Defective thyroid hormone transport to the brain leads to astroglial alterations.

Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.

Medical cannabis use in oncology and associated outcomes: A scoping review.

BACKGROUND: Natural and synthetic cannabinoids are being used worldwide to treat various symptoms in cancer patients. This study aims to map the therapeutic benefits and adverse effects associated with the use of cannabis-based drugs in these outcomes. METHODS: Following Joanna Briggs Institute guidelines a scoping review was conducted. The study protocol was available in the Open Science Framework public repository. An extensive search strategy involving databases like Cochrane Library, Embase, CINAHL, Medline/PubMed, Lilacs, Google Scholar, and Open Gray for gray literature analysis was executed by a skilled librarian. The inclusion criteria were primary studies (observational and randomized) that evaluated the efficacy and safety of cannabinoids in cancer patients. The review encompassed studies of diverse designs, publication years, and types, as long as they addressed cannabinoids' impact in oncology. RESULTS: Twenty-nine (82.86%) out of total of 35 were randomized and 6 (14.14%) were non-randomized. About 57.1% of studies utilized registered products as interventions, with THC being the most natural cannabinoid cited in variable doses and administration routes. Moreover, 62.85% of studies specified the cancer types (breast, lung, sarcomas, hematological and reproductive system), while only one study detailed cancer staging. The evaluated outcomes encompassed nausea and vomiting (77.14%), appetite (11.43%), pain (8.57%), and tumor regression (2.86%) across different proportions of studies. CONCLUSION: Cannabinoids show promise in managing pain, emesis, and anorexia/cachexia linked to cancer progression. New randomized clinical trials with a larger number of participants and observational studies on long-term safety are crucial to affirm their medicinal utility for cancer patients unresponsive to conventional drugs.

Microparticles derived from obese adipose tissue elicit a pro-inflammatory phenotype of CD16+, CCR5+ and TLR8+ monocytes.

Macrophage infiltration into adipose tissue (AT) is a hallmark of the chronic inflammatory response in obesity and is supported by an intense monocyte migration towards AT. Although it has been detected an increased proportion of circulating CD16+ monocyte subsets in obese subjects, the mechanisms underlying this effect and the contribution of these cells to the inflamed profile of obese AT are still poorly understood. We investigated whether factors secreted by human obese omental AT could polarize monocytes to CD16+ enriched phenotype, and how these changes could modify their migratory capacity towards adipose tissue itself. We show that explants of human obese omental AT, obtained during bariatric surgery, released higher levels of MIP1-α, TNFα, leptin and also VEGF, together with increasing amounts of microparticles (MP), when compared to explants of lean subcutaneous AT. A higher content of circulating MP derived from preadipocytes and leukocytes was also detected in plasma of obese subjects. Conditioned media or MP released from obese omental AT increased CD16 and CCR5 expression on CD14+CD16- monocytes and augmented their migratory capacity towards the conditioned media from obese omental AT, itself. This effect was inhibited when MIP1-α was neutralized. Additionally, we demonstrate that MP derived from obese omental AT carry and transfer TLR8 to monocytes, thus triggering an increase in CD16 expression in those cells. Our data shows a positive feedback loop between blood monocytes and obese omental AT, which releases chemotactic mediators and TLR8-enriched MP, thus inducing an up-regulation of CD16+ monocytes, favoring leukocyte infiltration in the obese omental AT.

Reformatted images improve the detection rate of acute traumatic subdural hematomas on brain CT compared with axial images alone.

Subdural hematomas (SDHs) comprise a significant percentage of missed intracranial hemorrhage on axial brain CT. SDH detection rates could be improved with the addition of reformatted images. Though performed at some centers, the potential additional diagnostic sensitivity of reformatted images has not yet been investigated. The purpose of our study is to determine if the addition of coronal and sagittal reformatted images to an axial brain CT increases the sensitivity and specificity for detection of acute traumatic SDH. We retrospectively reviewed consecutive brain CTs acquired for acute trauma that contained new SDHs. An equivalent number of normal brain CTs served as control. Paired sets of images were created for each case: (1) axial images only ("axial only") and (2) axial, coronal, sagittal images ("reformat added"). Three readers interpreted both the axial only and companion reformat added for each case, separated by 1 month. Reading times and SDH detection rates were compared. One hundred SDH and 100 negative examinations were collected. Sensitivity and specificity for the axial-only scans were 75.7 and 94.3 %, respectively, compared with 88.3 and 98.3 % for reformat added. There was a 24.3 % false negative (missed SDH) rate with axial-only scans versus 11.7 % with reformat added (p = <0.001). Median reader interpretation times were longer with the addition of reformatted images (125 versus 89 s), but this difference was not significant (p = 0.23). The addition of coronal and sagittal images in trauma brain CT resulted in improved sensitivity and specificity as well as a reduction in SDH false negatives by greater than 50 %. Reformatted images substantially reduce the number of missed SDHs compared with axial images alone.

