2.61), but not with the overall risk of death (relative risk, 1.21; 95 percent confidence interval, 0.93 to 1.58). CONCLUSIONS These findings indicate a strong association between the serum cholesterol level measured early in adult life in men and cardiovascular disease in midlife.
Comparison of Venous Admixture during High‐Frequency Ventilation and Conventional Ventilation in Oleic Acid‐Induced Pulmonary Edema in Dogs

High-frequency jet ventilation (HFJV) was compared with conventional ventilation during oleic acid-induced pulmonary edema in dogs. HFJV, when combined with positive end-expiratory pressure (PEEP), returned arterial Po2 (Pao2) and venous admixture to preoleic acid levels, even with tidal volumes as low as 4.8 ml/kg and rates of 300 min-1. When HFJV was compared with conventional (low-frequency, high tidal volume) ventilation at the same Fio2 and level of PEEP, Pao2 was lower and venous admixture higher with HFJV. However, venous admixture was lower with HFJV when comparisons were made at the same peak airway pressure, because of a higher level of PEEP compared with conventional ventilation. At each level of PEEP, cardiac and stroke indices were not different between the two methods of ventilation. The ability to eliminate CO2 with lower peak airway pressures or to increase PEEP without further increases in peak airway pressure are the primary advantages of HFJV during severe lung injury. Oxygenation is as efficient during HFJV as during conventional ventilation in this model of pulmonary edema when comparisons are made at the same peak airway pressure, but less efficient at the same PEEP.
Environmental sampling for evaluating verotoxigenic Escherichia coli O157

Verotoxigenic Escherichia coli O157:H7 is a zoonotic bacterial pathogen capable of causing severe disease in human beings. Cattle are considered to be the main reservoir of the bacterium. The objective of the current study was to compare environmental sampling (consisting of dust, overshoe, and pooled pat samples) with pooled, individual fecal sampling for determining the cattle herd status under field conditions in naturally infected dairy herds. Thirty-one dairy cattle farms in Sweden, where verotoxigenic E. coli O157:H7 had been previously detected, were visited. On each farm, dust, overshoe, and pooled pat sampling were performed in each of 3 different age categories: calves, young stock, and adults. In addition, up to 140 individual fecal samples were collected and analyzed as pooled samples. In total, 3,763 individual fecal and 270 environmental samples were collected and analyzed for the presence of verotoxigenic E. coli O157:H7. Overshoe sampling, alone or in combination with dust and pooled pat sampling, correctly classified 20 of the 24 (0.83, 95% CI: 0.63–0.95) herds detected with at least 1 positive pool. On 1 farm, a dust sample was positive although all other samples were negative. In 6 of the 31 farms, the bacteria could not be detected in any of the individual fecal samples or in the environmental samples. The results establish that environmental sampling is a reliable method for identifying cattle herds with animals shedding verotoxigenic E. coli O157:H7.
Impact of therapy on the outcome of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection is a dynamic state in which HBV replication is the key driving force of disease progression, resulting in the development of hepatic decompensation, cirrhosis and hepatocellular carcinoma (HCC). The primary aim of therapy is to eliminate or suppress HBV to reduce the activity of hepatitis thus reducing the risk of or slowing the progression of liver disease. Treatment with nucleos(t)ide analogues (Nuc) may result in rapid suppression of HBV replication with normalization of serum transaminases and restore liver function thus increasing survival in patients with hepatic decompensation. The long‐term benefits of a finite course of interferon α (IFN) therapy include a sustained and cumulative response, as well as a reduction in the progression of fibrosis and in the development of cirrhosis and/or HCC. Long‐term Nuc therapy may also result in histological improvement or reversal of advanced fibrosis and reduction in disease progression including the development of HCC. Hepatitis B surface antigen (HBsAg) seroclearance, a status close to a “cure”, may also occur in patients with a sustained or maintained viral response, especially in those with IFN‐based therapy. Pegylated IFN (PEG‐IFN) and newer Nucs may have even better long‐term outcomes because of improved efficacy and/or a low risk of drug resistance. However, treatment outcomes are still far from satisfactory. The development of more effective and safe but affordable anti‐HBV agents/strategies is needed to further improve outcomes.