Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Phosphodiesterases in the Regulation of Gonadotropin- Releasing Hormone Secretion in GT1 Cells

Increases in the level of cAMP stimulate the secretion of GnRH from GT1 GnRH neuronal cells. We hypothesized that cyclic nucleotide phosphodiesterases (PDEs), the enzymes that hydrolyze cAMP, may constitute a negative feedback signaling mechanism for GnRH regulation by decreasing the level of cAMP. GT1 cells were shown to express three PDEs by RT-PCR analysis: the cAMP-specific PDE4B and PDE4D and the calmodulin-dependent PDE1B. A splice variant of PDE4D, PDE4D3, which is activated when phosphorylated by cAMP-dependent protein kinase (PKA), was identified in GT1 cells by Western analysis. Consistent with PDEs negatively regulating GnRH secretion, treatment with the nonselective PDE inhibitor, IBMX, stimulated GnRH secretion 137% in 30-min static cultures. Furthermore, treatment with the PDE4-specific inhibitors Rolipram and RS-25344 increased GnRH secretion 48 and 125%, while treatment with the PDE1-specific inhibitor 8-MeoM-IBMX only caused a modest increase of 28%. In perifusion studies a rapid multi-fold stimulation of GnRH secretion was observed following treatment with IBMX, Rolipram or RS-25344. In conclusion, the level of PDE activity appears to be an important negative feedback signal for GnRH secretion. We hypothesize that activation of PDE4D3 by PKA may constitute a negative feedback signaling pathway which participates in the regulation of cAMP levels.
Metallic Taste in Cancer Patients Treated with Systemic Therapy: A Questionnaire-based Study

ABSTRACT A metallic taste is reported by cancer patients as a side effect of systemic therapy. Despite the high prevalence, this taste alteration has received limited attention. The present study investigated: 1) the prevalence of metallic taste in cancer patients treated with systemic therapy; 2) possible predictors of metallic taste; and 3) characteristics of metallic taste. A heterogeneous population of 127 cancer patients, who had received systemic treatment in the past year or were still on treatment, completed a questionnaire developed for this study. Fifty-eight of 127 (46%) patients reported taste changes in the preceding week. Of these patients, 20 (34%) reported a metallic taste. Patients treated with chemotherapy, concomitant radiotherapy, as well as targeted therapy reported metallic taste. Women experienced metallic taste more often than men. Patients experiencing a metallic taste also reported more frequently that they were bothered by sour food and that everything tasted bitter. The experience of metallic taste was highly variable among patients. In conclusion, metallic taste is a frequently experienced taste alteration by cancer patients. Patients treated with chemotherapy, concomitant radiotherapy, and targeted therapy are all at risk for this taste alteration. However, not all patients reported this alteration as bothersome.
Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial.

PURPOSE Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy. PATIENTS AND METHODS Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate. RESULTS Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%). CONCLUSION For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.
Intensive Care Unit delirium: A wide gap between actual prevalence and psychiatric referral

Background and Aims: The study aimed to assess the rates of delirium in an Intensive Care Unit (ICU) prospectively assessed with a delirium screening instrument and confirmed through psychiatrist evaluation. In addition, the referral rate to psychiatric consultation liaison services from the same ICU was assessed through the rates of psychiatric referral over the previous 10 years. Material and Methods: In the prospective part of the study, consecutive patients aged 16 years or more admitted to the ICU of a tertiary care hospital were assessed daily for delirium using confusion assessment method for the ICU, a validated instrument that can be used for both mechanically ventilated and nonventilated patient by trained heath care personnel. Retrospectively, records of patients referred to psychiatric referral team for delirium from the ICU over the last 10 years were drawn out and the referral rate was calculated. Results: In the prospective study, 109 patients were recruited of which 43 patients remained comatose throughout their ICU stay and could not be assessed for delirium. Of the 66 assessable patients, 45 (68.2% prevalence rate) patients developed delirium. Incidence rate of delirium was 59.6%. In contrast, the retrospective study showed that only 53 cases out of 3094 admissions in ICU over 10 years (1.71%) were referred to psychiatry consultation liaison team for management of delirium. In the prospective study, hypoactive delirium was the most common subtype of delirium. Conclusion: There is a mismatch between the incidence and prevalence of delirium in ICU patients prospectively diagnosed with structured, validated instruments and the diagnosis of delirium in cases referred to psychiatry consultation-liaison services.
On transitions in the behaviour of tabu search algorithm TabuCol for graph colouring

