Ιατρικά Άρθρα Αλέξανδρος Γ. Σφακιανάκης: 01/03/17

Τρίτη 3 Ιανουαρίου 2017

IJMS, Vol. 18, Pages 87: Evaluation of Magnetic Nanoparticle-Labeled Chondrocytes Cultivated on a Type II Collagen–Chitosan/Poly(Lactic-co-Glycolic) Acid Biphasic Scaffold

Chondral or osteochondral defects are still controversial problems in orthopedics. Here, chondrocytes labeled with magnetic nanoparticles were cultivated on a biphasic, type II collagen–chitosan/poly(lactic-co-glycolic acid) scaffold in an attempt to develop cultures with trackable cells exhibiting growth, differentiation, and regeneration. Rabbit chondrocytes were labeled with magnetic nanoparticles and characterized by scanning electron microscopy (SEM), transmission electron (TEM) microscopy, and gene and protein expression analyses. The experimental results showed that the magnetic nanoparticles did not affect the phenotype of chondrocytes after cell labeling, nor were protein and gene expression affected. The biphasic type II collagen–chitosan/poly(lactic-co-glycolic) acid scaffold was characterized by SEM, and labeled chondrocytes showed a homogeneous distribution throughout the scaffold after cultivation onto the polymer. Cellular phenotype remained unaltered but with increased gene expression of type II collagen and aggrecan, as indicated by cell staining, indicating chondrogenesis. Decreased SRY-related high mobility group-box gene (Sox-9) levels of cultured chondrocytes indicated that differentiation was associated with osteogenesis. These results are encouraging for the development of techniques for trackable cartilage regeneration and osteochondral defect repair which may be applied in vivo and, eventually, in clinical trials.

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Histological and Pathological Assessment of miR-204 and SOX4 Levels in Gastric Cancer Patients

Gastric cancer is one of the most common cancers and the efficient therapeutic methods are limited. Further study of the exact molecular mechanism of gastric cancer to develop novel targeted therapies is necessary and urgent. We herein systematically examined that miR-204 suppressed both proliferation and metastasis of gastric cancer AGS cells. miR-204 directly targeted SOX4. In clinical tissue research, we determined that miR-204 was expressed much lower and SOX4 expressed much higher in gastric cancer tissues compared with normal gastric tissues. Associated analysis with clinicopathological parameters in gastric cancer patients showed miR-204 was associated with no lymph node metastasis and early tumor stages whereas SOX4 was associated with lymph node metastasis and advanced tumor stages. In addition, miR-204 and SOX4 were negatively correlated in tissues from gastric cancer patients. Our findings examined the important role of miR-204 and SOX4 played in gastric cancer, and they could be used as candidate therapeutic targets for gastric cancer therapy.

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Hypothyroidism Reduces the Size of Ovarian Follicles and Promotes Hypertrophy of Periovarian Fat with Infiltration of Macrophages in Adult Rabbits

Ovarian failure is related to dyslipidemias and inflammation, as well as to hypertrophy and dysfunction of the visceral adipose tissue (VAT). Although hypothyroidism has been associated with obesity, dyslipidemias, and inflammation in humans and animals, its influence on the characteristics of ovarian follicles in adulthood is scarcely known. Control and hypothyroid rabbits were used to analyze the ovarian follicles, expression of aromatase in the ovary, serum concentration of lipids, leptin, and uric acid, size of adipocytes, and infiltration of macrophages in the periovarian VAT. Hypothyroidism did not affect the percentage of functional or atretic follicles. However, it reduced the size of primary, secondary, and tertiary follicles considered as large and the expression of aromatase in the ovary. This effect was associated with high serum concentrations of total cholesterol and low-density lipoprotein cholesterol (LDL-C). In addition, hypothyroidism induced hypertrophy of adipocytes and a major infiltration of CD68+ macrophages into the periovarian VAT. Our results suggest that the reduced size of ovarian follicles promoted by hypothyroidism could be associated with dyslipidemias, hypertrophy, and inflammation of the periovarian VAT. Present findings may be useful to understand the influence of hypothyroidism in the ovary function in adulthood.

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Familial Case of Pelizaeus-Merzbacher Disorder Detected by Oligoarray Comparative Genomic Hybridization: Genotype-to-Phenotype Diagnosis

Introduction. Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy characterized by nystagmus, spastic quadriplegia, ataxia, and developmental delay. It is caused by mutation in the PLP1 gene. Case Description. We report a 9-year-old boy referred for oligoarray comparative genomic hybridization (OA-CGH) because of intellectual delay, seizures, microcephaly, nystagmus, and spastic paraplegia. Similar clinical findings were reported in his older brother and maternal uncle. Both parents had normal phenotypes. OA-CGH was performed and a 436 Kb duplication was detected and the diagnosis of PMD was made. The mother was carrier of this 436 Kb duplication. Conclusion. Clinical presentation has been accepted as being the mainstay of diagnosis for most conditions. However, recent developments in genetic diagnosis have shown that, in many congenital and sporadic disorders lacking specific phenotypic manifestations, a genotype-to-phenotype approach can be conclusive. In this case, a diagnosis was reached by universal genomic testing, namely, whole genomic array.

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Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Idiosyncratic drug-induced liver injury (IDILI) is a significant source of drug recall and acute liver failure (ALF) in the United States. While current drug development processes emphasize general toxicity and drug metabolizing enzyme- (DME-) mediated toxicity, it has been challenging to develop comprehensive models for assessing complete idiosyncratic potential. In this review, we describe the enzymes and proteins that contain polymorphisms believed to contribute to IDILI, including ones that affect phase I and phase II metabolism, antioxidant enzymes, drug transporters, inflammation, and human leukocyte antigen (HLA). We then describe the various assays that have been developed to detect individual reactions focusing on each of the mechanisms described in the background. Finally, we examine current trends in developing comprehensive models for examining these mechanisms. There is an urgent need to develop a panel of multiparametric assays for diagnosing individual toxicity potential.

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Macrocell Protection Interference Alignment in Two-Tier Downlink Heterogeneous Networks

Conventional interference alignment (IA) has been developed to mitigate interference problems for the coexistence of picocells and macrocells. This paper proposes a macrocell protection interference alignment (MCP-IA) in two-tier MIMO downlink heterogeneous networks. The proposed method aligns the interference of the macro user equipment (UE) and mitigates the interference of the pico-UEs with a minimum mean squared error interference rejection combining (MMSE-IRC) receiver. Compared to the conventional IA, the proposed MCP-IA provides an additional array gain obtained by the precoder design of the macro BS and a diversity gain achieved by signal space selections. The degrees of freedom (DoF) of the proposed MCP-IA are equal to or greater than that of the conventional IA and are derived theoretically. Link level simulations show the link capacity and the DoF of the macro UE, and also exhibit the proposed MCP-IA attaining additional array gain and diversity gain. The system level simulation illustrates that the proposed method prevents the interference of the macro UE completely and preserves the throughput of the pico-UE irrespective of the number of picocells. For antenna configuration, the system level simulation demonstrates that the proposed MCP-IA throughput of the macro UE is not affected by the number of picocells and that the proposed MCP-IA throughput of the picocells approaches that of single-user MIMO (SU-MIMO) with a 3% loss.

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Qualitative Theory of Functional Differential and Integral Equations 2016

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Large Left Ventricular Thrombus in a Patient with Systemic and Venous Thromboembolism Secondary to Protein C and S Deficiency

58-year-old Hispanic female presented with an altered mental status. A CT scan of the head demonstrated multiple scattered infarcts and a large right temporal lobe infarct. We also diagnosed the patient with right popliteal and femoral vein thrombosis, bilateral pulmonary embolism, and a transient right radial artery occlusion. Her 12-lead EKG showed lateral ST elevation. Emergent coronary angiogram revealed normal coronaries. Echocardiogram demonstrated a large mobile mass attached to the anterolateral free wall with overall normal contractility of the left ventricle. The patient underwent surgical embolectomy to prevent further systemic embolization. Coagulability workup returned positive for protein C and S deficiency. The patient did well after surgery. Following her surgery, we initiated chronic oral anticoagulation. The presentation with intracardiac thrombus in a normal heart should raise a concern of a probable thrombophilia.

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EGCG Prevents High Fat Diet-Induced Changes in Gut Microbiota, Decreases of DNA Strand Breaks, and Changes in Expression and DNA Methylation of Dnmt1 and MLH1 in C57BL/6J Male Mice

Obesity as a multifactorial disorder involves low-grade inflammation, increased reactive oxygen species incidence, gut microbiota aberrations, and epigenetic consequences. Thus, prevention and therapies with epigenetic active antioxidants, ()-Epigallocatechin-3-gallate (EGCG), are of increasing interest. DNA damage, DNA methylation and gene expression of DNA methyltransferase 1, interleukin 6, and MutL homologue 1 were analyzed in C57BL/6J male mice fed a high-fat diet (HFD) or a control diet (CD) with and without EGCG supplementation. Gut microbiota was analyzed with quantitative real-time polymerase chain reaction. An induction of DNA damage was observed, as a consequence of HFD-feeding, whereas EGCG supplementation decreased DNA damage. HFD-feeding induced a higher inflammatory status. Supplementation reversed these effects, resulting in tissue specific gene expression and methylation patterns of DNA methyltransferase 1 and MutL homologue 1. HFD feeding caused a significant lower bacterial abundance. The Firmicutes/Bacteroidetes ratio is significantly lower in HFD + EGCG but higher in CD + EGCG compared to control groups. The results demonstrate the impact of EGCG on the one hand on gut microbiota which together with dietary components affects host health. On the other hand effects may derive from antioxidative activities as well as epigenetic modifications observed on CpG methylation but also likely to include other epigenetic elements.

