Recognition of others' interoceptive states in those with and without eating disorders.

BACKGROUND: The ability to recognize one's own emotions is associated with one's ability to recognize others' emotions. Beyond the domain of emotion, however, the relationship between recognition of one's own internal states (interoception) and others' interoceptive states has not been investigated, either in the typical population or clinical groups with interoceptive difficulties (e.g. eating disorders; EDs). METHOD: This study investigated recognition of one's own and others' internal states in adults with and without eating disorders, using a high frequency visual noise paradigm. Participants completed self-report measures of interoception, alexithymia (difficulties recognising one's own emotional internal states) and ED symptomatology, and the Heartbeat Counting Task measure of cardiac interoceptive accuracy. RESULTS: Alexithymia was significantly negatively correlated with recognition of others' interoceptive states. EDs were not associated with difficulties recognising others' interoceptive states. CONCLUSIONS: The ability to recognise one's own emotional internal states is associated with the recognition of others' interoceptive states, which may contribute to social skills and the ability to care for others.

Distinct characteristics of limbic-predominant age-related TDP-43 encephalopathy in Lewy body disease.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer's disease (AD). We aimed to identify the pathological, clinical, and genetic characteristics of LATE in LBD (LATE-LBD) by comparing it with LATE in AD (LATE-AD), LATE with mixed pathology of LBD and AD (LATE-LBD + AD), and LATE alone (Pure LATE). We analyzed four cohorts of autopsy-confirmed LBD (n = 313), AD (n = 282), LBD + AD (n = 355), and aging (n = 111). We assessed the association of LATE with patient profiles including LBD subtype and AD neuropathologic change (ADNC). We studied the morphological and distributional differences between LATE-LBD and LATE-AD. By frequency analysis, we staged LATE-LBD and examined the association with cognitive impairment and genetic risk factors. Demographic analysis showed LATE associated with age in all four cohorts and the frequency of LATE was the highest in LBD + AD followed by AD, LBD, and Aging. LBD subtype and ADNC associated with LATE in LBD or AD but not in LBD + AD. Pathological analysis revealed that the hippocampal distribution of LATE was different between LATE-LBD and LATE-AD: neuronal cytoplasmic inclusions were more frequent in cornu ammonis 3 (CA3) in LATE-LBD compared to LATE-AD and abundant fine neurites composed of C-terminal truncated TDP-43 were found mainly in CA2 to subiculum in LATE-LBD, which were not as numerous in LATE-AD. Some of these fine neurites colocalized with phosphorylated α-synuclein. LATE-LBD staging showed LATE neuropathological changes spread in the dentate gyrus and brainstem earlier than in LATE-AD. The presence and prevalence of LATE in LBD associated with cognitive impairment independent of either LBD subtype or ADNC; LATE-LBD stage also associated with the genetic risk variants of TMEM106B rs1990622 and GRN rs5848. These data highlight clinicopathological and genetic features of LATE-LBD.

In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics.

The microtubule-associated protein tau (tau) forms hyperphosphorylated aggregates in the brains of tauopathy patients that can be pathologically and biochemically defined as distinct tau strains. Recent studies show that these tau strains exhibit strain-specific biological activities, also referred to as pathogenicities, in the tau spreading models. Currently, the specific pathogenicity of human-derived tau strains cannot be fully recapitulated by synthetic tau preformed fibrils (pffs), which are generated from recombinant tau protein. Reproducing disease-relevant tau pathology in cell and animal models necessitates the use of human brain-derived tau seeds. However, the availability of human-derived tau is extremely limited. Generation of tau variants that can mimic the pathogenicity of human-derived tau seeds would significantly extend the scale of experimental design within the field of tauopathy research. Previous studies have demonstrated that in vitro seeding reactions can amplify the beta-sheet structure of tau protein from a minute quantity of human-derived tau. However, whether the strain-specific pathogenicities of the original, human-derived tau seeds are conserved in the amplified tau strains has yet to be experimentally validated. Here, we used biochemically enriched brain-derived tau seeds from Alzheimer's disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) patient brains with a modified seeding protocol to template the recruitment of recombinant 2N4R (T40) tau in vitro. We quantitatively interrogated efficacy of the amplification reactions and the pathogenic fidelity of the amplified material to the original tau seeds using recently developed sporadic tau spreading models. Our data suggest that different tau strains can be faithfully amplified in vitro from tau isolated from different tauopathy brains and that the amplified tau variants retain their strain-dependent pathogenic characteristics.

