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The article reports that the 6th Key Symposium on Nanomedicine was held from September 9-11, 2009 in Stockholm, Sweden. The symposium featured presentations from leading scientists and was divided into four sessions that is regenerative medicine, drug delivery, imaging and diagnostics, and finally, toxicology and risk assessment.

Objectives. Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. Methods. Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. Results. Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C→T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G→A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5′ end of exon 2 containing the W44X mutation was spliced out from the second transcript. Conclusions. We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations. [ABSTRACT FROM AUTHOR]

Rare diseases are frequently life-threatening or chronically debilitating and the impact on the quality of life of affected patients and their family members is thus significant. However, drug development for these conditions has been limited by a lack of understanding of the underlying mechanisms of disease and the relative unavailability of subjects for clinical trials, as well as the prohibitive cost of investing in a novel pharmaceutical agent with poor market potential. Nevertheless, the introduction of Orphan Drug legislations has provided important incentives for the development of orphan drugs (i.e. drugs that have been abandoned or ‘orphaned’ by major drug companies). Moreover, recent studies on rare diseases, including inherited immunodeficiencies and metabolic disorders, have served not only to alleviate the plight of patients with rare diseases, but also yielded valuable information on biological processes of relevance for other, more common conditions. These lessons, along with the crucial importance of cooperation between academic institutions, pharmaceutical companies, patient advocacy groups and society in the elucidation of rare diseases, are highlighted in the present review. [ABSTRACT FROM AUTHOR]

Apoptosis is a highly regulated process of cell deletion and plays a fundamental role in the maintenance of tissue homeostasis in the adult organism. Numerous studies in recent years have revealed that apoptosis is a constitutive suicide programme expressed in most, if not all cells, and can be triggered by a variety of extrinsic and intrinsic signals. Many human diseases can be attributed directly or indirectly to a derangement of apoptosis, resulting in either cell accumulation, in which cell eradication or cell turnover is impaired, or cell loss, in which the apoptotic programme is inadvertently triggered. In addition, defective macrophage engulfment and degradation of cell corpses may also contribute to a dysregulation of tissue homeostasis. An increased understanding of the signalling pathways that govern the execution of apoptosis and the subsequent clearance of dying cells may thus yield novel targets for therapeutic intervention in a wide range of human maladies. [ABSTRACT FROM AUTHOR]

The author discusses the aspects of nanosafety which deals with developing safe design of nanomedicines. He mentions that nanotoxicology aims to study undesirable interference between engineered nanomaterials and the nanoscale machineries of biological systems. He comments on that the safer design of nanomedicines needs an understanding of intrinsic properties of nanostructured materials along with their behaviour in biological systems.

Congenital neutropenia with autosomal recessive inheritance was first described by the Swedish paediatrician Rolf Kostmann who coined the term 'infantile genetic agranulocytosis'. The condition is now commonly referred to as Kostmann disease. These patients display a maturation arrest of the myelopoiesis in the bone marrow and reduced neutrophil numbers and suffer from recurrent, often life-threatening infections. The molecular mechanism underlying congenital neutropenia has been intensively investigated, and mutations in genes that impinge on programmed cell death have been identified. The present review provides an overview of these studies., (© 2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Severe congenital neutropenia (SCN) of autosomal recessive inheritance, also known as Kostmann disease, is characterised by a lack of neutrophils and a propensity for life-threatening infections. Using whole-exome sequencing, we identified homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) in three patients with Kostmann-like SCN, thus confirming the recent attribution of JAGN1 mutations to SCN. Using the human promyelocytic cell line HL-60 as a model, we found that overexpression of patient-derived JAGN1 mutants, but not silencing of JAGN1, augmented cell death in response to the pro-apoptotic stimuli, etoposide, staurosporine, and thapsigargin. Furthermore, cells expressing mutant JAGN1 were remarkably susceptible to agonists that normally trigger degranulation and succumbed to a calcium-dependent cell death programme. This mode of cell death was completely prevented by pharmacological inhibition of calpain but unaffected by caspase inhibition. In conclusion, our results confirmed the association between JAGN1 mutations and SCN and showed that SCN-associated JAGN1 mutations unleash a calcium- and calpain-dependent cell death in myeloid cells., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

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., (©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.)