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Activation of the Nrf2-Keap 1 Pathway in Short-Term Iodide Excess in Thyroid in Rats

Wistar rats were randomly divided into groups of varying iodide intake: normal iodide; 10 times high iodide; and 100 times high iodide on Days 7, 14, and 28. Insignificant changes were observed in thyroid hormone levels (). Urinary iodine concentration and iodine content in the thyroid glands increased after high consumption of iodide from NI to 100 HI (). The urinary iodine concentration of the 100 HI group on Days 7, 14, and 28 was 60–80 times that of the NI group. The mitochondrial superoxide production and expressions of Nrf2, Srx, and Prx 3 all significantly increased, while Keap 1 significantly decreased in the 100 HI group when compared to the NI or 10 HI group on Days 7, 14, and 28 (). Immunofluorescence staining results showed that Nrf2 was localized in the cytoplasm in NI group. Although Nrf2 was detected in both cytoplasm and nucleus in 10 HI and 100 HI groups, a stronger positive staining was found in the nucleus. We conclude that the activation of the Nrf2-Keap 1 antioxidative defense mechanism may play a crucial role in protecting thyroid function from short-term iodide excess in rats.

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Assessment of Resistance and Bioremediation Ability of Lactobacillus Strains to Lead and Cadmium

Cadmium (Cd) and lead (Pb) are heavy metals, important environmental pollutants, and potent toxicants to organism. Lactic acid bacteria (LAB) have been reported to remove Cd and Pb from solutions and therefore represent a useful tool for decontamination of food and beverages from heavy metals. Heavy metal ion binding by LAB was reported as metabolism-independent surface process. In this work ten Lactobacillus strains were investigated with respect to hydrophobicity, Lewis acid-base, and electrostatic properties of their outer cell surface in order to characterize their Cd and Pb removal capacity. Seven L. plantarum and L. fermentum strains were shown to remove Cd from culture medium. The metabolism-dependent accumulation mechanism of Cd removal was proposed based on extended character of Cd binding and lack of correlation between any of the surface characteristics and Cd removal. The results of this study should be considered when selecting probiotic strains for people at risk of Cd exposure.

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Cephalometrics of Pharyngeal Airway Space in Lebanese Adults

Purpose. The upper airway space is significant in orthodontic diagnosis and treatment planning. The objectives of this study are to assess the dimensions of soft tissue elements of the upper pharyngeal space and evaluate potential correlations with modifying variables such as gender, skeletal class, and anthropometric parameters. Materials and Methods. Lateral cephalograms were obtained from 117 healthy young adult Lebanese subjects. Nineteen cephalometric linear/angular measurements of the nasopharynx, oropharynx, and hypopharynx were recorded. Anthropometric parameters including body mass index and neck circumference were measured. Results. Significant differences were demonstrated for 12 out of the 19 parameters considered between genders. Uvula and tongue dimensions and the distances between epiglottis-posterior pharyngeal wall and epiglottis-posterior nasal spine were significantly larger in males. The anteroposterior inclination of the uvula and the distances between the uvula and posterior pharyngeal wall were significantly greater in females. No significant differences were found between skeletal classes relative to most of the variables. Body mass index and neck circumference were positively correlated with the dimensions of tongue and uvula. Conclusions. Sexual dimorphism relative to some cephalometric variables and anthropometric parameters may account partly for larger oronasopharyngeal spaces in females. Anthropometric data need to be accounted for in population-related comparisons.

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Visual Outcomes, Quality of Vision, and Quality of Life of Diffractive Multifocal Intraocular Lens Implantation after Myopic Laser In Situ Keratomileusis: A Prospective, Observational Case Series

Purpose. To report visual performance and quality of life after implantation of a bifocal diffractive multifocal intraocular lens (MIOL) in postmyopic laser in situ keratomileusis (LASIK) patients. Methods. Prospective, observational case series. Patients with prior myopic LASIK who had implantation of Tecnis ZMA00/ZMB00 MIOL (Abbott Medical Optics) at Hong Kong Sanatorium and Hospital were included. Postoperative examinations included monocular and binocular distance, intermediate and near visual acuity (VA), and contrast sensitivity; visual symptoms (0–5); satisfaction (1–5); spectacle independence rate; and quality of life. Results. Twenty-three patients (27 eyes) were included. No intraoperative complications developed. Mean monocular uncorrected VA at distance, intermediate, and near were (standard deviation), , and , respectively. Corresponding mean values for binocular uncorrected VA were , , and , respectively. No eyes lost >1 line of corrected distance VA. Contrast sensitivity at different spatial frequencies between operated and unoperated eyes did not differ significantly (all ). Mean score for halos, night glare, starbursts, and satisfaction were , , , and , respectively. Eighteen patients (78%) reported complete spectacle independence. Mean composite score of the quality-of-life questionnaire was out of 100. Conclusions. Implantation of the MIOL after myopic LASIK was safe and achieved good visual performance.

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Secondary Hemochromatosis due to Chronic Oral Iron Supplementation

Iron may accumulate in excess due to a mutation in the HFE gene that upregulates absorption or when it is ingested or infused at levels that exceed the body’s ability to clear it. Excess iron deposition in parenchymal tissue causes injury and ultimately organ dysfunction. Diabetes mellitus and hepatic cirrhosis due to pancreas and liver damage are just two examples of diseases that result from iron overload. Despite the rapid growth of information regarding iron metabolism and iron overload states, the most effective treatment is still serial phlebotomies. We present a patient who developed iron overload due to chronic ingestion of oral ferrous sulfate. This case illustrates the importance of querying geriatric patients regarding their use of nonprescription iron products without a medical indication.

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Endoscopic Resection of Skull Base Teratoma in Klippel-Feil Syndrome through Use of Combined Ultrasonic and Bipolar Diathermy Platforms

Klippel-Feil syndrome (KFS) is associated with numerous craniofacial abnormalities but rarely with skull base tumor formation. We report an unusual and dramatic case of a symptomatic, mature skull base teratoma in an adult patient with KFS, with extension through the basisphenoid to obstruct the nasopharynx. This benign lesion was associated with midline palatal and cerebral defects, most notably pituitary and vertebrobasilar arteriolar duplications. A multidisciplinary workup and a complete endoscopic, transnasal surgical approach between otolaryngology and neurosurgery were undertaken. Out of concern for vascular control of the fibrofatty dense tumor stalk at the skull base and need for complete teratoma resection, we successfully employed a tissue resection tool with combined ultrasonic and bipolar diathermy to the tumor pedicle at the sphenoid/clivus junction. No CSF leak or major hemorrhage was noted using this endonasal approach, and no concerning postoperative sequelae were encountered. The patient continues to do well now 3 years after tumor extirpation, with resolution of all preoperative symptoms and absence of teratoma recurrence. KFS, teratoma biology, endocrine gland duplication, and the complex considerations required for successfully addressing this type of advanced skull base pathology are all reviewed herein.

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CRLH Transmission Lines for Telecommunications: Fast and Effective Modeling

A different parameter extraction approach based on zero immittances for composite right/left-handed (CRLH) structure is presented. For lossless unit cell equivalent circuit model, LC parameters of series and parallel branches are extracted according to series resonance frequency and parallel resonance frequency, respectively. This approach can be applied to symmetric and unbalanced CRLH structures. The parameter extraction procedure is provided and validated by T-type unit cell model. The responses of distributed prototype and extracted equivalent LC circuit model are in good agreement. The equivalent circuit modeling can improve the degree of freedom in the CRLH TLs design. This parameter extraction method provides an effective and straightforward way in CRLH metamaterials design and applications in telecommunication systems.

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Manometric Measurement of the Sphincter of Oddi in Patients with Common Bile Duct Stones: A Consecutive Study of the Han Population of China

Objective. Role of dysfunction of the sphincter of Oddi (SO) in choledocholithiasis is controversial. This study was to evaluate SO motor activity in patients with common bile duct (CBD) stones in the Han population of China. Patients and Methods. In this study, 76 patients with CBD stones were enrolled in a single tertiary endoscopy center. Data of SO motor activities was prospectively evaluated by endoscopic manometry. Mean basal SO pressure, amplitude, and frequency were collected and analyzed. Results. The mean basal SO pressure, amplitude, and frequency were (1.60–171.1) mmHg, (14.9–115.5) mmHg, and (1.3–13.8)/min, respectively. The basal SO pressure was higher in patients with CBD stones

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Genome-Scale Metabolic Modeling of Archaea Lends Insight into Diversity of Metabolic Function

Decades of biochemical, bioinformatic, and sequencing data are currently being systematically compiled into genome-scale metabolic reconstructions (GEMs). Such reconstructions are knowledge-bases useful for engineering, modeling, and comparative analysis. Here we review the fifteen GEMs of archaeal species that have been constructed to date. They represent primarily members of the Euryarchaeota with three-quarters comprising representative of methanogens. Unlike other reviews on GEMs, we specially focus on archaea. We briefly review the GEM construction process and the genealogy of the archaeal models. The major insights gained during the construction of these models are then reviewed with specific focus on novel metabolic pathway predictions and growth characteristics. Metabolic pathway usage is discussed in the context of the composition of each organism’s biomass and their specific energy and growth requirements. We show how the metabolic models can be used to study the evolution of metabolism in archaea. Conservation of particular metabolic pathways can be studied by comparing reactions using the genes associated with their enzymes. This demonstrates the utility of GEMs to evolutionary studies, far beyond their original purpose of metabolic modeling; however, much needs to be done before archaeal models are as extensively complete as those for bacteria.

