Neutropenia (adjective neutropenic), from Latin prefix neutro- and Greek suffix -πενία (deficiency) is a hematological disorder characterized by an abnormally low number of a type of white blood cell called a neutrophil. Neutrophils usually make up 50-70% of circulating white blood cells and serve as the primary defense against infections by destroying bacteria in the blood. Hence, patients with neutropenia are more susceptible to bacterial infections and, without prompt medical attention, the condition may become life-threatening (neutropenic sepsis).
Cyclic neutropenia (or cyclical neutropenia) is a form of neutropenia which tends to occur every three weeks and lasting three to six days at a time due to changing rates of cell production by the bone marrow.[1]:811
It is often present among several members of the same family. Treatment includes G-CSF and usually improves after puberty.
Cyclic neutropenia is the result of autosomal dominantly inherited mutations in ELA2, the gene encoding neutrophil elastase.[2]
Function
Neutrophil
Being highly motile, neutrophils quickly congregate at a focus of infection, attracted by cytokines expressed by activated endothelium, mast cells, and macrophages. Neutrophils express[7] and release cytokines, which in turn amplify inflammatory reactions by several other cell types.
[edit] Phagocytosis
Neutrophils are phagocytes, capable of ingesting microorganisms or particles. They can internalise and kill many microbes, each phagocytic event resulting in the formation of a phagosome into which reactive oxygen species and hydrolytic enzymes are secreted. The consumption of oxygen during the generation of reactive oxygen species has been termed the "respiratory burst," although unrelated to respiration or energy production.
The respiratory burst involves the activation of the enzyme NADPH oxidase, which produces large quantities of superoxide, a reactive oxygen species. Superoxide dismutates, spontaneously or through catalysis via enzymes known as superoxide dismutases (Cu/ZnSOD and MnSOD), to hydrogen peroxide, which is then converted to hypochlorous acid (HOCl, also known as chlorine bleach) by the green heme enzyme myeloperoxidase. It is thought that the bactericidal properties of HOCl are enough to kill bacteria phagocytosed by the neutrophil, but this has not been proven conclusively.
[edit] Degranulation
Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation:
| Granule type | Protein |
| specific granules (or "secondary granules") | Lactoferrin and Cathelicidin |
| azurophilic granules (or "primary granules") | myeloperoxidase, bactericidal/permeability increasing protein (BPI), Defensins and the serine proteases neutrophil elastase and cathepsin G |
| tertiary granules | cathepsin and gelatinase |
Mechanisms by which Astragalus membranaceus injection regulates hematopoiesis in myelosuppressed mice.
Department of Pharmacology, School of Basic Medical Science, Peking University Health Science Center, 38 Xueyuan Road, Haidian Qu, Beijing 100083, China. xiaolingzhu88@yahoo.com.cn
The aim of this study was to investigate the mechanism underlying the effects of Astragalus membranaceus injection (AMI) on myelopoiesis in myelosuppressed mice. At 72 h after cyclophosphamide injection (250 mg/kg), the mice were administered AMI (500 mg/kg) intraperitoneally for 6 consecutive days or an equivalent volume of saline as a control. Murine colony-forming unit-fibroblast (CFU-F) formation, production of IL-6 and GM-CSF by bone marrow stromal cells (BMSC), and bcl-2 protein and mRNA expression in BMSC were measured by CFU-F assay, ELISA, immunohistochemistry and in situ hybridization. The results indicated that AMI improved the hematopoietic microenvironment by enhancing the BMSC survival and proliferation of CFU-F, production of IL-6 as well as GM-CSF by BMSC and bcl-2 protein and mRNA expression in BMSC, which promoted myelopoiesis. The data may provide a mechanistic basis for applying this ancient Chinese herb to promote hematopoiesis as an efficacious adjuvant therapy against myelosuppression induced by anti-cancer therapy. Copyright 2007 John Wiley & Sons, Ltd.
PMID: 17421056 [PubMed – indexed for MEDLINE]
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1: Blut. 1986 May;52(5):289-95.
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Plasma lactoferrin in patients with neutropenia.