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 16 years 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 100,000 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., (© 2012 Blackwell Publishing Ltd.)

Objective: Late-onset neutropenia following rituximab therapy is a well-recognized side effect in lymphoma patients, but only a few cases of late-onset neutropenia have been reported in patients with autoimmune disorders. The purpose of this study was to define the incidence, clinical features, and some of the underlying mechanisms of late-onset neutropenia in relation to rituximab use in several rheumatic diseases., Methods: We conducted a retrospective analysis of a cohort of 209 consecutive patients with rheumatic diseases who had been treated with rituximab at a university hospital between June 2003 and March 2009., Results: Eleven patients with late-onset neutropenia were identified. The highest incidence was observed in granulomatosis with polyangiitis (Wegener's) and systemic lupus erythematosus patients (23% and 20%, respectively), whereas the incidence in rheumatoid arthritis patients was 3%. The median time to onset of neutropenia was 102 days (range 40-362 days) and coincided with the entire period of B lymphocyte depletion; this depletion was more pronounced in patients with late-onset neutropenia (P = 0.002) than in a control group of 20 matched patients without late-onset neutropenia. Serum IgM levels decreased during the same time and to a significantly greater amount in patients with late-onset neutropenia than in controls (P = 0.027). No patient with late-onset neutropenia displayed specific antineutrophil antibodies. Seven patients were hospitalized because of infections (6 with sepsis and 1 with febrile neutropenia) that required intravenous antibiotics. Six were treated with granulocyte colony-stimulating factor., Conclusion: In patients treated with rituximab for rheumatic diseases, late-onset neutropenia is a clinically significant adverse event associated with marked B lymphocyte depletion and severe infections. The incidence of late-onset neutropenia appears to vary with autoimmune disease type., (Copyright © 2011 by the American College of Rheumatology.)

Syntaxin-11 is a member of a family of membrane-trafficking proteins referred to as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Recent studies have shown that syntaxin-11 is expressed in natural killer cells and cytotoxic T cells and is likely to play a role in the granule exocytosis pathway. However, the biological role of syntaxin-11 in other immune cells has remained elusive. This study found that stimulation with interferon-gamma upregulated syntaxin-11 expression in primary monocytes. Experiments using monocytes from patients with familial haemophagocytic lymphohistiocytosis harbouring mutations in the gene encoding syntaxin-11 (STX11), or monocytes from healthy individuals in which syntaxin-11 was downregulated using specific short-interfering RNA, demonstrated that syntaxin-11 was not required for antibody-dependent cellular cytotoxicity. On the other hand, silencing of syntaxin-11 expression in primary macrophages enhanced the phagocytosis of apoptotic target cells with a concomitant increase in macrophage secretion of tumour necrosis factor-alpha. Moreover, Fcgamma-receptor-mediated uptake of target cells was also enhanced following silencing of syntaxin-11 expression in macrophages. In addition, syntaxin-11 localized to the plasma membrane in macrophages ingesting apoptotic cell corpses. Syntaxin-11 thus appears to act as a negative regulator of human macrophage engulfment of apoptotic cells and IgG-opsonized red blood cells.

Unlabelled: 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.

Chronic neutropenia comprises several different diseases that vary in degree of severity and management. We analysed the levels of the neutrophil-derived protein pro-LL-37 in plasma of patients with chronic neutropenia to assess whether it could be used to differentiate different categories of chronic neutropenia. All patients with severe congenital neutropenia were pro-LL-37 deficient. This was in contrast to patients with autoimmune or idiopathic neutropenia, who exhibited normal pro-LL-37 levels while patients with cyclic neutropenia displayed an oscillation of pro-LL-37 in plasma. Plasma levels of pro-LL-37 may thus prove useful for differential diagnosis of chronic neutropenia.