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Complete necrosis of hepatocellular carcinoma after preoperative portal vein embolization: a case report

Hepatocellular carcinoma has a poor prognosis; few patients can undergo surgical curative treatment according to Barcelona Clinic Liver Cancer guidelines. Progress in surgical techniques has led to operations ...

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Prepancreatic postduodenal portal vein: a case report and review of the literature

Prepancreatic postduodenal portal vein is extremely rare, with only 13 cases reported in the literature.

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A stab wound to the axilla illustrating the importance of brachial plexus anatomy in an emergency context: a case report

Although open injuries involving the brachial plexus are relatively uncommon, they can lead to permanent disability and even be life threatening if accompanied by vascular damage. We present a case report of a...

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Double localization of a non-anastomotic pseudoaneurysm after an axillofemoral bypass: a case report and review of the literature

A traumatic non-anastomotic pseudoaneurysm is a rare complication of an axillofemoral bypass graft. Fewer than 20 cases have been reported in the literature. Our case is unusual in that we report a double loca...

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Hyperbaric oxygen therapy for a refractory skin ulcer after radical mastectomy and radiation therapy: a case report

Radiation therapy is performed as an adjuvant therapy when indicated following surgical resection of malignant tumors. However, radiation exposure induces acute or chronic dermatitis, depending on the radiatio...

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En mann med feber og leddsmerter

Leddsmerter kan ha mange årsaker. Traumatiske, immunologiske og infeksiøse lidelser må vurderes. En god anamnese kan sette oss på rett spor tidlig.

En norsk mann i 60-årene ble innlagt i medisinsk avdeling på grunn av sterke smerter i høyre ankel. Smertene var ledsaget av intermitterende feber over 39 °C. Han var tidligere stort sett frisk, bortsett fra at han var innlagt med malaria i 2011. Pasienten brukte Albyl-E 75 mg 1 · 1 som fast medikasjon som primærprofylakse mot hjertesykdom. Han kom hjem til Norge fra et utenlandsopphold fem dager i forveien. Under reisen og to uker før innleggelsen hadde han merket forbigående nesetetthet og ubehag i svelg. Ved innleggelsen hadde han tiltagende smerter fra høyre ankel. Han hadde tråkket over og forstuet ankelen en måned i forveien, men det var ingen større traumer i historien. Han oppga også generelle smerter i skuldre, rygg og venstre hofte. Pasienten var ved ankomst til sykehuset høyfebril med temperatur 39 °C, normalt blodtrykk (119/65), og puls var 86, regelmessig. Det var normale auskultasjonsfunn over hjerte og lunger. Han hadde diffus rubor både på medialsiden og lateralsiden av høyre ankel, samt varmeøkning og petekkialt utslett over ankelleddet (fig 1).

Blodprøver ved innkomst viste CRP 248 (9/l) med 19,4 nøytrofile granulocytter (1,7 – 8,2 · 10**⁹/l), trombocytter 186 (145 – 348 · 10**⁹/l), INR 1,3 (

Det ble rekvirert tilsyn fra ortoped i akuttmottak. Blodprøvesvar forelå da, og det ble funnet indikasjon for diagnostisk punksjon av ankelleddet. Det ble ikke funnet indikasjon for røntgenundersøkelse av ankelen. Det ble tappet 2 – 3 ml blakket leddvæske fra høyre ankel rundt midnatt innkomstdagen. På grunn av smerter fikk vi ikke tappet ut all leddvæske. Leddvæsken ble sendt til dyrking og mikroskopi, men ikke til celletelling.

Figur 1 Høyre ankel ved innkomst. Foto: Astrid Rykkje Heien

På dette tidspunktet valgte vi på empirisk grunnlag å dekke septisk artritt med kloksacillin og gentamicin intravenøst. Vi trodde initialt mest på reaktiv artritt, men en høy CRP-verdi og leukocytose med nøytrofili, i tillegg til høy feber, gjorde at vi i tillegg dekket med antibiotika.

Morgenen etter var pasienten fremdeles febril, og CRP-nivået hadde steget til 317. Omtrent samtidig kom det preliminært svar fra Mikrobiologisk avdeling om at mikroskopi av leddvæsken viste gramnegative kokker i par og rikelig med leukocytter. Mikrobene kunne ses intracellulært (fig 2).

Figur 2 Mikroskopifunn. Grampreparat som viser gramnegative diplokokker funnet ved punksjon av høyre ankel

Dette gjorde de klart hyppigste årsakene til septisk artritt – Staphylococcus aureus og Streptococcus species – mindre sannsynlig. Vi mistenkte nå ut fra mikroskopifunnet gonokokkinfeksjon og endret antibiotika til ceftriaxon 2 g intravenøst 1 · 1.

På bakgrunn av dette ble pasienten henvist poliklinikk for seksuelt overførbare sykdommer. Dette ble gjort første innleggelsesdag. Han var nå subfebril og hadde mindre smerter i ankelen.

Det ble tatt prøver fra urethra og tonsilleregionen med tanke på gonokokker og klamydia, i tillegg til serologi med tanke på syfilis, hiv og hepatittvirus. Anamnestisk kom det etter hvert frem at pasienten hadde hatt sex uten kondom i land utenfor Europa ved et par tilfeller det siste året.

Ankelen var hoven og rød, men med god bevegelighet to dager etter innleggelse. Vi punkterte ankelen på nytt, og det kom ut 1 ml blank væske. To dager etter gjentok vi punksjon av ankel og tappet 3 ml pussbefengt væske. I høyre kne ble pasienten på grunn av økende hevelse tappet for 5 ml strågul væske. På dette tidspunktet forelå også endelig mikrobiologisk svar med oppvekst av Neisseria gonorrhoeae, fra leddvæsken fra høyre ankel tappet ved innleggelsen, både på blodagar og sjokoladeagar. Mikroben var katalasepositiv og agglutinerte i serogruppe WI. Bekreftende identifikasjon av bakteriene ble gjort med både systemet Vitek II og massespekterbasert teknologi med systemet MaldiTof (bioMérieux). Mikroben var resistent for penicillin G, ampicillin og ciprofloxacin, men sensitiv for ceftriaxon, azitromycin og spectinomycin.

Vi vurderte fortløpende behovet for artroskopisk skylling. Imidlertid tilkom det biokjemisk og lokal bedring, så dette ble ikke gjort.

Etter ti dager med antibiotikabehandling hadde pasienten fremdeles feber og smerter. CRP-nivået var fortsatt forhøyet til 145. Vi valgte da å gi en prednisolonkur, initialt 40 mg 1 · 1 i fire dager, deretter gradvis nedtrapping over tre uker. To dager etter oppstart av prednisolon ble pasienten afebril, og CRP-nivået falt raskt. Syv dager etter dette kunne pasienten skrives ut med peroral azitromycin, og prednisolon i nedtrappende dosering. CRP-nivået var da 6. Han fikk belaste ankelen til smertegrensen og fikk instruks om øvelser av fysioterapeut.

Det ble ikke påvist gonokokker i sekret fra urethra og hals, og blodkulturer var negative. Chlamydia trachomatis DNA ble ikke påvist i urinprøve, og serologiske tester for syfilis (Treponema pallidum spesifikke antistoff) og hiv-antigen/antistoff var negative. Pasienten ble kontrollert ukentlig på poliklinikken. Hevelsen bedret seg gradvis, CRP-nivået forble normalt, og pasienten hadde mindre smerter. Prednisolon og antibiotika ble seponert etter henholdsvis 3 og 4,5 ukers behandling (18 dager intravenøst ceftriaxon, azitromycin · 3/uke i 2,5 uker).

Etter avsluttet behandling tilkom økende hydrops og smerter i høyre kne, ledsaget av CRP-stigning til 43. Han ble reinnlagt, og kneleddet ble tappet for 15 ml gulaktig væske. Denne ble analysert med celletelling (leukocytter 5,7 · 10⁹/l), men var mikroskopi- og dyrkingsnegativ. Revmatolog satte inn 2 ml Lederspan (et kortikosteroidpreparat) da vi antok at han nå hadde en postinfeksiøs reaktiv artritt. CRP-nivået falt da til 1 ved kontroll én uke senere. Senere fikk han på ny lett CRP-stigning til 17, og han ble behandlet med diklofenak 50 mg 1 · 3 i én uke. Ved avsluttende kontroll var CRP-verdien

Diskusjon

Ved feber og monoartritt overveies i første omgang septisk artritt, reaktiv artritt eller krystallartritt. Med polyartralgi i tillegg vil også systemsykdom som adult Stills sykdom eller virusinfeksjon med leddaffinitet være aktuelt. Hvis symptomene har oppstått ved reise til et tropisk område, øker de differensialdiagnostiske mulighetene. Det er avgjørende å punktere leddet for leddvæskeanalyser og ta blodkulturer.

