| 1. |
- Tesi, Bianca, et al.
(författare)
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Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms
- 2017
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Ingår i: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 129:16, s. 2266-2279
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Tidskriftsartikel (refereegranskat)abstract
- Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cis SAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34 1 hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-alpha or IFN-gamma induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with 27/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.
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| 2. |
- Carlsson, Göran, 1951, et al.
(författare)
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Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia.
- 2012
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Ingår i: British journal of haematology. - : Wiley. - 1365-2141 .- 0007-1048. ; 158:3, s. 363-369
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Tidskriftsartikel (refereegranskat)abstract
- Severe congenital neutropenia (SCN) is characterized by low blood neutrophil counts, early bacterial infections, and risk of leukaemia development. As yet, no population-based incidence estimates of SCN have been reported. Children less than 16years of age with SCN were sought in Sweden during the 20-year period 1987-2006 by a questionnaire to all Swedish Departments of Paediatrics and by reviewing the Swedish Health and Welfare Statistical Databases. Thirty-two patients were diagnosed with congenital neutropenia during this period. All received treatment with recombinant granulocyte-colony stimulating factor (G-CSF). Twenty-one patients were diagnosed as SCN or probable SCN, corresponding to 1·0 per 100000 live births. Nine (43%) had ELANE mutations, four (19%) HAX1 mutations and eight (38%) were children with disease of unknown genetic aetiology. Four out of 21 patients (19%) developed myelodysplastic syndrome/leukaemia and three (14%) died, all with leukaemia. The cumulative incidence of myelodysplastic syndrome/leukaemia was 31%. The observed incidence of SCN in this population-based study was higher than previously estimated, possibly because genetic testing now can identify SCN cases previously thought to be idiopathic or benign neutropenia. The risk of developing myelodysplastic syndrome/leukaemia is considerable. ELANE mutations are the most commonly identified genetic defects.
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| 3. |
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| 4. |
- Carlsson, Göran, et al.
(författare)
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Kostmann syndrome or infantile genetic agranulocytosis, part two : Understanding the underlying genetic defects in severe congenital neutropenia
- 2007
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 96:6, s. 813-819
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Forskningsöversikt (refereegranskat)abstract
- Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term 'infantile genetic agranulocytosis' for this condition, which is now known as Kostmann syndrome. Recent studies have revealed mutations in ELA-2, encoding the neutrophil granule protease, neutrophil elastase, in autosomal dominant neutropenia, and mutations in HAX-1, encoding an anti-apoptotic protein, in autosomal recessive neutropenia. Conclusion: Future studies should aim to clarify the mechanisms underlying the evolution of secondary malignancies in these patients.
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| 5. |
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| 6. |
- Klein, Christoph, et al.
(författare)
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HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:1, s. 86-92
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive severe congenital neutropenia (SCN) constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells, yet the underlying genetic defect remains unknown. Using a positional cloning approach and candidate gene evaluation, we identified a recurrent homozygous germline mutation in HAX1 in three pedigrees. After further molecular screening of individuals with SCN, we identified 19 additional affected individuals with homozygous HAX1 mutations, including three belonging to the original pedigree described by Kostmann. HAX1 encodes the mitochondrial protein HAX1, which has been assigned functions in signal transduction and cytoskeletal control. Here, we show that HAX1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Our findings suggest that HAX1 is a major regulator of myeloid homeostasis and underline the significance of genetic control of apoptosis in neutrophil development.
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| 7. |
- Sundén-Cullberg, Jonas, et al.
(författare)
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Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial
- 2023
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration.Methods: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 μg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery.Results: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly.Conclusion: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824).
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| 8. |
- Valdimarsdóttir, Unnur, et al.
(författare)
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Parents' intellectual and emotional awareness of their child's impending death to cancer: a population-based long-term follow-up study.
- 2007
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Ingår i: The lancet oncology. - 1470-2045 .- 1474-5488. ; 8:8, s. 706-14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We aimed to study care-related determinants of when parents gain awareness of their child's impending death to cancer, and whether the duration of this awareness affects the parents' long-term morbidity. METHODS: Between August 2001 and October 2001, 449 of 561 (80%) parents who had lost a child due to any malignancy in Sweden between Jan 1, 1992, and Dec 31, 1997 (identified on the Swedish Causes of Death Register), answered a 365-item postal questionnaire designed to ascertain when, before the child's actual death, they had become intellectually and emotionally aware of the child's impending death (awareness time). The primary endpoints were intellectual awareness time (defined as time between intellectual realisation that a disease is fatal and the actual time of death) and emotional awareness time (defined as time between emotional realisation that a disease is fatal and the actual time of death). Parents' awareness of less than 24 h was referred to as a short awareness time. FINDINGS: 436 parents answered the question about intellectual awareness and 433 parents answered the question about emotional awareness. 112 parents (26%) reported a short intellectual awareness time and 195 parents (45%) reported a short emotional awareness time. The risk of having short intellectual awareness time was increased if parents had absence of information on their child's fatal condition (mothers relative risk [RR] 3.6 [95% CI 2.3-5.5]; fathers 2.9 [1.8-4.5]) and if curative treatment was used towards the end of life (mothers 4.1 [2.6-6.5]; fathers 2.7 [1.7-4.2]). The risk of short emotional awareness time was increased if parents had absence of information indicating the child would die (mothers 1.5 [1.1-2.0]; fathers 1.8 [1.3-2.5]) and absence of talks about death with the other parent (mothers 1.5 [1.1-2.0]; fathers 1.7 [1.2-2.2]). Compared with fathers who had longer emotional awareness time, fathers with short emotional awareness time had an increased risk of depression (adjusted RR 1.8 [1.0-3.3]) and absence from employment due to sick leave or early retirement (RR 8.5 [1.1-67.8]) at follow-up. This difference was not noted for mothers. INTERPRETATION: Health-care professionals can influence parents' intellectual and emotional awareness of a child's impending death due to cancer. Short emotional awareness increases the risk of long-term depression in bereaved fathers.
