However, the use of an echinocandin + liposomal amphotericin B fo

However, the use of an echinocandin + liposomal amphotericin B formulation is a better option as indicated by both animal and human data.[31-35] All authors declare no conflicts of interest. “
“Immunocompromised patients have Decitabine mw a high risk for invasive fungal diseases (IFDs). These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Empirical treatment is regarded as the standard of care for granulocytopenic

patients who remain febrile despite broad-spectrum antibiotics. However, this strategy can bear a risk of overtreatment and subsequently induce toxicities and unnecessary treatment costs. Pre-emptive antifungal therapy is now increasingly used to close the time gap between delayed initiation for proven disease and empirical treatment for anticipated infection without further laboratory or radiological evidence of fungal disease. Currently, some new non-invasive microbiological and laboratory methods, like the Aspergillus-galactomannan sandwich-enzyme immunoassay (Aspergillus GM-ELISA), 1,3-β-d-glucan assay or PCR techniques

have been developed for a better diagnosis Nutlin-3 datasheet and determination of target patients. The current diagnostic approaches to fungal infections and the role of the revised definitions for invasive fungal infections, now IFDs, will be discussed in this review as well as old and emerging approaches to empirical, pre-emptive and targeted antifungal therapies in patients with haemato-oncological malignancies. “
“Prosthetic joint infections (PJI) are rarely due to fungal agents and if so they are mainly caused by Candida strains. This case represents a PJI caused by a multi-drug resistant Pseudallescheria apiosperma, with poor in vivo response to itraconazole and voriconazole. This case differs also by the way of infection, since the Sorafenib chemical structure joint infection did

not follow a penetrating trauma. In the majority of cases, Scedosporium extremity infections remain local in immunocompetent individuals. We report a persistent joint infection with multiple therapeutic failures, and subsequent amputation of the left leg. Detailed clinical data, patient history, treatment regime and outcome of a very long-lasting (>4 years) P. apiosperma prosthetic knee infection in an immunocompetent, 61-year-old male patient are presented with this case. The patient was finally cured by the combination of multiple and extensive surgical interventions and prolonged antifungal combination therapy with voriconazole and terbinafine. Prosthetic joint infection (PJI) is mainly caused by bacteria and rarely by human-pathogenic yeast such as Candida strains.1–4Aspergillus fumigatus5 or other filamentous fungi are only exceptionally involved.

1) Selectins are a family of three cell adhesion molecules known

1). Selectins are a family of three cell adhesion molecules known as L-, P- and E-selectin. Their primary role in recruitment involves weak binding Opaganib concentration to their specific ligand on the surface of monocytes and the

endothelium, which reduces their flow rate velocity and mediates rolling along the endothelium (Fig. 1). During this low-affinity rolling phase, monocytes are exposed to a plethora of secreted cytokines and chemoattractants, which subsequently induces the activation of integrins, which are a large family of heterodimeric transmembrane glycoproteins that connect cells to their microenvironment mediating cell-to-cell adhesion. Integrins present on the surface of monocytes include leukocyte SRT1720 purchase functioning associated antigen (LFA)-1, macrophage adhesion ligand (Mac)-1 commonly referred to as CD11b, and very late activation antigen (VLA)-4.

These integrins interact with their endothelial counter-receptors, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. Binding of LFA-1 and Mac-1 to ICAM-1, and VLA-1 to VCAM-1 mediates firm adhesion of monocytes to the endothelium allowing for diapedesis to occur into surrounding tissue (Fig. 1). Blockade of E- and P-selectins in rodent models of ischaemia–reperfusion (IR) injury reduces renal macrophage recruitment, which subsequently leads to amelioration of the pro-inflammatory response and reduced tubular damage and interstitial fibrosis production.[44-47] Knockout (KO) mice and neutralizing antibodies against ICAM-1 and its binding partners, LFA-1

