Miracle-dz/UniFAR-FTUs huggingface dataset:
Use-Dependent Block by Lidocaine but Not Amitriptyline Is More Pronounced in Tetrodotoxin (TTX)-Resistant Nav1.8 Than in TTX-Sensitive Na+ Channels

The excitability of sensory neurons depends on the expression of various voltage-gated Na+ channel isoforms. The tetrodotoxin-resistant (TTXr) Na+ channel Nav1.8 accounts for the electroresponsiveness of nociceptive neurons and contributes to inflammatory and neuropathic pain. Na+ channel blockers are clinically employed for chronic pain management, but side effects limit their use. There is conflicting information whether their potency to block tetrodotoxin-sensitive (TTXs) and TTXr Na+ channels differs. We analyzed the action of lidocaine and amitriptyline on TTXr Nav1.8 heterologously expressed in ND7/23 cells in comparison with TTXs Na+ channels endogenously expressed in ND7/23 cells. TTXr Nav1.8 and TTXs currents were investigated under whole-cell voltage-clamp. At a holding potential of –80 mV, lidocaine was 5-fold and amitriptyline 8-fold more potent to tonically block TTXs than Nav1.8 currents. This was due to a higher percentage of TTXs channels residing in the inactivated, high-affinity state at this potential. Tonic block of either resting or inactivated channels by lidocaine or amitriptyline revealed little differences between TTXs and Nav1.8 channels. Use-dependent block by amitriptyline was similar in TTXs and Nav1.8 channels. Surprisingly, use-dependent block by lidocaine was more pronounced in Nav1.8 than in TTXs channels. This result was confirmed in dorsal root ganglion neurons and is associated with the greater tendency of Nav1.8 to enter a slow inactivated state. Our data suggest that lidocaine could selectively block Nav1.8-mediated action potential firing. It is conceivable that the expression pattern of Na+ channels in sensory neurons might influence the efficiency of Na+ channel blockers used for chronic pain management.
Short Communication p53 Codon 72 Polymorphic Variants, Loss of Allele-Specific Transcription, and Human Papilloma Virus 16 and/or 18 E6 Messenger RNA Expression in Squamous Cell Carcinomas of the Head and Neck

A polymorphism at codon 72 of the human tumor suppressor p53 determines translation into either arginine or proline. Yet, the impact of this amino acid variability on the risk to develop malignant tumors, particularly carcinomas associated with human papilloma virus (HPV) infections, remains unresolved because of contradictory results. To address a potential correlation between the different genotypes and the manifestation of squamous cell carcinomas of the head and neck (SCCHN), we determined the p53 codon 72 in 193 healthy subjects and 122 unselected SCCHN with known HPV status. Furthermore, loss of allele-specific transcription was analyzed in p53 codon 72 heterozygous (Arg/Pro) SCCHN and correlated with HPV 16 and/or 18 E6 transcript expression. We found a moderately increased risk (odds ratio, 1.86; 95% confidence interval, 1.0-3.3) for individuals with germ line heterozygosity to develop SCC of the pharynx. On the other hand, p53 codon 72 polymorphic variants, most notably the Arg/Arg genotype, showed no association with the presence of HPV 16 and/or 18 E6 transcript. Moreover, there was no evidence for HPVdriven selection in SCCHN with allele-specific loss of transcription. Our data suggest that the p53 codon 72 polymorphism has a minor impact on the development of SCCHN. (Cancer Epidemiol Biomarkers Prev 2004;13(11):1805–9)
Heat-Shock Protein Induction in Rat Hearts

Background Previous studies have demonstrated that heatshock treatment results in the induction of 72-kD heat-shock protein (HSP72) and a reduction of infarct size after subsequent ischemia and reperfusion. Methods and Results To test the hypothesis that the degree of protection from ischemic injury in heat-shocked rats correlates with the degree of prior HSP72 induction, rats pretreated with 40°C, 41°C, or 42°C of whole-body hyperthermia followed by 24 hours of recovery and control rats (n=6 in each group) were quantitatively assessed for the presence of myocardial HSP72 by optical densitometry of Western blots and a primary antibody that is specific for HSP72 and a tertiary antibody labeled with `I. Although rats heat-shocked to 40°C had no significant induction of myocardial HSP72, rats heat-shocked to 41°C and 42°C demonstrated progressively increased
Multiple Diagnostic X-rays for Spine Deformities and Risk of Breast Cancer

