Manish Butte

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.

May 4, 2018 By Manish Butte

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.

J Neuroinflammation. 2017 Aug 04;14(1):156

Authors: Xu D, Lian D, Wu J, Liu Y, Zhu M, Sun J, He D, Li L

Abstract
BACKGROUND: Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo.
METHODS: In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay.
RESULTS: Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-κB-signaling pathway.
CONCLUSIONS: These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-κB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis.

PMID: 28778220 [PubMed – indexed for MEDLINE]

Flucloxacillin Results in Suboptimal Plasma Voriconazole Concentrations.

May 3, 2018 By Manish Butte

Flucloxacillin Results in Suboptimal Plasma Voriconazole Concentrations.

Antimicrob Agents Chemother. 2017 Sep;61(9):

Authors: Muilwijk EW, Dekkers BGJ, Henriet SSV, Verweij PE, Witjes B, Lashof AMLO, Groeneveld GH, van der Hoeven J, Alffenaar JWC, Russel FGM, van de Veerdonk F, Brüggemann RJM

Abstract
Combining voriconazole and flucloxacillin is indicated in patient cohorts experiencing both invasive aspergillosis and Gram-positive infections (e.g., patients with chronic granulomatous disease or postinfluenza pulmonary aspergillosis). We report a highly relevant interaction between voriconazole and flucloxacillin, resulting in subtherapeutic plasma voriconazole concentrations in more than 50% of patients, that poses a severe threat if not managed properly.

PMID: 28717040 [PubMed – indexed for MEDLINE]

Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model.

May 2, 2018 By Manish Butte

Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model.

J Clin Invest. 2018 May 01;:

Authors: Gao JL, Yim E, Siwicki M, Yang A, Liu Q, Azani A, Owusu-Ansah A, McDermott DH, Murphy PM

Abstract
For gene therapy of gain-of-function autosomal dominant diseases, either correcting or deleting the disease allele is potentially curative. To test whether there may be an advantage of one approach over the other for WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) syndrome – a primary immunodeficiency disorder caused by gain-of-function autosomal dominant mutations in chemokine receptor CXCR4 – we performed competitive transplantation experiments using both lethally irradiated wild-type (Cxcr4+/+) and unconditioned WHIM (Cxcr4+/w) recipient mice. In both models, hematopoietic reconstitution was markedly superior using bone marrow (BM) cells from donors hemizygous for Cxcr4 (Cxcr4+/o) compared with BM cells from Cxcr4+/+ donors. Remarkably, only ~6% Cxcr4+/o hematopoietic stem cell (HSC) chimerism post-transplantation in unconditioned Cxcr4+/w recipient BM supported >70% long-term donor myeloid chimerism in blood and corrected myeloid cell deficiency in blood. Donor Cxcr4+/o HSCs differentiated normally and did not undergo exhaustion as late as 465 days post-transplantation. Thus, disease allele deletion resulting in Cxcr4 haploinsufficiency was superior to disease allele repair in a mouse model of gene therapy for WHIM syndrome, allowing correction of leukopenia without recipient conditioning.

PMID: 29715199 [PubMed – as supplied by publisher]

High Incidence of Severe Combined Immunodeficiency Disease in Saudi Arabia Detected Through Combined T Cell Receptor Excision Circle and Next Generation Sequencing of Newborn Dried Blood Spots.

May 2, 2018 By Manish Butte

High Incidence of Severe Combined Immunodeficiency Disease in Saudi Arabia Detected Through Combined T Cell Receptor Excision Circle and Next Generation Sequencing of Newborn Dried Blood Spots.