Gonokokkartritt er en kjent, men forholdsvis sjelden årsak til septisk artritt. I Norge påvises årlig 1 – 2 tilfeller med gonokokker i leddvæske (Øyvind Nilsen, MSIS, Folkehelseinstituttet, personlig meddelelse). Gonokokker forårsaker vanligvis uretritt og cervisitt, men fra litteraturen er det kjent at mellom 0,5 – 3 % av personer med mukosal gonokokkinfeksjon utvikler disseminert gonokokkinfeksjon (1 – 3). Flertallet av disseminerte gonokokkinfeksjoner, 42 – 85 %, vil presentere seg med artritt (2). I Norge har det de siste ti årene vært påvist 12 tilfeller av gonokokker i leddvæske, av totalt 3 682 tilfeller av gonokokkinfeksjon, tilsvarende 0,3 % (Øyvind Nilsen, personlig meddelelse).

Ved disseminert gonokokksykdom foreligger hovedsakelig purulent artritt eller et syndrom med tenosynovitt, dermatitt og polyartralgi, eventuelt en kombinasjon av dette (4, 5).

Denne pasienten hadde åpenbart septisk artritt, med purulent leddvæske og oppvekst av bakterier. I tillegg hadde han klinisk tenosynovitt, dermatitt og polyartralgi. Hovedsymptomene var sterke smerter i høyre ankel, ledsaget av høy feber og generelle smerter i kroppen. I tillegg fant vi ved undersøkelse erytem på høyre legg, petekkialt utslett på høyre fot og hydrops i høyre kne. Han hadde også generelle smerter i skuldre, rygg og venstre hofte.

Invasiv gonokokksykdom er assosiert med komplementmangel og systemisk lupus erythematosus (SLE). Pasienten hadde ikke hatt dette. Prøve på antinukleære antistoffer (ANA) var negativ, og komplementtest var normal.

Diagnostikk, resistens og behandlingslengde

Direkte mikroskopi av leddvæske har en høy forekomst av falskt negative funn ved septiske artritter, og sensitivitetstall fra under 50 % til 78 % er oppgitt (6, 7).

Metoden brukes likevel ved alvorlige infeksjoner der funn ved mikroskopi vil kunne ha konsekvens for valg av behandling. For vår pasient sikret metoden at det raskt ble skiftet behandling til korrekt antibiotika. Flere mikrobiologiske laboratorier i Norge kan nå også hurtig påvise gonokokker med nukleinsyreamplifiseringstester (PCR).

Isolatet var resistent for ampicillin og ciprofloksacin. Av antibiotika som isolatet var følsomt for, var kun ceftriaxon og azitromycin registrert i Norge, mens spectinomycin måtte bestilles med en leveringstid på cirka tre uker.

I litteraturen er det angitt at 7 – 10 dager samlet behandlingstid vanligvis er nok for gonokokkartritt (8). Vi valgte å gi betydelig lengre behandling på grunn av vedvarende smerter, febrilia og høye inflammasjonsmarkører. Vi valgte derfor intravenøs ceftriaxon initialt mens vi dekket med peroral azitromycin så lenge han fikk adjuvant steroidbehandling.

Adjuvant steroidbehandling ble valgt da vi oppfattet vedvarende febrilia til å være immunologisk utløst og hans hydrops i høyre kne til å være reaktiv artritt (8).

Kirurgisk behandling: Tapping versus skylling

Generelt anbefales artroskopisk skylling ved septisk artritt. Ved gonokokkartritt er det anbefalt enten skylling eller gjentatte punksjoner. Vi valgte gjentatte punksjoner (8). Det forelå svært beskjeden mengde leddvæske, slik at risikoen for leddskade syntes lav.

Årlig antas det å forekomme minst 78 millioner nye gonorétilfeller globalt (9). Funn av Neisseria gonorrhoeae er i Norge meldepliktig til Meldingssystem for smittsomme sykdommer (MSIS). Folkehelsesinstituttet har i de senere årene rapportert om stadig økende forekomst (10) (fig 3).

Figur 3 Oversikt over antall meldte gonorétilfeller, forekomst etter påvisningsmetode (10). Illustrasjonen er basert på Folkehelseinstituttets figur og gjengitt med tillatelse fra Øivind Nilsen

Man har også lenge sett en bekymringsfull økning i ciprofloksacinresistente isolat både i Norge og internasjonalt, noe som førte til at ciprofloksacin ble forlatt som empirisk behandling i norske retningslinjer fra 2013 (11, 12). Også cefalosporinresistens er økende globalt, og sykdommen blir stadig vanskeligere å behandle (13).

Vår pasient presenterte seg med atypisk klinisk bilde. Sykdommen er økende, og det er viktig at både helsearbeidere og personer i risikogruppene er oppmerksomme på sykdommen, også ved atypiske symptomer.

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Upregulation of microRNA-574-3p in a human gastric cancer cell line AGS by TGF-β1

Publication date: 20 March 2017
Source:Gene, Volume 605
Author(s): Renwen Zhang, Mingqi Wang, Pengcheng Sui, Lei Ding, Qing Yang
The mechanisms that regulate miR-574-3p expression in cells remain elusive. In the present study, we used real-time PCR assay to demonstrate TGF-β1-induced miR-574-3p upregulation in AGS cells, which was inhibited by TGF-β receptor I inhibitor SB431542. We used a computer search to identify Smad binding sites upstream of the miR-574-3p precursor sequence. We demonstrated that silencing Smad4, but not Smad2 or Smad3, significantly inhibited the TGF-β1-induced miR-574-3p upregulation in AGS cells. Furthermore, TGF-β1 significantly increased the activity of a dual-luciferase reporter that contains the Smad binding sites upstream of the miR-574 precursor sequence. Silencing Smad4 significantly inhibited the TGF-β1-induced increase in the activity of the reporter in AGS cells. ChIP assay showed that Smad4 directly bound to the promoter of miR-574-3p. MiR-574-3p inhibition was effective in eliminating the inhibition of AGS cell proliferation induced by TGF-β1, suggesting that TGF-β1 inducing upregulation of miR-574-3p is functionally significant.

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Thaulin-1: The first antimicrobial peptide isolated from the skin of a Patagonian frog Pleurodema thaul (Anura: Leptodactylidae: Leiuperinae) with activity against Escherichia coli

Publication date: 20 March 2017
Source:Gene, Volume 605
Author(s): Mariela M. Marani, Luis O. Perez, Alyne Rodrigues de Araujo, Alexandra Plácido, Carla F. Sousa, Patrick Veras Quelemes, Mayara Oliveira, Ana G. Gomes-Alves, Mariana Pueta, Paula Gameiro, Ana M. Tomás, Cristina Delerue-Matos, Peter Eaton, Silvia A. Camperi, Néstor G. Basso, Jose Roberto de Souza de Almeida Leite
Patagonia's biodiversity has been explored from many points of view, however, skin secretions of native amphibians have not been evaluated for antimicrobial peptide research until now. In this sense, Pleurodema thaul is the first amphibian specie to be studied from this large region of South America. Analysis of cDNA-encoding peptide in skin samples allowed identification of four new antimicrobial peptides. The predicted mature peptides were synthesized and all of them showed weak or null antimicrobial activity against Klebsiella pneumoniae, Staphylococcus aureus and Escherichia coli with the exception of thaulin-1, a cationic 26-residue linear, amphipathic, Gly- and Leu-rich peptide with moderate antimicrobial activity against E. coli (MIC of 24.7μM). AFM and SPR studies suggested a preferential interaction between these peptides and bacterial membranes. Cytotoxicity assays showed that thaulin peptides had minimal effects at MIC concentrations towards human and animal cells. These are the first peptides described for amphibians of the Pleurodema genus. These findings highlight the potential of the Patagonian region's unexplored biodiversity as a source for new molecule discovery.

Graphical abstract

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Amplified music exposure carries risks to hearing

Publication date: February 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 93
Author(s): Valéria Gomes da Silva, Carlos Augusto Costa Pires de Oliveira, Pedro Luíz Tauil, Isabella Monteiro de Castro Silva, André Luiz Lopes Sampaio
ObjectiveTo investigate the association between changes in the outer hair cells and exposure to amplified music in a group of high-school students.Materials and methodsIn this retrospective, case-control study, 86 subjects underwent audiometry, immittance audiometry, and distortion-product otoacoustic emission tests. The subjects were questioned about their listening habits and divided into 2 groups: exposed and unexposed.ResultsMost of the subjects had reduced function in their outer hair cells, mainly beginning at 8 kHz. Among 60 subjects—30 cases and 30 controls—75% were considered exposed and 25% unexposed. The exposed subjects were 9.33 times more likely to have altered outer hair cells than the unexposed subjects were.ConclusionExposure to amplified music is associated with reduced function in the hair cells.

