Miracle-dz/UniFAR-FTUs huggingface dataset:
Progression of Seed‐Induced Aβ Deposition within the Limbic Connectome

An important early event in the pathogenesis of Alzheimer's disease (AD) is the aberrant polymerization and extracellular accumulation of amyloid‐β peptide (Aβ). In young transgenic mice expressing the human Aβ‐precursor protein (APP), deposits of Aβ can be induced by the inoculation of minute amounts of brain extract containing Aβ aggregates (“Aβ seeds”), indicative of a prion‐like seeding phenomenon. Moreover, focal intracerebral injection of Aβ seeds can induce deposits not only in the immediate vicinity of the injection site, but, with time, also in distal regions of the brain. However, it remains uncertain whether the spatial progression of Aβ deposits occurs via nonsystematic diffusion from the injection site to proximal regions or via directed transit along neuroanatomical pathways. To address this question, we analyzed the spatiotemporal emergence of Aβ deposits in two different APP‐transgenic mouse models that had been previously inoculated with Aβ seeds into the hippocampal formation. The results revealed a specific, neuroanatomically constrained pattern of induced Aβ deposits in structures corresponding to the limbic connectome, supporting the hypothesis that neuronal pathways act as conduits for the movement of proteopathic agents among brain regions, thereby facilitating the progression of disease.
Effects of Sex Hormone Treatment on the Metabolic Syndrome in Transgender Individuals: Focus on Metabolic Cytokines

Context Hormonal treatment in transgender persons affects many components of the metabolic syndrome (MS). Objective To determine the role of direct hormonal effects, changes in metabolic cytokines, and body composition on metabolic outcomes. Design, Setting, and Participants 24 transwomen and 45 transmen from the European Network for the Investigation of Gender Incongruence were investigated at baseline and after 12 months of hormonal therapy. Outcome Measures Best predictors for changes in components of MS, applying least absolute shrinkage and selection operator regression. Results In transwomen, a decrease in triglyceride levels was best explained by a decrease in fat mass and an increase in fibroblast growth factor 21 (FGF-21); the decrease in total and low-density lipoprotein cholesterol levels was principally due to a decrease in resistin. A decrease in high-density lipoprotein cholesterol depended on an inverse association with fat mass. In contrast, in transmen, an increase in low-density lipoprotein cholesterol was predicted by a decrease in FGF-21 and an increase in the waist/hip ratio; a decrease in the high-density lipoprotein/total cholesterol ratio depended on a decline in adiponectin levels. In transwomen, worsened insulin resistance and increased early insulin response seemed to be due to a direct treatment effect; however, improvements in hepatic insulin sensitivity in transmen were best predicted by a positive association with chemerin, resistin, and FGF-21 and were inversely related to changes in the waist/hip ratio and leptin and adipocyte fatty acid-binding protein levels. Conclusions The effects of hormonal therapy on different components of the MS are sex-specific and involve a complex interplay of direct hormonal effects, changes in body composition, and metabolic cytokine secretion.
Calcimimetic Use in Familial Hypocalciuric Hypercalcemia—A Perspective in Endocrinology

Context: Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia that even persists after subtotal parathyroidectomy. Symptoms are usually mild. Past recommendations have often been for monitoring and against surgical or pharmacologic treatments. Methods: Review of publications about FHH, calcium‐sensing receptors (CaSRs), and calcimimetics. Results: FHH reflects heterozygous germline mutation of CASR, GNA11, or AP2S1. These mutations inactivate the CaSRs in the parathyroid cell. Thereby, they shift the serum calcium set point to higher values and cause hypercalcemia. Calcimimetic drugs enhance the effects of calcium on the CaSRs and thereby inhibit the parathyroid cell. Calcimimetic drugs are indicated in adults with primary hyperparathyroidism without a good surgical option. Calcimimetic safety and efficacy are not established in children younger than age 18 years. Recent case reports have described treatment of FHH with calcimimetics. Success was classified as combinations of subjective improvements and decreases of serum calcium levels, but not necessarily into the normal range. Treatment was successful in 14 of 16 cases (88%). Conclusion: Deductions based on these case reports have limitations. For example, failures of therapy may not have been reported. Cost of the drug might be rate limiting. Calcimimetics can be offered to adults with FHH and those in whom the serum calcium level is >0.25 mM (1 mg/dL) beyond the upper limit of normal or with possible symptoms of hypercalcemia. Calcimimetics can now be offered to more adults with FHH.
Die Erfassung psychosozialer Belastungen und Ressourcen in der Onkologie - Ein Literaturüberblick zu Screeningmethoden und Entwicklungstrends

