Renal fibrosis due to multiple cisplatin treatment is exacerbated by kinin B1 receptor antagonism.

Cisplatin is a widely used chemotherapeutic drug, but its side effects are a major limiting factor. Nephrotoxicity occurs in one third of patients undergoing cisplatin treatment. The acute tubular injury caused by cisplatin often leads to a defective repair process, which translates into chronic renal disorders. In this way, cisplatin affects tubular cells, and maladaptive tubules regeneration will ultimately result in tubulointerstitial fibrosis. Kinins are well known for being important peptides in the regulation of inflammatory stimuli, and kinin B1 receptor deficiency and antagonism have been shown to be beneficial against acute cisplatin nephrotoxicity. This study aimed to analyze the effects of kinin B1 receptor deletion and antagonism against repeated cisplatin-induced chronic renal dysfunction and fibrosis. Both the deletion and the antagonism of B1 receptor exacerbated cisplatin-induced chronic renal dysfunction. Moreover, the inhibition of B1 receptor increased tubular injury and tubulointerstitial fibrosis after repeated treatment with cisplatin. The balance between M1/M2 macrophage polarization plays an important role in renal fibrosis. Kinin B1 receptor antagonism had no impact on M1 markers when compared to cisplatin. However, YM1, an M2 marker and an important molecule for the wound healing process, was decreased in mice treated with kinin B1 receptor antagonist, compared to cisplatin alone. Endothelin-1 levels were also increased in mice with B1 receptor inhibition. This study showed that kinin B1 receptor inhibition exacerbated cisplatin-induced chronic renal dysfunction and fibrosis, associated with reduced YM1 M2 marker expression, thus possibly affecting the wound healing process.

Renal fibrosis due to multiple cisplatin treatment is exacerbated by kinin B1 receptor antagonism

Cisplatin is a widely used chemotherapeutic drug, but its side effects are a major limiting factor. Nephrotoxicity occurs in one third of patients undergoing cisplatin treatment. The acute tubular injury caused by cisplatin often leads to a defective repair process, which translates into chronic renal disorders. In this way, cisplatin affects tubular cells, and maladaptive tubules regeneration will ultimately result in tubulointerstitial fibrosis. Kinins are well known for being important peptides in the regulation of inflammatory stimuli, and kinin B1 receptor deficiency and antagonism have been shown to be beneficial against acute cisplatin nephrotoxicity. This study aimed to analyze the effects of kinin B1 receptor deletion and antagonism against repeated cisplatin-induced chronic renal dysfunction and fibrosis. Both the deletion and the antagonism of B1 receptor exacerbated cisplatin-induced chronic renal dysfunction. Moreover, the inhibition of B1 receptor increased tubular injury and tubulointerstitial fibrosis after repeated treatment with cisplatin. The balance between M1/M2 macrophage polarization plays an important role in renal fibrosis. Kinin B1 receptor antagonism had no impact on M1 markers when compared to cisplatin. However, YM1, an M2 marker and an important molecule for the wound healing process, was decreased in mice treated with kinin B1 receptor antagonist, compared to cisplatin alone. Endothelin-1 levels were also increased in mice with B1 receptor inhibition. This study showed that kinin B1 receptor inhibition exacerbated cisplatin-induced chronic renal dysfunction and fibrosis, associated with reduced YM1 M2 marker expression, thus possibly affecting the wound healing process.

A comparison between flow-regulated and adjustable valves used in hydrocephalus during infancy.

INTRODUCTION: Ventriculoperitoneal shunt insertion during the neonatal period and early infancy is associated with a high rate of shunt failure when compared to the adult population. Furthermore, the function of flow-regulated valves and differential pressure valves may be different in neonatal hydrocephalus. METHODS: A retrospective case series of all primary shunt procedures carried out during or immediately following the neonatal period, from August 2011 to February 2018 at Sheffield Children's Hospital. The total sample size was 55. This included 34 patients with adjustable valves (Miethke ProGav) and 21 with flow-regulated valves (Orbis-Sigma); however, only 53 had adequate follow-up. RESULTS: The overall 1 year shunt survival was 34% (18/53), and there was no significant difference depending on which shunt valve was implanted. The primary shunt infection rate was 11% (6/53) with S. aureus being the most common causative organism. During the first year of life, clinical signs of shunt overdrainage were seen more frequently in patients with adjustable valves than in those with flow-regulated valves (59% [19/32] versus 24% [5/21], p = 0.02). Furthermore, 2 patients in the adjustable valve group developed sagittal craniosynostosis secondary to shunt overdrainage. CONCLUSION: Shunt failure is high when inserted during or immediately following the neonatal period. Overdrainage may be less common in patients with flow-regulated valves. However, if overdrainage is observed, adjusting the setting of a differential pressure valve can effectively treat the overdrainage without the need for invasive shunt revision surgery.

Anopheles gambiae (Diptera: Culicidae) Susceptibility to Insecticides and Knockdown Resistance Genes Prior to Introduction of Indoor Residual Spraying in 11 Districts in Ghana.

BACKGROUND: An insecticide susceptibility study was carried out on Anopheles gambiae sensu lato vectors in 11 districts in Ghana between October 2012 and January 2013. METHODS: An. gambiae s.l. larvae were collected, bred under standard conditions, and 3-5 d postemerged females were used for bioassay. Between 22 and 25 female An. gambiae s.l. fed only 10% sugar were used for testing. Exposure was for 1 h (2 h for fenitrothion). An gambiae that were knocked down were recorded every 10 min and mortalities recorded 24 h posttest. Eleven insecticides from four chemical classes were used: organochlorines, organophosphates, carbamates, and pyrethroids. Subsamples of An gambiae were analyzed by polymerase chain reaction for species and knockdown resistance (kdr) allele determination. RESULTS: Malathion was effective in killing An. gambiae in seven districts, fenitrothion in three districts, and propoxur in one district. The organophosphate and carbamate insecticides were effective in killing An. gambiae compared to pyrethroids and organochlorines. Of the limited samples analyzed, An. gambiae sensu stricto (39/110), An. coluzzii (66/110), and An. arabiensis (5/110) were identified. Few kdr (11/110) susceptible mosquitoes were detected. Homozygous kdrRR (65/110) and heterozygous kdrRS (8/110) genotypes were identified. CONCLUSIONS: An organophosphate insecticide is considered appropriate for indoor residual spraying (IRS) in the 11 districts earmarked for the IRS program in Ghana.