Caloric Restriction Improves Spatial Learning Deficits in Tau Mice.

Background: Caloric restriction (CR) has been recognized for its benefits in delaying age-related diseases and extending lifespan. While its effects on amyloid pathology in Alzheimer's disease (AD) mouse models are well-documented, its effects on tauopathy, another hallmark of AD, are less explored. Objective: To assess the impact of a short-term 30% CR regimen on age-dependent spatial learning deficits and pathological features in a tauopathy mouse model. Methods: We subjected male PS19 tau P301S (hereafter PS19) and age-matched wildtype mice from two age cohorts (4.5 and 7.5 months old) to a 6-week 30% CR regimen. Spatial learning performance was assessed using the Barnes Maze test. Tau pathology, neuroinflammation, hippocampal cell proliferation, and neurogenesis were evaluated in the older cohort by immunohistochemical staining and RT-qPCR. Results: CR mitigated age-dependent spatial learning deficits in PS19 mice but exhibited limited effects on tau pathology and the associated neuroinflammation. Additionally, we found a decrease in hippocampal cell proliferation, predominantly of Iba1+ cells. Conclusions: Our findings reinforce the cognitive benefits conferred by CR despite its limited modulation of disease pathology. Given the pivotal role of microglia in tau-driven pathology, the observed reduction in Iba1+ cells under CR suggests potential therapeutic implications, particularly if CR would be introduced early in disease progression.

Chronic social and psychological stress impact select neuropathologies in the PS19 mouse model of tauopathy.

OBJECTIVE: Despite advances toward understanding the etiology of Alzheimer's disease (AD), it remains unclear which aspects of this disease are affected by environmental factors. Chronic life stress increases risk for aging-related diseases including AD. The impact of stress on tauopathies remains understudied. We examined the effects of stress elicited by social (chronic subordination stress, CSS) or psychological/physical (chronic restraint stress, CRS) factors - on the PS19 mouse model of tauopathy. METHODS: Male PS19 mice (average age 6.3 months) were randomized to receive CSS, CRS, or to remain as singly-housed controls. Behavioral tests were used to assess anxiety-like behaviors and cognitive functions. Immunofluorescence staining and western blotting analysis were used to measure levels of astrogliosis, microgliosis and tau burden. Immunohistochemistry was used to assess glucocorticoid receptor expression. RESULTS: PS19 mice exhibit neuroinflammation (GFAP, t-tests; p = 0.0297; Iba1, t-tests; p = 0.006) and tau hyperphosphorylation (t-test, p = 0.0446) in the hippocampus, reduced anxiety (post hoc, p = 0.046), and cognitive deficits, when compared to wild type mice. Surprisingly, CRS reduced hippocampal levels of both total tau and phospho-tauS404 (t-test, p = 0.0116), and attenuated some aspects of both astrogliosis and microgliosis in PS19 mice (t-tests, p = 0.068 to p = 0.0003); however, this was not associated with significant changes in neurodegeneration or cognitive function. Anxiety-like behaviors were increased by CRS (post hoc, p = 0.046). Conversely, CSS impaired spatial learning in Barnes Maze without impacting tau phosphorylation or neurodegeneration and having a minimal impact on gliosis. CONCLUSIONS: Our results demonstrate that social or psychological stress can differentially impact anxiety-like behavior, select cognitive functions, and some aspects of tau-dependent pathology in PS19 male mice, providing entry points for the development of experimental approaches designed to slow AD progression.

Senescent alveolar macrophages promote early-stage lung tumorigenesis.

Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16INK4a and Cxcr1, are distinct from previously defined subsets and are sensitive to senolytic interventions, and suppress cytotoxic T cell responses. Their removal attenuates adenoma development and progression in mice, indicating their tumorigenesis-promoting role. Importantly, we found that alveolar macrophages with these properties increase with normal aging in mouse lung and in human lung adenocarcinoma in situ. Collectively, our study indicates that a subset of tissue-resident macrophages can support neoplastic transformation through altering their local microenvironment, suggesting that therapeutic interventions targeting senescent macrophages may attenuate lung cancer progression during early stages of disease.