Background: Ionizing radiation is a well-established human mammary carcinogen. Women historically monitored by radiography at young ages for abnormal spinal curvature are an exposed population suitable for investigating radiation-related risk and its variation by modifying factors. In this historic cohort, 95% of daily dose increments (when exposure to the breast occurred) were under 2.4 cGy, with mean 1.1 cGy. Methods: A retrospective cohort of 3,010 women, diagnosed with spinal curvature between 1912 and 1965 in 14 U.S. pediatric orthopedic centers and who completed a questionnaire by telephone interview or mail survey in 1992, were studied for risk of breast cancer by radiation dose to the breast (mean, 12 cGy) after adjustment for established breast cancer risk factors. Results: A borderline-significant radiation dose response (excess relative risk/Gy = 2.86; P = 0.058; one-tailed P = 0.029) was observed during 118,905 woman-years of follow-up (median, 35.5 years) based on 78 cases of invasive breast cancer. The dose response was significantly greater (P = 0.03) for women who reported a family history of breast cancer in first- or second-degree relatives (excess relative risk/Gy = 8.37; 95% confidence interval, 1.50-28.16). Radiation-related risk did not vary significantly by stage of reproductive development at exposure. Conclusions: Assuming that repair of radiation-related DNA damage requires at most a few hours, our data argue against existence of a low-dose threshold on the order of 1 to 3 cGy for radiation exposure contributing to breast carcinogenesis. The possibility that a family history of breast cancer may have enhanced a carcinogenic radiation effect requires confirmation in other studies. (Cancer Epidemiol Biomarkers Prev 2008;17(3):605–13)
Reduced residual gene expression of nuclear factor of activated T cells‐regulated genes correlates with the risk of cytomegalovirus infection after liver transplantation

Pharmacokinetic monitoring of calcineurin inhibitors (CNIs) is unsatisfactory because, at comparable blood concentrations, side effects vary considerably. We recently confirmed the applicability of a pharmacodynamic (PD) assay that measures the suppression of CNI target genes, specifically the suppression of nuclear factor of activated T cells (NFAT)‐regulated genes in liver transplant (LT) recipients. The aim of this prospective study was to prove the clinical reliability of this assay. Therefore, we quantified the residual gene expression (RGE) of NFAT‐regulated genes and evaluated the association between the RGE of NFAT‐regulated genes and the incidence of cytomegalovirus (CMV) infection.
Local circuit neurons immunoreactive for calretinin, calbindin D‐28k or parvalbumin in monkey prefronatal cortex: Distribution and morphology

In the cerebral cortex, local circuit neurons provide critical inhibitory control over the activity of pyramidal neurons, the major class of excitatory efferent cortical cells. The calciumbinding proteins, calretinin, calbindin, and parvalbumin, are expressed in a variety of cortical local circuit neurons. However, in the primate prefrontal cortex, relatively little is known, especially with regard to calretinin, about the specific classes or distribution of local circuit neurons that contain these calcium‐binding proteins. In this study, we used immunohistochemical techniques to characterize and compare the morphological features and distribution in macaque monkey prefrontal cortex of local circuit neurons that contain each of these calcium‐binding proteins.
Use of Formalin-Fixed Paraffin-Embedded Samples for Gene Expression Studies in Breast Cancer Patients

