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The temporomandibular joint (TMJ) is an essential structure that allows the jaw to open and close, and its degeneration can cause pain and dysfunction. This literature review begins by highlighting the importance of understanding all the underlying biological mechanisms of TMJ degeneration to develop better treatment approaches. This review aims to gather all the information on the molecular mechanisms, hormonal and genetic factors involved in signaling pathways and interactions that are potentially related to jaw disorders. The literature was selected by searching electronic databases. It was determined that in the face of an inflammatory and degenerative process of the TMJ, the presence of several proteins, molecules, hormones, and increased gene expression is present in large volume, however, future research with larger samples is needed to improve understanding in diagnostic and therapeutic approaches in this field., A articulação temporomandibular (ATM) é uma estrutura essencial que permite a abertura e o fechamento da mandíbula, e sua degeneração pode causar dor e disfunção. Esta revisão da literatura começa destacando a importância de compreender todos os mecanismos biológicos subjacentes à degeneração da ATM para desenvolver melhores abordagens de tratamento. O objetivo desta revisão é reunir todas as informações sobre os mecanismos moleculares, fatores hormonais e genéticos envolvidos nas vias de sinalização e interações potencialmente relacionadas aos distúrbios da mandíbula. A literatura foi selecionada por meio de pesquisa em bancos de dados eletrônicos. Foi determinado que, diante de um processo inflamatório e degenerativo da ATM, a presença de várias proteínas, moléculas, hormônios e aumento da expressão gênica está presente em grande volume; no entanto, pesquisas futuras com amostras maiores são necessárias para melhorar a compreensão das abordagens diagnósticas e terapêuticas nesse campo., La articulación temporomandibular (ATM) es una estructura esencial que permite la apertura y el cierre de la mandíbula, y su degeneración puede causar dolor y disfunción. Esta revisión de literatura comienza destacando la importancia de comprender todos los mecanismos biológicos subyacentes de la degeneración de la ATM para desarrollar mejores enfoques de tratamiento. Esta revisión tiene como objetivo recopilar toda la información sobre los mecanismos moleculares, factores hormonales y genéticos implicados en las vías de señalización e interacciones que están potencialmente relacionadas con los trastornos mandibulares. La literatura se seleccionó mediante una búsqueda en las bases de datos electrónicas. Se determinó que, ante un proceso inflamatorio y degenerativo de la ATM, existe en gran volumen la presencia de varias proteínas, moléculas, hormonas y aumento en la expresión genética, sin embargo, es necesario, investigaciones futuras con muestras más amplias para mejorar la compresión en el diagnóstico y los enfoques terapéuticos en este campo.

Aim: Disruption in cerebellar inputs, as well as dysfunction of Purkinje cells (PCs), causes a change in the timing of electrical signaling in the cerebellum resulting in disorders such as cerebellar ataxia. Although much clinical and molecular genetics research has been conducted to understand this disorder, there is no specific treatment for cerebellar ataxia. As cannabinoid type 1 receptors (CB1Rs) are highly expressed in the cerebellum and have been suggested as a therapeutic strategy, we determined whether AM251, a cannabinoid receptor antagonist, was neuroprotective of PCs in a rat cerebellar ataxic model.Materials and methods: To this end, we conducted behavioral and histological tests in the 3-acetylpyridine (3AP) rat cerebellar ataxia model, to explore whether AM251 was protective against induction of ataxia and cell death.Results: Rats with chemical degeneration of the inferior olive induced by 3AP (55 mg/kg, i.p.) clearly showed cerebellar ataxic symptoms. The locomotor activity and motor coordination of the ataxic animals were clearly disrupted compared to the control group. Further, histological analysis showed cell death and PCs degenerated with loss of cell membrane integrity associated with 3AP. Pre-treatment by AM251 improved the locomotor activity of the ataxic animals, and AM251 almost prevented PCs neuronal degeneration.Conclusion: Our data which show protection of cerebellar PCs and motor improvement in the ataxic rat model by treatment with AM251 suggests that targeting cannabinoid receptors should be considered for therapeutic intervention in cerebellar ataxia.

Syfte: Syftet med den här studien var att undersöka om 4 veckors övervakad slyngträning påverkar smärta och funktionsförmåga hos enskilda individer med långvarig ländryggssmärta. Metod: Studiens design är en Single-System Experimental Design med AB-design. Tre deltagare med långvarig ländryggssmärta inkluderades i studien genom ett ändamålsenligt urval. Interventionen bestod av övervakad slyngträning tre gånger i veckan under fyra veckor. Smärta mättes med Visual Analogue Scale (VAS 0–100 mm) och funktionsförmåga mättesmed Oswestry Disability Index (ODI). Mätningar utfördes tre gånger i veckan under baslinjefasen och tre gånger i veckan under interventionsfasen. Resultat: Hos två av deltagarna sågs effekt på smärta efter introduktion av interventionen medan ingen effekt kunde säkerställas för en. Hos två av deltagarna sågs effekt på funktionsförmåga efter introduktion av interventionen medan ingen signifikant effekt kunde indikeras för en. Följsamheten till interventionen var god och deltagarnas upplevelser visade att de kände sig starkare och upplevde minskad rörelserädsla. Slutsats: Interventionen uppvisade potential att förbättra smärta och funktionsförmåga hos enskilda individer med ländryggssmärta. Resultaten kan inte generaliseras till andra patienter och miljöer utan replikering., Objective: The purpose of the current study was to assess the influence of 4 weeks supervised sling exercise on pain and dysfunction in subjects with chronic low back pain. Methods: A Single-System Experimental Design with AB-design was applied. Three participants with chronic lower back pain were recruited by purposive sample. The intervention consisted of 4 weeks of supervised sling exercises thrice a week. Pain was rated with Visual Analogue Scale (VAS 0-100 mm) and disability was rated with Oswestry disability Index (ODI). Measurements was performed trice a week during baseline phase and trice a week during the intervention phase. Results: The results showed a decrease in pain for two participants after introduction of the intervention while it showed no effect for one participant. Improvement in dysfunction was shown for two participants after introduction of the intervention while no effect was shown for one participant. Compliance was good and the participants experienced feeling stronger and reduced fear of movement. Conclusions: A 4 weeks supervised sling exercise programme indicates potential in improving pain and dysfunction in individuals with lower back pain. The results cannot be generalized to other patients or contexts without replication.