and CD11b, also prevent monocyte recruitment medroxyprogesterone and consequently induce less severe damage in several renal disease models including glomerulonephritis (GN),[48-51] diabetic nephropathy,[52-54] unilateral ureteral obstruction (UUO)[55] and IR injury.[56] Following selectin-mediated adhesion of monocytes to the endothelium, increased expression of chemokines and chemokine receptors induce a chemotactic gradient that promotes firm integrin-mediated adhesion and transmigration across the vasculature and into tissue (Fig. 1). Most kidney cells including tubular epithelial cells (TECs), podocytes, mesangial and endothelial cells have the potential to produce chemokines and express chemokine receptors, with a rapid expression induced by the following pro-inflammatory cytokines and mediators TNF-α, IL-1β, interferon (IFN)-γ, lipopolysaccharide (LPS) and reactive oxygen species. CCL2 is the most important chemokine in mobilizing monocytes to the kidney following damage. CCL2 binds to its receptor CCR2, which is highly expressed on inflammatory monocytes.[16] Along with CCL2/CCR2 signalling, CX3CL1, CCL5, CCL3, CCL4, CXCL8, and their corresponding receptors CX3CR1, CCR1, CCR5 and CXCR2 have also been implicated in monocyte recruitment during renal inflammation as recently reviewed.

Using OVA peptide variants with different affinity for the OVA-sp

Using OVA peptide variants with different affinity for the OVA-specific OT-I TCR, it was shown that peptides with high affinity induce high amounts of IRF4 [22, 25], whereas peptides with intermediate or low affinity provoke intermediate or low quantities of IRF4, respectively. This dependency of IRF4 expression amounts on the peptide affinity for OT-I TCR was demonstrated in vitro and also in vivo during infection with recombinant Listeria monocytogenes that expressed the respective peptide variants [22]. At the molecular level, IRF4 expression levels seem to depend on the activity of mammalian target of rapamycin (mTOR). Thus, high IRF4 expression following strong TCR stimulation by high-affinity

ligands correlated with elevated activity of mTOR, whereas inhibition of the mTOR pathway caused downregulation of IRF4 [25]. As recently shown, IRF4 expression is also dependent on the activity of IL-2-inducible T-cell kinase (ITK) [26]. Using inhibitors for both selleck ITK and mTOR, it was demonstrated that these two signaling pathways cooperate for IRF4 induction [25]. Earlier studies had already concluded that the transcription factor C-REL, a member of the NF-κB family, is also crucial for the induction of IRF4 in response to TCR

stimulation [27]. Moreover, treatment with cyclosporine Buparlisib in vitro A blocked upregulation of IRF4, suggesting that NFAT signaling also contributes to this process [3]. Finally, FOXP3 regulates IRF4 expression in regulatory T (Treg) cells [19], as do STAT3 in T helper 17 (Th17) cells [28] and STAT6 in Th9 cells [29], whereas T-BET directly represses IRF4 expression in Th1 and Th17 cells [30]. In response to signals induced by antigen recognition

and cytokines, naïve CD4+ T cells differentiate into distinct subpopulations that are characterized by specific effector functions and cytokine profiles. This subdivision is based on the expression of lineage-specific transcription factors, which function as “master regulators” for specific Th-subset properties (Fig. 1). IL-12 drives the differentiation of Th1 cells, which produce IFN-γ, express the transcription factor T-BET (encoded by T-box 21), and clear intracellular Gemcitabine concentration pathogens. Th2 cells are induced by IL-4, secrete IL-4, IL-5, and IL-13, and express the master regulator GATA-binding protein 3 (GATA3). IL-4 in combination with transforming growth factor-β (TGF-β) induces the differentiation of Th9 cells, which produce high levels of IL-9 and IL-10. The lineage-specifying transcription factor for Th9 cells was suggested to be PU.1, which however was previously considered by the same group to characterize an IL-4 low producing subset of Th2 cells [31]. Although Th2 and Th9 cell subsets both contribute to immunity against helminths, Th9 cells are additionally involved in antitumor immunity. The cytokines IL-6 or IL-21 can act alone to induce T follicular helper (Tfh) cells, which express the master regulator BCL-6.

However, we showed that anti-M3R antibodies against these linear

However, we showed that anti-M3R antibodies against these linear epitopes exactly influenced Ca influx via M3R in HSG cells. Therefore, we suggest that these linear peptides might consist of the conformational epitopes on the M3R. Several B cell epitopes were identified on the extracellular domains, and some SS patients were reactive to several extracellular domains other than the second extracellular loop. The second extracellular loop of M3R has been the focus of our interest in epitopes and function of anti-M3R antibodies [4,5,9,10]. Recently, Koo et al.[6] reported that the third extracellular loop represents a functional ZVADFMK epitope bound by SS-IgG. Selleckchem GSK3 inhibitor In contrast