Abstract Even though tabu search is one of the most popular metaheuristic search strategies, its understanding in terms of behavioural transitions and parameter tuning is still very limited. In this paper, we present a theoretical and experimental study of a popular tabu search algorithm TabuCol for graph colouring. We show that for some instances, there are sharp transitions in the behaviour of TabuCol, depending on the value of tabu tenure parameter. The location of this transition depends on graph structure and may also depend on its size. This is further supported by an experimental study of success rate profiles, which we define as an empirical measure of these transitions. We study the success rate profiles for a range of graph colouring instances, from 2-colouring of trees and forests to several instances from the DIMACS benchmark. These reveal that TabuCol may exhibit a spectrum of different behaviours ranging from simple transitions to highly complex probabilistic behaviour.
Intent to use a web-based psychological intervention for partners of cancer patients: Associated factors and preferences

ABSTRACT This study examined partners of cancer patients intention to use a web-based psychological intervention, their preferences regarding its preconditions, functionalities and topics, and factors related to their intention. One hundred and sixty-eight partners completed a questionnaire about these aspects. Forty-eight percent of the partners would (maybe) make use of a web-based intervention. Partners who intended to participate were significantly younger, used the Internet more often, and perceived more caregiver strain. Most partners preferred an intervention that takes less than 1 hour/week, lasts five weeks or more, and contains information and peer support. Half of the partners would like to receive online guidance.
Effect of Interferon-beta-1b on Cognitive Functions in Multiple Sclerosis

Introduction: Multiple sclerosis (MS) is recognised as a central nervous system disease also affecting cognition. The rate of cognitive dysfunction in MS is in the range of 45–65% and adversely affect the quality of life. Objective: To evaluate the effect of 1 year of treatment with interferon-beta-1b (IFNβ-1b) on cognitive functions in patients suffering from relapsing-remitting MS. Methods: A battery of cognitive tests was used to assess verbal learning, delayed recall, visual learning and recall, complex attention, concentration and verbal fluency at baseline and after 1 year of treatment with IFNβ-1b. A group of 23 relapsing-remitting MS patients matched for neurological disability served as controls. Results: Eighteen of 23 patients treated with IFNβ-1b (74%) completed the study. In the IFNβ-1b-treated group, complex attention, concentration as well as visual learning and recall improved significantly (p = 0.024, p = 0.006 and p = 0.005, respectively), while no deterioration was observed in the other dimensions. In the control group, complex attention, verbal fluency, as well as visual learning and recall deteriorated significantly (p = 0.02, p = 0.004 and p = 0.01, respectively), while no deterioration was observed in the other dimensions. Conclusion: Immunomodulating drugs that reduce the relapse rate and slow the disease progression also inhibit cognitive deterioration in patients with MS.
Working memory in healthy aging and in Parkinson’s disease: evidence of interference effects

ABSTRACT Focusing on relevant information while suppressing the irrelevant one are critical abilities for different cognitive processes. However, their functioning has been scarcely investigated in the working memory (WM) domain, in both healthy and pathological conditions. The present research aimed to study these abilities in aging and Parkinson’s disease (PD), testing three groups of healthy participants (young, older and elderly) and one of PD patients, employing a new experimental paradigm. Results showed that the transient storing of irrelevant information in WM causes substantial interference effects, which were remarkable in elderly individuals on both response latency and accuracy. Interestingly, PD patients responded faster and were equally accurate compared to a matched control group. Taken together, findings confirm the existence of similar mechanisms for orienting attention inwards to WM contents or outwards to perceptual stimuli, and suggest the suitability of our task to assess WM functioning in both healthy aging and PD.
High intensity focused ultrasound in the treatment of breast fibroadenomata: results of the HIFU-F trial

Abstract Objectives: Breast fibroadenomata (FAD) are the most common breast lumps in women. High intensity focused ultrasound (HIFU) is a non-invasive ablative technique that can be used to treat FAD but is associated with prolonged treatment times. In the HIFU-F trial, we evaluated the change in volume over time with circumferential HIFU treatment of FAD and compared this to no treatment. Methods: Patients ≥18 years, diagnosed with symptomatic, palpable FAD, visible on ultrasound (US) were recruited. Twenty patients were treated using US-guided HIFU under local anaesthesia. Another 20 participants underwent an US 6 months after diagnosis. Outcome measures included: reduction in treatment time compared to whole lesion ablation; feasibility to achieve a 50% reduction in volume after 6 months; decrease in volume compared to a control group and reduction in symptoms. Results: Circumferential ablation reduced the mean treatment time by 37.5% (SD 20.1%) compared to whole lesion ablation. US demonstrated a significant mean reduction in FAD volume of 43.5% (SD 38.8%; p = 0.016, paired t-test) in the HIFU group compared to 4.6% (SD 46.0%; p = 0.530) in the control group after 6 months. This mean reduction in FAD volume between the two groups was significant in favour of the HIFU group (p = 0.002, grouped t-test). Pre-treatment pain completely resolved in 6 out of 8 patients 6 months post-treatment. Conclusion: Circumferential HIFU ablation of FAD is feasible, with a significant reduction in pain and volume compared to control participants. It provides a simple, non-invasive, outpatient-based alternative to surgical excision for FAD.
MeCP2 interacts with chromosomal microRNAs in brain

