Immunodeficiency, auto-inflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic auto-inflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1, a component the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin-1β (IL-1β) was compromised in the patients’ fibroblasts. By contrast, the patients’ mononuclear leukocytes, particularly monocytes, were hyperresponsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of auto-inflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1β responses differently in different cell types

Euclid Near Infrared Spectrometer and Photometer instrument concept and first test results obtained for different breadboards models at the end of phase C

The Euclid mission objective is to understand why the expansion of the Universe is accelerating through by mapping the geometry of the dark Universe by investigating the distance-redshift relationship and tracing the evolution of cosmic structures. The Euclid project is part of ESA's Cosmic Vision program with its launch planned for 2020 (ref [1]). The NISP (Near Infrared Spectrometer and Photometer) is one of the two Euclid instruments and is operating in the near-IR spectral region (900- 2000nm) as a photometer and spectrometer. The instrument is composed of: - a cold (135K) optomechanical subsystem consisting of a Silicon carbide structure, an optical assembly (corrector and camera lens), a filter wheel mechanism, a grism wheel mechanism, a calibration unit and a thermal control system - a detection subsystem based on a mosaic of 16 HAWAII2RG cooled to 95K with their front-end readout electronic cooled to 140K, integrated on a mechanical focal plane structure made with molybdenum and aluminum. The detection subsystem is mounted on the optomechanical subsystem structure - a warm electronic subsystem (280K) composed of a data processing / detector control unit and of an instrument control unit that interfaces with the spacecraft via a 1553 bus for command and control and via Spacewire links for science data This presentation describes the architecture of the instrument at the end of the phase C (Detailed Design Review), the expected performance, the technological key challenges and preliminary test results obtained for different NISP subsystem breadboards and for the NISP Structural and Thermal model (STM)

I hur stor utsträckning använder patienter vid apotek receptfria läkemedel tillsammans med sina förskrivna läkemedel? : En intervjustudie vid apotek