to these results, we found in the present study that antibodies to the second extracellular loop of M3R inhibited the increase of (Ca2+)i induced by cevimeline hydrochloride in a functional assay using HSG cells. This inhibitory effect of anti-M3R antibodies might explain the reduction in salivary secretion in some SS patients. Our data also demonstrated that antibodies against the third extracellular loop did not have an effect on the increase in (Ca2+)i, while antibodies against the N-terminal and first extracellular

loop enhanced the increase in (Ca2+)i. These results indicate that the effects of anti-M3R antibodies on the secretion of saliva could be different from these epitopes, although further experiments using antibodies from more patients are necessary. Although the molecular mechanisms on the difference among individual B cell epitopes have not been elucidated, we could propose the following three possibilities. The first is that antibodies against the second extracellular domain GNAT2 of M3R directly inhibit

the intracellular signal pathway, resulting in the decrease of Ca2+ influx and reduction of saliva. In contrast, antibodies against N-terminal region and the first extracellular domain of M3R might enhance the intracellular signalling and increase of Ca2+ influx. The second is that anti-M3R antibodies binding to the second extracellular domain could inhibit the M3R agonist, and then antibodies suppress indirectly the stimulation of Ca2+ influx. The third is that anti-M3R antibodies influence the expression of M3R molecules on HSG. Some antibodies which target the N-terminal region or the first extracellular loop of M3R may be able to up-regulate expression of M3R and enhance Ca2+ influx, whereas the other antibodies against the second extracellular domain might down-regulate the expression of M3R on HSG, resulting in a reduction of Ca2+ influx. It has been reported that the expression of M3R in salivary glands could be affected by anti-M3R antibodies in patients with SS [1].

Thus, this study reveals that pneumolysin induces the proinflamma

Thus, this study reveals that pneumolysin induces the proinflammatory cytokine expression in a time-dependent manner. Inflammation triggered by infections is one of the counteractions that occur

in the host to facilitate pathogen clearance by recruitment of leukocytes. An excessive inflammatory response, however, is harmful to the host because it causes severe tissue damage (Hersh et al., 1998). Tight control of inflammation is thus critical for host immune defense and can be achieved by balancing the expression of proinflammatory FK506 price cytokines and anti-inflammatory cytokines (Dinarello, 2000). Proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) serve to promote inflammation by promoting a diverse

BYL719 order range of activities including the induction of adhesion molecules required for the transmigration of leukocytes to infection sites (Dinarello, 2000). The release of proinflammatory cytokines can be triggered by various bacterial products including LPS of Gram-negative bacteria, peptidoglycan of Gram-positive bacteria or specific molecules from diverse microorganisms (Henderson et al., 1996). Gram-positive bacterium Streptococcus pneumoniae is an important cause of morbidity and mortality in humans, especially among young children (Bluestone et al., 1992). Among the numerous virulence factors identified in PDK4 S. pneumoniae to date, the cell wall plays an important role in initiating inflammation during infection, which is characterized by the production of proinflammatory cytokines and leukocyte influx (Tuomanen

et al., 1985; Bruyn & van Furth, 1991; Cundell et al., 1995). The cell wall components consist of polysaccharides and teichoic acid, which are recognized by Toll-like receptor 2 (TLR2) (Yoshimura et al., 1999). On the surface of the cell wall, there are a range of cell surface-associated proteins involved in the pathogenesis of S. pneumoniae during infection, including autolysin, pneumococcal surface protein A (PspA), PspC, hyaluronidase, neuraminidase, and pneumococcal surface antigen A (PsaA) (Mitchell, 2006). On the other hand, pneumolysin, which is 53 kDa in size, is localized in the cytoplasm and seems to be released during infections by the action of pneumococcal autolysis from virtually all clinical isolates (Canvin et al., 1995; Wheeler et al., 1999). However, it has been reported recently that the pneumolysin is also localized to the cell wall compartment (Price & Camilli, 2009). The upper respiratory tract is the ecological niche for various bacterial species including S. pneumoniae and nontypable Haemophilus influenzae (NTHi) (Faden et al., 1990; Givon-Lavi et al., 2002). NTHi has been identified as a major pathogen causing otitis media (OM) and pneumonia along with S. pneumoniae (Gok et al., 2001; Ozyilmaz et al., 2005).

