Pathological and neurophysiological outcomes of seeding human-derived tau pathology in the APP-KI NL-G-F and NL-NL mouse models of Alzheimer's Disease.

The two main histopathological hallmarks that characterize Alzheimer's Disease are the presence of amyloid plaques and neurofibrillary tangles. One of the current approaches to studying the consequences of amyloid pathology relies on the usage of transgenic animal models that incorporate the mutant humanized form of the amyloid precursor protein (hAPP), with animal models progressively developing amyloid pathology as they age. However, these mice models generally overexpress the hAPP protein to facilitate the development of amyloid pathology, which has been suggested to elicit pathological and neuropathological changes unrelated to amyloid pathology. In this current study, we characterized APP knock-in (APP-KI) animals, that do not overexpress hAPP but still develop amyloid pathology to understand the influence of protein overexpression. We also induced tau pathology via human-derived tau seeding material to understand the neurophysiological effects of amyloid and tau pathology. We report that tau-seeded APP-KI animals progressively develop tau pathology, exacerbated by the presence of amyloid pathology. Interestingly, older amyloid-bearing, tau-seeded animals exhibited more amyloid pathology in the entorhinal area, isocortex and hippocampus, but not thalamus, which appeared to correlate with impairments in gamma oscillations before seeding. Tau-seeded animals also featured immediate deficits in power spectra values and phase-amplitude indices in the hippocampus after seeding, with gamma power spectra deficits persisting in younger animals. Both deficits in hippocampal phase-amplitude coupling and gamma power differentiate tau-seeded, amyloid-positive animals from buffer controls. Based on our results, impairments in gamma oscillations appear to be strongly associated with the presence and development of amyloid and tau pathology, and may also be an indicator of neuropathology, network dysfunction, and even potential disposition to the future development of amyloid pathology.

Neurophysiological effects of human-derived pathological tau conformers in the APPKM670/671NL.PS1/L166P amyloid mouse model of Alzheimer's disease.

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by two main pathological hallmarks: amyloid plaques and intracellular tau neurofibrillary tangles. However, a majority of studies focus on the individual pathologies and seldom on the interaction between the two pathologies. Herein, we present the longitudinal neuropathological and neurophysiological effects of a combined amyloid-tau model by hippocampal seeding of human-derived tau pathology in the APP.PS1/L166P amyloid animal model. We statistically assessed both neurophysiological and pathological changes using linear mixed modelling to determine if factors such as the age at which animals were seeded, genotype, seeding or buffer, brain region where pathology was quantified, and time-post injection differentially affect these outcomes. We report that AT8-positive tau pathology progressively develops and is facilitated by the amount of amyloid pathology present at the time of injection. The amount of AT8-positive tau pathology was influenced by the interaction of age at which the animal was injected, genotype, and time after injection. Baseline pathology-related power spectra and Higuchi Fractal Dimension (HFD) score alterations were noted in APP.PS1/L166P before any manipulations were performed, indicating a baseline difference associated with genotype. We also report immediate localized hippocampal dysfunction in the electroencephalography (EEG) power spectra associated with tau seeding which returned to comparable levels at 1 month-post-injection. Longitudinal effects of seeding indicated that tau-seeded wild-type mice showed an increase in gamma power earlier than buffer control comparisons which was influenced by the age at which the animal was injected. A reduction of hippocampal broadband power spectra was noted in tau-seeded wild-type mice, but absent in APP.PS1 animals. HFD scores appeared to detect subtle effects associated with tau seeding in APP.PS1 animals, which was differentially influenced by genotype. Notably, while tau histopathological changes were present, a lack of overt longitudinal electrophysiological alterations was noted, particularly in APP.PS1 animals that feature both pathologies after seeding, reiterating and underscoring the difficulty and complexity associated with elucidating physiologically relevant and translatable biomarkers of Alzheimer's Disease at the early stages of the disease.

Textile Aging Characterization on New Generations of Explanted Commercial Endoprostheses: A Preliminary Study.