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| 9. |
- Akefeldt, Selma O, et al.
(författare)
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Langerhans cell histiocytosis in children born 1982-2005 after in vitro fertilization
- 2012
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Ingår i: Acta Paediatrica. - : Wiley-Blackwell. - 0803-5253 .- 1651-2227. ; 101:11, s. 1151-1155
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Tidskriftsartikel (refereegranskat)abstract
- Aim: In a recent Swedish study, comparing data from the Swedish Cancer Register with the Medical Birth Register including data on IVF, an increased risk of Langerhans cell histiocytosis (LCH) was found in children born 19822005 after IVF. Here, we aimed to verify the LCH diagnoses and examine whether any special forms of the disease were overrepresented in this population. Methods: Medical records for all children with LCH conceived by IVF were acquired and the diagnosis confirmed or discarded. Disease characteristics were compared with data from children diagnosed with LCH 19922001 in the Stockholm County. Results: We verified LCH in seven children born after IVF, all born prior to 2002. These children did not have milder disease forms. The odds ratio (OR) to develop LCH for the whole group born after IVF was 3.2 [95% confidence interval (CI), 1.47.3] and for children born before 2002, 5.2 [95% CI, 2.311.9], compared with children in Stockholm County 19922001. Conclusion: LCH was overrepresented in children born after IVF prior to 2002. Affected children did not have milder disease forms. These findings may be valuable to understand LCH aetiology. Additional studies on a putative correlation between IVF and LCH in the offspring are encouraged.
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| 10. |
- Bergsten, Elisabet, et al.
(författare)
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Confirmed efficacy of etoposide and dexamethasone in HLH treatment : long-term results of the cooperative HLH-2004 study
- 2017
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 130:25, s. 2728-2738
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Tidskriftsartikel (refereegranskat)abstract
- Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P =020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.
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| 11. |
- Carlsson, Goran, et al.
(författare)
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Ovarian failure in HAX1-deficient patients : is there a gender-specific difference in pubertal development in severe congenital neutropenia or Kostmann disease?
- 2013
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 102:1, s. 78-82
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Tidskriftsartikel (refereegranskat)abstract
- Aim Severe congenital neutropenia (SCN) is a rare disorder of myelopoiesis characterized by neutropenia, recurrent bacterial infections and a maturation arrest of the myelopoiesis in the bone marrow. Homozygous mutations in the HAX1 gene were described in patients with autosomal recessive SCN or Kostmann disease. Some of these patients display neurological disease. We noted, during the course of clinical management of patients with Kostmann disease, insufficient pubertal development in female patients, but not in our male patients. The study objective was to provide a detailed account of this phenotype and its possible relation to HAX1 mutations. Methods Detailed clinical histories and laboratory investigations of three patients with Kostmann disease belonging to the original kindred in northern Sweden described by Rolf Kostmann are reported. Results We report one male patient with normal puberty and two female patients with insufficient pubertal development. Elevated levels of LH and FSH were recorded in both patients. All three patients harbour the same p.Glu190X mutation in the HAX1 gene. Conclusions We show for the first time that female patients with Kostmann disease display primary gonadal insufficiency. This suggests a possible role for HAX1 in the development and/or function of the human ovary.
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| 12. |
- Fadeel, Bengt, et al.
(författare)
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Langerhans´ cellhistiocytos: nytt ljus över patogenesen. 75 år sedan Sture Siwes klassiska arbete om »systemisk retikuloendotelios«
- 2008
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Ingår i: Läkartidningen. - 0023-7205. ; 105:51-52, s. 3737-3742
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Tidskriftsartikel (refereegranskat)abstract
- Langerhans´ cellhistiocytos (LCH) benämndes tidigare histiocytosis X, vilket i sin tur var ett samlingsnamn för diagnoserna eosinofilt granulom, Hand–Schüller–Christians sjukdom och Letterer–Siwes sjukdom. Sjukdomen kännetecknas av granulom av langerhanska dendritiska celler och andra immunceller i skelett och/ eller hud/hörselgång, lungor, lever/mjälte och lymfkörtlar samt även andra organ såsom centrala nervsystemet. LCH förekommer dels i en lindrig och ibland rent av självläkande form som begränsas till enstaka organ, dels som en svårare multiorgansjukdom med i vissa fall dödlig utgång. Den bakomliggande patogenesen har länge varit oklar, men senare tids forskning stödjer tanken att LCH orsakas av en obalans i kroppens immunförsvar, inklusive ökad produktion av interleukin-17a, och att denna obalans avspeglar en reaktiv (infektiös) sjukdom snarare än en malign process.