Background: Medications are used to prevent, cure and treat different kinds of diseases. The use of medicines by the patients should be according to the prescription from a physician. For safe and appropriate prescribing of medications the physicians should be able to get information about all of a patients’ current medications, to avoid drug-drug interactions. Beside the prescribed medicines patients can use medications without a prescription, so called Over-the-Counter (OTC) medicines. OTC-medicines are used in the same way as prescribed medicines, but the patient needs to read the included package leaflet to know how the medicines should be used. In year 2020, 65 % of the population in Sweden received prescribed medicines. Physicians, pharmacists and patient use different electronical medication lists to know what medicines the patient is using. The lists are not always updated with the latest information because not all of the electronic journal systems are linked together which can be seen as a risk for patient safety. Many patients have OTC-medicines at home and many use it frequently. One of the risk with OTC-medicines is that drug-drug interactions can occur with the patient’s prescribed medicines or other OTC-medicines and cause adverse drug reactions (ADR). In Sweden 44 % of the medication packages is OTC-medicines. Objective: To analyze the extent of OTC-medicines are used together with prescribed medication in different ages and genders. Methods: A structured interview study that was done with patients visiting pharmacies who had three or more recipes at their medication list, could talk Swedish and was collecting medication for themselves. The structured interviews were performed at pharmacies and included questions about their use of different kind of medication lists and if they use any OTC-medicines. Together with the patient the list was checked for errors or non-current medications. The results were analyzed using descriptive statistics.  Results: A total of 215 patients were interviewed, where 63 % were women. The largest age group was patients born in the 1940’s followed by patients born in the 1950’s and 1960’s. OTC-medicines were used by 53 % of the patients in the study who all had at least three prescribed medications and the use were almost the same for men (51 %) and women (53 %.) The most frequent users of OTC-medicines were patients born in the 1970’s and younger. The proportion of patient’s using OTC-medicines were reduced by the age of the patient. The most frequently used OTC-medicines were medication for pain and fever followed by vitamins and minerals. The use of OTC-medicines was most frequent used by patients who had four or less prescriptions medications on their medication list.   Conclusions: In the study OTC-medicines were used by the majority of the patients who also have several prescribed medications. Men and women use OTC-medicines in almost the same amount in the total population, but there are some differences in the age’s categories. Physicians and pharmacists need to have an updated and correct medication list. The new nationally shared medication was recently implemented, aiming to improve patient safety. Medication use could be further improved if the shared medication list also would include OTC-medicines used, hopefully this can be implemented in the in the future. Introduktion: Läkemedel är framtagna för att förebygga, lindra eller bota sjukdomar. För att få en god läkemedelsbehandling krävs att läkaren får information om patientens alla läkemedel. Med dagens system har det inte funnits någon sammanhållen lista för patientens alla aktuella läkemedel om de fått läkemedel från flera olika vårdgivare. Patienterna, farmaceuter och hälso-sjukvårdspersonal hämtar inte information från samma källa vilket medför att risk för felmedicinering om inte alla källor uppdateras med patientens senaste ordination. Patienten har ett eget ansvar för sin läkemedelsanvändning genom att använda läkemedlet efter läkarens ordination. Patienter kan även använda receptfria läkemedel som kan interagera med patientens receptförskrivna läkemedel och skapa risker för patienten. Receptfria läkemedel används i stor utsträckning och står för 44 % av alla läkemedelsförpackningar sålda i Sveriges under år 2020. Syfte: Syftet med denna studie var att analysera vilken utsträckning receptfria läkemedel används tillsammans med förskrivna läkemedel samt hur användningen ser ut i relation till kön och ålder. Metod: Studien genomfördes genom strukturerade intervjuer med patienter som skulle hämta ut recept vid apoteket. Intervjuerna genomfördes av farmaceutstudenter vid olika apotek i Sverige under våren 2021. Inklusionskriterier var att patienterna skulle ha tre eller flera recept i läkemedelslistan ”Mina sparade recept”, vara över 18 år, hämta läkemedel till sig själv samt kunna tala svenska. Intervjuerna skedde utifrån ett frågeformulär. Svaren sammanställdes och analyserades i Excel. Resultat: Den procentuellt största gruppen som hämtade läkemedel vid Apoteken var patienter födda på 1940-talet följt av de födda på 1950- och 1960-talet samt att kvinnorna hämtade läkemedel i större utsträckning än män. Drygt hälften av de tillfrågade patienterna använder receptfria läkemedel. Vid jämförelse inom åldersgrupperna använde de yngsta åldersgrupperna i störst utsträckning receptfria med en fallande procent till de äldsta. Receptfria läkemedel som användes mest frekvent var mot värk och feber följt av vitaminer och mineraler. Patienter med fyra eller färre läkemedel på sin lista ”Mina sparade recept” använde mest frekvent receptfria. Slutsats: Receptfria läkemedel används av drygt hälften 53 % av det totala antalet patienterna som deltog i studien. Kvinnorna och männen använde i nästan samma utsträckning receptfria läkemedel. Då en stor del av patienter med förskrivna läkemedel samtidigt använder receptfria läkemedel är det viktigt att detta kan ses av läkare för att de ska kunna se den totala helhetsbilden av patientens läkemedelsanvändning. NLL är ett steg i rätt riktning och att kunna anteckna receptfria läkemedel i listan vore en ytterligare förbättring i framtiden