Front Immunol. 2018;9:782

Authors: Al-Mousa H, Al-Dakheel G, Jabr A, Elbadaoui F, Abouelhoda M, Baig M, Monies D, Meyer B, Hawwari A, Dasouki M

Abstract
Severe combined immunodeficiency disease (SCID) is the most severe form of primary immunodeficiency disorders (PID). T-cell receptor excision circle (TREC) copy number analysis is an efficient tool for population-based newborn screening (NBS) for SCID and other T cell lymphopenias. We sought to assess the incidence of SCID among Saudi newborn population and examine the feasibility of using targeted next generation sequencing PID gene panel (T-NGS PID) on DNA isolated from dried blood spots (DBSs) in routine NBS programs as a mutation screening tool for samples with low TREC count. Punches from 8,718 DBS collected on Guthrie cards were processed anonymously for the TREC assay. DNA was extracted from samples with confirmed low TREC count, then screened for 22q11.2 deletion syndrome by real-time polymerase chain reaction and for mutations in PID-related genes by T-NGS PID panel. Detected mutations were confirmed by Sanger sequencing. Sixteen out of the 8,718 samples were confirmed to have low TREC copy number. Autosomal recessive mutations in AK2, JAK3, and MTHFD1 were confirmed in three samples. Two additional samples were positive for the 22q11.2 deletion syndrome. In this study, we provide evidence for high incidence of SCID among Saudi population (1/2,906 live births) and demonstrate the feasibility of using T-NGS PID panel on DNA extracted from DBSs as a new reliable, rapid, and cost-effective mutation screening method for newborns with low TREC assay, which can be implemented as part of NBS programs for SCID.

PMID: 29713328 [PubMed]

Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management.

May 2, 2018 By Manish Butte

Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management.

Hum Immunol. 2018 Apr 27;:

Authors: Vince N, Mouillot G, Malphettes M, Limou S, Boutboul D, Guignet A, Bertrand V, Pellet P, Gourraud PA, Debré P, Oksenhendler E, Théodorou I, Fieschi C, DEFI Study Group

Abstract
The precise diagnosis of an immunodeficiency is sometimes difficult to assess, especially due to the large spectrum of phenotypic variation reported among patients. Common variable immunodeficiency disorders (CVID) do not have, for a large part, an identified genetic cause. The identification of a causal genetic mutation is important to confirm, or in some cases correct, the diagnosis. We screened >150 male patients with hypogammaglobulinemia for mutations in three genes involved in pediatric X-linked primary immunoglobulin deficiency: CD40LG, SH2D1A and BTK. The SH2D1A screening allowed to reclassify two individuals with an initial CVID presentation as XLP after mutations identification. All these mutations were associated with a lack of protein expression. In addition, 4 patients with a primary diagnosis of CVID and one with a primary IgG subclass deficiency were requalified as XLA after identifying BTK mutations. Interestingly, two out of these 5 patients carried a damaging coding BTK mutation associated with a lower, but detectable, BTK expression in monocytes, suggesting that a dysfunctional protein explains the disease phenotype in these patients. In conclusion, our results advocate to include SH2D1A and BTK in newly developed targeted NGS genetic testing, to contribute to providing the most appropriate medical treatment and genetic counselling.

PMID: 29709555 [PubMed – as supplied by publisher]

Chronic Mucocutaneous Candidosis due to Gain-of-Function Mutation in STAT1.

April 28, 2018 By Manish Butte

Chronic Mucocutaneous Candidosis due to Gain-of-Function Mutation in STAT1.

Oral Dis. 2018 Apr 27;:

Authors: Carey B, Lambourne J, Porter S, Hodgson T

Abstract
Chronic mucocutaneous candidiasis (CMC) is a heterogenous group of primary immunodeficiency diseases characterised by susceptibility to chronic or recurrent superficial Candida infection of skin, nails and mucous membranes. Gain-of-function mutations in the STAT1 gene (STAT1-GOF) are the most common genetic aetiology for CMC, and mutation analysis should be considered. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17), which, depending on the mutation, also predispose to infection with Staphylococci, Mycobacteria & Herpesviridae. We describe the clinical and genetic findings for three patients with CMC due to gain-of-function mutations in the STAT1 gene. This article is protected by copyright. All rights reserved.

