The manuscript was published with permission of the Director of V

The manuscript was published with permission of the Director of VIDO as manuscript Dabrafenib mw number 529. The authors do not have any conflicting interests.

“Citation Ticconi C, Rotondi F, Veglia M, Pietropolli A, Bernardini S, Ria F, Caruso A, Di Simone N. Antinuclear autoantibodies in women with recurrent pregnancy loss. Am J Reprod Immunol 2010; 64: 384–392 Problem  To investigate the possibility that antinuclear antibodies (ANA) are involved in recurrent pregnancy loss (RPL). Methods  Case–control study carried out on 294 women (194 cases and 100 controls) in two University hospitals. The presence, the serum titers and the indirect

immunofluorescence (IIF) patterns of ANA were determined in women with RPL and in control women. Results  Antinuclear antibodies at titers ≥ 1:80 were detected in 97 (50%) women with RPL and in 16 (16%) control women. Elevated ANA titers (≥1:180) were detected only in RPL women, whereas all control women had ANA titers no greater than 1:80. No differences could be detected in the IIF patterns between RPL and control women. No differences in ANA positivity PI3K inhibitor could be detected according to the type (primary or secondary) or number (>2 versus ≥3) of losses. Conclusions  ANA could be of some value in identifying women with RPL with potential, although still not fully defined, immune abnormalities. “
“Eosinophils are multi-functional leucocytes that play a role in inflammatory processes including allergy and infection. Although bone marrow (BM) inflammatory cells are the main source

of eosinophil-basophil (Eo/B) differentiation-inducing cytokines, a recent role has been Tolmetin demonstrated for cytokine induction through Toll-like receptor (TLR)-mediated signalling in BM progenitors. Having previously demonstrated that cord blood (CB) progenitors induce Eo/B colony-forming units (CFU) after lipopolysaccharide (LPS) stimulation, we sought to investigate the intracellular mechanisms by which LPS induces Eo/B differentiation. Freshly isolated CD34-enriched human CB cells were stimulated with LPS (and/or pharmacological inhibitors) and assessed for alterations in haematopoietic cytokine receptor expression and signalling pathways by flow cytometry, Eo/B CFU in methylcellulose cultures, and cytokine secretion using Luminex assays. The LPS stimulation resulted in a significant increase in granulocyte–macrophage colony-stimulating factor (GM-CSF)-responsive, as opposed to interleukin-5-responsive, Eo/B CFU, which also correlated with significant increases in CD34+ cell GM-CSFRα expression.

Although Tamoxifen injection promoted Ag presentation by only 4–8

Although Tamoxifen injection promoted Ag presentation by only 4–8% of DCs in DIETER mice, it induced robust CD8+ T-cell tolerance that could not be broken by a subsequent LCMV infection. Importantly, the resulting CD8+ T-cell

tolerance was entirely Ag specific, as it did not affect T-cell responses against LCMV epitopes other than the ones expressed by the transgene. This suggested that a T-cell-intrinsic mechanism, such as inactivation or deletion of Ag-specific T cells, rather click here than a dominant mechanism is involved in the induction of peripheral tolerance by steady-state DCs in this model. Indeed, naïve T cells that were adoptively transferred into previously tolerized DIETER mice remained responsive [17]. Negative costimulation through inhibitory cell-surface receptors of the CD28 family Selleckchem MK-8669 seems to be crucial for induction of T-cell tolerance by steady-state DCs. When coinhibitory signaling through programmed cell death 1 (PD1) or CTL protein 4 (CTLA4) was inhibited in DIETER mice, steady-state DCs failed to tolerize T cells, and CTLs were found to be massively primed when both receptors were blocked [17]. These findings demonstrated that PD1 and CTLA4 have nonredundant and complementary functions in T-cell tolerance induction by steady-state DCs. Interestingly, the costimulatory ligands CD80 and

CD86, which engage CTLA4, as well as the PD1 ligands PD-L1 and PD-L2, are expressed to higher levels on activated DCs than on steady-state DCs [18].