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Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment in bleeding patients: a systematic review with meta-analysis and trial sequential analysis

Summary

Coagulopathy and severe bleeding are associated with high mortality. We evaluated haemostatic treatment guided by the functional viscoelastic haemostatic assays, thromboelastography or rotational thromboelastometry in bleeding patients. We searched for randomised, controlled trials irrespective of publication status, publication date, blinding status, outcomes published or language from date of inception to 5 January 2016 in six bibliographic databases. We included 17 trials (1493 participants), most involving cardiac surgery. Thromboelastography or rotational thromboelastometry seemed to reduce overall mortality compared to any of our comparisons (3.9% vs. 7.4%, RR (95% CI) 0.52 (0.28–0.95); I² = 0%, 8 trials, 717 participants). However, the quality of evidence is graded as low due to the high risk of bias, heterogeneity, imprecision and low event rate. Thromboelastography or rotational thromboelastometry significantly reduced the proportion of patients transfused with red blood cells (RR (95% CI) 0.86 (0.79–0.94); I² = 0%, 10 trials, 832 participants), fresh frozen plasma (RR (95% CI) 0.57 (0.33–0.96); I² = 86%, 10 trials, 832 participants) and platelets (RR (95% CI) 0.73 (0.60–0.88); I² = 0%, 10 studies, 832 participants). There was no difference in proportion needing surgical re-interventions (RR (95% CI) 0.75 (0.50–1.10); I² = 0%, 9 trials, 887 participants). Trial sequential analysis of mortality suggests that only 54% of the required information size has been reached so far. Transfusion strategies guided by thromboelastography or rotational thromboelastometry may reduce the need for blood products in patients with bleeding, but the results are mainly based on trials of elective cardiac surgery involving cardiopulmonary bypass, with low-quality evidence.

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Bar code app aims to cut sugar intake

Public Health England (PHE) has launched a Sugar Smart app to help parents clearly see how much sugar everyday food and drink contains, after research showed that children consume half of their daily...

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Under half of new cancer drugs increase survival by three months, study finds

New cancer drugs vary greatly in improving overall survival and the quality of life they achieve when compared with previous treatments, says a study systematically evaluating health technology...

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En mann med feber og leddsmerter

Leddsmerter kan ha mange årsaker. Traumatiske, immunologiske og infeksiøse lidelser må vurderes. En god anamnese kan sette oss på rett spor tidlig.

Blodprøver ved innkomst viste CRP 248 (9/l) med 19,4 nøytrofile granulocytter (1,7 – 8,2 · 10**⁹/l), trombocytter 186 (145 – 348 · 10**⁹/l), INR 1,3 (

Figur 1 Høyre ankel ved innkomst. Foto: Astrid Rykkje Heien

Figur 2 Mikroskopifunn. Grampreparat som viser gramnegative diplokokker funnet ved punksjon av høyre ankel

På bakgrunn av dette ble pasienten henvist poliklinikk for seksuelt overførbare sykdommer. Dette ble gjort første innleggelsesdag. Han var nå subfebril og hadde mindre smerter i ankelen.

Vi vurderte fortløpende behovet for artroskopisk skylling. Imidlertid tilkom det biokjemisk og lokal bedring, så dette ble ikke gjort.

Diskusjon

Ved disseminert gonokokksykdom foreligger hovedsakelig purulent artritt eller et syndrom med tenosynovitt, dermatitt og polyartralgi, eventuelt en kombinasjon av dette (4, 5).

Diagnostikk, resistens og behandlingslengde

Direkte mikroskopi av leddvæske har en høy forekomst av falskt negative funn ved septiske artritter, og sensitivitetstall fra under 50 % til 78 % er oppgitt (6, 7).

Adjuvant steroidbehandling ble valgt da vi oppfattet vedvarende febrilia til å være immunologisk utløst og hans hydrops i høyre kne til å være reaktiv artritt (8).

Kirurgisk behandling: Tapping versus skylling

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Giant prolactinomas: Multi-modal approach to achieve tumor control

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Dynamic Analysis of a Rotor-Bearing-SFD System with the Bearing Inner Race Defect

In this paper, the dynamic behavior of a rotor-bearing-SFD system with the inner race defect of bearing is investigated. The contact force between the rolling element and the race is calculated in Hertzian contact and elastohydrodynamic lubrication condition. The supporting force of the SFD is simulated by integrating the pressure distribution derived from Reynolds’s equation. The equations of motion of the rotor-bearing-SFD system are derived and solved using the fourth-order Runge-Kutta method. The dynamic behavior and the fault characteristics are analyzed with two configurations of the SFD: mounted on the unfaulted bearing and mounted on the faulty bearing. According to the analysis of time-frequency diagram, waterfall plot, and spectral diagram, the results show that the characteristics of inner race defects on bearing frequencies are related to the characteristic multiple frequency of the inner race defect and the fundamental frequency. The speed and defect width have different influence on the distribution and amplitude of frequency. The SFD can enhance the system stability under the bearing fault but the enhancement decreases with the increasing speed. Meanwhile, the beneficial effect of the SFD varies according to the mounted position in the rotor system.

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Comparative genomic analysis of the genus Enterococcus

Publication date: Available online 3 January 2017
Source:Microbiological Research
Author(s): Zhi Zhong, Wenyi Zhang, Yuqin Song, Wenjun Liu, Haiyan Xu, Xiaoxia Xi, Bilige Menghe, Heping Zhang, Zhihong Sun
As important lactic acid bacteria, Enterococcus species are widely used in the production of fermented food. However, as some strains of Enterococcus are opportunistic pathogens, their safety has not been generally accepted. In recent years, a large number of new species have been described and classified within the genus Enterococcus, so a better understanding of the genetic relationships and evolution of Enterococcus species is needed. In this study, the genomes of 29 type strains of Enterococcus species were sequenced. In combination with eight complete genome sequences from the Genbank database, the whole genomes of 37 strains of Enterococcus were comparatively analyzed. The average length of Enterococcus genomes was 3.20 Mb and the average GC content was 37.99%. The core- and pan- genomes were defined based on the genomes of the 37 strains of Enterococcus. The core-genome contained 605 genes, a large proportion of which were associated with carbohydrate metabolism, protein metabolism, DNA and RNA metabolism. The phylogenetic tree showed that habitat is very important in the evolution of Enterococcus. The genetic relationships were closer in strains that come from similar habitats. According to the topology of the time tree, we found that humans and mammals may be the original hosts of Enterococcus, and then species from humans and mammals made a host-shift to plants, birds, food and other environments. However, it was just a evolutionary scenario, and more data and efforts were needed to prove this postulation. The comparative genomic analysis provided a snapshot of the evolution and genetic diversity of the genus Enterococcus, which paves the way for follow-up studies on its taxonomy and functional genomics.

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Src Family Kinases Are Regulated in Multiple Myeloma Cells by Phosphatase of Regenerating Liver-3

Phosphatase of regenerating liver-3 (PTP4A3/PRL-3) is a dual-specificity phosphatase that is upregulated in various types of cancers and is related to poor prognosis and aggressive tumor behavior. The expression level of PRL-3 is elevated in response to several antiapoptotic cytokines, including IL6, in cancer cells from patients with multiple myeloma (MM) and can promote survival and migration. Here, it is demonstrated that PRL-3 activates Src kinase in the IL6-dependent MM cell line INA-6. Inhibition of PRL-3 by a small-molecule inhibitor of PRL-3 or by shRNA resulted in inactivation of Src. In addition to activation of Src, PRL-3 also activated the Src family kinase (SFK) members LYN and HCK in INA-6 cells. Forced expression of catalytically inactive mutant PRL-3 decreased the activation of these three SFK members while the total level of HCK and FYN remained elevated. Inhibitors of Src increased sensitivity of cells overexpressing PRL-3 to the PRL-3 inhibitor through joint downregulation of both PRL-3 and Mcl-1. In conclusion, PRL-3 protected MM cells against apoptosis by dysregulating both the total levels and the activation levels of specific SFK members that are important for IL6 signal transduction in MM cells. Eventually, this led to increased levels of Mcl-1.

Implications: This study suggests PRL-3 and SFKs are key mediators of the IL6-driven signaling events and points to both PRL-3 and SFK members as potential targets for treatment of MM. Mol Cancer Res; 15(1); 69–77. ©2016 AACR.

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Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes

Carcinoma-associated fibroblasts (CAF) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumor progression. However, evidence of both cancer-promoting and -restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared with nonsenescent control CAFs using in vitro Transwell invasion models and in vivo xenograft mouse models. Screening by gene expression microarray and cytokine ELISA assays revealed IL8 to be upregulated in senescent CAFs. Experimental modulation through IL8 overexpression or receptor inhibition implicates the IL8 pathway as a mediator of the proinvasive effects of senescent CAFs. In a cohort of human pancreatic cancer cases, more abundant stromal senescence as indicated by p16 immunohistochemistry correlated with decreased survival in patients with early-stage disease. These data support senescent fibroblasts as a pathologically and clinically relevant feature of pancreatic cancer. The inhibition of senescent stroma–cancer signaling pathways has the potential to restrain pancreatic cancer progression.

Implications: Findings show that senescent cancer-associated fibroblasts secret excess IL8 to promote pancreatic cancer invasion and metastasis; thus, senescent CAFs represent a phenotypic subtype, challenging conventional assumptions that CAFs are a homogeneous population. Mol Cancer Res; 15(1); 3–14. ©2016 AACR.