Wide posterior gluteal-thigh propeller flap for reconstruction of perineal defects.

INTRODUCTION: With increasing popularity of minimally invasive approaches to abdominoperineal resection (APR), thigh-based flaps are becoming the preferred option for reconstruction. The gluteal-thigh flap provides sufficient bulk, albeit with a high complication rate. We reevaluated the vascularization and design of the gluteal-thigh flap. The purpose of this study is to highlight the importance of the vascularization of the posterior thigh skin by the descending branch of the inferior gluteal artery (IGA) and the profunda femoris artery (PFA) perforators to design a more reliable and versatile gluteal thigh flap. This flap is indicated in selected cases in which use of vertical rectus abdominis musculocutaneous flap is not feasible. METHODS: Eleven fresh cadavers were used. The course, distribution, and diameter of IGA and PFA perforators were recorded. A wide posterior gluteal-thigh propeller flap (WPGTPF) was designed including the distance between the ischiatic tuberosity and greater trochanter; and extending it to within 8 cm of the popliteal fossa to improve flap reliability. Ten patients (mean age of 58.7 ± 10.6 years) underwent APR due to anal cancer (2) and rectal cancer (8); the approach was open in 3, laparoscopic in 6, and robotic in 1. All 10 patients received unilateral flap with a width of 12 ± 3.3 cm and surface of 405.5 ± 175.9 cm2 . RESULTS: The descending branch of the IGA was dominant in 72.7% of the specimens. In 22.7% of the specimens, the pedicle of the flap derived from the first or second PFA perforators. In one case, there was a double vascularization. Descending branch of the IGA was mapped at 46 ± 7.96 mm on the X-axis (horizontal line from the ischial tuberosity [IT] to the greater trochanter) and -12.1 ± 17.9 mm on the Y-axis (vertical line from the IT to the Medial Femoral condyle). Its average caliber measured 2.18 ± 0.3 mm. The first and second PFA perforators were located at 101.6 ± 17.9 mm and 104.5 ± 15.5 mm on the X-axis; 35.9 ± 27.1 mm and 89.2 ± 37.6 mm on the Y-axis. Their average diameters were 1.84 ± 0.41 mm and 1.48 ± 0.3 mm. In two cases, the flap was based on the first PFA perforator, the rest were on the descending branch of the IGA. Neither complete nor partial flap necrosis was observed. One patient developed coccyx osteomyelitis treated and resolved with bone debridement and one patient developed a seroma of the lateral thigh that was treated conservatively. Three patients underwent a debulking procedure by a combination of liposuction and resection to improve the gluteal symmetry. All ten flaps survived completely. CONCLUSIONS: Harvest of a wide flap that includes the PFA perforators and implementation of the propeller design increase the survival and versatility of the flap.

External Approach to Buccal Fat Excision in Facelift: Anatomy and Technique.

BACKGROUND: Masculinization of the face is a common finding in facelift patients. It is attributed to deflation and decent of the midface-jowls coupled with skin laxity. Fullness is evident lateral to the jowl in a small percentage due to prominent buccal fat pad (BFP). OBJECTIVES: The authors sought to examine the anatomy of the BFP, triangulate the prominent BFP with surgical landmarks, and describe an external approach to excise the BFP during facelift surgery. METHODS: Eighteen cadaveric dissections were performed. Facelift flap was elevated and the prominent buccal extension of the BFP protruding through the superficial-musculo-aponeurotic-system was identified. Measurements were taken from the BFP to surgical landmarks: zygomatic arch, tragus, and gonial angle. The locations of the facial nerve, parotid duct, and vascular pedicle relative to the BFP were calculated. RESULTS: BFP was 4.1 cm inferior to the zygomatic arch, 7.5 cm anterior the tragus, and 4.5 cm medial the gonial angle. The middle facial artery supplied the BFP on the inferior-lateral quadrant in 61% and inferior-medial quadrant in 39% of specimens . In all specimens, the parotid duct traversed the BFP superiorly, and the buccal branches of the facial nerve traversed the capsule superficially. CONCLUSIONS: The buccal extension of the BFP can pseudoherniate in the aging face. Excision may improve lower facial contour. Measurements from facial landmarks may help surgeons identify the buccal extension of the BFP intraoperatively. The surgeon must be careful of the vascular pedicle, parotid duct, and the facial nerve. The external approach safely excises buccal fat during facelift dissection while avoiding intraoral incisions and unnecessary contamination.