Syfte: Syftet med den här studien var att undersöka om 4 veckors övervakad slyngträning påverkar smärta och funktionsförmåga hos enskilda individer med långvarig ländryggssmärta. Metod: Studiens design är en Single-System Experimental Design med AB-design. Tre deltagare med långvarig ländryggssmärta inkluderades i studien genom ett ändamålsenligt urval. Interventionen bestod av övervakad slyngträning tre gånger i veckan under fyra veckor. Smärta mättes med Visual Analogue Scale (VAS 0–100 mm) och funktionsförmåga mättesmed Oswestry Disability Index (ODI). Mätningar utfördes tre gånger i veckan under baslinjefasen och tre gånger i veckan under interventionsfasen. Resultat: Hos två av deltagarna sågs effekt på smärta efter introduktion av interventionen medan ingen effekt kunde säkerställas för en. Hos två av deltagarna sågs effekt på funktionsförmåga efter introduktion av interventionen medan ingen signifikant effekt kunde indikeras för en. Följsamheten till interventionen var god och deltagarnas upplevelser visade att de kände sig starkare och upplevde minskad rörelserädsla. Slutsats: Interventionen uppvisade potential att förbättra smärta och funktionsförmåga hos enskilda individer med ländryggssmärta. Resultaten kan inte generaliseras till andra patienter och miljöer utan replikering., Objective: The purpose of the current study was to assess the influence of 4 weeks supervised sling exercise on pain and dysfunction in subjects with chronic low back pain. Methods: A Single-System Experimental Design with AB-design was applied. Three participants with chronic lower back pain were recruited by purposive sample. The intervention consisted of 4 weeks of supervised sling exercises thrice a week. Pain was rated with Visual Analogue Scale (VAS 0-100 mm) and disability was rated with Oswestry disability Index (ODI). Measurements was performed trice a week during baseline phase and trice a week during the intervention phase. Results: The results showed a decrease in pain for two participants after introduction of the intervention while it showed no effect for one participant. Improvement in dysfunction was shown for two participants after introduction of the intervention while no effect was shown for one participant. Compliance was good and the participants experienced feeling stronger and reduced fear of movement. Conclusions: A 4 weeks supervised sling exercise programme indicates potential in improving pain and dysfunction in individuals with lower back pain. The results cannot be generalized to other patients or contexts without replication.

Abierto en la web del editor, Purpose.: To determine photopic and mesopic distance high-contrast visual acuity (HC-VA) and low-contrast visual acuity (LC-VA) in eyes with early age-related macular degeneration (AMD). Methods.: Measurements were made in 22 subjects with early AMD and 28 healthy control subjects. Inclusion criteria included a photopic HC-VA of 20/25 or better. Distance VA was measured using HC (96%) and LC (10%) Bailey-Lovie logMAR letter charts under photopic (85 cd/m2) and mesopic (0.1–0.2 cd/m2) luminance conditions. Results.: Mean mesopic distance HC-VA and LC-VA were significantly worse (0.1 logMAR and 0.28 logMAR, respectively) in the early AMD group than in the control group. Under mesopic conditions, the mean difference between LC-VA and HC-VA was significantly greater in the early AMD (0.45 logMAR) than the control group (0.27 logMAR). Mean differences between mesopic versus photopic HC-VA and mesopic versus photopic LC-VA were significantly greater in the early AMD than the control group (0.13 and 0.32 logMAR of difference between the means, respectively). Sensitivity and specificity were significantly greater for mesopic LC-VA than for mesopic HC-VA (Receiver Operating Characteristics, area under the curve [AUC], 0.94 ± 0.030 and 0.76 ± 0.067, respectively). AUC values for photopic HC-VA and LC-VA were below 0.70. Conclusions.: Visual acuity testing under low luminance conditions emerged as an optimal quantitative measure of retinal function in early AMD., Fundación Investigación Médica Mutua Madrileña, Banco Santander-Universidad Complutense de Madrid, Depto. de Optometría y Visión, Fac. de Óptica y Optometría, TRUE, pub

Aims Hypertensive heart disease (HHD) is recognized as a key clinical precursor to heart failure with preserved ejection fraction (HFPEF). However, pathophysiological transition from HHD to HFPEF is not well understood. We sought determine whether regional differences in impaired myocardial function may underlie the greater mechanical dysfunction seen in HFPEF compared to HHD.Methods and results We used standardized echocardiography to assess regional myocardial deformation in a cohort of n = 327 adults with preserved left ventricular (LV) ejection fraction (=45%), including: n = 129 with HFPEF, n = 158 with HHD and no heart failure, and n = 40 normotensive controls. From detailed measurements of LV systolic strain performed in multiple views, we derived and then compared regional measures of basal, mid-ventricular, and apical longitudinal strains. In models adjusting for clinical covariates, basal and mid-ventricular LV myocardial deformation was more impaired in HHD than in controls (P = 0.003), whereas apical deformation was more impaired in HFPEF than in HHD (P = 0.005). In multivariable-adjusted analyses, only apical strain remained independently associated with HFPEF vs. HHD status [odds ratio 1.18 (1.02-1.37), P = 0.030 per 1% decrease in apical strain]. Compared to other regional strains, apical longitudinal strain optimally differentiated HFPEF from HHD (area under the receiver operating curve: apical longitudinal strain = 0.67; mid-ventricular longitudinal strain = 0.59; basal longitudinal strain = 0.60).Conclusion We found that while apical mechanical function is preserved in HHD, it was impaired in HFPEF and may contribute to the transition from an asymptomatic heart disease to a symptomatic heart disease.

Subjects with type 2 diabetes mellitus (T2D) are at increased risk for heart failure (HF). The cardiac-specific (FABP3) and adipose-tissue-specific (FABP4) types of the fatty acid binding proteins have been associated with both all-cause and cardiovascular (CV) mortality. The aim of this study was to explore the prognosis value of FABP3 and FABP4 in ambulatory subjects with chronic HF (CHF), with and without T2D. A prospective study involving 240 ambulatory CHF subjects was performed. Patients were followed-up for a mean of 5.78 ± 3.30 years and cause of death (if any) was recorded. Primary endpoints were defined as all-cause and CV death, and a composite endpoint that included CV death or hospitalization for HF was included as a secondary endpoint. Baseline serum samples were obtained and the serum FABP3 and FABP4 concentrations were assessed by sandwich enzyme-linked immunosorbent assay. Survival analysis was performed with multivariable Cox regressions, using Fine and Gray competing risks models when needed, to explore the prognostic value of FABP3 and FABP4 concentrations, adjusting for potential confounders. Type 2 diabetes mellitus was highly prevalent, accounting for 47.5% for total subjects with CHF. Subjects with T2D showed higher mortality rates (T2D: 69.30%; non-T2D: 50.79%, p = 0.004) and higher serum FABP3 (1829.3 (1104.9–3440.5) pg/mL vs. 1396.05 (820.3–2362.16) pg/mL, p = 0.007) and FABP4 (45.5 (27.6–79.8) ng/mL vs. 34.1 (24.09–55.3) ng/mL, p = 0.006) concentrations compared with non-T2D CHF subjects. In the whole study cohort, FABP3 was independently associated with all-cause death, and both FABP3 and FABP4 concentrations were associated with CV mortality. The predictive values of these two molecules for all-cause (FABP3: HR 1.25, 95% CI 1.09–1.44; p = 0

There is continued debate regarding Parkinson’s disease etiology and whether it originates in the brain or begins in the gut. Recently, evidence has been provided for both, with Parkinson’s disease onset presenting as either a “body-first” or “brain-first” progression. Most research indicates those with Parkinson’s disease have an altered gut microbiome compared to controls. However, some studies do not report gut microbiome differences, potentially due to the brain or body-first progression type. Based on the etiology of each proposed progression, individuals with the body-first progression may exhibit altered gut microbiomes, i.e., where short-chain fatty acid producing bacteria are reduced, while the brain-first progression may not. Future microbiome research should consider this hypothesis and investigate whether gut microbiome differences exist between each type of progression. This may further elucidate the impact of the gut microbiome in Parkinson’s disease and show how it may not be homogenous across individuals with Parkinson’s disease.