Atmospheric aging enhances the ice nucleation ability of biomass-burning aerosol.

Ice-nucleating particles (INPs) in biomass-burning aerosol (BBA) that affect cloud glaciation, microphysics, precipitation, and radiative forcing were recently found to be driven by the production of mineral phases. BBA experiences extensive chemical aging as the smoke plume dilutes, and we explored how this alters the ice activity of the smoke using simulated atmospheric aging of authentic BBA in a chamber reactor. Unexpectedly, atmospheric aging enhanced the ice activity for most types of fuels and aging schemes. The removal of organic carbon particle coatings that conceal the mineral-based ice-active sites by evaporation or oxidation then dissolution can increase the ice activity by greater than an order of magnitude. This represents a different framework for the evolution of INPs from biomass burning where BBA becomes more ice active as it dilutes and ages, making a larger contribution to the INP budget, resulting cloud microphysics, and climate forcing than is currently considered.

Insights from In Vivo Studies of Cellular Senescence.

Cellular senescence is the dynamic process of durable cell-cycle arrest. Senescent cells remain metabolically active and often acquire a distinctive bioactive secretory phenotype. Much of our molecular understanding in senescent cell biology comes from studies using mammalian cell lines exposed to stress or extended culture periods. While less well understood mechanistically, senescence in vivo is becoming appreciated for its numerous biological implications, both in the context of beneficial processes, such as development, tumor suppression, and wound healing, and in detrimental conditions, where senescent cell accumulation has been shown to contribute to aging and age-related diseases. Importantly, clearance of senescent cells, through either genetic or pharmacological means, has been shown to not only extend the healthspan of prematurely and naturally aged mice but also attenuate pathology in mouse models of chronic disease. These observations have prompted an investigation of how and why senescent cells accumulate with aging and have renewed exploration into the characteristics of cellular senescence in vivo. Here, we highlight our molecular understanding of the dynamics that lead to a cellular arrest and how various effectors may explain the consequences of senescence in tissues. Lastly, we discuss how exploitation of strategies to eliminate senescent cells or their effects may have clinical utility.

Implicating endothelial cell senescence to dysfunction in the ageing and diseased brain.

Cerebrovascular endothelial cells (CECs) are integral components of both the blood-brain barrier (BBB) and the neurovascular unit (NVU). As the primary cell type of the BBB, CECs are responsible for the tight regulation of molecular transport between the brain parenchyma and the periphery. Additionally, CECs are essential in neurovascular coupling where they help regulate cerebral blood flow in response to regional increases in cellular demand in the NVU. CEC dysfunction occurs during both normative ageing and in cerebrovascular disease, which leads to increased BBB permeability and neurovascular uncoupling. This MiniReview compiles what is known about the molecular changes underlying CEC dysfunction, many of which are reminiscent of cells that have become senescent. In general, cellular senescence is defined as an irreversible growth arrest characterized by the acquisition of a pro-inflammatory secretory phenotype in response to DNA damage or other cellular stresses. We discuss evidence for endothelial cell senescence in ageing and cardiovascular disease, and how CEC senescence may contribute to age-related cerebrovascular dysfunction.

Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS.

OBJECTIVE: The intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS. DESIGN: 39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states. RESULTS: Patients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota. CONCLUSION: A subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.

Minimally invasive anterior pelvic internal fixation: An anatomic study comparing Pelvic Bridge to INFIX.