Continuous force measurements reveal no inhibitory control deficits in Parkinson's disease.

Suppression of unwanted motor responses can be disrupted by Parkinson's disease. People with Parkinson's (PwP) can show maladaptive reward-driven behaviours in the form of impulse control behaviours, which are associated with the use of the dopaminergic treatments used to alleviate the motor symptoms of the disease. However, the effects of Parkinson's itself on impulsive behaviour and control are unclear-empirical studies have yielded mixed findings, and some imaging studies have shown a functional deficit in the absence of a measurable change in behaviour. Here, we investigated the effects of Parkinson's on response activation and control by studying the dynamics of response in standard inhibitory control tasks-the Stop Signal and Simon tasks-using a continuous measure of response force. Our results are largely in favour of the conclusion that response inhibition appears to be intact in PwP, even when using a more sensitive measure of behavioural control relative to traditional button-press measures. Our findings provide some clarity as to the effects of Parkinson's on response inhibition and show continuous response force measurement can provide a sensitive means of detecting erroneous response activity in PwP, which could also be generalised to studying related processes in other populations.

Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology.

INTRODUCTION: The level of the presynaptic protein growth-associated protein 43 (GAP-43) in cerebrospinal fluid (CSF) has previously been shown to be increased in Alzheimer's disease (AD) and thus may serve as an outcome measure in clinical trials and facilitate earlier disease detection. METHODS: We developed an enzyme-linked immunosorbent assay for CSF GAP-43 and measured healthy controls (n = 43), patients with AD (n = 275), or patients with other neurodegenerative diseases (n = 344). In a subpopulation (n = 93), CSF GAP-43 concentrations from neuropathologically confirmed cases were related to Aß plaques, tau, α-synuclein, and TDP-43 pathologies. RESULTS: GAP-43 was significantly increased in AD compared to controls and most neurodegenerative diseases and correlated with the magnitude of neurofibrillary tangles and Aß plaques in the hippocampus, amygdala, and cortex. GAP-43 was not associated to α-synuclein or TDP-43 pathology. DISCUSSION: The presynaptic marker GAP-43 is associated with both diagnosis and neuropathology of AD and thus may be useful as a sensitive and specific biomarker for clinical research.

Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain.

Pathological tau aggregates occur in Alzheimer's disease (AD) and other neurodegenerative tauopathies. It is not clearly understood why tauopathies vary greatly in the neuroanatomical and histopathological patterns of tau aggregation, which contribute to clinical heterogeneity in these disorders. Recent studies have shown that tau aggregates may form distinct structural conformations, known as tau strains. Here, we developed a novel model to test the hypothesis that cell-to-cell transmission of different tau strains occurs in nontransgenic (non-Tg) mice, and to investigate whether there are strain-specific differences in the pattern of tau transmission. By injecting pathological tau extracted from postmortem brains of AD (AD-tau), progressive supranuclear palsy (PSP-tau), and corticobasal degeneration (CBD-tau) patients into different brain regions of female non-Tg mice, we demonstrated the induction and propagation of endogenous mouse tau aggregates. Specifically, we identified differences in tau strain potency between AD-tau, CBD-tau, and PSP-tau in non-Tg mice. Moreover, differences in cell-type specificity of tau aggregate transmission were observed between tau strains such that only PSP-tau and CBD-tau strains induce astroglial and oligodendroglial tau inclusions, recapitulating the diversity of neuropathology in human tauopathies. Furthermore, we demonstrated that the neuronal connectome, but not the tau strain, determines which brain regions develop tau pathology. Finally, CBD-tau- and PSP-tau-injected mice showed spatiotemporal transmission of glial tau pathology, suggesting glial tau transmission contributes to the progression of tauopathies. Together, our data suggest that different tau strains determine seeding potency and cell-type specificity of tau aggregation that underlie the diversity of human tauopathies.SIGNIFICANCE STATEMENT Tauopathies show great clinical and neuropathological heterogeneity, despite the fact that tau aggregates in each disease. This heterogeneity could be due to tau aggregates forming distinct structural conformations, or strains. We now report the development of a sporadic tauopathy model to study human tau strains by intracerebrally injecting nontransgenic mice with pathological tau enriched from human tauopathy brains. We show human tau strains seed different types and cellular distributions of tau neuropathology in our model that recapitulate the heterogeneity seen in these human diseases.

