APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading

Alzheimer\u27s disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque-associated tau seeding and spreading in the form of neuritic plaque-tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Aβ deposition and peri-plaque NP-tau pathology in the presence of APOE4 but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep-deprived APPPS1:E4 mice injected with AD-tau had significantly altered sleep behaviors compared with APPPS1:E3 mice. These findings suggest that the APOE-ε4 genotype is a critical modifier in the development of AD pathology in response to SD

Association between phthalate exposure and lower handgrip strength in an elderly population: a repeated-measures study

Background Decreased muscle strength can lead to adverse health outcomes in the elderly. A potential association between phthalate exposure and muscle strength was suggested previously, but has not been investigated directly. We hypothesized that phthalate exposure is associated with lower handgrip strength and that the association is modified by the dietary omega-6 to omega-3 ratio. Methods We analyzed 1,228 participants (≥60 years of age) recruited in Seoul and Asan, Republic of Korea. The study participants were surveyed up to three times between 2012 and 2015. At every survey, we collected urine samples and measured handgrip strength twice for each hand. The associations between urine phthalate metabolite concentrations and handgrip strength were evaluated using linear mixed models. Based on dietary information from 391 individuals who participated in the first survey in Seoul, we evaluated the heterogeneity of the association for those with high and low omega-6 to omega-3 ratios, using 8.81 (the 75th quantile) as a cutoff value. Results Log-transformed creatinine-adjusted concentrations of mono-(2-ethyl-5-oxohexyl phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-n-butyl phthalate (MnBP) were inversely associated with all measured handgrip strengths (β = −0.69 to −0.42, all p-values < 0.05). Associations between phthalate biomarkers and handgrip strength did not differ by sex. When the dietary subgroup was stratified by the omega-6 to omega-3 ratio, the associations were stronger among participants with high ratios. Conclusions We found inverse associations between phthalate biomarkers and handgrip strength in the elderly; this association was modified by the dietary omega-6 to omega-3 ratio

High Prevalence of Cefotaxime Resistant Bacteria in Grazing Beef Cattle: A Cross Sectional Study

Although the over-use of antibiotics during food animal production is a potential driver of antimicrobial resistant microorganisms (ARMs), a high prevalence of cefotaxime resistant bacteria (CRB) has been observed in grazing animals raised without antibiotic supplementation. In this cross-sectional study, the prevalence and concentration of CRB in beef cattle on grazing farms were investigated. Fecal samples from the recto-anal junction of cattle (n = 840) and environmental samples (n = 258) were collected from 17 farms in North and Central Florida in the United States, and a survey of farm characteristics, animal husbandry practices, and antibiotic usage was conducted. CRB were detected in fecal samples from 47.4% of all cattle, with the prevalence ranging from 21.1 to 87.5% on farms, and significantly higher (P &lt; 0.001) in calves compared to adult cows (54.1 vs. 41.8%). Environmental samples had a higher prevalence than fecal samples (P &lt; 0.001), with CRB detected in 88.6% of water, 98.7% of soil, and 95.7% of forage samples. Compared to the concentration (log CFU/g) of CRB in fecal samples (2.95, 95% CI: 2.89, 3.02), the concentration of CRB was higher (P &lt; 0.001) in soil and forage samples (5.37, 95% CI: 5.16, 5.57) and lower (P &lt; 0.001) in water samples (1.08, 95% CI: 0.82, 1.36). Soil microbiota from farms with high prevalence of CRB clustered closer together and the proportion of Phylum Proteobacteria was higher on farms with high prevalence of CRB resistance. Large farming operations were associated with a 58% higher likelihood of CRB detection in fecal samples. Regular cleaning of drinking troughs and the addition of ionophores to feed were associated with CRB reduction in fecal samples. Taken together, the widespread of CRB into both cattle seldom treated with cephalosporin antibiotics and the surrounding environment suggests the environment is a natural source of antimicrobial resistance in beef cattle

