“
“Please cite this paper as: Gopinath, Baur, Wang, Teber, Liew, Cheung, Wong and Mitchell (2010). Smaller Birth Size is Associated With Narrower Retinal Arterioles in Early Adolescence. Microcirculation17(8), 660–668. Objective:  In the current study, we aimed to examine the associations of low birth weight with retinal vascular caliber and vascular fractal dimension during early adolescence.

Methods:  A population-based study of 12-year-old schoolchildren (2353/3144 [75.3%]) recruited from a random cluster sample of 21 schools. Birth weight, birth length and head circumference were obtained via parent report of the child’s birth record. Retinal images were taken and vessel diameter and fractal dimension were quantified using validated EPZ-6438 concentration computer-based methods. Results:  After buy BMN 673 adjusting for age, sex, ethnicity, body mass index, iris color, axial length, mean arterial blood pressure, prematurity and fellow retinal vascular caliber, children in the lowest quartiles of birth weight had ∼2.5 μm narrower mean retinal arteriolar caliber than those in the highest quartiles (p for trend = 0.001). Associations were observed between shorter birth length and smaller head circumference with narrower retinal arterioles. Smaller head circumference was associated with decreased fractal dimension (p for trend = 0.03). Conclusions:  Children with lower birth weight

were more likely to have narrower retinal arterioles, while those with smaller head circumference

were more likely to have reduced complexity of their retinal microvasculature. These variations in microvascular structure in adolescence could reflect a susceptibility to cardiovascular disease during adulthood, resulting from a disadvantaged growth environment in utero. “
“Please cite this paper as: Muller-Delp, Gurovich, Christou, and Leeuwenburgh (2012). Redox Balance in the Aging Microcirculation: New Friends, New Foes, and New Clinical Directions. Microcirculation 19(1), 19–28. Cardiovascular aging is associated Protein kinase N1 with a decline in the function of the vascular endothelium. Considerable evidence indicates that age-induced impairment of endothelium-dependent vasodilation results from a reduction in the availability of nitric oxide (NO•). NO• can be scavenged by reactive oxygen species (ROS), in particular by superoxide radical (O2•−), and age-related increases in ROS have been demonstrated to contribute to reduced endothelium-dependent vasodilation in numerous large artery preparations. In contrast, emerging data suggest that ROS may play a compensatory role in endothelial function of the aging microvasculature. The primary goal of this review is to discuss reports in the literature which indicate that ROS function as important signaling molecules in the aging microvasculature.

3B). These experiments confirmed that the reduced response to FO-1 was dependent on the defective expression (Fig. 2A) of specific activating NK receptors. selleck chemical As expected, all the receptors analyzed (with the exception of CD16) also displayed lower capability of inducing target cell killing in “hypoxic” NK cells (see redirected killing assay in Supporting Information Fig. 2). In addition, “hypoxic” NK cells displayed a reduced ability to kill different

targets including MeCoP and FO-1 melanoma cell lines and the EBV+ 721.221 B-cell line (Fig. 4A). These results are in line with the concept that the activating NK receptors targeted by hypoxia are involved in the recognition and killing of a wide panel of NK target cells. Since our data indicate that hypoxia does not affect CD16 expression and function, we further analyzed whether “hypoxic” NK cells maintained ADCC capability. NK cells were cultured under normoxic or hypoxic conditions and tested in a cytolytic assay against the 721.221 HLA-DR+ AZD1208 target cell

line with or without an anti-HLA-DR mAb (to promote ADCC). As shown in Figure 4B, NK cells exposed to hypoxia were not cytolytic against this target (see also Fig. 4A, right panel). In contrast, they acquired a strong killing capability upon the addition of the anti-HLA-DR mAb (Fig. 4B) thus indicating that hypoxia did not prevent NK cells from performing ADCC. Due to the lack of basal killing (i.e. in the absence of mAbs), the overall lytic activity of “hypoxic” NK cells remained lower than that of “normoxic” NK cells; nevertheless, similar increases