To obtain gene expression profiles from samples collected in clinical trials, we conducted a pilot study to assess feasibility and estimate sample attrition rates when profiling formalin-fixed, paraffin-embedded specimens. Ten matched fresh-frozen and fixed breast cancer samples were profiled using the Illumina HT-12 and Ref-8 chips, respectively. The profiles obtained with Ref 8, were neither technically nor biologically reliable since they failed to yield the expected separation between estrogen receptor positive and negative samples. With the use of Affymetrix HG-U133 2.0 Plus chips on fixed samples and a quantitative polymerase chain reaction -based sample pre-assessment step, results were satisfactory in terms of biological reliability, despite the low number of present calls (M = 21%±5). Compared with the Illumina DASL WG platform, Affymetrix data showed a wider interquartile range (1.32 vs 0.57, P<2.2 E-16,) and larger fold changes. The Affymetrix chips were used to run a pilot study on 60 fixed breast cancers. By including in the workflow the sample pre-assessment steps, 96% of the samples predicted to give good results (44/46), were in fact rated as satisfactory from the point of view of technical and biological meaningfulness. Our gene expression profiles showed strong agreement with immunohistochemistry data, were able to reproduce breast cancer molecular subtypes, and allowed the validation of an estrogen receptor status classifier derived in frozen samples. The approach is therefore suitable to profile formalin-fixed paraffin-embedded samples collected in clinical trials, provided that quality controls are run both before (sample pre-assessment) and after hybridization on the array.
Conserved Expression Patterns Predict microRNA Targets

microRNAs (miRNAs) are major regulators of gene expression and thereby modulate many biological processes. Computational methods have been instrumental in understanding how miRNAs bind to mRNAs to induce their repression but have proven inaccurate. Here we describe a novel method that combines expression data from human and mouse to discover conserved patterns of expression between orthologous miRNAs and mRNA genes. This method allowed us to predict thousands of putative miRNA targets. Using the luciferase reporter assay, we confirmed 4 out of 6 of our predictions. In addition, this method predicted many miRNAs that act as expression enhancers. We show that many miRNA enhancer effects are mediated through the repression of negative transcriptional regulators and that this effect could be as common as the widely reported repression activity of miRNAs. Our findings suggest that the indirect enhancement of gene expression by miRNAs could be an important component of miRNA regulation that has been widely neglected to date.
Liver Protection from Apoptosis Requires Both Blockage of Initiator Caspase Activities and Inhibition of ASK1/JNK Pathway via Glutathione S-Transferase Regulation*

Hepatoprotection mediated by free radical scavenging molecules such as dimethyl sulfoxide (Me2SO) arose the question as to whether this effect involved one or several anti-apoptotic signals. Here, using primary cultures of rat hepatocytes and in vivothioacetamide-induced liver failure, we showed that Me2SO failed to prevent any cleavage of initiator caspase-8 and -9 but constantly inhibited procaspase-3 maturation and apoptosis execution, pointing to an efficient inhibition of cleaved initiator caspase activities. Evidence was recently provided that apoptosis might require both caspase and ASK1/JNK-p38 activities. We demonstrated that this kinase pathway was strongly inhibited in the presence of Me2SO whereas overexpression of ASK1 was able to restore caspase-3 activity and apoptosis. Interestingly, we also found that GST Μ1/2 and GST Α1/2 dropped under apoptotic conditions; furthermore transfection of GST Μ1, A1, or P1 to cells overexpressing ASK1, abolished caspase-3 activity and restored viability. This role of GSTs was further assessed by showing that their high expression level was tightly associated with inhibition of ASK1 activity in Me2SO-protected hepatocytes. Together, these results demonstrate that Me2SO-mediated hepatoprotection involves a dual inhibition of cleaved initiator caspase and ASK1/JNK-p38 activities. Furthermore, in highlighting the control of apoptosis by GSTs, these data provide new insights for analyzing the complex mechanisms of hepatoprotection.
Olive oil bioactive compounds increase body weight, and improve gut health and integrity in gilthead sea bream (Sparus aurata)

