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Type 2 diabetes, insulin resistance, and obesity are strongly associated and are a major health problem worldwide. Obesity largely results from a sustained imbalance between energy intake and expenditure. Therapeutic approaches targeting metabolic rate may counteract body weight gain and insulin resistance. Bone morphogenic protein 7 (BMP7) has proven to enhance energy expenditure by inducing non-shivering thermogenesis in short-term studies in mice treated with the recombinant protein or adenoviral vectors encoding BMP7 . To achieve long-term BMP7 effects, the use of adeno-associated viral (AAV) vectors would provide sustained production of the protein after a single administration. Here, we demonstrated that treatment of high-fat-diet-fed mice and ob/ob mice with liver-directed AAV-BMP7 vectors enabled a long-lasting increase in circulating levels of this factor. This rise in BMP7 concentration induced browning of white adipose tissue (WAT) and activation of brown adipose tissue, which enhanced energy expenditure, and reversed WAT hypertrophy, hepatic steatosis, and WAT and liver inflammation, ultimately resulting in normalization of body weight and insulin resistance. This study highlights the potential of AAV-BMP7-mediated gene therapy for the treatment of insulin resistance, type 2 diabetes, and obesity., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Aggregation of α-synuclein is associated with neurodegeneration and a hallmark pathology in synucleinopathies. These aggregates are thought to function as prion-like particles where the conformation of misfolded α-synuclein determines the traits of the induced pathology, similar to prion diseases. Still, little is known about the molecular targets facilitating the conformation-specific biological effects, but their identification could form the basis for new therapeutic interventions. High-throughput screening of annotated compound libraries could facilitate mechanistic investigation by identifying targets with impact on α-synuclein aggregation. To this end, we developed a FRET-based cellular reporter in HEK293T cells, with sensitivity down to 6.5 nM α-synuclein seeds. Using this model system, we identified GF109203X, SB202190, and SB203580 as inhibitors capable of preventing induction of α-synuclein aggregation via inhibition of p38 MAPK and PKC, respectively. We further investigated the mechanisms underlying the protective effects and found alterations in the endo-lysosomal system to be likely candidates of the protection. We found the changes did not stem from a reduction in uptake but rather alteration of lysosomal abundance and degradative capacity. Our findings highlight the value high-throughput screening brings to the mechanistic investigation of α-synuclein aggregation while simultaneously identifying novel therapeutic compounds., (© 2021. The Author(s).)

Malaria liver stage infection is an obligatory parasite development step and represents a population bottleneck in Plasmodium infections, providing an advantageous target for blocking parasite cycle progression. Parasite development inside hepatocytes implies a gross cellular insult evoking innate host responses to counteract intra-hepatocytic infection. Using primary hepatocyte cultures, we investigated the role of Kupffer cell-derived hepatocyte growth factor (HGF) in malaria liver stage infection. We found that Kupffer cells from Plasmodium -infected livers produced high levels of HGF, which trigger apoptosis of infected hepatocytes through a mitochondrial-independent apoptosis pathway. HGF action in infected hepatocyte primary cultures results in a potent reduction of parasite yield by specifically sensitizing hepatocytes carrying established parasite exo-erythrocytic forms to undergo apoptosis. This apoptosis mechanism is distinct from cell death that is spontaneously induced in infected cultures and is governed by Fas signaling modulation through a mitochondrial-dependent apoptosis pathway. This work indicates that HGF and Fas signaling pathways are part of an orchestrated host apoptosis response that occurs during malaria liver stage infection, decreasing the success of infection of individual hepatocytes. Our results raise the hypothesis that paracrine signals derived from Kupffer cell activation are implicated in directing death of hepatocytes infected with the malaria parasite.

