Miracle-dz/UniFAR-FTUs huggingface dataset:
AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Alterations in metabolic and bioenergetic homeostasis contribute to sepsis-mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3β signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteria ex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3β inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicate P. aeruginosa in the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF-1α as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression.
Effects of Cimetidine and Ranitidine on Local Anesthetic Central Nervous System Toxicity in Mice

The effects of cimetidine (5–200 mg/kg), ranitidine (1–100 mg/kg), or saline on local anesthetic central nervous system toxicity was studied when administered 20 min before the administration of lidocaine (30–80 mg/kg) or 2-chloropro-caine (50–250 mg/kg) to female white CD-1 mice. All drugs were administered intraperitoneally. The 50% convulsive dose (CD50) was determined for each drug and dose combination. Pretreatment with cimetidine resulted in a significant, dose-dependent decrease in the CD50 of lidocaine, whereas ranitidine pretreatment did not significantly alter the lidocaine CD50. A dose of cimetidine (15 mg/kg) that caused a significant decrease in 2-choloroprocaine CD50 (from 180 to 110 mg/kg) caused only an insignificant decrease in lidocaine CD50 (from 59 to 54 mg/kg). If these results can be applied to clinical doses in humans, ranitidine may be a safer premedicant than cimetidine with regard to interactions with local anesthetics.
Efficacy and Safety of Pantoprazole Delayed-release Granules for Oral Suspension in a Placebo-controlled Treatment-withdrawal Study in Infants 1–11 Months Old With Symptomatic GERD

Objective: The objective of this study was to assess the efficacy of pantoprazole in infants with gastroesophageal reflux disease (GERD). Materials and Methods: Infants ages 1 through 11 months with GERD symptoms after 2 weeks of conservative treatment received open-label (OL) pantoprazole 1.2 mg · kg−1 · day−1 for 4 weeks followed by a 4-week randomized, double-blind (DB), placebo-controlled, withdrawal phase. The primary endpoint was withdrawal due to lack of efficacy in the DB phase. Mean weekly GERD symptom scores (WGSSs) were calculated from daily assessments of 5 GERD symptoms. Safety was assessed. Results: One hundred twenty-eight patients entered OL treatment, and 106 made up the DB modified intent-to-treat population. Mean age was 5.1 months (82% full-term, 64% male). One third of patients had a GERD diagnostic test before OL study entry. WGSSs at week 4 were similar between groups. WGSSs decreased significantly from baseline during OL therapy (P < 0.001), when all patients received pantoprazole. The decrease in WGSSs was maintained during the DB phase in both treatment groups. There was no difference in withdrawal rates due to lack of efficacy (pantoprazole 6/52; placebo 6/54) or time to withdrawal during the DB phase. The greatest between-group difference in WGSS was slightly worse with placebo at week 5 (P = 0.09), mainly due to episodes of arching back (P = 0.028). No between-group differences in adverse event frequency were noted. Serious adverse events in 8 patients were considered unrelated to treatment. Conclusions: Pantoprazole significantly improved GERD symptom scores and was well tolerated. However, during the DB treatment phase, there were no significant differences noted between pantoprazole and placebo in withdrawal rates due to lack of efficacy.
Selectivity of partial agonists related to oxotremorine based on differences in muscarinic receptor reserve between the guinea pig ileum and urinary bladder.

The muscarinic effects of analogs of oxotremorine were compared on strips of the guinea pig ileum and urinary bladder. In a series of eight analogs, full or nearly full contractile responses compared to carbachol were observed on the ileum. On the bladder, the analogs were full agonists, partial agonists, or competitive antagonists. Although EC50 values estimated on the bladder were 10- to 20-fold greater than those obtained on the ileum, the dissociation constant and relative efficacy of each agonist were similar in the two tissues, as were dissociation constants of competitive antagonists including pirenzepine. The ability to discriminate between responses in the ileum and bladder was related to intrinsic efficacy. Highly efficacious compounds such as carbachol and oxotremorine-M were full agonists in both tissues, although less potent on the bladder. Compounds having intermediate intrinsic efficacy, e.g., oxotremorine, were partial agonists on the bladder, whereas BM 5, having low intrinsic efficacy, was a competitive antagonist. These results suggest a mechanism, based on tissue differences in receptor reserve, by which selectivity may be achieved among muscarinic stimulants, even in the absence of distinct subtypes of muscarinic receptors.
Follicular dendritic cells confirm lymphoid organization in the minor salivary glands of primary Sjögren's syndrome.