Abstract An olive oil bioactive extract (OBE) rich in bioactive compounds like polyphenols, triterpenic acids, long-chain fatty alcohols, unsaturated hydrocarbons, tocopherols and sterols was tested (0, 0·08, 0·17, 0·42 and 0·73 % OBE) in diets fed to sea bream (Sparus aurata) (initial weight: 5·4 (sd 1·2) g) during a 90-d trial (four replicates). Fish fed diets containing 0·17 and 0·42 % OBE were 5 % heavier (61·1 (sd 1·6) and 60·3 (sd 1·1) g, respectively) than those of the control group (57·0 (sd 0·7) g), although feed conversion ratio and specific feed intake did not vary. There were no differences in lipid peroxidation (LPO) levels, catalase, glutathione reductase and glutathione S-transferase activities in the intestine and liver, although there was a tendency of lower intestinal and hepatic LPO levels in fish fed OBE diets. No differences in villus size were found among treatments, whereas goblet cell density in the control group was on average14·3 % lower than in fish fed OBE diets. The transcriptomic profiling of intestinal markers, covering different biological functions like (i) cell differentiation and proliferation, (ii) intestinal permeability, (iii) enterocyte mass and epithelial damage, (iv) IL and cytokines, (v) pathogen recognition receptors and (vi) mitochondria function, indicated that among the eighty-eight evaluated genes, twenty-nine were differentially expressed (0·17 % OBE diet), suggesting that the additive has the potential of improving the condition and defensive role of the intestine by enhancing the maturation of enterocytes, reducing oxidative stress, improving the integrity of the intestinal epithelium and enhancing the intestinal innate immune function, as gene expression data indicated.
Necrotizing Sarcoid Granulomatosis: Possibly Veiled Disease in Endemic Area of Mycobacterial Infection

Necrotizing sarcoid granulomatosis (NSG) is a rare granulomatous disease that primarily affects the lung and presents as nodular masses of confluent sarcoid-like granulomas with extensive necrosis and vasculitis [1]. Proper diagnosis and treatment are challenging for clinicians, radiologists, and pathologists because of the rarity and diagnostic difficulty of this disease [2-4]. Since it was first described by Liebow [1], only 135 cases have been reported [2,4,5]. In addition to its rarity, the similarity of the clinical, radiological, and pathological features of NSG to other granulomatous diseases, such as granulomatous infection, nodular sarcoidosis, and Wegener’s granulomatosis (WG), is the largest obstacle in its proper diagnosis. The initial symptoms are non-specific or frequently do not present at all [2-4]. Radiologically, NSG can present as cavitary lesions, ill-defined pneumonic consolidations, or even as a solitary nodule or a mass [6,7]. Pathologically, NSG shares features of sarcoidosis and WG [1,4]. Thus, it is not surprising that NSG is often easily mistaken for granulomatous infections, such as tuberculosis, especially in endemic areas. Although the general level of hygiene in Korea has dramatically improved, the reported incidence of pulmonary tuberculosis remains the highest among the Organization for Economic Cooperation and Development member countries [8,9]. Identification of causal microorganisms is essential for proper treatment of tuberculosis; however, empirical treatment with anti-tuberculosis medication is often performed in endemic countries like Korea, in spite of tests failing to show any causative microorganisms [9]. Here, we report the first two cases of NSG in Korean patients, one of whom showed a dramatic response to immediate application of systemic corticosteroids, and the other of whom showed no response to empirical treatment with anti-tuberculosis medication.
TgCDPK3 Regulates Calcium-Dependent Egress of Toxoplasma gondii from Host Cells

The phylum Apicomplexa comprises a group of obligate intracellular parasites of broad medical and agricultural significance, including Toxoplasma gondii and the malaria-causing Plasmodium spp. Key to their parasitic lifestyle is the need to egress from an infected cell, actively move through tissue, and reinvade another cell, thus perpetuating infection. Ca2+-mediated signaling events modulate key steps required for host cell egress, invasion and motility, including secretion of microneme organelles and activation of the force-generating actomyosin-based motor. Here we show that a plant-like Calcium-Dependent Protein Kinase (CDPK) in T. gondii, TgCDPK3, which localizes to the inner side of the plasma membrane, is not essential to the parasite but is required for optimal in vitro growth. We demonstrate that TgCDPK3, the orthologue of Plasmodium PfCDPK1, regulates Ca2+ ionophore- and DTT-induced host cell egress, but not motility or invasion. Furthermore, we show that targeting to the inner side of the plasma membrane by dual acylation is required for its activity. Interestingly, TgCDPK3 regulates microneme secretion when parasites are intracellular but not extracellular. Indeed, the requirement for TgCDPK3 is most likely determined by the high K+ concentration of the host cell. Our results therefore suggest that TgCDPK3's role differs from that previously hypothesized, and rather support a model where this kinase plays a role in rapidly responding to Ca2+ signaling in specific ionic environments to upregulate multiple processes required for gliding motility.
Variability in Hemodynamic Evaluation of Pulmonary Hypertension at Large Referral Centers