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology.

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson's disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid ß (Aß), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aß neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with ß-amyloid plaque pathology.

Medical findings in 1,026 consecutive adult inpatient-residential eating disordered patients.

OBJECTIVE: Eating disorders are associated with multiple medical complications. We report contemporary medical data, for newly admitted adult inpatient and residential level of care patients. METHOD: Medical records of a transdiagnostic sample of 1,026 patients, with eating disorders, were retrospectively reviewed for the presence of a broad array of medical complications at time of admission. The prevalence of physiologically relevant medical complications was assessed across major eating disorder categories. RESULTS: Of the patients, 93.6% were female, and they had an average age of 28.1 (SD = 10.1, range 17-69). The average admission body mass index was 16.1 (SD = 2.3). The prevalence of abnormal laboratory values varied by eating disorder subtype. In patients with anorexia nervosa-restricting subtype, 51.4% had low prealbumin, 36.1% were leukopenic, 34.3% had osteoporosis, 30.0% vitamin D deficiency, 16.8% metabolic alkalosis, 16.0% had hyponatremia, 14.2% hypokalemia, and 7.1% hypoglycemia. These patients had normal average QTc intervals. In patients with anorexia nervosa-binge purging subtype, 42.4% had hypokalemia, 33.3% metabolic alkalosis, osteoporosis in 21.1%, and they had longer QTc intervals (433.9 ms, p < .001). Only 6.0% of patients with anorexia nervosa had hypophosphatemia. Patients with bulimia nervosa demonstrated hypokalemia in 26.2%, and metabolic alkalosis in 23.4%; the QTc interval was longer than in AN-R patients (437.9 ms, p < .001), but still in the normal range. DISCUSSION: Numerous medical complications are associated with severe eating disorders. As the severity increases, the number of complications increase and are related to the presence or absence of purging behaviors.

Continuous Positive Airway Pressure Thresholds for Nasolacrimal Air Regurgitation in a Cadaveric Model.

PURPOSE: To elucidate the mechanisms underlying nasolacrimal air regurgitation (AR) in the setting of continuous positive airway pressure therapy. METHODS: Twelve nasolacrimal systems of 6 fresh female human cadavers were evaluated individually for AR using continuous positive airway pressure therapy before any nasolacrimal procedure. Cadavers were then randomly assigned to undergo nasolacrimal duct probing or endoscopic dacryocystorhinostomy and then each hemisystem was again evaluated for AR. The pressure where AR was first observed (discovery pressure) or maximum possible pressure in systems without AR was recorded. In systems that demonstrated AR, the pressure was then gradually decreased to the lowest pressure where regurgitation persisted. This pressure was recorded as the secondary threshold pressure. RESULTS: None of the 12 unoperated nasolacrimal systems or the 6 systems that underwent nasolacrimal duct probing demonstrated AR through the maximum continuous positive airway pressure therapy (30 cm H2O). After endoscopic dacryocystorhinostomy, all 6 nasolacrimal systems demonstrated AR. The mean discovery pressure was 16.0 cm H2O (range, 14.0-18.0 cm H2O) and mean secondary threshold pressure was 7.25 cm H2O (range, 6.5-8.0 cm H2O). CONCLUSIONS: Air regurgitation during continuous positive airway pressure therapy in the setting of prior endoscopic dacryocystorhinostomy can be replicated in a cadaver model. The secondary threshold pressures required for AR in this model were similar to AR pressures reported clinically. Prior to dacryocystorhinostomy, patients using continuous positive airway pressure therapy should be counseled on AR, and physicians should consider this phenomenon when evaluating ophthalmic complaints in postoperative patients on positive airway pressure therapy.

Effect of 4-Week Ingestion of Tomato-Based Carotenoids on Exercise-Induced Inflammation, Muscle Damage, and Oxidative Stress in Endurance Runners.