Infarct patterns, collaterals and likely causative mechanisms of stroke in symptomatic intracranial atherosclerosis.

BACKGROUND: There are limited data on the specific mechanisms of stroke in patients with intracranial atherosclerotic stenosis (ICAS). We undertook this study to describe infarct patterns and likely mechanisms of stroke in a large cohort of patients with ICAS, and to evaluate the relationship of these infarct patterns to angiographic features (collaterals, stenosis location and stenosis severity). METHODS: We evaluated infarct patterns in the territory of a stenotic intracranial artery on neuroimaging performed at baseline and during follow-up if a recurrent stroke occurred in patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. We defined the likely mechanism of stroke (artery-to-artery embolism, perforator occlusion, hypoperfusion or mixed) according to the site of ICAS and based on the infarct patterns on neuroimaging. Collaterals were assessed using American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grades, and stenosis severity using the WASID trial's measurement technique. We evaluated the association of infarct patterns with angiographic features using χ(2) tests. RESULTS: The likely mechanisms of stroke based on the infarct patterns at baseline in the 136 patients included in the study were artery-to-artery embolism (n = 69; 50.7%), perforator occlusion (n = 34; 25%), hypoperfusion (n = 12; 8.8%) and mixed (n = 21; 15.5%). Perforator-occlusive infarcts were more frequent in the posterior circulation, and mixed patterns were more prevalent in the anterior circulation (both p < 0.01). Most of the mixed patterns in the anterior circulation combined small pial or scattered multiple cortical infarcts with infarcts in border-zone regions, especially the cortical ones. Isolated border-zone infarcts were not significantly associated with a poor grading for collaterals or the severity of stenosis. Among 47 patients with a recurrent infarct during follow-up, the infarct patterns suggested an artery-to-artery embolic mechanism in 29 (61.7%). CONCLUSIONS: Artery-to-artery embolism is probably the most common mechanism of stroke in both the anterior and the posterior circulations in patients with ICAS. An extension of intracranial atherosclerosis at the site of stenosis into adjacent perforators also appears to be a common mechanism of stroke, particularly in the posterior circulation, whereas hypoperfusion as the sole mechanism is relatively uncommon. Further research is important to accurately establish the specific mechanisms of stroke in patients with ICAS, since preliminary data suggest that the underlying mechanism of stroke is an important determinant of prognosis.

[Meaning of living with external fixation for grade III open fracture of lower limbs: patient view]. / Significado de conviver com fixação externa por fratura exposta grau III em membros inferiores: o olhar do paciente.

The present study is aimed to understand the meaning of living with an external fixation device for grade III open fractures of the lower limbs from the perspective of the patient. The data were collected with six young adults who were undergoing outpatient orthopedic treatment in a public hospital in the city of São Paulo, through semi-structured interviews with open questions, between June and August 2010. Seeking to understand the meaning of this experience, we have maintained a phenomenological attitude during the analysis, which made it possible to reveal the phenomenon "try to live in spite of feeling trapped in a cage." Patients said that their personal desire and support from others helped them reorganize their lives, despite the several challenges they had to overcome to adapt to the fastener attached to their body and the fear of the future and doubts about the success of treatment.

The Impact of Cervical Spinal Disease on Pharyngeal Swallowing Function.