above controls (i.e. mAb-induced cytotoxicity) were detected under hypoxic and normoxic conditions (Fig. 4B). The aim of the present study was to assess how NK cells could be influenced in their killing capability by the variation of pO2 in the surrounding microenvironment. Our experiments demonstrate that low levels of pO2, comparable to those hypoxic areas of certain solid tumors or infection sites or even normal lymphoid tissues, may greatly interfere with the expression ID-8 and function of major activating NK-cell receptors. The receptors affected by hypoxia play a major role in recognition and lysis of a wide panel of NK-cell targets. Accordingly, under hypoxia, NK cells strongly reduced their ability to kill both EBV-infected and tumor cells. The inhibitory effects of hypoxia, together with a series of recently identified suppressive mechanisms occurring at the tumor site, suggest that the efficacy of NK cells in clearing pathogens or tumor cells in vivo may have been overestimated. Indeed, the assays to evaluate NK-cell-mediated cytolysis are routinely performed under atmospheric O2 concentration. Our experiments indicate that hypoxia can both influence NK cells in their “resting status” and effectively counteract the stimulatory effect of the main cytokines activating the NK-cell function (including IL-2, IL-15, IL-12, and IL-21).

A number of endogenous and exogenous factors, such as cytokines and growth factors as well as certain antifungal agents have been found that they influence innate immune response to these organisms. Used alone or especially in combination have been shown to this website exert antifungal effects against Mucorales species. These findings suggest novel ways of adjunctive therapy for patients with invasive mucormycosis. Infections caused by Mucorales have been reported with increasing frequency in recent years and still cause unacceptably high morbidity

and mortality. A number of risk factors are known to be associated with invasive mucormycosis, including haematologic malignancies and transplantation, iron overload, diabetes and ketoacidosis, birth prematurity and possibly prior exposure to certain Aspergillus-active antifungal agents [i.e. voriconazole (VRC) and caspofungin (CAS)].[1-3] In the haematology

patients, the cumulative incidence of mucormycosis in Europe and the United States has been increasing during the last decade, recording high mortality rates and suboptimal outcomes with currently available therapy.[4-7] Among clinically relevant Mucorales, the most frequent species are Rhizopus oryzae and Rhizopus microsporus. Cunninghamella bertholletiae is less Alvelestat commonly encountered but associated with more severe infections.[8] By comparison, Lichtheimia corymbifera is a less virulent and infrequent Rho pathogen.[9] Sporangiospores of Mucorales invade into patients through either airways

or mucosa of alimentary tract or through the skin. The alimentary tract is the route of invasion in premature neonates with gastrointestinal mucormycosis. Similarly, Mucorales colonising gauzes, wooden sticks or other materials used into contact with the skin have caused outbreaks of cutaneous or invasive mucormycosis in neonates and other patients.[10] Mucorales can also enter subcutaneous tissues through catheter sites. When sporangiospores enter tissues, they progress to hyphae. The initial host defences against sporangiospores of Mucorales are intact barriers, i.e. skin and respiratory as well as intestinal mucosa. Innate immune cells such as neutrophils, monocytes/macrophages and dendritic cells are important in the host defences against these organisms. Immunosuppression is among the most important risk factors for mucormycosis. Rhizopus oryzae is recognised by Toll-like receptor-2 and up-regulates release of a number of cytokines and chemokines from phagocytes, among which are TNF-α and IL-6.[11, 12] Toll receptors in Drosophila play a significant role in innate immune response to R. oryzae.[11] This organism is more resistant to phagocytosis and hyphal damage than A. fumigatus.[13, 14] There are several lines of in vitro evidence showing that R.

Deterioration of renal function was observed in only one patient, which was deemed to be due to diabetes mellitus. The limitation of the present study is the relatively

small sample Copanlisib supplier size and short follow up. This was predominantly due to the limited enrollment period and stringent criteria for enrollment. Moreover, due to a lack of resources, standardized pads were not used to quantify the degree of incontinence. Nevertheless, it presents a comprehensive clinico-urodynamic analysis of lower urinary tract function in patients with orthotopic neobladder and incites researchers for larger and longitudinal studies on urethral function evaluation in this patient-group using urethral pressure profilometry. To conclude, in patients undergoing cystoprostatectomy, Lumacaftor W-configured detubularized ileal neobladder with extramural serosal-tunnel non-refluxing uretero-ileal anastomosis has acceptable functional characteristics in terms of good capacity, compliance, absence of reflux and ability to empty without having to resort to CIC. However, A significant proportion of patients do have urinary incontinence (night > day) impacting quality of life. Regular pelvic floor muscle training consisting of strengthening and relaxation exercises may help improve lower urinary tract function. There is no conflict

of interest to disclose by any author. S. no Questions 1 2 3 4 5 Evacuation of urine             1 Way of evacuation of urine Voluntary Only by self catheterization Voluntary voiding followed by CIC On perurethral catheter   2 Subjective voiding time Normal Slightly prolonged Moderately