Despite consensus guidelines for right heart catheterization (RHC) in the diagnosis of pulmonary arterial hypertension (PAH), considerable differences exist in the performance of RHC, interpretation of hemodynamic data, and frequency of RHC performance in patients with established disease. These differences may lead to variability in diagnosis or treatment of PAH. We sought to gather information on the standard practice of RHC for the diagnosis and management of PAH from experienced pulmonary vascular disease specialists. We developed a semiquantitative online survey of diagnosis and treatment patterns of pulmonary hypertension and distributed it to physicians at pulmonary hypertension centers in the United States. Thirty of 50 physicians completed the survey: 20 pulmonologists and 10 cardiologists, all of whom reported treating >100 patients with PAH in the past year. All respondents perform RHC in ≥90% of patients with suspected PAH. All physicians determine the pulmonary wedge pressure at end expiration; however, only half of respondents personally review tracings. Physicians differed in frequency of vasodilator testing (8 of 24 performed testing in >90% of patients with PAH), fluid challenge and exercise (19 of 30 performed testing in <25% of patients with PAH for both). Most physicians (70%) report repeating RHC between 6 months and 1 year after PAH treatment initiation. Variability exists in the interpretation of hemodynamic tracings and performance of vasodilator, fluid, and exercise challenges in the management of PAH by experienced physicians in the United States. Additional consensus guidelines delineating appropriate adjunctive testing to standardize the diagnosis of PAH are needed.
Executive function predicts the development of play skills for verbal preschoolers with autism spectrum disorders

Executive function and play skills develop in early childhood and are linked to cognitive and language ability. The present study examined these abilities longitudinally in two groups with autism spectrum disorder—a group with higher initial language (n = 30) and a group with lower initial language ability (n = 36). Among the lower language group, concurrent nonverbal cognitive ability contributed most to individual differences in executive function and play skills. For the higher language group, executive function during preschool significantly predicted play ability at age 6 over and above intelligence, but early play did not predict later executive function. These results suggested that factors related to the development of play and executive function differ for subgroups of children with different language abilities and that early executive function skills may be critical in order for verbal children with autism to develop play. Autism Res 2016, 9: 1274–1284. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
Myoelectric responses at flexors and extensors of human wrist to step torque perturbations.

1. Torque-step perturbations were applied to flex or extend the wrists of normal human subjects. The electromyographic activity (EMG) of two of the stretched muscles, flexor carpi radialis and extensor carpi radialis, was monitored. 2. Based on functional characteristics and temporal bursting patterns, the EMG responses were partitioned into four distinct temporal intervals : 30-60, 60-120, 120-200, and greater than 200 ms after the onset of the torque step. The last interval continues for the duration of the step input: 200- 400 ms was chosen to represent activity in this interval. 3. EMG responses in the first two intervals show short, stable latencies and amplitudes that depend on the level of muscle contraction prior to the torque step. They are facilitated by any instruction requiring a reaction by the subject. They are reflexes that cannot be voluntarily suppressed by instruction to the subject. 4. The third EMG response is a triggered response. It is not a reflex because its appearance or absence is absolutely under voluntary control. Unlike true voluntary responses, there exists no dichotomy in responses latency or variability between known versus unknown directions of torque steps. 5. We consider that a truly voluntary response to a torque perturbation does not begin until about 200 ms after the step, which is on the order of visual or auditory reaction times. 6. The EMG responses were similar in both the wrist flexor and extensor studied. Ankle flexors and extensors do not show such similarity. 7. The EMG responses at the wrist and ankle are compared and shown to have many similarities. A general scheme for their classification is discussed.
Iodine Deficiency in Northern Paris Area: Impact on Fetal Thyroid Mensuration

Introduction Iodine is essential for normal fetal and neonatal development. We studied the prevalence and impact on fetal thyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation. Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4, FT3, and TSH. Fetal thyroid gland size was assessed using ultrasonography. Results We found evidence of widespread iodine deficiency (mean UIE, 49.8 µg/L [standard deviation, 2.11]). Iodine deficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlation with fetal thyroid gland size (rho = 0.25, P = 0.02). Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroid gland. Clinical Trials.gov NCT00162539