PMID: 29702748 [PubMed – as supplied by publisher]

Primary pulmonary amebic abscess in a patient with pulmonary adenocarcinoma: a case report.

April 28, 2018 By Manish Butte

Primary pulmonary amebic abscess in a patient with pulmonary adenocarcinoma: a case report.

Infect Dis Poverty. 2018 Apr 27;7(1):34

Authors: Liu YY, Ying Y, Chen C, Hu YK, Yang FF, Shao LY, Cheng XJ, Huang YX

Abstract
BACKGROUND: Primary pulmonary amoeba is very rare and here we report a case of a 68-year-old man presenting with primary pulmonary amoeba after undergoing chemotherapy for lung adenocarcinoma.
CASE PRESENTATION: In October 2016, the man aged 68 was admitted to our hospital because of repeated cough for 8 months and hemoptysis for 1 month. He was diagnosed lung adenocarcinoma and underwent surgery in 2012 without receiving chemotherapy. In March 2016, the patients suffered recurrence of cancer and was treated with chemotherapy. After 2 months of chemotherapy, the patient had consistent cough with white sputum, and chest CT showed a local lung nodule. The physicians suspected that the patient had pulmonary infectious diseases, and he was treated with empirical antibacterial treatment. However, his symptom wasn’t relieved and later the percutaneous lung biopsy found trophozites of Entamoeba histolytica. After administration of metronidazole, the symptoms of the patient were markedly relieved and the lesions were absorbed.
CONCLUSIONS: In such cases where patients with pulmonary nodules were in immunodeficiency state and had adequate but ineffective anti-bacterial treatment, Entamoeba histolytica infection could be one of the rare causes. Percutaneous lung biopsy should be recommended and specific dying for parasites should be done when necessary.

PMID: 29699585 [PubMed – in process]

An evaluation of the budget impact of a new 20% subcutaneous immunoglobulin (Ig20Gly) for the management of primary immunodeficiency diseases in Switzerland.

April 26, 2018 By Manish Butte

An evaluation of the budget impact of a new 20% subcutaneous immunoglobulin (Ig20Gly) for the management of primary immunodeficiency diseases in Switzerland.

Clinicoecon Outcomes Res. 2018;10:223-229

Authors: Pollock RF, Meckley LM

Abstract
Introduction: While most individual primary immunodeficiency diseases (PID) are rare, the collective prevalence of PID results in a substantial economic and clinical burden. The aim of this study was to evaluate the budgetary implications of Ig20Gly (Immune Globulin Subcutaneous [human] 20% solution; CUVITRU ® , Baxalta US Inc, now part of Shire Plc, Westlake Village, CA, USA) as a treatment for PID relative to intravenous immunoglobulin (IVIG) and other subcutaneous immunoglobulin (SCIG) formulations in the Swiss health care setting.
Materials and methods: A budget impact model was developed in Microsoft Excel to capture the estimated prevalence of PID in Switzerland, the proportion of patients treated in different health care settings, and the costs of administering SCIG and IVIG in each setting. Unit costs were based on a recent cost-minimization analysis of SCIG in Lausanne, and drug costs were taken from the Spezialitätenliste. All costs were reported in 2016 Swiss Francs (CHF), and future costs were not discounted.
Results: The total cost of treating PID in Switzerland was estimated to be CHF 11.16 m over 3 years, comprising CHF 9.28 m of drug costs and CHF 1.87 m of ancillary costs, including health care professional time and other administration costs, such as pumps and needle sets. The analysis showed that using Ig20Gly in place of other SCIG formulations would be cost neutral, while using Ig20Gly in place of IVIG would result in savings of 4.0%.
Conclusion: Ig20Gly would be cost neutral relative to existing SCIG products and would result in cost savings relative to IVIG in patients with PID in Switzerland, even with modest uptake.

PMID: 29692618 [PubMed]

Diffuse large B-cell lymphoma chemotherapy reveals a combined immunodeficiency syndrome in cartilage hair hypoplasia.