PURPOSE: Spinal pathology is very common with advancing age and can cause dysphagia; however, it is unclear how frequently these pathologies affect swallowing function. This study evaluates how cervical spinal pathology may impact swallowing function in dysphagic individuals observed during videofluoroscopic swallowing studies (VFSSs). METHOD: A retrospective case-control study was performed on 100 individuals with dysphagia as well as age-/gender-matched healthy controls (HCs) with available VFSS. Spinal anatomy of patients was classified into two predetermined categories, and a consensus decision of whether spinal pathology influenced swallowing physiology was made. Validated swallow metrics, including Modified Barium Swallow Impairment Profile (MBSImP) component scores, Penetration-Aspiration Scale (PAS) maximum scores, and 10-item Eating Assessment Tool (EAT-10) scores, were compared between the spine-associated dysphagia (SAD), non-SAD (NSAD), and HC groups using Kruskal-Wallis one-way analysis of variance. RESULTS: Most patients with dysphagia had spinal pathology. Spinal pathology was judged to be the primary etiology of dysphagia in 16.9% of patients with abnormal spine pathology. Median EAT-10 scores were statistically different among the three groups, with the NSAD group scoring the highest and the HC group scoring the lowest. Similarly, median PAS scores were significantly different between dysphagic groups and HCs. Median MBSImP Oral Total scores were significantly different only between the NSAD group and HCs, whereas Pharyngeal Total score was not significantly different among the groups. CONCLUSIONS: Spinal pathology is commonly observed during VFSS and can contribute to dysphagia, resulting in worse swallowing-related outcomes when compared with HCs. Patients judged to have SAD tended to have better outcomes than patients with dysphagia from other etiologies, perhaps due to the progressive nature of spinal disease that allows for compensatory swallowing physiology over time.

A Primary Gastrointestinal Presentation and Novel Genetic Variant of Dyskeratosis Congenita in a Pediatric Patient.

Dyskeratosis congenita (DC) is a rare telomerase disorder affecting high turnover cells. Malfunction of protective proteins in DC results in patient genomes with shortened germline telomeres leading to genetic instability, cellular apoptosis, and overall cellular lifespan degradation. Classically, reports of DC described a triad of dysplastic nails, reticular skin pigmentation, and oral leukoplakia. However, more recent reports have focused on disease presentation affecting other high turnover organ systems including the gastrointestinal system. Patients may present with dysphagia because of esophageal stricture/web, diarrhea secondary to enteropathy or enterocolitis. We present a pediatric patient who presented with feeding difficulty secondary to an esophageal stricture as the primary manifestation of DC. She was diagnosed with Revesz Syndrome, a rare subtype of DC, along with a novel genetic variant not previously reported. This report serves to bring awareness to gastroenterologists that DC, though classically thought to present with dermatological findings, can present with primary gastrointestinal manifestations.

Antinociceptive activity of (-)-(2S,6S)-(6-ethyl-tetrahydropyran-2-yl)-formic acid on acute pain in mice.

Pain is a major cause of distress, both physical and psychological. There is a continuous search for new pharmacologically active analgesic agents with minor adverse effects. Recently, the synthesis of (-)-(2S,6S)-(6-ethyl-tetrahydropyran-2-yl)-formic acid [tetrahydropyran derivative (TD)] was described. The objective of this study was to investigate antinociceptive effects of TD. Its activity was compared with the activity of morphine. The effects of TD and morphine were evaluated in models of inflammatory and noninflammatory pain. TD (6-1200 µmol/kg, intraperitoneally) significantly reduced the nociceptive effects induced by acetic acid or formalin in mice. TD also demonstrated an antinociceptive effect in the tail-flick and hot-plate model. The opioid receptor antagonist, naloxone (at 15 µmol/kg, intraperitoneally), reversed the antinociceptive activity of TD in all the models evaluated. Morphine and TD induced tolerance in mice. However, the onset of tolerance to TD was delayed compared with that induced by morphine. These results indicate that TD develops significant antinociceptive activity and, at least part of its effects seems to be mediated by the opioid system.

Natural history of Christianson syndrome.

Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types. Gilfillan et al.2008] reported mutations in SLC9A6, the gene encoding the sodium/hydrogen exchanger NHE6, in the family first reported and in three others. They also noted the clinical similarities to Angelman syndrome and found cerebellar atrophy on MRI and elevated glutamate/glutamine in the basal ganglia on MRS. Here we report on nonsense mutations in two additional families. The natural history is detailed in childhood and adult life, the similarities to Angelman syndrome confirmed, and the MRI/MRS findings documented in three affected boys.

Meningovascular syphilis with fatal vertebrobasilar occlusion.