OBJECTIVE/BACKGROUND: The goal of the present study was to assess the aging phenomena on second-generation textile endoprostheses (EPs) through explant analysis and to establish a preliminary classification of observed defects and material damages. METHODS: From January 2011 to June 2016 110 second- and recent-generation EPs were collected as a part of a European collaborative retrieval program. The analysis focused on the first 41 consecutive commercial EPs collected between 2011 and 2014 and made from polyethylene terephthalate. Explants were submitted to a standardized evaluation protocol, which included data recording, eye-naked evaluation, cleaning of organic remnants, and structural analysis under numerical optical microscopy. Observations were reported using a classification based on 15 features evaluating the fabric, the stitches between the fabric and the stents, and the stents. The total surface area of the holes within the fabric was measured. RESULTS: EPs were implanted for thoracic and abdominal procedures in 12 and 29 cases, respectively. The mean ± SD duration of implantation was 34 ± 26 months (range 2 days-8 years). Sixty-four percent of the samples demonstrated at least one defect caused by compression damage potentially related to the insertion of the EP within the delivery system, which promoted holes and tears. Ninety-five percent of all EPs demonstrated at least one type of abrasion on the stitches. The degradation of the stitches and the number of ruptures increased with duration of implantation. Stent degradation was rare and consisted of corrosion and rupture. Cumulated holed surface area increased with time and was measured up to 13.5 mm2. CONCLUSION: Various aging-related phenomena on commercial textile EPs were identified and classified. Main damaging mechanisms were related to compression and abrasion leading to tears and holes in the fabric and rupture of stitches.

Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology.

A recent genome-wide association meta-analysis for Alzheimer's disease (AD) identified 19 risk loci (in addition to APOE) in which the functional genes are unknown. Using Drosophila, we screened 296 constructs targeting orthologs of 54 candidate risk genes within these loci for their ability to modify Tau neurotoxicity by quantifying the size of >6000 eyes. Besides Drosophila Amph (ortholog of BIN1), which we previously implicated in Tau pathology, we identified p130CAS (CASS4), Eph (EPHA1), Fak (PTK2B) and Rab3-GEF (MADD) as Tau toxicity modulators. Of these, the focal adhesion kinase Fak behaved as a strong Tau toxicity suppressor in both the eye and an independent focal adhesion-related wing blister assay. Accordingly, the human Tau and PTK2B proteins biochemically interacted in vitro and PTK2B co-localized with hyperphosphorylated and oligomeric Tau in progressive pathological stages in the brains of AD patients and transgenic Tau mice. These data indicate that PTK2B acts as an early marker and in vivo modulator of Tau toxicity.

[Skeletal muscle ischemia-reperfusion and ischemic conditioning pathophysiology-clinical applications for the vascular surgeon]. / Physiopathologie de l'ischémie-reperfusion et du conditionnement ischémique du muscle squelettique ­ applications cliniques pour le chirurgien vasculaire.

Ischemia-reperfusion, which is characterized by deficient oxygen supply and subsequent restoration of blood flow, can cause irreversible damage to tissue. The vascular surgeon is daily faced with ischemia-reperfusion situations. Indeed, arterial clamping induces ischemia, followed by reperfusion when declamping. Mechanisms underlying ischemia-reperfusion injury are complex and multifactorial. Increases in cellular calcium and reactive oxygen species, initiated during ischemia and then amplified upon reperfusion are thought to be the main mediators of reperfusion injury. Mitochondrial dysfunction also plays an important role. Extensive research has focused on increasing skeletal muscle tolerance to ischemia-reperfusion injury, especially through the use of ischemic conditioning strategies. The purpose of this review is to focus on the cellular responses associated with ischemia-reperfusion, as well as to discuss the effects of ischemic conditioning strategies. This would help the vascular surgeon in daily practice, in order to try to improve surgical outcome in the setting of ischemia-reperfusion.

Is there any range-of-motion advantage to using bearings larger than 36mm in primary hip arthroplasty: A case-control study comparing 36-mm and large-diameter heads.