, 1999) Imiquimod at 0 5 μg mL−1 was optimal for human PBMC prod

, 1999). Imiquimod at 0.5 μg mL−1 was optimal for human PBMC production of TNF-α, IFN-γ, IL-1, IL-6, IL-8, IL-10, IL-12, GM-CSF, G-CSF, and MIP-1α, with a 24-h incubation (Stanley, 2002). Although we H 89 nmr did not define in the present

study as to which cells in murine PBMC elaborate the cytokines we identified, other studies, with imiquimod, have indicated that the cells in human PBMC producing proinflammatory cytokines are monocyte/macrophages and B cells (Megyeri et al., 1995). Analysis of cellular requirements in human PBMC for cytokine production induced by imiquimod indicated that T-lymphocytes were responsible for IFN-γ production, but required IL-12 and IFN-γ from imiquimod-stimulated macrophages (Wagner et al., 1999). Other studies with TLR-7 agonists suggest that monocytes are the main cells found in abundance in human peripheral blood that are responsive. This was also true of the stronger response induced by TLR-8 and TLR-7/8 agonists, as would be relevant to 3M-003 (Gorden et al., 2005). Although responses of mouse spleen learn more cells to imiquimod

have been reported (Wagner et al., 1999), we are not aware of studies using mouse PBMC and imiquimod. Here, we report novel findings that 3M-003-stimulated mouse PBMC produce high levels of TNF-α and IL-12, but little to no IFN-γ in the time frame examined. Supernatants from mouse PBMC cultures containing high levels of TNF-α and IL-12 were sufficient to induce enhanced candidacidal activity in macrophages, neutrophils, and monocytes. That macrophages are upregulated by PBMC-produced factors in supernatants was evidenced by the 3M-003 carryover in supernatants being much less than the concentrations we show required for consistent direct macrophage activation. Supernatant neutralization and/or addition (e.g. TNF-α, IL-12, or TNF-α+IL-12) experiments are warranted to further elucidate the phagocyte activation mechanism induced by supernatants. These compounds are potentially useful for antifungal therapy.

This could especially be important in the common entity, neonatal candidiasis (Chapman & Faix, 2003), because TLR-8 agonists appear to be particularly potent activators of the neonatal immune system (Philbin & Levy, 2007). It would be of interest to ascertain whether the antifungal activity would extend to hyphal forms and to other fungi. Systemic use of these CYTH4 compounds is under study as an antineoplastic (Dudek et al., 2007; Harrison et al., 2007; Smith et al., 2007). Cytokine induction has been noted after oral administration (Dahl, 2002; Harandi et al., 2003). An additional possible mechanism of action of the imidazoquinolines is TLR-independent immunomodulation by antagonism of adenosine receptors (Philbin & Levy, 2007). Agonists of human TLR-8 can also reverse the function of regulatory T cells; caution may need to be exercised for possible overabundance of an inflammatory response with such agents (Philbin & Levy, 2007).

Akt2 and Akt3 seem not to play a major role in placental angiogen

Akt2 and Akt3 seem not to play a major role in placental angiogenesis because Akt2-null mice display a type-II diabetes-like syndrome and mild growth retardation and age-dependent loss of adipose tissue [121] and Akt3 has been shown to be important in postnatal brain development [31]. The potent vasodilator NO is generated during the conversion of l-arginine to l-citrulline by a family of NO synthases (NOS), including eNOS, inducible NOS (iNOS) and neuronal NOS (nNOS) [106]. Placental

NO production increases during pregnancy, which selleck products is highly correlated with eNOS, but neither iNOS nor nNOS expression [127, 88], suggesting that eNOS is the major NOS isoform responsible for the increased NO in the placenta. During normal sheep pregnancy placental NO production increases [127, 69] in association with elevated local expression of VEGF and FGF2, vascular density, and blood flow to the placentas [128, 9], suggesting that eNOS-derived NO is important in placental angiogenesis. Indeed, the eNOS-derived NO is critical for the VEGF and FGF2- stimulated angiogenesis in vitro [76, 24] and in vivo [44]. The eNOS-derived

NO is also a potent vasodilator in the perfused human muscularized fetoplacental vessels [87], which might be critical for the maintenance of low vascular resistance in the fetoplacental circulation in pregnant sheep in vivo [18]. Early studies have shown that pharmacological NOS inhibition by l-NG-nitroarginine methyl ester results in preeclampsia-like symptoms and reduced litter size in rats [11]. This has been confirmed in eNOS-null mice whose dams develop proteinuria

