The airways of cystic fibrosis (CF) patients with chronic Pseudomonas Selumetinib in vivo aeruginosa infection represent a complex environment which shapes evolution of the bacteria (Yang et al., 2011). The complexity of the environment is due to differences in the inflammatory process and antibiotic penetration in the

different focal areas of infection which occur in the compartments of the respiratory tree: paranasal sinuses, are conductive and respiratory zones where the bacteria form biofilms (Bjarnsholt et al., 2009; Hoiby et al., 2010). The biofilm mode of growth is the main reason for the failure of antibiotic treatment to eradicate airway infection, allowing the bacteria to persist for decades in the CF lung. It has been shown that P. aeruginosa might survive in the CF lung for more than 200 000 generations, during which evolution through adaptive mutagenesis occurs (Yang et al., 2011). The biofilm mode of growth has been shown to play an important role in the evolution of bacterial diversification (Boles & Singh, 2008). Oxidative stress has been shown to trigger the diversification process both inside (Boles & Singh, 2008; Driffield et al., 2008; Conibear et al., 2009) and outside the biofilm due to inflammation and antibiotic treatment (Ciofu et al., 2005; Kohanski et al.,

2007). As a consequence of bacterial evolution in the CF airways, P. aeruginosa CF strains often exhibit remarkable phenotypic diversity, as documented from the appearance of multiple colony morphology variants, including the mucoid phenotype, the development of hypermutability Selleck KPT 330 and various degree of antimicrobial resistance (Doggett, 1969; Hoiby, 1977; Ciofu et al., 1994; Oliver et al., 2000). It has been proposed that this diversity is associated with specialized adaptation

to the different compartments in the CF airways (Bjarnsholt et al., 2009; Hassett et al., 2010; Mowat et al., 2011). The tolerance of biofilms to antibiotics is a physiological condition that does not involve mutations in resistance genes and allows the bacteria to survive, but not necessarily grow, in the presence of antibiotic concentrations above their planktonic minimal inhibitory concentration (MIC) (Ciofu & Tolker-Nielsen, 2011). Recent research has shown that biofilm tolerance DNA ligase is multifactorial, involving restricted penetration, differential metabolic/physiological activity in bacterial subpopulations of biofilms, presence of persisters and activation of biofilm-specific genes (Fux et al., 2005; Williamson et al., 2012). Here we address the question of how the antibiotic tolerance of biofilms is affected by mucoidy, hypermutability and antibiotic resistance of planktonic cells, based on in vitro investigations. A discussion of the therapeutic recommendations in light of the in vitro results is presented.

The previous study had shown that GT inhibited human organic anion transporting polypeptides (OATPs). Moreover, Epigallocatechin-3-gallate (EGCG), a major catechins derivative, Sirolimus decreased P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) expressions

and functions. Our preliminary study demonstrated that GT could inhibit transport of [3H]MPP+ (1-methyl-4-phenylpyridinium), a prototypical organic cation, in rat renal slices. There is no evidence whether consumption of green tea during cationic drugs treatment interfere with drug efficiency and drug secretion. Therefore, the present study aimed to elucidate the interaction of GT and its catechins on a major renal basolateral organic cation transporter, OCT2. Methods: The uptake of [3H] https://www.selleckchem.com/products/VX-765.html MPP+

was measured in the second segment of the renal proximal tubule (S2) cells stably expressing human OCT2 (S2-hOCT2) and rat Oct2 (S2-rOct2) in the presence of GT and its catechins. The IC50 values of GT and catechins were determined. Results: GT and (-)epicatechin-3-gallate (ECG), but not EGCG inhibited the OCT2-mediated [3H]MPP+ transport with IC50 values higher than 1 mg/ml and 1 mM, respectively, in S2-hOCT2 and S2-rOct2. This IC50 values were higher than the plasma concentration of catechins in daily tea consumption. Conclusion: The weak interaction of GT and its catechins with renal organic cation transporter OCT2 indicates that consumption of green tea beverage or catechins supplements does not interfere PDK4 with therapeutic organic cationic drugs that secreted via OCT2 in kidney. MINATOGUCHI SHUN1,2, OZEKI TOSHIKAZU1,2, WARTANABE MITSURU1,2, MURAI YUKARI1,2, KAWATO RUI1,2, RYUGE AKIHIRO1,2, OZEKI TAKAYA1,2, KIDA TAKASHI1,2,