prolonged Much prolonged   3 Voiding posture Sitting Standing Squatting     4 Hesitancy on voiding None < 10 sec 10–30 sec 30–60 sec > 1 min 5 Intermittency on voiding None Only at end of voiding Only at Initiation Throughout voiding   6 Abdominal straining None Only at end of voiding Only at Initiation Throughout voiding   7 Degree of abdominal 17-DMAG (Alvespimycin) HCl straining None Mild Moderate Excessive   8 Crede’s maneuver None Occasionally Performed Always performed     9 Sense of residual urine Absent Occasionally present Always present     10 Force of urine stream Excellent Good Weak Poor Dribbling 11 Voiding compared to preoperative status Excellent Slightly better Same Slightly poor Worse Storage of urine             12 Frequency of micturition 1 2 3 4 5 13 Sense of desire to void None Abdominal fullness Sense of urinary leak Pain   14 Presence of incontinence Absent Present       15 Type of incontinence None With urge With stress Continuous On prolong retention 16 Frequency of Incontinence None Day only Night only Both day and night   17 Grade of day time incontinence None A few drops Underwear wetting Cloths wetting   18 Grade of night time incontinence None A few drops Underwear wetting Cloth wetting Bed wetting 19 Wearing of pad during day time None Occasionally Always for protection Always   20 No.

1). Total TLR5 was clearly detected in mock-infected cells (fluorescence intensity value of 169.4 ± 56) with significantly more intensity than in FITC-control cells (4.7 ± 0.3). HB101 interaction did not significantly alter total TLR5 detection (160.0 ± 56.5). Neither E2348/69 nor E22 infection changed TLR5 detection (248.4 ± 92.9 for E2348/69 and 271.1 ± 93.4 for E22) (Fig. 1A). These results confirmed that TLR5 expression is not altered by EPEC infection. However, in non-permeabilized cells (TLR5 on the cell Doxorubicin cost surface), we found a clear difference between infected and non-infected cells (Fig. 1B). In mock-infected cells, surface TLR5 detection was low (average fluorescence value of 22.0 ± 0.4), but still higher than

in the FITC-control cells (5.7 ± 0.2). This result indicates that in non-stimulated cells, most TLR5 is in intracellular compartments and poorly represented on the cell surface.

HB101 interaction did not modify surface TLR5 detection (22.2 ± 0.4). Remarkably, in cells infected with EPEC (either E2348/69 or E22), detection of surface TLR5 was clearly superior to the FITC-control and significantly higher than in mock-infected cells (E2348/69 = 76.0 ± 1.4 and E22 = 54.1 ± 1.0). These increases in surface Galunisertib TLR5 detection were the very first evidence indicating that EPEC induces TLR5 re-localization and accumulation on the cell surface of infected cells. To understand the relationship between TLR5 re-localization and EPEC virulence factors, we analysed TLR5 localization in HT-29 epithelial cells infected over for 4 h with EPEC E22 Δeae, ΔescN, and ΔfliC mutants by flow cytometry (Fig. 1C, D). Total TLR5 detection was not statistically different in cells infected with E22Δeae (245.4 ± 86.8), E22ΔescN (208.7 ± 52.5) and E22ΔfliC (172.6 ± 43.4) from the value for E22 WT-infected cells (Fig. 1C). Interestingly, in the case of surface TLR5 (Fig. 1D), we found a reduced TLR5 detection on cells infected with E22ΔescN (39.0 ± 0.7) or E22ΔfliC (37.7 ± 0.7) than in E22 WT-infected cells (54.1 ± 1.0). However, in E22Δeae-infected

cells (50.2 ± 2.4), detection of surface TLR5 was almost the same as in E22 WT-infected cells. Even so, infection with any E22 strain (wild-type or its isogenic mutants) induced a slight increase in TLR5 surface expression in comparison with mock-infected cells (22.0 ± 0.4). These data indicate that EPEC T3SS and flagellin participate in TLR5 recruitment towards the cell surface, while the participation of intimin appears to be weak or null. To corroborate EPEC-induced TLR5 surface re-localization, we analysed TLR5 localization in immunofluorescence preparations of non-permeabilized cells, treated with HB101, E2348/69, E22 WT, E22Δeae, E22ΔescN, E22ΔespA or E22ΔfliC. Besides surface TLR5 detection, we used the membrane-permeable reagent TO-PRO-3 to stain DNA as a reference for cell localization. Permeabilized cells were used as a control for total TLR5 detection (data not shown).