: A substantial percentage of cancer patients suffers from psychosocial distress to severe mental disorders and psychosocial crisis during the course of the illness and cancer treatment. However, only a small percentage of patients with severe psychosocial distress and mental disorders in the present oncological practice is accurately identified, diagnosed, and appropriately treated. Therefore, sufficient knowledge about psychosocial distress and mental disorders as well as screening procedures are urgent concerns to improve psychosocial care for cancer patients. First, the article provides an overview of psychosocial distress and the epidemiology of mental disorders in cancer patients. Then a few of the most important objectives and problems of psychosocial assessment in cancer patients will be explained. The following part will offer an overview of questionnaires and screening procedures that are frequently used to assess psychosocial distress, mental disorders, personal and social resources, and health related quality of life in cancer patients.
Working with standardised patients for teaching and learning

‘S tandardised patients’, also referred to as ‘patient instructors’, ‘simulated patients’, or ‘programmed patients’, are individuals, with or without ‘real’ symptoms, who are trained by medical educators to act as patients. They can assist in teaching, and are able to assess the clinical and interpersonal skills of individuals such as medical students, resident medical officers and foreign medical graduates. Barrows has attempted to clarify the differences between the terminologies used, and here we use his understanding of ‘standardised patient’. He explains that a ‘simulated patient’ is one who has been trained to portray accurately the history and physical symptoms of an actual patient, whereas a ‘standardised patient’ is a simulated or actual patient trained to present ‘his or her’ illness in a standardised manner that does not alter across consultations.
Quantification of menstrual blood loss

Menorrhagia is one of the most significant causes of ill health in women. It accounts for a significant number of gynaecological outpatient referrals and once referred to a gynaecologist, more than half of these women will have had a hysterectomy within five years. Objective menorrhagia is taken to be a total measured menstrual blood loss in excess of 80 millilitres per cycle. The objective diagnosis of menorrhagia can pose a clinical challenge. This article reviews the different methods currently used for the objective estimation of menstrual blood loss.
Targeted delivery of doxorubicin through conjugation with EGF receptor–binding peptide overcomes drug resistance in human colon cancer cells

Induction of multidrug resistance by doxorubicin (DOX), together with non‐specific toxicities, has restricted DOX‐based chemotherapy. Recently, we demonstrated that DOX conjugated with an EGF receptor‐binding peptide (DOX‐EBP) had enhanced anticancer efficacy and reduced systemic toxicity when targeting EGF receptor‐overexpressing tumours. Here we investigated whether DOX‐EBP is able to overcome drug resistance and the underlying molecular mechanisms.
Notoginsenoside R1 attenuates cardiac dysfunction in endotoxemic mice: an insight into oestrogen receptor activation and PI3K/Akt signalling

Notoginsenoside R1 (NG‐R1), a novel phytoestrogen isolated from Panax notoginseng, is believed to have anti‐inflammatory, anti‐oxidative and anti‐apoptotic properties. However, its cardioprotective properties and underlying mechanisms are largely unknown. Here we have assessed the contribution of the anti‐inflammatory effects of NG‐R1 to the amelioration of septic cardiac dysfunction and inflammation in mice.
Cardiovascular responses to retigabine in conscious rats – under normotensive and hypertensive conditions

Retigabine is a recently approved antiepileptic agent which activates Kv7.2–7.5 potassium channels. It is emerging that these channels have an important role in vascular regulation, but the vascular effects of retigabine in the conscious state are unknown. Hence, in the present study we assessed the regional haemodynamic responses to retigabine in conscious rats.
Insulin-like growth factors (IGFs) and IGF binding proteins in active Crohn's disease treated with ω-3 or ω-6 fatty acids and corticosteroids

Objective. Catabolism and growth impairment are well-known complications of inflammatory bowel disease (IBD). This may be caused by the disease activity itself and/or the medical treatment, and both may lead to changes in the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. The aim of the present study was to examine the effects of enteral nutrition, Impact Powder®, as adjuvant therapy to corticosteroid treatment on changes in the GH/IGF-I axis in patients with Crohn's disease (CD). Material and methods. The patients were randomized to 3-IP (ω-3-fatty acid (FA), 3 g/day) or 6-IP (ω-6-FA, 9 g/day). Changes in total IGF-I (tIGF-I) and total IGF-II (tIGF-II), free IGF-I (fIGF-I), IGF binding proteins (IGFBP-1 and IGFBP-3), IGFBP-3 protease activity and insulin levels were examined in 31 patients with active CD (CDAI: 186–603) during treatment with prednisolone (40 mg for 1 week) and tapering the dose by 5 mg/week. Clinical and biochemical markers of inflammation were studied at day 0, and after 5 and 9 weeks. Results. There were no differences at baseline between the two groups. During the treatment period, tIGF-I, fIGF-I and IGFBP-3 increased significantly in both groups compared to baseline (p<0.05) without differences between the groups. Insulin and IGFBP-1 showed no significant changes throughout the treatment period. Conclusions. There was no difference between 3-IP and 6-IP as adjuvant enteral nutrition on the GH/IGF-I axis. The changes observed in the GH/IGF-I axis are in line with previously published studies and may be explained by corticosteroid treatment; however, we cannot exclude an additional effect of ω3-/ω6 FA as adjuvant enteral nutrition.
β-Cell Function, Insulin Sensitivity, and Glucose Tolerance in Obese Diabetic and Nondiabetic Adolescents and Young Adults