This double-blind, randomized, placebo-controlled crossover trial determined if ingestion of a supplement containing a tomato complex with lycopene, phytoene, and phytofluene (T-LPP) and other compounds for 4 weeks would attenuate inflammation, muscle damage, and oxidative stress postexercise and during recovery from a 2-hr running bout that included 30 min of -10% downhill running. Study participants ingested the T-LPP supplement or placebo with the evening meal for 4 weeks prior to running 2 hr at high intensity. Blood samples and delayed onset muscle soreness ratings were taken pre- and post-4-week supplementation, and immediately following the 2-hr run, and then 1-hr, 24-hr, and 48-hr postrun. After a 2-week washout period, participants crossed over to the opposite treatment and repeated all procedures. Plasma lycopene, phytoene, and phytofluene increased significantly in T-LPP compared with placebo (p < .001 for each). Significant time effects were shown for serum creatine kinase, delayed onset muscle soreness, C-reactive protein, myoglobin, 9- and 13-hydroxyoctadecadienoic acids, ferric reducing ability of plasma, and six plasma cytokines (p < .001 for each). The pattern of increase for serum myoglobin differed between T-LPP and placebo (interaction effect, p = .016, with lower levels in T-LPP), but not for creatine kinase, delayed onset muscle soreness, C-reactive protein, the six cytokines, 9- and 13-hydroxyoctadecadienoic acids, and ferric reducing ability of plasma. No significant time or interaction effects were measured for plasma-oxidized low-density lipoprotein or serum 8-hydroxy-2'-deoxyguanosine. In summary, supplementation with T-LPP over a 4-week period increased plasma carotenoid levels 73% and attenuated postexercise increases in the muscle damage biomarker myoglobin, but not inflammation and oxidative stress.

Effective medical treatment strategies to help cessation of purging behaviors.

OBJECTIVE: Herein we review the major medical issues involved in the "detoxing" of patients who engage in purging behaviors and the pathophysiology of why they occur. METHODS: Given a limited evidence base of randomized controlled trials, we conducted a thorough qualitative review to identify salient literature with regard to the medical issues involved in "detoxing" patients from their purging behaviors. RESULTS: Pseudo Bartter's Syndrome is the root cause of much of the medical difficulties which can arise when purging behaviors are abruptly discontinued. However, this is imminently treatable and even preventable with a judicious medical treatment plan which targets the increased serum aldosterone levels which would otherwise promote salt and water retention and a propensity towards severe edema formation. Effective recommendations are provided which can make this process much less vexing for patients attempting to cease their purging behaviors. CONCLUSIONS: "Detoxing" from purging behaviors can be fraught with medical complications which frustrate these patients and can lead to unsuccessful outcomes. Medical providers should become familiar with the pathophysiology which is the basis for Pseudo Bartter's Syndrome and the effective medical treatments which can lead to a successful outcome.

Longitudinal cohort study on medical student retention of anatomical knowledge in an integrated problem-based learning curriculum.

BACKGROUND: When modifying a curriculum to accommodate changes in the methods of subject matter presentation or fit within a shortened time frame, student retention of knowledge remains an important issue. AIM: This study evaluates medical student retention of anatomical knowledge as they matriculate through an anatomy curriculum where the instruction hours are less than half of the current national average. METHOD: Medical students completed an assessment tool developed to evaluate their baseline level of anatomical knowledge at the beginning of the first year. They then completed the instrument at the end of their 1st, 2nd, 3rd, and 4th years to assess their retention of anatomical knowledge during medical school. Data collection began in September 2010 and concluded in June 2015. RESULTS: Results demonstrate that students began medical school with a low level of anatomical knowledge (baseline), that knowledge increased during their first year (p < 0.001), continued to increase during their second year (p < 0.001), but was over 90% maintained through years 3 and 4. CONCLUSION: In conclusion, an anatomy course with reduced hours (∼60), using active learning methods, contextual learning, cadaver demonstrations, increased exposure to imaging, and longitudinal reinforcement can help students build a strong foundation of anatomical knowledge.

Frontalis Muscle Asymmetry and Lateral Landmarks.