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| 13. |
- Gavhed, Desiree, et al.
(författare)
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Biomarkers in the Cerebrospinal Fluid and Neurodegeneration in Langerhans Cell Histiocytosis
- 2009
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 53:7, s. 1264-1270
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Tidskriftsartikel (refereegranskat)abstract
- Background. Progressive neurodegeneration may result in potentially severe cognitive and motor dysfunctions as a complication of Langerhans cell histiocytosis (LCH), a suggested IL-17A-associated inflammatory condition. To detect this complication (CNS-LCH) early and to evaluate the potential efficacy of therapeutic interventions, biomarkers detecting and measuring ongoing neurodegeneration Would be valuable. We evaluated cerebrospinal fluid (CSF) biomarkers of ongoing neurodegeneration in CNS-LCH patients. Procedure. Nine patients with endocrine, neuromotor, cognitive or/and behavioral abnormalities as well as neuroradiological evidence of CNS-LCH were evaluated 4-12 years after LCH diagnosis for CSF levels of neurofilament protein light chain (NF-L), glial fibrillary acid protein (GFAp), and total tau protein (TAU). Two patients were analyzed longitudinally. One hundred ten children with newly diagnosed acute lymphoblastic leukemia (ALL) served as controls. Results. NF-L, TAU, and GFAp levels were elevated in four, six, and eight of nine patients studied, respectively. NF-L (P < 0.001) and GFAp (P < 0.001) were higher in patients than in controls (TAU not analyzed in controls). The patient with most severe clinical and neuroradiological CNS-LCH displayed the highest levels of NF-L and GFAp whereas three patients without signs of systemic disease had low TAU levels and normal/slightly elevated NF-L. NF-L tended to be higher at radiological progression of neurodegeneration than at Status quo (P = 0.07). Notably, we experienced frequent lumbar puncture complications in these patients. Conclusions. CSF levels of NF-L, TAU, and GFAp appear to be elevated in CNS-LCH. It would be valuable if these markers were validated in order to serve as markers for early CNS-LCH, to monitor disease progression and to evaluate various treatment attempts for CNS-LCH. Pediatr Blood Cancer 2009;53:1264-1270. (C) 2009 Wiley-Liss, Inc.
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| 14. |
- Greenwood, Tatiana von Bahr, et al.
(författare)
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Clinical and laboratory signs of haemophagocytic lymphohistiocytosis associated with pandemic influenza A (H1N1) infection in patients needing extracorporeal membrane oxygenation A retrospective observational study
- 2021
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Ingår i: European Journal of Anaesthesiology. - : Lippincott Williams & Wilkins. - 0265-0215 .- 1365-2346. ; 38:7, s. 692-701
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Severe pandemic influenza has been associated with the hyperinflammatory condition secondary haemophagocytic lymphohistiocytosis (HLH).OBJECTIVES: To determine the frequency, degree, character and possible cause of influenza-associated HLH in critically ill patients with severe acute respiratory distress syndrome due to influenza A (H1N1) infection requiring extracorporeal membrane oxygenation (ECMO) support at our hospital.DESIGN: A retrospective observational study.PATIENTS AND SETTING: Medical data were retrieved retrospectively from 11 consenting patients of thirteen adults infected with pandemic influenza A (H1N1) 2009 requiring ECMO between July 2009 and January 2010 at the ECMO Centre of Karolinska University Hospital, Stockholm, Sweden. All patients were evaluated for HLH using HLH-2004 criteria and HScore.RESULTS: Eleven patients (median age 31 years) were included in the study and all survived. All patients showed signs of multiple organ dysfunction and pronounced inflammation, more severe in the four patients with HLH who had significantly higher peak serum concentrations of ferritin (P = 0.024), alkaline phosphatase (P = 0.012) and gamma-glutamyl transferase (P = 0.024), lower concentration of albumin (P = 0.0086) and more frequently hepatomegaly (P = 0.048). Abnormal lymphocyte cytotoxicity (lytic units <10) and a low proportion of natural killer (NK) cells were observed in three of four patients with HLH. Notably, we found a significant inverse correlation between serum ferritin concentration and NK cell and cytotoxic T lymphocyte percentages (r(s) = -0.74, P = 0.0013 and r(s) = -0.79, P = 0.0025, respectively). One HLH patient received HLH-directed cytotoxic therapy, another intravenous immunoglobulin and the other two no specific HLH-directed therapy.CONCLUSION: Critically ill patients, including healthy young adults, with pandemic influenza may develop HLH and should be monitored for signs of hyperinflammation and increasing organ dysfunction, and evaluated promptly for HLH because HLH-directed therapy may then be beneficial. The association of low NK percentages with hyperferritinaemia may suggest a role for reduced NK cell numbers, possibly also cytotoxic T lymphocytes, and subsequently reduced lymphocyte cytotoxicity, in the pathogenesis of hyperinflammation and secondary HLH.
