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cyclic neutropenia

Vahagn Makaryan, Merideth L Kelley, Breanna Fletcher, Audrey Anna Bolyard, Andrew Aprikyan, David C Dale
Mutations in ELANE, the gene for neutrophil elastase (NE), a protease expressed early in neutrophil development, are the most frequent cause of cyclic (CyN) and severe congenital neutropenia (SCN). We hypothesized that inhibitors of NE, acting either by directly inhibiting enzymatic activity or as chaperones for the mutant protein, might be effective as therapy for CyN and SCN. We investigated β-lactam-based inhibitors of human NE (Merck Research Laboratories, Kenilworth, NJ, USA), focusing on 1 inhibitor called MK0339, a potent, orally absorbed agent that had been tested in clinical trials and shown to have a favorable safety profile...
July 28, 2017: Journal of Leukocyte Biology
Karolina Bukowska-Strakova, Maciej Ciesla, Krzysztof Szade, Witold Norbert Nowak, Robert Straka, Agata Szade, Malgorzata Tyszka-Czochara, Karolina Najder, Anna Konturek, Maciej Siedlar, Jozef Dulak, Alicja Jozkowicz
Heme oxygenase-1 (HO-1) is stress-inducible, cytoprotective enzyme degrading heme to carbon monoxide (CO), biliverdin and Fe(2+). We showed that HO-1 knock-out mice (HO-1(-/-)) have a twofold higher level of granulocytes than wild type (WT) mice, despite decreased concentration of granulocyte colony-stimulating factor (G-CSF) in the blood and reduced surface expression of G-CSF receptor on the hematopoietic precursors. This suggests the effect of HO-1 on granulopoiesis. Here we aimed to determine the stage of granulopoiesis regulated by HO-1...
June 2017: Immunobiology
M Bakšienė, E Benušienė, A Morkūnienė, L Ambrozaitytė, A Utkus, V Kučinskas
Barth syndrome (BTHS) is a rare X-linked disease characterized by dilated cardiomyopathy, proximal skeletal myopathy and cyclic neutropenia. It is caused by various mutations in the tafazzin (TAZ) gene located on Xq28 that results in remodeling of cardiolipin and abnormalities in mitochondria stability and energy production. Here we report on a novel c.285-1G>C splice site mutation in intron 3 of the TAZ gene that was detected prenatally.
December 1, 2016: Balkan Journal of Medical Genetics: BJMG
Onyemaechi N Okolo, Emmanuel Katsanis, Seongseok Yun, Candace Y Reveles, Faiz Anwer
Objective and Importance. Cyclic neutropenia (CyN) is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk of infection. Case...
2017: Case Reports in Hematology
Michael Wiesmeier, Sanjivan Gautam, Susanne Kirschnek, Georg Häcker
Severe congenital neutropenia (SCN) is characterised by a differentiation block in the bone marrow and low neutrophil numbers in the peripheral blood, which correlates with increased risk of bacterial infections. Several underlying gene defects have been identified in SCN patients. Mutations in the neutrophil elastase (ELANE) gene are frequently found in SCN and cyclic neutropenia. Both mislocalization and misfolding of mutant neutrophil elastase protein resulting in ER stress and subsequent induction of the unfolded protein response (UPR) have been proposed to be responsible for neutrophil survival and maturation defects...
2016: PloS One
Laura Mihaela Trandafir, Madalina Ionela Chiriac, Smaranda Diaconescu, Ileana Ioniuc, Ingrith Miron, Daniel Rusu
BACKGROUND: Recurrent fever syndrome, known as the Marshall syndrome (MS), is a clinical entity that includes several clinical features, such as: fever (39-40°C) that occurs repeatedly at variable intervals (3-8 weeks) and in episodes of 3 to 6 days, cervical adenopathy, pharyngitis, and aphthous stomatitis. The diagnosis of MS is one of exclusions; laboratory data is nonspecific and no abnormalities correlated with MS have been detected thus far. METHODS: The authors report the case of a 2-year-old girl admitted to a tertiary pediatric center for repeated episodes of fever with aphthous stomatitis and laterocervical adenopathy...
November 2016: Medicine (Baltimore)
Vidyavathi H Patil, Shivayogi M Hugar, Girish Balikai, Sudha Patil
Congenital cyclic neutropenia syndrome is a constitutional genetic disorder which is characterized by very low number of neutrophils (neutropenia). Patients suffering from this disorder clinically present with neutropenia at early age, history of recurrent fever, ulcerations in the oral cavity, gingivitis, and other recurrent infections. This paper describes a case report of a child with recurrent mouth ulcers, fever, and later diagnosed with severe congenital cyclic neutropenia. This also emphasizes the importance of identification of rare causes of immunosuppressive conditions in children presenting with recurrent oral ulcers and poor dental hygiene, to prevent long-term complications of oral cavity and also morbidity and mortality secondary to neutropenic sepsis...