BackgroundLoss of fine motor skills is observed in many neurological diseases, and remote monitoring assessments can aid in early diagnosis and intervention. Hand function can be regularly assessed to monitor loss of fine motor skills in people with central nervous system disorders; however, there are challenges to in-clinic assessments. Remotely assessing hand function could facilitate monitoring and supporting of early diagnosis and intervention when warranted.ObjectiveRemote assessments can facilitate the tracking of limitations, aiding in early diagnosis and intervention. This study aims to systematically review existing evidence regarding the remote assessment of hand function in populations with chronic neurological dysfunction.MethodsPubMed and MEDLINE, CINAHL, Web of Science, and Embase were searched for studies that reported remote assessment of hand function (ie, outside of traditional in-person clinical settings) in adults with chronic central nervous system disorders. We excluded studies that included participants with orthopedic upper limb dysfunction or used tools for intervention and treatment. We extracted data on the evaluated hand function domains, validity and reliability, feasibility, and stage of development.ResultsIn total, 74 studies met the inclusion criteria for Parkinson disease (n=57, 77% studies), stroke (n=9, 12%), multiple sclerosis (n=6, 8%), spinal cord injury (n=1, 1%), and amyotrophic lateral sclerosis (n=1, 1%). Three assessment modalities were identified: external device (eg, wrist-worn accelerometer), smartphone or tablet, and telerehabilitation. The feasibility and overall participant acceptability were high. The most common hand function domains assessed included finger tapping speed (fine motor control and rigidity), hand tremor (pharmacological and rehabilitation efficacy), and finger dexterity (manipulation of small objects required for daily tasks) and handwriting (coordination). Although validity and reliability data were

BackgroundLoss of fine motor skills is observed in many neurological diseases, and remote monitoring assessments can aid in early diagnosis and intervention. Hand function can be regularly assessed to monitor loss of fine motor skills in people with central nervous system disorders; however, there are challenges to in-clinic assessments. Remotely assessing hand function could facilitate monitoring and supporting of early diagnosis and intervention when warranted.ObjectiveRemote assessments can facilitate the tracking of limitations, aiding in early diagnosis and intervention. This study aims to systematically review existing evidence regarding the remote assessment of hand function in populations with chronic neurological dysfunction.MethodsPubMed and MEDLINE, CINAHL, Web of Science, and Embase were searched for studies that reported remote assessment of hand function (ie, outside of traditional in-person clinical settings) in adults with chronic central nervous system disorders. We excluded studies that included participants with orthopedic upper limb dysfunction or used tools for intervention and treatment. We extracted data on the evaluated hand function domains, validity and reliability, feasibility, and stage of development.ResultsIn total, 74 studies met the inclusion criteria for Parkinson disease (n=57, 77% studies), stroke (n=9, 12%), multiple sclerosis (n=6, 8%), spinal cord injury (n=1, 1%), and amyotrophic lateral sclerosis (n=1, 1%). Three assessment modalities were identified: external device (eg, wrist-worn accelerometer), smartphone or tablet, and telerehabilitation. The feasibility and overall participant acceptability were high. The most common hand function domains assessed included finger tapping speed (fine motor control and rigidity), hand tremor (pharmacological and rehabilitation efficacy), and finger dexterity (manipulation of small objects required for daily tasks) and handwriting (coordination). Although validity and reliability data were

ObjectiveThe DSM-5 Alternative Model of Personality Disorders distinguishes core personality dysfunction common to all personality pathology from maladaptive traits that delineate specific variants of disorder. Previous research shows the convergence between maladaptive and normal range trait domains as well as substantial correlations between maladaptive traits and core dysfunctions, leading some to conclude that personality traits and dysfunction are redundant. This study sought to examine the potential utility of the concept of core dysfunctions as a means of clarifying the nature of the relationship between maladaptive and normal-range traits.MethodThree nonclinical samples (n = 178, 307, and 1,008) were evaluated for personality dysfunction, maladaptive traits, and normal-range traits using different measures.ResultsResults indicated that: (1) normal trait domains and core dysfunction contribute independently to understanding maladaptive traits; (2) the correlation of a normal trait domain with its putative maladaptive equivalent is consistently accounted for in part by core dysfunction; and (3) the multitrait multimethod matrices of normal and maladaptive personality trait domains demonstrate appreciable discriminant validity problems that are clarified by a consideration of core dysfunction.ConclusionThese results suggest that maladaptive traits reflect the distinguishable contributions of core personality dysfunction (problems) and normal-range personality traits (person).

Maintenance of systemic homeostasis by kidney requires the coordinated response of diverse cell types. The use of single-cell RNA sequencing (scRNAseq) for patient tissue samples remains fraught with difficulties with cell isolation, purity, and experimental bias. The ability to characterize immune and parenchymal cells during transplant rejection will be invaluable in defining transplant pathology where tissue availability is restricted to needle biopsy fragments. Herein, we present feasibility data for multiplexing approach for droplet scRNAseq (Mux-Seq). Mux-Seq has the potential to minimize experimental batch bias and variation even with very small sample input. In this first proof-of-concept study for this approach, explant tissues from six normal and two transplant recipients after multiple early post-transplant rejection episodes leading to nephrectomy due to aggressive antibody mediated rejection, were pooled for Mux-Seq. A computational tool, Demuxlet was applied for demultiplexing the individual cells from the pooled experiment. Each sample was also applied individually in a single microfluidic run (singleplex) to correlate results with the pooled data from the same sample. Our applied protocol demonstrated that data from Mux-Seq correlated highly with singleplex (Pearson coefficient 0.982) sequencing results, with the ability to identify many known and novel kidney cell types including different infiltrating immune cells. Trajectory analysis of proximal tubule and endothelial cells demonstrated separation between healthy and injured kidney from transplant explant suggesting evolving stages of cell- specific differentiation in alloimmune injury. This study provides the technical groundwork for understanding the pathogenesis of alloimmune injury and host tissue response in transplant rejection and normal human kidney and provides a protocol for optimized processing precious and low input human kidney biopsy tissue for larger scale studies.

BackgroundMost patients are listed for liver transplant (LT) following extensive workup as outpatients ("conventional evaluation"). Some patients undergo urgent evaluation as inpatients after being transferred to a transplant center ("expedited evaluation"). We hypothesized that expedited patients would have inferior survival due to disease severity at the time of transplant and shorter workup time.MethodsPatients who underwent evaluation for LT at our institution between 2012 and 2016 were retrospectively reviewed. The expedited and conventional cohorts were defined as above. Living donor LT recipients, combined liver-kidney recipients, acute liver failure patients, and re-transplant patients were excluded. We compared patient characteristics and overall survival between patients who received a transplant following expedited evaluation and those who did not, and between LT recipients based on expedited or conventional evaluation.ResultsFive-hundred and nine patients were included (110 expedited, 399 conventional). There was no difference in graft or patient survival at 1 year for expedited versus conventional LT recipients. In multivariable analysis of overall survival, only Donor Risk Index (HR 1.97, CI 1.04-3.73, P = .037, per unit increase) was associated with increased risk of death.ConclusionsPatients who underwent expedited evaluation for LT had significant demographic and clinical differences from patients who underwent conventional evaluation, but comparable post-transplant survival.

