Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

© 2017 The Author(s). Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-ΰ B translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-ΰ B signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-k B translocation into the nucleus that resulted in high NF-k B transcription activity. The overall magnitude of NF-k B transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-k B translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-k B transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-k B transcription factor

Are mesenchymal stromal cells immune cells?

Mesenchymal stromal cells (MSCs) are considered to be promising agents for the treatment of immunological disease. Although originally identified as precursor cells for mesenchymal lineages, in vitro studies have demonstrated that MSCs possess diverse immune regulatory capacities. Pre-clinical models have shown beneficial effects of MSCs in multiple immunological diseases and a number of phase 1/2 clinical trials carried out so far have reported signs of immune modulation after MSC infusion. These data indicate that MSCs play a central role in the immune response. This raises the academic question whether MSCs are immune cells or whether they are tissue precursor cells with immunoregulatory capacity. Correct understanding of the immunological properties and origin of MSCs will aid in the appropriate and safe use of the cells for clinical therapy. In this review the whole spectrum of immunological properties of MSCs is discussed with the aim of determining the position of MSCs in the immune system

Let’s talk about SEX: Sexuality and fertility in people with a medical history in pediatric urology

In this article we describe fertility and the sexual aspects of several (pediatric) urological conditions: hypospadias, spina bifida and bladder exstrophy-epispadias. Hypospadias is a very common condition. Especially males with a more severe, proximal hypospadias can develop problems with sexual wellbeing. Approximately 10% experience difficulties with erections and ejaculation. The overall sexual wellbeing seems to be comparable to that of men without hypospadias. Spina bifida patients are sexually active and have just as much sexual desire as the general population. Fertility in general is reduced and female patients need adjusted doses of folic acid preconception. Urine- and fecal incontinence are important negative factors for sexual wellbeing. Bladder exstrophy-epispadias is very rare, but the complexity of this condition requires transition of care and long-term follow-up. Extensive reconstructions may be associated with problems in various phases of life. The cosmetic appearance of the penis is often a point of concern due to a short and wide aspect despite reconstruction. Urological involvement during pregnancy is preferable in mothers with exstrophy. In general, patients with these conditions are in need of good education and guidance. Preferably pro-active, thus initiated by the doctor, and with easy access to a psychologist and/sexologist

Let’s talk about SEX:Sexuality and fertility in people with a medical history in pediatric urology

In this article we describe fertility and the sexual aspects of several (pediatric) urological conditions: hypospadias, spina bifida and bladder exstrophy-epispadias. Hypospadias is a very common condition. Especially males with a more severe, proximal hypospadias can develop problems with sexual wellbeing. Approximately 10% experience difficulties with erections and ejaculation. The overall sexual wellbeing seems to be comparable to that of men without hypospadias. Spina bifida patients are sexually active and have just as much sexual desire as the general population. Fertility in general is reduced and female patients need adjusted doses of folic acid preconception. Urine- and fecal incontinence are important negative factors for sexual wellbeing. Bladder exstrophy-epispadias is very rare, but the complexity of this condition requires transition of care and long-term follow-up. Extensive reconstructions may be associated with problems in various phases of life. The cosmetic appearance of the penis is often a point of concern due to a short and wide aspect despite reconstruction. Urological involvement during pregnancy is preferable in mothers with exstrophy. In general, patients with these conditions are in need of good education and guidance. Preferably pro-active, thus initiated by the doctor, and with easy access to a psychologist and/sexologist.</p

CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases : A Genome-wide Association Study Among Patients with Obstructive Uropathies

Background: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. Objective: To identify genetic variants associated with kidney injury in patients with obstructive uropathy. Design, setting, and participants: We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase. Outcome measurements and statistical analysis: Signs of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at &lt;45%. We used χ2 tests to calculate p values and odds ratios for &gt;600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues. Results and limitations: Despite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10–7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization. Conclusions: This study identified CDH12 as a candidate gene for kidney injury in PUV. Patient summary: We found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition

CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases:A Genome-wide Association Study Among Patients with Obstructive Uropathies

Background: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. Objective: To identify genetic variants associated with kidney injury in patients with obstructive uropathy. Design, setting, and participants: We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase