Unraveling the directional relationship of sleep and migraine-like pain.

Migraine and sleep disorders are common co-morbidities. Patients frequently link their sleep to migraine attacks suggesting a potential causal relationship between these conditions. However, whether migraine pain promotes or disrupts sleep or whether sleep disruption can increase the risk of migraine remains unknown. We assessed the potential impact of periorbital allodynia, a measure consistent with migraine-like pain, from multiple preclinical models on sleep quantity and quality. Additionally, we evaluated the possible consequences of sleep deprivation in promoting susceptibility to migraine-like pain. Following the implantation of electroencephalogram/electromyography electrodes to record sleep, mice were treated with either single or repeated systemic injections of nitroglycerin at the onset of their active phase (i.e. nocturnal awake period). Neither single nor repeated nitroglycerin affected the total sleep time, non-rapid eye movement sleep, rapid eye movement sleep, sleep depth or other measures of sleep architecture. To account for the possible disruptive effects of the surgical implantation of electroencephalogram/electromyography electrodes, we used immobility recordings as a non-invasive method for assessing sleep-wake behaviour. Neither single nor repeated nitroglycerin administration during either the mouse sleep (i.e. daylight) or active (i.e. night) periods influenced immobility-defined sleep time. Administration of an inflammatory mediator mixture onto the dura mater at either sleep or active phases also did not affect immobility-defined sleep time. Additionally, inhalational umbellulone-induced migraine-like pain in restraint-stressed primed mice did not alter immobility-defined sleep time. The possible influence of sleep disruption on susceptibility to migraine-like pain was evaluated by depriving female mice of sleep over 6 h with novel objects, a method that does not increase circulating stress hormones. Migraine-like pain was not observed following acute sleep deprivation. However, in sleep-deprived mice, subthreshold doses of systemic nitroglycerin or dural calcitonin gene-related peptide induced periorbital cutaneous allodynia consistent with migraine-like pain. Our data reveal that while migraine-like pain does not significantly disrupt sleep, sleep disruption increases vulnerability to migraine-like pain suggesting that a therapeutic strategy focused on improving sleep may diminish migraine attacks.

Establishing an updated consensus on the conceptual and operational definitions of Making Every Contact Count (MECC) across experts within research and practice: an international Delphi Study.

OBJECTIVES: The Making Every Contact Count (MECC) initiative is broadly defined as an opportunistic approach to prevention by making use of the thousands of conversations service providers have with service users every day. However, since its conception, the application of MECC has diverged and developed considerably. Thus, the current study aimed to revise the definition according to current research and practice to better describe what is and is not included. STUDY DESIGN: A consensus building classic Delphi methodology, completed by an expert panel. METHODS: Round 1 asked open questions around the definition of MECC. Content analysis of round 1 identified statements that were rated for agreement in round 2. Statements achieving ≥80% agreement were included in a short, long, or operational definition of MECC that were rated for agreement in round 3 (the minimum number required). An agreement of ≥80% indicated consensus. RESULTS: Forty out of 100 contacted experts completed three rounds. Experts in practice and research were recruited internationally although most were from England. From round 1, 274 statements were generated, of which 96 achieved consensus and were included within round 3. The short and long definition received consensus in round 3, the operational definition required four rounds to reach consensus. CONCLUSIONS: MECC is a person-centred approach to health behaviour change that, provided an individual possesses the relevant skills, can be delivered by anyone and anywhere. The distinguishing feature of MECC is not in its duration, target behaviour, or conditions for delivery, but rather in the approach taken and the mechanisms applied to conversations. Implications for research and practice are discussed, and the limits for applicability acknowledged.

Selection of preferred thermal environment and cold-avoidance responses in rats rely on signals transduced by the dorsal portion of the lateral funiculus of the spinal cord.