ABSTRACT Although methyl CpG binding domain protein-2 (MeCP2) is commonly understood to function as a silencing factor at methylated DNA sequences, recent studies also show that MeCP2 can bind unmethylated sequences and coordinate gene activation. MeCP2 displays broad binding patterns throughout the genome, with high expression levels similar to histone H1 in neurons. Despite its significant presence in the brain, only subtle gene expression changes occur in the absence of MeCP2. This may reflect a more complex regulatory mechanism of MeCP2 to complement chromatin binding. Using an RNA immunoprecipitation of native chromatin technique, we identify MeCP2 interacting microRNAs in mouse primary cortical neurons. In addition, comparison with mRNA sequencing data from Mecp2-null mice suggests that differentially expressed genes may indeed be targeted by MeCP2-interacting microRNAs. These findings highlight the MeCP2 interaction with microRNAs that may modulate its binding with chromatin and regulate gene expression.
Five‐year impact of catheter ablation for atrial fibrillation in patients with a prior history of stroke

Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach. Patients with a prior history of a stroke (CVA) represent a unique high‐risk population for recurrent thromboembolic events. The role of antiarrhythmic treatment on the natural history of stroke recurrence in these patients is not fully understood.
Iron-Deficient Erythropoiesis in Neonatal Rats

Anemia in premature infants is extremely common. Precise quantitation of iron status and determination of iron incorporation into erythrocytes are important in monitoring therapy for anemia in premature infants, especially when treating with recombinant human erythropoietin (rhEPO). However, the traditional indices of the iron status have limited usefulness in this population. The goal of the current work is to develop an experimental animal model system that addresses the clinical issue relating to quantitation of iron delivery to erythrocytes. We first determined normal hematological values for nontreated, dam-suckled Sprague-Dawley rats by measuring markers of erythropoiesis and iron status during the first 12 postnatal days (PND). The experimental group of rats were administered parenteral rhEpo (430 IU·kg–1 · day–1) for 8 days (from PND 4 until PND 12) in the absence (rhEpo–Fe) or presence (rhEpo+Fe) of oral iron supplementation (6 mg·kg–1·day–1). Rat pups receiving oral iron only (control+Fe) and pups that were sham fed with the orogastric tube (control–Fe) were included as controls. Hematological parameters were measured in blood and bone marrow. In a pattern similar to that seen in premature infants during the first 2 months of life, the levels of these hematopoietic markers were dynamic and changed during the first 12 PND. After challenging experimental animals with subcutaneous rhEpo, evidence of iron-deficient erythropoiesis was seen in the rhEpo–Fe group. Red blood cell levels and absolute reticulocyte counts were higher in both groups receiving rhEpo as compared with the controls. However, the rhEpo–Fe group experienced a lower hemoglobin level, a lower mean red cell volume, a greater red cell distribution width, and a higher zinc protoporphyrin/heme (ratio than the rhEpo+Fe group. The neonatal rat is an excellent model of iron-deficient erythropoiesis and will be useful in designing future mechanistic studies examining the interplay between iron and erythropoiesis in the anemic, iron-challenged premature neonate.
Revisiting subcortical brain volume correlates of autism in the ABIDE dataset: effects of age and sex

Background Autism spectrum disorders (ASD) are characterized by substantial clinical, etiological and neurobiological heterogeneity. Despite this heterogeneity, previous imaging studies have highlighted the role of specific cortical and subcortical structures in ASD and have forwarded the notion of an ASD specific neuroanatomy in which abnormalities in brain structures are present that can be used for diagnostic classification approaches. Method A large (N = 859, 6–27 years, IQ 70–130) multi-center structural magnetic resonance imaging dataset was examined to specifically test ASD diagnostic effects regarding (sub)cortical volumes. Results Despite the large sample size, we found virtually no main effects of ASD diagnosis. Yet, several significant two- and three-way interaction effects of diagnosis by age by gender were found. Conclusion The neuroanatomy of ASD does not exist, but is highly age and gender dependent. Implications for approaches of stratification of ASD into more homogeneous subtypes are discussed.
Hyperhexosemia Induced Functional and Structural Changes in the Kidneys: Role of Endothelins