Limited case series describe conflicting results regarding the safety of checkpoint inhibitors (CPI) prior to liver transplantation (LT). We reviewed single-center data on all consecutive patients who underwent LT for hepatocellular carcinoma treated with CPI between January 1, 2018, and January 30, 2021. Time from CPI to LT, immunosuppression, biopsy-proven acute cellular rejection (BPACR), graft loss and death were evaluated. Five patients with a mean age 65 (range 61-71) years underwent LT after CPI with nivolumab. Time from last CPI to LT ranged from 0.3 to 11 months. Two patients with <3 months from the last dose of CPI to LT developed BPACR and severe hepatic necrosis, one of whom required retransplantation with recurrent BPACR but without recurrent graft loss over 38 months of follow up. None of the patients who underwent LT >3 months from the last dose of CPI had BPACR. In conclusion, pretransplant use of CPIs, particularly within 90 days of LT, was associated with BPACR and immune-mediated hepatic necrosis. Future multicenter studies should consider a sufficient interval from the last dose of CPI to LT to mitigate the risk for adverse immune-mediated outcomes and graft loss.

Neuroinflammation has an essential role in various neurodegenerative diseases including Parkinson's disease (PD). Microglial activation as a result of neuroinflammation exacerbates the pathological consequences of the disease. The toxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes alpha-synuclein (alpha-synuclein) accumulation, which leads to dopaminergic neuron death in the MPTP-induced mouse model. Toll-like receptor 4 (TLR4) stimulates release of cytokine through NF-kB by activating glial cells, thus resulting in the death of dopaminergic neurons. Melatonin has the ability to cross the blood-brain barrier and protect neurons through anti-inflammatory properties. We hypothesized that melatonin could suppress TLR4-mediated neuroinflammation, decrease cytokine release due to the inflammatory response, and reduce dopaminergic neuron loss in the MPTP-induced mouse model. In the MPTP-induced mouse model, we aimed to assess the neuroinflammatory responses caused by TLR4 activation as well as the effect of melatonin on these responses. Three-month-old male C57BL/6 mice were randomly divided into five groups; Control (Group-C), Sham (Group-S), Melatonin-treated (Group-M), MPTP-injected (Group-P), and MPTP + melatonin-injected (Group-P + M). MPTP toxin (20 mg/kg) was dissolved in saline and intraperitoneally (i.p.) injected to mice for two days with 12 h intervals. The total dose per mouse was 80 mg/kg. Melatonin was administered (20 mg/kg) intraperitoneally to Group-M and Group-P + M twice a day for five days. Eight days after starting the experiment, the motor activities of mice were evaluated by locomotor activity tests. The effects on dopamine neurons in the SNPc was determined by tyrosine hydroxylase (TH) immunohistochemistry. TLR4, alpha-synuclein, and p65 expression was evaluated by immunostaining as well. The amount of TNF-alpha in the total brain was evaluated by western blot analysis. In our results seen that locomotor activity was lower i, Akdeniz University Scientific Research ProjectsAkdeniz University [TYL-2018-3972], This study was supported by Akdeniz University Scientific Research Projects with project number TYL-2018-3972 and a Master of Science thesis of Sendegul YILDIRIM.

Neuroinflammation has an essential role in various neurodegenerative diseases including Parkinson's disease (PD). Microglial activation as a result of neuroinflammation exacerbates the pathological consequences of the disease. The toxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes alpha-synuclein (alpha-synuclein) accumulation, which leads to dopaminergic neuron death in the MPTP-induced mouse model. Toll-like receptor 4 (TLR4) stimulates release of cytokine through NF-kB by activating glial cells, thus resulting in the death of dopaminergic neurons. Melatonin has the ability to cross the blood-brain barrier and protect neurons through anti-inflammatory properties. We hypothesized that melatonin could suppress TLR4-mediated neuroinflammation, decrease cytokine release due to the inflammatory response, and reduce dopaminergic neuron loss in the MPTP-induced mouse model. In the MPTP-induced mouse model, we aimed to assess the neuroinflammatory responses caused by TLR4 activation as well as the effect of melatonin on these responses. Three-month-old male C57BL/6 mice were randomly divided into five groups; Control (Group-C), Sham (Group-S), Melatonin-treated (Group-M), MPTP-injected (Group-P), and MPTP + melatonin-injected (Group-P + M). MPTP toxin (20 mg/kg) was dissolved in saline and intraperitoneally (i.p.) injected to mice for two days with 12 h intervals. The total dose per mouse was 80 mg/kg. Melatonin was administered (20 mg/kg) intraperitoneally to Group-M and Group-P + M twice a day for five days. Eight days after starting the experiment, the motor activities of mice were evaluated by locomotor activity tests. The effects on dopamine neurons in the SNPc was determined by tyrosine hydroxylase (TH) immunohistochemistry. TLR4, alpha-synuclein, and p65 expression was evaluated by immunostaining as well. The amount of TNF-alpha in the total brain was evaluated by western blot analysis. In our results seen that locomotor activity was lower i, Akdeniz University Scientific Research ProjectsAkdeniz University [TYL-2018-3972], This study was supported by Akdeniz University Scientific Research Projects with project number TYL-2018-3972 and a Master of Science thesis of Sendegul YILDIRIM.

Skeletal muscle is greatly affected by aging, resulting in a loss of metabolic and physical function. However, the underlying molecular processes and how (lack of) physical activity is involved in age-related metabolic decline in muscle function in humans is largely unknown. Here, we compared, in a cross-sectional study, the muscle metabolome from young to older adults, whereby the older adults were exercise trained, had normal physical activity levels or were physically impaired. Nicotinamide adenine dinucleotide (NAD(+)) was one of the most prominent metabolites that was lower in older adults, in line with preclinical models. This lower level was even more pronounced in impaired older individuals, and conversely, exercise-trained older individuals had NAD(+) levels that were more similar to those found in younger individuals. NAD(+) abundance positively correlated with average number of steps per day and mitochondrial and muscle functioning. Our work suggests that a clear association exists between NAD(+) and health status in human aging.

PurposeResults from large scale cardiovascular outcome trials in patients with type 2 diabetes mellitus (DM2) have found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular death and hospitalization for heart failure, but the mechanisms behind the beneficial cardiovascular effects are not fully understood. We tested the hypothesis that the SGLT2i, empagliflozin, improves non-endothelial dependent coronary microvascular function, thereby leading to better cardiac function.MethodsPatients with DM2 followed at the endocrinology outpatient clinic at Bispebjerg University Hospital were included in a double blinded, placebo-controlled cross-over study. Participants were allocated equally to each treatment sequence using simple randomization and treated with empagliflozin 25 mg and placebo for 12 weeks, interrupted by 2 weeks wash-out period. The primary outcome was coronary microvascular function, assessed as coronary flow velocity reserve (CFVR) and measured with transthoracic doppler echocardiography. Echocardiographic parameters of cardiac function were measured, and blood samples were analyzed for a broad panel of cardiovascular biomarkers.ResultsThirteen patients were randomized to each sequence and 10 and 9 completed the study according to protocol, respectively, and were included in the analysis of outcome parameters. We found no improvement in CFVR (change in the empagliflozin period was -0.16 (SD 0.58)). There were no effects on cardiac systolic function or indicators of cardiac filling pressure. Well-known effects of empagliflozin were obtained, such as weight loss and reduction in Hba1c level. Creatinine level increased but remained within normal range. We observed a clear trend of reduction in cardiovascular biomarkers after empagliflozin treatment and increased levels after the placebo period. No serious adverse reactions were reported.ConclusionsDespite effect on weight-loss, Hba1c