OYAMA YUKAKO1,2, HAMADA TAKUYA3, NOMURA ATSUSHI1,2, TOMINO TATSUHITO1,2, SHIMIZU HIDEAKI1,2, FUJITA YOSHIROU1,2 1Chubu-Rosai Hospital, Nephrology; 2Chubu-Rosai Hospital, Rheumatology; 3Chubu-Rosai Hospital, Internal Medicine Introduction: We report the case of myoglobin-induced acute kidney injury(AKI) caused by compartment syndrome(CS) after percutaneous cardiopulmonary support(PCPS) applied to deal with cardiac arrest secondary to acute myocardial infarction (AMI) and massive gastrointestinal hemorrhage due to cytomegalo-virus (CMV) colitis. Methods & Results: A 34-year-old man went into cardiac arrest due to AMI, and we conducted PCI and PCPS. The right external iliac artery was damaged by accident during cannulation and we performed massive blood transfusion and fluid infusion (more than 20 L) for treating the massive hemorrhage. On the day of admission, ischemic symptoms developed in his left lower limb after PCPS use. He was diagnosed as having CS of the left lower limb because of highly elevated compartment pressure. On the 2nd day, he had anuria caused by myoglobin-induced AKI and we started hemodialysis. On the 6th day, liver functions were abnormal. On the 13th day, massive melena developed and he required blood transfusions.

However, presence of diffuse axonal expression of

Nav1.6 was more frequent within plaques with T cells infiltrate and microglial hyperplasia. On the other hand, Nav1.2 diffuse axonal expression seemed Autophagy activator to be independent of the neuropathological environment of the plaque. The cellular environment of the axon influences the differential expression of Nav channels. A better understanding of the influence of the inflammation on sodium channels mediated axonal degeneration could offer therapeutic perspectives. “
“This study was aimed to assess whether bone marrow stromal cells (BMSC) could ameliorate brain damage when transplanted into the brain of stroke-prone spontaneously hypertensive rats (SHR-SP). The BMSC or vehicle was stereotactically engrafted into the striatum of male SHR-SP at 8 weeks of age. Daily loading with 0.5% NaCl-containing water was started from 9 weeks. MRIs and histological analysis were performed at 11 and 12 weeks, respectively. Wistar-Kyoto

rats were employed as the control. As a result, T2-weighted images demonstrated neither cerebral infarct nor intracerebral hemorrhage, but identified abnormal dilatation of the lateral ventricles in SHR-SP. HE staining demonstrated selective neuronal injury in their neocortices. Double fluorescence immunohistochemistry revealed that they had a decreased density of the collagen IV-positive microvessels and a decreased number of the microvessels Erlotinib datasheet with normal integrity between basement membrane and astrocyte end-feet. BMSC transplantation significantly ameliorated the ventricular dilatation and the breakdown of neurovascular integrity. These findings strongly suggest that long-lasting hypertension may primarily damage neurovascular integrity and neurons, leading to tissue atrophy and ventricular dilatation prior to the occurrence of cerebral stroke. The BMSC may ameliorate these damaging processes when directly transplanted into the brain, opening the possibility of prophylactic Chorioepithelioma medicine to prevent microvascular

and parenchymal-damaging processes in hypertensive patients at higher risk for cerebral stroke. “
“S. L. Rankin, G. Zhu and S. J. Baker (2012) Neuropathology and Applied Neurobiology38, 254–270 Insights gained from modelling high-grade glioma in the mouse High-grade gliomas (HGGs) are devastating primary brain tumours with poor outcomes. Advances towards effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches.

Methods: Using Western analysis and immunohistochemistry

we evaluated post mortem frontal cerebral cortex from patients with severe AD (mean age 76 years, range 66–91, n = 11, all male), and from control cases without serious central nervous system illness (mean age 77 years, range 61–95, n = 12, all male). We also examined brains of Tg2576 transgenic mice (males, aged 16–21 months), a model for chronic amyloid-induced brain injury. Results: Immunohistochemical labelling showed DAPK1 expression in cortical neurones of human cortex and axonal tracts within subcortical white matter, both in AD and in control PF-6463922 mouse brains. Western analysis confirmed DAPK1 expression in all samples, although expression was very low in some control cases. DAPK1 abundance in the AD group was not significantly different from that in controls (P = 0.07, Mann–Whitney test). In brains of Tg2576 mice DAPK1 abundance was very similar to that in wild-type littermates (P = 0.96, Mann–Whitney test). Conclusion: We found that DAPK1 was expressed in neurones of aged human frontal cortex,

