Neurokinin-1 Receptor Antagonist Treatment in Polymicrobial Sepsis: Molecular Insights

Neurokinin-1 receptor blocking has been shown to be beneficial against lung injury in polymicrobial sepsis. In this paper, we evaluated the possible mediators and the mechanism involved. Mice were subjected to cecal ligation and puncture (CLP-) induced sepsis or sham surgery. Vehicle or SR140333 [1 mg/kg; subcutaneous (s.c.)] was administered to septic mice either 30 min before or 1 h after the surgery. Lung tissue was collected 8 h after surgery and further analyzed. CLP alone caused a significant increase in the activation of the transcription factors, protein kinase C-α, extracellular signal regulated kinases, neurokinin receptors, and substance P levels in lung when compared to sham-operated mice. SR140333 injected pre- and post surgery significantly attenuated the activation of transcription factors and protein kinase C-α and the plasma levels of substance P compared to CLP-operated mice injected with the vehicle. In addition, GR159897 (0.12 mg/kg; s.c.), a neurokinin-2 receptor antagonist, failed to show beneficial effects. We conclude that substance P acting via neurokinin-1 receptor in sepsis initiated signaling cascade mediated mainly by protein kinase C-α, led to NF-κB and activator protein-1 activation, and further modulated proinflammatory mediators

What is the function of the ANKH protein in the kidney?

Pyrophosphate (PPi) has been known since the 1960s as an inhibitor of calcium renal stone formation. Naturally occurring mutations in a putative PPi transporter, ANK, causes renal calcification in mice. We hypothesised that the human homologue, ANKH, plays a role in PPi transport in the human kidney. Immunocytochemical localisation of ANKH in human kidney showed greater abundance in the cortical collecting duct than elsewhere in the nephron. The transport function of ANKH was investigated by heterologous expression of ANKH in Xenopus oocytes. Despite confirmation of ANKH expression at the oocyte plasma membrane, neither ANKH-mediated PPi efflux (the physiological mode of operation) nor influx was detectable compared to water-injected oocytes. Pyrophosphatase activity was detected at the surface of oocytes, suggesting hydrolysis of PPi to inorganic phosphate. Screening using a yeast two-hybrid method of the N-terminal of ANKH against a mouse renal library identified a possible protein-protein interaction with the fatty acid transporter SLC27A2, whose acyl-CoA synthetase activity yields PPi as an end product. This suggests that ANKH and protein partners such as SLC27A2 may form a biochemical couple whereby PPi is sequestered by transmembrane transport rather than by hydrolysis. Since there is no pyrophosphatase activity in peroxisomes, we suggest that the ANKH/SLC27A2 complex is a candidate protein for the peroxisomal membrane PPi transporter. AVP mediates increased expression and localisation of ANK to the apical membrane of a collecting duct model (mpkCCDcl4) in vitro, suggesting physiologically appropriate regulation, analogous to that of aquaporin-2. These findings offer insights into the cellular homeostasis of PPi. Instead of cytosolic hydrolysis, coupling of PPi generation and ANKH-mediated transport as part of a protein complex may allow PPi to be compartmentalised, preserving it for use within vesicular structures elsewhere in the cell or allowing export to the extracellular medium to assist in the regulation of apatite deposition.EThOS - Electronic Theses Online ServiceNorthern Counties Kidney Research Fund : Wellcome TrustGBUnited Kingdo

A comparison of motion sickness prevalence between seafarers and non-seafarers onboard naval platforms