PurposeResults from large scale cardiovascular outcome trials in patients with type 2 diabetes mellitus (DM2) have found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular death and hospitalization for heart failure, but the mechanisms behind the beneficial cardiovascular effects are not fully understood. We tested the hypothesis that the SGLT2i, empagliflozin, improves non-endothelial dependent coronary microvascular function, thereby leading to better cardiac function.MethodsPatients with DM2 followed at the endocrinology outpatient clinic at Bispebjerg University Hospital were included in a double blinded, placebo-controlled cross-over study. Participants were allocated equally to each treatment sequence using simple randomization and treated with empagliflozin 25 mg and placebo for 12 weeks, interrupted by 2 weeks wash-out period. The primary outcome was coronary microvascular function, assessed as coronary flow velocity reserve (CFVR) and measured with transthoracic doppler echocardiography. Echocardiographic parameters of cardiac function were measured, and blood samples were analyzed for a broad panel of cardiovascular biomarkers.ResultsThirteen patients were randomized to each sequence and 10 and 9 completed the study according to protocol, respectively, and were included in the analysis of outcome parameters. We found no improvement in CFVR (change in the empagliflozin period was -0.16 (SD 0.58)). There were no effects on cardiac systolic function or indicators of cardiac filling pressure. Well-known effects of empagliflozin were obtained, such as weight loss and reduction in Hba1c level. Creatinine level increased but remained within normal range. We observed a clear trend of reduction in cardiovascular biomarkers after empagliflozin treatment and increased levels after the placebo period. No serious adverse reactions were reported.ConclusionsDespite effect on weight-loss, Hba1c

Background Mutations in ATP1A2 gene encoding the Na,K-ATPase alpha(2) isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K-ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results Mice heterozygous for the familial hemiplegic migraine type 2-associated G301R mutation in the Atp1a2 gene (alpha(+/G301R)(2) mice) and matching wild-type controls were compared. Reduced expression of the Na,K-ATPase alpha(2) isoform and increased expression of the alpha(1) isoform were observed in hearts from alpha(+/G301R)(2) mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8-month-old alpha(+/G301R)(2) mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3-month-old alpha(+/G301R)(2) mice were similar to wild-type mice. Amplified Na,K-ATPase-dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen-activated protein kinase) signaling was observed in hearts from 8-month-old alpha(+/G301R)(2) mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure-associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5 ',6,6 '-tetrachloro-1,1 ',3,3 '-tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8-month-old alpha(+/G301R)(2) mice. Conclusions Our findings suggest that ATP1A2 muta

Aims Technical advancements in 2D-speckle tracking echocardiography (2DSTE) have allowed for quantification of layer-specific global longitudinal strain (GLS) and circumferential strain (GCS) of the left ventricle (LV). The aim of this study was to establish age- and sex-based reference ranges of peak systolic layer-specific GLS and GCS and to assess normal values of regional strain. Methods and results We performed 2DSTE analysis of 1997 members of the general population from the fifth round of the Copenhagen City Heart Study, who were free of cardiovascular disease and risk factors. The mean age was 46 +/- 16 years (range 21-97) and 62% were female. Mean values for peak systolic whole wall GLS (GLS(WW.Sys)), endomycardial (GLS(Endo.Sys)), and epimyocardial (GLS(Epi.Sys)) were 19.9 +/- 2.1% (prediction interval [PI]: 15.8-24.0%), 23.5 +/- 2.5% (PI: 18.6-28.4%), and 17.3 +/- 1.9% (PI: 13.6-21.1%), respectively. Mean peak systolic whole wall GCS (GCS(WW.Sys)), was 21.6 +/- 3.7% (PI: 14.3-28.9%), endomyocardial (GCS(Endo.Sys)) was 31.9 +/- 4.7% (PI: 22.7-41.1%), and epimyocardial (GCS(Epi.Sys)) was 14.3 +/- 3.8% (PI: 6.8-21.8%). A significant discrepancy in normal strain values between males and females was observed. Men had lower mean values and lower reference limits for all strain parameters. Furthermore, GLS and GCS changed differently with age in males and females. Finally, regional LS decreased from the apical to the basal LV region in both sexes, and regional CS varied significantly by LV segment. Conclusion In this study, we reported age- and sex-based reference ranges of layer-specific GLS and GCS. These reference ranges varied significantly with sex and age.

[Resumen] La obesidad es definida por la Organización Mundial de la Salud (OMS) como una “acumulación anormal o excesiva de grasa que puede ser perjudicial para la salud”. En los últimos años la prevalencia de esta patología se ha triplicado a nivel mundial, llegando a alcanzar el 13 % de la población adulta. Se trata de una enfermedad que puede prevenirse, pero aun así existen diversos tratamientos, que van desde opciones convencionales y farmacológicas hasta quirúrgicas, como la cirugía bariátrica, que es la opción más efectiva a largo plazo. Además de su efecto en el peso corporal, se sabe que la cirugía bariátrica mejora, o incluso revierte por completo, comorbilidades asociadas a la obesidad como la diabetes mellitus tipo 2 (DM2). Sin embargo, su efecto sobre otros aspectos generales de la calidad de vida del paciente, como puede ser la vida sexual, no han sido estudiados en profundidad. Por esta razón, el principal objetivo de este proyecto es estudiar la calidad de vida sexual de los pacientes sometidos a cirugía bariátrica. Metodología: Se llevará a cabo un estudio prospectivo de tipo cualitativo desde una perspectiva fenomenológica y experimental. Realizaremos varios cuestionarios específicos que evalúen la calidad de vida general y la calidad de vida sexual de la población de estudio seleccionada, que estará constituida por hombres y mujeres de 18 a 60 años que hayan sido sometidos a cirugía bariátrica en el Área Sanitaria de Coruña y Cee., [Resumo] A obesidade é definida pola Organización Mundial da Saúde (OMS) como “una acumulación anormal ou excesiva de graxa que pode ser prexudicial para a saúde”. Nos últimos anos, a prevalencia desta patoloxía triplicouse en todo o mundo, chegando ao 13 % da poboación adulta. É unha enfermidade que se pode previr, pero aínda así existen diversos tratamentos, que van dende opcións convencionais e farmacolóxicas ata cirúrxicas, como a cirurxía bariátrica, que é a opción máis efectiva a longo prazo. Ademais do seu efecto sobre o peso corporal, sábese que a cirurxía bariátrica mellora, ou mesmo reverte por completo, as comorbilidades asociadas á obesidade, como a diabetes mellitus tipo 2 (DM2). Non obstante, o seu efecto noutros aspectos xerais da calidade de vida do paciente, como a vida sexual, non foi estudado en profundidade. Por iso, o principal obxectivo deste proxecto é estudar a calidade de vida sexual dos pacientes sometidos a cirurxía bariátrica. Metodoloxía: Realizarase un estudo cualitativo prospectivo dende unha perspectiva fenomenolóxica e experimental. Realizaremos varios cuestionarios específicos que avalían a calidade de vida xeral e a calidade de vida sexual da poboación de estudo seleccionada, que estará constituída por homes e mulleres de entre 18 e 60 anos que se someteron a cirurxía bariátrica na Area Sanitaria da Coruña. e Cee., [Abstract] Obesity is defined by the World Health Organization (WHO) as an "abnormal or excessive fat accumulation that can be harmful to health.". In recent years, the prevalence of this pathology has tripled worldwide, reaching 13% of the adult population. It is a disease that can be prevented, but even so there are various treatments, ranging from conventional and pharmacological to surgical ones, such as bariatric surgery, which is the most effective option in the long term. In addition to its effect on body weight, bariatric surgery is known to improve, or even completely reverse, comorbidities associated with obesity such as type 2 diabetes mellitus (T2DM); however, its effect on other general aspects of the patient's quality of life, such as sexual life, has not been studied in depth. For this reason, the main objective of this project is to study the quality of sexual life of patients who have undergone bariatric surgery. Methodology: A prospective qualitative study will be carried out from a phenomenological and experimental perspective. We will draft several specific questionnaires to evaluate the general quality of life and sexual quality of life of the selected studied population, which in this case will be made up of men and women aged 18 to 60 who have undergone bariatric surgery in the Health Area of Coruña and Cee.

