Development and Immunogenicity of a Brazilian Glycoconjugate vaccine against Meningococcal W in a Pilot Scale

Glycoconjugate Journal - Recent changes in the epidemiology of meningococcal have been reported and meningococcal group W (MenW) has become the third most prevalent group isolated in Brazil in the...     

Proteinase K-sensitive disease-associated ovine prion protein revealed by conformation-dependent immunoassay

PrPSc [abnormal disease-specific conformation of PrP (prion-related protein)] accumulates in prion-affected individuals in the form of amorphous aggregates. Limited proteolysis of PrPSc results in a protease-resistant core of PrPSc of molecular mass of 27-30 kDa (PrP27-30). Aggregated forms of PrP co-purify with prion infectivity, although infectivity does not always correlate with the presence of PrP27-30. This suggests that discrimination between PrPC (normal cellular PrP) and PrPSc by proteolysis may underestimate the repertoire and quantity of PrPSc subtypes. We have developed a CDI (conformation-dependent immunoassay) utilizing time-resolved fluorescence to study the conformers of disease-associated PrP in natural cases of sheep scrapie, without using PK (proteinase K) treatment to discriminate between PrPC and PrPSc. The capture-detector CDI utilizes N-terminal- and C-terminal-specific anti-PrP monoclonal antibodies that recognize regions of the prion protein differentially buried or exposed depending on the extent of denaturation of the molecule. PrPSc was precipitated from scrapie-infected brain stem and cerebellum tissue following sarkosyl extraction, with or without the use of sodium phosphotungstic acid, and native and denatured PrPSc detected by CDI. PrPSc was detectable in brain tissue from homozygous VRQ (V136 R154 Q171) and ARQ (A136 R154 Q171) scrapie-infected sheep brains. The highest levels of PrPSc were found in homozygous VRQ scrapie-infected brains. The quantity of PrPSc was significantly reduced, up to 90% in some cases, when samples were treated with PK prior to the CDI. Collectively, our results show that the level of PrPSc in brain samples from cases of natural scrapie display genotypic differences and that a significant amount of this material is PK-sensitive.     

Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated mouse

Diastolic heart failure is a major cause of mortality in the elderly population. It is often preceded by diastolic dysfunction, which is characterized by impaired active relaxation and increased stiffness. We tested the hypothesis that senescence-prone (SAMP8) mice would develop diastolic dysfunction compared with senescence-resistant controls (SAMR1). Pulsed-wave Doppler imaging of the ratio of blood flow velocity through the mitral valve during early (E) vs. late (A) diastole was reduced from 1.3 ± 0.03 in SAMR1 mice to 1.2 ± 0.03 in SAMP8 mice (P < 0.05). Tissue Doppler imaging of the early (E') and late (A') diastolic mitral annulus velocities found E' reduced from 25.7 ± 0.9 mm/s in SAMR1 to 21.1 ± 0.8 mm/s in SAMP8 mice and E'/A' similarly reduced from 1.1 ± 0.02 to 0.8 ± 0.03 in SAMR1 vs. SAMP8 mice, respectively (P < 0.05). Invasive hemodynamics revealed an increased slope of the end-diastolic pressure-volume relationship (0.5 ± 0.05 vs. 0.8 ± 0.14; P < 0.05), indicating increased left ventricular chamber stiffness. There were no differences in systolic function or mean arterial pressure; however, diastolic dysfunction was accompanied by increased fibrosis in the hearts of SAMP8 mice. In SAMR1 vs. SAMP8 mice, interstitial collagen area increased from 0.3 ± 0.04 to 0.8 ± 0.09% and perivascular collagen area increased from 1.0 ± 0.11 to 1.6 ± 0.14%. Transforming growth factor-β and connective tissue growth factor gene expression were increased in the hearts of SAMP8 mice (P < 0.05 for all data). In summary, SAMP8 mice show increased fibrosis and diastolic dysfunction similar to those seen in humans with aging and may represent a suitable model for future mechanistic studies.     

Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease

Obesity-related renal lipotoxicity and chronic kidney disease (CKD) are prevalent pathologies with complex aetiologies. One hallmark of renal lipotoxicity is the ectopic accumulation of lipid droplets in kidney podocytes and in proximal tubule cells. Renal lipid droplets are observed in human CKD patients and in high-fat diet (HFD) rodent models, but their precise role remains unclear. Here, we establish a HFD model in Drosophila that recapitulates renal lipid droplets and several other aspects of mammalian CKD. Cell type–specific genetic manipulations show that lipid can overflow from adipose tissue and is taken up by renal cells called nephrocytes. A HFD drives nephrocyte lipid uptake via the multiligand receptor Cubilin (Cubn), leading to the ectopic accumulation of lipid droplets. These nephrocyte lipid droplets correlate with endoplasmic reticulum (ER) and mitochondrial deficits, as well as with impaired macromolecular endocytosis, a key conserved function of renal cells. Nephrocyte knockdown of diglyceride acyltransferase 1 (DGAT1), overexpression of adipose triglyceride lipase (ATGL), and epistasis tests together reveal that fatty acid flux through the lipid droplet triglyceride compartment protects the ER, mitochondria, and endocytosis of renal cells. Strikingly, boosting nephrocyte expression of the lipid droplet resident enzyme ATGL is sufficient to rescue HFD-induced defects in renal endocytosis. Moreover, endocytic rescue requires a conserved mitochondrial regulator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α). This study demonstrates that lipid droplet lipolysis counteracts the harmful effects of a HFD via a mitochondrial pathway that protects renal endocytosis. It also provides a genetic strategy for determining whether lipid droplets in different biological contexts function primarily to release beneficial or to sequester toxic lipids.

A high-fat diet model of chronic kidney disease in Drosophila reveals that boosting triglyceride lipolysis in renal cells is sufficient to rescue renal cell function via a pathway involving PGC1 alpha and mitochondria.     

Effects of cardiac oscillations and lung volume on acinar gas mixing during apnea

We evaluated the importance of cardiogenic gas mixing in the acini of 13 dogs during 2 min of apnea. 133Xe (1-2 mCi in 4 ml of saline) was injected into an alveolar region through an occluded pulmonary artery branch, and washout was measured by gamma scintillation scanning during continued occlusion or with blood flow reinstated. The monoexponential rate constant for Xe washout (XeW) was -0.4 +/- 0.08 (SE) min-1 at functional residual capacity (FRC) with no blood flow in the injected region. It decreased by more than half at lung volumes 500 ml above and 392 ml below FRC. With intact pulmonary blood flow, XeW was -1.0 +/- 0.08 (SE) min-1 at FRC, and it increased with decreasing lung volume. However, if calculated Xe uptake by the blood was subtracted from the XeW measured with blood flow intact, resulting values at FRC and at FRC + 500 ml were not different from XeW with no blood flow. Reasonable calculation of Xe blood uptake at 392 ml below FRC was not possible because airway closure, increased shunt, and other factors affect XeW. After death, no significant XeW could be measured, which suggests that XeW caused by molecular diffusion was small. We conclude that 1) the effect of heart motion on the lung parenchyma increases acinar gas mixing during apnea, 2) this effect diminishes above or below FRC, and 3) there is probably no direct effect of pulmonary vascular pulsatility on acinar gas mixing.     