OBJECTIVES: Anterior external fixation for pelvic ring fractures has shown to effectively improve stability and reduce mortality. However, these fixators can be associated with substantial morbidity such as pin tract infection, premature loss of fixation, and decreased quality of life in patients. Recently, two new methods of subcutaneous anterior pelvic internal fixation have been developed; the INFIX and the Pelvic Bridge. These methods have the purported advantages of lower wound complications, less surgical site pain, and improved quality of life. We sought to investigate the measured distances to critical anatomic structures, as well as the qualitative and topographic differences notable during implantation of both devices in the same cadaveric specimen. MATERIALS AND METHODS: The Pelvic Bridge and INFIX were implanted in eleven fresh cadavers. Distances were then measured to: the superficial inguinal ring, round ligament, spermatic cord, lateral femoral cutaneous nerve (LFCN), femoral nerve, femoral artery, and femoral vein. Observations regarding implantation and topography were also recorded. RESULTS: The INFIX had greater measured distances from all structures except for the LFCN, in which its proximity placed this structure at risk. Neither device appears to put other critical structures at risk in the supine position. Significant implantation and topographic differences exist between the devices. The INFIX application lacked "safety margins" concerning the LFCN in 10/11 (90.9%) specimens, while Pelvic Bridge placement lacked "safety margins" with regard to the right superficial ring (1/11, 9%) and the right spermatic cord (1/11, 9%). CONCLUSIONS: Both the Pelvic Bridge and INFIX lie at safe distances from most critical pelvic structures in the supine position, though INFIX application places the LFCN at risk.

Does Surgical Approach Affect Patient-reported Function After Primary THA?

BACKGROUND: Total hip arthroplasty (THA) relieves pain and improves physical function in patients with hip osteoarthritis, but requires a year or more for full postoperative recovery. Proponents of intermuscular surgical approaches believe that the direct-anterior approach may restore physical function more quickly than transgluteal approaches, perhaps because of diminished muscle trauma. To evaluate this, we compared patient-reported physical function and other outcome metrics during the first year after surgery between groups of patients who underwent primary THA either through the direct-anterior approach or posterior approach. QUESTIONS/PURPOSES: We asked: (1) Is a primary THA using a direct-anterior approach associated with better patient-reported physical function at early postoperative times (1 and 3 months) compared with a THA performed through the posterior approach? (2) Is the direct-anterior approach THA associated with shorter operative times and higher rates of noninstitutional discharge than a posterior approach THA? METHODS: Between October 2008 and February 2010, an arthroplasty fellowship-trained surgeon performed 135 THAs. All 135 were performed using the posterior approach. During that period, we used this approach when patients had any moderate to severe degenerative joint disease of the hip attributable to any type of arthritis refractory to nonoperative treatment measures. Of the patients who were treated with this approach, 21 (17%; 23 hips) were lost to followup, whereas 109 (83%; 112 hips) were available for followup at 1 year. Between February and September 2011, the same surgeon performed 86 THAs. All 86 were performed using the direct-anterior approach. During that period, we used this approach when patients with all types of moderate to severe degenerative joint disease had nonoperative treatment measures fail. Of the patients who were treated with this approach, 35 (41%; 35 hips) were lost to followup, whereas 51 (59%; 51 hips) were available for followup at 1 year. THAs during the surgeon's direct-anterior approach learning period (February 2010 through January 2011) were excluded because both approaches were being used selectively depending on patient characteristics. Clinical outcomes included operative blood loss; allogeneic transfusion; adverse events; patient-reported Veterans RAND-12 Physical (PCS) and Mental Component Summary (MCS) scores, and University of California Los Angeles (UCLA) activity scores at 1 month, 3 months, and 1 year after surgery. Resource utilization outcomes included operative time, length of stay, and discharge disposition (home versus institution). Outcomes were compared using logistic and linear regression techniques. RESULTS: After controlling for relevant confounding variables including age, sex, and BMI, the direct-anterior approach was associated with worse adjusted MCS changes 1 and 3 months after surgery (1-month score change, -9; 95% CI, -13 to -5; standard error, 2), compared with the posterior approach (3-month score change, -9; 95% CI, -14 to -3; standard error, 3) (both p < 0.001), while the direct-anterior approach was associated with greater PCS improvement at 3 months compared with the posterior approach (score change, 6; 95% CI, 2-10; standard error, 2; p = 0.008). There were no differences in adjusted PCS at either 1 month or 12 months, and no clinically important differences in UCLA scores. Although the PCS score differences are greater than the minimum clinically important difference of 5 points for this endpoint, the clinical importance of such a small effect is questionable. At 1 year after THA, there were no intergroup differences in self-reported physical function, although both groups had significant loss-to-followup at that time. Operative time (skin incision to skin closure) between the two groups did not differ (81 versus 79 minutes; p = 0.411). Mean surgical blood loss (403 versus 293 mL; p < 0.001; adjusted, 119 more mL; 95% CI, 79-160; p < 0.001) and in-hospital transfusion rates (direct-anterior approach, 20% [17/86] versus posterior approach, 10% [14/135], p = 0.050; adjusted odds ratio, 3.6; 95% CI, 1.3-10.1; p = 0.016) were higher in the direct-anterior approach group. With the numbers available, there was no difference in the frequency of adverse events between groups when comparing intraoperative complications, perioperative Technical Expert Panel complications, and other non-Technical Expert Panel complications within 1 year of surgery, although this study was not adequately powered to detect differences in rare adverse events. CONCLUSIONS: With suitable experience, the direct-anterior approach can be performed with expected results similar to those of the posterior approach. There may be transient and small benefits to the direct-anterior approach, including improved physical function at 3 months after surgery. However, the greater operative blood loss and greater likelihood of blood transfusions, even when the surgeon is experienced, may be a disadvantage. Given some of the kinds of bias present that we found, including loss to followup, the conclusions we present should be considered preliminary, but it appears that any benefits that accrue to the patients who had the direct-anterior approach would be transient and modest. Prospective randomized studies on the topic are needed to address the differences between surgical approaches more definitively. LEVEL OF EVIDENCE: Level III, therapeutic study.