Background Mutations in ATP1A2 gene encoding the Na,K-ATPase alpha(2) isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K-ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results Mice heterozygous for the familial hemiplegic migraine type 2-associated G301R mutation in the Atp1a2 gene (alpha(+/G301R)(2) mice) and matching wild-type controls were compared. Reduced expression of the Na,K-ATPase alpha(2) isoform and increased expression of the alpha(1) isoform were observed in hearts from alpha(+/G301R)(2) mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8-month-old alpha(+/G301R)(2) mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3-month-old alpha(+/G301R)(2) mice were similar to wild-type mice. Amplified Na,K-ATPase-dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen-activated protein kinase) signaling was observed in hearts from 8-month-old alpha(+/G301R)(2) mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure-associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5 ',6,6 '-tetrachloro-1,1 ',3,3 '-tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8-month-old alpha(+/G301R)(2) mice. Conclusions Our findings suggest that ATP1A2 muta

Background Chronic diseases are often associated with sexual dysfunction (SD). Little is known about the practice patterns of general practitioners (GPs) regarding sexual care for chronically ill patients. Therefore, the aim of this study was to examine; to what extent GPs discuss SD with chronically ill patients; the barriers that may stop them; and the factors associated with discussing SD. Methods A cross-sectional survey using a 58-item questionnaire was sent to 604 Dutch GPs. Descriptive statistics and associations were used for analysis of the data. Results Nearly 58% (n = 350) of all GPs approached gave a response and 204 questionnaires were analysable (33.8%). Almost 60% of respondents considered discussing SD with patients important (58.3%, n = 119). During the first consultation, 67.5% (n = 137) of the GPs reported that they never discussed SD. The most important barrier stopping them was lack of time (51.7%, n = 104). The majority (90.2%, n = 184) stated that the GP was responsible for addressing SD; 70.1% (n = 143) indicated that the GP practice somatic care nurse (GPN) was also responsible. Nearly 80% (n = 161) of respondents were unaware of agreements within the practice on accountability for discussing SD. This group discussed SD less often during first and follow-up consults (p = 0.002 and p < 0.001, respectively). Of the respondents, 61.5% (n = 116) felt that they had received insufficient education in SD and 74.6% (n = 150) stated that the subject is seldom discussed during training. Approximately 62% of the GPs (n = 123) wanted to increase their knowledge, preferably through extra training. According to 53.2% of the GPs (n = 107) it was important to improve the knowledge of the GPN. The most frequently mentioned tool that could help improve the conversation about SD was the availability of information brochures for patients (n = 123, 60.3%). Conclusions This study indicates that Dutch GPs do not discus

Background Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min) are offered parathyroidectomy (PTX) to protect them from further complications. Surprisingly, two recent uncontrolled cohort studies have suggested a further decrease in kidney function following PTX. We aimed to examine the effects of PTX compared to non-surgical surveillance on kidney function in pHPT patients. Methods Historic cohort study. From the Danish National Patient Registry (NPR) and major medical biochemistry laboratories in Denmark, we identified 3585 patients with biochemically confirmed pHPT among whom n = 1977 (55%) were treated with PTX (PTX-group) whereas n = 1608 (45%) were followed without surgery (non-PTX group). Baseline was defined as time of diagnosis and kidney function was re-assessed 9-15 months after PTX (PTX group) or 9-15 months after diagnosis (non-PTX group). Results At follow-up, eGFR had decreased significantly in the PTX- compared to the non-PTX-group (median - 4% vs. - 1%, p < 0.01). Stratification by baseline eGFR showed that the decrease was significant for those with a baseline eGFR value of 80-89 and > 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function. Conclusion Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.

Background Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min) are offered parathyroidectomy (PTX) to protect them from further complications. Surprisingly, two recent uncontrolled cohort studies have suggested a further decrease in kidney function following PTX. We aimed to examine the effects of PTX compared to non-surgical surveillance on kidney function in pHPT patients. Methods Historic cohort study. From the Danish National Patient Registry (NPR) and major medical biochemistry laboratories in Denmark, we identified 3585 patients with biochemically confirmed pHPT among whom n = 1977 (55%) were treated with PTX (PTX-group) whereas n = 1608 (45%) were followed without surgery (non-PTX group). Baseline was defined as time of diagnosis and kidney function was re-assessed 9-15 months after PTX (PTX group) or 9-15 months after diagnosis (non-PTX group). Results At follow-up, eGFR had decreased significantly in the PTX- compared to the non-PTX-group (median - 4% vs. - 1%, p < 0.01). Stratification by baseline eGFR showed that the decrease was significant for those with a baseline eGFR value of 80-89 and > 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function. Conclusion Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Objective: People living with HIV (PLWH) have an increased cardiovascular risk (CVR) owing to dyslipidemia, insulin resistance, metabolic syndrome, and HIV/combination antiretroviral therapy (cART)-associated lipodystrophy (HALS). Atherosclerosis and inflammation are related to growth differentiation factor-15 (GDF15). The relationship between metabolic disturbances, HALS, and CVR with GDF15 in PLWH is not known. Research design and methods: Circulating GDF15 levels in 152 PLWH (with HALS = 60, without HALS = 43, cART-naïve = 49) and 34 healthy controls were assessed in a cross-sectional study. Correlations with lipids, glucose homeostasis, fat distribution, and CVR were explored. Results: PLWH had increased circulating GDF15 levels relative to controls. The increase was the largest in cART-treated PLWH. Age, homeostatic model assessment of insulin resistance 1 (HOMA1-IR), HALS, dyslipidemia, C-reactive protein, and CVR estimated with the Framingham score correlated with GDF15 levels. The GDF15-Framingham correlation was lost after age adjustment. No correlation was found between GDF15 and the D:A:D Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) score estimated CVR. CVR independent predictors were patient group (naïve, HALS−, and HALS+) and cumulated protease inhibitor or nucleoside reverse transcriptase inhibitor exposure. Conclusions: PLWH, especially when cART-treated, has increased GDF15 levels—this increase is associated with dyslipidemia, insulin resistance, metabolic syndrome, HALS, and inflammation-related parameters. GDF15 is unassociated with CVR when age-adjusted.

Background: Current recommendations for echocardiographic assessment of diastolic function (2016 guidelines of the American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) in patients with metabolic syndrome and overweight/obesity result in a significant number of patients with indeterminate diastolic dysfunction (LVDD). The aim of this article is to study whether the use of the left atrial strain criterion (LALS) reduces the number of indeterminate patients. Methods: 229 patients were studied with a complete echocardiographic study that included left ventricular longitudinal strain (LVLS) analysis, LALS and a maximal ergospirometry test with assessment of oxygen uptake (VO2max). Results: The mean age was 65 ± 5 years, 153 (67%) males, with a mean EF of 60 ± 5%. The mean LVLS was ?19.4 ± 2% and the LALS Reservoir was 23.8 ± 7%. There were 140 patients who did not meet LVDD criteria and 82 who did meet the indeterminate LVDD criterion. When the left atrial volume index (LAVI) >34 ml/m2 criterion was replaced in the 2016 ASE/EACVI algorithm by LALS Reservoir ?20%, the number of indeterminate patients was reduced from 36% to 23% (p < 0.001) at the expense of increasing normal studies (61% and 74%). Adding the LALS Reservoir criterion ?23% in the 82 patients of the indeterminate group resulted in two groups with a different VO2max (11.6 ± 3 and 18 ± 5 ml/kg/min, p:0.081). Conclusions: This study confirms the low prevalence of diastolic dysfunction in overweight/obese patients with metabolic syndrome. Adding left atrial strain criterion to the current recommendations significantly reduces the number of indeterminate patients by reclassifying them as normal. © 2021 Elsevier B.V.