The absorbance was measured as before at 520 nm following vortex mixing for 5 s. The hydrophobicity was expressed as described

previously, as the percentage reduction in optical density of the test suspension compared with the control.[24, 25] Thus, the greater the change in absorbance, the greater the shift in Candida from the bulk medium to the interface (i.e. the more hydrophobic the Candida strain). Suspensions Selleckchem Nutlin3a without xylene were used as the negative controls. C. albicans ATCC 90028 was used as a reference strain for all experiments and all these experiments were repeated on three separate occasions with duplicate determinations on each occasion. The effect of nystatin on each isolate was statistically analysed as done in similar previous studies.[18-20, 22-25] The data obtained from all three adhesion to BEC, germ tube and CSH assays were analysed using anova Dunnett’s t-tests, which treat one group as a control (unexposed

to nystatin), and compare the other group (exposed to nystatin) against it. Regression analysis by Pearson Selleck Ibrutinib correlation coefficient (r) was used to determine the relationship between nystatin-induced suppressive effect on adhesion to BEC, germ tube formation and relative CSH of C. dubliniensis isolates. A P < 0.05 was considered statistically significant. The MIC (μg/ml) values of 20 isolates of C. dubliniensis to nystatin ranged from 0.09 to 0.78. Based on the equation PAFE = T-C, the mean in vitro PAFE (hours) on 20 oral isolates of C. dubliniensis following 1 h exposure and subsequent removal of nystatin was 2.17 h (Table 1). For instance, for the isolate CD1 the mean T was 4.25 h and mean C was 2.125 h. Hence, the PAFE (T-C) was 2.13 h. For all other isolates tested, the mean T and C values were approximately 4 and 2 h, respectively, giving an overall mean PAFE value of 2.17 h

for the tested isolates (Table 1). Mean SEM 2.17 0.045 74.45 0.71 95.92 0.29 34.81 1.38 The mean adhesion to BEC (yeast/50 BEC) of the 20 C. dubliniensis isolates unexposed to nystatin and following brief exposure to the drug was 208.51 and 53.21, respectively, giving a 74.45% mean Silibinin percentage reduction (P < 0.0001; Tables 1 and 2). The percentage GT-positive cells of the 20 C. dubliniensis isolates unexposed to nystatin and following limited exposure to this antifungal was 25.31 and 1.01 respectively. Hence, compared with the control, exposure to nystatin almost completely inhibited GT formation with a mean percentage reduction of 95.92% (P < 0.0001; Tables 1 and 2). The mean CSH of the 20 C. dubliniensis isolates, unexposed controls and following limited exposure to nystatin, drug removal and subsequent determination of CSH by the biphasic aqueous-hydrocarbon assay was 14.89 and 9.84, respectively, with a mean percentage reduction of 34.81% (P < 0.05; Tables 1 and 2).

Consistent with published reports [79,80], we found that HIV-1 selleck chemicals llc infection of DC inhibited autologous T cells proliferation. This impaired T cell proliferation occurred despite the fact that HIV-1 had no effect on MHC-I expression (data not shown). This indicates that the degree of MHC-I expression does not appear to be a factor in the observed HIV-1 effects on T cell proliferation.

Because a critical aspect of immature DC physiology concerns appropriate MAPK responses to pathogenic stimulation that trigger the maturation of DC [3], we next investigated whether HIV-1 had any effect on LPS-induced MAPK signalling. Interestingly, we found that HIV-1 infection had no effect on the p38, JNK or ERK MAPK signalling pathways in immature DC or in-vitro matured DC. This was consistent with

our phenotypic observations that HIV-1 did not affect CD14 expression on DC (data not shown), which is necessary for TLR-4 recognition of bacterial LPS [3]. Despite some conflicting reports, it is generally accepted that HIV-1 inhibits DC maturation. This is based largely on the effects of HIV-1 on the expression of cell surface markers associated with the state of DC maturation. Within the present comprehensive set TSA HDAC of experiments, not only have we confirmed that HIV-1 alters cell surface marker expression consistent with the inhibition of maturation, but for the first time have clearly linked these changes with a number of aspects of DC function (endocytosis, antigen presentation). The fact that HIV-1 interferes with important aspects of DC function has implications in both HIV-1 pathogenesis as it relates to the immunological control of HIV replication, and in the immunodeficiency and risk of opportunistic