Barn som far illa : Ur ett lärarpespektiv

SAMMANFATTNING Växjö universitet Institutionen för pedagogik Pedagogik med inriktning mot ungdoms- och missbrukarvård, C- uppsats 10p Titel: Barn som far illa ur ett lärarperspektiv. Engelsk titel: Children who suffer of negligence -from teachers point of view. Författare: Camilla Israelsson och Anne Olofsson. Handledare: Ylva Benderix. Datum: Mars 2007. Antal sidor: 30 Nyckelord: Barn som far illa, lärarrollen, pedagogik, psykologi, anknytning. SAMMANFATTNING: Studiens syfte är att belysa lärares erfarenheter av barn som far illa, hur lärare uppmärksammar barnet och vilka insatser som görs i skolan när ett barn far illa. Vi har använt hermeneutisk vetenskapstradition, kvalitativ metod med halvstrukturerade intervjufrågor. Bowlby och von Wright har använts som teoretiska utgångspunkter. Deltagare i studien var sju låg- och mellanstadielärare, med olika lång yrkeserfarenhet inom skolan. Resultaten visar vidden av barn som far illa ur ett lärarperspektiv, samt att omsorgssvikt och föräldrarnas brister oftast var den största orsaken. Insatserna som utfördes varierade från fall till fall, med olika utfall, anmälan eller inte. Lärarna efterlyser mer utbildning kring området i lärarutbildning och fortbildning. Avsaknaden av utbildning om barn som far illa för lärare, gör att vi anser att framtida forskning är högst relevant för att minimera risken att dessa barn inte uppmärksammas av skolans personal

Barn som far illa : Children who suffer of negligence- from teachers point of view

SAMMANFATTNING Växjö universitet Institutionen för pedagogik Pedagogik med inriktning mot ungdoms- och missbrukarvård, C- uppsats 10p Titel: Barn som far illa ur ett lärarperspektiv. Engelsk titel: Children who suffer of negligence -from teachers point of view. Författare: Camilla Israelsson och Anne Olofsson. Handledare: Ylva Benderix. Datum: Mars 2007. Antal sidor: 30 Nyckelord: Barn som far illa, lärarrollen, pedagogik, psykologi, anknytning. SAMMANFATTNING: Studiens syfte är att belysa lärares erfarenheter av barn som far illa, hur lärare uppmärksammar barnet och vilka insatser som görs i skolan när ett barn far illa. Vi har använt hermeneutisk vetenskapstradition, kvalitativ metod med halvstrukturerade intervjufrågor. Bowlby och von Wright har använts som teoretiska utgångspunkter. Deltagare i studien var sju låg- och mellanstadielärare, med olika lång yrkeserfarenhet inom skolan. Resultaten visar vidden av barn som far illa ur ett lärarperspektiv, samt att omsorgssvikt och föräldrarnas brister oftast var den största orsaken. Insatserna som utfördes varierade från fall till fall, med olika utfall, anmälan eller inte. Lärarna efterlyser mer utbildning kring området i lärarutbildning och fortbildning. Avsaknaden av utbildning om barn som far illa för lärare, gör att vi anser att framtida forskning är högst relevant för att minimera risken att dessa barn inte uppmärksammas av skolans personal

Allocating colorectal cancer patients to different risk categories by using a five-biomarker mRNA combination in lymph node analysis

Background and aims: Curative surgery saves approximate to 50% of all patients with colorectal cancer (CRC) while remaining patients have synchronous or will develop metachronous metastases. Presently, the single most important prognostic factor is histopathological detection of disseminated tumor cells in regional lymph nodes. However, the routine method has several limitations. The aim was to identify biomarker mRNAs that could be combined in a formula that would allow better prediction of patients' survival after surgery. Methods: Screening for biomarker mRNAs overexpressed in CRC was performed by genome-wide hybridization bead array, with verification by qRT-PCR. Specific qRT-PCR assays with copy standards were developed for 5 selected genes and mRNA expression levels determined in lymph nodes from 174 CRC patients (517 nodes) and 24 control patients (118 nodes). Prognostic value of biomarker mRNAs was estimated. A cut-off was set using univariate Cox regression analysis and used for calculation of differences between patient groups in disease-free survival 12 years after surgery (Kaplan-Meier survival model) and risk for recurrent disease (Cox's regression analysis). A formula was constructed for evaluation of the prognostic value of the biomarkers in combination. Results: Two new biomarkers, SLC35D3 and POSTN with prognostic value were identified. SLC35D3 was expressed in the epithelium derived tumor cells and POSTN in fibroblasts. Combined with CEACAM5, KLK6 and MUC2 they could be used to identify risk groups. A formula was constructed using CEACAM5 as denominator for KLK6, SLC35D3 and MUC2 and 18S rRNA as denominator for POSTN. The formula yielded 5 categories (-1, 0, 1, 2, 3). Categories (-1 and 0) had good prognosis, categories (1 and 2) relatively poor prognosis and category (3) very poor prognosis. Conclusion: Lymph node analysis using 5 selected biomarker mRNAs and 18S rRNA in combination allowed allocation of CRC patients to different risk categories with respect to recurrent disease