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| 15. |
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| 16. |
- Gustavsson, Peter, et al.
(författare)
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Familial transient erythroblastopenia of childhood is associated with the chromosome
- 2002
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Ingår i: Br J Haematol. - 0007-1048. ; 119:1, s. 261-4
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Tidskriftsartikel (refereegranskat)abstract
- Transient erythroblastopenia of childhood (TEC) is a rare condition, which at onset may be difficult to distinguish from Diamond-Blackfan anaemia (DBA). We have previously shown that mutations in the ribosomal protein S19 gene (RPS19) cause DBA. In order to clarify whether TEC and DBA are allelic, we investigated the segregation of markers spanning the RPS19 gene region on chromosome 19q13.2 and performed sequence analysis of all exons in the RPS19 gene in seven TEC sibling pairs. Linkage analysis supported allelism for TEC and DBA at the RPS19 gene locus and implies molecular mechanisms other than structural mutations in the RPS19 gene.
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| 17. |
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| 18. |
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| 19. |
- Herold, Nikolas, et al.
(författare)
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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
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Tidskriftsartikel (refereegranskat)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
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| 20. |
- Ideström, Maja, et al.
(författare)
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Pediatric Crohn's disease from onset to adulthood : granulomas are associated with an early need for immunomodulation
- 2014
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 49:8, s. 950-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Childhood onset Crohn's disease (CD) is considered more aggressive than adult onset disease. Epithelioid cell granulomas in intestinal biopsies are one, non-obligate, criterion of CD. We investigated granulomas as markers of CD severity in children followed to adulthood.MATERIAL AND METHODS: Forty-five individuals with childhood onset CD were studied from diagnosis until attainment of final height, with data on disease location, medical and surgical management and with detailed growth data analyses. A blinded review of diagnostic biopsies was also performed.RESULTS: We found granulomas in 22/45 (49%) children at diagnosis, altogether in 28/45 (62%) patients during the disease course (median overall follow-up - 12.3 years, range 9.3-18). Granulomas were found in 9/11 (82%) with upper gastrointestinal involvement (cumulatively 17/20, 85%) (p = 0.017 and p = 0.006, respectively). The time from diagnosis to initiating immune modulating treatment (median 4.5 months, range 0-75) was shorter in the granuloma-positive group (16/22) compared to the granuloma-negative group (18/23) (median 33 months, range 2-105; p = 0.01). The median standard deviation score height at diagnosis and final adult height (both adjusted for target height) did not correlate to findings of granulomas.CONCLUSIONS: Epithelioid cell granulomas were associated with a shorter time to initiating immune modulating drugs, as a possible sign of more severe disease, but growth was not affected.
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| 21. |
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| 22. |
- Jalmsell, Li, et al.
(författare)
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Children with cancer share their views : tell the truth but leave room for hope
- 2016
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 105:9, s. 1094-1099
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Tidskriftsartikel (refereegranskat)abstract
- AimOne in five children diagnosed with cancer will die from the disease. The aim of the study was to explore how children with cancer want to receive bad news about their disease, such as when no more treatment options are available. MethodsWe conducted individual interviews with ten children with cancer, aged seven to 17 years, at a single paediatric oncology unit in central Sweden. Interviews were audio-taped and analysed with systematic text condensation. Bad news was defined as information about a potentially fatal outcome, such as a disease relapse, or information that the treatment administered was no longer working and that there was no more treatment possible. ResultsAll children expressed that they wanted truthful information and they did not want to be excluded from bad news regarding their illness. They wanted to be informed as positively as possible, allowing them to maintain hope, and in words that they could understand. They also wanted to receive any bad news at the same time as their parents. ConclusionChildren with cancer want to be fully informed about their disease, but they also wanted it to be relayed as positively as possible so that they could stay hopeful.
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| 23. |
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| 24. |
- Jalmsell, Li, et al.
(författare)
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On the child's own initiative : parents communicate with their dying child about death
- 2015
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Ingår i: Death Studies. - : Informa UK Limited. - 0748-1187 .- 1091-7683. ; 39:2, s. 111-117
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Tidskriftsartikel (refereegranskat)abstract
- Open and honest communication has been identified as an important factor in providing good palliative care. However, there is no easy solution to if, when, and how parents and a dying child should communicate about death. This article reports how bereaved parents communicated about deathwith their child, dying from a malignancy. Communication was often initiated by the child and included communication through narratives such as fairy tales and movies and talking more directly about death itself. Parents also reported that their child prepared for death by giving instructions about his or her grave or funeral and giving away toys.