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Highlights of This Issue

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ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma is characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich stroma associated with this disease has been implicated as a barrier to drug penetration, although stromal depletion strategies have had mixed clinical success. It remains less clear how interactions with ECM, acting as a biophysical regulator of phenotype, not only a barrier to drug perfusion, regulate susceptibilities and resistance to specific therapies. In this context, an integrative approach is used to evaluate invasive behavior and motility in rheologically characterized ECM as determinants of chemotherapy and photodynamic therapy (PDT) responses. We show that in 3D cultures with ECM conditions that promote invasive progression, response to PDT is markedly enhanced in the most motile ECM-infiltrating populations, whereas the same cells exhibit chemoresistance. Conversely, drug-resistant sublines with enhanced invasive potential were generated to compare differential treatment response in identical ECM conditions, monitored by particle tracking microrheology measurements of matrix remodeling. In both scenarios, ECM-infiltrating cell populations exhibit increased sensitivity to PDT, whether invasion is consequent to selection of chemoresistance, or whether chemoresistance is correlated with acquisition of invasive behavior. However, while ECM-invading, chemoresistant cells exhibit mesenchymal phenotype, induction of EMT in monolayers without ECM was not sufficient to enhance PDT sensitivity, yet does impart chemoresistance as expected. In addition to containing platform development with broader applicability to inform microenvironment-dependent therapeutics, these results reveal the efficacy of PDT for targeting the most aggressive, chemoresistant, invasive pancreatic ductal adenocarcinoma associated with dismal outcomes for this disease.

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Exosomal Annexin II Promotes Angiogenesis and Breast Cancer Metastasis

Tumor-derived exosomes are emerging mediators of tumorigenesis and tissue-specific metastasis. Proteomic profiling has identified Annexin II as one of the most highly expressed proteins in exosomes; however, studies focused on the biological role of exosomal Annexin II (exo-Anx II) are still lacking. In this study, mechanistic insight was sought regarding exo-Anx II and its function in angiogenesis and breast cancer metastasis. Multiple in vitro and in vivo techniques were used to study the role of exo-Anx II in angiogenesis. Using atomic force microscopy and Western blotting, exo-Anx II expression was characterized in normal and breast cancer cells. In addition, organ-specific metastatic breast cancer cells and animal models were used to define the role exo-Anx II in breast cancer metastasis. Results revealed that exo-Anx II expression is significantly higher in malignant cells than normal and premetastatic breast cancer cells. In vitro and in vivo studies demonstrated that exo-Anx II promotes tPA-dependent angiogenesis. Furthermore, in vivo analysis indicated that metastatic exosomes create a favorable microenvironment for metastasis, and exo-Anx II plays an important role in this process, as priming with Anx II-depleted exosomes reduces brain (~4-fold) and lung (~2-fold) metastasis. Upon delineating the mechanism, it was discovered that exo-Anx II causes macrophage-mediated activation of the p38MAPK, NF-B, and STAT3 pathways and increased secretion of IL6 and TNFα. These data demonstrate an important role for exo-Anx II in breast cancer pathogenesis.

Implications: Exosome-associated Annexin II plays an important role in angiogenesis and breast cancer metastasis, which can be exploited as a potential biomarker as well as a therapeutic target for diagnosis and treatment of metastatic breast cancer. Mol Cancer Res; 15(1); 93–105. ©2016 AACR.

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Autophagy Induction Results in Enhanced Anoikis Resistance in Models of Peritoneal Disease

Peritoneal carcinomatosis and peritoneal sarcomatosis is a potential complication of nearly all solid tumors and results in profoundly increased morbidity and mortality. Despite the ubiquity of peritoneal carcinomatosis/peritoneal sarcomatosis, there are no clinically relevant targeted therapies for either its treatment or prevention. To identify potential therapies, we developed in vitro models of peritoneal carcinomatosis/peritoneal sarcomatosis using tumor cell lines and patient-derived spheroids (PDS) that recapitulate anoikis resistance and spheroid proliferation across multiple cancer types. Epithelial- and mesenchymal-derived cancer cell lines (YOU, PANC1, HEYA8, CHLA10, and TC71) were used to generate spheroids and establish growth characteristics. Differential gene expression analyses of these spheroids to matched adherent cells revealed a consensus spheroid signature. This spheroid signature discriminates primary tumor specimens from tumor cells found in ascites of ovarian cancer patients and in our PDS models. Key in this gene expression signature is BNIP3 and BNIP3L, known regulators of autophagy and apoptosis. Elevated BNIP3 mRNA expression is associated with poor survival in ovarian cancer patients and elevated BNIP3 protein, as measured by IHC, and is also associated with higher grade tumors and shorter survival. Pharmacologic induction of autophagy with rapamycin significantly increased spheroid formation and survival while decreasing the induction of apoptosis. In contrast, the autophagy inhibitor hydroxychloroquine abrogated spheroid formation with a clear increase in apoptosis. Modulation of BNIP3 and the critical autophagy gene Beclin-1 (BECN1) also caused a significant decrease in spheroid formation. Combined, these data demonstrate how modulation of BNIP3-related autophagy, in PDS and in vitro spheroid models, alters the survival and morphology of spheroids.

Implications: Development of BNIP3/BNIP3L-targeting agents or autophagy-targeting agents may reduce morbidity and mortality associated with peritoneal carcinomatosis and sarcomatosis. Mol Cancer Res; 15(1); 26–34. ©2016 AACR.

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Interplay between Cytoplasmic and Nuclear Androgen Receptor Splice Variants Mediates Castration Resistance

Androgen receptor splice variants (AR-V) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often coexpressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL. Here, it is demonstrated that AR-V1, -V4, and -V6 can dimerize with both AR-V7 and AR-FL. Consequently, AR-V7 and androgen-bound AR-FL induced nuclear localization of AR-V1, -V4, and -V6, and these variants, in turn, mitigated the ability of the antiandrogen enzalutamide to inhibit androgen-induced AR-FL nuclear localization. Interestingly, the impact of nuclear localization of AR-V4 and -V6 on AR transactivation differs from that of AR-V1. Nuclear localization leads to an increased ability of AR-V4 and -V6 to transactivate both canonical AR targets and AR-V–specific targets and to confer castration-resistant cell growth. However, although AR-V1, which lacks inherent transcriptional activity, appears to activate AR-FL in an androgen-independent manner, it significantly antagonizes AR-V7 transactivation. Together, these data demonstrate that the complex interactions among different AR-Vs and AR-FL play a significant role in castration-resistant disease.

Implications: This study suggests important consequences for clinical castration resistance due to simultaneous expression of AR-FL and AR-Vs in patient tumors and suggests that dissecting these interactions should help develop effective strategies to disrupt AR-V signaling. Mol Cancer Res; 15(1); 59–68. ©2016 AACR.

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Exploitation of Castration-Resistant Prostate Cancer Transcription Factor Dependencies by the Novel BET Inhibitor ABBV-075

Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/superenhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here, the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the androgen receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075. DHT-stimulated transcription of AR target genes was inhibited by ABBV-075 without significant effect on AR protein expression. Furthermore, ABBV-075 disrupted DHT-stimulated recruitment of BET family member BRD4 to gene-regulatory regions cooccupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition disrupted the composition and function of AR-occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and inhibition of enhancer RNA transcription. ABBV-075 displayed potent antiproliferative activity in multiple models of resistance to second-generation antiandrogens and inhibited the activity of the AR splice variant AR-V7 and ligand-binding domain gain-of-function mutations, F877L and L702H. ABBV-075 was also a potent inhibitor of MYC and the TMPRSS2-ETS fusion protein, important parallel transcription factor drivers of CRPC.

Implications: The ability of BET family inhibitor ABBV-075 to inhibit transcription activation downstream of the initiating events of transcription factors like AR and TMPRSS2:ETS fusion proteins provides a promising therapeutic option for CRPC patients who have developed resistance to second-generation antiandrogens. Mol Cancer Res; 15(1); 35–44. ©2016 AACR.

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Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells

Epithelial ovarian cancer (EOC) cells metastasize within the peritoneal cavity and directly encounter human peritoneal mesothelial cells (HPMC) as the initial step of metastasis. The contact between ovarian cancer cells and the single layer of mesothelial cells involves direct communications that modulate cancer progression but the mechanisms are unclear. One candidate mediating cell–cell communications is exosomes, 30–100 nm membrane vesicles of endocytic origin, through the cell–cell transfer of proteins, mRNAs, or microRNAs. Therefore, the goal was to mechanistically characterize how EOC-derived exosomes modulate metastasis. Exosomes from ovarian cancer cells were fluorescently labeled and cocultured with HPMCs which internalized the exosomes. Upon exosome uptake, HPMCs underwent a change in cellular morphology to a mesenchymal, spindle phenotype. CD44, a cell surface glycoprotein, was found to be enriched in the cancer cell–derived exosomes, transferred, and internalized to HPMCs, leading to high levels of CD44 in HPMCs. This increased CD44 expression in HPMCs promoted cancer invasion by inducing the HPMCs to secrete MMP9 and by cleaning the mesothelial barrier for improved cancer cell invasion. When CD44 expression was knocked down in cancer cells, exosomes had fewer effects on HPMCs. The inhibition of exosome release from cancer cells blocked CD44 internalization in HPMCs and suppressed ovarian cancer invasion. In ovarian cancer omental metastasis, positive CD44 expression was observed in those mesothelial cells that directly interacted with cancer cells, whereas CD44 expression was negative in the mesothelial cells remote from the invading edge. This study indicates that ovarian cancer–derived exosomes transfer CD44 to HPMCs, facilitating cancer invasion.