October 2016: International Journal of Applied and Basic Medical Research
Karolina Bukowska-Strakova, Maciej Ciesla, Krzysztof Szade, Witold Norbert Nowak, Robert Straka, Agata Szade, Malgorzata Tyszka-Czochara, Karolina Najder, Anna Konturek, Maciej Siedlar, Jozef Dulak, Alicja Jozkowicz
Heme oxygenase-1 (HO-1) is stress-inducible, cytoprotective enzyme degrading heme to carbon monoxide (CO), biliverdin and Fe(2+). We showed that HO-1 knock-out mice (HO-1(-/-)) have a twofold higher level of granulocytes than wild type (WT) mice, despite decreased concentration of granulocyte colony-stimulating factor (G-CSF) in the blood and reduced surface expression of G-CSF receptor on the hematopoietic precursors. This suggests the effect of HO-1 on granulopoiesis. Here we aimed to determine the stage of granulopoiesis regulated by HO-1...
October 21, 2016: Immunobiology
Kegan Jessamy, Fidelis O Ojevwe, Ezinnaya Ubagharaji, Anuj Sharma, Obiajulu Anozie, Christy Ann Gilman, Sekou Rawlins
Clostridium septicum is a highly virulent pathogen which is associated with colorectal malignancy, hematological malignancy, immunosuppression, diabetes mellitus and cyclical neutropenia. Presentation may include disseminated clostridial infection in the form of septicemia, gas gangrene, and mycotic aortic aneurysms. We report the case of a 62-year-old female presenting with necrotizing fasciitis of her left thigh and subsequently developing rectal bleeding. While she was being treated with empiric antibiotics, her blood culture was found to be positive for C...
May 2016: Case Reports in Gastroenterology
Masataka Umeda, Jin Ikenaga, Tomohiro Koga, Toru Michitsuji, Toshimasa Shimizu, Shoichi Fukui, Ayako Nishino, Yoshikazu Nakasima, Sin-Ya Kawashiri, Naoki Iwamoto, Kunihiro Ichinose, Yasuko Hirai, Mami Tamai, Hideki Nakamura, Tomoki Origuchi, Atsushi Kawakami
A 78-year-old woman diagnosed with cyclic neutropenia 5 years previously had been treated with recombinant granulocyte-colony stimulating factor (G-CSF). She developed fever, tenderness and distension of temporal arteries after the treatment with G-CSF. Magnetic resonance imaging and ultrasonography revealed wall thickening of the temporal arteries. She was therefore diagnosed with giant cell arteritis (GCA). Small vessel vasculitis has been reported as a complication of G-CSF. However, the development of large vessel vasculitis after G-CSF treatment is quite rare...
2016: Internal Medicine
Maksim Klimiankou, Sabine Mellor-Heineke, Cornelia Zeidler, Karl Welte, Julia Skokowa
Acquired mutations in the intracellular part of CSF3R (colony stimulating factor 3 receptor, granulocyte) have been detected with a frequency of more than 30% in severe congenital neutropenia (CN) patients. CN is a preleukemic syndrome with a risk of approximately 20% to develop leukemia. More than 80% of CN patients who develop acute myeloid leukemia or myelodysplastic syndrome reveal CSF3R mutations, suggesting that they are involved in leukemogenesis. Using deep-sequencing technology, we were able to analyze large cohorts of CN patients for the entire CSF3R sequence as well as to identify cell clones carrying mutations in the intracellular part of CSF3R with very high sensitivity...
April 2016: Annals of the New York Academy of Sciences
Behdad Navabi, Julia Elizabeth Mainwaring Upton
BACKGROUND: Eosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia. However, the list of PIDs typically reported with eosinophilia is small and the literature lacks an inclusive list of PIDs which have been reported with eosinophilia. This motivated us to review the literature for all PIDs which have been described to have elevated eosinophils as this may contribute to an earlier diagnosis of PID and further the understanding of eosinophilia...
2016: Allergy, Asthma, and Clinical Immunology
Maksim Klimiankou, Sabine Mellor-Heineke, Olga Klimenkova, Elisa Reinel, Murat Uenalan, Siarhei Kandabarau, Julia Skokowa, Karl Welte, Cornelia Zeidler
No abstract text is available yet for this article.