Thus, although ligation of PD1 and CTLA4 on T cells is crucial for tolerance induction by steady-state DCs, the expression level of their ligands on DCs does not govern the decision between tolerance and immunity. Another mechanism of induction of cell-intrinsic peripheral tolerance by steady-state DCs involves tryptophan metabolism. The rate-limiting enzyme of tryptophan catabolism indoleamine 2,3-dioxygenase (IDO) is expressed by steady-state DCs. DC-derived IDO promotes T-cell tolerance not only through mechanisms that depend on the catalytic function of IDO — such as local tryptophan depletion [19] and Janus kinase (JAK) knyureine production [20] — but also through signaling events that involve IDO but are independent of its catalytic activity [21]. Together these different mechanisms of inducing T-cell intrinsic tolerance allow steady-state DCs to purge the naïve-T-cell repertoire in an Ag-specific manner of autoreactive T cells that have escaped negative selection in the thymus. In addition to promoting T-cell-intrinsic mechanisms of peripheral tolerance, steady-state DCs have been found to be essential for dominant peripheral tolerance, which mainly depends on the function of CD4+FOXP3+ regulatory T (Treg) cells.

cerevisiae or those not immunized Furthermore, oral immunization

cerevisiae or those not immunized. Furthermore, oral immunization induced T helper 1-type immune responses mediated via increased serum concentrations of IgG2a and an increase predominantly of IFN-γ-producing cells in their spleens and lamina propria. Our findings suggest that surface-displayed ApxIIA#5-expressed on S. cerevisiae may be a promising candidate for an oral vaccine delivery system for eliciting systemic and mucosal immunity. Saccharomyces cerevisiae, which is typically used in oral vaccines and drugs, is classified as a GRAS organism [1, 2]. Currently, there is great interest in developing mucosal, particularly oral, vaccines, because such vaccines would not only induce locally and

systemically protective immune responses MLN0128 cell line against infectious disease, but would also be safe and convenient to administer. Several oral delivery systems NVP-BEZ235 datasheet using live oral vaccines such as a Salmonella typhimurium mutant, Lactobacillus spp., or S. cerevisiae [3-5] have been attempted. Among these delivery systems, the S. cerevisiae yeast expression system has several advantages: high expression levels, ease of scale-up, low cost and the adjuvant potential of yeast cell-wall components such as β-1,3-D-glucan and mannan [6]. Yeast-based expression systems have been developed and successfully used to produce

recombinant proteins [2, 6]. These systems have been employed in pharmaceutical, livestock feed and food industry applications [7]. Recently, the genetic engineering technique of yeast cell-surface Ribose-5-phosphate isomerase display has been used to display heterologous proteins on the surfaces of yeast cells [2, 7-9]. This system could be a good candidate for a live oral vaccine carrier because it stably maintains surface-expressed epitopes with a high density of proteins [8]. Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia, a highly contagious endemic disease of pigs that results in significant economic losses worldwide [10, 11]. A. pleuropneumoniae can result in various clinical signs ranging from peracute to chronic, infected pigs typically having hemorrhagic, necrotizing pneumonia,

often associated with fibrinous pleuritis [10]. The ApxII toxin, which is believed to be involved in the virulence of A. pleuropneumoniae, has been used as a vaccine protein [12]. The antigenic determinant of ApxIIA (ApxIIA#5) has been shown to induce a strong protective immune response against A. pleuropneumoniae [13]. ApxIIA, expressed in either S. cerevisiae or Nicotiana tabacum, has previously been reported to be capable of inducing protective immune responses against A. pleuropneumoniae in mice [3, 12, 14]. Moreover, surface-displayed expression of ApxIIA#5 on S. cerevisiae has been studied and induction of antigen-specific immune responses and protection against A. pleuropneumoniae in mice assessed [9]. In the present study, we demonstrated that surface-displayed expression of ApxIIA#5 on S.

Molecular genetic analysis demonstrated that the patient had comp

Molecular genetic analysis demonstrated that the patient had compound heterozygous mutations in

the cysteine-rich loop (A1017T and Y1088C) of the NPC1 gene. To our knowledge there has been no previous report of the A1017T mutation. The pathological features of this patient support the notion that NPC has an aspect of α-synucleinopathy, and long-term survivors of NPC may develop a frontotemporal-predominant distribution of brain atrophy. Niemann-Pick disease type C (NPC, MIM 257220) is this website an autosomal recessive neurovisceral lysosomal lipid storage disorder characterized by abnormal intracellular trafficking of endocytosed cholesterol with sequestration of unesterified cholesterol and glycolipids in the endosomal/lysosomal system.[1, 2] NPC is caused by mutations in either the NPC1 (95% of cases) or NPC2 gene. NPC is neuropathologically characterized by the combination of abnormal lysosomal storage in neurons and glia and the presence of NFTs.[3, 4] In contrast to relatively constant microscopic features, the distribution of gross brain atrophy varies among cases: some patients develop frontal atrophy, others exhibit pronounced brainstem and cerebellar atrophy, and still others have no obvious gross abnormalities.[2, 3, 5] In addition to NFTs, Saito et al. reported accumulation of phosphorylated α-synuclein in NPC patients with NPC1 mutations and suggested that NPC could be categorized filipin as an α-synucleinopathy.[6]