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AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance, and metastasis. The mechanistic role of upstream mediators of EMT has not yet been well characterized. Recently, we showed that non–small cell lung cancers (NSCLC) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBC) and head and neck squamous cell carcinomas (HNSCC), and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to chemotherapy, radiotherapy, and targeted therapy. Because the DNA repair pathway is also altered in patient tumor specimens overexpressing AXL, it is hypothesized that modulation of AXL in cells that have undergone EMT will sensitize them to agents targeting the DNA repair pathway. Downregulation or inhibition of AXL directly reversed the EMT phenotype, led to decreased expression of DNA repair genes, and diminished efficiency of homologous recombination (HR) and RAD51 foci formation. As a result, AXL inhibition caused a state of HR deficiency in the cells, making them sensitive to inhibition of the DNA repair protein, PARP1. AXL inhibition synergized with PARP inhibition, leading to apoptotic cell death. AXL expression also associated positively with markers of DNA repair across TNBC, HNSCC, and NSCLC patient cohorts.

Implications: The novel role for AXL in DNA repair, linking it to EMT, suggests that AXL can be an effective therapeutic target in combination with targeted therapy such as PARP inhibitors in several different malignancies. Mol Cancer Res; 15(1); 45–58. ©2016 AACR.

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Overcoming EGFR Bypass Signal-Induced Acquired Resistance to ALK Tyrosine Kinase Inhibitors in ALK-Translocated Lung Cancer

Activation of the EGFR pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non–small cell lung cancers (NSCLC) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well-defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway–induced acquired resistance to ALK-TKIs. To this end, ceritinib-resistant cells (H3122-CER) were established from the H3122 NSCLC cell line harboring the ALK gene rearrangement via long-term exposure to ceritinib. H3122-CER cells acquired resistance to ceritinib through EGFR bypass pathway activation. Furthermore, H3122 cells that became resistant to ceritinib or alectinib through EGFR pathway activation showed cross-resistance to other ALK-TKIs. Ceritinib and afatinib combination treatment partially restored the sensitivity to ceritinib.

Implications: This study proposes a preclinical rationale to use ALK-TKIs and afatinib combination therapy for ALK-translocated lung cancers that have acquired resistance to ALK-TKIs through EGFR pathway activation. Mol Cancer Res; 15(1); 106–14. ©2016 AACR.

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En mann med feber og leddsmerter

Leddsmerter kan ha mange årsaker. Traumatiske, immunologiske og infeksiøse lidelser må vurderes. En god anamnese kan sette oss på rett spor tidlig.

Blodprøver ved innkomst viste CRP 248 (9/l) med 19,4 nøytrofile granulocytter (1,7 – 8,2 · 10**⁹/l), trombocytter 186 (145 – 348 · 10**⁹/l), INR 1,3 (

Figur 1 Høyre ankel ved innkomst. Foto: Astrid Rykkje Heien

Figur 2 Mikroskopifunn. Grampreparat som viser gramnegative diplokokker funnet ved punksjon av høyre ankel

På bakgrunn av dette ble pasienten henvist poliklinikk for seksuelt overførbare sykdommer. Dette ble gjort første innleggelsesdag. Han var nå subfebril og hadde mindre smerter i ankelen.

Vi vurderte fortløpende behovet for artroskopisk skylling. Imidlertid tilkom det biokjemisk og lokal bedring, så dette ble ikke gjort.

Diskusjon

Ved disseminert gonokokksykdom foreligger hovedsakelig purulent artritt eller et syndrom med tenosynovitt, dermatitt og polyartralgi, eventuelt en kombinasjon av dette (4, 5).

Diagnostikk, resistens og behandlingslengde

Direkte mikroskopi av leddvæske har en høy forekomst av falskt negative funn ved septiske artritter, og sensitivitetstall fra under 50 % til 78 % er oppgitt (6, 7).

Adjuvant steroidbehandling ble valgt da vi oppfattet vedvarende febrilia til å være immunologisk utløst og hans hydrops i høyre kne til å være reaktiv artritt (8).

Kirurgisk behandling: Tapping versus skylling

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Psykogene ikke-epileptiske anfall hos barn

Psykogene ikke-epileptiske anfall er anfall av epilepsilignende karakter som ikke har et hjerneorganisk korrelat. Som navnet indikerer, antar man at psykologiske prosesser spiller en rolle. Vårt inntrykk ved Spesialsykehuset for epilepsi er at forekomsten av slike anfall blant barn og unge har økt de siste årene.

Psykogene ikke-epileptiske anfall, i internasjonal litteratur gjerne forkortet PNES (psychogenic non-epileptic seizures), er som den viktigste differensialdiagnosen til epilepsi godt kjent i voksennevrologien og er tidligere omtalt i Tidsskriftet (1, 2). Vårt inntrykk er at slike anfall er mindre kjent blant pediatere, skoleleger og fastleger.

Man antar at psykogene ikke-epileptiske anfall hovedsakelig er et symptom på en konversjonslidelse (3, 4). I diagnoseklassifikasjonssystemene DSM-5 og ICD-10 blir tilstanden kategorisert som henholdsvis en konversjons- og dissosiasjonstilstand. I motsetning til i ICD-10 kreves det ikke at man har holdepunkter for en psykisk årsak for å sette diagnosen i det nylig reviderte amerikanske DSM-5. Klinisk kan det, særlig i den første utredningsfasen, være vanskelig å oppdage bakenforliggende psykiske belastninger.

Anfallene ses noe sjeldnere hos barn enn hos voksne (5). De er imidlertid en stor belastning ikke bare for den det gjelder, men også for familie, skole og samfunn. Barna er ofte gjenstand for gjentatte akuttinnleggelser og mange unødvendige undersøkelser. Mange får dessuten etter hvert et stort forbruk av lite virksomme legemidler (4).

Psykogene ikke-epileptiske anfall hos barn skiller seg fra slike anfall hos voksne på flere måter, blant annet er de bakenforliggende årsakene (3, 6 – 8), anfallsutformingen (9, 10) og prognosen noe forskjellig (11).

Hensikten med denne artikkelen er å gi en kort oversikt over forekomst, risikofaktorer, ytringsformer, diagnostikk og behandling av slike anfall hos barn. Artikkelen er basert på søk i PubMed med søkeordet «psychogenic non-epileptic seizures» og forfatternes kliniske erfaring.

Forekomst

Den eksakte prevalensen av psykogene ikke-epileptiske anfall blant barn er ikke kjent (5). Første anfall opptrer som oftest i 8 – 15-årsalderen (10, 12, 13), men diagnostiseringen er gjerne forsinket (10, 14). Tilstanden er sett hos barn helt ned til 4 – 5-årsalderen.

Hos barn hvor man mistenker epilepsi, er prevalensen av psykogene ikke-epileptiske anfall funnet å være 5 – 13 % (5, 15). I materialer bestående av barn henvist til video-EEG for en diagnostisk utredning av forskjellige typer anfall, har man funnet tilstanden hos 3,5 – 20 % (12, 16, 17). Blant barn henvist til pediatriske epilepsisentra for intraktabel epilepsi er det funnet en forekomst av barn med slike anfall på 10 – 23 % (8, 18).

Blant ungdom og voksne med tilstanden er 70 – 80 % kvinner (4, 19, 20). Kjønnsforskjellen er ikke så uttalt blant barn (18).

Som hos voksne er det ikke helt uvanlig at psykogene ikke-epileptiske anfall koeksisterer med epilepsi (18). Men hvor ofte en blanding av begge anfallsformer forekommer, er usikkert og angis svært forskjellig (21).

Risikofaktorer

Psykogene ikke-epileptiske anfall ses på som et symptom på underliggende kroniske konflikter eller stressorer (22). Oppvekst i en dysfunksjonell familie, faglige vansker på skolen, mobbing eller andre problemer i kameratflokken er hyppig assosiert med tilstanden hos barn (4, 22). Fysisk eller seksuelt misbruk er ikke like vanlig blant barn med slike anfall som hos voksne (23), selv om en studie viste at 21 % og 6 % hadde opplevd henholdsvis seksuelt eller fysisk misbruk (3).

I en kontrollert studie ble 55 barn med psykogene ikke-epileptiske anfall sammenlignet med sine søsken (4). Gjennomsnittsalderen var 14,3 år, og 71 % var jenter. Man fant at alle barna hadde en konversjonslidelse. Sammenlignet med kontrollgruppene hadde de en signifikant økt nevrologisk (inkludert epilepsi), medisinsk og psykiatrisk morbiditet, økt medisinbruk, hyppigere intensivbehandling, en innadvendt mestringsstrategi, flere skolevansker, mer skolefravær, de var mer utsatt for mobbing, og de hadde større interpersonlige problemer (4).

I en spørreundersøkelse blant danske barnenevrologer var det en alminnelig oppfatning at slike anfall var assosiert med stress, fysiske og/eller psykiske traumer og seksuelt misbruk (24).

Personlighetstester har vist at mange barn med slike anfall har et høyt spenningsnivå med mye angst, depresjon og mistilpassede personlighetstrekk (24). Opptil en tredel av barna har en forsinket psykomotorisk utvikling (21).

Anfallsutforming

Det er funnet interessante forskjeller i anfallssemiologien, dvs. hvordan anfallene ytrer seg klinisk, mellom barn og voksne (8 – 10, 12, 19, 24). Anfallene hos barna er gjerne «fredeligere» og mer stereotype enn hos voksne. Hos voksne ses ofte lukkede øyne, voldsomme bevegelser, vokalisering og opistotonus. Anfallene hos barn er ofte av dialektisk art, dvs. at de ytrer seg ved langvarig kontaktløshet. Er det motoriske symptomer, dreier det seg oftest om tremor eller grove, asynkrone bevegelser av ekstremitetene samt et fluktuerende forløp (22). Når barna kommer i puberteten, blir anfallsutformingen mer lik den som man ser hos voksne. Anfallene starter og slutter gjerne abrupt (21).