Thermoregulatory behaviors are powerful effectors for core body temperature (Tc) regulation. We evaluated the involvement of afferent fibers ascending through the dorsal portion of the lateral funiculus (DLF) of the spinal cord in "spontaneous" thermal preference and thermoregulatory behaviors induced by thermal and pharmacological stimuli in a thermogradient apparatus. In adult Wistar rats, the DLF was surgically severed at the first cervical vertebra bilaterally. The functional effectiveness of funiculotomy was verified by the increased latency of tail-flick responses to noxious cold (-18°C) and heat (50°C). In the thermogradient apparatus, funiculotomized rats showed a higher variability of their preferred ambient temperature (Tpr) and, consequently, increased Tc fluctuations, as compared to sham-operated rats. The cold-avoidance (warmth-seeking) response to moderate cold (whole-body exposure to ~17°C) or epidermal menthol (an agonist of the cold-sensitive TRPM8 channel) was attenuated in funiculotomized rats, as compared to sham-operated rats, and so was the Tc (hyperthermic) response to menthol. In contrast, the warmth-avoidance (cold-seeking) and Tc responses of funiculotomized rats to mild heat (exposure to ~28°C) or intravenous RN-1747 (an agonist of the warmth-sensitive TRPV4; 100 µg/kg) were unaffected. We conclude that DLF-mediated signals contribute to driving spontaneous thermal preference, and that attenuation of these signals is associated with decreased precision of Tc regulation. We further conclude that thermally and pharmacologically induced changes in thermal preference rely on neural, presumably afferent, signals that travel in the spinal cord within the DLF. Signals conveyed by the DLF are important for cold-avoidance behaviors but make little contribution to heat-avoidance responses.

A Gamified Social Media-Based Head and Neck Radiology Education Initiative of the American Society of Head and Neck Radiology: Viewership and Engagement Trends at 3 Years.

BACKGROUND AND PURPOSE: Social media has made inroads in medical education. We report the creation and 3-year (2018-2021) longitudinal assessment of the American Society of Head and Neck Radiology Case of the Week (#ASHNRCOTW), assessing viewership, engagement, and impact of the coronavirus disease 2019 (COVID-19) pandemic on this Twitter-based education initiative. MATERIALS AND METHODS: Unknown cases were tweeted from the American Society of Head and Neck Radiology account weekly. Tweet impressions (number of times seen), engagements (number of interactions), and new followers were tabulated. A social media marketing platform identified worldwide distribution of Twitter followers. Summary and t test statistics were performed. RESULTS: #ASHNRCOTW was highly visible with 2,082,280 impressions and 203,137 engagements. There were significantly greater mean case impressions (9917 versus 6346), mean case engagements (1305 versus 474), case engagement rates (13.06% versus 7.76%), mean answer impressions (8760 versus 5556), mean answer engagements (908 versus 436), answer engagement rates (10.38% versus 7.87%), mean total (case + answer) impressions (18,677 versus 11,912), mean total engagements (2214 versus 910), and total engagement rates (11.79% versus 7.69%) for cases published after the pandemic started (all P values < .001). There was a significant increase in monthly new followers after starting #ASHNRCOTW (mean, 134 versus 6; P < .001) and significantly increased monthly new followers after the pandemic started compared with prepandemic (mean, 178 versus 101; P = .003). The American Society of Head and Neck Radiology has 7564 Twitter followers throughout 130 countries (66% outside the United States). CONCLUSIONS: Social media affords substantial visibility, engagement, and global outreach for radiology education. #ASHNRCOTW viewership and engagement increased significantly during the COVID-19 pandemic.

Immobilization and Application of the Recombinant Xylanase GH10 of Malbranchea pulchella in the Production of Xylooligosaccharides from Hydrothermal Liquor of the Eucalyptus (Eucalyptus grandis) Wood Chips.

