Progranulin: a growth factor, a novel TNFR ligand and a drug target

Progranulin (PGRN) is abundantly expressed in epithelial cells, immune cells, neurons, and chondrocytes, and reportedly contributes to tumorigenesis. PGRN is a crucial mediator of wound healing and tissue repair. PGRN also functions as a neurotrophic factor and mutations in the PGRN gene resulting in partial loss of the PGRN protein cause frontotemporal dementia. PGRN has been found to be a novel chondrogenic growth factor and to play an important role in cartilage development and inflammatory arthritis. Although research has shown that PGRN exhibits anti-inflammatory properties, the details about the exact molecular pathway of such effects, and, in particular, the PGRN binding receptor, have not been identified so far. Recently, researchers have shown that PGRN binds to tumor necrosis factor (TNF)-receptors (TNFR), interfering with the interaction between TNFα and TNFR. They further demonstrated that mice deficient in PGRN are susceptible to collagen-induced arthritis, an experimental model of rheumatoid arthritis, and that administration of PGRN reversed the arthritic process. An engineered protein made of three PGRN fragments (Atsttrin), displayed selective TNFR binding and was more active than natural PGRN. Both PGRN and Atsttrin prevented inflammation in various arthritis mouse models and inhibited TNFα-induced intracellular signaling pathways. Thus, PGRN is a key regulator of inflammation and it may mediate its anti-inflammatory effects, at least in part, by blocking TNF binding to its receptors. As we discuss here, TNFR-based interventions may both stimulate and suppress the growth of cancer cells, and the same may be true in analogy for Atsttrin as a new player.     

Sporadic hemangioblastoma of the kidney: a clinicopathologic study of three cases and a literature review

Much attention has been paid to renal hemangioblastoma, but there are still challenges in its differential diagnosis. Three cases (2 men, 1 woman; age: 40–56 years) presented with renal tumors. The tumors were surrounded by a thick fibrous capsule, well-demarcated from the surrounding renal parenchyma, and composed of sheets or nests of polygonal to short spindle-shaped tumor cells with a rich capillary network. In cases 1 and 3, the large polygonal tumor cells contained abundant pale or eosinophilic cytoplasm, and some possessed intracytoplasmic lipid vacuoles. In case 2, tumor cells were characterized by a uniform size, mild, clear, or lightly stained cytoplasm, and typical "clear cell" appearance. Immunohistochemistry revealed that the polygonal stromal cells were strongly and diffusely positive for α-inhibin, neuron-specific enolase (NSE), S100 protein, and vimentin. Cluster of differentiation (CD)10 and paired box gene (PAX)8 were positive, while epithelial membrane antigen (EMA) and cytokeratin (CK) were focally positive in case 3. CD34 and CD31 outlined the contours and distribution of the vascular networks. Renal hemangioblastoma is rare and prone to misdiagnosis; more attention should be paid to the morphological features and reasonable application of immunohistochemistry in the diagnosis of hemangioblastoma.     

Photochemical internalisation of a macromolecular protein toxin using a cell penetrating peptide-photosensitiser conjugate

Photochemical internalisation (PCI) is a site-specific technique for improving cellular delivery of macromolecular drugs. In this study, a cell penetrating peptide, containing the core HIV-1 Tat 48-57 sequence, conjugated with a porphyrin photosensitiser has been shown to be effective for PCI. Herein we report an investigation of the photophysical and photobiological properties of a water soluble bioconjugate of the cationic Tat peptide with a hydrophobic tetraphenylporphyrin derivative. The cellular uptake and localisation of the amphiphilic bioconjugate was examined in the HN5 human head and neck squamous cell carcinoma cell line. Efficient cellular uptake and localisation in endo/lysosomal vesicles was found using fluorescence detection, and light-induced, rupture of the vesicles resulting in a more diffuse intracellular fluorescence distribution was observed. Conjugation of the Tat sequence with a hydrophobic porphyrin thus enables cellular delivery of an amphiphilic photosensitiser which can then localise in endo/lysosomal membranes, as required for effective PCI treatment. PCI efficacy was tested in combination with a protein toxin, saporin, and a significant reduction in cell viability was measured versus saporin or photosensitiser treatment alone. This study demonstrates that the cell penetrating peptide-photosensitiser bioconjugation strategy is a promising and versatile approach for enhancing the therapeutic potential of bioactive agents through photochemical internalisation.     