PURPOSE: To investigate frontalis muscle asymmetry and characterize its lateral interdigitation with the orbicularis oculi muscle. METHODS: After making a mid-coronal incision and bluntly dissecting to the orbital rim, the frontalis muscle was exposed, marked, and photographed. The right and left muscle bellies were analyzed and compared in both pixels and cm ratios generated with NIH ImageJ software. A ratio of ≥1.5 was considered significantly asymmetric. The lateral interdigitation of the frontalis and orbicularis oculi muscles was measured from the supraorbital notch with a metric ruler. Data were analyzed using 2-sample t tests, paired t tests, log scales, and nonparametric tests were performed for sensitivity analyses. A p value of ≤0.05 was considered statistically significant. RESULTS: Fifty-eight hemifaces of 29 Caucasian cadavers were studied for muscle belly asymmetry. Thirty-six hemifaces of 18 Caucasian cadavers (9 males) were dissected for lateral landmarks and average age of these specimens was 73 years (range: 35-91 years). Significant asymmetry in muscle belly area was found in 6/29 (20%) specimens, with the right muscle belly larger in all 6 specimens. On average, the right muscle belly area was 1.23 times that of the left (p = <0.001). The average frontalis-orbicularis interdigitation occurred 3.4 cm lateral to the supraorbital notch. CONCLUSIONS: Significant frontalis muscle belly asymmetry exists in 20% of Caucasians cadavers. The right muscle belly was larger on average and in all cases of significant asymmetry. The frontalis muscle interdigitates with the orbicularis oculi on average 3.4 cm lateral to the supraorbital notch.

Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections.

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed (Iba et al., J Neurosci 33:1024-1037, 2013) that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle-bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle-bearing neurons gradually cleared tau pathology by 6-12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique opportunities to elucidate mechanisms underlying the selective vulnerability of neurons to acquire tau pathology and succumb to or resist tau-mediated neurodegeneration.

Oat avenanthramide-C (2c) is biotransformed by mice and the human microbiota into bioactive metabolites.

BACKGROUND: Avenanthramides (AVAs), which are found exclusively in oats, may play an important role in anti-inflammation and antiatherogenesis. Although the bioavailability of AVAs has been investigated previously, little is known about their metabolism. OBJECTIVES: The aim of the present study was to investigate the metabolism of avenanthramide-C (2c), one of the major AVAs, in mice and by the human microbiota, as well as to elucidate the bioactivity of its major metabolites with the goal of finding new exposure markers to precisely reflect oat consumption. METHODS: For the mouse study, 10 CF-1 female mice were divided into control (vehicle-treated) and 2c intragastrically treated (200 mg/kg) groups (5 mice/group). Twenty-four-hour urine and fecal samples were collected with use of metabolic cages. For the batch culture incubations, 2c was cultured with fecal slurries obtained from 6 human donors. Incubated samples were collected at various time points (0, 12, 24, 48, 72, 96, and 120 h). Metabolites were identified via HPLC with electrochemical detection and LC with electrospray ionization/mass spectrometry. To investigate whether 2c metabolites retain the biological effects of 2c, we compared their effects on the growth of and induction of apoptosis in HCT-116 human colon cancer cells. RESULTS: Eight metabolites were detected from the 2c-treated mouse urine samples. They were identified as 5-hydroxyanthranilic acid (M1), dihydrocaffeic acid (M2), caffeic acid (M3), dihydroferulic acid (M4), ferulic acid (M5), dihydroavenanthramide-C (M6), dihydroavenanthramide-B (M7), and avenanthramide-B (M8) via analysis of their MS(n) (n = 1-3) spectra. We found that the reduction of 2c's C7'-C8' double bond and the cleavage of its amide bond were the major metabolic routes. In the human microbiota study, 2c was converted into M1-M3 and M6. Moreover, interindividual differences in 2c metabolism were observed among the 6 human subjects. Subjects B, C, E, and F could rapidly metabolize 2c to M6, whereas subject D metabolized little 2c, even up to 120 h. In addition, only subjects A, B, and F could cleave the amide bond of 2c or M6 to form the cleaved metabolites. Furthermore, we showed that 2c and its major metabolite M6 are bioactive compounds against human colon cancer cells. M6 was more active than 2c with the half-inhibitory concentration (IC50) of 158 µM and could induce apoptosis at 200 µM. CONCLUSION: To our knowledge, the current study demonstrates for the first time that avenanthramide-C can be extensively metabolized by mice and the human microbiota to generate bioactive metabolites.

Ansa to recurrent laryngeal neurorrhaphy in the setting of laryngeal nerve sacrifice: a cadaveric study to evaluate a reconstructive option.