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| 25. |
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| 26. |
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| 27. |
- Jalmsell, Li, 1980-
(författare)
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Towards Good Palliation for Children with Cancer : Recognizing the Family and the Value of Communication
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pediatric cancer imposes a threat on the child’s life and approximately every fifth child diagnosed with cancer will die due to his or her disease. The overall aim of this thesis was to explore palliative care of children with cancer and bereaved family members. The thesis includes data collected retrospectively from medical records, a nationwide questionnaire directed to bereaved parents, a nationwide questionnaire for bereaved siblings and individual interviews with children in cancer care.Most children dying from cancer were recognized as being beyond cure at time of death; for some this recognition occurred close to death, leaving little time for potential personal preferences (Paper I). Bereaved parents and siblings noticed extensive suffering in the child close to death (Paper II, VI), with physical fatigue being the most commonly reported symptom irrespectively of age and diagnosis of the child (Paper II). Bereaved parents’ psychological well-being appears to be closely related to experiencing suffering in the dying child (Paper III) but also to high-intensity treatment (with bone marrow transplant as the example) of a child that still dies from his or her disease (Paper IV). Bereaved siblings experience a lack in information at the end of their brother’s or sister’s life and report feeling poorly prepared for the loss. An increased risk of anxiety was seen in siblings whom nobody talked to about what to expect at the time of death of their brother or sister (Paper VI). When caring for children with cancer it is vital to take the individual child’s awareness and preferences regarding information into consideration. Bereaved parents who have communicated with their child about death expressed that this often occurred at the child’s own initiative (Paper V) and simple means such as fairy tales could be used to facilitate communication. Ill children themselves expressed in interviews wanting honest, but still hopeful information regarding bad news (Paper VII).The results of this thesis stress the importance of striving to achieve good communication and keeping a family perspective throughout care of children with cancer.
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| 28. |
- Jalmsell, Li, et al.
(författare)
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Transition to noncurative end-of-life care in paediatric oncology : a nationwide follow-up in Sweden
- 2013
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 102:7, s. 744-748
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Tidskriftsartikel (refereegranskat)abstract
- Aim To estimate whether and when children dying from a malignancy are recognized as being beyond cure and to study patterns of care the last weeks of life. Methods A nationwide retrospective medical record review was conducted. Medical records of 95 children (60% of eligible children) who died from a malignancy 2007-2009 in Sweden were studied. Results Eighty-three children (87%) were treated without curative intent at the time of death. Children with haematological malignancies were less likely to be recognized as being beyond cure than children with brain tumours [relative risks (RR) 0.7; 95% confidence interval (CI) 0.6-0.9] or solid tumours (RR 0.8; 0.6-1.0). The transition to noncurative care varied from the last day of life to over four years prior to death (median 60days). Children with haematological malignancies were treated with a curative intent closer to death and were also given chemotherapy (RR 5.5; 1.3-22.9), transfusions (RR 2.0; 1.0-4.0) and antibiotics (RR 5.3; 1.8-15.5) more frequently than children with brain tumours the last weeks of life. Conclusion The majority of children dying from a malignancy were treated with noncurative intent at the time of death. The timing of a transition in care varied with the diagnoses, being closer to death in children with haematological malignancies.
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| 29. |
- Kokkinou, Efthymia, et al.
(författare)
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The single-cell transcriptional landscape of innate and adaptive lymphocytes in pediatric-onset colitis
- 2023
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Ingår i: Cell reports medicine. - 2666-3791. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- Innate lymphoid cells (ILCs) are considered innate counterparts of adaptive T cells; however, their common and unique transcriptional signatures in pediatric inflammatory bowel disease (pIBD) are largely unknown. Here, we report a dysregulated colonic ILC composition in pIBD colitis that correlates with inflammatory ac-tivity, including accumulation of naive-like CD45RA+CD62L- ILCs. Weighted gene co-expression network analysis (WGCNA) reveals modules of genes that are shared or unique across innate and adaptive lympho-cytes. Shared modules include genes associated with activation/tissue residency, naivety/quiescence, and antigen presentation. Lastly, nearest-neighbor-based analysis facilitates the identification of most in-flamedand least inflamedlymphocytes in pIBD colon with unique transcriptional signatures. Our study reveals shared and unique transcriptional signatures of colonic ILCs and T cells in pIBD. We also provide insight into the transcriptional regulation of colonic inflammation, deepening our understanding of the poten-tial mechanisms involved in pIBD.
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| 30. |
- Kreicbergs, Ulrika, et al.
(författare)
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A population-based nationwide study of parents' perceptions of a questionnaire on their child's death due to cancer
- 2004
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 364:9436, s. 787-789
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Tidskriftsartikel (refereegranskat)abstract
- A proposed nationwide postal questionnaire to Swedish parents who had lost a child due to cancer between 1992 and 1997 was denied approval by the local ethics committee. However, a pilot study to assess the harm and benefit of the questionnaire was approved. 95% of parents found the pilot study valuable; thus, we were allowed to proceed with the main study, which consisted of 129 questions about the child's care and death and five about the parents' perceptions of the study. 423 (99%) parents found the investigation valuable, 285 (68%) were positively affected, and 123 (28%) were negatively affected (10 [2%] of whom, very much). Although the numerical data cannot be directly translated to ethical conclusions, they can provide guidance for future ethical decisions.