This study examines the role of plasma lactoferrin in the assessment of neutropenia. In particular, we have studied lactoferrin as an inhibitor of granulopoiesis and as an indicator of the size of the total blood granulocyte pool (TBGP). Plasma lactoferrin concentration was determined in a heterogeneous group of 30 patients with neutropenia. Serial plasma lactoferrin levels in a patient with cyclic neutropenia correlated with the cycles of the neutrophil count. Patients with splenomegaly had a grossly elevated lactoferrin:neutrophil ratio. Most chronic idiopathic neutropenia patients had no real clinical problems and a normal plasma lactoferrin level. The results provide further evidence to support the concept that plasma lactoferrin indicates the size of the TBGP and the lactoferrin: neutrophil ratio indicates the degree of granulocyte margination. There was no evidence to suggest that lactoferrin acting as a feedback inhibitor of granulopoiesis caused neutropenia in these patients.
PMID: 3635417 [PubMed – indexed for MEDLINE]
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1: Curr Pharm Des. 2007;13(8):801-11.
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Antibiotic properties and applications of lactoferrin.
Department of Biology and Program in Medical Sciences, Indiana University, Bloomington, IN 47405, USA. eweinber@indiana.edu
Lactoferrin (Lf), a mammalian iron scavenging defense protein, constitutively is present in exocrine secretions that consistently are exposed to microbial flora: milk, tears, tubotympanum and nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus, and seminal fluid. Additionally, Lf is promptly delivered by circulating neutrophils to sites of microbial invasion. At these sites, the protein effectively scavenges iron at pH values as low as 3.5. Recombinant bovine and human lactoferrin is now available for development into nutraceutical/preservative/pharmaceutical products. Among conditions for which the products are being investigated are: angiogenesis; bone remodeling; food preservation; infection in animals, humans, plants; neoplasia in animals, humans; inflammation in intestine, joints; wound healing; as well as enhancement of antimicrobial and antineoplastic drugs, and prevention of iron induced oxidation of milk formula.
PMID: 17430182 [PubMed – indexed for MEDLINE]
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1: Expert Opin Investig Drugs. 2003 May;12(5):841-51.
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The therapeutic potential of lactoferrin.
Department of Biology and Programme in Medical Sciences, Indiana University, Bloomington, Indiana, USA. eweinber@indiana.edu
Lactoferrin (Lf), a natural defence iron-binding protein, is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus and seminal fluid. Additionally, Lf is produced in polymorphonuclear leukocytes and is deposited by these circulating cells in septic sites. A principal function of Lf is that of scavenging non-protein-bound iron in body fluids and inflamed areas so as to suppress free radical-mediated damage and decrease accessibility of the metal to invading bacterial, fungal and neoplastic cells. Adequate sources of bovine and recombinant human Lf are now available for development of commercial applications. Among the latter are use of Lf in food preservation, fish farming, infant milk formula and oral hygiene. Other readily accessible body compartments for Lf administration include skin, throat and small intestine. Further research is needed for possible medicinal use in colon and systemic tissues. Although Lf is a natural product and should be highly biocompatible, possible hazards have been documented.
PMID: 12720494 [PubMed – indexed for MEDLINE]
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1: Cell Prolif. 2009 Jun;42(3):330-8. Epub 2009 Apr 21.
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Progenitor cell self-renewal and cyclic neutropenia.
Division of Hematology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. dingli.david@mayo.edu
OBJECTIVES: Cyclic neutropenia (CN) is a rare genetic disorder where patients experience regular cycling of numbers of neutrophils and various other haematopoietic lineages. The nadir in neutrophil count is the main source of problems due to risk of life-threatening infections. Patients with CN benefit from granulocyte colony stimulating factor therapy, although cycling persists. Mutations in neutrophil elastase gene (ELA2) have been found in more than half of patients with CN. However, neither connection between phenotypic expression of ELA2 and CN nor the mechanism of cycling is known. MATERIALS AND METHODS: Recently, a multicompartment model of haematopoiesis that couples stem cell replication with marrow output has been proposed. In the following, we couple this model of haematopoiesis with a linear feedback mechanism via G-CSF. RESULTS: We propose that the phenotypic effect of ELA2 mutations leads to reduction in self-renewal of granulocytic progenitors. The body responds by overall relative increase of G-CSF and increasing progenitor cell self-renewal, leading to cell count cycling. CONCLUSION: The model is compatible with available experimental data and makes testable predictions.
PMID: 19397594 [PubMed – indexed for MEDLINE]
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1: Med Sci (Paris). 2008 Mar;24(3):284-9.