[68] and fetuses PI3K inhibitor are growth restricted [68, 67, 66]. In eNOS-null pregnant mice, uteroplacental remodeling is impaired and their vascular adaptations to pregnancy are dysregulated [66, 114], resulting in decreased uterine and placental blood flows and greatly reduced vascularization in the placenta [67, 66]. These Lonafarnib concentration studies suggest that eNOS is critical for both vasodilation and angiogenesis, that is, the two rate-limiting mechanisms for blood flow regulation at the maternal–fetal interface. Numerous studies have shown that activation of the MAPK (ERK1/2, JNK1/2, and p38MAPK), PI3K/Akt1, and eNOS/NO pathways is critical for VEGF- and FGF2-stimulated angiogenesis in various endothelial cells. In placental endothelial cells, we have shown that activation of the MAPK pathways are important for the differential regulation of placental endothelial cell proliferation, migration, and tube formation (i.e., in vitro angiogenesis) in response to VEGF and FGF2 stimulation in vitro [130, 82, 35, 36]. Inhibition of the ERK1/2 pathway partially attenuates the FGF2-stimulated cell proliferation, whereas it completely blocks the VEGF-stimulated cell proliferation as well as the VEGF- and FGF2-stimulated cell migration [75, 76, 130, 35, 36].

001); controls had a coronary calcium score of 0 (IQR 0) Black r

001); controls had a coronary calcium score of 0 (IQR 0). Black race remained a significant negative predictor for coronary calcification after adjustment, prevalence ratio = 0.14 and 95% confidence interval (CI): 0.0–0.53. Vascular

calcification was not associated with any ambulatory blood pressure parameter. Using receiver operator characteristic curves, an abdominal aorta calcification score of ≥1 showed an area under the curve of 0.83 to predict a coronary calcium score ≥ 10. Conclusion:  Black race appears to protect from vascular calcification in South African CKD-5D patients and this warrants further study regarding find more the underlying mechanism. The abdominal X-ray is a useful screening tool for coronary calcification. “
“Aim:  Continuous ambulatory peritoneal dialysis (CAPD) is a major form of therapy for chronic end stage renal disease patients, which may lead to CAPD-associated peritonitis. The spectrum of organisms associated with CAPD peritonitis varies geographically. Not much data is available regarding this from southern India. The aim of this study was to characterize the spectrum of organisms associated with CAPD peritonitis in

see more this region and observe the utility of automated blood culture systems to culture peritoneal dialysate. Methods:  Ninety episodes of peritonitis were cultured over a span of 3 years using an automated blood culture system. Results:  The yield of culture positivity was 50%. The most predominant organism was found to be coagulase-negative Staphylococcus spp. (21.1%) followed by Enterobacteriaceae (12.2%). Other organisms isolated were non-fermenting Gram-negative bacilli (4.4%), Pseudomonas aeruginosa (3.3%), α-haemolytic Streptococci (3.3%), before Candida spp. (2.2%), Staphylococcus aureus (1.1%), β-haemolytic Streptococci (1.1%) and Micrococci (1.1%). A high degree of resistance to third generation cephalosporins (66.7%) was noted amongst the Gram-negative bacilli. Also, all the Gram-negative bacilli isolated from patients who had prior empirical antibiotic therapy of ceftazidime before arrival at

the centre, were resistant to third generation cephalosporins. Conclusion:  A varied spectrum of organisms isolated from peritoneal dialysate compared to the global scenario was observed. Also, a high degree of third generation cephalosporin resistance was noted amongst the Gram-negative bacilli. Thus, it is suggested that the empirical therapy should be dependent on the local epidemiology. “
“Preterm birth (birth prior to 37 completed weeks of gestation) may occur at a time when the infant kidney is very immature and nephrogenesis is often ongoing. In autopsied preterm human kidneys and in a baboon model of preterm birth it has been shown that nephrogenesis continues after preterm birth, with a significant increase in the number of glomerular generations and number of nephrons formed within the kidney after birth.