Identification of three new genes and estimation of the size of the carcinoembryonic antigen family

Using carcinoembryonic antigen (CEA) subgroup-specific degenerate PCR primers, we have identified three new CEA gene family member L/N exons (CGM9, CGM10, and CGM11) and all previously reported L/N exons of the CEA subgroup (CEA, BGP, NCA, CGM1, CGM2, CGM6, CGM7, and CGM8). This suggests that the CEA subgroup contains 11 genes. CGM9, CGM10, and CGM11 seem to be pseudogenes. A deletion of an asparagine in CGM9 results in loss of a glycosylation site, which is conserved throughout the CEA gene family. We have previously suggested the number of genes in the pregnancy-specific glycoprotein (PSG) subgroup to be 11, which together with this study indicates that the CEA gene family contains 22 genes in all. Parsimony analysis of the CEA subgroup interrelationships suggests that CGM7 occupies the most primitive position within the CEA subgroup, being a sister group to the rest. CEA, BGP, NCA, and CGM1 form a fairly well-supported group within the CEA subgroup

Lymph node CXCL17 messenger RNA : A new prognostic biomarker for colon cancer

Lymph node metastasis is the most important prognostic characteristic of colorectal cancer. Carcinoembryonic antigen messenger RNA was shown to detect tumor cells that have disseminated to lymph nodes of colorectal cancer patients and to be at least as good as the hematoxylin and eosin method to predict survival in colorectal cancer patients. CXCL17 was recently shown to be ectopically expressed in colon cancer tumors. Therefore, CXCL17 may serve as prognostic marker alone or in combination with carcinoembryonic antigen. CXCL17 and carcinoembryonic antigen messenger RNA levels were determined using quantitative reverse transcription polymerase chain reaction with RNA copy standard in 389 lymph nodes of 120 colon cancer patients (stages I–IV) and 67 lymph nodes of 12 control patients with inflammatory bowel disease as well as in 68 primary tumors and 30 normal colon tissue samples. Lymph nodes of colon cancer patients were analyzed for CXCL17 and carcinoembryonic antigen protein expression by immunohistochemistry. CXCL17 messenger RNA was expressed in primary tumors at high levels, while it was barely detected in normal colon tissue (p < 0.0001). Similarly, CXCL17 messenger RNA levels were significantly higher in hematoxylin- and eosin-positive (hematoxylin and eosin (+)) lymph nodes compared to hematoxylin- and eosin-negative nodes (p < 0.0001). CXCL17 messenger RNA levels were investigated in lymph nodes grouped according to carcinoembryonic antigen messenger RNA levels: low (–), intermediate (int), and high (+). CXCL17 messenger RNA levels were higher in the carcinoembryonic antigen (int) and carcinoembryonic antigen (+) groups compared to the carcinoembryonic antigen (−) group (p = 0.03 and p < 0.0001, respectively). In lymph nodes of stage III and IV patients, CXCL17 messenger RNA levels correlated with carcinoembryonic antigen messenger RNA levels (p < 0.0001, r = 0.56 and p = 0.0002, r = 0.66, respectively). Staining of consecutive lymph node sections for CXCL17 and carcinoembryonic antigen demonstrated that the same cells expressed both proteins. Altogether, these results indicate that CXCL17 in lymph nodes is expressed by tumor cells. Patients were grouped according to the CXCL17 mRNA levels in the highest lymph node with low levels (−) and high levels (+). CXCL17(+) CC patients showed 2.2 fold increased risk for recurrence (P = 0.03) and decreased mean disease-free survival time of 33 months compared to CXCL17(−) CC patients (P = 0.03). CXCL17(+) carcinoembryonic antigen (int) colon cancer patients showed increased risk for recurrence by 8.3 fold (p = 0.04) and decreased mean disease-free survival time of 46 months compared to CXCL17(−) carcinoembryonic antigen (int) colon cancer patient at follow-up after 12 years (p = 0.02). The presence of tumor cells expressing CXCL17 in regional lymph nodes is a sign of poor prognosis. Analysis of CXCL17 messenger RNA is particularly useful to detect less differentiated colon cancer tumors expressing relatively low carcinoembryonic antigen messenger RNA levels. Thus, CXCL17 messenger RNA in combination with carcinoembryonic antigen messenger RNA may be used as a complementary tool to the hematoxylin and eosin method for detection of poorly differentiated, aggressive tumors

