Placental Toll-Like Receptor 3 and Toll-Like Receptor 7/8 Activation Contributes to Preeclampsia in Humans and Mice

Preeclampsia (PE) is a pregnancy-specific hypertensive syndrome characterized by excessive maternal immune system activation, inflammation, and endothelial dysfunction. Toll-like receptor (TLR) 3 activation by double-stranded RNA (dsRNA) and TLR7/8 activation by single-stranded RNA (ssRNA) expressed by viruses and/or released from necrotic cells initiates a pro-inflammatory immune response; however it is unknown whether viral/endogenous RNA is a key initiating signal that contributes to the development of PE. We hypothesized that TLR3/7/8 activation will be evident in placentas of women with PE, and sufficient to induce PE-like symptoms in mice. Placental immunoreactivity and mRNA levels of TLR3, TLR7, and TLR8 were increased significantly in women with PE compared to normotensive women. Treatment of human trophoblasts with the TLR3 agonist polyinosine-polycytidylic acid (poly I:C), the TLR7-specific agonist imiquimod (R-837), or the TLR7/8 agonist CLO97 significantly increased TLR3/7/8 levels. Treatment of mice with poly I:C, R-837, or CLO97 caused pregnancy-dependent hypertension, endothelial dysfunction, splenomegaly, and placental inflammation. These data demonstrate that RNA-mediated activation of TLR3 and TLR7/8 plays a key role in the development of PE

The use of a string with a stent for self-removal following ureteroscopy: A safe practice to remain

Abstract objectives: To examine the safety and effectiveness of the use of a stent with a string attached after ureteroscopy (URS) for self-removal of the stent by the patient. Patients and methods: After Institutional Review Board approval, a retrospective chart review was performed concerning patients who underwent URS and received an indwelling stent with or without a string attached to the stent (94 vs 349, respectively). Amongst the string group patients received a single- or a double-arm-stringed stent (31 vs 63, respectively). Statistical analyses included chi-squared and Student’s t-tests. Results: The string group consisted of 94 procedures, in which 59.6% of the patients were male with a mean (SD) age of 50.0 (16.5) years. In the no-string group, 51.3% of the 349 procedures were performed in males and the mean (SD) age was 54.9 (18.1) years. Complication rates were 12.8% in the string group and 14.0% in the no-string group (P = 0.867). In the string group, 17.0% of the patients returned to the Emergency Department, whilst 15.8% of the no-string patients returned (P = 0.753). The complication rate in the single- and double-arm groups were 12.9% and 12.7%, respectively (P > 0.910). Self-removal of stents was successful in 94.7% of patients (89/94). Conclusions: The use of a stent with a string after URS appears safe and effective. Few patients had difficulty removing their stents and complication rates were similar in the groups with and without a string attached to their stents. Single- and double-arm-stringed stents have similar complication rates. Keywords: Ureteric stent, Ambulatory care, Endourology, Urinary tract obstruction, Obstructive uropathy, Outpatient procedur

Intraabdominal pressure in women during CrossFit exercises and the effect of age and parity

To determine intraabdominal pressure (IAP) in women during CrossFit and to determine whether parity, age, or CrossFit experience affects IAP during CrossFit exercises, we evaluated 10 women: 5 experienced and active CrossFitters and 5 who were not regularly engaged in CrossFit. A Laborie urodynamics abdominal pressure probe with the Goby wireless system measured IAP during 10 repetitions of 13 different CrossFit exercises. Women had a mean age of 36 years. A significant difference was found between mean peak IAP of the 5 parous vs the 5 nulliparous women (P = 0.009). Experience with CrossFit did not affect mean peak IAP achieved with exercise. In some exercises, there was a significant change in IAP as participants progressed through repetitions (P = 0.003 for back squats and 0.04 for sit-ups). Participants achieved IAP values that were markedly higher than those previously published

Targeting newly identified ERβ/TGF‐β1/SMAD3 signals with the FDA‐approved anti‐estrogen Faslodex or an ERβ selective antagonist in renal cell carcinoma

Renal cell carcinoma (RCC) has the third highest mortality rate among urological tumors, and 20–30% of RCC patients present with metastatic RCC at the time of diagnosis. Although recent studies have indicated that estrogen receptor β (ERβ) could play promoting roles in RCC progression, the detailed mechanisms remain to be clarified. In the present study, we found that expression of ERβ, but not ERα, increases with tumor stage and grade, and also observed that modification of ERβ signals using estrogens/anti‐estrogens, shRNA knockdown of ERβ and overexpression of ERβ using ectopic cDNA affects RCC cell proliferation, migration and invasion. Mechanism analysis revealed that ERβ can promote RCC cell invasion via an increase in transforming growth factor β1 (TGF‐β1)/SMAD3 signals, and interrupting TGF‐β1/SMAD3 signals with a TGFβR1 inhibitor can reverse/block ERβ‐increased RCC cell migration. Importantly, preclinical analyses using in vivo mouse models of RCC revealed that targeting of this newly identified ERβ/TGF‐β1/SMAD3 pathway with either the FDA‐approved anti‐estrogen ICI182,780 (Faslodex) or a selective ERβ antagonist 4‐[2‐phenyl‐5,7 bis(trifluoromethyl)pyrazolo[1,5‐a]pyrimidin‐3‐yl]phenol can significantly reduce RCC tumor growth and invasion, which may be suitable as the basis for novel therapies to more effectively suppress metastatic RCC

TLR3/7/8 activation in pregnant mice caused PE-like symptoms.

<p>Measures of (A) urinary protein concentration, (B) maternal body weight, (C) spleen weight/body weight, (D) litter weight, and (E) number of total pups/litter and fetal demise/litter in pregnant mice treated with the TLR3 agonist poly I:C, the TLR7 agonist R837, or the TLR7/8 agonist CLO97. Results are expressed as mean + SEM and n = 9 in each group. *p<0.05 vs. P.</p

TLR3/7/8 activation in mice caused pregnancy-dependent hypertension and endothelial dysfunction.

<p>Measures of (A) systolic blood pressure, (B) aortic endothelium-dependent relaxation induced by acetylcholine, and (C) aortic endothelium-independent relaxation induced by sodium nitroprusside in non-pregnant (top panels) and pregnant (bottom panels) mice treated with TLR3 agonist poly I:C, the TLR7 agonist R837, or the TLR7/8 agonist CLO97. Results are expressed as mean ± SEM and the n is given in parentheses. *p<0.05 vs P.</p

Inflammation-related genes significantly (p<0.05 vs. P) altered in placentas of mice treated with a TLR3, TLR7, or TLR7/8 agonist during pregnancy.

<p>P = pregnant, P+TLR3 = pregnant+TLR3 agonist poly I:C, P+TLR7 = pregnant+TLR7 agonist R837, P+TLR7/8 = pregnant+TLR7/8 agonist CLO97. All p<0.05 vs. P, n>3 in each group.</p