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[Granulopoeisis and leukemogenesis: lessons from congenital neutropenia]
[Article in French]
Service d’Hémato-oncologie Pédiatrique, Registre français des neutropénies congénitales, Hôpital Trousseau, 26 avenue du Docteur Arnold Netter, 75012 Paris, France. jean.donadieu@trs.aphp.fr
Congenital neutropenia are extremely rare diseases, defined by a permanent or cyclic decrease of blood neutrophils. Molecular basis of several congenital neutropenia has been recently determined, involving gene coding for the neutrophil elastase gene (ELA2), GFI1, WAS protein and mitochondrial HAX1 protein. These mutations, dominant (ELA2, GFI1), X-linked (WAS) and autosomal recessive (HAX1), result in instability of the contents of the granules- particularly the neutrophil elastase- or in abnormalities of the cytoskeleton, and possibly, in an increased apoptosis. ELA2 mutations resulting both in profound and permanent neutropenia, and in cyclic–pseudo sinusoidal–neutropenia lead to consider that time pattern is very close in the two apparently distinct phenotypes. This observation suggests that temporal variations of neutrophils could be represented by non linear functions. Congenital neutropenia, specifically ELA2 mutated, are also characterized by a high rate of leukemia (about 15% at 20 years of age). Leukemia risk does not appear to be related to an oncogenic effect of ELA2 mutations, but much likely to the deepness of the neutropenia, and the intensity of G-CSF therapy.
PMID: 18334177 [PubMed – indexed for MEDLINE]
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(synthetic G-CSF (granulocyte-colony stimulating factor, e.g., filgrastim, lenograstim).)
Severe congenital neutropenia does not appear to have a genetic origin, in a mouse model.
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1: Blood. 2002 Nov 1;100(9):3221-8.
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Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis.
Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA.
Severe congenital neutropenia (SCN) is a syndrome characterized by an isolated block in granulocytic differentiation and an increased risk of developing acute myeloid leukemia (AML). Recent studies have demonstrated that the majority of patients with SCN and cyclic neutropenia, a related disorder characterized by periodic oscillations in the number of circulating neutrophils, have heterozygous germline mutations in the ELA2 gene encoding neutrophil elastase (NE). To test the hypothesis that these mutations are causative for SCN, we generated transgenic mice carrying a targeted mutation of their Ela2 gene ("V72M") reproducing a mutation found in 2 unrelated patients with SCN, one of whom developed AML. Expression of mutant NE mRNA and enzymatically active protein was confirmed. Mice heterozygous and homozygous for the V72M allele have normal numbers of circulating neutrophils, and no accumulation of myeloid precursors in the bone marrow was observed. Serial blood analysis found no evidence of cycling in any of the major hematopoietic lineages. Rates of apoptosis following cytokine deprivation were similar in wild-type and mutant neutrophils, as were the frequency and cytokine responsiveness of myeloid progenitors. The stress granulopoiesis response, as measured by neutrophil recovery after cyclophosphamide-induced myelosuppression, was normal. To define the leukemogenic potential of V72M NE, a tumor watch was established. To date, no cases of leukemia have been detected. Collectively, these data suggest that expression of V72M NE is not sufficient to induce an SCN phenotype or leukemia in mice.
PMID: 12384420
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#162800 GeneTests, Links CYCLIC HEMATOPOIESIS
Alternative titles; symbols
NEUTROPENIA, CYCLIC
Gene map locus
TEXT
A number sign (#) is used with this entry because mutations in the gene encoding neutrophil elastase (ELA2; 130130) have been shown to cause cyclic neutropenia.
Cyclic neutropenia is a rare blood disease characterized by regular 21-day cyclic fluctuations in the numbers of blood neutrophils, monocytes, eosinophils, lymphocytes, platelets, and reticulocytes. Patients with the disease typically have regularly recurring symptoms of fever, malaise, mucosal ulcers, and, occasionally, life-threatening infections during periods of neutropenia. Most patients with cyclic neutropenia are given the diagnosis in childhood, but its onset later in life in some patients suggests that it may also be an acquired disorder. Hahneman and Alt (1958) described a 29-year-old man who from an early age had neutropenia that recurred every 21 days and was accompanied by infection. Complete remission occurred at age 18 years. The man’s daughter was seen at the age of 2 years with similar periodic disease recurring every 14 days. Torrioli-Riggio (1958) also reported cases. Morley et al. (1967) described 20 cases in 5 families. Clinical manifestations usually began in childhood and improved thereafter. The commonest were fever, oral ulcerations and skin infections. Neutropenia occurred at intervals of 15 to 35 days. It was often accompanied by monocytosis and sometimes by anemia, eosinophilia, or thrombocytopenia. Male-to-male transmission occurred. 
Cyclic neutropenia in the collie dog is accompanied by gray fur, leads to early death from pyogenic infections, and is an autosomal recessive (Dale et al., 1970). Weiden et al. (1974) showed by transplantation of grey collie bone marrow into normal dogs which had been irradiated that the basic defect is in the stem cell. There are sufficient similarities between the canine and human diseases (Guerry et al., 1972) to suggest that the same may be true in man. Krance et al. (1982) confirmed this when a patient, in the process of bone marrow transplantation as treatment for acute lymphoblastic leukemia in relapse, acquired cyclic neutropenia from her histocompatible donor sib. Seven persons in 4 sibships of her family had cyclic neutropenia. In dogs, the disease can be transferred and cured through bone marrow transplantation (Jones et al., 1975). The disease in collie dogs differs from the human disease principally in the length of the cycle (12 rather than 21 days).
Hammond et al. (1989) found that granulocyte-colony stimulating factor (CSF3; 138970) is effective treatment. Inoue et al. (1992) identified cyclic neutropenia in a 34-year-old woman, her 3 sons, and her mother. Oscillations in the blood neutrophil counts were rather regular, with a periodicity of 21 days. The granulocyte colony-stimulating factor level in her serum was persistently high, with the peak occurring during the neutropenic phase. The patient’s serum appeared to contain an inhibitory factor. To control infections, Inoue et al. (1992) administered recombinant human GCSF for 7 days around the early neutropenic phase.
On the basis of studies in 9 families, Palmer et al. (1996) found no clinical evidence of decreased penetrance or heterogeneity. However, the pattern of expression suggested anticipation: no families appeared to display milder phenotypes in successive generations, and the most severe cases occurred in children in the youngest generations. The spectrum of severity included death from necrotizing enterocolitis in 4 subjects ranging in age from 6 to 17 years. In 3 of the 9 pedigrees, the proband appeared to represent a new mutation. While cyclic hematopoiesis is commonly described as ‘benign,’ 4 children in 3 of the 9 families died of Clostridium or E. coli colitis, documenting the need for urgent evaluation of abdominal pain. Misdiagnosis with other neutropenias was common but can be avoided by serial blood counts in index cases. Palmer et al. (1996) found that treatment with human CSF3 resulted in dramatic improvement of neutropenia and morbidity.
In cyclic hematopoiesis, circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes, and reticulocytes also cycle with the same 21-day period frequency. Horwitz et al. (1999) used a genomewide screen and positional cloning to map the cyclic neutropenia locus to 19p13.3. They identified 7 different single-basepair substitutions in the ELA2 gene, encoding a neutrophil elastase (EC 3.4.21.37, also known as leukocyte elastase, elastase-2, and medullasin). In each of 13 families studied, a mutation in ELA2 was found on a unique haplotype; the haplotype carrying a new mutation in a sporadic case was also unique. Neutrophil elastase is a target for protease inhibition by alpha-1-antitrypsin (also called protease inhibitor-1; PI; 107400), and its unopposed release destroys tissue at sites of inflammation. Horwitz et al. (1999) hypothesized that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate mechanisms governing the clock-like timing of hematopoiesis.
Peng et al. (2000) described a family in which all 4 male members, the father and 3 sons, had hereditary cyclic neutropenia starting in childhood with a cycle of approximately 21 days. Recurrent mucosa and skin infections with fever had occurred frequently, but gradually decreased in severity as they reached adulthood. Monocytosis was found during the neutrophil nadirs in all 4 patients. Decreased sperm count and motility were demonstrated in the 2 elder sons. Chromosome analysis showed a pericentric inversion of the Y chromosome in all of the men. The chromosome anomaly was inv(Y)(p11.2;q11.23).
SEE ALSO
Dale et al. (1972); Dale et al. (1972); Meuret and Fliedner (1970); Page and Good (1957); Wright et al. (1981)
REFERENCES
- 1. Dale, D. C.; Alling, D. W.; Wolff, S. M. :
- Cyclic hematopoiesis: the mechanism of cyclic neutropenia in grey collie dogs. J. Clin. Invest. 51: 2197-2204, 1972.