Background/Aims: Glomerular basement membrane (GBM) thickening and mesangial matrix expansion are characteristic features of diabetic nephropathy. The present study investigates the role of endothelins (ETs) in the pathogenesis of such changes in diabetic nephropathy. Methods: Diabetic (streptozotocin-induced, 65 mg/kg), galactose-fed (30%) and control animals were followed up for 1 and 6 months. Animal groups also included diabetic and galactose fed animals on dual ETA/ETB receptor antagonist bosentan (100 mg/kg). A semi-quantitative reverse transcription polymerase chain reaction method was used to quantify mRNA expression of ET-1, ET-3, ETA, ETB, fibronectin and collagen α2(IV). Histological analyses of the kidneys and ET-1, ET-3 and fibronectin immunohistochemistry were performed. Morphometric assessment of the GBM after 6 months was performed. Results: Diabetes increased mRNA expression of ET-1, ET-3, ETA, ETB, fibronectin and collagen α2(IV) after one and six months. In contrast, although increased ETA and ETB mRNAs were present following galactose feeding both at 1 and 6 months, ET-1, ET-3, fibronectin and collagen α2(IV)mRNAs were increased after 6 months. Both diabetes and galactose feeding caused increased GBM thickening. Furthermore, diabetes caused an increase in mesangial matrix production. Bosentan prevented increased fibronectin and collagen α2(IV) mRNA expression, increased mesangial matrix deposition and GBM thickening. Conclusion: This study has demonstrated that diabetes and galactose feeding induced functional and structural changes in the kidney are mediated via ETs.
Interleukin‐10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis

Recently, the benefit of mesenchymal stem cells (MSCs) as a cell‐based therapy for acute liver failure (ALF) has gained much attention, although the mechanism of action of MSCs in the treatment of ALF remains elusive. Pyroptosis is a novel form of programmed cell death with an intense inflammatory response. The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects through inhibiting pyroptosis in ALF.
Testing biomechanical models of human lumbar lordosis variability.

OBJECTIVES Lumbar lordosis (LL) is a key adaptation for bipedalism, but factors underlying curvature variations remain unclear. This study tests three biomechanical models to explain LL variability. MATERIALS AND METHODS Thirty adults (15 male, 15 female) were scanned using magnetic resonance imaging (MRI), a standing posture analysis was conducted, and lumbar range of motion (ROM) was assessed. Three measures of LL were compared. The trunk's center of mass was estimated from external markers to calculate hip moments (Mhip ) and lumbar flexion moments. Cross-sectional areas of lumbar vertebral bodies and trunk muscles were measured from scans. Regression models tested associations between LL and the Mhip moment arm, a beam bending model, and an interaction between relative trunk strength (RTS) and ROM. RESULTS Hip moments were not associated with LL. Beam bending was moderately predictive of standing but not supine LL (R2 = 0.25). Stronger backs and increased ROM were associated with greater LL, especially when standing (R2 = 0.65). The strength-flexibility model demonstrates the differential influence of RTS depending on ROM: individuals with high ROM exhibited the most LL variation with RTS, while those with low ROM showed reduced LL regardless of RTS. DISCUSSION Hip moments appear constrained suggesting the possibility of selection, and the beam model explains some LL variability due to variations in trunk geometry. The strength-flexibility interaction best predicted LL, suggesting a tradeoff in which ROM limits the effects of back strength on LL. The strength-flexibility model may have clinical relevance for spinal alignment and pathology. This model may also suggest that straight-backed Neanderthals had reduced lumbar mobility.
Multi-event waveform-retrieved distributed optical fiber acoustic sensor using dual-pulse heterodyne phase-sensitive OTDR.

We demonstrate a novel type of distributed optical fiber acoustic sensor, with the ability to detect and retrieve actual temporal waveforms of multiple vibration events that occur simultaneously at different positions along the fiber. The system is realized via a dual-pulse phase-sensitive optical time-domain reflectometry, and the actual waveform is retrieved by heterodyne phase demodulation. Experimental results show that the system has a background noise level as low as 8.91×10-4 rad/√Hz with a demodulation signal-to-noise ratio of 49.17 dB at 1 kHz, and can achieve a dynamic range of ∼60 dB at 1 kHz (0.1 to 104 rad) for phase demodulation, as well as a detection frequency range from 20 Hz to 25 kHz.