In-hospital mortality from femoral shaft fracture depends on the initial delay to fracture fixation and Injury Severity Score: a retrospective cohort study from the NTDB 2002-2006.

BACKGROUND: Optimal surgical timing for definitive treatment of femur fractures in severely injured patients remains controversial. This study was performed to examine in-hospital mortality for patients with femur fractures with regard to surgical timing, Injury Severity Score (ISS), and age. METHODS: The National Trauma Data Bank version 7.0 was used to evaluate in-hospital mortality for patients presenting with unilateral femur fractures. Patients were stratified into four groups by surgical timing (ST) and four groups by ISS. χ tests were used to evaluate baseline interrelationships. Binary regression was used to examine the association between time to surgery, ISS score, age, and mortality after adjusting for patient medical comorbidities, and personal demographics. RESULTS: A total of 7,540 patients met inclusion criteria, with a 1.4% overall in-hospital mortality rate. For patients with an isolated femur fracture, surgical delay beyond 48 hours was associated with nearly five times greater mortality risk compared with surgery within 12 hours (adjusted relative risk, 4.8; 95% confidence interval, 1.6-14.1). Only severely injured patients (ISS, 26+) had higher associated mortality with no delay in surgical fixation (ST1 < 12 hours) relative to ST2 of 13 hours to 24 hours with an adjusted relative risk of 4.2 (95% confidence interval, 1.0-16.7). The association between higher mortality rates and surgical delay beyond 48 hours was even stronger in the elderly patients. CONCLUSION: This study supports the work of previous authors who reported that early definitive fixation of femur fractures is not only beneficial, particularly in the elderly, but also consistent with more recent studies recommending at least 12-hour to 24-hour delay in fixation in severely injured patients to promote better resuscitation. LEVEL OF EVIDENCE: Therapeutic study, level III.

A new classification system predictive of complications in surgically treated pediatric humeral lateral condyle fractures.