Som hos voksne varer anfallene lenger enn de epileptiske anfallene. En pediatrisk studie viste en gjennomsnittlig varighet av psykogene ikke-epileptiske anfall på 269 sekunder mot 83 sekunder for epileptiske anfall (12).

Ifølge danske barnenevrologer er typiske trekk hos barn med slike anfall lukkede øyne, motstand mot å åpne øynene, sjelden anfallsrelaterte skader, anfallene kommer som oftest i sosiale settinger, fravær av postiktale symptomer og manglende effekt av antiepileptiske legemidler (24).

I tabell 1 kan man se noen forskjeller mellom psykogene ikke-epileptiske anfall hos barn, psykogene ikke-epileptiske anfall hos voksne og epileptiske anfall.

Tabell 1 Noen forskjeller mellom psykogene ikke-epileptiske anfall hos barn og hos voksne og genuine epileptiske anfall. Tabellen er dels basert på egne erfaringer og dels på sentrale artikler fra området, bl.a. Alessi og medarbeidere (9)
	Psykogene ikke-epileptiske anfall hos barn	Psykogene ikke-epileptiske anfall hos voksne	Genuine epileptiske anfall
Anfallsutforming	Ofte «stille» anfall, manglende kontakt	Ofte dramatiske anfall med motorisk uro, asynkrone rykninger, eventuelt opistotonus	Mange typer anfall – fra absenser til tonisk-kloniske anfall
Varierende intensitet av anfallet underveis	Vanlig	Vanlig	Sjelden
Hodebevegelser fra side til side	Vanlig	Vanlig	Sjelden
Motstand mot passive bevegelser, inkludert øyelokk	Vanlig	Vanlig	Sjelden
Lukkede øyne under anfallet	Vanlig	Vanlig	Sjelden
Gråt under anfallet	Forekommer	Forekommer	Sjelden
Rask oppvåkning etter anfallet	Vanlig	Vanlig	Sjelden
Nattlige anfall	Svært sjelden	Svært sjelden	Forekommer, avhengig av epilepsiformen
Anfallsvarighet	Som oftest mer enn to minutter	Som oftest mer enn to minutter	Som oftest mindre enn to minutter
Effekt av antiepileptika	Ingen	Ingen	Som oftest god
Iktale EEG-funn	Ingen epileptiform aktivitet	Ingen epileptiform aktivitet	Som regel epileptiform aktivitet
Anfallsprognose	Som regel god	Varierende, men dårligere enn hos barn	Avhengig av epilepsiform

Diagnostikk

Alle barn med hyppige epilepsilignende anfall til tross for behandling, anfall som for epilepsi er atypiske når det gjelder ytringsform og varighet, samt flere normale EEG, bør vekke mistanke om psykogene ikke-epileptiske anfall (21).

Det finnes ingen internasjonale retningslinjer for diagnostikk og behandling av slike anfall hos barn (24). Mange av barna får epilepsidiagnose og årelang behandling med antiepileptika. I en studie fra India var det tilfelle hos 33 av 56 barn med slike anfall (10). De som først får epilepsidiagnose, har gjerne lært at anfallene resulterer i økt oppmerksomhet, noe som kan vedlikeholde anfallstendensen.

En spørreundersøkelse blant danske barnenevrologer viste ingen enighet verken når det gjaldt terminologi eller kodebruk. Kun 49 % av barnenevrologene anga at de brukte video-EEG i diagnostikken (25).

Etter vårt skjønn bør diagnostikken av slike anfall hovedsakelig bygge på en grundig sykehistorie, inkludert komparentopplysninger, med nøyaktig kartlegging av omstendighetene rundt anfallsopptredenen, selve anfallsutformingen og registrering av typiske anfall på video-EEG. Det bør være holdepunkter for at pasienten har emosjonelle belastninger som kan forklare utviklingen av anfallene, selv om dette altså ikke er obligatorisk ifølge DSM-5.

Spesialsykehuset for epilepsi har landsfunksjon for diagnostisering og initial oppfølging av barn og voksne med psykogene ikke-epileptiske anfall. Alle pasienter med epilepsilignende anfall av uklar natur kan henvises til et kartleggingsopphold ved sykehuset.

I det første oppholdet inngår en grundig anamnese med særlig oppmerksomhet rettet mot barnets psykososiale miljø, omstendighetene rundt anfallene og selve anfallsutformingen. I tillegg foretas langtids video-EEG med målsetting om å registrere anfallene. Dersom anfallene ikke har EEG-korrelat, og sykehistorie og anfallssemiologi gir mistanke om psykogene ikke-epileptiske anfall, er vi rimelig sikre på anfallenes natur.

Det er imidlertid viktig å understreke at man ikke kan bygge diagnosen på manglende iktalt EEG-korrelat alene. Det finnes nemlig flere typer epileptiske anfall, særlig utgående fra frontallappen, der man ikke finner slikt korrelat (26).

Behandling

Generelt bør behandlingen være rettet mot det man i hvert tilfelle antar ligger til grunn for anfallene. Både hos voksne og barn har psykoedukasjon, stressreduserende tiltak samt læring av avspenningsteknikker og fysioterapi vist seg effektivt (27). Mange har nytte av å lære bedre og mer adekvate mestringsstrategier. I noen tilfeller kan familieterapi, kognitiv terapi og støttebehandling være indisert (27).

Dersom barnet bruker antiepileptiske legemidler bør disse trappes gradvis ned til full seponering. I tilfeller der det foreligger en blanding av epileptiske og psykogene ikke-epileptiske anfall kan det være aktuelt å forenkle medikasjonen fordi mange av disse etter hvert får en omfattende multifarmasi.

Under det andre oppholdet ved Spesialsykehuset for epilepsi bearbeides barnets og pårørendes reaksjon på diagnosen av et spesialtrenet team. Det blir foretatt en tverrfaglig kartlegging av barnets psykisk helse, trivsel i hjem og skole og skoleprestasjoner. Den psykiske helsen kartlegges ved hjelp av spørreskjemaer, og de kognitive evnene måles av spesialpedagog i samarbeid med nevropsykolog. Mot slutten av oppholdet arrangeres det en videokonferanse med barnets lokale hjelpeapparat med tanke på informasjonsoverføring og råd om videre behandling samt takling av eventuelle fremtidige anfall. Avdekker man symptomer på psykisk sykdom, henvises pasienten til lokal barne- og ungdomspsykiatrisk poliklinikk.

Dersom det har vært mye dramatikk på barnets skole i forbindelse med anfallene og mange akuttinnleggelser på sykehus, besøker deler av teamet skolen for å trygge lærere og eventuelt medelever. Dersom barnet har et høyt stressnivå på grunn av faglig tilkortkomming, kan det være aktuelt med spesielt tilrettelagt undervisning.

Barn og unge med slike anfall føler seg ofte stigmatisert og mistrodd (28). Noen opplever dette så vanskelig at de trekker seg tilbake sosialt, eller de blir overbeskyttet av foreldrene. Dersom ungdommene selv har en god sykdomsforståelse, er det lettere å håndtere reaksjonene fra omgivelsene. Det er derfor viktig å bruke god tid på formidling av diagnosen. Dette bør gjøres på en empatisk og ikke-konfronterende måte. Diskusjoner om de mulige underliggende mekanismene ved slike anfall er helt essensielt for barnas mestring (28). Vi benytter en biopsykososial forklaringsmodell som bygger på en forståelse av at både psykososiale og biologiske forhold kan være predisponerende, utløsende og vedlikeholdende faktorer. En slik forklaring kan gjøre det enklere for barna selv å forstå hvorfor de har utviklet anfall og å identifisere seg med diagnosen (29).

For noen barn og pårørende oppleves det som en lettelse å høre at anfallene ikke er ledd i en hjerneorganisk sykdom som krever årelang medisinering, og at anfallene opptrer ubevisst, dvs. at de ikke er viljestyrte.

De sammensatte problemene som ofte ligger bak slike anfall, fordrer en multidisiplinær tilnærming (13). Vi søker å oppnå en terapeutisk allianse og en felles forståelse med pasient og pårørende om hva som forårsaker og vedlikeholder anfallene.

I noen særlig terapiresistente tilfeller kan det være behov for langvarig behandling. Slik behandling må foregå lokalt.

Prognose

Sammenlignet med voksne med psykogene ikke-epileptiske anfall er utsiktene til anfallsfrihet bedre blant barn og unge med slike anfall, kanskje fordi det hos disse er lettere å identifisere en ytre årsak (6). Rundt 70 – 80 % av barna blir kvitt anfallene (11, 13).

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Πληροφορίες

Τρίτη 3 Ιανουαρίου 2017

Diskusjon

Diagnostikk, resistens og behandlingslengde

Kirurgisk behandling: Tapping versus skylling

Graphical abstract

Summary

Diskusjon

Diagnostikk, resistens og behandlingslengde

Kirurgisk behandling: Tapping versus skylling

Diskusjon

Diagnostikk, resistens og behandlingslengde

Kirurgisk behandling: Tapping versus skylling

Forekomst

Risikofaktorer

Anfallsutforming

Diagnostikk

Behandling

Prognose

Δημοφιλείς αναρτήσεις