OBJECTIVE: In certain cases, the recurrent laryngeal nerve (RLN) has to be sacrificed. This often results in an inadequate length of residual RLN to be used in a reinnervation procedure. We investigated the length of the distal stump of the RLN from the inferior border of the inferior pharyngeal constrictor muscle (IPCM), where it is frequently compromised, to its entrance into the larynx. Our objective was to determine whether this residual nerve stock was sufficient for margin clearance and neurorrhaphy. STUDY DESIGN: Cadaveric study METHODS: Recurrent laryngeal nerves were identified in fresh frozen cadavers. The IPCM was divided, revealing the distal stump of the RLN, which was measured. RESULTS: Dissection was performed in 20 cadavers (40 nerves). The average length of the right RLN and the left RLN from the IPCM until it entered the larynx was 15mm and 14mm, respectively. All residual RLN remnants were of sufficient length for neurorrhaphy. CONCLUSION: Concomitant RLN reinnervation procedures in the setting of nerve sacrifice are not well described. A barrier to reinnervation in this setting may be insufficient residual nerve length for a neurorrhaphy. Often, when the RLN is sacrificed intraoperatively either iatrogenically or due to tumor invasion, it is close to the cricoarytenoid joint, at the inferior border of the IPCM. This study demonstrates that by splitting the IPCM, sufficient length can be obtained for neurorrhaphy.

Anatomy and histology of the frontalis muscle.

PURPOSE: To determine the gross and histologic configurations of the medial and lateral frontalis muscle. METHODS: After making a midcoronal incision and bluntly dissecting to the orbital rim, the frontalis muscle was marked and measured. A protractor was used to measure the frontalis-orbicularis angle (FOA) and, when present, the angle of central bifurcation (AOB). Three strips of full-thickness forehead soft tissue measuring 0.5 cm × 8 cm were excised 3, 4.5, and 6 cm above the supraorbital notch and analyzed histologically for the presence of skeletal muscle fibers. Data were analyzed using 2-sample t tests, paired t tests, Pearson correlations, and mixed effect models. A p value of ≤ 0.05 was considered statistically significant. RESULTS: Sixty-four hemifaces of 32 cadavers (16 males) were dissected. All specimens were Caucasian. The average age was 78.2 years (range, 56-102 years). The average FOA was 88.7° (13.0°), and the average AOB was 90.0° (26.4°). A visible midline bifurcation occurred in 28 of 32 subjects (88%) at an average height of 4.7 cm (range, 2.4-7.2 cm) superior to the supraorbital notch. Continuous skeletal muscle fibers were present within the midline bifurcation histologically in 89%, 75%, and 11% of specimens 3.5, 5.0, and 6.5 cm above the supraorbital notch, respectively. In 46% of individuals, skeletal muscle fibers were continuously present microscopically within the gross bifurcation. CONCLUSION: While a medial frontalis muscle bifurcation occurs grossly in most senescent Caucasians, muscle fibers exist microscopically within this zone in nearly half of individuals.

Microanatomical Location of Hyaluronic Acid Gel Following Injection of the Temporal Hollows.

PURPOSE: To examine the microanatomical location of hyaluronic acid gel injected within the temporal hollows of cadaver specimens. METHODS: The temporal hollows were injected subcutaneously with hyaluronic acid gel in 6 fresh frozen human cadaver hemifaces. Temporal soft tissues were dissected to a preperiosteal plane and fixated in 95% alcohol. A soft tissue section extending from skin to temporal bone was obtained for each specimen. Histologic examination was performed using hematoxylin and eosin stain. RESULTS: In 5 of 6 specimens, at least 95% of the hyaluronic acid was located within the subcutaneous fat. In 1 of 6 specimens, approximately 35% of the material was located within the subcutaneous fat and 60% was located within the superficial temporal fascia. Two specimens had 5% located within the temporalis muscle. In 1 specimen, hyaluronic acid was found to encompass a superficial muscular artery within the superficial temporal fascia. CONCLUSIONS: This study elucidates the location of hyaluronic acid gel after subcutaneous injection within the temporal hollow. Histology confirmed consistent placement of the gel within the subcutaneous tissues, but it also showed that injection in this region may produce unintended deeper location of filler, and a significant perivascular collection of the material. The proximity of dense temporal fascial and muscle arterial networks in this region may pose risk for perivascular injection and associated complications.