We report the case of a young patient with meningovascular syphilis who suffered fatal vertebrobasilar occlusion despite thrombolytic treatment and endovascular interventions. A 35-year-old man without any known medical history presented with an acute ischemic stroke and was initially treated with intravenous tissue plasminogen activator. He was then transferred to the stroke center, where he underwent endovascular recanalization of his occluded vertebrobasilar system. Despite initial successful recanalization, he suffered recurrent vertebrobasilar occlusion, and a second endovascular treatment attempt was unsuccessful. He subsequently developed a pontine hemorrhage and acute hydrocephalus and died secondary to transtentorial herniation. Laboratory findings were suggestive of prior spirochetal infection, and autopsy revealed necrotizing vasculitis and extensive adventitial inflammation involving the basilar and vertebral arteries, supporting the diagnosis of meningovascular syphilis.

Ascending and plunging ranula in a pediatric patient.

A plunging ranula is a rare phenomenon that represents mucous extravasation extending through or behind the mylohyoid. The mucous dissects the tissue planes inferiorly and usually manifests as a swelling in the submental or submandibular regions. Some plunging ranulas are believed to result from disruption of excretory ducts that originate from the sublingual gland. The currently accepted definitive treatment of a plunging ranula is resection of the ipsilateral sublingual gland and evacuation of the cyst with removal of the pseudocapsule. There have been no reported cases of "ascending" ranulas into the parapharyngeal or pterygomaxillary space. The following represents the first known case that involved an extensive ascending and plunging ranula in a pediatric patient, which recurred despite complete excision of the ranula and sublingual gland. IRB approval was not required per institutional policy on retrospective case reports.

[Health didactics: undergraduates' nursing representations and the use of an innovative teaching strategy]. / Didatica em saúde: representações de graduandos em enfermagem e utilização de metodologia inovadora de ensino.

This study aimed at analyzing the representations regarding the relationships between Nursing and Education practices, to reveal expectations regarding the course Fundamentals, Methods and Techniques of Teaching and evaluate the use of the Projects Method. Method this is a qualitative evaluation research performed between April and June 2007 with first-year nursing students of a Baccalaureate Degree Program. The data were analyzed based on the Social Representations framework and the constructivist postulates. The students revealed that their learning expectations were related with the contents of didactics, human communication, and the teaching-learning process. The Projects Method was considered capable of providing dynamism, interest towards the content, and the ability to associate theory and practice, in addition to having favored the amplitude and appreciation of the educate/care binomial. In conclusion, health didactics contents are capable of generating students' interest, especially when an innovative methodology is used.

[Humanization of nursing care: what is it?]. / Humanização do cuidado de enfermagem: o que é isso?

The study was conducted with the purpose of identifying how nursing professionals understand the expression 'humanized care'. This is a qualitative research, accomplished according to the historic oral thematic method. Seven nurses of a major São Paulo hospital were chosen to partake on this study. According to the analysis and understanding of the meanings expressed on the different speeches it was possible to identify that the expression 'humanized care' has been used with the intension of expressing dehumanization, associated both with nursing professionals dehumanization, from the patient's perspective, and with dehumanization associated with the institution from the nursing professionals point of view. It was identified that this term has been used without the full understanding of its meaning.

Sulcal FLAIR hyperintensity after CSF removal in two patients with intracranial hypertension.

Sulcal hyperintensity on fluid-attenuated inversion recovery (FLAIR) sequence is a frequently encountered finding that could be due to an abnormality of cerebrospinal fluid, a secondary finding related to an intracranial pathologic process, or be artifactual or iatrogenic. Here we present two cases of sulcal FLAIR hyperintensity in the setting of intracranial hypotension after CSF removal for intracranial hypertension.

Inhibition of mTOR Signaling and Clinical Activity of Rapamycin in Head and Neck Cancer in a Window of Opportunity Trial.