BACKGROUND Sjögren's syndrome (SS) is an autoimmune chronic inflammatory disorder affecting the salivary and lacrimal glands. The aim of this study was to explore immunophenotypic features of chronic inflammatory reactions in the minor salivary glands in patients with primary SS (pSS). METHODS Formalin-fixed, paraffin-embedded labial minor salivary gland tissue sections from randomly selected patients with pSS (n = 60) were investigated for the expression of CD21, CD23, CD35 and IgD by immunohistochemistry. RESULTS Based on the distribution and staining pattern of CD21, CD23, CD35 and IgD in lymphoid aggregates, several stages of chronic inflammatory reactions were observed. In 12/60 (20%) patients, lymphoid infiltrates with germinal centre (GC)-like features such as extensive networks of CD21-, CD23- and CD35-positive cells were observed in the minor salivary gland tissue. Smaller networks and /or focal infiltrates with scattered CD21(+), CD23(+) and CD35(+) cells were observed in the remaining 48/60 (80 %) cases. When dividing patients according to the presence (GC+) or the absence (GC-) of GC in the minor salivary glands, the mean focus score was significantly higher in the GC+ patients (P < 0.05). Double staining of the minor salivary glands revealed focal infiltrates with follicular dentritic cell networks and B cells resembling normal GCs in tonsillar tissue. CONCLUSION A particular cellular profile was demonstrated in a sub-group of patients with pSS and could be linked to serological aberrations. These findings warrant further prospective studies.
Detection of Malingering Using Atypical Performance Patterns on Standard Neuropsychological Tests

Cut-off scores defining clinically atypical patterns of performance were identified for five standard neuropsychological and psychological tests: Benton Visual Form Discrimination (VFD), Fingertapping (FT), WAIS-R Reliable Digit Span (RDS), Wisconsin Card Sorting Failure-to-Maintain Set (FMS), and the Lees-Haley Fake Bad Scale (FBS) from the MMPI-2. All possible pair-wise combinations of scores beyond cut-off (e.g., for VFD and FT; for RDS and FBS), correctly identified 21 of 24 subjects (87.5%) meeting criteria for definite malingered neurocognitive dysfunction, and 24 of 27 (88.9%) subjects with moderate to severe closed head injury. On cross-validation, 15 of 17 subjects (88.2%) meeting criteria for probable malingered neurocognitive dysfunction were correctly identified, with 13 of 13 nonlitigating neurologic patients, and 14 of 14 nonlitigating psychiatric patients correctly classified as having motivationally-preserved performance. Combining the derivation and cross-validation samples yielded a sensitivity of 87.8%, specificity of 94.4%, and combined hit rate of 91.6%.
Association of salivary Streptococcus mutans with caries in young children: effect of dental health education on salivary levels.

AIM This study aimed to determine the effect of a long-term dental health education (DHE) for mothers with young children on the level of salivary Streptococci mutans (SM) and their association with caries in young children. METHODS A randomly selected cohort of 228 children born between 1 January and 30 September 1995, in a low socioeconomic high caries suburb of Leeds (UK), was divided into the following groups: A) DHE focused on diet; B) DHE focused on oral hygiene instruction (OHI) using fluoride toothpaste; C) DHE by a combined diet and OHI message. DHE was given using an interview and counselling for at least 15 minutes in each child's home, every three months for the first two years and twice a year in the third year of the study. A fourth group D was given diet and OHI, at home, but once a year only. The children in a fifth group E (control), received no DHE and were never visited, but examined at three years of age only. All children and mothers were examined for caries using the BASCD criteria. The levels of salivary SM were determined by sampling of bacteria from the oral cavity with a 1.8 cm wide wooden spatula, after giving the mother a paraffin pellet to chew for a minute and in children using unstimulated saliva. Bacteria were plated out and counted using image analysis for counting colonies. RESULTS At three years of age the difference in the level of salivary SM between groups was not statistically significant. However, in group E there was a statistically significant relationship (p<0.05) between salivary SM and caries in children. CONCLUSION The difference in the level of salivary SM between groups given various programs of dental health education was not statistically significant. There was a statistically significant (p<0.05) relationship between salivary MS and caries in children.
Establishment of an endobronchial ultrasound‐guided transbronchial fine needle aspiration service with rapid on‐site evaluation: 2 years experience of a single UK centre

Endobronchial ultrasound (EBUS)‐guided transbronchial fine needle aspiration (TBFNA) is now well established as a minimally invasive, effective investigation which can provide information on both diagnosis and stage of lung cancer and is also useful in the investigation of mediastinal lymphadenopathy of uncertain aetiology. The service can be provided with or without rapid on‐site evaluation (ROSE) for specimen triage and provisional diagnosis. We outline our experience from the first 2 years of providing an EBUS service with ROSE, highlighting the practicalities of service provision, pitfalls encountered and lessons learned.
Recent UK trends in the unequal burden of coronary heart disease