Postoperative outcomes for Indigenous Peoples in Canada: a systematic review

Background:Substantial health inequities exist for Indigenous Peoples in Canada. The remote and distributed population of Canada presents unique challenges for access to and use of surgery. To date, the surgical outcome data for Indigenous Peoples in Canada have not been synthesized.Methods:We searched 4 databases to identify studies comparing surgical outcomes and utilization rates of adults of First Nations, Inuit or Métis identity with non-Indigenous people in Canada. Independent reviewers completed all stages in duplicate. Our primary outcome was mortality; secondary outcomes included utilization rates of surgical procedures, complications and hospital length of stay. We performed meta-analysis of the primary outcome using random effects models. We assessed risk of bias using the ROBINS-I tool.Results:Twenty-eight studies were reviewed involving 1 976 258 participants (10.2% Indigenous). No studies specifically addressed Inuit or Métis populations. Four studies, including 7 cohorts, contributed adjusted mortality data for 7135 participants (5.2% Indigenous); Indigenous Peoples had a 30% higher rate of death after surgery than non-Indigenous patients (pooled hazard ratio 1.30, 95% CI 1.09–1.54; I² = 81%). Complications were also higher for Indigenous Peoples, including infectious complications (adjusted OR 1.63, 95% CI 1.13–2.34) and pneumonia (OR 2.24, 95% CI 1.58–3.19). Rates of various surgical procedures were lower, including rates of renal transplant, joint replacement, cardiac surgery and cesarean delivery.Interpretation:The currently available data on postoperative outcomes and surgery utilization rates for Indigenous Peoples in Canada are limited and of poor quality. Available data suggest that Indigenous Peoples have higher rates of death and adverse events after surgery, while also encountering barriers accessing surgical procedures. These findings suggest a need for substantial re-evaluation of surgical care for Indigenous Peoples in Canada to ensure equitable access and to improve outcomes. Protocol registration:PROSPERO-CRD42018098757

Safe, timely and affordable access to surgical care is essential to overall population health, as conditions amenable to surgical intervention account for one-third of the global burden of disease.^1,2 Surgery is responsible for 65% of cancer cure and control, it is key to trauma management, and access to cesarean delivery reduces neonatal deaths by up to 70%.¹ The magnitude and ubiquity of surgical conditions makes tracking their prevalence and treatment within local and national monitoring systems essential to fully capture the health and welfare of populations in Canada, including Indigenous Peoples.About 1.67 million people in Canada are Indigenous, representing 4.9% of the total population (58% First Nations, 4% Inuit, 35% Métis).³ Health inequities exist for the Indigenous population; life expectancy at birth is 5–11 years shorter than for non-Indigenous Peoples^4,5 and higher rates of communicable and noncommunicable diseases, unintentional injury and suicide are well documented.^4,6–14 These health inequities are direct impacts of the social determinants of health, which are in turn effects of colonialism and government policies, including the Indian residential school system.^8,11 People living in remote regions have less access to publicly funded health care than other people in Canada, with worse outcomes.¹⁵Given the substantial impact of surgical disease on population health and the recognized disparities in health care access for Indigenous Peoples in Canada, understanding access to surgical services and subsequent outcomes is a key step to addressing health inequities. To date, limited research has been conducted on surgical and postoperative care involving Indigenous Peoples in Canada and the available literature has not been synthesized. Our objective was to systematically review studies comparing postoperative outcomes between Indigenous and non-Indigenous Peoples in Canada.     

Light emitting diode-red light for reduction of post-surgical scarring: Results from a dose-ranging,split-face,randomized controlled trial

Scarring has significant esthetic and functional consequences for patients. A need exists for anti-scarring therapeutics. Light emitting diode-red light (LED-RL) has been shown to modulate skin fibrosis. The aim of this study is to evaluate the safety and efficacy of LED-RL to reduce post-operative scarring. Cutaneous Understanding of Red-light Efficacy on Scarring was a randomized, mock-controlled, single-blind, dose-ranging, split-face phase II clinical trial. Starting 1 week post-surgery, patients received LED-RL irradiation and temperature-controlled mock therapy to incision sites at fluences of 160, 320 or 480 J/cm², triweekly for 3 weeks. Efficacy was assessed at 1, 3 and 6–12 months. The primary endpoint was difference in scar pliability between LED-RL-treated and control sites. Secondary outcomes included Patient and Observer Scar Assessment Scale, collagen and water concentration, and adverse events. There were no significant differences in scar pliability between treated and control scars. At certain fluences, treated scars showed greater improvements in observer rating and scar pliability, reflected by greater reductions in induration, from baseline to 6 months compared to control scars. Treatment-site adverse events included blistering (n = 2) and swelling (n = 1), which were mild and resolved without sequelae. LED-RL phototherapy is safe in the early postoperative period and may reduce scarring.