Objective: To describe the incidence, predisposing factors and management of postoperative vesicoureteral reflux (VUR) after high-pressure balloon dilation to treat primary obstructive megaureter (POM)., Materials and Methods: We have reviewed patients that underwent endoscopic treatment for POM from May 2008 to November 2013. All patients were evaluated with renal ultrasound, voiding cystourethrography and diuretic renogram. Endoscopic treatment was done with high-pressure balloon dilation of the ureterovesical junction under general anesthesia; a double-J stenting was done in all patients. Follow-up was performed with ultrasonography, voiding cystourethrography and a diuretic renogram in all patients., Results: Fifteen boys and five girls with a mean age of 14.18 months (3-103) were reviewed. A total of 22 ureters underwent HPBD to treat POM. Ureterohydronephrosis improves in 19 ureters. After endoscopic treatment, six ureters developed VUR. Four ureters were managed surgically, and in the other two, VUR disappeared in a second cystogram. The presence of parameatal diverticulum in the preoperative cystography and those patients with bilateral POM are factors related to postoperative VUR (p < 0.05). Urinary tract infection after HPBD was observed in four patients, but only one of them was affected with VUR.

Objective: To report the results of fetal cystoscopic laser ablation of posterior urethral valves (PUV) in a consecutive series in two referral centers., Methods: Twenty pregnant women with a presumptive isolated PUV were treated with fetal cystoscopy under local anesthesia. Identification and fulguration of the PUV by one or several firing-contacts with diode laser were attempted. Perinatal and long-term outcomes were prospectively recorded., Results: The median gestational age at procedure was 18.1 weeks (range 15.0-25.6), and median operation time was 24 min (range 15-40). Access to the urethra was achieved in 19/20 (95%) cases, and postoperative, normalization of bladder size and amniotic fluid was observed in 16/20 (80%). Overall, there were 9 (45%) terminations of pregnancy and 11 women (55%) delivered a liveborn baby at a mean gestational age of 37.3 (29.1-40.2) weeks. No infants developed pulmonary hypoplasia and all were alive at 15-110 months. Eight (40% of all fetuses, 72.7% of newborns) had normal renal function and 3 (27.3%) had renal failure awaiting renal transplantation., Conclusion: Fetoscopic laser ablation for PUV can achieve bladder decompression and amniotic fluid normalization with a single procedure in selected cases with anyhydramnios. There is still a significant risk of progression to renal failure pre or postnatally., (© 2014 S. Karger AG, Basel.)

Purpose: The aim of our study is to compare the outcomes of open and laparoscopic pyeloplasty in children less than 12 months of age., Patients and Methods: We reviewed all medical charts of patients less than 12 months old who underwent pyeloplasty from January 2007 to February 2013. We divided them in two groups: Open pyeloplasty (OP) and laparoscopic pyeloplasty (LP). The following data were analyzed: age, sex, weight, US measurements, operative time, hospital stay, complications, and success rate. Quantitative data were analyzed with the Student t test or Mann-Whitney U test, and chi-square test or Fisher test for qualitative data., Results: Fifty-eight patients (46 boys and 12 girls) with a mean age of 4.66 months (±3.05) were included. Mean age was 4.25 months and 5.15 months in OP and LP group respectively. Mean weight was 6.78 kg and 7.02 kg in OP and LP groups. There were no statistical differences in age, weight, and sex between OP and LP groups. There were no statistical differences in preoperative ultrasonography measurements. Mean posterior-anterior (PA) pelvis diameter was 28.57 mm and 23.94 mm in OP and LP groups, respectively. Mean calices diameter were 10.86 mm and 10.96 mm in OP and LP groups, respectively. Mean operative time was 129.53 minutes in the OP group and 151.92 minutes in the LP group with statistical differences (P=0.018). Mean hospital stay was 6.34 days in the OP group and 3.46 in the LP group with statistical differences (P<0.05). No intraoperative and postoperative complications were found in either group. Hydronephrosis improved in all patients, and no patient needed a repeated pyeloplasty., Conclusion: The laparoscopic approach of Anderson-Hynes pyeloplasty in patients less than 12 months old is a safe procedure with the same outcomes as the open approach.