April 25, 2018 By Manish Butte

Diffuse large B-cell lymphoma chemotherapy reveals a combined immunodeficiency syndrome in cartilage hair hypoplasia.

Swiss Med Wkly. 2018 Apr 24;148:w14606

Authors: Ngyen A, Martin Silva N, de Boysson H, Damaj G, Aouba A

Abstract
Cartilage hair hypoplasia (CHH) is a rare autosomal recessive ribosomopathy characterised by skeletal and integumentary system manifestations. It may also present with varied forms and intensities of haematopoietic and/or immune disorders. We report a 27-year-old female who presented a picture of combined immunodeficiency after receiving an adriamycin-based chemotherapy regimen followed by autologous stem cell transplantation. Her medical history indicated neonatal dwarfism, recurrent ear, nose and throat and respiratory infections, and hypogammaglobulinaemia, which were suggestive of a primary minor B-cell immune deficiency. Taken together, the diagnosis of cartilage hair hypoplasia was suspected and confirmed by means of molecular biological analysis. Here, we discuss the causal relationship and molecular mechanisms existing between both primary immunodeficiency and lymphoma conditions and between chemotherapy cytotoxicity and aggravation of the immune system and associated hematopoietic dysfunction, considering the role of all these components in light of the initially undiagnosed cartilage hair hypoplasia. Finally, this case highlights the importance of screening for primary immunodeficiencies in the setting of a diagnosis of lymphoma and/or dwarfism; moreover, CHH must be distinguished from other causes of small size; its diagnosis and complete check-up must include the molecular characterisation, and its management must be global in collaboration with haematologists, immunologists and internists.

PMID: 29688570 [PubMed – in process]

Takayasu arteritis in childhood: misdiagnoses at disease onset and associated diseases.

April 25, 2018 By Manish Butte

Takayasu arteritis in childhood: misdiagnoses at disease onset and associated diseases.

Rheumatol Int. 2018 Apr 23;:

Authors: Clemente G, Silva CA, Sacchetti SB, Ferriani VPL, Oliveira SK, Sztajnbok F, Bica BERG, Cavalcanti A, Robazzi T, Bandeira M, Terreri MT

Abstract
Juvenile-Takayasu arteritis (j-TA) is a difficult diagnosis and some patients develop uncommon manifestations and associated diseases that may contribute to the delayed diagnosis. Our aim was to identify the misdiagnoses, the associated diseases and the atypical manifestations observed in a j-TA Brazilian multicentre study. 71 children and adolescents who met the classification criteria for j-TA were included. The misdiagnoses, the associated diseases and the atypical manifestations were evaluated. 19 (26.8%) patients had misdiagnoses. The most common of them was aortic coarctation in six (8.4%) patients, followed by rheumatic fever in five (7.0%) and one patient presented with both former diagnoses. Limb pain (two patients), spondyloarthropathy, juvenile idiopathic arthritis (JIA), spinal arteriovenous malformation, polyarteritis nodosa (PAN) and fever of unknown origin (FUO) were other misdiagnoses. Patients who had misdiagnoses previously to j-TA diagnosis presented a trend to have a longer diagnosis delay. 11 (15.5%) patients had 14 TA-associated diseases, such as pulmonary tuberculosis (5 patients), rheumatic fever (2 patients), spondyloarthropathy, polyarticular JIA, Crohn’s disease, Prader-Willi disease, diabetes mellitus, Moyamoya and primary immunodeficiency. 7 (9.9%) patients presented 10 atypical manifestations, such as pyoderma gangrenosum, erythema nodosum, myositis, chorea, enthesitis, episcleritis, uveitis, hepatomegaly, splenomegaly and necrosis of extremities. Our study emphasizes the main misdiagnoses, associated diseases and atypical manifestations that occur in patients with j-TA and warns of the features that may alert paediatricians to this diagnosis, such as constitutional symptoms and elevated inflammatory markers.

PMID: 29687155 [PubMed – as supplied by publisher]