BACKGROUND: The most commonly cited classification system for lateral condyle fractures (Milch) has not been shown to be predictive of outcome or recommend treatment. PURPOSE: To determine whether a classification system and treatment based on fracture displacement and articular congruity correlates with the complication rate after pediatric lateral humeral condyle fractures. METHODS: A retrospective review of all children with lateral condyle fractures treated operatively at one institution from 1996 to 2003 was performed. All fractures were classified by the following system: A Type I fracture is displaced less than 2 mm. In a Type II fracture there is > or = 2 mm of displacement with intact articular cartilage, as demonstrated by arthrogram (65 patients). In a Type III fracture there is > or = 2 mm of displacement and the articular surface is not intact (93 patients). The 158 patients with types 2 and 3 fractures underwent surgery and are the focus of this study. Complication rates were compared between groups 2 and 3, and with regard to patient age, length of time between injury and surgery, and duration of casting. RESULTS: The overall complication rate was 25% (39 of 158). The most common complications included radiographic and/or clinical bump (16 of 158 or 10%), and infection treated with oral antibiotics (4 of 158 or 2.5%). There were 6% major complications (10 of 158) defined as those with presumptive long-term effects or requiring reoperation, including 1 nonunion (0.6%). There were no acute complications at the time of injury or surgery. If lateral bump is excluded as a complication, then the overall complication rate is 14.6% (23 of 158). The overall complication rates for types 2 and 3 fractures were statistically significantly different (P<0.03): 11% (7 of 65) for type 2 and 34% (32 of 93) for type 3 fractures. Major complication rates were 1.5% (1 of 65) for type 2 fractures and 10% (9 of 93) for type 3 fractures, whereas minor complications occurred in 9% (6 of 65) of type 2 fractures, and 25% (23 of 93) of type 3 fractures (P=0.03). There was no correlation between complication rate and patient age, number of days between fracture and surgery (all patients were treated within 16 d of their fracture), or duration of casting. We found that all 65 patients with Type II fractures had <4 mm of fracture displacement on pre-operative radiographs, and all fractures Type III fractures had > or = 4 mm of displacement. This may aid in predicting which fractures can be treated with closed pinning prior to an operative arthrogram. CONCLUSIONS: This is the largest series of operatively treated lateral condyle fractures reported in the literature. This classification system and treatment based on fracture displacement and articular congruity predicts the risk of complications, which were more than 3 times as likely to occur in type 3 fractures as type 2 fractures.

Nanoscale double emulsions stabilized by single-component block copolypeptides.

Water-in-oil-in-water emulsions are examples of double emulsions, in which dispersions of small water droplets within larger oil droplets are themselves dispersed in a continuous aqueous phase. Emulsions occur in many forms of processing and are used extensively by the foods, cosmetics and coatings industries. Because of their compartmentalized internal structure, double emulsions can provide advantages over simple oil-in-water emulsions for encapsulation, such as the ability to carry both polar and non-polar cargos, and improved control over release of therapeutic molecules. The preparation of double emulsions typically requires mixtures of surfactants for stability; the formation of double nanoemulsions, where both inner and outer droplets are under 100 nm, has not yet been achieved. Here we show that water-in-oil-in-water double emulsions can be prepared in a simple process and stabilized over many months using single-component, synthetic amphiphilic diblock copolypeptide surfactants. These surfactants even stabilize droplets subjected to extreme flow, leading to direct, mass production of robust double nanoemulsions that are amenable to nanostructured encapsulation applications in foods, cosmetics and drug delivery.

Fetal hepatic haematopoiesis is modulated by arterial blood flow to the liver.

We describe an as yet unrecognised relationship between fetal hepatic haematopoiesis and arterial blood flow to the liver. To increase hepatic arterial flow, the common bile duct (CBD) was ligated in fetal lambs. Reduction of hepatic arterial flow was accomplished in age-matched animals by hepatic artery (HA) ligation. Multiple analyses performed before term showed a significant increase in haematopoietic cell density in CBD animals when compared with sham controls and HA animals. In contrast, HA animals demonstrated a decrease in liver haematopoietic activity. Fetal hepatic haematopoiesis is dependent upon arterial blood flow to the liver.

Image segmentation using association rule features.

A new type of texture feature based on association rules is described. Association rules have been used in applications such as market basket analysis to capture relationships present among items in large data sets. It is shown that association rules can be adapted to capture frequently occurring local structures in images. The frequency of occurrence of these structures can be used to characterize texture. Methods for segmentation of textured images based on association rule features are described. Simulation results using images consisting of man made and natural textures show that association rule features perform well compared to other widely used texture features. Association rule features are used to detect cumulus cloud fields in GOES satellite images and are found to achieve higher accuracy than other statistical texture features for this problem.