Optimal balance of efficacy and tolerability of oral triptans and telcagepant: a review and a clinical comment

Dose–response curves for headaches relief and adverse events (AEs) are presented for five triptans: sumatriptan, zolmitriptan, naratriptan, almotriptan, and frovatriptan, and the CGRP antagonist telcagepant. The upper part of the efficacy curve of the triptans is generally flat, the so-called ceiling effect; and none of the oral triptans, even in high doses, are as effective as subcutaneous sumatriptan, In contrast, AEs increases with increasing dose without a ceiling effect. The optimal dose for the triptans is mainly determined by tolerability. Telcagepant has an excellent tolerability and can be used in migraine patients with cardiovascular co-morbidity. Based on the literature the triptans and telcagepant are rated in a table for efficacy and tolerability.     

Percutaneous creation of a hepaticojejunostomy

A procedure is described whereby a direct anastomosis may be created percutaneously between the biliary system and a Roux-en-Y limb; in effect a percutaneous hepaticojejunostomy. Although it will have limited applications, it represents a further extension of percutaneous techniques in the biliary system for complex problems.     

鞍区黄色肉芽肿1例报告

目的 探讨鞍区黄色肉芽肿的临床特点、诊断及治疗。方法 本文提供了我院诊治鞍区黄色肉芽肿一例,并进行文献复习。结果 本例患者为33岁女性,因“停经伴头痛10月”入院,术前激素水平下降,鞍区增强MRI考虑囊性占位。行“神经内镜下经蝶入路肿瘤切除术”,术后病理提示黄色肉芽肿。术后随访1年且预后良好。结论 尽管 XG病例的十分罕见,但提高对XG的认识在临床上具有重要意义。     

Hepatocellular carcinoma in a non‐cirrhotic liver with a tumor thrombus

Young adults with HCC tend to have a poor prognosis because of advanced disease despite preserved liver function. Screening and early diagnosis for HCC are needed for young adults to demonstrate an improved prognosis, especially in HBsAg positive patients.     

获得性低磷骨软化症两例

低磷骨软化症是一种少见的代谢性骨病,按照病因分为遗传性、肿瘤性和获得性,通常表现为骨痛、骨折等,临床较少见,易误诊、漏诊。该文报道2例获得性低磷性骨软化症患者,分别为37岁的男性及33岁的女性,均以骨痛为主诉入院,明确低磷骨软化症后进一步查找病因,追查到1例为药物所致,另1例继发于原发性干燥综合征合并肾小管酸中毒,再对其临床特点、鉴别诊断及治疗进行分析以拓宽临床医师对该病的诊治思路。     

A Müllerian cyst in a male adolescent: a case report and literature review

Müllerian duct cyst is a congenital anomaly that originates from an abnormality in the degradation of the Müllerian system and remnants of the Müllerian duct. Müllerian cyst is rarely reported in male adolescents younger than 18 years of age. In this case report, a 17-year-old male adolescent presented with a scrotal mass of 6 years’ duration. Ultrasonography and computed tomography revealed a left scrotal mass, and the patient underwent open surgical resection of the cyst. Histologically, the cyst consisted of tall columnar cells and was consistent with a Müllerian duct cyst. We discuss the presentation and imaging findings in this case, drawing attention to the diagnosis and treatment.     

Severe invasive Listeria monocytogenes rhombencephalitis mimicking facial neuritis in a healthy middle-aged man: a case report and literature review

Neurolisteriosis is a foodborne infection of the central nervous system that is easily misdiagnosed, especially in healthy adults with atypical symptoms. A 50-year-old man presented with a 3-day history of distortion of the oral commissure. Facial neuritis was diagnosed and treated with intravenous dexamethasone. His condition deteriorated rapidly, and he presented with a slow pharyngeal reflex, stiff neck, and signs of peripheral facial paralysis. Brain magnetic resonance imaging revealed multiple ring-enhanced foci in the brainstem. Routine and biochemical cerebrospinal fluid (CSF) analyses showed increased white blood cells and microproteins. Blood culture and high-throughput genome sequencing revealed Listeria monocytogenes DNA in the CSF. Ampicillin, amikacin, and meropenem were administered, and the patient was transferred from the intensive care unit to a standard medical ward after 2 months. The patient could walk and eat normally; however, he required intermittent mechanical ventilation at 11 months after discharge. Although L. monocytogenes meningitis is rare in healthy immunocompetent adults, it must be considered as a differential diagnosis, especially in adults whose conditions do not improve with cephalosporin antibiotic administration. L. monocytogenes rhombencephalitis mimics facial neuritis and develops quickly. Prompt diagnosis is essential for rapid initiation of antibiotic therapy to achieve the best outcome.     