Lymph node CEA and MUC2 mRNA as useful predictors of outcome in colorectal cancer

The aim was to explore the utility for staging and prognostic impact of carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor, and bone morphogenic protein 1) containing domain protein 1 (CDCP1) and mucin 2 (MUC2) mRNA levels in mesenteric lymph nodes of colorectal cancer (CRC) patients. Lymph nodes were collected at surgery and bisected; one half was subjected to biomarker mRNA analysis using real-time quantitative RT-PCR and the other half to routine histopathology. Lymph nodes from 174 CRC patients and 24 controls were analyzed. The median follow-up time was 59 (range 17-131) months. Cut-off levels were defined by analyzing quintiles by Cox regression model. CEA mRNA showed the best discriminating power between patients with recurrence in CRC after surgery and patients who were apparently disease-free (p = 0.015). The risk of recurrence for the CEA(+) patients was 4.6 times greater than for the CEA(-) patients (p < 0.0001). The other biomarkers gave lower hazard ratios. Cumulative survival analysis demonstrated that the average survival time was 99 months for CEA(-) patients compared to 39 months for CEA(+) patients, a difference of 60 months (p < 0.0001). Six to nine percent of the Stage I and Stage II patients [H&E(-)] had CEA(+), CK20(+), GCC(+) and/or MUC2(+) lymph nodes. Two of these patients died from recurrent CRC. Low lymph node MUC2/CEA mRNA ratio identified patients with high risk for recurrence (p = 0.011). Thus, quantitative reverse transcriptase-polymerase chain reaction of CEA mRNA is a sensitive method to identify tumor cells in lymph nodes of CRC patients and, in combination with MUC2 mRNA, allows improved prediction of clinical outcome

Utility of G protein-coupled receptor 35 expression for predicting outcome in colon cancer

The utility of mRNA and protein determinations of G protein-coupled receptor 35, that is, GPR35a (GPR35 V1) and GPR35b (GPR35 V2/3), as indicators of outcome for colon cancer patients after curative surgery was investigated. Expression levels of V1 and V2/3 GPR35, carcinoembryonic antigen and CXCL17 mRNAs were assessed in primary tumours and regional lymph nodes of 121 colon cancer patients (stage I–IV), colon cancer cell lines and control colon epithelial cells using real-time quantitative reverse transcriptase-polymerase chain reaction. Expression of G protein-coupled receptor 35 was investigated by two-colour immunohistochemistry and immunomorphometry. GPR35 V2/3 mRNA, but not V1 mRNA, was expressed in colon cancer cell lines, primary colon tumours and control colon epithelial cells. Haematoxylin and eosin positive (H&amp;E(+)), but not H&amp;E(–), lymph nodes expressed high levels of GPR35 V2/3 mRNA (P&lt;0.0001). GPR35b and carcinoembryonic antigen proteins were simultaneously expressed in many colon cancer tumour cells. Kaplan–Meier and hazard ratio analysis revealed that patients with lymph nodes expressing high levels of GPR35 V2/3 mRNA and, in particular, in the group of patients with lymph nodes also expressing carcinoembryonic antigen mRNA, had a short disease-free survival time, 67 months versus 122 months at 12-year follow-up (difference: 55 months, P = 0.001; hazard ratio: 3.6, P = 0.002). In conclusion, high level expression of G protein-coupled receptor 35 V2/3 mRNA in regional lymph nodes of colon cancer patients is a sign of poor prognosis