Plasmodium liver stage infection is a target of interest for the treatment of and vaccination against malaria. Here we used forward genetics to search for mechanisms underlying natural host resistance to infection and identified triggering receptor expressed on myeloid cells 2 (TREM2) and MHC class II molecules as determinants of Plasmodium berghei liver stage infection in mice. Locus belr1 confers resistance to malaria liver stage infection. The use of newly derived subcongenic mouse lines allowed to map belr1 to a 4-Mb interval on mouse chromosome 17 that contains the Trem2 gene. We show that Trem2 expression in the nonparenchymal liver cells closely correlates with resistance to liver stage infection, implicating TREM2 as a mediator of the belr1 genetic effect. Trem2-deficient mice are more susceptible to liver stage infection than their WT counterparts. We found that Kupffer cells are the principle cells expressing TREM2 in the liver, and that Trem2(-/-) Kupffer cells display altered functional activation on exposure to P. berghei sporozoites. TREM2 expression in Kupffer cells contributes to the limitation of parasite expansion in isolated hepatocytes in vitro, potentially explaining the increased susceptibility of Trem2(-/-) mice to liver stage infection. The MHC locus was also found to control liver parasite burden, possibly owing to the expression of MHC class II molecules in hepatocytes. Our findings implicate unexpected Kupffer-hepatocyte cross-talk in the control Plasmodium liver stage infection and demonstrate that TREM2 is involved in host responses against the malaria parasite.

Objective: To report our experience of laparoscopic heminephroureterectomy (Hnu) in pediatric patients with duplex anomalies, in comparison to open surgery., Patients and Methods: Retrospective review of data from patients who underwent Hnu from 2005 to 2008 was performed. The patients were divided into two groups: laparoscopic (LHnu) and open surgery (OHnu). Laparoscopic surgery was performed by transperitoneal approach in majority of cases. Open surgery was performed by retroperitoneal approach in all cases., Results: Group LHnu: nine patients (8 females, 1 male) with median age of 14 months (range 3-205). Transperitoneal approach was performed in eight patients. Mean operative time was 182 min (CI 95% 146-217). No conversion to open surgery was necessary and there were no complications. Mean hospital stay was 2.44 days (CI 95% 1.37-3.52). Group OHnu: eight patients (3 females, 5 males) underwent nine heminephrectomies at median age of 6.9 months (range 1-12). Mean operating time was 152 min (CI 95% 121-183). There were no complications and mean hospital stay was 4.38 (CI 95% 2.59-6.16) days. Statistical analysis showed no statistically significant difference (P>0.05) in operating time between groups while mean hospital stay was significant (P=0.021)., Conclusion: The laparoscopic approach is feasible, safe, reduces hospital stay, does not increase operating time and has better cosmetic results. We believe this should be the first option for heminephrectomy., (Copyright © 2009 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

LPS is a strong stimulator of the innate immune system and inducer of B lymphocyte activation. Two TLRs, TLR4 and RP105 (CD180), have been identified as mediators of LPS signaling in murine B cells, but little is known about genetic factors that are able to control LPS-induced cell activation. We performed a mouse genome-wide screen that aside from identifying a controlling locus mapping in the TLR4 region (logarithm of odds score, 2.77), also revealed that a locus closely linked to the MHC region (logarithm of odds score, 3.4) governed B cell responsiveness to LPS stimulation. Using purified B cells obtained from MHC congenic strains, we demonstrated that the MHC(b) haplotype is accountable for higher cell activation, cell proliferation, and IgM secretion, after LPS stimulation, when compared with the MHC(d) haplotype. Furthermore, B cells from MHC class II(-/-) mice displayed enhanced activation and proliferation in response to LPS. In addition, we showed that the MHC haplotype partially controls expression of RP105 (a LPS receptor molecule), following a pattern that resembles the LPS responsiveness phenotype. Together, our results strongly suggest that murine MHC class II molecules play a role in constraining the B cell response to LPS and that genetic variation at the MHC locus is an important component in controlling B cell responsiveness to LPS stimulation. This work raises the possibility that constraining of B cell responsiveness by MHC class II molecules may represent a functional interaction between adaptive and innate immune systems.