Pain Controlling and Cytokine-regulating Effects of Lyprinol, a Lipid Extract of Perna Canaliculus, in a Rat Adjuvant-induced Arthritis Model

Using an adjuvant-induced arthritis rat model, we investigated the effects of a lipid extract of Perna canaliculus (Lyprinol(R)) on pain. Radiological examinations, as well as levels of pro- and anti-inflammatory (AI) cytokines, were measured aiming to provide independent objective data to the pain controlling investigation. We confirmed the ability of Lyprinol(R) to control pain at the initial phase of its administration; with similar efficacy to that observed with Naproxen. The pain scores slowly increased again in the group of rats treated with Lyprinol(R) after day 9-14. The Naproxen-treated rats remained pain-free while treated. Both Naproxen and Lyprinol(R) decreased the levels of the pro-inflammatory cytokines TNF-alpha and IFN-gamma, and increased that of IL-10. Extra-virgin olive oil was ineffective on cytokine secretion. Rats treated with Lyprinol(R) were apparently cured after 1 year. This study confirms the AI efficacy of this lipid extract of P. canaliculus, its initial analgesic effect, its perfect tolerance and its long-term healing properties.     

Creating a Sensory-Friendly Pediatric Emergency Department

IntroductionFor children with autism spectrum disorder (ASD) and sensory-processing disorder (SPD), an unexpected visit to the emergency department can be an overwhelming experience that creates intensifying behaviors and an unsafe clinical interaction for the child, nurses, and providers. Although resources exist to help nurses work with this specialized group, there are limited examples of the challenges and opportunities of modifying an emergency department to be a place where nurses can provide sensory-informed care.MethodsGuided by Watson’s Theory of Caring, nurses and child life specialists in our pediatric emergency department initiated a practice improvement (PI) project to create a sensory-friendly emergency department. The nurses (1) engaged with community members and families, (2) examined current practices, (3) modified the patient care environment, (4) collaborated in an interprofessional educational session, and (5) created a shared vision for the modified patient-care environment.ResultsThis article describes the nurse-initiated PI process and the journey to create an evidence-based sensory-friendly pediatric emergency department. A model is presented so that other facilities can embark on their own initiative, and case studies are used to evaluate project outcomes.DiscussionIntegrating current evidence, staff suggestions, community input, and expert advice allowed us to find creative solutions to the unique sensory needs of children who visit our emergency department. Modifying both the patient-care environment and the patient-flow process to accommodate for the needs of children with ASD/SPD created a more peaceful and healing environment for children and their families and gave nurses the support they needed to provide sensory-informed care.     

介绍一种带压力监测安全装置的呼吸复苏气囊

目的 :设计带压力监测装置的呼吸复苏气囊 ,为在紧张的心肺复苏中帮助急诊医师随时掌握病人近端气道压力的大小。方法 :心搏骤停或呼衰病人气管插管时做血气分析 ,用带压力监测装置的复苏气囊面罩正压通气或插管后用该气囊正压通气 30min ,压力控制在黄色区 (4kPa)以内 ,然后连     

Novel Use of a Nurse-Led Telemedicine Team in Acute Stroke: A Retrospective Review of the Impact on a Regional Health Care System

IntroductionDespite the increasing incidence of acute ischemic stroke in the United States, many health care facilities remain unprepared to manage patients with acute stroke, including the administration of intravenous alteplase (recombinant tissue plasminogen activator [rTPA]). This has led to an opportunity for telemedicine systems to facilitate these evaluations and acute medical stroke treatment decisions. However, even telemedicine systems can fail to provide timely evaluation and management of the patient with acute stroke. The purpose of this retrospective study was to compare stroke outcome metrics pre- and postimplementation of a hybrid, local nurse-led “stroke-responder” telemedicine system.MethodsA retrospective chart review was performed on 21 patients at a regional community hospital between the years of 2014 and 2016. Data were collected pre- and postimplementation of a local stroke-responder system. Outcomes obtained included door-to-alert time, door-to-computerized tomography (CT) time, door-to-rtPA order time, and door-to-rtPA bolus dose administration time. Outcomes were compared among years.ResultsBetween 2014 and 2016, 21 charts were reviewed. Decreased mean times were observed for all metrics. The mean time for door-to-alert decreased from 21.19 to 5.84 minutes (P = 0.021), door-to-CT from 29.9 to 12.2 minutes (P = 0.022), door-to-rtPA order 88.4 to 53 minutes (P = 0.021), and door-to-rtPA administration from 106.94 to 64.65 minutes (P = 0.001).ConclusionIn an acute stroke telemedicine system, implementation of a local nurse-led “stroke responder” system resulted in significantly decreased acute stroke metrics for a community hospital within a regional hospital system.     