PubMed ID : 5054472 - 2. Dale, D. C.; Kimball, H. R.; Wolff, S. M. :
- Studies of cyclic neutropenia in gray collie dogs. (Abstract) Clin. Res. 18: 402 only, 1970.
- 3. Dale, D. C.; Ward, S. B.; Kimball, H. R.; Wolff, S. M. :
- Studies of neutrophil production and turnover in grey collie dogs with cyclic neutropenia. J. Clin. Invest. 51: 2190-2196, 1972.
PubMed ID : 5054471 - 4. Guerry, D. D.; Dale, D. C.; Omine, M.; Perry, S.; Wolff, S. M. :
- Studies on the mechanism of human cyclic neutropenia. (Abstract) Brit. J. Haemat. 40: 951 only, 1972.
- 5. Hahneman, B. M.; Alt, H. L. :
- Cyclic neutropenia in a father and daughter. JAMA 168: 270-272, 1958.
- 6. Hammond, W. P., IV; Price, T. H.; Souza, L. M.; Dale, D. C. :
- Treatment of cyclic neutropenia with granulocyte colony-stimulating factor. New Eng. J. Med. 320: 1306-1311, 1989.
PubMed ID : 2469956 - 7. Horwitz, M.; Benson, K. F.; Person, R. E.; Aprikyan, A. G.; Dale, D. C. :
- Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nature Genet. 23: 433-436, 1999.
PubMed ID : 10581030 - 8. Inoue, T.; Tani, K.; Tajiri, M.; Ishida, Y.; Seguchi, M.; Tanaka, H.; Asano, S.; Kaneko, T.; Matsumoto, N. :
- A case report of familial cyclic neutropenia. Tohoku J. Exp. Med. 167: 107-113, 1992.
PubMed ID : 1282277 - 9. Jones, J. B.; Yang, T. J.; Dale, J. B.; Lange, R. D. :
- Canine cyclic haematopoiesis: marrow transplantation between littermates. Brit. J. Haemat. 30: 215-223, 1975.
PubMed ID : 127610 - 10. Krance, R. A.; Spruce, W. E.; Forman, S. J.; Rosen, R. B.; Hecht, T.; Hammond, W. P.; Blume, K. G. :
- Human cyclic neutropenia transferred by allogeneic bone marrow grafting. Blood 60: 1263-1266, 1982.
PubMed ID : 6753968 - 11. Meuret, G.; Fliedner, T. M. :
- Zellkinetik der Granulopoiese und des Neutrophilensystems bei einem Fall von zyklischer Neutropenie. Acta Haemat. 43: 48-63, 1970.
PubMed ID : 4986188 - 12. Morley, A. A.; Carew, J. P.; Baikie, A. G. :
- Familial cyclical neutropenia. Brit. J. Haemat. 13: 719-738, 1967.
PubMed ID : 6050865 - 13. Page, A. R.; Good, R. A. :
- Studies on cyclic neutropenia. A clinical and experimental investigation. Am. J. Dis. Child. 94: 623-661, 1957.
- 14. Palmer, S. E.; Stephens, K.; Dale, D. C. :
- Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am. J. Med. Genet. 66: 413-422, 1996.
PubMed ID : 8989458 - 15. Peng, H.-W.; Chou, C.-F.; Liang, D.-C. :
- Hereditary cyclic neutropenia in the male members of a Chinese family with inverted Y chromosome. Brit. J. Haemat. 110: 438-440, 2000.
PubMed ID : 10971405 - 16. Torrioli-Riggio, G. :
- Considerazioni su una famiglia di granulopenici. Acta Genet. Med. Gemellol. 7: 237-248, 1958.
- 17. Weiden, P. L.; Robinett, B.; Graham, T. C.; Adamson, J.; Storb, R. :
- Canine cyclic neutropenia. A stem cell defect. J. Clin. Invest. 53: 950-953, 1974.
PubMed ID : 4591036 - 18. Wright, D. G.; Dale, D. C.; Fauci, A. S.; Wolff, S. M. :
- Human cyclic neutropenia: clinical review and long-term follow-up of patients. Medicine 60: 1-13, 1981.
PubMed ID : 7453561
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1: J Cell Biochem. 2005 Oct 1;96(2):278-84.
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Parathyroid hormone (PTH) and hematopoiesis: new support for some old observations.