BACKGROUND: Large-diameter (>36mm) total hip arthroplasty (THA) has developed rapidly since the advent of ceramic-on-ceramic (CoC) bearings and highly cross-linked polyethylene. Theoretically, the increase in diameter reduces the risk of instability, although the advantage of calibers beyond 36mm has not been demonstrated in terms of range-of-motion recovery. We conducted a comparative study with a single prosthesis model to determine whether increasing the caliber beyond 36mm provides: (1) better recovery of range-of-motion, (2) a higher functional score, and (3) reduction of the dislocation rate. HYPOTHESIS: Increasing the range-of-motion by increasing the caliber beyond 36mm provides better range-of-motion. MATERIAL AND METHODS: We analyzed two consecutive, single-operator cementless THA series performed via the mini posterior approach, which differed only in the bearing system (51 metal-on-metal [MoM] with a mean caliber of 45mm±3.3 [range, 40-54] and 61 CoC with a 36-mm caliber). Both series were comparable preoperatively in terms of age, diagnosis, functional scores, preoperative range-of-motion, body mass index, UCLA activity level, and Charnley score. We compared the joint range of movement at follow-up and the gains in range of movement, onset of dislocation, and functional scores (Oxford, Postel-Merle d'Aubigné [PMA]). RESULTS: The mean overall joint range-of-motion was 254°±39° (range, 150-310°) for an 81°±44° (range, -50 to 180°) gain in the MoM group and 256°±23° (range, 200-280°) for an 84°±40° (range, 0-160°) gain in the CoC group (NS). The MoM group presented the following results: Oxford=13.71±3.66 (range, 12-33) for a gain of 24.82 points±7.9 (range, -1 to 40), PMA=17.75±1.06 (range, 11-18) for a gain of 7.78 points±4.01 (range, 2-15). The CoC group had: Oxford=14.98±4.42 (range, 12-36) for a gain of 24.75 points±6.55 (range, 12-40), PMA 17.66±0.7 (range, 14-18) for a gain of 8 points±3.77 (range, 1-15). None of the gains and scores at follow-up differed significantly between the two groups. No episode of dislocation was identified. DISCUSSION: The current trend of increasing femoral head diameters beyond 36mm to improve the gains in joint range-of-motion and function is not warranted. The potential side effects of increasing the caliber call for even greater caution in the use of large-diameter heads because our hypothesis has not been confirmed. LEVEL OF EVIDENCE: Case-control study, level III.

Five Year Outcomes of Surgical Treatment for Popliteal Artery Entrapment Syndrome.

OBJECTIVE/BACKGROUND: The aim of this study was to evaluate long-term outcomes following surgery for popliteal artery entrapment syndrome. METHODS: A retrospective study of all patients that underwent surgery for popliteal artery entrapment syndrome between January 2003 and December 2009 was performed. Patient demographic data, clinical features, imaging modalities, and surgical management were recorded. The primary outcome was 5 year patency. RESULTS: Eighteen patients (25 limbs) underwent surgery. The mean age at the time of surgical procedure was 35 (median 35 years; range 15-49). Presentation was bilateral in seven patients (39%). Diagnosis was made using various imaging modalities, including position stress test, Duplex ultrasonography, computed tomography angiography, magnetic resonance imaging and conventional angiography. In four limbs the popliteal artery was compressed and undamaged (16%), and treatment consisted of musculo-tendinous division alone. In 16 limbs the popliteal artery was damaged with lesions limited to the popliteal artery (64%) where treatment consisted of venous interposition. In five limbs lesions extended beyond the popliteal artery (20%) and procedures included one below knee femoro-popliteal bypass, three femoro-posterior tibial bypasses, and one popliteo-posterior tibial bypass. Musculo-tendinous division was associated with vascular reconstruction in 19 limbs (90%). Mean follow up was 82 months (median 81 months, range 60-120). Five year patency was 84%. CONCLUSION: Long-term outcomes of surgical procedures performed for popliteal artery entrapment syndrome can be considered satisfactory.

[Contribution of mathematical models and biomechanical properties in predicting the risk of abdominal aortic aneurysm rupture]. / Apport des modèles mathématiques et des études biomécaniques dans la prédiction du risque de rupture des anévrysmes de l'aorte abdominale.

INTRODUCTION: Rupture is the worst outcome of abdominal aortic aneurysm (AAA). The decision to operate should include counterbalancing the risk of aneurysm rupture against the risk of aneurysm repair, within the context of a patient's overall life expectancy. Current surgical guidelines are based on population studies, and important variables are missed in predicting individual risk of rupture. METHODS: In this literature review, we focused on the contribution of biomechanical and mathematical models in predicting risk of AAA rupture. RESULTS: Anatomical features as diameter asymmetry and lack of tortuosity are shown to be anatomical risk factors of rupture. Wall stiffness (due to modifications of elastin and collagen composition) and increased inflammatory response are also factors that affect the structural integrity of the AAA wall. Biomechanical studies showed that wall strength is lower in ruptured than non-ruptured AAA. Intra-luminal thrombus also has a big role to play in the occurrence of rupture. Current mathematical models allow more variables to be included in predicting individual risk of rupture. CONCLUSION: Moving away from using maximal transverse diameter of the AAA as a unique predictive factor and instead including biological, structural and biomechanical variables in predicting individual risk of rupture will be essential in the future and will help gain precision and accuracy in surgical indications.

Technique to treat iliopsoas irritation after total hip replacement: Thickening of articular hip capsule through an abridged direct anterior approach.