infections associated with HIV disease. This work was supported by a Canadian Institutes of Health grant to JBA (grant no. HOP-98830). J.B.A. is supported by a Career Scientist Award from the Ontario HIV Treatment Network. None of the authors has conflicts of interest to declare, or any relevant financial interest, in any company or institution that might benefit from this publication. “
“NK cells are important components of innate and adaptive either immunity. Functionally, they play key roles in host defense against tumors and infectious pathogens. Within the past few years, genomic-scale experiments have provided us with a plethora of gene expression data that reveal an extensive molecular and biological map underlying gene expression programs. In order to better explore and take advantage of existing datasets, we review here the genomic expression profiles of NK cells and their subpopulations in resting or stimulated states, in diseases, and in different organs; moreover, we contrast these expression data to those of other lymphocytes. We have also compiled a comprehensive list of genomic profiling studies of both human and murine NK cells in this review.

In clinical studies of CGD [23–30], the disorder has presented most often with pneumonia, infectious dermatitis, osteomyelitis, and recurrent or severe abscess formation in the skin and organs of the reticuloendothelial Bortezomib molecular weight system. Tissue examination typically shows microscopic granulomas [31]. Infections are caused generally by bacteria such as Staphylococcus aureus and gram-negative bacilli, and fungi such as Aspergillus and Candida [22, 29]. Unusual pathogens characteristic of CGD include Burkholderia cepacia, Chromobacterium violaceum, Nocardia and invasive Serratia marcescens.

The management of CGD includes prophylactic antibiotics, antifungals and IFN-γ, along with aggressive and prolonged treatment of infections as they occur [22, 32]. Prophylactic trimethoprim/sulfamethoxazole (5 mg/kg/day based on trimethoprim) reduces the frequency of major infections from about once every year to once every 3.5 years, preventing staphylococcal and

skin infections without increasing the frequency of serious fungal infections. Itraconazole prophylaxis showed marked efficacy in the prevention of fungal BMS-354825 mouse infection in CGD (100 mg daily for patients <13 years or <50 kg; 200 mg daily for those ≥13 years or ≥50 kg). IFN-γ reduces the frequency of severe infections and the length of hospitalization for infections and is well tolerated [33], although not all centres use the drug. Therefore, the current recommendations include prophylaxis with trimethoprim/sulfamethoxazole, itraconazole and IFN-γ (50 μg/m2) in CGD [22]. Bone marrow transplantation and gene therapy offer Rebamipide potential cure of CGD, although with considerable risk and toxicity. Several transplant approaches are in

use, ranging from full myeloablation resulting, when successful, in complete engraftment, to non-myeloablative conditioning regimens, leading to stable hematopoietic chimerism [22]. Gene therapy for CGD has shown marking of cells in the periphery for several months, but clinical benefit has been elusive, presumably because of the low numbers of corrected cells in the circulation (<0.01%). In contrast to severe combined immunodeficiency, where the growth advantage of corrected cells enables small numbers to fill the T-cell compartment, restoring the NADPH oxidase in neutrophils does not seem to offer any apparent selective growth advantage to these cells, making it more difficult for CGD gene therapy to achieve long-term correction [22]. However, even temporary correction of a small proportion of cells can provide short-term clinical benefit [34, 35]. A multinational group has achieved successful gene therapy in patients with X-linked CGD, using liposomal busulfan conditioning followed by infusion with autologous CD34+ peripheral blood stem cells transduced with a retroviral vector, in which gp91phox expression is driven by the spleen focus-forming virus long terminal repeat [36–38].

In this system, DDA targets the vaccine antigen to APCs while TDB provides proinflammatory stimuli, triggering a Th-1 cytokine response via a TLR-independent pathway (Agger et al., 2008). CAF01 has proven to be highly efficacious, inducing cellular and humoral responses simultaneously in animal models more effectively than the single antigens administered alone. In addition to its priming activity, this vaccine has also been demonstrated to have a BCG booster effect (Doherty et al., 2004; Davidsen et al., 2005). AS01B, developed by Corixa

and GlaxoSmithKline Hydroxychloroquine supplier Biologicals, contains the TLR4 ligand MPL and the saponin derivative QS-21 in a liposomal formulation including the fusion molecule Mtb72F. The Mtb72F antigen is comprised of the PPE family member Rv1196 inserted into the middle selleck chemicals llc of the putative serine protease Rv0125, which is thus present as two fragments (Mtb32C–Mtb39–Mtb32N) (Skeiky et al., 2004). In the AS01B or AS02A formulations, this vaccine has also been demonstrated to have priming and BCG booster effects (Brandt et al.,