However, cortical and brainstem-type Lewy bodies (LBs) were observed in only two of 12 cases examined,[6] and to our knowledge few other investigators have described accumulation of α-synuclein in NPC brains. Here, we report an autopsy case of juvenile-onset NPC with marked brain atrophy that predominantly affected the frontal and temporal lobes. In addition, the concurrence of LBs in the cerebral cortices and brainstem was found in this patient. Molecular genetic analysis revealed compound heterozygous mutations of the NPC1 gene, one of which is a missense mutation in the cysteine-rich loop that to our knowledge has not previously been reported. The patient was a 37-year-old man with no family history of neurological diseases or consanguineous marriage. His parents first noticed learning difficulties and a gait disturbance at 8 years of age. During the following several years, there was progressive deterioration of verbal communication, memory and fine motor control of fingers. He also developed dysphagia, fecal incontinence, problems in social interaction/behavior, and grand mal seizures. At 11 years of age, neurological examination revealed bilateral pyramidal signs in the lower extremities, truncal and limb ataxia, vertical supranuclear ophthalmoplegia, dysarthria and dysphagia. Computed tomography revealed atrophy in the cerebrum, brainstem and cerebellum.

5% in 2007 to 48 5% in 2012 However the prevalent patients remai

5% in 2007 to 48.5% in 2012. However the prevalent patients remaining on peritoneal dialysis dropped from 91.4% in 2007 to 66.9% in 2012, amounting

to drop of 24.5%. Among the causes that lead to downward trend during the above period was that more patients were being transplanted accounting to 16.1% in 2012 compared to 6.1% in 2007 followed by other causes like being palliated, infection and transferred to haemodialysis and other centres. Conclusion: The results of our study showed that although the incident patients entering the peritoneal dialysis programme increased, there is a downward trend in patients remaining on peritoneal dialysis at our centre as more patients are being transplanted SB203580 and palliated. 250 OPTIMISING PAEDIATRIC DIALYSIS: A COMPARISON OF ADAPTED AND CONVENTIONAL PERITONEAL DIALYSIS L SHAW1, Z MILLARD1, C QUINLAN1,2 1The Royal Children’s Hospital, Melbourne, Victoria; 2The Murdoch Children’s Research Institute, Melbourne, Victoria, Australia Aim: To compare the efficacy of Conventional peritoneal dialysis (Con-PD) and Adapted PD (Ad-PD) in children. Background: Con-PD is delivered as a series of identical exchanges. Ad-PD consists of several initial

short, low volume cycles, followed by several long, higher volume cycles. A recent randomised trial by Fischbach et al. showed significantly increased ultrafiltration (UF) and greater clearance of urea, creatinine and phosphate

Akt inhibitor with lower metabolic cost as measured by glucose absorption in a trial in 19 adults. Methods: Patients are randomised to 6 weeks of Ad-PD followed by 6 weeks of Con-PD or vice versa. All patients are seen 2-weekly for clinical assessment and assessment of dialysis adequacy using electrolyte samples of blood, urine and dialysate. Results: This is an ongoing study, to date 9 children have been recruited and 3 have commenced Ad-PD. The first 2 were low transporters and were withdrawn in the first week due to Mannose-binding protein-associated serine protease a clinically significant decrease in UF volume. The third child was a high transporter and had a significant increase in UF (from 100 to 400 mL) and a significant decrease in phosphate and potassium, such that supplementation was commenced. We await the full results which will be presented at the meeting. Conclusion: The results of the adults Ad-PD trial were very encouraging but the initial results from our study, the first paediatric trial of Ad-PD, show that it does not work for every child. However the child that had increased UF was failing Con-PD with consideration of haemodialysis and thus this has been an excellent result for her. It is possible that outcomes are dependent on transporter status but further results are necessary to confirm this initial finding.