PURPOSE: We studied the impact of mTOR signaling inhibition with rapamycin in head and neck squamous cell carcinoma (HNSCC) in the neoadjuvant setting. The goals were to evaluate the mTOR pathway as a therapeutic target for patients with advanced HNSCC, and the clinical safety, antitumor, and molecular activity of rapamycin administration on HNSCC. PATIENTS AND METHODS: Patients with untreated stage II-IVA HNSCC received rapamycin for 21 days (day 1, 15 mg; days 2-12, 5 mg) prior to definitive treatment with surgery or chemoradiation. Treatment responses were assessed clinically and radiographically with CT and FDG-PET. Pre- and posttreatment biopsies and blood were obtained for toxicity, immune monitoring, and IHC assessment of mTOR signaling, as well as exome sequencing. RESULTS: Sixteen patients (eight oral cavity, eight oropharyngeal) completed rapamycin and definitive treatment. Half of patients were p16 positive. One patient had a pathologic complete response and four (25%) patients met RECIST criteria for response (1 CR, 3 PR, 12 SD). Treatment was well tolerated with no grade 4 or unexpected toxicities. No significant immune suppression was observed. Downstream mTOR signaling was downregulated in tumor tissues as measured by phosphorylation of S6 (P < 0.0001), AKT (P < 0.0001), and 4EBP (P = 0.0361), with a significant compensatory increase in phosphorylated ERK in most patients (P < 0.001). Ki67 was reduced in tumor biopsies in all patients (P = 0.013). CONCLUSIONS: Rapamycin treatment was well tolerated, reduced mTOR signaling and tumor growth, and resulted in significant clinical responses despite the brief treatment duration, thus supporting the potential role of mTOR inhibitors in treatment regimens for HNSCC.

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.

Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.

Antineoplasic activity of Copaifera multijuga oil and fractions against ascitic and solid Ehrlich tumor.

The aim of this study was to investigate the effect of chronic treatment with C. multijuga oil on Ehrlich tumor evolution. C. multijuga was fractionated in a KOH impregnated silica gel column chromatography to give three distinct fractions, i.e., hexanic, chloroformic, and methanolic, mainly composed by hydrocarbon sesquiterpenes, oxygenated sesquiterpenes and acidic diterpenes, respectively. Results demonstrated that the C. multijuga oil, the hexanic, and chloroformic fractions did not develop toxic effects. The oil, hexanic and chloroformic fractions (doses varying between 100 and 200mg/kg) showed antineoplasic properties against Ehrlich ascitic tumor (EAT) and solid tumor during 10 consecutive days of treatment inhibiting ascitic tumor cell number, reverting medulla and blood cell counts to values similar to control group, and inhibiting the increase on several inflammatory mediators (total protein, PGE(2), nitric oxide, and TNF) on ascitic fluid. The treatment also inhibited the increase in paw volume on tumor-inoculated mice. In conclusion, C. multijuga as well as its fractions demonstrated antineoplasic effect even after oral administration confirming its use by traditional medicine.

RADIATION DOSE AND IMAGE QUALITY IN PEDIATRIC HEAD CT.

Our goal was to define a pediatric head CT protocol able to provide images of diagnostic quality, using the least amount of radiation, in children <10 years of age, while using a filtered back projection reconstruction algorithm. Image quality of 119 pediatric head CTs was assessed using a 5-point scoring system. Exams with scores ≥2.5 were considered of sufficient diagnostic quality. The contrast-to-noise ratio (CNR) was also measured. For children <1 year and 1-9 years, all studies performed with CTDIvol ≥ 20.1 mGy (range: 9-46 mGy) and CTDIvol ≥ 27.5 mGy (range: 15-60 mGy) yielded images of diagnostic quality. All diagnostic studies had a minimum CNR of 1.4. These CTDIvol values represent a good balance between image quality and radiation burden. This information can be helpful in designing pediatric head CT protocols with further dose-reduction, namely, iterative reconstruction algorithms and automated exposure control.

Isatins inhibit cyclooxygenase-2 and inducible nitric oxide synthase in a mouse macrophage cell line.

Isatin is a versatile compound with a diversity of effects. We designed to investigate the inhibitory effect of isatin derivatives on lipopolysaccharide/interferon-gamma-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, production of prostaglandin E(2) (PGE(2)), nitric oxide (NO), tumor necrosis factor (TNF-alpha), and their capacity to scavenge NO. Isatins inhibit TNF-alpha production and iNOS and COX-2 protein expression resulting on reduced levels of NO and PGE(2). Our results indicate isatin and it derivatives as inhibitors of iNOS and COX-2 enzymes, which might be used as anti-inflammatory and antitumoral agents.