The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy.

The NOD-like receptor protein 3 (NLRP3) inflammasome is a multi-protein signalling complex integral to the chronic inflammatory response, activated in response to sterile and non-sterile cellular damage. The assembly and activation of the NLRP3 inflammasome comprise a two-step process involving nuclear factor kappa B (NFkB)-mediated priming, followed by canonical, non-canonical or alternative signalling pathways. These result in the maturation and release of inflammatory cytokines interleukin 1 beta (IL1ß) and interleukin-18 (IL18), which are associated with chronic inflammatory conditions including diabetic kidney disease. Diabetic nephropathy is a condition affecting ∼40% of people with diabetes, the key underlying pathology of which is tubulointerstitial inflammation and fibrosis. There is growing evidence to suggest the involvement of the NLRP3 inflammasome in this chronic inflammation. Early deterioration of kidney function begins in the glomerulus, with tubular inflammation dictating the progression of late-stage disease. Priming and activation of the NLRP3 inflammasome have been linked to several clinical markers of nephropathy including proteinuria and albuminuria, in addition to morphological changes including mesangial expansion. Treatment options for diabetic nephropathy are limited, and research that examines the impact of directly targeting the NLRP3 inflammasome, or associated downstream components are beginning to gain favour, with several agents currently in clinical trials. This review will explore a role for NLRP3 inflammasome activation and signalling in mediating inflammation in diabetic nephropathy, specifically in the glomerulus and proximal tubule, before briefly describing the current position of therapeutic research in this field.

Risky business in Georgia's wild birds: contact rates between wild birds and backyard chickens is influenced by supplemental feed.

Backyard chickens are increasingly popular, and their husbandry varies widely. How backyard chickens are housed may influence the accessibility of chicken feed and water to wild birds, and thus, the contact rates between both groups. Increased contacts have implications for pathogen transmission; for instance, Newcastle disease virus or avian influenza virus may be transmitted to and from backyard chickens from contaminated water or feed. Given this potentially increased pathogen risk to wild birds and backyard chickens, we examined which wild bird species are likely to encounter backyard chickens and their resources. We performed a supplemental feeding experiment followed by observations at three sites associated with backyard chickens in North Georgia, USA. At each site, we identified the species of wild birds that: (a) shared habitat with the chickens, (b) had a higher frequency of detection relative to other species and (c) encountered the coops. We identified 14 wild bird species that entered the coops to consume supplemental feed and were considered high-risk for pathogen transmission. Our results provide evidence that contact between wild birds and backyard chickens is frequent and more common than previously believed, which has crucial epidemiological implications for wildlife managers and backyard chicken owners.

Non reducible inguinal hernias in Malawi: an occupational hazard.

PURPOSE: Inguinal hernias are one of the most common surgical conditions worldwide. Due to limited surgical access in low- and middle-income countries, many hernias present emergently; however, data on the resultant outcome disparities is limited. We, therefore, sought to describe the epidemiology, clinical features, and outcomes of incarcerated inguinal hernias at a tertiary center in Malawi. METHODS: This is a retrospective analysis of the acute care surgery registry at Kamuzu Central Hospital in Lilongwe, Malawi. All patients > 13 years admitted with a non-reducible inguinal hernia from 2013 to 2019 were included. The primary outcome was in-hospital mortality. A Poisson multivariable regression determined factors associated with increased risk of mortality. RESULTS: A total of 297 patients presented with non-reducible inguinal hernias, the majority of which were young (median age 38), male (93.6%), farmers (47.8%). Of the 81% who underwent surgery, 55% were delayed ≥ 24 h. 19.5% of hernias were strangulated. Overall mortality was 5.4%. Increased age (RR 1.06, 95% CI 1.01-1.12), shock index ≥ 1 (RR 4.82, 95% CI 1.45-16.09), and delay ≥ 24 h from presentation to operative intervention (RR 11.24, 95% CI 1.55-81.34) resulted in an increase in relative risk of mortality. CONCLUSION: Non-reducible inguinal hernias largely affect young male farmers in Malawi. Delays to care can limit economic productivity for this rural population, as well as, yield considerable risk of mortality. While specific patient and institutional factors must be further elucidated, increased awareness, public health prioritization, and surgical capacity building is needed to reduce further hernia-related morbidity and mortality.

ORION laser target diagnostics.