Background: Motion sickness may crucially affect the operational performance of soldiers at sea and this differs between individuals and environments. Objectives: To report on the prevalence and understand the risk factors for motion sickness among Singaporean sailors (seafarers) and attached army servicemen (nonseafarers) onboard naval platforms. Methodology: Cross sectional study using self-administered survey of 503 personnel over the monsoon period from January to April 2001. Results: The prevalence of motion sickness was distinctly higher in the army (59.2%) personnel compared with the navy (38.3%) over a series of sea states. The most common symptoms were headache, nausea and dizziness. The Motion Sickness Susceptibility Questionnaire was used to score susceptibility and appeared to correlate better among non-seafarers rather than seafarers. The discomfort experienced in one's environment was perceived to contribute towards onset and smoking appeared to be protective against motion sickness. Regular sailing appears to be an important factor in minimising motion sickness. Conclusion: While we understand motion sickness to be a continuum of physiological responses to the whole body vibration, it is especially apparent among the non-seafarers. Seafarers by themselves will become less susceptible with regular sailing and they are also more cognizant of the modalities available to alleviate symptoms

Rare variants in the sodium-dependent phosphate transporter gene SLC34A3 explain missing heritability of urinary stone disease

Urinary stone disease (USD) is a major health burden affecting over 10% of the United Kingdom population. While stone disease is associated with lifestyle, genetic factors also strongly contribute. Common genetic variants at multiple loci from genome-wide association studies account for 5% of the estimated 45% heritability of the disorder. Here, we investigated the extent to which rare genetic variation contributes to the unexplained heritability of USD. Among participants of the United Kingdom 100,000-genome project, 374 unrelated individuals were identified and assigned diagnostic codes indicative of USD. Whole genome gene-based rare variant testing and polygenic risk scoring against a control population of 24,930 ancestry-matched controls was performed. We observed (and replicated in an independent dataset) exome-wide significant enrichment of monoallelic rare, predicted damaging variants in the SLC34A3 gene for a sodium-dependent phosphate transporter that were present in 5% cases compared with 1.6% of controls. This gene was previously associated with autosomal recessive disease. The effect on USD risk of having a qualifying SLC34A3 variant was greater than that of a standard deviation increase in polygenic risk derived from GWAS. Addition of the rare qualifying variants in SLC34A3 to a linear model including polygenic score increased the liability-adjusted heritability from 5.1% to 14.2% in the discovery cohort. We conclude that rare variants in SLC34A3 represent an important genetic risk factor for USD, with effect size intermediate between the fully penetrant rare variants linked with Mendelian disorders and common variants associated with USD. Thus, our findings explain some of the heritability unexplained by prior common variant genome-wide association studies

ePHex: a phase 3, double-blind, placebo-controlled, randomized study to evaluate long-term efficacy and safety of Oxalobacter formigenes in patients with primary hyperoxaluria

Oxabact; Oxalobacter formigenes; Primary hyperoxaluriaOxabact; Oxalobacter formigenes; Hiperoxaluria primariaOxabact; Oxalobacter formigenes; Hiperoxalúria primàriaBackground Primary hyperoxalurias (PHs) are rare genetic diseases that increase the endogenous level of oxalate, a waste metabolite excreted predominantly by the kidneys and also the gut. Treatments aim to improve oxalate excretion, or reduce oxalate generation, to prevent kidney function deterioration. Oxalobacter formigenes is an oxalate metabolizing bacterium. This Phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of orally administered Oxabact™, a lyophilized O. formigenes formulation, at reducing plasma oxalate levels in patients suffering from PH. Methods Subjects (≥ 2 years of age) with a diagnosis of PH and maintained but suboptimal kidney function (mean estimated glomerular filtration rate at baseline < 90 mL/min/1.73 m2) were eligible to participate. Subjects were randomized to receive Oxabact or placebo twice daily for 52 weeks. Change from baseline in plasma oxalate concentration at Week 52 was the primary study endpoint. Results Forty-three subjects were screened, 25 were recruited and one was discontinued. At Week 52, O. formigenes was established in the gut of subjects receiving Oxabact. Despite decreasing plasma oxalate level in subjects treated with Oxabact, and stable/increased levels with placebo, there was no significant difference between groups in the primary outcome (Least Squares mean estimate of treatment difference was − 3.80 μmol/L; 95% CI: − 7.83, 0.23; p-value = 0.064). Kidney function remained stable in both treatments. Conclusions Oxabact treatment may have stabilized/reduced plasma oxalate versus a rise with placebo, but the difference over 12 months was not statistically significant (p = 0.06). A subtle effect observed with Oxabact suggests that O. formigenes may aid in preventing kidney stones.The study was designed, funded, and managed by OxThera Intellectual Property AB (Stockholm, Sweden)

PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2

Chronic kidney disease; Pediatric nephrology; UrologyMalaltia renal crònica; Nefrologia pediàtrica; UrologiaEnfermedad renal crónica; Nefrología pediátrica; UrologíaNedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90–180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs −1664 [1190], respectively; difference, 5172; 95% CI 2929–7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH

A study on the differential protein profiles in liver cells of heat stress rats with and without turpentine treatment

<p>Abstract</p> <p>Background</p> <p>Heat stress (HS) and related illnesses are a major concern in military, sports, and fire brigadiers. HS results in physiologic responses of increased temperature, heart rate and sweating. In heat stroke, inflammatory response plays an important role and it is evidenced that turpentine (T) induced circulating inflammatory cytokines reduced survival rate and duration at 42°C. Here we report the alteration in the protein expression in liver cells upon HS with and without T treatment using two dimensional gel electrophoresis (2-DE), tryptic in-gel digestion and MALDI-TOF-MS/MS approaches</p> <p>Results</p> <p>The effects of HS and T treatments alone and a combined treatments (T+HS) was performed in Wistar rat models. Proteomic analysis of liver in the HS and T+HS groups were analyzed compared to liver profiles of resting control and T treated groups. The study revealed a total of 25 and 29 differentially expressed proteins in the HS and T+HS groups respectively compared to resting control group. Fourteen proteins showed altered expression upon T treatment compared to resting control group. Proteins that are involved in metabolic and signal transduction pathways, defense, redox regulation, and cytoskeletal restructuring functions were identified. The altered expression of proteins reflected in 2D gels were corroborated by quantitative real time RT-PCR analysis of 8 protein coding genes representing metabolic and regulatory pathways for their expression and normalized with the house keeping gene β-actin</p> <p>Conclusion</p> <p>The present study has identified a number of differentially expressed proteins in the liver cells of rats subjected to T, HS and T+HS treatments. Most of these proteins are implicated in cell metabolism, as well as adaptive response to incurred oxidative stress and tissue damage due to T+HS and HS effects.</p

Parecoxib Reduces Systemic Inflammation and Acute Lung Injury in Burned Animals with Delayed Fluid Resuscitation

Burn injuries result in the release of proinflammatory mediators causing both local and systemic inflammation. Multiple organ dysfunctions secondary to systemic inflammation after severe burn contribute to adverse outcome, with the lungs being the first organ to fail. In this study, we evaluate the anti-inflammatory effects of Parecoxib, a parenteral COX-2 inhibitor, in a delayed fluid resuscitation burned rat model. Anaesthetized Sprague Dawley rats were inflicted with 45% total body surface area full-thickness scald burns and subsequently subjected to delayed resuscitation with Hartmann's solution. Parecoxib (0.1, 1.0, and 10 mg/kg) was delivered intramuscularly 20 min after injury followed by 12 h interval and the rats were sacrificed at 6 h, 24 h, and 48 h. Burn rats developed elevated blood cytokines, transaminase, creatinine, and increased lung MPO levels. Animals treated with 1 mg/kg Parecoxib showed significantly reduced plasma level of CINC-1, IL-6, PGEM, and lung MPO. Treatment of 1 mg/kg Parecoxib is shown to mitigate systemic and lung inflammation without significantly affecting other organs. At present, no specific therapeutic agent is available to attenuate the systemic inflammatory response secondary to burn injury. The results suggest that Parecoxib may have the potential to be used both as an analgesic and ameliorate the effects of lung injury following burn