Xylooligosaccharides (XOS) are widely used in the food industry as prebiotic components. XOS with high purity are required for practical prebiotic function and other biological benefits, such as antioxidant and inflammatory properties. In this work, we immobilized the recombinant endo-1,4-ß-xylanase of Malbranchea pulchella (MpXyn10) in various chemical supports and evaluated its potential to produce xylooligosaccharides (XOS) from hydrothermal liquor of eucalyptus wood chips. Values >90% of immobilization yields were achieved from amino-activated supports for 120 min. The highest recovery values were found on Purolite (142%) and MANAE-MpXyn10 (137%) derivatives, which maintained more than 90% residual activity for 24 h at 70 °C, while the free-MpXyn10 maintained only 11%. In addition, active MpXyn10 derivatives were stable in the range of pH 4.0−6.0 and the presence of the furfural and HMF compounds. MpXyn10 derivatives were tested to produce XOS from xylan of various sources. Maximum values were observed for birchwood xylan at 8.6 mg mL−1 and wheat arabinoxylan at 8.9 mg mL−1, using Purolite-MpXyn10. Its derivative was also successfully applied in the hydrolysis of soluble xylan present in hydrothermal liquor, with 0.9 mg mL−1 of XOS after 3 h at 50 °C. This derivative maintained more than 80% XOS yield after six cycles of the assay. The results obtained provide a basis for the application of immobilized MpXyn10 to produce XOS with high purity and other high-value-added products in the lignocellulosic biorefinery field.

Elemental profile of dietary supplements and agricultural byproducts evaluated by neutron activation analysis.

Dietary supplements and agricultural byproducts were characterized by neutron activation analysis. The nutritional potential of supplements was evaluated according to alternative and commercial categories, using analysis of variance and cluster analysis, and recommended dietary intake for children. The results indicated statistically significant differences between both categories for the elements Cs, K, Na, and Rb. For the nutritional elements Ca, Co, Fe, K, Na, and Zn, the categories were similar in cluster analysis. The similarity between elemental profiles of alternative supplements and agricultural byproducts was calculated using a dissimilarity matrix, showing that rice and wheat are the predominant ingredients.

The Cochlea in Branchio-Oto-Renal Syndrome: An Objective Method for the Diagnosis of Offset Cochlear Turns.

BACKGROUND AND PURPOSE: An "unwound" or "offset" cochlea has been described as a characteristic imaging feature in patients with branchio-oto-renal syndrome, and recently recognized to be associated in particular to those with EYA1 gene mutations. Determination of this feature has traditionally relied on subjective visual assessment. Our aim was to establish an objective assessment method for cochlear offset (the cochlear turn alignment ratio) and determine an optimal cutoff turn alignment ratio value that separates individuals with EYA1-branchio-oto-renal syndrome from those with SIX1-branchio-oto-renal syndrome and healthy controls. MATERIALS AND METHODS: Temporal bone CT or MR imaging from 40 individuals with branchio-oto-renal syndrome and 40 controls was retrospectively reviewed. Cochlear offset was determined visually by 2 independent blinded readers and then quantitatively via a standardized technique yielding the cochlear turn alignment ratio. The turn alignment ratio values were compared between cochleae qualitatively assessed as "not offset" and "offset." Receiver operating characteristic analysis was used to determine the ability of the turn alignment ratio to differentiate between these populations and an optimal cutoff turn alignment ratio value. Cochlear offset and turn alignment ratio values were analyzed for each branchio-oto-renal syndrome genotype subpopulation and for controls. RESULTS: The turn alignment ratio can accurately differentiate between cochleae with and without an offset (P < .001). The optimal cutoff value separating these populations was 0.476 (sensitivity = 1, specificity = 0.986, J = 0.986). All except 1 cochlea among the EYA1-branchio-oto-renal syndrome subset and all with unknown genotype branchio-oto-renal syndrome had a cochlear offset and a turn alignment ratio of <0.476. All except 1 cochlea among the SIX1-branchio-oto-renal syndrome subset and all controls had no offset and a turn alignment ratio of >0.476. CONCLUSIONS: There is a statistically significant difference in turn alignment ratios between offset and nonoffset cochleae, with an optimal cutoff of 0.476. This cutoff value allows excellent separation of EYA1-branchio-oto-renal syndrome from SIX1-branchio-oto-renal syndrome and from individuals without branchio-oto-renal syndrome or sensorineural hearing loss. The turn alignment ratio is a reliable and objective metric that can aid in the imaging evaluation of branchio-oto-renal syndrome.