both in AD and in control cases. “
“Recent evidence has placed MAPK Inhibitor Library cost the unfolded protein response (UPR) at the centre of pathological processes leading to neurodegenerative disease. The translational repression caused by UPR activation starves neurons of the essential proteins they need to function and survive. Restoration of protein synthesis, via genetic Methamphetamine or pharmacological means is neuroprotective in animal models, prolonging survival. This is of great interest due to the observation of UPR activation in the post-mortem brains of patients with Alzheimer’s, Parkinson’s, tauopathies and prion diseases. Protein synthesis is also an

essential step in the formation of new memories. Restoring translation in disease or increasing protein synthesis from basal levels has been shown to improve memory in numerous models. As neurodegenerative diseases often present with memory impairments, targeting the UPR to both provide neuroprotection and enhance memory provides an extremely exciting novel therapeutic target. “
“R. Paudel, J. Hardy, T. Revesz, J. L. Holton and H. Houlden (2012) Neuropathology and Applied Neurobiology38, 520–534 Genetics and neuropathology of primary pure dystonia Neuropathology has been the key to understanding the aetiology of many neurological disorders such as Alzheimer’s disease, Parkinson’s disease, frontotemporal degeneration and cerebellar ataxias.

major-vaccinated mice. IL-6 treatment also resulted in a decrease of IFN-γ expressing CD4+CD25lo/med T cells (effector Th1 cells in our system 16) (Fig. 2B). As before, IL-6 neutralization also significantly increased the number of CD25hi IL-10+ T cells (Treg in our system 11, 16) (Supporting Information Fig. 1). These data demonstrate that vaccine-induced IL-6 modulates the development of Th17 cells in the Lm/CpG-vaccinated mice. They also suggest that Th17 cells are required for the recruitment or development of Th1 responses. To determine whether Th17 cells have a role in early parasite killing in Lm/CpG-vaccinated animals, we treated mice with anti IL-17 and/or anti IFN-γ neutralizing antibodies (or isotype

control), and examined the frequency of IL-17, IFN-γ-producing cells, and Treg during the selleck chemicals “silent” phase (wk 2). Antibody treatment decreased the frequency of CD4+ T cells in Lm/CpG-vaccinated animals, but did not significantly affect the frequency of CD4+ T cells in the dermis of L. major-vaccinated animals at wk 2 (Supporting Information Fig. 2); in this case, it is possible that the low frequency of Th1 and Th17 cells in the ears of the latter mice did not allow detecting any differences cause by treatment. As expected, parasite burden was high at wk 2 in L. major-vaccinated animals (>1.5×105 parasites per ear, Fig. 3A), and significantly reduced (fivefold) in

mice vaccinated with Lm/CpG. Neutralization of either anti IL-17 and/or anti IFN-γ did not produce an increase in parasite killing in the L. major-vaccinated group. This was expectable because the number of cytokine positive cells in these mice is very low at wk 2. In contrast, SAHA HDAC neutralization of IL-17 increased parasite burden in the ears of Lm/CpG-vaccinated mice by tenfold. Similarly, neutralization of IFN-γ or IL-17 plus IFN-γ increased parasite numbers by fivefold, suggesting that both IL-17 and IFN-γ are required for the control of parasite expansion after Lm/CpG vaccination. Differences among antibody-treated groups were not statistically significant. Parasite growth was associated

with an expansion in the number of Treg. Figure 3B shows that the absolute number of Treg significantly increased following antibody Carbachol treatments in the Lm/CpG-vaccinated group. The increased frequency of Treg may have also contributed to the expansion in parasite numbers. No additive effect was found when the two cytokines were neutralized at the same time, suggesting that the production of the cytokines may be sequential. We immunized IL-17-receptor-deficient mice (IL-17R−/−) and WT C57BL/6 with the live vaccines. As expected, WT mice vaccinated with Lm/CpG did not develop leishmaniasis, and L. major-vaccinated mice did (Fig. 4A). Disease pathology was slightly accelerated in L. major-vaccinated IL-17R−/− mice. Most importantly, IL-17R−/− mice immunized with Lm/CpG developed large lesions, further indicating that IL-17 is involved in protection.