Autophagy in ischemic aged livers

Ischemia/reperfusion (I/R) injury inevitably occurs during liver resection and transplantation. Elderly patients poorly recover from these surgeries. This reduced reparative capacity with aging is causatively associated with decreased mitochondrial function after reperfusion. Mitochondrial autophagy (mitophagy) is a vital cellular process that timely clears abnormal and dysfunctional mitochondria. Impaired or insufficient autophagy can contribute to hepatocyte death after I/R. This review describes our current understanding of I/R injury and highlights new mechanistic correlation between sirtuin 1 (SIRT1), mitofusin 2 (MFN2), and autophagy in the pathogenesis of age-dependent hypersensitivity to reperfusion injury. The deacetylation of MFN2 by SIRT1 plays a pivotal role in the recovery from reperfusion injury by modulating the onset of autophagy. Targeting the SIRT1-MFN2 axis could be a new therapeutic target to reduce I/R injury in aged livers. Keywords: Hepatocytes, Autophagy, Mitochondrial autophagy (mitophagy), Aging, Ischemia/reperfusion (I/R), Sirtuin 1-mitofusin 2 (SIRT1-MFN2) axi

Pneumatic-type surgical robot end-effector for laparoscopic surgical-operation-by-wire

Background Although minimally invasive surgery (MIS) affords several advantages compared to conventional open surgery, robotic MIS systems still have many limitations. One of the limitations is the non-uniform gripping force due to mechanical strings of the existing systems. To overcome this limitation, a surgical instrument with a pneumatic gripping system consisting of a compressor, catheter balloon, micro motor, and other parts is developed. Method This study aims to implement a surgical instrument with a pneumatic gripping system and pitching/yawing joints using micro motors and without mechanical strings based on the surgical-operation-by-wire (SOBW) concept. A 6-axis external arm for increasing degrees of freedom (DOFs) is integrated with the surgical instrument using LabVIEW® for laparoscopic procedures. The gripping force is measured over a wide range of pressures and compared with the simulated ideal step function. Furthermore, a kinematic analysis is conducted. To validate and evaluate the systems clinical applicability, a simple peg task experiment and workspace identification experiment are performed with five novice volunteers using the fundamentals of laparoscopic surgery (FLS) board kit. The master interface of the proposed system employs the hands-on-throttle-and-stick (HOTAS) controller used in aerospace engineering. To develop an improved HOTAS (iHOTAS) controller, 6-axis force/torque sensor was integrated in the special housing. Results The mean gripping force (after 1,000 repetitions) at a pressure of 0.3 MPa was measured to be 5.8 N. The reaction time was found to be 0.4 s, which is almost real-time. All novice volunteers could complete the simple peg task within a mean time of 176 s, and none of them exceeded the 300 s cut-off time. The systems workspace was calculated to be 11,157.0 cm3. Conclusions The proposed pneumatic gripping system provides a force consistent with that of other robotic MIS systems. It provides near real-time control. It is more durable than the existing other surgical robot systems. Its workspace is sufficient for clinical surgery. Therefore, the proposed system is expected to be widely used for laparoscopic robotic surgery. This research using iHOTAS will be applied to the tactile force feedback system for surgeons safe operation

Association between phthalate exposure and lower handgrip strength in an elderly population: a repeated-measures study