Introduction The burden of coronary heart disease (CHD) in the UK is substantial. However, recent trends and associated socioeconomic inequalities are not well studied. We aim to identify and analyse these trends stratified by age, gender and socioeconomic quintiles. Methods We quantified the CHD burden and analysed trends from 1999 to 2007 in all adults aged over 25 years resident in England. Data sources included deaths (from ONS), health surveys, and hospital admissions (from Hospital Episode Statistics), all using ICD9 and ICD10 coding. Socioeconomic inequalities were calculated in both absolute and relative terms. Results In 2007, the CHD burden comprised approximately 205 000 hospital admissions (acute and elective), including approximately 110 000 admissions with acute coronary syndrome. There were approximately 1.5 million CHD patients with chronic disease living in the community. Approximately 67 500 of these were admitted during 2007 for revascularisation. There were approximately 173 000 CHD patients living with heart failure, of whom some 14% required hospital admission during 2007. Between 1999 and 2007, age-specific hospital admission rates generally decreased by 20%–35%. Community prevalence decreased by 10%–20%. Strong socioeconomic gradients were apparent in all patient groups, persisting or worsening between 1999 and 2007. Conclusions The burden of CHD is immense, costly and unequal. Hospital admissions attract more attention than the far more numerous patients living with chronic disease in the community. Population-based rates for hospital admissions and CHD prevalence have been declining by 3%–4% per annum. However, marked socioeconomic gradients have persisted or worsened—there is no room for complacency.
Measuring Quality beyond Test Scores: The Impact of Regional Context on Curriculum Implementation (in Northern Uganda).

Although global initiatives have brought attention to the lack of quality in education systems worldwide; the question remains, how do we implement quality education? Teachers, a vital component of the education process, are not usually included in these global conversations; this results in government initiatives missing key obstacles faced by teachers daily. In this article, we used a rights-based approach to examine the Quality Educators Initiative, specifically its curricular component, as it tries to assist teachers in northern Uganda, an area whose schools and communities are vastly under-resourced and dealing with post-conflict effects. Using a mixed-methods approach, we highlight teachers’ experiences with the National Thematic Curriculum and reveal through our findings that regional contextual factors, and teachers’ voices and changing roles due to these factors, must be taken into consideration when rolling out new education policies. The full text of the article can be found at 10.18275/fire201704011110
Viral and Cellular Determinants of the Hepatitis C Virus Envelope-Heparan SulfateInteraction

ABSTRACT Cellular binding and entry of hepatitis C virus (HCV) are the first steps of viral infection and represent a major target for antiviral antibodies and novel therapeutic strategies. We have recently demonstrated that heparan sulfate (HS) plays a key role in the binding of HCV envelope glycoprotein E2 to target cells (Barth et al., J. Biol. Chem. 278:41003-41012, 2003). In this study, we characterized the HCV-HS interaction and analyzed its inhibition by antiviral host immune responses. Using recombinant envelope glycoproteins, virus-like particles, and HCV pseudoparticles as model systems for the early steps of viral infection, we mapped viral and cellular determinants of HCV-HS interaction. HCV-HS binding required a specific HS structure that included N-sulfo groups and a minimum of 10 to 14 saccharide subunits. HCV envelope binding to HS was mediated by four viral epitopes overlapping the E2 hypervariable region 1 and E2-CD81 binding domains. In functional studies using HCV pseudoparticles, we demonstrate that HCV binding and entry are specifically inhibited by highly sulfated HS. Finally, HCV-HS binding was markedly inhibited by antiviral antibodies derived from HCV-infected individuals. In conclusion, our results demonstrate that binding of the viral envelope to a specific HS configuration represents an important step for the initiation of viral infection and is a target of antiviral host immune responses in vivo. Mapping of viral and cellular determinants of HCV-HS interaction sets the stage for the development of novel HS-based antiviral strategies targeting viral attachment and entry.
Keyhole Limpet Hemocyanin for Carcinoma in situ of the Bladder: A Long-Term Follow-Up Study

Objective: Keyhole limpet hemocyanin (KLH) is a nonspecific immunomodulator, demonstrated to be clinically effective in superficial bladder cancer. The present study investigated the clinical efficacy of intravesical KLH in patients with carcinoma in situ (CIS) with a long-term follow-up. Methods: Thirteen patients with CIS grade III were treated with intravesical instillations of KLH, 20 mg for 6 weeks, then monthly for 1 year and bimonthly for 2 subsequent years. Patients not responding to 2 courses of KLH were treated with bacillus Calmete-Guérin (BCG, 81 mg Connaught strain). Results: The follow-up period ranged from 12 to 84 months. Two patients were free of tumor after KLH instillations with a follow-up of 66 and 82 months, respectively. All patients who did not respond to the primary KLH course, but to the ‘rescue’ instillation of BCG, experienced recurrences after 42, 48, 56 and 60 months after the first KLH instillation treatment. Three patients with recurrent CIS and who were not cystectomized had recurrences after prolonged remission (4–5 years). Patients progressing despite KLH and BCG instillations underwent cystectomy. Conclusions: KLH demonstrates efficacy and induces long- term remissions against CIS in a limited number of cases. In the present study, most patients with CIS progressed over time whatever the substance instilled, whether KLH or BCG. CIS remains a very aggressive neoplasm requiring a lifelong follow-up. Further studies are necessary to define the precise role of KLH in patients with CIS.
Human Immunodeficiency Virus Type 1-Induced Macrophage Gene Expression Includes the p21 Gene, a Target for Viral Regulation