Context: Type 2 diabetes mellitus (T2DM) is estimated to account for 10–45% of incident pediatric diabetes cases. Objective: Our objective was to characterize the metabolic defects underlying T2DM in adolescents and young adults. Design, Setting, and Patients: We conducted a cross-sectional study of islet function and insulin sensitivity in 16 adolescents with T2DM and 13 obese (OB) and 13 lean (LN) age-matched nondiabetic subjects at a University Medical Center. Intervention: We provided oral and iv glucose tolerance tests. Main Outcome Measures: We measured insulin and glucagon levels, insulin sensitivity, acute insulin responses to iv glucose, and the ratio of proinsulin to immunoreactive insulin. Results: The diabetic subjects had elevated fasting insulin levels and significantly reduced insulin sensitivity (P < 0.05). The acute insulin response to iv glucose was comparable in the T2DM and LN groups (P < 0.05 for the OB vs. LN and T2DM), but insulin secretion adjusted for insulin resistance, the dispo.
Neuronal AChE splice variants and their non‐hydrolytic functions: redefining a target of AChE inhibitors?

AChE enzymatic inhibition is a core focus of pharmacological intervention in Alzheimer's disease (AD). Yet, AChE has also been ascribed non‐hydrolytic functions, which seem related to its appearance in various isoforms. Neuronal AChE presents as a tailed form (AChE‐T) predominantly found on the neuronal synapse, and a facultatively expressed readthough form (AChE‐R), which exerts short to medium‐term protective effects. Notably, this latter form is also found in the periphery. While these non‐hydrolytic functions of AChE are most controversially discussed, there is evidence for them being additional targets of AChE inhibitors. This review aims to provide clarification as to the role of these AChE splice variants and their interplay with other cholinergic parameters and their being targets of AChE inhibition: AChE‐R is particularly involved in the mediation of (anti‐)apoptotic events in cholinergic cells, involving adaptation of various cholinergic parameters and a time‐dependent link to the expression of neuroprotective factors. The AChE‐T C‐terminus is central to AChE activity regulation, while isolated AChE‐T C‐terminal fragments mediate toxic effects via the α7 nicotinic acetylcholine receptor. There is direct evidence for roles of AChE‐T and AChE‐R in neurodegeneration and neuroprotection, with these roles involving AChE as a key modulator of the cholinergic system: in vivo data further encourages the use of AChE inhibitors in the treatment of neurodegenerative conditions such as AD since effects on both enzymatic activity and the enzyme's non‐hydrolytic functions can be postulated. It also suggests that novel AChE inhibitors should enhance protective AChE‐R, while avoiding the concomitant up‐regulation of AChE‐T.
Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women

Pharmacological response depends on multiple factors and one of them is sex–gender. Data on the specific effects of sex–gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex–gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex–gender influences pharmacogenomics and pharmacogenetics. Sex‐related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex–gender‐based approach with the aim of tailoring therapies to an individual's needs and concerns.
Direct Health Care Costs of Occupational Asthma in Spain : An Estimation From 2008

Background: Occupational asthma (OA) is the most common work-related disease in industrialised countries. In 2008, only 556 cases of OA had been diagnosed in Spain, which is quite far from even the most conservative estimates. In this context, the aim of this paper is to estimate the number of asthma cases attributable to the work setting in Spain in 2008 as well as the related health care costs for the same year. Methods: The number of cases of OA was calculated from estimates of attributable risk given by previous studies. The cost estimation focused on direct health-care costs and it was based both on data from the National Health System’s (NHS) analytical accounting and from secondary sources. Results: The number of prevalent cases of work-related asthma in Spain during 2008 ranges between 168 713 and 204 705 cases based on symptomatic diagnosis, entailing an associated cost from 318.1 to 355.8 million Euros. These figures fall to a range between 82 635 and 100 264 cases when bronchial hyperreactivity is included as a diagnostic criterion, at a cost of 155.8–174.3 million Euros. Slightly more than 18 million Euros represent the health-care costs of those cases requiring specialised care. Conclusions: Estimations of OA are very relevant to adequately prevent this disease. The treatment of OA, which involves a significant cost, is being financed by the NHS, although it should be covered by Social Security. © 2012 SEPAR. Published by Elsevier España, S.L. All rights reserved. Costes sanitarios directos del asma de origen laboral en España: una estimación para el año 2008
The TRPM4 channel inhibitor 9‐phenanthrol