Re-Examining the Cochlea in Branchio-Oto-Renal Syndrome: Genotype-Phenotype Correlation.

BACKGROUND AND PURPOSE: Temporal bone imaging plays an important role in the work-up of branchio-oto-renal syndrome. Previous reports have suggested that the unwound or offset cochlea is a highly characteristic marker for branchio-oto-renal syndrome. Our goals were to examine the prevalence of this finding in a branchio-oto-renal syndrome cohort and analyze genetic-phenotypic associations not previously established. MATERIALS AND METHODS: This multicenter retrospective study included 38 ears in 19 unrelated individuals with clinically diagnosed branchio-oto-renal syndrome and confirmed mutations in the EYA1 or SIX1 genes. Two blinded neuroradiologists independently reviewed and documented temporal bone imaging findings in 13 categories for each ear. Imaging phenotypes were correlated with genotypes. RESULTS: There was excellent interrater agreement for all 13 phenotypic categories (κ ≥ 0.80). Of these, 9 categories showed statistically significant differences between patients with EYA1-branchio-oto-renal syndrome and SIX1-branchio-oto-renal syndrome. Cochlear offset was present in 100% of patients with EYA1-branchio-oto-renal syndrome, but in only 1 ear (12.5%) among patients with SIX1-branchio-oto-renal syndrome. A short thorny appearance of the cochlear apical turn was observed in most patients with SIX1-branchio-oto-renal syndrome. CONCLUSIONS: An offset cochlea is associated with the EYA1-branchio-oto-renal syndrome genotype. The SIX1-branchio-oto-renal syndrome genotype is associated with a different cochlear phenotype that almost always is without offset and has a short thorny tip as the apical turn. Therefore, cochlear offset is not a characteristic marker for all patients with branchio-oto-renal syndrome. The lack of a cochlear offset in a patient with clinically suspected branchio-oto-renal syndrome does not exclude the diagnosis and, in fact, may be predictive of the SIX1 genotype.

Characterization of Regulatory T Cells in Patients Infected by Leishmania Infantum.

High IL-10 levels are pivotal to parasite survival in visceral leishmaniasis (VL). Antigenic stimuli induce IL-10 expression and release of adenosine by CD39/CD73. Due their intrinsic ability to express IL-10 and produce adenosine from extracellular ATP, we evaluated the IL-10, CD39, and CD73 expression by Regulatory T cells (Treg) correlated with VL pathology. Using flow cytometry, Treg cells was analyzed in peripheral blood samples from VL patients (in the presence and absence of Leishmania infantum soluble antigen (SLA)) and healthy individuals (negative endemic control-NEC group), without any treatment. Additionally, IL-10 levels in leukocytes culture supernatant were measured in all groups by ELISA assay. VL patients presented more Treg frequency than NEC group, independently of stimulation. ELISA results demonstrated that SLA induced higher IL-10 expression in the VL group. However, the NEC group had a higher Treg IL-10+ compared to the VL group without stimulation and SLA restored the IL-10 in Treg. Additionally, an increase in Treg CD73+ in the VL group independently of stimuli compared to that in the NEC group was observed. We suggest that Treg are not the main source of IL-10, while the CD73 pathway may be an attempt to modulate the exacerbation of immune response in VL disease.

Characteristic Cochlear Hypoplasia in Patients with Walker-Warburg Syndrome: A Radiologic Study of the Inner Ear in α-Dystroglycan-Related Muscular Disorders.