These results demonstrate the beneficial role of Emodin in attenuating the LPS-induced

microcirculatory disturbance, and support the use of Emodin for patients with endotoxemia. “
“Please cite this paper as: Correa D, Segal SS(2012). Neurovascular AZD9291 cell line proximity in the diaphragm muscle of adult mice. Microcirculation 19: 306–315, 2012. Objective:  Regional blood flow to the diaphragm muscle varies with the workload of inspiration. To provide anatomical insight into coupling between muscle fiber recruitment and oxygen supply, we tested whether arterioles are physically associated with motor nerve branches of the diaphragm. Methods:  Following vascular casting, intact diaphragm muscles of C57BL/6 and CD-1 mice were stained for motor innervation. Arteriolar networks and nerve networks were mapped (∼2 μm resolution) to evaluate their physical proximity. Results:  Neurovascular proximity was similar between muscle regions and mouse strains. Of total mapped

nerve lengths (C57BL/6, 70 ± 15 mm; CD-1, 87 ± 13 mm), 80 ± 14% and 67 ± 10% were ≤250 μm from the nearest arteriole and associated predominantly with arterioles ≤45 μm in diameter. Distances to the nearest arteriole encompassing 50% of total nerve length (D50) were consistently within 200 μm. With nerve networks repositioned randomly within muscle borders, D50 values nearly doubled (p < 0.05). Reference lines within anatomical boundaries reduced proximity to arterioles (p < 0.05) as they deviated from the original location of motor nerves. Conclusion:  Across Ku-0059436 price two strains of mice, motor nerves and arterioles of the diaphragm muscle are more closely associated than can be explained by chance. We hypothesize that neurovascular proximity facilitates local perfusion Avelestat (AZD9668) upon muscle fiber recruitment. “
“The mechanical forces acting on SMC in the vascular wall are known to regulate processes such as vascular remodeling and contractile differentiation. However,

investigations to elucidate the underlying mechanisms of mechanotransduction in smooth muscle have been hampered by technical limitations associated with mechanical studies on pressurized small arteries, due primarily to the small amount of available tissue. The murine portal vein is a relatively large vessel showing myogenic tone that in many respects recapitulates the properties of small resistance vessels. Studies on stretched portal veins to elucidate mechanisms of mechanotransduction in the vascular wall have shown that stretch-sensitive regulation of contractile differentiation is mediated via Rho-activation and actin polymerization, while stretch-induced growth is regulated by the MAPK pathway. In this review, we have summarized findings on mechanotransduction in the portal vein with focus on stretch-induced contractile differentiation and the role of calcium, actin polymerization and miRNAs in this response.

However, these purification techniques can lead to a loss of specific subsets or result in some activation due to the reagents used and hence introduce artefacts. Recently, a whole blood (WB) stimulation

assay was developed to study TLR-mediated activation of human peripheral blood DC [29]. Subsequent staining with a panel of monoclonal antibodies (mAb) to discriminate the pDC and mDC subsets in combination with either CD83, CD80 maturation markers or tumour necrosis factor (TNF)-α, IL-12, IFN-α intracellular cytokines allowed for simultaneous selleck products analysis of the response in these defined subsets upon stimulation [29]. In this study we performed this assay to study DC function in peripheral blood of rhesus macaques in a direct comparison with whole blood samples of human volunteers. Surprisingly, we observed that pDC in macaques express IL-12p40 upon TLR-7/8 stimulation, in contrast to human pDC exposed to the same ligand. Similar results were obtained following TLR-9 [cytosine–phosphate–guanosine (CpG-C)] stimulation, while TLR-4 [lipopolysaccharide (LPS)] did not induce IL-12p40 expression in pDC, in agreement with reported TLR

expression profiles [25]. Induction of IL-12p40 expression was confirmed further by polymerase chain reaction (PCR) using purified fluorescence activated cell sorted (FACS) pDC. Our results show that in rhesus macaques pDC in peripheral blood express