The ORION laser facility is one of the UK's premier laser facilities which became operational at AWE in 2010. Its primary mission is one of stockpile stewardship, ORION will extend the UK's experimental plasma physics capability to the high temperature, high density regime relevant to Atomic Weapons Establishment's (AWE) program. The ORION laser combines ten laser beams operating in the ns regime with two sub ps short pulse chirped pulse amplification beams. This gives the UK a unique combined long pulse/short pulse laser capability which is not only available to AWE personnel but also gives access to our international partners and visiting UK academia. The ORION laser facility is equipped with a comprehensive suite of some 45 diagnostics covering optical, particle, and x-ray diagnostics all able to image the laser target interaction point. This paper focuses on a small selection of these diagnostics.

Patient specific cutting blocks are currently of no proven value.

Patient specific cutting guides generated by preoperative Magnetic Resonance Imaging (MRI) of the patient's extremity have been proposed as a method of improving the consistency of Total Knee Arthroplasty (TKA) alignment and adding efficiency to the operative procedure. The cost of this option was evaluated by quantifying the savings from decreased operative time and instrument processing costs compared to the additional cost of the MRI and the guide. Coronal plane alignment was measured in an unselected consecutive series of 200 TKAs, 100 with standard instrumentation and 100 with custom cutting guides. While the cutting guides had significantly lower total operative time and instrument processing time, the estimated $322 savings was overwhelmed by the $1,500 additional cost of the MRI and the cutting guide. All measures of coronal plane alignment were equivalent between the two groups. The data does not currently support the proposition that patient specific guides add value to TKA.

Environmental enrichment: effects on spatial memory and hippocampal CREB immunoreactivity.

Environmental enrichment has been shown to improve performance in tests of spatial memory, induce neurogenesis in the hippocampus, enhance survival of newly formed granule cells, and inhibit spontaneous apoptosis. Although neuroplasticity of the mammalian brain declines with age, recent evidence suggests that the adult brain exhibits significant plasticity in response to environmental stimulation. The present study was designed to evaluate the effect of environmental enrichment on spatial memory and on immunoreactivity to cAMP response element binding protein (CREB) from the hippocampus. C57/BL/6 mice were trained in a Morris water maze after exposure to an enriched environment, either from 35 to 94 days or from 100 to 159 days of age. Hippocampal tissue from representative animals was later analyzed by Western blot for CREB immunoreactivity. Results indicate that environmental enrichment (particularly during the earlier period) improved performance on the Morris water maze and tended to increase immunoreactivity to CREB in the hippocampus. Social interaction by itself did not result in significant differences in navigational performance. Results with regard to social interaction and CREB immunoreactivity were mixed. Results are discussed in terms of evaluating the construct of enrichment, the correlation of CREB transcription and behavior change, and the importance of the developmental period for enrichment.

The long internal loop of the alpha 3 subunit targets nAChRs to subdomains within individual synapses on neurons in vivo.

Different types of neurotransmitter receptors coexist within single neurons and must be targeted to discrete synaptic regions for proper function. In chick ciliary ganglion neurons, nicotinic acetylcholine receptors (nAChRs) containing alpha 3 and alpha 5 subunits are concentrated in the postsynaptic membrane, whereas alpha-bungarotoxin receptors composed of alpha 7 subunits are localized perisynaptically and excluded from the synapse. Using retroviral vector-mediated gene transfer in vivo, we show that the long cytoplasmic loop of alpha 3 targets chimeric alpha 7 subunits to the synapse and reduces endogenous nAChR surface levels, whereas the alpha 5 loop does neither. These results show that a particular domain of one subunit targets specific receptor subtypes to the interneuronal synapse in vivo. Moreover, our findings suggest a difference in the mechanisms that govern assembly of interneuronal synapses as compared to the neuromuscular junction in vertebrates.

Severe exacerbation of post traumatic syringomyelia after lithotripsy. Case report.

A case of post traumatic thoracic syringomyelia is reported which presented with an acute and severe worsening of the spinal cord condition after extracorporeal shock wave lithotripsy was performed for ureteral stone. The worsening was probably caused by the shock waves reverberating the fluid within the intramedullary cavity producing further damage to the spinal cord.

Use of arteriovenous shunts and right atrial catheters for daily granulocyte collection.

Between June 1982 and April 1984, 67 adult granulocyte donors were randomized to receive external arteriovenous shunts or modified right atrial catheters as vascular access for daily granulocyte collections using blood cell separators. Six of 32 donors with shunts and 2 of 35 donors with right atrial catheters experienced failure of the access method. Local infection occurred in one donor with a shunt and one donor with a right atrial catheter. Bacteremia occurred in one donor with a right atrial catheter. Specified whole blood flow rates of 50-65 ml/minute were achieved with 28 of 32 shunts and 29 of 35 right atrial catheters (P = NS). The majority of the donors in each group tolerated the vascular access without significant problems. This study demonstrates that modified right atrial catheters can be successfully used as method of vascular access for single donor granulocyte collection with blood cell separators.