BACKGROUND AND PURPOSE: Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy are α-dystroglycan-related muscular disorders associated with brain malformations and eye abnormalities in which no structural inner ear abnormality has been described radiologically. We collected patients from 6 tertiary pediatric hospitals and reported the radiologic features and frequency of inner ear dysplasias. MATERIALS AND METHODS: Patients previously diagnosed clinicoradiologically with Walker-Warburg syndrome, muscle-eye-brain disease, or Fukuyama congenital muscular dystrophy were included. We recorded the pathogenic variant, when available. Brain MR imaging and/or CT findings were reviewed in consensus, and inner ear anomalies were classified according to previous description in the literature. We then correlated the clinicoradiologic phenotype with the inner ear phenotype. RESULTS: Thirteen patients fulfilled the criteria for the Walker-Warburg syndrome phenotype, 8 for muscle-eye-brain disease, and 3 for Fukuyama congenital muscular dystrophy. A dysplastic cochlea was demonstrated in 17/24. The most frequent finding was a pronounced cochlear hypoplasia type 4 with a very small anteriorly offset turn beyond the normal-appearing basal turn (12/13 patients with Walker-Warburg syndrome and 1/11 with muscle-eye-brain disease or Fukuyama congenital muscular dystophy). Two of 8 patients with muscle-eye-brain disease, 1/3 with Fukuyama congenital muscular dystrophy, and 1/13 with Walker-Warburg syndrome showed a less severe cochlear hypoplasia type 4. The remaining patients without Walker-Warburg syndrome were healthy. The vestibule and lateral semicircular canals of all patients were normal. Cranial nerve VIII was present in all patients with diagnostic MR imaging. CONCLUSIONS: Most patients with the severe α-dystroglycanopathy Walker-Warburg syndrome phenotype have a highly characteristic cochlear hypoplasia type 4. Patients with the milder variants, muscle-eye-brain disease and Fukuyama congenital muscular dystrophy, more frequently have a normal cochlea or milder forms of hypoplasia.

The effect of high doses of ω-3 fatty acid on the structure of the gastrocnemius muscle and on the lipidic profile of Wistar rats submitted to swimming.

OBJECTIVES: Evidence suggests that ω-3 fatty acids (FA) may have an anabolic effect on skeletal muscle. However, questions about dosage, frequency, combined protein supplementation, or different physical exercises remain unanswered. The aim of this study was to quantify by stereology whether supplementation with high dosages of ω-3 FA combined with swimming has an anabolic effect on the skeletal musculature and on the lipid profile of rats. METHODS: Sixty male Wistar rats were divided into four groups: placebo sedentary (PS), ω-3 FA sedentary (ω-3 S), placebo exercise (PE), and ω-3 FA exercise (ω-3 E). The animals in the PE and ω-3 E groups were submitted to swimming 5 d/wk, with an overload of 15% of body weight. The animals received ω-3 FA or olive oil (placebo) by gavage. After sacrifice, blood samples and the gastrocnemius muscle were collected for analysis. RESULTS: Results from this study did not show a difference in the cross-sectional areas of the gastrocnemius muscle between groups. The administration of high doses of ω-3 FA reduced plasmatic concentrations of low-density lipoprotein. Additionally, an interaction effect was observed between physical exercise and supplementation with ω-3 on levels of high-density lipoprotein. Therefore, the association between these two treatments increased high-density lipoprotein levels. CONCLUSIONS: The administration of high doses of ω-3 associated with physical activity may be beneficial in the treatment of dyslipidemia. High doses of ω-3 FA do not cause muscle mass alteration.