Radiological features of Adenomatoid odontogenic tumor: Report of a maxillary case and a mandibular one

We present two cases of AOT, the first case concerns a 23‐year‐old patient with an AOT located in the maxilla and the second case involves a 37‐year‐old patient presenting an AOT with mandibular localization.     

Accidental hypothermia: a survivor of 12 episodes

Accidental hypothermia is defined as an environmentally induced reduction of the core body temperature to 35 degrees C or below, where there is no primary endocrine or preoptic anterior hypothalmic dysfunction. We report a survivor of 12 episodes of accidental hypothermia. A comparison of his rewarming rates with passive external versus active core rewarming by inhalation of heated humidified oxygen via nasotracheal tube is provided. Multiple predisposing factors contributed to the repeated episodes of hypothermia. Anatomic causes of repeated nonaccidental hypothermia were excluded.     

The problem of low variance voxels in statistical parametric mapping; a new hat avoids a 'haircut'

Statistical parametric mapping (SPM) locates significant clusters based on a ratio of signal to noise (a ‘contrast’ of the parameters divided by its standard error) meaning that very low noise regions, for example outside the brain, can attain artefactually high statistical values. Similarly, the commonly applied preprocessing step of Gaussian spatial smoothing can shift the peak statistical significance away from the peak of the contrast and towards regions of lower variance. These problems have previously been identified in positron emission tomography (PET) (Reimold et al., 2006) and voxel-based morphometry (VBM) (Acosta-Cabronero et al., 2008), but can also appear in functional magnetic resonance imaging (fMRI) studies. Additionally, for source-reconstructed magneto- and electro-encephalography (M/EEG), the problems are particularly severe because sparsity-favouring priors constrain meaningfully large signal and variance to a small set of compactly supported regions within the brain. (Acosta-Cabronero et al., 2008) suggested adding noise to background voxels (the ‘haircut’), effectively increasing their noise variance, but at the cost of contaminating neighbouring regions with the added noise once smoothed. Following theory and simulations, we propose to modify - directly and solely - the noise variance estimate, and investigate this solution on real imaging data from a range of modalities.     

Lipid-nanoparticle-encapsulated mRNA vaccines induce protective memory CD8 T cells against a lethal viral infection

It is well established that memory CD8 T cells protect susceptible strains of mice from mousepox, a lethal viral disease caused by ectromelia virus (ECTV), the murine counterpart to human variola virus. While mRNA vaccines induce protective antibody (Ab) responses, it is unknown whether they also induce protective memory CD8 T cells. We now show that immunization with different doses of unmodified or N(1)-methylpseudouridine-modified mRNA (modified mRNA) in lipid nanoparticles (LNP) encoding the ECTV gene EVM158 induced similarly strong CD8 T cell responses to the epitope TSYKFESV, albeit unmodified mRNA-LNP had adverse effects at the inoculation site. A single immunization with 10 μg modified mRNA-LNP protected most susceptible mice from mousepox, and booster vaccination increased the memory CD8 T cell pool, providing full protection. Moreover, modified mRNA-LNP encoding TSYKFESV appended to green fluorescent protein (GFP) protected against wild-type ECTV infection while lymphocytic choriomeningitis virus glycoprotein (GP) modified mRNA-LNP protected against ECTV expressing GP epitopes. Thus, modified mRNA-LNP can be used to create protective CD8 T cell-based vaccines against viral infections.     

Epigenetic strategies to boost CAR T cell therapy

Chimeric antigen receptor (CAR) T cell therapy has led to a paradigm shift in cancer immunotherapy, but still several obstacles limit CAR T cell efficacy in cancers. Advances in high-throughput technologies revealed new insights into the role that epigenetic reprogramming plays in T cells. Mechanistic studies as well as comprehensive epigenome maps revealed an important role for epigenetic remodeling in T cell differentiation. These modifications shape the overall immune response through alterations in T cell phenotype and function. Here, we outline how epigenetic modifications in CAR T cells can overcome barriers limiting CAR T cell effectiveness, particularly in immunosuppressive tumor microenvironments. We also offer our perspective on how selected epigenetic modifications can boost CAR T cells to ultimately improve the efficacy of CAR T cell therapy.