At 7 months, by contrast, infants appear to react to the higher f

At 7 months, by contrast, infants appear to react to the higher frequency of coronal consonants (Experiment 3a & b). The present study thus demonstrates that infants become sensitive to nonadjacent phonological dependencies between 7 and 10 months. It further establishes a change between

these two ages from sensitivity to local properties to nonadjacent dependencies in the phonological domain. “
“Effortful CH5424802 cell line control (EC) refers to the ability to inhibit a dominant response to perform a subdominant one and has been shown as protective against a myriad of difficulties. Research examining precursors of EC has been limited to date, and in this study, infancy contributors to toddler EC were examined. Specifically, parent/family background variables (e.g., education, selleck chemicals llc income), maternal temperament, perceived stress, and internalizing symptoms were addressed, along with infant temperament: positive

affectivity/surgency (PAS), negative emotionality (NE), and regulatory capacity/orienting (RCO); and laboratory observation-based indicators of attention. Infant attention indexed by the latency to look away after initially orienting to the presented stimuli emerged as an important predictor of later EC, after accounting for other child and parent/family attributes, with shorter latencies predicting higher levels of EC. Mothers’ extraversion and parenting stress were the only parent/family attributes to significantly contribute to

the prediction of toddler EC, with the former promoting and the latter undermining the development of EC. Infant temperament factors were also examined as a moderator of parent/family influences, with results indicating a significant interaction between mothers’ EC and infant RCO, so that children with greater RCO and mothers high in EC exhibited the highest EC scores in toddlerhood. “
“Two preferential-reaching experiments explored 5- and 7-month-olds’ sensitivity to pictorial depth cues. In the first experiment, infants viewed a display in which texture gradients, linear perspective of the surface contours, and relative height in the visual field Urease provided information that two objects were at different distances. Five- and 7-month-old infants reached preferentially for the apparently nearer object under monocular but not binocular viewing conditions, indicating that infants in both age groups respond to pictorial depth cues. In the second experiment, texture gradients and linear perspective of the surface contours were eliminated from the experimental display, making relative height the sole pictorial depth cue. Seven-month-olds again reached more often for the apparently nearer object under monocular, but not binocular viewing conditions.

11 FGF-23 is a 251 amino acid protein that is predominantly synth

11 FGF-23 is a 251 amino acid protein that is predominantly synthesized and secreted by cells from an osteoblast lineage,12,13 and has an estimated half-life in the circulation

of 58 min.14 FGF-23 can be detected with an enzyme-linked immunosorbent assay, in which antibodies detect N-terminal and C-terminal portions. An alternative C-terminal assay recognizes only the C-terminal fragments selleck products of active and inactive FGF-23.15 Early debate focused on whether the circulating FGF-23 is biologically active or whether the available assays also detect inactive compounds. A recent study compared the immune-based and intact FGF-23 assays with an assessment of FGF-23 bioactivity and western blot characterization of circulating FGF-23.16 The assays strongly correlated with each other and with FGF-23 bioactivity. The western blot detected only intact FGF-23 suggesting that virtually all circulating FGF-23 is biologically active. About 80% of total body phosphate is present in bone, 9% in skeletal muscle and only 0.1% in extracellular fluid.17 The distal duodenum is responsible for most phosphate absorption, a process actively mediated by calcitriol.18,19 In the kidneys about 95% of filtered phosphate is reabsorbed in the proximal tubular cells, a process driven by a high extracellular sodium gradient that is actively maintained

by a Na+-K+-ATPase.18 This is further facilitated by Na-P co-transporters on the luminal side of the tubular cells, which are modulated by parathyroid hormone (PTH) and calcitriol.20 FGF-23 induces phosphaturia by reducing the number selleck screening library of co-transporters on the renal tubular cells, as well as mitigating the effects of calcitriol on intestinal absorption.21 Leukocyte receptor tyrosine kinase PTH can stimulate phosphaturia in a similar manner; however, studies from transgenic mice suggest that FGF-23 induced phosphaturia is not PTH dependent.22 The biological effects of FGF-23 are exerted through activation of FGF receptors (FGF-R). Klotho is a trans-membrane

protein originally described in mice with a phenotype of accelerated ageing and atherosclerosis.23 Klotho directly interacts with FGF-R, allowing it to bind FGF-23 with a higher affinity and increased specificity.13,24 The activation of FGF-R therefore occurs in a Klotho-dependent manner.24 Klotho-deficient mice manifest a similar phenotype to FGF-23 deficient mice despite high circulating levels of the FGF-23.8 The tissue selectivity of FGF-23 may be conferred by Klotho expression in the renal tubule and parathyroid glands.25 The expression of FGF-R and Klotho in the parathyroid glands also supports a regulatory effect of FGF-23 on PTH secretion.26 The main known physiological role of FGF-23 is to regulate urinary phosphate excretion and maintain a stable serum phosphate (Fig. 1).27 An important secondary role is the counter-regulation (against PTH) of vitamin D biosynthesis.