Determinação do limiar anaeróbio pela carga crítica superestima teste de lactato mínimo / Determination the anaerobic threshold for critical workload overestimates lactate minimum test

Introdução: A utilização de métodos específicos de mensuração é de fundamental importância para a identificação da capacidade aeróbia e prescrição da intensidade de exercício. Normalmente esta definição é feita pela determinação do limiar anaeróbio (Lan) que corresponde à máxima fase estável entre produção e remoção de lactato sanguíneo (MFEL). Dentre as mais variadas formas de se det ermin ar a MFEL estão os testes de lactato mínimo (LM) e carga crítica (CC). No entanto, não se sabe se a utilização dessas formas de avaliação pode acarretar em resultados distintos. Objetivo: O objetivo do presente estudo foi comparar os valores de Lan obtidos por meio dos testes de CC e de LM em rat o s W istar. Método : Foram utilizados 32 ratos machos (Wistar), com peso médio 411,0 (± 4 0 ,7 gramas), o s quais fo ram submetidos às baterias de testes de CC e de LM. O teste de LM foi realizado com a indução à hiperlactacidemia com dois estímulos correspondentes a 13% do peso corporal (PC), seguido de intervalo passivo de nove minutos e teste incremental composto por estágios com duração de cin co m inut os e cargas equivalentes a 4.0, 4.5, 5.0, 5.5, 6.0 e 7.0 % do PC. Já a CC foi obtida p o r m eio da in dução ao exercício em quatro diferentes estímulos randomizados, com cargas correspondentes a 7, 9, 11 e 1 3 % do PC. Resultados: Os resultados demonstraram que o Lan médio determinado pelo Teste de CC foi de 5,8 ± 1,2% do peso corporal (PC) e 4,9 ± 0,6% do PC determinado pelo Teste de LM. Co nclusão: P ode ­ se concluir que o limiar anaeróbio determinado por meio do teste CC superestimou em 18,4% o valor obtido por meio do teste de LM...(AU)

Introduction: The utilization of specific measurement methods is of fundamental importance for the identification of aerobic capacity and prescription of exercise. This determination is usually m ade through measurement of the anaerobic threshold (Lan) which corresponds to the maximal lactate st eady state (MLSS). Among the more varied forms of determination of MLSS are the minimum lactate (LM) and critical overload tests (CC). However, it is not known if the utilization of these forms o f ev aluatio n can lead to different results. Objective: The aim of this study was to compare the Lan v alues o btained through the CCand LM tests in Wistar rats. Method: For this purpose, 32 male Wistar rats were used, with an average weight of 411.0 ± 40.7 grams, submitted to CC and LM tests. The LM test was performed fo r the induction of a hyperlactacidemia with two stimuli corresponding to 13% of body weight (BW), followed by a passive interval of nine minutes and an incremental test composed of stages with a duratio n of five minutes and loads equivalent to 4.0, 4.5, 5.0, 5.5, 6.0, and 7.0% of BW . T he CC was o bt ain ed through induced exercise in four randomized stimuli, with loads corresponding to 7, 9 , 1 1, and 1 3 % o f BW. Results: It was observed that the mean anaerobic threshold determined by CC was 5.8 ± 1 .2 % BW , and determined by LM was 4.9 ± 0.6% BW. Conclusion: It is concluded that th e an aero bic th resho ld determined through the critical workload test overestimates the value obtained through the lactate minimum test by 18.4%, thus impeding its use as an aerobic training intensity predictor in Wistar rats. Keywords: Lactic acid, Critical load, Anaerobic threshold, Wistar rats...(AU)

The Brazilian TP53 mutation (R337H) and sarcomas.

Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.

Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis.

Antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel alter body temperature (Tb) in laboratory animals and humans: most cause hyperthermia; some produce hypothermia; and yet others have no effect. TRPV1 can be activated by capsaicin (CAP), protons (low pH), and heat. First-generation (polymodal) TRPV1 antagonists potently block all three TRPV1 activation modes. Second-generation (mode-selective) TRPV1 antagonists potently block channel activation by CAP, but exert different effects (e.g., potentiation, no effect, or low-potency inhibition) in the proton mode, heat mode, or both. Based on our earlier studies in rats, only one mode of TRPV1 activation - by protons - is involved in thermoregulatory responses to TRPV1 antagonists. In rats, compounds that potently block, potentiate, or have no effect on proton activation cause hyperthermia, hypothermia, or no effect on Tb, respectively. A Tb response occurs when a TRPV1 antagonist blocks (in case of hyperthermia) or potentiates (hypothermia) the tonic TRPV1 activation by protons somewhere in the trunk, perhaps in muscles, and - via the acido-antithermogenic and acido-antivasoconstrictor reflexes - modulates thermogenesis and skin vasoconstriction. In this work, we used a mathematical model to analyze Tb data from human clinical trials of TRPV1 antagonists. The analysis suggests that, in humans, the hyperthermic effect depends on the antagonist's potency to block TRPV1 activation not only by protons, but also by heat, while the CAP activation mode is uninvolved. Whereas in rats TRPV1 drives thermoeffectors by mediating pH signals from the trunk, but not Tb signals, our analysis suggests that TRPV1 mediates both pH and thermal signals driving thermoregulation in humans. Hence, in humans (but not in rats), TRPV1 is likely to serve as a thermosensor of the thermoregulation system. We also conducted a meta-analysis of Tb data from human trials and found that polymodal TRPV1 antagonists (ABT-102, AZD1386, and V116517) increase Tb, whereas the mode-selective blocker NEO6860 does not. Several strategies of harnessing the thermoregulatory effects of TRPV1 antagonists in humans are discussed.

Comparative larval ontogeny of two fish species (Characiformes and Siluriformes) endemic to the São Francisco River in Brazil.

The aim of the present study was to perform comparative histological analyses of the ontogenetic development of two fish species endemic to the São Francisco River in Brazil: Prochilodus argenteus and Lophiosilurus alexandri. Histological analyses were performed every 24 h from the moment of hatching until 14 days post-hatching (dph) for the observation of larval development and until 39 dph for the observation of gonadal development. Whole larvae were fixed in Bouin's solution and the histological slides were stained with haematoxylin-eosin. Lophiosilurus alexandri larvae had a larger body size compared with P. argenteus larvae since hatching. Lophiosilurus alexandri larvae had mouth opening and pigmentation of the eyes upon hatching, whereas these events were observed at 1 dph in P. argenteus larvae. The visualisation and the inflation of the swim bladder occurred at 1 and 3 dph, respectively, in the P. argenteus, whereas these events occurred at 2 and 8 dph, respectively, in L. alexandri. Yolk granules were absorbed at 4 dph in P. argenteus and the 10 dph in L. alexandri. At 7 dph, the digestive tube was more differentiated in L. alexandri than P. argenteus and at 14 dph, the digestive system of both species had features of their eating habits: broad stomach and short intestine in L. alexandri, typical of carnivorous habits; stomach with a mechanical function and long intestine in P. argenteus, typical of detritivorous habits. The epithelial lining tissue, formed by a single layer of cells in the newly hatched larvae (0 dph), differentiated throughout the study, exhibiting scales in P. argenteus and numerous club cells in the middle epithelial region of L. alexandri at 39 dph. Undifferentiated gonads with somatic cells and primordial germ cells were observed at 39 dph, with caudal-cranial migration since 1 dph in both species. The anatomic changes during the ontogeny of P. argenteus and L. alexandri larvae are directly associated with the evolutionary history of each species, which explains their feeding habits, behaviour and distribution in the environment: Prochilodus argenteus is detritivorous and actively swims in the water column, whereas L. alexandri is carnivorous and inhabits bottom regions. At 39 dph neither species exhibited sexual differentiation.

Correction: The induction of core pluripotency master regulators in cancers defines poor clinical outcomes and treatment resistance.

The original version of this article contained an error in Fig. 5a where the colours of the labels representing the Hinge and LBD of the AR were incorrect and did not match the corresponding exons. The corrected version of this Figure now appears in the article. The conclusions of this paper were not affected. The authors apologise for this error and any confusion caused.