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| 31. |
- Kreicbergs, Ulrika, et al.
(författare)
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Talking about death with children who have severe malignant disease.
- 2004
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 351:12, s. 1175-1186
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: One of the questions faced by the parents of a child who is terminally ill with a malignant disease is whether or not they should talk about death with their child.METHODS: In 2001, we attempted to contact all parents in Sweden who had lost a child to cancer between 1992 and 1997. Among 561 eligible parents, 449 answered a questionnaire, and 429 stated whether or not they had talked about death with their child.RESULTS: None of the 147 parents who talked with their child about death regretted it. In contrast, 69 of 258 parents (27 percent) who did not talk with their child about death regretted not having done so. Parents who sensed that their child was aware of his or her imminent death were more likely to regret not having talked about it (47 percent, as compared with 13 percent of parents who did not sense this awareness in their child; relative risk, 3.7; 95 percent confidence interval, 2.3 to 6.0). The same variable was related to having talked about death (50 percent vs. 13 percent; relative risk, 3.8; 95 percent confidence interval, 2.6 to 5.6), as was being religious (42 percent vs. 25 percent; relative risk, 1.7; 95 percent confidence interval, 1.2 to 2.3). The child's age was related to both having talked about death and the parents' regretting not having talked about it.CONCLUSIONS: Parents who sense that their child is aware of his or her imminent death more often later regret not having talked with their child than do parents who do not sense this awareness in their child; overall, no parent in this cohort later regretted having talked with his or her child about death.
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| 32. |
- Kvedaraite, Egle, et al.
(författare)
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Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142−/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142−/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Löfstedt, Alexandra, et al.
(författare)
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Haploinsufficiency of UNC13D increases the risk of lymphoma
- 2019
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Ingår i: Cancer. - : John Wiley & Sons. - 0008-543X .- 1097-0142. ; 125:11, s. 1848-1854
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Experimental models have demonstrated that immune surveillance by cytotoxic lymphocytes can protect from spontaneous neoplasms and cancer. In humans, defective lymphocyte cytotoxicity is associated with the development of hemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome. However, to the best of the authors' knowledge, the degree to which human lymphocyte cytotoxicity protects from cancer remains unclear. In the current study, the authors examined the risk of lymphoma attributable to haploinsufficiency in a gene required for lymphocyte cytotoxicity.METHODS: The authors exploited a founder effect of an UNC13D inversion, which abolishes Munc13-4 expression and causes hemophagocytic lymphohistiocytosis in an autosomal recessive manner. Within 2 epidemiological screening programs in northern Sweden, an area demonstrating a founder effect of this specific UNC13D mutation, all individuals with a diagnosis of lymphoma (487 patients) and matched controls (1844 controls) were assessed using polymerase chain reaction for carrier status.RESULTS: Among 487 individuals with lymphoma, 15 (3.1%) were heterozygous carriers of the UNC13D inversion, compared with 18 controls (1.0%) (odds ratio, 3.0; P = .002). It is interesting to note that a higher risk of lymphoma was attributed to female carriers (odds ratio, 3.7; P = .004).CONCLUSIONS: Establishing a high regional prevalence of the UNC13D inversion, the authors have reported an overrepresentation of this mutation in individuals with lymphoma. Therefore, the results of the current study indicate that haploinsufficiency of a gene required for lymphocyte cytotoxicity can predispose patients to lymphoma, suggesting the importance of cytotoxic lymphocyte-mediated surveillance of cancer. Furthermore, the results of the current study suggest that female carriers are more susceptible to lymphoma.
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| 38. |
- Machaczka, Maciej, et al.
(författare)
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Development of classical Hodgkin’s lymphoma in an adult with biallelic STXBP2 mutations
- 2013
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Ingår i: Haematologica. - Stockholm : Karolinska Institutet, Dept of Medicine, Huddinge. - 0390-6078 .- 1592-8721.
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Tidskriftsartikel (refereegranskat)abstract
- Experimental model systems have delineated an important role for cytotoxic lymphocytes in the immunosurveillance of cancer. In humans, perforin-deficiency has been associated with occurrence of hematologic malignancies. Here, we describe an Epstein-Barr virus-positive classical Hodgkin's lymphoma in a patient harboring biallelic mutations in STXBP2, a gene required for exocytosis of perforin-containing lytic granules and associated with familial hemophagocytic lymphohistocytosis. Cytotoxic T lymphocytes were found infiltrating the tumor, and a high frequency of Epstein-Barr virus-specific cytotoxic T lymphocytes were detected in peripheral blood. However, lytic granule exocytosis and cytotoxicity by cytotoxic T lymphocytes, as well as natural killer cells, were severely impaired in the patient. Thus, the data suggest a link between defective lymphocyte exocytosis and development of lymphoma in STXBP2-deficient patients. Therefore, with regards to treatment of familial hemophagocytic lymphohistocytosis patients with mutations in genes required for lymphocyte exocytosis, it is important to consider both the risks of hemophagocytic lymphohistocytosis and malignancy.
