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.

A microtubule stabilizer ameliorates protein pathogenesis and neurodegeneration in mouse models of repetitive traumatic brain injury.

Tau pathogenesis is a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Although the events leading to initial tau misfolding and subsequent tau spreading in patient brains are largely unknown, traumatic brain injury (TBI) may be a risk factor for tau-mediated neurodegeneration. Using a repetitive TBI (rTBI) paradigm, we report that rTBI induced somatic accumulation of phosphorylated and misfolded tau, as well as neurodegeneration across multiple brain areas in 7-month-old tau transgenic PS19 mice but not wild-type (WT) mice. rTBI accelerated somatic tau pathology in younger PS19 mice and WT mice only after inoculation with tau preformed fibrils and AD brain-derived pathological tau (AD-tau), respectively, suggesting that tau seeds are needed for rTBI-induced somatic tau pathology. rTBI further disrupted axonal microtubules and induced punctate tau and TAR DNA binding protein 43 (TDP-43) pathology in the optic tracts of WT mice. These changes in the optic tract were associated with a decline of visual function. Treatment with a brain-penetrant microtubule-stabilizing molecule reduced rTBI-induced tau, TDP-43 pathogenesis, and neurodegeneration in the optic tract as well as visual dysfunction. Treatment with the microtubule stabilizer also alleviated rTBI-induced tau pathology in the cortices of AD-tau-inoculated WT mice. These results indicate that rTBI facilitates abnormal microtubule organization, pathological tau formation, and neurodegeneration and suggest microtubule stabilization as a potential therapeutic avenue for TBI-induced neurodegeneration.

A live dengue virus vaccine carrying a chimeric envelope glycoprotein elicits dual DENV2-DENV4 serotype-specific immunity.

The four dengue virus serotypes co-circulate globally and cause significant human disease. Dengue vaccine development is challenging because some virus-specific antibodies are protective, while others are implicated in enhanced viral replication and more severe disease. Current dengue tetravalent vaccines contain four live attenuated serotypes formulated to theoretically induce balanced protective immunity. Among the number of vaccine candidates in clinical trials, only Dengvaxia is licensed for use in DENV seropositive individuals. To simplify live-virus vaccine design, we identify co-evolutionary constraints inherent in flavivirus virion assembly and design chimeric viruses to replace domain II (EDII) of the DENV2 envelope (E) glycoprotein with EDII from DENV4. The chimeric DENV2/4EDII virus replicates efficiently in vitro and in vivo. In male macaques, a single inoculation of DENV2/4EDII induces type-specific neutralizing antibodies to both DENV2 and DENV4, thereby providing a strategy to simplify DENV vaccine design by utilizing a single bivalent E glycoprotein immunogen for two DENV serotypes.

SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice.

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted SARS-CoV-2 strain MA10 produces an acute respiratory distress syndrome in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days after virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of profibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early antifibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

Inhibition of CK2 mitigates Alzheimer's tau pathology by preventing NR2B synaptic mislocalization.

Alzheimer's disease (AD) is a neurodegenerative disorder that exhibits pathological changes in both tau and synaptic function. AD patients display increases in hyperphosphorylated tau and synaptic activity. Previous studies have individually identified the role of NR2B subunit-containing NMDA receptors in AD related synaptic dysfunction and aggregated tau without reconciling the conflicting differences and implications of NR2B expression. Inhibition of extrasynaptically located NR2B mitigates tau pathology in AD models, whereas the inhibition of synaptic NR2B replicates tau-associated hyperactivity. This suggests that a simultaneous increase in extrasynaptic NR2B and decrease in synaptic NR2B may be responsible for tau pathology and synaptic dysfunction, respectively. The synaptic location of NR2B is regulated by casein kinase 2 (CK2), which is highly expressed in AD patients. Here, we used patient brains diagnosed with AD, corticobasal degeneration, progressive supranuclear palsy or Pick's disease to characterize CK2 expression across these diverse tauopathies. Human derived material was also utilized in conjunction with cultured hippocampal neurons in order to investigate AD-induced changes in NR2B location. We further assessed the therapeutic effect of CK2 inhibition on NR2B synaptic distribution and tau pathology. We found that aberrant expression of CK2, and synaptically translocated NR2B, is unique to AD patients compared to other tauopathies. Increased CK2 was also observed in AD-tau treated neurons in addition to the mislocalization of NR2B receptors. Tau burden was alleviated in vitro by correcting synaptic:extrasynaptic NR2B function. Restoring NR2B physiological expression patterns with CK2 inhibition and inhibiting the function of excessive extrasynaptic NR2B with Memantine both mitigated tau accumulation in vitro. However, the combined pharmacological treatment promoted the aggregation of tau. Our data suggests that the synaptic:extrasynaptic balance of NR2B function regulates AD-tau pathogenesis, and that the inhibition of CK2, and concomitant prevention of NR2B mislocalization, may be a useful therapeutic tool for AD patients.

A model of persistent post SARS-CoV-2 induced lung disease for target identification and testing of therapeutic strategies.

COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

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.

Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin.