Iliopsoas irritation due to acetabular cup component impingement following total hip arthroplasty (THA) is usually treated by infiltration or by distal iliopsoas tenotomy in case of recurrence; however, this can result in an active flexion deficit of the thigh. To prevent this complication, we developed an original technique that we performed between 2012 and 2014 in patients with recurrent impingement following extraarticular corticosteroid injections. This included 5 patients (mean age: 64 [53-75] years old) in whom we performed an ambulatory bursectomy by the Hueter approach and placed a polyglactin 910 (Vicryl™) mesh plate on the entire anterior hip capsule. After a mean follow-up of 12months (9-29months), anterior pain had decreased in all patients with improvement and an increase in the Oxford-12 (mean: 15 points [10-19]), Merle d'Aubigné (mean: 2.5 points [1-5]) and Harris (mean: 18 points [10-29]) scores. No flexion deficits were observed. An infected postoperative hematoma had to be drained but was cured at follow-up. This simple procedure provides satisfactory results and preserves THA function. It does not jeopardize future procedures and is an alternative option in case of unsuccessful conservative treatment.

Gender related Long-term Differences after Open Infrainguinal Surgery for Critical Limb Ischemia.

OBJECTIVE: The role of gender on long-term infrainguinal open surgery outcomes still remains uncertain in critical limb ischemia patients. The aim of this study is to evaluate the gender-specific differences in patient characteristics and long-term clinical outcomes in terms of survival, primary patency and limb salvage among patients undergoing infrainguinal open surgery for CLI. MATERIAL AND METHODS: All consecutive patients undergoing infrainguinal open surgery for critical limb ischemia between 2003 and 2012 were included. Survival, limb salvage and primary patency rates were assessed. Independent outcome determinants were identified by the Cox proportional hazard ratio using age and gender as adjustment factors. RESULTS: 584 patients (269 women and 315 men, mean age 76 and 71 years respectively) underwent 658 infrainguinal open surgery (313 in women and 345 in men). Survival rate at 6 years was lower among women compared to men with 53.5% vs 70.9% (p < 0.001). The same applied to primary patency (35.9% vs 52.4%, p < 0.001) and limb salvage (54.3% vs 81.1%, p < 0.001) at 6 years. Female-gender was an independent factor predicting death (hazard ratio 1.50), thrombosis (hazard ratio 2.37) and limb loss (hazard ratio 7.05) in age and gender-adjusted analysis. CONCLUSION: Gender-related disparity in critical limb ischemia open surgical revascularization outcomes still remains.

Popliteal artery entrapment syndrome.

Intermittent claudication is frequently encountered in vascular surgical practice in atherosclerotic patients. However, it may also be observed in a younger subset of patients without any cardiovascular risk factors and can represent a challenging diagnosis. Popliteal artery entrapment syndrome is rare but can cause intermittent claudication in young people. There is a lack of consensus about optimal strategies or diagnosis and management, particularly for variants such as functional popliteal entrapment. Since the first description in 1959, knowledge of the pathology and the underlying anatomic abnormalities was advanced through sporadic publications of case reports and small case series, but popliteal artery entrapment syndrome still remains a rare anatomic abnormality. It can be difficult to differentiate from other causes of lower limb pain in young patients, and diagnosis can be challenging. We propose to review clinical symptomatology, classification, radiological diagnosis and treatment of popliteal entrapment syndrome.

A genome-wide association meta-analysis of plasma Aß peptides concentrations in the elderly.

Amyloid beta (Aß) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aß peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aß peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aß-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aß1-40 and Aß1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aß1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aß1-42 secretion. In conclusion, our study results suggest that plasma Aß peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

Lower pole vessels in children with pelviureteric junction obstruction: laparoscopic vascular hitch or dismembered pyeloplasty?

OBJECTIVE: To choose between laparoscopic "vascular hitch" (VH) and dismembered pyeloplasty (DP) in treatment of aberrant lower pole crossing vessels potentially responsible for pelviureteric junction obstruction (PUJO) in older children. PATIENTS AND METHODS: Retrospective study of 19 patients treated laparoscopically for PUJO. Based on videos of the procedures, we studied the anatomical relationship between the renal pelvis, the pelviureteric junction, and the aberrant vessels. RESULTS: Eight patients had laparoscopic VH and 11 had DP. All patients with DP needed drainage. In the VH group, 7/8 patients were asymptomatic and had decreased pelvic dilation. Half of them accepted MAG3 scintigraphy, and in these patients the obstructive syndrome disappeared completely. The last patient in this group was lost to follow-up. We observed three anatomical variations in the location of polar vessels: type 1 (in front of the dilated pelvis), type 2 (in front of the pelviureteric junction), type 3 (under the pelviureteric junction, resulting in ureteral kinking). CONCLUSION: Laparoscopic VH is a simple technique involving no urinary anastomosis or drainage, but we cannot guarantee that the crossing vessels are the sole etiology for PUJO. Following our experience, only patients with type 3 anatomical variations and with a normal pelviureteric junction should be proposed for VH.