ABSTRACT In contrast to CD4+ T cells, human immunodeficiency virus type 1 (HIV-1)-infected macrophages typically resist cell death, support viral replication, and consequently, may facilitate HIV-1 transmission. To elucidate how the virus commandeers the macrophage's intracellular machinery for its benefit, we analyzed HIV-1-infected human macrophages for virus-induced gene transcription by using multiple parameters, including cDNA expression arrays. HIV-1 infection induced the transcriptional regulation of genes associated with host defense, signal transduction, apoptosis, and the cell cycle, among which the cyclin-dependent kinase inhibitor 1A (CDKN1A/p21) gene was the most prominent. p21 mRNA and protein expression followed a bimodal pattern which was initially evident during the early stages of infection, and maximum levels occurred concomitant with active HIV-1 replication. Mechanistically, viral protein R (Vpr) independently regulates p21 expression, consistent with the reduced viral replication and lack of p21 upregulation by a Vpr-negative virus. Moreover, the treatment of macrophages with p21 antisense oligonucleotides or small interfering RNAs reduced HIV-1 infection. In addition, the synthetic triterpenoid and peroxisome proliferator-activated receptor γ ligand, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), which is known to influence p21 expression, suppressed viral replication. These data implicate p21 as a pivotal macrophage facilitator of the viral life cycle. Moreover, regulators of p21, such as CDDO, may provide an interventional approach to modulate HIV-1 replication.
Heparin‐induced amyloid fibrillation of β2‐microglobulin explained by solubility and a supersaturation‐dependent conformational phase diagram

Amyloid fibrils are fibrillar deposits of denatured proteins associated with amyloidosis and are formed by a nucleation and growth mechanism. We revisited an alternative and classical view of amyloid fibrillation: amyloid fibrils are crystal‐like precipitates of denatured proteins formed above solubility upon breaking supersaturation. Various additives accelerate and then inhibit amyloid fibrillation in a concentration‐dependent manner, suggesting that the combined effects of stabilizing and destabilizing forces affect fibrillation. Heparin, a glycosaminoglycan and anticoagulant, is an accelerator of fibrillation for various amyloidogenic proteins. By using β2‐microglobulin, a protein responsible for dialysis‐related amyloidosis, we herein examined the effects of various concentrations of heparin on fibrillation at pH 2. In contrast to previous studies that focused on accelerating effects, higher concentrations of heparin inhibited fibrillation, and this was accompanied by amorphous aggregation. The two‐step effects of acceleration and inhibition were similar to those observed for various salts. The results indicate that the anion effects caused by sulfate groups are one of the dominant factors influencing heparin‐dependent fibrillation, although the exact structures of fibrils and amorphous aggregates might differ between those formed by simple salts and matrix‐forming heparin. We propose that a conformational phase diagram, accommodating crystal‐like amyloid fibrils and glass‐like amorphous aggregates, is important for understanding the effects of various additives.
Biodegradable Interference Screw Fixation Exhibits Pull-Out Force and Stiffness Similar to Titanium Screws

Recently, increased interest in biodegradable interference screws for bone-tendon-bone graft fixation has led to numerous screws becoming available. The implants are made from different polymers and have different designs, which might influence their mechanical properties. Several studies have reported a wide range of mechanical results for these screws using different biomechanical models. The aim of the present study is to compare reliable biomechanical data for six different biodegradable interference screws, consisting of five different polymers, with a conventional titanium screw in a standardized model. Seventy proximal calf tibias were used to determine maximal pull-out force, stiffness of fixation, and insertion torque for interference screw fixation of bone-tendon-bone grafts. Additionally, maximal torque at failure was determined. Data were analyzed with respect to aspects of screw design, such as drive and thread shape. Five of the six biodegradable screws provided initial pull-out force and stiffness of fixation comparable with that of a conventional titanium screw. Torque at failure can be greatly increased by adapting the drive design to the mechanical properties of the polymeric raw material. A correlation between pull-out force and thread height indicates that fixation rigidity depends on screw design, even in a biodegradable implant.