Institute for Biological Sciences, Montreal Road Campus, National Research Council of Canada, Ottawa, Ontario, Canada, K1A 0R6. pthosteo@rogers.com
Forty-seven years ago, the parathyroid hormone (PTH) in one injection of Lilly’s old bovine parathyroid extract, PTE, was found to greatly increase the 30-day survival of heavily X-irradiated rats when given from 18 h before to as long as 3 h after irradiation but no later. This was the first indication that PTH might stimulate hematopoiesis. Recent studies have confirmed the relation between PTH and hematopoiesis by showing that hPTH-(1-34)OH increases the size of the hematopoietic stem cell pool in mice. The peptide operates through a cyclic AMP-mediated burst of Jagged 1 production in osteoblastic cells lining the stem cells’ niches on trabecular bone surfaces. The osteoblastic cells’ Jagged 1 increases the hematopoietic stem cell pool by activating Notch receptors on attached stem cells. PTH-triggered cyclic AMP signals also directly stimulate the proliferation of the hematopoietic stem cells. However, the single PTH injection in the early experiments using PTE probably increased the survival of irradiated rats mainly by preventing the damaged hematopoietic progenitors from irreversibly initiating self-destructive apoptogenesis during the first 5 h after irradiation. It has also been shown that several daily injections of hPTH-(1-34)OH enable lethally irradiated mice to survive by stimulating the growth of transplanted normal bone marrow cells. If the osteogenic PTHs currently entering or on the verge of entering the market for treating osteoporosis can also drive hematopoiesis in humans as well as rodents, they could be potent tools for reducing the damage inflicted on bone marrow by cytotoxic cancer chemotherapeutic drugs and ionizing radiation. Copyright (c) 2005 Wiley-Liss, Inc.
PMID: 16088941 [PubMed – indexed for MEDLINE]
"Transient neutropenia often accompanies viral infections (eg, early-stage infectious mononucleosis), and sepsis is a particularly serious cause of neutropenia. Neutropenia associated with common childhood viral diseases occurs during the first 1 to 2 days of illness and may persist for 3 to 8 days. It usually corresponds to a period of acute viremia and is related to virus-induced redistribution of neutrophils from the circulating to the marginal pool. Neutrophil sequestration may occur after viral tissue damage. Moderate to severe neutropenia may also be associated with a wide variety of other infections (see Table 135-2).
Chronic neutropenia often accompanies HIV infection, the result of impaired production of neutrophils and accelerated destruction of neutrophils by antibodies (see Ch. 145). Autoimmune neutropenias may be associated with the presence of circulating antineutrophil antibodies and may occur in isolation or with associated diseases." (Merk Manual).
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1: J Pediatr. 2009 Jun;154(6):842-8. Epub 2009 Feb 23.
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- Comment in:
- J Pediatr. 2009 Jun;154(6):A1.
Very low birth weight infants born to cytomegalovirus-seropositive mothers fed with their mother’s milk: a prospective study.
Department of Obstetrical, Gynecological, and Pediatric Sciences, Operative Unit of Neonatology, St. Orsola-Malpighi General Hospital, University of Bologna, Bologna, Italy. mariagrazia.capretti@virgilio.it
OBJECTIVE: To assess the risk of post-natal cytomegalovirus (CMV) transmission to very low birth weight (VLBW) infants fed with their mother’s fresh milk. STUDY DESIGN: Prospective, observational study of 80 VLBW infants and their 68 mothers. Infants’ urine and their own mother’s fresh breast milk were tested for CMV by means of culture tests once a week until discharge. CMV in infected milk and urine were genotyped. The clinical course, laboratory findings, and outcome of infants infected with CMV at 2 years of age are reported. RESULTS: Fifty-three mothers (78%) were CMV-seropositive at delivery. CMV was detected in the milk of 21 of 53 seropositive mothers (40%), and CMV was in the urine in 9 of 26 infants (35%) fed with CMV-positive milk. The same gN-genotype was found in milk and urine. Three infected infants <28 weeks gestational age (GA) had a mild sepsis-like illness. Five more infants had neutropenia, conjugated hyperbilirubinaemia, or both. Post-natal CMV infection occurred in 1 of 19 infants with a GA<28 weeks who were treated at birth with intravenous immunoglobulin versus 3 of 5 non-treated infants (P < .02). Symptomatic CMV infection was associated with bronchopulmonary dysplasia. No neurosensorial sequelae were found at 2 years of corrected age. CONCLUSIONS: CMV infection via fresh human milk is mild, self-limiting, and without sequelae. Very-low GA and pre-existing chronic diseases are associated with symptomatic infection.