The induction of core pluripotency master regulators in cancers defines poor clinical outcomes and treatment resistance.

Stem cell characteristics have been associated with treatment resistance and poor prognosis across many cancer types. The ability to induce and regulate the pathways that sustain these characteristic hallmarks of lethal cancers in a novel in vitro model would greatly enhance our understanding of cancer progression and treatment resistance. In this work, we present such a model, based simply on applying standard pluripotency/embryonic stem cell media alone. Core pluripotency stem cell master regulators (OCT4, SOX2 and NANOG) along with epithelial-mesenchymal transition (EMT) markers (Snail, Slug, vimentin and N-cadherin) were induced in human prostate, breast, lung, bladder, colorectal, and renal cancer cells. RNA sequencing revealed pathways activated by pluripotency inducing culture that were shared across all cancers examined. These pathways highlight a potential core mechanism of treatment resistance. With a focus on prostate cancer, the culture-based induction of core pluripotent stem cell regulators was shown to promote survival in castrate conditions-mimicking first line treatment resistance with hormonal therapies. This acquired phenotype was shown to be mediated through the upregulation of iodothyronine deiodinase DIO2, a critical modulator of the thyroid hormone signalling pathway. Subsequent inhibition of DIO2 was shown to supress expression of prostate specific antigen, the cardinal clinical biomarker of prostate cancer progression and highlighted a novel target for clinical translation in this otherwise fatal disease. This study identifies a new and widely accessible simple preclinical model to recreate and explore underpinning pathways of lethal disease and treatment resistance.

Intracerebral Injection of Streptozotocin to Model Alzheimer Disease in Rats.

Animal models have promoted meaningful contribution to science including Alzheimer's disease (AD) research. Several animal models for AD have been used, most of them related to genetic mutations observed in familial AD. However, sporadic form of AD, also named late-onset is the most frequent form of the disease, which is multifactorial, being influenced by genetic, environmental and lifestyle factors. Here, we describe a protocol of an AD-like pathology of the sporadic form using Wistar rats by a single bilateral intracerebroventricular (icv) injection of streptozotocin (STZ, 2 mg/kg). Icv injection of STZ induces brain resistance to insulin and other pathological alterations related to those observed in AD, such as cognitive impairment and accumulation of phosphorylated tau protein and ß-amyloid in the brain. Thus, icv injection of STZ is a useful tool to investigate the pathological mechanisms and the metabolic alterations involved in AD and to propose new therapeutic approaches and neuroprotective drugs.

A Fatal Case of Louping-ill in a Dog: Immunolocalization and Full Genome Sequencing of the Virus.

Louping-ill (LI), caused by louping-ill virus (LIV), results in a frequently fatal encephalitis primarily affecting sheep and red grouse (Lagopus lagopus scotica), but it does occur in other species. An adult male Border collie dog was definitively diagnosed with fatal LI and the lesion profile, LIV antigen distribution and full genome sequence of the LIV responsible were investigated to determine if this differed significantly from sheep-derived LIV. No gross lesions were present. The histological lesions were confined to the central nervous system and comprised of lymphocytic perivascular cuffs, glial foci, neuronal necrosis and neuronophagia. Immunolocalization of viral antigen showed small amounts present in neurons only. These histological and immunohistochemical findings were similar to those reported in affected sheep. Compared with published full genome sequences of sheep-derived LIV, only very minor differences were present and phylogenetically the virus clustered individually between a subclade containing Scottish strains, LIV 369/T2 and G and another subclade containing an English isolate LIV A. The LIV isolated from the dog shares a common progenitor with LIV A. These findings suggest there is no canine-specific LIV strain, dogs are susceptible to sheep-associated strains of LI and with the increase in tick prevalence, and therefore exposure to LIV, a safe, effective vaccine for dogs may be required.