Unlabelled: 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 demonstrated a lack of antibacterial peptides and severe periodontitis in these patients despite recombinant growth factor treatment. Moreover, an increased degree of apoptosis of myeloid progenitor cells in the bone marrow has been shown., Conclusion: Future studies should aim to clarify the underlying molecular genetic defect in Kostmann syndrome.

Warts, hypogammaglobulinaemia, infections, myelokathexis (WHIM) syndrome is an inherited immune disorder associated with CXCR4 gene mutations. Recent studies suggested that impaired receptor downregulation and enhanced chemotactic responsiveness to stromal-derived factor-1 (SDF-1), the sole cognate ligand for CXCR4, may account for the characteristic features of WHIM patients. This study evaluated whether the interaction of SDF-1 with CXCR4 could block constitutive apoptosis of peripheral blood neutrophils from congenital neutropenia patients and controls. SDF-1 was found to be a potent anti-apoptotic factor for WHIM neutrophils harbouring a truncating CXCR4 mutation, but not for neutrophils from control individuals, thus supporting the notion that such mutations may confer enhanced functional responses.

Treatment with granulocyte colony-stimulating factor plus erythropoietin may improve haemoglobin levels in patients with ringsideroblastic anaemia (RARS) and reduce bone marrow apoptosis. We studied bone marrow from 10 RARS patients, two of whom were also investigated after successful treatment. Mononuclear, erythroid and CD34+ cells were analysed with regard to proliferation, apoptosis, clonogenic capacity and oncoprotein expression, in the presence or absence of Fas-agonist, Fas-blocking antibody 2 and caspase-3 inhibitor. During culture, RARS bone marrow cells showed higher spontaneous apoptosis (P < 0.05) and caspase activity (P < 0.05)) than bone marrow cells from healthy donors. Eight out of nine patients had reduced growth of erythroid colony-forming units (CFU-E) (< 10% of control) and granulocyte-macrophage CFU (CFU-GM) (< 50% of control) from CD34+ cells. Fas ligation increased apoptosis and decreased colony growth equally in RARS and controls, but caused significantly more caspase activation in RARS (P < 0.01). Fas-blocking antibody showed no significant inhibitory effect on spontaneous apoptosis or ineffective haematopoiesis, as measured using phosphatidylserine exposure, the terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling technique, caspase activity or clonogenic growth. Caspase inhibition reduced apoptosis, increased proliferation and enhanced erythroid colony growth from CD34+ cells in RARS, but showed no effect on normal cells. CFU-E improved > 1000% after successful treatment. Thus, erythroid apoptosis in RARS is initiated at the CD34+ level and growth factor treatment may improve stem cell function. Enhanced caspase activation at the stem cell level, albeit not mediated through endogenous activation of the Fas receptor, contributes to the erythroid apoptosis in RARS.

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare and uniformly fatal disorder of early childhood characterized by fever, hepatosplenomegaly, cytopenia and widespread infiltration of vital organs by activated lymphocytes and macrophages. In order to test whether the massive accumulation of immune cells in these patients is associated with a perturbation of apoptosis, lymphocytes were isolated from eight patients and subjected to the chemotherapeutic agent etoposide or agonistic anti-Fas monoclonal antibodies in vitro. These stimuli elicited a normal apoptotic response in FHL patient cells when compared to healthy controls, as determined by phosphatidylserine exposure, DNA fragmentation, in vitro cleavage of the caspase-3-like substrate aspartate-glutamate-valine-aspartate-7-amino-4-methyl-coumarin (DEVD-AMC) and proteolysis of the anti-apoptotic protein Bcl-2. In addition, the degree of constitutive and Fas-triggered apoptosis in freshly isolated neutrophils was monitored in three children, with similar results. These studies indicate that immune cells derived from FHL patients are not inherently resistant to apoptosis induction. Specifically, etoposide-induced and Fas-triggered activation of intracellular caspases appears to remain intact in these individuals. However, the degree of spontaneous activation of caspase-3-like enzymes in activated lymphocytes was attenuated in three of the four patients tested prior to initiation of therapy, suggesting a possible biological deficiency in these individuals.