Dabrafenib molecular weight IL-12p40 upon TLR-7/8 and TLR-9 stimulation, which could potentially affect their response to vaccination and viral infection. This study was performed in mature captive-bred Indian origin rhesus monkeys (Macaca mulatta) that were housed at the Biomedical Primate Research Center, Rijswijk, the Netherlands. All procedures were in accordance with the why international guidelines for non-human primate care and use (The European Council Directive 2010/63/EU and Convention ETS 123, including the revised Appendix A). The Institutional Animals Care and Use Committee (DEC-BPRC) approved the study protocols developed according to strict international ethical and scientific standards and guidelines. Human peripheral blood was obtained from informed healthy volunteer donors via the Netherlands Red Cross Blood Bank. The following mAb were used; CD20V450 (clone L27), CD45V500 (clone TU116), CD3FITC (clone SP34), CD16FITC (clone 3G8), CD80PE (clone L307·4), anti-IL12p40/70PE (clone C11·5), anti-TNF-αPE (clone Mab11), CD123PerCP-Cy5 (clone 7G3), CD11cAPC (clone S-HCL3), anti-TNF-αPE-Cy7 (clone Mab11) and HLA-DRAPC-CY7 (clone L243), all from Becton Dickinson (San Jose, CA, USA), CD8FITC (clone DK25; Dako, Glostrup, Denmark), CD14PE-TxRed (clone RM052; Beckman Coulter, Brea, CA, USA), IL-12p40/70PE (clone C8·6; Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) and CD83PE (clone HB15a; Beckman Coulter).

706, 95%CI 0.43–0.861; P < 0.001). In all subjects, the greatest expression of CCR4 was found on CD14++ CD16+ PBMs. Expansion of CD14++ CD16+ monocytes in the peripheral blood with subsequent mobilization of those cells after allergen challenge may facilitate the

development of AHR in Dp-APs. In the respiratory system, mononuclear phagocytes play an important role in the regulation of the inflammatory response to antigen challenge [1, 2]. Alveolar macrophages (AMs) of asthmatic patients are characterized by a decreased inhibitory effect on T cell proliferation [2]. Moreover, in animal asthma models, AMs have been shown GSI-IX in vivo to play a role in the development of asthma and airway hyper responsiveness (AHR) [3]. Peripheral blood monocytes (PBMs) migrate to the peripheral tissues spontaneously and in response to inflammatory mediators [4, 5]. Different chemotactic factors and different receptors are responsible for the spontaneous migration and stimulated extravasation of monocytes [4, 5]. Application of different monoclonal antibodies demonstrated that PBMs represent a heterogeneous population of cells differing in expression www.selleckchem.com/products/pexidartinib-plx3397.html of surface receptors and in profile of secreted mediators [4]. When PBMs are divided according to their expression of the lipopolysaccharide receptor CD14 and the low affinity immunoglobulin G

receptor CD16, three major subpopulations can be distinguished [6, 7]. Those include CD14++ CD16− PBMs also referred to as ‘classical’ CHIR-99021 mw monocytes, CD14++ CD16+ PBMs called ‘intermediate’ monocytes and CD14+ CD16++ PBMs called ‘non-classical’ monocytes [7]. The CD14++ CD16+ PBMs express high level of CD163

and at least under certain conditions may release predominantly anti-inflammatory mediators such as interleukin-10 (IL-10) [6, 8]. However, other laboratories demonstrated strong pro-inflammatory potential of those cells [9]. Moreover, analysis of gene expression profiles demonstrated that CD14++ CD16+ cells express many mediators crucial for tissue remodelling and angiogenesis indicating potential role of CD14++ CD16+ cells in those processes [10]. Therefore, quantitative differences in the number of PBM subsets infiltrating peripheral tissues may affect the outcome of the inflammatory response [11]. We have already demonstrated that in asthmatic patients, elevated numbers of CD14++ CD16+ PBMs are found being the greatest in patients with severe asthma [6]. However, glucocorticoid therapy preferentially affects the number of circulating non-classical monocytes. During systemic glucocorticoid therapy of asthma exacerbation, clinical improvement was associated with decrease in the number of CD14+ CD16++ PBMs [6]. Allergic asthma patients exposed to a relevant allergen develop immediate bronchoconstriction [early asthmatic reaction (EAR)], which usually lasts <60 min and is dependent on mediators secreted by mast cells [12].