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| 39. |
- Meeths, Marie, et al.
(författare)
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Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden.
- 2015
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Ingår i: Pediatric blood & cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 62:2, s. 346-352
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Tidskriftsartikel (refereegranskat)abstract
- Primary hemophagocytic lymphohistiocytosis (HLH) represents a group of inherited hyperinflammatory immunodeficiencies, including familial HLH (FHL), Griscelli syndrome type 2 (GS2), and X-linked lymphoproliferative syndrome (XLP). We previously reported an annual incidence of suspected primary HLH in Sweden 1971-1986 of 0.12 per 100,000 children. Here, we determined if the incidence had increased with concomitant awareness.
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| 40. |
- Rudd, Sean, et al.
(författare)
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Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy
- 2020
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Ingår i: EMBO Molecular Medicine. - : Blackwell Publishing Ltd. - 1757-4676 .- 1757-4684.
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Tidskriftsartikel (refereegranskat)abstract
- The deoxycytidine analogue cytarabine (ara-C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara-C efficacy by hydrolysing the active triphosphate metabolite ara-CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1-mediated barrier to ara-C efficacy in primary blasts and mouse models of AML, displaying SAMHD1-dependent synergy with ara-C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara-CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara-C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML. © 2020 The Authors. Published under the terms of the CC BY 4.0 license
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| 41. |
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| 42. |
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| 43. |
- Stålemark, Helen, et al.
(författare)
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Incidence of Langerhans cell histiocytosis in children : a population-based study
- 2008
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 51:1, s. 76-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Langerhans cell histiocytosis is a rare disease of unknown etiology. We wanted to assess the population-based incidence of LCH in a well-defined cohort of children. METHODS: We identified all children <15-years old treated with LCH during the 10 years period 1992-2001 at the Department of Pediatrics, Karolinska University Hospital in Stockholm, the referral center for children with LCH in Stockholm County. We also contacted the Departments of Dermatology, Orthopedics, and Neurosurgery for possible additional patients. RESULTS: Twenty-nine children (16 males) with LCH were identified, with a median age at diagnosis of 3.8 years (2 months-13.7 years). All children but one had a definitive diagnosis of LCH. The minimum incidence of LCH is estimated to 8.9/10(6) children per year. At diagnosis, 20 children (69%) had single system (SS) and 9 (31%) multisystem (MS) manifestations. Five of the 20 children with SS eventually developed MS disease, thus 14 (48%) had MS involvement at the maximal extent of disease (4.3/10(6) children per year). Interestingly, 22 children (76%) were diagnosed during the fall (September-November, n = 12) and winter (December-February, n = 10) seasons, as compared to seven children during the spring (March-May = 1) and summer (June-August = 6) seasons (P = 0.005, Chi-square). CONCLUSIONS: The incidence of childhood LCH in our study is higher than previously reported. In our patient cohort, LCH was more commonly diagnosed during the fall and winter season as compared to the spring and summer season. Whether this seasonal variation can be confirmed in larger studies and whether it has relevance for LCH pathophysiology remains to be elucidated.
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| 44. |
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| 45. |
- Tesi, Bianca, et al.
(författare)
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Spectrum of atypical clinical presentations in patients with biallelic PRF1 missense mutations.
- 2015
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Ingår i: Pediatric blood & cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 62:12, s. 2094-2100
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Tidskriftsartikel (refereegranskat)abstract
- Perforin, encoded by PRF1, is a pore-forming protein crucial for lymphocyte cytotoxicity. Biallelic PRF1 nonsense mutations invariably result in early-onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic PRF1 missense mutations may give rise to later-onset disease and more variable manifestations.
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| 46. |
- Tesi, Bianca, et al.
(författare)
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Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation
- 2016
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Ingår i: Journal of Clinical Immunology. - : Springer Science and Business Media LLC. - 0271-9142 .- 1573-2592. ; 36:5, s. 480-489
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Autosomal recessive mutations in LRBA, encoding for LPS-responsive beige-like anchor protein, were described in patients with a common variable immunodeficiency (CVID)-like disease characterized by hypogammaglobulinemia, autoimmune cytopenias, and enteropathy. Here, we detail the clinical, immunological, and genetic features of a patient with severe autoimmune manifestations. Methods: Whole exome sequencing was performed to establish a molecular diagnosis. Evaluation of lymphocyte subsets was performed for immunological characterization. Medical files were reviewed to collect clinical and immunological data. Results: A 7-year-old boy, born to consanguineous parents, presented with autoimmune hemolytic anemia, hepatosplenomegaly, autoimmune thyroiditis, and severe autoimmune gastrointestinal manifestations. Immunological investigations revealed low immunoglobulin levels and low numbers of B and NK cells. Treatment included immunoglobulin replacement and immunosuppressive therapy. Seven years after disease onset, the patient developed severe neurological symptoms resembling acute disseminated encephalomyelitis, prompting allogeneic hematopoietic stem cell transplantation (HSCT) with the HLA-identical mother as donor. Whole exome sequencing of the patient uncovered a homozygous 1 bp deletion in LRBA (c.7162delA:p.T2388Pfs*7). Importantly, during 2 years of follow-up post-HSCT, marked clinical improvement and recovery of immune function was observed. Conclusions: Our data suggest a beneficial effect of HSCT in patients with LRBA deficiency.