2004). IC31, also developed by the Statens Serum Institute, consists of a vehicle combining the synthetic antimicrobial peptide KLKL5KLK, which actively loads APCs with antigen, and the immunostimulatory TLR9 ligand ODN1a, with the fusion proteins H1 and Ag85B–TB10.4 (Agger et al., 2006; Lingnau et al., 2007). This vaccine confers protective immunity in murine tuberculosis models and was recently shown to safely induce strong T-cell responses with a mixed Th-1/Th-2 cytokine profile in both neonates and adults (Kamath et al., 2008). CAF01, AS01B and IC31 are currently undergoing clinical Phase I/II trials. Mtb72F/AS01B is being tested in Lausanne, Switzerland, in individuals previously only exposed to BCG or previously treated individuals

currently infected with Mtb. H1 in IC31 and CAF01 are being tested in Leiden, the Netherlands, in purified protein derivative (PPD)-negative subjects. These adjuvants share the same basic combination of a delivery vehicle and a Th-1-skewing immunomodulator, conferring more potent protection against tuberculosis infection than single immunomodulators (CpG or MPL) or delivery vehicles lacking immunomodulators (liposomes or niosomes) (Agger et al., 2006). LTK63, a modified and detoxified heat-labile toxin derived from E. coli, has been combined with the fusion protein H1 for nasal immunization and has passed Phase I clinical trials (in London, UK, with PPD-negative subjects). A strong and sustained Th-1 response mediated by IFN-γ-secreting CD4+ T cells was observed, leading to long-lasting protection against tuberculosis and boosting prior BCG-induced immunity (Dietrich et al., 2006; Badell et al., 2009).

Local and systemic inflammation ensued without any apparent trigger or autoimmune aetiology (see accompanying Viewpoint by Meng and Strober 6). Characterization of the causative mutations in NLRP3 underlying CAPS has had a direct impact on the clinic, leading to successful therapy of CAPS in the form of IL-1 blockade (Anakinra) 7–11. Interestingly, gout, an inflammatory condition caused by chronic activation of the NLRP3 inflammasome in response to tissue-derived monosodium urate crystals 12, also seems to benefit from IL-1 blockade therapy 13. Nonetheless despite this significant progress, there remain a significant number of patients with recurrent fever syndromes who

respond to IL-1 inhibition but with no demonstrable NLRP3 mutations. A check details recent study has identified mutations in NLRP12 that cause hereditary periodic fever syndromes 14, demonstrating a crucial regulatory role of NLRP12 in the inflammasome pathway and reinforcing the possibility of as yet undiscovered disease-causing mutations in genes along the inflammasome-IL-1β axis. Other well-characterized inflammasomopathies include familial Mediterranean fever 15), pyogenic CT99021 ic50 arthritis with pyoderma gangrenosum and acne syndrome 16), recurrent hydatidiform mole 17, 18 and vitiligo 19, 20. Positional cloning techniques mapped the causative mutations in familial Mediterranean fever to the MEFV gene encoding pyrin, to

the gene encoding PSTPIP1 in pyogenic arthritis with pyoderma gangrenosum and acne

syndrome and to NLRP7 in recurrent hydatidiform mole, whereas SNP association analyses identified NLRP1 as a risk factor for vitiligo and recently linked NLRP3 to CD 21 (see below). The precise mechanisms by which these mutations or SNP lead to disease are not clearly understood (Table 1). For instance, it is unclear whether pyrin is a negative or positive regulator of IL-1β release. It has been suggested that through its direct interaction with the inflammasome adaptor ASC, pyrin inhibits IL-1β activation by competing with caspase-1 and NLRP3 for ASC 15, 22, 23. Paradoxically, Phosphatidylinositol diacylglycerol-lyase pyrin has also been reported to assemble an ASC pyroptosome that activates caspase-1 and induces pyroptosis and IL-1β release 24, 25. PSTPIP1 interacts with pyrin and mutations in PSTPIP1 were shown to enhance this binding, modulating pyrin functions 16, 26. NLRP7 has been proposed as a negative regulator of IL-1β production 27, yet it remains to be determined whether the NLRP7 mutations inactivate this function. Our understanding of how NLR-coupled inflammasomes function in vivo in both normal and disease states will undoubtedly continue to advance over the next few years. Although excessive production of IL-1β by caspase-1 is harmful, as discussed above, its regulated production is critical for the control of pathogenic infections and of severe sepsis.