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.

Proper astroglial functioning is essential for the development and survival of neurons and oligodendroglia under physiologic and pathological circumstances. Indeed, malfunctioning of astrocytes represents an important factor contributing to brain injury. However, the molecular pathways of this astroglial dysfunction are poorly defined. In this work we show that aging itself can drastically perturb astrocyte viability with an increase of inflammation, cell death and astrogliosis. Moreover, we demonstrate that oxygen glucose deprivation (OGD) has a higher impact on nutritive loss in aged astrocytes compared to young ones, whereas aged astrocytes have a higher activity of the anti-oxidant systems. P38MAPK signaling has been identified to be upregulated in neurons, astrocytes and microglia after ischemic stroke. By using a pharmacological p38 alpha specific inhibitor (PH-797804), we show that p38MAPK pathway has an important role in aged astrocytes for inflammatory and oxidative stress responses with the subsequent cell death that occurs after OGD.

The temporomandibular joint is a receptor organ that is mobile in three directions, connected to the proprioceptors of the periodontal and masticatory muscles and transmits information to the Central nervous system about the position of the lower jaw for controlling and regulating masticatory movements (Alabin I. V., Mitrofanenko V. P., 2002).

The temporomandibular joint is a receptor organ that is mobile in three directions, connected to the proprioceptors of the periodontal and masticatory muscles and transmits information to the Central nervous system about the position of the lower jaw for controlling and regulating masticatory movements (Alabin I. V., Mitrofanenko V. P., 2002).

The temporomandibular joint is a receptor organ that is mobile in three directions, connected to the proprioceptors of the periodontal and masticatory muscles and transmits information to the Central nervous system about the position of the lower jaw for controlling and regulating masticatory movements (Alabin I. V., Mitrofanenko V. P., 2002).

The temporomandibular joint is a receptor organ that is mobile in three directions, connected to the proprioceptors of the periodontal and masticatory muscles and transmits information to the Central nervous system about the position of the lower jaw for controlling and regulating masticatory movements (Alabin I. V., Mitrofanenko V. P., 2002).

The temporomandibular joint is a receptor organ that is mobile in three directions, connected to the proprioceptors of the periodontal and masticatory muscles and transmits information to the Central nervous system about the position of the lower jaw for controlling and regulating masticatory movements (Alabin I. V., Mitrofanenko V. P., 2002).

The temporomandibular joint is a receptor organ that is mobile in three directions, connected to the proprioceptors of the periodontal and masticatory muscles and transmits information to the Central nervous system about the position of the lower jaw for controlling and regulating masticatory movements (Alabin I. V., Mitrofanenko V. P., 2002).

Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School Allied Health Sciences, Griffith Health, Background. Left ventricular (LV) dysfunction, which is the inability of the LV to pump blood effectively, constitutes the final common pathway for a host of cardiac disorders. The morbidity, mortality and healthcare cost associated with heart failure make the detection and prevention an attractive option before irreversible myocardial damage occurs. Initial diagnosis of LV dysfunction is through echocardiography, which, predominately relies on two-dimensional ejection fraction (EF) however, is fraught with limitation. Global longitudinal strain (GLS) is an established method for subclinical diagnosis of heart disease, however, is sensitive to changes in afterload leading to misinterpretation of true contractile function. Myocardial work (MW) is a recent echocardiographic modality derived from non-invasive LV pressure-strain loops and addresses the afterload limitation of GLS. Aims. The thesis investigates the use of MW against conventional echocardiographic parameters in hypertensive heart disease, ischaemic and non-ischaemic cardiomyopathy and ischaemic heart disease. It is hypothesised that MW indices will be more sensitive than GLS and provide a new dimension in the clinical evaluation of LV dysfunction. Methods. Patients enrolled in the CATHARSIS research program performed at The Prince Charles Hospital who have comprehensive echocardiographic studies followed by invasive coronary angiography will be investigated. All echocardiographic measurements were performed in according to the current echocardiographic guidelines. GLS and MW analysis was calculated utilising speckle tracking echocardiography via vendor specific modules (EchoPAC Version 202, GE Vingmed Ultrasound, Norway). MW was derived from derived from non-invasive LV pressurestrain loops indexed to brachial systolic blood pressure. MW indices obtained include: Global myocardial work index (GWI) – a global representation of MW; Constructive MW (CW) – the sum of positive work due to myocardial shortening

Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.

BACKGROUND: Anorectal Chlamydia trachomatis (CT) may be clinically relevant for women in general practice. Although anorectal CT testing in this setting may prevent underdiagnosis and undertreatment, its feasibility is questioned as GPs currently rarely order anorectal CT tests, for yet unknown reasons.OBJECTIVE: To explore the feasibility of anorectal CT testing in women in general practice.METHODS: GPs across the Netherlands were invited directly (n = 1481) and by snowball sampling (n = 330) to join an online cross-sectional survey that asked about the acceptability of and barriers for (standard) anorectal testing in women during CT-related consultations. Data were analysed with univariable and multivariable logistic regression models.RESULTS: The questionnaire was opened by 514 respondents (28%, 514/1811) and 394 fully completed it. GPs' acceptability of anorectal testing by either self-sampling or provider-sampling was high (86%). Twenty-eight percent of GPs felt neutral, and 43% felt accepting towards standard anorectal testing. Nevertheless, 40% of GPs had never tested for anorectal CT in women, which was associated with a reported difficulty in asking about anal sex (odds ratio [OR]: 3.07, 95% confidence interval [CI]: 1.21-7.80), infrequency of anal sexual history taking (OR: 11.50, 95% CI: 6.39-20.72), low frequency of urogenital CT testing (OR 3.44, 95%-CI: 1.86-6.38) and with practicing in a non-urban area (OR: 2.27, 95% CI: 1.48-3.48). Acceptability of anorectal testing was not associated with the studied factors.CONCLUSION: This quantitative survey shows that anorectal CT testing is feasible based on its acceptability, but is likely hindered by a lower awareness of (anorectal) CT in GPs.

Aims This systematic review and meta-analysis aims to evaluate the role of pre-operative transthoracic echocardiography in predicting post-operative atrial fibrillation (POAF) after cardiac surgery.Methods and results Electronic databases were searched for studies reporting on pre-operative echocardiographic predictors of POAF in PubMed, Cochrane library, and Embase. A meta-analysis of echocardiographic predictors of POAF that were identified by at least five different publications was performed. Forty-three publications were included in this systematic review. Echocardiographic predictors for POAF included surrogate parameters for total atrial conduction time (TACT), structural cardiac changes, and functional disturbances. Meta-analysis showed that prolonged pre-operative PA-TDI interval [5 studies, Cohen's d=1.4, 95% confidence interval (CI) 0.9-1.9], increased left atrial volume indexed for body surface area (LAVI) (23 studies, Cohen's d=0.8, 95% CI 0.6-1.0), and reduced peak atrial longitudinal strain (PALS) (5 studies, Cohen's d=1.4, 95% CI 1.0-1.8), were associated with POAF incidence. Left atrial volume indexed for body surface was the most important predicting factor in patients without a history of AF. These parameters remained important predictors of POAF in heterogeneous populations with variable age and comorbidities such as coronary artery disease and valvular disease.Conclusion This meta-analysis shows that increased TACT, increased LAVI, and reduced PALS are valuable parameters for predicting POAF in the early post-operative phase in a large variety of patients.