Background Decreased muscle strength can lead to adverse health outcomes in the elderly. A potential association between phthalate exposure and muscle strength was suggested previously, but has not been investigated directly. We hypothesized that phthalate exposure is associated with lower handgrip strength and that the association is modified by the dietary omega-6 to omega-3 ratio. Methods We analyzed 1,228 participants (≥60 years of age) recruited in Seoul and Asan, Republic of Korea. The study participants were surveyed up to three times between 2012 and 2015. At every survey, we collected urine samples and measured handgrip strength twice for each hand. The associations between urine phthalate metabolite concentrations and handgrip strength were evaluated using linear mixed models. Based on dietary information from 391 individuals who participated in the first survey in Seoul, we evaluated the heterogeneity of the association for those with high and low omega-6 to omega-3 ratios, using 8.81 (the 75th quantile) as a cutoff value. Results Log-transformed creatinine-adjusted concentrations of mono-(2-ethyl-5-oxohexyl phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-n-butyl phthalate (MnBP) were inversely associated with all measured handgrip strengths (β = −0.69 to −0.42, all p-values < 0.05). Associations between phthalate biomarkers and handgrip strength did not differ by sex. When the dietary subgroup was stratified by the omega-6 to omega-3 ratio, the associations were stronger among participants with high ratios. Conclusions We found inverse associations between phthalate biomarkers and handgrip strength in the elderly; this association was modified by the dietary omega-6 to omega-3 ratio

General acts passed by the General Court of Massachusetts

Imprint varies.Vols. for 1915-19 published in 2 v.: General acts; Special acts.Vols. for some years issued in parts.Separate vols. issued for extra session, 1916, and for extra session, 1933.Vol. 12 (May 1831-Mar. 1833) in Jan. session, 1833; Jan. 1834-Apr. 1836 in vol. for extra session 1835/Jan. session 1836; May 1824-Mar. 1828; June 1828-June 1831, Jan. 1832-Apr. 1834, Jan. 1835-Apr. 1838, each bound with corresponding vol.Resolves issued separately, 1780-1838

Laparoscopic cholecystectomy in a swine model using a novel near-infrared fluorescent IV dye (BL-760)

BACKGROUND AND OBJECTIVES: Bile duct injury during laparoscopic cholecystectomy has an incidence rate of 1%-2% and commonly appears under conditions of severe inflammation, adhesion, or unexpected anatomical variations. Despite the difficulties and rising concerns of identifying bile duct during surgeries, surgeons do not have a specific modality to identify bile duct except intraoperative cholangiography. While no biliary-specific fluorescent dye exists for clinical use, our team has previously described the development of a preclinical biliary-specific dye, BL-760. Here, we present our study of laparoscopic cholecystectomy using the fluorescent dye in a swine model. STUDY DESIGN/MATERIALS AND METHODS: With an approval from Institutional Animal Care and Use Committee, two 20-25 kg swine underwent laparoscopic abdominal surgery using a Food and Drug Administration-cleared fluorescent laparoscopic system. Images of the liver and gallbladder were taken both before and after intravenous injection of the novel fluorescent dye. The dye was dosed at 60 μg/kg and injected via the ear vein. The amount of time taken to visualize fluorescence in the biliary tract was measured. Fluorescent signal was observed after injection, and target-to-background ratio (TBR) of the biliary tract to surrounding cystic artery and liver parenchyma was measured. RESULTS: Biliary tract visualization under fluorescent laparoscopy was achieved within 5 min after the dye injection without any adverse effects. Cystic duct and extrahepatic duct were clearly visualized and identified with TBR values of 2.19 and 2.32, respectively, whereas no fluorescent signal was detected in liver. Cystic duct and artery were successfully ligated by an endoscopic clip applier with the visual assistance of highlighted biliary tract images. Laparoscopic cholecystectomy was completed within 30 min in each case without any complications. CONCLUSIONS: BL-760 is a novel preclinical fluorescent dye useful for intraoperative identification and visualization of biliary tract. Such fluorescent dye that is exclusively metabolized by liver and rapidly excreted into biliary tract would be beneficial for all types of hepato-biliary surgeries. With the validation of additional preclinical data, this novel dye has potential to be a valuable tool to prevent any iatrogenic biliary injuries and/or bile leaks during laparoscopic abdominal and liver surgeries

Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy

International audienceAlzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage. Methods We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity. Results Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA. Conclusion In a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction. </jats:sec