One of the foremost mysteries about iNKT cells is how they are ab

One of the foremost mysteries about iNKT cells is how they are able to mediate such contrasting immunological effects

as Adriamycin purchase promoting tumour rejection or clearance of microbial infections, and preventing or ameliorating autoimmune diseases. Previous studies have established that the iNKT cell population contains functionally distinct subsets; for example, CD4− iNKT cells appear to be biased towards production of Th1 cytokines and expression of perforin, whereas CD4+ iNKT cells produce both Th1 and Th2 cytokines and are more notable for up-regulating FAS-ligand after stimulation.37 Thus, it is possible that different iNKT cell subsets become activated in different situations, and mediate distinct effects. This could be a result of differential anatomical localization of iNKT subsets, or of different costimulation requirements. However, as described in the next paragraph, it is not clear that different iNKT cell subsets recognize distinct antigens. Because of their canonical TCR rearrangements, all iNKT cells share the ability to recognize a specific molecular ‘pattern’ in which a galactose or glucose sugar is attached in an α-anomeric conformation to the polar head group of a lipid.38,39 The prototypical synthetic lipid of this type, α-galactosylceramide

(α-GalCer), is a highly potent agonist for iNKT cells.15 Lipids with structural similarity to α-GalCer have been identified from several microbial sources, including a pathogenic Borrelia species.40–43 However, these microbial analogues Crizotinib price of α-GalCer generally appear to be substantially weaker TCR agonists than α-GalCer

itself. Importantly, mammalian cells do not seem to produce glycolipids in which the first sugar is attached to the lipid via an α-linkage, and thus the self antigens Verteporfin manufacturer recognized by iNKT cells apparently do not contain this molecular pattern. The nature of the self antigens recognized by iNKT cells will be discussed at the end of the review; suffice it to note here that there is also as yet no clear evidence that iNKT self-antigen specificities differ according to subset. Another possibility (not mutually exclusive with the subset model) is that the same iNKT cell can mediate distinct functional effects as a result of variations in the activation stimuli in different contexts. We have recently shown that iNKT cells produce cytokines hierarchically in response to increasing TCR signal strength: granulocyte–macrophage colony-stimulating factor (GM-CSF) and IL-13 are activated by exposure to low doses of α-GalCer, higher levels of α-GalCer increase secretion of these cytokines and also induce IFN-γ and IL-4, and production of IL-2 requires the highest amounts of antigen.

These kinases mediate the phosphorylation of phosphatidylinositol

These kinases mediate the phosphorylation of phosphatidylinositol precursors on the 3′ position of the inositol ring [2]. The resulting products act as second messengers that mediate the recruitment and activation of downstream kinases and other effectors, usually through binding to pleckstrin homology (PH) domains [2]. Class I PI3Ks consist of a catalytic subunit (p110α, β, δ), which is recruited to active signaling complexes by an adaptor subunit of 85 kD (p85α, β). The best-characterized downstream effectors for PI3K are the Akt proteins [3], PH domain-containing serine/threonine kinases that regulate cellular survival, metabolism, and activation [3]. The proper regulation of PI3K and its products is

critical to normal cellular homeostasis.

Activating mutations and amplification of p85, p110, and Akt learn more have been implicated in various cancers [4, 5]. Conversely, at least two negative regulators of signaling downstream of PI3K are known to be tumor suppressors, INCB018424 i.e. the lipid phosphatases phosphatase and tensin homolog (PTEN), which removes the phosphate from the 3′ position of the inositol ring of PIP3 [4], and inositol polyphosphate-4-phosphatase, type II (INPP4B), which acts on the 4′ phosphate of PI(3,4)P2 [6]. Recently, another type of negative regulator of PI3K has been described that acts more proximally to inhibit PI3K activity. PI3K interacting protein 1 (PIK3IP1) is a transmembrane protein, and contains an extracellular kringle domain. Its cytoplasmic domain contains a motif that is homologous to the inter-SH2, p110-binding, domain of p85 [7]. Interference with p110 activation, possibly through an allosteric mechanism, is the proposed

mechanism by which PIK3IP1 inhibits the PI3K pathway [7]. Recent data also suggest that PIK3IP1 can function as a tumor suppressor [8, 9]. Here we demonstrate selleck screening library that PIK3IP1 is expressed in T cells. Furthermore, while ectopic expression of PIK3IP1 inhibits signaling pathways associated with T-cell activation, decreasing the expression of this protein augments the same pathways. Thus, our data indicate that PIK3IP1 is a novel regulator of T-cell activation. Recent studies indicated that PIK3IP1 is a negative regulator of PI3K, at least in certain cell types [7, 8]. Before exploring a possible function for PIK3IP1 in T cells, we determined whether it is expressed in T cells, both at the message and protein levels. To assess the former, we performed searches using two on-line gene expression databases. As shown in Fig. 1A, analysis of gene expression in mouse tissues via the BioGPS portal ( revealed relatively robust expression of PIK3IP1 in a number of hematopoietic lineages, including T cells. Analysis of expression data from the Immunological Genome Project ( also revealed the presence of PIK3IP1 message in T cells and other immune cells (data not shown).