The phenanthrene‐derivative 9‐phenanthrol is a recently identified inhibitor of the transient receptor potential melastatin (TRPM) 4 channel, a Ca2+‐activated non‐selective cation channel whose mechanism of action remains to be determined. Subsequent studies performed on other ion channels confirm the specificity of the drug for TRPM4. In addition, 9‐phenanthrol modulates a variety of physiological processes through TRPM4 current inhibition and thus exerts beneficial effects in several pathological conditions. 9‐Phenanthrol modulates smooth muscle contraction in bladder and cerebral arteries, affects spontaneous activity in neurons and in the heart, and reduces lipopolysaccharide‐induced cell death. Among promising potential applications, 9‐phenanthrol exerts cardioprotective effects against ischaemia‐reperfusion injuries and reduces ischaemic stroke injuries. In addition to reviewing the biophysical effects of 9‐phenanthrol, here we present information about its appropriate use in physiological studies and possible clinical applications.
Analgesic synergy between opioid and α2‐adrenoceptors

Opioid and α2‐adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co‐administered. These supra‐additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α2‐adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α2‐adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both μ and δ opioid receptors can produce synergy with α2‐adrenoceptor agonists and that α2‐adrenoceptor agonists can mediate synergy through either the α2A or the α2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid–adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed.
Assessment of the Hand in Tetraplegia Using the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP)

Objective: To refine the Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) as a measure of upper limb impairment following cervical SCI. Method: A cross-sectional study assessed a cohort of neurologically stable patients with tetraplegia using a preliminary version of the GRASSP. Regression analysis was performed to determine the association between subcomponents of the GRASSP (impairment) and measures of function. The GRASSP was modified based on results. Results: Eliminated static two-point discrimination, tone, and one muscle. Conclusion: The GRASSP Version I consists of Semmes Weinstein monofilaments, manual muscle testing, and qualitative and quantitative prehension testing.
Research resource: the Endometrium Database Resource (EDR).

In order to understand the biology of the endometrium and potentially develop new diagnostic tools and treatments for endometrial diseases, the highly orchestrated gene expression/regulation that occurs within the uterus must first be understood. Even though a wealth of information on endometrial gene expression/regulation is available, this information is scattered across several different resources in formats that can be difficult for the average bench scientist to query, integrate, and utilize. The Endometrium Database Resource (EDR) was created as a single evolving resource for protein- and micro-RNA-encoding genes that have been shown by gene expression microarray, Northern blot, or other experiments in the literature to have their expression regulated in the uterus of humans, mice, rats, cows, domestic pigs, guinea pigs, and sheep. Genes are annotated in EDR with basic gene information (eg, gene symbol and chromosome), gene orthologs, and gene ontologies. Links are also provided to external resources for publication/s, nucleic and amino acid sequence, gene product function, and Gene Expression Omnibus (GEO) phase expression graph information. The resource also allows for direct comparison of relative gene expression in different microarray experiments for genes shown in the literature to be differentially expressed in the uterus. It is available via a user-friendly, web-based interface and is available without charge or restriction to the entire scientific community. The EDR can be accessed at http://edr.research. bcm.edu.
Avanços no uso de células-tronco em ortopedia

Primordial cells or stem cells are multipotent undifferentiated cells with the capacity to originate any type of cell in the organism. They may have their origins in the blastocyst and thus are classified as embryonic, or tissues developed in fetuses, newborns or adults and thus are known as somatic stem cells. Bone marrow is one of the main locations for isolating primordial cells, and there are two lineages: hematopoietic and mesenchymal progenitor cells. There are several uses for these undifferentiated cells in orthopedics, going from cartilaginous lesions in osteoarthrosis, osteochondritis dissecans and patellar chondromalacia, to bone lesions like in pseudarthrosis or bone losses, or nerve lesions like in spinal cord trauma. Studying stem cells is probably the most promising field of study of all within medicine, and this is shortly going to revolutionize all medical specialties (both clinical and surgical) and thus provide solutions for diseases that today are difficult to deal with.