To determine the association between quadriceps muscle strength (QMS) and endurance (QME) and exercise capacity in patients with COPD after stratification for sex and resting lung function (LF). Data were collected from 3,246 patients with COPD (60% men, 64 +/- 9yr), including measures of exercise capacity [peak aerobic capacity (peakVo(2)), 6-min walk distance (6MWD)] and isokinetic QMS and QME. Patients were stratified for sex, forced expiratory volume in 1s (>50/50/140/o(2) (r range: 0.47-0.61 and 0.49-0.65 for men and 0.53-0.66 and 0.48-0.67 for women, respectively) and 6MWD (r range: 0.29-0.42 and 0.44-0.55 for men and 0.25-0.54 and 0.34-0.55 for women, respectively) (P < 0.001). Regression models demonstrated that QMS and QME were significant determinants of peako(2) (explained variance R-2 range: 35.6%-48.8% for men and 36.8%-49.0% for women) and 6MWD (R-2 range: 24.3%-43.3% for men and 28.4%-40.3% for women), independent of age and fat-free mass. Quadriceps muscle function was significantly associated with peakVo(2) and 6MWD in male and female patients with COPD after stratification for resting LF, in which QME appear to be a more important determinant than QMS. This underlines the importance of systematically evaluating both quadriceps muscle strength and endurance in in all patients with COPD.NEW & NOTEWORTHY Our findings identified quadriceps muscle function as an important determinant of exercise capacity across a wide spectrum of lung function. Quadriceps muscle endurance appears to be a more important determinant than quadriceps muscle strength, underlining the importance of including both the measurement of quadriceps muscle strength and endurance in routine assessment for all patient with COPD.

Stroke is the 5th leading cause of death in the United States according to the 2019 CDC Mortality Data. There are ~795,000 new incidences of stroke each year, and this prevalence is increasing in correlation with the aging population of the United States [159]. At 4-6 hours post-stroke, there is breakdown of the blood brain barrier (BBB). The BBB is comprised of brain microvascular endothelial cells that line the cerebral microvasculature. Functionally, the BBB provides a physical and biochemical barrier between the brain and the systemic circulation. Barrier properties of the BBB are provided by tight junctions and transporters that control selective passage of substances into the brain. During stroke, tight junction integrity and transporter expression is considerably altered, leading to significant leakage of substances from the systemic circulation. Of particular significance, BBB dysfunction also results in edema and swelling in the brain. Following the leak is a generalized immune response that exacerbates the ischemic insult in the brain [236]. Neurons start to die because of the inflammation. If this edema is not controlled within the first 24 hours, cognitive damage is permanent, and death may result [160]. Thus, preservation of the BBB during ischemic injury is critical to maintaining the health of the individual and preventing BBB dysfunction. Due to the limited therapeutic options available, it is critical to discover novel strategies for treatment of stroke and preservation of BBB integrity. In this dissertation, stroke pathophysiology is reviewed with an emphasis on BBB dysfunction. Research methods that can be used to identify new stroke therapeutics that have vascular protective properties will also be highlighted. This discussion will focus on statins, a class of therapeutics that are commonly administered to stroke patients due to their known ability to improve post-stroke neurological outcomes.

Aim: Multiomics delivers more biological insight than targeted investigations. We applied multiomics to patients with heart failure (HF) and reduced ejection fraction (HFrEF), with machine learning applied to advanced ECG (AECG) and echocardiography artificial intelligence (Echo AI). Patients & methods: In total, 46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography–mass spectrometry and solid-phase microextraction volatilomics in plasma and urine. HFrEF was defined using left ventricular (LV) global longitudinal strain, EF and N-terminal pro hormone BNP. AECG and Echo AI were performed over 5 min, with a subset of patients undergoing a virtual reality mental stress test. Results: A-ECG had similar diagnostic accuracy as N-terminal pro hormone BNP for HFrEF (area under the curve = 0.95, 95% CI: 0.85–0.99), and correlated with global longitudinal strain (r = -0.77, p < 0.0001), while Echo AI-generated measurements correlated well with manually measured LV end diastolic volume r = 0.77, LV end systolic volume r = 0.8, LVEF r = 0.71, indexed left atrium volume r = 0.71 and indexed LV mass r = 0.6, p < 0.005. AI-LVEF and other HFrEF biomarkers had a similar discrimination for HFrEF (area under the curve AI-LVEF = 0.88; 95% CI: -0.03 to 0.15; p = 0.19). Virtual reality mental stress test elicited arrhythmic biomarkers on AECG and indicated blunted autonomic responsiveness (alpha 2 of RR interval variability, p = 1 × 10-4) in HFrEF. Conclusion: Multiomics-related machine learning shows promise for the assessment of HF.

Proper astroglial functioning is essential for the development and survival of neurons and oligodendroglia under physiologic and pathological circumstances. Indeed, malfunctioning of astrocytes represents an important factor contributing to brain injury. However, the molecular pathways of this astroglial dysfunction are poorly defined. In this work we show that aging itself can drastically perturb astrocyte viability with an increase of inflammation, cell death and astrogliosis. Moreover, we demonstrate that oxygen glucose deprivation (OGD) has a higher impact on nutritive loss in aged astrocytes compared to young ones, whereas aged astrocytes have a higher activity of the anti-oxidant systems. P38MAPK signaling has been identified to be upregulated in neurons, astrocytes and microglia after ischemic stroke. By using a pharmacological p38 alpha specific inhibitor (PH-797804), we show that p38MAPK pathway has an important role in aged astrocytes for inflammatory and oxidative stress responses with the subsequent cell death that occurs after OGD.

Takotsubo syndrome (TTS) can develop after liver transplant (LT), but its predisposing factors are poorly understood. In this study, we aimed to determine if perioperative factors were associated with posttransplant TTS. Adult patients who underwent primary LT between 2006 and 2018 were included. Patients with and without TTS were identified and matched by propensity scores. Of 2181 LT patients, 38 developed postoperative TTS with a mean left ventricular ejection fraction of 25.5% (±7.8%). Multivariable logistic regression revealed two preoperative risk factors (alcoholic cirrhosis and model for end-stage liver disease-sodium scores) for TTS. Post-propensity match analyses showed that TTS patients had significantly higher doses of epinephrine and lower doses of fentanyl during LT compared with non-TTS patients. A higher dose of epinephrine and a lower dose of fentanyl was associated with a higher predicted probability of TTS. All TTS patients had full recovery of cardiac function and had comparable 1-year survival. In conclusion, TTS occurred at a rate of 1.7% after LT and was associated with two pretransplant risk factors. The higher doses of epinephrine and lower doses of fentanyl administered during LT were associated with posttransplant TTS. More studies on the relationship between intraoperative medications and TTS are warranted.

Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.