Pathogenic bacteria are those that are harmful to the host. TAM Receptor inhibitor Microbial biofilm communities on the subgingival tooth surfaces subjacent to the gingival tissues are composed of approximately 700 species [8,14]. The microbial ecology of the subgingival environments of periodontally healthy and periodontally diseased sites are distinct [6,8,14]. Accumulation of tooth-associated bacterial biofilm (plaque) elicits gingival inflammation as a result of bacterial virulence factors and vascular dilation. In sites colonized by

pathogen-dominated biofilms the inflammatory response results in destruction of connective tissue and alveolar bone, the classic features of periodontitis. The tissue destruction is actually a result of the host response elicited by the pathogens, rather than direct toxic/noxious actions

of the bacterial virulence factors [15,16]. The immune system is comprised of both innate and adaptive immune responses that are used to manage bacterial infections. The adaptive immune response results from a cognate interaction of receptors on immune cells engaging antigens as ligands, resulting in the initiation of cell-mediated and/or https://www.selleckchem.com/products/jq1.html humoral immune responses. Antigenic triggering of immunoglobulin receptors on B cells leads to maturation and differentiation into plasmacytes that produce antibody are the effector molecules of humoral immunity [16,17]. Important to the objectives of this project, the host oral cavity is colonized routinely by a range of commensal bacteria, as well as a varied number of potentially pathogenic species. While these bacteria all represent ‘non-self’, it remains

unclear how the immune system differentiates commensals that are important to maintain for health from those bacteria with greater virulence capabilities [8]. It has been suggested that the immune system has the ability to recognize commensal bacteria differently from pathogens, thus leading to heptaminol a different type of immune response [13,17,18]. However, the details of these characteristics, specifically with regard to the oral cavity, remain to be determined. Various environmental factors affect the microbial composition in the oral cavity, as well as the host response. While smoking is a well-recognized risk factor for periodontal attachment loss, smokers often exhibit less gingival bleeding than would be predicted [19]. This is due probably to effects of the toxic cigarette chemicals on the local vascular functions [19,20]. Minimal data are available to compare the potential effect of smoking on the immune system discrimination of commensals from pathogenic oral bacteria. Data analysis was performed to address two central objectives for the study: (i) to determine the level of immunoglobulin (Ig)G antibody to periodontal pathogens and oral commensal bacteria in smokers; and (ii) to determine how antibody responses are affected by the extent of smoking and degree of periodontal disease.

To our knowledge, this is the first case in which this mutation is spontaneously reversed in vivo in an ADA-deficient see more patient. Interestingly, it has been demonstrated in vitro that this mutation results in almost no ADA activity and correlates well with the severity of the disease [5]. Our patient showed severe lymphopenia from the age of 1 month and developed a neonatal life-threatening severe infection, showing that this mutation had a causative effect in the phenotype observed initially. Moreover our patient continued

to suffer from recurrent and chronic infections that eventually led to failure to thrive as well as organ damage. However, he survived past 4 years only with antimicrobials and IVIG; therefore, the progressive retention of ADA activity in the revertant cells not only increased his T cell counts in time (although we did not observe lymphoproliferation to PHA), but also ameliorated his clinical condition. This is in contrast to other revertant patients in which their mutations have been associated with a milder phenotype from the initial diagnosis, making it difficult

to establish the actual contribution of the somatic reversion to the phenotypes [20,13]. Revertant somatic mosaicism leading to unusual phenotypes continues to be reported in the literature suggesting that these events might be more common than initially considered. In these patients, the reversions resulted from multiple mechanisms (reviewed in [21]), however back mutations like the one found in our patient, are most likely random and may reflect an increased mutation check details rate because of the accumulation of mutagenic metabolites [22]. As our patient was not eligible for HSCT or GT, we placed him on ERT with PEG-ADA at the age of 50 months. However, we believe that the impact of this therapy Ergoloid was marginal because although his clinical condition improved during the first months (gain of weight and less severe and frequent infections), he also developed sclerosing cholangitis just after

2 months of ERT, a complication linked to opportunistic infections with protozoa in patients with other PID [23]; however, we could not identify any microorganism in the biliary tract of our patient. Furthermore, we could not find any reports of this complication in patients with ADA deficiency, therefore we don’t know if this might have had an impact in the response to the ERT therapy. Known complications that contribute to mortality during treatment with PEG-ADA include refractory haemolytic anaemia, chronic pulmonary insufficiency, lymphoproliferative disorders and solid tumours in the liver [6, 24, 25]. However, these have been identified in patients under different circumstances, and their relationship to the ERT has not been established. Finally, our patient is the first to our knowledge in which a rare and aggressive germinal cell tumour has been identified.