Chemical control of Loxosceles intermedia (Araneae: Sicariidae) with pyrethroids: field and laboratory evaluation.

Bites from the recluse or brown spiders (genus Loxosceles) can cause necrotic lesions and systemic effects in humans throughout the world. In the state of Paraná, Brazil, loxoscelism is considered a serious public health problem, and Loxosceles intermedia Mello-Leitão (Araneae: Sicariidae) is associated with the majority of reported accidents. In the present research we evaluated the susceptibility of L. intermedia to pyrethroid insecticides currently used for the control of spiders in both field and laboratory conditions. In laboratory tests, the most active pesticides in descending order were microencapsulated lambda-cyhalothrin (LC50 = 0.023 mg/kg), nonmicroencapsulated lambda-cyhalothrin (LC50 = 0.047 mg/kg), deltamethrin (LC50 = 0.26 mg/kg), and cypermethrin (LC50 = 1.38 mg/kg). Cockroaches, Phoetalia circumvagans (Burmeister) (n = 30), killed with microencapsulated lambdacyalothrin, were offered to the spiders. L. intermedia fed on 63.3% of the dead cockroaches during the first 6 h of experiment; none of the spiders died during the subsequent 15 d. Microencapsulated lambdacyalothrin was chosen for application in two contiguous houses. The mean volume applied was 22.8 mg (AI)/m2. Dead spiders were found during all the inspections up to 60 d after the initial application. In total, 297 dead spiders were collected; 65.7% in the attic shared by the two homes, 10.8% inside the house that had most cracks and crevices sealed and 23.6% in the control house. The use of lambda-cyhalothrin-based products for L. intermedia control is discussed.

Isolation and structure elucidation of a highly haemolytic saponin from the Merck saponin extract using high-field gradient-enhanced NMR techniques.

Saponins SAPO50 and SAPO30, of which SAPO50 is highly haemolytic, have been isolated from the commercial Merck Saponin. Their structures have been determined exclusively by high-field gradient-enhanced NMR methods. The 1H and 13C NMR spectra of these saponins in pyridine-deuterium oxide have been assigned by homonuclear and heteronuclear correlation experiments. Anomeric configurations were obtained by combined use of 1JCH, 3JH-1.H-2, and 1D-NOESY data. Sugar residues were identified by use of 3JHH values obtained from their subspectra recorded using an optimized 1D-zeta-TOCSY sequence. Linkage assignments were made using the ge-HMBC and 1D-NOESY spectra. This study shows that SAPO50 represents a hitherto undescribed saponin with the following structure: 3-O-beta-D-xylopyranosyl-(1-->3)-[beta-D-galactopyranosyl- (1-->2)]-beta-D-glucuronopyranosyl gypsogenin 28-O-(6-deoxy-beta-D-glucopyranosyl)-(1-->4)-[beta-D-xylopyranosyl-(1--> 3)- beta-D-xylopyranosyl-(1-->4)]-alpha-L-rhamnopyranosyl-(1-->2)-beta-D- fucopyranoside. SAPO30, however, corresponds to a saponin previously described [D. Frechet, B. Christ, B. Monegier du Sorbier, H. Fischer, and M. Vuilhorgne, Phytochemistry, 30 (1991) 927-931].

[Thrombocytopenia induced by heparin. Apropos of 10 cases]. / Thrombocytopénies induites par l'héparine. A propos de 10 cas.

The authors report ten observations of thrombocytopenia induced by heparin complicated with two arterial thrombosis and four deep venous thrombosis. Two deaths and two amputations are to mention. This retrospective study leads to a review of literature: this iatrogenic disease, which frequency is variously estimated, has no relation with the dose and the mode of administration of Heparin. It's mechanism might be immuno-allergic. It's diagnosis depends mainly on the repetition of platelet numerations at the outset period of treatment, and on the rapid and lasting climbing of platelet countings when heparin is stopped. This uncommon and unforeseeable complication indicates to stop Heparin and to start K antivitamin's if necessary.