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| 47. |
- Van't Hooft, Ingrid, et al.
(författare)
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Neuropsychological sequelae in patients with neurodegenerative Langerhans cell histiocytosis
- 2008
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 51:5, s. 669-74
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with Langerhans cell histiocytosis (LCH) may develop neurodegeneration and significant CNS sequelae, affecting a significant proportion of the patients. We here aimed to investigate the neuropsychological consequences in more detail. METHODS: Using an extensive neuropsychological test battery, we evaluated nine LCH patients, 6-20 years old, with radiological signs indicative of neurodegeneration. RESULTS: Altogether 3/9 patients performed below 1 SD of normal for age on full IQ. Detailed analysis revealed that 4/9 had deficient performance IQ, whereas 1/9 had subnormal verbal IQ (defined as below 1 SD). Furthermore, 3/8 patients showed slow speed of performance for age. Notably, 8/9 (89%) had deficient verbal working memory and 7/8 (88%) performed below normal on visual-spatial working memory. CONCLUSIONS: The results indicate a specific, uneven neuropsychological profile in patients affected by CNS-LCH, with a decline particularly on perceptual tasks whereas the verbal performance was not as negatively influenced. Furthermore, verbal and visual-spatial working memory functions were below normal for age in all but one patient studied. LCH may easily be misdiagnosed, but it is important that individuals affected by CNS-LCH are diagnosed to provide advice and support. It remains a challenge to find a treatment reducing this unfortunate neurodegeneration.
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| 48. |
- von Bahr Greenwood, Tatiana, et al.
(författare)
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Elevated ferritin and soluble CD25 in critically ill are associated with parameters of (hyper)inflammation and lymphocyte cytotoxicity
- 2019
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Ingår i: Minerva Anestesiologica. - : Edizioni Minerva Medica. - 0375-9393 .- 1827-1596. ; 85:12, s. 1289-1298
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Critically ill may develop a potentially fatal hyperinflammation, secondary (acquired) hemophagocytic lymphohistiocytosis (sHLH), the cause of which is unclear. We evaluated serum ferritin and soluble CD25 (sCD25) in critically ill, and their association with other parameters of inflammation and critical illness. Moreover, aiming to better understand the pathogenesis of sHLH, we also evaluated lymphocyte cytotoxicity parameters and correlations with the inflammatory markers ferritin and sCD25.METHODS: In a prospective observational study, 32 patients with ferritin ≥500 μg/L (24 with sepsis) were studied on admission to an intensive care unit (ICU) with regard to ferritin and corresponding clinical and laboratory features including sCD25, and detailed lymphocyte cytotoxicity and genetic analyses whenever possible.RESULTS: Critically ill patients had elevated, positively correlated levels of serum ferritin and sCD25 (rs=0.465, p=0.008); both associated with other risk factors of poorer outcome in critically ill, such as thrombocytopenia (rs=-0.534, p=0.002 and rs=-0.421, p=0.018, respectively), and sCD25 with hypoalbuminemia (rs=-0.678, p<0.001) and life support treatments (rs=0.479, p=0.006). Interestingly, ferritin levels were inversely associated with NK- cell cytotoxicity (rs=-0.462, p=0.047) and degranulation (rs=-0.504, p=0.030). Moreover, of four patients with abnormally low cytotoxicity, three (75%) had <5% circulating NK-cells.CONCLUSIONS: Our study suggests that hyperferritinemia and sCD25 correlate with other laboratory parameters indicative of severe hyperinflammation and organ dysfunction in critically ill ICU-patients, indicating their value in identifying hyperinflammatory critically ill patients for early intervention. Furthermore, it suggests that hyperferritinemia and hyperinflammation may partly be associated with a low percentage circulating NK-cells, and hence, the associated low lymphocyte cytotoxicity.
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| 49. |
- Zheng, Chengyun, et al.
(författare)
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VEGF reduces astrogliosis and preserves neuromuscular junctions in ALS transgenic mice
- 2007
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 363:4, s. 989-993
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting from motor neuron loss in the spinal cord and brain stem. In the present study, we found that systemic administration of recombinant vascular endothelial growth factor (VEGF) significantly diminished astrogliosis and increased the number of neuromuscular junctions in a Cu/Zn superoxide dismutase (SOD1) transgenic mouse model of ALS. Our results thus demonstrate a novel regulatory role of VEGF on astrocytes and are suggestive of protective effects of VEGF both in the peripheral and central nervous system in the SOD1 transgenic mouse model. These findings warrant further evaluation of the mechanism(s) of regulatory effects of VEGF on neuronal and non-neuronal cells, and the relation of these events to motor neuron degeneration and the onset and progression of ALS.
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