PMID: 19230896 [PubMed – indexed for MEDLINE]
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1: Blood. 2007 Jun 1;109(11):4716-23. Epub 2007 Feb 20.
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G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms.
Department of Pathology, Section of General Pathology, University of Verona, Italy.
The treatment of children affected by severe congenital neutropenia (SCN) with G-CSF strongly reduces the risk of sepsis by reversing neutropenia. However, SCN patients who respond to the treatment with the growth factor still have an elevated risk of succumbing to sepsis. Because the disease is usually caused by heterozygous mutations of ELA2, a gene encoding for neutrophil elastase (NE), we have investigated in G-CSF-responder and nonresponder patients affected by SCN the expression of polypeptides that constitute the antimicrobial machinery of these cells. In peripheral blood-derived neutrophils of patients with heterozygous mutations of ELA2 who were treated with G-CSF, NE was nearly absent as detected by immunofluorescence and immunoblotting, suggesting that production of the mutant protein interferes with normal gene expression. This defect was associated with abnormal expression of other granule-associated proteins such as myeloperoxidase, lactoferrin, cathepsin G, and human-neutrophil-peptide. Moreover, in one patient with partial response to G-CSF, we observed an impairment of neutrophil antimicrobial activity against Candida albicans, and, to a lower extent against Escherichia coli. Thereby, we propose that the treatment with G-CSF is not sufficient to correct all of the functional deficiency of neutrophils, and this might account for the consistent risk of infections observed in SCN patients.
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1: Curr Mol Med. 2008 Jun;8(4):282-98.
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The role of microbiota and probiotics in stress-induced gastro-intestinal damage.
Department of Clinical and Experimental Medicine, Division of Surgery, University Hospital, SE-581 85 Linköping, Sweden. johda@ibk.liu.se.
Stress has a major impact on gut physiology and may affect the clinical course of gastro-intestinal diseases. In this review, we focus on the interaction between commensal gut microbiota and intestinal mucosa during stress and discuss the possibilities to counteract the deleterious effects of stress with probiotics. Normally, commensal microbes and their hosts benefit from a symbiotic relationship. Stress does, however, reduce the number of Lactobacilli, while on the contrary, an increased growth, epithelial adherence and mucosal uptake of gram-negative pathogens, e.g. E. coli and Pseudomonas, are seen. Moreover, intestinal bacteria have the ability to sense a stressed host and up-regulate their virulence factors when opportunity knocks. Probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host", and mainly represented by Lactic Acid Bacteria. Probiotics can counteract stress-induced changes in intestinal barrier function, visceral sensitivity and gut motility. These effects are strain specific and mediated by direct bacterial-host cell interaction and/or via soluble factors. Mechanisms of action include competition with pathogens for essential nutrients, induction of epithelial heat-shock proteins, restoring of tight junction protein structure, up-regulation of mucin genes, secretion of defensins, and regulation of the NFkappaB signalling pathway. In addition, the reduction of intestinal pain perception was shown to be mediated via cannabinoid receptors. Based on the studies reviewed here there is clearly a rationale for probiotic treatment in patients with stress-related intestinal disorders. We are however far from being able to choose the precise combination of strains or bacterial components for each clinical setting.
PMID: 18537636
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1: Ann N Y Acad Sci. 2007 Jun;1106:143-51. Epub 2007 Mar 14.
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LEF-1 is a decisive transcription factor in neutrophil granulopoiesis.
Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
We found that lymphoid enhancer-binding factor 1 (LEF-1) is a decisive transcription factor in granulopoiesis controlling proliferation, proper lineage commitment, and granulocytic differentiation via regulation of its target genes C/EBP-alpha, cyclin D1, c-myc, and survivin. Myeloid progenitor cells of patients with severe congenital neutropenia (CN) showed a severe downregulation of LEF-1 and its target genes expression. Expression of neutrophil elastase (NE) is also severely reduced in CN myeloid progenitors. Intriguingly, ELA2 gene promoter is positively regulated by direct binding of LEF-1 or LEF-1 target gene C/EBP-alpha. In summary we demonstrated that LEF-1 is not only crucial in lymphopoiesis, but also in myelopoiesis, documenting new functions of LEF-1.
PMID: 17360796 [PubMed – indexed for MEDLINE]
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Correction of human cyclic neutropenia with prednisolone (if autoimmune, i.e. viral infection)