In the presence of belatacept and lower MSC/effector cell ratios

In the presence of belatacept and lower MSC/effector cell ratios we even observed an additive suppressive effect.

MSC exert their immunomodulatory function not only by suppressing the proliferation of various immune cells; in a previous study we have shown that MSC also induce functional de-novo regulatory T cells (Treg) [63]. CD28/B7 co-stimulation in Treg is required for their differentiation [64]. Treg-specific deficiency of CD28 and CTLA-4 leads to an impaired immunosuppression by Treg and the development of autoimmunity and rejection in transplant models [65, 66]. The effect of CTLA-4-Ig therapy on Treg is controversial. Administration of CTLA-4-Ig to a skin transplant mouse model abolished Treg-dependent graft acceptance and expansion Doxorubicin in vivo of Treg [67]. In contrast, CTLA-4-Ig therapy in rheumatoid arthritis Galunisertib concentration patients reduced the frequency of peripheral Treg but enhanced their function [68]. Therefore, alongside the alloreactive CD8+CD28− T cells that escape belatacept therapy,

the possible diminution of Treg in patients receiving belatacept might contribute to the increased frequency of acute rejections reported for belatacept-treated kidney graft recipients [25]. In conclusion, CD8+CD28− T cells sustain their proliferative capacity in the presence of belatacept, and secrete cytolytic and cytotoxic effector molecules. As MSC are able to control these CD8+CD28− T cells by inhibiting their proliferation, our study suggests a potential for MSC–belatacept combination therapy to prevent alloreactivity after solid organ over transplantation. A. U. E. performed the experiments and participated in the writing of the manuscript. M. G. H. B. participated in

the writing of the manuscript. C. C. B, N. H. R. L., M. F., W. W. and M. J. H. participated in the study design and the writing of the manuscript. The authors of this manuscript have no financial or commercial conflicts of interest to disclose. “
“Natural killer T (NKT) cells are a heterogeneous population of lymphocytes that recognize antigens presented by CD1d and have attracted attention because of their potential role linking innate and adaptive immune responses. Peripheral NKT cells display a memory-activated phenotype and can rapidly secrete large amounts of pro-inflammatory cytokines upon antigenic activation. In this study, we evaluated NKT cells in the context of patients co-infected with HIV-1 and Mycobacterium leprae. The volunteers were enrolled into four groups: 22 healthy controls, 23 HIV-1-infected patients, 20 patients with leprosy and 17 patients with leprosy and HIV-1-infection. Flow cytometry and ELISPOT assays were performed on peripheral blood mononuclear cells. We demonstrated that patients co-infected with HIV-1 and M. leprae have significantly lower NKT cell frequencies [median 0.022%, interquartile range (IQR): 0.007–0.051] in the peripheral blood when compared with healthy subjects (median 0.077%, IQR: 0.032–0.405, P < 0.

2C, top) The same results were obtained when viral titers in IgM

2C, top). The same results were obtained when viral titers in IgMi mice after

LCMV Docile infection were analyzed (Fig. 2C, bottom). Taken together, these data suggested that Abs induced in the early phase of an LCMV Docile selleck compound infection were required to prevent T-cell exhaustion and viral persistence. Due to the phenotype of Ab-deficient mice after LCMV Docile infection, we used this viral strain for all subsequent experiments of this study. Next, we determined the kinetics of the LCMV-specific Ab response in B6 mice using a newly established sensitive sandwich ELISA as detailed in the Material and methods. LCMV-specific IgG titers in serum of LCMV Docile infected mice strongly increased between days 6 and 8 and reached maximal levels 2 weeks p.i. (Fig. 3A, filled circles). The IgG response was T-cell help dependent since Ab titers were strongly decreased in CD4+ T-cell-depleted mice (Fig. 3A, open circles). The viral antigen specificity of immune serum taken from LCMV Docile infected mice at d20 p.i. was analyzed by immunoprecipitation and immunoblotting. The results revealed that LCMV immune serum predominantly

contained Abs specific for LCMV NP (Fig. 3B) confirming previous data [14]. Importantly, virus neutralizing activity was never observed in these LCMV immune sera even when used at a high concentration (Fig. 3C). To provide additional evidence for the lack of virus neutralizing activity, virus serum mixes (90% AMPK activator serum) were incubated overnight before inoculation into mice. Two days after inoculation,