Sleep is an essential component of overall human health but is so tightly regulated that when disrupted can cause or worsen certain ailments. An important part of this process is the presence of the well-known hormone, melatonin. This compound assists in the governing of sleep and circadian rhythms. Previous studies have postulated that dysregulation of melatonin rhythms is the driving force behind sleep and circadian disorders. A computer-aided search spanning the years of 2015-2020 using the search terms melatonin, circadian rhythm, disorder yielded 52 full text articles that were analyzed. We explored the mechanisms behind melatonin dysregulation and how it affects various disorders. Additionally, we examined associated therapeutic treatments including bright light therapy (BLT) and exogenous forms of melatonin. We found that over the past 5 years, melatonin has not been widely investigated in clinical studies thus there remains large gaps in its potential utilization as a therapy.

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.

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.

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.

Insoluble Tau From Human FTDP-17 Cases Exhibit Unique Transmission Properties In Vivo.

One hallmark of neurodegenerative diseases is the intracellular accumulation of hyperphosphorylated tau protein, a neuronal microtubule-associated protein, into structures known as neurofibrillary tangles. Tauopathies are heterogeneous neurodegenerative diseases caused by the misfolding of the tau protein. It has been previously shown that the tau protein can spread from cell to cell in a prion-like manner. Tauopathies can be sporadic or familial, with the identification of pathogenic mutations in the microtubule-associated protein tau gene on chromosome 17 in the familial cases. Different frontotemporal dementia with parkinsonism-17 (FTDP-17) cases are associated with varying clinical presentations and types of neuropathology. We previously demonstrated that insoluble tau extracted from sporadic tauopathy human brains contain distinct tau strains, which underlie the heterogeneity of these diseases. Furthermore, these tau strains seeded tau aggregates that resemble human tau neuropathology in nontransgenic and 6hTau mice in vivo. Here, we show insoluble tau from human brains of FTDP-17 cases transmit different patterns of neuronal and glial tau pathology in vivo, similar to the sporadic tauopathies. This suggests that each of these tau mutations has unique properties that underlie the heterogeneity of FTDP-17 cases.

Is QTc-Interval Prolongation an Inherent Feature of Eating Disorders? A Cohort Study.

BACKGROUND: Anorexia nervosa is associated with a markedly increased risk of sudden cardiac death, but the mechanism has not been elucidated. Whether QT prolongation is an intrinsic feature of eating disorders is uncertain because previous studies are limited by small sample size, and extrinsic factors associated with QT prolongation were inconsistently reported. This study set to determine population-mean heart-rate-corrected QT interval (QTc) in an unselected cohort of patients with eating disorders. METHODS: Electrocardiogram (ECG) data from 1026 consecutive adults admitted into residential treatment were stratified by subtype: anorexia nervosa (caloric restriction only), anorexia nervosa binge-purge, and bulimia nervosa. Eating disorders not otherwise specified were excluded. Population-mean Fridericia-corrected QTc and categorical QTc threshold analysis were performed. Multivariable regression, controlling for age sex, duration of illness, body mass index (BMI), hypokalemia, QTc-prolonging drugs, purging behaviors, and laxatives was assessed. RESULTS: Among 906 patients, population-mean QTc (424 ± 25 standard deviation [SD]) was normal and lowest among patients with anorexia nervosa (417.3 ± 22.3, P <0.001 vs other subgroups). Only 1.2% (N = 11) had marked QTc prolongation (QTc >500 ms); all 11 patients had hypokalemia and were receiving QTc-prolonging medications or laxatives. After controlling for clinically relevant covariates, differences in mean QTc across eating disorder subtypes diminished yet persisted (P = 0.048). CONCLUSIONS: In the largest study of patients with eating disorders, population-mean QTc was normal and varied by subtype. Marked QTc prolongation occurred solely in the presence of extrinsic factors, suggesting that QTc prolongation is not intrinsic to eating disorders. Therefore, further study is needed to define the etiology of sudden death in patients with eating disorders.

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.

Transmission of tauopathy strains is independent of their isoform composition.

The deposition of pathological tau is a common feature in several neurodegenerative tauopathies. Although equal ratios of tau isoforms with 3 (3R) and 4 (4R) microtubule-binding repeats are expressed in the adult human brain, the pathological tau from different tauopathies have distinct isoform compositions and cell type specificities. The underlying mechanisms of tauopathies are unknown, partially due to the lack of proper models. Here, we generate a new transgenic mouse line expressing equal ratios of 3R and 4R human tau isoforms (6hTau mice). Intracerebral injections of distinct human tauopathy brain-derived tau strains into 6hTau mice recapitulate the deposition of pathological tau with distinct tau isoform compositions and cell type specificities as in human tauopathies. Moreover, through in vivo propagation of these tau strains among different mouse lines, we demonstrate that the transmission of distinct tau strains is independent of strain isoform compositions, but instead intrinsic to unique pathological conformations.

Facelift: History and Anatomy.

In this article, we review the history of the facelift operation and how it evolved from skin excision only to the modern superficial musculoaponeurotic system operation. We describe the critical surgical anatomy of the facial layers, retaining ligaments of the face, facial spaces, the 3-dimensional complex course of the facial nerve branches, and the pertinent anatomy of the neck. This article is supplemented by fresh cadaver anatomic dissections.