May 26, 2016: Blood
Rainer Nustede, Maksim Klimiankou, Olga Klimenkova, Inna Kuznetsova, Cornelia Zeidler, Karl Welte, Julia Skokowa
A number of studies have demonstrated induction of the unfolded protein response (UPR) in patients with severe congenital neutropenia (CN) harbouring mutations of ELANE, encoding neutrophil elastase. Why UPR is not activated in patients with cyclic neutropenia (CyN) carrying the same ELANE mutations is unclear. We evaluated the effects of ELANE mutants on UPR induction in myeloid cells from CN and CyN patients, and analysed whether additional CN-specific defects contribute to the differences in UPR induction between CN and CyN patients harbouring identical ELANE mutations...
January 2016: British Journal of Haematology
Turkan Patiroglu, H Haluk Akar
Clericuzio-type poikiloderma with neutropenia (PN) is characterized by poikiloderma, non-cyclic neutropenia, recurrent sinopulmonary infections, pachyonychia, and palmo-plantar hyperkeratosis. Mutations in the C16orf57 gene, which is located on chromosome 16q13, have been identified as the cause of PN. PN was first described by Clericuzio in Navajo Indians. Herein, we reported the clinical presentations and laboratory investigations of PN in three siblings from Turkey. The older siblings presented with typical cutaneous poikiloderma, plantar keratoderma, pachyonychia of toenails, and recurrent upper respiratory infections...
June 2015: Iranian Journal of Allergy, Asthma, and Immunology
Sibilah Breen, David Ritchie, Penelope Schofield, Ya-Seng Hsueh, Karla Gough, Nick Santamaria, Rose Kamateros, Roma Maguire, Nora Kearney, Sanchia Aranda
BACKGROUND: Outpatient chemotherapy is a core treatment for haematological malignancies; however, its toxicities frequently lead to distressing/potentially life-threatening side-effects (neutropenia/infection, nausea/vomiting, mucositis, constipation/diarrhoea, fatigue). Early detection/management of side-effects is vital to improve patient outcomes, decrease morbidity and limit lengthy/costly hospital admissions. The ability to capture patient-reported health data in real-time, is regarded as the 'gold-standard' to allow rapid clinical decision-making/intervention...
2015: Trials
Nedeljka Glavan, Jelena Roganović, Lana Glavan-Gačanin, Nives Jonjić
Our experience in the treatment of a 4-year-old boy with cyclic neutropenia who was admitted for urgent appendectomy is described. The postoperative course was uneventful with high daily doses of granulocyte colony-stimulating factor and antimicrobial therapy. The purpose of this report is to highlight the importance of immediate appendectomy in neutropenic patients, wherein low absolute neutrophil count should not be considered as a contraindication for urgent surgical procedure.
2015: Therapeutics and Clinical Risk Management
Vadim Shchepachev, Harry Wischnewski, Charlotte Soneson, Andreas W Arnold, Claus M Azzalin
Mpn1 is an exoribonuclease that modifies the spliceosomal small nuclear RNA (snRNA) U6 by trimming its oligouridine tail and introducing a cyclic phosphate group (>p). Mpn1 deficiency induces U6 3' end misprocessing, accelerated U6 decay and pre-mRNA splicing defects. Mutations in the human MPN1 gene are associated with the genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Here we present the deep sequencing of the >p-containing transcriptomes of mpn1Δ fission yeast and PN cells. While in yeast U6 seems to be the only substrate of Mpn1, human Mpn1 also processes U6atac snRNA...
August 19, 2015: FEBS Letters
Michael S Block, Marco Brindis, Celeste A Block, Joaquin M Berron
The purpose of this report is to discuss the treatment of a patient with cyclic neutropenia. This patient presented with flared teeth, thin alveolar bone, and mobile teeth. A staged approach was used to remove her teeth, augment the bone, use immediate fixed provisional to determine the type of final prostheses, and ultimately to use cone-shaped overdenture attachments to retain her final prostheses. The result was rehabilitation of the patient with esthetic full-arch fixed-removable dentures with no adverse sequelae in this patient with this systemic disease...
September 2015: Journal of Oral and Maxillofacial Surgery
Osamu Hirata, Satoshi Okada, Miyuki Tsumura, Shuhei Karakawa, Itaru Matsumura, Yujiro Kimura, Toshiro Maihara, Shin'ichiro Yasunaga, Yoshihiro Takihara, Osamu Ohara, Masao Kobayashi
PURPOSE: To confirm and characterize mosaicism of the cyclic neutropenia (CyN)-related mutation in the ELANE gene identified in the asymptomatic mother of patients with CyN. METHODS: We identified sibling cases with CyN due to a novel heterozygous splicing site mutation, IVS4 +5SD G>T, in the ELANE gene, resulting in an internal in-frame deletion of 30 nucleotides (corresponding to a ten amino acid deletion, V161-F170). The mutated allele was also detected in their asymptomatic mother but at low frequency...
July 2015: Journal of Clinical Immunology
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