LCMV titers in spleens were enumerated. The neutralizing LCMV GP specific mAb KL25 was used as a positive control in these assays. As shown in Fig. 3D, treatment with mAb KL25 completed prevented infection whereas preincubation with LCMV immune serum did not affect initial viral replication. Having shown that mice with impaired humoral immunity were unable to control LCMV Docile infection, we next wondered whether transfer of LCMV immune serum could accelerate virus clearance. First, LCMV Docile infected MD4 and IgMi mice were treated Bupivacaine with LCMV immune sera free of infectious virus that were obtained from infected wild-type mice at day 20 p.i. Viral titers in spleen, liver, and lungs were determined 14 days later. This treatment was able to lower viral titers in some mice but the antiviral effects were variable, particularly when using MD4 mice (Fig. 4). To obtain a more robust read-out for the potential antiviral activity of LCMV-specific Abs, we next tested B6 wild-type mice as hosts. Mice were infected with LCMV Docile and at day 1 serum from healthy uninfected mice (= normal serum) or LCMV immune serum was injected i.p. and the kinetics of viral elimination was followed. At day 2 and day 4 p.i., viral load between the two groups did not significantly differ (Fig. 5).

Levels of spontaneous apoptosis in HUVEC control cultures varied

Levels of spontaneous apoptosis in HUVEC control cultures varied between 10·00 and 12·50%. The mean percentage of EC apoptosis induced by cell starvation and staurosporine was 55·46 and 66·80%, respectively. As demonstrated by the enumeration of hypoploid GSK1120212 solubility dmso cells, purified IgG from the AECA-positive SLE patients induced a significantly higher percentage of apoptosis of HUVECs in comparison to AECA-negative SLE patients (P = 0·001) and healthy controls (P < 0·0001) (Fig. 2). Purified

IgG from the AECA-positive PAH patients did not induce a higher percentage of apoptosis of HUVECs compared to the AECA-negative PAH patients (P = 0·92) and healthy controls (P = 0·08), as assessed by the enumeration of hypoploid cells (Fig. 2). Also in the SSc cohort, no induction of apoptosis was observed (Fig. 2). Further analysis of the PAH cohort demonstrated that IgG from the AECA-positive IPAH patients did not induce a significantly higher percentage of apoptosis of HUVECs compared to the AECA-negative PAH patients (P = 0·94) and healthy controls (P = 0·09), as assessed by the enumeration of hypoploid cells. Incubation with IgG from AECA-positive SLE (n = 3) patients induced a significant decrease in the CI value compared to IgG from AECA-negative SLE (n = 3) patients (P = 0·050) and healthy controls (P = 0·020) (Fig. 3). In fact,

IgG from AECA-positive SLE patients induced a decrease in CI value of 79%, which was comparable with the decrease in CI values induced by cell starvation click here (82%) and incubation with 5 nmol/ml staurosporine (93%). Incubation of HUVECs with IgG from the AECA-positive PAH (n = 8) and SSc (n = 6) patients, however, did not alter the CI value significantly compared to IgG from the

AECA-negative PAH (n = 8) and SSc (n = 6) patients (P = 0·248 and P = 0·749, respectively) and healthy controls (P = 0·121 and P = 0·337, respectively). The aetiology of PAH is still poorly understood, and it is postulated that dysfunction of pulmonary ECs plays Uroporphyrinogen III synthase an important role in the pathophysiology of PAH [5]. EC dysfunction may lead to pulmonary vascular remodelling and ultimately to the development of PAH [4, 5]. Mounting evidence suggests an important role for EC apoptosis in this process. Taraseviciene-Stewart et al. demonstrated that selective blockade of the vascular endothelial growth factor receptor 2 (VEGFR-2) resulted in severe irreversible pulmonary hypertension associated with precapillary arterial endothelial cell proliferation in chronically hypoxic rats [7]. EC apoptosis following VEGFR-2 blockade was a prerequisite for endothelial proliferation, because caspase inhibition throughout the course of chronic hypoxia and VEGFR-2 blockade prevented EC proliferation and the development of severe pulmonary hypertension [7].